Versatile Scope of a Masked Aldehyde Nitrone in 1,3-Dipolar Cycloadditions

Article abstract of DOI:10.1021/acs.orglett.5b02662

A new masked aldehyde-containing nitrone 1 that is easily available through a facile one-step procedure has been developed. It undergoes a [3 + 2]-thermal cycloaddition with a wide range of dipolarophiles, affording isoxazolidine cycloadducts that are suitable for versatile postcycloaddition modifications. The acetal cycloadducts are acid-stable, but allow for acetal hydrolysis under mildly basic conditions. The isoxazolidine ring can be opened via an efficient one-pot procedure to give amine-protected γ-alcohols that can be further converted to furanose derivatives.

Full text of DOI:10.1021/acs.orglett.5b02662

Letter
pubs.acs.org/OrgLett
Versatile Scope of a Masked Aldehyde Nitrone in 1,3-Dipolar
Cycloadditions
Jorin Hoogenboom,† Han Zuilhof,†,‡ and Tom Wennekes*,†
†Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
‡Department of Chemical and Materials Engineering, King Abdulaziz University, Jeddah, Saudi Arabia
S
* Supporting Information
ABSTRACT: A new masked aldehyde-containing nitrone 1
that is easily available through a facile one-step procedure has
been developed. It undergoes a [3 + 2]-thermal cycloaddition
with a wide range of dipolarophiles, affording isoxazolidine
cycloadducts that are suitable for versatile postcycloaddition
modifications. The acetal cycloadducts are acid-stable, but
allow for acetal hydrolysis under mildly basic conditions. The
isoxazolidine ring can be opened via an efficient one-pot
procedure to give amine-protected γ-alcohols that can be further converted to furanose derivatives.
and derivatization of the resulting cycloadducts to allow further
modification.
he nitrone−olefin [3 + 2] cycloaddition reaction is a
Tpowerful tool in organic chemistry for the stepwise
construction of the backbone of a wide range of complex
molecules.1 A key feature of this reaction is that it allows for the
introduction of three new stereogenic centers in a single step. For
example, several classes of alkaloid derivatives2 and non-natural
amino acids3 that contain multiple neighboring stereogenic
centers have been synthesized using a [3 + 2] cycloaddition as a
key step. Most examples of regio- and enantioselective
cycloadditions that use structurally small and easily accessible
nitrones, however, involve C- and/or N-aryl-substituted nitrones.
This limits the options for subsequent synthetic modification of
the cycloaddition product.4 One of the few examples of easily
accessible and simple nitrones that are more suitable for post-
cycloaddition modification are α-amino ester-derived nitrones,
possessing a masked carboxylic acid and a deprotectable N-
substituent.5 In our ongoing synthetic investigations toward
novel glycomimetics for studying phenomena in glycobiology,6
we required a small (masked) aldehyde-containing nitrone.
However, to the best of our knowledge no precedent existed for
such a compound, so we set out to develop one. We here present
a new and readily accessible nitrone 1 (Figure 1) for the facile
synthesis of synthetically versatile, masked aldehyde-containing
cycloadducts.
Initial efforts focused on the synthesis of nitrone 2, containing
a thioacetal, starting from 1,3-dithiane. We were able to obtain 2
via a two-step procedure in moderate yield. However, nitrone 2
proved to be ineffective for use in nitrone−olefin [3 + 2]
cycloaddition reactions, as the nitrone was not reactive at low
temperatures and quickly degraded upon heating (see
Supporting Information (SI) for details).
The thermal instability of nitrone 2 in this reaction led us to
focus on the synthesis of acetal 1 from readily available N-
benzylhydroxylamine and dimethoxyacetaldehyde. These com-
pounds reacted readily to give 1 in excellent yield on a multigram
scale (Scheme 1). In addition, this reaction does not require a
Scheme 1. Synthesis of Nitrone 1
purification step, whereas similar nitrones that are synthesized in
this fashion usually require purification through chromatography
or crystallization.5a,7 The purification step could be avoided by
performing the reaction at 0 °C and performing a basic workup.
An initial scope study of nitrone 1 in the 1,3-dipolar
cycloaddition reaction with a variety of achiral olefins and
other dipolarophiles was performed using a general reaction
protocol (Scheme 2). The syn/anti stereoselectivity of the
resulting cycloadducts was assigned using NOESY experiments.
