CuH-Catalyzed Regioselective Intramolecular Hydroamination for the Synthesis of Alkyl-Substituted Chiral Aziridines

Article abstract of DOI:10.1021/jacs.7b04816

This report details a general and enantioselective means for the synthesis of alkyl-substituted aziridines. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. Readily accessed ally

Full text of DOI:10.1021/jacs.7b04816

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Communication
CuH-Catalyzed Regioselective Intramolecular Hydroamination
for the Synthesis of Alkyl-Substituted Chiral Aziridines
Haoxuan Wang, Jeffrey Chih-Yeh Yang, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2017
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CuH-Catalyzed Regioselective Intramolecular Hydroamination for
the Synthesis of Alkyl-Substituted Chiral Aziridines
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Haoxuan Wang,† Jeffrey C. Yang,† and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Supporting Information Placeholder
[Paste publicationꢀsize TOC graphic here]
ABSTRACT: This report details a general and enantioselective means for the synthesis of alkylꢀsubstituted aziridines. This protoꢀ
col offers a direct route for the synthesis of alkylꢀsubstituted chiral aziridines from achiral starting materials. Readily accessed alꢀ
lylic hydroxylamine esters undergo copper hydrideꢀcatalyzed intramolecular hydroamination with a high degree of regioꢀ and enanꢀ
tiocontrol to afford the aziridine products in good to excellent yield in highly enantioenriched form. The utility of the products deꢀ
rived from this method is further demonstrated through the derivatization of chiral aziridine products to a diverse array of functionꢀ
alized enantioenriched amines.
Optically active aziridines constitute a key functional group
present in several classes of natural products and pharmaceutiꢀ
cal agents.1 Stereochemically wellꢀdefined aziridines also
serve as useful building blocks or intermediates for the syntheꢀ
sis of a range of biologically active, nitrogenꢀcontaining comꢀ
pounds.2 For instance, aziridines readily participate in nucleoꢀ
philic ring opening and ring expansion reactions, as well as in
cycloadditions with dipolarophiles.2 Importantly, the stereoꢀ
chemistry embedded in the heterocycle can often be transꢀ
ferred to the final product to provide configurationallyꢀpure
amines. Consequently, a number of synthetic strategies for the
stereoselective synthesis of aziridines have been developed.3
Prominent techniques include metalꢀcatalyzed nitrene cyꢀ
cloadditions with olefins,4 carbene additions to imines,5 the
azaꢀDarzens reaction,6 stereoselective azirine reductions7 and
C–H activationꢀbased approaches.8 Despite the utility of these
methods, they are generally limited to the preparation of aziriꢀ
dines with electronꢀwithdrawing Nꢀsubstituents or require
particular substitution patterns for productive reactivity. In
general, alkylꢀsubstituted aziridines, are especially challenging
to access in a catalytic, enantioselective manner. One recent
approach, disclosed by Lindsley, leverages the previously
established enantioselective αꢀchlorination9 of aldehydes in a
threeꢀstep oneꢀpot protocol (Figure 1a).10 Nevertheless, no
synthetic method allows for the direct preparation of chiral Nꢀ
alkyl aziridines from achiral starting materials in a catalytic
and asymmetric manner. We hypothesized that this synthetic
challenge could be addressed through the intramolecular hyꢀ
droamination of an allylic hydroxylamine ester 1, enabled by a
catalytically generated chiralꢀphosphine ligated copper(I) hyꢀ
dride (CuH) species.
problematic when unsymmetrical olefins were employed as
substrates. Our own experience11c,eꢀk and an example from the
Figure 1. Lindsley’s approach for the synthesis of chiral Nꢀalkyl
aziridines and the development of our strategy.
recent literature11m suggested that a proximal polar substituent
on alkenes could influence the regioselectivity of
hydrocupration of the alkene by polarizing the C=C double
bond. In the proposed aziridine synthesis (Figure 1c), we
postulated that the presence of an allylic hydroxylamine ester
would enforce the hydrocupration of the internal alkene to
provide high regioselectivity for the desired regioisomer
(favoring 2a over 2b). Following hydrocupration, the
organocopper intermediate would undergo intramolecular
amination to furnish chiral aziridine 3, in preference to the
regioisomeric azetidine 4.
