The stereoselective total synthesis of (-)-cleistenolide

Article abstract of DOI:10.1016/j.tetlet.2011.02.025

The stereoselective total synthesis of (-)-cleistenolide is described employing the Barbier allylation, MacMillan α-hydroxylation, Stille-Gennari olefination, and CeCl₃·7H₂O mediated lactonization as key steps.

Full text of DOI:10.1016/j.tetlet.2011.02.025

Tetrahedron Letters 52 (2011) 2306–2308
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The stereoselective total synthesis of (ꢀ)-cleistenolide
⇑
B. V. Subba Reddy , B. Phaneendra Reddy, T. Pandurangam, J. S. Yadav
Organic Division 1, 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 (ꢀ)-cleistenolide is described employing the Barbier allylation,
Received 31 December 2010
Revised 1 February 2011
Accepted 7 February 2011
Available online 13 February 2011
MacMillan
steps.
a
-hydroxylation, Stille–Gennari olefination, and CeCl3ꢁ7H2O mediated lactonization as key
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cleistenolide
a
,b-Unsaturated-d-lactones
MacMillan -hydroxylation
Stille–Gennari reaction
a
O
The Cleistochlamys kirkii oliver belongs to the family of an
annonaceae species with its origins from Tanzania and Mozam-
bique.1 The extracts of which are used in traditional medicine as
a remedy for the treatment of wound infections, rheumatism,
and tuberculosis.2 The annonaceous acetogenins are powerful phy-
tochemicals that are found only in the plant family annonaceae
and are known to exhibit a wide range of biological activities. They
constitute one of the most rapidly growing classes of new natural
products and offer exciting anthelminitic, antitumor, antimalarial,
antimicrobial, antiprotozoal, and pesticidal activities. In 2007,
Nkunya et al. have discovered two novel constituents, (ꢀ)-clei-
stenolide and cleistodienol from the annonaceae.3
O
OH
O
O
Ph
OBz
OH OH
OAc OAc
(-)-Cleistenolide (1)
O
(+)-Goniotriol (2)
O
O
OH
O
HO
O
Ph
OH
O
Ph
Ph
O
The 5-hydroxy-a,b-unsaturated-d-lactone structural motif is
(+)-Crassalactone A (3)
(-)-Altholactone (4)
frequently found in many natural products, such as (ꢀ)-cleisteno-
lide (1), (+)-goniotriol (2), (+)-crassalactone A (3), and (ꢀ)-altholac-
tone (4) (Fig. 1). Due to their fascinating structural features and
potential biological activity, the synthesis of these molecules has
attracted many synthetic chemists. Consequently, there have been
Figure 1. Examples of some 5-hydroxy-
ural products.
a
,b-unsaturated-d-lactone containing nat-
pound 9 via the cis-olefination of the aldehyde. The intermediate 9
could be prepared from compound 5 through the Barbier allylation
and MacMillan a-hydroxylation. The compound 5 could in turn be
some reports on the total synthesis of 5-hydroxy-a,b-unsaturated-
d-lactone containing natural products.4 However, only a few meth-
ods are reported for the total synthesis of the (ꢀ)-cleistenolide.5
As part of our interest on the total synthesis of biologically ac-
tive molecules,6 we herein report a novel strategy for the synthesis
prepared from optically active
D-mannitol using a known protocol
(Scheme 1).
Accordingly, the synthesis of target molecule (1) began from the
commercially available -mannitol. Initially, -mannitol was
D
D
of (ꢀ)-cleistenolide (1) employing
D-mannitol as a cost-effective
converted into (R)-glyceraldehyde 1,2-acetonide 5 using a known
protocol.7 The zinc-mediated allylation of compound 5 in aqueous
medium under Luche’s8 conditions gave the anti-homoallylic alco-
hol 6 in a highly diastereoselective manner (syn/anti = 5:95%). Pro-
tection of the resulting alcohol 6 with MOMCl in the presence of
Hunig’s base afforded MOM ether 7 in 92% yield. Dihydroxylation
of compound 7 with OsO4/NMO system followed by sodium
and readily available precursor.
Our retro-synthetic analysis of (ꢀ)-cleistenolide (1) reveals that
it could be synthesized by means of CeCl3ꢁ7H2O catalyzed lacton-
ization of precursor 12, which in turn could be prepared from com-
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
periodate oxidation resulted in aldehyde 8. Subsequent, a-amino-
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.025

