Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach

Article abstract of DOI:10.1016/j.tetlet.2014.02.010

A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal using syn aldol reaction via intramolecular S_N2 displacement reaction for the first time towards the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation, asymmetric aldolization under Crimmins condition, intramolecular S_N2 displacement, and Mitsunobu esterification reaction.

Full text of DOI:10.1016/j.tetlet.2014.02.010

Accepted Manuscript
Convergent synthesis of panclicin-D via intramolecular SN2 displacement ap-
proach
Jhillu Singh Yadav, Soma Shekar Dachavaram, Adithya Peddapuram, Saibal
Das
PII:
S0040-4039(14)00231-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.010
TETL 44197
Reference:
Tetrahedron Letters
To appear in:
Received Date:
17 December 2013
Please cite this article as: Yadav, J.S., Dachavaram, S.S., Peddapuram, A., Das, S., Convergent synthesis of
panclicin-D via intramolecular SN2 displacement approach, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.02.010
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Jhillu Singh Yadav,* Soma Shekar Dachavaram, Adithya Peddapuram, Saibal Das.

1
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Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach
Jhillu Singh Yadav,* Soma Shekar Dachavaram, Adithya Peddapuram, Saibal Das
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, Andhra Pradesh, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal
using syn Aldol reaction via intramolecular SN2 displacement reaction for the first time towards
the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation,
asymmetric Aldolisation under Crimmins condition, intramolecular SN2 displacement and
Mitsunobu esterification reaction.
Received in revised form
Accepted
Available online
Keywords:
Total Synthesis
Panclicin-D
2013 Elsevier Ltd. All rights reserved.
Anti β- lactones
4- membered lactones
SN2 displacement.
The bioactivities of these compounds are dependent critically
not only on the presence of β-lactone ring but also on the
absolute configurations of the stereogenic centers on the lactone
ring. Hence the construction of the trans di-substituted β-lactone
ring is one of the key task in the synthesis of these compounds
and attracted much attention from the synthetic community.
Obesity has become a serious challenge worldwide effecting
health of individual’s, which has increased by two folds since
1980.1 It is closely connected to life-style-related diseases and
with passing time the situation is grim with an amplified risk of
complications on insulin resistance, hypertension, dyslipidemia,
diabetes mellitus and atherosclerosis.2 Among available effective
therapeutics to address this concern, Pancreatic lipase inhibitors
is playing an active role as an effective anti-obesity agent known
to reduces the fat absorption from the diet by the inhibition of
hydrolysis of triglycerides.3 In this class, panclicins A-E are
found to be potent pancreatic lipase inhibitors isolated from
streptomyces sp. NR 0619.4 Structurally all of these contains a β-
lactone core with two alkyl chains, one of which has an N-
formylglycoxy substituent (Figure 1). The structure and relative
configurations has been elucidated and determined based on their
NMR and FAB-MS experiments. Among all these, panclicin-D
with IC50 0.66 µM, in particular was found to have twice the
inhibitory activity towards the pancreatic lipase compared to that
of well known tetrahydrolipstatin based marketed drugs.5-9
In the last decade, a number of impressive efforts toward the
synthesis of these β-lactones have appeared in the literature.10
Initial synthesis were reported by Romo et. al. based on ZnCl2-
mediated tandem Mukaiyama aldol-lactonisation11-12 between an
aldehyde and a ketene derivatives. Then after, Kocienski and
Pons et. al. described a diastereoselective Lewis acid catalyzed
[2+2] cycloaddition approach using silyl ketene and β-
hydroxyaldehyde derivative.12 Due to its significant biological
property and its unique structural features, herein we describe the
total synthesis based on syn-aldolization strategy using Crimmins
chiral auxiliary with better enantio and dia-stereo selectivities. It
is a well established fact that trans β-lactones can be directly be
derived from an anti-aldols moiety but the scope is limited when
syn-aldols are utilized.11
Figure 1: Structure of panclicin A-D
____________________________
* Corresponding author. Tel.: +91-40- 2719 -3737; fax: +91-40-
2716-0512. E-mail address: yadavpub@iict.res.in
Scheme 1: Retrosynthesis of panclicin-D

