Synthesis of substituted morpholines using stereodivergent aza-michael reactions catalyzed by Bronsted acids

Article abstract of DOI:10.1021/cs400031p

A diastereoselective intramolecular aza-Michael reaction between N-Cbz carbamates and enones was studied. The investigation revealed that Bronsted acids with different strengths produce different diastereomers. The catalysts TfOH and TFA were used to generate differential outcomes in the aza-Michael reaction.

Full text of DOI:10.1021/cs400031p

Research Article
pubs.acs.org/acscatalysis
Synthesis of Substituted Morpholines Using Stereodivergent
Aza-Michael Reactions Catalyzed by Brønsted Acids
Cheng Zhong, Yikai Wang, Conor O’Herin, and Damian W. Young*
Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142,
United States
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138,
United States
S
* Supporting Information
ABSTRACT: A diastereoselective intramolecular aza-Michael
reaction between N-Cbz carbamates and enones was studied.
The investigation revealed that Brønsted acids with different
strengths produce different diastereomers. The catalysts TfOH
and TFA were used to generate differential outcomes in the
aza-Michael reaction.
KEYWORDS: Brønsted acid, aza-Michael, diastereoselective, morpholine, heterocycle
to give the cis- or trans-isomers of morpholines, respectively
ubstituted morpholines are highly represented among small
Smolecules that are biologically and therapeutically relevant,
including many natural products.1 Morpholine scaffolds have
also been widely utilized in the agrochemical industry for their
antibacteriacidal and antifungicical properties,2 and as chiral
auxiliaries in asymmetric synthesis.3 The predominant method
for the preparation of chiral C-substituted morpholines employs
amino acids as precursors owing to the availability of such starting
materials from the chiral pool.4 However, toward the preparation
of more stereodiverse substituted analogues, the generation of
additional stereogenic centers from these precursors within the
morpholine skeleton has been limited.5 Given the prevalence and
importance of this family, we sought a general methodology to
produce stereochemically and structurally diverse morpholines
for biological evaluation. Herein, we report a facile access to both
disastereomers of various substituted morpholines in an aza-
Michael reaction using Brønsted acids with different acidity.
The aza-Michael reaction has been widely applied for C−N
bond formation, especially in the preparation of biologically
active small molecules.6 Enantioselective aza-Michael reactions
promoted by organocatalysts and transition-metal complexes
have been extensively studied.7 However, despite steady advances
in this area,8 progress toward diastereoselective intramolecular
aza-Michael reactions has lagged, mainly because of the difficulty
in achieving stereochemical control.9 We envisioned that the
ability to obtain either diastereoisomer of di-or tri-substituted
morpholines from a common precursor would be highly attrac-
tive because of efficiency. Typically a chiral catalyst and its antipode
are used to achieve this goal. However, we have previously demon-
strated that the achiral (MeCN)2PdCl2 and TfOH, could effectively
promote the intramolecular aza-Michael reaction diastereoselectively
(Scheme 1).10
Scheme 1. Diastereoselective Intramolecular aza-Michael
Addition by Different Achiral Catalysts
We became interested in probing the origins of the stereo-
selectivity of these reactions toward the generation of other
stereodiverse morpholines. Although both catalysts had been
previously reported to catalyze the aza-Michael reaction, there
were no studies detailing issues related to stereoselectivity.11
Moreover, in the case of Pd(II) catalysis, the reaction mechanism
was a subject of debate. One argument favors the palladium
species serving as a Lewis acid to activate the enone carbonyl
group or the CC bond.11d,11e An alternative explanation, based
on the fact that Brønsted acids can also catalyze aza-Michael
reactions, is that the operative catalyst is a proton generated
during transition-metal hydrolysis resulting from adventitious
water in the reaction system. Spencer and co-workers reported in
Received: January 16, 2013
Revised: February 18, 2013
Published: February 19, 2013
© 2013 American Chemical Society
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Research Article
2006 a detailed study supporting the hydrolysis theory.11c Following
their studies, we also performed water titration experiments as well
as the addition of acid scavengers to the reaction.12 The outcomes
from both experiments were consistent with Spencer’s observations,
suggesting that catalysis by protic acid is the dominant pathway for
the Pd(II) reaction (Scheme 1).
Table 2. Diastereoselectivity Comparison between
Pd(MeCN)2Cl2, TFA-and TfOH-Catalysis
a
With the knowledge that protic acid functions under both con-
ditions and leads to opposing stereoselectivity of 3,5-disubstituted
morpholines, we explored this phenomena more extensively. The
results of different Brønsted acids are summarized in Table 1. The
Table 1. Brønsted Acids in aza-Michael Reaction
a
b
c
d
NMR yield. Based on crude NMR. 30% AcOH solution. 50%
aqueous solution, 20% MeCN as solvent.
intramolecular aza-Michael reaction reached nearly full con-
version within 15 min when strong Brønsted acids (TfOH or
Tf2NH) were used (Table 1, entry 1, 2). The diastereoselectivity
favored the trans isomer with a diastereomer ratio (d.r.) of 13:87
(cis/trans). When HBr (30% AcOH solution) and HBF4 (50% in
water) were used, longer reaction times were required with lower
selectivity, but still favoring the trans isomer (Table 1, entry 3, 4).
