Synthetic studies toward pondaplin: Total synthesis of pondaplin analogues

Article abstract of DOI:10.1016/j.tetlet.2005.06.145

Syntheses of synthetic analogues of pondaplin 1 have been achieved. Final macrolide construction was accomplished using a Keck macrolactonization reaction.

Full text of DOI:10.1016/j.tetlet.2005.06.145

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6145–6148
Synthetic studies toward pondaplin: total synthesis of
pondaplin analoguesq
Gowravaram Sabitha,* R. Swapna, R. Satheesh Babu and J.S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 March 2005; revised 10 June 2005; accepted 24 June 2005
Available online 26 July 2005
Abstract—Syntheses of synthetic analogues of pondaplin 1 have been achieved. Final macrolide construction was accomplished
using a Keck macrolactonization reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Pondaplin 1,1 a novel cyclic prenylated phenylpropa-
noid was recently isolated from Annona glabra L.
(Annonaceae).2,3 A number of bioactive Annonaceous
acetogenins had been earlier isolated from this spe-
cies.2,4–6 Pondaplin 1 (Fig. 1) was reported to show
selective cytotoxicities in six human solid tumor cell
lines. Many related phenylpropanoids exhibit a broad
range of biological activities such as antimicrobial, anti-
cancer, and hypotensive properties.7–9 Moreover, phenyl
propanoid derivatives are known to inhibit enzymes
such as cAMP phosphodiesterase and prostaglandin
synthetase.10,11
of 1 starting from 4-hydroxybenzadehyde 2 using ring-
closing metathesis (RCM)12 as the key step (Scheme
1). Disappointingly 7 did not provide the target mole-
cule but instead gave an oligomer. In order to access
the core structure of pondaplin, diallyl ether 9 was pre-
pared from 6 and subjected to RCM conditions. This
attempt also failed to give the expected compound,
an oligomer was isolated again (Scheme 1). After this
work was completed, similar observations were pub-
lished by Bressy and Piva.13
Since the RCM strategy had failed, an alternative
approach was established to achieve the total synthesis
of pondaplin. Propargyl alcohol was protected as trityl
ether 10, which was subjected to methoxycarbonylation
to afford 11 in 86% yield. The conjugate addition of lith-
ium dimethylcuprate to 11 in ether at ꢀ100 to ꢀ85 °C
provided Z-ester 12 as the sole product in 90% yield.
The reduction of 12 with LAH/AlCl3 afforded the corre-
sponding Z-allylic alcohol 13 in 74% yield. Standard
bromination conditions furnished bromide 14 in 62%
yield.14 Bromide 14 was used in an alkylation reaction
with 4-hydroxybenzaldehyde 2 to give O-alkylated
compound 15 in 63% yield. Modified Wadsworth–
Emmons condensation15 on 4-substituted benzaldehyde
15 using bis(2,2,2-trifluoroethyl)(methoxycarbonyl-
methyl)phosphonate in THF at ꢀ78 °C afforded Z-ethyl
ester 16 in 88% yield. Removal of the trityl group fol-
lowed by saponification of 17 afforded the correspond-
ing Z-hydroxy acid 1816 in 99% yield. The olefinic
protons in 16–18 (H-7 and H-8) showed coupling con-
stants of 12.6 Hz. Subjecting hydroxy acid 18 to intra-
molecular Keck coupling conditions in the presence of
The simple and interesting structure of pondaplin 1 and
its significant biological profile against human solid
tumor cell lines made it an intriguing target for total
synthesis. We devised a strategy for the total synthesis
3
2
4
1
7
O
8
1'
5
6
4'
O
3'
2'
O
5'
Pondaplin, 1
Figure 1. Structure of pondaplin.
Keywords: Pondaplin; Analogues; Keck macrolactonization; Dimer.
q IICT Communication No: 050310.
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail: sabitha@
iictnet.org
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.145

