Rapid synthesis of bicyclic lactones: Via palladium-catalyzed aminocarbonylative lactonizations

Article abstract of DOI:10.1039/c7cc02494k

A novel and efficient palladium-catalyzed aminocarbonylative lactonization of amino propargylic alcohols has been developed to provide rapid access to various bicyclic lactones especially dihydropyrrole-fused furanones, which are novel structures and have

Full text of DOI:10.1039/c7cc02494k

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Rapid synthesis of bicyclic lactones via palladium-
catalyzed aminocarbonylative lactonizations†
Cite this:DOI: 10.1039/c7cc02494k
Xianglin Yin,a Haroon Mohammad,b Hassan E. Eldesouky,b Ahmed Abdelkhalek,b
ac
Mohamed N. Seleem*bc and Mingji Dai
*
Received 31st March 2017,
Accepted 28th April 2017
DOI: 10.1039/c7cc02494k
rsc.li/chemcomm
A
novel and efficient palladium-catalyzed aminocarbonylative
lactonization of amino propargylic alcohols has been developed
to provide rapid access to various bicyclic lactones especially
dihydropyrrole-fused furanones, which are novel structures and
have not been explored in biological and medicinal settings. This
method can also be used to access b-lactone products such as 16.
Preliminary biological evaluations revealed that compounds 13h and
13s demonstrated promising activity against Clostridium difficile and
compounds 13h, 13k, 13s, and 16b showed activity against several
important fungal pathogens.
Our recent efforts1–3 in developing tandem palladium-catalyzed
carbonylation reactions4–8 for complex natural product synthesis
have resulted in a novel method to synthesize oxaspirolactones
from hydroxyl cyclopropanol starting materials (Fig. 1A).2 We
envisioned that this new synthetic capability could be potentially
used to synthesize oxaspirolactone 5, an important precursor
for the total syntheses of stemofoline alkaloids (cf. 4).9–14 We
Fig. 1 Background and research design.
proposed a tandem process to prepare 5 from 7 via a tandem chemistry remain unknown. Therefore, we decided to develop and
Mannich reaction and ketalization. Compound 7 could be derived generalize the proposed palladium-catalyzed aminocarbonylative
from hydroxyl cyclopropanol 8 via the palladium-catalyzed carbony- lactonizations to provide expedient avenues toward dihydropyrrole-
lative oxaspirolactonization we have developed. Compound 8 could fused furanones.
be synthesized from dihydropyrrole-fused furanone 10. In order to
Significant advances have been made in the area of metal-
quickly access 10, we envisioned another palladium-catalyzed catalyzed carbonylation of alkynes.15 In 1979, Murray and Norton
amino-carbonylative lactonization of amino propargylic alcohol 11. reported an elegant palladium-catalyzed carbonylation of homo-
Surprisingly, there was no documented synthesis of dihydropyrrole- propargylic alcohols to synthesize a-methylene g-lactones.16,17 Since
fused furanone (cf. 10), which turned out to be a novel scaffold. then, many palladium-catalyzed cyclocarbonylations of alkynes
Their potential biological activities and use in medicinal have been reported. Notably, Alper and co-workers reported
carbonylative syntheses of 2(5H)-furanones from propargylic
alcohols;18–20 Yang,21–25 Akita,26 Gabriele27–29 and others30–34
have reported oxy or amino-palladation-alkoxycarbonylation of
a Department of Chemistry and Center for Cancer Research, Purdue University, West
Lafayette, Indiana, 47907, USA. E-mail: mjdai@purdue.edu; Tel: +1-765-496-7898
b Department of Comparative Pathobiology, Purdue University College of Veterinary
Medicine, West Lafayette, IN 47907, USA. E-mail: mseleem@purdue.edu;
Tel: +1-765-494-0763
alkynes to synthesize various heterocycles. Despite these progresses,
the intramolecular aminopalladation-carbonylative lactonization of
amino propargylic alcohols of type 11 to synthesize dihydropyrrole-
fused furanones (cf. 10) has not been reported. Herein, we describe
elements of our recent efforts in developing such transformations to
rapidly construct dihydropyrrole-fused furanones, which would not
only facilitate total syntheses of complex natural products such as
c Purdue Institute for Drug Discovery and Institute for Inflammation, Immunology,
and Infectious Diseases, West Lafayette, IN 47907, USA
† Electronic supplementary information (ESI) available. CCDC 1540287 and
1540288. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c7cc02494k
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Table 1 Reaction condition optimizations
Entry
Reaction conditions (equiv.)
