Annulation of Oxime-Ether Tethered Donor–Acceptor Cyclopropanes

Article abstract of DOI:10.1002/chem.201904521

Novel oxime-ether tethered cyclopropanes, when exposed to Yb(OTf)₃ and heat, annulate to generate hydropyrrolo-oxazines products that can be taken to their respective pyrrolidines via hydrogenative N?O bond cleavage. The hydropyrrolo-oxazines are generated in a diastereoselective manner isolating the cis or trans product based on the temperature of the reaction. 20 examples of selective cis and trans hydropyrrolo-oxazines were generated in high yields by temperature control.

Full text of DOI:10.1002/chem.201904521

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Accepted Article
Title: Annulation of Oxime-Ether Tethered Donor-Acceptor
Cyclopropanes
Authors: Michael Andre Kerr, Lauren Irwin, Meredith Allen, and
Matthew Vriesen
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To be cited as: Chem. Eur. J. 10.1002/chem.201904521
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Annulation of Oxime-Ether Tethered Donor-Acceptor
Cyclopropanes
Lauren C. Irwin, Meredith A. Allen, Matthew R. Vriesen and Michael A. Kerr*[a]
Abstract: Novel oxime-ether tethered cyclopropanes when exposed
to Yb(OTf)3 and heat, annulate to generate hydropyrrolo-oxazines
products that can be taken to their respective pyrrolidines via
hydrogenative N-O bond cleavage. The hydropyrrolo-oxazines are
generated in a diastereoselective manner isolating the cis or trans
product based on the temperature of the reaction. 20 examples of
selective cis and trans hydropyrrolo-oxazines are generated in high
yields by temperature control.
cyclopropanes are convenient starting materials for the synthesis
of the pyrrolidines in question.8
In previous work we showed that with O-hydroxylamine
tethered cyclopropanes (5) as a divergent starting material, the
addition of an aldehyde followed by Yb(OTf)3 generated the
hexahydropyrrolo-isoxazoles (6-cis/trans). The order of addition
between the Lewis acid and aldehyde defined the diastereomeric
outcome of the annulation (6-cis/trans, Scheme 1).9 However,
these cyclopropanes (5) were not exceptionally stable and tended
to cyclize on themselves if left to sit. Accessing the O-
hydroxylamine cyclopropanes (5) took 9 steps and we did not
explore any variation of the tether length between the donor
acceptor cyclopropane and nucleophilic moieties.
Donor-acceptor cyclopropanes (DAC’s) have been well-
established as important building blocks for the synthesis of
heterocyclic compounds.1 Heterocycles, and specifically those
containing nitrogen, have widespread occurrence in highly sought
natural products and bio-active molecules.2 Our interest lies in the
importance of pyrrolidine containing molecules and the
precursors to access such scaffolding, such as hydropyrrolo-
oxazines (1a,1b).3 Figure
1 showcases bio-active natural
products alsaphorazine A and B (1a, 1b)4, preussin C (4)5 and 5-
methyl 2-(N-methyl-pyrrolidinane) (2)6 that have yet to see their
total syntheses realized. Also exhibited is Abbott’s influenza
neuraminidase inhibitor; A-315675 (3), yet another important
pyrrolidine containing molecule.7
Scheme 1. Current and related research from our group. [a] NaCN, DMSO,
140 °C [b] Pd/C (10 mol%), H2(g) (1 atm), AcCl, MeOH
The work herein aimed to address issues with the initial
research and to discover a method for which more elaborate
products could be prepared. We describe a high yielding,
temperature controlled, diastereoselective route to hydropyrrolo-
oxazines 11-cis/trans. The hydropyrrolo-oxazines can be taken
to their respective diastereospecific pyrrolidines in a single step
via hydrogenative N-O bond cleavage (Scheme 1). From a short
and high yielding 2-step synthesis of oxime-ether tethered
cyclopropanes (10a-o, Scheme 1) an intramolecular annulation
proceeded under the influence of catalytic Lewis acid. The
reaction took place in high yield and with high diastereoselectivity
that is controlled by the reaction temperature (11-cis/trans).
