Organic Letters
Letter
(4) Jonathan, L. T.; Gbeassor, M.; Che, C.-T.; Fong, H. H. S.;
Farnsworth, N. R.; LeBreton, G. C.; Venton, D. L. J. Nat. Prod. 1990, 53,
1572.
(5) (a) Castellino, A. J.; Rapoport, H. J. Org. Chem. 1986, 51, 1006.
(b) Civitello, E. R.; Rapoport, H. J. Org. Chem. 1994, 59, 3775.
(c) Casillas, L. K.; Townsend, C. A. J. Org. Chem. 1999, 64, 4050.
(d) Graybill, T. L.; Casillas, E. G.; Pal, K.; Townsend, C. A. J. Am. Chem.
Soc. 1999, 121, 7729. (e) Eastham, S. A.; Ingham, S. P.; Hallett, M. R.;
Herbert, J.; Modi, A.; Morley, T.; Painter, J. E.; Patel, P.; Quayle, P.;
Ricketts, D. C.; Raftery, J. Tetrahedron 2008, 64, 936.
opposite supports their enantiomeric purity and relationship. On
the basis of these findings, it is possible that some of these
naturally occurring substances are not present inthe enantiomeri-
cally enriched compounds but rather as mixtures of the
enantiomers.22
In summary, we have developed an enantioselective synthesis
of the aflatoxin system via a sequence of asymmetric Michael−
acetalization−reduction−Nef reaction with high enantioselectiv-
ities (90−99% ee). The structures and absolute configurations of
the products ( )-6b, (+)-8, and dihydroaflatoxin D2, (−)-1, have
been unambiguously confirmed by single-crystal X-ray crystallo-
graphic analyses. The multiple-step reaction sequence can be
conducted with only a one-step purification, constituting a one-
pot synthesis strategy. The process provides an efficient and
expedited synthesis of dihydroaflatoxin D2 that constitutes a
formal total synthesis of aflatoxin B2. Our synthetic method
culminated in the first total synthesis of (+)- and (−)-micro-
minutinin and led to a revision of the absolute configuration of
naturally occurring microminutinin. The results not only provide
a seminal example of the total synthesis of these types of natural
products butalso permitassignment of the absolute configuration
of these naturally occurring compounds for which there had
previously been insufficient evidence to draw a conclusion; in
particular, the ambiguity of the absolute configuration of some
Tephrosia flavones existing in the literature has puzzled
investigators for decades. Given the prevalent occurrence of the
aflatoxins and their analogues in nature and their biological
significances, this efficient and asymmetric process could provide
an effective protocol for related natural product syntheses.
(7) Bando, T.; Shishido, K. Synlett 1997, 1997, 665.
(8) Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958.
(9) For other enantioselective total syntheses of other aflatoxins, see:
(a)Trost, B. M.;Toste, F. D. J. Am. Chem. Soc. 1999, 121,3543. (b)Trost,
B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.
(10) For other synthetic approaches to 2,3,3a,8a-tetrahydrofuro[2,3-b]
benzofuran, see: (a) Borrajo-Calleja, G. M.; Bizet, V.; Mazet, C. J. Am.
Chem. Soc. 2016, 138, 4014. (b) Roggenbuck, R.; Schmidt, A.; Eilbracht,
P. Org. Lett. 2002, 4, 289. (c) Marino, J. P.; Kieler, K. A.; Kim, M.-W.
Tetrahedron 2011, 67, 837.
(11) (a) Klier, L.; Tur, F.; Poulsen, P. H.; Jørgensen, K. A. Chem. Soc.
Rev. 2017, 46, 1080. (b) Pellissier, H. Tetrahedron 2012, 68, 2197.
(c) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703. (d) Hong, B.-C. In
Enantioselective Organocatalyzed Reactions II; Mahrwald, R., Ed.;
Springer: Dordrecht, 2011; Chapter 3, p 187.
