An efficient total synthesis of (-)-anamarine

Article abstract of DOI:10.1016/j.tetlet.2012.05.099

An efficient synthesis of (-)-anamarine is described using d(+)-mannitol and (R)-epichlorohydrin. The synthesis is achieved starting from easily accessible d(+)-mannitol using a selective benzoylation, regioselective epoxide ring opening, a selective acetonide deprotection, tosylation and cross metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.099

Tetrahedron Letters 53 (2012) 4008–4011
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An efficient total synthesis of (ꢀ)-anamarine
⇑
Palakuri Ramesh, H. M. Meshram
Organic Chemistry 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:
An efficient synthesis of (ꢀ)-anamarine is described using
D(+)-mannitol and (R)-epichlorohydrin. The
synthesis is achieved starting from easily accessible D(+)-mannitol using a selective benzoylation, regio-
Received 9 May 2012
Revised 21 May 2012
Accepted 22 May 2012
Available online 2 June 2012
selective epoxide ring opening, a selective acetonide deprotection, tosylation and cross metathesis
reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Mannitol
(R)-Epichlorohydrin
Tosylation
Lactonization
Cross metathesis
Grubb’s catalyst
The d-lactone ring system is found in a number of natural prod-
ucts and is also featured in many intermediates that are required
for the synthesis of biologically important compounds.1 In particu-
conjugated d-lactones (Fig. 1), and it is believed that the presence
of a Michael acceptor moiety in their skeleton is responsible for
their biological activity. d-Pyranone is a ubiquitous structural unit
lar,
a,b-unsaturated lactones have been shown to exhibit a wide
range of biological activities.2 Spicegerolide,3 synrotolide,4 hypto-
lide,5 (ꢀ)-anamarine and (+)-anamarine6 belong to this class of
O
OAc OAc
OAc OAc
O
O
O
OAc
OAc
O
OAc OAc
O
(-)-Anamarine (1)
OAc
OAc
OAc
OAc
O
S
(+)-anamarine (2)
(-)-anamarine (1)
OAc OAc
OAc OAc
PMBO
S
O
+
5
3
O
OAc
OAc
2
OAc
OAc
O
OAc
OAc
O
O
O
O
Cl
OAc
O
synrotolide (3)
OTBDPS
synargentolide A (4)
OH
HO
(R)-epichlorohydrin
4
Figure 1. Chemical structure of polyhydroxy d-pyranone products.
D-(+)-Mannitol
⇑
Corresponding author.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Scheme 1. Retrosynthesis of (ꢀ)-anamarine.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.099

P. Ramesh, H. M. Meshram / Tetrahedron Letters 53 (2012) 4008–4011
4009
metrization of tartaric acid amide. But all of them involved multi-
ple steps and afforded rather low yields.
(i) CaCO , MeI,
3
S
CH CN:H O (9:1)
PMBO
3
2
OPMB
Ref- 17
Cl
S
O
45 °C, 3h
Recently, we have initiated a research programme for the total
CO2Me
synthesis of bioactive natural products from chiral sources.16,17
(ii) (F CO) OP-CH CO Me,
3
2
2
2
5
(R)-epichlorohydrin
6
NaH, THF, -78 °C-rt, 75%
Our efforts on the use of D-(+)-mannitol as a six-carbon, four-hy-
droxy synthon culminated in the synthesis of a variety of natural
products including bioactive lactones.16c Herein, we report the
O
synthesis of (ꢀ)-anamarine from
D-(+)-mannitol and (R)-epichloro-
TFA, CH Cl ,
O
2
2
hydrin. Our synthesis confirms the absolute configuration assigned
to (ꢀ)-anamarine. As depicted in the retro synthetic analysis of
(ꢀ)-anamarine, the crucial vinyl dihydropyran-2-one was prepared
from (R)-epichlorohydrin. Compound 2 would be prepared from
TBDPS, acetonide protected diol 4. Precursor 4 would be con-
0 °C-r.t, 12h, 60%.
3
Scheme 2. Synthesis of fragment 3.
structed from natural chiral template D-Mannitol through the reg-
ioselective deprotection of acetonide and monobenzoylation
(Scheme 1).
