Enantioselective Synthesis of Functionalized Quaternary Stereocenters

Article abstract of DOI:10.1002/ejoc.201500985

An enantioselective synthesis of functionalized quaternary stereocenters was developed from amino alcohol derived (bromoalkylidene)morpholinones. Stereoselective cross-coupling of the morpholinones with arylboronic acids or alkyl trifluoroborates provided a variety of disubstituted alkylidenemorpholinones. A highly stereoselective Prins reaction of the cross-coupling products generated the target quaternary stereocenter. The Prins products are readily converted into a variety of acyclic, enantiomerically enriched, functionalized building blocks with a quaternary stereocenter.

Full text of DOI:10.1002/ejoc.201500985

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500985
Enantioselective Synthesis of Functionalized Quaternary Stereocenters
Amarender Manchoju,[a] Rakesh G. Thorat,[a] and Sunil V. Pansare*[a]
Keywords: Synthetic methods / Enantioselectivity / Quaternary stereocenters / Cross-coupling / Reduction
An enantioselective synthesis of functionalized quaternary
stereocenters was developed from amino alcohol derived
(bromoalkylidene)morpholinones. Stereoselective cross-cou-
pling of the morpholinones with arylboronic acids or alkyl
trifluoroborates provided a variety of disubstituted alkylid-
enemorpholinones. A highly stereoselective Prins reaction of
the cross-coupling products generated the target quaternary
stereocenter. The Prins products are readily converted into a
variety of acyclic, enantiomerically enriched, functionalized
building blocks with a quaternary stereocenter.
sor. In recent years, this has limited its availability for re-
search. Treatment of 1 and 2 with ethylmagnesium bromide
or propylmagnesium chloride provided the corresponding
hemiacetals, which were dehydrated to furnish the alkylid-
enemorpholinones 3[5b] (96%), 4[5c] (98%), 5 (74%) and 6
(54%, Scheme 1). These were converted into the key (Z-
bromoalkylidene)morpholinones 7, 8, 9 and 10, respectively
by conversion to the bromohemiacetals (Br2/H2O) and sub-
sequent dehydration. Notably, under optimized conditions
(Scheme 1), the corresponding E-isomers were generally not
obtained. The Z-alkene geometry in 7, 8 and 10 was as-
signed on the basis of anisotropic deshielding (1H NMR) of
the γ-hydrogen atoms[7] in the embedded butenamide motif
(methyl group in 7 and methylene group in 8, 10) as com-
pared to the corresponding E-isomers [(E)-7, (E)-8 and (E)-
10 respectively], which were occasionally obtained in trace
amounts [Ͻ5%, (E)-7 and (E)-8] or obtained by dehy-
dration of the corresponding bromohemiacetal at elevated
temperature [ca. 5% at 50 °C for (E)-10].[8] The morphol-
inone (E)-9 could not be obtained for comparison with 9.
However, since dehydration of the bromohemiacetal ob-
Introduction
Quaternary stereocenters are interesting structural mo-
tifs, which present a unique synthetic challenge. They are
encountered as structural units in several natural products
and hence enantioselective approaches to quaternary
stereocenters have been intensely investigated in recent
years.[1] Several non-catalytic[2] as well as catalytic[3] enan-
tioselective methods have been developed for assembling
quaternary stereocenters. While some of these efforts are in
the realm of natural product synthesis,[1a,1c] other studies
showcase methodology for the construction of quaternary
stereocenters by employing suitably functionalized starting
materials.[1d,2,3] In this context, opportunities exist for the
construction of quaternary centers in acyclic fragments that
have functionality for further elaboration.[4] To explore this
prospect, we chose to examine the synthesis of hydroxy
aldehydes and carboxylic acids with a quaternary α-
stereocenter. Herein, we describe preliminary results toward
this objective.
Results and Discussion
The focus of our strategy is the stereoselective function-
alization of amino alcohol derived alkylidenemorpholin-
ones. The synthesis of these morpholinones begins with
morpholinediones 1[5] and 2 (Scheme 1), which are readily
prepared by the reaction of ethyloxalyl chloride with 1R,2S-
ephedrine hydrochloride and of oxalyl chloride with S-2-
(methylamino)-1,1-diphenylpropanol[6] respectively. The
amino alcohol used for making 2 was chosen as a potential
alternative to ephedrine, which is a controlled drug precur-
[a] Department of Chemistry, Memorial University,
St. John’s, Newfoundland, Canada A1B 3X7
E-mail: spansare@mun.ca
http://www.chem.mun.ca/zfac/svp.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500985.
Scheme 1. Synthesis of (bromoalkylidene)morpholinones.
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A. Manchoju, R. G. Thorat, S. V. Pansare
SHORT COMMUNICATION
tained from 6 at ambient temperature had provided 10 as Table 1. Suzuki–Miyaura cross-coupling of 7–10.
the only isolable product, 9 was assigned the Z-geometry
by analogy.
