Chemo and diastereoselective conjugate addition of Grignard reagents on parthenin, a bioactive natural sesquiterpene lactone

Article abstract of DOI:10.1016/j.tetlet.2012.12.043

The conjugate addition on a natural bioactive pseudoguaianolide sesquiterpene lactone parthenin with various Grignard reagents leads to 13-C alkylated products chemo and diastereoselectively in fair overall yields. Compared with other Grignard reagents vinyl and smaller straight chain alkyl Grignard reagents gave better yields.

Full text of DOI:10.1016/j.tetlet.2012.12.043

Tetrahedron Letters 54 (2013) 1634–1637
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Tetrahedron Letters
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Chemo and diastereoselective conjugate addition of Grignard reagents
on parthenin, a bioactive natural sesquiterpene lactone q
⇑
Jajula Kashanna, Paramesh Jangili, Rathod Aravind Kumar, Bethapudirr Rama Rao
Cell Tech Laboratory–NPL, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The conjugate addition on a natural bioactive pseudoguaianolide sesquiterpene lactone parthenin with
various Grignard reagents leads to 13-C alkylated products chemo and diastereoselectively in fair overall
yields. Compared with other Grignard reagents vinyl and smaller straight chain alkyl Grignard reagents
gave better yields.
Received 12 October 2012
Revised 10 December 2012
Accepted 12 December 2012
Available online 19 December 2012
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Parthenin analogues
Grignard reagents
Mono nucleophilic addition
Chiral products
Diastereoselectivity
Organometallic reagents provide one of the most important syn-
thetic routes to construct C–C bond in organic chemistry.1–3 These
reagents undergo addition reaction with a range of active amides,
Cu(I)I and (R)-BINOL mediated Grignard reactions of parthenin
with vinyl magnesium bromide in dry toluene at À78 °C afforded the
formation of b-oriented product, which was isolated by column chro-
matography and characterized as 3a on the basis of its spectral data.
Compound 3a was obtained as a viscous material. Its molecular
formula was determined to be C17H22O4 from elemental analysis,
and MS showed a peak at m/z 313[M+Na]. The structure of
esters, thioesters, anhydrides,4 acid chlorides5 and
a,b-unsaturated
carbonyl derivatives.6 The conjugate addition (1,4 addition) of
organocopper reagents and copper(I) mediated Grignard reagents
to
a,b-unsaturated carbonyl derivatives is another fundamental
operation in the construction of carbon–carbon bonds.7 These addi-
tion reactions give enantioselective and regioselective products in
the presence of chiral ligands.8Parthenin (Fig. 1) is a pseudoguaiano-
lide sesquiterpene lactone which occurs in an exotic noxious
proliferating weed Parthenium hysterophorus Linn (Compositae).
The molecule has a central seven-membered saturated carbocyclic
ring (B) which was fused to two essentially planar five membered
rings-one is a carbocyclic cyclopentenone ring and the other is a
14
HO
10
2
9
7
1
5
B
8
A
3
6
4
O
13
C
15
O
12
11
O
heterocyclic a-methylene c-lactone moiety (C).
The compound possesses significant anticancer,9 antibacte-
rial,10 antifungal,11 antimalarial,12 anti-HCV,13 allelopathic proper-
ties,14 herbicides, antifeedant, insecticides, nematicides15 and
amoebicides.16
Figure 1.
HO
HO
In continuation of our work on chemical transformation of par-
thenin herein, we report a chemo and diastereoselective conjugate
addition of Grignard reagents with exocyclic double bond of par-
thenin (Scheme 1), which could efficiently proceed with Cu(I)I as
catalyst and (R)-BINOL as ligand.
Cu(I)I, (R)-BINOL
RMgX
+
dry Toluene
-78oC, 4-6 h
O
O
O
O
R
O
O
2
3a
1
q
Part 2 in the series ‘Synthetic studies on natural products’.
