10.1002/adsc.201800987
Advanced Synthesis & Catalysis
380.1492; found 380.1494. Enantiomeric excess of 8a was
determined by chiral stationary phase HPLC analysis using
a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0
mL/min, λ = 254 nm), major enantiomer: tR = 35.5 min,
minor enantiomer: tR = 57.3 min.
which then hemiacetalizes to give 7a. While the
possibility of pathway b cannot be ruled out, we favor
pathway a. As mentioned above, diastereodivergence
was not observed in this reaction when pseudo-
diastereomeric MDOs were used (Table 1, entry 1 vs.
entry 8; entry 5 vs. entry 10). If pathway b is indeed
involved, these results suggest a complete substrate
control during the formation of the intermediate 14.
However, our previous study has demonstrated that
formation of compounds similar to the intermediate 14
via the carba-Michael reaction is subject to strong
catalyst control and diastereodivergence can be easily
achieved.[5a] thus, we believe the lacking of
diastereodivergence in the current reaction indicates
that product 7a is formed through pathway a via a
domino Michael-hemiacetalization-Michael reaction
and the stereochemistry during the formation of 7a
from 12 is totally substrate-controlled.
Acknowledgements
We gratefully acknowledge the generous financial support of this
research by the Welch Foundation (Grant No. AX-1593) and the
National Science Foundation (Grant No. CHE 1664278). Some of
the NMR data reported in this paper were collected on an NMR
spectrometer acquired with the funding from the NSF (Grant No.
CHE-1625963). The HRMS used in this research was supported
by a grant from the National Institute on Minority Health and
Health Disparities (G12MD007591) from the National Institutes
of Health. The authors also thank Dr. Wendell P. Griffith for help
with the HRMS analysis of the samples.
In summary, we have developed a highly
stereoselective synthesis of 3-oxabicyclo[3.3.1]nonan-
2-one derivatives with four contiguous stereogenic
centers, including one tetrasubstituted stereogenic
center, using a domino Michael-hemiacetalization-
Michael reaction (E)-3-aryl-2-nitroprop-2-enols and
(E)-7-aryl-7-oxo-hept-5-enals uniquely catalyzed by
the MDOs followed by oxidation with PCC. Although
this reaction looks like other similar reactions
involving nitroalkenes and aldehydes, it is different:
The reaction is not catalyzed by the Hayashi-Jørgensen
catalyst and is not subject to the MDO-controlled
diastereodivergent catalysis.
References
[1] For reviews, see: a) L. F. Tietze, Chem. Rev. 1996, 96,
115–136; b) L. F. Tietze, G. Brasche, K. M. Gericke, in:
Domino Reactions in Organic Synthesis, Wiley-VCH,
Weinheim, 2006; c) H. Pellissier, in: Asymmetric
Domino Reactions, The Royal Society of Chemistry,
Cambridge, 2013; d) Domino Reactions: Concepts for
Efficient Organic Synthesis, L. F. Tietze Ed. Wiley-
VCH, Weinheim, 2014.
[2] For reviews, see: a) Recent Developments in Asymmetric
Organocatalysis H. Pellissier Ed., The Royal Society of
Chemistry, Cambridge, 2010; b) M. Waser, in:
Asymmetric Organocatalysis in Natural Product
Syntheses, Springer, Berlin, 2012; c) Comprehensive
Enantioselective Organocatalysis: Catalysts, Reactions
and Applications, P. I. Dalko Ed., Wiley-VCH,
Weinheim, 2013.
