First Total Synthesis of the Proposed Structure of Pandangolide 1

Article abstract of DOI:10.1002/ejoc.201800675

The first total synthesis of the proposed structure of pandangolide 1 is reported. The synthesis was carried out using both an organocatalytic approach and a chiral-pool approach. The required stereochemistry at C-3 and C-5 was installed by using an organocatalytic aldol reaction and a stereoselective ketone reduction. The construction of the 12-membered core was achieved by 2-methyl-6-nitrobenzoic anhydride-mediated Shiina lactonization. The structure of target molecule was confirmed unambiguously by single-crystal X-ray analysis, but the optical rotation and NMR spectroscopic data of the synthetic pandangolide 1 were found to be inconsistent with the natural product.

Full text of DOI:10.1002/ejoc.201800675

A Journal of
Accepted Article
Title: First total synthesis of the proposed structure of pandangolide 1
Authors: Pradeep Kumar, Krishanu Show, and Rajesh Gonnade
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800675
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10.1002/ejoc.201800675
European Journal of Organic Chemistry
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First total synthesis of the proposed structure of pandangolide 1
Krishanu Show,a Rajesh G. Gonnade,b and Pradeep Kumar*a
Abstract: The first total synthesis of proposed structure of
pandangolide 1 is reported via both organocatalytic as well as chiral
pool approach. The required stereochemistry at C-3 and C-5 was
installed by using organocatalytic aldol reaction and stereoselective
keto reduction. The construction of the 12-membered core was
achieved via MNBA-mediated Shiina lactonization method. The
structure of target molecule was confirmed unambiguously by the
single crystal X-ray analysis, though the optical rotation and NMR
data of synthesized pandangolide 1 were found to be inconsistent
with the proposed structure.
But the absolute configuration of pandangolide 1(1) was not
known until 2005, when Carmeli and co-workers reported
the isolation as well as determination of complete
stereostructure (by 1D and 2D NMR techniques and mass
spectrometric
pandangolide 1a (
pandangolide 1 ( ) and iso-cladospolide B (5)
data)
), along with its known diastereomers
from ethyl
of
new
hexaketide
lactone
2
1
acetate extract of the same Cladosporium sp., isolated from
the Red Sea sponge Niphates rowi.5a The absolute
configuration of the stereocentres was determined using
Rigurera’s method and circular dichroism. Later, Hartanti
et al.5b and W.C. Tayone5c also reported the isolation of
Introduction
pandangolide 1 (1) from the culture broth of Cladosporium
oxysporum and L. brunneola fungus respectively.
Marine fungi, which have already proved to be a significant
source of structurally novel and biologically active
secondary metabolites are attracting increased attention as
As a part of a research program directed towards the
synthesis of biologically important natural products
containing the lactone ring,6 we became interested in the
12-membered natural macrolide not only for their diverse
a
potential source of new pharmaceuticals and
pharmaceutical leads.1 Among the isolated secondary
metabolites, 12-membered macrolides are of special
interest due to their exceptional biological activities and
hence have been subject to chemical modifications for the
determination of structure-activity relationship. The Gross
range of physiological activities (such as sporiolide A (
3)
and B ( exhibit excellent cytotoxicity against murine
4
)
lymphoma L1210 cell line with IC50 values of 0.13 and 0.81
µg /mL, respectively as well as very promising antifungal
and antibacterial activity)7 but also due to their unique
molecular structure. If we scrutinize the structure of
structure of pandangolide 1 (
reported by Ireland et al.2 Later, in 2004 Kobayashi et al.
not only reported the isolation3 of pandangolide 1 (
) and
sporiolide and from cultured broth of
1) and its isolation was first
pandangolide 1 (1) and 1a (2), we can assume that
1
presence of α-hydroxy keto stereocenters at 3- and 5-
positions which are prone to epimerization, can lead to both
the compounds from the same bio-precursor. Even a viable
epimerization path can generate other possible
stereoisomers at both 3- and 5-center, which might have
different bioactivities. Apart from this, it is interesting to note
A
(3
)
B (4)
Cladosporium sp. separated from Okinawan marine brown
algae Actinotrichia fragilis and the Red Sea sponge
Niphates rowi but also proposed the chemical structure of
sporiolide A (
.
3) and B (4
).4
that both pandangolide 1 (1) and 1a (2) and sporiolide A (3)
and B ( ), isolated from the same natural source have
4
identical structures with substituent variation only at 3-
position. However, to date neither a synthetic study nor a
biological evaluation of pandangolide has been reported,
although the structurally similar both sporiolide A (
) have already been synthesized.7 So, intrigued by all
these observations, pandangolide 1 ( ) was selected as the
3) and B
Figure
1. Structures of macrolides isolated from marine fungi
(4
Cladosporium sp.
1
initial synthetic target anticipating its potential and unique
bioactivity. Herein we describe the first total synthesis of
[a]
[b]
K. Show, P. Kumar
Organic Chemistry Division
CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha
Road, Pune-411008, India.
E-mail: pk.tripathi@ncl.res.in
proposed structure of pandangolide
organocatalytic aldol reaction and
1
(
1
)
using
intramolecular
lactonization as the key steps.
http://academic.ncl.res.in/pk.tripathi
R. G. Gonnade
Centre for Material Characterization, CSIR-National Chemical
Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune-411008,
India
Results and Discussion
Supporting information for this article is given via a link at the end of
the document.
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While devising
pandangolide
for 3-hydroxy functionalities would be
a
retrosynthetic route to the target
), the choice of suitable protecting group
necessary
With substantial amount of
9
and 10 in hand, efforts were
1
(
1
focused on the crucial L-proline catalyzed diastereo- and
enantioselective aldol reaction (Scheme 3).10 All initial
efforts using reported general conditions (such as stirring
the reaction mixture using DMSO, DMF, CHCl3 as solvent
with different ratio of ketone and aldehyde) provided the
desired hydroxy ketone 11 in low yield (Table 1,
entries 1–7). This is probably due to the unwanted self-aldol
reaction of the reactive aldehyde. NMR analysis and HRMS
data of the reaction mixture clearly indicated the formation
of self-aldol product. After extensive experimentation, we
observed that using 5 equiv. of ketone (with respect to
aldehyde) and storing the reaction mixture (without stirring,
a
requirement. Keeping this in mind, we expected that the
target molecule could be obtained from the final stage
simultaneous double deprotection of suitably functionalized
lactone 27 (P, indicates required protecting group) while
lactone 27 could be prepared via intramolecular
lactonization of seco-acid 36 (Scheme 1). The seco-acid 36
in turn could be obtained either from cyanation or one
carbon homologation of compound 22. The protected diol
22, could be accessed by regioselective opening of PMB
acetal 21. The acetal compound that contains two of the
o
required stereocenters of pandangolide
1
(1
) could be
using DMF as a solvent) at 4 C for 3 days, the expected
obtained from stereoselective keto reduction of 11 whereas
the hydroxy ketone 11 could be obtained from L-proline
catalyzed aldol reaction between dioxanone 10 and
aldehyde 9.
hydroxy ketone 11 could be successfully obtained in 65%
yield with excellent diastereo- and enantiomeric excesses
(de > 95% by NMR, ee = 97% by HPLC).
Table 1: Optimization for aldol reaction between 10 and 9
We then examined the diastereoselective reduction of
hydroxy ketone 11 to afford syn diol 12. After screening
several reaction conditions (Table 2, entries 1–10),
reduction using L-selectride afforded the major syn diol 12
in 80% yield.
Scheme 1. Retrosynthetic analysis of Pandangolide 1
The synthesis of pandangolide 1 (
preparation of aldol partner dioxanone 10 and of aldehyde
. For the synthesis of aldehyde, the chiral (S)-propylene
oxide was regioselectively opened with Grignard reagent
1) began with the
9
6
hex-5-enylmagnesium bromide (in situ prepared from 6-
Table 2: Optimization for stereoselective keto reduction of
aldol adduct 11
bromohex-1-ene and magnesium in THF) in the presence
of CuI to afford secondary alcohol
was protected as its TBDPS ether
spectral and analytical data of
accordance with the reported data.8 Oxidative cleavage of
furnished the TBDPS-protected aldehyde in 90% yield
7
in good yield, which
in 91% yield. The
and were in full
8
7
8
8
9
(Scheme 2). Meanwhile, dioxanone 10 was prepared from
tris(hydroxymethyl)aminomethane hydrochloride in two
steps following a literature procedure.9
Scheme 2. Reagents and conditions: (a) 6-bromohex-1-ene, Mg, THF, CuI,
-30 oC, 4 h, 65%; (b) TBDPSCl, Imidazole, CH2Cl2, r.t., 5 h, 91%; (c) OsO4,
NaIO4, dioxane-H2O (3:1), 12 h, r.t., 90%.
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(j) Ph3P, I2, Imidazole, toluene, 88%; (k) (i) KCN, DMF, r.t., 24 h; (ii) KCN,
DMF, 100 oC, 24 h; (iii) KCN, DMSO, r.t., 48 h; (iv) KCN, DMSO,100 oC, 24 h;
(v) KCN, 18-crown-6, toluene, 110 oC, 24 h; (vi) Bu4NCN, toluene, 100 oC, 24
h; (vii) Bu4NCN, DMF, 100 oC, 12 h.
Meanwhile, to establish the syn relative configuration of the
newly generated hydroxyl centre in 12, we followed the
Rychnovsky method.11 Accordingly, the diol was protected
with 2, 2-DMP in the presence of PPTS to give acetonide
To circumvent the above problem, we then decided to carry
out one carbon homologation by olefination of the aldehyde
28 (in situ prepared by oxidation of primary alcohol 22) as
outlined in Scheme 4. Thus, oxidation of primary alcohol 22
using Dess-Martin periodinane gave aldehyde 28 which
was immediately subjected to Tebbe olefintion to provide
the terminal olefin 29 albeit in low yield (10%).12 However,
Wittig reaction using methylenetriphenylphosphorane
(prepared from methyltriphenylphosphonium bromide and
n-butyllithium) furnished 29 in 46% yield but with partial
racemization. To our delight, the addition of aldehyde 28 to
the rhodium catalyzed “salt free’’ phosphorus ylide using
Lebel protocol13 (in situ generated from TMSCHN2, 2-
propanol, PPh3 and RhCl(PPh3)3) produced the terminal
olefin 29 in 66% yield without any racemization.