Corresponding author. Tel./fax: +91 40 27160387.
E-mail address: bethapudirr@rediffmail.com (B.R. Rao).
61-84 %
⇑
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.043

J. Kashanna et al. / Tetrahedron Letters 54 (2013) 1634–1637
1635
Table 1
protons appeared at 5.87–5.73 (1H, m) and 5.19–5.09 (2H, m).
The 1H NMR and 13C NMR data were assigned from COSY, HSQC
and HMBC experiments allowing the identification of vinylic moi-
ety attached at C-13 carbon. The DQF-COSY spectrum showed a
correlation between H-12 and H-6. The HMBC experiment also
showed that H-13 protons were correlated to the vinyl group con-
firming the placement of the vinyl group attached at C-13. In the
NOESY experiment, Me-14 and Me-15 were correlated but they
were not related to H-12 which was related to H-6, H-7. These cor-
relations suggested b-orientation of Me-14, Me-15 and CH2-13.
Thus the structure of the product clearly settled as 13-carbon, b-
oriented alkylated product of parthenin.
We first studied a reaction between parthenin (Fig 1) and vinyl
Grignard reagent by screening the reaction conditions. In order to
determine optimum conditions, we examined the influence of the
reaction temperature, the reaction time and the amount of catalyst.
The effect of temperature on the yields of products was studied by
performing the conjugate addition reaction at 0 °C, À40 °C and
À78 °C respectively (entries 2, 5, 7). The results show that lower
the temperature, the more selectively the reaction could proceed
without formation of any side products. Further the yield and
selectivity could not be improved by the addition of Lewis base,
only slight excess of Grignard reagents was required to deproto-
nate the BINOL. In all the reactions, the conditions were optimized
for 95% conversion. It could be seen that the best result was
Effect of temperature on the synthesis of b-alkylated parthenin derivatives
Entrya Amount of Cu(I)I
(mol %)
Temperature
(°C)
Yieldb
(%)
dr
def
1
2
3
4
5
6
7
8
10
20
10
20
10
20
10
20
10
10
10
0
0
41
46
55
56
69
72
83
84
86
77
80
74:26 48
75:25 50
78:22 56
80:20 60
85:15 70
86:14 72
96:4
95:5
60:40 20
86:14 72
À20
À20
À40
À40
À78
À78
À78
À78
À78
92
90
9c
10d
11e
95:5
90
a
Reaction conditions Cu(I)I (as mentioned in column 2), BINOL (10 mol %,
0.028 g), vinyl magnesium bromide (0.458 mmol, 0.0595 g in THF), parthenin
(0.100 g, 0.382 mmol in THF solution); reaction performed for 4 h in dry toluene
(5 mL).
b
Isolated yields after purification.
The reaction conducted in the absence of (R)-BINOL.
The reaction conducted with (S)-BINOL.
Reaction performed with NEt3.
c
d
e
f
Determined by HPLC.
compound 3 was established from its IR and NMR studies includ-
ing 2D experiment. In the 1H NMR spectrum, the signals for
H2–13 were absent and two additional proton signals for allylic
Table 2
Synthesis of b-alkylated parthenin derivatives
Entrya
Grignard reagents (2)
Productb(3)
Time(h)
4
Yieldc (%)
dr
ded
92
Mg
Br
HO
a
83
96:4
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Mg
Br
HO
O
b
c
d
e
f
4
4
5
4
6
5
84
81
65
69
61
77
93:7
86
82
68
78
54
68
Mg
Br
HO
91:9
O
Mg
Br
HO
84:16
89:11
77:23
84:16
O
Mg
Br
HO
O
Mg
Br
12
HO
12
O
Mg
Br
HO
g
O
O
(continued on next page)

1636
J. Kashanna et al. / Tetrahedron Letters 54 (2013) 1634–1637
Table 2 (continued)
Entrya
Grignard reagents (2)
Productb(3)
MeO
Time(h)
5
Yieldc (%)
dr
ded
74
MeO
MeO
Mg
HO
OMe
OMe
Br
h
79
87:13
O
OMe
O
O
HO
O
Mg
Br
i
5
71
74:26
48
O
O
a
Reaction conditions Cu(I)I (10 mol %, 0.019 g), (R)-BINOL (10 mol %, 0.028 g), vinyl magnesium bromide (0.458 mmol, 0.0595 g in THF), parthenin (0.100 g, 0. 382 mmol in
THF solution); reaction performed for 4 h at À78 °C in dry toluene (5 mL).
