Multicomponent cis- and trans-Aziridinatons in the Syntheses of All Four Stereoisomers of Sphinganine

Article abstract of DOI:10.1021/acs.orglett.7b00697

All four stereoisomers of sphinganine can be synthesized by a multicomponent aziridination of an aldehyde, an amine and an α-diazo carbonyl compound mediated by a BOROX catalyst with high asymmetric induction (≥96% ee). The threo isomers are available from ring-opening of cis-aziridines by an oxygen nucleophile with inversion at the C-3 position and the erythro-isomers are likewise available from trans-aziridines.

Full text of DOI:10.1021/acs.orglett.7b00697

Letter
pubs.acs.org/OrgLett
Multicomponent cis- and trans-Aziridinatons in the Syntheses of All
Four Stereoisomers of Sphinganine
Yubai Zhou, Munmun Mukherjee, Anil K. Gupta, and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: All four stereoisomers of sphinganine can be synthesized by a multicomponent aziridination of an aldehyde, an
amine and an α-diazo carbonyl compound mediated by a BOROX catalyst with high asymmetric induction (≥96% ee). The
threo isomers are available from ring-opening of cis-aziridines by an oxygen nucleophile with inversion at the C-3 position and
the erythro-isomers are likewise available from trans-aziridines.
and antipsoriatic drug9 and has been investigated for its ability
phinganine is one of three core structures present in
to inhibit protein kinase C.10 As a consequence of this and
other differences in bioactivities, all of the isomers of
Ssphingolipids, which exist in several subclasses and are
sphinganines have been prepared and their biological properties
Scheme 1. Sphinganines via cis- and trans-Aziridination
investigated.1−3
The history of the synthesis of sphinganines has been quite
extensive11,12 and dates back to the first synthesis in 1951.13
The most successful applications with asymmetric catalysis
involve the use of either the Sharpless asymmetric dihydrox-
ylation14 the Sharpless asymmetric epoxidation15 and the
Sharpless kinetic resolution of allylic alcohols,16 although it
has not been demonstrated if these methods can be used for all
four of the stereoisomers of the sphinganines. Other catalytic
asymmetric methods utilized in the synthesis sphinganines are
asymmetric hydrogenation of β-oxo esters,17 a proline based
Mannich reaction,18 and again, it has not been demonstrated
that either can be used for the preparation of all four of the
stereoisomers of sphinganine. A catalytic asymmetric nitro aldol
reaction (Henry reaction) with a lanthanum BINOL complex
between 2-nitroethanol and hexadecanal has also been reported
but is limited to the threo-isomers.19 Likewise, an organo-
catalytic based catalyst with a prolinol derivative has been
reported12c but is also limited to the threo-isomers (sphinganine
itself is erythro).
involved in many aspects of cell structure and regulation.1−3
Errors in sphingolipid metabolism have led to several inherited
human diseases including diabetes,4 cancers,5 Alzheimer’s
disease,6 heart disease and an array of neurological syndromes.7
Sphingolipids are involved in nearly all aspects of cell
regulation, including proliferation, differentiation, adhesion,
neuronal repair, and signal transduction.8 The natural
configuration of sphinganine is the D-erythro configuration 6,
however, it has been found that the stereochemistry can play a
large role in their bioactivity. For example, the L-threo
diastereomer of sphinganine (safingol 9) is an antineoplastic
The goal of the present work is to demonstrate that the
asymmetric catalytic aziridination reaction can be adapted to
the synthesis of all four sphinganines (Scheme 1). We have
Received: March 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Multicomponent trans-Aziridination of Aryl and
Aliphatic Aldehydes
Scheme 3. Ring-Opening of Aziridine 5b and Recycling of
BUDAM amine 14
then hydrolysis to an amino alcohol. However, it was
envisioned that the erythro-sphinganines could be obtained
directly from trans-aziridines via ring-opening at the C-3
position by an oxygen nucleophile with inversion. The
diastereo-selectivity of the aziridination can be switched from
cis- to trans- by changing the diazo substrate from a diazo
acetate to a diazo acetamide beginning from preformed
imines.22 We present here the first examples of the multi-
component trans-aziridination of aldehydes with an amine and
a diazoacetamide using a BOROX catalyst and its application to
the synthesis of erythro-sphinganines.
