Olefin cross-metathesis based approach for the stereoselective total synthesis of (+)-cardiobutanolide

Article abstract of DOI:10.1016/j.tetlet.2009.09.077

Olefin cross-metathesis approach to (+)-cardiobutanolide has been achieved starting from d-mannitol utilizing Sharpless kinetic resolution and Sharpless asymmetric dihydroxylation.

Full text of DOI:10.1016/j.tetlet.2009.09.077

Tetrahedron Letters 50 (2009) 6676–6679
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Olefin cross-metathesis based approach for the stereoselective total synthesis
of (+)-cardiobutanolide
*
Palakodety Radha Krishna , E. Shiva Kumar
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Olefin cross-metathesis approach to (+)-cardiobutanolide has been achieved starting from
utilizing Sharpless kinetic resolution and Sharpless asymmetric dihydroxylation.
D-mannitol
Received 4 August 2009
Revised 11 September 2009
Accepted 15 September 2009
Available online 18 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Olefin cross-metathesis
Grubbs’ catalyst
Sharpless kinetic resolution
Sharpless asymmetric dihydroxylation
D-Mannitol
The potent polyketide constituent of the annonaceae plant fam-
this logic, a flexible strategy was developed that could potentially
generate a library of natural product-like molecules by adopting
an olefin cross-metathesis reaction between a variety of aryl vinyl
carbinols (or any predesigned aryl constituents) and vinyl butyro-
lactone moieties, the product(s) of which on asymmetric dihydr-
ily,1 (+)-cardiobutanolide 1, pharmacologically active2 product was
isolated from the stem bark of Goniothalamus cardiopetalus, along
with three known styryllactones.3 Styryllactones possess pesti-
cidal, ratogenic, and cytotoxic activity against human tumor cell
lines.2 The first total synthesis of cardiobutanolide was reported
by Murga and co-workers by employing an anti-selective boronate
oxylation reaction with either AD-mix-a or -b afforded the whole
gamut of stereoisomers as well. Alongside this, the first synthesis
of C(5), C(6)-epi-cardiobutanolide 15, a non-natural product is also
reported emanating from the minor product of asymmetric dihydr-
oxylation reaction.
The retrosynthetic analysis of (+)-1 is shown in Scheme 1. The
envisioned strategy derives C(3) and C(4) stereocenters of 1 from
aldol reaction of
L
-erythrulose derivative.4a So far, four total
syntheses and a formal approach have been disclosed toward the
synthesis of 1 since the isolation.4,5 Of the four total syntheses of
1, we reported a chiron approach-based strategy, using diacetone
D
-glucose5 as the starting material involving the key steps of Mits-
unobu stereoinversion, ethyl diazoacetate addition, and selective
reduction of the ketone. In continuation with our program on the
total synthesis of bio-active natural products,6 we revisited the
synthesis of cardiobutanolide based on an olefin cross-metathesis
C(3) and C(4) of D-mannitol while other stereocenters are differ-
ently generated. Thus, compound 1 could be obtained from the
corresponding allylic alcohol 2 by an asymmetric dihydroxylation,
which in turn could be obtained from olefin cross-metathesis reac-
tion between vinyl 3-hydroxy butyrolactone derivative 3 and phe-
nyl vinyl carbinol 4a. The butyrolactone derivative 3 could be
approach starting from D-mannitol. Herein, we report a flexible
and practical synthesis of (+)-1, the key features of which include
olefin cross-metathesis and Sharpless asymmetric dihydroxylation.
With renewed interest we undertook the synthesis of this mol-
ecule in a bid to develop a schematically different route viz. olefin
cross-metathesis protocol. Since styryllactones also possess,
amongst varied biological activities, cytotoxicity with remarkable
anti-tumor properties,2,3 congeners of 1 may have comparable pro-
file. Consequently, it was thought that the presence of diverse aryl
moieties may contribute or amplify the activity. Taking a cue from
synthesized from D-mannitol, while the phenyl vinyl carbinol 4a
can be accessed easily from Sharpless kinetic resolution protocol.