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2306–2308
2307
O
h
Undesired
product
OBn
O
O
O
OBn
O
O
O
O
OMe
OBz
OMe
O
O
OMOM
OAc OAc
OMOM
i
1
12
12
OH
OBn
13
OH
O
OH
O
O
O
OH
H
O
O
O
OMOM
O
9
5
O
k
OH
OBz
Scheme 1. Retrosynthetic analysis of (ꢀ)-cleistenolide (1).
OR OH
OAc OAc
j
13; R = Bn
14; R = H
(-)-Cleistenolide (1)
Scheme 3. Reagents and conditions: (h) p-TSA, MeOH; (i) CeCl3ꢁ7H2O, CH3CN,
reflux, 12 h, 65%; (j) TiCl4, CH2Cl2, 0 °C to rt, 30 min, 75%; (k) (i) BzCl, Et3N, DMAP,
4 h, 92%; (ii) Ac2O, Et3N, DMAP, 24 h, 88%.
O
O
a
Ref 8
O
O
H
D-Mannitol
OH
O
5
6
In summary, we have developed an efficient synthetic route for
O
O
c
b
O
d
the stereoselective total synthesis of the (ꢀ)-cleistenolide starting
O
O
from readily available D-mannitol. The synthetic strategy involves
OMOM
7
OMOM
8
a tandem zinc-mediated allylation, MacMillan
a-hydroxylation,
Still–Gennari cis-olefination, and CeCl3ꢁ7H2O mediated lactonisa-
tion as key steps which allow the preparation of target molecule
in an efficient way.
O
OH
OBn
O
e
f
O
O
OH
OTBS
OMOM
9
OMOM
O
10
Acknowledgments
g
B.P.R. and T.P. thank CSIR, and UGC, respectively for the award
of fellowships.
OBn
OBn
O
O
O
O
OH
OMe
OMOM
OMOM
11
12
References and notes
Scheme 2. Reagents and conditions: (a) Zn, allyl bromide, THF, saturated solution
of NH4Cl (cat), 6 h, 90%; (b) DIPEA, MOMCl, DCM, 0 °C, 2 h, 92%; (c) (i) OsO4
(0.5 mol %), NMO, acetone–H2O, rt, 4 h; (ii) NaIO4, rt, 2 h, 92%; (d) (i) D-proline,
nitrosobenzene, DMSO; (ii) NaBH4, MeOH, 0.5 h, 70% (over two steps); (e) (i) TBSCl,
imidazole, DCM, 1 h, 91%; (ii) BnBr, NaH, TBAI, THF, 0 °C to rt, 2 h, 88%; (f) TBAF,
THF, 0 °C to rt, 85%; (g) (i) IBX, DMSO/CH2Cl2, 90%, rt, 3 h; (ii) (CF3CH2O)2P(O)CH2-
CO2CH3, NaH, THF, 75%.
1. Nkunya, M. H. H. Pure Appl. Chem. 2005, 77, 1943.
2. Verzar, R.; Petri, G. J. Ethnopharmacol. 1987, 19, 67.
3. Samwel, S.; Mdachi, S. J. M.; Nkunya, M. H. H.; Irungu, B. N.; Moshi, M. J.;
Moulton, B.; Luisi, B. S. Nat. Prod. Commun. 2007, 2, 737.
4. (a) Sharma, G. V. M.; Mallesham, S. Tetrahedron: Asymmetry 2010, 21, 2646; (b)
Shekhar, V.; Kumar Reddy, D.; Suresh, V.; Babu, D. C.; Venkateswarlu, Y.
Tetrahedron Lett. 2010, 51, 946.
5. (a) Schmidt, B.; Kunz, O.; Biernat, A. J. Org. Chem. 2010, 75, 2389; (b) Cai, C.; Liu,
J.; Du, Y.; Linhardt, R. J. J. Org. Chem. 2010, 75, 5754.
6. (a) Yadav, J. S.; Premalatha, K.; Harshavardhan, S. J.; Reddy, B. V. S. Tetrahedron
Lett. 2008, 49, 6765; (b) Yadav, J. S.; Pandurangam, T.; Reddy, V. V. B.; Reddy, B.
V. S. Synthesis 2010, 24, 4300; (c) Yadav, J. S.; Reddy, U. V. S.; Anusha, B.; Reddy,
B. V. S. Tetrahedron Lett. 2010, 51, 5529; (d) Yadav, J. S.; Thrimurtulu, N.;
Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 6617; (e)
Yadav, J. S.; Lakshmi, K. A.; Reddy, N. M.; Prasad, A. R.; Reddy, B. V. S.
Tetrahedron 2010, 66, 334; (f) Yadav, J. S.; Reddy, N. R.; Harikrishna, V.; Reddy,
B. V. S. Tetrahedron Lett. 2009, 50, 1318; (g) Yadav, J. S.; Rao, T. S.; Ravindar, K.;
Reddy, B. V. S. Synlett 2009, 2828.
7. Xu, Y.; Prestwich, G. D. J. Org. Chem. 2002, 67, 7158.
8. (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910; (b) Einhorn, C.; Luche, J. L.
J. Organomet. Chem. 1987, 322, 177.
9. (a) Yadav, J. S.; Reddy, U. V. S.; Reddy, B. V. S. Tetrahedron Lett. 2009, 50, 5984;
(b) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3697; (c)
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
10. (a) Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531; (b)
Rajiv, T. S.; Suresh, B. W. Tetrahedron 2009, 65, 1599.
oxylation9 of compound 8 with nitrosobenzene in the presence of
D
-proline at ꢀ10 °C, followed by treatment with NaBH4 in MeOH
gave the crude aminooxy alcohol. Treatment of aminooxy alcohol
with 30 mol % CuSO4ꢁ5H2O afforded the chiral diol10 9 in 70% over-
all yield with 95% de. Monosilylation of diol 9 was achieved using
TBSCl and imidazole. The resulting primary TBDMS ether was trea-
ted with benzyl bromide and NaH in THF, to furnish the benzyl
ether 10. Desilylation of compound 10 with TBAF resulted in the
formation of primary alcohol 11 in 88% yield. Oxidation of 11 using
IBX in DMSO/CH2Cl2 gave the aldehyde, which was subjected di-
rectly to a homologation under Still–Gennari conditions11 to give
(Z)-unsaturated ester, 12 in 75% yield with excellent
stereoselectivity.
11. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
12. Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav, J. S. Org. Lett. 2001, 3,
1149.
Interestingly, the deprotection of acetonide and MOM ether
followed by lactonisation of 12 were achieved in one-pot using
CeCl3ꢁ7H2O in CH3CN at reflux conditions (Scheme 3).12 On the
other hand, treatment of 12 with p-TSA in methanol under acidic
conditions gave the undesired product. Debenzylation of lactone
13 was achieved by TiCl4 in dichloromethane at 0 °C to give the
triol 14. Finally, benzoyl protection of primary alcohol 14 followed
by the acetylation of secondary alcohols gave the target molecule
(ꢀ)-cleistenolide (1, Scheme 2). The spectroscopic and physical
13. Spectral data for compound 9: colorless liquid, ½a D25
ꢂ
+10.4 (c 0.25, CHCl3): IR
(neat): mmax 3393, 2926, 2855, 1457, 1377, 1325, 1257, 1154, 1033, 846,
; d 4.71 (q, J = 6.7 Hz, 2H), 4.20 (q,
770 cmꢀ1 1H NMR (300 MHz, CDCl3):
J = 6.0 Hz, 1H), 4.03–4.14 (m, 2H), 3.86–3.92 (m, 1H), 3.68–3.76 (m, 2H), 3.61–
3.67 (m, 1H), 3.41 (s, 3H), 2.0 (s, 1H), 2.03 (s, 1H), 1.40 (s, 3H), 1.34 (s, 3H); 13
C
NMR (75 MHz, CDCl3): d 109.5, 98.3, 76.2, 67.2, 62.5, 55.3, 43.6, 42.7, 31.0. ESI-
MS: m/z: 259 (M+Na)+; HRMS calcd for C10H20O6Na: 259.1157; found:
259.1151. Compound 13: white semi-solid, ½a D25
ꢀ84.8 (c 0.25, CHCl3); IR
ꢂ
(neat): mmax 3424, 2926, 1723, 1585, 1402, 1341, 1261, 1092, 799, 748 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.28–7.40 (m, 5H), 6.93–6.99 (m, 1H), 6.17 (d,
J = 9.9 Hz, 1H), 4.68 (q, J = 10.9 Hz, 2H), 4.34–4.41 (m, 1H), 4.22–4.38 (m, 1H),
4.16–4.21 (m, 1H), 3.86–3.97 (m, 1H), 3.66–3.80 (m, 1H), 2.66–2.72 (m, 2H);
data (1H and 13C NMR, IR, ½a 2D5
ꢂ
) of compound (1) were identical
in all respects to the data reported in the literature.5,13

