Asymmetric synthesis of (-)-leiocarpin A via (-)-(S)-goniothalamin employing Julia-Kocienski olefination

Article abstract of DOI:10.1080/00397911.2015.1128546

A concise and enantioselective syntheses of antileukemic natural products such as (-)-(S)-goniothalamin and (-)-leiocarpin A has been accomplished in excellent yields. By employing reported conditions on suitable substrates via Julia-Kocienski olefination

Full text of DOI:10.1080/00397911.2015.1128546

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Asymmetric Synthesis of (-)-Leiocarpin A via (-)-
(S)-Goniothalamin Employing Julia-Kocienski
Olefination
Meruva Suresh Babu, Raghavendra Rao Kamaraju, Aaseef Mohammed, Vilas
H. Dahanukar, Syam Kumar U.K. & P. K. Dubey
To cite this article: Meruva Suresh Babu, Raghavendra Rao Kamaraju, Aaseef Mohammed,
Vilas H. Dahanukar, Syam Kumar U.K. & P. K. Dubey (2015): Asymmetric Synthesis of (-)-
Leiocarpin A via (-)-(S)-Goniothalamin Employing Julia-Kocienski Olefination, Synthetic
Communications, DOI: 10.1080/00397911.2015.1128546
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1128546
View supplementary material
Accepted author version posted online: 18
Dec 2015.
Submit your article to this journal
Article views: 6
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [La Trobe University]
Date: 04 January 2016, At: 20:21

Asymmetric Synthesis of (-)-Leiocarpin A via (-)-(S)-Goniothalamin Employing
Julia-Kocienski Olefination
1
,2
1
1
Suresh Babu Meruva , Raghavendra Rao Kamaraju , Aaseef Mohammed , Vilas H.
1
1
2
Dahanukar , U. K. Syam Kumar , P. K. Dubey
1
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s
2
Laboratories Ltd., Hyderabad, India, Department of Chemistry, College of Engineering,
JNTUH, Hyderabad, India
Corresponding author. Suresh Babu Meruva and U. K. Syam Kumar, Email:
sureshbabum@drreddys.com, syam_kmr@yahoo.com
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
A concise and enantioselective syntheses of antileukemic natural products such as (-)-(S)-
goniothalamin and (-)-leiocarpin A has been accomplished in excellent yields. By
employing reported conditions on suitable substrates via Julia-Kocienski olefination,
intramolecular lactonization and subsequently dehydroxylative olefination synthesized (-
)-(S)-goniothalamin. Then Sharpless asymmetric dihydroxylation-intramolecular Michael
addition on (-)-(S)-goniothalamin provided (-)-leiocarpin A.
Graphical Abstract:
1

KEYWORDS: Julia-Kocienski olefination, Acetonide deprotection, Lactonization,
Saturated and unsaturated pyranone, Sharpless asymmetric dihydroxylation and Michael
addition
INTRODUCTION
Chiral unsaturated lactones are one of the core skeletal fragment found in a
variety of biologically active natural products. The nuclear export signal inhibiting agents
like ratjadone, and callystatin-A possess unsaturated dihydro-2-pyranone with conjugated
[
1]
diene in their structural frame works. (+)-(R)-Goniothalamin (1) and its variants such as
+)-9-deoxygoniopypyrone (3a), (R)-(+)-goniothalamin oxide (4), (+)-
dehydroxygoniotriol (5) and (+)-4-dehydroxygoniotriol (6) are also an interesting group
(
[
2-9]
of dihydro-2-pyranones based natural products.
(+)-(R)-Goniothalamin (1) was
[10-12]
isolated from dried bark of Cryptocarya caloneura by Hlubucek, J. R et al in 1967
[
13]
and it exhibits antifungal,
anti-inflammatory activities along with potential antitumor
The structural variants of 1 has demonstrated significant bioactivity
towards human tumor cell lines and act as selective cytotoxic agent against human lung
[
14]
properties.
[
15-17]
cancer cells (A-549).
3c) and leiocarpin C (3d) (Fig. 1) are styryl lactones isolated from the barks of
Goniothalamus leiocarpus (Annonaceae). These compounds exhibits cytotoxic activity
The natural products such as leiocarpin A (3b), leiocarpin B
(
[
18-19]
against several human tumor cell lines.
-deoxygoniopypyrone (3a) and differ in the stereo chemical configurations. Despite the
interesting cytotoxic properties of leiocarpin A (3b), the total synthesis of this compound
Leiocarpin A (3b) is structurally related to
9
[
20]
has been reported only by few research groups.
2