Thus, the synthesis of 1 began following the literature proce-
dure (Scheme 2). For instance, the known7 6 obtained from
D-man-
nitol, was subjected to hydroboration followed by the oxidation
with H2O2 in THF resulted in the desired regioisomer as the major
product 7a in a ratio of 85:15 (65%). Alcohol 7a was protected
(TPSCl/imidazole/CH2Cl2/0 °C to rt) as its TPS ether 7b (95%). Cleav-
8
age of the 1,2-o-isopropylidine group with ZnNO3 in acetonitrile
at 60 °C provided the diol 8, followed by a one-step conversion
(TPP/imidazole/I2/toluene/100 °C) that provided the olefin 5a
* Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.077

P. Radha Krishna, E. Shiva Kumar / Tetrahedron Letters 50 (2009) 6676–6679
6677
TBSO
OH OH
OH
OH
OH
OTBS
O
3
6
4
5
7
2
+
1
O
O
OH
O
3
2
4a
O
1
O
OH OH
HO
6
1
5
HO
3
4
2
OH
O
OH OH
D-mannitol
O
5
Scheme 1. Retrosynthetic analysis.
O
O
O
O
a
RO
ref . 7
D-mannitol
O
O
7a, R = H
7b,
O
O
b
6
7
R = TPS
O
RO
HO
O
d
f
c
O
O
TPSO
O
OH
O
O
HO
5
8
9
5a, R = TPS
5b, R = H
e
OTBS
O
OH
g
h
O
O
O
3
10
Scheme 2. Reagents and conditions: (a) (i) BH3ꢀDMS, THF, 0 °C, 3 h; (ii) H2O2, aq NaOH, 0 °C, 4 h, 65% (over two steps); (b) imidazole, TPSCl, CH2Cl2, 0 °C to rt, 30 min, 95%; (c)
ZnNO3, CH3CN, 60 °C, 8 h; (d) PPh3, imidazole, I2, toluene, 100 °C, 3 h, 60% (over two steps); (e) TBAF, THF, 0 °C, 2 h, 80%; (f) PDC, DMF, rt, overnight, 50%; (g) PTSA, MeOH, 8 h,
70%; (h) imidazole, TBSCl, CH2Cl2, 2 h, 85%.
(60%, over two steps). The deprotection (TBAF/THF/0 °C) of silyl
ether 5a resulted in alcohol 5b (80%), which was then oxidized
(PDC/DMF/rt/12 h) to acid 9 (50%). Treatment of acid 9 with
PTSA/MeOH resulted in the deprotection of 3,4-o-isopropylidine
group with the simultaneous lactone ring formation to afford 10
(70%).
ratio resulted in 12 (70%) as an exclusively E-isomer without self
dimerisation of lactone (Scheme 4). But we were unable to sepa-
rate allyl alcohol 12 in pure form due to its co-elution with Grubbs’
catalyst. Hence, a practical way thought out by us was to protect
(TBSCl/imidazole/CH2Cl2/rt/2 h) the 3-hydroxyl group of the
lactone 10 as its TBS ether 3 first and conduct the cross-metathesis
reaction. Accordingly, the cross-metathesis reaction between lac-
tone 3 and phenyl vinyl carbinol 4a under the above-cited reaction
conditions furnished compound 2 (60%) as an exclusive E-isomer.
Later, allyl alcohol 2 was purified and subjected to asymmetric
dihydroxylation to result in an unisolable mixture of products.
Consequently, allyl alcohol 2 was treated with TBSCl under con-
ventional conditions to afford disilyl ether 13 (80%). Asymmetric
On the other hand, the fragment 4a was synthesized starting
from acrolein (Scheme 3), which on Grignard reaction (PhMgBr/
THF/0 °C to rt) gave the phenyl vinyl carbinol9 4 (75%). Later, 4
on Sharpless kinetic resolution furnished enantiomerically pure
phenyl vinyl carbinol 4a (40%).10
Olefin cross-metathesis6a,11 reaction (Grubbs’ cat-II/CH2Cl2/rt)
between the lactone 10 and phenyl vinyl carbinol 4a in a 1:1.5
OH
OH
OH
O
O
a
b
+
H
11
4
4a
4b
Scheme 3. Reagents and conditions: (a) PhMgBr, THF, 0 °C, 40 min, 75%; (b) (+)-DIPT (0.6 equiv), Ti(OiPr)4 (0.5 equiv), CHP (0.6 equiv), CH2Cl2, ꢁ24 °C.