Hydroboration-oxidation of 29 furnished the primary alcohol
30 in 70% yield. The alcohol obtained was oxidized using
TEMPO/BAIB to the silyl protected seco-acid 31. However,
desilylation of compound 31 using TBAF (1.0 M in THF)
gave only a complex reaction mixture under the basic
reaction medium.
13
.
Analysis of the 13C NMR spectrum of 13 revealed
chemical shift of 19.3 and 29.5 ppm for the two methyl
group and 99.8 ppm for the quaternary carbon, which
correspond to syn acetonide (see supporting information
page S-6).
The two free hydroxy groups in 12 represent the C-3 and
C-5 functionalities in the target molecule, therefore their
protection/deprotection can have an impact in successful
synthesis as discussed earlier. So, having established the
stereochemistry of newly generated centres, we further
proceeded by protecting both the hydroxyl group of 12 as
benzyl ether with benzyl bromide in the presence of NaH to
give compound 14 in 79% yield. Acetonide cleavage of 14
using PPTS in methanol, followed by immediate protection
of the diol as PMP-acetal using anisaldehyde
dimethylacetal provided compound 15 in 71% yield.
Regioselective opening of PMP-acetal 15 using DIBAL-H
gave primary alcohol 16 in 70% yield. Next, we planned to
substitute the activated hydroxy group of 16 to the required
cyano group via SN2 substitution. However, the reaction of
corresponding tosylate (17), mesylate (18) and iodide (19
)
with different cyanating agents under various reaction
conditions proved to be futile. This could probably be
attributed to the steric hindrance around the leaving group
caused by the adjacent bulky benzyl group which prevented
the substitution reaction of activated hydroxy group with the
cyanide ion.
Scheme 4. Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2,
r.t., 3 h; (b) RhCl(Ph3P)3,Ph3P, 2-Propanol, TMSCHN2, THF, 3 h, r.t., 66% (2
steps); (c) (i) 9-BBN, THF, 0oC to r.t., 4 h; (ii) H2O2/ NaOH, 0oC to r.t., 6 h, 70%
(2 steps); (d) TEMPO, BAIB, CH3CN/ H2O (3:1), r.t., 6 h, 62%; (e) TBAF, THF,
4 h, r.t.; 85% for 33; (f) (i) TEMPO, NaBr, nBu4NBr, NaOCl, NaHCO3, NaClO2,
2-methyl-2-butene, r.t., 2 h; (f) (ii) MNBA, DMAP, CH2Cl2, r.t., 12 h; (f) (iii)
DDQ, CH2Cl2/ H2O (18:1), r.t., 45 min, 16% (3 steps); (g) Dess-Martin
periodinane, CH2Cl2, r.t., 3 h; 88%; (h) 6 (M) HCl in THF, r.t., 24 h, 52%.
Therefore, we decided to reverse the order by carrying out
the desilylation reaction first followed by selective oxidation
of primary alcohol to acid to avoid exposure of seco-acid to
the moderately basic TBAF conditions. Towards this end,
desilylation of 30 using TBAF furnished the compound 33 in
good yield. Selective oxidation of primary alcohol 33
employing Huang protocol14 gave seco-acid 34 but it was
Scheme 3. Reagents and conditions: (a) L-proline (30 mol %), DMF, 3 days,
4
oC, 65%; (b) L-Selectride, THF, 2 h, -78 oC, 80%; (c) 2,2-DMP, PPTS,
CH2Cl2, r.t., 4 h, 88%; (d) BnBr, NaH, cat. TBAI, THF, r.t., 12 h, 79%; (e)
MOMCl, DIPEA, CH2Cl2, 12 h, 85%; (f) (i) PPTS, MeOH, 12 h, r.t.; (ii)
Anisaldehyde dimethylacetal, PPTS, CH2Cl2, 24 h, r.t., 71% for 15 and 82% for
21 (after 2 steps); (g) DIBAL-H, CH2Cl2, -78 oC, 3 h, 70% for 16 and 78% for
22; (h) TsCl, NEt3, CH2Cl2, 4 h, r.t., 85%; (i) MsCl, NEt3, CH2Cl2, 1 h, r.t., 80%;
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10.1002/ejoc.201800675
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found to decompose during chromatographic purification
using silica gel. So, we decided to use the crude seco-acid
34 directly for the next lactonization. We tried several
lactonization protocols to find the best one. Eventually, after
screening different reaction conditions (such as Yamaguchi
mixed-anhydride method15 or S-pyridyl ester lactonization
method16), MNBA-mediated Shiina lactonization17 protocol
furnished the desired lactone along with unidentified
impurities from which the required product could not be
separated even after repeated chromatographic purification.
However, this impurity did not interfere in the subsequent
PMB deprotection with DDQ, affording compound 35 in
16% yield (over three steps). Oxidation of 35 with
Dess-Martin periodinane gave ketone 36 in 85% yield.
Unfortunately, the optical rotation value and NMR spectra of
synthetic pandangolide 1 (1) differ significantly from the
data reported for isolated sample.5a For example, for the
synthetic compound, the CH2 of C-2 appeared at δ 2.82ppm
(dd, J=10.7, 15.1 Hz, 1H) and 2.72 ppm (dd, J=3.6, 15.1Hz,
1H) respectively while the same methylene protons
appeared at δ 3.15 ppm (dd, J=5.1, 19.2 Hz, 1H) and 3.30
ppm (dd, J=3.5, 19.2 Hz, 1H) for the isolated one.
Furthermore, the chemical shift observed for CH of C-3 and
CH of C-5 in synthetic compound are δ 4.76 (dd, J=3.5,
10.6 Hz, 1H), 4.90 (dd, J= 2.2, 6.7) whereas the same
protons for natural compound were reported at δ 4.42 (dd,
J=3.3, 5.1 Hz), 4.10 (dd, J=2.8, 7.8 Hz). Likewise, in the 13
C
NMR spectrum of synthetic 1, carbon signals due to C-1,
C-2, C-3, C-4, C-5 and C-11 appeared at δ 171.0, 38.9,
69.2, 210.5, 73.9, 72.5 ppm respectively, while the
corresponding carbons for the natural sample were
resonated at δ 175.3, 43.9, 66.9, 213.0, 77.4, 74.6 ppm
respectively (for detailed comparison see supporting
information, page S-20). In order to confirm the framework
of our synthesized product, COSY, NOESY, HSQC and
HMBC were carried out which clearly indicated the structure
of macrocycle core moiety.
Finally, the stage was set to deprotect both the MOM
groups simultaneously. We studied its deprotection under
several sets of reaction conditions (Table 3, entries 1–9).
We initially attempted at the TMSOTf-2,2'-Bipyridyl
method,18 which is one of the best deprotection methods
known under mild conditions. However it gave only the
mono-MOM deprotected lactone. Similar results were
obtained when we treated the lactone 36 with TMSCl in
t
MeOH and PPTS in BuOH. Next, the deprotection with
routine TFA in DCM and BF3.OEt2 in Me2S method resulted
into decomposition of starting material. Eventually the
deprotection with HCl in dioxane produced the desired
product only in 10% yield. Then the yield was improved to
23% by changing solvent from dioxane to 3 M HCl in THF.
Finally increasing the concentration of HCl solution from 3M
We feared the acidic deprotection condition might lead to
the epimerization of one or both α-centers to ketone. As the
final compound is solid, we chose to crystallize for single
crystal X-ray analysis for unambiguous structure
determination rather than Riguera’s method employed by
the isolation group.5a It is likely that following Riguera’s
method, the compound could undergo epimerization due to
the addition of Ba(ClO4)2 salt (which may act as a Lewis
acid also) during the NMR experiment itself. The good
to 6 M afforded the target pandangolide 1 (1) as a white
solid in 52% yield.
Table 3: Optimization for simultaneous double MOM
deprotection of Lactone 36
quality single crystal of synthesized pandangolide 1 (1) was
obtained from the crystallization from methanol. The single
crystal X-ray diffraction data collection was carried out with
Cu (Cu Kα = 1.54178 Å) radiation which unambiguously
determined the absolute configuration of Pandangolide 1
(1) and clearly established that our synthesized compound
has (3R, 5S, 11S) configuration which exactly matched
with proposed structure (Figure 2).5a The absolute
configuration was established by anomalous dispersion
effect (Flack parameter, 0.09(5)) in X-ray diffraction
measurements (for details see supporting information;
CCDC No: 1506724).
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Figure 2. ORTEP view of synthesized pandangolide 1 drawn with 50%
probability displacement ellipsoid and H-atoms are shown as small spheres of
arbitrary radii.
compound 42 was determined by Rychnovsky method.11
Accordingly, the diol was protected as its acetonide
derivative, followed by simultaneous deprotection of PMB
group to give compound 43. Analysis of the 13C NMR
spectrum of 43 revealed chemical shift of 19.2 and 29.8
ppm for the two methyl groups and 98.9 ppm for the
quaternary carbon, which correspond to syn acetonide (see
supporting information S-31).
As the crucial macrolactonization step provided
unsatisfactory yield, we decided to explore an alternate
strategy for 1 (1). As outlined in Scheme 5, we envisioned
that the common penultimate lactone 36 could be prepared
via ring closing metathesis (RCM) of diene ester 52 which
in turn could be assembled from esterification of acid
fragment 51 and alcohol fragment 37. For the acid fragment
33 (protected at C-3 and C-5 position) D-glucose was
identified as a suitable chiral precursor whereas the alcohol
fragment 37 could be synthesized from chiral (S)-propylene
oxide 6.
