Addition of lithiated enol ethers to nitrones and subsequent Lewis acid induced cyclizations to enantiopure 3,6-dihydro-2H-pyrans - An approach to carbohydrate mimetics

Article abstract of DOI:10.3762/bjoc.6.75

A stereodivergent synthesis of enantiopure 3,6-dihydro-2H-pyrans is presented. The addition of lithiated enol ethers to carbohydrate- derived nitrones afforded syn- or anti-configured hydroxylamine derivatives 4a-d that were cyclized under Lewis acidic conditions to yield functionalized dihydropyrans cis- or trans-5a-d containing an enol ether moiety. This functional group was employed for a variety of subsequent reactions such as dihydroxylation or bromination. Bicyclic enol ether 19 was oxidatively cleaved to provide the highly functionalized ten-membered ring lactone 20. The synthesized enantiopure aminopyrans 24, 26, 28 and 30 can be regarded as carbohydrate mimetics. Trimeric versions of 24 and 28 were constructed via their attachment to a tricarboxylic acid core.

Full text of DOI:10.3762/bjoc.6.75

Addition of lithiated enol ethers to nitrones
and subsequent Lewis acid induced cyclizations
to enantiopure 3,6-dihydro-2H-pyrans – an approach
to carbohydrate mimetics
Fabian Pfrengle and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 75. doi:10.3762/bjoc.6.75
Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustrasse 3, D-14195 Berlin, Germany
Received: 14 May 2010
Accepted: 08 June 2010
Published: 09 July 2010
Email:
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
Associate Editor: D. Y. Gin
* Corresponding author
© 2010 Pfrengle and Reissig; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aminopyrans; carbohydrate mimetics; Lewis acids; lithiated enol
ethers; nitrones; oxidative cleavage; stereodivergent synthesis
Abstract
A stereodivergent synthesis of enantiopure 3,6-dihydro-2H-pyrans is presented. The addition of lithiated enol ethers to carbo-
hydrate-derived nitrones afforded syn- or anti-configured hydroxylamine derivatives 4a–d that were cyclized under Lewis acidic
conditions to yield functionalized dihydropyrans cis- or trans-5a–d containing an enol ether moiety. This functional group was
employed for a variety of subsequent reactions such as dihydroxylation or bromination. Bicyclic enol ether 19 was oxidatively
cleaved to provide the highly functionalized ten-membered ring lactone 20. The synthesized enantiopure aminopyrans 24, 26, 28
and 30 can be regarded as carbohydrate mimetics. Trimeric versions of 24 and 28 were constructed via their attachment to a tricar-
boxylic acid core.
Introduction
The pyran structural motif can be found in numerous bioactive mimetics [3-7]. Moreover, pursuing a similar strategy, we
natural products. Possible strategies towards their efficient described the stereocontrolled preparation of 3,6-dihydro-2H-
preparation include Prins cyclizations, intramolecular substitu- pyrans D as precursors for the synthesis of enantiopure
tions, ring closure metathesis, and hetero Diels–Alder reactions aminopyrans E (Scheme 1). The sequence of nucleophilic add-
[1,2]. Our group recently reported the synthesis of enantiopure ition of lithiated enol ethers A to nitrones B and Lewis acid
aminopyrans employing as the key step a Lewis acid induced promoted cyclization of the resulting 1,3-dioxolanyl-substi-
rearrangement of 1,2-oxazines to bicyclic ketones. This strategy tuted hydroxylamine derivatives C, delivered the enantiopure
allowed a simple access to unusual carbohydrates with dihydropyrans D in a highly stereodivergent fashion [8]. In this
C2-branched 4-amino sugar units and related carbohydrate report we disclose full details about this new method, including
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Beilstein J. Org. Chem. 2010, 6, No. 75.
Scheme 1: Synthesis of 3,6-dihydro-2H-pyrans D.
expansion of the reaction scope and further evaluation of the When lithiated enol ethers 1 were used as the organometallic
synthetic potential of the easily accessible functionalized species in the addition to nitrones 2 [12-14], either syn- or anti-
dihydropyrans D.
configured hydroxylamine derivatives 3 were obtained,
depending strongly on the reaction conditions (Table 1) [15,16].
