Chiral Br?nsted Acid-Catalyzed Asymmetric Synthesis of N-Aryl-cis-aziridine Carboxylate Esters

Article abstract of DOI:10.1002/anie.201611990

We report a multi-component asymmetric Br?nsted acid-catalyzed aza-Darzens reaction which is not limited to specific aromatic or heterocyclic aldehydes. Incorporating alkyl diazoacetates and, important for high ee's, ortho-tert-butoxyaniline our optimized reaction (i.e. solvent, temperature and catalyst study) affords excellent yields (61–98 %) and mostly >90 % optically active cis-aziridines. (+)-Chloramphenicol was generated in 4 steps from commercial starting materials. A tentative mechanism is outlined.

Full text of DOI:10.1002/anie.201611990

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611990
German Edition: DOI: 10.1002/ange.201611990
Asymmetric Catalysis
Chiral Brønsted Acid-Catalyzed Asymmetric Synthesis of N-Aryl-cis-
aziridine Carboxylate Esters
Sean P. Bew,* John Liddle, David L. Hughes, Paolo Pesce, and Sean M. Thurston
Abstract: We report a multi-component asymmetric Brønsted
acid-catalyzed aza-Darzens reaction which is not limited to
specific aromatic or heterocyclic aldehydes. Incorporating
alkyl diazoacetates and, important for high eeꢀs, ortho-tert-
butoxyaniline our optimized reaction (i.e. solvent, temperature
and catalyst study) affords excellent yields (61–98%) and
mostly > 90% optically active cis-aziridines. (+)-Chloram-
phenicol was generated in 4 steps from commercial starting
materials. A tentative mechanism is outlined.
Scheme 1. Multicomponent asymmetric synthesis of N-aryl-cis-aziri-
dines 4.
S
uch is the versatility of organocatalysis and its ability to
mediate a plethora of diverse reaction types[1] it is, now, an
indispensable “tool” in the synthetic chemists “toolbox”.[2]
Indeed, improving atom- and reaction-efficiency is a key
driver to developing new reactions and protocols; in this
context organocatalysis has demonstrated its importance by
efficiently mediating many different convergent reactions or
multi-component syntheses. The work here supports these
aspects by generating structure and function-diverse motifs
via fewer synthetic, isolation and purification steps.
generated or commercially available aldehydes (1), amines
(2) and alkyl diazoacetates (3, Scheme 1).
=
Activating the C N bond of an imine with a BINOL
phosphoric acid[5] lowers its LUMO energy and generates an
imminium ion pair that can, but not always will, react with
a nucleophile. Seminal work by Akiyama et al. established
chiral BINOL phosphoric acids [pKa ꢀ 13 (CH3CN)[6]] acti-
vate aldimines (derived from, specifically, arylglyoxals and p-
anisidine) and react with ethyl diazoacetate (EDA) affording
cis-aziridines in 92–97% ee.[7] Similarly, other Brønsted
acids[8] and pyridinium triflate activate a diverse array of
imines, including for example, 2-pyridyl derived 5, enabling
the presumed imminium ion-pair (not shown) to react with
EDA and afford cis-rac-aziridine (8, 83% yield)
(Scheme 2).[9] With these racemic studies complete our
Optically active aziridines have many diverse uses,
especially as key intermediates[3] “on route” to important
“secondary” products for example, a-/b-amino acids, poly-
mers, azasugars, auxilaries, oxazolidinones, imidazolidines, b-
lactams and pyrrolidines. Further applications include syn-
thesis of non-aziridine containing bioactive compounds for
example, kainoids, (À)-mesembrine, (À)-platynesine, actino-
mycin and feldamycin, in addition to synthetic bioactive
aziridines for example, NSC676892 as well as natural products
for example, azinomycin and maduropeptide.[4]
Using a BINOL N-triflylphosphoramide Brønsted acid
a 61–98% yielding asymmetric aza-Darzens reaction affords
N-aryl-cis-aziridines in, mostly, 90–99% ee. The reaction is
straightforward to set up and has minimal requirements for
strictly anhydrous or anaerobic conditions, furthermore it
does not require organocatalyst pre-generation or activation,
or an “activated” arylglyoxal starting material. Exploiting the
protocol synthesis of aziridines based on 4 uses readily
Scheme 2. Failed attempts at synthesising cis-8 and cis-9.