6678
P. Radha Krishna, E. Shiva Kumar / Tetrahedron Letters 50 (2009) 6676–6679
OH
OH
a
4a
+
10
O
O
12
OTBS
OTBS
O
OH
OTBS
O
b
a
4a
+
3
O
O
13
2
OH OH
OTBS OH
OH
O
OTBS
O
d
OH
O
OH
O
1
14a
c
13
OTBS OH
OH OH
OT BS
O
OH
O
d
OH
O
OH
15
O
14b
Scheme 4. Reagents and conditions: (a) Grubbs’ II (10 mol %), CH2Cl2, rt, 60%; (b) imidazole, TBSCl, CH2Cl2, 2 h, 80%; (c) AD-mix-b, OsO4, tBuOH/H2O (1:1), 70%; (d) Amberlyst
15, CH3CN, 90%.
5. Radha Krishna, P.; Reddy, P. V. N. Tetrahedron Lett. 2006, 47, 4627–4630.
6. (a) Radha Krishna, P.; Dayakar, G. Tetrahedron Lett. 2007, 48, 7279–7282; (b)
dihydroxylation of 13 with AD-mix-b provided the desired product
as the major isomer 14a (70%) in a ratio of 90:10. Treatment of the
Radha Krishna, P.; Sreeshailam, A. Synlett 2008, 2795–2798; (c) Radha Krishna,
P.; Srinivas Reddy, P. Synlett 2009, 209–212.
major isomer with Amberlyst 15 resin in acetonitrile gave the de-
sired natural product 1 {½a D25
ꢂ
+7.4 (c 0.30, MeOH)} in 90% yield.
7. Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 5232–5234.
8. (a) Babjak, M.; Kapitán, P.; Gracza, T. Tetrahedron 2005, 61, 2471–2479; (b)
Vijayasaradhi, S.; Jaimala, S.; Indrapal, S. A. Synlett 2000, 110–112.
9. (a) Shibata, T.; Iwahashi, K.; Kawasaki, T.; Soai, K. Tetrahedron: Asymmetry 2007,
18, 1759–1762; (b) Briot, A.; Baehr, C.; Brouillard, R.; Wagner, A.; Mioskowski,
C. J. Org. Chem. 2004, 69, 1374–1377.
Similarly, the minor isomer 14b was also treated with Amberlyst
15 resin in acetonitrile to give the diastereoisomer 15 in compara-
ble yields. The physical and spectroscopic data of the synthetic
sample 1 were identical to those of the reported natural and syn-
thetic products.4,5,12 Though the overall yield obtained herein is
5% through a 12-step sequence in comparison to 9% obtained in
a 11-step linear synthesis,4b,5 the combinatorial advantages of
the strategy remain intact.
10. Hardouin, C.; Burgaud, L.; Valleix, A.; Doris, E. TetrahedronLett. 2003, 44, 435–437.
11. (a) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41,
3171–3174; (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140; (c)
Nolen, E. G.; Kurish, A. J.; Wong, K. A.; Orlando, M. D. Tetrahedron Lett.
2003, 44, 2449–2453.
12. Spectral data for selected compounds: Compound 9: colorless sirup. ½a D25
ꢁ9.26 (c
ꢂ
1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.85–5.75 (m, 1H), 5.34 (d, 1H,
J = 17.3 Hz), 5.26 (d, 1H, J = 10.2 Hz), 4.05 (d, 2H, J = 3.5 Hz), 2.55 (t, 2H,
J = 2.3 Hz), 1.4 (d, 6H, J = 4.7 Hz); 13C NMR (75 MHz, CDCl3): d 176.2, 134.4,
119.8, 109.7, 82.5, 76.3, 36.7, 27.0, 26.9; IR (KBr): 3510, 3075, 2942, 1720,
In conclusion, we have performed a divergent, stereoselective
synthesis of (+)-cardiobutanolide by means of a versatile strategy.
Olefin cross-metathesis, asymmetric dihydroxylation, and Sharp-
less kinetic resolution were the key steps involved to accomplish
the synthesis of (+)-cardiobutanolide 1.12
1640, 1465, 1410, 1370, 990 cmꢁ1. Compound 10: colorless sirup. ½a 2D5
ꢂ
+118.95
(c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.02–5.90 (m, 1H), 5.54 (dt, 1H,
J = 17.3, 1.3 Hz), 5.48 (dt, 1H, J = 10.5, 1.3 Hz), 4.85 (t, 1H, J = 5.6 Hz), 4.48 (td,
1H, J = 5.2, 1.3 Hz), 2.79 (dd, 1H, J = 5.2, 17.5 Hz) 2.52 (dd, 1H, J = 1.3, 17.3 Hz);
IR (neat): 3485, 3065, 2932, 1760, 1642, 1412, 1375, 995 cmꢁ1; EIMS: m/z 100
(Mꢁ28)+; Anal. Calcd for C6H8O3: C, 56.24; H, 6.29. Found: C, 56.22; H, 6.32.