Subsequent treatment under basic conditions with tert-
Results and Discussion
The addition of organometallic species to nitrones has been butyldimethylsilyl triflate afforded TBS-protected compounds
extensively studied in the past. Highly stereoselective reactions syn- and anti-4 in good overall yields [17]. The stereochemical
of enantiopure nitrones allow rapid access to functionalized outcome of the reaction is in line with the addition of other
intermediates that have been elegantly used for the preparation nucleophiles to nitrone 2a [9-11]. The configurations of com-
of a wide range of natural products [9]. It is known that pre- pounds 4 could be unambiguously assigned by X-ray crystallo-
complexation of carbohydrate-derived nitrones by Lewis acids graphic analysis of an aminopyran derivative derived from anti-
can reverse the stereochemical outcome of these reactions [10] 4b (compound 29, Scheme 12) [8]. The enol ethers used, i.e.,
allowing, for example, a stereodivergent access to enantiopure ethyl vinyl ether, dihydropyran, and dihydrofuran, all added
1,2-oxazines [11].
smoothly to glyceraldehyde-derived nitrones 2a or 2b after lith-
Table 1: Stereodivergent additions of lithiated enol ethers 1 to glyceraldehyde-derived nitrones 2.
Yield and
diastereomeric ratio
Lithiated enol ether
Nitrone
Conditionsa
Product
syn: 61%
anti: 9%
a)
(d.r. = 88:12)
syn: 4%
anti: 48%
(d.r. = 93:7)
1a
2a
b)
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Table 1: Stereodivergent additions of lithiated enol ethers 1 to glyceraldehyde-derived nitrones 2. (continued)
syn: 44%
anti: 18%
(d.r. = 72:28)
2a
2a
2a
2a
a)
b)
a)
b)
syn: 8%
anti: 56%
(d.r. = 88:12)
1b
syn: 58%
anti: 10%
(d.r. = 86:14)
syn: 9%
anti: 54%
1c
(d.r. = 86:14)
syn: 70%
(d.r. > 95:5)
a)
aCondition a): 1. THF, −78 °C, 1 h (1.5 equiv of enol ether); 2. TBSOTf, 2,6-lutidine, 30 min; Condition b): 1. 2 + Et2AlCl, THF, 5 min, then addition to
1, THF, −78 °C, 15 min (5 equiv of enol ether); 2. TBSOTf, 2,6-lutidine, 30 min.
iation with tert-butyllithium. Whereas in the reaction with complexes. Despite this, diastereomeric ratios in favour of the
uncomplexed nitrones, 1.5 equivalents of the respective lithi- anti-products were generally excellent.
ated enol ether were sufficient to obtain the desired syn-
products with good yields and stereoselectivities, 5 equivalents Lithiated ethyl vinyl ether was also added to pre-complexed
of the nucleophile were necessary to achieve reasonable yields D-arabinose-derived nitrone 2c (Scheme 2). After a subsequent
in the addition to the nitrone/chlorodiethylaluminium TBS-protection step, the desired hydroxylamine derivative anti-
Scheme 2: Addition of lithiated enol ether 1a to nitrone 2c/Et2AlCl.
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4e was obtained in low yield, but with excellent diastereose- proceeded in moderate to excellent yields when two equival-
lectivity.
ents of trimethylsilyl triflate were used as Lewis acid. Catalytic
amounts of Lewis acid were not sufficient to obtain the
Next, the protected hydroxylamine derivatives syn-4 and anti-4 dihydropyrans, even after prolonged reaction times. The reac-
were treated with Lewis acid to provide enantiopure 3,6- tions with stoichiometric amounts of TMSOTf gave mono-
dihydro-2H-pyrans cis- and trans-5 (Table 2). The cyclization cyclic, bicyclic, and spirocyclic dihydropyrans depending on
Table 2: Lewis acid promoted cyclization of 1,3-dioxolanyl-substituted enol ethers syn- and anti-4 to 3,6-dihydro-2H-pyrans cis- and trans-5.
