Copper-Catalyzed Formal [2+2+1] Heteroannulation of Alkenes, Alkylnitriles, and Water: Method Development and Application to a Total Synthesis of (±)-Sacidumlignan D

Article abstract of DOI:10.1002/anie.201604528

A copper-catalyzed three-component reaction of alkenes, alkylnitriles, and water affords γ-butyrolactones in good yields. The domino process involves an unprecedented hydroxy-cyanoalkylation of alkenes and subsequent lactonization with the creation of three chemical bonds and a quaternary carbon center. The synthetic potential of this novel [2+2+1] heteroannulation reaction was illustrated by a concise total synthesis of (±)-sacidumlignan D.

Full text of DOI:10.1002/anie.201604528

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604528
German Edition: DOI: 10.1002/ange.201604528
Multicomponent Reactions
Copper-Catalyzed Formal [2+2+1] Heteroannulation of Alkenes,
Alkylnitriles, and Water: Method Development and Application to
a Total Synthesis of (Æ)-Sacidumlignan D
Tu M. Ha, Claire Chatalova-Sazepin, Qian Wang, and Jieping Zhu*
Abstract: A copper-catalyzed three-component reaction of
alkenes, alkylnitriles, and water affords g-butyrolactones in
good yields. The domino process involves an unprecedented
hydroxy-cyanoalkylation of alkenes and subsequent lactoni-
zation with the creation of three chemical bonds and a quater-
nary carbon center. The synthetic potential of this novel
[2+2+1] heteroannulation reaction was illustrated by a concise
total synthesis of (Æ)-sacidumlignan D.
C
opper-catalyzed difunctionalization of unactivated alkenes
À
À
involving a C C and a C X bond formation is one of the most
attractive transformations in organic chemistry. Although
copper-mediated and copper-catalyzed carboamidation,[1]
carbooxygenation,[2] carboboration,[3] and other difunctional-
ization reactions of alkenes have been intensively investi-
gated,[4] most of them involve the intramolecular formation of
Scheme 1. Difunctionalization of alkenes to g-butyrolactones: A
copper-catalyzed three-component reaction of alkenes, alkylnitriles,
and water.
2
3
À
a C(sp ) C(sp ) bond using substrates in which one of the
reaction partners is tethered to the alkene. The copper-
catalyzed intermolecular carbooxygenation of alkenes are
limited mainly to those reactions initiated by aryl radicals[5]
developing a novel synthesis of g-lactones (3) by a copper-
catalyzed three-component [2+2+1] heteroannulation of
alkenes (1), alkylnitriles (2), and water (Scheme 1). The
underlying principle is outlined in Scheme 1. Addition of the
in situ generated a-cyanoalkyl radical 4 to an alkene 1 would
afford the adduct radical 5, which could be further oxidized to
the carbenium ion 6.[16] Trapping of the latter by water would
afford the g-hydroxy alkylnitrile 7, which, upon intramolec-
ular cyclization, would provide the cyclic imidate 8. Acidic
work-up would then convert 8 into the g-butyrolactone 3. For
the desired domino sequence to proceed towards the for-
mation of 3, the catalytic conditions should satisfy the
following mechanistic criteria: a) selective generation of 4,
which adds rapidly to the double bond of 1, b) fast oxidation
of the resulting nucleophilic radical 5 to 6 to avoid the
dimerization of the former, c) rapid addition of water to 6 to
avoid its cationic polymerization with the remaining alkene,
and d) proper activation of the cyano group to accelerate the
lactonization process. The realization of this synthetic scheme
and its application to the total synthesis of (Æ)-sacidum-
lignan D (9)[17] is reported herein.
Using a-methyl styrene (1a) and acetonitrile (2a) as test
substrates, the reaction conditions were surveyed by varying
the copper sources, the ligands, the oxidants, the bases, and
the additives (for details, see the Supporting Information).
Preliminary results indicated that the reaction can indeed
take place, thus providing, after acidic treatment (1.0n HCl,
808C), the lactone 3a in 60% yield (NMR; Table 1, entry 1).
