Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

Article abstract of DOI:10.3762/bjoc.10.182

An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki crosscouplings. The key compound, a p-bromophenyl- substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N-O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers.

Full text of DOI:10.3762/bjoc.10.182

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics
Maja Kandziora and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1749–1758.
Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustraße 3, D-14195 Berlin, Germany
doi:10.3762/bjoc.10.182
Received: 19 March 2014
Accepted: 23 June 2014
Published: 30 July 2014
Email:
Hans-Ulrich Reissig* - hans.reissig@chemie.fu-berlin.de
* Corresponding author
This article is part of the Thematic Series "Multivalent glycosystems for
nanoscience".
Keywords:
carbohydrate mimetics; hydrogenolysis; multivalent glycosystems;
1,2-oxazines; samarium diiodide; Suzuki cross-coupling
Guest Editor: B. Turnbull
© 2014 Kandziora and Reissig; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is
described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-
couplings. The key compound, a p-bromophenyl-substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a
D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle
provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue.
After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form
biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the pres-
ence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked
C-glycosyl dimers.
Introduction
Carbohydrates are the class of biomolecules with the highest which possess structural and functional aspects of the corres-
structural diversity [1,2]. Specific carbohydrates are respon- ponding carbohydrates, these disadvantages can be overcome,
sible for cell-type specific interactions [3] and they are involved resulting in an improved bioavailability, higher affinities and
in different diseases such as cancer [4], inflammation [5], and improved selectivities [8-13]. Recent results indicate that
infections [6]. However, the use of carbohydrates as drugs has divalent rigid carbohydrate conjugates may have even
been strongly limited due to the hydrolytic lability of the higher binding affinities and specificities than their flexible
glycosidic bond [7] and the weak binding affinities of single multivalent equivalents [14,15]. The rigidity of the system is
molecules. With the development of artificial C-glycosides supposed to improve the overall activity of the ligands by over-
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coming the entropic penalty of flexible multivalent scaffolds lent analogues 2 (Scheme 1). Structurally similar aminopyrans
[16].
without aryl groups have intensively been studied as carbohy-
drate mimetics in our group [24,25]. When they are coupled by
Cross-coupling reactions are among the best methods to prepare amide bonds to gold nanoparticle and O-sulfated these conju-
C-arylglycosides, C-nucleosides and C-glycosidic oligomers gates gave extremely high binding affinities towards L- and
when new artificial pharmacophores are approached [17]. With P-selectin in sub-nanomolar concentrations. These results were
Suzuki cross-couplings C-glycoside analogues of phloriain with achieved by a multivalent presentation (ca. 1000–1200 ligands
antidiabetic properties [18] or aryl-scaffolded dimers and per nanoparticle) of the sulfated pyrans [26,27]. We were
trimers were successfully prepared [19]. The Suzuki cross- therefore interested to prepare inhibitors offering only a
coupling is particularly suitable for carbohydrate chemistry due small number of ligands to get better information about struc-
to the mild reaction conditions and its tolerance to a variety of ture–activity relationships and to study the influence of the flex-
functional groups [20]. In addition, the reactions are easy to ible and rigid spacer units.
perform and the required boronic acids exhibit exceptional
stabilities to heat, air and moisture compared to other In this report we present methods for the synthesis of divalent
organometallic reagents [21]. Up to now there are not many compounds 1 with p-terphenyl spacers and of β-D-2-amino-
examples of nanorod-like carbohydrate dimers with aryl-linked talose- or β-D-2-aminoidose-configured carbohydrate mimetics
divalent glycosides. A mannopyranoside dimer was generated 2 (Scheme 1). These novel carbohydrate mimetics represent
by a palladium-catalyzed Ullmann-type reductive homo- unique structures, combining the features of C-aryl-glycosides
coupling [22] and biphenyl-linked dimers were prepared by and aminosugars. The p-bromophenyl-substituted bicyclic 1,2-
Lewis acid-catalyzed glycosidations [23]. All these examples oxazine derivative 3 was used as key building block for the
possess an acid-labile O-glycosidic bond and are labile to Suzuki cross-coupling reaction to synthesize p-terphenyl-linked
hydrolysis and enzymes. Therefore, new approaches to the syn- derivatives 1. The key intermediate 3 was prepared by a Lewis
thesis of rigid multivalent C-arylglycosides should be a valu- acid-induced rearrangement of 3,6-dihydro-2H-oxazine 4,
able extension of compounds with potential biological activity. that origins from a stereoselective [3 + 3]-cyclization of
In order to achieve this goal we investigated the synthesis of D-isoascorbic acid-derived (Z)-nitrone 6 and lithiated TMSE-
divalent compounds of general structure 1 and their monova- allene 5.
