Oxyenamides as Versatile Building Blocks for a Highly Stereoselective One-Pot Synthesis of the 1,3-Diamino-2-ol-Scaffold Containing Three Continuous Stereocenters

Article abstract of DOI:10.1002/anie.202109752

A highly diastereoselective one-pot synthesis of the 1,3-diamino-2-alcohol unit bearing three continuous stereocenters is described. This method utilizes 2-oxyenamides as a novel type of building block for the rapid assembly of the 1,3-diamine scaffold containing an additional stereogenic oxygen functionality at the C2 position. A stereoselective preparation of the required (Z)-oxyenamides is reported as well.

Full text of DOI:10.1002/anie.202109752

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Accepted Article
Title: Oxyenamides as Versatile Building Blocks for a Highly
Stereoselective One-Pot Synthesis of the 1,3-Diamino-2-ol-
Scaffold Containing Three Continuous Stereocenters
Authors: Sara-Cathrin Krieg, Jennifer Grimmer, Philipp Kramer,
Michael Bolte, Harald Kelm, and Georg Manolikakes
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Oxyenamides as Versatile Building Blocks for a Highly
Stereoselective One-Pot Synthesis of the 1,3-Diamino-2-ol-
Scaffold Containing Three Continuous Stereocenters
Sara-Cathrin Krieg,‡[a] Jennifer Grimmer‡[a], Philipp Kramer,[a] Michael Bolte,[b] Harald Kelm,[a] Georg
Manolikakes*[a]
Dedicated to Prof. Konstantin Karaghiosoff on the occasion of his 65th birthday.
Abstract: A highly diastereoselective one-pot synthesis of the 1,3-
diamino-2-alcohol unit bearing three continuous stereocenters is
described. This method utilizes 2-oxyenamides as a novel type of
building block for the rapid assembly of the 1,3-diamine-scaffold
containing an additional stereogenic oxygen functionality at the
C2-position.
A
stereoselective preparation of the required
(Z)-oxyenamides is reported as well.
The synthesis of acyclic molecules containing multiple
stereogenic centers in a rapid manner with precise control over all
formed stereocenters still represents a formidable challenge for
any organic chemist.[1] Usually a stepwise synthesis, viz. the
creation of a single stereocenter and/or a single carbon-carbon-
bond in one chemical step, offers a reliable access to the desired
scaffold. However, such a stepwise construction will result in a
time- and resource-intensive route. Therefore, the controlled
synthesis of several bonds and stereocenters in a simple one-pot
operation is receiving increasing attention as an attractive and
more efficient alternative for the construction of structurally
complex molecules.[2],[3] The 1,3-diamino-2-alcohol unit
represents such a structurally complex scaffold. This moiety
contains three adjacent functional groups attached to three
continuous stereocenters. The 1,3-diamino-2-alcohol motif can be
found in various drugs or natural products, e.g. the bromopyrrole
alkaloid manzacidin B[4] (Figure 1). Interestingly, several HIV-
protease inhibitors, such as fosamprenavir, amprenavir and
nelfinavir contain this core motif.[5] The preparation of such
molecules usually requires a multistep synthesis. In the last years
several groups have shown that enamides or encarbamates are
highly useful building blocks for a rapid and stereocontrolled
construction of the parent 1,3-diamine unit (Scheme 1a).[6],[7]
However, the highly relevant 1,3-diamino-2-alcohol motif cannot
be accessed directly with these methods. We envisioned, that
Figure 1. Biologically active 1,3-diamino-2-alcohols.
starting from the corresponding oxyenamides of type 1, one
should be able to directly access the 1,3-diamino-2-ol core
structure in a similar manner (Scheme 1b). However, reactions
with oxyenamides have been scarcely reported so far.[8] Indeed,
even methods for their synthesis are rare.[9] Considering the
potential utility of oxyenamides not only as building block for the
construction of the 1,3-diamino-2-alcohol unit, but as a general
tool for the stereoselective synthesis of the 1,2-aminoalcohol
[a]
S.-C. Krieg, J. Grimmer, Dr. P. Kramer, Dr. H. Kelm, Prof. Dr. G.
