A new ring closure approach to enantiopure 3,6-dihydro-2H-pyrans: Stereodivergent access to carbohydrate mimetics

Article abstract of DOI:10.1021/ol902354f

"Chemical Equation Presented" A set of enantiopure carbohydrate mimetics has been synthesized via Lewis acid promoted cyclization of 1,3-dioxolanyl-substituted enol ethers as a crucial new step providing highly functionalized 3,6-dihydro-2H-pyran derivati

Full text of DOI:10.1021/ol902354f

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5534-5537
A New Ring Closure Approach to
Enantiopure 3,6-Dihydro-2H-pyrans:
Stereodivergent Access to Carbohydrate
Mimetics
Fabian Pfrengle, Dieter Lentz,† and Hans-Ulrich Reissig*
Institut fu¨r Chemie und Biochemie, Freie UniVersita¨t Berlin, Takustr. 3,
14195 Berlin, Germany
hans.reissig@chemie.fu-berlin.de
Received October 12, 2009
ABSTRACT
A set of enantiopure carbohydrate mimetics has been synthesized via Lewis acid promoted cyclization of 1,3-dioxolanyl-substituted enol
ethers as a crucial new step providing highly functionalized 3,6-dihydro-2H-pyran derivatives. The flexible approach starting from glyceraldehyde-
derived nitrone is comprised of only six simple steps smoothly allowing synthetic modifications at the different stages of the sequence. All
reactions proceeded with good to excellent stereocontrol and can be performed with either of the two enantiomers.
Substituted pyran derivatives are structural subunits of a wide
range of natural products and bioactive compounds. Their
selective preparation in enantiopure form remains a continu-
ous challenge for synthetic chemists.1 Our group recently
reported a new access to aminopyran derivatives such as 4,
which can be regarded as mimetics of C2-branched 4-amino
sugars (Scheme 1).2 A serendipitously discovered Lewis acid
promoted rearrangement of 1,2-oxazines 2 furnished bicyclic
compounds 3 as key intermediates. The required 3,6-dihydro-
2H-1,2-oxazines 2 were obtained by stereoselective [3 + 3]-
cyclizations of lithiated alkoxyallenes and D- or L-glyceral-
dehyde-derived nitrones 1.3 This sequence can be performed
in a controlled stereodivergent manner allowing access to
four possible stereoisomers of 3.
With this achievement in mind, we envisioned the
synthesis of aminopyrans such as 5, employing a related
strategy (Scheme 2). We considered 3,6-dihydropyran 6 as
the key intermediate, which should be accessible by Lewis
† Responsible for X-ray analysis.
(1) For recent reviews on pyran synthesis, see: (a) Larrosa, I.; Romea,
P.; Urp´ı, F. Tetrahedron 2008, 64, 2683–2723. (b) Clarke, P. A.; Santos,
S. Eur. J. Org. Chem. 2006, 2045–2053. For selected recent examples, see:
(c) Hu, X.-H.; Liu, F.; Loh, T.-P. Org. Lett. 2009, 11, 1741–1743. (d)
McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402–403. (e)
O’Neil, G. W.; Fu¨rstner, A. Chem. Commun. 2008, 4294–4296. (f) Posp´ısˇil,
J.; Marko´, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517. (g) Ichige, T.;
Okano, Y.; Kanoh, N.; Nakata, M. J. Am. Chem. Soc. 2007, 129, 9862–
9863. (h) Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480–
16481. (i) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 16044–16045.
(2) (a) Al-Harrasi, A.; Reissig, H.-U. Angew. Chem., Int. Ed. 2005, 44,
6227–6231. (b) Al-Harrasi, A.; Pfrengle, F.; Prisyashnyuk, V.; Yekta, S.;
Koo´sˇ, P.; Reissig, H.-U. Chem.-Eur. J. 2009, 15, 11632-11641. (c)
Pfrengle, F.; Lentz, D.; Reissig, H.-U. Angew. Chem., Int. Ed. 2009, 48,
3165–3169.
(3) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632–634. (b) Helms,
M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-Harrasi, A.; Fisˇera, L.;
Hlobilova´, I.; Zahn, G.; Reissig, H.-U. Eur. J. Org. Chem. 2005, 1003–
1019.
10.1021/ol902354f CCC: $40.75
Published on Web 11/02/2009
 2009 American Chemical Society

