Stereoselective synthesis of oxa-bowls by nucleophilic addition to oxonium ions: Observation of nucleophile-dependent hydride migration

Article abstract of DOI:10.1002/ejoc.201301052

A simple and reliable platform was developed for the synthesis of symmetrical oxa-bowls through the Lewis acid mediated etherification of dimethyl acetals. An intramolecular hydride transfer was observed with the use of electron-rich aryl nucleophiles, which also gave access to unsymmetrical oxa-bowls. A general strategy is developed for the stereoselective synthesis of symmetrical oxa-bowls through the Lewis acid mediated generation of oxonium ions from bis-acetals and their subsequent trapping with a variety of nucleophiles. Hydride migration is observed with the use of trimethoxybenzene as a nucleophile with rigid acetal precursors. This method is extended to the synthesis of unsymmetrically substituted oxa-bowls. Copyright

Full text of DOI:10.1002/ejoc.201301052

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301052
Stereoselective Synthesis of Oxa-Bowls by Nucleophilic Addition to Oxonium
Ions: Observation of Nucleophile-Dependent Hydride Migration
Santosh J. Gharpure*[a,b][‡] and Suheel K. Porwal[a]
Keywords: Cage compounds / Polycycles / Nucleophiles / Ozonolysis / Lewis acids / Hydride transfer
A simple and reliable platform was developed for the synthe-
sis of symmetrical oxa-bowls through the Lewis acid medi-
ated etherification of dimethyl acetals. An intramolecular
hydride transfer was observed with the use of electron-rich
aryl nucleophiles, which also gave access to unsymmetrical
oxa-bowls.
Introduction
Polycyclic cage compounds with unusual shapes, sym-
metries, and chemically distinct surfaces have attracted con-
siderable attention from synthetic chemists.[
1–4]
[n]-Oxa-[n]-
peristylanes A–C are a family of symmetrical bowl-shaped
molecules containing acetal linkages at the periphery (Fig-
ure 1). Oligocyclic oligoacetals D synthesized by using five-
membered rings as repetitive units revealed a helical ar-
rangement of the subunits in the solid state.[ All of these
are saturated hydrocarbons bearing heteroatoms with an
aesthetically pleasing, topologically novel molecular archi-
tecture. One of the main reasons for studying hetero-bowls
and cage compounds is the desire to compare their reactiv-
ity pattern with that of the carbocyclic analogues. In ad-
dition, the synthesis of oxa-, aza-, and thia-cage com-
pounds is pursued with hope that these molecules, which
have distinct hydrophilic and hydrophobic surfaces, may
also potentially find applications as ligands for metal ions
5]
Figure 1. Aesthetically pleasing, topologically novel oxacyclic com-
pounds.
that possess only a couple of heteroatoms at the periphery.
These molecules will have fewer rings attached to the cen-
tral core ring than peristylanes, yet they will have distinct
concave and convex surfaces. Further, substitution of the
acetal linkage with an ether linkage would make these oxa-
bowls more stable, and thus these compounds might prove
to be more robust ligands. In continuation of our interest
in the synthesis of oxa- and aza-bowls and cages,[ herein
we describe an approach to symmetrical oxa-bowls through
the stereoselective addition of nucleophiles to oxonium
ions.
and in chemical transportation phenomena.[
6]
8]
The most common strategy for the synthesis of such
strained oxa-bowls and cages involves subjecting a poly-
olefin to ozonolysis followed by cyclization through the for-
mation of acetals in the presence of acids such as amberlyst-
7]
1
5, an acidic resin.[ Most of the methods described in the
literature for the synthesis of alicyclic bowl-shaped mo-
lecules are related to peristylane-type structures. Not much
is known about “semiperistylanes” or those compounds
Results and Discussion
A Lewis acid mediated etherification reaction based
strategy conceived for the construction of symmetrical,
[
a] Department of Chemistry, Indian Institute of Technology
“semicorannulene” oxa-bowl structures is outlined in
Madras,
Chennai 600036, India
http://chem.iitm.ac.in/professordetails/profsantoshjgharpure/
index.htm
Scheme 1. It was envisaged that oxa-bowls 1 could be read-
ily prepared by the addition of a nucleophile to bis-
oxonium ion 2 derived from dimethyl acetal 3 in the pres-
ence of a Lewis acid. It was further argued that the nucleo-
phile would preferentially add to the oxonium ion from the
less-hindered convex face. Dimethyl acetal 3 could in turn
be obtained from ozonolysis of readily available diol 4. The
advantage of this approach is that it obviates the need to
protect the hydroxy groups of diol 4. However, it was also
[
[
b] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
http://www.chem.iitb.ac.in/people/Faculty/prof/sjg.html
‡] Current address: Indian Institute of Technology Bombay,
Powai, Mumbai 400076, India
E-mail: sjgharpure@iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301052.
