Total synthesis of novel bioactive natural product paracaseolide A and analogues: Computational evaluation of a 'proposed' biomimetic Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2014.09.072

A short and generally applicable synthesis of bioactive tetracyclic natural product paracaseolide A has been accomplished employing a 'proposed' biomimetic Diels-Alder reaction as the key strategic step. The Diels-Alder precursors for this purpose were readily assembled through a versatile Suzuki coupling on preformed α-halo butenolides. The mechanistic aspects of the 'putative' biomimetic Diels-Alder reaction have been probed using computational methods, which suggest that this [4+2]-cycloaddition proceeds through a step-wise process and product profile is thermodynamically governed.

Full text of DOI:10.1016/j.tet.2014.09.072

Tetrahedron 70 (2014) 8488e8497
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of novel bioactive natural product paracaseolide A
and analogues: computational evaluation of a ‘proposed’ biomimetic
DielseAlder reaction
Laxmaiah Vasamsetty , Debashis Sahu , Bishwajit Ganguly ,*, Faiz Ahmed Khan a,*,
Goverdhan Mehta
a
a
b
b
c
,
*
Department of Chemistry, Indian Institute of Technology, Hyderabad 502 205, India
Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt and Marine Chemicals Research
b
Institute, Bhavnagar 364 002, India
c
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and generally applicable synthesis of bioactive tetracyclic natural product paracaseolide A has
been accomplished employing a ‘proposed’ biomimetic DielseAlder reaction as the key strategic step.
The DielseAlder precursors for this purpose were readily assembled through a versatile Suzuki coupling
Received 14 September 2014
Accepted 22 September 2014
Available online 4 October 2014
on preformed
a-halo butenolides. The mechanistic aspects of the ‘putative’ biomimetic DielseAlder
reaction have been probed using computational methods, which suggest that this [4þ2]-cycloaddition
proceeds through a step-wise process and product profile is thermodynamically governed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Singlet oxygen
Suzuki coupling
Alkenyl butenolides
DielseAlder dimerization
Gaussian 09 suite
1. Introduction
be formally considered as a dimer derived from a a-alkenyl bute-
nolide precursor 2. The compact tetracyclic architecture of 1, har-
boring six contiguous stereogenic centers and three quaternary
carbons has many distinctive features. The extensive oxy-
functionalization present in it is localized within a triquinane seg-
Diversely embellished
a
-substituted butenolides have been
frequently encountered in nature either as wholesome entities or
as a substructure among more complex natural products and are
known to display wide range of biological activities (Fig. 1).1
5
ment that constitutes the rim of its ‘bowl-like’ scaffolding. The two
As a result,
a
-substituted butenolide embodying natural prod-
long, protruding, cis oriented hydrophobic alkyl chains on the outer
surface of its oxygen dotted cyclic framework, imparts the molecule
a bipolarofacial character, reminiscent of many bioactive chemical
entities.
ucts have elicited considerable attention as targets of total syn-
2
thesis and the chemical space around them has been extensively
3
explored to evaluate their therapeutic potential. Indeed, search for
new
a
-substituted butenolides from diverse natural sources con-
During bioactivity screens, paracaseolide A (1) exhibited good
inhibitory activity against dual-specificity phosphatase CDC25B,
which has a role in activating the cyclin dependent kinase cdc2 by
tinues to receive attention.
4
Guo and co-workers in 2011, while investigating previously
unexplored species Sonneratia paracaseolaris collected from an
endemic mangrove in Guangdong Province of China, reported the
removing two phosphate groups, which is required for entry into
4
mitosis, with an IC50 value of 6.44
m
M. This is a promising bio-
isolation and structure determination of a novel
a
-alkenyl bute-
activity attribute as CDC25B is a proto-oncogene in humans and
shown to be over expressed in a number of cancers and is impli-
nolide dimer and named it paracaseolide A (1). The structure of this
unusual molecule was adduced from detailed 2D NMR (HSQC,
6
cated in cell cycle progression in tumors. Very recently, a group
4
7
HMBC, COSY, ROESY) correlations. As a molecular construct, 1 can
from China has further shown that paracaseolide A (1) is also
a potent inhibitor (IC50 1.5
mM) of protein tyrosine phosphotase 1B
(PTP1B), an enzyme encoded in humans by the PTPN1 gene and is
a known negative regulator of the insulin signaling pathway con-
sidered a promising potential therapeutic target, in particular for
treatment of type 2 diabetes (Fig. 2).
*
Corresponding authors. Tel.: þ91 40 23134848; fax: þ91 40 23010785; e-mail
addresses: gmehta43@gmail.com, gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in
G. Mehta).
8
(
http://dx.doi.org/10.1016/j.tet.2014.09.072
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
0

L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
8489
Fig. 1. Examples of biologically active a-substituted butenolide natural products.
Vassilikogiannakis9a while reporting the first total synthesis of
4
paracaseolide A (1) along the proposed biomimetic pathway rec-
ognized that an endo DielseAlder reaction in 2 (see Scheme 2) and
subsequent intramolecular ketalization in 4 would lead to an in-
0
termediate 5 wherein the two hydrophobic chains at C2 and C7
would be trans disposed. Since the DielseAlder dimerization of 2, in
the hands of these authors, led only to the natural product 1 with
cis disposition of substituent chains at C2’ and C7, an unlikely epi-
9
a
Fig. 2. Structure of paracaseolide A and
a
-alkenyl butenolide.
merization at C7 was invoked to account for the observed for-
9
c
mation of 1 (Scheme 2). Our group had also independently
pursued a biomimetically patterned synthesis of 1 from 2 and our
finding was that dimerization of 2 is not stereoselective and led to
both 1 and 5 and the two diastereomers were observed to be non-
interconvertible under the reaction regime. This observation of
ours has been subsequently confirmed by others. Thus, the
presumptive biomimetic DielseAlder type dimerization of 2
needed critical mechanistic scrutiny. In this full report, we pro-
The complex, unusual cage-like molecular architecture of 1,
coupled with its distinctive bioactivity attributes, renders it an al-
luring target for total synthesis and analoguing. Not surprisingly,
practitioners of art of synthesis have been quick to pick-up the
9c
9d
7,9
gauntlet and six total syntheses have been accomplished in the
9
c
past two years including our own. At the strategy level, most of
these total synthesis efforts have been patterned along the pro-
10
vide additional examples en route our total synthesis of para-
caseolide A (1) and also detail computational analyses of the
DielseAlder reaction of 2 by modeling its dimerization.
4
posed ‘putative’ biosynthetic pathway. It was during the structure
4
elucidation of paracaseolide A (1) that Guo et al. hypothesized that
this natural product could originate through a [4þ2]-cycloaddition
(
DielseAlder reaction) between two molecules of a a-alkenyl
butenolide precursor 2 to an intermediate 3, followed by intra-
molecular ketalization (dehydration) (Scheme 1). Quite in-
triguingly, the stereochemical course of the DielseAlder
dimerization leading to 1 from 2, and in particular the resultant cis
0
disposition of the two long hydrophobic appendages at C2 and C7
4
was not commented upon by the authors. However, Noutsias and
Scheme 1. Proposed biosynthetic pathway for paracaseolide A (1) by Guo et al.