Figure 1. Heterocyclic compounds of interest
The task of synthesizing pyrrolidines in a diastereoselective
manner is a central challenge in the synthesis of target molecules
of academic and industrial importance. In efforts to address this
challenge, we and others have shown that donor-acceptor
[a]
Prof. Michael A. Kerr
Department of Chemistry
To commence this research, we required an accessible
method for the synthesis of oxime-ether tethered cyclopropanes
(10a-o). We envisioned that via simple SN2-type displacement
with an oxime nucleophile to a donor acceptor cyclopropane
The University of Western Ontario
1151 Richmond St, London, ON, Canada N6A 3K7
E-mail: makerr@uwo.ca
Supporting information for this article is given via a link at the end of
the document.
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bearing a haloalkane substituent we could realize these products.
(Figure 2, see Supplementary Information for optimization).10
The tolerance of the procedure outlined in Figure 2 was
robust and all oxime-ethers we sought to synthesize were made
successfully. Synthesis of the aromatic-substituted E oxime-ether
cyclopropanes proceeded smoothly in high yield (10a-c, 10e-g)
Yields for the Z oxime ether CPs (10d and 10o) and for the
aliphatic examples (10i, 10j, 10k) were modest in comparison. E
and Z oxime-ether cyclopropanes 10m and 10o were made from
an alternate benzyl bromo cyclopropane (see Supplementary
Information) for which a synthesis had already been reported.13
The standard SN2 reaction conditions outlined in Figure 2 yielded
these cyclopropanes (10m and 10o) in a 66% and 18% yield
respectively.
Figure 2. Synthesis of oxime-ether tethered donor-acceptor cyclopropanes
With access to the desired starting materials cemented,
experimentation with the annulation reaction was initiated and a
few interesting scenarios arose. Oxime-ether 10c reacted in the
presence of 5 mol% of Yb(OTf)3 in refluxing toluene to access our
desired bicyclic hydropyrrolo-oxazine 11c in a quantitative yield
(Scheme 2, Entry 1) . We were thrilled to discover a single isomer
of annulation product 11c had been synthesized.
Scheme 2. Initial findings during the annulation reaction of oxime-ether 10c and
10d
Repeating this reaction with the Z-oxime (10d) (Scheme 2,
Entry 2) resulted in isolating the exact same isomer, 11c,
observed in the previous reaction with the E oxime-ether 10c.
Isolating the same isomer proved perturbing to our insight of the
mechanism for this annulation. The result implied that the
geometry of the oxime does not control which isomer of the
annulation product is formed.
At this time, it could not be confirmed whether the cis or
trans isomer of 11c had formed using 1H or 13C NMR
spectroscopy. NOESY experiments failed to provide any
correlation between the benzylic and the bridge-head protons.
Fortunately, we later confirmed by single crystal X-ray
crystallography that we had isolated the cis isomer of annulation
product 11c at 120 °C in both of the cases in Scheme 2 (see
Figure 3 vide infra).
[a] Yield of combined E and Z isomers. Isolated yield of E isomer 46%
[b] Determined from crude 1H NMR
It is important to note that in accordance with literature
reports, the E-oximes were synthesized selectively when making
aromatic substituted oximes.11 Synthesizing aliphatic oximes
resulted in inseparable mixtures of E:Z oximes that could be
separated after synthesizing the oxime-ether cyclopropane
(Figure 2, 10k). The geometry of the oxime was retained during
the SN2 reaction as confirmed by 1H NMR and single X-ray
crystallography of 10c (Figure 3) .12
Prior to conclusive determination by X-ray diffraction, and to
provide some insight on which isomer we might be isolating, we
turned to computational calculations of the molecular energies of
the cis and trans isomers (Table 1.)
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of the annulation reaction of oxime-ether 10c, evidence of
the other isomer became apparent (11c-trans, Scheme 3A).