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S. J. Gharpure, S. K. Porwal
SHORT COMMUNICATION
noted that the synthesis of acetal 3 would require a different Table 1. Synthesis of acetals 3 from diols 4.
set of conditions, as diols such as 4 are known to furnish
[
9]
trioxa-cage compounds upon ozonolysis in CH Cl .
2
2
Scheme 1. Retrosynthetic analysis for the synthesis of oxa-bowls.
Synthesis of acetal 3 was the first task to test the feasibil-
ity of this approach. It is known that ozonolysis of diols 4
leads to the formation of trioxa-cages 5. Thus, initial efforts
were directed towards circumventing the formation of 5
from diol 4. It was argued that changing the solvent from
CH Cl to MeOH and using a catalytic amount of acid
2
2
after reductive workup would ensure the formation of the
acetal as opposed to the trioxa-cage compound. Thus,
ozonolysis of diol 4a followed by reductive workup with
dimethyl sulfide followed by treatment with a catalytic
amount of H SO in methanol indeed furnished dimethyl
2
4
acetal 3a in 87% yield (Table 1, entry 1).
The method was extended successfully to acetals 3b–f
with varying ring sizes and substitutions. Interestingly, un-
der the reaction conditions employed, no formation of
trioxa-cage 5 was detected. Having acetals 3a–f in hand,
attention was turned toward ascertaining the feasibility of
generating the oxonium ion and its trapping with an appro-
priate nucleophile.
After initial screening with triethylsilane as the source of
the hydride nucleophile, TMSOTf was found to be the
Lewis acid of choice. Thus, upon treatment of dimethyl
acetal 3a with triethylsilane (6a) and TMSOTf in CH Cl2
2
at –10 °C, desired oxa-bowl 1aa was obtained in excellent
[
10]
yield (Scheme 2). The reaction was found to be general,
and acetals bearing four-, five-, and six-membered rings as
well as allylic and benzylic alkoxy substitutions furnished
corresponding oxa-bowls 1ba–fa in excellent yields.
[a] Yield of isolated product.
Buoyed by the success of the approach, reaction of di-
methyl acetal 3a with other nucleophiles was also at-
tempted. A variety of nucleophiles were found to be useful
in trapping the oxonium ion generated from acetal 3a in
the presence of TMSOTf. Thus, the reaction of acetal with
TMSOTf and allyltrimethylsilane (6b) furnished bisallyl
oxa-bowl 1ab in good yield as a single detectable dia-
stereomer. Allenyltributyltin (6c) was used as a nucleophile
to furnish oxa-bowl 1ac in good yield and excellent dia-
stereoselectivity (Scheme 3). If the silyl enol ether of aceto-
phenone (6h) was used as the nucleophile, corresponding
oxa-bowl 1ah was formed in good yield, albeit with poor
diastereoselectivity. On the contrary, if TMSN was used as
3
the nucleophile, corresponding bis-azide 1ae was obtained
in very good yield as a single detectable diastereomer.
Interestingly, the oxonium ion intermediate generated
Scheme 2. Synthesis of symmetrical oxa-bowls 1.
under Lewis acidic conditions could be oxidized to corre- ion intermediate could be trapped with triethyl phosphite
sponding bis-lactone 1ai by using meta-chloroperoxyben- (6g) to afford bis-phosphonate ester bearing oxa-bowl 1ag.
zoic acid (mCPBA, 6i). In another direction, the oxonium Oxa-bowl 1af bearing a furyl heteroaryl ring could also be
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Stereoselective Synthesis of Oxa-Bowls
During the synthesis of oxa-bowls 1ab–ai, reaction of the
oxonium ion with electron-rich aromatic nucleophiles was
also attempted. Thus, 1,3,5-trimethoxybenzene (6k) was
treated with acetal 3f in the presence of TMSOTf. However,
the product obtained was not oxa-bowl 1fk; instead, keto
alcohol 7 was obtained as the sole product in excellent yield
(Scheme 4). Formation of keto alcohol 7 could be explained
as follows. In the first step, the initial oxonium ion formed
from acetal 3f reacts with 1,3,5-trimethoxybenzene (6k) to
generate the monoacetal product. In the second step, the
acetal reacts with the Lewis acid to generate oxonium ion
8. Oxonium ion 8, rather than getting trapped intermo-
lecularly with 1,3,5-trimethoxybenzene (6k), is trapped by
intramolecular hydride shift, which generates more stable
oxonium ion 9. Upon trapping with a water molecule, 9
[
14]
generates hemiacetal 10.