Scheme 2. Vassilikogiannakis proposed route for the dimerization of 2 to deliver the
natural product 1.

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L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
2
. Results and discussions
the projected DielseAlder type dimerization. Indeed, thermal ac-
tivation of 14 (neat, sealed tube,100 C) eventuated in the projected
ꢀ
Our approach to the natural product 1 was centered on pro-
visioning a short access to a prototypal a-alkenyl butenolide pre-
[4þ2]-cycloaddition-intermolecular ketalization cascade to deliver
a mixture of diastereomeric teracycles 15 and 16 (2:3) in 52% iso-
lated yield (Scheme 4). The lack of stereoselectivity in the [4þ2]-
cursor 6 with elements of generalization and diversity creation
embedded into it. Thermal activation of 6 was expected to trigger
the projected biomimetic DielseAlder type dimerization and if el-
ements of intramolecular ketalization were already implanted, it
would generate the tetracyclic framework of the natural product in
type dimerization in
a-alkenyl-g-hydroxy butenolide 14 was an
unexpected outcome and required that the structures of the two
diastereomers to be settled beyond the realm of any ambiguity.
1
13
There were distinguishing features in the H and C NMR spectra
of the two diastereomers 15 and 16 but it was the extensive 2D
NMR studies (COSY, HSQC, HMBC, ROESY) that revealed their ster-
eostructures. Key connectivities that enabled these assignments are
displayed in Fig. 3. In addition, a single crystal X-ray structure de-
a single pot operation.
sought to be accessed via the versatile Suzuki cross coupling re-
action between -halo butenolides 7 and the desired alkenyl bor-
a-alkenyl-g-methoxy butenolides 6 were
a
onate ester and the former could arise from the oxidation of
appropriate furan precursor 8 through an oxidative dearomatiza-
tion protocol and a-halgenation (Scheme 3).
12
termination on 16 fully secured the relative stereochemical as-
signment in the two diastereomers (Scheme 4). Since formation of
the two diastereomers 15 and 16, epimeric at C7, was an un-
anticipated result, it was important to show that they are non-
interconvertible and formed independently. When subjected to
the conditions of thermal activation for the DielseAlder type di-
merization, both 15 and 16 maintained their integrity and there
was no indication of either undergoing any epimerization at C7.
Scheme 3. Retrosynthesis for accessing key a-alkenyl-g-methoxy butenolides 6.
With this backdrop, we initiated some model studies as a pre-
lude to targeting the natural product 1. In this context, cheap,
commercially available furfural 9 was elaborated to
g-methoxy
butenolide 10 via dye sensitized photo-oxygenation following
11
a known procedure. A simple brominationedehydrobromination
in situ) sequence on 10 delivered the requisite -bromo-g-
(
a
methoxy butenolide 11 (Scheme 4). Concurrently, 14C pinacolbor-
onate 12 was synthesized and its Pd-mediated Suzuki cross cou-
pling with 11 furnished
a-alkenyl-g-methoxy butenolide 13.
Methoxy deprotection in 13 to 14 was smooth and set the stage for
Fig. 3. Key HMBC, COSY, ROESY connectivities of compound 15, 16.
Our initial foray towards the construction of the paracaseolide A
core, outlined above, established the overall feasibility of the ap-
proach and set the stage for a go at the natural product. Accordingly,
5-methyl-2-furfural (17) was photooxygenated to g-methoxy-g-
methyl butenolide 18 (Scheme 5). In the case of 18, a bromina-
tionedehydrobromination sequence was not very productive and
therefore an iodination in situ dehydro-iodination protocol was
resorted and delivered 19 quite uneventfully. Pd-mediated Suzuki
cross coupling between 19 and 14C pinacolboronate 12 proceeded
smoothly to furnish
a-alkenyl-g-methoxy-g-methyl buteolide 20
(Scheme 5). Acid mediated methoxy deprotection in 20 led to the
key precursor 21. Thermal activation of 21 (neat, sealed tube) to
induce [4þ2]-dimerization, essentially replicated our previous
observation (vide supra) and furnished paracaseolide A (1), di-
astereomeric compound 5 and a ring opened compound 22
(4.9:1:2.4) in 66% overall yield (Scheme 5). While the identity of 1
was established through usual spectral comparison with the nat-
ural product, structure of 5 was secured by evaluating its distinctive
1
13
H and C NMR spectral features and through incisive 2D NMR
COSY, HSQC, HMBC, ROESY) studies (Fig. 4). Once again, formation
of two diastereomers 1 and 5 during the DielseAlder type di-
merization of -alkenyl- -hydroxy- -methyl butenolide 21 was
contrary to a contemporaneous report and our own expectation.
Scheme 4. Reagents and conditions: (a) (i) 1
O
, MeOH; (ii) MeOH, reflux, 3 d; (b)
2
(
ꢀ
ꢀ
1
.2 equiv Br
2
, 0.08 equiv PBr
3 4
, CCl , 0 Cert, 12 h; py, 0 Cert, 4 h, 65%; (c) 1.5 equiv 12,
ꢀ
3
mol % PdCl
2
dppf, 4.0 equiv CsF, 1.0 equiv TBAB, THF/H
2
O (4:1),
m
W, 100 C, 4 min, 41%
ꢀ
ꢀ
a
g
g
(
(
d) TFA/acetone/H O (1:1:1), 0 Cert, 2 h, 59%; (e) neat, sealed tube, 100 C, 14.5 h, 52%
15:16¼2:3).
2
9
a

L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
8491
Scheme 5. Reagents and conditions: (a) 1
O
, MeOH; (b) 4.0 equiv I
2
2 4
, py/CCl (1:1),
ꢀ
0
H
Cert, 24 h, 50% (c) 1.5 equiv 12, 3 mol % PdCl dppf, 4 equiv CsF, 1 equiv TBAB, THF/
2
ꢀ
ꢀ
2
O (4:1),
m
W, 120 C, 40 min, 60% (d) TFA/acetone/H
2
O (1:1:1), 0 Cert, 13 h, 82%; (e)
ꢀ
neat, sealed tube, 110 C, 12 h, 66% (1:5:22¼4.9:1:2.4).
Scheme 6. Reagents and conditions: (a) 1.5 equiv 23, 3 mol % PdCl
2
dppf, 4.0 equiv CsF,
ꢀ
ꢀ
1
.0 equiv TBAB, THF/H
2
O (4:1),
m
W, for 24 100 C, 4 min, 24%, for 25 120 C, 25 min, 72%
ꢀ
(b) TFA/acetone/H
2
O (1:1:1), 0 Cert, for 26 4 h, 52%; for 27 12 h, 80% (c) neat, sealed
ꢀ
ꢀ
tube, for 28, 29, 100 C, 12 h, 57% (28:29¼1:1.9); for 30, 31, 32 110 C, 12 h, 41%
30:31:32¼2.8:1:1.3).
