Exploiting non-covalent interactions in synthesis: Macrocyclization employing amide-based auxiliaries

Article abstract of DOI:10.1002/adsc.200800365

Efficient macrocyclic olefin and en-yne metathesis can be conducted employing benzyl ester auxiliaries that engage in quadrupolar interactions. The use of amide linkers in place of esters results in higher overall yields. Computational studies suggest that amide auxiliaries stabilize conformers conducive to macrocyclization over 22 times more efficiently than an ester linkage. Molecular modelling studies also suggest a preference for engaging in quadrupolar interaction for the amide auxiliaries, in contrast to the lone-pair (lp):π interactions predicted for ester-based auxiliaries.

Full text of DOI:10.1002/adsc.200800365

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DOI: 10.1002/adsc.200800365
Exploiting Non-Covalent Interactions in Synthesis:
Macrocyclization Employing Amide-Based Auxiliaries
Yassir El-Azizi,a Joseph E. Zakarian,a Lisa Bouillerand,a Andreea R. Schmitzer,a
and Shawn K. Collinsa,*
a
Department of Chemistry, UniversitØ de MontrØal, C.P. 6128 Station Downtown, MontrØal, QuØbec, Canada H3C 3J7
Fax : (+1)-514-343-7586; e-mail: shawn.collins@umontreal.ca
Received: June 11, 2008; Published online: September 26, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800365.
Abstract: Efficient macrocyclic olefin and en-yne
metathesis can be conducted employing benzyl
ester auxiliaries that engage in quadrupolar interac-
tions. The use of amide linkers in place of esters re-
sults in higher overall yields. Computational studies
suggest that amide auxiliaries stabilize conformers
conducive to macrocyclization over 22 times more
efficiently than an ester linkage. Molecular model-
ling studies also suggest a preference for engaging
in quadrupolar interaction for the amide auxiliaries,
in contrast to the lone-pair (lp):p interactions pre-
dicted for ester-based auxiliaries.
methylphenyl groups which can engage in either lone-
pair (lp):p[5] or p:p interactions[6] with the aromatic
group of the substrate. These non-covalent interac-
tions result in stabilizing conformations of the sub-
strate that are conducive to ring closing. For example,
molecular modelling investigations have suggested
that the ester 1 can adopt an “open” conformation 1-
O, whereby the auxiliary is extended and not involved
in any non-covalent interactions with the central ben-
zene ring. This conformer would exist in equilibrium
favoring 1-S, in which the perfluorophenyl ring is
folded inwards and engages in a lone-pair:p interac-
tion with oxygens connected to the central benzene
ring (Scheme 1). As a result of the lone-pair:p inter-
action, 1-S is favored by À0.20 kcalmolÀ1 over 1-O. It
is remarkable that such small differences in energy
can be responsible for the “gearing” of 1 towards pro-
ductive macrocyclization.
Keywords: cyclophanes; macrocyclization; natural
product synthesis; olefin metathesis; quadrupolar
interactions
In examining the structure of conformer 1-S, we no-
ticed two conformational characteristics that could
The number of isolated biologically active macrocy- contribute against the stabilization of such conform-
clic natural products continues to expand, reinforcing ers. The first conformational element of the auxiliary
the importance of developing new synthetic methods examined was the esterꢀs conformation, which was of
for macrocyclic compounds. Macrocyclization via the s-trans type. The second conformational element
olefin metathesis has evolved into one of the most ef- was that the carbonyl moiety is rotated out of conju-
ficient synthetic methods available to construct mac- gation with the phenyl ring. Therefore, we reasoned
rocycles.[1] However, in some cases the predisposition that further energy stabilization of conformers such as
of the substrate towards macrocyclization can be diffi- 1-S might be achieved through replacing the ester-
cult to overcome. This has been observed in the syn- based auxiliary with an amide-based auxiliary, in an
thesis of macrolide natural products[2] as well as mac- effort to further favor an s-trans conformation and
rocyclic peptides.[3] In such cases, the availability of electronically stabilize the auxiliary. These studies
methodologies to enable macrocyclization becomes would also indicate whether the use of perfluorophen-
increasingly important. Recently our group disclosed yl-based auxiliaries could be applied to the synthesis
that the formation of strained paracyclophane struc- of cyclic peptides, where an amide linker would likely
tures was possible using ester-based auxiliaries.[4] We be employed. Herein, we report the investigation of
have demonstrated that these auxiliaries are effective amide-based auxiliaries for macrocyclization using
in forming strained ring systems either by ring-closing both chemical synthesis and molecular modelling in
olefin or ring-closing en-yne metathesis.[5] The auxilia- parallel.