focus shifted to developing a substrate enhanced and diverse,
multi-component asymmetric aza-Darzens reaction. Inspired
by the work of Akiyama et al.[7] and the Mannich reaction
reported by Yamanaka et al. we considered the inclusion of 5
may generate a constrained hydrogen-bonded and activated
complex similar to 11; we were drawn to the use of 5 to
generate 11 due to similarities in the chiral non-racemic rigid
environment proposed by Yamanaka (using a N-(2-hydroxy-
phenyl)imine starting material).[10] Screening chiral non-
racemic BINOL and VANOL phosphoric acids, as well as
a H-QUIN-BAM triflate salt[11] we were disappointed no
reactions were observed. We attribute the failure using 5, as
[*] Dr. S. P. Bew, D. L. Hughes, P. Pesce, S. M. Thurston
School of Chemistry, Norwich Research Park
University of East Anglia
Norwich, NR4 7TJ (UK)
E-mail: s.bew@uea.ac.uk
Homepage: http://www.uea.ac.uk/cap/people/faculty/spb
J. Liddle
Department of Medicinal Chemistry, GlaxoSmithKline
Gunnels Wood Road, Stevenage, Hertfordshire (UK)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611990.
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well as other alternative imines, to the low pKaꢀs of the
Brønsted acids and their inability to generate a sufficiently
“activated” form of 10 or 11.
Switching to the more acidic BINOL N-triflylphosphor-
amides for example, pKa 14 ꢀ 6 (CH3CN)[6] (Figure 1) the
synthesis of (S)-3,3’-bis(phenyl)-14, (S)-3,3’-bis(4-methyl-
Encouraged by the results with 6, sterically encumbered
tert-butyl ester 7 was investigated. A gradual increase in ee
was observed but, overall, the levels of stereoinduction were,
generally, inferior. So, N-benzyl 5 was substituted for a rota-
tionally less flexible N-4-(methoxyphenyl) or N-PMP group.
Reacting the corresponding imine (not shown) with 7
mediated by 21 afforded the cis-aziridine in an 81% yield
(J2,3 6.8 Hz). Further verifying the importance of including
the, presumed, rotationally less flexible N-PMP the product
was afforded with a significantly improved 67% ee. Exchang-
ing the N-PMP for the regioisomeric N-2-methoxyphenyl
imine 22 (Scheme 3) its activation (21) and reaction with tert-
Figure 1. Enamides and 3,3’-bis(aryl) (S)-BINOL N-triflylphosphor-
amides.
phenyl)-15 and sterically encumbered (S)-3,3’-bis(4-tert-
butylphenyl)-16 was straightforward.[12] By using 10 mol%
all three catalysts, independently, at room temperature
mediated the synthesis of cis-aziridine 8 in 73%, 85% and
87% yields, respectively. 1H-NMR of the unpurified reactions
confirmed no enamide[5] i.e. Z-12 or Z-13 (Figure 1) or trans-8
(J2,3 ꢀ 2 Hz, not shown) had formed. Disappointingly, chiral
column HPLC analysis established cis-8 was racemic when
generated using 14 or 15; in contrast, 16 afforded non-racemic
cis-8 but in a poor 16% ee (Table 1, Entries 1–3 respectively).
