Stereospecific Synthesis of Tetrahydronaphtho[2,3-b]furans Enabled by a Nickel-Promoted Tandem Reductive Cyclization

Article abstract of DOI:10.1021/acs.orglett.6b02665

A Ni-mediated cascade to a stereoselective synthesis of trans-tetrahydronaphtho[2,3-b]furans is efficiently achieved for the first time. The mild reductive system can be easily generated from inexpensive and air-stable materials and shows a broad positional tolerance of substituents that were previously difficult or impossible to access by other methods. Facile syntheses toward new analogues of therapeutic agents (iso)deoxypodophyllotoxin are also reported. In addition, the inherent substrate control is disclosed for the observed unique stereoselectivities during cyclizations.

Full text of DOI:10.1021/acs.orglett.6b02665

Letter
pubs.acs.org/OrgLett
Stereospecific Synthesis of Tetrahydronaphtho[2,3‑b]furans Enabled
by a Nickel-Promoted Tandem Reductive Cyclization
Yu Peng,* Jian Xiao, Xiao-Bo Xu, Shu-Ming Duan, Li Ren, Yong-Liang Shao, and Ya-Wen Wang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
S
* Supporting Information
ABSTRACT: A Ni-mediated cascade to a stereoselective
synthesis of trans-tetrahydronaphtho[2,3-b]furans is efficiently
achieved for the first time. The mild reductive system can be
easily generated from inexpensive and air-stable materials and
shows a broad positional tolerance of substituents that were
previously difficult or impossible to access by other methods.
Facile syntheses toward new analogues of therapeutic agents (iso)deoxypodophyllotoxin are also reported. In addition, the
inherent substrate control is disclosed for the observed unique stereoselectivities during cyclizations.
rivileged skeletons with tetrahydronaphtho[2,3-b]furans
(tetrahydronaphtho = THN) can be found in a wide array
when substrates had o- or m-aryl substituents. Efficient and
complementary synthetic methods are still in high demand.
Recently, Ni-catalyzed reductive coupling of alkyl (pseudo)-
halides have become a valuable tool for the formation of C−C
bonds.4−10 Our previous research mainly focused on intra-
molecular reactions and stereoselective tandem cyclizations.11
Herein, we present an unprecedented and stereospecific
synthesis of trans-THN[2,3-b]furans with the sequential
formation of two C−C bonds enabled by Ni/EC (ethyl
crotonate) (Scheme 1, bottom). This method led to a
convenient preparation of (iso)deoxypodophyllotoxin ana-
logues.
P
of natural products, pharmaceuticals, and agrochemicals.1
Several synthetic methodologies toward the construction of
this scaffold have thus emerged, such as [2 + 2] cycloaddition
followed by Baeyer−Villiger oxidation,2a oxo-Pauson−Khand
reactions of o-allyl aryl ketones,2b and Friedel−Crafts cyclization
of acid chloride.2c Recently, several groups reported new tactics
using oxidative cyclizations catalyzed by transition metals
(Scheme 1, top).3 A Pd(II)-catalyzed cascade that generated
Scheme 1. Oxidative versus Reductive Cyclization
First, optimization studies of the proposed reductive cascade
were carried out (Table 1) with the β-bromo acetal 1a that was
easily prepared from 1-o-iodobenzyl allyl alcohol and ethyl vinyl
ether (EVE). We chose Ni(0)·2EC·Py to perform this
transformation, and the desired tandem cyclization of 1a indeed
occurred in DMF at room temperature, affording tricylic acetal
2a in 51% isolated yield within 12 h (entry 1). A facile oxidation
of 2a as a pair of inconsequential diastereomers mediated by m-
CPBA and BF3·Et2O12 led to the sole lactone 3a in almost
quantitative yield. The unique trans-fused stereochemistry was
confirmed through its single-crystal structure (Table 1 inset).13
By comparison, less reactive dibromide 1aa resulted in the lower
yield of 2a under identical conditions (entry 2). The utilization
