Stereoselective synthesis of a: Podophyllum lignan core by intramolecular reductive nickel-catalysis

Article abstract of DOI:10.1039/c8cc00001h

A Ni-catalyzed reductive cascade to a diastereocontrolled construction of THN[2,3-c]furan, is developed. The mild reaction conditions led to the tolerance of broad functional groups that can be placed in almost every position of this skeleton with good yields. The conformational control for the observed trans- or cis-fused selectivity during this tandem cyclization-coupling is also proposed.

Full text of DOI:10.1039/c8cc00001h

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Stereoselective synthesis of a Podophyllum lignan
core by intramolecular reductive nickel-catalysis†
Cite this:DOI: 10.1039/c8cc00001h
ab
Jian Xiao,a Xiao-Wei Cong,a Gui-Zhen Yang,a Ya-Wen Wangab and Yu Peng
*
Received 1st January 2018,
Accepted 29th January 2018
DOI: 10.1039/c8cc00001h
rsc.li/chemcomm
A Ni-catalyzed reductive cascade to a diastereocontrolled construc- access to any members of the podophyllum family with trans- or
tion of THN[2,3-c]furan, is developed. The mild reaction conditions cis-fused stereochemistry.
led to the tolerance of broad functional groups that can be placed in
First of all, model studies with the b-bromo acetal 2a as
almost every position of this skeleton with good yields. The con- two diastereomers for the above designed tandem reductive
formational control for the observed trans- or cis-fused selectivity coupling were performed as shown in Table 1. This cyclization
during this tandem cyclization-coupling is also proposed.
precursor was conveniently synthesized using commercially
available allyl alcohol and enol methyl ether derived from
Over the past decade, the renaissance of nickel catalysis in 6-bromopiperonal according to general procedure A-1 in the
cross-coupling reactions especially with alkyl partners, has ESI.† Ethyl crotonate10 (EC) as a ligand was chosen to run this
appeared and received considerable attention1,2 from synthetic reaction in DMA at 24 1C using a stoichiometric Ni(0) complex,
chemists due to the earth-abundance and unique properties of and the expected transformation occurred smoothly, providing
this transition-metal. In particular, nickel-catalyzed reductive
coupling,3,4 featuring direct use of electrophiles instead of
organometallic reagents, has already evolved into a practical
Table 1 Optimization of conditions for reductive tandem cyclizationa
method for the formation of carbon–carbon bonds under mild
conditions. However, research progress in this promising field
has mainly focused on various intermolecular couplings5 while
our interest was intramolecular reactions6 and stereocontrolled
tandem cyclizations.7 Further applications in the synthesis of
bioactive natural products and pharmaceuticals remain elusive
and thus in high demand. In this communication, we devised a
new synthetic route to the core of the natural product podo-
phyllotoxin (1), a typical aryltetralin lignan8 for the treatment of
anogenital warts which also serves as the key starting material
Isolated yield [%]
for cancer chemotherapy drugs like etoposide and teniposide.9
Entry Ni salt (equiv.)
Ligandc
EC
Solvent 3a
3a0
Ni-catalyzed reductive cyclization of a dihalide A invented by us
will lead to the generation of a tetrahydronaphtho[2,3-c]furan
(tetrahydronaphtho = THN) core B embedded in this kind of
lignan in one step. And the formation of two C–C bonds was
diastereodivergent in this tandem process, therefore enabling
1
2
3
NiCl2 (1.0)
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
54
57
56
56
7
35
25
35
29
27
26
28
28
28
2
13
9
18
14
13
24
13
15
NiCl2ꢀDME (1.0) EC
NiCl2ꢀDME (0.5) EC
NiCl2ꢀDME (0.2) EC
NiCl2ꢀDME (0.1) EC
4
5b
6
NiBr2 (0.2)
NiI2 (0.2)
EC
EC
7
8
9
10
11
12
13
NiCl2ꢀDME (0.2) 2,20-bpy
NiCl2ꢀDME (0.2) dtbbpy
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: pengyu@lzu.edu.cn
b School of Life Science and Engineering, Southwest Jiaotong University,
NiCl2ꢀDME (0.2) dMeobpy DMA
NiCl2ꢀDME (0.2) EC
NiCl2ꢀDME (0.2) EC
NiCl2ꢀDME (0.2) EC
CH3CN 50
DMF
DMPU
38
38
Chengdu, 610031, China
† Electronic supplementary information (ESI) available. CCDC 1811053–1811056.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8cc00001h
a
b
The reaction was run on
a
0.6 mmol scale.