RESULTS & DISCUSSION
The core dihydro-2-pyranone frame work in (+)-(R)-goniothalamin (1), and its
[
21-29, 32]
non-natural enantiomer (-)-(S)-goniothalamin (2)
is synthesized either by Grubs
[30-31]
[25]
metathesis,
enantioselective hetero Diels–Alder or Wittig-Horner reaction. The
dihydroxylation of the exocyclic olefinic double bond, intramolecular Michael addition-
heteroannulation protocol is reportedly adapted for the synthesis of (+)-9-
[
33-34]
deoxygoniopypyrone (3a) starting from (+)-(R)-goniothalamin (1).
For the synthesis
of 2 there are various approaches in the literature, out of which majorly utilized Grubs
metathesis as key step. However there are several straight forward and short synthesis
reported in the literature to assemble the styryl lactones and related compounds but we
have attempted with the available suitable synthons which enhances the scalability of 2.
Therefore as part of our continued efforts to develop new methodologies for the synthesis
[
35-38]
of biologically active natural and unnatural products,
herein we describe a concise,
and highly enantioselective total synthesis of (-)-leiocarpin A (3b). Our strategy for the
synthesis of (-)-leiocarpin A (3b) via (-)-(S)-goniothalamin (2) is illustrated (Scheme 1).
However we began to aim for the synthesis of 3a from 2 and optimized the
reaction conditions and the isolated compound subjected for characterization considering
that obtained compound might be 3a. Latter based on the single cell X-ray
crystallographic data it was confirmed as (-)-Leiocarpin A (3b). The 3b could be obtained
by the in situ enantioselective dihydroxylation-intramolecular Michael addition
[
39]
methodology with 2 under the Sharpless asymmetric dihydroxylation conditions.
The
key precursor (-)-(S)-goniothalamin (2) required for the synthesis could be obtained from
3

[
40]
β-hydroxy lactone 7. The stereo controlled Julia-Kocienski olefination
of the aldehyde
[41-42]
1
1 with sulphone 10
followed by a series of transformations involving ester
hydrolysis, acetonide deprotection and intramolecular lactonization would afford the β-
hydroxy lactone 7.
The synthesis of (-)-(S)-goniothalamin (2) is begin with Julia-Kocienski olefination of
sulphone 10, and benzaldehyde (11). The Sulphone 10 was prepared as per the literature
[
41]
procedure with minor modifications. We have been reported the synthesis 9 using
[
42]
Julia-Kocienski olefination
and it was studied in detail to get high E:Z selectivity
under various conditions (Scheme 2). The Julia-Kocienski reaction was performed at
[
40]
various conditions, Barbier conditions
using LiHMDS and LDA and employed pre-
t
metallic conditions with other bases such as NaH, KO Bu, NaHMDS and KHMDS (Table
1
).
During the optimization of the suitable conditions for Julia-Kocienski olefination reaction
we have concluded that, the lithium enolate of sulfone 10 is stable at -70 °C. If the
temperature is above -65 °C the sulfone 10 was undergone self-degradation. Whereas in
the case of sodium or potassium enolates of sulfone it was observed more stable enolates.
This might be concluding that when employed the Barbier conditions with lithium,
observed higher E isomer over Z isomer. The Julia-Kocienski olefination reaction when
carried out with NaHMDS, the olefin was formed in good yield (80%); however with
diminished E:Z ratio. The use of bases like LDA and NaH in the olefination reaction
t
resulted in low conversion as well as deteriorated E/Z ratios. Though the use of KO Bu,
4

KHMDS were provided the olefinic ester 9 with improved yields, diminished E/Z ratio
were observed. However when the olefination reaction was carried out with LiHMDS in
THF, the product was formed in 90% (by HPLC) with 11.5:1, E:Z ratios. The crude
olefinic ester 9 thus obtained was then purified by column chromatography and the
required E olefin was isolated in 85% yield.
[
43-45]
After the synthesis of olefin in good yield, we have converted 9 to lactone 7
via step wise process involving acetonide deprotection (12a), hydrolysis of ester and
intramolecular lactonization. The acetonide deprotection of 9 when carried out using TFA
[
41-42]
in acetonitrile-water 10:2 ratios, due to the extended conjugation epimerization
of
C5-OH group was observed. The epimerization is found inconsistent, and always resulted
in a mixture of 12a and 12b. The acetonide deprotection of 9 when attempted with other
acids such as pyridine para-toluenesulfonate, trichloroacetic acid, PTSA, and 0.05 N HCl
in solvents like acetonitrile, THF, and toluene, higher content (range 4 to 10%) of epimer
was observed. However the acetonide deprotection when attempted with oxalic acid,
though the epimerization was able to control well below 3% (by HPLC); the rate of
reaction is very slow and about 20% of 9 was remained unreacted (Scheme 3).
To circumvent afore mentioned issues, altered the reactions and performed hydrolysis of
olefinic ester 9 first under basic conditions, followed by acetonide deprotection
subsequently lactonization. Thus 9 was subjected for ester hydrolysis using aqueous
NaOH solution in MeOH at reflux temperature followed by pH adjustment afforded the
crude acid 8a. The crude acid 8a thus obtained was taken for acetonide deprotection
5