amine derivative syn-10 was isolated after TBS protection
in good yield and diastereoselectivity (Scheme 3).6 As
expected,7 precomplexation of nitrone 1a with Et2AlCl before
addition of 1a switched the stereochemical outcome toward
formation of anti-configured products, providing anti-10 in
slightly lower yield but with excellent diastereoselectivity.
Protection of the primarily obtained hydroxylamine deriva-
tives with the TBS group was essential for their stability
during column chromatography, which smoothly allowed
separation of the diastereomers.8 The protected hydroxyl-
amine derivatives syn- and anti-10 were treated with
Scheme 1. Synthesis of Aminopyrans 4 via Lewis Acid
Promoted Rearrangements of 1,2-Oxazines 2
Scheme 3
.
Synthesis of Diastereomeric 3,6-Dihydro-2H-pyrans
11 and 12
acid induced cyclization of protected hydroxylamine deriva-
tive 7. Similarly to the approach to 1,2-oxazines 2, the
addition of lithiated enol ethers 8 to glyceraldehyde-derived
nitrones 1 should afford the required hydroxylamine inter-
mediates with a high level of stereocontrol.
Scheme 2. Retrosynthetic Analysis of Aminopyrans 5
TMSOTf, smoothly affording the diastereomeric 3,6-dihy-
dropyrans 11 or 12 in high yields. The new key cyclization
step can be regarded as a Lewis acid promoted intramolecular
aldol type reaction of an acetal with an enol ether or as a
Prins type reaction.9
The enol ether moiety of 11 and 12 was subsequently
exploited for functionalizations such as hydrolysis or dihy-
To the best of our knowledge, the addition of lithiated
enol ethers4 to nitrones has not been described so far. The
major concern we had about the feasibility of Scheme 2 was
the cyclization step 7 f 6, which has to occur without the
geometrical constraint exhibited by the 1,2-oxazine moiety.
We were also uncertain whether this step would proceed
without the TMSE group undergoing a fast fragmentation
in the transformation of 2 f 3 (Scheme 1).
(6) For selected recent examples of the addition of organolithium
compounds to nitrones, see: (a) Dondoni, A.; Nuzzi, A. J. Org. Chem. 2006,
71, 7574–7582. (b) Dullin, A.; Dufrasne, F.; Gelbcke, M.; Gust, R.
ChemMedChem 2006, 1, 644–653. (c) Yu, C.-Y.; Huang, M.-H. Org. Lett.
2006, 8, 3021–3024. (d) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.;
Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008,
2929–2947. Review: (e) Lombardo, M.; Trombini, C. Synthesis 2000, 759–
774.
(7) For the stereodivergent addition of organometallic reagents to
carbohydrate-derived nitrones, see: Dondoni, A.; Franco, S.; Junquera, F.;
Mercha´n, F. L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem.sEur. J. 1995,
1, 505–520.
Gratifyingly, when lithiated ethyl vinyl ether 95 was
reacted with D-glyceraldehyde-derived nitrone 1a, hydroxyl-
(8) Merino, P.; Tejero, T.; Mannucci, V.; Prestat, G.; Madec, D.; Poli,
G. Synlett 2007, 944–948.
(4) Review: Friesen, R. W. J. Chem. Soc., Perkin Trans. 1 2001, 1969–
2001.
(9) For related reactions, see: (a) Cockerill, G. S.; Kocienski, P. J. Chem.
Soc., Perkin Trans. 1 1985, 2093–2100. (b) Das, S.; Li, L.-S.; Sinha, S. C.
Org. Lett. 2004, 6, 123–126.
(5) Lithiation of the enol ether was carried out under standard conditions:
Friesen, R. W.; Sturino, C. F. Sci. Synth. 2005, 8, 841–862.
Org. Lett., Vol. 11, No. 23, 2009
5535