Lowering the reaction temperature from 120 °C to 90 °C
(Scheme 3A, Entry 2) resulted in a mixture of the cis:trans isomers
of 11c in a 1:2 ratio. Lowering the temperature further to 60 °C
resulted in isolating only the trans isomer 11c-trans (Scheme 3A,
Entry 3). This exciting result confirmed that, from the E-oxime-
ether CPs, we could gain access to both the cis and trans isomer
of the hydropyrrolo-oxazines (11). To solidify our findings, taking
the trans isomer 11c-trans isolated at 60 °C and subjecting it to
5 mol% Yb(OTf)3 at 120 °C (Scheme 3B) resulted in quantitative
conversion to the cis isomer, confirming that the cis isomer is our
thermodynamic product. This finding also proved that the
annulation is reversible, and access to the cis isomers is possible
from the trans isomers, but that the cis isomer cannot revert to the
trans because it is the thermodynamic sink.14 Crystal structures of
E-oxime cyclopropane 10c and the cis isolated product 11c-cis
were collected to confirm our identification of the isomers isolated
(Figure 3).
Table 1. DFT calculations of molecular energies for 11a-cis and 11a-trans
In all DFT calculations the cis isomer (11a-cis) was
favoured by an average -21.42 kJ/mol. These results indicated we
were dealing with two relatively stable isomers, that varied only
slightly in their energy difference, and that both isomers should be
isolable.
Figure 3. ORTEP drawing of 10c and 11c-cis
Intrigued by this interesting result, simple construction via
molecular model kit informed us that, likely, the E-isomer 10a
would more easily form the trans isomer of annulation product
11a-trans and that the Z-oxime-ether would access the cis
product 11a-cis. However, we needed to experimentally prove
this hypothesis and determine why both E- and Z-isomers yielded
the same diastereomer of the product.
11c-cis
10c
We hypothesized that perhaps this reaction did not require
such forcing conditions and that lowering the reaction
temperature would provide different results. This was to curb
either the annulation product reversibly opening and re-closing to
a single isomer, or, to prevent the oxime from isomerizing before
opening the cyclopropane. Both scenarios would explain the
interesting findings. To our delight, as we altered the temperature
The proposed mechanism for the formation of both cis/trans
isomers is outlined in Scheme 4.
Scheme 4. Proposed mechanism of the cyclopropane ring opening, cyclization
reaction
Coordination of ytterbium to the methyl ester carbonyls (I)
makes the cyclopropane susceptible to attack via the oxime
Scheme 3. Effects of temperature on the annulation of oxime-ether tethered
cyclopropanes
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Figure 4. Substrate scope for the annulation reaction of oxime-ether
cyclopropanes
nitrogen. Opening the cyclopropane results in zwitterionic species
(II), and from the oxime E-isomer, the protons of interest are trans
to each other. Closure via attack of the anionic carbon alpha to
the esters results in desired product III as the trans isomer. Once
closed, the lone-pair of the nitrogen atom can break the formed
ring, resulting in intermediate IV again. At this point, closure from
the opposite face occurs resulting in the thermodynamic cis
isomer V.
Having developed a better understanding of the factors
affecting the formation of each of the cis and trans isomers of 11c,
we could expand the annulation reaction to all the oxime-ether
CPs, generating the products outlined in Figure 4 (11a-m-
cis/trans).
Initial trends revealed that electron withdrawing
substituents on the oxime aromatic ring resulted in high yields of
the cis isomer at 120 °C (11b-cis, 11c-cis, 11d-cis). Accessing
the trans isomer at 60 °C also worked well in good yields for the
electron withdrawing examples (11b-trans, 11c-trans, 11d-
trans). However, examining more electron neutral examples (like
11a) a mixture of the isomers was observed at 60 °C, but were
easily separated by column chromatography. This trend
continued with electron-donating examples 11f and 11g, in which
the cis isomer was isolated at both 120 °C and 60 °C. To combat
the ease in which these examples annulated to the
thermodynamic cis isomer, we lowered the reaction temperature
further to 25 °C. The change resulted in electron-rich examples
forming the trans isomer but in lower yields than their electron-
withdrawing counterparts. In the case of 11f-trans, the reaction
had unreacted starting material after 48 h. It can be rationalized
through the proposed mechanism (Scheme 4) that the electron
rich examples provide
a more favourable and stabilized
intermediate of III (Scheme 4) and that closure to the cis product
could occur with greater ease.
