Lewis acid catalyzed cascade annulation of alkynols with α-ketoesters: A facile access to γ-spiroketal-γ-lactones

Article abstract of DOI:10.1039/c7cc03668j

A novel Lewis acid catalyzed intermolecular cascade annulation of alkynols with α-ketoesters has been developed. This simple and efficient cascade annulation proceeds through a 5-exo-dig cyclization of alkynols followed by annulation with α-ketoester to provide a wide variety of unsaturated γ-spiroketal-γ-lactones (1,6-dioxaspiro[4.4]non-3-en-2-ones) related to many natural products.

Full text of DOI:10.1039/c7cc03668j

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Lewis acid catalyzed cascade annulation of alkynols with α-
ketoesters: A facile access to γ-spiroketal-γ-lactones
Received 00th January 20xx,
Accepted 00th January 20xx
Digambar A. Kambale,a,b Sagar S. Thorat,a,b Madhukar S. Pratapure,a,b Rajesh G. Gonnadeb,c and
Ravindar Kontham*,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel Lewis acid catalyzed intermolecular cascade annulation of
alkynols with α-ketoesters has been developed. This simple and
efficient cascade annulation proceeds through
a 5-exo-dig
cyclization of alkynols followed by annulation with α-ketoester to
provide a wide variety of unsaturated γ-spiroketal-γ-lactones (1,6-
dioxaspiro[4.4]non-3-en-2-ones) related to many natural products.
Figure 1. Unsaturated γ-spiroketal-γ-lactone containing bioactive natural products
Spiroketals and oxa-spirolactones are frequently found
structural units in biologically potent natural products.1-2 In
addition, it has been shown that simplified spiroacetals
derived from natural products retain their biological
properties. Hence, these scaffolds essentially contribute to
pharmacological activities and represent privileged
pharmacophores in drug discovery.3 In the recent years,
also present in the literature.15 All of these approaches had
limitations such as usage of prefunctionalized starting
materials,
stoichiometric amount of Lewis acids and multiple steps. Thus,
the development of new intermolecular approach to
unsaturated -spiroketal- -lactones from easily available
protection
and
deprotection
sequence,
a
γ
γ
several bioactive natural products with unsaturated γ-
spiroketal- -lactone (1,6-dioxaspiro[4.4]non-3-en-2-one)
fragments is of considerable importance from the point of
view of diversity-oriented synthesis.15
γ
appendage were isolated and have become an important sub-
group of spiroketals, which include tuberostemonamide,4
massarinoline A,5 aphagrandinoid A,6 pyrenolide D,7
crassalactone D,8 levantenolide,9 papyracillic acid C,9
acutissimatriterpene A and many others (Figure 1).8,10
Inspired by the emerging importance of cascade/domino
reactions16 involving alkynols17,18 and as part of our research
interest in Lewis acid-promoted cascade reactions involving
alkynols,19 we herein report a protocol for the construction of
unsaturated
catalyzed cascade annulation of alkynols (4-pentyn-1-ol
derivatives) and -ketoesters, where hydroalkoxylation of
alkynol and/or furnish the exocyclic enol ether via 5-exo-
dig mode of cyclization, which in the proximal presence of an
activated -ketoester would undergo an annulation reaction
γ-spiroketal-γ-lactones comprising Bi(OTf)3
Despite their potential properties, only a few synthetic
methods have been documented in the literature. For
instance, Mitsunobu’s protocol of photo-oxidation of
unprotected prefunctionalized furyl-alkanols, which was
further developed by Vassilikogiannakis et al.11 and others.12
Kitching et al. reported a strategy starting from 3-butyn-1-ol
via saturated oxa-spirolactone in total number of 8 steps.13 In
2006, Shi and co-workers reported using SnCl4 (stoichiometric
α
1
4
5
α
2
to furnish the desired product
3 and/or 6 in a cascade manner
(Scheme 1).
amount,
40 oC) mediated annulation of cyclopropyl-alkyl
-ketoesters.14 Few other miscellaneous reports
To explore the feasibility of this proposed strategy, the
reaction between known alkynol 1a (1.0 eq) and ethylpyruvate
ketones and
α
(
2a, 1.0 eq) with commercially available Bi(OTf)3 (99%, 20 mol
%) in anhydrous CH2Cl2 at room temperature was performed
(Table 1). Gratifyingly, both starting materials were completely
consumed in 12 h at room temperature and gave the desired
a.Organic Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune-411008 (India).
b.Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
c. Centre for Materials Characterization, CSIR-National Chemical Laboratory, Dr.
