Formal synthesis of dysiherbaine

Article abstract of DOI:10.1016/j.tetlet.2013.10.038

A formal synthesis of dysiherbaine was achieved from D-mannitol using Grignard addition on chiral imine, RCM and Michael addition as key steps.

Full text of DOI:10.1016/j.tetlet.2013.10.038

Tetrahedron Letters 54 (2013) 6931–6933
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formal synthesis of dysiherbaine
⇑
Maddimsetti Venkateswara Rao, Annavareddi Naresh, Gudipati Saketh, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of dysiherbaine was achieved from
imine, RCM and Michael addition as key steps.
D
-mannitol using Grignard addition on chiral
Received 5 September 2013
Revised 8 October 2013
Accepted 9 October 2013
Available online 16 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Imine formation
Grignard reaction
Lactal formation
Silyl protection
Ring closing metathesis
Michael addition
(ꢀ)-Dysiherbaine isolated from a Micronesian sponge Dysidea
herbacea by Sakai et al. is a potent neuroexcitotoxin and a selective
agonist of non-NMDA (N-methyl-D-aspartate) type glutamate
commercially available D-mannitol (Scheme 2) which was con-
verted into mannitol diacetonide using the literature procedure.4a
Oxidative cleavage of mannitol diacetonide yielded aldehyde 5
which upon condensation with p-methoxy benzylamine in the
presence of 4 Å molecular sieves afforded chiral imine 6, which
was used as such for the next step without any further purification
(Scheme 2).
receptors in the central nervous system.1 Similar compounds have
been isolated from different sources and they have been showing
excellent biological activities. Dysiherbaine 1 and neodysiherbaine
A 3 have a cis-fused hexahydrofuro [3,2-b] pyran bicyclic ring sys-
tem having a glutamic acid substructure. Malayamycin A 2 another
member of this family exhibits potent fungicidal activity.2 Ezomy-
cin A2 4 is a bicyclic N-nucleoside and (Fig. 1) exhibits antifungal
and antibiotic activities.3 (ꢀ)-Dysiherbaine 1 which is the first
example and core structure of this class of compounds has at-
tracted the attention of many synthetic chemists.10,11 In 2000
Masaki et al. reported the total synthesis of (ꢀ)-dysiherbaine from
17A in 10 steps and the key intermediate 17A was synthesized in
16 steps.10b In 2008 Pradilla et al. also synthesized the ent-17A in
13 steps in which ent-17B was converted into ent-17A by treating
with MeI.11 Later in 2011 Tamura et al. also synthesized 17A in 14
steps. In our opinion the key intermediate 17 will be a good start-
ing material not only for the synthesis of dysiherbaine but also for
other related molecules. Therefore we have undertaken the syn-
thesis of 17B and herein we report its synthesis in 12 steps from
Treatment of imine 6 with vinyl magnesium bromide in THF at
0 °C gave anti-amino olefin 7 as an exclusive isomer.4 The amino
functionality in compound 7 was protected as its Cbz derivative
by treatment with benzyloxy carbonyl chloride in the presence of
NaHCO3 in MeOH to afford compound 8 in 88% yield.5 The isopro-
pylidene group in compound 8 was cleaved off using 60% AcOH to
give diol 9. The N-Cbz protective group was advantageously
H2N
Me
O
O
HN
O
HN
H2N
O
HO
MeO
O
CO2H
NH
NH
O
CO2H
O
OH
1
Dysiherbaine
Malayamycin A 2
easily available D-mannitol diacetonide with high stereoselectivity
NH2
H2N
OH
O
and good yielding reactions. The key features of our synthesis are a
Grignard addition on chiral imine 64 followed by a RCM reaction,
a methodology which we have been using for the synthesis of
several heterocyclic (Scheme 1). Our synthesis starts from
OH
O
O
H2N
HN
O
HO
O
CO2H
HO2C
O
NH
CO2H
O
O
HO2C
O
NH
OH
neodysiherbaine A
3
4
Ezomycin A2
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
Figure 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.038