Cyclization precursor
Product
Yield
79%
84%
74%
82%
85%
55%
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Table 2: Lewis acid promoted cyclization of 1,3-dioxolanyl-substituted enol ethers syn- and anti-4 to 3,6-dihydro-2H-pyrans cis- and trans-5.
(continued)
90%
–
the 1,3-dioxolanyl-substituted enol ether employed (Table 2). leading to a ring opening and formation of a stabilized
Unfortunately, attempts to generate an eight-membered (or six- carbenium ion 6 (Scheme 3). Subsequent attack of the
membered) ring by cyclization of anti-4e were unsuccessful, oxocarbenium ion on the enol ether moiety leads to ring closure
only decomposition was observed.
affording the cationic pyran intermediate 7. Subsequent proton
transfer to the (moderately basic) hydroxylamine nitrogen
As a mechanistic rationale, shown below for the transformation re-establishes the enol ether moiety. During aqueous work-up
of syn-4a into cis-5a, we propose that the Lewis acid coordin- the OTMS-group is apparently removed due to the fairly acidic
ates to the distal oxygen atom of the dioxolane moiety in 4 conditions to produce cis-5a. Overall, the described cyclization
can be classified as an aldol-type reaction of an enol ether to an
acetal, or as a Prins-type reaction.
Encouraged by these results, we decided to try a related
Friedel–Crafts-type cyclization. Thus, 2-lithiofuran was added
to nitrone 2a [18] and then protected with TBSOTf to give
hydroxylamine derivative syn-4f in 55% (Scheme 4). Remark-
ably, subsequent treatment with 2 equiv of TMSOTf did not
lead to the desired bicyclic product. Since no conversion was
observed, the lower reactivity of syn-4f, caused by the consider-
ably weaker nucleophilicity of the furan compared to an enol
ether [19], might in the future be overcome with more forcing
reaction conditions.
The enol ether moiety in dihydropyrans 5 represents a very
Scheme 3: Mechanistic proposal for the transformation of syn-4a into
cis-5a in the presence of TMSOTf.
versatile handle for further synthetic modifications (Scheme 5
and Scheme 6). Starting from cis-5a, acidic hydrolysis with
Scheme 4: Unsuccessful attempt to cyclize hydroxylamine derivative syn-4f.
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Scheme 5: Functionalizations of the enol ether moiety of cis-5a leading to compounds 8–11.
Scheme 6: Transformations of the enol ether moiety of trans-5a leading to products 13–15.
concurrent loss of the TBS-group by treatment with saturated nor with aqueous HCl. After dihydroxylation, a partial hydro-
methanolic HCl followed by the addition of a saturated solution lysis of the hemiacetal initially formed in the dihydroxylation
of NaHCO3 in water gave ketone 8 in good yield (Scheme 5 and was observed leading to an inseparable mixture of compounds
Scheme 6). Dihydroxylation using the K2OsO4/N-methylmor- 13 and 14. The TBS-protection group was completely removed
pholinoxide-system afforded α-hydroxyketone 9 via in situ during bromination of the enol ether moiety with the formation
hydrolysis of an initially formed hemiacetal. Bromination with of compound 15 in good yield [20].
NBS in MeCN/H2O led to α-bromoketone 10 and its desilylated
The internal enol ether moiety of the bicyclic compound trans-
5b could also be converted into the corresponding α-bromo-
ketone with the bromination reagent NBS to give the ring
opened product 16 (Scheme 7). The two possible diastereomers
derivative 11 as single diastereomers. We presume that the NBS
attacks the enol ether moiety, as is also the case with the
dihydroxylation reagent OsO4, from the sterically less hindered
side, leading to incorporation of the bromo substituent trans to
the hydroxymethyl and the bulky hydroxylamine moiety. The
partial removal of the TBS-group is undoubtedly caused by HBr
formed in the course of the reaction.
