Asymmetric total synthesis of (+)-cardiobutanolide via an iterative asymmetric dihydroxylation in PEG

Article abstract of DOI:10.1016/j.tetlet.2010.05.122

The stereoselective total synthesis of (+)-cardiobutanolide, a polyhydroxylated natural product, is achieved in high yield through Lu and Guo diene synthesis, Sharpless asymmetric dihydroxylation, and one-pot deprotection-lactonization. The utility of a r

Full text of DOI:10.1016/j.tetlet.2010.05.122

Tetrahedron Letters 51 (2010) 4058–4060
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Tetrahedron Letters
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Asymmetric total synthesis of (+)-cardiobutanolide via an iterative asymmetric
dihydroxylation in PEG
*
S. Chandrasekhar , N. Kiranmai
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of (+)-cardiobutanolide, a polyhydroxylated natural product, is
achieved in high yield through Lu and Guo diene synthesis, Sharpless asymmetric dihydroxylation, and
one-pot deprotection–lactonization. The utility of a recyclable reagent system in PEG for asymmetric
dihydroxylation is demonstrated.
Received 1 April 2010
Revised 25 May 2010
Accepted 26 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Polyhydroxylated five- and six-membered ring lactones are
common scaffolds present in natural products isolated from sev-
eral species of Annonanceae family.1,2 These include (+) cardiobut-
anolide 1a, goniofufurone (1b), etharvendiol (1c), and altholactone
(1e) besides others (Fig. 1). These natural products can be consid-
ered as consisting of an aryl group, a polyhydroxy component, and
a lactone ring. The plants from which these compounds have been
isolated display various therapeutic activities in traditional medi-
cine in the treatment of rheumatism, edema, and as mosquito
repellents.3 Extensive investigations from the research group of
McLaughlin resulted in the isolation and characterization of a ser-
ies of styryllactones, possessing pesticidal, ratogenic, and embryo-
toxic activity and significant to marginal cytotoxic activity against
human tumor cell lines.4 The styryllactone, namely, cardiobutano-
lide was isolated from the stem bark of Goniothalamus cardiopeta-
lus together with four known styryllactones.5
Herein, we wish to communicate a short and high yielding total
synthesis of (+)-cardiobutanolide.6 The key steps are the not so
well-exploited diene ester synthesis, double Sharpless asymmetric
dihydroxylation in polyethylene glycol (PEG), and one-pot depro-
tection–lactonization. Accordingly, we envisaged the retrosynthet-
ic pathway (Scheme 1). The title compound (1a) can be obtained
from globally protected aryl pentol acid 2, through one-pot depro-
tection–lactonization. Compound 2 was prepared from compound
3, which in turn was obtained by means of double asymmetric
OH OH OH
H
H
HO
Ph
O
O
O
O
OH
H
HO
O
(+) - Cardiobutanolide (1a)
Goniofurfurone (1b)
O
O
OH OH OH
O
O
O
OTBS
OH
O
OH
O
MeO
O
Ph
Ph
OH
O
O
O
OH OEt
OH OH
1d
1a
2
Goniotriol (
)
1c
Etharvendiol (
)
H
O
O
H
O
CO2Et
TBSO
O
CO2Et
TBSO
Ph
O
HO
Ph
4
O
O
O
O
O
3
H
HO
HO
H
CO2Et
Altholactone (1e)
Goniopyrone (1f)
TBSO
Figure 1. Structure of styryllactones.
OH
5
* Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.122

S. Chandrasekhar, N. Kiranmai / Tetrahedron Letters 51 (2010) 4058–4060
4059
OH
H
c
d
e
a, b
OH
TBSO
CO2Et
5
4
HO
TBSO
O
OEt
.
