Asymmetric Synthesis of β-Amino-α-hydroxy Aldehyde Derivatives Bearing a Quaternary Stereogenic Center

Article abstract of DOI:10.1002/ejoc.201600872

An organocatalytic approach for the stereoselective synthesis of β-amino-α-hydroxy aldehydes bearing a fully substituted stereogenic center in the α-position with respect to the aldehyde moiety is presented. It utilizes a one-pot reaction cascade involvin

Full text of DOI:10.1002/ejoc.201600872

A Journal of
Accepted Article
Title: Asymmetric Synthesis of β-Amino-α-hydroxyaldehyde Derivatives Bearing a
Quaternary Stereogenic Center
´
Authors: Piotr Drelich; Anna Skrzynska; Łukasz Albrecht
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European Journal of Organic Chemistry
10.1002/ejoc.201600872
COMMUNICATION
Asymmetric
Synthesis
of
β-Amino-α-hydroxyaldehyde
Derivatives Bearing a Quaternary Stereogenic Center
Piotr Drelich,a Anna Skrzyńska,a and Łukasz Albrechta,*
a
Institute of Organic Chemistry, Łódź University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
lukasz.albrecht@p.lodz.pl
http://www.chorg.p.lodz.pl/index.php/en/research-teams/zespol-dr-albrechta-en
Received:
Supporting information for this article is available on the WWW
contemporary organic and medicinal chemistry.[5] It
Abstract. An organocatalytic approach for the
stereoselective synthesis of β-amino-α-
is worth to stress out that the quaternary stereogenic
centers are very often present in natural products and
bioactive molecules.[6] Importantly, synthetic
strategies leading to targets possessing such structural
features remain limited.[7] In this context, asymmetric
organocatalysis, where simple and chiral organic
molecules are employed to promote stereocontrolled
transformations, has recently introduced some novel
and interesting solutions.[8]
hydroxyaldehydes bearing a fully substituted stereogenic
center in the α-position with respect to the aldehyde
moiety is presented. It utilizes a one-pot reaction
cascade involving aziridination reaction followed by the
sodium-methoxide-initiated rearrangement. In order to
control the chemoselectivity of the rearrangement a new
aziridinating reagent enabling the introduction of a nosyl
protecting group at the nitrogen atom has been designed
and introduced. Products of the reaction have thus been
obtained as dimethyl acetal, exclusively. The possibility
to deprotect the aldehyde moiety with the preservation
of the introduced optical purity has also been
demonstrated.
Keywords: organocatalysis; cascade reactions; β-
amino-α-hydroxyaldehydes; 1,2-aminoalcohol;
quaternary stereogenic center
The α-hydroxyaldehyde structural motif is a key
constituent of many natural products and bioactive
molecules (Scheme 1, top).[1] It is also a useful
building block widely employed in the synthesis of
biologically relevant compounds.[2] Additionally, 1,2-
aminoalcohols are common in nature and present in
numerous compounds important for the life science
such as e.g. amino- and iminosugars (Scheme 1,
middle).[3] Synthetic methodologies for the direct and
stereocontrolled introduction of 1,2-aminoalcohol
moiety into a target molecule are limited and rely
mainly on the Sharpless aminohydroxylation
reaction.[4] Notably, the main drawbacks of that
methodology are related to the cost and toxicity of
osmium and problems with the control of
regioselectivity of the process. Furthermore, the
incorporation of a fully substituted carbon atom into a
structure of either α-hydroxyaldehyde or 1,2-
aminoalcohol in an enantioselective fashion is a
highly challenging and important task in the
Scheme 1. The relevance of α-hydroxyaldehyde and 1,2-
aminoalcohol moieties and the synthetic objectives of this
work.
Herein, we report our studies on the enantioselective
synthesis of β-amino-α-hydroxyaldehydes bearing a
quaternary stereogenic center (Scheme 1, bottom).
Postulated mechanism of the devised cascade
reactivity is outlined in the Scheme 2. It is initiated
by the conjugate addition of the nitrogen nucleophile
3 to the iminium-ion derived from α-substituted
acroleins 1.[9] Subsequently, aziridine ring is formed
1