Scheme 1: Approach to divalent carbohydrate mimetics 1 with rigid spacer and monovalent analogues 2.
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Results and Discussion
next step of our anticipated sequence, the Lewis acid-induced
For our synthesis of new divalent carbohydrate mimetics we rearrangement, converts the dioxolane C-2 carbon into an sp2-
required 1,2-oxazine derivatives derived from (Z)-nitrone 6 and hybridized carbon and hence the configuration of the precursor
lithiated alkoxyallenes. The 4-bromophenyl group should allow does not play a role for this reaction.
transition metal-promoted coupling reactions to a variety of new
compounds. For this purpose the D-erythrose-configured ester
7, easily available from D-isoascorbic acid [28], was converted
into nitrone 6 in a three step procedure (Scheme 2). Its reduc-
tion with lithium aluminum hydride was performed under stan-
dard conditions providing diol 8 in excellent yield in multigram
scale (up to 20 g). Attention should be paid to a possible reduc-
tive removal of the bromine substituent that can occur at higher
temperature or longer reaction times as the resulting debromi-
nated product is hard to remove from diol 8 by column chroma-
tography. According to the protocol of Dondoni et al. [29]
glycol cleavage of diol 8 afforded the corresponding aldehyde
that was directly treated with N-benzylhydroxylamine to furnish
the desired (Z)-nitrone 6. All compounds in this sequence of
reactions are mixtures of the two diastereomers at the diox-
olane C-2 (ratios close to 1:1).
Scheme 3: [3 + 3]-Cyclization of (Z)-nitrone 6 with lithiated allene 9.
Conditions: a) n-BuLi, THF, 15 min, −40 °C; b) 1. THF, 2 h, −78 °C;
2. H2O, 1 h, −78 °C → rt.
An alternative route to prepare 1,2-oxazine 4 is depicted in
Scheme 4. The preparation of the 4-bromophenyl-1,3-diox-
olane moiety started from diol 10 that has successfully been
used earlier for the preparation of phenylthio-substituted 1,2-
oxazine derivatives [32]. Compound 10 is easily accessible by a
mild cleavage of the corresponding acetonide by an indium
trichloride-mediated hydrolysis [33]. By using cerium am-
monium nitrate as Lewis acid [34] in high concentration
(13 mmol/mL) as well as an excess of 1-bromo-4-(dimethoxy-
methyl)benzene enabled the synthesis of syn-1,2-oxazine 4. The
conversion of this reaction was high (>80%) giving the two
diastereomers of 4 (ca. 1:1), but only one diastereomer was
isolated in pure form. The second diastereomer could hardly be
Scheme 2: Synthesis of (Z)-nitrone 6. Conditions: a) LiAlH4, THF, 1 h,
rt; b) 1. NaIO4, CH3CN/H2O, 1 h, rt; 2. N-benzylhydroxylamine,
MgSO4, CH2Cl2, 18 h, rt.