In the case of TFA (0.1 equiv.), the reaction slowed sig-
nificantly (79% conversion in 60 h). However, the d.r. was over
95:5 favoring the cis isomer (Table 1, entry 5). Higher TFA
concentrations led to an increased reaction rate, but the
selectivity was diminished (Table 1, entry 6, 7). Weak acids
such as AcOH did not catalyze the aza-Michael reaction to any
extent over 48 h even when used as solvent (Table 1, entry 8).
The Pd(II) complexes with different ligands or counteranions
were also tested and compared, which provided strong sup-
porting evidence to the hydrolysis theory. Complexes with more
electron-donating ligands did not catalyze the reaction likely
because of attenuation of the hydrolysis process whereas less
electron donating ligands did catalyze the reaction providing a
range of diastereoselectivities (see Supporting Information).12
Combining the results from different Pd(II) complexes and
acids, we concluded that the acidity of the Brønsted acid is the
key factor controlling the diastereoselectivity in the intramole-
cular aza-Michael reaction between the Cbz carbamate and
enone. Accordingly, we selected TfOH and TFA as catalysts to
explore the scope of this complementary diastereoselectivity.
Substrates in our previous report were revisited using TFA
as a catalyst. Identical (or better) cis selectivity was obtained
compared to Pd(MeCN)2Cl2 (Table 2 1a, 1b). Moreover, for
a substrate found to poison the Pd(II) catalyst (Table 1c), the
TFA condition provided good yield and high cis selectivity.
a
See Supporting Information for reaction details.
More complex aza-Michael precursors were also prepared and
tested (Table 1 1d−1f), with similar reactivity and selectivity
observed. For the t-Bu substituted precursor 1g, the reaction
rates were dramatically decreased under both conditions. The
TfOH-catalyzed reaction gave 84% yield (cis/trans 23:77) at
room temperature over 8 h, while treatment with TFA provided a
modest 53% yield after 4 days, slightly favoring the trans isomer.
To probe the reaction mechanisms, both purified cis and trans
isomers of 2a were isolated and resubjected to the reaction con-
ditions at room temperature (Table 3). For 2a-cis, no detectable
Table 3. Lack of Reversibility with Both Diastereoisomers
a
b
Room temperature with 0.2 M concentration of 2a. NMR yield.
c
Determined by crude NMR after 24 h.
trans isomer was observed under both TFA and TfOH con-
ditions; however, minor decomposition was observed using
stronger Brønsted acid. Resubjection of 2a-trans did not result in
conversion to the cis isomer under TFA conditions; however,
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a 13:87 d.r. (cis:trans) was observed with 78% recovery under
TfOH condition over 24 h at room temperature. These data
indicate that both TFA and TfOH catalyzed reactions are largely
under kinetic control. Therefore, different transition states account
for the preferences in diastereoselectivity.
We next sought to examine the methodology toward preparing
morpholines with other substitution patterns. Accordingly, sub-
strates having different regiochemical and stereochemical con-
figurations were prepared and tested under both conditions
(Scheme 2). Interestingly, when the stereogenic center was moved
in the pseudo-equatorial position. Alternatively, we cannot rule
out that the transition state may proceed through a twisted-boat
conformation to minimize the repulsions.15 Results from substrate
4a are also in accord with the proposed model, having the phenyl
group on the equatorial position in transition states under both
conditions. In the case of 4b, TFA treatment results in similar
selectivity favoring trans isomers, and TfOH conditions yield
slightly diminished selectivity favoring the cis isomer. This might
be due to steric repulsion between the equatorial phenyl group
and the axial enone (Scheme 2 IV). These studies demonstrate
that the aza-Michael reaction can be invoked to generate both
stereoisomers of 3,5-, 2,5-, and 2,3-disubstituted morpholine ring
systems.
Scheme 2. Mechanistic Rationale of the Diastereoselective
Intramolecular aza-Michael Addition
We also studied the diastereoselective aza-Michael reactions in
the context of generating trisubstituted morpholines. The transition-
state model proposed above is also applicable to substrates prepared
from norephedrine (Scheme 3). As a combination of 1b and 4a,
Scheme 3. Further Investigation of Steric Effect on
Diastereoselective aza-Michael Reaction
adjacent to the oxygen (4a), the diastereoselectivity was reversed
from the previous trend. Treatment with TFA gave the trans
isomer as the dominant product, while TfOH was selective toward
the cis isomer. Substrate 4b gave similar selectivity compared to 4a,
although with slightly diminished selectivity. Taking these observa-
tions into account, we propose that the intramolecular aza-Michael
reaction between carbamate to enone proceeds through an early
chairlike transition state (Scheme 2). When employing TFA as a
catalyst, in the case of 1a, the lower energy chairlike confor-
mation places the substitutents in equatorial positions. Because
of the lower acidity of TFA, the proton may serve only to activate
the electrophilic enone. A face-on addition of the nitrogen
p-orbital of the nucleophilic carbamate can engage the lowest
unoccupied molecular orbital (LUMO) of the enone positioned
equatorially, providing the cis products (Scheme 2 I vs II).