Clearly, the bulky 4-tert-butyl group had a positive stereo-
chemical advantage over 14 and 15. Increasing 3,3’-steric
congestion at the 2- and 6- positions using (S)-3,3’-bis(2,4,6-
Scheme 3. Asymmetric synthesis of N-(alkoxyphenyl)-cis-aziridines 25–
27.
butyl ester-7 afforded cis-25 with a 72% ee. Evidently, the 2-
methoxyphenyl had a positive influence on the stereochem-
ical outcome of the aza-Darzens reaction. The steric effect
was probed using 2-isopropoxyphenyl-23, 2-n-butoxyphenyl
(not shown) and 2-tert-butoxyphenyl-24 (Scheme 3) each
reacted, independently, with 7 and 21. In this series and at
ambient temperature the tert-butoxy group on 24 afforded cis-
27 with a 74% ee.
Table 1: Probing the asymmetric synthesis of cis-8 and cis-9 using 14–21.
A solvent and temperature study using 1 mol% of 21
established chloroform at À608C was the optimum combina-
tion for transforming 2-(tert-butoxyphenyl)-24 into cis-27 with
an excellent 98% ee and 95% yield. Probing the catalytic
activity of 21 at 0.5 and 0.25 mol% loadings the reaction times
increased to 48 and 62 hours. In both examples cis-27 was
afforded in very similar 87%/86% ee and 98%/95% yield,
respectively.
The synthesis of 38–47 (Scheme 4) was examined using 21
(1 mol%) in CHCl3 at À608C. Incorporating (E)-2-(tert-
butoxyphenyl)-28 cis-38 was afforded in an excellent 91% ee
and 90% yield. Confirming reaction versatility electron-
withdrawing 4-cyano imine-30 and 4-nitrophenyl imine-31
were transformed into cis-40 and cis-41 with excellent optical
purities both 98% and yields that is, 98% and 97%
respectively (Scheme 4). Similarly, electron-rich 4-hydroxy-
benzaldehyde (O-Fmoc protected) afforded cis-42 in a 90%
ee and 91% yield. Cis-43 to cis-47 were synthesized in
excellent yields and eeꢀs; 4-bromophenyl-cis-45 (93% ee) and
4-iodophenyl-cis-46 (92% ee) appear readily amenable to
further elaboration via transition-metal mediated transfor-
mations.
Entry Catalyst 8 (R=Et, ee)
Entry Catalyst 9 (R=tBu, ee)
1
2
3
4
5
6
7
8
14
15
16
17
18
19
20
21
racemic
racemic
16%
23%
28%
26%
35%
47%
9
10
11
12
13
14
15
16
14
15
16
17
18
19
20
21
racemic
18%
13%
racemic
20%
20%
22%
31%
triisopropyl)phenyl-17 returned cis-8 in excellent yield and
increased 23% ee (entry 4).
The 69% increase in ee when 2- and 6-isopropyl groups
were incorporated (17) suggests these “lateral” positions have
key roles in reaction stereoselectivity. Probing this, multicyclic
1-naphthyl (18), 2-naphthyl (19), 9-phenanthryl (20) and 9-
anthryl (21) were incorporated (10 mol%) into our “test”
reaction (Scheme 2). All afforded excellent yields of cis-8. A
gradual increase in ee was observed as the “lateral” groups
were added. Thus catalyst 14 afforded rac-8, whereas 1-
naphthyl-18 offered cis-8 with a 28% ee. An almost identical
26% ee was provided by 2-naphthyl-19 and 9-phenanthryl-20
gave an improved 35% ee, finally, 9-anthryl-21 generated cis-
8 in a respectable 47% ee.
