First stereoselective total synthesis of panaxjapyne C

Article abstract of DOI:10.1016/j.tetlet.2012.04.087

The first stereoselective total synthesis of polyacetylene panaxjapyne C is described. The key reactions include regioselective opening of the epoxide and Cadiot-Chodkiewicz cross-coupling reactions. l-Ascorbic acid was used as a chiral pool material for the construction of the both terminal acetylenes.

Full text of DOI:10.1016/j.tetlet.2012.04.087

Tetrahedron Letters 53 (2012) 3703–3705
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First stereoselective total synthesis of panaxjapyne C
Pallavi Thakur a, B. Kumaraswamy a, , G. Raji Reddy a, Rakeshwar Bandichhor b, , K. Mukkanti c
⇑
⇑
a Maithili Life Sciences Pvt. Ltd., Plot No.146 A, Phase-II, IDA, Mallapur, Hyderabad 500 076, India
b Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur, R.R. District 500 073, Andhra Pradesh, India
c Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective total synthesis of polyacetylene panaxjapyne C is described. The key reactions
Received 22 February 2012
Revised 18 April 2012
Accepted 19 April 2012
Available online 7 May 2012
include regioselective opening of the epoxide and Cadiot–Chodkiewicz cross-coupling reactions.
acid was used as a chiral pool material for the construction of the both terminal acetylenes.
L-Ascorbic
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Polyacetylene
Araliaceae
Regioselective opening of epoxide
Cadiot–Chodkiewicz cross coupling
L
-ascorbic acid
Plants of araliaceae contain various secondary metabolites such
potent
a-glucosidase inhibitors resulted in the isolation of three
as lignans,1 saponins,2,3 sesquiterpenes,4,5 polyacetylenes6,7 and
anthraquinones.8 Specifically the roots of panax species (Aralia-
ceae) contain polyacetylenes and dammarane saponins. These
polyacetylenes and conjugated dienes have been shown to possess
anti-tumor, anti-inflammatory, anti-microbial and anti-viral activ-
ities.9 Research interests have increasingly shifted towards poly-
acetylenes, and it has been reported that the araliaceae family is
new polyacetylenes, panaxjapynes A–C (Fig. 1), from the active
CHCl3-soluble portion of the roots of Panax japonicus Meyer var.
major.12 The structures of panaxjapynes A–C were established
based on spectroscopic and chemical methods.12 Herein we report
the first stereoselective total synthesis of panaxjapyne C (Fig. 1)
using a convergent approach.
Retrosynthetically, we envisaged that the target molecule could
be obtained in a convergent fashion wherein two fragments 3 and
4 are coupled together by Cadiot–Chodkiewicz cross-coupling to
a notable rich source of C17 polyacetylenes.10
a-Glucosidase, a
hydrolytic enzyme, is essential for digestion of carbohydrates and
in the biosynthesis of glycoproteins.11 Recent investigations for
Panaxjapyne C1
OH
Panaxjapyne A
OH
OH
OH
2
Panaxjapyne B
OH
OH
OP
Br
+
OH
OH
OP
4
OH
Panaxjapyne C
3
O
OH
O
O
Figure 1. Panaxjapynes A–C.
5
⇑
Corresponding authors. Tel.: +91 4027150243; fax: +91 4040062330.
E-mail addresses: kumarboyapally@gmail.com (B. Kumaraswamy), rakeshwarb
L-Ascorbic acid
@drreddys.com (R. Bandichhor).
Scheme 1. Retrosynthetic scheme for panaxjapyne C.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.087

3704
P. Thakur et al. / Tetrahedron Letters 53 (2012) 3703–3705
i. Et3N, Cat.Bu2SnO,
TsCl, 0 °C- rt, 5 h.
CuI,
O
O
O
O
BrMg(CH2)4CHCH2
O
O
L-Ascorbic acid
OH
O
ii. NaH, THF, 0 °C- rt
4 h, 72%.