using oxalic acid in aqueous acetonitrile to yield the dihydroxy olefinic acid 8. The 6-
exo-trig cyclization of the crude dihydroxy olefinic acid 8 to lactone 7 is carried out in
toluene at its boiling temperature, and the lactone 7 was isolated in overall 58% yield
starting from 9. Our efforts to isolate pure 8a and 8 were not successful, as these products
always contaminated with some percentages of lactone 7. Finally the elimination of
hydroxyl group in 7 was done smoothly to yield (-)-(S)-goniothalamin (2) as per the
[
46]
reaction conditions reported by Kaneko and co-workers (scheme 4).
The (-)-(S)-goniothalamin (2) thus obtained was purified by column chromatography, and
the product was obtained in 80% yield. The spectral and analytical data of (-)-(S)-
goniothalamin (2) thus synthesized was found to be in accordance with the reported
25
values [mp 82 °C; Reported 81-82 °C. specific optical rotation, [α]D = •111.6 (c, 0.3
2
5
2h
w/v, CHCl ); Reported [α]D = -112.7 (c, 0.3 w/v, CHCl )].
3
3
After the successful completion of (-)-(S)-goniothalamin (2) synthesis in overall good
yield, we have directed our effort towards the conversion of 2 to (-)-leiocarpin A (3b). As
described in our retrosynthetic strategy, the Sharpless asymmetric dihydroxylation on (-)-
(S)-goniothalamin (2) followed by intramolecular hydroxylative Michael addition and
heteroannulation reaction yielded (-)-leiocarpin A (3b) in a single pot operation. Lin and
1
1b
co-workers reported the synthesis of (+)-9-deoxygoniopypyrone (3a) by employing the
dihydroxylation conditions on (+)-(R)-goniothalamin (1) with AD-mix-α and obtained
enantiomer of 6 and subsequently obtained the 3a. Similarly when employed the AD-
mix-β on (+)-(R)-goniothalamin (1) obtained the 6-Epi-goniodiol (6) under the Sharpless
6

conditions. Intrigued by this literature report, we have attempted the Sharpless
dihydroxylation of (S)-goniothalamin (2) with AD-mix-β under various conditions for the
synthesis of (-)-leiocarpin A (3b).
The in situ Sharpless dihydroxylation-intramolecular hydroxylative Michael addition-
heteroannulation reaction initially was carried out using 1 mmol of olefin, 0.86 mmol of
AD-mix-β and 1 mmol of methane sulfonamide, the required product (-)-leiocarpin A
(3b) was obtained in about 5% after maintaining the reaction mixture over a period of
2
4h at 0 °C in a mixture of tert-butanol and water. However, when the reaction was
carried out at 30 °C for 24 h, by keeping the same mole ratio of substrate to reagents as
described above, the required product 3b was obtained in 25% yield. When this reaction
was conducted with higher Eqv. of AD-mix-β (1.24 mmol) and 1.25 mmol of methane
sulfonamide, the complete consumption of the starting material was observed over a
period of 20 h at 30 °C and the isolated product in 65% yield (scheme 5) and it was
characterized by spectral and analytical methods.
Then structure of (-)-leiocarpin (3b) is confirmed by spectral and analytical methods and
compared with literature reported data. The specific optical rotation of 3b was recorded
25
using ethanol and specific optical rotation is [α]D = -9.8 (c, 0.2 w/v, EtOH); and further
the structural elucidation was carried out with 2D-spectroscopic experiments such as
NOESY, COSY, and HSQC. Finally the single crystal of (-)-leiocarpin (3b) was
generated from CHCl and single cell X-ray crystallography was recorded. The ORTEP
3
[
47]
diagram
of the product thus obtained is conclusively proved the stereo chemical
7

orientation of the product, with configuration 1S,5S,7R,8S and confirmed the structure of
b as (-)-leiocarpin A (Fig. 2).
3
EXPERIMENTAL
General methods: All reactions were carried out in oven dried glassware under an
1
13
atmosphere of N H & C NMR spectra were recorded in CDCl & DMSO-d on
2
.
3
6
Varian Gemini 400 MHz FT spectrometers. Proton chemical shifts (δ) are relative to
tetramethylsilane (TMS, δ 0.00) as internal standard and expressed in ppm. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet) and m (multiplet). Coupling
constants (J) are given in Hertz. Mass spectra were obtained on a HP-5989A Mass
Spectrometer. Thin layer chromatography was performed on silica gel plates (SRL 230-
4
00 mesh). All solvents used are commercially available and were distilled before use.
Synthesis of tert-Butyl 2-((4R, 6S)-2,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-yl)acetate
[
42]
(
9). To a stirred solution of tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((1-phenyl-1H-
tetrazol-5-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate 10 (50.0 g, 0.11 mol) in dry THF
500 mL) was added benzaldehyde 13 (14.0 g, 0.13 mol).The reaction mixture was
(
cooled to -75 °C. To the reaction mixture was added LiHMDS 22% THF solution (100
mL, 0.13mol) in 60 minutes. The reaction mixture maintained at that temperature for
about 1 h and it was allowed to room temperature and stirred for 1-2 h. Then based on
TLC indication for absence of starting material it was quenched with 5% aq. KHCO3
solution and separated the THF layer. The organic layer was washed with saturated brine
solution and dried over anhydrous sodium sulphate and concentrated to dryness. The
8