At this stage, the morpholinones 7–10 possess one
(methyl or ethyl) of three substituents that would eventually
adorn the quaternary α-carbon in the target carboxylic
acids or aldehydes. The next objective was the introduction
of an additional substituent by cross-coupling of the vinyl
bromide moiety in 7–10. Clearly, the stereoselectivity of this
Morpholinone
R
Product
R1
R2
Yield [%]
C–C bond forming step was critical for the formation of
a stereodefined (at the alkene) alkylidenemorpholinone.[9]
Initial attempts to introduce an alkyl substituent in 7 by the
Negishi or Kumada cross-coupling of alkylmetal reagents
with the vinyl bromide were uniformly unsuccessful under
a variety of conditions. These reactions either proceeded in
very low yield or resulted in reduction of the vinyl bromide
to the corresponding alkene. Attempted Suzuki–Miyaura
cross-couplings of 7 with alkylboronic acids[10a] or B-alkyl
MIDA boronates[10b] were similarly unsuccessful. Fortu-
nately, the use of potassium alkyltrifluorobrates[11] as the
cross-coupling partners provided the required products in
7
H
H
H
H
H
H
H
H
H
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
Me
Bu
92
80
72
75
92
96
94
88
89
85
87
93
64
iBu
Bn[a]
cyclopropyl
Ph
2-naphthyl
4-OMe-C6H4
4-NHZ-C6H4
4-CO2MeC6H4
Bn
8
9
(Z)-12
Et
Ph (Z)-13a
Ph 13b
Ph (E)-13a
Me
Me
Et
Et
4-Me-C6H4
Me
10
good yields and a variety of primary alkyltrifluoroborates [a] Pinacolate of benzylboronic acid was used.
were successfully coupled with morpholinones 7–10
(Table 1). With the exception of cyclopropyltrifluoroborate, NMR) in the reactions of 8/(E)-8 and 10/(E)-10, all of the
secondary alkylboronic acids or secondary alkyltrifluoro- cross-coupling reactions of 7–10 were assumed to proceed
borates did not furnish the expected cross-coupling prod- with retention of configuration to provide the morpholin-
ucts. However, cross-coupling reactions of 7, 8 and 9 with ones 11–13. As in the bromoalkenes, the stereochemical as-
arylboronic acids proceeded smoothly and provided the signments for the cross-coupling products are based on the
corresponding alkyl/aryl-substituted morpholinones 11–13. anisotropic deshielding of the γ-hydrogen atoms in the alk-
These results are summarized in Table 1.
ene substituent that is syn to the morpholinone carbonyl
The stereoselectivity of the cross-coupling reaction was group.[7]
ascertained by the conversion of diastereomerically pure
With the disubstituted alkylidenemorpholinones in hand,
bromoalkenes to diastereomeric cross-coupling products. the stage was set for the final step in the construction of
Thus, cross-coupling of bromoalkene 8 with potassium the quaternary stereocenter. To this effect, the alkylidene-
benzyltrifluoroborate provided the alkylidenemorpholinone morpholinones were subjected to a Prins-type reaction[12]
(Z)-12, whereas (E)-8 gave the diastereomeric (E)-12 with paraformaldehyde. Depending on the substrate, two
(Scheme 2). Similarly, the cross-coupling of 10 with potas- methods were developed for this reaction, one employing
sium methyltrifluoroborate provided (E)-13a, but (Z)-13a TFA as the solvent (at ambient temperature or at 0 °C),
was obtained from a similar reaction of (E)-10 (Scheme 2). and the other employing the more classical acetic acid/cat.
Notably, the cross-coupling of 9 with potassium ethyltri- H2SO4 protocol with heating if necessary. Pleasingly, these
fluoroborate also provided (Z)-13a. Since none of the dia- reactions generated the spiromorpholinones 14–26 in good
stereomeric cross-coupling product was detected (1H yield (Scheme 3).
Scheme 2. Diastereoselective cross-coupling reactions of (bromoalkylidene)morpholinones.
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Enantioselective Synthesis of Quaternary Stereocenters
temperature for 30 min (Scheme 4). Presumably, initial C–
O and C–N bond cleavage in the morpholinone generates
an intermediate, which undergoes fragmentation of the di-
oxane ring to provide a α-keto amide, which is reduced fur-
ther to the dihydroxy amide. Thus, four transformations are
accomplished in one step. Notably, products arising from
reduction of the phenyl ring on the dioxane portion in 18
were not observed. Furthermore, stirring the quenched re-
action mixture, obtained from 14, at ambient temperature
for 8 h directly provided the hydroxy acid 27 in good yield
(86%).
Scheme 3. Prins reactions of alkylidenemorpholinones.
Scheme 4. Dissolving metal reduction of spiromorpholinones 14
and 18.
The yield of 20, from morpholinone 11g, is relatively low
(32%) due to competing substitution on the aromatic ring.