Acknowledgments
Compound 3: colorless sirup. ½a D25
ꢂ
ꢁ51.76 (c 0.85, CHCl3); 1H NMR (300 MHz,
One of the authors (E.S.K.) thanks CSIR, New Delhi, for financial
support in the form of a fellowship.
CDCl3): d 5.90 (ddd, 1H, J = 3.0, 10.5, 16.9 Hz), 5.25 (d, 1H, J = 16.9 Hz), 5.16 (d,
1H, J = 10.5 Hz), 4.13–4.08 (m, 1H), 3.61 (s, 1H), 2.48 (dd, 1H J = 2.2, 15.8 Hz),
2.15 (dd, 1H, J = 8.6, 15.4 Hz), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 175.9, 131.7, 119.9, 85.5, 70.7, 39.2, 25.6, ꢁ4.9; IR (neat): 3070, 2932,
1760, 1640, 1465, 1415, 1375, 990, 910 cmꢁ1; ESIMS: m/z 265 (M+Na)+, 260
(M+NH4)+ 243 (M+H)+; Anal. Calcd for C12H22O3Si: C, 59.46; H, 9.15. Found: C,
References and notes
59.44; H, 9.16. Compound 2: light yellow solid. ½a D25
ꢂ
+12.09 (c 0.55, CHCl3); 1H
1. (a) Cavé, A.; Figadére, B.; Laurens, A.; Cortés, D. Prog. Chem. Org. Nat. Prod. 1997,
70, 81–288; (b) Zafra-Polo, M. C.; Figadére, B.; Gallardo, T.; Tormo, J. R.; Cortés,
D. Phytochemistry 1998, 48, 1087–1117.
2. (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540; (b)
Zafra-Polo, M. C.; Figadère, B.; Gallardo, T.; Tormo, J. R.; Cortés, D.
Phytochemistry 1998, 48, 1087–1117; (c) Mondon, M.; Gesson, J. P. Curr. Org.
Synth. 2006, 3, 41–75.
3. Hisham, A.; Toubi, M.; Shuaily, W.; Bai, M. D. A.; Fujimoto, Y. Phytochemistry
2003, 62, 597–600.
4. (a) Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2005, 70, 713–716; (b)
Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett. 2006, 47, 1371–1374; (c)
Garg, A.; Singh, R. P.; Singh, V. K. Tetrahedron 2006, 62, 11240–11244; (d)
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2916–2919.
NMR (300 MHz, CDCl3): d 7.32–7.25 (m, 5H), 6.04 (dd, 1H J = 4.9, 15.8 Hz), 5.92
(dd, 1H J = 6.7, 15.8 Hz), 5.25 (d, 1H, J = 4.9 Hz), 4.78 (dd, 1H, J = 4.1, 6.7 Hz),
4.45 (br s, 1H), 2.65 (dd, 1H, J = 5.2, 16.9 Hz), 2.41 (dd, 1H, J = 1.5, 16.9 Hz), 0.88
(s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3): d 175.1, 142.0, 138.0, 128.5,
127.9, 126.2, 123.8, 84.6, 74.0, 70.6, 39.3, 25.5, ꢁ4.8, ꢁ4.9; IR (KBr): 3460, 3020,
2938, 1762, 1675, 1472, 1380, 970 cmꢁ1; ESIMS: m/z 371 (M+Na)+; Anal. Calcd
for C19H28O4Si: C, 65.48; H, 8.10. Found: C, 65.47; H, 8.13. Compound 13: light
colorless sirup. ½a D25
ꢂ
ꢁ25.97 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.34–
7.31 (m, 5H), 5.99 (d, 2H, J = 3.3 Hz), 5.29 (s, 1H), 4.76 (dd, 1H, J = 3.3, 6.4 Hz),