crude residue purified by column chromatography (eluent: ethyl acetate/hexanes =
0
0
1
1
.5/9.5) to yield 31 g (85%) of 9 as pale yellow liquid and upon holding in refrigerator at
2
5
-10 °C an off-white solid was obtained. Yield = 85%; mp 53.2-55.4 °C. [α]D = -2.5 (c,
1
w/v, CHCl3). H NMR: (400 MHz, CDCl ) δ: 1.41 (s, 12H), 1.45 (m, 1H,), 1.48(s, 3H),
3
.73-1.69 (td, J = 2.4, 7.6 Hz, 1H), 2.27 (dd, J = 6.8, 8.4 Hz, 1H), 2.48 (dd, J = 6.8, 8.4
Hz, 1H), 4.56 (m, 1H), 4.36 (m, 1H), 6.17 (dd, J = 6.4, 16 Hz, 1H), 6.62 (d, J = 16 Hz,
1
3
1
H), 7.24 (d, J = 4.8 Hz, 1H), 7.31 (t, J = 5.6Hz, 2H), 7.38 (d, J = 1.8 Hz, 2H). C NMR
(100 MHz, CDCl3) δ: 170.1, 136.5, 132.5, 130.7, 128.6, 128.2, 127.3, 126.4, 98.9, 80.2,
+
6
9.9, 65.7, 42.5, 36.6, 30.1, and 19.7. Mass (ESI) m/z [M+] 355.2. HPLC purity: 91.9 E
isomer, 8.1 Z Isomer; Column: Kinetex, C18, diameter: 100 x 4.6, 2.5 μ. Mobile phase B:
Acetonitrile: methanol 40:60; Mobile phase A: 20 mm Ammonium acetate: methanol
6
0:40.
Synthesis of (4R, 6S)-4-hydroxy-6-((E)-styryl)tetrahydro-2H-pyran-2-one (7).
Aqueous NaOH solution (3.6 g, 0.09 mol) was added to a solution of 9 (10 g, 0.03 mol.)
in MeOH (80 mL) and the reaction mixture was refluxed for 2-4 h. MeOH was removed
under reduced pressure; the residue was diluted with water (30 mL). Aqueous layer
washed with AcOEt (25 mL) and layers were separated. Adjusted the aqueous layer pH to
1
.5 - 2.5 using aqueous sodium bisulphate solution. Extracted the product into MTBE (50
mL) and evaporated under reduced pressure. Residue was diluted with acetonitrile (100
mL) and oxalic acid (4.0 g, 0.045 mol), water (12 mL) was added to it. Reaction mixture
was stirred for 30-60 minutes at 25-35 °C and then based on TLC indication for starting
material content approximately 5% it was diluted with saturated brine solution. Layers
9

were separated and the acetonitrile layer was dried over anhydrous sodium sulphate and
concentrated to dryness. Toluene (60mL) was added to the residue and it was refluxed for
5
h. Cooled the reaction mass to room temperature and toluene layer washed with 2%
sodium bicarbonate solution and concentrated to dryness under reduced pressure. The
crude residue was purified by column chromatography using AcOEt / hexane (60:40) and
obtained the 3.8g of 7 as white color solid (over all yield for 3 steps is 58%); White solid;
27
27
D
mp 112-112.9 °C. [α]D = 10.8 (c, 0.8 w/v, CHCl ); Reported [α] = 9.8 (c, 0.8 w/v,
3
[
28] 1
CHCl3).
H), 7.26 (d, J = 6.8 Hz, 1H), 6.68 (d, J = 16 Hz, 1H), 6.17 (dd, J = 6.4, 16 Hz, 1H), 5.38
m, 1H), 4.45 (m, 1H), 2.82 (dd, J = 4.8, 12.8 Hz, 2H), 2.70-2.65 (td, J = 2.4, 15.2 Hz,
H NMR: (400 MHz, CDCl ) δ: 7.38 (d, J = 6.8 Hz, 2H), 7.33 (t, J = 7.2 Hz,
3
2
(
1
3
2
1
H) and 1.98 (t, 1H). C NMR (125 MHz, CDCl3) δ: 170.7, 135.7, 132.4, 128.5, 128.1,
26.5, 126.4, 76.4, 62.3, 38.5, and 30.0. Mass: [M+1] = 219.2, [M+23] = 241.0.
(
S)-6-((2R, 3R)-3-phenyloxiran-2-yl)-5,6-dihydro-2H-(1.05 gm, 9 mmol) was added to
a solution of 7 (1.0 gm, 4.5 mmol) and TEA (1.85 gm, 18.3 mmol) in DCM (25 mL) at -
5 °C. Stirring was continued for 4 h and by TLC indication for absent of starting
3
material the reaction mixture washed with brine solution and the organic layer dried over
anhydrous Na SO . The organic layer was concentrated to dryness under reduced
2
4
pressure and the obtained residue was purified by column chromatography (hexane and
2
5
ethyl acetate 60:40) to yield 2 as white color solid. Yield: 80%; mp 82 °C. [α]D = •111.6
2
5
1
(
c, 0.3 w/v, CHCl ); Reported [α] = -112.7 (c, 0.3 w/v, CHCl ). HNMR: (400 MHz,
3 D 3
CDCl ) δ: 7.38 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 5.2 Hz, 1H), 6.93
3
1
0