We observed that cycloadditions involving both electron-
deficient (providing 3−4) and electron-rich olefins (providing
This nitrone displays selective reactivity with a wide range of
1,3-dipolarophiles combined with mild subsequent deprotection
Figure 1. Nitrones possessing a masked aldehyde for the synthesis of
versatile cycloadducts.
Received: September 14, 2015
© XXXX American Chemical Society
A
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Letter
protonation of the nitrogen atom in the isoxazolidine ring in
close proximity to the acetal might be suppressing methoxy
protonation and thus the acidic hydrolysis.
Scheme 2. Substrate Scope of Nitrone 1 with Different 1,3-
Dipolarophiles in [3 + 2] Cycloaddition Reactions
a b
,
To validate this hypothesis, several neutral and basic
conditions were tested for liberation of the aldehyde.10 Neutral
conditions using iodine, however, led to degradation, and TMS-I
gave only minute amounts of product. In contrast, the use of
TMSOTf under basic conditions gave the desired product in
reasonable yield (Scheme 3). Even though many examples of
similar acetal/ketal-substituted isoxazolidines exist in literature,11
this is the first successful example of acetal hydrolysis on such a
substrate.
We also wanted to identify conditions to selectively modify the
N−O ring through hydrogenation, followed by an in situ
protection of the liberated amine with a versatile set of protecting
groups (Table 1). An initial hydrogenolysis attempt of substrate
Table 1. Mild One-Pot Hydrogenation/Protection
Optimization
a
b
Isolated yield after column chromatography. Syn/anti ratio
1
determined by H NMR and assigned by NOESY.
5−6) proceeded rapidly, leading to complete conversion within
2 h at 110 °C in toluene. For a sterically bulky, disubstituted
alkene a longer reaction time (38 h) was required to obtain
cycloadduct 7 in good yield. A trisubstituted olefin also showed
lower reactivity, but still gave complete conversion to products 8
and 9 after 2 days. The occurrence of two regioisomers (8 and 9),
instead of the two syn- and anti-diastereomers observed in most
cases, is common for cycloadditions with α-alkyl trisubstituted
olefins.8
After these encouraging results for nitrone 1 with olefins, we
evaluated several different dipolarophiles such as nitriles and
alkynes. First, 1 was reacted with benzonitrile and selectively gave
one major isomer (10) in good yield. Next, a cycloaddition with a
cyclooctyne yielded cycloaddition product 11 within 5 min at rt.
Cyclooctynes have recently been reported to react with nitrones
in so-called SPANC click reactions.9 The nitrones reported in
literature for this click reaction with strained alkynes were either
cyclic nitrones9a or produced cycloadducts possessing N-methyl
groups,9b,c complicating further modification compared to 11.
The cycloadditions described in Scheme 2 overall show that
nitrone 1 allows for the synthesis of a variety of cycloadducts in
reasonable to excellent yield, while tolerating a variety of
functional groups, including esters, alcohols, and aldehydes.
Encouraged by these results, we next attempted to liberate the
aldehyde by selectively deprotecting the dimethyl acetal (Scheme
3). Surprisingly, when using typical acidic hydrolysis conditions
no conversion was observed even after testing a variety of acidic
conditions (e.g., TFA, HCOOH, HClO4). We hypothesize that
a
Conditions: (A) 10% Pd/C, H2 (1 bar), MeOH, rt, 3 d; (B) (i)
Raney-Ni, H2 (1 bar), THF, rt, 30 min; (ii) 10% Pd/C, C6H10, THF,
reflux, 3 h; (iii) Fmoc-OSu, NaHCO3, THF, H2O, 0−20 °C, o/n; (C)
(i) Raney-Ni, H2 (1 bar), THF, rt, 1.5 h; (ii) Pd/C, H2 (5 bar), rt, 5 h;
(iii) for entries 3 and 4: Fmoc-OSu or Boc2O, NaHCO3, THF, H2O,
0−20 °C, o/n; for entry 5: Diazotransfer reagent, K2CO3, CuSO4·
b
5H2O. Isolated yield after purification by column chromatography.