European Journal of Organic Chemistry
10.1002/ejoc.201600872
via an intramolecular nucleophilic substitution
reaction. At this stage stereochemical information is
transferred from the stereogenic center originating
from the chiral aminocatalyst to the newly generated
quaternary stereocenter. The reaction occurs from the
side opposite to the bulky substituent present at C-2
of the pyrrolidine framework.[10] Hydrolytic cleavage
of the catalyst 2 liberates the 2,3-aziridine aldehyde 4
that is subjected to the sodium methoxide initiated
rearrangement in a one-pot fashion.[11] 1,2-Addition
of methoxide anion to the aldehyde moiety in 4
initiates this stereospecific reaction. The alkoxide 8
thus obtained undergoes the aza-Payne-type reaction
that leads to the formation of the epoxide 9. Notably,
at this stage a full inversion of the absolute
configuration at the C-2 stereogenic center occurs.
Epoxide-ring-opening takes place in the next step of
the cascade to yield the corresponding oxocarbenium
ion 10. At this point, two different reaction pathways
are possible. The intramolecular cyclization with the
nitrogen atom serving as a nucleophilic species leads
to the formation of the corresponding N,O-acetal 6
(Scheme 2, path a). The different reaction pathway
relies on the 1,2-addition of a second methoxide
anion to the oxocarbenium ion moiety in 10 to give
the corresponding dimethyl acetal 5 as a final product
(Scheme 2, path b).
as a mixture of the corresponding dimethyl acetal 5a
and the azetidine 6a in which the acetal 5a dominated.
This observation is in marked contrast to the outcome
of the reaction observed for linear α,β-unsaturated
aldehydes.[11a] The solvent screening performed in the
next stage of optimization studies (Table 1 entries 1-
6) enabled to identify toluene as the most suitable
choice for the one-pot cascade (Table 1 entry 6).
Furthermore, it was found that lowering the reaction
temperature to
0 °C was beneficial for its
stereoselectivity (Table 1 entry 7). Subsequent
catalyst screening (Table 1 entries 7-10) revealed that
increasing the bulkiness of the silyl protecting group
in 2 had no major influence on the reaction
enantioselectivity (Table 1 entries 7-9). To our
delight, the stereochemical reaction outcome could be
improved by using 2d as the catalyst[9a] (Table 1 entry
10). Disappointingly, the mixture of 5a and 6a was
still formed in the course of the rearrangement
reaction. However, it was postulated that a proper
choice of an aziridinating reagent might enable the
rearrangement to occur according to only one
reaction pathway facilitating selective formation of
one of the products. Therefore, further optimization
studies were directed towards finding an aziridinating
reagent that
Table 1. Enantioselective synthesis of β-amino-α-
hydroxyaldehyde dimethyl acetals 5 bearing a quaternary
stereogenic center – optimization studies.a)
Scheme 2. Enantioselective synthesis of β-amino-α-
hydroxyaldehyde dimethyl acetals 5 bearing a quaternary
stereogenic center – mechanistic considerations.
Solvent
Cat./Azir.
reagent
Yield.
[%]b)
5:6
ratioc)
erd)
CCl4
CHCl3
CH2Cl2
Et2O
Hexane
Toluene
Toluenec
Toluenec
Toluenec
Toluenec
Toluenec
1
2
3
4
5
6
2a/3a
2a/3a
2a/3a
2a/3a
2a/3a
2a/3a
2a/3a
2b/3a
2c/3a
2d/3a
2d/3b
66
65
63
37
36
64
68
51
60
75
<5
5:1
5:1
4:1
4:1
6:1
3:1
4:1
4:1
3:1
4:1
nd
74:26
77:33
65:35
77:23
80:20
77:23
80:20
Optimization studies were performed employing 2-
benzylacroleine 1a as a model α,β-unsaturated
aldehyde, diphenylprolinol trimethylsilyl ether 2a as
the catalyst and 3a as a model aziridinating reagent[12]
(Table 1). To our delight, the one-pot reaction
cascade consisting of initial aminocatalytic
aziridination reaction and subsequent sodium
methoxide initiated rearrangement proceeded
efficiently (Table 1 entry 1). Interestingly, the desired
α-hydroxy-β-aminoaldehyde derivative was formed
7e)
8e)
9e)
10e)
11e)
80:20
79:21
90:10
nd
2

