10.1002/chem.201702459
Chemistry - A European Journal
COMMUNICATION
O
OEt
N
O
OEt
N
O
OEt
References and Notes
HCOOH
°
25
C
H
H
§both authors contributed equally to this work.
H
20 min
Me
NBoc
Me
Me
+
92%
1. (a) C. L. Schardl, D. G. Panaccione, P. Tudzynski,. in The Alkaloids, Vol. 63
(Ed.: G. A. Cordell), Academic Press, San Diego, 2006, pp. 45–86. (b) M.
Somei, Y. Yokoyama, Y. Murakami, I. Ninomiya, T. Kiguchi, T. Naito, In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 2000; Vol. 54,
pp 191-257.
=
dr 2:1
23
24
TsN
(major)
(minor)
TsN
91%
TsN
6-endo
-trig
3
°
LiAlH4
0
C
,
chromatographic
separation
=
dr 2:1
30 min
THF,
HO
HO
HO
HO
2. (a) H. G. Floss, Tetrahedron 1976, 32, 873. (b) D. D. Schwarzer, P. J.
Gritsch, T. Gaich, Synlett 2013, 24, 1025. (c) C. Wallwey, S.-M. Li,. Nat. Prod.
Rep. 2011, 28, 496.
MeOH
Mg,
rt,
H
H
H
MeOH
30 min
H
Mg,
rt,
NMe
NMe
NMe
NMe
+
30
min
3. (a) E. C. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann, D. Morrison, R.
G. Jones, R. B. Woodward, J. Am. Chem. Soc. 1956, 78, 3087. (b) W,
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95%
93%
HN
+
HN
TsN
TsN
26
+
1b
)
25
1d
(
)-lysergol (
(
)-isolysergol (
)
Scheme 5. Total syntheses of lysergol (1b) and isolysergol (1d).
To our delight, upon treatment of 3 with HCOOH at rt, the
reaction followed an aza-Michael reaction to afford 23 and 24
bearing the requisite functionalities in 2:1 dr in favour of 23. 21
Thus, the final stage was set for the completion of the total
synthesis of lysergol (1b), and isolysergol (1d) (Scheme 5).
Towards this, LiAlH4-reduction of mixture of 23 and 24 gave
chromatographically separable diastereomers of 25 and 26,
respectively. Finally, deprotection of the p-Ts group of 25 and 26
using Mg/MeOH completed total syntheses of lysergol (1b) and
isolysergol (1d), respectively.
4. a) I.-K. Park, J. Park, C.-G. Cho, Angew. Chem. Int. Ed. 2012, 51, 2496. b)
D. Shan, Y. Gao, Y. Jia, Angew. Chem. Int. Ed. 2013, 52, 4902. c) S. P.
Breazzano, Y. B. Poudel, D. L. Boger, J. Am. Chem. Soc. 2013, 135, 1600. d)
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Miura, Y. Funakoshi, M. Murakami, J. Am. Chem. Soc. 2014, 136, 2272.
In conclusion, we developed a novel entry to direct construction
of an ergot alkaloid skeleton based on a 6-endo-trig cyclisation
of
a cross-conjugated α,β-unsaturated ester, which was
5. (a) For a racemic approach to ergot alkaloids via Micheal reaction of
nitronate, see; M. Somei, F. Yamada, H. Ohnishi, Y. Makita, M. Kuriki,
Heterocycles 1987, 26, 2823. (b) For an enantioselective approach using
chiral phosphoric acid, see; S. Romanini, E .Galletti, L. Caruana, A. Mazzanti,
F. Himo, S. Santoro, M. Fochi, L. Bernardi, Chem. -Eur. J. 2015, 21, 17578.
synthesized under catalytic enantioselective thio-urea-catalyzed
intramolecular Michael reaction of nitronate onto α,β-
unsaturated ester in 97% ee. Utilizing this methodology, we
have shown first total syntheses of ergot alkaloids, festuclavine
(1c), and pyroclavine (1e) as well as unified total syntheses of
other congeners, such as lysergol (1b), and isolysergol (1d).
Further application of intramolecular Michael reaction for total
synthesis of other complex alkaloids are under active
investigations.
6. (a) W. J. Nodes, D. R. Nutt, A. M. Chippindale, A. J. A. Cobb, J. Am.
Chem. Soc. 2009, 131, 16016. (b) Z.-X. Jia, Y.-C, Luo, X.-N. Cheng, P.-F.
Xu, Y.-C. Gu, J. Org. Chem. 2013, 78, 6488. (c) For an intermolecular version,
see; S. Rajkumar, K. Shankland, G. D. Brown, A. J. A. Cobb Chem. Sci.
2012, 3, 584.
7. P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K, 1992.
8. For selected reviews, see: (a) T. Ooi, K. Maruoka, Acc. Chem. Res. 2004,
37, 526. (b) W. Notz, F. Tanaka, C. F. Barbas III Acc. Chem. Res. 2004, 37,
580. (c) S. –K. Tian, Y. Chen, J. Hang, L. Tang, P. Mcdaid, L. Deng, Acc.
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Experimental Section
Electronic Supplementary Information (ESI) available: Experimental
procedures, additional reaction optimization, details of stoichiometric
reactions, spectroscopic data for all new compounds.
9. For selected examples: (a) Y. K. Chen, M. Yoshida, D. W. C. MacMillan, J.
Am. Chem. Soc. 2006, 128, 9328. (b) H.-H. Lu, X.-F. Wang, C.-J. Yao, J.-M.
Zhang, H. Wu, W.-J. Xiao, Chem. Commun. 2009, 4251. (c) C. Rabalakos, W.
D. Wulff, J. Am. Chem. Soc. 2008, 130, 13524.
Acknowledgements
10. Vinyl sulfones and phosphonates have recently emerged as Michael
acceptors in organocatalytic processes. S. Sulzer-Mossé, A. Alexakis, J.
Mareda, G. Bollot, G. Bernardinelli, Y. Filinchuk, Chem. -Eur. J. 2009, 15,
3204.
Financial supports from the DST [SR/S1/OC-54/2011] and CSIR
[02(0013)/11/EMR-II], Govt. of India are gratefully acknowledged.
S. B. and S.C. thank the CSIR and UGC for Senior Research
Fellowships, respectively. We sincerely thank the Department of
Chemistry and Central Instrumentation Facility (CIF), IISER
Bhopal for infrastructure. AB sincerely thank the Director, IISER
Bhopal for creating excellent research facilities.
11. For examples, see: (a) T. Marcelli, R. N. S. van der Haas van, J. H
Maarseveen, H. Hiemstra, Angew. Chem., Int. Ed. 2006, 45, 929. (b) T.
Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625.
For recent reviews of bifunctional organocatalysts, see: (c) S. J. Connon,
Chem. Commun. 2008, 2499; (d) M. S. Taylor, E. N. Jacobsen, Angew.
Chem., Int. Ed. 2006, 45, 1520.
Keywords: Michael reaction, thio-urea-catalyzed, 6-endo-trig
12. (a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672. (b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119. (c) S. H. McCooey, S. J. Connon,. Angew.
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cyclisation, total synthesis, ergot alkaloids
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