6146
G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6145–6148
O
O
a
b
EtO
O
OHC
OHC
OH
O
5 E(3%)
+
2
3
O
c
d
O
OEt
OH
f
O
4
O
O
6
O
Z (97%)
7
PCy3
Cl
Cl
Ph
e
Ru
O
g
oligomer
PCy3
8
PCy3
Ru
O
Cl
Cl
Ph
oligomer
O
9
PCy3
8
Scheme 1. Reagents and conditions: (a) allyl bromide, acetone, K2CO3, reflux, 1 h, 83%; (b) Ph3P@CHCOOEt, MeOH, 0 °C, 6 h, 98%; (c) ethanol,
20% NaOH, 4 h, 96%; (d) 2-methyl-2-propen-1-ol, DCC, DMAP, ether, 20 °C, 79%; (e) benzene, reflux; (f) allyl alcohol, DCC, DMAP, ether, 20 °C,
90%; (g) benzene, reflux.
O
c
TrO
a
TrO
TrO
b
OMe
COOMe
10
12
11
f
TrO
TrO
d
e
OHC
O
Br
OH
15
14
13
TrO
O
O
h
i
O
O
O
O
OMe
OH
HO
O
O
RO
O
18
O
R = Tr
16
17
g
dimer
R = H
Scheme 2. Reagents and conditions: (a) EtMgBr, THF, 0 °C, 1 h, then ClCOOMe, 2 h, 86%; (b) Me2CuLi, THF, ꢀ100 to ꢀ85 °C, 3 h, 90%; (c)
LAH, AlCl3, ether, 0 °C, 3 h, 74%; (d) MsCl, LiBr, Et3N, MeCN, 0 °C, 2.5h, 62%; (e) NaH, p-hydroxybenzaldehyde 2, THF, 0 °C, 4 h, 63%; (f)
NaH, (CF3CH2O)2P(O)CH2COOMe, 0 °C, 1 h, ꢀ78 °C, 2 h, 88%; (g) PPTS, 5:1 DCM–MeOH, rt, 2 h, 67%; (h) aq LiOH, MeOH, rt, 4 h, 99%; (i)
DCC, DMAP, DCM, 0 °C–rt, 12 h, 55%.
1,3-dicyclohexylcarbodiimide and DMAP in DCM
at 0 °C did not give the expected product 1, instead a
dimer17 was formed (Scheme 2).
by intramolecular cyclization using Keck coupling
conditions.
Since both these approaches gave unsatisfactory results
in the final step, we next investigated an alternative
strategy as shown in Scheme 3. Trityl ether 15 was
deprotected to give alcohol 19, which was acylated with
bromoacetyl bromide to give the bromo ester 2019 in
nearly quantitative yield. Further treatment of bromide
20 with P(OEt)3 and an in situ Horner–Wadsworth–
The 1H NMR spectrum of the dimer showed the olefinic
protons (H-7 and H-8) at 6.50 ppm (J = 14.8 Hz) and
7.60 ppm (J = 15.6 Hz), respectively, indicating a trans
1
double bond. Our H NMR data match with the dimer
reported by Joullie and co-workers,14b but interestingly
a recent paper18 reports the total synthesis of pondaplin

G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6145–6148
6147
OHC
O
OHC
Br
O
O
a
EtOOC
b
HO
21
HO
19
O
c
O
20
X
HO
O
O
O
22
Scheme 3. Reagents and conditions: (a) BrCOCH2Br, 2,6-lutidine, 0 °C, 99%; (b) NaH, P(OEt)3, reflux, 2 h, 62%; (c) SmI2, THF, 0 °C, 2 h.
Emmons reaction in the presence of NaH at reflux did
not provide the required product 1 but instead gave an
a,b-unsaturated ester 21.20 The coupling constants of
the newly formed double bond in compound 21 were
15.8 Hz (H-7 and H-8), indicating the trans nature of
the olefinic double bond. 1H NMR, 13C NMR, and
mass spectroscopy support the assigned structure. Yet
another alternative approach was employed on bromide
20, but treatment with SmI2 also failed to afford the nat-
ural product 1.
We considered that the double bond reduction of the
a,b-unsaturated ester might favor the cyclization. To
examine this, the hydroxy ester 24 was prepared from
4-hydroxybenzaldehyde 2 in two steps. The two carbon
Wittig olefination, followed by ester double bond reduc-
tion with Mg/MeOH afforded 24 in 94% overall yield for
the two steps. O-Alkylation of 24 with bromide 14 fol-
lowed by deprotection of the trityl ether afforded allyl
alcohol 26. Ester hydrolysis of 26 followed by intra-
molecular cyclization using Keck coupling conditions
OH
OH
b
a
c
OHC
OH
OMe
O
O
OMe
24
23
2
O
O
e
O
f
OMe
RO
OH
HO
O
O
O
O
27
I
25 R = Tr
26 R = H
d
Scheme 4. Reagents and conditions: (a) Ph3P@CHCOOMe, MeOH, 6 h, 98%; (b) Mg/MeOH, reflux, 6 h, 90%; (c) NaH, THF, 14, rt, 4 h, 60%; (d)
PPTS, 5:1 DCM–MeOH, rt, 2 h, 67%; (e) aq LiOH, MeOH, rt, 4 h, 99%; (f) DCC, DMAP, DCM, 12 h, 55%.
O
OH
O
c
b
a
OMe
OMe
OMe
O
O
O
24
CHO
29
28
O
O
e
d
O
OMe
OH
O
O
O
O
HO
HO
31
30
II
Scheme 5. (a) Prenyl bromide, acetone, K2CO3, reflux, 1 h, 92%; (b) SeO2, EtOH, reflux, 4 h, 50%; (c) NaBH4, MeOH, 85%; (d) aq LiOH, MeOH,
4 h, 98%; (e) DCC, DMAP, DCM, 0 °C–rt, 12 h, 55%.

