Tandem oxidative radical fragmentation-rearrangement of 2-amino-1,3-benzylidene acetals: A short entry to densely functionalised fully differentiated oxazolidinones

Article abstract of DOI:10.1039/c3ra40218e

The discovery of a novel tandem fragmentation-rearrangement process from N-Boc-protected benzylidene acetals is reported. The reaction proceeds via free-radical initiation and terminates through a 5-exo-tet ionic fragmentation process leading to biologically useful, densely functionalised oxazolidinones.

Full text of DOI:10.1039/c3ra40218e

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Tandem oxidative radical fragmentation–
rearrangement of 2-amino-1,3-benzylidene acetals: a
short entry to densely functionalised fully
differentiated oxazolidinones3
Cite this: DOI: 10.1039/c3ra40218e
Received 14th January 2013,
Accepted 5th March 2013
DOI: 10.1039/c3ra40218e
James McNulty* and Janice Calzavara
www.rsc.org/advances
The discovery of a novel tandem fragmentation–rearrangement
process from N-Boc-protected benzylidene acetals is reported. The
reaction proceeds via free-radical initiation and terminates
through
a 5-exo-tet ionic fragmentation process leading to
biologically useful, densely functionalised oxazolidinones.
Benzylidene acetals 2 are commonly employed as dual protecting
groups for 1,2- and 1,3-diols 1 (Scheme 1), being readily
introduced and removed with a number of widely available
reagents.1 Such acetals can also provide added synthetic versatility
through partial cleavage, which can be performed using a variety
of regioselective reductive2 or oxidative3,4 fragmentation processes
leading to derivatives of type 3, 4, 5 and 6 (Scheme 1). These
processes have been applied extensively in the carbohydrate area,
allowing easy access to useful differentially functionalised chirons
and other fragments. The oxidative fragmentation of benzylidene
acetals using N-bromosuccinimide (NBS),3c,4 known as the
Hanessian–Hullar reaction, is of particular interest from both a
mechanistic standpoint and the utility of the differentiated
brominated products that are produced. This reaction is initiated
and proceeds via a free radical process in the presence of NBS but,
through a cross-over process, terminates via a polar ion-pair
recombination, involving a formal 1,3-bromide shift, yielding
products of type 5.4 We previously demonstrated completely
reversed regioselectivity in this reaction through the incorporation
of an allylic alcohol (5, R9 = alkenyl) into the benzylidene, resulting
in the exclusive formation of products of type 6.4c
Scheme 1 Formation and regioselective reductive or oxidative cleavage of
benzylidene acetals.
chlorobenzene at 70 uC with either benzoyl peroxide (BPO) or
azoisobutyronitrile (AIBN) initiation, product 9 was not observed.
Instead, the fully differentiated oxazolidinone 8a was formed as
the exclusive product and could be isolated in good yield (77%).
Functionalized oxazolidinones have proven to be privileged
subunits, having numerous applications within organic and
medicinal chemistry (such as in chiral auxiliaries 10,6 antibiotics
such as linezolid 11,7,8 muscle relaxant metaxalone 129,10 and the
antimigraine zolmitriptan 1311).
A summary of previous
approaches towards the synthesis of oxazolidinones indicated
the above tandem fragmentation–rearrangement to be novel.12 We
As part of a research program aimed at the synthesis of
sphingolipids and analogues,5 we had occasion to perform the
Hanessian–Hullar reaction on the 2-N-Boc-amino-1,3-diol derived
benzylidene 7a (Scheme 2) with the expectation of accessing the
primary bromide 9. Under standard conditions, using NBS in
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main
Street West, Hamilton, ON, L8S 4M1, Canada. E-mail: jmcnult@mcmaster.ca;
Fax: 905-522-2509; Tel: 905-525-9140 Ext. 27393
Electronic supplementary information (ESI) available: Experimental procedures
3
Scheme 2 Fragmentation of benzylidene acetal 7a to give oxazolidinone 8a and
a snapshot of the valuable oxazolidinone intermediates and pharmacologically
active products.
and characterisation data for new compounds. CCDC reference number for
compound 30, 897799. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ra40218e
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Scheme 4 Formation of N-Boc protected benzylidene isomers 16 and 19 and
their dichotomous Hanessian–Hullar fragmentation–rearrangement. (a) Boc2O,
DMF. (b) PhCH(OMe)2, PTSA (cat.). (c) NBS, BPO, PhCl, 70 uC.