Homi Bhabha Road, Pune-411008 (India).
unsaturated γ-spiroketal-γ-lactone 3aa in 80% yield (entry 1).
Reaction in other solvents such as toluene, acetonitrile and
tetrahydrofuran did not result in any improvement in the yield
(entries 2-4). Notably, various Lewis (entries 5-15) and
Brønsted acids (entries 16-18) were also
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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products 3ca-cd in moderate yields of 52-62%. 2,2-Diphenyl
substituted alkynol furnished corresponding products 3da and
3db in 62% and 70% yield. Alkynol having benzylic-OH group
was well tolerated in the reaction with ethylpyruvate and lead
to the product 3ea (dr, 1:1). trans-Cyclohexane fused alkynol
possessing two alkyne functionalities gave 3fa and 3fa1 (dr,
7:3). The reaction of indane-derived alkynol with ethylpyruvate
gave the corresponding products 3ga and 3ga1 (dr, 8:2),
whereas with ethyl phenylglyoxylate provide 3gb (dr, 1:1).
Tetralin-fused alkynol (having two alkyne functionalities) with
ethylpyruvate provided 3ha and 3ha1 (dr, 7:3) in good yield,
Scheme 1. Synthesis of unsaturated γ-spiroketal-γ-lactones from alkynols and α-
ketoesters
tested in this reaction, where some of them found moderately
active and gave 60-70% yields. To our delight, initially
identified conditions of 20 mol % Bi(OTf)3 in CH2Cl2 at rt was
found to produce the best yield of the product 3aa (entry 1).21
Further tuning of the other parameters like molar ratios of the
substrates, catalyst loading and temperature did not lead to
any noticeable change in the outcome of the reaction (Table
1).20
where as with ethyl phenylglyoxylate gave 3hb (dr, 8:2). α,β-
Unsaturated ketoester also proceeded smoothly and delivered
the product 3bf in good yield of 63%. The relative
stereochemistry of diastereomers was assigned based on NOE
analysis. Structures of 3ad and 3bc were rigorously confirmed
by single crystal X-ray analysis, all other products were
confirmed by analogy (Scheme 2).20
Taking our protocol a step further, we examined the
reactivity of alkynols possessing internal alkyne functionality
under standard reaction conditions. Cyclohexyl and
cyclopentyl fused 4-pentyn-1-ols (with alkyl aryl substituents
on alkyne termini) successfully reacted with various alkyl and
With the optimal conditions in hand, we next investigated
the scope of this annulation with respect to the alkynols
possessing terminal alkyne functionality and
(Scheme 2). Reaction of cyclohexane and cyclopentane fused
4-pentyn-1-ols with several alkyl and aryl -ketoesters gave
α-ketoesters
α
corresponding oxa-spirolactones 3aa-be in good yields (70-
80%), which clearly states that the electronic nature of the
phenyl substitution of α-ketoesters has a little influence on the
outcome. Unsubstituted 4-pentyn-1-ol provided desired
Table 1. Optimization of the reaction conditions
entry
1
catalyst
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Cu(OTf)2
Sc(OTf)3
Fe(OTf)2
In(OTf)3
Hg(OTf)2
Hg(OTf)2
Yb(OTf)3
FeCl3
solvent
CH2Cl2
toluene
CH3CN
THF
yield (%)b
80
70
64
65
60
-
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
THF
6
7
40
68
70
50
-
8
9
10
11
12
13
14
15
16
17
18
50
-
FeCl3
AgOTf
70
60
-
AgOTf
PTSA
CH3NO2
THF
PTSA
62
-
TfOH
CH2Cl2
aReaction condition unless otherwise specified: 1a (1.0 mmol), 2a (1.0 mmol), and
catalyst (20 mol %) in the indicated solvent (anhydrous) at rt. bIsolated yields of
3aa. rt = room temperature, Tf = triflate (CF3SO2), THF = Tetrahydrofuran.