(m, 1H), 6.75 (d, J = 15.6 Hz, 1H), 6.29 (dd, J = 5.6, 10 Hz, 1H), 6.10 (td, J = 1.6, 6.4
Hz, 1H), 5.09 (q, J = 7.0 Hz, 1H), 2.54 (m, 2H). Mass: [M+1] = 201.0.
Synthesis of (1S,5S,7R,8S)-8-hydroxy-7-phenyl-2,6-dioxabicyclo[3.3.1]nonan-3-one.
[
(-)-Leiocarpine A] (3b): A 25-mL round-bottomed flask, equipped with a magnetic
stirrer, was charged with 5 mL of tert-butyl alcohol, 5 mL of water, AD-mix-β (2.0 g ,
.23 mmol) and methane sulfonamide (125 mg, 1.25 equiv based on 1 mmol of olefin)
1
was added. The mixture was cooled to 0 °C whereupon some of the dissolved salts
precipitated. Goniothalamin (0.2 g, 1 mmol) was added at once, and the heterogeneous
slurry was stirred vigorously at 0 °C for 2h and then allowed to room temperature and it
was stirred at that temperature for 20h, progress was monitored by TLC. Solid sodium
sulfite (1.5 g) was added at room temperature and stirred for 30-60 min. Ethyl acetate (10
mL) was added to the reaction mixture, and after separation of the layers, the aqueous
phase was further extracted with ethyl acetate (5 mL). The combined organic layers were
washed with 2 N KOH. The combined organic extracts were dried over anhydrous
sodium sulfate and concentrated to give the crude product. This crude product purified by
flash column chromatography (230-400 mesh silica gel) and eluted with 40%
EtOAc/hexanes and afforded 3b. Yield: 65%; white crystalline solid, mp 214-219 °C.
2
5
25
[3] 1
[
α]D = -9.8 (c, 0.2 w/v, EtOH); Reported [α]D -94.9 (c 0.4, CHCl3). HNMR: (500
6
MHz, DMSO d ) δ: 7.36 (d, 2H, J = 7.5 Hz), 7.30 (t, 2H, J = 7.5 Hz), 7.23 (t, 1H, J =
7
3
.0 Hz), 5.13 (d, 1H, J = 6.5 Hz, OH), 4.73 (s, 1H) 4.66 – 4.63 (m, 1H), 4.37 (brs, 1H),
.74 (s, 1H), 3.01 (dd, 1H, J = 5.5 & 13.5 Hz), 2.77 (d, 1H, J = 19 Hz), 2.40 (dd, 1H, J =
1
1