6
OH
9
7
TBSO
TBSO
O
8
O
O
O
O
g, h
O
O
O
k
i, j
f
CO2Et
3
TBSO
OMe
TBSO
N
O
10
O
O
O
O
12
11
O
O
OTBS
OH
l
m
q
OH OH
O
O
OH
o, p
RO
n
2
TBSO
O
O
O
OH
O
O
14 R = TBS;
15 R = H;
13
O
(de 3:1)
(+)-cardiobutanolide (1a)
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, 30 min, 78%; (b) (COCl)2, DMSO, ꢀ78 °C, 2 h, 87%; (c) ethyl propiolate, LiHMDS, THF, ꢀ78 °C, 2 h, 77%; (d)
PPh3, benzene, rt, 3 h, 82%; (e) (DHQD)2PHAL (2 mol %), OsO4 (0.5 mol %), NMOꢁH2O, PEG-400 MW, 0 °C, 30 h, 84%; (f) 2,2-DMP, CSA (5 mol %), CH2Cl2, 0 °C, 30 min, 85%; (g)
(DHQD)2PHAL (2 mol %), OsO4 (0.5 mol %), PEG-400 MW (recovered system from step e) and NMOꢁH2O, 0 °C, 30 h, 80%; (h) 2,2-DMP, CSA (5 mol %), CH2Cl2, rt, 2 h, 75%; (i)
LiOH, THF–H2O (7:3), 0 °C, 3 h; (j) NH(Me)(OMe)ꢁHCl, DCC, TEA, DMAP, CH2Cl2, rt, 3 h (80% for two steps); (k) PhMgBr, THF, rt, 1 h, 85%; (l) NaBH4, CeCl3ꢁ7H2O, MeOH, ꢀ78 °C,
30 min, 74%; (m) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1 h, 82%; (n) CSA (cat), MeOH, 20 °C, 2 h, 85%; (o) BAIB, TEMPO, CH3CN–H2O (1:1), 0 °C to rt, 3 h; (p) CH2N2, ether, 0 °C,
30 min, 90% (for two steps); (q) TFA–H2O (9:1), concd HCl, CH2Cl2, 0 °C to rt, 3 h, 80%.
dihydroxylation of diene ester 4. Compound 4 was obtained from
the isomerization of 4-hydroxy-2-ynoic acid 5, which was in turn
prepared from 1,4-butane-diol (6) and ethyl propiolate.
The synthesis commenced from commercially available 1,4-
butanediol (6) which was transformed to the c-hydroxy ethyl pro-
piolate derivative (5), a critical intermediate for diene synthesis.
The selective mono silylation of diol 6 followed by Swern oxidation
of alcohol using oxalyl chloride and DMSO in dichloromethane at
ꢀ78 °C gave aldehyde 7. This was then subjected to the crucial step
to append the ethyl propiolate group. The lithiated ethyl propiolate
dichloromethane was achieved with TBSOTf/2,6-lutidine at 0 °C
for 1 h to give 14 in 82% yield. The selective deprotection of the pri-
mary silyl ether was accomplished with catalytic CSA in methanol
at 20 °C to get the alcohol 15. The exhaustive oxidation of primary
alcohol 15 to carboxylic acid followed by esterification furnished
globally protected aryl pentol acid 2 in 90% yield (for two steps).
The obvious deprotection under aq TFA in the presence of a drop
of concd HCl in dichloromethane at 0 °C allowed concomitant re-
moval of isopropylidine groups and silyl ether and also lactoniza-
tion to furnish the natural product (+)-cardiobutanolide.13 The
spectral features were in complete agreement with those reported
in the literature5,6 (Scheme 2).14
in THF was added to aldehyde 7 at ꢀ78 °C to yield
c-hydroxy ethyl
propiolate derivative 5. Following the protocol reported by Lu and
Guo,7 the hydroxy ethyl propiolate 5 was stirred in benzene in the
presence of PPh3 to yield the (E,E) diene ester 4 in 82% yield via al-
lene intermediate 8 which isomerizes to stable diene ester. The
enantio and regioselective Sharpless asymmetric dihydroxylation8
of diene ester 4 was achieved in a stepwise manner for easy isola-
tion. Thus 4 on exposure to (DHQD)2PHAL/OsO4/NMOꢁH2O in PEG
as reported by us9 provided diol 9 (>90% ee by HPLC). The
acetonide was prepared under standard conditions using 2,2-dime-
thoxypropane (2,2-DMP) and catalytic camphor sulfonic acid (CSA)
in dichloromethane for 30 min at 0 °C provided 10 in 85% yield.
Acetonide (10) was subjected to second Sharpless asymmetric
dihydroxylation10 under the same reaction medium to provide
diisopropylidine derivative 3 after acetonide formation with 2,2-
DMP and CSA in dichloromethane at room temperature for 2 h in
75% yield with good diastereoselectivity (8:2).11
In conclusion, the total synthesis of (+)-cardiobutanolide was
achieved through the application of diene ester synthesis, Sharp-
less asymmetric dihydroxylation protocol in PEG, and global
deprotection–lactonization in one-pot as key steps.
