Stereocontrol in a combined allylic azide rearrangement and intramolecular schmidt reaction

Article abstract of DOI:10.1021/ja300369c

Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The syn

Full text of DOI:10.1021/ja300369c

Communication
pubs.acs.org/JACS
Stereocontrol in a Combined Allylic Azide Rearrangement and
Intramolecular Schmidt Reaction
Ruzhang Liu,† Osvaldo Gutierrez,‡ Dean J. Tantillo,‡ and Jeffrey Aube*,†
́
†Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive,
Lawrence, Kansas 66045, United States
‡Department of Chemistry, University of California, Davis, California 95616, United States
S
* Supporting Information
bond can take part in a downstream intramolecular reaction.4g
ABSTRACT: Pre-equilibration of an interconverting set
of isomeric allylic azides is coupled with an intramolecular
Schmidt reaction to afford substituted lactams stereo-
selectively. The effect of substitution and a preliminary
mechanistic study are reported. The synthetic potential of
this method is demonstrated in the context of an
enantioselective synthesis of an advanced intermediate
leading toward pinnaic acid.
Recently, Craig and co-workers reported the dependence of the
product stereochemistry on the relative and interconverting
configurations of a bystander azide adjacent to a reactive olefin
participating in a Claisen rearrangement.5 However, we are
unaware of other examples where the Winstein rearrangement
is used to control the stereochemistry of an emerging C−N
bond.
It occurred to us that it might be possible to engage a mixture
of allylic azides 1a−d in an intramolecular Schmidt reaction to
form 2a selectively (Scheme 1). Our proposal was based on the
he intramolecular Schmidt reaction of alkyl azides, as exem-
plified in eq 1, is a useful means of converting 3-azidopropyl
T
Scheme 1
ketones into fused lactams.1 Although most applications of this
reaction in total synthesis have R = H as defined in eq 1, the
general issue of how to establish the relative stereochemistry
between an azide-bearing stereocenter and the rest of the
molecule arises more frequently in complex synthetic projects.2
One approach is to establish fully the relevant stereochemistry
of the ketone reactant, since the ring-expansion step occurs
with retention of configuration.1b However, this is often
impractical or awkward, and we have sought alternative ways
to couple the stereochemistry of the α-azido stereocenter with
that adjacent to the ketone. In this paper, we present a strategy
for accomplishing this goal using the kinetically controlled
reaction of a rapidly equilibrating mixture of allylic azides and
describe an application of this approach in alkaloid synthesis. In
addition, through a combination of experiments and density
functional theory (DFT) calculations, we have uncovered
previously unknown details about the stereochemical course of
the intramolecular Schmidt reaction of cyclohexanone-contain-
ing substrates.
The rearrangement of allylic azides, which is facile at room
temperature, was first discovered by Winstein and co-workers
in 19603 and has since become well-known.4 Previous researchers
have sought to carry out selective reactions from one allylic azide
of a rapidly equilibrating pair by freezing out the rearrangement at
low temperature,4a by taking advantage of significant stereo-
chemical differences between potential substrates,4d,e or by rigg-
ing the substrates so that only one isomeric azide or double
following reasoning: (1) 1a−d would equilibrate faster than the
Schmidt reaction would occur; (2) formation of lactams would
be kinetically controlled via the preferential formation of the
intermediates Aeq and Aax (both arising from equatorial attack
of the azide onto the ketone6); (3) trans alkene 1a would be
Received: January 12, 2012
Published: April 10, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
unreactive, and the cis isomer 1b would be nearly so;7 and (4)
the stereochemical outcome of the reaction would reflect the
relative stabilities of Aeq and Aax, favoring compound 2a by a
ratio that would roughly reflect the A value of a vinyl group
(1.49−1.68 kcal/mol8), or ca. 93:7 dr. The practical value
of this procedure would lie in the ability to introduce the azide
by displacement of a terminal leaving group prior to the ring-
expansion reaction without having to preset the ultimately
reacting secondary center.