Scheme 2. Synthesis of unsaturated γ-spiroketal-γ-lactones from alkynols (possessing
terminal alkyne) . a48 h (reaction time); binseparable diastereomers.
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aryl-
sterically demanding
yields. Phenyl substituted 4-pentyn-1-ol gave products 6ea
6ee in moderate yields. Triphenyl substituted alkynol led to
α
-ketoesters, and furnished highly substituted and in situ generated water on to
-spiroketal- -lactones (6aa-6de) in good the release of EtOH from
unsaturated -spiroketal- -lactone
To understand this proposed mechanistic pathway, few
F
gives the intermediate
G. Next,
γ
γ
G leads to the formation of
-
γ
γ
3.
the product 6fa in 62% yield. trans-Cyclohexane fused alkynol supporting experiments were performed (Scheme 4). Reaction
furnished 6ga and 6ga1 (dr, 1:1). Products 6ac and 6cd were of 1b with 2a in the absence of the catalyst failed to give the
confirmed by single crystal X-ray diffraction analysis (Scheme desired product (Eq. 1). The role of the in situ released water
3).20
in lactone formation step (E→F→G) was confirmed by carrying
The reactivity of internal alkynols is little slower than those out the reaction in the presence of activated MS-4 Å (Eq. 2).
of the corresponding terminal alkynols. Best yields were Formation of exocyclic-enol ether intermediate (1b-C) from 1b
observed for
α
compared to unsubstituted 4-pentyn-1-ols (3ca
or
β
-disubstituted alkynols as substrates and release of EtOH in the cascade annulation (
1
G
→
3
) were
-3cd & 6ea-
established by real-time H NMR analysis (Eq. 3) (Scheme 4),20
6ee; Scheme 2 & Scheme 3) can be attributed by Thorpe- and these observations are consistent with earlier reports by
Ingold effect (angle compression).22 All the 42 examples Marks et al.23
reported in this work were noteworthy, since the presence of
α,β-unsaturated lactone functionality provides the platform
for later product modification through reduction and oxidation
(vide infra).
While the precise reaction mechanism requires further
18-21
studies, a plausible mechanism based on recent reports
and the results obtained in this work is proposed (Scheme 4).
Bismuth triflate mediated hydroalkoxylation (5-exo-dig;
activation) of alkynol to give via A, followed by proto-
debismuthination gives the corresponding enol-ether , which
then reacts with the activated ( -activation) ketone group of
-ketoester to give the oxocarbenium ion intermediate
Intramolecular attack of ester oxygen on to the oxocarbenium
ion to give followed by Bi(OTf)3 facilitated release of water
from generates the intermediate . Subsequent addition of
π-
1
B
C
σ
α
2
D.
D
E
E
F
Scheme 4. Postulated reaction mechanism and supporting experiments
The synthetic utility of this method was further explored by
a couple of key transformations. Reduction of unsaturated
spiroketal- -lactone 3ba using Pd/C, H2 (1 atm, balloon) gave
the saturated product in 76% yield (dr, 3:1). Dihydroxylation
of 3ba with OsO4-NMO gave the corresponding diol as a
γ-
γ
7
8
single diastereomer, which structure was unambiguously
confirmed by single crystal X-ray analysis (Scheme 5).20
Scheme 3. Synthesis of unsaturated γ-spiroketal-γ-lactones from alkynols (possessing
internal alkyne functionality). a48 h (reaction time).
Scheme 5. Synthetic utility
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