THF, -40 °C
5 h, 75%
OH
OH
6
5
7
NaH,
OH
OH
Cat.PTSA
Li/acetylide EDA complex
HMPA, THF, 0 °C-rt, 73%;
O
tosylimidazole
HO
5
MeOH, 0 °C-rt
6 h, 83%
5
8
THF, 0 °C-rt
2 h, 79%
OH
OH
OH
9
4
Scheme 2. Synthesis of fragment 4.
1:1 CH3CN/
1 M HCl
OH
CuI, MeMgI
O
O
NaH, PMBBr
5
HO
O
O
rt, 3 h, 87%
THF, 0 °C-rt
6 h, 84%
Et2O, -40 °C
4 h, 75%
OPMB
O
OPMB
OH
12
O
11
10
1) NaIO4, 60%
CH3CN/H2O
Br
P
OMe
OMe
NBS, Cat.AgNO3
acetone, 1 h, 97%
13
2) , K2CO3,
N2
OPMB
MeOH, 10 h, 82%
OPMB
13
14
3
Scheme 3. Synthesis of fragment 3.
OH
OH
(i) TFA, CH2Cl2
3
, CuCl
rt, 30 h
30% n-C4H9NH2
OH
2
OH
4
82%
NH2OH.HCl, 30 min
0 °C- rt, 94%
Panaxjapyne C 1
OPMB
OH
Scheme 4. Synthesis of panaxjapyne C.
give the intermediate 2. Intermediate 2 can be easily converted
into the final target molecule using a single deprotection step. Both
the fragments 3 and 4 can be obtained from the readily available
2.16 Finally, deprotection of the PMB group with TFA afforded the
target molecule, panaxjapyne C (Scheme 4). The spectroscopic
data17 were found to be identical with that of the natural product
data reported earlier.12
In conclusion, we have accomplished the total synthesis of pan-
axjapyne C. This synthesis employed a divergent chiral pool ap-
L
-ascorbic acid utilizing a chiral pool approach (Scheme 1).
Accordingly, 3,4-O-isopropylidene-
-threitol13 (6, derived from
-ascorbic acid) was treated with p-TsCl and Et3N in the presence
L
L
of a catalytic amount of dibutyltin oxide in CH2Cl2 at room temper-
ature (Scheme 2) to furnish the monotosylate of the primary hy-
droxyl group, which on treatment with NaH provided epoxide 5.
Regioselective epoxide opening with 5-hexenyl magnesium bro-
mide in the presence of copper iodide gave the compound 7
(Scheme 2). Acetonide deprotection with a catalytic amount of
para toluene sulfonic acid in methanol afforded triol 8. In situ tosy-
lation of the primary alcohol and treatment with NaH afforded
epoxide 9. The epoxide so obtained was treated with lithium acet-
ylide to afford key building block 4 (Scheme 2).14
The other key fragment, bromo alkyne 3, was synthesized start-
ing from epoxide 5, common to both fragments. Accordingly, epox-
ide 5 was treated with methyl magnesium iodide in the presence of
copper iodide to get alcohol 10.13c PMB protection of compound 10
yielded the corresponding PMB ether 11, which was treated with
1 M HCl to get diol 12. Treatment of diol 12 with NaIO4 achieved
the required oxidative cleavage to the corresponding aldehyde,
which was converted into alkyne 14 employing Ohira–Bestmann
reagent 13.15 The free terminal acetylene was converted into the
intermediate bromo alkyne 3 using NBS and catalytic silver nitrate
in 97% yield (Scheme 3).14
proach, with all three stereocentres deriving from L-ascorbic acid.
Regioselective epoxide openings and a successful Cadiot–Cho-
dkiewicz cross-coupling were of critical importance in achieving
the target synthesis. The synthesis of other panaxjapynes and their
analogs is currently being investigated for their utility towards bio-
logical evaluation.
Acknowledgment
We are thankful to Dr. Reddy’s Laboratories Ltd for support and
Maithili Life Sciences Pvt. Ltd. for financial assistance.