2
Hence our investigation was directed towards the construction
of anti-lactones using syn-aldol moieties. Accordingly, the
retrosynthetic approach (Scheme 1) was planned, a convergent
protocol, the target compound was envisaged from two key
intermediates, fragment 3, which could be prepared via Keck
asymmetric allylation from simple 1-octanal followed by
ozonolysis and fragment 4 from a chiral auxiliary in simple steps.
The stereochemistry at position’s C-8, C-10 and C11 were
visualized to be available via Mitsunobu inversion,
intramolecular SN2 displacement and Evans-aldol reactions
respectively.
Now adduct 2 was subjected to reductive removal of the
chiral auxiliary to furnish the corresponding acid 10 in 87%
yield, (Scheme 5) which was then subjected to intramolecular
hydroxyl group activation (HGA) under Mitsunobu condition at
0oC to room temperature.17
MOMO
OH O
b
a
OH
2
11
10
To begin our synthesis, fragment 3 was taken up (Scheme 2),
octanal 5 prepared from the oxidation of 1-octanol was used as a
starting material. Asymmetric allylation in presence of
allyltributyltin under the influence of in-situ generation of (S,S)-
bis-Ti(IV)oxide in DCM at 0oC for 12 hours, afforded the homo-
allylic secondary alcohol 6 in 87% yield.13 Treatment of 6 with
methoxymethyl (MOM)-chloride, i-Pr2NEt mediated protection
in DCM produced the corresponding protected alcohol 7 in 87%
yield. Further ozonolysis,14 of terminal olefin furnished the
aldehyde 3 in 79% yield.
Scheme 5. Reagents and conditions: (a) LiOH.H2O, THF: H2O (4:1),
0oC to r.t., 87%. (b) TPP, DIAD, 0oC to r.t., 12h.
To our surprise, the formation of the desired β-lactone 11 was
unsuccessful, (Scheme 5) instead undesired olefin 13 was
obtained in quantitative yield which may be attributed to
decarboxylation and dehydration in a concerted reaction. Now,
the β-hydroxy group in Evans syn-aldol adduct
2 was
mesylated18 using MsCl, Et3N in DCM resulting β-mesyloxy syn-
aldol 12 in 88% yield, which may act as a good leaving group for
the forthcoming SN2 displacement reaction19 making it a key
intermediate towards the construction of the required trans β-
lactone (Scheme 6).
Scheme 2. Reagents and conditions: (a) (S,S)-bis-Ti(IV)oxide, Ag2O,
Allyltributyl stannane, CH2Cl2, 0oC, 12h, 87%; (b) MOMCl, DIPEA,
CH2Cl2, 0°C to r.t., 3h, 87%, (c) O3, CH2Cl2, -78°C, 1h, 79%.
On the other hand, preparation for the required Crimmins
chiral auxiliary 4 was achieved easily using suitable aliphatic
acid, lauric acid, 8 and oxazolidinone chiral auxiliary, (S)-4-
benzyloxazolidin-2-one 9,15 along with pivolyl chloride, Et3N &
LiCl in THF under inert atmosphere in 88% yield (Scheme 3).
Scheme 6. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0°C to
r.t., 0.5 h, 88%. (b) LiOH.H2O, THF: H2O (4:1), 0oC to r.t., 10h.
Treatment of 12 with LiOH.H2O in THF:H2O (4:1) furnished
the desired β-lactone 11 and undesired olefin 13 in 5:1 ratio with
72% and 15 % isolated yield respectively (Table 1, entry 1). The
major product 11, with inversion of configuration at C-10
position was obtained via reductive removal of the chiral
auxiliary followed by intramolecular SN2 displacement reaction
(Scheme 7). Different combinations (Table 1) of solvent systems
have been screened with a desire to obtain the required β-lactone
11 in better yields.
Scheme 3. Reagents and conditions: (a) Pivolyl Chloride, LiCl,
Et3N, THF, -20oC to r.t., 1h, 85%.
In order to proceed towards the required β-lactone moiety,
aldehyde 3 was subjected to an Evans syn-aldol reaction16 under
Crimmins conditions (1.05equiv. of TiCl4, 1.1equiv.) of
diisopropylethylamine and 1 equiv. of N-methyl-2-pyrrolidinone)
with the obtained imide 4 in DCM (Scheme 4). The desired
Evans syn-aldol adduct 2 was obtained in 87% yield as major
diastereomer (94%de) which was separable from its minor
diastereomer with column chromatography (hexane/EtOAc, 8:2).
However, in our hands, the same reaction met with limited
success towards the formation of desired aldol product when the
secondary
tertiarybutyldimethylsilyl or benzyl group.
alcohol
in
3
was
protected
as
MOMO
OH
O
O
a
N
O
3
+ 4
Scheme 7. Proposed pathways
Bn
When DMSO, DCM and acetonitrile in combination with
water was used (Table 1: entry 3, 4 and 5) starting material was
recovered without formation of any products. In case of acetone,
THF:acetonitrile and DMF with water (Table 1: entry 2, 6 and 8)
2
Scheme 4. Reagents and conditions: (a) TiCl4, DIPEA, NMP,
CH2Cl2, 0°C, 2h, 87%.