The preparation of syn-1,2-oxazine 4 was achieved in good separated from the excess of 1-bromo-4-(dimethoxymethyl)-
yields ranging from 67–77% by stereocontrolled addition of benzene by column chromatography or distillation. Besides,
lithiated (trimethylsilyl)ethoxyallene 9 to (Z)-nitrone 6 at Brønsted acids like trifluoroacetic acid, p-toluenesulfonic acid,
−78 °C (Scheme 3). Although the formation of four stereoiso-
mers is possible only two were observed. Due to the complexa-
tion of lithiated allene 9 to the nitrone 6 an exclusive formation
of the two syn-1,2-oxazines 4 was observed. This result sug-
gests that the configuration at C-2 of the dioxolane moiety has
no influence on the stereochemical outcome of the reaction. The
model suggested by Dondoni et al. [30] can also be employed
for this process to rationalize the observed diastereoselectivity
of the addition step. The subsequent [3 + 3]-cyclization to 3,6-
dihydro-2H-1,2-oxazine 4 follows the previously reported
mechanism [31]. In the presented sequence syn-1,2-oxazine 4
was successfully prepared in six steps with an overall yield of
Scheme 4: Synthesis of 1,2-oxazine 4 by acetal formation from 10.
Conditions: a) 1-bromo-4-(dimethoxymethyl)benzene (10 equiv.), CAN,
CH2Cl2, 3 d, rt.
46%. The diastereomers can easily be separated by column
chromatography, but this turned out not to be mandatory. The
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that are usually used to generate ketals, or weaker acids like yield. In accordance with previous observations of reductions of
pyridine/hydrogen fluoride led to a side product [35].
related phenylthio-substituted bicyclic compounds [25], a
hydride attack from the side of the pyran moiety is assumed
The Lewis acid-promoted rearrangement of 1,3-dioxolanyl- since the 1,2-oxazine side is more hindered by the bulky
substituted 1,2-oxazines to bicyclic ketones has been described N-benzyl moiety. The secondary hydroxy group of 12a was
in many examples [24]. Gratifyingly, starting from 1,2-oxazine protected employing t-butyldimethylsilyl trifluoromethanesul-
4 with tin(IV) chloride as Lewis acidic promoter the corres- fonate and 2,6-lutidine in quantitative yield.
ponding ketone was obtained in excellent stereoselectivity. The
subsequent protection of the primary hydroxy group as TBS The Lewis acid-promoted rearrangement of 1,2-oxazine deriva-
ether under standard conditions provided 11 in very good yields tive 4 and the direct reduction of the unpurified ketone 14
of up to 82% (Scheme 5). In order to perform the Lewis acid- furnished bicyclic diol 15 in good overall yield of 58%
promoted rearrangement and the protection in one step, we also (Scheme 6). The reduction of unprotected ketone 14 with
employed TBSOTf as Lewis acid for the rearrangement step L-selectride was less stereoselective and provided a 72:28 mix-
[24], however, no product formation could be observed in this ture of 15. The higher selectivity of the TBS-protected com-
case. The mechanism of the rearrangement 4 → 11 can be pound 11 may be explained by an indirect effect of the bulky
described as an aldol-type cyclization process. The Lewis acid TBS-group, possibly pushing the N-benzyl moiety to the top of
coordinates to the sterically less hindered oxygen atom of the the ring shielding the 1,2-oxazine side more efficiently. Sep-
dioxolane ring of 4 opening this ring and forming a carbenium aration of the two diastereomers and protection of the primary
ion that intramolecularly attacks the enol ether moiety. A six- hydroxy group of 15a with trityl chloride provided compound
membered chair-like transition state with the bulky 4-bromo- 16 in 83% yield. This protecting group should allow its removal
phenyl group in an equatorial position for this crucial step ratio- together with the benzyl group during hydrogenolysis. Surpris-
nalizes the product configuration as shown.
ingly, a benzyl protection under the same conditions was not
possible.