We have previously reported that switching the diazo
compound from a diazo acetate to a 2° diazo acetamide will
produce trans-aziridines rather than cis-aziridines from
preformed imines with a BOROX catalyst generated from
either the VANOL or VAPOL ligand.22,23 As an example, the
BUDAM imine 10 prepared from benzaldehyde and BUDAM
amine 14 reacts with the N-phenyl diazoacetamide 11 to give
the trans-aziridine 12 in 74% yield with 89% ee and with a 27:1
selectivity for the trans-isomer (Scheme 2).24 We had
previously determined that both amines and imines are basic
enough to cause self-assembly of the BOROX catalyst from a
molecule of the ligand and three equivalents of B(OPh)3.25
However, our initial attempts at translation of this reaction into
a multicomponent version from aryl aldehydes were not
successful. For example, the reaction of benzaldehyde, BUDAM
amine 14 and diazo acetamide 11 only gave the aziridine 12 in
14% yield along with the imine 10 in 59% yield. Given this
previously reported20 the synthesis of the threo-sphinganines
from cis-aziridines which were generated by the catalytic
asymmetric multicomponent cis-aziridination21 of hexadecanal,
an amine and ethyl diazoacetete mediated by a BOROX
catalyst. The cis-aziridines were ring-opened at the C-3 position
by an oxygen nucleophile with inversion. In this work access to
the erythro-sphinganines was also achieved from the cis-
aziridines in a multistep process involving the removal of the
N-protecting group and then installation of an N-Boc group,
ring expansion to an oxazolidinone (with retention at C-3), and
a
Table 1. Optimization of the Multicomponent trans-Aziridination of Aliphatic Aldehyde 1
b
c
d
entry
amine
PG
ligand
R
aziridine
trans/cis
% yield trans aziridine
% ee trans aziridine
1
2
3
4
5
6
7
14
14
14
14
14
17
17
BUDAM
BUDAM
BUDAM
BUDAM
BUDAM
MEDAM
MEDAM
(S)-VANOL
(S)-VANOL
(S)-VANOL
(R)-VANOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
Ph
5a
5b
5b
5b
5b
5c
5c
6:1
70
85
88
86
91
67
79
68
96
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
24:1
28:1
30:1
14:1
8:1
e
96
ef
,
−96
91
88
15:1
86
a
Unless otherwise specified, all reactions were performed at 0.2 M in amine in toluene with 0.2 mmol of amine and 1.1 equiv of 1 and 1.2 equiv of
diazo compound with 10 mol % catalyst, which was prepared by heating 0.1 equiv of ligand, 0.3 equiv of B(OPh)3 and 1.0 equiv of amine in toluene
at 80 °C for 30 min. The catalyst was cooled to rt, and then the aldehyde and 4 Å molecular sieves were added, and then the mixture was
b
c
immediately cooled to −10 °C, and the diazo compound was added. Determined by 1H NMR analysis of the crude reaction mixture. Isolated yield
d
e
f
of purified trans-aziridine. Determined on purified trans-aziridine by HPLC. Reaction run on 3.0 mmol scale. (2S,3R)-5b is produced.
B
DOI: 10.1021/acs.orglett.7b00697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of all Four Stereoisomers of Sphinganine via Asymmetric Catalytic Multicomponent cis- and trans-
Aziridinations
result, it was surprising to find that the same multicomponent
reaction with the aliphatic aldehyde hexadecanal 1 gave the
trans-aziridine 5a in 70% yield and in 68% ee with a 6:1 trans/
cis ratio.
Fortunately, the major regioisomer resulted from nucleophilic
opening at the C-3 position in a 4:1 ratio which could be
enhanced to 8:1 by decreasing the concentration (Scheme 3).