4.46 (t, 1H, J = 5.2 Hz), 2.70 (dd, 1H, J = 4.9, 16.9 Hz), 2.48 (dd, 1H, J = 1.5,
16.9 Hz), 1.51 (br s, OH), 0.96 (s, 18H), 0.11 (s, 12H); IR (neat): 3025, 2932,
1760, 1670, 1471, 1375, 965 cmꢁ1; ESIMS: m/z 480 (M+NH4)+; Anal. Calcd for

P. Radha Krishna, E. Shiva Kumar / Tetrahedron Letters 50 (2009) 6676–6679
6679
C25H42O4Si2: C, 64.88; H, 9.15. Found: C, 64.86; H, 9.13. Compound 14b:
1257 cmꢁ1; ESIMS: m/z 514 (M+NH4)+, 497 (M+H)+; HRMS: calcd m/z 519.2574
(C13H16O6Na). Found m/z 519.2563, ppm error ꢁ2.1494. Compound 15: light
colorless sirup. ½a D25
ꢂ
+15.55 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.37–
7.29 (m, 5H), 5.23 (br s, OH), 5.21 (d, 1H, J = 3.0 Hz), 5.03 (t, 1H, J = 3.0 Hz), 4.73
(d, 1H, J = 4.1 Hz), 4.24 (br s, 1H), 3.86 (t, 1H, J = 2.6 Hz), 2.67 (d, 2H, J = 4.9 Hz),
0.91 (s, 18H), 0.12 (s, 12H); IR (thin film): 3485, 2932, 1760, 1458, 1372,
1246 cmꢁ1; ESIMS: m/z 514 (M+NH4)+; Anal. Calcd for C25H44O6Si2: C, 60.44; H,
yellow sirup. ½a D25
ꢂ
+73.86 (c 0.22, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.43–
7.27 (m, 5H), 5.29 (br s, OH), 5.16 (d, 1H, J = 4.5 Hz), 5.02 (t, 1H, J = 4.1 Hz), 4.79
(d, 1H, J = 3.7 Hz), 4.34 (br s, 1H), 4.06 (dd, 1H, J = 3.0, 4.5 Hz), 2.69–2.66 (m,
1H), 2.34–2.25 (m, 1H). Compound 1: White crystalline solid. ½a D25
ꢂ
+7.47 (c 0.30,
8.93. Found: C, 60.46; H, 8.95. Compound 14a: White solid. ½a D25
ꢂ
ꢁ51.76 (c 1.2,
MeOH); 1H NMR (300 MHz, acetone-d6): d 7.44 (t, 2H, J = 6.9 Hz), 7.35–7.23 (m,
3H), 4.87 (t, 1H, J = 6.9 Hz), 4.61 (d, 1H, J = 3.02 Hz), 4.50–4.44 (m, 1H), 4.34–
4.05 (br s, 1H), 3.80–3.71 (m, 1H), 2.84 (m, 1H, overlapped by residual water),
2.32 (dd, 1H, J = 6.0, 17.3 Hz); 13C NMR (75 MHz, acetone-d6): d 176.8, 144.1,
129.8, 129.2, 128.9, 83.7, 76.7, 69.6, 69.5, 69.4, 40.5; IR (KBr): 3510, 3468, 2932,
1760, 1471, 1210 cmꢁ1; HRMS: calcd m/z 291.0844 (C13H16O6Na). Found m/z
291.0832, ppm error ꢁ4.3224.
CHCl3); 1H NMR (500 MHz, CDCl3): d 7.31–7.24 (m, 5H), 4.73 (d, 1H, J = 7.8 Hz),
4.50 (t, 1H, J = 3.6 Hz), 4.24 (dd, 1H, J = 3.1, 9.3 Hz), 3.81 (d, 1H, J = 7.8 Hz), 3.60
(t, 1H, J = 9.3 Hz), 2.91 (br s, OH), 2.59 (dd, 1H, J = 4.6, 17.1, 21.8 Hz), 2.28 (t, 1H,
J = 5.2 Hz), 0.89 (s, 9H), 0.78 (s, 9H), 0.03 (s, 12H); 13C NMR (75 MHz, CDCl3): d
178.7, 140.1, 128.4, 128.1, 127.4, 127.1, 82.4, 76.4, 75.0, 75.0, 68.6, 65.8, 39.8,
25.7, 25.5, ꢁ4.4, ꢁ4.8, ꢁ5.1, ꢁ5.3; IR (KBr): 3490, 2955, 1760, 1468, 1370,