(
by manipulating the hydrophobic appendage through alkenyl
boronate partner for Suzuki coupling. Secondly, and more impor-
tantly, the key DielseAlder type of dimerization of
a-alkenyl-g-
hydroxy butenolides was consistently non-stereoselective and
furnished two diastereomers in each case. It was firmly demon-
strated that the four pairs of diastereomers reported here 15 & 16, 1
Fig. 4. Key HMBC, COSY, ROESY connectivities of compound 5.
&
5, 28 & 29 and 30 & 31 did not interconvert under thermal acti-
vation that fully mimicked the conditions of DielseAlder di-
merization. Furthermore, any possibility of any catalysis by some
‘rogue’ acid contamination was also ruled out by performing the
reactions in base washed tubes. This consistent trend pointed to the
formation of each pair of diastereomers through independent
pathway and put a question mark on the proposed9a biomimetic
pathway (Scheme 2) to paracaseolide A (1), which invoked an
epimerization in a dimeric product formed through endo selective
It was also shown that 1 and 5 did not interconvert even under
amplified (longer reaction time) reaction conditions of thermal
activation. It thus became clear that the formation of two di-
astereomers 1 and 5, arguably quite independently, required closer
mechanistic scrutiny. We will revert to this key issue later in this
report.
At this stage, it was of added interest to diversify a bit and scope
our strategy to access new analogues. In particular, truncation of
the hydrophobic appendages at C2 and C7 on the posterior of the
DielseAlder reaction (Scheme 2) in a a-alkenyl-g-hydroxy-g-
methyl butenolide precursor 2. Thus, the basic premise that traced
the biosynthetic origin of 1 through a [4þ2]-cycloaddition-
0
hydrophilic oxa-bowl central core could be a way to fine tune the
bipolarofacial character of the molecule and gauge its effect on the
biological activity. With this intent, synthesis of lower analogues of
dimerization in a a-alkenyl-g-hydroxy-g-methyl butenolide pre-
cursor remains tenable but the mechanistic details of the Diel-
seAlder cycloaddition needed further probing. This has been done
computationally and the results are presented in the following
section.
0
natural product 1, with 8C and 6C hydrophobic arms at C2 and C7,
respectively, was undertaken. This required implementation of Pd-
mediated Suzuki coupling of
a-halo butenolides 11, 19 with the
newly prepared 8C pinacolboronate 23 to furnish 24 and 25, re-
spectively (Scheme 6). Acid promoted methoxy deprotection in 24
and 25 was along expected lines and delivered the corresponding
2.1. Computational studies
a
-alkenyl-
g
-hydroxy butenolides 26 and 27, respectively. Thermal
The mechanism for the formation of paracaseolide A (1) through
a proposed biomimetic pathway involving [4þ2]-cycloaddition-
ꢀ
activation of 26 (neat, sealed tube, 100 C) led to diastereoisomeric
tetracycles 28 and 29 (1:1.9) in 57% yield (Scheme 6). Similarly,
thermally induced dimerization in 27 (neat, sealed tube, 110 C) led
dimerization in
a-alkenyl-g-hydroxy-g-methyl butenolide 2 has
ꢀ
been examined through DFT calculations. There were two primary
concerns to address, viz. (i) Is a concerted DielseAlder (DA) path-
way operative? If so, is an epimerization at C7, post DA reaction,
a feasible option? (ii) Is the biomimetic DA reaction in the present
case a step-wise process? If so, does it involve diradical in-
termediates? In the present mechanistic evaluation, the two linear
to diastereomers 30 and 31 along with a degraded product 32
(
2.8:1:1.3) in 41% overall yield. Stereostructures of synthetic ana-
logues 28e31 of paracaseolide A were gleaned from the charac-
teristic spectral ( H and C NMR) profile of the each diastereomeric
pair (28, 29 and 30, 31).
1
13
The foregoing results indicated two trends. Firstly, our synthetic
strategy was straightforward, concise and amenable to diversity
creation through the choice of an appropriate furan precursor and
alkyl chains (eC12
methyl butenolide 2 have been modeled by replacing them with
eCH groups for computational simplicity. To begin with, the
H25) of the reactant, a-alkenyl-g-hydroxy-g-
3

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L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
relative energies of all the possible geometrical forms of the re-
actant molecule 2, modeled with a eCH group, were examined at
possible geometrical forms of the reactant dienes and dienophiles
have also been examined (see Supplementary data, Table S1). Such
combinations were found to be higher in energy. These results in-
volving a concerted DA reaction are not in agreement with the
experimental results. It is also may be noted that formation of s-
cisoid-E,Z-form of the diene 35, from the s-cisoid-E,E-form 33 or s-
transoid-E,E-form 34 is difficult through the rotation around the
double bond (Fig. 5). Therefore, the formation of the two di-
astereomers (major and minor) is less likely via a [4þ2]-type con-
certed reaction mechanism.
3
B3LYP/6-31G(d) level of theory (Fig. 5). The calculated free energy
results showed that the s-cisoid-E,E-form of the model reactant 33
is higher in energy than the s-transoid-E,E-form 34 by 1.0 kcal/mol.
The corresponding s-cisoid-E,Z-form 35 is higher in energy than the
s-transoid-E,E-form 34 by 3.0 kcal/mol (Fig. 5).
2.3. Epimerizaton pathway
Next, the proposal of biosynthesis of Paracaseolide A (1) in-
9
a
s-cisoid-E,E-form 33
ΔG= 1.0
s-transoid-E,E-form 34
ΔG = 0.0
volving a terminal C7 epimerization (vide supra) was examined in
this effort, the free energies of all the corresponding transition
states and intermediates for the formation of the epimerized
product 41 from 40 through proton transfer process have been
calculated (Scheme 8). This approach was akin to that reported in
the literature in the context of epimerization leading to tetracy-
13
clines. During the epimerization process, the alkyl substituent
modeled as eCH ) at the C7 position of the oxa-bowl compound 40
s-cisoid-E,Z-form 35
(
3
ΔG = 3.0
is repositioned from the concave face to the convex face to form 41.
This necessitates sequential proton transfer processes 42e48 in-
dicated in Scheme 8. The B3LYP/6-31G(d) calculated results for the
epimerization process are energetically much higher than either
the concerted or the stepwise processes (vide infra), with the
highest energy barrier in this process being 84.2 kcal/mol (Fig. 7)
and therefore discount such an intervention. The experimental
studies also indicate that the interconversion between di-
astereomers, like 1 and 5 is not observed even after prolonged
heating.
Fig. 5. B3LYP/6-31G(d) calculated relative free energies (kcal/mol) of the 33, 34 and 35.