3a with Pd/C in MeOH under atmospheric pressure (entry 1)
resulted in very slow conversion. Complete hydrogenation of 3a
was only observed after 3 days at rt, at which point significant
degradation had occurred. Degradation of 3a might be caused by
partial unwanted hydrogenation of the benzylic C−O bond in
the isoxazolidine ring before desired cleavage of the N−O. This
side reaction has been reported for similar compounds.12 We
therefore investigated whether the known ability of Raney-Ni to
selectively cleave N−O bonds would prevent C−O hydro-
genation. Hydrogenolysis with Raney-Ni indeed quantitatively
cleaved the N−O bond of substrate 3a within 1 h and left the C−
O and N−Bn bonds intact. However, subsequent N-benzyl
removal using transfer hydrogenation with refluxing cyclo-
hexene, followed by in situ protection with Fmoc-OSu, gave 13 in
only 21% yield (entry 2), probably due to thermal degradation of
the starting material or intermediate during reflux. It was
therefore decided to perform the second hydrogenation step
under pressure in a Parr apparatus at rt. This allowed for the
removal of the benzyl group in 5 h, and the resulting primary
amine could be converted in situ to Fmoc-protected amine 13 in
80% yield (entry 3).
Scheme 3. Hydrolysis of Isoxazolidine Acetal 3a
The advantage of this approach is that the whole sequence can
be carried out in one pot, since Raney-Nickel can be conveniently
a
1
Crude yield determined by H NMR; isolated yield: 40%.
B
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Letter
removed using a magnet, before adding 10% Pd/C to liberate the
primary amine.13 The optimized conditions of this staged
hydrogenation could also be used to install a Boc protecting
group (entry 4; 14) or an azide (entry 5; 15).
The acetal-masked aldehyde in this ring-opened substrate (13)
could now be liberated under standard acid hydrolysis conditions
to furanose 16 (Scheme 4), indicating that earlier attempts to
hydrolyze substrate 3 were indeed hampered by the vicinity of
the basic isoxazolidine ring.
regioisomer 19a as the major isomer, owing to the attack of
the oxygen atom on the nitrone at the α-position of the α,β-
unsaturated alkene.15 Asymmetric cycloadditions were then
carried out with the enol ether in carbohydrate derivatives to
obtain cycloadducts 20 and 21. These cycloaddition reactions
with D-glucal- and D-galactal derivatives, which are known for
their low reactivity,16 resulted in only limited conversion of the
dipolarophiles after 2 days. We were unable to increase the
conversion significantly beyond ∼33% by using a high excess of 1
or by increasing the duration of the reaction, since 1 slowly
degrades over the course of several days, probably via
dimerization as indicated by MS and NMR analysis. As the
degradation of 1 by dimerization was thought to be the limiting
step we opted to add 1 portionwise at 165 °C in mesitylene to
limit this. Consequently we were able to reach 56% conversion
for D-glucal derived 20, which is good considering there is only
one other reported successful cycloaddition of an acyclic nitrone
on a glycal.16a The D-glucal and D-galactal derived cycloadducts
were obtained as a single product, illustrating the high regio- and
stereoselectivity of these reactions. Furthermore, the uncon-
verted D-glucal and D-galactal derivatives could be recovered
through column chromatography. The reaction of nitrone 1 with
a trisubstituted steroid also proved to be very regio- and
stereoselective, providing 22 as a single product in good yield.
However, the regioselectivity of this reaction was reversed
compared to other electron-poor dipolarophiles. There is
precedent in literature8a,17 for similar reversed nitrone cyclo-
addition results, and this indicates that steric factors may change
the dominant frontier molecular orbital interactions between a
nitrone and a dipolarophile, thus changing the regiochemical
outcome.
Scheme 4. Acid-Catalyzed Hydrolysis of Acetal 13
Encouraged by the synthetic versatility of the racemic
isoxazolidine substrates, we searched for an asymmetric approach
toward these building blocks, since these compounds could
represent a promising point for the enantioselective synthesis of
functionalized carbohydrate derivatives. The first approach
toward chiral isoxazolidine derivatives employed chiral olefins
in [3 + 2] cycloaddition reactions with achiral nitrone 1 (Scheme
5); in a second approach (vide infra) chiral derivatives of nitrone
1 were reacted with achiral alkenes (Table 2).
ab
,
Scheme 5. Scope of 1 in cycloadditions with chiral olefins
Finally, the olefin in an enantiopure lactam was reacted with 1,
providing regioisomers 23 and 24 in a total yield of 82%.
Surprisingly, although two regioisomers were formed, none of
the other six possible stereoisomers were observed. We
hypothesize that the two isolated cycloadducts represent the
most stable isomers, resulting from the least steric hindrance
during the cycloaddition. To validate this hypothesis, the
geometries of all eight possible stereo- and regioisomers of the
nitrone reaction on the unsaturated lactam were sequentially
optimized by molecular mechanics MMFF94 calculations and
density functional theory M11-L/6-311+G(d,p) calculations.