Recently, our group and others have adopted CuH catalysis
as
a
general platform for the enantioselective
hydrofunctionalization
of Among these
olefins.11
transformations, the enantioselective hydroamination was
successfully applied to symmetric and unactivated internal
olefins (Figure 1b).11e However, regioselectivity became
Allylic hydroxylamine ester 1aa (Table 1) was chosen as a
model substrate to begin our study. Subjecting 1aa to a
solution of CuH catalyst (generated from Cu(OAc)2, (S)ꢀ
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DTBMꢀSEGPHOS (L1)) and a stoichiometric amount of 9). Lastly, further optimization of reaction temperature (4 °C)
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dimethoxymethylsilane as the hydride source, resulted in the
formation of the desired aziridine product 3a12 in 74% yield
and 88% ee. Competing N–O bond reduction by the CuH
catalyst accounted for the major side product, amine 5a. In orꢀ
and concentration (1 M) allowed the desired product to be
obtained in 89% yield by GC analysis (81% isolated yield)
with an excellent level of enantioselectivity (98% ee, entry
10).
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6
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8
Table 1. Optimization of CuH-catalyzed chiral aziridine
synthesisa
Having identified optimized conditions, the substrate scope
of the Nꢀsubstituent was explored (Table 2). In most cases,
substituents on the nitrogen atom of varying electronic and
steric properties were wellꢀtolerated and their transformation
proceeded with high yields and excellent enantioselectivities.
In addition, an aziridine with a pendant aryl chloride (3e) was
successfully prepared, allowing crossꢀcoupling technology to
be considered for downstream derivatization. A substrate
containing a methyl ester and a free phenol (3i) was
transformed to product with excellent efficiency and
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stereoselectivity.
Moreover, structurally diverse Nꢀalkyl
groups including a silyloxyethyl (3j), a cyclohexyl (3k) and a
simple methyl group (3l) could all be employed using our
procedure. The presence of an orthoꢀisopropyl group on the N-
benzyl
substituent
(3h)
resulted
in
diminished
enantioselectivity and represents a limitation of the current
procedure, although a smaller orthoꢀmethyl group (3g) was
readily accommodated.
Table 2. Substrate scope of CuH-catalyzed chiral aziridine
synthesis – variation of substitution on the nitrogen atoma
aYields determined by GC analysis with 1ꢀdodecane as internal
standard, 0.1 mmol scale. bPrepared from Cu(OAc)2/L1/PPh3
c
(1:1.1:1.1). 2 mol % catalyst loading, 1 M concentration, 18 h.
dIsolated yield on a 0.5 mmol scale.
der to suppress this deleterious reduction pathway, the reaction
of substrates containing different hydroxylamine esters were
examined. While use of electronꢀdeficient pꢀtrifluoromethyl
benzoate 1ab exhibited a higher tendency towards reduction,
sterically hindered 2,4,6ꢀtrimethylbenzoate 1ad provided 3a in
comparable yield but lower enantioselectivity (entries 2 and
4). The incorporation of electronꢀrich pꢀN,Nꢀdimethylamino
benzoate 1ac gave 3a in higher yield and improved
enantioselectivity (80% yield, 94% ee, entry 3). By switching
to pivalate 1ae, the enantioselectivity was further improved to
96% ee (entry 5). These last two results are in line with what
we have seen in olefin hydroamination processes.13 In all
cases, only a trace amount of the analogous azetidine was
seen.14 Use of other commercially available chiral
bisphosphine ligands (L2-L4) did not result in any
enhancement over our initial choice of ligand, DTBMꢀ
SEGPHOS (L1) (entries 5ꢀ8). The benchꢀstable precomplexed
copper catalyst (S)ꢀCuCatMix13, consisting of a mixture of
Cu(OAc)2/L1/PPh3 in a 1:1.1:1.1 ratio, offered a slightly
improved yield and also simplified the reaction protocol (entry
aAll yields represent average isolated yields of two runs conductꢀ
b
c
ed on a 0.5 mmol scale. 40 °C reaction temperature. 5 mol %
catalyst used. d3 equivalents of (MeO)2MeSiH were used.