Acknowledgment
N.K. thanks the UGC, New Delhi, for financial support.
References and notes
1. For a review on styryllactones from Goniothalamus species, see: Blàzquez, M.
A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes, D. Phytochem. Anal. 1999, 10, 161.
2. (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504; (b) Zafra-
Polo, M. C.; Figadère, B.; Gallardo, T.; Tormo, J. R.; Cortès, D. Phytochemistry
1998, 48, 1087; (c) Cavè, A.; Figadère, B.; Laurens, A.; Cortés, D. Prog. Chem. Org.
Nat. Prod. 1997, 70, 81.
Hydrolysis of ester 3 with LiOH and amidation with Weinreb
salt provided amide 11 in 80% yield (for two steps). Exposure of
this to PhMgBr in THF at room temperature for 1 h gave aryl ketone
12 in 85% yield. This reaction and the previous asymmetric dihydr-
oxylation reaction allow in theory to create diversity in both ste-
reochemistry of hydroxyl groups and also in introducing
substituted aryl groups for analoging. The diastereoselective
reduction of prochiral ketone 12 using NaBH4 and CeCl3ꢁ7H2O in
MeOH at ꢀ78 °C produced the desired alcohol 13 with reasonable
diastereoselectivity (3:1), which was separated by silica gel chro-
matography.12a–c The silylation of the benzylic hydroxyl group in
3. On the cytotoxic activity and other bioactivity of styryllactones, see: Mereyala,
H. B.; Joe, M. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 293.
4. For a review on the synthesis of styryllactones until 2004, see: Mondon, M.;
Gesson, J. P. Curr. Org. Synth. 2006, 3, 175.
5. Hisham, A.; Toubi, M.; Shuaily, W.; Bai, M. D. A.; Fujimoto, Y. Phytochemistry
2003, 62, 597.
6. For earlier synthetic approaches of (+)-cardiobutanolide, see: (a) Krishna, P. R.;
Kumas, E. S. Tetrahedron Lett. 2009, 50, 6676; (b) Prasad, K. R.; Gholap, S. L. J.
Org. Chem. 2008, 73, 2916; (c) Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org.
Chem. 2005, 70, 713; (d) Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett.
2006, 47, 1371; (e) Krishna, P. R.; Reddy, P. V. N. Tetrahedron Lett. 2006, 47,
4627; (f) Garg, A.; Singh, R. P.; Singh, V. K. Tetrahedron 2006, 62, 11240.
7. Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394.
8. Xu, D.; Crispino, G.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–7571.

4060
S. Chandrasekhar, N. Kiranmai / Tetrahedron Letters 51 (2010) 4058–4060
9. Chandrasekhar, S.; Narasihmulu, Ch.; Sultana, S. S.; Reddy, N. R. Chem. Commun.
2003, 1716.
10. Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 6, 1069.
Compound 13: Colorless oil; ½a D28
ꢂ
+11.5 (c 0.6, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.40–7.27 (m, 5H), 5.01 (d, J = 3.7 Hz, 1H), 4.34 (m, 1H), 3.99–3.89 (m,
2H), 3.61 (m, 2H), 2.60 (d, J = 1.1 Hz, 1H), 2.34 (dd, J = 8.8, 1.1 Hz, 1H), 1.41–
1.24 (m, 14H), 0.90 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 139.7, 128.5, 128.4, 126.9, 109.9, 108.5, 80.8, 80.7, 79.0, 75.8, 74.7, 73.7, 59.9,
35.7, 29.6, 27.4, 27.2, 26.8, 26.4, 25.8, 18.2, ꢀ5.3; (ESI-MS): m/z 489 (M++Na);
HRMS: calcd for C25H42NaO6Si: 489.2643, (M++Na), found: 489.2606.
11. The double dihydroxylation was also achieved in a similar sequence using AD
mix b, the product was obtained in similar yield and selectivity albeit requiring
longer reaction times (3–5 days).
12. (a) Murphy, P. J.; Dennison, S. T. Tetrahedron 1993, 49, 6695; (b) Yi, X.; Meng, Y.;
Hua, X.; Li, Ch. J. Org. Chem. 1998, 63, 7472; (c) Seyden-Penne, J. Reductions by
the Alumino and Borohydridesin Organic Synthesis; VCH: New York, 1991.