1
3
6
4
1
.5 & 9.5 Hz), 1.85 (dd, 1H, J = 4.0 & 10.0 Hz). CNMR (100 MHz, DMSO d ) δ:
69.2, 138.9, 127.5, 126.9, 126.8, 75.4, 70.2, 67.0, 65.5, 35.8, and 23.2.
+
+
Mass: [M+1] = 235.0. HRMS (EI): calcd. m/z for C H O [M+1] 235.0970, found.
13
15
4
2
35.0964.
ACKNOWLEDGEMENTS
The authors S. B. Meruva, M. Asif and R. R. Kamaraju would like to thank Dr. H. Rama
Mohan of Dr. Reddy’s Laboratories Ltd. for his encouragement. Also would like to thank
Dr. J. Moses Babu of analytical department for providing the analytical support.
REFERENCES
1
.
Quitschalle, M.; Christmann, M.; Bhatt, U.; Kalesse, M. Synthesis of unsaturated
lactone moieties by asymmetric hetero Diels–Alder reactions with binaphthol-titanium
complexes. Tetrahedron Lett. 2001, 42, 1263.
2
.
Pospisil, J.; Marko, I. E. Total Synthesis of (R)-(+)-Goniothalamin and (R)-(+)-
Goniothalamin Oxide: First Application of the Sulfoxide-Modified Julia Olefination in
Total Synthesis. Tetrahedron Lett. 2006, 47, 5933.
3
.
Nagaiah, K.; Sreenu, D.; Purnima, K. V.; Rao, R. S.; J. S. Yadav. Stereo selective
total syntheses of leiocarpin A and (-)-galantinic acid starting from D-mannitol. Synthesis
2
009, 8, 1386.
. Sam, T. W.; Sew-Yeu, Chew, S. Y.; Sabirin, M.; Gan, E. K.; Dzulkifli, R.; Abdul
4
L. M. Goniothalamin oxide: An embryotoxic compound from Goniothalamus
macrophyllaus (Annonaceae). Tetrahedron Lett. 1987, 28, 2541.
1
2

5
.
Cilene, M.; Pilli, R. A.; Fatima, A.; Kohn, L. K.; Ruiz, A. T. G.; Carvalho, J. E.
Asymmetric total synthesis and antiproliferative activity of goniothalamin oxide isomers.
Bioorganic Chemistry, 2009, 37, 52.
6
.
Surivet, J. P.; Vatèle, J. M. First total synthesis of (−)-8-epi-9-
deoxygoniopypyrone. Tetrahedron Lett. 1998, 39, 9681.
Surivet, J. P.; Vatèle, J. M. Total synthesis of antitumor Goniothalamus
styryllactones Tetrahedron 1999, 55, 13011.
Dhaware, G. M.; Prasad, R. K. Stereo selective Total Synthesis of (-)-9-
Deoxygoniopypyrone. Synlett 2007, 7, 1112.
Aneta, K.; Lucie, D.; Jana, R.; Martin, K.; Irena, V. Lewis Base Catalyzed
Enantioselective Allylation of α,β-Unsaturated Aldehydes. Chem. A. Eur. Journal. 2010,
7
.
8
.
9
.
1
6, 9442.
0. Hlubucek, J. R.; Robertson, A. V. (+)-(5S)-δ-Lactone of 5-hydroxy-7-
1
phenylhepta-2,6-dienoic acid, a natural product from Cryptocarya caloneura (Scheff.)
Kostermans. Aust. J. Chem. 1967, 20, 2199.
1
1.
Konfiguration des natürlichen (+)-Goniothalamins. Liebig’s Ann. Chem. 1979, 484.
2. Davies-Coleman, M. T.; Rivett, D. E. Naturally occurring 6-substituted 5, 6-
dihydro-α-pyrones. Progress in the Chemistry of Organic Natural Products; 1989, 55, 1.
3. Jewers, J. R.; Davies, J. B.; Dougan, J.; Manchanda, A. H.; Blunden, G.; Kyi, A.;
Meyer, H. H. Synthesen von (-)-(S)- und (+)-(R)-Goniothalamin; absolute
1
1
Wetchainan, S. Goniothalamin and its distribution in four Goniothalamus species.
Photochemistry 1972, 11, 2025.
1
3

1
4.
Tanaka, S.; Yoichi, S.; Ao, L.; Matumoto, M.; Morimoto, K.; Akimoto, N.; Honda,
G.; Tabata, M.; Oshima, T.; Masuda, T.; bin Asmawi, M. Z.; Ismail, Z.; Yusof, S. M.; Din,
L. B.; Said, I. M. Phytother. Res. 2001, 15, 681.
1
5.
Am. Chem. Soc. 2001, 123, 4161.
6. Saeed, M.; Abbas, M.; Khan, K. M.; Voelter, W. Z. Total Synthesis of S-(+)-
Argentilactone Naturforsch. 2001, 325.
Boger, D. L.; Ichikawa, S.; Zhong, W. Total Synthesis of Fostriecin (CI-920). J.
1
1
1
7.
8.
Hansen, T. V. Synthesis of (R)-(−)-argentilactone. Tet. Asymm. 2002, 13, 547.
Mu, Q.; Tang, W.; Li, C.; Lu, Y.; Sun, H.; Zheng, X.; Wu, N.; Lou, B.; Xu, B.
Four New Styryllactones form Goniothalamus leiocarpus. Heterocycles 1999, 12, 2969.
9. Mu, Q.; Li, C. M.; He, Y. N.; Sun, H. D.; Zheng, H. L.; Lu, Y.; Zheng, Q. T.;
Jiang, W. Three new styryl pyrones from Goniothalamus leiocarpus. Chin. Chem. Lett.
1
1
999, 10, 135.
0. Chen, J.; Lin, G. Q.; Liu, H. Q. Stereo selective synthesis of the styryllactones, 7-
2
epi-goniodiol and leiocarpin A, isolated from Goniothalamus leiocarpus. Tetrahedron
Lett. 2004, 45, 8111.
2
1.
Tetrahedron Lett. 1986, 27, 5201.
2. Bennett, F.; Knight, D. W. An Alternative Approach to Mevinic Acid Analogues
from Methyl-(3R)-3-Hydroxy-5-Hexenoate and an Extension to Rational Syntheses of
+)-(6R)-Goniothalamin and its Non-natural (-)-(6S)-Enantiomer. Tetrahedron Lett. 1988,
9, 4625.
O’Connor, B.; Just, G. Syntheses of argentilactone and Goniothalamin.
2
(
2
1
4