Experimental Section
General experimental procedure for synthesis of 3-
oxabicyclo[3.3.1]nonan-2-ones via the domino Michael-
hemiacetalization-Michael reaction followed by an
oxidation reaction: To a vial were added sequentially the
precatalyst modules 9b (6.3 mg, 0.010 mmol, 10.0 mol %)
and 10e (1.69 mg, 0.010 mmol, 10.0 mol %) and dry toluene
(1.0 mL). The resulting mixture was stirred at room
temperature for 15 min. Compound 1a (20.2 mg, 0.10
mmol) was then added and the mixture was further stirred
for 5 min. before the addition of compound 5a (21.4 mg,
0.12 mmol, 1.2 equiv.). The resulting solution was stirred at
room temperature for 15 h until the reaction was complete
(monitored by TLC). Then the reaction mixture was
concentrated in vacuum and the residue was purified by
flash column chromatography to give the hemiacetal 7a as
a colorless solid (32.0 mg). A solution of the hemiacetal 7a
(32.0 mg, 0.084 mmol) in CH2Cl2 (3.0 mL) and PCC (54.1
mg, 0.252 mmol, 3.0 equiv.) was stirred at room
temperature for 24 h until the completion of reaction
(monitored by TLC). The suspension was filtered through
a short pad of silica gel and washed with ethyl acetate.
Removing the solvents under vacuum afforded the crude
product 8a, which was then purified by flash
chromatography with 30:70 EtOAc/hexane to afford
product 8a. (27.3 mg, 72%) as a white solid. m.p. 220-
222 °C. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz,
2H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.38
(dd, J = 5.1, 2.0 Hz, 3H), 7.18 (dd, J = 6.7, 2.7 Hz, 2H), 4.93
(dd, J = 12.8, 1.9 Hz, 1H), 4.72 (dd, J = 12.7, 1.9 Hz, 1H),
3.81 (s, 1H), 3.55 – 3.50 (m, 1H), 3.26 (q, J = 2.9 Hz, 1H),
3.15 (dd, J = 16.8, 10.4 Hz, 1H), 2.82 (dd, J = 16.9, 2.0 Hz,
1H), 2.33 – 2.17 (m, 3H), 1.66-1.57 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 195.8, 170.0, 136.3, 135.2, 133.8, 129.4,
128.9, 128.8, 128.1, 87.8, 65.2, 51.3, 43.4, 42.3, 39.0, 30.7,
26.6. νmax ( neat, cm-1): 1747, 1679, 1538, 1464, 1336, 1179,
1080. HRMS (ESI): m/z calcd for C22H22NO5+ ([M + H]+):
[3] For reviews, see: a) H. Pellissier, Adv. Synth. Catal.
2012, 354, 237-294; b) P. Chauhan, S. Mahajan, U. Kaya,
D. Hack, D. Enders, Adv. Synth. Catal. 2015, 357, 253-
281; c) R. Ardkhean, D. F. J. Caputo, S. M. Morrow, H.
Shi, Y. Xiong, E. A. Anderson, Chem. Soc. Rev. 2016,
45, 1557-1569; d) P. Chauhan, S. Mahajan, D. Enders,
Acc. Chem. Res. 2017, 50, 2809-2821; e) T. Chanda, J.
C.-G. Zhao, Adv. Synth. Catal. 2018, 360, 2-79.
[4] a) S. Chandrasekhar, K. Mallikarjun, G.
Pavankumarreddy, K. V. Rao, B. Jagadeesh, Chem.
Commun. 2009, 4985-4987; b) C.-L. Cao, Y.-Y. Zhou,
J. Zhou, X.-L. Sun, Y. Tang, Y.-X. Li, G.-Y. Li, J. Sun,
Chem. Eur. J. 2009, 15, 11384-11389; c) Y. Wang, S.
Zhu, D. Ma, Org. Lett. 2011, 13, 1602-1605; d) j) G.
Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew.
Chem. 2012, 124, 4180-4183; Angew. Chem. Int. Ed.
2012, 51, 4104-4107; e) Z.-W. Guo, J.-W. Xie, C. Chen,
W.-D. Zhu, Org. Biomol. Chem. 2012, 10, 8471-8477; f)
B.-C. Hong, D.-J. Lan, N. S. Dange, G.-H. Lee, J.-H.
Liao, Eur. J. Org. Chem. 2013, 2472-2478; g) C. D. Cruz,
R. Mose, G. C. Villegas, S. V. Torbensen, M. S. Larsen,
5
This article is protected by copyright. All rights reserved.