ries can contain perfluorophenyl or bis-3,5-trifluoro-
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We decided to investigate the use of amide-based
auxiliaries for macrocyclization through molecular
modelling using a model system similar to that used
in our previous studies.[5] Previous reports of the
stacking interactions of perfluoroarenes and other
arenes in the solid state point towards a preference
for a face-to-face orientation.[7,8] However, our previ-
ous molecular modelling studies using a DFT geomet-
ric and energy analysis[9] suggested that a conformer
exhibiting an oxygen lone pair:arene (lp:p) interac-
tion[10,11] was responsible for the gearing of the system
towards macrocyclization.
DFT calculations showed that the conformer 1-S
was favored by À0.20 kcalmolÀ1 compared to the con-
former 1-O. As noted above, the auxiliary does not
overlap efficiently with the arene core, instead opting
to sit over the pendant oxygen atoms in these systems
(Figure 1). The analysis of the analogous amide 3 was
performed in the following manner. Starting with the
conformers obtained for 1-S from AM1 calculations,
the oxygen atom was exchanged for a NH group to
give 3. Subsequently, 3 was refined using AM1 level
of theory in which only the torsion angles about the
amide functionality were allowed to vary. The result-
ing conformers was then further refined via a DFT
geometric and energy analysis. We again observed
Scheme 1. Macrocyclization to form [12]paracyclophanes
mediated by a pentafluorobenzyl ester auxiliary.
Figure 1. Molecular modelling of 1 and 3 to compare pentafluorobenzyl ester and amide auxiliaries.
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two distinct conformations, in which the “stacked”
conformer 3-S was preferred over the “open” confor-
mer 3-O by À4.56 kcalmolÀ1 (Figure 1). These calcu-
lations suggest that both stacked conformers 1-S and
3-S are preferred compared to their respective open
conformers. The calculations suggest, however, that
the amide auxiliary stabilizes its respective stacked
conformer (3-S) over 22 times more efficiently than
the corresponding ester (1-S). This suggests that the
conformer 3-S is highly likely to predominate in solu-
tion and could result in higher yields in macrocycliza-
tion processes.
Scheme 2. Synthesis of 2,3,4,5,6-pentafluorobenzylamine hy-
drochloride 7.
Interestingly, the molecular modelling calculations
also suggest that the amide auxiliary would result in ment of bromide from 5 with tritylamine lead to
3-S engaging in p–p quadrupolar interactions and not amine 6 is quantitative yield. The trityl protecting
lp–p interactions as was calculated for the ester con- group could be removed under acidic conditions and
former 1-S. Figure 2 depicts the two different non-co- the corresponding HCl salt isolated via filtration. The
valent interactions calculated for 1-S and 3-S. The HCl salt of 7 was observed to be bench-stable for
switch in non-covalent interactions could be due to many months. The hydrochloride salt 7 was used in
the added rigidity in 3-S afforded by the amide auxili- the synthesis of various amide precursors for their
ary.
evaluation in macrocyclization.[15]
The amide-based auxiliaries were first evaluated in
olefin metathesis macrocyclizations; esters 1,10 and
15 and amides 3, 12 and 17 were each subjected to
identical macrocyclization conditions (Scheme 3). The
ester 1 was found to afford the macrocycle 2 in 41%
isolated yield.[4a] When the cyclization of amide 3 was
performed, in which the ester linkage was replaced
with an amide linkage, the corresponding macrocycle
9 was obtained in an improved yield of 53%, repre-
senting an increase of 12%. Increases in the isolated
yield was also found with 3,5-bis(trifluoromethyl)ben-
zyl auxiliaries. The 3,5-bis(trifluoromethyl)benzyl
ester 10 afforded the [12]paracyclophane 11 in 41%
yield upon macrocyclization. However, the corre-
sponding amide 12 cyclized to give 13 in 63% yield –
an increase of 22%!