The vinyl lactone fragment 3 was prepared from (R)-epichlorohy-
drin. The PMB protected dithane 5 was prepared from (R)-epichloro-
hydrin.17 The dithane 5 hydrolysis furnished the aldehyde,18 which
was subjected directly to a homologation using Still-Gennari condi-
tions to give Z-unsaturated ester. The alkene ester 6 was submitted
to cyclization in a one step reaction with TFA in CH2Cl2 conditions to
found in a number of bioactive natural products of therapeutic sig-
nificance. Natural products and their analogues possessing this
moiety exhibit a number of pharmacological properties such as
anti-cancer7 and anti-leukemic8 activity, inhibits HIV protease,9 in-
duce apoptosis10,11 and bioactivities in many other biological
processes.12
Until now, three total syntheses were reported for (ꢀ)-anama-
rine (1) in the literature.13–15 Early syntheses by Valverde et al.13
and by Lorenz and Lichtenthaler14 involved an arduous approach
from glucanolactone precursors and suffered from low yields. Very
recently, synthesis of (ꢀ)-anamarine was reported by Prasad
obtain a,b-unsaturated lactone 3 with 60% yield (Scheme 2).
The other required component for accomplishing the final syn-
thesis of (ꢀ)-anamarine (1) is the olefinic tetraacetate fragment 2
et al.15 from the
D-(ꢀ)-tartaric acid based on a strategy of desym-
which was prepared from D-mannitol. The monobenzoyl alcohol
O
(i) Ms-Cl, Et3N, CH2Cl2
-80 °C to-20 °C, 83%
O
O
O
Ref-19, 16c
OBz
D(+)-Mannitol
OH
O
O
O
(ii) K2CO3, MeOH
0 °C-rt, 82%
O
O
7
8
O
O
(Me)3S+I-, n-BuLi
O
TBDPS-Cl, imidazole
DMAP(cat.), CH2Cl2
O
CuCl2.2H2O, CH3CN
0 °C, 45 min, 99%
THF, -10 °C, 2h, 76%
HO
O
OTBDPS
O
O
0 °C-rt, 6h, 92%
O
9
(including with recovered
starting material)
10
O
O
O
O
O
O
LiAlH4, THF
Ts-Cl, Et3N, Bu2SnO
CH2Cl2, rt, 12h, 84%
OTBDPS
OTBDPS
OH
11
OH
HO
OH
OH
0 °C-rt, 6h, 73%
TsO
4
12
O
OAc OAc
Gr-II (10 mol%), 3
TFA, CH2Cl2, 6h
then NEt3, Ac2O
OAc OAc
OAc OAc
O
CH2Cl2, reflux
DMAP(cat.), 4h, 62%
8h, 62%
OAc OAc
(-)-Anamarine (1)
2
MesN
NMes
Cl
Cl
Ru
PCy3
Ph
Gr-II
Scheme 3. Synthesis of (ꢀ)-anamarine.

4010
P. Ramesh, H. M. Meshram / Tetrahedron Letters 53 (2012) 4008–4011
R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas, C. M. K. Tetrahedron 2001, 57, 47;
Kumar, K. S.; Reddy, C. S. Org. Biomol. Chem. 2012, 10, 2647.
7. Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63, 2929.
8. Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.; Amagai, A.; Kubohara, Y.; Ohsima,
Y. Bioorg. Med. Chem. 2004, 12, 3203.
9. (a) Agrawal, V. K.; Singh, J.; Mishra, K. C.; Khadikar, P. V.; Jaliwala, Y. A. ARKIVOC
2006, ii, 162; Hagen, S. E.; Domagala, J. M.; Gajda, C.; Lovdahl, M.; Tait, B. D.;
Wise, E.; Holler, T.; Hupe, D.; Nouhan, C.; Urumov, A.; Zeikus, G.; Zeikus, E.;
Lunney, E. A.; Pavlovsky, A.; Gracheck, S. J.; Saunders, J. M.; Vander, R. S.;
Brodfuehrer, J. J. Med. Chem. 2001, 44, 2319; (c) Hagen, S. E.; Vara-Prasad, J. V.
N.; Tait, B. D. Adv. Med. Chem. 2000, 5, 159; (d) Aristoff, P. A. Drugs Future 1998,
23, 995; (e) Romines, K. R.; Chrusciel, R. A. Curr. Med. Chem. 1995, 2, 825.
