In Situ Conformational Fixation of the Amide Bond Enables General Access to Medium-Sized Lactams via Ring-Closing Metathesis

Article abstract of DOI:10.1021/acs.orglett.8b03320

In this work, a novel phenethylamine-derived protecting group is introduced, which is able to significantly enhance the Grubbs I-catalyzed formation of 9- to 12-membered lactams through charge-induced conformational fixation under acidic conditions. As the new approach is particularly valuable for 10- and 11-membered ring systems, for which no related precedence was available so far, the overall strategy now offers general access to medium-sized lactams via ring closing metathesis. Cleavage of the protecting group can be achieved through a mild sequence combining N-oxidation and Cope elimination or alternatively under standard hydrogenation conditions.

Full text of DOI:10.1021/acs.orglett.8b03320

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In Situ Conformational Fixation of the Amide Bond Enables General
Access to Medium-Sized Lactams via Ring-Closing Metathesis
Nina Hegmann, Lea Prusko, Nina Diesendorf, and Markus R. Heinrich*
̈
̈
Department of Chemistry and Pharmacy; Pharmaceutical Chemistry, Friedrich-Alexander-Universitat Erlangen-Nurnberg,
Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
S
* Supporting Information
ABSTRACT: In this work, a novel phenethylamine-derived
protecting group is introduced, which is able to significantly
enhance the Grubbs I-catalyzed formation of 9- to 12-membered
lactams through charge-induced conformational fixation under
acidic conditions. As the new approach is particularly valuable for
10- and 11-membered ring systems, for which no related
precedence was available so far, the overall strategy now offers
general access to medium-sized lactams via ring closing metathesis.
Cleavage of the protecting group can be achieved through a mild sequence combining N-oxidation and Cope elimination or
alternatively under standard hydrogenation conditions.
etathesis reactions in general and ring-closing meta-
thesis (RCM) in particular belong to the most
preorganization but could also suppress the complexation of
the catalyst, in which the carbonyl unit is involved. Typically,
and not relying on covalent conformational restraints8,12 or
particular substituent effects on the alkenyl chains,5b,7d,e,13
medium sized lactams are prepared from amides bearing a
benzyl protecting group on the nitrogen atom14,15 (Scheme
1A).
M
important transformations in modern chemistry,1 which was
also prominently pointed out by the award of the Nobel Prize
in 2005.2 The large diversity of catalysts that is available today
enables a broad variety of applications under manifold reaction
conditions.1d,e,g,3 Along with these valuable achievements, a
broad range of carbo- and heterocyclic ring systems4 were
made accessible by ring-closing metathesis, and it opened
attractive synthetic routes to numerous natural products5 as
well as compounds with applications in medicinal chemistry6
including various cyclic peptides.7
Scheme 1. Ring-Closing Metathesis for the Synthesis of
Medium-Sized 8- to 12-Membered Lactams
However, significant difficulties still arise when ring-closing
metathesis is applied in the preparation of medium-sized ring
systems.8 This is due to enthalpic (ring strain in the product)
and entropic (probability of suitable conformations in the
reaction course) factors, and as a result, the yield of dimers and
oligomers often largely prevails over that of the desired cyclic
compound. Besides working under high dilution, a common
countermeasure against such side reactions is structural
modifications to improve the conformational preorganization
of the reactant with regard to the desired C−C bond
formation.9 Regarding cyclizations of amides and esters to
medium-sized lactams and lactones, such transformations may
additionally suffer from the formation of stable substrate−
catalyst chelate complexes.1c,10 Although this effect can be
partially overcome by the addition of a cocatalyst or by
sterically shielding the metal-coordinating centers,7d,11 these
countermeasures often impose significant limitations on the
reaction scope.11a
The presence of the benzyl group is thereby essential, as the
related secondary amide would almost fully adopt the
unfavorable trans conformation.13a,14 In the presence of the
benzyl group, an approximately 1:1-mixture of the cis and trans
rotamer is usually formed, from which ring closing metathesis
can proceed but still with the above-mentioned limitations,
which are largely due to ring size.14
Against this general background and the particular
challenges associated with the synthesis of lactams using
ring-closing metathesis, we reasoned that a carefully chosen
protecting group on the nitrogen atom of the amide not only
might be able to enhance the intended cyclization by
Received: October 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03320
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With this work, we now introduce a phenethylamine-derived
protecting group, which not only can enhance cyclization by
preorganization but also is likely to suppress complexation of
the catalyst through the presence of the positive charge
(Scheme 1B). The effect of preorganization does thereby rely
on the conformational fixation of amides induced by proximate
positive charges.16
Table 1. Preoptimization of Reaction Conditions for the 8-
Membered Lactam 4a
a
Within the intended strategy (Scheme 2), the acyclic amide
1 is assembled starting from aziridinium methanesulfonate 2,
b
Grubbs I
(mol %)
TsOH
(equiv)
CH2Cl2
(mL)
yield 4a [1a]
entry
time (h)
(%)
1
2
3
10
10
10
10 + 5
10 + 5
10 + 5
1
1
2
2
2
2
150
50
50
50
50
50
24
48
24
20+ 25
5+ 19
32 [20]
40 [10]
28 [51]
23 [54]
54 [41]
15 [53]
Scheme 2. Intended Synthetic Strategy for Medium-Sized
Lactams 5
d
4
d
5
d
6
19+ 5
a
b
For detailed reaction conditions, see SI. Reaction course was
c
1
monitored by TLC and HPLC-MS. Yields determined by H NMR
using dimethyl terephthalate as internal standard. Additional 6 (5
d
mol %) was added after the first time interval.