TBS-protected bicyclic ketone 11 was subsequently reduced
with sodium borohydride at −40 °C to form alcohols 12a Before approaching divalent compounds such as 1 we wanted to
and 12b as 81:19 mixture of diastereomers in 72% yield convert our building blocks into simple monocyclic carbohy-
(Scheme 5). In contrast, the reduction with L-selectride at drate mimetics. To prepare phenyl-substituted aminopyrans the
−10 °C selectively furnished pure diastereomer 12a in 73% N–O bond of bicyclic compounds 15a and 15b was cleaved by
Scheme 5: Synthesis of bicyclic ketone 11 by Lewis acid-induced rearrangement and reduction to alcohols 12a and 12b and protection of 12a to 1,2-
oxazine derivative 13. Conditions: a) 1. SnCl4, CH3CN, 4 h, −30 °C → rt; 2. TBSCl, imidazole, THF, 4 h, rt; b) NaBH4, EtOH, 4 h, −40 °C, 72%, dr
81:19; c) L-selectride, THF, 2 h, −10 °C, 73%, only 12a; d) TBSOTf, 2,6-lutidine, THF, 2 h, 0 °C.
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Scheme 6: Synthesis of bicyclic diols 15 and of trityl-protected bicyclic 1,2-oxazine 16. Conditions: a) SnCl4, CH3CN, 18 h, −30 °C → rt, b) 1) L-selec-
tride, THF, 4 h, −15 °C, dr 72:28; 2) separation by column chromatography (silica gel, hexanes/EtOAc 1:1 → 1:2); c) TrtCl, DMAP, pyridine, 3 d, rt.
hydrogenolysis. These reactions are challenging because the
resulting aminopyrans are apparently poisoning the catalyst and
hence large amounts of palladium on charcoal are required for
full conversion. We did not add acid to diminish catalyst
poisoning since we were afraid of other side reactions of the
complex product. In addition, the resulting products are very
polar and difficult to purify. In our recent report [28] related
compounds were reduced in methanol as solvent providing
several side products and the yield of the reactions were not
fully reproducible. Nevertheless, 1,2-oxazine 15a was con-
verted into aminopyran 17a (Scheme 7) by hydrogenolysis
under standard conditions in methanol in a yield of 78%, but
this yield was not fully reproducible and the conditions were
optimized. We found that isopropanol as solvent and addition of
one equivalent triethylamine were more reliable and the yield of
17a could be slightly improved. Triethylamine was added to
neutralize the formed acid [36] that is generated in the first step
by a very fast debromination. The debenzylation and the N–O
Scheme 7: Hydrogenolyses of bicyclic 1,2-oxazine derivatives 15a
and 15b. Conditions: a) H2, Pd/C, MeOH, EtOAc, 20 h, rt; b) H2, Pd/C,
iPrOH, EtOAc, NEt3, 18 h, rt.
bond cleavage occur as next steps. Under these improved condi- of this reaction. The desired product 18 was obtained in 81%
tions the isomeric bicyclic 1,2-oxazine 15b was converted into yield (Scheme 8) and the subsequent hydrogenolysis furnished
aminopyran 17b in a good yield of 77%. The formed aminopy- carbohydrate mimetic 19 bearing a biphenyl substituent.
rans 17a and 17b can be regarded as amino C-glycosides. Com-
pound 17a is related to compounds with β-D-talose configur- The smooth transformation of bicyclic compound 15a into a
ation that are rarely found in nature, an exception being the biphenyl compound by Suzuki cross-coupling encouraged us to
antibiotic amino glycoside hygromycin B [37]. Aminopyran aim the synthesis of divalent compound 21. 1,4-Phenylenedi-
17b correlates to β-D-idopyranose; iduronic acid is a compo- boronic acid (20) was used as precursor and coupled to two
nent of sulfated glycosamine glycans such as chrondroitin equivalents of 12a to afford the desired p-terphenyl compound
sulfate and heparan sulfate [38].
21 in excellent 84% yield (Scheme 9). Unfortunately, the subse-
quent hydrogenolysis of this compound under conditions as
The prepared p-bromophenyl-substituted bicyclic 1,2-oxazine above led to a complex product mixture and no product could
derivatives 12, 13, 15 and 16 provide options to perform cross- be observed. An alternative method for N–O cleavage employs
coupling reactions such as Buchwald/Hartwig, Heck, Hiyama, elemental zinc in the presence of acid [39], conditions that
Kumada, Sonogashira or Stille couplings. In order to examine should simultaneously cleave the TBS protective groups. For
the conditions for Suzuki cross-couplings we subjected bicyclic the conversion of 21 into 22 long reaction times were required
compound 15a to phenylboronic acid under standard conditions and the high acidity led to the formation of side products.