Alternatively, under TfOH treatment, we suggest on the basis
of NMR probing experiments that the carbamate carbonyl is
protonated and tautomerized into a carboimidate intermediate.13
A fully sp2 hybridized nitrogen nucleophile undergoes a head-on
addition to the enone. To minimize the pseudo-A(1,3) repulsion14
between the carboimidate and the electrophile (Scheme 2 III),
the enone may adopt an axial position, leading to the trans isomer
(Scheme 2 IV). In the case of a phenyl substitution adjacent to
nitrogen, an equatorial orientation induces a pseudo-A(1,3) inter-
action under the TfOH conditions, which enforces the alternative
chair transition state with the phenyl disposed axially and the enone
both substitutents in 4c are presumably in the equatorial posi-
tions, which should reinforce the diastereoselectivity based on
the proposed model. As expected, high yield and excellent dia-
stereoselectivity are obtained under both TFA and TfOH
conditions. In the case of 4d using TFA, diminished chemical
yields and poor diastereoselectivity resulted. This may be attri-
buted to the steric effects raised by the pseudo-axial substituent in
the proposed iso-energetic transition states. However, under
TfOH conditions, good yield and excellent trans selectivity are
achieved. As shown in Scheme 3, to avoid the possible double
pseudo-A(1,3) and pseudo-axial interactions, the trans isomer is
favored in the proposed chairlike model.16 Therefore, with the
exception of one instance, the diasteromeric 2,3,5-trisubstituted
morpholines were produced in excellent yield, demonstrating the
broad utility of this reaction methodology. Taken together, this
study represents the most general construction of substituted
morpholines arising from a common bond forming strategy.
In conclusion, we have demonstrated a robust stereodivergent
strategy leading to substituted morpholines employing Brønsted
acid catalyzed intramolecular aza-Michael reactions. Previously
examined Pd(II) complexes were found to promote the reaction
by hydrolysis to release protons as the active catalysts. Furthermore,
the acidity of Brønsted acids was determined to influence the dia-
stereoselectivity of the reaction. In the generation of 3,5-disubstituted
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generated from these studies suggests a possible means to access
other types of aza-heterocycles with tunable diastereoselective
control, and our efforts in this direction will be reported in due
course.
́
(d) Fustero, S.; del Pozo, C.; Mulet, C.; Lazaro, R.; Sμnchez-Rosello, M.
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ASSOCIATED CONTENT
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(8) For examples, see: (a) Takasu, K.; Maiti, S.; Ihara, M. Heterocycles.
2003, 59, 51. (b) Bandini, M.; Eichholzer, A.; Tragni, M.; Unami-
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S
* Supporting Information
Experimental details are provided as Supporting Information.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(9) For a diastereoselective intramolecular aza-Michael reaction of a
tosyl amine to an enal, see: Ying, Y.; Kim, H.; Hong, J. Org. Lett. 2011,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dyoung@broadinstitute.org.
Notes
Tetrahedron: Asymmetry 2008, 19, 2153.
For intramolecular
hydroamination example, see: Cochran, B. M.; Michael, F. E. Org.
Lett. 2008, 10, 329.
(10) Zhong, C.; Wang, Y.; Hung, A. W.; Schreiber, S. L.; Young, D. W.
Org. Lett. 2011, 13, 5556.
The authors declare no competing financial interest.
(11) (a) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25. (b) Wabnitz,
T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141. (c) Wabnitz, T. C.; Yu, J. Q.;
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Dalton Trans. 2006, 4987. (e) Reiter, M.; Turner, H.; Gouverneur, V.
Chem.Eur. J. 2006, 12, 7190.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Professor Stuart L. Schreiber from
the Broad Institute for his mentorship and support of this work.
This work was funded by the NIGMS-sponsored Center of Excellence
in Chemical Methodology and Library Development (Broad Institute
CMLD; P50 GM069721).
(12) See Supporting Information for the titration of water experiment
and detailed screening of different Pd(II) complexes.
(13) Carbamate 3 was prepared for an NMR study to probe the
differences between TfOH and TFA conditions. See Supporting
Information for details.
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NOTE ADDED AFTER ASAP PUBLICATION
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D’hooghe, T.; Vanlangendonck, K. W.; Tornroos, N.; De Kimpe. J. Org.
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Due to a production error, the version of this paper that was
published ASAP on March 11, 2013, was missing the graphic with
reference 16. The corrected version was reposted March 15,
2013.
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