The comparison of amides versus esters was also
conducted with more challenging substrates, such as
ester 15, and 19 and amide 17 (Scheme 4). Macrocyc-
lization of these substrates is made possible by ex-
ploiting a relay ring-closing metathesis strategy.[16]
Thus, the metathesis catalyst reacts with the terminal
olefin and undergoes an intramolecular ring-closing
event and then subsequently undergoes macrocycliza-
Figure 2. Calculations suggest that 1-S and 3-S are stabilized
by different non-covalent interactions.
We next decided to evaluate the amide-based auxil- tion. Treatement of 15 with Grubbs 2nd generation
iaries based on both 2,3,4,5,6-pentafluorobenzyl and catalyst 14 forms a trisubstituted olefin and affords
3,5-bis(trifluoromethyl)benzyl groups.[12] Synthesis of macrocycle 16 with a rigidified [14]paracyclophane
the respective amides (such as 3) would most likely skeleton due to the presence of three stereodefined
require access to both 1,3-bistrifluoromethylbenzyl- olefins. The isolated yield of the macrocycles 16 and
amine, or 2,3,4,5,6-pentafluorophenylbenzylamine. The 20 using the ester-based auxiliaries was 28% and
former is commercially available,[13] and the latter has 37%, respectively. Gratifyingly, switching to a penta-
been previously prepared.[14] However, pentafluoro- fluorobenzylamide auxiliary nearly doubled the isolat-
phenylbenzylamine has been observed to polymerize ed yield of the macrocyclic product and the macrocyc-
on standing and is volatile. As such, we developed a lization of 17 afforded the macrocyclic amide 18 in
new protocol to access 7 starting from 2,3,4,5,6-penta- 55% yield. The synthesis of macrocycles 16, 18 and 20
fluorobenzyl bromide, 5 (Scheme 2). The displace- is noteworthy as the carbon skeleton of the macrocy-
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Scheme 3. Evaluation of new amide auxiliaries in macrocyclic olefin metathesis.
Scheme 4. Evaluation of new amide auxiliaries in challenging macrocyclizations.
cle is identical to that observed in the longithorone proximately 10% higher than the analogous cycliza-
family of natural products.[17]
tion of ester 22 to give the same core macrocycle 23
Amide-based auxiliaries bearing both a 2,3,4,5,6- (49%).[5] In addition, the E:Z ratio of the products
pentafluorobenzyl and a bis-3,5-(trifluoromethyl)ben- was improved, with the Z-isomer still predominating
zyl group were also evaluated in macrocyclizations (1:6.0 E:Z for 25). The same improved yields and E:Z
using en-yne metathesis substrates (Scheme 5).[18] ratios were observed during cyclizations of ester 26
When the amide 24 underwent macrocyclization with and amide 28. While the ester 26 afforded the macro-
Grubbs–Hoveyda catalyst 21, the [12]paracyclophane cyclic diene 27 in 47% yield (E:Z 1:6.0), the corre-
25 was isolated in 59% yield following purification by sponding amide 28 afforded the analogous macrocy-
silica gel chromatography.[19] The yield of 25 was ap- clic amide 29 in an increased yield of 60% (E:Z 1:10).
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Scheme 5. Evaluation of amide-based auxiliaries in macrocyclic en-yne metathesis.
Similar results were obtained using 2,3,4,5,6-penta- While it is difficult to make a direct comparison of
fluorobenzyl auxiliary series. The ester 30 afforded the energies of these interactions, some computational
the cyclophane 31 in 33% yield, however, treatment investigations have studied the interactions of hexa-
of the corresponding amide 32 with the same catalyst fluorobenzene with water (3.77 kcalmolÀ1)[10a,11a] and
21 afforded a 46% yield of the macrocycle 33. Not benzene (~4–5 kcalmolÀ1),[20] suggesting that the
only was the isolated yield increased by 13%, but the latter may be stronger and hence more effective for
E:Z ratio of the amide 33 was slightly improved com- gearing the conformation of molecules. In the cases of
pared to the analogous ester 31 (1: 5.0 vs. 1: 3.3 E:Z). en-yne metathesis, an increase in the preference for
The ester 34, in which the alkynyl and alkenyl side- the Z-isomer was observed. Although molecular mod-
chains have been reversed with respect to ester 30, elling studies suggest a thermodynamic preference for
was also compared in macrocyclizations with the the Z-isomers,[5] there is no clear cut explanation, it is
amide 36. A modest 7% increase in the isolated yield clear that each auxiliary exerts an influence during
of macrocyclic amide 37 versus the macrocyclic ester the formation of the macrocycle. It is reasonable to
35 was observed.