The magnitude of an aziridine coupling constant (J2,3)
indicates the relative stereochemical assignment of the C2,3-
substituents that is, J2,3 5–9 Hz = cis and 2–6 Hz = trans. For
2
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4-Trifluoromethylbenzaldehyde and pentafluorobenz-
aldehyde afforded cis-50 and cis-51 in excellent 89% and
90% eeꢀs, respectively. Integrating bicyclic quinoline-2-car-
boxyaldehyde was also straightforward; optically active cis-52
was afforded in a 98% ee. Interestingly, the formation of cis-
27 and cis-52 was faster than for example 40, 41, 49–50; the
rapid evolution of, presumably, N2 was attributed to forma-
tion of a more reactive intramolecular chelated hydrogen
bond (cf. 11). Combining benzene-1,4-dicarboxyaldehyde and
48 (1 equiv) a one-pot, single asymmetric aziridination
afforded mono-aziridine cis-54. Alternatively, 2 equiv of 48
generated bis-aziridine cis-55. Both reactions worked very
well, cis-54 was afforded in a 70% yield and 90% ee and bis-
aziridine cis-55 with a 99% ee. Seemingly, the installation of
the second aziridine on optically active cis-54 to generate cis-
55 was not negatively influenced by the first optically active
cis-aziridine. (À)-Chloramphenicol is an important natural
product with antibiotic properties. A one-pot multicompo-
nent aziridination using 4-nitrobenzaldehyde, amine 56 and
tert-butyl diazoester 7 afforded cis-57 in near quantitative
yield and an excellent 96% ee. By using cerium(IV)
ammonium nitrate in aqueous acetonitrile an important
objective was to establish the cleavage “potential” of the 2-
tert-butoxy-4-methoxyphenyl on cis-57; NH-cis-58 was
afforded in an unoptimized 67% yield, this was ring-opened
to amide 59 with dichloroacetic acid, finally reducing the tert-
butyl ester generated primary alcohol 60 (79% yield).
Physicochemical analysis and comparison with the literature
Scheme 4. Asymmetric synthesis of structure and function diverse
N-(2-tert-butoxyphenyl)-cis-aziridines 38–47 and the X-ray structure of
cis-45.
38–47 we tentatively assigned a cis-ste-
reochemical relationship; confirming this
was essential. Recrystallising 45 [J2,3 6.7-
(4) Hz] afforded colorless orthorhombic
plates. X-ray diffraction established the
cis-stereochemical relationship between
the 4-bromophenyl and the tert-butyl
carboxylate ester (Scheme 4).[13]
Generating aziridines via multicom-
ponent asymmetric syntheses is advanta-
geous, they are however, still, rare.[14] It
was crucial to verify 21 mediated the
multicomponent synthesis of cis-aziri-
dines.
A three-component, two-step,
one-pot protocol generated 2-pyridyl-27,
4-cyanophenyl-40 and 4-nitrophenyl-41
in excellent yields that is, 74–96% and
eeꢀs that is, 27 (96%) 40, (99%) and 41
(96%, Scheme 5). These eeꢀs are, within
experimental error, identical to those
generated via the pre-synthesis imine
route (Scheme 4). Incorporating 4-thio-
methyl-, 4-trifluoromethyl- and penta-
fluorobenzaldehyde afforded cis-49 to
cis-51. The efficient synthesis of thioether
cis-49 is worthy of note; Davis et al.
exploited similar (S)-N-(4-toluenesul-
finyl)-derived aziridines transforming
them into thiamphenicol and florfeni-
col.[15]
Scheme 5. Asymmetric synthesis of cis-aziridines and (+)-chloramphenicol.
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confirmed (+)-chloramphenicol 60 had been synthesized
using (S)-21 in 4 steps and an overall 40% yield.[16]
Scheme 6 outlines a tentative mechanism for cis-aziridine
diastereoselectivity. Initial N-protonation of 31 via Brønsted
acid (S)-21 [pKa ꢀ 6 (CH3CN)],[6] affords imminium-phos-
imine Si face is, now, inhibited by the two sterically bulky
groups. Thus, formation of a-diazonium b-amino ester 63 and
trans-41 is disfavoured. The crude 1H-NMRs of our reactions
afforded no evidence of trans-41 or a-diazonium b-amino
ester 63.
