Arylboronic Acid-Catalyzed C-Allylation of Unprotected Oximes: Total Synthesis of N-Me-Euphococcine

Article abstract of DOI:10.1021/acs.orglett.0c00727

O-Unprotected keto-and aldoximes are readily C-allylated with allyl diisopropyl boronate in the presence of arylboronic acid catalysts to yield highly substituted N-α-secondary and tertiary homoallylic hydroxylamines. The method was used in the total synthesis of the trace alkaloid N-Me-Euphococcine.

Full text of DOI:10.1021/acs.orglett.0c00727

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Letter
Arylboronic Acid-Catalyzed C‑Allylation of Unprotected Oximes:
Total Synthesis of N‑Me-Euphococcine
́
́
̈
Juha H. Siitonen, Padmanabha V. Kattamuri, Muhammed Yousufuddin, and Laszlo Kurti*
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ABSTRACT: O-Unprotected keto- and aldoximes are readily C-
allylated with allyl diisopropyl boronate in the presence of
arylboronic acid catalysts to yield highly substituted N-α-secondary
and tertiary homoallylic hydroxylamines. The method was used in
the total synthesis of the trace alkaloid N-Me-Euphococcine.
compared to α-tertiary homoallylic amines, the corresponding
hydroxylamines are capable of undergoing a wide range of
further complexity-building transformations, including 1,3-
dipolar cycloadditions with aldehydes (Scheme 1D).2,3 In
addition, via cleavage of the weak N−O bond of the
hydroxylamine, both O and N atoms can be incorporated
into the structure in a stereocontrolled fashion.2,3
umerous alkaloids feature a structural motif consisting of
Nan α-tertiary amine moiety with a nearby oxygenated
functionality (alcohol or ketone) (Scheme 1A).1 We
considered α-tertiary homoallylic hydroxylamines as highly
suitable precursors for the construction of this motif, because
Scheme 1. (a) α-Tertiary Amine Substructures in
However, compared to the plethora of methods availabe for
C-allylation of protected ketimines and aldimines, there are
very few methods for constructing homoallylic α-tertiary
hydroxylamines.4 The only general method for the preparation
of such α-trisubstituted homoallylic hydroxylamines requires
the partial reduction of the corresponding allylated aliphatic
nitro compounds with aluminum amalgam (Scheme 1B).5a−e
This approach has a number of inherent problems, such as
limited access to aliphatic α-tertiary nitro compounds, the use
of a toxic amalgam, and the lack of functional group tolerance.
Due to these limitations, only 10 examples of α-tertiary
homoallylic hydroxylamines have been described in the
literature.5a−e The simplest imaginable transformation would
be the direct C-allylation of unprotected oximes. Unfortu-
nately, a general 1,2-addition of allylmetal reagents to
unprotected ketoximes remains elusive due to concomitant
deprotonations and rearrangements.6
Oxygenated Alkaloids, (b) Comparison of This Work with
the Current State of the Art for Making α-Fully Substituted
Allylated Hydroxylamines, (c) Allylation Method Described
in This Work, and (d) Synthetic Utility of Homoallylic
Hydroxylamines Including 1,3-Dipolar Cycloadditions
Allyl boronates would conceptually be suitable candidates
for such direct 1,2-addition reactions to oximes as these
compounds are virtually non-Brønsted basic (Scheme 1C).
Also, upon coordination to the nitrogen atom of the
unprotected oxime, their nucleophilicity increases, while the
Received: February 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00727
© XXXX American Chemical Society
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d
Scheme 2. Scope of Substrates for the Allylation Reaction
a
b
Full conversion based on 1H NMR, lowered isolated yield due to the volatility of the product. 3,5-bis-CF3-C6H3B(OH)2 (7b, 0.1 equiv) used as a
c
d
catalyst. Relative stereochemistry determined by reduction to a known amine (see the Supporting Information). Reagents and conditions: oxime
(5, 0.5 mmol unless otherwise noted, 1.0 equiv), AllB(OiPr)2 (6, 1.5 equiv), and 3,5-di-F-C6H3B(OH)2 (7b, 0.1 equiv) in 1,2-DCE (0.5 M) at 50
°C for 18 h.
binding interaction simultaneously activates the oxime for the
1,2-addition. This choice of strategy is supported by a seminal
work of R. W. Hoffman and co-workers, who demonstrated
that reactive aldoximes can be allylated by refluxing with
AllB(OMe)2 for prolonged periods of time in tetrachloro-
methane.7,8
However, in our hands, only a trace of the allylation product
was formed (<5% conversion) when acetophenone oxime (5a)
was reacted with commercially available AllBpin or AllB-
(OiPr)2 reagents in either tetrachloromethane or dichloro-
ethane. We observed improved conversion (17%) when an
older batch of the AllB(OiPr)2 reagent was used. This
improved conversion was attributed to the likely presence of
boronate ester hydrolysis products, such as boronic acids.