References and notes
1. Dou, D.-Q.; Hu, X.-Y.; Zhao, Y.-R.; Kang, T.-G.; Liu, F.-Y.; Kuang, H.-X.; Smith, D.
C. Nat. Prod. Res. 2009, 23, 334–342.
2. Wang, G.-S.; Yang, X.-H.; Xu, J.-D. Acta Pharm. Sin. 2004, 39, 354–358.
3. Qin, Z.; Hu, X. Zhongcaoyao 1989, 20, 447–448.
4. Minato, H.; Ishikawa, M. J. Chem. Soc., C 1967, 423–427.
5. Takeda, K.; Minato, H.; Ishikawa, M. Tetrahedron 1966, 22, 219–225.
6. Xu, L.; Wu, X. H.; Zheng, G. R.; Cai, J. C. Chin. Chem. Lett. 2000, 11, 213–216.
7. Kobaisy, M.; Abramowski, Z.; Lermer, L.; Saxena, G.; Hancock, R. E. W.; Towers,
G. H. N.; Doxsee, D.; Stokes, R. W. J. Nat. Prod. 1997, 60, 1210–1213.
8. Xu, S.; Liang, H. Zhongcaoyao 1998, 29, 222–223.
9. Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45(7), 1034.
10. (a) Bohlmann, F.; Burkhardt, F.; Zdero, C. Naturally Occurring Acetylenes;
Academic Press: London, 1973; (b) Hansen, L.; Boll, P. M. Phytochemistry 1986,
25, 285–293.
With intermediates 3 and 4 in hand, the stage was set for cou-
pling them together to complete the assembly of the panaxjapyne
C carbon skeleton. Thus, compound 4 was cross-coupled with alky-
nyl bromide 3 under Cadiot–Chodkiewicz conditions to yield diyne

P. Thakur et al. / Tetrahedron Letters 53 (2012) 3703–3705
3705
11. Ma, C. M.; Hattori, M.; Daneshtalab, M.; Wang, L. J. Med. Chem. 2008, 51, 6188–
(M+Na)+; HRMS for C12H20NaO2:calcd 219.1360; found: 219.1354.
3 :
6194.
Yellowish liquid ½a D29
ꢀ
ꢁ105.5 (c 0.9, CHCl3); IR (CHCl3): 2962, 2936, 2874,
12. Chan, H. H.; Sun, H. D.; Reddy, M. V. B.; Wu, T. S. Phytochemistry 2010, 7, 1360–
1364.
13. (a) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102, 6304–6311; (b)
Abushnab, E.; Venishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu, D.
C. J.; Saibaba, R.; Panzica, P. J. Org. Chem. 1988, 53, 2598–2602; (c) Jung, M. E.;
Yoo, D. Org. Lett. 2007, 9, 3543–3546.
14. Yun, H.; Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519–4522.
15. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Muller, S.; Liepold, B.; Roth,
G. J.; Bestmann, H. J. Synlett 1996, 521–522; (c) Roth, G. J.; Liepold, B.; Muller, S.
J.; Bestmann, H. J. Synthesis 2004, 59–62.
16. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67(1), 6841–6844.
