Organic & Biomolecular Chemistry
Communication
Acknowledgements
We thank the SERB, New Delhi and WRCB, IIT Bombay for
financial support. We thank Mr Darshan Mhatre of the X-ray
facility of the Department of Chemistry, IIT Bombay for collect-
ing the crystallographic data and IRCC, IIT Bombay for
funding central facilities. We are grateful for the award of
research fellowships to S. K. N. and D. J. F. (CSIR, New Delhi).
Scheme 5 Diastereoselective synthesis of linearly-fused ladder-like
polyethers.
References
1 (a) T. J. Grinsteiner and Y. Kishi, Tetrahedron Lett., 1994, 35,
8333; (b) K. Audouze, E. Ø. Nielsen and D. Peters, J. Med.
Chem., 2004, 47, 3089; (c) R. Wijtmans, M. K. S. Vink,
H. E. Schoemaker, F. L. van Delft and R. H. Blaauw,
Synthesis, 2004, 641; (d) Z. Zhao, J. Ruan, J. Jin, J. Zou,
D. Zhou, W. Fang and F. Zeng, J. Nat. Prod., 2006, 69, 265;
(e) G. Sharma, J. Y. Park and M. S. Park, Bioorg. Med. Chem.
Lett., 2008, 18, 3188; (f) C. J. Gerry and S. L. Schreiber, Nat.
Rev. Drug Discovery, 2018, 17, 333; (g) H. Liu, H. Tan,
Y. Chen, X. Guo, W. Wang, H. Guo, Z. Liu and W. Zhang,
Org. Lett., 2019, 21, 1063.
2 (a) L. Yet, Chem. Rev., 2000, 100, 2963; (b) G. A. Molander,
Acc. Chem. Res., 1998, 31, 603; (c) T. Iwai, H. Okochi, H. Ito
and M. Sawamura, Angew. Chem., Int. Ed., 2013, 52, 4239;
(d) W. Zhao, Z. Li and J. A. Sun, J. Am. Chem. Soc., 2013,
135, 4680; (e) W. Zhao, Z. Wang and J. Sun, Angew. Chem.,
Int. Ed., 2012, 51, 6209; (f) M. H. Shaw, R. A. Croft,
W. G. Whittingham and J. F. Bower, Strategy, J. Am. Chem.
Soc., 2015, 137, 8054; (g) N. Wang, Q.-S. Gu, Z.-L. Li, Z. Li,
Y.-L. Guo, Z. Guo and X.-Y. Liu, Angew. Chem., Int. Ed.,
2018, 57, 14425.
3 For reviews on hydroalkoxylation: (a) H. Huang, Y. Zhou
and H. Liu, Beilstein J. Org. Chem., 2011, 7, 897; (b) X. Zeng,
Chem. Rev., 2013, 113, 6864; (c) R. Dorel and
A. M. Echavarren, Chem. Rev., 2015, 115, 9028.
4 (a) A. A. Peshkov, A. A. Nechaev, O. P. Pereshivko,
J. L. Goeman, J. Van der Eycken, V. A. Peshkov and
E. V. Van der Eycken, Eur. J. Org. Chem., 2015, 4190;
(b) S. S. Scully, S.-L. Zheng, B. K. Wagner and
S. L. Schreiber, Org. Lett., 2015, 17, 418; (c) A. Diéguez-
Vázquez, C. C. Tzschucke, W. Y. Lam and S. V. Ley, Angew.
Chem., Int. Ed., 2008, 47, 209; (d) I. J. Barve, T. U. Thikekar
and C.-M. Sun, Org. Lett., 2017, 19, 2370.
Scheme 6 Stereoselective synthesis of medium ring bridged tricyclic
ketals.
8-exo-dig hydroalkoxylation would be preferred leading to the
formation of Int D (path B). These intermediates Int-C and
Int-D then lead to the corresponding linearly-fused chromenes
9d–r and spiro-cyclic chromenes 12a–c, respectively.
Linearly-fused ladder-like polyethers are present in many
bioactive natural products.11 We envisioned that the developed
cascade process can be employed to gain rapid access to this
motif.
Thus, the D-glucal derived alkynol 6b upon reaction with
salicylaldehyde (8a) afforded ladder-like polycyclic ether-fused
chromene derivative 10c as the sole product with excellent
diastereoselectivity (Scheme 5).
Finally, we decided to functionalize the obtained products
to enhance the synthetic utility of the developed reaction
cascade. To this end, we envisioned that generation of a
bridged tricyclic ketal would be challenging. Thus, oxathiepino
chromene 11a was subjected to a reaction with diazo malonate
13 in the presence of Rh2(OAc)4 in benzene. Gratifyingly, the
bridged tricyclic ketal 14a was obtained with an excellent
yield and stereoselectivity (Scheme 6). To the best of our
knowledge, this is the first example of a tandem sulfonium
ylid formation-[2,3]-sigmatropic shift that leads to a bridged
bicyclic system.12
In conclusion, the Lewis acid promoted 8-exo and 8/9-endo-
mode of the hydroalkoxylation-formal-[4 + 2] cycloaddition
cascade was developed for the synthesis of medium ring het-
erocycle-fused chromenes in a highly stereoselective manner.
Linearly-fused ladder-like polyethers could be successfully syn-
thesized in a stereoselective manner using the developed
hydroalkoxylation cascade. Furthermore, the product obtained
was transformed into medium ring heterocycle-fused bridged
tricyclic ketals via a tandem sulfonium ylid generation-[2,3]-
sigmatropic shift.
5 For an example of 8-exo-dig hydroalkoxylation-[1,3]
rearrangement, see: B. Zhou, Y.-Q. Zhang, K. Zhang,
M.-Y. Yang, Y.-B. Chen, Y. Li, Q. Peng, S.-F. Zhu, Q.-L. Zhou
and L.-W. Ye, Nat. Commun., 2019, 10, 1.
6 (a) M. Costa, T. A. Dias, A. Brito and F. Proenca, Eur. J. Med.
Chem., 2016, 123, 487; (b) D. Harel, D. Schepmann,
H. Prinz, R. Brun, T. J. Schmidt and B. Wunsch, J. Med.
Chem., 2013, 56, 7442.
7 (a) S. J. Gharpure and J. V. K. Prasad, J. Org. Chem., 2011,
76, 10325; (b) S. J. Gharpure and J. V. K. Prasad, Eur. J. Org.
Chem., 2013, 2076; (c) S. J. Gharpure, A. Dandela,
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 8806–8810 | 8809