Notably, the Prins products were obtained as single dia-
Although the in-situ reduction of the α-keto amides is
stereomers, the only exception being 26, which was ob- not diastereoselective (1:1 dr), we expect that the α-stereo-
tained as a 5:1 mixture of diasteromers. In this case, purifi- center can be manipulated by oxidation of a suitably pro-
cation provided diastereomerically pure 26 (71%). The ste- tected derivative to the ketone followed by diastereoselec-
reochemistry at the newly formed quaternary carbon atom tive reduction.[13] If required, the diastereomers of 27 and
and at the spiroacetal stereocenter in 14–26 is assigned by 28 can be easily separated by chromatography. α,γ-Di-
analogy to other reactions of the morpholinone tem- hydroxy acids and amides such as 27 and 28 are precursors
plate,[5b,5c] which proceed from the less-substituted face of of β,β-disubstituted γ-butyrolactones that are analogs of
the morpholinone ring. The reason for the moderate dia- pantolactone.[14] Such lactones provide synthetic panto-
stereoselectivity for 26 is not clear at present.
thenamides (N-modified α,γ-dihydroxy amides) by amino-
Having constructed the quaternary stereocenter, we next lysis.[15] Recent studies[16] have shown that the biological ac-
examined the removal of the amino alcohol portion in the tivity of pantothenamides depends on the substitution at,
spiromorpholinones in order to liberate the functionalized and the configuration of, the quaternary carbon atom. No-
quaternary carbon atom bearing building blocks that were tably, these key structural features can be controlled with
the objective of this study. Previous studies[5b,5c] on eph- the modular assembly of quaternary stereocenters described
edrine-derived morpholinones had shown that dissolving for 27 and 28.
metal reduction accomplishes cleavage of the benzylic C–O
Determination of the absolute configuration of the qua-
bond as well as the C–N bond β to the phenyl group in the ternary carbon atom in the hydroxy acids required their
morpholinone. Hence, we anticipated that dissolving metal conversion to known aldehydes or carboxylic acids for cor-
reduction of the spiromorpholinones prepared in this study relation. This conversion would also achieve our objective
would generate hydroxy amides based on the 1,3-dioxanyl of preparing quaternary stereocenter containing acyclic mo-
scaffold.
tifs that are amenable to functionalization. Hence, in order
In initial studies two representative spiromorpholinones, to demonstrate the generality of the amino alcohol removal
one with two alkyl groups at the quaternary carbon atom and conversion of the α-hydroxy acid products into the
(14) and the other with an alkyl and an aryl substituent targets, selected spiromorpholinones derived either from
(18), were subjected to dissolving metal reduction (Na/ 1R,2S-ephedrine or from S-2-(methylamino)-1,1-di-
NH3). Unexpectedly, but pleasingly, the reduction of 18 phenylpropanol, both bearing alkyl, aryl or arylalkyl sub-
provided the α,γ-dihydroxy amide 28 (56%) after quenching stituents were converted into functionalized, quaternary
the reaction with MeOH/water followed by stirring at room stereocenter containing building blocks (Scheme 5).
Eur. J. Org. Chem. 2015, 5939–5943
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A. Manchoju, R. G. Thorat, S. V. Pansare
SHORT COMMUNICATION
Acknowledgments
These investigations were supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC) and the
Canada Foundation for Innovation.
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Scheme 5. Conversion of spiromorpholinones to functionalized
quaternary stereocenters.
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The crude carboxylic acid obtained from the dissolving
metal reduction of the spiromorpholinones was subjected
to a two-step protocol involving reduction with borane fol-
lowed by oxidative cleavage of the resulting vicinal diol to
an aldehyde.[17] The aldehyde was directly employed in a
Horner–Wadsworth–Emmons (HWE) reaction to provide
29 or oxidized to the corresponding carboxylic acid 30
(from 14). Similarly, 31, 32 and 33 were obtained from
morpholinones 18, 25 and 23 respectively (Scheme 5). Com-
parison of the optical rotations of the acids 31[18] and 32[19]
with reported values confirmed the “R” configuration. The
formation of the “R” enantiomer also confirms the stereo-
chemical outcome of the Prins reaction. The configurations
of 29, 30 and 33 are assigned by analogy.
Notably, the methyl ester of the hydroxy acid 32 prepared
in this study serves as a key starting material in the synthe-
sis of (+)-α-cuparenone, a quaternary stereocenter contain-
ing sesquiterpene. We anticipate that the other spiro-
morpholinones prepared in this study will also provide qua-
ternary stereocenter containing hydroxy aldehydes or carb-
oxylic acids by employing a protocol similar to the one de-
scribed in Scheme 5.[20]
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Conclusions
In conclusion, we have developed a modular synthesis of
functionalized quaternary carbon containing building
blocks by sequential, stereoselective C–C bond forming re-
actions on chiral amino alcohol derived morpholinones.
The methodology has the potential to rapidly assemble a
variety of quaternary carbon atoms that are adorned with
a selection of alkyl and aryl substituents. This study has
also identified S-2-(methylamino)-1,1-diphenylpropanol as
a potential replacement for 1R,2S-ephedrine in the morph-
olinone template based methodology. Current efforts focus
on other applications of the alkylidenemorpholinones.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for all com-
pounds.
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Enantioselective Synthesis of Quaternary Stereocenters
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Received: July 27, 2015
Published Online: August 17, 2015
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