a
Table 1. Intramolecular Schmidt Reactions of Allylic Azides
When compound 3 was subjected to Lewis acid (LA)
treatment, an 83% yield of 4 was obtained, verifying that an
allylic azide can be a suitable partner for the intramolecular
Schmidt reaction (Table 1, entry 1). In this case, allylic re-
arrangement is redundant, and only a single racemic product is
possible. Azide 5 (prepared from 2,2-dimethyl-1-phenylhex-5-
en-1-one via cross-metathesis with allyl bromide and subse-
quent azide displacement9) rapidly reached a steady-state equi-
librium of azides once formed, favoring the trans alkene 5a but
containing a significant amount of rearranged isomer c bearing
a secondary azide (see Scheme 1 for the structures of isomer
types a−d). Subjecting this mixture to the established condi-
tions for the azido-Schmidt reaction led to lactam 6, which re-
sulted from selective reaction of the internal azide. In this case,
the overall yield of lactam exceeded the percentage of 5c in the
starting azide, indicating that 1,3-allylic transposition effectively
competed with the Schmidt step. Having established this, we
similarly prepared a mixture of azides 1a−d and subjected it to
the azido-Schmidt conditions. Although the reaction proceeded
well, a nearly equimolar mixture of stereoisomeric lactams was
obtained (entry 3), suggesting that the stereochemical hypo-
thesis presented in Scheme 1 is, minimally, incomplete.
Some insight into this process was obtained by making and
reacting conformationally biased azide sets 7a and 9a (Table 1,
entries 4 and 5). The former afforded product in a slightly
higher ratio than did 1a, but the reaction of axial-side-chain-
containing 9a led to a much higher ratio of products in favor of
compound 10a. The most significant difference in this case is
that the azide in the latter is obligated to react from only a
single face, rendering the ratio dependent on a competition
between transition structures containing equatorial versus axial
vinyl substituents as originally proposed (Figure 1). As depicted
for the reactive isomers of compounds 1, each isomeric allylic
azide can react in principle by equatorial or axial attack.
Equatorial attack is favored for the intramolecular additions of
azides attached to the ketone substrate via oxonium ions (forming
a spirocyclic intermediate6), which is why we initially proposed an
equatorial trajectory for the addition of azide to ketone here.
However, the low to modest stereoselectivities observed for 1, 7,
and 15 suggest that an axial approach that also displays the vinyl
group in an equatorial orientation (i.e., D in Figure 1a) might be
competitive. On the other hand, constraining the azide-bearing
side chain into a pseudoaxial orientation (as in compounds 9)
limits the molecule to a single mode of axial azide attack onto the
carbonyl. In this instance, the selectivity should be solely
controlled by the expected preference for an equatorial vinyl
group adjacent to the lactam nitrogen atom (Figure 1b). DFT
calculations carried out on transition states emanating from
intermediates A−D (Figure 1a) support this view, suggesting
that 2a and 2b primarily arise from intermediates A and D,
respectively.11 These experiments provide the first evidence
that intramolecular Schmidt reactions of cyclohexanone-
containing substrates can occur via competitive equatorial or
axial azide addition.
a
b
Conditions: 1.5 equiv of SnCl4, CH2Cl2, reflux. Ratio determined
by NMR analysis of the purified allylic azides and crude reaction
c
mixtures of lactams; see Scheme 1 for structures a−d. In this case, the
secondary azides are enantiomers and lead to a single racemic product.
d
A ca. 2% yield of a third lactam, assigned as a bridged isomer,10 was
e
also observed. Conditions: 1.5 equiv of SnCl4, ClCH2CH2Cl, reflux.
f
g
Conditions: 1.5 equiv of TiCl4, ClCH2CH2Cl, reflux. A ca. 3% yield
of a third lactam, 20c, was also observed (see Scheme 1 and the SI).
Similarly, intermediates B and D can be disfavored by the
appropriate placement of geminal dimethyl groups on C3,
where they would incur a syn-pentane interaction upon the
formation of a cis-fused azidohydrin intermediate (Figure 1c).
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populations of the internal allylic azide isomers 17c and 17d
(<2%), which ultimately lead to the reaction products; this
provides an impressive example of the ability of the azide
equilibration step to occur in the context of an intramolecular
Schmidt reaction.