Hemiacetal 10 then leads to
more stable keto alcohol 7. Interestingly, in a similar reac-
tion with 1,3,5-trimethoxybenzene (6k), acetal 3a generated
a complex mixture of products. On the contrary, under sim-
ilar conditions acetal 3c gave rise to keto alcohol 11.
Scheme 3. Synthesis of differently disubstituted oxa-bowls 1ab–ai.
Reagents, conditions, and yields: (a) Allyltrimethylsilane (6b),
TMSOTf, CH
TMSOTf, CH
TMSOTf, CH
TMSOTf, CH
2
Cl
Cl
Cl
Cl
Cl , –10 °C, 3 h, 57%. (f) P(OEt)
°C to r.t., 6 h, 76%. (g) PhC(OTMS)=CH
2
, –78 °C, 3 h, 87%. (b) allenyltributyltin (6c),
2
2
, –10 °C, 3 h, 86%. (c) TMS uracil (6d),
2
2
, 0 °C to r.t., 6 h, 88%. (d) TMSN
–10 °C, 3 h, 79%. (e) Furyl-SnBu
3
3
(6e),
(6f),
2
2
,
TMSOTf, CH
2
2
3
(6g), TMSOTf,
2
(6h), TMSOTf,
0
CH
CH
2
Cl
Cl
2
, –10 °C, 3 h, 81% (dr = 2:1). (h) mCPBA (6i), TMSOTf,
, –10 °C, 3 h, 55%.
2
2
synthesized in good yield and diastereoselectivity by using
-tributylstannylfuran (6f) as the nucleophile.[
11]
Finally,
2
upon using silylated uracil (6d) as the nucleophile, the corre-
sponding bis-uracil-substituted oxa-bowl 1ad was obtained
in good yield as a single detectable diastereomer.[ Single-
crystal X-ray diffraction analysis (Figure 2) of oxa-bowl 1ad
12]
[
13]
revealed that the uracil moiety was in the exo position.
This is consistent with the fact that uracil traps the oxonium
ion from the less-hindered convex face. The stereochemistry
shown for the other products is in analogy to this example
and is also supported by H NMR spectroscopy, which
showed very similar coupling constants for the anomeric
protons of the substituted furan ring of the molecule.
Scheme 4. Formation of unsymmetrical oxa-bowl through intramo-
lecular hydride transfer.
1
Also, upon reaction with acetal 3c or 3f, other nucleo-
philes such as allenyltributyltin (6c), allyltrimethylsilane
(6b), and allyltributyltin (6bЈ) furnished the corresponding
oxa-bowls in good yield with excellent diastereoselectivity
(Scheme 5).
On the basis of these results, it is quite apparent that the
nature of the nucleophile affects the propensity for hydride
migration. Thus, the migration of the hydride took place
only for cases in which a more stable oxonium ion was gen-
erated. Another important aspect is the conformation of
the molecule – the possibility of 1,5-hydride shift does not
ensure that it will happen. Acetals 3f and 3c have a more
rigid conformation than acetal 3a. Therefore, the reactions
of the former were cleaner than those of the latter. A similar
Figure 2. ORTEP plot (50% ellipsoid probability) of bis-uracil de-
rivative of oxa-bowl 1ad.
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S. J. Gharpure, S. K. Porwal
SHORT COMMUNICATION
At this juncture, it was contemplated that if this mecha-
nism was indeed operating, it might be possible to trap
oxonium ion 9 generated after intramolecular hydride
transfer with another nucleophile. Thus, acetal 3f was
treated with 1,3,5-trimethoxybenzene (6k) and TMSOTf,
which was followed by the addition of allyltributyltin (6bЈ,
Scheme 7). Gratifyingly, oxa-cage 13 was obtained as the
sole product, which clearly supported the mechanism.