of 2,2′-bipyridine as a ligand also caused a decrease in yield
(entry 3). To our delight, CH3CN was identified as a superior
solvent for this cascade. The yield of 2a increased substantially,
up to 70% when the reaction time was shortened to a half,
presumably due to the unstable nature of this acetal product
upon long periods in the reaction medium (entries 4 and 5
versus entry 1). Further evaluation of solvents proved that DMA
is the best choice, and 2a was isolated in 78% yield (entry 6). A
slight decrease of yield was observed when the reaction was run
C−O and C−C bonds successively for construction of
THN[2,3-b]furan-2-ones was first developed by Stephenson
and co-workers.3a However, these researchers demonstrated
only two examples, both as a mixture of almost 1:1 cis/trans-
fused isomers. Some oxidative dearomatization side products
were also observed, especially in the case of substrates bearing
electron-rich benzene rings. Later, Chemler et al. expanded the
scope of THN[2,3-b]furan via a Cu(II)-catalyzed, MnO2-
mediated alkene carboetherification.3b,c The good cis-stereo-
selectivity diminished severely when substituent groups at ring-
junction positions were removed (i.e., R, R′ = H). Notably, the
above reactions involved Csp2−H functionalization; therefore,
the formation of regioisomeric products cannot be avoided
Received: September 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02665
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Table 1. Optimization of Cyclization Conditions
Scheme 2. Synthesis of trans-THN[2,3-b]furan-2-ones*
a
entry
compd
ligand
solvent
2a, yield (%)
1
2
3
4
5
6
1a
EC
EC
DMF
51
28
20
63
70
78
63
14
17
6
1aa
1a
DMF
2,2′-bipy
EC
DMF
1a
CH3CN
CH3CN
DMA
DMA
DMA
DMA
DMA
DMA
DMA
1a
EC
1a
EC
b
7
1a
EC
8
1a
4,4′-di-tBu-2,2′-bipy
4,4′-di-OMe-2,2′-bipy
1,10-phen
9
1a
10
11
12
13
1a
1a
4,7-di-Ph-1,10-phen
EC
46
c
1ab
1ac
0
d
EC
DMA
0
a
b
Isolated yield with 1 equiv of Ni complexes. The reaction was
c
d
conducted at 40 °C. 2ab was isolated in 50% yield. 2ac was isolated
in 80% yield.
at elevated temperature in order to accelerate the transformation
(entry 7). Screening of other bidentate ligands including
phenanthrolines gave no improvements (entries 8−11). No
2a could be observed when the C−I bond was replaced by the
C−H bond in 1ab. Instead, monocyclization product 2ab was
obtained in 50% yield (entry 12), suggesting that a homolytic
aromatic substitution process14 during the second cyclization
seems impossible. Attempts to direct access to tricylic lactone 3a
from α-bromo ester 1ac only afforded the partial reduction
product 2ac in 80% yield (entry 13). The attempted catalytic
reactions and a gram-scale experiment are included in the SI. We
were pleased to find that this bicylization event still proceeded
smoothly under substoichiometric Ni, providing 2a in 72%
yield.
With these optimized conditions in hand, a scope of this
tandem cyclization mediated by nickel was then investigated. As
shown in Scheme 2, reductive cascades of various β-bromo
acetals 1 can give trans-THN[2,3-b]furan-2-ones 3 in moderate
and good yields after oxidation of the intermediate tricyclic
acetals 2 (not shown). We first studied the tolerance of
functional groups on the benzene ring of substrates (3b−k).
The reaction of dimethoxyphenyl iodide 1b worked well under
the present conditions, and a single crystal of one of the
resulting diastereomeric acetals was obtained, clearly demon-
strating that two tertiary hydrogen atoms at C3a and C9a adopt
a trans-orientation.13 Upon oxidation, lactone 3b was generated
in 66% overall yield. Other electron-rich benzene-derived
precursors also gave similar results, as exemplified in the cases
of 3d and 3e with a Me group at either C7 or C8 position.