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Scheme 8: Suzuki cross-coupling of 15a leading to biphenyl derivative 18 and hydrogenolysis to 19. Conditions: a) phenylboronic acid, Pd(PPh3)4,
2 M Na2CO3 aq, THF, 70 °C, 48 h; b) H2, Pd/C, iPrOH, THF, rt, 24 h.
Scheme 9: Synthesis of N-benzylated p-terphenyl derivative 21 by Suzuki cross-coupling of 12a with 20 and subsequent reduction with zinc. Condi-
tions: a) Pd(PPh3)4, 2 M Na2CO3 aq, THF/DMF (8:2), 70 °C, 48 h; b) Zn, AcOH, THF, 60 °C, 18 h.
Nevertheless, the target compound 22 was isolated in a moder- under formation of the pyrrolidine moiety. This process is
ate yield of 59%.
possibly promoted by samarium(III) which can act as Lewis
acid and by the steric demanding TBS group which decreases
As a milder alternative, samarium diiodide was examined for the distance between the two functional groups. This unex-
the N–O bond cleavage [40-45]. With this selective reagent a pected side reaction leading to 24 indicates that in the above
TBS protected aminopyran dimer 23 was expected that should mentioned unclean reaction of samarium diiodide with dimer 21
be well soluble in organic solvents and therefore more suitable similar complications may lead to the observed mixture.
for subsequent transformations (Scheme 10). Disappointingly, a
samarium diiodide solution converted compound 21 in a com- To overcome these difficulties dimer 21 was deprotected with
plex reaction mixture. For a better understanding of this unex- tetra-n-butylammonium fluoride giving the poorly soluble poly-
pected result the reductive cleavage was examined with the hydroxylated compound 26 (Scheme 11). Due to the
simpler bicyclic 1,2-oxazine derivative 12a. Here the unex- amphiphilic character this compound was only soluble in pyri-
pected bicyclic compound 24 was isolated as major product in dine that makes purification and subsequent reactions fairly
79% yield together with the desired aminopyran derivative 25 difficult. The conversion of the deprotection step was high but
in 14% yield. It was observed by 1H NMR spectroscopy that the yield after purification was only 30%. The reduction with
aminopyran 25 is not stable and slowly cyclizes to 24; after two samarium diiodide was then performed in a methanol/tetra-
days in CDCl3 solution approximately 20% of aminopyran 25 hydrofuran mixture in which compound 26 was scarcely
were converted into 24. This result indicates that the N–O bond soluble. Gratifyingly, after one hour reaction time and purifica-
cleavage of 12a preceded as expected, but that the produced tion by column chromatography aminopyran 22 was isolated in
amino group of the pyran ring seems to be in close proximity to 30% yield. Interestingly, no cyclization product similar to 24
the C-5 hydroxy group and leads to a nucleophilic substitution was detected in this case.
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Scheme 10: Attempted reductive cleavage of the N–O bond of compound 21 by samarium diiodide and reaction of 12a. Conditions: a) SmI2 (0.09 M
in THF), MeOH, rt, 60 min; b) SmI2 (0.1 M in THF), THF, rt, 45 min.
Scheme 11: Deprotection of compound 21 and samarium diiodide-mediated reaction of 26. Conditions: a) TBAF, THF, rt, 2 d; b) SmI2 (0.09 M in
THF), MeOH, rt, 60 min.