When these reaction conditions were applied to the diastereo-
meric dihydropyran trans-5a, different behaviour was noted
(Scheme 6). A smooth hydrolysis of the enol ether moiety
leading to ketone 12 was neither feasible with methanolic HCl
Scheme 7: Bromination of bicyclic dihydropyran trans-5b affording 16.
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Beilstein J. Org. Chem. 2010, 6, No. 75.
were formed in a ratio of 92:8, as indicated by 1H NMR spec-
troscopy and have not been separated.
Bromination of the cyclohexylidene-substituted dihydropyran
cis-5d afforded α-bromo ketone 17 which, upon treatment with
NaBH4, produced epoxypyran 18 (Scheme 8). Epoxide 18 was
obtained as a single diastereomer and should be a promising
substrate for subsequent nucleophilic addition reactions leading
to another series of enantiopure aminopyrans.
An additional option for the use of the enol ether moiety is
oxidative cleavage [21]. Thus, benzyl protection of compound
cis-5b followed by treatment of the resulting 19 with RuCl3 and
NaIO4 gave the ten-membered ring lactone 20 by selective
cleavage of the internal double bond (Scheme 9).
Scheme 10: Transformation of α-bromoketone 15 into nitrone 21 by an
internal redox reaction.
With the objective of preparing a diaminopyran, we attempted
to substitute the bromide atom in compound 15 with the azido 22 probably undergoes base induced epimerization to generate
group. Surprisingly, instead of the desired α-azido ketone, the the thermodynamically more stable trans-substituted nitrone 21.
formation of nitrone 21 was observed, which apparently As shown below, the nitrone moiety of 21 can be regarded as a
involves an unusual internal redox reaction (Scheme 10). masked hydroxylamine, however, it should also be very useful
Sodium azide presumably acts as base to initiate the reaction by for further diversification of our pyran derivatives, e.g., by 1,3-
deprotonation of the hydroxylamine moiety. A hydride shift dipolar cycloaddition leading to isoxazole derivatives [22] or,
from the benzylic position to the 3-position of the pyran ring by addition of nucleophiles to this electrophilic unit [9].
produces the nitrone moiety of 21 and simultaneously displaces
the axially positioned bromo substituent by an intramolecular Compounds 8 and 21 proved to be excellent precursors for the
substitution. This mechanistic hypothesis was supported by the stereoselective preparation of enantiopure aminopyrans with
fact that heating 15 in DMF in the absence of NaN3 did not lead high structural similarities to carbohydrates. Reduction of the
to conversion of the substrate.
carbonyl group of 8 by NaBH4 followed by hydrogenolysis of
the N,O- and N-benzyl-bonds furnished aminopyran 24
When the diastereomeric α-bromoketone 11 was reacted with (Scheme 12). Similarly, nitrone 21 was smoothly converted to
sodium azide, the identical nitrone 21 was obtained in moderate the diastereomeric aminopyran 26 by analogous reductive trans-
yield (Scheme 11). We presume that an initially formed nitrone formations.
Scheme 8: Synthesis of epoxypyran 18 by bromination of cis-5d.
Scheme 9: Oxidative cleavage of dihydropyran 19 to lactone 20.
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Beilstein J. Org. Chem. 2010, 6, No. 75.
Scheme 11: Transformation of α-bromoketone 11 into nitrone 21.
Scheme 12: Synthesis of diastereomeric aminopyrans 24 and 26.
α-Hydroxyketones 9 and 13 were used as precursors for the ture of compounds 13 and 14, which was formed during
preparation of compounds with an additional hydroxyl group, dihydroxylation of dihydropyran cis-5a (Scheme 6), was also
such as aminopyrans 28 and 30 (Scheme 13). Reduction of 9 treated with NaBH4 to afford the diastereomeric compound 29
with NaBH4 in the presence of CeCl3 and subsequent hydrogen- [23]. A final hydrogenation step gave aminopyran 30 in high
olysis furnished compound 28 in excellent yield. The presence overall yield. Aminopyrans 24, 26, 28 and 30 can be regarded
of CeCl3 during the reduction of the carbonyl group proved to as mimetics of differently configured (2-deoxy) 4-amino sugars
be essential to achieve excellent diastereoselectivity. The mix- [24-26].