Having discerned the apparent need for a high degree of
diastereofacial selectivity to obtain high product ratios in the
presumably chairlike examples shown so far, we examined other
ring systems capable of exerting a similar bias. The six-membered
ring within the norcamphor bicyclic system is constrained into a
boat conformation; nucleophilic additions in such systems are well
known to occur via exo attack.12 For 19, we propose that reaction
through boatlike intermediate G, bearing a pseudoequatorial vinyl
group, was favored to give lactams 20a and 20b in a >20:1 ratio
(Figure (1e).
We wished to demonstrate the utility of this scheme for
stereocontrol in the context of a synthetic approach to pinnaic
acid, which was isolated by Uemura and co-workers in 1996
(Scheme 2).13,14 Specifically, we targeted an asymmetric route
Scheme 2
Figure 1. Pathways for 1,3-allylic rearrangement/Schmidt reactions of
(a) 1c and 1d (or substituted cyclohexanones bearing an equatorial
side chain, e.g., 7a) and (b) 9c and 9d. In (a), the numbers in paren-
theses indicate calculated energies of the transition-state structures for
the paths from the indicated intermediates to the corresponding LA-
complexed lactam products (CPCM(DCM)-B3LYP/6-31G(d,p)-
[SDD for Sn], relative to the lowest-energy transition-state structure).
(c) Disfavored intermediates from isomers of 11. (d, e,) Proposed
intermediates from isomers of (d) 13 and (e) 19.
Thus, azides formed upon rearrangement of 11a afford 12a and
12b in a >20:1 ratio (Table 1, entry 6). Placement of the geminal
dialkyl group elsewhere in the molecule also enhances the ratio,
if less impressively, as seen in the results for compound 13
(entry 7). Here the reason for the enhanced selectivity is not
obvious. In this case, the axial C5 methyl group encounters a 1,3-
diaxial interaction with an O−metal bond following equatorial
azide attack (i.e., leading to A or C) or an N(alkyl)(N2+) group for
the alternative axial attack (Figure 1d). The reaction of 17,
whose C5 methyl group is forced into an axial position by the
existence of the bulky C2 side chain, further supports the role
that distal substituents can have on the reaction selectivity
(cf. entry 9 vs entry 8). Moreover, we note the very low
to lactam 28, which was an advanced intermediate in the formal
synthesis of ( )-pinnaic acid reported by Kibayashi and co-
workers in 2004.15 We proposed that a [3.2.0] bicyclic ring
system ought to result in a highly diastereoselective Schmidt
reaction controlled exclusively by the placement of the vinyl group
in the product as a result of exclusive attack from the exo face.
Conversion of known acid 2316 to the chiral amide 24 set up
an asymmetric [2 + 2] cycloaddition using the protocol of
Ghosez17 that afforded 25 following basic hydrolysis of the
intermediate iminium ions (a bridged isomer of 25 was also
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obtained; see the SI for details). Following cross-metathesis,18
NaN3 displacement gave an interconverting mixture of allylic
azides 26a−d in 71% yield. The best results for the
isomerization/Schmidt reaction sequence were obtained using
TiCl4 treatment, which afforded a separable mixture of lactams
27a and 27b in a ca. 10:1 ratio and 68% yield. The preference
for the former is presumed to result from the placement
of the vinyl group in a pseudoequatorial orientation in 27a
(see the ball-and-stick model shown in the scheme). Finally,
hydroboration/oxidation gave Kibayashi’s pinnaic acid inter-
mediate 2815 in 83% yield.
In conclusion, we have demonstrated that it is possible to
combine allylic azide rearrangement and the intramolecular
Schmidt reaction to afford substituted lactams stereoselectively.
We are currently carrying out experimental and theoretical
studies to explore further the scope and applications of this
combined reaction sequence.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, characterization data, copies of H
and 13C NMR spectra of all new compounds, and details of the
DFT calculations. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jaube@ku.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Michal Szostak, Thomas C. Coombs, and Erik
Fenster for helpful discussions. J.A. acknowledges the financial
support of the National Institute of General Medical Sciences
(GM-049093). D.J.T. and O.G. acknowledge support from the
National Science Foundation (CHE030089, Pittsburgh Super-
computer Center).
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