Manolikakes
Department of Chemistry, Technical University Kaiserslautern,
Erwin-Schrödinger-Str. Geb 54, 67663 Kaiserslautern, Germany
Email: manolikakes@chemie.uni-kl.de
Homepage: https://www.chemie.uni-kl.de/manolikakes
Dr. M. Bolte
[b]
Institute of Inorganic and Analytical Chemistry
Goethe University Frankfurt am Main
Max-von-Laue-Strasse 7, 60438, Frankfurt am Main (Germany)
‡ These two authors made equal contribution to this paper.
Scheme 1. Established procedures for the assembly of 1,3-diamines from
enamides and the analogous synthesis of 1,3-diamino-2-alcohol scaffold from
2-oxyenamides.
Supporting information and the ORCID identification number of the
corresponding author can be found under: LINK.((Please delete this
text if not appropriate))
1
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scaffold, a systematic study on their synthesis and application
would be highly desirable. Herein we describe a first uniform
approach for the stereoselective synthesis of (Z)-oxyenamides
and their application in a one-pot transformation for the
construction of the 1,3-diamino-2-alcohol substructure (Scheme
1b). This experimentally facile, sequential one-pot operation
offers a rapid and highly stereoselective access to the 1,3-
diamino-2-ol motif with up to three continuous stereocenters.
At the onset of our studies, we decided to investigate the
synthesis and application of vinyl ester-type enamides (1) due to
the following reasons. An electron-withdrawing residue on the
oxygen atom should render the enamide moiety more nucleophilic
than the enol ether/ester functionality embedded in the same
chloride in the presence of NEt3 afforded the desired
oxyenamides (1) in 56-73 % yield. In all cases exclusive formation
of the (Z)-isomer was observed (E/Z ≤ 2:98). We assume that
stabilization of the (Z)-enolate via intramolecular hydrogen
bonding leads to the observed stereoselective formation of the
(Z)-oxyenamides (Scheme 3b). Using this approach, the benzoyl,
pivaloyl and acetyl protected oxyenamides 1a-c as well as the
Boc- and the Cbz-protected enecarbamates 1d and 1e could be
prepared in only three steps from 2-aminoethanol. We have
utilized this streamlined procedure for the routine synthesis of
oxyenamides of type 1 on a 1 g scale. With sufficient quantities of
the oxyenamides (1) at hand, we started to explore their
application in the construction of the 1,3-diamino-2-alcohol
scaffold. Therefore, the oxyenamides (1) were reacted with
acylimine precursor 3a in the presence of different Lewis acids
(Scheme 4).
molecule.[10] Thereby,
a
chemoselective reaction with
electrophiles at the -carbon (highlighted in blue) can be expected
(Scheme 2).[11] This type of compounds should be readily
accessible from the corresponding protected amino aldehydes 2,
which leads back to 2-aminoethanol as common starting material.
Furthermore, the incorporated ester functionality should enable a
facile liberation of the free alcohol functionality in the final product.
Scheme 2. Retrosynthetic rationale towards ester-protected oxyenamides and
their expected reactivity.
To our delight, oxyenamides of type 1 could be synthesized in
three steps using the envisioned approach. Selective acylation of
the amine functionality followed by alcohol oxidation afforded the
N-protected -amino aldehydes in 63-64 % overall yield (Scheme
3a). Treatment of the aldehydes 2a-c with a carboxylic acid
Scheme 4. Addition-reduction-sequence (both sequential and one-pot). Given
yields refer to isolated yield of the major diastereomer; The reported
diastereomeric ratio (d.r.) refers to the diastereomeric ratio of the crude reaction
mixture as determined by 1H NMR [a] From reduction of the N,O-acetal. [b] Via
one-pot reaction with SiCl4 and K-Selectride. [c] Via one-pot reaction with
BF3•OEt2 and L-Selectride.
Although
a variety of Lewis acids could mediate this
transformation, best results were obtained with SiCl4. The desired
addition products 4a-e were obtained in 76-88 %.[12] Reduction of
the newly formed N,O-acetals (4) with Et3SiH in the presence of
BF3·OEt2 furnished the 1,2-syn-1,3-diamino-2-alcohol products
Scheme 3. Synthesis of oxyenamides of type 1. Given yields refer to isolated
yield of the analytically pure product [a] Yield over two steps. Bz=benzoyl;
Piv=pivaloyl; Ac=acetyl; Boc= tert-butoxycarbonyl; Cbz=benzyloxycarbonyl.