3
mmol scale.
c
0.72 mmol for EC and 0.24 mmol for other nitrogen ligands.
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separable THN[2,3-c]furans 3a and 3a0 in 80% combined yield choice, and both acetals 3a and 3a0 could be isolated in 84%
(entry 1). The less polar isomer was identified as 3a through its combined yield (entries 11–13 vs. entry 4). The addition of
single-crystal structure,11 where cis-fused stereochemistry and TBABr or TBAI (ref. 5n) led to a decrease (10–15%) in yields. The
the pseudo-axial orientation of the methoxy group could be detailed screening of reaction parameters is summarized in the
observed clearly. The more polar product was also isolated and ESI† (Tables S1–S4). The corresponding precursor dibromide
assigned as 3a0 by its single-crystal analysis.11 In comparison 2aa (X = Y = Br) and b-iodo acetal 2ab (X = I, Y = Br), whose
to 3a, the latter demonstrated a trans-fused stereochemistry preparation can be found the ESI,† resulted in lower yields of 3a
relationship in the newly-formed bicyclic moiety. The desired and 3a0 (65% and 70%, respectively) under the identical con-
diastereodivergent cyclization results (3a vs. 3a0) during this ditions of entry 1. Its cost cannot compete with 2a although the
reductive cascade have thus been achieved. The better yields of diiodide 2ac (X = Y = I) provided the same yield as that of 2a.
tetracyclic acetals 3a and 3a0 were obtained when the in situ
With the above optimized conditions in hand, the scope of
generated complex from NiCl2ꢀDME was employed (entry 2). To this cascade catalyzed by nickel was then investigated. We first
our delight, the loading of this stable Ni(II) salt could be replaced the methylenedioxy group on the benzene ring in 2a
lowered to 20 mol% and almost same yields of 3a and 3a0 were with hydrogens, the corresponding products 3b and 3b0 could
maintained (entries 3 and 4). Further decrease in the Ni catalyst be isolated in 53% and 31% yields, respectively (Scheme 1A).
afforded a detrimental result (entry 5). Screening of other nickel Reductive tandem cyclization of other b-bromo acetals tethered
halides did not give superior outcomes (entries 6 and 7). to the electron-rich iodobenzene moiety all produced stereo-
Evaluation of some nitrogen ligands12 such as bipyridine defined THN[2,3-c]furans 3c(c0)–3k(k0) in good combined
resulted in yield decrease of this tandem cyclization event yields. As demonstrated in the cases of tricyclic acetals
(entries 8–10), suggesting the importance of olefin EC as p 3c(c0)–3f(f0), a methyl group can be placed at any of the
ligands.13 Investigation of solvents proved that DMA is the best remaining positions of the benzene ring (C5–C8), with an
a
Scheme 1 Stereoselective synthesis of THN[2,3-c]furan: investigation of functional groups at the benzene ring. Substrate 2 (X = Br, Y = I) was used
b
c
generally unless otherwise stated, and isolated yields of 3 were reported. 2e and 2o (X = Br, Y = Br) were used. NiCl2ꢀDME (30 mol%) was used.