b
The structures of the products were established from their spectral (IR,1H and 13C NMR, ESI-MS) data.
Isolated yields after purification.
Determined by HPLC.
c
d
(R)-BINOL + CuI + RMgBr
HO
R
I
O
O
BrMg
HO
Cu
O
O
O
O
R
O
OMgBr
HO
HO
R III
Cu
I
Mg
Br
O
O
R
Cu
I
O
O
O
O
O
O
O
O
MgBr
Scheme 2.
obtained with 10 mol % of Cu(I)I and 10 mol % of (R)-BINOL at
À78 °C (Table 1). In the absence of (R)-BINOL, a mixture of products
(2:1) was obtained which could not be easily separated by column
chromatography, while the conjugate addition of ethenyl magne-
sium bromide reagent can also be performed with (S)-BINOL lead-
Alkyl Grignard reagents in the presence of Cu(I)I and BINOL
form a complex, this complex interacts with -methylene and
oxygen atom of -lactone from bottom face to form a -complex,
the -complex undergoes intramolecular rearrangement to form a
Cu(III) complex, where Cu(III) forms a -bond with b-carbon of
-methylene -lactone moiety which enhances the stereopreference
a
c
p
p
r
ing to the
a
-isomer product with 72% de. However, here we were
a
c
reporting the reactions only with (R)-BINOL.
of enolate quenching and leads to an enolate, this enolate was
quenched by proton which was approaching from bottom face
to give b-isomer as exclusively major product (3a). Although both
endocyclic and exocyclic bonds are active towards nucleophilic
addition, polar conjugate addition takes place selectively across
the exocyclic double bond possibly due to more steric-hindrance
at endocyclic double bond and sterically unhindered exocyclic
double bond. Due to these reasons the addition takes place exclu-
sively at exocyclic double bond. In the absence of ligand the
nucleophile approaches both orientation of exocyclic double
bond which would be leading to a mixture of products (Table 1,
entry 9).18
After optimizing the conditions, we next checked the generality.
Several commonly used Grignard reagents were screened (Table 2).
It was observed that short chain alkyl Grignard reagent achieved
higher yield than long chain alkyl Grignard reagents. As a general
trend, branched aliphatic alkyl Grignard reagents gave lower yields
compared to linear alkyl Grignard reagents. The vinyl, allyl and aryl
Grignard reagents underwent additions smoothly and gave good
yield at À78 °C.
On the basis of current information the possible mechanism for
alkylation of Grignard reagents with parthenin is shown in
Scheme 2.17

J. Kashanna et al. / Tetrahedron Letters 54 (2013) 1634–1637
1637
17. (a) Harutyunyan, S. R.; Hartog, T. D.; Geurts, K.; Minnaard, A. J.; Feringa, B. L.
Chem. Rev. 2008, 108, 2824–2852; (b) Gou, S.; Ye, Z.; Shi, L.; Qing, D.; Zhang,
W.; Wang, Y. Appl. Organomet. Chem. 2010, 24, 517–522; (c) Lopez, F.; Minnard,
A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 188–197.