was shortened to 5 h, satisfactory yields of 54% for 4a and 41%
for 1a were obtained (entry 5). A control experiment under
identical conditions, in which the time intervals of 5 and 19 h
were switched, demonstrated the importance of a relatively
short first interval (entry 6).
As the cyclization precursors 1a−e for ring sizes 8 to 12 can
be expected to behave differently under the metathesis
conditions determined so far (Table 1), we studied the single
reactions in more detail. One particular question was how far
the concentration could be increased through the use of the
new protecting group inducing conformational fixation. The
results obtained for the 8- and 9-membered ring systems are
summarized in Scheme 3.
which can itself be prepared on large scale over only two steps
from styrene oxide (see Supporting Information (SI) for
details).17 In this way, the synthesis of the metathesis precursor
1 does not require more steps as if 2 would be replaced by
conventional benzyl chloride or benzaldehyde (via reductive
amination) (cf. Scheme 1A). Ring-closing metathesis under
acidic conditions should then benefit from conformational
fixation and carbonyl shielding (via 3), so that the cyclic
product 4 is obtained.16 For the cleavage of the phenethyl-
amine-derived protecting group to give lactam 5, we reasoned
that an N-oxidation/Cope elimination sequence18,19 might be
an attractive option, as such pathway would leave the double
bond in the lactam unit intact, which is typically not the case
when benzylic groups are cleaved by catalytic hydrogenation.20
In preliminary studies, the conformational fixation of the five
Scheme 3. Synthesis of 8- and 9-Membered Lactams 4a and
4b
1
lactam precursors 1a−e was validated by H NMR under the
addition of trifluoroacetic acid (see SI for details). As
dichloromethane is often reported as the solvent of choice
for RCM reactions and gave satisfying results in the NMR
study (cis/trans ratios >95:5), the reactions aimed at the
optimization of the RCM step were carried out in this solvent.
In the course of the early optimization, trifluoroacetic acid was
replaced by p-toluenesulfonic acid (TsOH).21 The Grubbs I
catalyst 6 was chosen due to its cost-effectiveness and to allow
comparison with earlier attempts to prepare medium-sized
lactams by RCM. Moreover, Grubbs II-type catalysts have
been reported to cause partial double bond isomerization in
syntheses of lactams.13a Selected results from the variations
regarding the amount of catalyst and the reaction time are
summarized in Table 1.
An experiment using 10 mol % Grubbs I catalyst 6 and 1
equiv of TsOH provided 4a in a yield of 32%, but only 20% of
1a could be recovered (entry 1). By reducing the amount of
solvent to 50 mL and prolonging the reaction time to 48 h, the
yield of 4a could be increased to 40% (entry 2). A
breakthrough regarding the recovery of 1a was then achieved
by doubling the amount of TsOH (entry 3), thereby showing
that a higher acid concentration can protect unconverted 1a
from decomposition. The addition of a second batch of 6 (5
mol %) under prolongation of the reaction time did at first not
improve the overall result (entry 4), but when the first interval
For both ring sizes, the best yields were obtained at a 5 mM
concentration (0.1 mmol 1a/b in 20 mL) at a total reaction
time of 24 h (5 h + 19 h). While the concentration could not
be further increased for the 9-membered system (1b → 4b, n =
2) without significant losses in yield, a good result was also be
achieved for 1a → 4a (56%) at 10 mM and at a shortened
reaction time of 9 h (5 h + 4 h). To evaluate the performance
of the new protecting group in comparison to the classical
B
DOI: 10.1021/acs.orglett.8b03320
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Organic Letters
Letter
benzyl group, the reference lactams 7a and 7b were prepared
under the best yield conditions, but under the omission of
TsOH. In these experiments, 7a and 7b were produced in
significantly lower yields than 4a and 4b, and much less
uncyclized starting material could be recovered. The maximum
RCM yields that can be found in literature for lactams closely
comparable to 7 are 74−80% for the 8-membered ring (with
no starting material recovered) and 59% for the 9-membered
system along with 25% of starting material.14 This data shows
that the new protecting group does not yet have a clear benefit
over benzyl for 8-membered lactams but that the so far best
literature result could be exceeded for the 9-membered system.