3
were tried, undesired acid 14 was produced in major amounts
along with trace of undesired olefin 13. When THF:H2O solvent
system was used, the hydrolysis paved the desired β-lactone 11 in
good yield.
protons of β-lactone ring at C-10, C-11 with JHa,Hb: 4.1, 4.5 Hz
in H1-NMR attributes for trans stereochemistry. To confirm, the
NMR data and optical rotation for 16 matched very well with
those reported in the literature.11a Finally the resulted hydroxy
lactone 16 was treated with TPP and DIAD in presence of N-
formyl glycine24 under Mitsunobu condition17 to furnish the
desired target compound, Panclicin-D, 125 in 72% isolated yield.
The spectroscopic data obtained were in agreement with the
reported literature.5
Table 1: Results for various conditions towards SN2 displacement
reactions
% of Conversionc
Entry
Solvent
Time
β-lactone Olefin
Acid
-14
-11
-13
In conclusion, we believe that this reaction sequence is
considerably short to complete an enantioselective total synthesis
of the natural product panclicin-D, a potent anti-obesity agent.
The first stereogenic center at C-8 was established via
asymmetric C-allylation and the rest two stereogenic centers at
C-10 and C-11 in the target molecule were constructed through
chiral auxiliary induced asymmetric aldolization under the
Crimmins conditions and intramolecular SN2 displacement
respectively. However, up to now direct use of syn-aldols in the
synthesis of the anti β-lactones as represented in panclicin-D and
tetrahydrolipstatin has been elusive. The present work
successfully favors simultaneous removal of chiral auxiliary and
intramolecular SN2 displacement followed by lactonization to
form the anti β-lactones.
1
2
3
4
5
6
7
8
THF:H2Oa
ACETONE:H2Oa
DMSO:H2Oa
DCM:H2Oa
10
8
72
15
-
80
0
0
0
0
0
0
0
0
Trace
8
0
0
8
0
CH3CN:H2Oa
THF:CH3CN:H2Ob
Et2O:H2Oa
8
0
0
8
Trace
0
95
Trace
90
8
DMF:H2Oa
10
Trace
a Solvent ratio (4:1),
Solvent ratio (2:2:2), c Ratio for the conversion from starting material (SM)
to products (11:13:14). Temperature for the reaction was maintained at 0oC to
room temperature.
b
Acknowledgments
Now the sensitive β-lactone 11 was subjected to BF3.OEt2,
ethanedithiol20 in DCM at 0oC to form the expected MOM-
deprotected hydroxy lactone 16, but yielded the undesired21 six
membered δ-lactone 15 (Scheme 8) in 86% as major product
along with the desired four membered lactone 16 in 10% yield.
Formation of undesired six membered δ-lactone 15 was
DSS thank the Council of Scientific and Industrial Research
(CSIR), New Delhi for fellowships. The authors thank the