Experimental Section
A flame dried Radleys tube and stirrer bar was
charged with 4-cyanobenzaldehyde (34 mg,
0.26 mmol)
and
2-tert-butoxy-phenylamine
(43 mg, 0.26 mmol). Anhydrous chloroform
(1 mL) and (S)-21 (2 mg, 0.0025 mmol, 1 mol%)
were added followed by 40 mg of freshly powdered
4 ꢁ molecular sieves. The reaction was stirred for 6
hours. Cooling the tube to À608C, 7 (40 mL,
0.29 mmol) was added via syringe. The reaction
was stirred at À608C and monitored via TLC
(hexane/ether:80/20) until the starting materials
had been consumed. In vacuo removal of solvent
allowed flash purification on silica gel (hexane/
ether:80/20). Physicochemical analysis confirmed
the identity of the solid as cis-40. Chiral column
analytical HPLC established cis-40 had an ee of
99%.
Scheme 6. Mechanistic rational for the synthesis of cis-41 and not trans-41.
Acknowledgements
phoramide anion 60 (Path A, Scheme 6) whilst the weaker
triflate salts and phosphoric acids (see Supporting Informa-
tion, page 3) do not form sufficiently reactive imminium-
triflate/phosphate anions.
This work was supported via an EPSRC GSK CASE award.
Supporting protonation, not hydrogen-bond activation,[17]
Houk et al. described a mechanism and origins of catalysis Conflict of interest
DFT and experimental study in which a similarly N-proton-
ated, to 60, reactive hydrazonium-phosphoramide[18] anion
(not shown) was formed from a BINOL N-triflylphosphor-
amide and a hydrazone. Activation of 31 is crucial; the widely
accepted aza-Darzens mechanism[19] invokes attack of a diazo
nucleophile (i.e. 7) on an imminium cation (i.e. 60) generating
an a-diazonium b-amino ester (i.e. 61, see Path A). The
importance of the latter, from a reaction kinetics and
enantioselectivity point of view has been established by the
reluctance of these intermediates to undergo a retro-Mannich
reaction.[20] Generating, presumed, kinetic product 61 with
excellent enantioselectivity is possible only if 7, with its
heterotopic faces that is, 7Re and 7Si, efficiently discriminates
between the Si and Re faces of optically active 60. Path A
outlines how anti-diazonium intermediate 62 (Scheme 6)
forms when the sterically encumbered heterotopic 7Re face
approaches the Si face of imine 60 minimising the steric
interactions between the intramolecularly hydrogen bonded
bulky ortho-(tert-butoxy)phenyl imminium and the tert-butyl
ester on 7Re. Although we have no direct evidence (1H-NMR)
for the backbone rigidifying hydrogen bond in 60 similar
intramolecular hydrogen bonds in ortho-substituted Schiff
baseꢀs are known.[21] Newman projection 62 affords a detailed
depiction of the minimized steric interactions between the
tert-butyl ester and ortho-tert-butylphenyl ether. An intra-
molecular SN2 cyclization (release of N2) between the anti-
periplanar amine and diazonium groups affords cis-41. Path B
proceeds via ion-pair 60, however approach of 7Si onto the
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · aziridine · Brønsted acids ·
multicomponent reactions
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Manuscript received: December 9, 2016
Revised: February 22, 2016
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
S. P. Bew,* J. Liddle, D. L. Hughes,
P. Pesce, S. M. Thurston
&&&& — &&&&
Chiral Brønsted Acid-Catalyzed
Asymmetric Synthesis of N-Aryl-cis-
aziridine Carboxylate Esters
Nice and easy: An efficient one-pot syn-
thesis of chiral non-racemic aziridines
was achieved by using 1 mol% of a read-
ily available Brønsted acid catalyst. The
introduction of an ortho-tert-butoxy group
on the N-aryl ring was critical to inducing
high levels of optical activity in the
products. By using this protocol a simple
4-step synthesis of the antibiotic
(+)-chloramphenicol was realized.
6
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