17. Spectroscopic data for representative examples: Compound 8: colourless liquid ;
2837, 2205, 1612, 1513, 1249, 1036 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.32–
;
7.24 (m, 2H), 6.91–6.85 (m, 2H), 4.72 (d, J = 11.3 Hz, 1H), 4.43 (d, J = 11.3 Hz,
1H), 4.01 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.81–1.68 (m, 2H), 0.99 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 159.2, 129.8, 129.6, 113.8, 79.4, 70.4, 70.3,
55.2, 45.0, 28.8, 9.3.2: brown colour liquid ½a D29
= ꢁ110.3 (c 0.6, CHCl3) IR
ꢀ
(Neat): 3387, 2934, 2858, 2253, 1640, 1249, 772 cmꢁ1;1H NMR (300 MHz;
CDCl3): d 7.27–7.20 (m, 2H), 6.86–6.79 (m, 2H), 5.86–5.68 (m, 1H), 5.01–4.87
(m, 2H), 4.68 (d, J = 11.3, 1H), 4.39 (d, J = 11.3, 1H), 3.98 (t, J = 6.8 Hz, 1H), 3.80
(s, 3H), 3.66–3.52 (m, 2H), 2.60–2.53 (M, 2H), 2.12–2.00 (M, 2H), 1.81–1.67(m,
2H), 1.64–1.45(m, 4H), 1.45–1.23(m, 4H), 1.00 (t, J = 7.5, 3H). 13C NMR
(75 MHz, CDCl3): d 159.2, 138.9, 129.6, 129.7, 114.3, 113.7, 77.2, 76.8, 75.9,
73.0, 72.1, 70.4, 69.8, 66.8, 55.2, 33.6, 33.4, 29.0, 28.7 (2C) 25.4, 24.9, 9.6.
½
a 2D9
ꢀ
= ꢁ9.5 (c 1.6, CHCl3); IR (neat): 3379, 2930, 2858, 1641, 1451, 1072 cmꢁ1
;
ESIMS: m/z 421 (M+Na)+; Panaxjapyne C (1): Yellowish liquid ½a 2D9
ꢀ
= +17.3
1H NMR (300 MHz, CDCl3): d 5.82-5.67 (m, 1H), 4.93 (td, J = 17.7, 1.7 Hz, 2H),
4.78–3.91 (br s, 3H), 3.69-3.40 (m, 4H), 2.03 (q, J = 6.8 Hz, 2H), 1.54–1.18 (m,
8H).;13C NMR (75 MHz, CDCl3): d 138.8, 114.3, 74.1, 72.4, 64.5, 33.6, 33.3, 29.0,
28.8, 25.4.;ESIMS: m/z 211 (M+Na)+; HRMS for C10H20NaO3:calcd.; 211.1310;
(c = 0.2, MeOH); lit.12 a 2D9
½ ꢀ = +20.6 (c 0.02, MeOH); IR (neat): 3437, 2928, 2855,
2228, 2142, 1612, 1513, 1249, 1105, 1037 cmꢁ1 1H NMR (300 MHz, CDCl3): d
;
5.86–5.70 (m, 1H), 5.00 (dd, J = 10.6, 1.5 Hz 1H) 4.94 (dd, J = 10.6, 1.5 Hz 1H),
4.36 (t, J = 6.7 Hz 1H), 3.68–3.57 (m, 2H), 2.61 –2.54 (m, 2H), 2.30 (br s, 2H),
2.10–2.00 (m, 2H), 1.80–1.68 (m, 2H), 1.67–1.57 (m, 2H), 1.52–1.28 (m, 6H),
1.02 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 139.0, 114.3, 77.3 (2C), 73.0,
72.1, 69.5, 66.7, 64.0, 33.6, 33.5, 30.7, 29.0, 28.7, 25.4, 25.0, 9.4.ESIMS: m/z :301
(M+Na)+ : HRMS for C17H10NO3 calcd 296.222, found 296.2212.
found: 211.1318. Compound 4: ½a D29
= ꢁ5.5 (c 1.4, MeOH); IR (neat):3441,
ꢀ
2927, 2855, 2084, 1638, 772 cmꢁ1 1H NMR (300 MHz, CDCl3): d 5.84–5.67 (m,
1H), 4.94 (td, J = 18.8, 1.5 Hz, 2H), 3.62–3.50 (m, 2H), 2.44(dd, J = 6.0, 3.0 Hz,
2H), 2.10–1.91 (m, 2H), 1.55–1.07 (m, 8H). 13C NMR (75 MHz, CDCl3): d 138.7,
114.4, 80.6, 73.0, 72.1, 71.0, 33.27, 33.5, 29.1, 28.8, 25.5, 24.1.ESIMS: m/z 219