Convergent and stereodivergent synthesis of complex 1-aza-7-oxabicyclo[2.2. 1]heptanes

Article abstract of DOI:10.1021/ja202900h

A convergent and stereodivergent pathway to highly substituted 1-aza-7-oxabicyclo[2.2.1]heptanes is described. It begins with a coupling reaction involving allylic alcohol, aldehyde, and LiHMDS to produce stereodefined primary homoallylic amines. Subsequent N-oxidation and condensation with formaldehyde or glyoxylate defines a convenient entry to densely functionalized homoallylic nitrones whose intramolecular annulation can be controlled to deliver one of two distinct heterocyclic skeletons, each with ≤20:1 stereoselection. Control of the stereochemistry in these reactions results from both control of the nitrone geometry and selective partitioning of the reaction pathway between direct [3 + 2] cycloaddition and tandem [3,3] rearrangement/[3 + 2] cycloaddition.

Full text of DOI:10.1021/ja202900h

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pubs.acs.org/JACS
Convergent and Stereodivergent Synthesis of Complex
1-Aza-7-oxabicyclo[2.2.1]heptanes
Dexi Yang and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
S Supporting Information
b
ABSTRACT: A convergent and stereodivergent pathway to
highly substituted 1-aza-7-oxabicyclo[2.2.1]heptanes is de-
scribed. It begins with a coupling reaction involving allylic
alcohol, aldehyde, and LiHMDS to produce stereodefined
primary homoallylic amines. Subsequent N-oxidation and
condensation with formaldehyde or glyoxylate defines a
convenient entry to densely functionalized homoallylic
nitrones whose intramolecular annulation can be controlled
to deliver one of two distinct heterocyclic skeletons, each
with g20:1 stereoselection. Control of the stereochemistry
in these reactions results from both control of the nitrone
Figure 2. Convergent route to 1-aza-7-oxabicyclo[2.2.1]heptanes.
geometry and selective partitioning of the reaction pathway
between direct [3 þ 2] cycloaddition and tandem [3,3]
rearrangement/[3 þ 2] cycloaddition.
Since LeBel and Lumma’s early reports2 and Oppolzer’s sub-
sequent investigation of regio- and stereoselectivity,3 intramolecular
cycloaddition of homoallylic nitrones has been accepted as a general
strategy for the synthesis of substituted 1-aza-7-oxabicyclo[2.2.1]-
heptanes and, upon reductive cleavage of the σNꢀO bond, 4-hydro-
xypiperidines.4 The vast majority of applications in this regard have
involved intramolecular reactions of sparsely functionalized homo-
allylic nitrones, and few reports have described the utility of this
cycloaddition for the stereoselective synthesis of densely function-
alized of 1-aza-7-oxabicyclo[2.2.1]heptanes. This apparent lack of
utility was thought to be due in part to (1) the difficulties associated
with accessing the requisite highly substituted and stereodefined
homoallylic nitrone starting materials and (2) the lack of stereo-
chemical control in the cycloaddition reaction.5
We began with the development of a synthetic method for preparing
highly substituted and stereodefined homoallylic hydroxylamines.
Previous studies in our laboratory had established an asymmetric
route to stereodefined homoallylic secondary amines based on the
union of preformed imines with chiral allylic alcohols (eq 1).6 While
a deprotection (removal of R2)/N-oxidation sequence could allow
this process to intersect with the annulation chemistry of homo-
allylic nitrones, we opted to pursue a more direct approach, namely,
coupling of allylic alcohols with preformed oximes (eq 2). Unfortu-
nately, all attempts to accomplish such a bond construction failed.
lkaloids are a broad class of natural products that possess a
A
diverse array of biological properties. While examples in-
clude a vast array of molecular architectures, structurally complex
polycyclic alkaloids have played a prominent role in the devel-
opment of modern organic chemistry, providing inspiration for
the development of synthetic methods suitable for the prepara-
tion of their intricate stereodefined skeletons. Densely function-
alized piperidines are a common motif in complex alkaloids
(Figure 1), and despite the variety of chemical methods available
to access this type of nitrogen-containing heterocycle, the
asymmetric synthesis of highly substituted piperidines remains
a significant challenge in chemical synthesis.1 Here we describe a
convergent, asymmetric, and stereodivergent entry into tri- and
tetrasubstituted 1-aza-7-oxabicyclo[2.2.1]heptanes (6 and 7)
that derives from the union of an allylic alcohol (3) with two
carbonyl electrophiles (1 and 5) and LiHMDS (2) (Figure 2).