(12) (a) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014,
114, 2390. (b) Hong, B.-C.; Dange, N. S. Cascade Reactionsin
Stereoselective Synthesis. In Stereoselective Synthesis of Drugs and Natural
Products;Andrushko, V., Andrushko, N., Eds.;Wiley, 2013;Chapter21, p
581.
(13) (a) Hayashi, Y. Chem. Sci. 2016, 7, 866. (b) Hong, B.-C.; Raja, A.;
Sheth, V. M. Synthesis 2015, 47, 3257. (c) Marson, C. M. Chem. Soc. Rev.
2012, 41, 7712.
(14) For a preceeding related study, see: Hong, B.-C.; Kotame, P.; Liao,
J.-H. Org. Biomol. Chem. 2011, 9, 382.
(15) For a related example, see: Ramachary, D. B.; Reddy, P. S.; Prasad,
M. S. Eur. J. Org. Chem. 2014, 2014, 3076.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
(16) For related examples of the Michael reactions of 3e to nitrostrene
(not hydroxynitrostyrene 2a, but the one without the ortho hydroxy
group): (a) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew.
Chem., Int. Ed. 2008, 47, 4722. (b) Qiao, Y.; He, J.; Ni, B.; Headley, A. D.
Adv. Synth. Catal. 2012, 354, 2849. (c) Alza, E.; Sayalero, S.; Kasaplar, P.;
Experimental procedures and characterization data (PDF)
X-ray crystallographic data for compound ( )-6b (CIF)
X-ray crystallographic data for compound (+)-8 (CIF)
X-ray crystallographic data for compound (−)-1 (CIF)
Almasi
̧
, D.; Pericas
̀
, M. A. Chem. - Eur. J. 2011, 17, 11585. (d) Enders, D.;
Krull, R.; Bettray, W. Synthesis 2010, 2010, 567.
̈
AUTHOR INFORMATION
■
(17) Prepared from the Michael-aldol reaction with pyrrolidine−
PhCO2H as a standard for HPLC enantiomeric excess analysis.
(18) (a) Kamperdick, C.; Phuong, N. M.; Sung, T. V.; Schmidt, J.;
Adam, G. Phytochemistry 1999, 52, 1671. (b) Rahmani, M.; Taufiq-Yap,
Y. H.; Ismail, H. B. M.; Sukari, A.; Waterman, P. G. Phytochemistry 1994,
37, 561. (c) Ito, C.; Otsuka, T.; Ruangrungsi, N.; Furukawa, H. Chem.
Pharm. Bull. 2000, 48, 334. (d) Lakornwong, W.; Kanokmedhakul, K.;
Kanokmedhakul, S. Nat. Prod. Res. 2014, 28, 1015.
(19) Structures of (−)-semiglabrin and (−)-pseudosemiglabrin have
been corrected as 7aR,10aS; see: (a) Pirrung, M. C.; Lee, Y. R. J. Am.
Chem. Soc. 1995,117, 4814. However, (−)-semiglabrinhasrecentlybeen
corrected as7aS,10aR;see: (b)Hassan, L. E. A.;Ahamed, M. B. K.;Majid,
A. S.A.;Iqbal, M. A.;AlSuede, F. S.R.;Haque, R.A.;Ismail, Z.;Ein, O. C.;
Malik, A.; Majid, S. A. PLoS One 2014, 9, e90806.
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We acknowledge financial support for this study from the
Ministry of Science and Technology (MOST, Taiwan) and thank
the instrument center of MOST for analyses of compounds. We
thank Mr. Yu-You Hsieh (NCCU) for his help.
(20) (a) Vleggaar, R.;Smalberger, T. M.;vanden Berg, A. J. Tetrahedron
1975, 31, 2571. (b) Gom
Rios, T. Phytochemistry 1992, 31, 2925.
́ ́
ez-Garibay, F.; Quijano, L.; Hernandez, C.;
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(21) (+)-22 was prepared from the reaction, catalyzed by (R)-I.
(22) Sporadically, both enantiomers occur in nature; for an excellent
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