Enantioselective synthesis of functionalized medium-sized oxacycles

Article abstract of DOI:10.1021/ol062484v

(Diagram presented) Enantioselective routes to functionalized, seven-, eight-, and nine-membered oxacycles that are amenable to further elaboration have been developed. Salient features of the methodology include highly diastereoselective and regioselecti

Full text of DOI:10.1021/ol062484v

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5897-5899
Enantioselective Synthesis of
Functionalized Medium-Sized Oxacycles
Sunil V. Pansare* and Vikrant A. Adsool
Department of Chemistry, Memorial UniVersity of Newfoundland,
St. John’s, Newfoundland, Canada A1B 3X7
spansare@mun.ca
Received October 9, 2006
ABSTRACT
Enantioselective routes to functionalized, seven-, eight-, and nine-membered oxacycles that are amenable to further elaboration have been
developed. Salient features of the methodology include highly diastereoselective and regioselective transformations of an ephedrine-derived
epoxy morpholinone to functionalized precursors of the oxacycles. The ephedrine scaffold exerts remote stereocontrol in the functionalization
of the appended oxacycle.
Functionalized, heteroatom-containing rings are found in
several natural products, and simplified analogues as well
as structural motifs resembling these natural products are
interesting synthetic targets. In particular, the synthesis of
medium-sized oxacycles1 has attracted considerable attention,
and general2 as well as target-oriented3 strategies that address
the stereoselective assembly of such ring systems have been
extensively investigated in recent years. We chose to examine
the enantioselective construction of seven-, eight-, and nine-
membered oxacycles that are readily amenable to further
functionalization. Herein, we describe preliminary results
toward this objective.
of the oxacycle. We targeted unsaturated oxacycles bearing
the R-hydroxy acid functionality because the hydroxy and
carboxamide groups can be exploited for transannular
reactions and the alkene in the ring can be employed in
various addition processes.4 The precursors to the target
oxacycles are obtained from a common starting material, an
ephedrine-derived morpholine dione 1,5 which is readily
prepared (85%) from commercially available (1R,2S)-
(3) Recent reports: (a) Lee, H.; Kim, H.; Yoon, T.; Kim, B.; Kim, S.;
Kim, H.-D.; Kim, D. J. Org. Chem. 2005, 70, 8723. (b) Posner, G. H.;
Hatcher, M. A.; Maio, W. A. Org. Lett. 2005, 7, 4301. (c) Kaliappan, K.
P.; Kumar, N. Tetrahedron 2005, 7461. (d) Kadota, I.; Uyehara, H.;
Yamamoto, Y. Tetrahedron 2004, 60, 7361. (e) Batchelor, R.; Hoberg, J.
O. Tetrahedron Lett. 2003, 44, 9043. (f) Denmark, S. E.; Yang, S. M. J.
Am. Chem. Soc. 2002, 124, 15196. (g) Crimmins, M. T.; Emmitte, K. A.
Org. Lett. 1999, 1, 2029. (h) Crimmins, M. T.; Choy, A. L. J. Am. Chem.
Soc. 1999, 121, 5653. (i) Krueger, J.; Hoffmann, R. W. J. Am. Chem. Soc.
1997, 119, 7499. (j) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.;
Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483. (k)
Matthias, B.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem.
Soc. 1995, 117, 5958.
(4) Recent reports on transannular etherification: (a) Nguyen, G.;
Perlmutter, P.; Rose, M. L.; Vounatsos, F. Org. Lett. 2004, 6, 893. (b) Petri,
F. A.; Bayer, A.; Maier, M. E. Angew. Chem., Int. Ed. 2004, 43, 5821.
Recent reports on the halolactonization reaction: Mellegard, S. R.; Tuge,
J. A. J. Org. Chem. 2004, 69, 8979 and refs therein.
(5) (a) Rudchenko, V. F.; Shtamburg, V. G.; Pleshkova, A. P.; Kostyan-
ovskii, R. G. Bull. Acad. Sci. USSR DiV. Chem. Sci. (Engl. Transl.) 1981,
30, 825. (b) Pansare, S. V.; Bhattacharyya, A. Tetrahedron Lett. 2001, 42,
9265. For synthetic applications of other aminoalcohol-derived morpholi-
nones, see: (c) Cox, G. G.; Harwood, L. M. Tetrahedron: Asymmetry 1994,
9, 1669. (d) Williams, R. M. Aldrichimica Acta 1992, 25, 11.
The focus of our approach is the incorporation of
functional groups that can be utilized for further elaboration
(1) For reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004,
104, 2127. (b) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301. (c)
Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2001, 2303.
(2) Recent reports: (a) Perez, M.; Canoa, P.; Gomez, G.; Teijeira, M.;
Fall, Y. Synthesis 2005, 411. (b) Fujiwara, K.; Goto, A.; Sato, D.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465. (c) Mukai, C.; Ohta, M.;
Yamashita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867. (d) Sibi, M. P.;