Since the intermediate 7a (R1 = Ph, R2 = Me, R3 = R4 = H;
Scheme 1) was detected before the acidic treatment, various
Lewis acids were tested to accelerate the lactonization step.
and the CF3 radical.[6,7] In this regard, one notable and
3
À
important exception involving the formation of a C(sp )
C(sp3) bond is the manganese(III) acetate mediated annula-
tion of olefins with acetic acid, thus leading to g-butyrolac-
tones [2.0 equiv of Mn(OAc)3 in refluxing acetic acid].[8] g-
Butyrolactone is an important core structure found in many
biologically active natural products[9] and is also a useful
synthetic building block.[10] It is therefore not surprising that
many different strategies have been developed for the
efficient synthesis of this heterocycle. For example, Jiang
and co-workers have recently reported a copper-catalyzed
formal [3+2] heteroannulation of terminal alkenes with acetic
anhydride for the synthesis of g-butyrolactones.[11,12]
Our group has recently initiated a research program
aimed at developing copper-catalyzed alkylative difunction-
alization of alkenes using alkylnitriles as a key reactant.[13–15]
As a continuation of this project, we became interested in
[*] T. M. Ha, Dr. C. Chatalova-Sazepin, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Dr. C. Chatalova-Sazepin
Visiting Ph.D. student from Department of Chemistry, University of
British Columbia (Canada)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604528.
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Table 1: Copper-catalyzed formal [2+2+1] annulation of 1a, 2a, and
water to 3a: optimization of reaction conditions.
Entry
Base (equiv)
Lewis acid (equiv)
Yield [%][b]
1
K3PO4 (0.1)
none
60
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.2)
Na3PO4 (0.2)
KOtBu (0.1)
LiOtBu (0.1)
DBU (0.15)
DBN (0.15)
N-methylimidazole (0.15)
2,6-lutidine (0.15)
In(OTf)3 (0.2)
Yb(OTf)3 (0.2)
Mg(OTf)2 (0.2)
Ca(ClO4)2 (0.2)
Mg(ClO4)2 (0.2)
Zn(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
Ca(OTf)2 (0.2)
66
69
68
65
79
75
81 (69)[c]
74
75
56
Scheme 2. Substrate scope. [a] Standard reaction conditions. [b] DTBP
(2.5 equiv) under otherwise identical conditions. [c] d.r.=1:1.
54
89 (73)[c]
79
79
56
functionalized alkyl-substituted styrenes participated in the
reaction without event to provide the corresponding g-
butyrolactones (3j–n). 1,1-Diaryl-substituted alkenes are
excellent substrates leading to the corresponding lactones
(3o–t). Importantly, trisubstituted alkenes participated in the
reaction equally well to efficiently give the 3,4,4-trisubstituted
g-butyrolactones 3r–t. Propionitrile, butyronitrile, valeroni-
trile, and 3-methoxypropionitrile are competent alkylating
agents to initiate the domino process leading to the corre-
sponding g-butyrolactones 3u–3x as a mixture of two
diastereomers. Pleasingly, reaction of trisubstituted alkenes
with propionitrile afforded the 2,3,4,4-tetrasubstituted g-
butyrolactone 3y, albeit in a slightly reduced yield (47%).
The reaction of methyl-4-phenylpent-4-enoate (10) with
acetonitrile under standard reaction conditions afforded the
lactone 3z in which the cyano group remained untouched
(Scheme 3a). Similarly, methyl 2-(prop-1-en-2-yl)benzoate
(11) was converted, under identical reaction conditions, into
the lactone 3aa (Scheme 3b). The observed highly chemo-
selective cyclization could be accounted for by the direct
interception of the benzylic cation by the tethered methoxy-
carbonyl function.
[a] Reaction was performed in a sealed tube: 1a (0.1 mmol), Cu-
(BF4)2·6H2O (0.2 equiv), H2O (30 equiv), Bipy (0.6 equiv), DTBP
(4.0 equiv), base and Lewis acid in MeCN (0.025m), N2 atmosphere,
1408C, 3.5 h, then 1.0n HCl, 808C, 45 min. [b] Yield was determined by
1H NMR spectroscopy with CH2Br2 as an internal standard. [c] Yield of
isolated product. Bipy=2,2’-bipyridine, DBN=1,5-diazabicyclo-
[4.3.0]non-5-ene, DTBP=di-tert-butyl peroxide, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, Tf=trifluoromethanesulfonyl.