10. (a) Chan, K. M.; Rajab, N. F.; Ishak, M. H. A.; Ali, A. M.; Yusoff, K.; Din, L. B.;
Inayat-Hussain, S. H. Chem.-Biol. Interact. 2006, 159, 129; (b) Inayat-Hussain, S.
H.; Annuar, B. O.; Din, L. B.; Ali, A. M.; Ross, D. Toxicol. in Vitro. 2003, 17, 433; (c)
Inayat-Hussain, S. H.; Annuar, B. O.; Din, L. B.; Taniguchi, N. Toxicol. Lett. 2002,
131, 153.
7
is readily accessible from tri-O-isopropylidene-D-(+)-mani-
tol.19,16c The hydroxyl group of compound 7 was protected with
Ms-Cl in the presence of Et3N/CH2Cl2 followed by treatment with
K2CO3/MeOH to give epoxide 8 in 82% yield. The epoxide 8 was
regioselectively opened with (Me)3S+Iꢀ, n-BuLi, THF, ꢀ10 °C and
the resulting secondary allylic alcohol 9 was obtained in 76%
yield.20 The secondary allylic hydroxyl group in 9 was protected
with tert-butyldiphenylsilyl chloride (TBDPS-Cl) and imidazole/
DMAP to afford the silyl ether 10 in 92% yield. The 1,2-O-isopropyl-
idene group of compound 10 was selectively deprotected by using
CuCl2ꢁ2H2O in CH3CN to afford diol 4 in 99% yield (with some start-
ing material).21 Diol 4 on monotosylation (TsCl/Bu2SnO/Et3N/
CH2Cl2) provided 11 with 84% yields. The tosylated compound 11
followed by treatment with LiAlH4 provided detosylated and desi-
lylated olefin diol 12 in good yield.22 Completion of the fragment
synthesis required deprotection of acetonide 12 and acetylation
of the four secondary alcohols. This was most conveniently
achieved as a one-flask reaction in CH2Cl2 by addition of TFA/
CH2Cl2/0 °C to rt stirred for 12 h and subsequently the addition of
Et3N/DMAP and acetic acid anhydride to afford tetracetate 2 in
62% yield. Finally coupling of both the fragments, that is, tetraace-
tate fragment 2 and the vinyl lactone fragment 3 was achieved via
an olefin cross-metathesis reaction by using Grubb’s second gener-
ation (G-II) catalyst23 to give (ꢀ)-anamarine (1) in 62% yield
(Scheme 3). Synthetic (ꢀ)-anamarine (1) exhibited identical spec-
tral data24 (IR, 1H NMR, 13C NMR and Mass) to that of the natural
product.13–15
11. For further literature related to this important biological property, see, for
example: (a) Huang, Z. W. Chem. Biol. 2002, 9, 1059; (b) Blatt, N. B.; Glick, G. D.
Bioorg. Med. Chem. 2001, 9, 1371.
12. See, for example: (a) Koizumi, F.; Ishiguro, H.; Ando, K.; Kondo, H.; Yoshida, M.;
Matsuda, Y.; Nakanishi, S. J. Antibiot. 2003, 56, 603; (b) Richetti, A.; Cavallaro,
A.; Ainis, T.; Fimiani, V. Immunopharmacol. Immunotoxicol. 2003, 25, 441; (c)
Larsen, A. K.; Escargueil, A. E.; Skladanowski, A. Pharmacol. Ther. 2003, 99, 167;
(d) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L. Curr. Med. Chem. 2005,
2002, 9; Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.; Simonyi, M.;
Antus, S.; Randriantsoa, A.; Hostettmann, K. Helv. Chim. Acta. 2001, 84, 3470;
(f) Nagashima, H.; Nakamura K.; Goto, T Biochem. Biophys. Res. Commun. 2001,
287, 829; (g) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.;
Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiot. 1983, 36,
1601.
13. Valverde, S.; Hernandez, A.; Herradon, B.; Rabanal, R. M.; Martin-Lomas, M.
Tetrahedron 1987, 43, 3499.
14. Lorenz, K.; Lichtenthaler, F. W. Tetrahedron Lett. 1987, 28, 47.
15. Prasad, K. R.; Penchalaiah, K. J. Org. Chem. 2011, 76, 6889.
16. (a) Meshram, H. M.; Kumar, D. A.; Goud, P. R. Helv. Chemi. Acta. 2010, 93, 1422;
(b) Reddy, B. C.; Meshram, H. M. Tetrahedron Lett. 2010, 51, 4020; (c) Ramesh,
P.; Meshram, H. M. Tetrahedron Lett. 2011, 52, 2443.