2
3.
Rahman, S. S.; Wakefield, B. J.; Roberts, S. M.; Dowle, M. D. Intramolecular
nucleophilic addition to photo chemically generated ketenes as a versatile route to
lactones and lactams; synthesis of a mosquito pheromone, goniothalamin, argentilactone,
and the Streptomyces L-factor. J. Chem. Soc. Chem. Commun. 1989, 303.
2
4.
Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki, Y.; Tsubuki, M. Enantioselective
syntheses of (+)-acetylphomalactone and (6R)-(+)-goniothalamin from 2-furylmethanols
J. Chem. Soc. Perkin Trans. 1. 1990, 1733.
2
5
3
2
5.
Tsubuki, M.; Kanai, K.; Honda, T. Enantioselective Synthesis of 6-Substituted
,6-Dihydro-α-pyranones, (+)-Goniothalamin and (-)-Argentilactone. Heterocycles 1993,
5, 281.
6.
Fuganti, C.; Pedrocche-Fantoni, G.; Sarra, A.; Servi, S. Stereochemistry of Baker's
yeast mediated reduction of α,β-unsaturated δ-lactones in the goniothalamin series
Tetrahedron Asymm. 1994, 5, 1135.
2
7.
Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Asymmetric synthesis of
goniothalamin, hexadecanolide, massoia lactone, and parasorbic acid via sequential
allylboration–esterification ring-closing metathesis reactions. Tetrahedron Lett. 2000, 41,
5
2
83.
8.
Takano, S.; Kamikubo, T.; Sugihara, T.; Ogasawara, K. Stereocontrolled route to
the δ-benzylidenemethyl-β-hydroxy-δ-lactone system utilizing a new chiral
epoxyacetylene building block. Tetrahedron Asymm. 1992, 3, 853.
2
9.
Henkel, B.; Kunath, A.; Schick, H. Enantioselective Lactonization of Methyl 3,5-
Dihydroxyalkanoates. – An Access to (3R,5S,6E)-3-Hydroxy-7-phenyl-6-hepten-5-olide
1
5

by Enzyme-Catalyzed Kinetic Resolution in Organic Solvents. Liebig’s Ann. Chem. 1992,
8
3
09.
0.
Sundby, E.; Perk, L.; Anthonsen, T.; Aasen, A. J.; Hansen, T. V. Synthesis of (+)-
goniothalamin and its enantiomer by combination of lipase catalyzed resolution and
alkene metathesis. Tetrahedron 2004, 60, 521.
3
1.
Barcelos, R. C.; Pastre, J. C.; Caixeta, V.; Vendramini-Costa, D. B.; de Carvalho,
J. E.; Pilli, R. A. Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-
pyrones and their in vitro evaluation against human cancer cells. Bioorg. Med. Chem.
2
012, 20, 3635.
2. Job, A.; Wolberg, M.; Muller, M.; Enders, D. Asymmetric Synthesis of S-(+)-
3
Argentilactone and S-(-)-Goniothalamin. Synlett 2001, 1796.
3. Liu, Zhi-Yu; Ji, Jian-Xin; Li, Bo-Gang. Efficient synthesis of the styryllactones,
+)-goniothalamin, (+)-7-epi-goniodiol and (+)-9-deoxygoniopypyrone Jour. Chem. Res.
3
(
2
004, 1, 61.
4. Jian, C., Lin, G. Q., Wang, Z. M., Liu, H. Q. A Short and General Approach to the
3
Synthesis of Styryllactones:(+)-Goniodiol, its Acetates and β-Trifluoromethyl Derivative,
+)-7-epi-Goniodiol and (+)-9-Deoxygoniopypyrone. Synlett 2002, 8, 1265.
5. Shankar, R.; More, S. S.; Madhubabu, M. V.; Vembu, N.; Syam Kumar, U. K.
(
3
Synthesis of Isoquinoline Alkaloids via Oxidative Amidation-Bischler-Napieralski
Reaction. Synlett 2012, 7, 1013.
3
6.
Shankar, R.; B. Wagh. M. B; Madhubabu, M. V.; Vembu. N.; Syam Kumar, U. K.
A Concise and Cascade Synthesis of Batracylin and Substituted Isoindolo-[1,2-
b]quinazolin-12(10H)-ones Synlett 2011, 06, 844
1
6