Scheme 7. Reagents and conditions: (a) Ref.20; (b) (i) 9-BBN, THF, 6 h, r.t.;
(ii) NaOH-H2O2, 4 h, 76%; (c) PMBCl, NaH, TBAI, 6 h, r.t., 88%; (d) 60%
AcOH-H2O, r.t., 50 oC, 12 h; (e) PPh3Br, nBuLi, 0oC to r.t., 4 h, 65% (2 steps);
(f) (i) 2,2-DMP, PPTS, CH2Cl2, r.t., 4 h, (ii) DDQ, CH2Cl2-H2O (18:1); 0.5 h,
r.t.63% (after 2 steps) (g) TEMPO/BAIB, CH3CN-H2O (3:1), 7 h, r.t., 69%.
Scheme 5. Retrosynthetic analysis for pandangolide 1 (1)
Synthesis of alcohol fragment 37:
Attempted esterification through coupling of acid
fragment 44 and alcohol fragment 37 (Route 1, Scheme
8):
For synthesis of the alcohol fragment, the chiral
(S)-propylene oxide
6 was regioselectively opened with
3-butenyl magnesium bromide to afford the alcohol
fragment 37 in 75% yield. The spectral and analytical data
of 37 was in complete accordance with the reported data
(Scheme 6).19
Apart from determination of relative stereochemistry of both
the hydroxyl group at C-3 and C-5 position (which is syn),
we wanted to take the advantage of this acetonide
protection to complete the synthesis of acid fragment.
Towards this end, compound 43 was subjected to one pot
oxidation
using
2,2,6,6-tetramethylpipridine-1-oxyl
(TEMPO) and bis(acetoxy)iodobenzene (BAIB) in
CH3CN/H2O (3:1) to furnish acid 44 in 69% yield.
Scheme 6. Reagents and conditions: (a) butenyl bromide, Mg, CuI, -20 oC, 6 h,
75%.
But to our surprise, attempted esterification of acid 44 with
alcohol 37 under known conditions (like Yamaguchi, Shiina,
Steglich) was fruitless.
Synthesis of acid fragment 44 (Route 1, Scheme 7):
The journey for synthesis of the acid fragment commenced
from known olefin 38, which was prepared from D-glucose
diacetonide in
3
steps (Scheme 7).20 Hydroboration-
oxidation of olefin 38 using 9-BBN furnished the primary
alcohol 39 in 76% yield. The primary hydroxyl group of 39
was protected as p-anisyl ether in the presence of NaH,
PMBCl, and cat. TBAI to give compound 40 in 88% yield.
Acidic hydrolysis of isopropylidene acetal 40 with acetic
acid-water (3:2) gave an anomeric mixture of the
hemiacetal 41, which was immediately subjected to one
carbon Wittig homologation using CH2=PPh3 (in situ
generated from treatment of Ph3PCH3Br with n-BuLi)
produced hydroxyl olefin 42 in 65% yield.
Scheme 8. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, NEt3,
DMAP, CH2Cl2; (b) DCC, DMAP, CH2Cl2; (c) MNBA, NEt3, DMAP, CH2Cl2
.
The failure of this reaction could probably be attributed to the
restricted mobility of acid moiety due to the presence of
acetonide group.
Synthesis of acid fragment 47 (Route 2, Scheme 9):
In an alternative route to the esterification reaction, we
considered revising the synthetic plan by protecting both
the hydroxyl group as TBS ether. It was hoped that by
Relative syn stereochemistry of the newly generated
stereogenic hydroxyl group at C-3 and C-5 position of
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Scheme 11. (a) (i) MOMCl, DIPEA, 0 oC to r.t., 5 h, (ii) DDQ, CH2Cl2-H2O
(18:1), 0.5 h, r.t., 80% (2 steps); (b) TEMPO/BAIB, CH3CN-H2O (3:1), 7 h, r.t.,
72%.
changing the cyclic acetonide to acyclic TBS ether, the
rigidity of the acid moiety would diminish in order to perform
the esterification reaction smoothly as well as at the final
stage it could be deprotected easily. Thus, the protection of
both hydroxyl groups as TBS ether followed by cleavage of
PMB group with DDQ gave alcohol 46, which was oxidized
with TEMPO and BAIB to give acid 47 in 65% yield
Completion of the synthesis of pandangolide 1 (1) by
coupling of acid fragment (51) and alcohol fragment
(37) through RCM (Scheme 12):
With both the cross coupling partners 51 and 37 in hand,
the coupling of these two fragments using Shiina’s
esterification protocol provided diene ester 52 in 90% yield.
Treating 52 with Grubb’s II catalyst (10 mol%) in CH2Cl2 at
reflux under high dilution (0.001M) led to crude lactone 53
(Scheme 12). The RCM reaction was little bit sluggish and
also the separation of resulting lactone from the crude
Scheme 9. Reagents and conditions: (a) (i) TBSCl, Imidazole, CH2Cl2, 8 h; (ii)
DDQ, CH2Cl2-H2O (18:1); 0.5 h, r.t., 53% (after 2 steps) (b) TEMPO/BAIB,
CH3CN-H2O (3:1), 7 h, r.t., 65%.
Attempted synthesis of pandangolide 1(1) by coupling
of acid fragment (47) and alcohol fragment (37) through
RCM (Scheme 10):
Esterification of acid 47 with alcohol 37 under Shiina’s
condition17 gave diene ester 48 in only 30% yield
(Yamaguchi and Steglich conditions gave only 10-15%
yield). The diene ester was then subjected to the RCM
reaction but unfortunately using variety of Grubbs’ catalyst
and different reaction condition (like using CH2Cl2, toluene,
benzene solvent in different dilutions), we did not get our
desired lactone 49. Failure may be attributed to the steric
hindrance of bulky TBS protecting groups and as per some
Scheme 12. Reagents and conditions: (a) 2-Methyl-6-nitrobenzoic anhydride,
NEt3, DMAP, CH2Cl2, 12 h, 90%; (b) (i) Grubbs II catalyst (10 mol %), CH2Cl2,
reflux, 24 h; (ii) H2, Pd/C , MeOH, 8 h; (iii) Dess-Martin periodinane, CH2Cl2, 3
h, 57% (after 3 steps). (c) 6 M HCl in THF, r.t., 24 h, 52%.
reaction mixture was found to be difficult. Even after
repeated chromatographic purification, it was always found
to be contaminated with catalyst impurity. In this context,
crude RCM reaction mixture 53 was directly subjected to
hydrogenation. Thus hydrogenation of crude lactone 53
with Pd/C (10%) under H2 atmosphere (with a balloon)
reduced both benzyl and double bond, afforded the
secondary alcohol accompanied by an unidentified impurity
(both appears at same Rf). Oxidation of the secondary
alcohol with Dess-Martin periodinane gave the ketone 36 in
good yield (60% over 3 steps). Finally deprotection of
Scheme 10. Reagents and conditions: (a) 2-Methyl-6-nitrobenzoic anhydride,
NEt3, DMAP, CH2Cl2, 12 h, 30%.
literature precedences, the presence of bulky group in the
vicinity of the RCM site might hinder the progress of the
reaction thus disfavoring the RCM reaction. Moreover,
replacement of TBS ether by relatively less bulky benzoate
groups also failed to form the macrolide under same
reaction conditions.
lactone 36 under same condition (Table 3, entry
9) provided
the target pandangolide 1 ( ) which was identical in every
1
respect to the previous synthetic one (single crystal
structure analysis also confirmed that the relative
configuration at C-3 and C-5 are 3R, 5S with respect to the
reference chiral center 11S at C-11, for details, see
supporting information for details, see supporting
information S23-S27).
Synthesis of acid fragment 51 (Route 3, Scheme 11):
Finally, we decided to again protect the hydroxyl group of
compound 42 as MOM ether. Towards this end, both the
hydroxyl group of compound 42 was protected as MOM
ether followed by deprotection of PMB group to give
compound 50 in 80% yield. One- pot oxidation of 50 using
TEMPO and BAIB afforded the desired acid 51 in 72% yield.
After synthesizing proposed structure of pandangolide 1(1)
by both strategies, we contacted the isolation group5a for
the sample of natural product. The group expressed
inability to provide the sample (due to unavailability of
sample) and therefore we could not make the direct
comparison of our synthesized compound with the isolated
one. Since the NMR spectra of our synthetic material did
not match with the spectra reported for the isolated one,
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10.1002/ejoc.201800675
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FULL PAPER
2.0, CHCl3); IR (CHCl3, cm-1) max: 3545, 3029, 2934, 2860, 1732, 1323,
832, 756; 1H NMR (500 MHz, CDCl3):δ= 7.75 - 7.63 (m, 4 H), 7.47 - 7.30
(m, 6 H), 4.26 (d, J = 17.4 Hz, 1 H), 4.14 - 3.98 (m, 2 H), 3.85 (td, J = 5.7,
11.7 Hz, 2 H), 2.95 (br. s., 1 H), 1.64 - 1.57 (m, 2 H), 1.45 (s, 3 H), 1.48
(s, 3 H), 1.40 - 1.20 (m, 8 H), 1.06 (s, 12 H);13C NMR (125 MHz, CDCl3):
δ = 211.2, 135.9, 135.6, 135.0, 134.6, 129.4, 129.3, 127.5, 127.4, 127.3,
100.9, 75.9, 70.5, 69.5, 66.7, 39.4, 32.1, 29.6, 27.0, 25.2, 24.9, 23.8,
23.5, 23.2, 19.3; HRMS (ESI) for C30H44O5NaSi (M + Na)+ found
535.2855, calcd 535.2850.
there is still a need to revisit the isolated natural product
which could be a closely related isomer of pandngolide 1
(1).
Conclusions
In summary, we have efficiently synthesized the proposed
structure of pandangolide 1 using both organocatalytic
approah as well as chiral pool approach. The proposed
structure of target molecule was unambiguously confirmed
by single crystal X-ray analysis. Currently the screenings of
various antifungal, antibacterial activity as well as cytotoxic
activities against different cell lines using synthetic
pandangolide 1 are under progress and will be reported in
due course.