In conclusion, we have established an efficient C–C coupling at
b-position of -methylene -lactone moiety of parthenin with ali-
phatic, aromatic, vinyl and allyl Grignard reagents using Cu(1)I and
(R)-BINOL as simple catalyst system without protecting the alcohol
moiety.
a
c
18. General experimental procedure for the preparation of b-alkylated parthenin
derivatives (3a–3i): Cu(I)I (10 mol %, 0.019 g) was taken in an oven-dried 25 ml
two necked RB. It is cooled to À78 °C and, (R)-BINOL (10 mol %, 0.028 g)
dissolve in dry toluene (5 mL) and vinyl magnesium bromide (0.458 mmol,
0.0595 g in THF) were added under nitrogen atmosphere, stirred for 5 min,—
Then parthenin (0.100 g, 0. 382 mmol in THF) was added and stirred for 4 h.
The reaction mixture was concentrated in vacuo and extracted with EtOAc
(3 Â 30 mL). The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The residue on purification by column chromatography
(ethyl acetate/hexane, 40:60) afforded pure products.
Acknowledgments
The authors thank the CSIR and UGC New Delhi for the financial
assistance. We are also thankful to Dr. Biswanath Das for his expert
suggestions.
The spectral and analytical data of some representative products are given
below:
References and notes
13b-ethenyl-11,13-dihydroparthenin (3a).
IR: 3451, 2960, 2875, 1664, 1620, 1380, 1200 cmÀ1 1H NMR (200 MHz, CDCl3):
;
d 7.49 (1H, d, J = 6.0 Hz), 6.19 (1H, d, J = 6.0 Hz), 5.87–5.73 (1H, m), 5.19–5.09
(2H, dd), 4.91 (1H, d, J = 8.0 Hz), 2.80–2.70 (H, m), 2.55–2.27 (3H, m), 2.17–2.01
(3H, m), 1.68–1.59 (2H, m), 1.33 (3H, s), 1.13 (3H, d, J = 8.0 Hz); 13CNMR
(50 MHz, CDCl3): d 210.5, 178.9, 162.5, 134.0132.0, 118.5, 84.9, 78.8, 59.2, 47.8,
45.5, 40.6, 35.5, 30.4, 27.0, 18.6, 17.0; ESIMS: m/z 291 [M+H]+. Anal. calcd for
1. (a) Wakefield, B. J. Organomagnesium Methods in Organic Chemistry; Academic
press: San Diego, 1995; (b) Silverman, G. S.; Rakita, P. E. Hand Book of Grignard
Reagents; Marcel Dekker: New York, 1996; (c) Richey, H. G., Jr. Grignard
Reagents: New Development; Wiley: Chichester, 2000.
2. Reviews: (a) Lai, Y.-H. Synthesis 1981, 585–604; (b) Eish, J. J. Organometallics
2002, 21, 5439–5463; (c) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302–4320.
3. Inoue, A.; Shinokubo, H.; Oshima, K. I. Synth. Org. Chem. Jpn. 2003, 61, 25–36.
4. (a) Meyer, A. I.; Comins, D. L. Tetrahedron Lett. 1978, 19, 5179–5182; (b) Nahm,
S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818; (c) Mukaiyama, T.;
Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95, 4763–4765.
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2005, 7, 5593–5595.
6. Kelly, B. G.; Gelheany, D. G. Tetrahedron Lett. 2002, 43, 887–890.
7. Dambrm, V.; Villieras, M.; Janvier, P.; Toupet, L.; Amri, H.; Lebreton, J.; Villieras,
J. Tetrahedron 2001, 57, 2155–2170.
8. Fernando, L.; Adriaan, J. M.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–188.
9. (a) Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem. 1971, 14. 1147-1052;
(b) Mew, D.; Balza, F.; Towers, G. H. N.; Levy, J. G. Planta Med. 1982, 45, 23–27.