assume that the increased rigidity afforded by the
The improved macrocyclizations via olefin or en- amides may restrict the various degrees of freedom of
yne metathesis are likely a result of the improved the sidechains in the macrocyclization precursors, per-
preference for conformers such as 3-S, where non-co- haps influencing the preference for the Z-isomer.
valent interactions between the auxiliary and aromat-
In summary, the substitution of an ester linker for
ic core enable a conformation conducive to cycliza- an amide linker results in higher overall yields and
tion. In addition, the improved yields of products may better E:Z ratios in macrocyclic olefin and en-yne
be due to the fact that the amide auxiliaries enable metathesis. Macrocyclizations employing olefin meta-
quadrupolar p–p interactions over lp–p interactions. thesis were improved by 12–27% in terms of isolated
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yields, while macrocyclizations employing en-yne General Experimental Procedure for En-Yne
metathesis were improved by 7–13%. Improved mac- Metathesis Macrocyclization
rocyclizations were observed with both the 2,3,4,5,6-
pentafluorobenzyl and bis-3,5-(trifluoromethyl)benzyl
equipped with a magnetic stirrer, reflux condenser, and
A flame-dried, 500-mL, three-neck, round-bottom flask,
series and each auxiliary type gave similar increases.
Calculations suggest that conformer 3-S is highly fa-
vored over 3-O, which may be responsible for the effi-
cient macrocyclization. The molecular modelling stud-
ies also suggest that quadrupolar interactions may be
responsible for the gearing of the amide auxiliaries, in
contrast to the lp–p interactions predicted for 1-S.
Despite the large energetic stabilization provided the
amide linkage in 3-S compared to the ester linkage in
1-S, further increases in yields are likely to be ob-
tained only by exploiting stronger non-covalent inter-
actions, such as pyridinium (cation)–p interactions. Of
note is the molecular modelling calculations that sug-
gest the selective preference for p–p interactions with
the amide auxiliaries. These results bode well for fur-
ther application of these auxiliaries in macrocycliza-
tion of more complex and densely functionalized sub-
strates containing numerous heteroatoms. Of interest
would be the application of these auxiliaries in the
synthesis of bioactive macrocyclic peptides. Further
development of these new auxiliaries through the
preparation of chiral versions and investigations in
atroposelective macrocyclization is also being studied
in our laboratories.
isobar addition funnel or a syringe pump system was
charged with Grubbs–Hoveyda 2nd generation catalyst (20
mol%) and anhydrous toluene (volume is determined by
the amount needed to afford a final concentration of [M]=
0.4”10À4 M after complete addition of the precursor solu-
tion). The catalyst solution was then placed at reflux 1108C
(toluene). The metathesis precursor in solution (approxi-
mately 50 mL) was placed in the addition funnel or the sy-
ringe pump system and added over 1 h. After addition, the
solution was allowed to stir at reflux for 1 additional hour to
ensure complete conversion. The reaction mixture was con-
centrated under vacuum, dry-packed and purified by flash
column silica chromatography (hexanes/ethyl acetate, 20/1)
to afford the desired 1,3-diene paracyclophanes.
Supporting Information
Experimental procedures and characterization data for all
new compounds are available as Supporting Information.
Acknowledgements
We thank NSERC (Canada), FQRNT (QuØbec), CFI
(Canada), Boehringer Ingelheim (Canada) Ltd., Merck
Frosst Centre for Therapeutic Research and the UniversitØ de
MontrØal for generous financial support.
Experimental Section
Representative experimental procedures for macrocyclic
olefin and en-yne metathesis reactions are described below.
Complete experimental details can be found in the Support-
ing Information.
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