(4S,5R)-4-((1S,7S)-7-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyoctyl)-
2,2-dimethyl-1,3-dioxan-5-ol (12):
To a stirred solution of 11 (0. 437 g, 0.85 mmol) in dry THF, L-selectride
(1.02 mL, 1.0 M in THF, 1.02 mmol) was added dropwise at -78 °C and
the reaction mixture was stirred for 2 h at same temperature. After
completion of the reaction (TLC), reaction mixture was quenched with
water, the organic layer was extracted with ether (4 × 20 mL) and dried
over Na2SO4, then the solvent was removed under reduced pressure.
The crude residue was purified by column chromatography (100-200
mesh silica gel, eluent: 45% EtOAc in pet ether) to give the product 12
(80% yield, 0.351 g) as colourless thick liquid. [α]D25: –18.9 (c 5.8,
CHCl3); IR (CHCl3, cm-1) max::3445, 3392, 3029, 2934, 2860, 1732, 1323,
832, 756; 1H NMR (400 MHz, CDCl3): δ = 7.73 - 7.65 (m, 4 H), 7.47 -
7.33 (m, 6 H), 3.95 - 3.89 (m, 1 H), 3.87 - 3.76 (m, 2 H), 3.75 - 3.67 (m, 1
H), 3.63 (dd, J = 8.5, 11.3 Hz, 1 H), 3.49 - 3.41 (m, 1 H), 3.33 (br. s., 1
H), 2.24 (br. s., 1 H), 1.72 - 1.58 (m, 1 H), 1.55 - 1.48 (m, 1 H), 1.47 (s, 3
H), 1.45 - 1.39 (m, 2 H), 1.38 (s, 3 H), 1.35 - 1.16 (m, 6 H), 1.06 (s, 12
H);13C NMR (100 MHz, CDCl3): δ= 135.9, 135.6, 134.9, 134.6, 129.5,
129.4, 129.3, 127.5, 127.4, 98.7, 75.6, 74.8, 69.5, 67.1, 64.1, 39.3, 33.3,
29.5, 28.2, 27.0, 26.9, 25.1, 24.8, 23.2, 19.6, 19.2; HRMS (ESI) for
C30H46O5NaSi (M + Na)+ found 537.3007, calcd 537.3005.
Experimental Section
General Experimental Methods:
All reactions were carried out under anhydrous conditions, using flame-
dried glassware under a positive pressure of argon unless otherwise
mentioned. CH2Cl2, Et3N, and iPr2NEt were distilled from CaH2; Et2O and
THF was distilled from Na/benzophenone. Other reagents were obtained
from commercial suppliers and used as received. Air sensitive reagents
and solutions were transferred via syringe or cannula and were
introduced to the apparatus via rubber septa. Reactions were monitored
by thin layer chromatography (TLC) with 0.25 mm precoated silica gel
plates (60 F254). Visualization was accomplished with either UV light,
iodine adsorbed on silica gel, or by immersion in ethanolic solution of
phosphomolybdic acid (PMA), p-anisaldehyde, or KMnO4 followed by
heating with a heat gun for ∼15 s. Flash chromatography was performed
on silica gel (230−400 mesh). All 1H NMR and 13C NMR spectra were
obtained using a 200, 400, or 500 MHz spectrometer in CDCl3 or CD3OD.
Coupling constants were measured in Hertz. All chemical shifts were
quoted in ppm, relative to TMS, using the residual solvent peak as a
reference standard. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, quin = quintet, m =
multiplet, and br = broad. HRMS (ES+) were recorded on an ORBITRAP
(5S,11S)-5-((4S,5R)-5-(Methoxymethoxy)-2,2-dimethyl-1,3-dioxan-4-
yl)-11,14,14-trimethyl-13,13-diphenyl-2,4,12-trioxa-13-
silapentadecane (20) :
To the precooled solution of 12 (0.140 g, 0.27 mmol) and DIPEA (0.38
mL, 2.18 mmol) in DCM (10 mL) at 0 oC, MOMCl (0.08 mL, 1.08 mmol)
was added slowly and the reaction mixture allowed to attain room
temperature. The reaction mixture was stirred at room temperature for
another 12 h at which time TLC showed the consumption of starting
material. Then the solution was diluted with saturated NH4Cl and
extracted with DCM (4 x 10 mL). The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo to
furnish an crude oil, which was purified by column chromatography (100-
200 mesh silica gel, eluent: 10% EtOAc in pet ether) to give the product
20 as a pale yellow liquid (0.139 g , 85%). [α]D25: – 25.2 (c 1.2, CHCl3); IR
(CHCl3, cm-1) max: 3031, 2909, 2245, 1523, 716; 1H NMR (200 MHz,
CDCl3): δ = 7.74 - 7.63 (m, 4 H), 7.47 - 7.31 (m, 6 H), 4.85 - 4.76 (m, 1 H),
4.70 - 4.60 (m, 3 H), 4.02 - 3.78 (m, 3 H), 3.77 - 3.60 (m, 3 H), 3.40 (s, 3
H), 3.36 (s, 3 H), 1.66 - 1.48 (m, 4 H), 1.47 (s, 3 H), 1.39 (s, 3 H), 1.36 -
1.14 (m, 6 H), 1.11 - 0.99 (m, 12 H).13C NMR (50 MHz, CDCl3): δ = 135.8,
135.5, 134.9, 134.5, 129.4, 129.3, 127.5, 127.4, 127.3, 98.8, 96.33,
96.31, 77.6, 74.1, 71.1, 69.5, 63.1, 55.7, 39.4, 29.9, 29.6, 27.7, 27.0,
26.8, 26.2, 25.2, 23.2, 19.9, 19.2. HRMS (ESI) for C34H54O7NaSi
(M + Na)+ found 625.3532, calcd 625.3531.
mass analyzer. Infrared (IR) spectra were recorded on
a FT-IR
spectrometer as thin films using NaCl plates, wave numbers are
indicated in cm−1. Optical rotations were measured using a polarimeter
with a 1 dm path length. Chemical nomenclature was generated using
Chem Bio Draw Ultra 14.0.
(S)-4-((1S,7S)-7-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyoctyl)-2,2-
dimethyl-1,3-dioxan-5-one (11):
To a stirred solution of dioxanone 10 (1.70 g, 13.08 mmol) and L-proline
(0.09 g, 0.78 mmol) in DMF (10 mL) was added aldehyde 9 (1.00 g, 2.61
mmol) in one portion. The reaction mixture was stored at 4oC under
argon for 3 days. Progress of the reaction was monitored by TLC. To the
reaction mixture cold water was added, extracted with Et2O (3 × 20 mL)
and the combined organic layers were washed with brine, dried over
Na2SO4 and evaporated in vacuo. The crude product was purified by
column chromatography (100-200 mesh silica gel, eluent: 30% EtOAc in
pet ether) to give the aldol product 11 (0.871 g, 65%) as colourless liquid.
(de> 98% by NMR, ee = 97% by HPLC, Chiralcel ODH, pet ether–iPrOH,
10: 90; major isomer 8.01 min, minor isomer 8.75 min). [α]D25: –72.0 (c
(5S,11S)-5-((4S,5R)-5-(Methoxymethoxy)-2-(4-methoxyphenyl)-1,3-
dioxan-4-yl)-11,14,14-trimethyl-13,13-diphenyl-2,4,12-trioxa-13-
silapentadecane (21):
To a stirred solution of 20 (0.493 g, 0.82 mmol) in MeOH (10 mL) was
added PPTS (0.021g, 0.08 mmol) and then stirred at room temperature
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10.1002/ejoc.201800675
European Journal of Organic Chemistry
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for 12h. After completion of the reaction, a saturated aq.NaHCO3 solution
(10 mL) was added to the reaction mixture and then concentrated under
reduced pressure and extracted with CH2Cl2 (4 x 15 mL). The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated in vacuo. The crude diol was used for next step without
purification.
To the red coloured stirred solution of PPh3 (0.135 g, 0.51 mmol) and
RhCl(PPh3)3 (0.005 g, 0.006 mmol) in THF, 2-propanol was added
followed by crude aldehyde (0.320 g, 0.47 mmol). After stirring for
another 5 minute at room temperature, TMSCHN2 (0.4 ml, 0.66 mmol)
was added to the reaction mixture. The reaction mixture was stirred at
room temperature for another 3 h. After completion of the reaction, the
reaction mixture was diluted with water and extracted with EtOAc. The
combined organic layer was washed with brine, dried and concentrated
in vacuo. The resulting crude olefin was purified by column
To the solution of crude diol (0.410 g, 0.73 mmol) in dry CH2Cl2 (10 mL),
anisaldehyde dimethylacetal (0.19 mL, 1.09 mmol) and PPTS (0.018 g,
0.07 mmol) was added and the reaction mixture was stirred at room
temperature for 24 h. After completion of reaction the mixture was diluted
with saturated aq.NaHCO3 solution (10mL) and extracted with CH2Cl2
(3 x 15 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated in vacuo. The crude acetal was purified
by column chromatography (100-200 mesh silica gel, eluent: 5% EtOAc
in pet ether) to give the product 21 as colourless liquid (0.457 g , 82%).