17. Ramesh, P.; Reddy, B. C.; Meshram, H. M. Tetrahedron Lett. 2012. http://
dx.doi.org/10.1016/j.tetlet.2012.04.118; The (R)-epichlorohydrin anion derived
from 1,3-dithane to give epoxide in 67% yield. The epoxide was opened with
(Me)3S+Iꢀ, n-BuLi, THF, ꢀ10 °C and the resulting secondary allylic alcohol on
treatment with p-methoxy benzyl bromide (PMB-Br) in the presence of NaH
gave 5 in 82% yield
In summary, we have achieved the total syntheses of (ꢀ)-ana-
marine from a common precursor simply by changing the se-
quence of carbinol protection and thus allowing the formation of
d-lactone. Key features of the present route to (ꢀ)-anamarine are
the efficient utilization of the C2-symmetry of the starting material
(D-(+)-mannitol), a selective benzoylation, a selective acetonide
deprotection, detosylation, desilylation and a cross metathesis
reaction. The syntheses of related compounds of this family are
underway in our laboratory.
n-BuLi
(Me)3S+I-, n-BuLi
S
OH
S
1,3-dithane
O
O
S
S
THF, -10 °C
Cl
(R)-epichlorohydrin
THF, -40 °C, 67%
1h, 90%
Acknowledgments
S
OPMB
P.R. thanks CSIR for the award of a fellowship and Dr. J. S. Yadav,
Director IICT, for his support and encouragement.
NaH, PMB-Br
S
TBAI, THF, 0° -rt, 82%
5
References and notes
18. Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K. J. Am. Chem. Soc. 2009,
131, 17087.
19. (a) Wiggins, L. F. J. Chem. Soc. 1946, 13; (b) Yadav, V. K.; Agrawal, D. Chem.
Commun. 2007, 5232.
20. Lcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Shin, D. S.; Falck, J. R.
Tetrahedron Lett. 1994, 35, 5449.
21. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tetrahedron Lett.
1998, 39, 3091.
22. Nobuyasu, M.; Sakae, A.; Kibayashi, C. Tetrahedron Lett. 2000, 41, 1199.
23. (a) Sabitha, G.; Fatima, N.; Gopal, P.; Reddy, C. N.; Yadav, J. S.
Tetrahedron:Assymmetry 2009, 20, 184; (b) Sabitha, G.; Fatima, N.; Gopal, P.;
Reddy, C. N.; Yadav, J. S. Tetrahedron Lett. 2009, 50, 6298.
24. Spectral data of selected compounds: (S)-6-vinyl-5,6-dihydro-2H-pyran-2-one (3):
1. (a) Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett. 1969, 1966, 18; (b) Laurence,
B. R. Chem. Commun. 1982, 59; (c) Wilkinson, A. L.; Hanefeld, U.; Wilkinson, P.
F.; Staunton, J. Tetrahedron Lett. 1998, 39, 9827; Sato, M.; Nakashima, H.;
Keisuke, H.; Hayashi, M.; Honzumi, M.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2001, 42, 2833; (d) Hinterding, K.; Singhanat, S.; Oberer, L.
Tetrahedron Lett. 2001, 42, 8463; (e) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z. L.; Hu,
Q.; Shi, W. J. Org. Chem. 2002, 11, 3802; (f) Yadav, J. S.; Reddy, P. M. K.; Reddy, P.
V. Tetrahedron Lett. 2007, 48, 1037; (g) Chakraborty, T. K.; Tapadar, S.
Tetrahedron Lett. 2003, 44, 2541; (h) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793.
2. (a) Stierle, D. B.; Stierle, A. A.; Ganser, B. J. Nat. Prod. 1997, 60, 1207; (b) Ali, A.;
Mackeen, M. M.; Hamid, M.; Aun, Q. B.; Zauyah, Y.; Azimahtol, H. L. P.; Kawazu,
K. Planta Med. 1997, 63, 81; (c) Falomir, E.; Murga, J.; Cardaa, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 539; (d) Chenevert, R.; Courchesne, G.; Caron, D.
Tetrahedron: Asymmetry 2003, 14, 2567.