6148
G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6145–6148
3464–3474; (b) Leonard, M. S.; Carroll, P. J.; Joullie, M.
M. J. Org. Chem. 2004, 69, 2526–2531.
allowed macrolactonization to proceed to give the
saturated analogue I21 of pondaplin in good yield
(Scheme 4).
15. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4407.
16. Compound 18: 1H NMR (200 MHz, CDCl3): d 1.88 (s,
3H, –CH3), 4.18 (s, 2H, –OCH2), 4.58 (d, J = 6.7 Hz, 2H,
–OCH2), 5.65 (t, 1H, J = 6.8 Hz), 5.82 (d, 1H,
J = 12.6 Hz), 6.82 (d, 2H, J = 8.9 Hz, ArH), 6.92 (d, 1H,
J = 12.6 Hz), 7.66 (d, 2H, J = 8.9 Hz, ArH).
Another pondaplin analogue II was synthesized from
saturated ester 24 (Scheme 5). Compound 24 was sub-
jected to alkylation with prenyl bromide to afford O-pre-
nyl ether 28 in 92% yield. Further allylic oxidation was
achieved using SeO2 to afford E-aldehyde 29. The alde-
hyde was reduced with NaBH4 in MeOH to give the cor-
responding E-allylic alcohol 30 in 85% yield. Ester
hydrolysis followed by intramolecular cyclization with
DCC/DMAP in CH2Cl2 at 0 °C afforded the saturated
analogue II (Scheme 5).22
1
17. Dimer: mp 142–146 °C; IR (KBr): 1710 cmꢀ1; H NMR
(200 MHz, CDCl3): d 1.80 (s, 6H, –CH3), 4.60 (br s, 8H,
–OCH2), 5.62 (t, 2H, J = 6.8 Hz), 6.50 (d, 2H,
J = 14.8 Hz, H-8), 6.80 (d, 4H, J = 8.8 Hz, ArH), 7.39
(d, 4H, J = 8.8 Hz, ArH), 7.60 (d, 2H J = 15.6 Hz, H-7).
13C NMR (75MHz, CDCl 3): d 166.0, 160.2, 143.3, 137.6,
127.5, 127.2, 122.6, 119.6, 114.0, 68.5, 65.8, 20.3. FAB
Mass: 461 (M+1).
In conclusion, syntheses of two pondaplin analogues
have been achieved. Further studies directed toward
the total synthesis of pondaplin 1 are currently under-
way in our laboratory and the results of these investiga-
tions will be reported in due course.
18. Cheng, Q.; Zhang, Y. W.; Zhang, X.; Oritani, T. Chin.
Chem. Lett. 2003, 14, 1215–1218.
19. Compound 20: liquid, 1H NMR (200 MHz, CDCl3): d
1.88 (s, 3H, –CH3), 3.81 (s, 2H, –CH2Br), 4.72 (d, 2H, J =
6.7 Hz, –OCH2), 4.78 (s, 2H, –OCH2), 5.72 (t, 1H,
J = 6.8 Hz), 6.98 (d, 2H, J = 8.9 Hz, ArH), 7.82 (d, 2H,
J = 8.9 Hz, ArH), 9.89 (s, 1H, –CHO).
20. Compound 21: mp. 67–70 °C, IR (KBr): 1709 cmꢀ1 1H
;
Acknowledgements
NMR (200 MHz, CDCl3): d 1.33 (t, 3H, J = 7.1 Hz,
–CH2CH3), 1.88 (s, 3H, –CH3), 4.21 (s, 2H, –OCH2), 4.26
(q, 2H, J = 7.1, 14.2 Hz, –OCH2CH3), 4.60 (d, 2H,
J = 6.7 Hz, –OCH2), 5.6 (t, 1H, J = 6.8 Hz, olefinic),
6.25(d, 1H, J = 15.8 Hz), 6.80 (d, 2H, J = 8.7 Hz, ArH),
7.42 (d, 2H, J = 8.7 Hz, ArH), 7.60 (d, 1H, J = 15.8 Hz);
13C NMR (75MHz, CDCl 3): 167.29, 160.3, 144.1, 140.9,
129.6, 127.4, 122.2, 115.9, 115.0, 64.0, 61.9, 60.3, 21.3,
14.3; FAB Mass: 277 (M+1).
R.S. and R.S.B. thank CSIR, New Delhi, for their
fellowships.
References and notes
1. Liu, X.-X.; Pilarinou, E.; McLaughlin, J. L. Tetrahedron
