A general, enantioselective synthesis of protected morpholines and piperazines

Article abstract of DOI:10.1021/ol301203z

A short, high yielding protocol has been developed for the enantioselective and general synthesis of C2-functionalized, benzyl protected morpholines and orthogonally N,N′-protected piperazines from a common intermediate.

Full text of DOI:10.1021/ol301203z

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2910–2913
A General, Enantioselective Synthesis
of Protected Morpholines and Piperazines
Matthew C. O’Reilly and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville,
Tennessee 37232, United States
craig.lindsley@vanderbilt.edu
Received May 2, 2012
ABSTRACT
A short, high yielding protocol has been developed for the enantioselective and general synthesis of C2-functionalized, benzyl protected
morpholines and orthogonally N,N0-protected piperazines from a common intermediate.
Morpholines and piperazines are saturated aza-hetero-
cycles commonly employed as bases in organic synthesis.1
These heterocycles have also become key components of
pharmaceuticalcompositions, typicallywithchiralC-func-
tionalization at C2.2,3 However, chemistry to access en-
antiopure C2-functionalized morpholines and piperazines
is limited, relying on the chiral pool, stoichiometric aux-
ilaries, or HPLC resolution of racemic mixtures.1ꢀ6 Based
on our earlier efforts to access chiral β-fluoroamines and
N-termialaziridinesvia organocatalysis,7ꢀ9 weappliedthis
strategy to the enantioselective synthesis of C2-functiona-
lized morpholines and piperazines (Figure 1). Here, an
organocatalytic, enantioselective chlorination of aldehyde
1 produced 2,10,11 which was used without purification. A
subsequent reductive amination step occurred with an
amine containing an embedded ‘O’ or ‘N’ nucleophile (3
or4), suchthat, after base-inducedcyclization of either5 or
6, N-benzyl protected morpholines 7 and orthogonally
N,N0-protected piperazines 8, respectively, were prepared
with C2-functionalization.12 While this result was gratifying,
the methodology suffered from two key limitations: (1) the
(1) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft,
F. L.; Blaauw, R. H. Synthesis 2004, 5, 641–662 and references therein.
(2) Kumar, R.; Kumar, A.; Jain, S.; Kaushik, D. Eur. J. Med. Chem.
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(3) Stachel, S. J.; Steele, T. G.; Petrocchi, A.; Haugbook, S. J.;
McGaughey, G.; Holloway, K. M.; Allison, T.; Munshi, S.; Zuck, P.;
Colussi, D.; Tugasheva, K.; Woolfe, A.; Graham, S. L.; Vacca, J. P.
Bioorg. Med. Chem. Lett. 2012, 22, 240–244.
(4) Hajos, M.; Fleishaker, J. C.; Filipak-Reisner, J. K.; Brown, M. T.;
Wong, E. H. F. CNS Drug Rev. 2004, 10, 23–44.
(5) Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.;
Moriguchi, A.; Yamamoto, K.; Ikeda, Y.; Kawakita, T. Bioorg. Med.
Chem. Lett. 1998, 8, 2185–2190.
(6) Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.; Mawer, I. M.;
Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S. B.; Marwood, R.;
Patel, S.; Ragan, C. I.; Leeson, P. D. J. Med. Chem. 1996, 39, 1941–1942.
(7) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 943–946.
(8) Schulte, M. L.; Lindsley, C. W. Org. Lett. 2011, 13, 5684–5687.
(9) Fadeyi, O. O.; Schulte, M. L.; Lindsley, C. W. Org. Lett. 2010, 12,
3276–3278.
Figure 1. First generation organocatalytic approach for the
enantioselective synthesis of C2-functionalized, N-protected
morpholine and orthogonally N,N0-protected piperazines.
r
10.1021/ol301203z
Published on Web 05/22/2012
2012 American Chemical Society