Encouraged by this finding, we next turned to lactams with
ring sizes in the range of 10 to 12 (Scheme 4). Remarkably, not
successful for the 8-membered system (Scheme 3, n = 1), did
again not increase the outcome. Similar to what was observed
for ring size 10, the reference reactions to the benzyl-protected
lactams 7d and 7e were unable to provide even trace amounts
of the desired products at 1 mM concentration. Regarding the
literature, maximum yields of 44−53% were just recently
reported for the preparation of 12-membered benzyl-protected
lactams comparable to 7e, but with no remaining starting
material.23,24 Moreover, the related reactions were carried out
in the presence of the more expensive second generation
Hoveyda Grubbs catalyst, so that the new strategy is beneficial
in two ways.
Structural variations on the protecting group (Scheme 5)
showed that quaternary ammonium salts such as 8 are less well
Scheme 4. Synthesis of 10- to 12-Membered Lactams 4c−e
Scheme 5. Variations of the Protecting Group and Cleavage
Group through N-Oxidation and Cope Elimination or
Catalytic Hydrogenation
suited precursors since a lower yield for 9 (45%) and a lower
reactant recovery (0%) were observed than in the standard
procedure leading to 4b from 1b (69% yield, 29% recovery, cf.
Scheme 3). A comparison of the truncated derivatives 10 and
12 revealed that the charge effect is more important than steric
interactions as a minor drop in yield and reactant recovery
occurred for 12 → 13 compared to the related standard
protocol converting 1c to 4c (68% yield, 30% recovery, cf.
Scheme 4).
In the final stage, we studied the removal of the novel
phenethylamine-derived protecting group (Scheme 5). Prior to
this, the 9-membered lactam 4b was prepared on a larger 0.5
mmol scale applying the optimized conditions shown in
Scheme 3. The drop in yield from 68% to 54% thereby seems
to be due to a slowed reaction, as a high combined yield (96%)
of recovered amide 1b and lactam 4b could still be determined.
Selective N-oxidation in the presence of the C−C double bond
could be achieved for 4b by using meta-chloroperoxybenzoic
acid (mCPBA) in the presence of potassium carbonate.25 After
changing the solvent to toluene, Cope elimination under mild
conditions (90 °C) provided vinyl amine 14 (55% over 2 steps,
not optimized), which was finally cleaved with trifluoroacetic
acid to give the unsaturated lactam 15 in quantitative yield.
Hydrogenation of lactam 4a led to removal of the protecting
group and the double bond to give 16 in 74% yield.
a single example for the successful synthesis of 10- and 11-
membered lactams by RCM can be found in the literature so
far, if covalent fixation and side-chain substitution are
excluded.22 The synthesis of the 10-membered lactam 4c (m
= 1) proceeded best at a 2 mM concentration after 24 h
reaction time, but shortening the reaction time to 9 h at 5 mM
did not give a satisfactory result. The high value of the
conformational fixation of amide 1c under the acidic reaction
conditions became obvious when the cyclization was
attempted with the corresponding benzyl-protected amide to
give lactam 7c. At 2 mM concentration and after 24 h reaction
time, 7c could not even be detected in traces in the product
mixture.
Regarding the results for lactams 4d and 4e with ring sizes of
11 and 12 (m = 2, 3), these cyclic systems appear the most
challenging to prepare, as the so far highest dilution of 1 mM
had to be applied to achieve the maximum yields of 38% for 4d
and 62% for 4e after 24 h. Shortening the reaction time to 9 h
at the higher concentration of 5 mM, as it had before been
In conclusion, we herein present the first generally applicable
RCM approach to medium-sized lactams, which is based on a
novel, readily available phenethylamine-derived protecting
C
DOI: 10.1021/acs.orglett.8b03320
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Organic Letters
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ASSOCIATED CONTENT
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03320.
Experimental details and 1H and 13C NMR-spectra of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Markus.Heinrich@fau.de. Tel: +49-9131-85-65670
ORCID
(8) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073.
(9) (a) Park, H.; Kang, E.-H.; Muller, L.; Choi, T.-L. J. Am. Chem.
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Markus R. Heinrich: 0000-0001-7113-2025
Notes
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Synthesis 2015, 47, 1317. (c) Shen, X.; Nguyen, T. T.; Koh, M. J.; Xu,
D.; Speed, A. W. H.; Schrock, R. R.; Hoveyda, A. H. Nature 2017,
541, 380.
The authors declare no competing financial interest.
(10) (a) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
̈
ACKNOWLEDGMENTS
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The authors are grateful for the financial support of this project
by the Deutsche Forschungsgemeinschaft (DFG, HE5413/6-
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