We next examined the scope of substituents that could be
appended to the olefin (Table 3). The analogous 3ꢀ
ethylaziridine 3m was successfully obtained from the
corresponding crotyl hydroxylamine ester in 62% isolated
yield and 93% ee. A benzyl ether (3n), an Nꢀtosylate (3r), a
silylether (3t), and a ketal (3v) were also compatible with the
reaction conditions. Furthermore, high yields and
enantioselectivities were observed in products derived from
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substrates that contained heterocyclic fragments. Among the
Chiral aziridines are well known as versatile intermediates
in organic synthesis.2 To showcase the synthetic utility of Nꢀ
alkyl aziridines, aziridine 3o was converted into a series of
chiral amines (Scheme 1). Terminal aziridine 3o underwent
regioselective ring opening with azide15 and acetic acid16 to
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3
4
5
6
7
8
substrates tested, a pyridine (3p), a quinoline (3q), a furan (3f,
Table 2), a benzoxazole (3s), a benzothiazole (3t), and a tosylꢀ
protected benzimidazoles (3r) were all wellꢀtolerated under
this CuHꢀcatalyzed protocol. Substrates bearing large alkene
substituents such as a diphenylmethyl (3l and 3o) and a
cyclohexyl (3p) group also underwent the desired aziridination
provide chiral azido amine
6 and amino alcohol 8,
respectively. Subjecting 3o to hydrogenation conditions
provided chiral secondary amine 7. Further, LiIꢀcatalyzed
insertion of carbon dioxide into 3o afforded oxazolidones 9 as
Table 3. Substrate scope of alkene substituents and hetero-
cyclic substituentsa
9
Scheme 1. N-alkyl aziridine derivatizationa and X-ray
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crystallographic structure of 10
aAll yields represent average isolated yields of two runs conductꢀ
ed on a 0.5 mmol scale. b5.0 mmol scale, 0.5 mol % catalyst used,
40 h reaction time. c5 mol % catalyst used. d48 h reaction time.
aReaction conditions: a) TMSN3 (5 equiv), AcOH (5 equiv),
MeCN, rt. b) Pd/C (10 mol %), H2 (1 atm), MeOH, rt. c) AcOH (5
equiv), CH2Cl2, rt. d) LiI (1 equiv), CO2 (1 atm), 40 °C. e) PPTS
(1.5 equiv), CH2Cl2, rt.
reaction without loss of efficiency or selectivity. Notably, other
C=C double bonds in positions distal to the hydroxylamine
ester (3u) were left intact, suggesting that the hydroxylamine
ester group not only controls the regioselectivity but also
activates the adjacent alkene for chemoselective
hydrocupration. The presence of a homoallylic benzyl ether
did not perturb the regioselectivity of the reaction (3n). Also, a
hydroxylamine ester containing a chiral ketal group (1v) can
be converted to aziridine 3v with greater than 20 : 1
diastereoselectivity. To demonstrate the scalability of this
procedure, product 3o was synthesized on a 5.0 mmol scale.
Full conversion of the substrate was achieved with a reduced
catalyst loading of 0.5 mol % to efficiently provide aziridine
3o (1.78 g of 3o, 90% yield, 98% ee).
a 9.5 : 1 mixture of regioisomers.17 In a reaction for which we
could find no precedent, treatment of 3o with PPTS afforded
chiral pyridinium salt 10·OTs, which allowed the absolute
stereochemistry of aziridine product 3o to be established by
Xꢀray crystallography.18
In summary, a highly enantioselective aziridination reaction
was achieved through CuHꢀcatalyzed regioselective
intramolecular hydroamination. The mild reaction conditions
of this protocol allow for compatability of a wide range of
functional groups and heterocyclic substitutents. Efforts to
extend this intramolecular hydroamination strategy to
encompass more types of nitrogenꢀcontaining heterocycles are
currently under way.
During the course of our studies, we found that the nature of
olefin geometry had a significant influence on reactivity and
enantioselectivity. Under the optimized aziridination
conditions, a low conversion of (Z)ꢀ1ae (Table 2) was
observed, with only trace amounts of aziridine product 3a
detected. Although full conversion could be achieved by
raising the reaction temperature to 40 °C, the aziridine product
3a was obtained in only 12% isolated yield and 71% ee. The
majority of the mass balance was accounted for by reductive
cleavage of the N–O bond 5a, a side reaction exacerbated by
the low reactivity of the (Z)ꢀconfigured alkene.11g
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data for all comꢀ
pounds (PDF)
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L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892. (c) Hashimoto,
AUTHOR INFORMATION
T.; Nakatsu, H.; Yamamoto, K.; Maruoka, K. J. Am. Chem. Soc.
