Enantiospecific Synthesis of Nepetalactones by One-Step Oxidative NHC Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b04034

An efficient oxidative NHC-catalyzed one-step transformation of (S)-or (R)-8-oxocitronellal to nepetalactone (NL) in enantio- A nd diastereomerically pure form has been developed. Several new and "easy to make" N-Mes-or N-Dipp-substituted 1,2,4-triazolium salts carrying nitroaromatic groups on N1 were synthesized and evaluated as precatalysts in combination with base and stoichiometric organic oxidant. Under optimized conditions, NLs are accessible in very good yields and diastereomerically pure under mild conditions. The oxidant used could be recovered and recycled under operationally simple conditions.

Full text of DOI:10.1021/acs.orglett.9b04034

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantiospecific Synthesis of Nepetalactones by One-Step Oxidative
NHC Catalysis
Wacharee Harnying,* Jorg-M. Neudorfl, and Albrecht Berkessel*
†
̈
̈
Department of Chemistry (Organic Chemistry), University of Cologne, Greinstrasse 4, 50939 Cologne, Germany
S
* Supporting Information
ABSTRACT: An efficient oxidative NHC-catalyzed one-step trans-
formation of (S)- or (R)-8-oxocitronellal to nepetalactone (NL) in
enantio- and diastereomerically pure form has been developed. Several
new and “easy to make” N-Mes- or N-Dipp-substituted 1,2,4-
triazolium salts carrying nitroaromatic groups on N1 were synthesized
and evaluated as precatalysts in combination with base and
stoichiometric organic oxidant. Under optimized conditions, NLs
are accessible in very good yields and diastereomerically pure under
mild conditions. The oxidant used could be recovered and recycled
under operationally simple conditions.
epetalactones (NLs, 1)1 are essential oils in a class of
monoterpenoids produced by plants of the genus Nepeta
Recently, we reported the first NHC-catalyzed one-step
bicyclization of 8-oxocitral (2) to rac-nepetalactone, using 1,4-
bis-Mes/Dipp-1,2,4-triazolium salts (3/4, Scheme 1) as
N
in the mint family (Lamiaceae).2 Generally, the (7S)-
nepetalactones are found in natural sources and exist as a
mixture of varying amounts of diastereomers, predominantly
1a and 1b, depending on the Nepeta species and the specific
source (Figure 1).2,3 For example, the oils obtained from the
Scheme 1. One-Step Synthesis of Nepetalactone by NHC
Catalysis
Figure 1. Four possible diastereomeric forms of (7S)-nepetalactones.
steam distillation of catmint plants (N. cateria) from different
suppliers contain different ratios of cis−trans-nepetalactone
(1a) and trans−cis-nepetalactone (1b).4,5 Notably, the trans-
fused lactone 1b readily epimerizes to the thermodynamically
more stable cis-fused lactone 1a upon heating with base (DBU,
Cs2CO3, K2CO3).3,5
Nepetalactones are known to cause a euphoric effect in
cats;6 they are also components of aphid sex pheromones7 and
insect and mosquito repellents.4,8 In addition, (+)-1a has been
used by Christmann et al. as starting material in the total
synthesis of the highly biologically active englerin A, albeit its
antipode, (+)-englerin A, was obtained.9 To gain access to the
natural (−)-englerin A, (−)-1a is thus required. It is
noteworthy that (−)-1a, the enantiomer of (+)-1a, has never
been isolated from natural sources. Several methods for the
synthesis of optically active nepetalactone from citral,
citronellal, pulegone, or limonene have been reported, all of
which required several synthetic steps.10
precatalysts.11 Unfortunately, our attempts to employ chiral
NHCs to effect an enantioselective transformation of 8-
oxocitral (2) have thus far met with frustration. We therefore
turned our attention to an alternative approach, namely, the
use of (S)- and (R)-8-oxocitronellal (5) as chiral pool
substrates. The latter can easily be prepared from commercially
available (S)- and (R)-citronellal10a,b,12 or (S)- and (R)-
citronellol13 (Scheme 1). This strategy would require an
external stoichiometric oxidant in the NHC-catalyzed bicycli-
zation. On the other hand, as saturated aldehydes are less
functionalized and more prevalent than their respective α,β-
Received: November 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04034
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unsaturated counterparts, the resulting methodological im-
provement could be expected to be of broad applicability.