2
.2. Concerted pathways
At first, the concerted mechanism for the [4þ2]-dimerization in
the case of the reactant form 33 (s-cisoid-E,E-form), wherein one
molecule of it acts as a diene and the other as a dienophile was
examined. This eventuated in the formation of intermediate 36
corresponding to the minor diastereomer in our studies (vide su-
pra), Scheme 7. On the other hand, formation of the intermediate 37
corresponding to the major diastereomer can be realized with the
reactant form 35 (s-cisoid-E,Z-form) acting as a diene and the s-
cisoid-E,E-form 33 as a dienophile (Scheme 7). For these concerted
processes, the free energy activation barriers leading to the for-
mation of the major and minor product intermediates have been
2.4. Stepwise cycloaddition
Concurrently, a stepwise biradical [4þ2]-cycloaddition pathway
for the formation of the two diastereomeric intermediates 36 and
37 (minor and major) were explored using our model substrate. It
may be mentioned here that the singlet diradical pathway for the
Scheme 7. The concerted (TS) mechanism for the formation of intermediates 36 and 37 from the dimerization of the a-alkenyl-g-hydroxy-g-methyl butenolide.
calculated at B3LYP/6-31G(d) level of theory. These results show
that the transition state 38 leading to the minor diastereomeric
intermediate 36 is energetically lower than the transition state 39
forming the major diastereomeric intermediate 37 by 6.2 kcal/mol
dimerization of a-alkenyl-g-hydroxy-g-methyl butenolide was
only possible through the combination of 33 (s-cisoid-E,E-form) as
a diene and 34 (s-transoid-E,E-form) as the dienophile, (Scheme 9).
Other set of combinations failed to yield the transition state ge-
ometries with diradical character. It is to be recalled that a di-
merization reaction between the s-cis form of butadiene as diene
and the s-trans form as dienophile involving a stepwise biradical
(
Fig. 6). The final products 40 and 41 arise through intramolecular
ketalization in the of the concerted transition state intermediates
6 and 37, respectively (Scheme 7). It may be noted that other
3

L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
8493
3
.24
2
.96
1
.96
1.87
3
1.3
3
7.5
TS 38
TS 39
1
0.5
8.0
0
.0
0
.0
3
5
3
3
diene
diene
3
6
3
7
+
3
3
3
3
dienophile
dienophile
Fig. 6. The B3LYP/6-31G(d) calculated free energies (kcal/mol) mechanism for the dimerization of a-alkenyl-g-hydroxy-g
-methyl butenolide. All the distances are in ꢀA .
Scheme 8. The schematic presentation of the epimerization process for the formation of 41 from 40.
pathway is already reported in the literature.14 In the stepwise
in Fig. 8. The calculated reaction energies for the formation of the
intermediates 36 and 37 suggest that the latter is energetically fa-
vored compared to the former (Fig. 8). Therefore, the overall cal-
culated results seem to suggest that the thermodynamic factor may
be governing the formation of 37 in the stepwise biradical process.
The role of thermodynamics in governing the [4þ2]-
cycloaddition reaction also became more apparent from the cal-
culated results for the dimerization (between diene 54 and dien-
process, the biradical intermediate 50 is formed through reaction
between reactant forms 33 and 34 via the transition state 49. The
B3LYP/6-31G(d) calculated free energy of activation for the for-
mation of intermediate 50 is 34.7 kcal/mol (Fig. 8), In a subsequent
step, ring closure could deliver 36 via the biradical transition state
5
5
1. The calculated free energy of activation from 50 to intermediate
1 is 2.9 kcal/mol (Fig. 8). Concurrently, the intermediate 50 could
also lead to the biradicaloid intermediate 53 via the C eC rota-
3
4
ophile 55) of
a
-alkenyl-g-hydroxy butenolide, where the methyl
tional transition state 52 with the computed free energy of acti-
vation of 20.2 kcal/mol (Fig. 8). The formation of the second CeC
bond in biradicaloid intermediate 53 to the major intermediate 37
is barrier less in this case (Fig. 8). It may be recalled that a barrier
less ring closure process for the stepwise cycloaddition reaction
group at the hydroxyl bearing
potential energy surface calculated for this dimerization reaction
suggests that the product stability in this case is reversed compared
to the dimerization of methyl bearing
methyl butenolide (between 33 and 34, Fig. 8) and corroborates the
g
-carbon atom is absent (Fig. 9). The
a-alkenyl-g-hydroxy-g-
14
9c
between butadiene and ethylene has been noted in the literature.
observed experimental results.
2
The magnitude of the total spin operator, <S > values of all the
To examine the effect of larger alkyl chains on the energetics of
corresponding biradical species in this stepwise process also given
[4þ2]-cycloaddition reaction, additional calculations were also

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L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
2
.11
1
.61
1
.55
1
.32
1.76
1
.44
4
6
4
4
84.2
4
2
4
8
76.2
68.8
6
7.4
2
4.2
1
3.3
0
.0
-0.6
-
0.5
9
4
5
4
7
4
0
43
Fig. 7. The B3LYP/6-31G(d) calculated free energies (kcal/mol) for the epimerization process for the formation of 41 from 40.
performed on the real system embodying the long alkyl chain
25) and leading to the formation of paracaseolide A (1) and
(eC12H
its epimer 5 (see Supplementary data, Fig. S1). The B3LYP/6-31G(d)
level calculations in this case reveal that the potential energy sur-
face is quite similar to that observed with the smaller alkyl (eCH )
3
chain (Fig. 8). The potential energy surface shows that the forma-
tion of the major intermediate 3 corresponding to the natural
product 1 is thermodynamically more favored (2.3 kcal/mol) than
the minor intermediate 4 (see Supplementary data, Fig. S1). These
calculated results closely mimic those obtained with eCH
3
group
and are broadly in agreement with the experimental observations
(vide supra).
Thus, the results of extensive computational evaluation of the a-
alkenyl butenolide dimerization indicate that a step-wise DA pro-
cess is most likely operative and the product distribution is ther-
modynamically determined.
3. Conclusion
A concise total synthesis of the bioactive natural product par-
acaseolide A, following a projected biomimetic strategy has been
accomplished. Our approach emanates from readily available
starting materials like furfurals and involves Suzuki coupling
on preformed a-halo butenolides as the key step of general ap-
plicability to set-up the biomimetic-type DielseAlder
dimerization.
The mechanistic details of the ‘putative’ biomimetic DielseAlder
reaction have been probed computationally. The DFT calculations
on the dimerization of a-alkenyl butenolides suggest that the step-
wise mechanism is the likely pathway to account for the experi-
mental outcome and is thermodynamically controlled. Our findings
render other mechanisms like a concerted [4þ2] cycloaddition and
post-DA epimerization pathway less likely.
Scheme 9. Stepwise mechanism for the formation of 36 and 37 through the cyclo-
addition between 33 and 34.

L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
S2>=1.0221
8495
<
<
S2>=0.3235
<
S2>= 0.9981
1.94
TS 52
7.5
4
TS 49
4.7
INT 53
7.8
3
3
3
0.2
TS 51
27.3
2.72
1
0.1
8
.7
INT 50
S2>=0.9849
2
0
.0
<S >=0.3605
<
34
3
6
3
7
33
Fig. 8. The B3LYP/6-31G(d) calculated free energies (kcal/mol) of the stepwise pathway for the formation of the diastereomeric products 36 and 37 in the cycloaddition between 33
and 34.