Following this logic, we repeated the allylation of acetophe-
none oxime (5a) with AllB(OiPr)2 (6) and using 10 mol %
phenylboronic acid (7a) as a catalyst, which led to a markedly
improved 51% conversion to 8a.9−11 Further screening (see
page 11 of the Supporting Information) identified 3,5-
difluorophenylboronic acid (7b) as the best catalyst, resulting
in 64% conversion of 5a to 8a. Optimizing both the catalyst
and allyl boronate loading, as well as the reaction time, led to a
72% conversion (73% isolated yield) of 5a to 8a (Scheme 2).
These results suggest that the prolonged reaction times
reported by Hoffman, even with the more reactive AllB-
(OMe)2 reagent, were needed to decompose some of the
AllB(OMe)2 to give catalytically active boronic acid species.7
With the optimized catalytic conditions at hand, we
proceeded to allylate a range of aliphatic and aromatic
ketoximes to the corresponding α-tertiary hydroxylamines
(8a−8t) as shown in Scheme 2.12 Lower yields were observed
for products 8c and 8d that were derived from electron-
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deficient oximes 5c and 5d. Cyclic and acyclic aliphatic
ketoximes (5h−5m) were mostly well-tolerated (33−83%
yields). The allylation reaction is, however, somewhat sensitive
to substrate bulkiness; thus, 5-nonanone oxime 5j gave a
diminished (33%) yield of 8j, while menthone and camphor
oximes could not be allylated (see page 28 of the Supporting
Information). The allylation reaction is compatible with a
range of functional groups, such as ethers (8q), acetals (8p),
and amides (8r). α,β-Unsaturated cyclohexanone oxime 5n
was also amenable to allylation but with a lower yield (8n,
28%). We were also surprised to find that a silyl-protected
alcohol-derived oxime (5o) underwent desilylation under the
reaction conditions, leading to hydroxylamine product 8o in
80% yield. In addition, the relative configuration of hydroxyl-
amine 8s could be established by single-crystal X-ray
diffraction.13
Similarly, a range of aliphatic and aromatic aldoximes could
also be successfully allylated using the method to form the
corresponding α-secondary homoallylic hydroxylamines (9a−
9k). Compared to ketoximes, the aldoximes were much less
sensitive to electronic effects (p-Br, 76% yield of 9h vs 8% yield
of 8d). We were also pleased to find that the allylation
proceeds under acyclic stereocontrol (dr 81:19) in the case of
9k. In addition, for several lower-yielding cases (9b, 9c, 9e, and
9g), we found that using 3,5-bis-trifluoromethyl phenylboronic
acid (7c) as the catalyst improved the yields, even though with
acetophenone oxime the difluoro catalyst 7b performed better
than the bis-trifluoromethyl catalyst 7c (see page 11 of the
Supporting Information). We found that both acetophenone
O-Me oxime and acetophenone hydrazone were unaffected by
the reaction (see page 28 of the Supporting Information).
To showcase the designed complexity-building power of the
allylated hydroxylamine products, we embarked on the total
synthesis of N-Me-Euphococcine (1), a trace homotropane
alkaloid isolated from Colorado blue spruce Picea pungens.14,15
Acetal-protected hydroxylamine 8p was hydrolyzed in aqueous
hydrochloric acid, and the resulting nitrone heated in toluene
to induce a 1,3-dipolar cycloaddition, forging the homotropane
alkaloid core 14 in 57% yield over two steps (Scheme 3).16,3e
We then installed the N-methyl group by alkylating 14 with an
excess of MeI to form the corresponding ammonium salt 15 in
73% yield. Attempts to achieve a base-induced Hoffman-type
fragmentation of the salt 15 to form N-Me-Euphococcine (1)
directly were hampered by an undesired rearrangement (i.e.,
side reaction). With weaker bases, such as Ag2O, Et3N, and
K2CO3, the ammonium salt 15 remained unchanged. However,
with KOH/MeOH, the ammonium salt 15 rearranged to
tetrahydro-1,3-oxazine 17 together with traces of N-Me-
Euphococcine (1) (see Scheme 3, inset).17
Therefore, a two-step reduction−oxidation sequence was
employed.18 The N−O bridge of 15 was reduced with zinc,
transposing the hydroxylamine oxygen to the alkaloid core.