Yielda (%)
1
2
3
4
5
6
7
8
PdCl2 (0.1), A (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), A (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), B (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), C (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), D (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), E (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), Xantphos (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), F (0.1), BQ (1.5), PG = Ts
PdCl2(MeCN)2 (0.1), E (0.1), BQ (1.5), PG = Ts
Pd(tfa)2 (0.1), C (0.2), BQ (1.5), PG = Ts
0
63
58
63
58
53
Trace
33
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
41
51
61
0
31
72
81
42
69
0
Pd(tfa)2 (0.1), C (0.1), BQ (3.0), PG = Ts
Pd(tfa)2 (0.1), C (0.1), BQ (1.0), PG = Ts
Pd(tfa)2 (0.1), C (0.1), BQ (1.0), PG = Ts, Cs2CO3 (1.0)
Pd(tfa)2 (0.1), C (0.1), BQ (1.5), PG = Ts, CO (7 atm)
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), C (0.1), BQ (1.5), PG = Ts
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), G (0.1), BQ (1.5), PG = Ts
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), H (0.1), BQ (1.5), PG = Ts
[Pd(neoc)(OAc)]2(OTf)2 (0.1), BQ (1.5), PG = Ts
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), G (0.1), CuCl2 (1.5), PG = Ts
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), G (0.1), DDQ (1.5), PG = Ts
PdCl2(MeCN)2 (0.1)/AgOTf (0.2), G (0.1), DDQ (1.5), PG = Boc
Pd(tfa)2 (0.1), BQ (1.5), PG = Boc, MeOH
90
0
24b
a
b
Isolated yield. Yield of 14 with MeOH as the solvent.
the stemofoline alkaloids, but also provide novel molecules for the palladium catalyst and the ligand is not as good as 1 : 1.
therapeutic development. Increasing the amount of BQ from 1.5 equiv. to 3.0 equiv.
Our investigation started with model substrate 12a (Table 1), (entry 11) made the reaction messier with 51% yield of the
which was readily prepared via 1,2-addition of acetylide to desired product, and decreasing the amount to 1.0 equiv.
hydrocinnamaldehyde (see the ESI†). When the commonly slightly reduced the reaction yield (61%, entry 12). Adding a
used carbonylation catalyst PdCl2 was used in combination base such as Cs2CO3 was detrimental (entry 13) and increasing
with 2,2-bipyridine ligand A, no desired product 13a was the carbon monoxide pressure to 7 atm showed an inhibitory
obtained. We hypothesized that a more cationic and electron- effect (entry 14). To further improve the reaction yield, we
deficient palladium catalyst should function better to activate explored the more electron deficient Pd(OTf)2 (0.1 equiv.)
the triple bond for the aminopalladation step than the neutral complex generated from a combination of PdCl2(MeCN)2 and
PdCl2 catalyst. Thus, Pd(tfa)2 was explored next. To our delight, AgOTf (1 : 2 ratio). The yield did increase to 72% (entry 15).
the desired product 13a was produced in 63% yield with Ligand G (entry 16, 81% yield) was found to be superior to
p-benzoquinone (BQ, 1.5 equiv.) as an oxidant and MeCN as a ligand C (entry 4) and ligand H (entry 16). [Pd(neoc)(OAc)]2(OTf)2, a
solvent. We then investigated the effect of different ligands and cationic dimeric palladium complex developed by the Waymouth
several bipyridine and 1,10-phenanthroline-based ligands lab35 also worked for this transformation but with reduced reaction
(entries 3–6) were evaluated. These ligands are either the same yield. While CuCl2 as an oxidant was deleterious, 2,3-dichloro-5,6-
as ligand A or slightly less effective, but are much more effective dicyano-1,4-benzoquinone (DDQ) increased the yield to 90%
than BOX-ligand F (entry 8). Bidentate phosphine ligand Xantphos (entry 20). Interesting, when the nitrogen-protecting group was
(entry 7) turned off the reaction almost completely and only a trace changed to Boc (12a0), even the optimized reaction conditions
amount of 13a was obtained. We further found that a 1 : 2 ratio of did not give any desired product 13a0 (entry 21). When MeOH
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Table 2 Substrate scope
Fig. 2 Formation of b-lactone product.