<
S2>=0.2588
<
S2>= 0.2152
<
S2>=0.0250
4
7.3
TS 61
3
4.4
34.1
INT 62
TS 58
30.0
27.8
INT 59
3
.5
2
.3
0.0
Minor INT 57
TS60
54
2
2
<S >= 0.0292
+
<S >=0.2588
Major INT 56
55
Fig. 9. B3LYP/6-31G(d) calculated free energies (kcal/mol) for the formation of the major and minor product intermediates (56 & 57) in stepwise biradical mechanism.
4
4
. Experimental section
set.15 The restricted B3LYP/6-31G(d) was used for the closed-shell
species, like the different conformers of the -alkenyl butenolide
(33, 34, 35, 54 and 55), concerted transition structures (TS 38 and
TS 39) and all the intermediates and transition structures in the
epimerization process. The unrestricted UB3LYP/6-31G(d) was used
for the opened-shell species, like the transition structures and
a
.1. Computational details
Full geometrical optimizations were carried out in the gas phase
with employing the B3LYP functional with standard 6-31G(d) basis

8496
L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
biradical intermediates in the stepwise process. Frequency calcu-
lations of all the species were performed at their corresponding
same level of theory to confirm that each stationary point was
a local minimum (with zero imaginary frequency) or a transition
state (with one imaginary frequency). All calculations were per-
4
quenched with saturated NH Cl solution (15 mL). The organic layer
was separated and aqueous layer was extracted with EtOAc
(2ꢂ10 mL). The combined organic layers were washed with brine
(2ꢂ10 mL) and dried over anhydrous Na
2 4
SO . Solvent was removed
under reduced pressure and the resulting crude residue was puri-
16
formed by using the Gaussian 09 suite of program
.2. General information
All reactions were performed in oven-dried apparatus. All
fied using silica gel column chromatography (eluent: 2e3% EtOAc in
hexane) to afford
72%) as a colorless liquids; 24. R
hexane); IR (Neat): 2956, 2926, 2855, 1766, 1366, 1210, 1028, 980,
a
-alkenyl butenolides 24 (28 mg, 24%), 25 (68 mg,
4
f
¼0.60 (silica gel, 10% EtOAc in
ꢁ
1 1
938 cm ; H NMR (400 MHz, CDCl
3
)
d
: 6.85 (dt, J¼15.9, 7.0 Hz, 1H),
common reagents and commercial grade solvents were obtained
from local suppliers. Commercial grade solvents were distilled by
standard methods and all other common reagents were used
without further purification. Thin layer chromatography was per-
formed on microscopic slides coated with silica gel (GF-254 mesh,
Merck). Visualization of spots was accomplished by exposure to UV
6.77 (s, 1H), 6.09 (d, J¼15.9 Hz, 1H), 5.76 (s, 1H), 3.55 (s, 3H), 2.16 (q,
J¼7.0 Hz, 2H), 1.45e1.39 (m, 2H), 1.33e1.25 (m, 6H), 0.87 (t,
13
J¼6.8 Hz, 3H); C NMR (100 MHz, CDCl
3
) d: 169.8, 141.2, 138.8,
133.2, 117.9, 102.0, 56.7, 33.5, 31.6, 28.9, 28.6, 22.6, 14.1; HRMS
þ
(þAPCI) m/z calcd for C13
25. R
2856, 1763, 1660, 1460, 1377, 1175, 1072, 1032, 898 cm ; H NMR
(400 MHz, CDCl
: 6.84 (s,1H), 6.79 (dt, J¼16.0, 7.2 Hz,1H), 6.04 (d,
J¼16.0 Hz, 1H), 3.18 (s, 3H), 2.15 (q, J¼7.2 Hz, 2H), 1.60 (s, 3H),
H
21
O
3
(MþH) 225.1485, found 225.1477;
f
¼0.65 (silica gel, 10% EtOAc in hexane); IR (Neat): 2957, 2927,
ꢁ
1 1
4
radiation and/or iodine vapor and/or dipped in KMnO solution
followed by charring. Column chromatography was performed over
silica gel (100e200 mesh) and various combinations of ethyl ace-
tate and hexane were used as eluents. Melting points reported are
3
) d
13
1.43e1.37 (m, 2H), 1.32e1.26 (m, 6H), 0.87 (t, J¼6.6 Hz, 3H);
C
ꢁ
1
uncorrected. IR spectra were recorded in the range 4000e600 cm
NMR (100 MHz, CDCl : 169.4, 143.0, 140.9, 132.4, 117.8, 106.8, 51.1,
3
) d
1
with Bruker Tensor37 (FTIR) spectrophotometer as neat. H NMR
33.5, 31.6, 28.9, 28.6, 24.0, 22.5, 14.0; HRMS(þAPCI) m/z calcd for
13
(MþH)þ 239.1642, found 239.1639.
(
400 MHz), proton-decoupled C NMR (100 MHz), HMBC, HSQC,
COSY and ROESY spectra were recorded with BrukerAvance 400 in
CDCl . The chemical shifts (parts per million) and coupling con-
stants J (Hertz) are reported in the standard fashion with reference
14 23 3
C H O
3
d
4.2.3. Synthesis of
a-alkenyl g-hydroxy butenolide (26, 27). To
a stirred solution of the
a
-alkenyl butenolides 24 or 25 (80 mg) in
1
ꢀ
to CHCl
3
d
¼7.26 ppm (for H) and
d
¼77.0 ppm (central peak of
acetone (0.6 mL), water (0.6 mL) was added TFA (0.6 mL) at 0 C.
The reaction mixture was allowed to warm to ambient tempera-
ture, stirred for 4 h (26) and 12 h (27), respectively. The volatiles
were evaporated and the resulting crude residue was purified using
silica gel column chromatography (eluent: 14e20% EtOAc in hex-
13
triplet, for C). Data reported as follows: s¼singlet, d¼doublet,
dd¼doublet of doublet, dt¼doublet of triplet, t¼triplet, q¼quartet,
br¼broad, m¼multiplet. High resolution mass spectra (HRMS)
were recorded on Agilent 6538 UHD Q-TOF using multimode
source in þAPCI method.
ane) to afford
yellow color liquid, 52%); 27 (60 mg colorless liquid, 80%); 26.
¼0.15 (silica gel, 10% EtOAc in hexane); IR (Neat): 3377, 2926,
a-alkenyl g-hydroxy butenolide 26 (39 mg light
Experimental and spectral details of all compounds leading to
the synthesis of paracaseolide A (1), 5, 15 and 16 reported in the
R
f
9
c
ꢁ1 1
;
preliminary communication has already been submitted as
Supplementary data and is available (http://dx.doi.org/10.1016/
j.tetlet.2013.04.097). Only experimental details pertaining to the
new compounds reported here.
