Our synthesis of the lolines initiated from the protected
3-oxo-proline 7, which can be prepared in three steps from
glycine ethyl ester (in 25-48% overall yield10) or by a
competitive route that we developed starting from N-Boc-
2-azetidinone11 (5) (Scheme 1). In this newly developed
route, lithiation of ethyl diazoacetate in the presence of the
β-lactam 5 at -78 °C afforded the Claisen condensation
product 6 in 80% yield.12 Decomposition of the diazocar-
bonyl function with Rh2(OAc)4 and subsequent N-H
insertion cleanly delivered β-ketoester 7 (99% yield, cho-
matography not required).13
Scheme 1. Synthesis of Aminohydroxylation Precursor
We envisioned that two of the four contiguous stereo-
centers of loline could be selectively installed by whole-cell
bioreduction of β-ketoester 7 using Baker’s yeast under
nonfermenting conditions.14 On multigram-scale, we and
others found that efficient extraction of the product was
not possible and untenable yields of 40% or lower were
typically observed.14b In the interest of economy and
expedience, we decided to pursue the synthesis of loline
alkaloids with racemic cis-3-hydroxyproline, prepared by
reduction of 7 with NaBH4.15
Formation of 3-acetoxyproline 8 preceded kinetically
controlled enolization with LiHMDS. On warming to
-20 °C, Dieckmann condensation ensued delivering the
desired enol-lactone cyclization product 9 in respectable
yield (69%). The undesired elimination product10, a result
of deprotonation at the thermodynamically more favor-
able pyrrolidine ring R-proton and extrusion of acetate, is
formed in less than 10% yield and can be easily removed
during workup by extraction of 9 into aqueous base.
Enolization of 8 at temperatures above -78 °C or by
inverse addition of base to substrate produced a greater
amount of 10.
derived β-hydroxy lactone with a borane-tert-butyl amine
complex in methanol buffered with citric acid. Following
acylation of the resulting 5:1 mixture of hydroxyl diaste-
reomers, elimination was completed with DBU to give the
R,β-unsaturated lactone 11. This overall sequence required
two reaction vessels and cleanly provided 11 in 68% yield
without the need for purification of intermediates.
A reduction-elimination sequence emerged as a facile
operation to convert enol lactone 9 into the desired R,β-
unsaturated lactone 11. Enol lactone 9 was reduced to the
Hydrolysis of 11 to the derived carboxylate, followed by
esterification with methyl iodide, provided the intermedi-
ate Z-R,β-unsaturated ester. This material was moderately
slow to relactonize, permitting conversion of the hydroxyl
function to the primary carbamate 12 with trichloroacetyl
isocyanate (65% yield from 11). Analysis of carbamate 12
reveals the presence of an 1,3-allylic nonbonding interac-
tion enforced from the Z-R,β-unsaturated ester moiety (see
3-D illustration, Scheme 1).16 Minimizing for this interac-
tion, the carbamate in 12 is positioned on the re face of the
alkene. When we attempted to engage the carbamate in an
osmium-catalyzed tethered aminohydroxylation, the oxi-
dative transformation was not observed (Scheme 2).17,18
(6) Selected reviews of pyrrolizidine alkaloids: (a) Liddell, J. R. Nat.
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1989, 6, 577–589.
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(11) N-Boc-2-azetidinone is commercially available and easily pre-
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Tetrahedron 2009, 65, 2605–2609.
(12) Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1987, 28, 5351–
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(16) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
(17) For a recent review of aminohydroxylation, see: (a) Donohoe,
T. J.; Callens, C. K. A.; Flores, A.; Lacy, A. R.; Rathi, A. H. Chem.;
Eur. J. 2011, 17, 58–76. (b) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.;
Keenan, M. Chem. Commun. 2001, 2078–2079. (c) Donohoe, T. J.;
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12934–12935. (d) Donohoe, T. J.; Johnson, P. D.; Pye, R. J. Org. Biomol.
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(18) Leading references regarding TA: (a) Donohoe, T. J.; Johnson,
P. D.; Helliwell, M.; Keenan, M. Chem. Commun. 2001, 2078–2079. (b)
Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem.
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