5a-e
in
varying
yields
(15-79%)
and
excellent
diastereoselectivties (d.r. ≥ 98:2).[13] In general, better yields were
2
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10.1002/anie.202109752
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obtained with a modified one-pot protocol without isolation of the
intermediates of type 4. Reaction of the oxyenamides (1) with
acylimine precursors 3a in the presence of SiCl4 or BF3·OEt2,
followed by direct addition of either K-Selectride (for SiCl4) or L-
Selectride (for BF3·OEt2) afforded the desired 1,3-amino-2-
alcohols 5a-e in 49-76% yield with excellent diastereoselectivies.
In all cases only the 1,2-syn diastereomer could be observed in
only the formation of a single diastereomer could be observed.
For some reactive heterocycles the desired products (7e, 7g and
7h) were obtained with slightly lower stereoselectivties. The
reaction with pyrazole afforded the N-alkylated product 7i in 81%
yield and a diastereomeric ratio of 87:13. Employing NaN3 or
EtSH as terminal nucleophile furnished the products 7j and 7k,
containing a useful handle for further transformations, in 57% and
83% yield, albeit with slightly lower diastereoselectivities. So far,
the final trapping with a terminal nucleophile is mainly limited to
electron-rich (hetero)arenes. In case of less reactive nucleophiles
(e.g. anisole or allylsilane), we did only observe decomposition of
the crude reaction mixture (d.r.
≥ 98:2). These results
demonstrate, that oxyenamides of type 1 show a reactivity profile
similar to their -carbon-substituted counterparts and can be used
as building blocks for stereoselective transformations. Therefore,
we turned our attention towards the stereoselective construction
the intermediates of type
temperatures > 0°C.
4 upon prolonged stirring at
of
1,3-diamino-2-alcohols
containing three continuous
stereogenic centers. Accordingly, the reducing agent was
replaced with 1,3,5-trimethoxybenzene as terminal nucleophile
(Scheme 5). To our delight, this modified reaction directly afforded
Scheme 5. One-pot reaction with 1,3,5-trimethoxybenzene. Given yields refer
to the isolated yield of the major diastereomer. Values in parentheses represent
the overall isolated yield of all diastereomers. The reported diastereomeric ratio
(d.r.) refers to the diastereomeric ratio of the crude reaction mixture as
determined by 1H NMR. (TMP = 1,3,5-trimethoxyphenyl)
Scheme 6. One-pot reaction with different nucleophiles. Given yields refers to
the isolated yield of the major diastereomer. Values in parentheses represent
the overall isolated yield of all diastereomers. The reported diastereomeric ratio
(d.r.) refers to the diastereomeric ratio of the crude reaction mixture as
determined by 1H NMR. [a] Overall yield for both diastereomers, no separation
of diastereomers could be achieved in the case of 7k.
the 1,2-syn-2,3-anti-configurated products 6a-e in 58-90 % yield
in a simple one-pot operation. In case of oxyenamides 1a-c the
reaction proceeded with excellent stereoselectivities, furnishing
the products 6a-c essentially as a single diastereomer (d.r.
>98:<2:0:0). In case of the Cbz-derived encarbamate (1e) a lower
diastereoselectivity (d.r. = 71:29:0:0) was observed. For the Boc-
protected oxyenamide 1d, only trace amounts of the product
Next, we investigated reactions with different N-acylimine
precursors (3) (Scheme 7). In general, N,O-acetals derived from
aromatic aldehydes proved to be suitable starting materials for our
one-pot approach, leading to the formation of the 1,2-syn-2,3-anti-
configured products 8a-i in 55-95 % yield with excellent
diastereoselectivities in all cases (d.r. >98:<2:0:0). Different
electron-withdrawing or -donating substituents as well as different
substitution patterns were well tolerated. To our delight, also a
Cbz-derived carbamoyl imine precursor reacted smoothly,
affording the orthogonal protected 1,3-diamine-2-ol 8h in 56%
yield and perfect diastereoselectivity. Unfortunately, reactions
could be detected. Presumably,
a prolonged stirring of
intermediate 4d in the presence of SiCl4 leads to cleavage of the
Boc-group and side reactions with the free amine. In a similar
manner, other nucleophilic components could be utilized in this
one-pot process (Scheme 6). Reactions with different electron-
rich arenes or heteroaromatics lead to the formation of the 1,2-
syn-2,3-anti-1,3-diamino-2-alcohols 7a-h with three continuous
stereocenters in 69-87% yield with uniformly high
diastereoselectivities. Heterocycles, such as indole, furan or
methoxythiophene, performed particularly well. In most cases
3
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with alkyl aldehyde-derived as well as heterocyclic N,O-acetals,
did not furnish any desired product under the standard conditions.