2857, 1755, 1459, 1206, 1091, 974, 926 cm
CDCl
: 6.85 (s, 1H), 6.79 (dt, J¼16.0, 7.1 Hz, 1H), 6.12 (s, 1H), 6.07
(d, J¼16.0 Hz, 1H), 4.78 (br s, 1-OH), 2.15 (q, J¼7.1 Hz, 2H), 1.44e1.38
H NMR (400 MHz,
3
) d
13
(m, 2H), 1.30e1.23 (m, 6H), 0.87 (t, J¼6.8 Hz, 3H); C NMR
(100 MHz, CDCl
3
)
d
: 170.7, 141.2, 140.6, 132.6, 117.7, 96.5, 33.5, 31.6,
þ
4.2.1. (E)-4,4,5,5-Tetramethyl-2-(oct-1-en-1-yl)-1,3,2-dioxaborolane
28.8, 28.5, 22.5,14.0; HRMS (þAPCI) m/z calcd for C12
211.1329, found 211.1327; 27. R
hexane); IR (Neat): 3381, 2956, 2927, 2856, 1746, 1580, 1415, 1054,
H
19
O
3
(MþH)
(
23). This compound was prepared analogous to the reported
f
¼0.25 (silica gel, 30% EtOAc in
17
procedure. To a stirred 1-octyne (0.86 g, 7.803 mmol) neat was
added pinacol borane (1.00 g, 7.813 mmol) at ambient temperature.
Then the reaction mixture was stirred at 150 C for 48 h. The re-
ꢁ
1 1
970, 930 cm ; H NMR (400 MHz, CDCl : 6.83 (s, 1H), 6.78 (dt,
3
) d
ꢀ
J¼16.0, 7.4 Hz, 1H), 6.04 (d, J¼16.0 Hz, 1H), 3.74 (br s, 1-OH), 2.13 (q,
action mixture was purified using silica gel column chromatogra-
phy (eluent 0e5% EtOAc in hexane) to afford (E)-4,4,5,5-
tetramethyl-2-(oct-1-en-1-yl)-1,3,2-dioxaborolane (23) (1.67 g,
J¼7.4 Hz, 2H), 1.68 (s, 3H), 1.44e1.38 (m, 2H), 1.32e1.25 (m, 6H),
1
3
0.87 (t, J¼6.7 Hz, 3H); C NMR (100 MHz, CDCl
3
) d: 170.1, 144.0,
141.0, 130.8, 117.7, 104.0, 33.5, 31.7, 28.9, 28.6, 24.8, 22.6, 14.1; HRMS
8
2
0%) as colorless liquid. R
958, 2926, 2856, 1639, 1361, 1318, 1145, 971 cm ; H NMR
: 6.62 (dt, J¼18.0, 6.9 Hz, 1H), 5.40 (d, J¼18.0 Hz,
H), 2.12 (q, J¼6.9 Hz, 2H), 1.40e1.35 (m, 2H), 1.25 (br s, 18H), 0.86
f
¼0.2 (silica gel, hexane); IR (Neat): 2978,
(þAPCI) calcd for C13
H
21
O
3
(MþH)þ 225.1485, found 225.1481.
-
1
1
(
400 MHz, CDCl
3
)
d
4.2.4. Synthesis of paracaseolide-A analogues 28, 29. a-Alkenyl-g-
1
hydroxy butenolide 26 (34 mg, 0.162 mmol) neat was heated in
1
3
ꢀ
(
3
C
t, J¼6.8 Hz, 3H); C NMR (100 MHz, CDCl
3
)
d
: 154.8, 83.0, 35.8,
a sealed tube at 100 C for 12 h. The reaction mixture was allowed
1
1.7, 28.9, 28.2, 24.8, 22.6, 14.1; HRMS(þAPCI) m/z calcd for
to cool to ambient temperature and dissolved in CDCl
recorded. H NMR of the crude reaction mixture showed mixture of
8 and 29 in 2:2.5 ratio. The mixture was purified using silica gel
3
, H NMR was
þ
1
14
H
28BO
2
(MþH) 239.2177, found 239.2177.
2
4
.2.2. Synthesis of
a
-alkenyl butenolides (24, 25). This compound
column chromatography (eluent: 10e24% EtOAc in hexane) to af-
ford 28 as a colorless liquid (6.5 mg, 20%), 29 as a colorless liquid
was prepared by following literature procedure for a related com-
18
pound. To a stirred solution of
100 mg scale,1.0 equiv), (E)-4,4,5,5-tetramethyl-2-(oct-1-en-1-yl)-
,3,2-dioxaborolane 23 (1.5 equiv), PdCl2dppf (3 mol %), TBAB
1.0 equiv) in THF (2.5 mL) degassed with nitrogen gas for 10 min
a
-halo butenolides 11 or 19
(12 mg, 37%). R
f
¼0.60 (28), 0.50 (29) (silica gel, 30% EtOAc in hex-
(
1
(
ane); 28. IR (Neat): 2955, 2927, 2856, 1778, 1671, 1463, 1348, 1207,
ꢁ
1 1
1010, 897 cm ; H NMR (400 MHz, CDCl
3
)
d: 7.30 (dd, J¼7.5, 3.3 Hz,
1H), 6.20 (d, J¼5.8 Hz, 1H), 6.00 (d, J¼5.5 Hz, 1H), 5.79 (dt, J¼15.7,
6.9 Hz, 1H), 5.47 (d, J¼15.7 Hz, 1H), 3.65e3.60 (m, 1H), 3.56e3.50
(m, 1H), 3.13e3.09 (m, 1H), 2.10 (q, J¼7.5 Hz, 2H), 1.73e1.65 (m, 1H),
was added cesium fluoride (4.0 equiv) in water (0.5 mL) degassed
with nitrogen gas for 10 min at ambient temperature. Then the
reaction mixture was irradiated with microwave (for 24, 4 min at
13
3
1.39e1.20 (m, 17H), 0.89e0.86 (m, 6H); C NMR (100 MHz, CDCl )
ꢀ
ꢀ
100 C; for 25, 120 C, 25 min). The reaction mixture was allowed to
d: 175.3, 166.5, 145.9, 135.2, 127.3, 126.0, 106.6, 106.3, 57.5, 46.8,
cool to ambient temperature, diluted with EtOAc (10 mL) and
44.6, 40.9, 32.7, 31.6, 29.3, 28.8, 28.7, 28.2, 28.1, 22.6, 22.5, 14.04,

L. Vasamsetty et al. / Tetrahedron 70 (2014) 8488e8497
8497
þ
1
3
4.0; HRMS (þAPCI) m/z calcd for
C
24
H
33
O
4
(MþHeH
2
O)
References and notes
85.2384, found 385.2360; 29. IR (Neat): 2955, 2925, 2855, 1777,
ꢁ
1
1
1. (a) Reviews: On butenolides: Rao, Y. S. Chem. Rev. 1964, 64, 353; Rao, Y. S. Chem.