These studies are based on two central advances: (1) establish-
ment of a three-component coupling reaction for the stereo-
selective synthesis of primary homoallylic amines and (2) control
of the path selectivity in the annulation chemistry of highly
substituted homoallylic nitrones.
Received: March 30, 2011
Published: May 23, 2011
Figure 1. Piperidine-containing polycyclic alkaloids.
r
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Table 1. Primary Homoallylic Amines from Ti-Mediated
Couplinga
Figure 3. Stereochemical complexity of nitrone cycloaddition.
Figure 4. Direct [3 þ 2] cycloaddition versus tandem [3,3] rear-
rangement/[3 þ 2] cycloaddition.
delivers stereodefined (E)-anti-homoallylic amines as single diaster-
eomers in 53ꢀ87% yield.
Having secured a robust stereoselective process for the con-
vergent assembly of complex primary homoallylic amines, we
turned our attention to the evaluation of intramolecular nitrone
annulation chemistry as a means of generating highly substituted
heterocycles. After oxidation of homoallylic amine 10 to the
corresponding hydroxylamine 29,8 heating with formaldehyde at
50 °C leads to a complex product mixture (eq 3 in Figure 3).
While the rearranged nitrone 30 is formed in 67% yield,
cycloadducts 31 and 32 are generated in 17% combined yield
without substantial stereoselection (ds = 2.5:1). Interestingly,
after isolation of nitrone 30, heating at 120 °C in toluene results
in a highly stereoselective annulation (eq 4 in Figure 3). Here the
isomeric cycloadduct 33 is produced in 74% yield with very high
levels of stereoselection (ds g 20:1).
The difference in 2,3 stereochemistry between 33 and the
cycloadducts 31 and 32 is consistent with a complex competition
in reaction mechanism due to the relative rate of cycloaddition
versus sigmatropic rearrangement (Figure 4).5a,b,9 For example,
initial exposure of 29 to formaldehyde at 50 °C leads primarily to
the product of [3,3] rearrangement (30), with the minor
cycloadducts 31 and 32 deriving from direct [3 þ 2] cycloaddi-
tion of the intermediate nitrone A. After isolation of the rear-
ranged product 30, heating in toluene at 120 °C results in a
stereodivergent annulation via D to deliver 33 without contam-
ination by cycloadduct 31 or 32.
a Reaction conditions: RCHO (2 equiv), LiHMDS (2 equiv) (ꢀ78 °C
for aliphatic RCHO, ꢀ10 °C for aromatic RCHO), then Ti(Oi-Pr)4
(2ꢀ3 equiv), RLi or RMgCl (4ꢀ6 equiv), then lithium alkoxide of allylic
alcohol (1 equiv) (ꢀ78 °C to rt). For specific examples, see the
Supporting Information. Note: products are racemic.
To circumvent this impediment in reactivity, we pursued an
alternative coupling reaction capable of delivering a stereode-
fined primary homoallylic amine, a product whose subsequent
N-oxidation would deliver homoallylic hydroxylamines without
the need for intermediate protecting-group manipulations. As
depicted in Table 1, in situ generation of a TMS-imine7 proved
compatible with Ti-mediated allylic alcohol-based reductive
cross-coupling, defining a three-component coupling process
for the synthesis of stereodefined primary homoallylic amines.
Overall, exposure of an aldehyde to LiHMDS is followed by
introduction of Ti(Oi-Pr)4 and c-C5H9MgCl (Et2O, ꢀ78 to
ꢀ40 °C). Subsequent addition of a preformed allylic lithium
alkoxide results in overall reductive cross-coupling and, upon
aqueous workup, delivers primary homoallylic amines with out-
standing levels of regio- and stereocontrol. This reaction proceeds
effectively with a variety of aromatic and aliphatic aldehydes and
This tandem [3,3]-sigmatropic rearrangement/[3 þ 2] cy-
cloaddition is a useful stereoselective process for the production
of densely functionalized 2-aryl-substituted 1-aza-7-oxabicyclo-
[2.2.1]heptanes (Table 2). Entries 1 and 2 demonstrate that the
stereoselection of this process is highest with electron-deficient
aromatics R to the intermediate nitrone (dr g 20:1). Entries 3
and 4 depict annulation events that deliver products having
stereochemistry identical to that seen in entries 1 and 2, albeit
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Table 2. Stereoselective Synthesis of 2,3-syn-3,4-syn-4,5-syn-
5,6-anti-1-Aza-7-oxabicyclo[2.2.1]heptanesa
Table 3. Stereoselective Synthesis of 2,3-anti-3,4-syn-4,5-
anti-5,6-anti-1-Aza-7-oxabicyclo[2.2.1]heptanesa
a Notes: (1) The initial sigmatropic rearrangement for the reactions
summarized in entries 1 and 2 occurred in <2 h, whereas the substrates
depicted in entries 3 and 4 required up to 48 h. Similarly, the subsequent [3 þ
2] annulation in entries 3 and 4 required prolonged heating in comparison
with entries 1 and 2 (48 h at 120 °C vs 12 h at 120 °C). (2) The products are
racemic. b The minor product is epimeric at the highlighted (*) position.
