Enantioselective Synthesis of Cyclic Nitrones by Chemoselective Intramolecular Allylic Alkylation of Oximes

Article abstract of DOI:10.1002/anie.202100150

The enantio- and chemoselective iridium-catalyzed N-allylation of oximes is described for the first time. Intramolecular kinetic resolution provides access to cyclic nitrones and enantioenriched aliphatic allylic alcohols. Salient features of this transformation are its ability to employ E/Z-isomeric mixtures of oxime starting materials convergently and high functional group tolerance. The implementation of N-allylation/1,3-dipolar cycloaddition reaction sequences furnishes tricyclic isoxazolidines in highly enantio- and diastereoselective fashion. The synthetic utility of the approach is demonstrated by the efficient, formal synthesis of the marine natural product (+)-halichlorine.

Full text of DOI:10.1002/anie.202100150

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9913–9918
International Edition: doi.org/10.1002/anie.202100150
German Edition: doi.org/10.1002/ange.202100150
Homogeneous Catalysis
Hot Paper
Enantioselective Synthesis of Cyclic Nitrones by Chemoselective
Intramolecular Allylic Alkylation of Oximes
Tobias Sandmeier and Erick M. Carreira*
Abstract: The enantio- and chemoselective iridium-catalyzed
N-allylation of oximes is described for the first time. Intra-
molecular kinetic resolution provides access to cyclic nitrones
and enantioenriched aliphatic allylic alcohols. Salient features
of this transformation are its ability to employ E/Z-isomeric
mixtures of oxime starting materials convergently and high
functional group tolerance. The implementation of N-allyla-
tion/1,3-dipolar cycloaddition reaction sequences furnishes
tricyclic isoxazolidines in highly enantio- and diastereoselec-
tive fashion. The synthetic utility of the approach is demon-
strated by the efficient, formal synthesis of the marine natural
product (+)-halichlorine.
N
itrones are valuable intermediates for the synthesis of
nitrogen containing pharmaceuticals,[1] complex natural prod-
ucts,[2] functional materials,[3] and bioconjugates.[4] They can
function as electrophiles,[5,6] as directing groups in C H
ꢀ
functionalizations,[7] and as dipoles in 1,3-dipolar cycloaddi-
tions.[8] The latter stand out as particularly important tools for
synthetic chemists as they enable concomitant formation of
ꢀ
ꢀ
C C and C O bonds, heterocycle syntheses, and approaches
to b-lactams.[9] In particular, intramolecular 1,3-dipolar cyclo-
additions forge multiple rings in a single step and have found
widespread utility in complex target synthesis.[10]
Scheme 1. A) Intramolecular enantioselective hydroamination of
oximes by Zhang. B) Asymmetric synthesis of nitrones by Ir-catalyzed
chemoselective N-alkylation of oximes.
Racemic, cyclic nitrones are featured as key intermediates
in numerous, classic syntheses of fused rings and/or spiro-
cycles.[11] Some of the most famous examples include synthe-
ses of cocaine and a variety of poison dart frog toxins.[12] The
discovery of synthetically useful, asymmetric, catalytic
approaches to optically active, cyclic nitrones stands to
significantly impact the development of new synthetic strat-
egies in complex target synthesis. Herein, we report the
enantioselective synthesis of 5-, 6-, and 7-membered cyclic
nitrones by enantioselective N-allylation of hydroxy oximes
under dual catalyst control involving iridium(I) and Brønsted
acids (Scheme 1). Implementation of this strategy in tandem
N-allylation/dipolar cycloaddition sequences furnished oxa-
zatriquinanes in a highly stereo-controlled fashion, which is
showcased in the formal synthesis of (+)-halichlorine, an
inhibitor of vascular cell adhesion protein 1.[13]
There have been a number of key developments in
asymmetric catalysis for the preparation of acyclic, optically
active nitrones from oximes via intermolecular olefin hydro-
amination by the groups of Zhang,[14] Kobayashi,[15] and
Breit.[16] Yet, to date, only one example of catalytic, enantio-
selective synthesis of cyclic nitrones has appeared in the
literature (Scheme 1A). In 2019, Zhang reported the intra-
molecular hydroamination of olefins using a copper/bisphos-
phine catalyst.[17] The method prescribes the use of oximes
derived from g,d-unsaturated aryl ketones and furnishes
exclusively 5-membered nitrones. Optimal results were
reported with substrates that incorporate aryl ketoximes
with gem-dimethyl substitution at Ca (R1 = Me).