Rev. 1976, 76, 625; Slaughter, J. C. Biol. Rev. 1999, 74, 259; (b) Chen, I.-S.; Lai-
Yaun, I.-L.; Duh, C.-Y.; Tsai, I.-L. Phytochemistry 1998, 49, 745; (c) Paulitz, T.;
Nowak-Thompson, B.; Gamard, P.; Tsang, E.; Loper, J. J. Chem. Ecol. 2000, 26,
1352, 1208, 1005, 930 cm
3
; H NMR (400 MHz, CDCl ) d: 7.04 (t,
J¼3.8 Hz, 1H), 6.21 (d, J¼5.7 Hz, 1H), 5.90 (d, J¼5.4 Hz, 1H), 5.65 (dt,
J¼15.8, 6.7 Hz, 1H), 5.44 (d, J¼15.8 Hz, 1H), 3.55e3.49 (m, 1H),
1
8
515; (d) Hein, S. M.; Gloer, J. B.; Koster, B.; Malloch, D. J. Nat. Prod. 2001, 64,
3
.45e3.42 (m, 1H), 2.26e2.22 (m, 1H), 2.12e1.99 (m, 2H), 1.81e1.74
09; (e) Ospina, C. A.; Rodríguez, A. D.; S aꢁ nchez, J. A.; Ortega-Barria, E.; Capson,
(
m, 1H), 1.53e1.46 (m, 1H), 1.38e1.23 (m, 16H), 0.90e0.87 (m, 6H);
3
) d: 173.4, 166.1, 145.6, 135.2, 128.2, 126.4,
06.5, 106.1, 59.1, 52.2, 45.8, 41.7, 32.6, 31.7, 31.6, 29.0, 28.80, 28.76,
T. L.; Mayer, A. M. S. J. Nat. Prod. 2005, 68, 1519; (f) Xu, H.-X.; Dong, H.; Sim, K.-Y.
Phytochemistry 1996, 42, 149; Abas, F.; Lajis, N. H.; Shaari, K.; Israf, D. A.;
Stanslas, J.; Yusuf, U. K.; Raof, S. M. J. Nat. Prod. 2005, 68, 1090; (g) Wang, G. C.;
Li, J.-G.; Li, G.-Q.; Xu, J.-J.; Wu, X.; Ye, W.-C.; Li, Y.-L. J. Nat. Prod. 2012, 75, 2188;
1
3
C NMR (100 MHz, CDCl
1
2
8.6, 27.5, 22.6, 14.1, 14.0; HRMS (þAPCI) m/z calcd for C24
H34NaO
5
(h) Stonik, V. A.; Kapustina, I. I.; Kalinovsky, A. I.; Dmitrenok, P. S.; Grebnev, B. B.
þ
(
MþNa) 425.2298, found 425.2282.
Tetrahedron Lett. 2002, 43, 315; (i) Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis,
R. G.; Sanchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661.
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Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707; (c) Br u€ ckner, R. Curr. Org.
2
4
.2.5. Synthesis of paracaseolide-A analogues 30, 31 and a ring
-Alkenyl- -hydroxy- -methyl butenolide
7 (50 mg, 0.223 mmol) was heated in a sealed tube at 110 C for
2 h. The reaction mixture was allowed to cool to ambient tem-
opened butenolide 32.
2
1
a
g
g
Chem. 2001, 5, 679; (d) Langer, P. Synlett 2006, 369; (e) Li, N.; Shi, Z.; Tang, Y.;
Chen, J.; Li, X. Beilstein J. Org. Chem. 2008, 4, http://dx.doi.org/10.3762/bjoc.4.48;
ꢀ
(f) Zhang, J; Sarma, K. D.; Curran, T. T. Synlett 2013, 24, 0550; (g) Liu, X.; Lee, C.-
S. Org. Lett. 2012, 14, 2886; (h) Ma, N.; Yao, Y.; Zhao, B.-X.; Wang, Y.; Ye, W.-C.;
Jiang, S. Chem. Commun. 2014, 50, 9284.
1
1
perature and dissolved in CDCl3, H NMR was recorded. H NMR of
the crude reaction mixture showed mixture of 30, it’s C7-epimer
3. (a) Bermejo, A.; Figad eꢂ re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.;
Cortes, D. Nat. Prod. Rep. 2005, 22, 269; (b) Humphrey, A. J.; Galster, A. M.; Beale,
M. H. Nat. Prod. Rep. 2006, 23, 592; (c) Kojima, N.; Tanaka, T. Molecules 2009, 14,
(31), ring opened butenolide (32) in 3.2:1:1.7 ratio. The crude re-
action mixture was purified using silica gel column chromatogra-
phy (eluent: 9e25% EtOAc in hexane) to afford of 30 (11 mg, 23%) as
a white solid, it’s C7-epimer (31) (4 mg, 8%) as a white solid, ring
3
621; (d) Simone, R. D.; Andr eꢂ s, R. M.; Aquino, M.; Bruno, I.; Guerrero, M. D.;
Terencio, M. C.; Paya, M.; Riccio, R. Chem. Biol. Drug. Des. 2010, 76, 17; (e) Si-
mone, R. D.; Bruno, I.; Riccio, R.; Stadler, K.; Bauer, J.; Schaible, A. M.; Laufer, S.;
Werz, O. Bioorg. Med. Chem. 2012, 20, 5012.
opened butenolide (32) (5 mg, 10%) as a yellow oily liquid; R
f
¼0.70
30), 0.65 (31), 0.40 (32) (silica gel, 40% EtOAc in hexane); 30. IR
Neat): 2956, 2927, 2856, 1774, 1672, 1463, 1390, 1276, 1056,
4. Chen, X.-L.; Liu, H.-L.; Li, J.; Xin, G.-R.; Guo, Y.-W. Org. Lett. 2011, 13, 5032.
(
(
9
5
3
5. (a) Review: Gharpure, S. J.; Powal, S. K. Org. Prep. Proced. Int. 2013, 45, 81 For
synthetic work towards diverse bowl-like scaffolds from our group, see: (b)
Mehta, G.; Vidya, R. Tetrahedron Lett. 1997, 38, 4173; (c) Mehta, G.; Vidya, R.
Tetrahedron Lett. 1997, 38, 4177; (d) Mehta, G.; Vidya, R. Tetrahedron Lett. 1998,
39, 6403; (e) Mehta, G.; Vidya, R.; Venkatesan, K. Tetrahedron Lett. 1999, 40,
2417; (f) Mehta, G.; Vidya, R. J. Org. Chem. 2000, 65, 3497; (g) Mehta, G.; Vidya,
R. J. Org. Chem. 2001, 66, 6905; (h) Mehta, G.; Vidya, R. J. Org. Chem. 2001, 66,
ꢁ
1 1
14 cm ; H NMR (400 MHz, CDCl
3
)
d
: 7.25 (dd, J¼7.6, 3.4 Hz, 1H),
.83 (dt, J¼15.8, 7.0 Hz, 1H), 5.49 (d, J¼15.8 Hz, 1H), 3.37 (dd, J¼9.5,
.2 Hz, 1H), 3.30 (d, J¼9.5 Hz, 1H), 3.07e3.01 (m, 1H), 2.11 (q,
J¼7.0 Hz, 2H), 1.75 (s, 3H), 1.69e1.65 (m, 1H), 1.62 (s, 3H), 1.39e1.15
6913; (i) Khan, F. A.; Dwivedi, V.; Rout, B. Tetrahedron Lett. 2007, 48, 207; (j)
13
(
m, 17H), 0.89e0.85 (m, 6H); C NMR (100 MHz, CDCl
3
)
d
:175.1,
Khan, F. A.; Rao, C. N. Tetrahedron Lett. 2009, 50, 5751.
