10094
The requisite nitrogen functionality was installed via the brosylate to give azido lactone 18.
Aminolysis with the 3-amino-2,2-dimethylpropionamide moiety3 led to formation of the open
chain azido alcohol 19 in good yield. The synthesis was completed by azide hydrogenolysis and
formation of the hemifumarate salt, crystallisation of which removed the residual minor
(R)-epimer carried through from the Grignard addition step.
An alternative method for stereoselective incorporation of nitrogen utilising nucleophilic
attack on an imine prepared from 16 was also investigated. Although a variety of such
derivatives was readily obtained, they proved uniformly unreactive towards organometallics
prepared from 9.
In conclusion, we have described an approach to the novel renin inhibitor CGP60536B,
featuring pseudoephedrine amide alkylation to incorporate two of the chiral centres in >95% ee.
The formation of amide spiroacetal 12 has been exploited as a novel lactone protecting group,
allowing a stereoselective Grignard addition reaction, which is the linchpin of this convergent
synthesis. Moreover, the chemistry described herein is amenable to large-scale operation,
underscoring the utility of pseudoephedrine as an inexpensive and versatile chiral auxiliary.
Acknowledgements
We are grateful to Drs. Ju¨rgen Maibaum and Dirk Sartor for the supply of precursors and
reference compounds; to Dr. Brian Everatt for the NOE experiments and to Mr. Steven Collis,
Ms. Lindsay Hamilton, Mr. Steven McKown and Mr. Friedrich Schu¨rch for their invaluable
technical assistance.
References
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Symposium on Medicinal Chemistry, Edinburgh, UK; Abstract book, p. 230.
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9. Selected data for 12: lH (400 MHz, CDCl3) 0.85 (d, J 6.5, 3H), 0.97 (d, J 6.4, 3H), 1.03 (d, J 6.0, 3H), 1.70–2.0
(m, 4H), 2.27 (s, 3H), 2.81 (dq, J 6.9, 8.9, 1H), 3.34 (dd, J 6.6, 10.1, 1H), 3.39 (dd, J 4.2, 10.1, 1H), 4.25–4.30
(m, 1H), 4.38 (d, J 8.9, 1H), 7.20–7.35 (m, 5H); lC (100 MHz) 15.49, 21.34, 22.23, 28.64, 31.14, 32.77, 36.74,
45.33, 65.42, 72.45, 86.33, 122.25, 127.06, 127.39, 128.26, 140.39; wmax 2960, 1460 cm−1; mp 72–74°C (hexanes);
C18H26BrNO2 requires C, 58.70; H, 7.12; N, 3.80%, found C, 58.83; H, 7.23; N, 3.67%.
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