Based on our long-standing interest in iridium-catalyzed
allylic substitution reactions,[18,19] we sought to investigate
chiral catalysts derived from [Ir(cod)Cl]2 and phosphorami-
dite-olefin ligands for the enantioselective synthesis of cyclic
nitrones. In contrast to olefin hydroamination reactions, the
use of secondary allylic alcohols for the N-functionalization of
oximes introduces several complications (Scheme 2). In the
most general process, the starting material employed is
a mixture of 4 stereoisomers because the substrate allylic
alcohols are racemic and include oxime geometric isomers. At
the outset of our investigations, the compatibility of chiral
[*] T. Sandmeier, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie
HCI H335, Eidgençssische Technische Hochschule Zꢀrich
Vladimir-Prelog-Weg 3, 8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100150.
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ing stronger Brønsted acids such as trifluoroacetic acid led to
higher conversion accompanied by a significant decrease in
enantiomeric purity (58% yield, 78% ee, Table 1, entry 2).
Further experimentation revealed efficient kinetic resolution
of allylic alcohol 1a with dichloroacetic acid as a promoter,
furnishing cyclic nitrone 2a in 98% ee, along with recovered
starting material 1a in 94% ee (Table 1, entry 3).[26] Notably,
these reactions proceeded with complete chemoselectivity for
the N-allylated nitrone product. Employing achiral linear
carbonate 1ab (R = Boc) generally resulted in low conversion
and modest enantiomeric purity (Table 1, entry 4, see Sup-
porting Information). Interestingly, when linear carbonate
1ac was utilized in combination with Cs2CO3 and iridium(I)/
L2 complex,[27] O-alkylated oxazepane product 3a was
obtained exclusively, albeit with modest enantioselectivity
(71% yield, 61% ee, Table 1, entry 5).[28]
Scheme 2. Intramolecular enantio- and chemoselective allylation of
oximes.
iridium catalysts when confronted with this mixture was
uncertain, because both olefins and oximes may be ligands for
iridium.[20] Additionally, as oximes are ambident nucleo-
philes,[21] it was not clear whether oxime geometry or product
ring size might favor undesired O-alkylation.[22,23] In the ideal
process, a Curtin–Hammet scenario[24,25] would allow both
diastereomers of the oxime starting material to converge into
a single cyclic nitrone product.
We commenced our studies with allylic alcohol 1a
obtained as a 1:1 mixture of E/Z-oxime isomers (Table 1).
Initial screening experiments were conducted using
[Ir(cod)Cl]2 (3 mol%), (S)-L (12 mol%), and Zn(OTf)2
which has previously been established as a mild Lewis acid
promoter for the activation of aliphatic allylic alcohols.[19e]
These conditions furnished cyclic nitrone 2a as the sole
product in 31% yield and 97% ee while oxime 1a was
recovered with an enantiomeric purity of 58% ee, indicating
that kinetic resolution is operative (Table 1, entry 1). Employ-
With optimized conditions for the chemo- and enantiose-
lective synthesis of cyclic nitrones via kinetic resolution, we
focused on exploring substrate scope (Scheme 3). Ketoxime
1b (R = Me, R’ = H, n = 2), was readily converted to cyclic
nitrone 2b with excellent enantio- and chemoselectivity
(98% ee, N/O > 20:1). E/Z mixtures of ketoximes (E/Z = 1:1
to 1.5:1) bearing longer and bulkier aliphatic sidechains also
furnished the expected products (2c and 2d). In addition, we
could establish that different functional groups were well
tolerated, leading to products incorporating benzyl-substitu-
tion (2e), acetals (2 f), and silyl ethers (2g) in 41–46% yields
(max = 50%), 98–99% ee, and > 20:1 N/O-chemoselectivity.