Thiophene oxime-ether annulation product 11h cyclized to
the cis isomer at all temperatures explored, in a maximum yield of
78%. The aliphatic isopropyl oxime-ether product 10k failed to
yield annulation product 11k. Dimethyl oxime annulation product
11j was acquired in a 78% yield and spirocycle 11k in a lower
52% yield. The lower yield of product 11k is suspected to be the
result of a Beckmann rearrangement.
Exploring alternative chain-lengths, the 7-membered
product 11i required higher temperatures of 160 °C to
successfully annulate. Unfortunately, the 10-membered ring
annulation product 11m was not successfully isolated.
The phenyl side chain oxime-ether CP 10m annulated
smoothly at 120 °C to yield product 11e-trans in a 99% yield.
However, this product (11e-trans) had an unexpected chemical
shift of the benzylic proton in the 1H NMR spectrum at 5.74 ppm.
This seemed high because the trend for all examples has the cis
isomer benzylic proton at a lower chemical shift than the trans
isomer benzylic proton. When the reaction was performed at the
lower 60 °C and the same isomer resulted, it became apparent
that the phenyl side chain put alternative strain on this reaction
giving us a different isomer than expected.
[a] Synthesized from Z-oxime ether 10o to be able to access this cis product.
[b] Based on recovered starting material.
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To confirm these suspicions, X-ray crystallography of the
oxime-ether CP 10m confirmed we had made the E-isomer as
expected. And a crystal of 11e-trans confirmed the trans isomer
was being isolated in this case even at 120 °C (Figure 5).
Acknowledgements
We would like to thank the Natural Sciences and Engineering
Research Council of Canada for funding this work. Lauren C.
Irwin is the recipient of an NSERC PGSD award. We are
grateful to Doug Hairsine of the University of Western Ontario
Mass Spectrometry Facility for performing HRMS analyses. We
would especially like to thank Dr. Paul D. Boyle for the collection,
processing and solution of all X-ray crystallographic results.
Figure 5. ORTEP drawings of E oxime 10m and trans isomer 11e-trans
Keywords: oxime-ether
• donor-acceptor cyclopropane •
diastereoselective • pyrrolidine • natural products
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11e-trans
10m
Synthesis of the cis isomer (11e-cis) was possible using the
Z-oxime-ether CP (10o) which indeed, had a benzylic proton
chemical shift lower than that of the trans product 11e-trans (5.04
ppm). The findings further solidify the chemical shift trends
observed; that the cis products have a lower benzylic proton
chemical shift than the trans products.
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In summary, we have developed a protocol for 2-step
access to oxime-ether tethered cyclopropanes (10a-o) which
support the synthesis of varied chain lengths. The intramolecular
cyclopropane opening, and annulation reaction of the E oxime-
ether CPs are diastereocontrolled by varying the temperature to
provide access to both cis and trans hydropyrrolo-oxazines (11a-
m). We confirmed the isomeric configurations via single crystal X-
ray crystallography and the results were further supported by the
findings of DFT calculations. The hydropyrrolo-oxazines can be
taken to their respective pyrrolidines by reductive N-O bond
cleavage to access high-value heterocycles with tune-able
substitution and predictable stereochemistry.
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[12] H. Sharghi, M. H. Sarvari, Synlett, 2001, 1, 99-101.
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Lauren C. Irwin, Meredith A. Allen,
Matthew R. Vriesen and Michael A.
Kerr*
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Annulation of Oxime-Ether Tethered
Donor-Acceptor Cyclopropanes
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