[α]D25: –20.3 (c 1.0, CHCl3); IR (CHCl3, cm-1) max: 3130, 2869, 2245,
1603, 816; 1H NMR (500 MHz, CDCl3): δ = 7.72 - 7.64 (m, 4 H), 7.45 -
7.33 (m, 8 H), 6.88 (d, J = 8.9 Hz, 2 H), 5.43 (s, 1 H), 4.84 (d, J = 6.7 Hz,
1 H), 4.69 (dd, J = 3.7, 6.7 Hz, 2 H), 4.67 - 4.62 (m, 1 H), 4.40 (dd, J =
5.0, 10.5 Hz, 1 H), 3.86-3.84 (m, 3 H), 3.80 (s, 3 H), 3.78 - 3.73 (m, 1 H),
3.68 - 3.60 (m, 1 H), 3.41 (s, 3 H), 3.38 (s, 3 H), 1.58 - 1.20 (m, 10 H),
1.06 (s, 12 H);13C NMR (100 MHz, CDCl3): δ = 159.9, 135.8, 135.6,
134.9, 134.6, 130.3, 129.43, 129.4, 129.3, 127.5, 127.45, 127.4, 127.3,
113.5, 101.0, 96.7, 96.3, 81.9, 77.5, 70.0, 69.5, 68.7, 55.7, 55.6, 55.2,
39.4, 30.5, 29.6, 27.0, 26.8, 26.5, 25.2, 23.2, 19.2;HRMS (ESI) for
C39H56O8NaSi (M + Na)+ found 703.3637, calcd 703.3637.
chromatography (100-200 mesh silica gel, eluent: 10% EtOAc in pet
25
ether) to give olefin 29 as colourless liquid (0.230 g, 66%). [α]D
:
– 38.8 (c 1.2, CHCl3); IR (CHCl3, cm-1) max: 3089, 2035, 1498, 1163,
761; 1H NMR (500 MHz, CDCl3): δ= 7.61-7. 58 (m, 4 H), 7.36 - 7.25 (m,
6 H), 7.19 (d, J = 8.2 Hz, 2 H), 6.77 (d, J = 8.5 Hz, 2 H), 5.81 - 5.70 (m, 1
H), 5.27 - 5.19 (m, 2 H), 4.64 - 4.57 (m, 3 H), 4.56 - 4.46 (m, 3 H), 4.18 -
4.06 (m, 1 H), 3.79 - 3.72 (m, 1 H), 3.71 (s, 3 H), 3.65 - 3.57 (m, 1 H),
3.53-3.51 ( m, 1 H), 3.31 (s, 3 H), 3.29 (s, 3 H), 1.58 - 1.50 (m, 3 H), 1.44
- 1.36 (m, 1 H), 1.33-1.26 (m, 2 H), 1.18-1.13 (m, 4 H), 0.99 - 0.94 (m,
12 H);13C NMR (125 MHz, CDCl3): δ = 159.1, 135.8, 135.2, 134.9, 134.6,
130.8, 129.5, 129.4, 129.3, 127.5, 127.4, 127.3, 119.1, 113.6, 96.3, 93.7,
81.8, 78.2, 77.6, 73.4, 69.6, 55.9, 55.6, 55.2, 39.5, 30.1, 30.0, 29.7, 27.0,
25.4, 25.3, 23.2, 19.2.HRMS (ESI) for C40H58O7NaSi (M + Na)+ found
701.3842, calcd 701.3844.
(3R,4S,5S,11S)-11-((tert-Butyldiphenylsilyl)oxy)-4-((4-
methoxybenzyl)oxy)-3,5-bis(methoxymethoxy)dodecan-1-ol (30):
Olefinic compound 29 (0.230 g, 0.34mmol) was taken in 15 mL dry
THF and 9-BBN (1 mL, 0.51 mmol, 0.5 M in THF) was added to it drop
wise for 1 h period at 0 ºC. The reaction mixture was stirred at same
temperature for another 4 h. Then the reaction mixture was quenched
with 2 mL of water at 0 ºC and stirred for 5 mins. A solution of 3 N NaOH
(4 mL) followed by 30% H2O2 solution (4 mL) were added to the reaction
mixture and stirred for 6 h at room temperature. The mixture was
extracted with ethyl acetate for several times (3 x 50 mL). Combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated in vacuo. The crude residue was purified by column
chromatography (100-200 mesh silica gel, eluent: 15% EtOAc in pet
ether) to give alcohol 30 (0.165 g, 70%) as colourless liquid.
[α]D25: –12.3 (c 2.2, CHCl3);IR (CHCl3, cm-1) max: 3519, 2835, 1341,1236,
932, 845, 789; 1H NMR (400 MHz, CDCl3):δ = 7.71 - 7.65 (m, 4 H), 7.43 -
7.34 (m, 6 H), 7.27 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.83 (d,
J = 6.4 Hz, 1 H), 4.70 - 4.57 (m, 5 H), 4.00 - 3.91 (m, 1 H), 3.85 - 3.79 (m,
3 H), 3.79 (s, 3 H), 3.74 - 3.66 (m, 1 H), 3.64 - 3.54 (m, 1H), 3.42 (s, 3 H),
3.38 (s, 3 H), 1.71 - 1.61 (m, 3 H), 1.43 - 1.31 (m, 4 H), 1.21 - 1.12 (m, 5
H), 1.07 - 1.03 (m, 12 H); 13C NMR (100 MHz, CDCl3):δ= 159.3, 135.8,
134.9, 134.6, 130.4, 130.0, 129.4, 129.3, 127.4, 127.3, 113.8, 113.7,
98.1, 96.4, 81.8, 77.4, 76.9, 74.2, 69.6, 59.2, 56.0, 55.2, 39.4, 33.9, 30.5,
29.8, 29.7, 27.0, 25.8, 25.2, 23.2, 19.2. HRMS (ESI) for C40H60O8NaSi
(M + Na)+ found 719.38.
(2R,3S,4S,10S)-10-((tert-Butyldiphenylsilyl)oxy)-3-((4-
methoxybenzyl)oxy)-2,4-bis(methoxymethoxy)undecan-1-ol (22):
To a stirred solution of 21 (0.450 g, 0.66 mmol) in dry CH2Cl2 at -78 oC,
DIBAL-H (1 mL, 0.99 mmol, 1 M in Toluene) was added drop wise and
the reaction mixture was stirred at same temperature for another 3 h.
After completion of the reaction aqueous solution of sodium potassium
tartrate (20 mL) was added to it and stirred for 2 h followed by extraction
with CH2Cl2 (4 x 25 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The crude residue
was purified by column chromatography (100-200 mesh silica gel, eluent:
15% EtOAc in pet ether) to give the product 22 as colourless liquid
(0.350 g, 78%). [α]D25: – 4.5 (c 1.8, CHCl3);IR (CHCl3, cm-1) max: 3489,
2315, 1985, 1563, 761; 1H NMR (500 MHz, CDCl3): δ = 7.74 - 7.59 (m, 4
H), 7.44 - 7.32 (m, 6 H), 7.26 (d, J = 8.2 Hz, 2 H), 6.86 (d, J = 8.5 Hz, 2
H), 4.73 (t, J = 6.7 Hz, 2 H), 4.69 - 4.60 (m, 3 H), 4.57 (d, J = 11.0 Hz, 1
H), 3.86 - 3.75 (m, 6 H), 3.74 - 3.62 (m, 3 H), 3.40 (s, 3 H), 3.38 (s, 3 H),
3.06 (br. s., 1 H), 1.71 - 1.57 (m, 3 H), 1.56 - 1.44 (m, 2 H), 1.41 - 1.24 (m,
5 H), 1.04 (s, 12 H); 13C NMR (125 MHz, CDCl3): δ = 159.2, 135.8, 135.6,
134.9, 134.6, 130.3, 129.5, 129.4, 129.3, 127.5, 127.4, 127.3, 113.8,
96.7, 96.2, 80.5, 79.9, 77.8, 73.2, 69.5, 62.7, 55.9, 55.8, 55.2, 39.4, 30.4,
29.8, 27.0, 26.9, 25.8, 25.2, 23.2, 19.2. HRMS (ESI) for C39H58O8NaSi
(M + Na)+ found 705.3793, calcd 705.3793.
(3R,4S,5S,11S)-4-((4-Methoxybenzyl)oxy)-3,5-
bis(methoxymethoxy)dodecane-1,11-diol (33):
(5R,6S,7S,13S)-6-((4-Methoxybenzyl)oxy)-7-(methoxymethoxy)-
13,16,16-trimethyl-15,15-diphenyl-5-vinyl-2,4,14-trioxa-15-
silaheptadecane (29):
To a stirred soln. of 30 (0.160 g, 0.23 mmol) in dry THF (10 mL) was
added 1M TBAF (0.4 mL, 0.34 mmol) in THF at room temperature, and
the mixture was stirred for 4 h. The reaction was diluted with saturated aq
NH4Cl (2 x 10 mL), and the mixture was extracted with ethyl acetate (2 x
15 mL). The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (100-200 mesh, eluent: 25% EtOAc in
pet ether) to give 33 (0.089 g, 85%)as a light yellow oil. [α]D25: – 54.3 (c
3.2, CHCl3); IR (CHCl3, cm-1) max: 3639, 2903, 1457, 1376, 1236, 1086,
895, 759; 1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.6 Hz , 2 H), 6.88
The alcohol 22 (0.350 g, 0.51mmol) was dissolved in dry CH2Cl2 followed
by addition of Dess Martin Periodinane (0.324 g, 0.76 mmol). The
reaction mixture was stirred for 3 h at r.t.and monitored by TLC. After
completion of the reaction, saturated Na2SO3 was added to it and
extracted with CH2Cl2 (3 x 10 mL). The organic layer was washed with
brine, dried over Na2SO4 and concentrated. The crude unstable aldehyde
was immediately used for methylenation without further purification.
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10.1002/ejoc.201800675
European Journal of Organic Chemistry
FULL PAPER
(d, J = 8.6 Hz, 2 H), 4.84 (d, J = 6.6 Hz, 1 H), 4.73 - 4.58 (m, 5 H), 4.01 -
3.91 (m, 1 H), 3.89 - 3.73 (m, 6 H), 3.73 - 3.65 (m, 1 H), 3.65 - 3.57 (m, 1
H), 3.42 (s, 3 H), 3.39 (s, 3 H), 2.06 (br. s., 2 H), 1.95 (tdd, J = 4.6, 9.3,
14.1 Hz, 2 H), 1.74 - 1.53 (m, 3 H), 1.53 - 1.31 (m, 7 H), 1.19 (d, J = 6.1
Hz, 3 H);13C NMR (100 MHz, CDCl3): δ= 159.3, 130.3, 130.1, 113.7, 98.1,
96.4, 81.5, 77.2, 76.9, 74.1, 68.0, 59.1, 56.0, 55.3, 39.2, 33.9, 30.4, 29.6,
25.7, 23.5; HRMS (ESI) for C24H42O8Na (M + Na)+ found 481.2772; calcd
481.2767.