a Products are racemic.
with compromised levels of stereocontrol (dr = 6:1). Finally, entry
5 provides a glimpse of the potential utility of this process for the
synthesis of fully substituted heterocyclic systems. In this more
complex example, reaction with an aliphatic aldehyde produces
tetrasubstituted heterocycle 42 in 80% yield (dr = 4:1).10
The stereochemical control of the annulation events depicted
in Table 2 derives from the enhanced propensity of the initially
formed nitrones to undergo [3,3]-sigmatropic rearrangement,
with subsequent [3 þ 2] cycloaddition occurring by way of the
transposed nitrone (via D in Figure 4). With this model in mind,
we speculate that more electron-rich nitrones in intermediate D
have the potential to isomerize to the (E)-O-nitrone, a process
that we reason is in part responsible for the decreased levels of
stereoselection observed in entries 3 and 4 of Table 2. In cases
where the initial [3,3] rearrangement (B f C in Figure 4) is not
driven by thermodynamic stabilization of the resulting conju-
gated nitrone, attempted annulation reactions with formalde-
hyde or acetaldehyde result in a complex mixture of products.
To broaden the scope of this convergent route to complex
heterocycles, we aimed to define an alternative means of con-
trolling the mechanistic course of these annulation processes.
Specifically, we sought to identify conditions that would promote
the direct [3 þ 2] annulation of the initially formed nitrone as a path
to heterocycles having distinct substitution and stereochemistry.
Figure 5. Stereoselective annulation with ethyl glyoxylate.
Without a mechanistically lucid means of pursuing this goal, we
opted to make drastic changes in the electronic and stereochemical
features of the initially formed nitrone A (Figure 4).
With this goal in mind, the related annulation of homoallylic
hydroxylamines with ethyl glyoxylate was explored. In comparison
with nitrones resulting from condensation of hydroxylamines with
formaldehyde or acetaldehyde, nitrones derived from glyoxylates are
electronically and stereochemically distinct. While they are more
electron-deficient, these nitrones prefer an E geometry in hydro-
carbon solvents and exist in rapid equilibrium with their Z isomers.11
As illustrated in Table 3, we were delighted to find that
annulation with ethyl glyoxylate defines a stereochemically
unique path to highly substituted heterocycles, in this case
delivering 1-aza-7-oxabicyclo[2.2.1]heptane products containing
a 2,3-anti-3,4-syn-4,5-anti-5,6-anti stereochemical relationship.
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new diastereo- and enantioselective convergent synthesis of
(E)-anti-homoallylic primary amines, (2) N-oxidation, and (3)
a stereodivergent nitrone annulation process. On the basis of the
highly stereoselective nature of this synthesis pathway, the complex-
ity of the resulting products, and the frequency with which sub-
stituted piperidines appear in alkaloids, we look forward to future
applications of this method in target-oriented synthesis.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectroscopic data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Figure 6. Asymmetric entry to 1-aza-7-oxabicyclo[2.2.1]heptanes. Re-
action conditions: (a) PhCHO, LiHMDS (ꢀ10 °C), then Ti(Oi-Pr)4,
c-C5H9MgCl, then lithium alkoxide of allylic alcohol (1 equiv) (ꢀ78 °C
to rt); (b) (BzO)2, K2HPO4, DMF (rt); (c) NH2NH2, EtOH; (d) ethyl
glyoxylate, PhMe, 4 Å molecular sieves (100 °C) (e) (CH2O)n, PhMe,
4 Å molecular sieves (50 °C, then 120 °C) (f) C6H13CHO, LiHMDS
(ꢀ78 °C), then Ti(Oi-Pr)4, c-C5H9MgCl, then lithium alkoxide of
allylic alcohol (1 equiv) (ꢀ78 °C to rt). The ee values labeled with * were
determined by Mosher ester analysis of derivatives (see the Supporting
Information for details).