2011, 133, 9730. (d) Egloff, J.; Ranocchiari, M.; Schira, A.; Schotes,
C.; Mezzetti, A. Organometallics 2013, 32, 4690.
1
2
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Corresponding Author
* sbuchwal@mit.edu
6 For selected examples, see: (a) (a) Akiyama, T.; Suzuki, T.; Mori, K.
Org. Lett. 2009, 11, 2445. (b) De Fusco, C.; Fuoco, T.; Croce, G.;
Lattanzi, A. Org. Lett. 2012, 14, 4078. (c) Trost, B. M.; Saget, T.;
Hung, C.ꢀI. Angew. Chem. Int. Ed. 2017, 56, 2440.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
7 Roth, P.; Andersson, P. G.; Somfai, P. Chem. Commun. 2002, 1752.
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Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J. J. Am. Chem. Soc.
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2017, 139, 1412.
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ACKNOWLEDGMENT
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We acknowledge Novartis International AG and the National
Institutes of Health (GM58160) for supporting this work. We are
grateful to Dr. Benjamin Martin, Dr. Berthold Schenkel, and Dr.
Gerhard Penn for helpful discussions. We thank the National Sciꢀ
ence Foundation (CHEꢀ0946721) for funding the Xꢀray facility at
MIT. We thank Dr. Peter Mueller for Xꢀray crystallographic data
and Dr. Bruce Adams for his help in NMR analysis. We thank Dr.
Yiming Wang, Dr. Mycah Uehling, Dr. Nicholas White, Dr. Miꢀ
chael T. Pirnot and Dr. Christine Nguyen for assistance with the
preparation of this manuscript.
10
(a) Fadeyi, O. O.; Schulte, M. L.; Lindsley, C. W. Org. Lett. 2010,
12, 3276. (b) Senter, T. J.; O’Reilly, M. C.; Chong, K. M.; Sulikowꢀ
ski, G. A.; Lindsley, C. W. Tetrahedron Lett. 2015, 56, 1276.
11
For a review on recent advances in CuH catalysis, see: (a) Pirnot,
M. T.; Wang, Y.ꢀM.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016,
55, 48. (b) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Chem. Rev. 2016,
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2013, 135, 15746. (d) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M.
Angew. Chem. Int. Ed. 2013, 52, 10830. (e) Yang, Y.; Shi, S.ꢀL.; Niu,
D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62. (f) Wang, Y.ꢀM.;
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Soc. 2015, 137, 10524. (g) Niljianskul, N.; Zhu, S.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2015, 54, 1638. (h) Bandar, J. S.; Ascic, E.;
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Perry, I. B.; Lu, G.; Liu, P.; Buchwald, S. L. Science 2016, 353, 144.
(j) Shi, S.ꢀL.; Wong, Z. L.; Buchwald, S. L. Nature 2016, 532, 353.
(k) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Nat. Chem. 2016, 8, 144.
(l) Han, J. T.; Jang, W. J.; Kim, N.; Yun, J. J. Am. Chem. Soc. 2016,
138, 15146. (m) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F.
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McCoull, W.; Davis, F. A. Synthesis 2000, 10, 1347. (b) Huang, C.ꢀ
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KGaA: 2011, p 1. For selected examples of aziridines in natural prodꢀ
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12 The absolute stereochemistry was assigned in analogy to that of 3o.
See Scheme 3.
13
Bandar, J. S.; Pirnot, M. T.; Buchwald, S. L. J. Am. Chem. Soc.
2015, 137, 14812.
14
The ratio of aziridine 3a and 1ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀ
propylazetidine (see Supporting Information for synthesis of the auꢀ
thentic sample) was determined to be > 99 : 1 by GC analysis of the
crude reaction mixture for entries 1ꢀ5.
3
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18
The crystal structure obtained was that of 10ꢁCl. Pyridinium salt
10ꢁOTs was crystallized from a solvent mixture containing dichloroꢀ
methane, which is presumed to be the source of the chloride anion
observed by Xꢀray crystallography.
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Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 5643. (b) Huang,
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