Scheme 5. Synthesis of oxa-bowls. Reagents, conditions and yields:
(
8
4
a) Allyltributyltin (6bЈ), TMSOTf, CH
2
Cl
2% (for 1cb). (b) Allenyltributyltin (6c), TMSOTf, CH
2% (for 1fc), 83% (for 1cc).
2
, 0 °C, 78% (for 1fb),
2
Cl , 0 °C,
2
effect of the conformation was observed in our earlier stud-
ies on radical cyclizations.[ Notably, most of the reported
examples of hydride migration were observed in the absence
of a nucleophile, whereas the hydride migration observed
here is in the presence of a nucleophile.
8]
Scheme 7. Trapping oxonium ion generated by hydride migration.
Finally, to further expand the scope of the synthesis of
oxa-bowls, it was envisaged that the two oxonium ions
could be trapped with two different nucleophiles sequen-
tially. To test this concept, dimethyl acetal 3f was treated
with allenyltributyltin (6c) in the presence of TMSOTf in
To unambiguously assign the structure, it was decided
to convert alcohol 7 into its 3,5-dinitrobenzoate derivative.
Interestingly, subjecting alcohol 7 to reaction with 3,5-dini-
trobenzoic acid (3,5-DNB), N,NЈЈ-dicyclohexylcarbodiim-
ide (DCC), and 4-(N,N-dimethylamino)pyridine (DMAP)
furnished only isomerized keto alcohol 12 rather than the
requisite ester. Deliberate isomerization of keto alcohol 7
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was also at-
tempted, which also furnished ketone 12 (Scheme 6). The
overall structure and stereochemistry of oxa-cage 12 was
assigned on the basis of its spectroscopic data and was fur-
ther confirmed with the help of single-crystal X-ray diffrac-
tion analysis (Figure 3). This provided further support to
the structural assignment of oxa-cage 7.[
CH Cl2 at –10 °C to furnish monopropargyl-substituted
2
oxa-bowl 14. Reaction of oxa-bowl 14 with TMSN (6e)
3
and TMSOTf indeed furnished unsymmetrically substituted
oxa-bowl 15 (Scheme 8).
13]
Scheme 8. Synthesis of unsymmetrically disubstituted oxa-bowl 15.
Reagents, conditions, and yields: (a) Allenyltributyltin (6c),
TMSOTf, CH
2 2 3
Cl , –78 °C, 3 h, 43%. (b) TMSN (6e), TMSOTf,
CH Cl , –78 °C, 3 h, 65%.
2
2
Conclusions
Scheme 6. Isomerization of keto alcohol 7.
In conclusion, a new strategy for the synthesis of sym-
metrical oxa-bowls bearing ether linkages was developed.
Even unsymmetrical oxa-bowls could be accessed from bis-
acetals by judiciously sequencing the reaction by trapping
the successively generated oxonium ions with different
nucleophiles. An intramolecular hydride transfer was ob-
served with the use of electron-rich aryl nucleophiles, which
also gave access to unsymmetrical oxa-bowls. These oxa-
bowls can potentially function as ligands for metal-ion
complexation and in the synthesis of metal–organic frame-
works (MOFs) or coordination polymers. In fact, bis-nitrile
oxa-bowls prepared from 3a and 3f by using this strategy
were used in the synthesis of silver coordination polymers
[
15]
(
Ag-CP). Further efforts in this direction are ongoing in
our laboratory and will be reported in due course.
Supporting Information (see footnote on the first page of this arti-
Figure 3. ORTEP plot (50% ellipsoid probability) of oxa-bowl 12.
cle): Experimental procedures and characterization data along with
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Stereoselective Synthesis of Oxa-Bowls
copies of the 1H NMR and 13C NMR spectra for all new com-
pounds.
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Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi and the Department of Science and
Technology (DST), New Delhi, for financial support. We appreci-
ate the NMR facility provided by the DST under the IRPHA pro-
gram and the ESI-MS facility under the FIST program to the De-
partment of Chemistry, IIT Madras. The authors thank Mr.
Ramkumar of the X-ray facility of the Department of Chemistry
and Dr. Babu Vargeese (SAIF), IIT Madras, for collecting the crys-
tallographic data. We are grateful to CSIR, New Delhi, for the
award of a research fellowship to S. K. P.
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Received: July 16, 2013
Published Online: October 9, 2013
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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