Scheme 13: Synthesis of diastereomeric aminopyrans 28 and 30.
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Aminopyrans 24 and 28 have already been linked via amide
bonds to the thiol shell of gold nanoparticles (particle diameter
6 nm). After sulfation of the hydroxyl groups the multivalent
conjugates obtained displayed strong binding to P- and
Experimental
Addition of lithiated enol ethers to glyceralde-
hyde-derived nitrones without precomplexa-
L-selectins, thus demonstrating that compounds such as 24 and tion of the nitrone
28 are of interest for the development of new anti-inflam- The respective enol ether (1.5 equiv) was dissolved in THF
matory agents [27,28]. Inspired by these first findings, we (2 mL/mmol of enol ether) and cooled to −78 °C. tBuLi (1.6 M
decided to prepare also smaller conjugates for evaluation as in pentane, 1.5 equiv) was added and the reaction mixture
selectin ligands. Thus, the free hydroxyl groups of aminopyrans stirred for 1 h during which time it was allowed to warm to 0
24 and 28 were temporarily protected as TMS ethers in order to °C. After further stirring for 1 h at this temperature, it was
achieve smooth reaction with 1,3,5-benzenetricarboxylic acid cooled once more to −78 °C. A solution of the respective
chloride (Scheme 14) [29]. After successful conversion to the nitrone (1 equiv) in THF (0.7 mL/mmol nitrone) was added
triamide, the TMS-groups were removed by treatment with dropwise over a 15 min period. The mixture was stirred at this
trifluoroacetic acid to give the desired compounds 31 and 32. temperature for 1 h and the reaction quenched by the addition of
The low yield of 32 was due to difficulties encountered in the H2O. After the mixture reached room temperature it was
purification of the compound which was carried out by crystal- extracted three times with Et2O. The combined organic phases
lization.
were dried (Na2SO4) and the solvent was removed in vacuo.
The crude product (1 equiv) was dissolved in CH2Cl2 (2.5 mL/
mmol), and 2,6-lutidine (2 equiv) and TBSOTf (1.5 equiv) were
Conclusion
We have presented an approach to novel 3,6-dihydro-2H-pyrans added slowly at 0 °C. The mixture was stirred at room tempera-
that can be transformed into a series of new carbohydrate ture for 30 min and then the reaction was quenched by the add-
mimetics and into other enantiopure heterocycles. The stereodi- ition of a sat. NH4Cl solution. The layers were separated and
vergent addition of lithiated enol ethers to carbohydrate-derived the aqueous phase was extracted three times with CH2Cl2. The
nitrones produced 1,3-dioxolanyl-substituted hydroxylamine combined organic phases were dried (Na2SO4) and the solvent
derivatives as suitable substrates for Lewis-acid induced cycliz- was removed in vacuo. Purification by column chromatography
ations furnishing mono-, di-, or spirocyclic dihydropyrans. (silica gel, hexane/EtOAc = 20:1) yielded the products as
Subsequent reactions such as bromination, acidic hydrolysis or colourless oils.
dihydroxylation provided differently substituted and configured
Addition of lithiated enol ethers to glyceralde-
pyranone derivatives as precursors for the stereoselective syn-
hyde-derived nitrones precomplexated by
Et2AlCl
The respective enol ether (5 equiv) was dissolved in THF
(2 mL/mmol of enol ether) and cooled to −78 °C. tBuLi (1.6 M
in pentane, 5 equiv) was added and the reaction mixture stirred
thesis of aminopyran derivatives that can be regarded as carbo-
hydrate mimetics. Trimeric versions of these carbohydrate
mimetics were constructed via their attachment to a tricarboxyl-
ic acid core to produce novel polyhydroxylated compounds that
will be evaluated as potential selectin binders at a future date.
Scheme 14: Synthesis of triamides 31 and 32.
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Beilstein J. Org. Chem. 2010, 6, No. 75.
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