We also investigated the Suzuki cross-coupling of bicyclic com- The trityl protective groups enabled the deprotection of dimer
pound 16 with 1,4-phenylenediboronic acid (20) (Scheme 12). 27 in one step. The O-trityl and N-benzyl groups were removed
Although the trityl group is quite far away from the reacting by hydrogenolysis under acidic conditions to obtain a mixture
bromo substituent it led to longer reaction times and slightly of compounds 28 and 29 (Scheme 13). As solvent a 3:2 mix-
lower yields, but the expected product 27 was obtained in 51% ture of isopropanol/hexafluoro-2-propanol was used in order to
yield as a well soluble compound.
combine high polarity with product solubility and to avoid side
Scheme 12: Suzuki cross-coupling of compound 16. Conditions: Pd(PPh3)2Cl2, 2 M Na2CO3, DMF, 80 °C, 3 d.
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Scheme 13: Hydrogenolysis of compound 27 and samarium diiodide-mediated reaction leading to compounds 30 and 31. Conditions: a) H2, Pd/C,
TFA, HFIP, iPrOH, 8 h, rt; b) SmI2 (0.1 M in THF), MeOH, 30 min, rt. HFIP = hexafluoro-2-propanol.
product formation [26]. The ratio of mono-benzylated 28 and p-terphenyl-linked C-aryl glycoside using Suzuki cross-
fully deprotected p-terphenyl derivative 29 was 59:41 as couplings as key method. Starting from the D-isoascorbic acid-
confirmed by 1H NMR spectroscopy of the crude product. The derived diol 8, which was converted into the corresponding
reaction mixture was directly filtered through a pad of Celite® p-bromophenyl-substituted (Z)-nitrone, a stereoselective
and the solvents were removed in vacuo to provide a crude [3 + 3]-cyclization with lithiated TMSE-allene provided the
product that was used for the subsequent samarium diiodide- required 1,2-oxazine 4 in six steps with an overall yield of 46%.
mediated reduction without any purification. This reaction Alternatively, this 1,2-oxazine could be obtained under the for-
proceeded smoothly and furnished the very polar compounds 30 mation of a 4-bromophenyl-1’,3’-dioxolane moiety from diol 10
and 31. Removal of the formed samarium salts by size exclu- (actually derived from D-mannitol) which is a promising route
sion chromatography provided the two divalent carbohydrate to differently substituted 1,2-oxazines, introducing the diox-
mimetics in very good overall yield. The considerably better olane substituent at a late stage. The Lewis acid-induced
yield in this samarium diiodide-mediated reaction is probably rearrangement of the 1,2-oxazine 4 afforded the bicyclic ketone
due to the good solubility of compounds 28 and 29 in methanol/ 11 which can be regarded as an internally protected amino
THF.
sugar. After subsequent reduction of the carbonyl group the
resulting bicyclic compound 12 was used as substrate for
In summary, by optimizing the protective group strategy and the Suzuki cross-couplings to form a biphenyl-substituted amino-
reductive cleavage methods we were able to prepare the desired pyran or rigid C-aryl dimers in good yields. These p-terphenyl-
rigid p-terphenyl-linked carbohydrate mimetic 30 in twelve linked aminopyran derivatives 22, 30 and 31 have a dimension
steps starting from D-isoascorbic acid, but in only six steps with of approximately 2.0 nm.
respect to crucial intermediate 4. The overall yields of 6% or
13% are quite respectable. The distance between the two p-Bromophenyl-substituted intermediates such as 15 or 16 are
terminal amino groups is in the range of 2.0 nm (according to also useful precursors for the synthesis of other C-aryl glyco-
optimized molecular geometry obtained by MM2 calculations sides with potential biological activity. By simple hydrogeno-
performed by ChemBio3D Ultra 11.0 from ChemBioOffice lysis of the bicyclic compounds, three new aminopyrans could
2008).
be synthesized. Different methods for N–O bond cleavage like
palladium-catalyzed hydrogenolysis, zinc/acid or samarium
diiodide were tested. For each of the substrates the suitable
Conclusion
We successfully established methods for the efficient prepar- method has to be found. By the N–O bond cleavage of com-
ation of phenyl-substituted aminopyrans and rigid divalent pound 12a with samarium diiodide an unexpected bicyclic
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