Council of Scientific and Industrial Research (CSIR) New Delhi
for financial support through ORIGIN program under 12th five
year plan, J C Bose and CSIR Bhatnagar Fellowship.
1
confirmed by C=O stretching frequency at 1703 cm-1 and H &
13C -NMR data.
Supporting Information
Supplementary data associated with this article can be found, in
the online version.
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4
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found 440.33705, calcd for C25H46O5NNa (M + Na)+ 462.31903,
found 462.31899.
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22. (3S,4S)-3-decyl-4-((R)-2 (methoxymethoxy)nonyl)oxetan-2-one
(11): To the stirred solution of 12 (0.5 g, 0.76 mmol) in 4:1 ratio
of THF:H2O (5 mL) finely ground powder of LiOH.H2O (0.032 g,
0.76 mmol) was added at 0oC. The reaction mixture was stirred
for 10 h at room temperature. The organic layer was separated
with ether followed by brine washing, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude
residue was purified by column chromatography (2% ethyl acetate
in hexanes) to give lactone 11 (0.22 g, 72%) as a colorless oil. IR
(KBr): 3063, 3028, 2925, 2854, 1824, 1271, 1040, 962, 891, 864,
-1
745, 702 cm ; [α]32D: -15.6 (c 0.8, CHCl3); 1H NMR (300 MHz,
CDCl3): δ= 4.63 (dd, J= 6.79, 3.02 Hz, 2H), 4.38- 4.44 (m, 1H),
3.66 (m, 1H), 3.37 (s, 3H), 3.24 (m, 1H), 2.07- 2.16 (m, 1H), 1.89-
1.98 (m, 1H), 1.69-1.83 (m, 1H), 1.53-1.57 (m, 5H), 1.25-1.39 (m,
24H), 0.85-0.89 (s, 6H); 13C NMR (75 MHz, CDCl3): δ= 171.4,
95.6, 75.0, 74.8, 56.8, 55.7, 38.9, 34.1, 31.8, 31.7, 29.6, 29.5, 29.3,
29.2, 29.2, 27.7, 26.7, 25.2, 22.6, 14.0, 14.0.; MS (ESI) (m/z): 399
[M+H], 421 [M + Na]+; HRMS-ESI: calcd for C24H46O4Na:
421.32890, found 421.32883.
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25. (R)-1-((2S,3S)-3-decyl-4-oxooxetan-2-yl)nonan-2-yl2-
formamidoacetate (1) (Panclicin-D): Colorless oil. IR (KBr):
3351, 2926, 2856, 1823, 1744, 1686, 1519, 1464, 1381, 1218,
1201, 1119, 1046, 993 cm-1; [α]32D: -23 (c 0.3, CHCl3); 1H NMR
(300 MHz, CDCl3): δ= 8.25-8.26 (m, 1H), 6.10 (bs, 1H), 5.10-
5.15 (m, 1H), 4.33 (dt, J= 8.3, 4.1 Hz, 1H), 4.13 (dd, J= 18.3, 5.3
Hz, 1H), 4.04 (dd, J= 18.3, 5.3 Hz, 1H), 3.20 (dt, J= 7.4, 4.2 Hz,
1H), 2.13 (dt, J= 15.2, 8.4 Hz, 1H), 2.01 (dt, J= 15.2, 4.12 Hz,
1H), 1.57-1.85 (m, 4H), 1.24-1.35 (m, 26H), 0.87 (t, J= 6.5 H,
6H); 13C NMR (75 MHz, CDCl3): δ= 170.7, 160.9, 75.0, 72.9,
57.0, 40.4, 38.8, 34.0, 31.8, 31.6, 29.6, 29.5, 29.4, 29.2, 29.1, 29.0,
27.5, 26.7, 25.1, 22.6, 22.5, 21.9, 14.0, 14.0; MS (ESI) (m/z): 462
(M + Na)+ ; HRMS-ESI: calcd for C25H46O5N (M+H)+ 440.33737,