Yellow liquid;
½
a 2D5
ꢂ
ꢀ94.3 (c 0.1, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
(ppm) = 2.47–2.42 (m, 2H), 4.98–4.88 (m, 1H), 5.31–5.27 (dd, 1H,
J = 10.76 Hz), 5.43–5.37 (dd, 1H, J = 17.34 Hz), 6.06–5.88 (m, 2H), 6.89–6.83
(m, 1H); 13C NMR (CDCl3, 75 MHz): d (ppm) = 29.3, 77.7, 117.8, 121.6, 134.8,
144.3, 163.7; EI-MS: m/z 125 (M+H); ESI-HRMS: calcd 147.0429 (M+Na); found
147.0421 (M+Na). (2R,3R,4R,5S)-hept-6-ene-2,3,4,5-tetrayl tetraacetate (2): Light
´
3. (a) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcıa-Rojas, C. M.
Tetrahedron 2001, 57, 47; (b) Falomir, E.; Murga, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 539; (c) Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.;
Marco, J. A.; Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcıa Rojas, C. M.
J. Org. Chem. 2003, 68, 5672.
yellow oil; ½a 3D0
ꢂ
+12.4 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d (ppm) = 1.18
(d, 3H, J = 6.42 Hz), 2.0 (s, 3H), 2.09 (s, 6H), 2.41 (s, 3H), 2.80 (s, 1H), 4.92 (t, 1H,
J = 6.42 Hz), 5.22 (dd, 1H, J = 6.61, 3.58 Hz), 5.26-5.36 (m, 4H), 5.68-5.80 (m,
1H); 13C NMR (75 MHz, CDCl3): d (ppm) = 35.11, 40.02, 40.21, 40.29, 40.42,
86.85, 90.16, 91.09, 92.13, 139.70, 150.66, 189.15, 189.25, 189.30, 189.39; IR
(KBr): 2932, 1741, 1223, 1032, 906 cmꢀ1; ESI-MS: m/z 353 [M+Na]; ESI-HRMS:
Calculated for C15H22O8Na: 353.1212. Found: 353.1207. (ꢀ)-Anamarine (1):
4. Coleman, M. T. D.; English, R. B.; Rivett, D. E. A. Phytochemistry 1987, 26, 1497.
5. (a) Birch, A. J.; Butler, D. N. J. Chem. Soc. 1964, 4167; (b) Achmad, S. A.; Hyer, T.;
Kjaer, A.; Makmur, L.; Norrestam, R. Acta Chem. Scand. 1987, 41B, 599.
6. (a) Lorenz, F.; Lichtenthaler, W. Tetrahedron Lett. 1987, 28, 6437; (b) Diaz-Oltra,
S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2004, 60, 2979; (c)
Gao, D.; O’Doherty, G. A. J. Org. Chem. 2005, 70, 9932; (d) Sabitha, G.; Reddy, C.
N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5736; (e) Pereda-Miranda,
Gummy liquid;
½
a 2D5
ꢂ
ꢀ16.0 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
d
(ppm) = 1.18 (d, 3H, J = 6.42 Hz), 2.03 (s, 3H), 2.07 (s, 6H), 2.13 (s, 3H), 2.50-

P. Ramesh, H. M. Meshram / Tetrahedron Letters 53 (2012) 4008–4011
4011
2.40 (m, 2H), 4.91 (quint, 1H, J = 6.5 Hz), 4.97 (td, 1H, J = 12.6, 7.7 Hz), 5.18 (dd,
1H, J = 6.9, 3.5 Hz), 5.31 (dd, 1H, J = 7.3, 3.5 Hz), 5.36 (dd, 1H, J = 7.0, 6.0 Hz),
71.6, 71.9, 75.8, 121.5, 125.5, 133.0, 144.5, 163.5, 169.76, 169.83, 169.86,
170.0; IR (KBr): 2935, 1745, 1223, 1028 cm_1; ESI-MS: m/z 444 [M+NH4], 449
[M+Na]; ESI-HRMS for C20H26O10Na calcd 449.1424, found. 449.1422.
5.90-5.75 (m, 2H), 6.07 (d, 1H, J = 9.5 Hz), 6.89 (ddd, 1H, J = 9.3, 5.0, 3.5 Hz); 13
C
NMR (75 MHz, CDCl3): d (ppm) = 15.8, 20.6, 20.86, 20.91, 21.0, 29.1, 67.3, 70.4,