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Angewandte
Communications
Scheme 6. Axial-to-central chirality transfer.
ensure that this same transfer of axial chirality was operative
in the synthesis of these heterocycles, the synthesis of the
enantioenriched TBS-azetidinone (Scheme 6) was accom-
plished starting from (R)-(+)-3-butyn-2-ol, employing the
same methodology used to synthesize racemic analogues. The
enantioenriched azetidinone was derivatized by opening of
the sulfamate ring with thiophenol to provide a chromophore
for chiral HPLC analysis. The product 42 was isolated with
96% ee. The low yield was due to a side reaction initiated by
deprotonation of 41, followed by electrocyclic ring-opening
and hydrolysis to 43 (see SI for details). Nonetheless, this
experiment clearly showed effective transfer of the axial
chirality of the allene to the azetidin-3-one.
In conclusion, we have described a facile synthesis of
azetidin-3-ones and azetidines that proceeds through a highly
regioselective aziridination of the distal bond of homoallenic
sulfamates. One key feature of our new methodology is the
highly diastereocontrolled epoxidation of an endocyclic
bicyclic methyleneaziridine to yield reactive oxazaspiropen-
tanes that rapidly rearrange to the title azetidin-3-ones in
excellent d.r. Another key feature of this chemistry is the
flexibility of subsequent transformations that yield densely
functionalized azetidines with potentially useful biological
activity. Future studies are directed toward increasing the
reaction scope, exploring other electrophilic reagents that
react with the endocyclic methyleneaziridines and expanding
the chemical space that can be accessed through flexible
manipulations of various azetidin-3-ones.
Scheme 5. Transformations of H-substituted azetidin-3-one 10.
hydride nucleophiles were able to react, as treatment of 6 with
excess NaBH in EtOH gave a 49% yield of 32 resulting from
4
reduction and presumed 1,2-Brook rearrangement; the
remainder of the mass balance consisted of unreacted starting
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material. However, the TBS group was immune to removal
by standard desilylation protocols, including tetra-n-butyl-
ammoniumfluoride (TBAF), HF-pyridine, and tris(dimethyl-
amino)sulfonium difluorotrimethylsilicate (TASF). We were
pleased to find that this unexpected stability enabled strong,
bulky reducing agents, including L-selectride, to chemoselec-
tivily open the sulfamate group in lieu of carbonyl reduction,
providing products such as 33 in good yield with no erosion of
the diastereoselectivity. In a similar vein, hydrolysis of the
sulfamate protecting group gave the 1,3-aminoalcohol 34 in
excellent yield. Finally, treatment of 6 with concentrated HCl
in THF gave an excellent yield of the ring-opened product 35,
containing a useful leaving group positioned for further
reaction.
In contrast to the TBS-substituted azetidin-3-ones, utiliz-
ing the less bulky TMS group in the reaction sequence
permitted orthogonal reactivity of the resulting heterocycle
(
Scheme 5). This ability to remove the TMS group unlocks
the reactivity at the carbonyl group of the azetidin-3-one
scaffold. For example, subsequent treatment of 10 with L-
selectride enables a highly diastereoselective reduction to
yield the secondary alcohol 36 in excellent d.r. The relative
stereochemistry amongst the three stereogenic carbons of the Acknowledgements
azetidine was established as all syn through definitive nOe
studies (Scheme 5, see the Supporting Information (SI) for
additional details). Another advantageous feature of 10 is that
Grignard reagents, as illustrated by vinyl MgBr in Scheme 4,
react with the carbonyl in a highly diastereoselective manner
to yield a tertiary alcohol 37 in a d.r. > 19:1. Aryl groups could
be readily introduced into the azetidine products, as illus-
trated by the conversion of 10 to 39 in good yield and
excellent d.r. Finally, treatment of 10 with a stabilized
phosphonium ylide gave 38 in > 9:1 E/Z. Further diastereo-
selective transformations of the products illustrated in
Schemes 4 and 5 can be readily envisaged to provide
remarkable flexibility in using azetidin-3-one scaffolds for
the rapid extension of chemical space.
We thank Dr. Charles Fry and Nicholas Dolan for assistance
with NMR studies. Nels Gerstner is thanked for his efforts on
aryl-substituted allene substrates. J.M.S. thanks the NSF-
CAREER Award 1254397 and the NIH 1R01GM111412-01
for funding of this research. J.M.S. is an Alfred P. Sloan fellow.
The NMR facilities at UW-Madison are funded by the NSF
(CHE-9208463, CHE-9629688) and NIH (RR08389-01). The
National Magnetic Resonance Facility at Madison is sup-
ported by the NIH (P41GM103399, S10RR08438,
S10RR029220) and the NSF (BIR-0214394).
Keywords: allenes · azetidin-3-ones · aziridination ·
heterocycles · rearrangements
In our previous studies involving Rh-catalyzed aziridina-
tion of the proximal double bond of homoallenic sulfamates,
the transfer of axial to central chirality occurred with
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12097–12101
Angew. Chem. 2015, 127, 12265–12269
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excellent fidelity to give enantioenriched amines.
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Angew. Chem. Int. Ed. 2015, 54, 12097 –12101