6932
M. V. Rao et al. / Tetrahedron Letters 54 (2013) 6931–6933
Me
HN
O
O
O
R
NPMB
O
H2N
N
HO
O
Ref.11,10 b
CO2H
Michael addition
O
O
O
CO2H
O
TBDPSO
O
dysiherbaine
O
1
15
17A
R= Me
R= H 17B
O
O
O
NPMB
NPMB
RCM/ Acroylation
silyl protection
O
Grignard addition
Oxidation
OH
12
HO
10
HO
NHPMB
Grignard addition
NPMB
Oxazolidinone
formation
D-Mannitol
O
O
O
O
7
6
Scheme 1. Retro synthetic analysis of dysiherbaine.
utilized for the selective protection of the neighboring secondary
hydroxyl group of 9.6 Thus treatment of compound 9 with NaH
in THF gave oxazolidinone 10. Oxidative cleavage of terminal dou-
ble bond in 10 with O3 in CH2Cl2 at ꢀ78 °C produced lactal 11 in
87% yield (Scheme 3). Treatment of 11 with vinyl magnesium bro-
mide at ꢀ78 °C gave exclusively 12 in 77% yield. At 0 °C the forma-
tion of the other diastereoisomer is also observed. The primary
alcohol in 12 was protected as silyl ether using TBDPSCl and imid-
azole at 0 °C to produce 13.7 The secondary alcohol in 13 was ester-
ified with acrylic acid, DCC, and DMAP at 0 °C to give diene 14 in
80% yield.8 This diene 14, on reaction with Hoveyda–Grubbs sec-
ond generation catalyst in toluene under reflux9 afforded lactone
15. Desilylation of 15 with aq. HF in acetonitrile at room tempera-
ture followed by Michael addition of liberated alcohol produced
the tricyclic core 16 of dysiherbaine 110 in 79% yield. Reduction
of compound 16 with H2, Pd/C in methanol afforded the core struc-
ture of dysiherbaine 17B in 73% yield. The physical and spectro-
scopic data of compound 17B are in good agreement with the
literature values.11,12
Scheme 2. Reagents and conditions: (a) (i) NaIO4 on silica gel, CH2Cl2, 0 °C, 2h then,
(ii) PMBNH2, CH2Cl2, 0 °C, over night; (b) vinyl magnesium bromide, THF, 0 °C to rt,
1 h, 92%; (c) CBzCl, NaHCO3, MeOH, 0° C to rt, 2 h, 88%; (d) 60% CH3CO2H, 6 h, 80%;
(e) NaH, THF, 0 °C to rt, 84%; (f) O3, CH2Cl2, ꢀ78 °C, 87%.
In summary, we have developed a formal efficient synthesis of
dysiherbaine from cheaply available mannitol as starting material.
The conversion of the key intermediate 17A to other related mole-
cules will be investigated in future.
O
O
O
O
O
NPMB
NPMB
NPMB
OH
O
(g)
(h)
(i)
Acknowledgments
OH
OH
12
O
11
TBDPSO
HO
13
M.V.R. thanks CSIR, A.N. and G.S. thank UGC, New Delhi for fel-
lowship. We also thank CSIR for financial support in the form of XII
Five Year plan Programme under title DENOVA 0205 and also
thank Director, CSIR-IICT for the constant support and
encouragement.
O
O
O
O
O
O
NPMB
NPMB
O
NPMB
(j)
(k)
O
O
O
TBDPSO
TBDPSO
14
O
O
15
O
16
Supplementary data
Me
O
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.
038.
HN
H2N
NH
O
HO
O
CO2H
ref 11,10b
O
O
(l)
CO2H
1
O
Dysiherbaine
17B
References and notes
Scheme 3. Reagents and conditions: (g) vinyl magnesium bromide, THF, ꢀ78 °C to
rt, 6 h, 77%; (h) TBDPSCl, imidazole, 0 °C to rt, 1 h, 78%; (i) acrylic acid, DCC, DMAP,
0 °C to rt, 1 h, 80%; (j) Hoveyda–Grubbs second generation catalyst, toluene, reflux,
30 min, 85%; (k) aq HF, CH3CN, 0 °C to rt for 6 h then NaHCO3, 3 h, 79%; (l) H2–Pd/C,
MeOH, overnight, 73%.
1. Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc. 1997, 119,
4112.
2. (a) Benner, J. P.; Boehlendorf, B. G. H.; Kipps, M. R.; Lamber, N.E. P.; Luck, R.;
Molleyres, L-P.; Neff, S.; Schuez, T. C.; Stanley, P. D. WO, 03/062242, CAN