From compound 19, the most straightforward route to the
sphinganines would involve reduction of the amide to the
alcohol to give compound 21. Unfortunately, the screening of a
host of reducing agents including BH3·NH2Li26 did not lead to
the clean conversion of 19 to 21 but rather to complex mixtures
of compounds. This lack of selectivity was thought to be due to
the bulk of the BUDAM group and not to the presence of the
β-hydroxy group.26
A change in tactics then involved the conversion of the trans-
amide ent-5b to the trans-ester ent-22 prior to the ring-opening
(Scheme 4). Ring-opening of the trans-ester ent-22, like that of
the trans-amide ent-5b, did not give a single regioisomer but
rather a mixture of opening at C-3 and C-2 (2.5:1). The
regioisomers could be separated after the reduction of the ester
to give the amino diol ent-23 in 58% yield for 2 steps. The
regioisomer of ent-23 could be isolated in 23% yield and thus
the ring-opening of the trans-ester ent-22 is less regioselective
(2.5:1) than for the trans-amide ent-5b (8:1). Finally, the amino
group in ent-23 could be deprotected to give L-erythro-
sphinganine 7 in 85% yield. In a similar manner, the aziridine
5b could be converted to D-erythro-sphinganine (Scheme 4). It
is to be noted that the final cleavage of the BUDAM group in
With the successful multicomponent trans-aziridination of
hexadecanal, attention was turned to its optimization (Table 1).
It was found that if the N-substituent on the diazo was an n-
butyl instead of phenyl, the asymmetric induction increased to
96% ee (Table 1, entry 2). This reaction could be scaled up 15-
fold to give 2.12 g of aziridine (2R,3S)-5b in 96% ee and 88%
yield with a trans:cis ratio of 28:1 (entry 3). With the (R)-
BOROX catalyst the aziridine (2S,3R)-5b was obtained in 86%
yield and 96% ee (entry 4). The corresponding VAPOL-
BOROX catalyst was also effective but gave slightly lower
diastereo- and enantioselectivity (Table 1, entries 2 vs 5). The
VANOL and VAPOL catalysts were also compared with the
MEDAM amine but both were slightly less effective than
BUDAM amine (Table 1, entries 2 vs 6 and 5 vs 7).
We had previously shown that cis-aziridine-2-carboxylate
esters would undergo ring-opening with trifluoroacetic acid to
give exclusive opening at the C-3 position.20 We had not
previously examined the ring-opening of the trans-aziridine-2-
carboxamides with oxygen nucleophiles. The reaction of
aziridine (2R,3S)-5b with trifluoroacetic acid actually gave a
mixture of the regioisomers 19 and 20 (Scheme 3).
C
DOI: 10.1021/acs.orglett.7b00697
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Organic Letters
Letter
Dorta, G.; Donadel, O. J.; Martin, V. S.; Padron, J. M. J. Org. Chem.
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(13) Grob, C. A.; Jenny, E. F.; Utzinger, H. Helv. Chim. Acta 1951,
ent-23 (and also for 23) leads to the recovery of the bis-aryl
methane 26. BUDAM amine 14 can be recycled from 26 by
oxidation27 to the benzophenone 27 (85%) and then reductive
amination (89%) (Scheme 3).
We have described here the first examples of the multi-
component trans-aziridination of aldehydes and, together with
the multicomponent cis-aziridination, the synthesis of all four
stereoisomers of sphinganine.
34, 2249−2254.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00697.
(19) (a) Sasai, H.; Tokunaga, T.; Watnabe, S.; Suzuki, T.; Itoh, N.;
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(20) Mukherjee, M.; Zhou, Y.; Gupta, A. K.; Guan, Y.; Wulff, W. D.
Eur. J. Org. Chem. 2014, 2014, 1386.
Experimental protocols, characterization procedures
(PDF)
Spectral data for all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wulff@chemistry.msu.edu.
ORCID
(21) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13,
5866.
(22) (a) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132,
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(23) For other trans-aziridinations with diazoacetamides, see;
(a) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc.
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William D. Wulff: 0000-0002-5668-4312
Notes
The authors declare no competing financial interest.
(24) Desai, A. A. Ph. D. Thesis, 2010, Michigan State University, p
47.
(25) Gupta, A. K.; Mukherjee, M.; Hu, G.; Wulff, W. D. J. Org. Chem.
2012, 77, 7932.
ACKNOWLEDGMENTS
■
This work was supported by the National Institute of General
Medical Sciences (GM 094478).
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DOI: 10.1021/acs.orglett.7b00697
Org. Lett. XXXX, XXX, XXX−XXX