Our working hypothesis is demonstrated in Scheme 2. The
reaction between the NHC and the aliphatic aldehyde moiety
IBA byproduct obtained can be oxidized with aqueous
Oxone,19 providing 86% yield of recovered IBX. The desired
(S)-5 was obtained in 58% yield, over two steps, after
purification.
For NHC catalysts, our previous study had revealed that
only 1,2,4-triazolylidenes carrying mesityl (Mes) or 2,6-bis(2-
propyl)phenyl (Dipp) groups at N1 and N4 efficiently
catalyzed the one-step bicyclization of 8-oxocitral (2) to NL
1 (cf. Scheme 1).11 The synthesis of the triazolium precatalysts
mentioned required the use of Mes/Dipp-hydrazine hydro-
chlorides as one of the starting materials (cf. Scheme 4b). The
Scheme 2. Oxidative NHC-Catalyzed Bicyclization of 10-
Oxocitronellal (5)
Scheme 4. Synthesis of New Triazolium Salts Carrying Nitro
Groups as Precatalysts
of 5 would give the Breslow intermediate I.14,15 Subsequent
oxidation16,17 to the acyl azolium intermediate II followed by
deprotonation would provide the chiral azolium enolate III.
This key intermediate for bicyclization would induce the
generation of enantiomerically pure nepetalactone possessing
three chiral centers in a one-step fashion.11 This obvious
benefit prompted us to evaluate the feasibility of this concept
(Scheme 2). Herein, we report the first one-step and
diastereoselective conversion of (S)- or (R)-8-oxocitronellal
to enantiomerically pure nepetalactones by NHC-catalysis
under oxidative conditions. The stoichiometric oxidant could
be easily recovered. Furthermore, several new, highly efficient,
and “easy to make” triazolium precatalysts are disclosed.
Preparation of the substrate (S)-5 for oxidative NHC
catalysis studies was performed on multigram scale by two-step
oxidation of (S)-citronellol, based on literature precedent
(Scheme 3).13 After allylic oxidation with SeO2/t-BuOOH, the
latter were typically prepared from Mes/Dipp-Br via Grignard
reaction with di-tert-butyl azodicarboxylate (BocNNBoc),
followed by Boc-deprotection.11,20 The low purity and poor
stability (very sensitive to air) of mesitylhydrazine20b,21 and the
difficulties of purification (requiring column chromatogra-
phy)11 of the corresponding bis-Mes-triazolium salt 3,
prompted us to investigate the synthesis of new triazolium
derivatives bearing a nitro group (NO2) on the arylhydrazine
moiety (Scheme 4). We envisaged that the introduction of a
nitro group, owing to its electron withdrawing effect, would
reduce the reactivity of the proximal N of the hydrazine, and
consequently steer the condensation with imidoyl chloride to
the distal N, that is, to the formation of 12 (Scheme 4b). The
resulting absence of isomeric products would greatly facilitate
purification of the triazolium salt.
Pleasingly, the hydrazines 10a−d (Scheme 4a) could be
conveniently prepared from the corresponding anilines 8 in
two steps by nitration with nitric acid (1 or 2 equiv),22
followed by a diazotization/reduction process.20b,23 The free
hydrazines 10a−c are solids obtained in high purity by simply
washing with Et2O and are not sensitive to air. The free
hydrazine 10d is an oil, preferably stored as its hydrochloride
salt. Next, the triazolium salts were synthesized via a simple
Scheme 3. Synthesis of 5 from Citronellol
crude mixture of 6 and 7 obtained was directly subjected to
IBX oxidation in DMSO, furnishing 5 in moderate isolated
yield (25−44%, lit.13 79% crude yield). We found that some
impurities from the allylic oxidation have similar Rf to that of 5,
making purification of 5 in the end by column chromatography
(CC) difficult. Therefore, we applied a short CC for
purification of 6 and 7 prior to the IBX oxidation. We
additionally observed that performing the IBX oxidation in
MeCN as solvent was advantageous.18 After filtration, the solid
B
DOI: 10.1021/acs.orglett.9b04034
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
three-step sequence (purification only in the final step) starting
from the benzamide 11 (Scheme 4b), readily prepared in 50 g
scale from Mes/Dipp-aniline (see the SI). To our delight, the
new triazolium salts 13−19, derived from hydrazines 10a−d
and the commercially available 3-nitrophenylhydazine hydro-
chloride, could be easily purified by simply washing the crude
product with EtOAc several times.