Scheme 3 Synthesis of the MOM-ether 7b from THAM and fragmentation to give
oxazolidinone 8b. (a) MOM-Cl, Hunig’s base, CH2Cl2, 20 uC. (b) NBS, BPO,
chlorobenzene, 70 uC.
fragmentation conditions, with surprisingly dichotomous results.
Compound 16 underwent the tandem fragmentation–rearrange-
ment process as before, giving rise to the functionalized
oxazolidinone 17 with no trace of the primary bromide 18 being
observed. This result makes clear that the 5-exo-tet cyclization
process is once again kinetically favoured over the direct ion pair
recombination process that would, in this case, have led to the
primary bromide 18. When the isomeric compound 19 was
subject to the fragmentation conditions, the now expected
oxazolidinone 21 was not formed, and instead the product
observed was the primary bromide 20, the product of the classic
bromide-ion recombination. The results on fragmentation of
compound 19 are highly informative, providing several insights
into the fate of the rearrangement process. Three possible
outcomes can be envisioned for the process proceeding from
the benzylic oxidation of 19 involving either a 5-exo-tet or 6-exo-tet
ring closure, each yielding oxazolidinone products (21 and/or 22),
or a bromide ion attack yielding compound 20. In all other cases
presented, the 5-exo-tet closure was seen to be kinetically favoured,
however these substrates are non-sterically encumbered and
involve a carbamate attack at the back side of a substituted
primary alcohol. The fragmentation of compound 19, incorporat-
ing both a functionalized secondary alcohol (5-exo-tet closure) or
primary alcohol (6-exo-tet closure) proceeds through neither of the
possible cyclization modes. It appears that steric hindrance now
disfavours both the cyclisation processes relative to the bromide
ion recombination, resulting in the formation of compound 20. It
is also illustrative that compound 20 is favoured over the
alternative 6-exo-tet cyclisation process that would have given rise
to compound 22. Since compound 20 does not cyclise to 22 under
the reaction conditions, it is likely that the oxazolidinones shown
(Scheme 3 and Scheme 4, top) are the kinetic products of the
reaction, and are not produced through a bromide intermediate
via subsequent intramolecular cyclization. The overall sequence of
events is thus in accord with the mechanism postulated in
Scheme 3 (bottom). From these results it may be concluded that
the tandem fragmentation–rearrangement to give oxazolidinones
is successful in cases involving a 5-exo-tet closure onto a substrate
that incorporates a primary alcohol, otherwise alkyl bromide
products are to be expected.
therefore decided to investigate the scope of this new tandem
process in order to gain insight into the mechanism and assess its
synthetic potential.
We first wished to determine if the free primary alcohol in
compound 7a was incorporated into the oxazolidinone in 8a,
rather than one of the benzylidene oxymethyl groups through a
subsequent rearrangement process. In fact, Davies and co-workers
have previously shown that N-Boc-substituted 1,2-aminoalcohols
can cyclise to give oxazolidinones in the presence of a strong
base.12a In order to exclude this possibility in the present reaction,
the primary alcohol in 7a was protected as the MOM-ether 7b, as
shown in Scheme 3. Compound 7a was prepared in two steps
from the readily available starting material trishydroxymethylami-
nomethane (TRIS or THAM).5 The reaction of 7 with MOM-Cl in
the presence of a base gave 7b without incident. Under the
standard Hanessian–Hullar fragmentation conditions, compound
7b was also observed to undergo the smooth fragmentation–
rearrangement process, giving rise to the oxazolidinone 8b. This
result confirmed that the free hydroxymethyl substituent in 7a is
not required and plays no role in the oxazolidinone formation
leading from 7a/7b to 8a/8b.