Phenyl iodides bearing typical electron-withdrawing groups like
*
The substrate 1 (X = I, Y = Br) and Ni complexes (1 equiv) were
used generally unless otherwise stated. Overall yields of 3 were
reported, and monocyclization side products (10−20%) similar to 2ab
were observed in some cases. 1c (X,Y = Br) was used at 35 °C. 1n,
1p, 1r, and 1s (X, Y = I) were used at 40 °C. dr = 1.1:1. 1,10-phen
was used.
a
b
c
d
CF3 and Cl were also suitable, leading to 3f and 3g in moderate
yields. In particular, phenyl bromide 1c with a methylenedioxy
group also worked well under the identical conditions except at
slightly elevated temperature, in sharp contrast to that of
dibromide 1aa. The substrates bearing NMe2, OH, and OAc
groups afforded 3h−j in good yields as well. The naphthalene
derivative 1k also participated in this transformation to deliver
the tetracyclic lactone 3k in a serviceable yield.
In light of the limited exploration in previous reports,3 the
compatibility of substituents at two aliphatic rings in targets 3
was next evaluated (3l−t). When 1l derived from 1-o-
iodobenzyl 2-methylallyl alcohol was exposed to the indicated
system, the tricyclic lactone 3l with an all-carbon quaternary
stereocenter at C3a could be successfully obtained in 50%
overall yield. More importantly, a trans-relationship between
H9a and Me was still maintained, which was unambiguously
established by its single-crystal analysis.13 The angular-methyl
group could also be incorporated into the C9a position, thus
generating 3m with an oxo-quaternary carbon in a higher yield.
Amazingly, the present methodology allowed for the con-
B
DOI: 10.1021/acs.orglett.6b02665
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Scheme 3. Total Synthesis of Isodeoxypodophyllotoxin Analogue
struction of vicinal quaternary C3a and C9a with steric
congestion in 3n when the diiodide 1n was used. Besides the
substrates containing a terminal alkene, β-bromo acetals 1o and
1p derived from 1-o-iodobenzyl crotyl and cinnamyl alcohols
were compatible as well, providing C4-substituted lactones 3o
and 3p successfully albeit the latter had a lower yield. However,
subjection of 1q from prenyl alcohol to the Ni·Phen system led
to trans-fused lactone 3q in a normal yield, thus generating an
aryl-quaternary carbon.13 It is noteworthy that this unprece-
dented transformation represented the first Ni-promoted
intramolecular reductive cross-coupling of a formal tertiary
alkyl bromide and an aryl iodide.15 Moreover, the decoration of
the gem-dimethyl group at C9 in 3r also worked, although its
yield diminished as compared to 61% of 3q. Nonetheless, the
dehydrogenation congener of 3r, that is, cyclopropane 3s, could
be synthesized more efficiently. The expected trans-fused
stereochemistry of this THN[2,3-b]furan-2-one and its
interesting spiro-quaternary carbon structure were determined
by single-crystal analysis.13 Pleasingly, the Ni-triggered reductive
cascade of secondary bromide 1t gave the highest yield.
Oxidation of separable diastereomers of the resulting tricylic
acetal eventually afforded lactone 3t in 86% overall yield.
Podophyllotoxin (PT) has been paid extensive attention for
over half a century by the academic and industrial community.
Its derivatives have been developed as drugs for the treatment of
lung and testicular cancer, leukemia, etc.16 Not surprisingly,
numerous total syntheses of PT have appeared to date,17 and the
preparation of diverse analogues18,11c is also in high demand in
order to obtain superior therapeutic agents. Based on the
reductive cascade shown in Scheme 2, we next demonstrated a
versatile application in the synthesis of new isodeoxyPT
analogue 9 (Scheme 3). Our synthesis commenced with the
assembly of commercially or easily available 6-bromopiperonal
(6-BrPi) and 3,4,5-trimethoxybromobenzene (TpBr), according
to a series of standard protocols including Tp-Br/Li exchange,
the lithium reagent addition to the aldehyde, and Pi-Br/I
exchange reaction. The resulting carbinol was then converted to
the diaryl ketone 4 in 43% overall yield by oxidation with PDC.