1
3
66.2, 144.7, 135.1, 129.3, 126.3, 115.4, 113.8, 58.3, 50.2, 46.7, 45.1,
6. (a) Nishioka, K.; Doki, Y.; Shiozaki, H.; Yamamoto, H.; Tamura, S.; Yasuda, T.;
Fujiwara, Y.; Yano, M.; Miyata, H.; Kishi, K.; Nakagawa, H.; Shamma, A.; Mon-
den, M. Br. J. Cancer 2001, 85, 412; (b) Zhang, Z.; Zhang, G.; Kong, C. Tumor Biol.
2.7, 31.59, 31.58, 29.3, 29.0, 28.8, 28.2, 28.0, 26.6, 25.7, 22.6, 22.5,
þ
1
4.1, 14.0; HRMS (þAPCI) calcd for C26
39
H O
5
(MþH) 431.2792,
2014, 35, 2503; (c) Wu, C. F.; Liu, S.; Lee, Y.-C.; Wang, R.; Sun, S.; Yin, F.;
found 431.2774; 31. IR (Neat): 2955, 2926, 2855, 1773, 1465, 1390,
Bornmann, W. G.; Yu-Lee, L.-Y.; Gallick, G. E.; Zhang, W.; Lin, S.-H.; Kuang, J.
Oncogene 2014, 33, 2385.
ꢁ
1
1
1313, 1275, 1119, 1058, 913 cm ; H NMR (400 MHz, CDCl ) d: 6.98
3
7. Yin, J.-P.; Tang, C.-L.; Gao, L.-X.; Ma, W.-P.; Li, J.-Y.; Li, Y.; Li, J.; Nan, F.-J. Org.
(
3
2
t, J¼3.7 Hz,1H), 5.69 (dt, J¼15.7, 6.9 Hz,1H), 5.43 (d, J¼15.7 Hz, 1H),
Biomol. Chem. 2014, 12, 3441.
8. (a) Combs, A. P. J. Med. Chem. 2010, 53, 2333; (b) Lessard, L.; Stuible, M.;
Tremblay, M. L. Biochim. Biophys. Acta 2010, 1804, 613.
9. (a) Noutsias, D.; Vassilikogiannakis, G. Org. Lett. 2012, 14, 3565; (b) Guney, T.;
Kraus, G. A. Org. Lett. 2013, 15, 613; (c) Vasamsetty, L.; Khan, F. A.; Mehta, G.
Tetrahedron Lett. 2013, 54, 3522; (d) Giera, D. S.; Stark, C. B. W. RSC Adv. 2013, 3,
.27 (dt, J¼9.9, 2.6 Hz,1H), 3.20 (d, J¼9.9 Hz,1H), 2.14e2.09 (m, 3H),
.05e2.00 (m, 1H), 1.74 (s, 3H), 1.59 (s, 3H), 1.38e1.20 (m, 17H), 0.88
13
(
1
2
t, J¼6.6 Hz, 6H); C NMR (100 MHz, CDCl
3
)
d: 173.1, 165.8, 144.3,
35.3, 130.3, 127.3, 114.7, 113.7, 59.9, 55.3, 47.4, 45.9, 32.6, 31.7, 31.6,
21280; (e) Boukouvalas, J.; Jean, M.-A. Tetrahedron Lett. 2014, 55, 4248.
9.7, 29.04, 28.98, 28.8, 28.6, 27.5, 26.7, 25.62, 22.60, 22.58, 14.06,
ꢁ1
þ
10. Portions of this work have been reported previously as a preliminary com-
munication, see Ref. 9c.
11. (a) Feringa, B. L.; Lange, B. D. Tetrahedron 1988, 44, 7213; (b) Moradei, O. M.;
Paquette, L. A. Organic Syntheses, 2009, Coll. Vol. 11, p 128; (c) Review: Gollnick,
K.; Griesback, A. Tetrahedron 1985, 41, 2057.
1
4.05 cm ; HRMS (þAPCI) calcd for C26
H
39
O
5
(MþH) 431.2792,
found 431.2784. 32. IR (Neat): 2955, 2928, 2857, 1756, 1464, 1360,
ꢁ
1 1
1199, 1059, 971, 915 cm
3
; H NMR (400 MHz, CDCl ) d: 7.38 (d,
J¼1.2 Hz, 1H), 5.00e4.96 (m, 1H), 3.45 (s, 2H), 2.25 (s, 3H), 1.74e1.67
1
1
2. See Ref. 9c for X-ray data and CCDC number.
3. Greenwald, R. A.; Hillen, W.; Nelson, M. Tetracyclines in Biology, Chemistry and
auser, 2001; p 23.
13
(
(
3
m, 2H), 1.31e1.24 (m, 8H), 0.88 (t, J¼6.6 Hz, 3H); C NMR
100 MHz, CDCl : 203.1, 173.5, 152.2, 126.6, 82.1, 38.9, 33.4, 31.6,
0.3, 29.0, 24.9, 22.5, 14.0; HRMS(þAPCI) m/z calcd for C13
Medicine; Birkh
4. (a) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1993, 115, 7478; (b) Goldstein, E.; Beno, B.;
Houk, K. N. J. Am. Chem. Soc. 1996, 118, 6036.
5. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
€
3
) d
1
21 3
H O
þ
(
MþH) 225.1485, found 225.1478.
1
1
6. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.
M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman,
J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision B01; Gaussian:
Wallingford, CT, 2010.
Acknowledgements
L.V. and F.A.K. wish to thank the Council of Scientific and In-
dustrial Research in India for the award of a Research Fellowship
and research support, respectively. G.M. acknowledges the research
support from Eli Lilly and Jubilant-Bhartia Foundations and the
facilities extended by the University of Hyderabad.
Supplementary data
1
7. Neagu, I.; Roughton, A. L.; Diller, D.; Chan, J. -H.; Ohlmeyer, M.; Kingsbury, C.;
Maria, J. P.; Lommerse; Miranda, N.; Wijkmans, J. C. H. M. U.S. Patent App. US
B3LYP/6-31G(d) optimized Cartesian coordinates of all the ge-
1
13
ometries are provided. Copies of H and C NMR, spectra for the
new compounds. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.09.072.
2011/0046131 A1, 2011.
18. Aquino, M.; Bruno, I.; Riccio, R.; Gomez-Paloma, L. Org. Lett. 2006, 8, 4831.