Patil, K. P.; Rheault, T. R. Eur. J. Org. Chem. 2004, 372. (e) Alcazar, E.;
Pletcher, J. M.; McDonald, F. M. Org. Lett. 2004, 6, 3877. (f) Sawada, Y.;
Sasaki, M.; Takeda, K. Org. Lett. 2004, 6, 2277. (g) Martin, M.; Afonso,
M. M.; Galindo, A.; Palenzuela, J. A. Synlett 2001, 117. (h) Saitoh, T.;
Suzuki, T.; Onodera, N.; Sekiguchi, H.; Hagiwara, H.; Hoshi, T. Tetrahedron
Lett. 2003, 44, 2709. (i) Prasad, K. R. K.; Hoppe, D. Synlett 2000, 1067.
(j) Delgado, M.; Martin, J. D. J. Org. Chem. 1999, 64, 4798. (k) Mujica,
M. T.; Afonso, M. M.; Galindoa, A.; Palenzuela, J. A. J. Org. Chem. 1998,
63, 9728.
10.1021/ol062484v CCC: $33.50
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ephedrine hydrochloride and ethyloxalyl chloride. Treatment
of 1 with ethylmagnesium chloride and dehydration of the
resulting hemiacetal cleanly generated the alkylidene mor-
pholinone 26 (95%, Scheme 1). Epoxidation of 2 with
Scheme 2
Scheme 1
treatment of 3 with the sodium salt of 3-methyl-3-buten-1-
ol or propargyl alcohol cleanly generated the hemiacetals 8
and 9, respectively. Allylation of the hemiacetals provided
the diene 10 and enyne 11 as single diastereomers (Scheme
3). It is assumed that substitution proceeds with inversion at
m-CPBA provided the epoxide 3 (85%) as a single dia-
stereomer, which was stable to chromatography. The stereo-
chemistry of 3 was established by X-ray crystallographic
analysis,7 which indicated that the epoxidation of 2 had
occurred anti to the phenyl and methyl groups in the
morpholinone ring.
Scheme 3
Epoxide 3 served as the starting material for the construc-
tion of functionalized precursors to seven- and eight-
membered oxacycles. We initially explored the ring opening
of 3 with vinyl and butenyl magnesium bromide at low
temperature (-78 °C). Surprisingly, no reaction was ob-
served. Organocopper reagents were not beneficial, and
byproducts predominated when zinc chloride or BF3 etherate
was employed as a Lewis acid in these reactions. Attempted
allylation of 3 with TiCl4/allyltrimethylsilane provided the
chloroalcohol arising from epoxide ring opening with the
chloride ion at the hemiacetal carbon. The use of boron
trifluoride as the Lewis acid was beneficial, and the allylation
of 3 under these conditions proceeded with excellent dia-
stereocontrol8 (dr > 19:1, Scheme 2) at ambient temperature
to furnish the alcohol 4. Etherification of 4 with allyl bromide
and subsequent ring-closing metathesis9 of the diene 5 with
the Grubbs(I) catalyst generated the spirooxepine 6 (70%).
Dissolving metal reduction of 6 generated the seven-
membered oxacycle 7 as a single diastereomer.
the epoxide carbon. It may be noted that these ring-opening
reactions demonstrate the utility of 3 as an ambivalent
electrophile and also provide a tool for inverting the
stereochemistry at the nonacetal carbon of the epoxide. Thus,
in principle, the alkoxide opening/allylation procedure can
be used to provide the diastereomer of the product obtained
by an allylation/O-alkylation reaction sequence with 3. In
addition, the use of an enantiomerically pure secondary
alcohol in the epoxide opening reaction should allow for the
control of two stereocenters adjacent to the ether oxygen, a
structural motif that is found in the laurencin, obtusan, and
lauthisan classes of marine natural products.1
As anticipated, epoxide 3 reacted with alkoxide nucleo-
philes exclusively at the terminal carbon.10 For example,
(6) For a synthesis of 2 from ephedrine and 2-ketobutyric acid, see:
Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem. 1998, 63, 4120.
(7) See the Supporting Information for details. The crystallographic data
has been deposited with the Cambridge Crystallographic Data Centre,
reference number CDCC619165.
(8) The stereochemistry of allylation is assigned by analogy to other
reactions of the oxocarbenium ion intermediate in the ephedrine-derived
template (ref 6).
(9) For recent reviews on synthetic applications of metathesis reactions,
see: (a) Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10, 185. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490.
(10) For regioselective ring opening of glucose-derived spiro epoxides
under acidic or basic conditions, see: Lay, L.; Nicotra, F.; Panza, L.; Russo,
G. Synlett 1995, 167. For a recent review on the chemistry of epoxides,
see: Kas’yan, L. I.; Kas’yan, A. O.; Okovityi, S. I. Russ. J. Org. Chem.
2006, 42, 307.
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Org. Lett., Vol. 8, No. 25, 2006