The one-carbon homologation of 4 to the diaryl acetaldehyde 5
was realized by a Corey−Chaykovsky epoxidation and the
subsequent rearrangement mediated by ZnI2.19 The resulting
labile aldehyde was directly subjected to a freshly prepared
organocerium reagent from vinylmagnesium bromide and
anhydrous CeCl3 to afford two separable allyl alcohols 6 (dr =
1:1) in 48% overall yield. These two diastereomers that are
differentiated at C9 could be elaborated independently. For
example, upon exposure of the more polar isomer to a mixture
of NBS and EVE,20 β-bromo acetal 7 was obtained in 56% yield,
thus setting the stage for the key reductive cyclization enabled
by nickel. Smooth cascade of 7 with a C9-aryl substitution was
observed, affording the desired THN[2,3-b]furan 8 bearing
three contiguous stereocenters (C9−C9a−C3a) in 53% yield
with partial recovery (12%) of the starting material. The
expected trans-ring fusion was established by single-crystal
analysis (Scheme 3 inset) of 913 resulting from the oxidation of
8. To that end, a new analogue 9 of isodeoxyPT21 was achieved
by this seven-step synthetic sequence. In addition, a similar
route starting from 6 (less polar) also delivered the
corresponding analogue 9-epi of deoxyPT22 (see the Supporting
Information for details).
On the basis of the work of others4f,5a,c and our proposed
mechanism regarding intermolecular reductive coupling enabled
by nickel,11a,d a rational explanation for the intramolecular
cascade here is illustrated in Scheme 4 with 1a as an example.
Scheme 4. Proposed Mechanism
Homolysis of the Csp3−Br bond through a single-electron-
transfer process with in situ generated Ni0 complex provides
radical I, which adopts a pseudo-half-chair conformation.17d The
next stereospecific 5-exo-trig cyclization would quickly occur to
give a unique trans-substituted THF II. An alternative pathway
to the cis-isomer from I′ and II′ is a disfavored process since the
subsequent cyclization would be impossible. Radical II would
C
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then combine with LNiIBr to afford NiII intermediate III, which
can be reduced to NiI species IV by Zn. The following oxidative
addition of the Caryl−I bond in an intramolecular fashion would
furnish NiIIIacycle V,23 which would undergo a facile reductive
elimination to form the tricyclic acetal 2a while regenerating Ni0
upon the eventual reduction. The competitive protonation and
direct reduction to form 2ab (vide supra) during the
transformation of IV to V could occur when a less reactive
aryl bromide like 1aa was employed. On the other hand, a
corresponding secondary radical from 1q allowed the whole
cascade to proceed more efficiently due to its high reactivity,
therefore leading to the product in the highest yield. Inclusion of
TEMPO led to almost no formation of 2a, implying possible
involvement of radical intermediates.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02665.
Experimental procedures and characterization data
(PDF)
1H/13C NMR (PDF)
X-ray data for 2b (CIF)
X-ray data for 3a (CIF)
X-ray data for 3l (CIF)
X-ray data for 3q (CIF)
X-ray data for 3s (CIF)
X-ray data for 9 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pengyu@lzu.edu.cn.
(13) See the CIF file in the Supporting Information.
Notes
(14) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018.
(15) For the first intermolecular Ni-catalyzed reductive coupling of
tertiary alkyl halides and aryl bromides, see ref 6e.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) Stahelin, H. F.; von Wartburg, A. Cancer Res. 1991, 51, 5.
̈
This work was supported by the NNSFC (No. 21472075), and
MoE (PCSIRT-15R28, lzujbky-2016-ct02, and lzujbky-2016-
51). We thank Prof. Chun-An Fan (Lanzhou University) for his
helpful suggestions.
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