After completion of the reaction, saturated Na2S2O3 was added to it and
extracted with CH2Cl2 (3 x 10 ml). The organic layer was washed with
brine, dried over Na2SO4 and concentrated. The crude product was
purified by column chromatography (100-200 mesh silica gel, eluent:
20% EtOAc in pet ether) to afford keto compound 36 (0.061 g, 88%) as a
thick liquid. [α]D25: + 41.1 (c 0.4, CHCl3); IR (CHCl3,cm-1) max
: 2998,
2907,1721, 1698, 750.1H NMR (500 MHz, CDCl3)δ = 5.03 - 4.95 (m, 1 H),
4.79 - 4.73 (m, 2 H), 4.69 (dd, J = 2.7, 7.3 Hz, 1 H), 4.67- 4.61 (m, 2 H),
4.58 (d, J = 7.0 Hz, 1 H), 3.46 (s, 3 H), 3.36 (s, 3 H), 2.96 (dd, J = 10.4,
15.9 Hz, 1 H), 2.82 (dd, J = 3.1, 15.6 Hz, 1 H), 2.02 - 1.93 (m, 1 H), 1.93 -
1.84 (m, 1 H), 1.55 - 1.41 (m, 4 H), 1.34 - 1.24 (m, 4 H), 1.19 (d, J = 6.4
Hz, 3 H); 13C NMR(125 MHz, CDCl3) δ = 204.4, 168.6, 96.9, 95.4, 77.7,
74.1, 71.6, 56.3, 55.7, 35.4, 31.6, 28.1, 26.1, 19.5, 18.94, 18.9.HRMS
(ESI) for C16H28O7Na (M + Na)+ found 355.1729, calcd 355.1727.
(4R,5S,6S,12S)-5-Hydroxy-4,6-bis(methoxymethoxy)-12-
methyloxacyclododecan-2-one (35):
An aqueous solution of NaBr (1 M, 0.2 mL), an aqueous solution of
tetrabutylammonium bromide (1 M, 0.4 mL), TEMPO (0.016 g, 0.10
mmol) and a saturated aqueous solution of NaHCO3 (1 mL) were added
to a solution of alcohol 33 (0.154 g, 0.34 mmol) in CH2Cl2 (7 mL) and
water (1.5 mL) in an ice–water bath. The resulted mixture was treated
with an aqueous solution of NaOCl (1.1 mL) and continuously stirred for
1 hour as the temperature increased from 0 oC to room temperature. To
Pandangolide 1 (1):
6 M HCl (3 mL) was added to a solution of 36 (0.020 g, 0.06 mmol)
in THF (5 mL) and the resulting mixture stirred at r.t. for 24 h. After
careful quenching with excess sat.NaHCO3 (aq) solution the layers
were separated. The aqueous layer was extracted with EtOAc (4 x
10 mL), the combined organic layers were dried over Na2SO4 and
solvent evaporated in vacuo. The residue was purified by column
t
the reaction medium, BuOH (5.0 mL), 2-methylbut-2-ene in THF (2 M,
10.5 mL) and a solution of NaClO2 (0.370 g) and NaH2PO4 (0.300 g) in
water (2 mL) were added. The reaction mixture was kept at room
temperature for 2 h, diluted with saturated aqueous NaH2PO4 solution
(20 mL), and extracted with EtOAc (5 x 10 mL). The organic layers were
combined and dried over Na2SO4. After removal of the solvent, the
desired seco-acid 34 was used for next lactonization step without
purification.
chromatography (100-200 mesh silica gel, eluent: 35% EtOAc in pet
25
ether) to give compound
1 as a white solid (0.007 g, 52%). [α]D :
+102.6 (c 0.4, MeOH); lit5a[α]D25: - 30.0 (c 2.3, MeOH); IR (CHCl3,
cm-1) max = 3379, 2927, 1725, 1701, 1264, 838. 1H NMR (700
MHz, CD3OD at 278 K) δ= 4.99 - 4.92 (m, 1 H), 4.90 (dd, J = 2.2,
6.7 Hz, 1 H), 4.76 (dd, J = 3.5, 10.6 Hz, 1 H), 2.82 (dd, J = 10.7,
15.1 Hz, 1 H), 2.72 (dd, J = 3.6, 15.1 Hz, 1 H), 2.00 - 1.94 (m, 1 H),
1.94 - 1.87 (m, 1 H), 1.57 - 1.49 (m, 3 H), 1.44 - 1.39 (m, 1 H), 1.37
- 1.33 (m, 1 H), 1.29 - 1.24 (m, 2 H), 1.19 (d, J = 6.4 Hz, 3 H), 1.18 -
1.15 (m, 1 H); 13C NMR (175MHz, CD3OD) δ = 210.5, 171.0, 73.9,
72.5, 69.2, 38.9, 32.7, 30.8, 27.1, 20.8, 20.0, 19.1. HRMS (ESI) for
C12H20O5Na (M + Na)+ found 267.1200, calcd 267.1203.
To a solution of MNBA (0.08 g, 0.23 mmol) and DMAP ( 0.004 g, 0.03
mmol) in dichloromethane (40 mL) at room temperature was slowly
added a solution of the seco-acid 34 (0.088 g, 0.19 mmol) in CH2Cl2
(20 mL) with a mechanically driven syringe over a 12 h period. After
completion of reaction, the reaction mixture was diluted with water and
extracted with dichloromethane (2 x 10 mL). The organic layer was
washed with brine and water and dried over Na2SO4. After evaporation of
the solvent, the crude product was purified by column chromatography.
The product accompanied with some other impurities was used as such
for the next reaction.
2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5- yl)ethanol (39):
Olefinic compound 38 (2.5 g, 9.0 mmol) was taken in 30 mL
dry THF and 9BBN (27 mL, 13.5 mmol, 0.5 M in THF) was added
to it drop wise for 1 h period at 0 ºC. The reaction mixture was
stirred at same temperature for 2 h more. Then the reaction mixture
was quenched with 2 mL of water at 0 ºC and stirred for 5 min.
Then, 3 N NaOH solution (16 mL) followed by 30% H2O2 solution
(16 mL) were added to the reaction mixture and stirred for 3 h at
room temperature. The whole mixture was then extracted with ethyl
acetate (3 x 50 mL). The combined organic layer was dried over
sodium sulphate and concentrated under vacuum. The crude
residue was purified by column chromatography (100-200 mesh
silica gel, eluent 15% EtOAc / pet ether ) to obtain a yellowish thick
liquid 39 (2.02 g, 76%). [α]D25: –17.8 (c 2.0, CHCl3); IR (CHCl3,
This semi purified lactone (0.030 g, 0.06 mmol) was dissolved in 10 mL
of CH2Cl2-H2O (18:1) and DDQ (0.027 g, 0.12 mmol) was added to it and
the reaction mixture stirred for 45 minute. Completion of the reaction was
monitored by TLC. The reaction mixture was diluted with 5% NaHCO3
solution, water and brine and extracted with CH2Cl2 (3 x 20 ml). The
organic layer was dried over Na2SO4 and concentrated in vacuo. The
crude residue was purified by column chromatography (100-200 mesh
silica gel, eluent: 15% EtOAc in pet ether) to give compound 35 (0.018 g,
16% after 3 steps) as a colourless liquid. [α]D25: – 14.8 (c 0.8, CHCl3); IR
(CHCl3, cm-1) max: 3511, 2883, 1689, 1422, 1131, 764, 623; 1H NMR
(500MHz, CDCl3) δ = 5.20 - 5.09 (m, 1 H), 4.81 (d, J = 7.2 Hz, 1 H), 4.74
(dd, J = 7.1, 17.4 Hz, 2 H), 4.65 (d, J = 6.9 Hz, 1 H), 4.09 (td, J = 3.9, 8.2
Hz, 1 H), 3.94 (ddd, J = 2.7, 5.6, 8.1 Hz, 1 H), 3.77 (t, J = 5.1 Hz, 1 H),
3.44 (s, 3 H), 3.40 (s, 3 H), 2.83 (dd, J = 8.0, 13.7 Hz, 1 H), 2.75 (dd, J =
3.4, 13.7 Hz, 1 H), 1.95 - 1.90 (m, 1 H), 1.80 - 1.41 (m, 9 H), 1.22 (d, J =
6.5 Hz, 3 H);13C NMR (125 MHz, CDCl3): δ = 169.5, 96.1, 95.6, 75.8,
74.7, 71.1, 70.7, 56.0, 55.8, 37.2, 30.9, 26.6, 25.3, 20.8, 20.0, 18.3;
HRMS (ESI) for C16H30O7Na (M + Na)+ found 357.1878; calcd 357.1884.
cm-1)
max: 3502, 2953, 1638, 1453, 1100, 780. 1H NMR (400 MHz,
CDCl3): δ = 7.38 - 7.29 (m, 5 H), 5.93 (d, J = 4.1 Hz, 1 H), 4.72 (d,
J = 12.4 Hz, 1 H), 4.63 (d, J = 4.1 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1
H), 4.37 - 4.30 (m, 1 H), 3.84 (d, J = 3.2 Hz, 1 H), 3.76 (t, J = 6.0
Hz, 2 H), 2.15 - 2.00 (m, 2 H), 1.88 - 1.83 (m, 1 H), 1.50 (s, 3 H),
1.33 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 137.4, 128.5, 128.0,
127.7, 111.4, 104.7, 82.5, 82.1, 78.6, 71.7, 60.4, 30.9, 26.6,
26.1.HRMS (ESI) for C16H22O5Na (M + Na)+ found 317.1353, calcd
317.1359.
(4R,6S,12S)-4,6-bis(Methoxymethoxy)-12-methyloxacyclododecane-
2,5-dione (36):
(
3aR,5R,6S,6aR)-6-(Benzyloxy)-5-(2-((4-
Compound 35 (0.070 g, 0.21 mmol) was dissolved in dry CH2Cl2 followed
by addition of Dess Martin Periodinane (0.135 g, 0.32 mmol). The
reaction mixture was stirred for 3 h at r.t.and reaction monitored by TLC.
methoxybenzyl)oxy)ethyl)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxole (40):
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800675
European Journal of Organic Chemistry
FULL PAPER
To a stirred solution alcohol 39 (1.0 g, 3.40 mmol) in dry THF at
0 C, NaH was added (0.2 g, 5.1 mmol, 60% in mineral oil) portion
diluted with saturated NH4Cl and extracted with CH2Cl2 (4x10 ml).