3
7.
Convergent Synthesis of Luotonin B and E. Synlett 2011, 01, 84.
8. Meruva, S. B.; Raghunath, A.; Anil Kumar, N.; Vasudev, R.; Syam Kumar, U. K.;
Dubey, P. K. Synthesis of 5-aryl and 5-amidocamptothecins. J. Het. Chem. 2010, 48,
Wagh. M. B.; Shankar, R.; Syam Kumar, U. K.; Gill, C. H. A Concise and
3
5
3
40.
9.
Amberg, W.; Bennani, L. Y.; Crispino, A, G.; Hartung, J.; Kyu-Sung Jeong, K.;
Kwong, H.; Zhi-Min Wang, M. K.; Xu, D.; Zhang, X.; Sharpless, B, K. The osmium-
catalyzed asymmetric dihydroxylation: a new ligand class and a process improvement J.
Org. Chem., 1992, 57, 2768.
4
0.
Blakemore, P. R. The modified Julia olefination: alkene synthesis via the
condensation of metallated heteroarylalkylsulfones with carbonyl compounds J. Chem.
Soc., Perkin Trans. 1, 2002, 2563.
4
1.
Hobson, L. A.; Akiti, O.; Deshmukh, S. S.; Harper, S.; Katipally, K.; Lai, C. J.;
Livingston, R. C.; Lo, E.; Miller, M. M.; Ramakrishnan, S.; Shen, L.; Spink, J.; Tummala,
S.; Wei, C.; Yamamoto, K.; Young, J.; Parsons, R. L. Development of a Scaleable
Process for the Synthesis of a Next-Generation Statin. Org. Proc. Res. Dev. 2010, 14,
4
4
41.
2.
Meruva, S. B.; Ramamohan, M.; Raghunadh, A.; Raghavendra R., K.; Pratap, T.
V.; Vilas, H. D.; Kumar, U. K. S.; Dubey, P. K. Synthesis of tetrahedral diarylheptanoid
ent-diospongin A and epimer-diospongin B by employing Julia–Kocienski olefination
Tetrahedron Lett. 2014, 55, 4739.
1
7

4
3.
±)-(E)-3,5-dihydroxy-7-phenyl-6-heptenoates, - A comparison of the behaviour of syn-
and anti-compounds. Tetrahedron Asymm. 1993, 4, 153.
4. Hirokazu, U.; Tetsuji, M.; Fumie, S. New chiral blocks for introducing the side
chain of HMG-CoA reductase inhibitors. Tetrahedron Lett. 1992, 33, 4183.
5. Bhaskar, R. G.; Minami, T.; Hanomoto, T.; Hiyama, T. Enantioselective synthesis
Birgitta, H.; Annemarie, K.; Hans, S. Enzyme-catalyzed lactonization of methyl
(
4
4
of .beta.-hydroxy .delta.-lactones: a new approach to the synthetic congeners of 3-
hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J. Org. Chem. 1991, 56,
5
4
752.
6.
Sato, M; Sunami, S; Sugita, Y; Kaneko, C. Use of 1, 3-Dioxin-4-ones and Related
Compounds in Synthesis. XLIV. Asymmetric Aldol Reaction of 4-Trimethylsiloxy-6-
methylene-1, 3-dioxines : Use of Tartaric Acid-Derived (Acyloxy)borane Complex as the
Catalyst. Chem. Pharm. Bull. 1994, 42, 839.
4
7.
CCDC number 999384.
1
8

Table 1. Base screening for Julia-Olefination
S. No.
Base/ Eqv.
HPLC
Purity (9)
90
E/Z ratio
Yield٭ (%)
1
2
3
4
5
6
LiHMDS (1.2)
LDA (1.5)
92/08
60/40
67/33
55/45
74/26
75/25
85
20
80
35
75
78
40
NaHMDS (1.2)
NaH (1.2)
90
60
KHMDS (1.2)
90
t
KO Bu (1.2)
88
1
.2 eq. of benzaldehyde (11) was used for the reaction, conversion and E/Z ratios of 9 are
determined by HPLC method. ٭Isolated yields.
1
9

Figure 1. Natural products related to goniothalamins.
2
0

Figure 2 ORTEP diagram of (-)-leiocarpin A (3b).
2
1

Scheme 1. Retro synthetic scheme for (-)-leiocarpin A (3b).
2
2

Scheme 2. Synthesis of 9.
2
3

Scheme 3.
2
4

Scheme 4. Synthesis of 2
2
5

Scheme 5 Synthesis of 3b.
2
6