The resulting diastereomerically pure aminoalcohol 16 was
then oxidized with Dess−Martin periodinane to deliver N-Me-
Euphococcine (1). The spectroscopic data for synthetic N-Me-
Euphococcine (1) corresponded to those reported for the
semisynthetic material.14
In conclusion, we have discovered that arylboronic acids are
effective catalysts for the C-allylation of unprotected oximes
with allylboronates. The method displays remarkable func-
tional group tolerance, and thus, we were able to prepare
dozens of previously inaccessible highly substituted and
functionalized α-tertiary homoallylic hydroxylamines. The
utility of the resulting products is demonstrated by total
synthesis of the homotropane trace alkaloid N-Me-Euphococ-
cine (1). Further investigations into the synthetic applications
and the mechanism of this organocatalytic transformation are
currently ongoing in our laboratory and will be reported in due
course.
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00727.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1948852 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
AUTHOR INFORMATION
Scheme 3. Total Synthesis of N-Me-Euphococcine (1)
■
Corresponding Author
́
́
Laszlo Kurti − Department of Chemistry, Rice University,
̈
Houston, Texas 77030, United States; orcid.org/0000-
0002-3412-5894; Email: kurti.laszlo@rice.edu
Authors
Juha H. Siitonen − Department of Chemistry, Rice University,
Houston, Texas 77030, United States; orcid.org/0000-
0002-9816-637X
Padmanabha V. Kattamuri − Department of Chemistry, Rice
University, Houston, Texas 77030, United States; orcid.org/
0000-0002-5381-1347
Muhammed Yousufuddin − Life and Health Sciences
Department, The University of North Texas at Dallas, Dallas,
Texas 75241, United States
a
Reagents and conditions: (a) 1 M HCl(aq), rt, 30 min and then
PhMe, 100 °C, 10 h, 57% over two steps; (b) MeI (5.0 equiv), Et2O,
24 h, 73%; (c) Zn (10 equiv), AcOH/THF/H2O, 30 °C, 6 h, 75%;
(d) Dess−Martin periodinane (2.0 equiv), NaHCO3 (4.0 equiv),
THF, 0 °C to rt, 58%; (e) KOH, 10% MeOH, rt, 3 h, 65%.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00727
C
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(9) For related reactions, see: (a) Raducan, M.; Alam, R.; Szabo, K.
J. Palladium-catalyzed synthesis and isolation of functionalized
allylboronic acids: Selective, direct allylboration of ketones. Angew.
Chem., Int. Ed. 2012, 51, 13050−13053. (b) Alam, R.; Das, A.; Huang,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
́
G.; Eriksson, L.; Himo, F.; Szabo, K. J. Stereoselective allylboration of
■
imines and indoles under mild conditions. An in situ E/Z
isomerization of imines by allylboroxines. Chem. Sci. 2014, 5,
2732−2738. (c) Sakata, K.; Fujimoto, H. Quantum chemical study
of Lewis acid catalyzed allylboration of aldehydes. J. Am. Chem. Soc.
2008, 130, 12519−12526.
L.K. gratefully acknowledges the generous financial support of
Rice University, the National Institutes of Health (R01 GM-
114609-04), the National Science Foundation (CAREER:-
SusChEM CHE-1546097), the Robert A. Welch Foundation
(Grant C-1764), Amgen (2014 Young Investigators’ Award for
L.K.), and Biotage (2015 Young Principal Investigator Award)
that is greatly appreciated. J.H.S. gratefully acknowledges the
support from the Wiess Teaching Postdoctoral fund and Oskar
Huttunen Foundation.
(10) For reviews of boronic acid catalysis, see: (a) Hall, D. G.
Boronic Acids: Preparation and Applications in Organic Synthesis and
Medicine; Wiley-VCH Verlag GmbH & Co. KGaA, 2006. (b) Hall, D.
H. Boronic acid catalysis. Chem. Soc. Rev. 2019, 48, 3475−3496.
(11) Siitonen, J.; Kattamuri, P. V.; Yousufuddin, M.; Ku
̈
rti, L.
Arylboronic Acid-Catalyzed C-Allylation of Unprotected Oximes.
ChemRxiv 2019, DOI: 10.26434/chemrxiv.9728285.v1.
(12) Notably, some of the aliphatic hydroxylamines had a slight blue
tint to them, which is likely a result of areal oxidation to form traces of
corresponding highly colored nitroso compounds.
(13) Crystallographic data for hydroxylamine 8s have been
deposited with deposition number CCDC 1948852 and can be
obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: + 44(1223)
336033; E-mail: deposit@ccdc.cam.ac.uk; Web site: www.ccdc.cam.
ac.uk/conts/retrieving.html.
(14) Tawara, J. N.; Lorenz, P.; Stermitz, F. R. 4-Hydroxylated
Piperidines and N-Methyleuphococcinine (1-Methyl-3-granatanone)
from Picea (Spruce) Species. Identification and Synthesis. J. Nat. Prod.
1999, 62, 321−323.
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