M. V. Rao et al. / Tetrahedron Letters 54 (2013) 6931–6933
6933
139:132519.; (b) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org. Lett.
2003, 5, 4277; (c) Hanessian, Stephen; Ritson, Dougal J. J. Org. Chem. 2006, 71,
9807.
10. References for the synthesis of dysiherbaine: (a) Snider, Barry B.; Hawryluk,
Natalie A. Org. Lett. 2000, 2, 635; (b) Masaki, Hidekazu; Maeyama, Junji;
Kamada, Kazuko; Esumi, Tomoyuki; Iwabuchi, Yoshiharu; Hatakeyama,
Susumi J. Am. Chem. Soc. 2000, 122, 5216; (c) Sasaki, Makoto; Koike, Tatsuki;
Sakai, Ryuichi; Tachibana, Kazuo Tetrahedron Lett. 2000, 41, 3923; (d) Phillips,
Dean; Chamberlin, A. Richard J. Org. Chem. 2002, 67, 3194; (e) Takahashi,
Keisuke; Matsumura, Takashi; Ishihara, Jun; Hatakeyama, Susumi Chem.
Commun. 2007, 4158; (f) Sasaki, Makoto; Akiyama, Nobuyuki; Tsubone,
Koichi; Shoji, Muneo; Oikawa, Masato; Sakai, Ryuichi Tetrahedron Lett. 2007,
48, 5697; (g) Sasaki, Makoto; Tsubone, Koichi; Aoki, Kunimori; Akiyama,
Nobuyuki; Shoji, Muneo; Oikawa, Masato; Sakai, Ryuichi; Shimamoto, Keiko J.
Org. Chem. 2008, 73, 264; (h) Tamura, Osamu; Takeda, Kodai; Mita, Naka;
Sakamoto, Masanori; Okamoto, Iwao; Morita, Nobuyoshi; Ishibashi, Hiroyuki
Org. Biomol. Chem. 2011, 9, 7411; (i) Celindro, Nelma Carurucan; Kim, Tae Woo;
Kang, Sung Ho Chem. Commun. 2012, 6295; (j) Cachet, Xavier; Purée, Francois-
Hugues RSC, Adv. 2013, 3, 12466. references cited there in.
3. Sakata, K.; Sakurai, A.; Tamura, S. Tetrahedron Lett. 1975, 16, 3191.
4. (a) Cossy, Janine; Pevet, Isabelle; Meyer, Christophe Eur. J. Org. Chem. 2001, 15,
2841; (b) Madhan, A.; Rao, Venkateswara Tetrahedron Lett. 2003, 44, 5641; (c)
Chandrasekhar, B.; Madhan, A.; Rao, B. Venkateswara Tetrahedron 2007, 63,
8746.
5. Rao, Maddimsetti Venkateswara; Chandrasekhar, Bandari; Rao, Batchu
Venkateswara; Swarnalatha, Jasti Lakshmi Tetrahedron: Asymmetry 2011, 22,
1342.
6. Madhan, A.; Kumar, A. Ravi; Rao, B. Venkateswara Tetrahedron: Asymmetry
2001, 2009, 12.
7. (a) Reiss, Tomislav; Breit, Bernhard Chemistry—A European Journal 2009, 15,
6345; (b) Schmidt, Yvonne; Lehr, Konrad; Breuninger, Ulrich; Brand, Gabriel;
Reiss, Tomislav; Breit, Bernhard J. Org. Chem. 2010, 75, 4424.
8. Monasterolo, Claudio; Ballestri, Marco; Sotgiu, Giovanna; Guerrini, Andrea;
Dambruoso, Paolo; Pistone, Assunta; Varchi, Greta; Cesare, Michelandrea De;
Beretta, Giovanni Luca; Zunino, Franco; Benfenati, Valentina; Sparnacci, Katia;
Laus, Michele Bioorg. Med. Chem. 2012, 20, 6640.
9. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003;
(c) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis; Murahashi, S. I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004; p 153. Chapter 6; (d) Lozano-Vila,
A. M.; Monsaert, S.; Bajek, A.; Verpoort, F. Chem. Rev. 2010, 110, 4865.
´
11. Pradilla, R. F. de la.; Lwoff, N.; A guila, M. A.; Tortosa, M.; Viso, A. J. Org. Chem.
2008, 73, 8929.
12. Compound (17): ½a D30
+68.3 (C 0.8, acetone), IR vmax 2924, 2855, 1729, 1219,
ꢁ
772. 1H NMR (CD3OD, 500 MHz): d 4.53(ddd, 1H, J = 8.2, 2.1, 1.3 Hz), 4.51 (dd,
1H, J = 5.8, 3.9 Hz), 4.32(ddd, 1H, J = 6.1, 3.6, 2.3 Hz), 4.18(dd, 1H, J = 7.7,
5.8 Hz), 4.02(dd, 1H, J = 13.8, 1.2 Hz), 3.64 (dd, 1H, J = 14.0, 2.0 Hz), 2.85(dd, 1H,
J = 17.7, 5.7 Hz), 2.48(dd, 1H, J = 17.5, 2.1 Hz). 13C NMR (CD3OD, 75 MHz): d
176.5, 162.4, 76.4, 73.6, 73.5, 65.7, 50.5, 38.2. ESIMS m/z: 222 [M+Na]+, HRMS
(ESI) calcd for C8 H9 O5 N Na = 222.0372, found 222.0371.