13. The overall yield of 1a is 5.2% (15 mg of 1a was isolated from 500 g of stem
bark powder of Goniothalamus cardiopetalus).
Compound 2: Colorless oil; ½a D27
ꢂ
ꢀ1.3 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.70 (m, 1H), 7.52 (m, 2H), 7.31 (d, J = 4.5 Hz, 2H), 4.88 (d, J = 5.28 Hz, 1H),
4.34–4.27 (m, 1H), 4.20 (m, 1H), 4.07 (d, J = 6.0 Hz, 2H), 3.7 (s, 3H), 2.7 (m, 1H),
2.37 (m, 1H), 1.40–1.26 (m, 12H), 0.92 (s, 9H), 0.09 (s, 3H), ꢀ0.1 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 170.5, 140.0, 127.7, 127.3, 109.3, 108.9, 80.2, 79.2,
75.3, 74.3, 73.0, 51.6, 37.7, 29.7, 27.3, 26.7, 25.8, ꢀ4.8, ꢀ4.9; (ESI-MS): m/z 517
(M++Na); HRMS: calcd for C26H42NaO7Si: 517.2592 (M++Na), found: 517.2634.
14. Spectral data of selected compounds:
Compound 10: Colorless oil; ½a D29
ꢂ
+6.2 (c 0.75, CHCl3); 1H NMR (300 MHz,
CDCl3): d 6.92–6.84 (dd, J = 15.1, 5.2 Hz, 1H), 6.13–6.07 (dd, J = 15.1, 1.5 Hz,
1H), 4.27–4.14 (m, 3H), 3.89–3.66 (m, 3H), 1.84–1.77 (m, 2H), 1.39 (d, J = 9.8,
6H), 1.27 (t, J = 7.5 Hz, 3H), 0.86 (s, 9H), 0.03 (d, J = 1.5 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d 165.9, 143.9, 122.5, 109.1, 80.0, 77.6, 60.0, 59.4, 35.0, 27.1,
26.5, 25.8, 14.1, ꢀ5.4; (ESI-MS): m/z 359 (M++H); HRMS: calcd for
Compound 1: White crystalline solid; mp: 194–196 °C; ½a D27
ꢂ
+5.7 (c 0.3, MeOH)
[lit.5 mp 189–190 °C; [ +6.4 (c 0.28, MeOH)]; 1H NMR (300 MHz, acetone-
a]
D
d6): d 7.44 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 4.79
(d, J = 7.2 Hz, 1H), 4.77 (br s, 1H), 4.72 (d, J = 3.3 Hz, 1H), 4.62 (br s, 1H), 4.56
(m, 1H), 4.40 (d, J = 4.8 Hz, 1H), 4.05 (d, J = 6.4 Hz, 1H), 3.91 (d, J = 7.2 Hz, 1H),
3.84 (s, 1H), 2.91 (m, 1H, overlapped by residual water), 2.38 (d, J = 17.3 Hz,
1H); 13C NMR (150 MHz, acetone-d6): d 176.1, 144.2, 128.5, 127.9, 127.7, 86.7,
C
18H34NaO5Si: 381.2068 (M++Na), found: 381.2080.
Compound 3: Colorless oil; ½a D27
ꢂ
+14.7 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): d 4.55 (d, J = 7.5 Hz, 1H), 429–4.12 (m, 4H), 3.85–3.70 (m, 3H), 1.84–
1.75 (m, 2H), 1.46–1.24 (m, 15H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 170.4, 111.3, 108.8, 96.1, 79.7, 77.3, 75.5, 73.9, 61.3, 59.8, 35.9, 27.5,
26.5, 25.9, 14.2, ꢀ5.3; (ESI-MS): m/z 433 (M++H); HRMS: calcd for
75.4, 74.1, 70.2, 68.6, 40.4; IR tmax (KBr): 3434 (br, OH), 1759 (C@O) cmꢀ1
;
(ESI-MS): m/z 291 (M++Na); HRMS: calcd for C13H16NaO6: 291.0839 (M++Na),
found: 291.0838.
C
21H40NaO7Si: 455.2436 (M++Na), found: 455.2455.