Furthermore, gem-dimethyl substituted nitrone (2h) was
accessed in 46% yield and 99% ee. Alkynyl nitrone 2i was
prepared in 93% ee, and nitrones 2j–l were synthesized in
95% ee, 95% ee, and 92% ee, respectively. Interestingly, for
the preparation of 5-membered nitrone 2k,[29]
1H NMR analysis of unpurified products revealed
a 5:1 ratio of N/O-allylation products, marking the
Table 1: Selected optimization conditions.[a]
first time we observe O-cyclization. In addition to 5-
and 6-membered ring nitrones, 7-membered aze-
pane-derived nitrone 2m was accessed in 94% ee,
without any formation of the oxazocane. Finally,
cyclization of aromatic aldoxime 1n furnished dihy-
droisoquinoline N-oxide 2n in 99% ee and with
complete chemoselectivity for N-alkylation. Notably,
this kinetic resolution is highly efficient with selec-
tivity factors s > 50 for all substrates.[30]
Entry
1
L
Additive
Ratio
Product
Recovered 1 [% ee][c]
2a/3a yield[b] [% ee]
Subsequent experimentation was aimed at pre-
paring tricyclic ring systems via iridium-catalyzed
enantioselective oxime N-allylation followed by
intramolecular 1,3-dipolar cycloaddition. Grigg,[31]
Stockman,[12b,32] and Coldham[33] have reported
a series of cascade reactions of racemic nitrone
intermediates, which are accessed by aza-Michael
addition or N-alkylation of oximes and undergo
intramolecular 1,3-dipolar cycloaddition with ole-
fins.[34] Although these reactions proceed with excel-
lent diastereocontrol, catalytic enantioselective ver-
sions have remained elusive. Therefore, we prepared
oxime 1o and subjected the mixture of four stereo-
isomers to the optimized reaction protocol, where-
upon cycloadduct 4 was isolated in 43% yield and
1
2
3
1a
1a
1a
(S)-L Zn(OTf)2
(S)-L F3CCO2H
(S)-L Cl2HCCO2H 99:1
99:1
99:1
31 (97)
58 (78)
45 (98)
7 (45)
58 (41)
29 (89)
47 (94)
–
4
1ab (S)-L Cl2HCCO2H 99:1
1ac L2 Cs2CO3 1:99
5[d]
71 (61)
–
[a] Reaction conditions: 1 (1.0 equiv), [Ir(cod)Cl]2 (3 mol%), (S)-L (12 mol%),
additive (1.1 equiv). DCE (0.3 M), rt. [b] Determined by H NMR integration with
1,4-dinitrobenzene as internal standard. [c] Enantiomeric ratios determined by
supercritical fluid chromatography (SFC) or HPLC. [d] Reaction conditions: [Ir-
(cod)Cl]2 (2 mol%) and L2 (4 mol%), THF (0.2 m).
1
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Scheme 3. Reactions on 0.3 mmol scale. Numbers in parentheses refer to recovered starting material. Yields of isolated products. ee determined
1
by HPLC, SFC, or GC analysis on a chiral stationary phase. Ratio N- vs. O-alkylation (N/O) determined by H NMR analysis of the unpurified
reaction mixtures. Selectivity factors (s) were calculated by Kagan’s method.[30] [a] Yields determined by 1H NMR spectroscopy with 1,4-
dinitrobenzene as internal standard. [b] Reaction run at 08C.
94% ee, as a single diastereomer (Scheme 4A). Reductive
ride, oxime 13 was isolated in 73% yield over two steps.
Iridium-catalyzed chemoselective N-alkylation and thermal
1,3-dipolar cycloaddition cleanly afforded tricyclic isoxazoli-
dine 14 bearing four stereogenic centers in 42% yield,
98% ee, and 18:1 d.r. on 2.5 mmol scale. Isoxazolidine 14
was hydroborated and oxidized to the corresponding primary
alcohol 15 in nearly quantitative yield using 9-BBN and H2O2/
NaOH. A sequence involving Ley oxidation, Pinnick oxida-
tion and Steglich esterification provided access to ester 16 as
a single diastereomer in 61% overall yield. Finally, cleavage
of the silyl ether gave alcohol 9 in 91% yield and completed
the formal synthesis of (+)-halichlorine. Gratifyingly, SFC
analysis confirmed that isoxazolidine 9 was formed without
erosion of optical purity (98% ee).