functionality leads to a new acylimine III. Addition of MeOH affords
the N,O-acetal 4a. We assume that under the reaction conditions,
compounds II, III and 4a exist in an equilibrium. In the presence
of SiCl4 as coordinating Lewis acid, a 6-membered N-acylimine
intermediate of type IV can be formed.[16] Addition of the
nucleophile from the sterically less hindered side leads to the
selective formation of the third stereocenter and the 2,3-anti-
configured product.
Scheme 7. One-pot reaction with different imine precursors. Given yields refer
to the isolated yield of the major diastereomer. The reported diastereomeric ratio
(d.r.) refers to the diastereomeric ratio of the crude reaction mixture as
determined by 1H NMR. (TMP = 1,3,5-trimethoxyphenyl)
Scheme 9. Tentative reaction mechanisms for the diastereoselective formation
the three stereocenters.
In summary, we have reported a simple procedure for the
synthesis of (Z)-oxyenamides from common starting materials in
only three steps. These oxyenamides represent a highly useful
building block for the rapid assembly of the 1,3-diamino-2-alcohol
substructure, a common motif in natural products and drugs. A
Lewis-acid-mediated one-pot reaction between the oxyenamide
and an N-acylimine precursor followed by trapping with a terminal
nucleophile enables a rapid and highly modular assembly of the
1,3-diamino-2-alcohol scaffold containing up to three continuous
stereocenters in good yields and excellent diastereoselectivities.
Facile removal of the acyl group directly affords to unprotected
1,3-diamino-2-alcohol. Further research towards the controlled
synthesis of other stereoisomers, the development of an
asymmetric version and applications in the synthesis of bioactive
molecules as well as detailed mechanistic investigations are
currently performed in our laboratories.
Finally, we investigated the deprotection of the introduced
masked alcohol functionality on two selected examples. Removal
of the benzoyl group with sodium methoxide in MeOH[14]
proceeded smoothly, affording the unprotected 1,3-
diaminoalcohols 9a and 9b in high yields with complete retention
of configuration (Scheme 8).
Scheme 8. Deprotection of the benzoyl-protected 1,3-diamino-2-alcohols 5a
and 6a. Given yields refer to the isolated yield of the major diastereomer.
Acknowledgements
Based on the observed results and previous reports on similar
transformations with carbon-substituted enamides,[15a-c] we
assume the following reaction pathway for the first transformation.
In the presence of a Lewis acid, precursors 3a liberates a reactive
N-acylimine, a known electron-deficient heterodiene (Scheme
9a).[15d-f] An inverse electron-demand hetero-Diels-Alder reaction
between I and the oxyenamide 1a, proceeding in an endo-
fashion,[15c] furnishes the 1,2-syn-configured dihydrooxazine
intermediate II. Ring-opening via cleavage of the hemiaminal
Financial support by the DFG (MA 6093/10-1) and the research
unit NanoKat at the TU Kaiserslautern is gratefully acknowledged.
P. Kramer thanks the Polytechnische Gesellschaft Frankfurt am
Main (Germany) for a MainCampus PhD scholarship.
Keywords: enamides • stereoselective synthesis • 1,3-diamine •
Lewis acid • one-pot reaction
4
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Entry for the Table of Contents
Herein we introduce 2-oxyenamides as novel, highly versatile building blocks for the rapid construction of the 1,3-diamino-2-ol-
scaffold. A Lewis-acid mediated reaction of 2-oxyenamides with acylimine precursors and a terminal nucleophile enables a modular
assembly of the 1,3-diamino-2-ol-structure bearing three continuous stereocenters with excellent levels of diastereoselectivity.
Institute and/or researcher Twitter usernames: @ManolikakesLab
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