diastereoselective reduction of enantiopure substrate is the
most commonly used for chiral 1,3-aminoalcohols and
chiral amines.9 More recently, an organocatalytic iterative
approach has been reported for the enantiopure synthesis
of syn/anti-1,3-aminoalcohols.9h Another interesting strat-
egy for the construction of 1,3-aminoalcohols involves the
ring opening of substituted chiral piperidines.10 However,
many of these procedures involve the use of costly reagents
or precursors and toxic heavy metal catalysts such as Sm,
Ti, Pd, Rh, etc. Inspired by their unique biological proper-
ties and natural prevalence, we were interested to develop a
new protocol for the synthesis of anti-1,3-aminoalcohols.
Recently, the Prins cyclization has emerged as a power-
ful synthetic tool for the construction of tetrahydropyran
scaffolds.11 In our earlier reports, we have successfully
demonstrated the scope of Prins cyclization in the total
synthesis of polyketide natural products containing anti-
1,3-diol units through the reductive ring opening of
iodomethyltetrahydropyrans.12
Prins cyclization and its subsequent application to the
synthesis of bioactive natural products,15 we herein report
a novel method for the synthesis of anti-1,3-aminoalcohols
through a sequential PrinsꢀRitter reaction followed by
reductive opening of the resulting iodomethyl-4-amidote-
trahydropyran ring (Scheme 1).
Scheme 1. General Strategy for the Synthesis of anti-1,3-Ami-
noalcohols
Recently, we needed to generate 1,3-aminoalcohol li-
braries for our ongoing project on drug discovery. As a
consequence, we found an elegant process to produce anti-
1,3-aminoalcohols by reductive opening of iodomethyl-4-
amidotetrahydropyrans which are prepared easily by
Prins/Ritter amidation.13,14 Following our interest on
(9) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
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Zhang, X. Angew. Chem., Int. Ed. 2009, 48, 6052. (h) Jha, V.; Kondekar,
N. B.; Kumar, P. Org. Lett. 2010, 12, 2762 and references cited therein.
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The starting chiral homoallylic alcohols were synthe-
sized from the corresponding epoxides by Jacobsen’s
hydrolytic kinetic resolution (HKR).12,16 Chemoselective
protection of homoallylic diol 2 with TsCl in the presence
of dibutyltin oxide and triethyl amine gave the desired
homoallylic alcohol (3).17 Three-component coupling of
homoallylic alcohol 3, aldehyde 4, and nitrile 5 in the
presence of 20 mol % BF3 OEt2 afforded the substituted
3
4-amidotetrahydropyran 6 in good yields with high dia-
stereoselectivity (Table 1). The reaction proceeds through
a cascade of the Prins/Ritter reaction affording the cis-
diastereomer predominantly which is consistent with ear-
lier reports.14 The structure and stereochemistry were
established by NOE experiments in which all substituents
exist in equatorial positions. Substituents introduced
into a cyclic building block with stereocontrol translate
their stereochemistry when the tetrahydropyran ring is
opened.10,12 After establishing the 4-amidotetrahydropyr-
an structure, the tosylate 6 was converted into the corre-
sponding iodide 7 using NaI in acetone under reflux
conditions. Reductive ring opening of iodide 7 using Zn
dust in refluxing ethanol gave the corresponding anti-1,3-
aminoalcohol 8 in good yield (Table 1).
(13) (a) For a recent review on Ritter reactions, see: Guerinot, A.;
Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2012, 19.
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Bhikshapathi, M.; Nayak, S.; Yadav, J. S.; Ravi, R.; Kunwar, A. C.
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Next we examined the scope of this methodology using
various aldehydes and homoallyl alcohols in the presence
of different nitriles. The reaction shows a wide substrate
(16) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem.
1998, 68, 6776.
(17) (a) Shanzer, A. Tetrahedron Lett. 1980, 21, 221. (b) Martinelli,
M. J.; Nayyar, N, K.; Moher, E, D.; Dhokte, U. P.; Pawlak, J. M.;
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