The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo to furnish a crude oil, which was
used for next step without purification.
To the crude solution of di-MOM (1.22 g, 2.65 mmol) in 15 mL of
CH2Cl2-H2O (18:1), DDQ (0.90 g, 3.97 mmol) was added and the
reaction mixture stirred for 45 minute. Completion of the reaction
was monitored by TLC. The reaction mixture was diluted with 5%
NaHCO3 solution, water and brine and extracted with CH2Cl2 (3 x
20 mL). The organic layer was dried over Na2SO4 and concentrated
o
wise and stirred for 30 minutes. Then, PMBCl (0.6 mL, 4.08 mmol)
followed by catalytic amount of TBAI was added to it and the
reaction was monitored by TLC. After completion of the reaction,
cold water was added to it and extracted with ethylacetate (4 x 10
mL). The organic layers were washed with brine, dried over sodium
sulphate and concentrated under vacuum. The crude residue was
purified by column chromatography (100-200 mesh silica gel, eluent
8% EtOAc / pet ether) to give compound 40 (1.23 g, 88%) as a
colorless liquid. [α]D25: –7.60 (c 1.2, CHCl3), IR (CHCl3, cm-1) max
:
in vacuo. The
crude
residue was purified by column
3012, 2853, 1253, 1090, 680. 1H NMR (500 MHz, CDCl3): δ = 7.37
- 7.29 (m, 5 H), 7.27 - 7.22 (d, J = 8.5 Hz, 2 H), 6.89 - 6.84 (d, J =
8.5 Hz, 2 H), 5.92 (d, J = 4.0 Hz, 1 H), 4.67 (d, J = 11.9 Hz, 1 H),
4.61 (d, J = 4.0 Hz, 1 H), 4.45 - 4.40 (m, 2 H), 4.33 (ddd, J = 3.1,
5.5, 7.9 Hz, 1 H), 3.81 (s, 3 H), 3.80 - 3.75 (m, 2 H), 3.54 (t, J = 6.6
Hz, 2 H), 2.13 - 2.04 (m, 1 H), 1.98 (qd, J = 6.8, 13.5 Hz, 1 H), 1.50
(s, 3 H), 1.33 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ = 159.1,
137.5, 130.5, 129.3, 128.4, 127.8, 127.7, 113.7, 111.3, 104.6, 82.3,
82.2, 77.7, 72.7, 71.6, 67.1, 55.2, 28.5, 26.7, 26.2. HRMS (ESI) for
C24H30O6Na (M + Na)+ found 437.1931, calcd 437.1935.
chromatography (100-200 mesh silica gel, eluent 15% EtOAc / pet
ether) to give alcohol compound 50 (0.80 g, 80% after two steps) as
a colorless liquid. [α]D25: + 89.2 (c 0.6, CHCl3); IR (CHCl3, cm-1)

max: 3452, 3091, 2911, 1357, 1103, 812. 1H NMR (200 MHz,
CDCl3): δ = 7.40 - 7.30 (m, 5 H), 5.98 - 5.73 (m, 1 H), 5.39 - 5.23
(m, 2 H), 4.80 (d, J = 6.6 Hz, 1 H), 4.73 - 4.53 (m, 5 H), 4.25 (dd, J
= 4.4, 7.3 Hz, 1 H), 3.97 (ddd, J = 4.3, 6.3, 9.0 Hz, 1 H), 3.82 - 3.61
(m, 2 H), 3.47 (dd, J = 4.3, 6.3 Hz, 1 H), 3.40 (s, 3 H), 3.38 (s, 3 H),
2.70 (br. s., 1 H), 2.01 - 1.86 (m, 1 H), 1.77 - 1.65 (m, 1 H); 13C
NMR (100 MHz, CDCl3): δ = 138.0, 134.8, 128.4, 128.3, 127.8,
127.6, 118.7, 98.3, 94.0, 84.0, 76.9, 76.8, 75.2, 59.0, 56.0, 33.8,
26.5. HRMS (ESI) for C18H28O6Na (M + Na)+ found 363.1778, calcd
363.1778.
(3S,4S,5R)-4-(Benzyloxy)-7-((4-methoxybenzyl)oxy)hept-1-ene-
3,5-diol (42):
PMB protected compound 40 (1.80 g, 4.81 mmol) was dissolved in
60% aqueous acetic acid solution and heated at 50 C for 6 h. After
(3R,4S,5S)-4-(Benzyloxy)-3,5-bis(methoxymethoxy)hept-6-
enoic acid (51):
o
completion of the reaction, the reaction mixture was evaporated in
vacuo [for complete evaporation the residual part of reaction
mixture was treated with toluene (3 x 50 mL) and removed as
azeotrope mixture] to give lactol 41 which was directly used for next
step without further purification.
To a stirred solution of alcohol 50 (0.30 g, 0.9 mmol) in CH3CN (3
mL) and H2O (1 mL) were added TEMPO (0.029 g, 0.1 mmol) and
BAIB (0.90 g, 2.8 mmol) at 0 oC and reaction monitored by TLC.
The reaction mixture was stirred for 7 h, until TLC indicated the
complete consumption of starting material. The reaction was diluted
by the addition of saturated aqueous Na2SO3 (20 mL), and the
aqueous layer was extracted with EtOAc (3 x 20 mL). The
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (eluent 35%
EtOAc / pet ether ) to give acid compound 51 (0.225 g, 72%) as a
Crude lactol 41 (1.35 g, 3.6 mmol) was dissolved in dry THF and it
was added to the already generated 1-carbon Wittig ylide [in situ
generated by using triphenylphosphoniun iodide (14.5 g) and 1.6 M
BuLi solution in n-hexane (9.7 mL) in 50 mL dry THF for 1 h] at
0 ºC. After complete addition of the lactol, the temperature of the
reaction was warmed to room temperature and stirred for another 4
h at same temperature. After completion of the reaction, saturated
NH4Cl was added to it and extracted with ethylacetate (4 x 10 mL).
The organic layers were washed with brine, dried over Na2SO4 and
concentrated under vacuum. The crude residue was purified by
column chromatography (100-200 mesh silica gel, eluent 40%
EtOAc / pet ether ) to give diol compound 42 (1.04 g, 65% after two
steps) as a colorless liquid. [α]D25: - 16.1 (c 1.7, CHCl3); IR (CHCl3,
light yellow oil. [α]D25: - 39.2 (c 1.1, CHCl3); IR (CHCl3, cm-1) max
:
1
3112, 2911, 1706, 1410, 1320, 950. H NMR (500 MHz, CDCl3):
δ
= 7.39 - 7.25 (m, 5 H), 5.84 (ddd, J = 7.7, 10.3, 17.5 Hz, 1 H), 5.34 -
5.28 (m, 2 H), 4.81 - 4.75 (m, 1 H), 4.72 - 4.68 (m, 4H), 4.60 (d, J =
6.6 Hz, 1 H), 4.38 - 4.32 (m, 1 H), 4.17 - 4.09 (m, 1 H), 3.63 (t, J =
5.0 Hz, 1 H), 3.38 (s, 3 H), 3.34 (s, 3 H), 2.80 (dd, J = 5.1, 16.4 Hz,
1 H), 2.72 (dd, J = 7.0, 16.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ
= 177.0, 137.9, 134.7, 128.4, 128.3, 127.8, 119.0, 97.8, 94.1, 81.8,
77.3, 75.2, 74.8, 55.92, 55.9, 36.7. HRMS (ESI) for C18H26O7Na
(M + Na)+ found 377.1569, calcd 377.1571.
cm-1)

max: 3412, 3042, 3018, 2947, 2902, 1455, 1103, 799. 1H
NMR (200 MHz, CDCl3): δ = 7.41 - 7.29 (m, 5 H), 7.24 (d, J = 6.9
Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.96 (ddd, J = 5.6, 10.5, 17.2 Hz,
1 H), 5.40 (td, J = 1.6, 17.2 Hz, 1 H), 5.22 (td, J = 1.5, 10.5 Hz, 1
H), 4.79 - 4.59 (m, 2 H), 4.44 (s, 2 H), 4.36 (dd, J = 4.4, 5.4 Hz, 1
H), 4.02 - 3.89 (m, 1 H), 3.80 (s, 3 H), 3.67 - 3.55 (m, 2 H), 3.35 (t, J
= 4.0 Hz, 1 H), 2.82 (br. s., 2 H), 2.01 - 1.75 (m, 2 H). 13C NMR (50
MHz, CDCl3): δ = 159.2, 138.2, 137.9, 130.1, 129.3, 128.5, 128.0,
116.1, 113.8, 83.9, 75.1, 73.0, 72.9, 70.9, 67.8, 55.2, 33.6; HRMS
(ESI) for C22H28O5Na (M + Na)+ found 395.1827, calcd 395.1829.
(S)-Hept-6-en-2-yl-(3R,4R,5S)-4-(benzyloxy)-3,5-
bis(methoxymethoxy)hept-6-enoate (52):
To a stirred solution of triethylamine (0.066 g, 0.653 mmol) in dry
CH2Cl2 (5 mL) was added DMAP (0.003 g, 0.020 mmol) followed by
MNBA (0.083 g, 0.241 mmol) and acid 51 (0.085 g, 0.242 mmol).