Mechanistically, the tandem reaction sequence likely proceeds
through initial benzylic bromination (Scheme 3, bottom). In the
normal course of the Hanessian–Hullar process, ionization and
trapping with a bromide anion yields the brominated benzoate
ester. In the present case, the oxazolidinones 8a and 8b may be
envisioned as the products of a 5-exo-tet ring closure proceeding
via trapping of the carbamate oxygen atom onto the intermediate
carbocation (Scheme 3, shown as the ion-pair) with subsequent
loss of isobutylene and hydrogen bromide. This intramolecular
process competes effectively with the bromide trapping process to
deliver the oxazolidinone.
Further insight into the mechanism of the fragmentation–
rearrangement process was gained through investigation of the
substrate scope of the process with the two aminopropanediol
isomers 14 and 15, outlined in Scheme 4. Both 2-aminopropane-
1,3-diol 14 and the isomeric 1-aminopropane-2,3-diol 15 were
converted to their corresponding N-Boc protected benzylidene
acetals, 16 and 19, without incident. Each of these isomers was
then independently subjected to the standard Hanessian–Hullar
A remarkable feature of the fragmentation processes illustrated
above is the formation of only a single adduct in all cases, despite
the alternative modes available in the rearrangement step. This
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Fig. 1 Single crystal X-ray structure determination of oxazolidinone 30.3
in an enantiomerically pure form via phosphorylation of the
alcohol derived from oxazolidinone 28.14a The preparation of
FTY720 itself was recently reported through hydrogenation and a
one-step global acid mediated hydrolysis from intermediate 27.5
A related area of medicinal chemistry pertains to the design of
selective inhibitors of the enzyme sphingosine-1-kinase (SPhK1)
and investigation of their anticancer activity, mediated by their
interaction with sphingosine-1-phosphate receptors.14d The gene
encoding SPhK1 has been labelled an ‘‘oncogene’’ and is over
expressed in various tumor cells. A recent report described the
crystal structure of
a sphingosine-1-phosphate receptor in
Scheme 5 Differentially functionalised oxazolidinones from 7a. (a) Oxalyl chloride,
CH2Cl2, DMSO, 278 uC, Et3N (79%). (b) ArMgCl, Et2O, (82%, 24a). (c) PhCl, NBS,
BPO, 70 uC (65%, 25a). (d) See ref. 5. (e) 10% Pd/C, H2. (f) PhCl, BPO, 70 uC (54%).
(g) Tos-Cl, lutidine, 22 uC (87%). (h) DMF, NaN3, 80 uC, (95%). (i) CuI, CuOAc,
phenylacetylene, THF, 50 uC (71%, 31b). (j) CuI, dioxane, trans-1,2-diaminocyclohex-
ane, PhBr, K2CO3, 110 uC (62%).
conjunction with a sphingosine mimic (ML056), demonstrating
important interactions between the central aryl ring of this small
molecule and its receptor.14e The fragmented–rearranged inter-
mediate 8a appeared to be potentially valuable as a lead-in to
generating compound libraries of sphingosine-1-phosphate recep-
tor agonists/antagonists. To this end, compound 8a was trans-
formed into the crystalline azido derivative 30 in a straightforward
fashion via the tosylate derivative 29. A single crystal X-ray
structural analysis fully confirmed the structure of intermediate 30
(Fig. 1). Copper catalyzed Huisgen cycloaddition reactions (‘‘click’’
chemistry)15 were readily achieved using 30 and provided access to
1,2,3-triazole-containing sphingoids. For example, reaction of the
azide 30 with phenylacetylene and 5-chloro-1-pentyne under
standard copper catalyzed conditions, yielded the functionalized
triazole derivatives 31a and 31b. The azide unit in compound 30
could also be readily reduced to the amine (Pd/C, THF, H2 (1.0
atm), 99%) and acylated or phosphorylated. Thus a range of
densely functionalised sphingoid derivatives could readily be
obtained from intermediate 30, which is available in only five
steps (four chemical operations) from THAM, employing the new
fragmentation–rearrangement protocol.