carbon added between the nitrogen nucleophile and the triple
bond, in addition to the expected 6-endo-dig amino-palladation,
a 5-exo-dig amino-palladation becomes a potential competing
pathway. If the latter occurs, we would be expecting a strained
b-lactone product (cf. 16). Interestingly, under the optimal reaction
conditions for the formation of 5,5-fused furanones, no fused
product 17 was identified in the reaction mixture, instead
b-lactone product 16 was produced in 40% (R = Ph) or 18%
(R = Me) yield.37 The structure and double bond geometry of
16a were unambiguously validated by X-ray analysis (Fig. 2).36
Mechanistically, as shown in Fig. 3, after ligand exchange, a
hydroxyl group-directed activation of the alkyne with the Pd(II)
catalyst would trigger a 5-endo-dig anti-aminopalladation to form the
dihydropyrrole ring and produce vinyl-palladium species 19 from 18.
Carbon monoxide migratory insertion followed by lactonization
would lead to product 13 and a Pd(0) catalyst. The latter would be
oxidized to a Pd(II) catalyst by DDQ to continue the next catalytic
cycle. For the formation of 16, a 5-exo-dig anti-aminopalladation
overrides a 6-endo-dig amino-palladation. The trans double bond
geometry of 16 supported the anti-aminopalladation process over a
syn-aminopalladation process.
Due to the structural novelty of the aminocarbonylative
lactonization products, we evaluated them against several
important bacterial, yeast and mold pathogens (see the ESI†).
Our preliminary results showed that compounds 13h and 13s
exhibited promising activity against toxigenic strains of Clostridium
difficile with 128 mM and 64 mM minimum inhibitory concentration
(MIC) values. Interestingly, these two compounds did not show side
effects on the beneficial intestinal microflora and were nontoxic to
Caco-2 cell lines up to 256 mM. Compounds 13h, 13k, 13s, and 16b
was used as the solvent with Pd(tfa)2 as the catalyst and BQ as
the oxidant, product 14 was produced in 24% yield (entry 22),
which indicates that with the Boc-protected substrate, the
aminopalladation and alkoxycarbonylation steps could take
place, but not the lactonization step. These results suggest that
the formation of the furanone ring is the problematic step
presumably due to pseudo-A(1,3) interaction between the Boc
group and the alkyl side chain.
With optimized reaction conditions established, the substrate
scope of this new aminocarbonylative lactonization method was
assessed (Table 2). A variety of hydropyrrole-fused furanones can
be prepared. In general, for secondary propargylic alcohols with
an alkyl substituent, the reaction yield is excellent (cf. 13a–d).
The yield for secondary propargylic alcohols with an aryl sub-
stituent dropped slightly (cf. 13f–h) or significantly (cf. 13e, 13i–j)
presumably due to the ease of oxidizing the secondary alcohol to
a ketone and other undesired reaction pathways. A primary
propargylic alcohol substrate gave modest yield of the desired
hydropyrrole-fused furanone product (cf. 13k). Notably, sterically
hindered tertiary alcohols (13i–t) are excellent substrates and
high yields were obtained except for the case of 13q. Tricyclic
products 13l–o and 13r–t containing a spirocyclic ring system
were produced in excellent yields. The structure of 13o was
unambiguously confirmed by X-ray analysis.36 Due to the mild
reaction conditions, functional groups such as sulfonamide,
Boc-carbamate, bromide, and nitro group are well tolerated.
The reaction can also be conducted on a gram-scale (13p).
We then prepared substrate 15 and wondered the possibility
of forming a 5,6-fused furanone product (cf. 17, Fig. 2). With one
Fig. 3 Proposed catalytic cycle.
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access b-lactone product such as 16, another novel scaffold with
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(1553820). The NIH P30CA023168 supported shared NMR
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