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average yield of 79%. More electron-rich substrate 2g can also Besides terminal alkenes as suitable substrates, b-bromo acetal 2s
tolerate the mild reaction conditions, generating 3g(g0) in derived from cinnamyl alcohol was also compatible with the
almost equal yields. The reaction of phenyl iodides bearing reaction conditions same as those in Scheme 1, furnishing
two methoxy groups still worked well under the identical C4-phenyl substituted THN[2,3-c]furan in 75% combined yield.
conditions, affording the tetrasubstituted benzene derivatives An all trans-relationship among continuous stereogenic centers
3i(i0) and 3j(j0) in 65% and 73% yields, respectively. In parti- (C4–C3a–C9a–C1) in more polar diastereomer 3s0 was unambigu-
cular, a precursor with a –OTBS moiety, a typical protecting- ously established by its single-crystal analysis (Scheme 2, selected H
group for hydroxyl, participated in this reductive cyclization as atoms have been omitted for clarity).11 Finally, the reductive
well, affording 3k and 3k0 in a surprising 90% yield since this cascade of b-bromo acetal 2t derived from a secondary allyl alcohol
silyl group with steric hindrance is oriented at the ortho- triggered by nickel catalysis here proceeded uneventfully to
position of the reaction site. As shown in Scheme 1B, the generate stereodivergent tetrasubstituted tetrahydrofurans 3t(t0) in
extension of this tandem cyclization to electron-deficient 70% combined yield.
benzene-derived substrates also afforded good results. The
As shown in Scheme 3, a mechanistic hypothesis and
reaction of phenyl iodides bearing typical electron-withdrawing rationalization of stereoselectivities for this intramolecular
groups like F and Cl proceeded smoothly to provide the expected cross-electrophile coupling catalyzed by nickel is proposed.
products 3l(l0)–3n(n0) in serviceable yields. A single-crystal of 3l0 One of the diastereomeric b-bromo acetals 2 proceeds to
was obtained, whose structure clearly demonstrated that all produce radical C by a single-electron-transfer (SET) process
three tertiary hydrogen atoms at C3a, C9a and C1 adopt a with the Ni0 complex being in situ generated under reduction
trans-orientation (Scheme 1B inset; selected H atoms have been conditions. This secondary radical would adopt a pseudo-half-
omitted for clarity).11 The chlorine atom in THN[2,3-c]furans chair conformation, and provide a primary radical species D
3n(n0) could serve as a handle for further elaboration. Notably, upon cyclization. In this favored step, two labeled hydrogens
the ester group as exemplified by the case of tricyclic acetal 3o(o0) are oriented at the trans-position of the formed tetrahydrofuran
was also feasible under the mild reductive conditions; in con- ring in D. The remaining steps would follow the known NiI–NiIII
trast, this kind of electrophilic functional group is generally redox process14 via intermediates E, F, and G. The expected
incompatible in classical cross-coupling reactions because of the THN[2,3-c]furan 30 with a half-chair conformation and trans-
organometallic reagents involved. The acetates 3p(p0) that were fused stereochemistry was thus obtained after the formation of
obtained in combined 81% yield, showed another example the second carbon–carbon bond. The first 5-exo-trig type cycli-
which is difficult to produce in the traditional coupling reactions zation can also occur to give cis-isomer D0, but the subsequent
with nucleophilic reagents.
cyclization is difficult therefore this pathway (C0–D0) is disfa-
The tolerance of substituents at some positions of two other vored. The interception of D with Ni0 is also plausible, and the
rings in THN[2,3-c]furans 3 was evaluated next (Scheme 2). As generated NiII species15 H could be converted to G directly. The
shown in tricyclic acetals 3q(q0) and 3r(r0), angular-methyl and an axially disposed –OMe group in the other b-bromo acetal
all-carbon quaternary stereocenter at C9a or C3a could be efficiently isomer (top) of 2 causes huge steric repulsion thus severe
incorporated in 79% and 84% combined yields, respectively. destabilization. After rotation of the allylic C–O single bond,
it would equilibrate to conformer I, which adopts a pseudo-boat
conformation. Following the similar steps as those for 30,
Scheme 2 Investigation of substituents at the aliphatic rings. a Substrate 2
(X = Br, Y = I) was used generally unless otherwise stated, and isolated
b
yields of 3 were reported. 2q and 2s (X = Br, Y = Br) were used.
Scheme 3 Proposed mechanism.
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This work was supported by the National Natural Science
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Conflicts of interest
There are no conflicts to declare.
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