It is worth noting that most of the oximes employed for
nitrone formation are found as a mixture of E/Z geometric
isomers ranging from 1.5:1 to 1:1. Oximes 1h, 1n, and 1q are
exceptions, as expected because of overwhelming steric biases
inherent to the structures. To probe this remarkable con-
vergence of E/Z isomeric mixtures, nitrone 2e was prepared
using the catalytic, enantioselective conditions described, and
an aliquot was taken after 6 hours. Analysis by 1H NMR
spectroscopy revealed at this point in time a 1:1 ratio of
starting material to product as well as a 1:1 mixture of oxime
E/Z isomers (Scheme 6). All four stereoisomers of reisolated
starting material (S)-1e (E/Z = 1:1) were separated in one run
on HPLC using a chiral stationary phase, allowing confirma-
tion that both oxime diastereomers had identical enantio-
meric purities (98% ee). Collectively, these data suggest that
ꢀ
cleavage of the N O bond gave spirocyclic amino alcohol 5 in
91% yield. X-ray crystallographic analysis of 5·HCl allowed
unambiguous assignment of the absolute configuration.[35]
Similarly, reaction of 1p afforded oxazatriquinane 6 as
a single product in 90% ee (Scheme 4B). To showcase the
versatility of the method to access various ring scaffolds, we
investigated the cyclization/dipolar cycloaddition sequence of
oxime 1q. Gratifyingly, tricyclic isoxazolidine 7 was obtained
as a single stereoisomer in 99% ee (Scheme 4C).
To highlight the synthetic utility of the enantioselective
tandem N-allylation/cycloaddition reaction, we targeted the
formal synthesis of (+)-halichlorine (8). (+)-Halichlorine was
isolated from the marine sponge Halichondria okadai and
possesses an intriguing spirocyclic core structure. It was
shown to have interesting biological activities such as
inhibition of the vascular cell adhesion molecule VCAM-1,
which is of relevance in the treatment of inflammatory
diseases and in anti-cancer research.[13]
Racemic isoxazolidine 9 was prepared by the Stockman
group[32c] to intercept a synthetic route towards halichlorine
(via lactam 10) previously reported by Clive and co-work-
ers.[36] In pursuit of alcohol 9, we identified oxime 13 as
a suitable starting material for the iridium-catalyzed key step
(Scheme 5). The synthesis commenced with Grignard addi-
tion of 12 to racemic lactone 11.[37] Slow addition of 12 to
a solution of lactone 11 at ꢀ788C followed by warming to
ꢀ308C allowed selective mono-addition of the organometal-
lic reagent. After treatment with hydroxylamine hydrochlo-
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Scheme 4. Tandem N-alkylation/1,3-dipolar cycloaddition reactions.
For experimental details, see Scheme 3 and Supporting Information.
Numbers in parentheses refer to recovered starting materials. All
cycloadducts were formed in >20:1 d.r. Reagents and conditions:
Cycloadditions carried out in degassed toluene (0.025 m). a) Zn, H2O/
AcOH (2:1), 608C. [a] Thermal ellipsoids displayed at 50% probability,
chloride counterions were omitted for clarity.
Scheme 5. Formal synthesis of (+)-halichlorine. Reagents and condi-
tions: a) Grignard reagent 12, THF, ꢀ78!ꢀ308C; b) HONH2·HCl,
pyridine, EtOH; c) [Ir(cod)Cl]2 (3 mol%), (R)-L (12 mol%), DCE; d) p-
xylene, 1108C; e) 9-BBN, THF then H2O2, aq. NaOH, THF/H2O (3:1);
f) TPAP, NMO, CH2Cl2; g) NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH/H2O (3:1); h) EDCI, DMAP, EtOH, CH2Cl2; i) nBu4NF, THF.
E and Z oxime isomers interconvert rapidly under the
reaction conditions, thus enabling highly efficient kinetic
resolution of the allylic alcohols under Curtin–Hammet
regimes.[24]
In summary, we have developed the highly enantio- and
chemoselective iridium-catalyzed kinetic resolution of allylic
alcohols via N-allylation of oximes. The catalytic method
provides convenient access to optically active cyclic nitrones.
The approach employs readily available mixtures of oximes
(E/Z) and allylic alcohols (R and S). We document for the first
time entry into enantioselective tandem nitrone formation/
1,3-dipolar cycloaddition cascades which are highly relevant
for the asymmetric synthesis of complex molecules, as
demonstrated by the efficient formal synthesis of the marine
natural product (+)-halichlorine. More broadly, the approach
provides avenues for incorporating catalytic enantioselective
process in cascading reactions that furnish complex structures
in optically active form.
Scheme 6. Control experiment on oxime E/Z isomers.
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,3-dipolar cycloaddition ·
enantioselective catalysis · iridium · nitrones · oximes
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Acknowledgements
We are grateful to the ETH Zꢀrich and the Swiss National
Science Foundation (200020_172516) for financial support.
We also thank Dr. N. Trapp and M. Solar for X-ray crystallo-
graphic analyses.
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Manuscript received: January 5, 2021
Revised manuscript received: February 4, 2021
Accepted manuscript online: February 8, 2021
Version of record online: March 18, 2021
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