2308
B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2306–2308
13C NMR (75 MHz, CDCl3): d 162.6, 142.9, 128.6, 128.3, 127.9, 127.7, 124.0,
J = 9.7 Hz, 1H), 5.51 (ddd, J = 9.5, 4.2, 2.4 Hz, 1H), 5.40 (dd, J = 6.0, 2.6 Hz, 1H),
4.93 (dd, J = 12.5, 2.4 Hz, 1H), 4.80 (dd, J = 9.5, 2.6 Hz, 1H), 4.52 (dd, J = 12.5,
4.4 Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3): d 169.8, 169.5,
165.8, 161.0, 139.8, 133.2, 129.7, 129.6, 128.4, 125.3, 75.6, 67.7, 62.1, 59.7,
20.6, 20.5; ESI-MS: m/z: 363 (M+H)+. HRMS calcd for C18H19O8: 363.1080;
found: 363.1087.
78.6, 71.8, 68.7, 65.4, 62.6. ESI-MS: m/z: 265 (M+H)+; HRMS calcd for C14H17O5:
265.1075; found: 265.1088. Compound 1: colorless solid, mp 131–134 °C; ½a D25
ꢂ
ꢀ152.3 (c 0.5,CHCl3); IR (neat):
mmax 2965, 1728, 1454, 1369, 1260, 1215, 1125,
1086, 779, 752 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 8.01 (d, J = 7.7 Hz, 2H), 7.57
(t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.98 (dd, J = 9.5, 6.0 Hz, 1H), 6.30 (d,