A convergent stereoselective synthesis of quinolizidines and indolizidines: Chemoselective coupling of 2-hydroxymethyl-substituted allylic silanes with imines

Article abstract of DOI:10.1021/ja908504z

(Chemical Equation Presented) A convergent synthesis of stereodefined indolizidines and quinolizidines through chemoselective allyl transfer between 2-hydroxymethyl-substituted allylic silanes and imines is described. Overall, highly substituted heterocyc

Full text of DOI:10.1021/ja908504z

Published on Web 11/12/2009
A Convergent Stereoselective Synthesis of Quinolizidines and Indolizidines:
Chemoselective Coupling of 2-Hydroxymethyl-Substituted Allylic Silanes with
Imines
Dexi Yang and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458
Received October 6, 2009; E-mail: micalizio@scripps.edu
Substituted indolizidines and quinolizidines are heterocyclic motifs
encountered in a range of bioactive natural products (Figure 1).1 As
such, these heterocycles have been the topic of considerable interest
in organic and medicinal chemistry. Successful strategies for the
assembly of substituted indolizidines and quinolizidines embrace a large
swath of chemical reactivity spanning simple nucleophilic addition to
cycloaddition, sigmatropic rearrangement, radical cyclization, C-H
activation, iminium ion-based cyclization, and intramolecular reductive
coupling.2 The great wealth of strategies reported for accessing these
bicyclic heterocycles reflects the level of interest from the chemical
community and the challenges associated with the synthesis of these
often highly substituted and stereodefined systems. Here we report a
convergent stereoselective synthesis of substituted indolizidines and
quinolizidines (1) through chemoselective coupling of functionalized
allylsilanes with imines (2 + 3; Figure 2). This fragment union reaction,
envisioned to proceed by chemoselective allyl transfer, was sought as
a mechanism for delivering highly substituted and stereodefined
allylsilanes (4).3 Subsequent acid-promoted cationic annulation4 was
then anticipated to furnish substituted indolizidines and quinolizidines
(1) in a stereoselective manner.5,2i
substituted allylsilanes 2 and imines 3 would have the potential to
furnish homoallylic amines having the general structure 4. Here
allylation would proceed by a mechanism that engages the unique
reactivity of allylic alchohols8 in preference to the well-established
allyl transfer chemistry associated with allylic silanes.3 Overall, the
desired chemoselective coupling would deliver a product in which the
allylsilane moiety remains intact for subsequent heterocycle synthesis
(4 f 1).
Our initial exploration of the required chemoselective coupling
reaction is illustrated in Table 1. Overall, preformation of a Ti-imine
complex (5, Ti(Oi-Pr)4, c-C5H9MgCl, Et2O, -78 to rt)9 followed by
addition of a preformed lithium alkoxide of the allylic alcohol leads
to successful C-C bond formation. Interestingly, substitution at the
allylic position plays an important role in regioselection. Coupling of
the simple allylic silane 6 with aromatic imine 5 provides a 1,3-amino
alcohol as the major product. Here, C-C bond formation occurs at
C2 of the allylic alcohol and delivers product 7 containing a quaternary
center. With the secondary allyic alcohol 8, very high levels of chemo-
and stereoselectivity were observed in reductive cross-coupling with
imine 5. Here, allylsilane 9 is produced as a single isomer in 70%
yield. As depicted in entry 3, this chemoselective coupling reaction is
suitable for formation of allylsilanes 11 bearing tetrasubstituted alkenes.
Finally, use of an allylic alcohol that contains a trisubstituted alkene
Table 1. Initial Exploration of the Chemoselective Coupling Reaction
Figure 1. Introduction to indolizidines and quinolizidines.
While allylic silanes having the general structure 2 are useful for
the synthesis of pyrans (via oxocarbenium ion chemistry6) and
substituted five-membered rings (via metal-catalyzed TMM chemis-
try7), these substrates have not been described as allyl transfer reagents
of the type required here (2 + 3 f 4). Nevertheless, we speculated
that Ti-mediated chemoselective allyl transfer between hydroxymethyl-
a Reaction conditions: 5 (1 equiv), Ti(Oi-Pr)4 (1.5 equiv), c-C5H9MgCl
(3.0 equiv), allylic alkoxide (1.5 equiv), Et2O, -78 °C to rt. b The desired
homomoallylic amine product was isolated in 18% yield. c The relative
stereochemistry of 13 was assigned by analogy to previous examples.8
Figure 2. Indolizidine and quinolizidine synthesis via (top) chemoselective
allyl transfer followed by (bottom) cationic annulation.
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17548 J. AM. CHEM. SOC. 2009, 131, 17548–17549
10.1021/ja908504z  2009 American Chemical Society

C O M M U N I C A T I O N S
all-alkyl substitution (eq 3 in Figure 3). Again, indolizidine formation
occurs in high yield (95%) with superb stereoselection (dr g20:1) and
furnishes 7-exomethylene indolizidine 223D (22).11
Delighted that this synthetic strategy proved successful for the synthesis
of simple indolizidine and quinolizidine architectures (16, 19, and 22),
we questioned whether this process would be useful for the synthesis of
more complex polycyclic systems. As depicted in eqs 4-6 in Figure 3,
use of substrates containing additional functionality between the imine
and acetal leads to the formation of complex stereodefined polycyclic
heterocycles in a concise and stereoselective fashion.
In conclusion, we have defined a new convergent bond construction
that serves as a powerful foundation for heterocycle synthesis. A unique
chemoselective functionalization of hydroxymethyl-substituted allylic
silanes provides a facile and stereoselective entry to the indolizidine
and quinolizidine cores. In addition to highlighting the utility of this
heterocycle preparation in the synthesis of 7-exomethylene indolizidine
223D, we have demonstrated the basic coupling process for the
assembly of complex polycyclic heterocycles containing furans,
thiophenes, and indoles. While the control of absolute stereochemistry
in this annulation remains a challenge, the present contribution defines
a reaction sequence of broad utility for heterocycle synthesis. Because
of (1) the ubiquitous nature of indolizidines and quinolizidines in
natural products and small molecules of biomedical relevance, (2) the
ready availability of the coupling partners, (3) the functional-group
compatibility of the chemoselective allyl transfer reaction, (4) the
stereoselectivity of the cationic annulation, and (5) the inexpensive
nature of the reductive cross-coupling process, we look forward to
future developments that emerge from these initial findings.
Acknowledgment. We gratefully acknowledge financial support
of this work by the National Institutes of Health, NIGMS (GM80266
and GM80266-04S1).
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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