10. Pieman, A. K.; Towers, G. H. N. Biochem. Syst. Ecol. 1983, 11, 321–327.
11. Pieman, A. K.; Schneider, E. F. Biochem. Syst. Ecol. 1983, 21, 307–314.
12. Hopper, M.; Kirby, G. C.; Kulkarni, M. M.; Kulkarni, S. N.; Nagasampagi, B. A.;
O’Neill, M. J.; Philipson, J. D.; Rojatkar, S. R.; Warhurs, D. C. Eur. J. Med. Chem.
1990, 25, 717–723.
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O’Neil, J. M.; Fldrige, G. R. J. Nat. Prod. 2007, 70, 604–607.
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Sci. 1988, 57, 1178–1181; (c) Das, B.; Das, R. Allelopathy 1995, 57, 95–101.
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C17H22O4: C, 70.32; H, 7.58%; found: C, 70.18; H, 7.64.
13b-isopropyl-11,13-dihydroparthenin (3d).
IR: 3439, 2924, 2853, 1757, 1717, 1640, 1453; 1H NMR (200 MHz, CDCl3): d
7.55 (1H, d, J = 6.0 Hz), 6.14 (1H, d, J = 6.0 Hz), 4.87 (1H, d, J = 8.0 Hz), 2.71–2.60
(1H, m), 2.40–2.29 (1H, m), 2.20–2.05 (2H, m), 1.90–1.50 (6H, m), 1.31–1.20
(3H, m), 1.12 (3H, d, J = 8.0 Hz), 0.92 (6H, d, J = 7.0 Hz): 13CNMR (50 MHz,
CDCl3): d 208, 179.0, 158.2, 138, 84.9, 78.0, 69.1, 54.0. 47.3, 44.5, 41.0, 30.2,
28.4, 25.6, 24.2, 18.5, 17.0; ESIMS: m/z 307 [M+H]+. Anal. calcd for C18H26O4: C,
71.05; H, 8.49%; found: C, 70.93; H, 8.55.
13b-tetradecanyl-11,13-dihydroparthenin (3f).
IR: 3438, 2921, 2855, 1748, 1716, 1639, 1455; 1H NMR (200 MHz, CDCl3): d
7.46 (1H, d, J = 6.0 Hz), 6.2 (1H, d, J = 6.0 Hz), 4.90 (1H, d, J = 8.0 Hz), 2.77–2.70
(1H, m), 2.30–2.19 (3H, m,), 2.18–1.90 (3H, m), 1.5–1.25 (33H, m), 1.14 (3H, d,
J = 8.0 Hz): 13CNMR (50 MHz, CDCl3): d 209.2, 179.4, 161.0, 134.6, 83.9, 78.6,
59.4, 44.9, 42.0, 40.2, 30.1, 29.0, 27.8, 17.6, 18.5, 17.1; ESIMS: m/z 450 [M+H]+.
Anal. calc for C29H37O4: C, 77.50; H, 8.24%; found: C, 77.38; H, 8.30.
13b-phenyl-11,13-dihydroparthenin (3g).
IR: 3444, 2925, 2856, 1757, 1718, 1639, 1451; 1H NMR (200 MHz, CDCl3): d
7.47 (1H, d, J = 6.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.20 (1H,
dd), 6.21 (1H, d, J = 6.0 Hz), 4.78 (1H, d, J = 8.0 Hz), 3.10–3.05(1H, m), 3.00–2.92
(2H, m), 2.85–2.81 (1H, m), 2.34–2.24 (1H, m), 2.06–1.88 (2H, m), 1.80–1.55
(2H, m), 1.34 (3H, s), 1.11 (3H, d, J = 8.0 Hz); 13CNMR (50 MHz, CDCl3): d 204.2,
187.1, 167, 142.1, 132.5, 130.0, 128.0, 127.2, 81.2, 78.2, 59.1, 50.1. 46.7, 41.6,
33.2, 31.9, 29.8, 19.1, 18.4; ESIMS: m/z 341 [M+H]+. Anal. calc for C21H24O4: C,
74.11; H, 7.05%; found: C, 73.99; H, 7.11.