European Journal of Organic Chemistry
10.1002/ejoc.201600872
Toluenec
Toluenec
12e)
2d/3c
2d/3d
<5
80
nd
>20:1
nd
91:9
13e)
a)
Reactions performed on 0.25 mmol scale using 1a (1.0 equiv.)
and 2a (1.2 equiv) in 1.5 mL of the solvent (see Supporting
b)
Information for detailed reaction conditions).
Isolated yield
c)
1
over two steps. Determined by H NMR of a crude reaction
d)
e)
mixture.
Determined by a chiral stationary phase HPLC.
Reaction performed at 0 °C.
would ensure the selective formation of 5 (Table 1
entries 10-13). Interestingly, it was found that when
the carbamate protected aziridines 4 (Pg = Boc, Cbz)
were employed in the rearrangement reaction no
rearranged product formation was observed (Table 1
entries 11-12). Therefore, a novel aziridinating
reagent 3d bearing a o-nitrobenzenesulfonyl (Ns)
group on the nitrogen atom was designed and
synthesized. It was postulated that the presence of the
highly-electron-withdrawing nosyl moiety will enable
the rearrangement to occur with the exclusive
formation of dimethyl acetal 5b predominating for
steric reasons. Furthermore, the presence of the nosyl
group in the products 5 is beneficial as the it is easier
to remove when compared with a tosyl moiety. To
our delight, when 4d was employed in the reaction
sequence involving aziridination/NaOMe-initiated
rearrangement, the reaction proceeded with the
exclusive formation of 5b. Furthermore, the reaction
yield and enantioselectivity were high (Table 1 entry
13).
Successfully established the optimal conditions for
the devised one-pot reaction cascade, the scope of the
methodology was studied. Therefore, various α-
substituted acroleins 1a-h were tested in the
Scheme 3. Enantioselective synthesis of β-amino-α-
hydroxyaldehyde dimethyl acetals 5 bearing a quaternary
stereogenic center – α-substituted acrolein 1 scope. All
reactions were performed on 0.25 mmol scale (see
Supporting Information for detailed reaction conditions).
established one-pot reaction cascade (Scheme 3). It
was found that the replacement of a benzyl group
with unfunctionalized alkyl chains of different length
had no major influence on the reaction efficiency
(Scheme 3, compounds 5c-e). To our delight, the
reaction enantioselectivity increased. Interestingly, α-
branched alkyl chains were also well-tolerated as
demonstrated in the synthesis of 5f. Furthermore, the
possibility to introduce various functional group in
the side-chain of 1 was examined. Reactions
proceeded efficiently for the α-substituted acroleins
1f-h containing either triple bond, ether moiety or
protected amine group (Scheme 3, compounds 5g-i).
However, for aldehydes bearing heteroatom-
containing alkyl chains in the α-position 1g,h the
enantioselectivity of the cascade was decreased
(Scheme 3, compounds 5h,i).
Having studied the scope of the method with
regard to the α-substituted acroleins 1a-h, the next
task was to incorporate two adjacent stereogenic
centers (with at least one being a quaternary) into
target β-amino-α-hydroxyaldehyde dimethyl acetals 5
(Scheme 4). In order to accomplish this goal different
α,β-disubstituted-
and
β,β-disubstituted-α,β-
3