The reaction mixture was stirred for another 45 minute, then
hydroxy olefin 37 (0.023 g, 0.2 mmol) in dry CH2Cl2 was added to it
and progress of the reaction was monitored by TLC. Then this
reaction mixture was stirred for 12 h and quenched by addition of
saturated aqueous NH4Cl solution. The aqueous layer was
extracted with CH2Cl2 (3 x 20 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (100-200 mesh silica gel, eluent 20%
EtOAc /pet ether) to afford diene 52 (0.082 g, 90%) as a colorless
(3R,4S,5S)-4-(Benzyloxy)-3,5-bis(methoxymethoxy)hept-6-en-1-
ol (50):
To the pre-cooled solution of 42 (1.10 g, 2.95 mmol) and DIPEA
(4.1 mL, 23.6 mmol) in CH2Cl2 (20 mL) at 0 oC, MOMCl (0.9 mL,
11.8 mmol) was added slowly and the reaction mixture allowed to
attain room temperature. The reaction mixture was stirred at room
temperature for another 12 h at which time TLC showed the
complete consumption of starting material. Then the solution was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800675
European Journal of Organic Chemistry
FULL PAPER
liquid. [α]D25: + 46.3 (c 3.5, CHCl3); IR (CHCl3, cm-1)
max: 2998,
of INSA senior scientist programme to PK from INSA, New Delhi
is gratefully acknowledged.
1
2907, 1647, 1345, 750. H NMR (500 MHz, CDCl3): δ = 7.41 - 7.25
(m, 5 H), 5.92 - 5.71 (m, 2 H), 5.36 - 5.28 (m, 2 H), 5.08 - 4.86 (m, 3
H), 4.80 (d, J = 11.3 Hz, 1 H), 4.72 (d, J = 6.7 Hz, 1 H), 4.70 - 4.65
(m, 3 H), 4.61 (d, J = 6.7 Hz, 1 H), 4.38 - 4.34 (m, 1 H), 4.19 - 4.10
(m, 1 H), 3.63 (dd, J = 4.6, 5.5 Hz, 1 H), 3.38 (s, 3 H), 3.35 (s, 3 H),
2.77 (dd, J = 5.8, 16.2 Hz, 1 H), 2.69 (dd, J = 6.6, 16.0 Hz, 1 H),
2.13 - 1.98 (m, 2 H), 1.65-1.57 (m, 1 H), 1.54 - 1.31 (m, 3 H), 1.20
(d, J = 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3): δ = 171.1, 138.3,
138.1, 134.9, 128.4, 128.3, 127.7, 119.0, 114.8, 97.7, 94.0, 82.2,
77.5, 75.4, 75.1, 71.0, 55.9, 55.8, 37.0, 35.3, 33.5, 24.6, 19.9.
HRMS (ESI) for C25H38O7Na (M + Na)+ found 473.2510, calcd
473.2510.
Keywords: Macrolide • Aldol reaction • Macrolactonization •
Hydroboration-oxidation • Ring-closing metathesis
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a) J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote, P. R.
Prinsep, Nat. Prod. Rep. 2004, 21, 1; b) J. W. Blunt, B. R. Copp, M. H.
G. Munro, P. T. Northcote, P. R. Prinsep, Nat. Prod. Rep. 2006, 23, 26,
and references cited therein.
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C. J. Smith, D. Abbanat, V. S. Bernan, W. M. Maiese, M. Greenstein, J.
Jompa, A. Tahir and C. M. Ireland, J. Nat. Prod. 2000, 63, 142.
J. Kobayashi, M. Tsuda, Phytochem. Rev. 2004, 3, 267.
[3]
[4]
(4R,6S,12S)-4,6-bis(Methoxymethoxy)-12-
methyloxacyclododecane-2,5-dione (36):
H. Shigemori, Y. Kasai, K. Komatsu, M. Tsuda, Y. Mikami and J.
Kobayashi, Mar. Drugs. 2004, 2, 164.
[5]
(a) S. Gesner, N. Cohen, M. Iian, O. Yarden, S. Carmeli, J. Nat. Prod.
2005, 68, 1350; (b) D. Hartanti, D. I. Purwanti, H. S. Putro, M. E.
Rateb, S. Wongso, N. E. Sugijanto, R. Ebel, G. Indrayanto, Makara
Journal of Science, 2014, 18, 123; (c) W.C.Tayone, IOSR- Journal of
Applied Chemistry, 2016, 9, 39.
The diene 52 (0.16 g, 0.35 mmol) which was dissolved in 100 ml
freshly distilled CH2Cl2 (degassed for 15 minute through bubbling of
argon) was added drop wise (over 2 h) to the refluxing solution of
already dissolved Grubbs’ II catalyst (0.030 g, 10 mol%, in 1000 ml
degassed dry CH2Cl2). The reaction mixture was further refluxed for
another 24 h (completion of the reaction was checked by TLC). The
solvent was removed in vacuo and the crude product was purified
by silica gel column chromatography (100-200 mesh silica gel,
eluent 25% EtOAc/pet ether) to give compound 53 (0.11 g) as a
brownish oil contaminated with catalyst impurity.
The semi-purified lactone 53 (0.110 gm) was dissolved in methanol
and 10% Pd/C (0.002 mg) was added to it. The reaction mixture
was stirred under hydrogen atmosphere (balloon pressure) for 12 h.
Completion of the reaction was monitored by TLC. The reaction
mixture was filtered through a plug of celite and concentrated
in vacuo. The resulting crude secondary alcohol product was then
immediately subjected for next reaction without further purification.
The crude secondary alcohol (0.083 g, 0.25 mmol) was dissolved in
dry CH2Cl2 followed by addition of Dess-Martin Periodinane (0.156
g, 0.37 mmol). The reaction mixture was stirred for 4 h at rt and
reaction monitored by TLC. After completion of the reaction,
saturated Na2S2O3 was added to it and extracted with CH2Cl2 (3 x
10 mL). The organic layer was washed with brine, dried over
Na2SO4 and concentrated. The crude product was purified by
column chromatography (100-200 mesh silica gel, eluent 20%
EtOAc / pet ether) to afford keto compound 36 (0.068 g, 57% over 3
steps) as a thick liquid. [α]D25: + 38.5 (c 0.1, CHCl3); IR (CHCl3,
[6]
(a) P. Kumar, S. V. Naidu, P. Gupta, J. Org. Chem., 2005, 70, 2843;
(b) P. Kumar, S. V. Naidu, J. Org. Chem., 2005, 70, 4207; (c) P.
Kumar, P. Gupta, S. V. Naidu, Chem. Eur. J. 2006, 12, 1397; (d) P.
Kumar, S. V. Naidu, J. Org. Chem. 2006, 71, 3935; (e) P. Gupta, P.
Kumar, Eur. J. Org. Chem., 2008, 1195; (f) B. M. Sharma, A.
Gontala, P. Kumar, Eur. J. Org. Chem., 2016, 1215; (g) K. Show, P.
Kumar, Eur. J. Org. Chem., 2016, 4696 and references cited therein.
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(a) Y. Du, Q. Chen, R. J. Linhardt, J. Org. Chem. 2006, 71, 8446; (b) Y.
Du, Q. Chen, Carbohydr. Res. 2007, 342, 1405; (c) Y. Du. Q. Chen,
Tetrahedron Lett. 2006, 47, 8489; (d) Y. Venkateswarlu, D. K. Reddy,
K. Rajesh, V. Shekhar, D. C. Babu, Tetrahedron Lett. 2010, 51, 5440;
(e) S. Gattu, V. M. S. Gangavaram, Synth. Commun. 2016, 46, 314.
(a) V. K. Seema, C. Sucheta, G. Sunita, C. Subrata, S. Anubha,
Tetrahedron 2015, 71, 1732; (b) M. B. Andrew, A.B. Russell, J. Nat.
Prod. 2013, 76, 2054.
[8]
[9]
D. C. Forbes, D. G. Ene, M. P. Doyle, Synthesis 1998, 879.
[10] (a) D. Enders, C. Grondal, Angew. Chem. Int. Ed. 2005, 44, 1210. (b) D.
Enders, T. Violeta, P. Jirí, Synthesis 2008, 2278 and references cited
therein.
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(a) S. D. Rychnovsky, B. Rogers and T. I. Richardson, Acc. Chem. Res.
1998, 31, 9; (b) S. D. Rychnovsky and D. J. C. Skalitzky, Tetrahedron
Lett. 1990, 31, 945; (c) S. D. Rychnovsky, B. Rogers and B. Yang, J.
Org. Chem. 1993, 58, 3511.
cm-1) max: 2992, 2912, 1718, 1695, 751. 1H NMR (500 MHz, CDCl3)

δ = 5.03 - 4.97 (m, 1 H), 4.79 - 4.76 (m, 2 H), 4.70 (dd, J = 2.7, 7.3
Hz, 1 H), 4.67- 4.61 (m, 2 H), 4.59 (d, J = 6.7 Hz, 1 H), 3.47 (s, 3
H), 3.37 (s, 3 H), 2.97 (dd, J = 10.4, 15.6 Hz, 1 H), 2.83 (dd, J = 3.1,
15.6 Hz, 1 H), 2.02 - 1.95 (m, 1 H), 1.93 - 1.87 (m, 1 H), 1.55 - 1.43
(m, 4 H), 1.37 - 1.27 (m, 4 H), 1.20 (d, J = 6.4 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ = 204.4, 168.6, 97.0, 95.5, 77.9, 74.2, 71.6,
56.4, 55.7, 35.4, 31.7, 28.2, 26.2, 19.7, 19.02, 19.01; HRMS (ESI)
for C16H28O7Na (M + Na)+ found 355.1720, calcd 355.1727.
[12]
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10.1002/ejoc.201800675
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Key Topic* Total synthesis
Macrolide • Aldol reaction •
Macrolactonization • Hydroboration-
oxidation • Ring-closing metathesis
Krishanu Show(s), Rajesh. G. Gonnade(s)
and Pradeep Kumar(s)*
The first total synthesis of proposed structure of pandangolide 1 is reported. The
construction of the 12 membered core was achieved via both via MNBA-mediated
intramolecular Shiina lactonization and RCM protocol. The structure of target molecule
was confirmed unambiguously by the single crystal X-ray analysis, though the optical
rotation and NMR data of synthesized pandangolide 1 were found to be inconsistent
with the proposed structure.
Page No. – Page No.
Title First total synthesis of the proposed
structure of pandangolide 1
This article is protected by copyright. All rights reserved.