Corresponding Author
micalizio@scripps.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge financial support of this work by
the NIH, NIGMS (GM80266 and GM80266-04S1).
’ REFERENCES
(1) For reviews, see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
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Cycloaddition proceeds with hydroxylamines that have neigh-
boring aliphatic as well as aromatic substitution and delivers
stereodefined heterocycles in yields of 52ꢀ64% (entries 1ꢀ5; in
all cases, no evidence could be found for the production of
stereoisomeric cycloadducts).
The stereochemistry of the heterocycles depicted in Table 3 is
consistent with a reaction sequence that proceeds by direct
stereoselective intramolecular [3 þ 2] cycloaddition of the
initially formed electron-deficient nitrone E, uninterrupted by
[3,3] rearrangement (F f G in Figure 5). While this provides a
robust means of controlling the stereoselection in annulation
events involving homoallylic nitrones derived from aliphatic
aldehydes (entries 2 and 4), entries 1, 3, and 5 indicate that even
when the substrate possesses neighboring aromatic substitution
that has the potential to drive the [3,3]-sigmatropic rearrange-
ment, the reaction with ethyl glyoxylate proceeds in a highly
stereoselective manner that is apparently uncomplicated by this
process.12 The facial selectivity of the cycloaddition is further
supported by minimization of A-1,3 strain about the substituted
nitrone E, resulting in a pseudoequatorial disposition of R1 and
subsequently securing the orientation of R2 and R3 in the
transition state for cycloaddition.
Finally, this sequence for the synthesis of complex 1-aza-7-
oxabicyclo[2.2.1]heptanes is ideally suited for enantioselective
synthesis. In accord with previous observations,6 Ti-mediated
coupling of optically active allylic alcohols (Figure 6) proceeds
with exquisite levels of stereocontrol and delivers optically active
homoallylic amine products (52 and 56). As anticipated, a
sequence of N-oxidation followed by nitrone cycloaddition via
either direct [3 þ 2] annulation or tandem [3,3] rearrangement/
[3 þ 2] cycloaddition provides a convenient asymmetric entry to
complex tri- and tetrasubstituted 1-aza-7-oxabicyclo[2.2.1]
heptanes (54, 55, and 58).
(4) For an example, see: Hoffmann, R. W.; Endesfelder, A. Liebigs
Ann. Chem. 1986, 11, 1823.
(5) For a discussion concerning the observation of products derived
from aza-Cope/intramolecular [3 þ 2] nitrone cycloaddition, see:
(a) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957.
(b) Merino, P.; Mannucci, V.; Tejero, T. Eur. J. Org. Chem.
2008, 3943. For a review of [3 þ 2] nitrone cycloaddition, see:
(c) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
(6) (a) Takahashi, M.; McLaughlin, M.; Micalizio, G. C. Angew.
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J. Am. Chem. Soc. 2009, 131, 17548. (d) Chen, M. Z.; McLaughlin, M.;
Takahashi, M.; Tarselli, M. A.; Yang, D.; Umemura, S.; Micalizio, G. C.
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(8) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219.
(9) For a computational assessment related to the competition
between [3,3] rearrangement and [3 þ 2] cycloaddition reactions of
homoallylic nitrones, see: Merino, P.; Tejero, T.; Mannucci, V. Tetra-
hedron Lett. 2007, 48, 3385.
(10) See the Supporting Information for details.
(11) (a) Inouye, Y.; Hara, J.; Kakisawa, H. Chem. Lett. 1980, 1407.
(b) Inouye, Y.; Takaya, K.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1983, 56,
3541. It has also been proposed that intermolecular [3 þ 2] cycloaddi-
tion reactions occur faster by way of (E)-nitrones. See:(c) Burdisso, M.;
Gandolfi, R.; Gr€unanger, P.; Rastelli, A. J. Org. Chem. 1990, 55, 3427.
(12) These observations do not exclude control by the Curtinꢀ
Hammett principle, where reversible [3,3] rearrangement of the initially
formed glyoxylate-based nitrone is irrelevant in determining the product
distribution.
In summary, we have described a convergent asymmetric
entry to densely functionalized tri- and tetrasubstituted 1-aza-
7-oxabicyclo[2.1.1]heptanes. This sequence is defined by (1) a
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