three-step overall yield was low (13ꢀ50%) and (2) the % ee
was variable (55ꢀ98% ee) due to the epimerization prone
R-chloroaldehyde 2. In fact, one trial where the R-chlor-
oaldehyde 2 was left on the bench for hours prior to
subsequent reductive amination led to a % ee erosion of
greater than 30%. Furthermore, four separate trials of this
reaction sequence, with immediate use of the chloroalde-
hyde, afforded 78ꢀ94% ee immediately upon generation.
In addition to varying % ee, the incipient imine could also
be attacked by the latent oxygen nucleophile to form an
undesired hemiaminal that further compromised yields,
leading to recovered aldehyde starting material upon
workup. Thus, in this Letter, we report a general, high
yielding solution for the enantioselective synthesis of these
valuable aza-heterocycles that overcomes the limitations
of the first generation approach affording good overall
yields and high enantioselectivities.
Scheme 1. Organocatalytic, Enantioselective Synthesis of
2-Chloro Alcohols 9aꢀd
Scheme 2. Synthesis of Cyclization Substrates 5aꢀd and 6aꢀd
chemoselective displacement of the primary leaving group,
something not yet reported in the literature. After survey-
ing a number of potential primary leaving groups (mesylate,
tosylate, and iodide), the triflate emerged as the optimal
moiety to deliver congeners of 5 and 6. Here, treatment of
9aꢀd with triflic anhydride in DCM with lutidine at ꢀ78 °C
smoothly generated the corresponding triflates, which were
then immediately exposed to either secondary amine 3or 4to
generate 5aꢀd and 6aꢀd (Scheme 2) in good yields
(63ꢀ87%) for the two-step sequence.
Figure 2. Envisioned second generation organocatalytic approach
for the enantioselective synthesis of C2-functionalized, N-pro-
tected morpholine and orthogonally N,N0-protected piperazine.
In the original Jørgensen methodology for the organo-
catalytic R-chlorination of aldehydes,10,11 the aldehydes
could be immediately reduced with NaBH4 to the cor-
responding 2-chloro alcohols 9 without any loss in en-
antioselectivity; moreover, the alcohol derivatives were
configurationally stable. Thus, if we could convert the
hydroxyl moiety of the 2-chloro alcohol into an efficient
leaving group 10, followed by a chemoselective displace-
ment by 3 or 4, substrates 5 or 6 would result which could
be smoothly cyclized to form either 7 or 8 (Figure 2). This
envisioned approach was attractive as it would eliminate
the variable % ee, avoid the undesired hemiaminal forma-
tion, and, thus, improve the overall yields of 7 and 8.
To test this new approach, we prepared various 2-chloro
alcohol substrates 9aꢀd under standard conditions in high
yield (72ꢀ83%) over two steps and in high enantioselec-
tivity (80ꢀ98% ee) as expected from literature precedent
(Scheme 1).10ꢀ12 Now the challenge was to convert 9aꢀd
into the appropriate bis-electrophile that would allow for a
Scheme 3. Enantiospecific Cyclization To Afford Morpholines
7aꢀd
(10) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 4790–4791.
(11) Marigo, M.; Bachmann, S.; Halland, N.; Braunton, A.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2004, 43, 5507–5510.
(12) O’Reilly, M. C.; Lindsley, C. W. Tetrahedron Lett. 2012,53, 1539–1542.
With 5aꢀd in hand, we employed our optimized cy-
clization conditions (KOtBu, CH3CN, ꢀ20 °C) to afford
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Org. Lett., Vol. 14, No. 11, 2012