Lett. 1999, 40, 399–402.
2. Ohsawa, K.; Atsuzawa, S.; Mitsui, T.; Yamamoto, I.
J. Pesticide Sci. 1991, 16, 93–96.
3. Padmaja, V.; Thankamany, K.; Hara, N.; Fujimoto, Y.;
Hisham, A. J. Ethnopharmacol. 1995, 48, 21–24.
4. Liu, X.; Alali, F. Q.; Craig, D. C.; Rogers, L.; Pilarinou,
E.; McLaughlin, J. L. Bioorg. Med. Chem. 1998, 6, 959–
966.
5. Liu, X.; Alali, F. Q.; Pilarinou, E.; McLaughlin, J. L.
J. Nat. Prod. 1998, 61, 620–624.
6. Liu, X.; Alali, F. Q.; Pilarinou, E.; McLaughlin, J. L.
J. Phytochem. 1999, 50, 815–821.
7. Ducki, S.; Hadfield, J. A.; Lawrence, N. J.; Liu, C.-Y.;
McGown, A. T.; Zhang, X. Planta Med. 1996, 62, 185–
186.
8. Ojewole, J. A. O.; Adesina, S. K. Planta Med. 1983, 49,
46–50.
9. Perez, C.; Almonacid, L. N.; Trujillo, J. M.; Gonzalez, A.
G.; Alonso, S. J.; Navarro, E. Planta Med. 1995, 61, 535–
536.
10. Kitarawa, S.; Tsukomoto, H.; Hisada, S.; Nhisibe, S.
Chem. Pharm. Bull. 1984, 32, 1209–1213.
11. Hussein, M.; Samuelsson, G. Planta Med. 1992, 58, 14–
18.
12. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
13. Bressy, C.; Piva, O. Synlett 2003, 87–90.
14. (a) Nakata, M.; Ohashi, J.; Ohsawa, K.; Nishimura, T.;
Kinoshita, M.; Tatsuta, K. Bull. Chem. Soc. Jpn. 1993, 66,
21. Preparation of saturated analogue I: To a stirred solution
of N,N0-dicyclohexylcarbodiimide (DCC) (1.4 mmol) and
N,N-dimethylaminopyridine (DMAP) (1.4 mmol) in dry
CH2Cl2 at 0 °C was added a solution of 27 in CH2Cl2
slowly and the mixture allowed to stir at rt for 12 h.
Precipitated urea was then filtered off and the filtrate was
washed twice with 0.5N HCl and with saturated NaHCO 3
solution and then dried over MgSO4. The solvent was
removed by evaporation and the residue was purified by
silica gel column chromatography (hexane/ethyl acetate,
8:2) to afford saturated analogue I in 55% yield. mp 123–
125 °C; IR (KBr): 1733 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 1.80 (s, 3H, –CH3), 2.61 (t, 2H, J = 7.5Hz,
–CH2CH2), 2.90 (t, 2H, J = 8.3 Hz, –CH2CO), 4.51 (d,
2H, J = 6.6 Hz, –OCH2), 4.60 (s, 2H, –OCH2), 5.65 (t, 1H,
J = 5.7 Hz, olefinic), 6.78 (d, J = 8.9 Hz, 2H, ArH), 7.08
(d, 2H, J = 8.9 Hz, ArH); 13C NMR (75MHz, CDCl 3): d
173.2, 157.0, 139.7, 132.5, 129.0, 119.8, 114.5, 70.8, 67.4,
35.7, 29.9, 19.3; FAB Mass: 233 (M+1).
22. Preparation of saturated analogue II: procedure same as
above from 31. Mp 119–121 °C; IR (KBr): 1733 cmꢀ1; 1H
NMR (300 MHz, CDCl3): d 1.80 (s, 3H, –CH3), 2.61 (t,
2H, J = 7.5Hz, –CH2CH2), 2.90 (t, 2H, J = 8.3 Hz,
–CH2CO), 4.55 (d, J = 6.0 Hz, 2H, –OCH2), 4.61 (s, 2H,
–OCH2), 5.65 (t, 1H, J = 5.2 Hz, olefinic), 6.78 (d, 2H,
J = 8.9 Hz, ArH), 7.06 (d, 2H, J = 8.9 Hz, ArH); 13C
NMR (75MHz, CDCl 3): d 173.2, 157.0, 137.7, 132.5,
129.0, 119.8, 114.5, 75.1, 67.4, 35.7, 29.9, 13.7; FAB Mass:
233 (M+1).