This indeed yielded the lowest energies for compounds 23 and
24. All other isomers were less stable, largely due to
(significantly) increased steric hindrance (see SI for more
information).
Finally, for the second approach, an asymmetric cycloaddition
with achiral dipolarophiles was achieved using nitrone 25 as a
chiral derivative of nitrone 1. Nitrone 25 was easily obtained in
excellent yield in the same manner as 1, using (S)-N-(α-
methylbenzyl)hydroxylamine as a chiral precursor, and sub-
sequently employed in several nitrone−olefin [3 + 2] cyclo-
addition reactions with achiral olefins. These cycloadditions
proved to be quite effective, affording the different substrates in
very good to excellent yield (Table 2). While the facial selectivity
appeared to be moderate, the different major cycloadducts could
be isolated in very good yields.
In summary, a novel nitrone 1 containing a masked aldehyde
was prepared via a simple and scalable procedure in excellent
yield. Using this nitrone in [3 + 2] cycloaddition reactions with a
variety of olefins and other dipolarophiles afforded a set of
original isoxazolidines in reasonable to excellent overall yields.
These cycloadducts can be considered as a masked form of amino
a
b
Isolated yield after column chromatography. Syn/anti ratio
c
determined by 1H NMR and assigned by NOESY. Reaction
performed at 165 °C in mesitylene with 5 equiv of 1.
The reaction of 1 with a chiral furanone gave bicyclic
compound 17, which is a useful precursor to polyhydroxylated
piperidine derivatives.14 Compound 17 was obtained in good
yield with excellent regioselectivity and good stereochemistry.
Cycloaddition reaction of 1 with two D-mannitol-derived olefins
also proved to be stereoselective, providing cycloadducts 18−19.
Interestingly, while the E-olefin provided regioisomer 18b as a
minor cycloadduct, the Z-olefin provided the analogous
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a
1
Syn/anti ratio determined by H NMR and assigned by NOESY.
b
Isolated yield after column chromatography.
aldehydes, making them interesting from a synthetic point of
view. The synthetic versatility of these substrates was shown by
liberating the masked aldehyde under basic conditions, while the
amine could be liberated and immediately protected via an
efficient staged one-pot hydrogenolysis procedure. The stability
of the masked aldehyde toward acid hydrolysis before ring
opening enables facile acid-catalyzed modification of different
groups, while still allowing facile acid hydrolysis of the acetal after
N−O ring opening. Finally, a diverse set of chiral olefins led to
cycloadducts with high diastereopurity. We are currently
pursuing the application of nitrones 1 and 25 in cycloadditions
toward several complex glycomimetics,6 which will be duly
reported.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02662.
Experimental procedures, characterization data and copies
of 1H and 13C NMR spectra for all compounds (PDF)
́
(11) (a) Ibebeke-Bomangwa, W.; Hootele, C. Tetrahedron 1987, 43,
935. (b) Yu, J.; DePue, J.; Kronenthal, D. Tetrahedron Lett. 2004, 45,
7247. (c) de Meijere, A.; von Seebach, M.; Kozhushkov, S. I.; Boese, R.;
AUTHOR INFORMATION
Corresponding Author
Blaser, D.; Cicchi, S.; Dimoulas, T.; Brandi, A. Eur. J. Org. Chem. 2001,
̈
■
2001, 3789.
(12) Siriwardena, A.; Sonawane, D. P.; Bande, O. P.; Markad, P. R.;
Yonekawa, S.; Tropak, M. B.; Ghosh, S.; Chopade, B. A.; Mahuran, D. J.;
Dhavale, D. D. J. Org. Chem. 2014, 79, 4398.
*E-mail: tom.wennekes@wur.nl.
Notes
(13) An attempt to perform the hydrogenation with both metals (10%
Pd/C Please check: and Raney-Ni) at the same time only reached 30%
conversion after 5 h in the Parr apparatus (5 bar), after which no further
conversion was observed upon longer reaction times.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank The Netherlands Foundation for Scientific
Research (NWO) for funding this research via ChemThem:
Chemical Biology grant (728.011.105) and VENI grant
(722.011.006) to T.W. The authors thank Judith Firet
(Wageningen University) for synthesis of the D-mannitol derived
olefins.
(14) Ondrus,
1999, 55, 10425.
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DOI: 10.1021/acs.orglett.5b02662
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