N-benzyl protected morpholines 7aꢀd (Scheme 3) in good
yield (65ꢀ74%) and with excellent enantioselectivities
(80ꢀ98% ee). The only marginal % ee was in the silyl
ether substrate 7d, which resulted from the initial
R-chlorination step, and was expected based on literature
precedent.10,11 Overall yields for 7aꢀd from the commer-
cial aldehydes ranged from 35 to 46% for the new five-step
sequence, anotableimprovementoverthe13ꢀ19%overall
yields of the first generation, three-step approach as well as
improved % ee.12
activity from the patent literature.13 Chiral morpholine 15,
reported to be a specific dopamine subtype 4 (D4)
antagonist,6 was previously prepared in three steps, includ-
ing a preparative chiral HPLC separation, in 9.9% overall
yield (Scheme 5). Though they claim a single enantiomer of
15 to be more preferred, they did not disclose the absolute
stereochemistry or the differences in D4 potency.
Scheme 6. Enantioselective Synthesis of (R)-Morpholine 15
Scheme 4. Enantiospecific Cyclization To Afford Orthogonally
N,N0-Protected Piperazines 8aꢀd
Therefore, we took advantage of already synthesized
enantiopure (R)-morpholine 7b, removed the benzyl pro-
tecting group via hydrogenation, and alkylated with 14 to
deliver (R)-15 (Scheme 6). In contrast to the known route,
our methodology provided enantiopure (R)-15 in 98% ee
and in 35% overall yield, a significant improvement. In a
similar manner, racemic 15 was prepared, according to
Figure 2 utilizing D,L-proline as the organocatalyst, as well
as (S)-15, and all three were evaluated against the full
dopamine family of receptors, D1ꢀD4, in both radioligand
binding (Ki) and functional (IC50) assays (Table 1).14
Racemic (()-15 is devoid of activity at D1 and D2 (Ki
and IC50’s >100 μM), and highly selective for D4 versus
D3 (Ki and IC50 >10 μM). Upon evaluation of the pure
enantiomers (R)-15 and (S)-15, enantiospecific activity is
clearly present. As shown in Table 1, (S)-15 is uniformly
inactiveagainst D1ꢀD4 (IC50’s> 25 μM);however, (R)-15
is twice as potent (D4 Ki = 0.07 μM, IC50 = 0.18 μM) as
racemic (()-15, indicating that all of the activity of the
racemate is due to the (R)-enantiomer. These data further
highlight the utility of our methodology to afford high
yielding, enantioenriched access to chiral, C2-functiona-
lized morpholines and piperazines.
In a similar fashion (Scheme 4), but employing DMF as
the solvent, orthogonally N,N0-protected piperazines 8aꢀd
were arrived at in good yields (66ꢀ91%) and with high
enantioselectivities (75ꢀ95% ee). As discussed earlier, the
one low % eewas duetothe substrate. Onceagain, thisnew
methodology afforded comparable or improved overall
yields (35ꢀ60%) for the five-step sequence and uniformly
high % ee relative to the first generation approach
(15ꢀ50% overall yields and 55ꢀ96% ee). Thus, this new
five-step sequence for the enantioselective synthesis of C2-
functionalized, N-protected morpholines and piperazines
affords access to these valuable aza-heterocycles that often
cannot be accessed readily.
Scheme 5. Published Synthesis of Morpholine 15
Table 1. Biological Activity Data at D1ꢀD4 for Racemic and
Enantiopure Isomers of Morpholine 15
a
a
a
a
D1
D2
D3
D4
compd
Ki
IC50
Ki
IC50
Ki
IC50
Ki
IC50
(()-15 >100 >100 >100 >100 10.8 31.8 0.14
(R)-15 >100 >100 >100 >100 15.7 46.2 0.07
0.36
0.18
(S)-15 >100 >100 >100 >100 25.9 76.4 >100 >100
Finally, we applied this new methodolgy to a pharma-
ceutically relevant morpholine target with antipsychotic
a Ki and IC50 values are in μM and represent at least three
measurements.
(13) Merck, Sharpe &Dohme: WO95/14690, 1995.
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Org. Lett., Vol. 14, No. 11, 2012

In summary, we have developed an optimized five-step
procedure for the enantioselective synthesis of N-benzyl
protected morpholines and orthogonally N,N0-protected
piperazines with chiral alkyl groups installed at the C2
position of each heterocyclic core via organocatalysis. This
methodology allows for the rapid preparation of function-
alized, pharmaceutically relevant morpholines and piper-
azines in 35ꢀ60% overall yields and in 75ꢀ98% ee. This
new methodology addresses the major shortcomings
(variable % ee and low overall yields) of our first genera-
tion approach. Of major significance, this methodology
does not rely on the chiral pool; instead we can employ
simplealdehydes and commercialorganocatalysts, thereby
allowing access to either enantiomer of the corresponding
morpholines and piperazines. Application of this new
methodology to the synthesis and biological evaluation
of a known D4 antagonist further highlights the power of
the methodology and sheds light on the enantioselective
inhibition of dopamine receptors. Additional refine-
ments are under development and will be reported in
due course.
Acknowledgment. This work was supported, in part, by
the Department of Pharmacology, Vanderbilt University
Medical Center and the Vanderbilt Specialized Chemistry
Center for Accelerated Probe Development/MLPCN
(U54MH084659). M.C.O. acknowledges support from
an ACS Division of Medicinal Chemistry predocotral
fellowship. Funding for the NMR instrumentation was
provided in part by a grant from the NIH (S10 RR019022).
Supporting Information Available. Experimental pro-
cedures, characterization data, chiral HPLC traces, and
1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Biology performed at Ricerca: www.ricerca.com.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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