Some representative results are summarized in Table 1.
Adding lanthanide triflates (entries 2 and 3), Mg(OTf)2
(entry 4), and Ca(ClO4)2 (entry 5) to the reaction mixture
slightly increased the yield of 3a. A significant improvement
was observed by performing the reaction in the presence of
a catalytic amount of either Mg(ClO)4, Zn(OTf)2, or Ca-
(OTf)2 (entries 6–9),[18] with the latter furnishing the cleaner
reaction.[19] Including Ca(OTf)2 as a Lewis acid, the influence
of base on the reaction outcome was re-investigated. Na3PO4
(entry 10), DBN and N-methylimidazole (entries 14 and 15)
were as efficient as K3PO4, whereas a lower yield of 3a was
isolated when KOtBu, LiOtBu, and 2,6-lutidine (entries, 11,
12, and 16) were used as bases. Gratefully, a clear improve-
ment of the reaction efficiency was observed when the
reaction was performed in the presence of DBU (entry 13).
Overall, under optimum reaction conditions, 3a was isolated
in 73% yield. We note that the reaction proceeded equally
well in the dark.[19] Since three chemical bonds were created in
this domino process, the average yield per chemical bond
formation is around 90%.
Performing the reaction of 1a in MeCN under an oxygen
atmosphere with or without DTBP led only to the decom-
position of the alkenes. In contrast, performing the same
reaction under strictly inert atmosphere afforded 3a in 73%
yield. An isotope-labelling experiment was conducted to gain
further mechanistic insights. Reaction of 1a with acetonitrile
With the optimized reaction conditions [Cu(BF4)2·6H2O,
(0.2 equiv), Bipy (0.6 equiv), DBU (0.15 equiv), H2O
(30 equiv), Ca(OTf)2 (0.2 equiv), DTBP (4.0 equiv), 3.5 h,
N2 atmosphere, MeCN, 1408C, then 1.0 N HCl, 808C, 45 min],
the scope of this copper-catalyzed, formal [2+2+1] hetero-
annulation was investigated. As shown in Scheme 2, the a-
methyl styrenes with both electron-donating (Me, OMe) and
electron-withdrawing (Cl) substituents on the aromatic ring,
regardless of their positions, afforded the g-butyrolactones
3b–i in good yields. Methyl, ethyl, isopropyl, phenethyl, and
Scheme 3. Additional examples on the synthesis of functionalized g-
lactones. [a] Standard reaction conditions.
2
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Scheme 5. Total synthesis of (Æ)-sacidumlignan D (9): a) nBuLi,
EtCOCl, THF, 608C, then PTSA, toluene, reflux, 56%; b) Cu-
(BF4)2·6H2O (0.2 equiv), Bipy (0.6 equiv), DBU (0.15 equiv), H2O
(30 equiv), Ca(OTf)2 (0.2 equiv), DTBP (2.5 equiv), 1408C, in MeCN
(0.025m), 3.5 h; then 1.0 N HCl, 808C, 45 min, 60%; c) LHMDS
(5 equiv), MeOTf (4 equiv), THF, À788C, 12 h, 89%; d) LiAlH4, then
TFA, CH2Cl2, 91% (2 steps); e) H2, Pd/C, MeOH/EtOAc (1:1), 93%.
LHMDS=lithium hexamethyldisilazide, PTSA=p-toluene sulfonic acid,
TFA=trifluoroacetic acid, THF=tetrahydrofuran.
Scheme 4. 18O-Labeling and control experiments. [a] H218O (30 equiv),
under otherwise standard reaction conditions. [b] Standard reaction
conditions.