Finally, many biologically active oxazolidinones contain an
additional N-aryl group appended to the oxazolidinone ring.7,8
This structural feature is a required pharmacophoric element in
many of the antibacterial agents related to linezolid 11. We were
delighted to find that the copper-catalyzed N-arylation of 8b could
be carried out smoothly on the MOM-substituted oxazolidinone 8b
using bromobenzene, leading to the N-aryl derivative 32.16
Compound 8b appears to be an ideal differentiated scaffold for
the preparation of diverse analogues of medicinally related targets
(antibacterial agents, antidepressants etc.) based on the oxazolidi-
none core.
results in the formation of highly functionalised and fully
differentiated oxazolidinones 17 and 8a or 8b in only 3 or 4 steps
from inexpensive commodity chemicals as well as the functionally
differentiated aliphatic primary bromide 20 from the standard
Hanessian–Hullar fragmentation of 19.
In order to illustrate the synthetic potential of this new tandem
fragmentation–rearrangement process, we have investigated
extensive synthetic modifications on the adduct 7a, a selection
of which is summarized in Scheme 5. Swern oxidation of the
benzylidene 7a provided the aldehyde 23 which was converted to
the benzyl alcohol derivatives 24a and 24b on reaction with the
corresponding aryl Grignard reagent. The fragmentation–rearran-
gement protocol was now conducted separately on 24a/24b
yielding initially a mixture of oxidation and fragmentation
products which we attributed to partial benzylic oxidation on
24a/24b. Using a slight excess of NBS (3.0 eq.) the fragmented,
highly functionalised aryl ketone derivatives 25a/25b could be
isolated in good yield.
Alternatively, Wittig olefination on aldehyde 23 using the ylide
derived from a trialkylbenzyl phosphonium salt,5,13 gave a mixture
of the (E)/(Z) alkenes 27 which were hydrogenated and subjected to
the fragmentation–rearrangement protocol to yield the oxazolidi-
none derivative 28. Oxazolidinones such as 28 are valuable
intermediates in the preparation analogs of immunosuppressants
based on FTY720, a pharmaceutical recently introduced for the
treatment of relapsing MS (trade name Gilenya).14a–c The
preparation of differentiated analogues can be contemplated from
these intermediates, for example FTY720 phosphate was prepared
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Conclusions
In conclusion, we have discovered a novel tandem fragmentation–
rearrangement process from benzylidene and N-Boc protected
amino alcohols leading directly to highly functionalized and fully
differentiated oxazolidinones. The process is a variant of the
Hanessian–Hullar reaction in which the intermediate carbocation
is intercepted by an intramolecular attack of the carbamate oxygen
atom and a subsequent loss of isobutylene to yield the
oxazolidinone derivative. Structure–reactivity studies demonstrate
that this rearrangement process occurs exclusively through a 5-exo-
tet ring closure and should thus be applicable to a wide range of
carbohydrate and amino acid derived amino alcohol derivatives.
An array of synthetic interconversions from compound 7a was
investigated to highlight the potential in accessing drug-like
compounds and to illustrate the scope for the preparation of
differentiated oxazolidinones. All derivatives shown in Scheme 5
are available from the commodity chemical THAM in only a few
steps. Further exploration of the reaction process and biological
screening of the compound classes currently available are under
investigation
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Acknowledgements
We thank NSERC for financial support of this work and Ms.
Victoria Jarvis for the X-ray analysis of compound 30.
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