Table 1. Screening of Reaction Conditions for the NHC-
Catalyzed Transformation of (S)-5 to (+)-1a
a
We obtained crystalline samples of triazolium salts 14, 16,
17, and 18 suitable for single crystal X-ray structural analysis,
as shown in Figure 2. All crystal structures were similar in the
b
b
entry
catalyst
base (equiv)
yield (%)
1a ds (%)
1
2
3
4
5
6
7
8
3
4
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.2)
NaOAc (0.2)
LiOAc (0.2)
LiOAc (0.2)
DIPEA (0.2)
DIPEA (0.2)
92
95
90
92
92
60
93
92
92
45
68
82
0
59
91
90
79
92
91
>99
97
>99
>99
>99
88
97
96
96
44
13
14
15
16
17
18
19
20
21
22
23
14
14
14
14
14
14
9
10
11
12
13
14
15
Figure 2. X-ray crystal structures of 14, 16, 17, and 18.
>99
95
sense that the N-substituents carrying ortho,ortho′-disubstitu-
ents on the aryl group are almost perpendicular to the
triazolium ring, while the m-nitrophenyl ring at N1 of 16 is
almost coplanar with the triazolium core.
c
>99
>99
>99
>99
>99
>99
c
c
16
With the new triazolium precatalysts in hand, we set out to
investigate the one-step transformation of (S)-5 to nepeta-
lactone (+)-1a (Table 1). With K2CO3 as the base, among the
oxidants examined (MnO2, phenazine, riboflavin derivatives),
quinone A, an oxidant pioneered by Studer and co-workers for
NHC catalysis,24 was identified as the most effective one. In
the presence of 5 mol % triazolium 3 or 4, the desired (+)-1a
was obtained in excellent yields and diastereoselectivities
(entries 1 and 2). Various NHCs were then tested under
identical conditions. To our delight, all of the new triazolium
precatalysts 13−15 and 17−19 provided the product (+)-1a in
excellent yields and diastereoselectivities (entries 3−5 and 7−
9). On the other hand, the mono-Mes-substituted triazolium
salt 16 gave moderate yield and diminished diastereoselectivity
(entry 6), indicating the important role of the ortho,ortho′-
disubstitution of the N1-aryl group of the triazolium
precatalysts. The parent N-phenyl triazolium salt 20 (proto-
nated Enders−Teles carbene)25 showed moderate activity and
poor diastereoselectivity (entry 10). The bis-Mes/Dipp-
benzimidazolium salts 21 and 2215d also displayed excellent
diastereoselectivities, yet reactivities were lower than those of
the triazolium analogues (entries 11 and 12 versus entries 1
and 2). For this transformation, IMes (23) was catalytically
inactive (entry 13).
Interestingly, excellent diastereoselectivities were observed
with the group of N4-Mes-substituted precatalysts 3, 13−15,
and 21, affording (+)-1a as the only product isomer (entries 1,
3−5, and 11), while the group of N4-Dipp-substituted
precatalysts 4, 17−19, and 22 delivered slightly lower
selectivities (entries 2, 7−9, and 12). From the group of N4-
Mes-triazolium salts, 14 emerged as the catalyst of choice, due
to the ease of its purification and synthesis in high yield. With
14, we examined the effect of different bases. At higher
substrate concentration of 0.4 M in THF, K2CO3 showed low
c
c
c
,
d
d
17
18
19
,
a
Reaction was performed with 0.1 mmol of (S)-5 in THF (0.5 mL),
unless noted otherwise. For entries 1, 2, 4, 5, and 7−9, the substrate
was completely consumed after ca. 6 h, whereas in the cases ofentries
6, 10−12, the reactio did not go to completion after 16 h. “MS” stands
b
for molecular sieves. Determined by GC using dodecane as internal
standard; “yield” denotes to the sum of all diastereoisomers obtained;
“diastereoselectivity” indicates the percentage of (+)-1a present in the
total yield. Solvent = 0.25 mL, reaction time 5 h; in the cases of
entries 14 and 17, the reaction did not reach completion. The
c
d
reaction was performed in toluene.