(2a) in the presence of H218O (18O content 97%) under
otherwise standard reaction conditions afforded the double
and mono 18O-labeled products [18O2]-3a and [18O1]-3a,
respectively (Scheme 4a). The upfield shift of 13C NMR
signals of C1 and C4 in [18O2]-3a/[18O1]-3a relative to those
of 3a [Dd(C=O)16O-18O =+ 2.5 Hz, [Dd(C4)16O-18O =+ 4.9 Hz] is
in agreement with literature reports.[20] The results of these
control experiments indicated that the oxygen atoms in the
lactones 3 came from water rather than from adventitious
oxygen or DTBP (Scheme 1). Furthermore, submitting an
authentic sample of the tertiary alcohol 7a to the standard
reaction conditions afforded 3a in 92% yield, thus indicating
that the tertiary alcohol 7 could indeed be an intermediate on
the way to lactone 3 (Scheme 4b).
In the absence of Cu(BF4)2·6H2O or Bipy, only a trace
amount of 3a was formed. In contrast, without DTBP, 1a was
converted into 3a in 39% yield (NMR) in the presence of
a stoichiometric amount of Cu(BF4)2. These observations are
in accord with our previous conclusion that the copper
catalyst played a key role in the generation of the acetonitrile
radical 4 and that DTBP served mainly as an oxidant to
regenerate the copper(II) species.[21] In our initial survey of
reaction conditions, we isolated the dimer 12, resulting most
probably from the dimerization of the benzylic radical 5a (see
Scheme 1; R1 = Ph, R2 = Me, R3 = R4 = H) because of its
inefficient oxidation to 6a. Therefore, the copper catalyst
played a dual role in this transformation, that is, to generate
the cyanoalkyl radical and to selectively oxidize the adduct
radical to the carbenium ion.
acidic conditions to give the alkene 14. The key [2+2+1]
heteroannulaton of 14 with acetonitrile and water under our
standard reaction conditions proceeded smoothly to afford
the lactone 15 in 60% yield. Treatment of 15 with LHMDS
followed by methylation of the lithium enolate provided the
2,3-trans disubstituted lactone 16 as an only isolable stereo-
isomer. Reduction of 16 with LiAlH4 afforded the tetra-
hydrofuran 17, which was converted into 9 in 93% yield under
hydrogenolysis conditions.
In summary, we have developed the first examples of
copper-catalyzed three-component reactions of alkenes with
alkylnitriles and water. The domino process involved an
unprecedented copper-catalyzed hydroxy-cyanoalkylation of
alkenes and subsequent cyclization leading to g-butyrolac-
3
3
À
tones with concomitant formation of one C(sp ) C(sp ) bond
À
and two C O bonds. This novel [2+2+1] heteroannulation
reaction was featured as the key step in a concise total
synthesis of (Æ)-sacidumlignan D.
Acknowledgments
Financial support from the EPFL (Switzerland), the Swiss
National Science Foundation (SNSF), and Swiss National
Centers of Competence in Research NCCR-Chemical Biol-
ogy are gratefully acknowledged.
(Æ)-Sacidumlignan D (9) was isolated by Yue and co-
workers from the plant Sarcostemma acidum (Roxb.) col-
lected from Hainan island, China, where the local people use
it for the treatment of chronic cough and postnatal hypo-
galactia.[17,22] To illustrate the synthetic potential of our
heteroannulation process, a total synthesis of 9 was under-
taken (Scheme 5). Lithium–halogen exchange of the arylbro-
mide 13, readily synthesized in two steps from 2,6-dimethoxy-
phenol, followed by nucleophilic addition of the resulting
aryllithium species to propionyl chloride furnished a tertiary
alcohol, which, without purification, was dehydrated under
Keywords: alkenes · copper · heterocycles ·
multicomponent reactions · total synthesis
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Received: May 10, 2016
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Multicomponent Reactions
T. M. Ha, C. Chatalova-Sazepin, Q. Wang,
J. Zhu*
&&&& — &&&&
Copper-Catalyzed Formal [2+2+1]
Heteroannulation of Alkenes,
Alkylnitriles, and Water: Method
Development and Application to a Total
Synthesis of (Æ)-Sacidumlignan D
Water connections: The title reaction
affords g-butyrolactones with the creation
of three chemical bonds and a quaternary
carbon center. The domino process
involves an unprecedented copper-cata-
lyzed hydroxy-cyanoalkylation of alkenes.
A total synthesis of (Æ)-sacidumlignan D
was accomplished featuring this hetero-
annulation as a key step.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!