droxylation. Treatment of 11 with HCl in methanol furnished
ketone 13 by hydrolysis of the enol ether with concomitant
loss of the TBS group (Scheme 4). Stereoselective reduction
with NaBH4 and final hydrogenolysis using Pd/C provided
deprotected aminopyran 14 in good overall yield. To
introduce an additional hydroxyl group, the enol ether double
bond in 11 was dihydroxylated using a catalytic amount of
K2OsO4. Formation of an intermediate hemiacetal was not
observed, and R-hydroxy ketone 15 was directly isolated as
a single diastereomer. Subsequent reduction with NaBH4 and
final hydrogenolysis furnished deprotected aminopyran 16
in good overall yield. The presence of CeCl3 in the NaBH4
reduction of ketone 15 turned out to be essential to achieve
excellent diastereoselectivity.
Scheme 5. Synthesis of Carbohydrate Mimetics 19 and 22
Scheme 4. Synthesis of Carbohydrate Mimetics 14 and 16
configuration of 22 was proven by X-ray crystallographic
analysis of its protected precursor 21 (Figure 1).11
When diastereomeric dihydropyran 12 was exposed to
HCl, we could not achieve hydrolysis of the enol ether
moiety but mainly observed decomposition. Fortunately, we
were able to synthesize the desired aminopyran 19 by a
“detour” employing R-bromo ketone 17 smoothly obtained
by bromination of 12 with NBS (Scheme 5). During our
attempts to substitute the bromo substituent in 17 by azide,
we unexpectedly isolated nitrone 18 in high yield, apparently
formed by an unusual internal redox reaction.10 With this
intermediate in hand, the stereoselective synthesis of ami-
nopyran 19 could be performed in good overall yield. Unlike
its hydrolysis, dihydroxylation of 12 was easily feasible,
providing R-hydroxyketone 20 accompanied by considerable
amounts (20-50%) of the hydroxylated hemiacetal. After
reductive transformations of this mixture, aminopyran 22 was
isolated as a single diastereomer in good overall yield. The
Figure 1.
Molecule structure (ORTEP13) of aminopyran derivative
21.
Compounds 14, 16, 19, or 22 having a hydrolytically stable
gem-dimethyl group at C1 can be regarded as mimetics of
differently substituted and configured 4-amino carbohy-
(11) The configurations of aminopyrans 14, 16, and 19 were assigned
by comparison of their NMR data (see Supporting Information).
(10) For a mechanistic suggestion, see the Supporting Information.
5536
Org. Lett., Vol. 11, No. 23, 2009

representative example, reaction of lithiated dihydrofuran 23
with nitrone 1a followed by TBS protection smoothly
furnished hydroxylamine derivatives syn- and anti-25 (Scheme
6). Similarly, lithiated 2,3-dihydropyran 24 afforded syn- and
anti-26 in moderate yield and with reasonable diastereose-
lectivity.15 When syn-25 and syn-26 were exposed to
TMSOTf, bicyclic compounds 27 and 28 were obtained in
high yield. To demonstrate the synthetic potential of com-
pounds such as 28, we performed an oxidative ring cleavage
of its benzyl-protected derivative with RuCl3 hence providing
lactone 29 in good yield, which contains the L-γ-hydroxyl-
threonine moiety.16
Scheme 6
.
Synthesis of Bicyclic Dihydropyrans 27 and 28 and
Macrolactone 29
In conclusion, we developed a rapid access to a set of
novel carbohydrate mimetics via Lewis acid promoted
cyclizations of 1,3-dioxolanyl-substituted hydroxylamine
derivatives, which were obtained by stereodivergent addition
of lithiated enol ethers to D-glyceraldehyde-derived nitrone
1a. All of the reactions can be performed on a gram scale,
and they proceeded with good stereocontrol. It should be
emphasized that all compounds described in this com-
munication are as easily accessible as their enantiomers with
L-glyceraldehyde-derived nitrone as starting material. The
prepared compounds are candidates to be incorporated into
oligosaccharides or aminoglycosides, potentially leading to
compounds with interesting antibacterial properties. Further-
more, starting from lithiated 3,4-dihydropyran and 2,3-
dihydrofuran, bicyclic compounds 27 and 28 were prepared,
which should provide access to unusual enantiopure hetero-
cycles such as 29.
drates.12 Their C2-branched analogues 4 already exhibited
highly remarkable properties as ligands of gold nanoparticles
in their multivalent binding to selectins. We currently
evaluate the newly prepared aminopyrans toward their
potential as components of new anti-inflammatory agents.14
Finally, not only ethyl vinyl ether but also cyclic enol
ethers have been lithiated and reacted with nitrones. As a
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie (PhD-fellowship to FP) and the
Deutsche Forschungsgemeinschaft (SFB 765).
Supporting Information Available: Experimental pro-
cedures, characterization data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) For reviews on carbohydrate mimetics, see: (a) Sears, P.; Wong,
C.-H. Angew. Chem., Int. Ed. 1999, 38, 2301–2324. (b) Carbohydrate
Mimics-Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim,
1998.
OL902354F
(15) Pre-complexation of 1a switched the stereochemical outcome of
the reactions toward anti-25 and anti-26 as the main diastereomers (d.r.
86:14 and d.r. 88:12).
(16) Silva, L. F., Jr.; Vasconcelos, R. S.; Nogueira, M. A. Org. Lett.
2008, 10, 1017–1020.
(13) Farrugia, L. J. ORTEP-3 for windows. J. Appl. Crystallogr. 1997,
30, 565.
(14) Dernedde, J.; Enders, S.; Reissig, H.-U.; Roskamp, M.; Schlecht,
S.; Yekta, S. Chem. Commun. 2009, 932–934.
Org. Lett., Vol. 11, No. 23, 2009
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