activity, presumably because of poor solubility (entry 14),
whereas the use of NaOAc, LiOAc, and DIPEA resulted in
excellent yields (entries 15, 16, and 18). Changing the solvent
to toluene led to no noticeable change in results when DIPEA
was used as the base (entry 19). Lower reactivity was observed
with LiOAc, presumably because of lower solubility (entry 17).
With the optimized reaction conditions at hand, we further
developed the procedure for the synthesis of (+)-1a from (S)-5
on gram scale, at the same time aiming at recovering the
oxidant A/A-H2 from the reaction mixture to overcome
potential drawbacks of its stoichiometric use. Note that the
oxidant A was readily prepared from 2,6-di-tert-butylphenol on
50 g scale, simply by stirring open to air in the presence of
KOH in H2O/t-BuOH.26 The synthesis of (+)-1a was
performed on 10 mmol scale of (S)-5 using the triazolium
salt 14 (5 mol %), DIPEA (20 mol %), and the oxidant A (1.1
equiv) in THF at rt (Scheme 5). After completion of the
reaction, A-H2/A could be readily isolated by precipitation in
MeOH−H2O and filtration. Gratifyingly, the recovered A-H2
could be recycled to A in 90% yield (after recrystallization) by
C
DOI: 10.1021/acs.orglett.9b04034
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Enantiospecific Synthesis of the Nepetalactone
Enantiomers (+)-1a and (−)-1a
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: berkessel@uni-koeln.de.
*E-mail: wharnyin@uni-koeln.de.
ORCID
Albrecht Berkessel: 0000-0003-0470-7428
Author Contributions
†J.-M.N. performed X-ray crystallography.
applying the same method as described for the synthesis of A.
The nepetalactone was isolated by extraction and purified by
the Kugelrohr distillation, affording (+)-1a in 84% yield with
Notes
The authors declare no competing financial interest.
ds > 99% and ee = 97% {chiral GC; [α]20 +21.9 (c 0.25,
D
Et2O); lit.10b +20.6 (c 0.24, Et2O; > 95% ee by NMR)}.
(−)-1a was prepared in the same manner starting from (R)-5
on 2 mmol scale and obtained in 80% yield with ds > 99% and
ACKNOWLEDGMENTS
■
Support by the Deutsche Forschungsgemeinschaft (priority
program 1807 “Control of London Dispersion Interactions in
Molecular Chemistry”, Grant Nos. BE 998/14-1,2) and by the
Fonds der Chemischen Industrie is gratefully acknowledged.
ee > 99% {chiral GC; [α]20 −22.4 (c 0.25, Et2O); lit.10b
D
−21.0 (c 0.17, Et2O; > 95% ee by NMR)}. Note that the lower
ee of (+)-1a (97%) relative to the ee of (−)-1a (>99%) does
not result from an erosion of enantiopurity in the course of the
preparation of the dialdehyde (R)-5 or the oxidative
bicyclization of the latter to (+)-1a. Instead, analysis of the
commercial citronellol enantiomers used as starting materials
revealed 97% ee for the (S)-enantiomer, and >99% ee for its
(R)-antipode (see SI for the details of the analysis). In other
words, the enantiomeric compositions of the nepetalactone
products (−)-1a and (+)-1a correspond exactly to those of the
citronellol starting materials.
DEDICATION
■
Dedicated to the late Prof. Dieter Enders.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04034.
■
S
Detailed experimental procedures, spectral and X-ray
data (PDF)
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DOI: 10.1021/acs.orglett.9b04034
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