European Journal of Organic Chemistry
10.1002/ejoc.201600872
unsaturated aldehydes 1i-l were subjected to the
aziridination reaction under previously optimized
conditions. Subsequent sodium-methoxide-initiated
mediated aziridination reaction[9] and stereospecific
character
of
the
sodium-methoxide-initiated
rearrangement[5f,11a,b] (see Scheme 2 for a detailed
mechanism discussion). The relative configuration of
the additional stereogenic center present in the N,O-
acetals 6 was confirmed by the NOE experiment.
With the configurational assignments accomplished,
the possibility to deprotect the aldehyde moiety in 5
was attempted. Therefore, dimethyl acetal 5c was
selected as a model reactant. Initially, 5c was directly
subjected to hydrolytic acetal cleavage under
classical acidic conditions (Scheme 5, top). The
reaction proceeded efficiently affording 11a in a high
88% yield. Disappointingly, the enantiomeric
enrichment of 11a proved very low indicating that the
reaction proceeded with a racemization of the
quaternary stereogenic center presumably via
dehydratation-hydratation mechanism (SN1-type
reactivity) proceeding with the formation of a stable
tertiary carbocation. Therefore, a different route was
devised (Scheme 5, bottom). It involved initial
protection of the nitrogen atom with a benzyl group
to afford 12a. Subsequent treatment of 12a with
TMSOTf afforded after an aqueous workup 13a in
excellent yield.[13] Notably, the stereoselectivity
Scheme 4. Enantioselective synthesis β-amino-α-
hydroxyaldehyde derivatives 5 or 6 bearing an adjacent
tertiary and quaternary carbon atoms. All reactions were
performed on 0.25 mmol scale (see Supporting
Information for detailed reaction conditions).
Scheme 5. Preparation of β-amino-α-hydroxyaldehydes 11
and 13 via a cleavage of acetal moiety
rearrangement performed in the one-pot fashion
afforded desired products. Interestingly, careful
1
analysis of the H NMR spectra revealed that the
induced at the stage of aminocatalytic cascade was
fully preserved through the protection/deprotection
reactions sequence.
corresponding azetidines 6 were formed as major
products of the rearrangement. This indicated that
when the substituent is present in the β-position of the
starting aldehyde 1 the intramolecular reaction
pathway in the last stage of the cascade started to
dominate (Scheme 2, path b). Only in the case of 1-
cyclohexene-1-carboxaldehyde 1l the corresponding
dimethyl acetal 5m was predominantly formed.
Importantly, in all of the cases reaction proceeded
smoothly affording 5 or 6 in high yields. Furthermore,
both diastereoselectivity and enantioselectivity of the
cascade was high or excellent. These results indicated
the usefulness of the developed one-pot cascade in
accessing higher molecular and stereochemical
complexity.
In conclusion, a novel asymmetric organocatalytic
strategy for the preparation of β-amino-α-
hydroxyaldehydes was developed. It was based on
the aminocatalytic one-pot reaction cascade involving
enantioselective aziridination followed by the sodium
methoxide initiated rearrangement. The choice of
appropriate aziridinating reagent allowed for the
reaction to proceed with the chemo- and
stereoselective formation of nosyl-protected β-amino-
α-hydroxyaldehyde dimethyl acetals. The protocol for
the deprotection of aldehyde moiety proceeding with
the maintenance of optical purity of a starting acetal
was established. The developed cascade offers a
facile, efficient and general entry to a new group of
biologically relevant β-amino-α-hydroxyaldehydes
Notably, the absolute configuration of the products
5 and 6 was established by taking into account the
well-established mechanism of the iminium-ion
4

European Journal of Organic Chemistry
10.1002/ejoc.201600872
with a quaternary stereogenic center that can serve as
useful building blocks for organic synthesis.
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Experimental Section
[5] For selected examples, see: a) B. M. Trost, M. L.
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General procedure for the one-pot reaction cascade
An ordinary screw-cap vial was charged with a magnetic
stirring bar, catalyst 2d (0.2 equiv, 0.05 mmol, 29.9 mg),
sodium acetate (1.5 equiv, 0.375 mmol, 30.8 mg), toluene
(1.5 mL) and aldehyde (1.0 equiv, 0.25 mmol).
Subsequently, the mixture was cooled to 0 °C and 2-nitro-
N-(tosyloxy)benzenesulfonamide 3d (1.2 equiv, 0.30 mmol,
111.6 mg) was added and the reaction mixture was stirred
overnight or 24 h at 0 °C. Next, methanolic solution of
sodium methoxide (0.5 M, 2 equiv, 0.5 mmol, 1 mL) was
added and stirring was maintained for additional 6 or 24 h.
Reaction was quenched with water (15 mL), extracted with
dichloromethane (3x15 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure.
Crude product was purified by the flash chromatography
on silica gel.
[6] For selected examples, see: a) A. Steven, L. E.
Overman, Angew. Chem. Int. Ed. 2007, 46, 5488; b) G.
E. Veitch, E. Beckmann, B. J. Burke, A. Boyer, C.
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C.; Nicolaou, M.; Bella, D. Y.-K.; Chen, X.; Huang, T.;
Ling, S. A. Snyder, Angew. Chem. Int. Ed. 2002, 41,
3495.
Acknowledgements
This project was realized within the Homing Plus Programme
(cofinanced from European Union, Regional Development Fund)
from the Foundation for Polish Science (grant number HOMING
PLUS/2012-6/1).
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6

European Journal of Organic Chemistry
10.1002/ejoc.201600872
COMMUNICATION
Asymmetric Synthesis of β-Amino-α-
hydroxyaldehyde Derivatives Bearing a
Quaternary Stereogenic Center
Eur. J. Org. Chem. Year, Volume, Page – Page
Piotr Drelich, Anna Skrzyńska, and Łukasz
Albrecht*
A stereocontrolled synthesis of β-amino-α-hydroxyaldehyde derivatives with a fully substituted stereogenic
center in the α-position with respect to the aldehyde group is presented. The developed one-pot reaction
cascade involves aminocatalytic aziridination (with a new aziridinating reagent introducing a nosyl group at
the nitrogen atom) followed by the sodium-methoxide-initiated rearrangement.
7