We next investigated the ring-closing metathesis reactions
of 10 and 11. Reaction of 10 with the Grubbs(II) catalyst
was beneficial, and the spirooxocane 12 was obtained in good
yield (87%, Scheme 4). Removal of the ephedrine portion
Scheme 5
Scheme 4
stage, we decided to examine the functionalization of the
double bond in 20. Dihydroxylation of 20 (OsO4, NMO,
H2O/THF) followed by removal of the ephedrine portion
provided the diol 21 (∼7:1 mixture of diastereomers). The
major diastereomer was assigned the shown stereochemistry
on the basis of a preferred conformation for 20 (determined
by molecular modeling) in which the top face of the double
bond is shielded by the phenyl ring in the morpholinone
portion of the spirocycle. The chirality of the ephedrine can
thus be utilized not only for stereochemical control in the
morpholinone ring but also for remote stereocontrol in the
appended oxacycle. The spirooxocane 20 was thus converted
to the highly oxygenated oxocane 21, which was isolated as
a single diastereomer (30% (two steps), Scheme 5).
In conclusion, we have developed versatile approaches to
functionalized, enantiomerically pure oxacycles. The overall
strategy is quite flexible and permits the construction of
seven-, eight-, or nine-membered oxacycles from readily
available chiral precursors, the alkylidene morpholinone 2
and the epoxide 3. Incorporation of unsaturation and
positioning of the ring oxygen at specific locations in the
ring are achieved by judicious choice of starting materials.
We are currently investigating the application of these
methods in the synthesis of selected naturally occurring
oxacycles and their analogues.
in 12 provided 13 (dr > 19:1, 94% ee). At this stage, the
utility of the carboxamide for transannular functionalization
was demonstrated by bromolactonization of 13 to provide
the functionalized dioxabicyclo[5.2.1]decanone 14 as a single
diastereomer (Scheme 4). Although enyne metathesis of 11
proceeded smoothly with the Grubbs(I) catalyst to provide
the spirooxepine 15 (90%), subsequent dissolving metal
reduction generated a complex mixture of products and the
required product 16 could not be detected. Presumably, the
diene functionality in 15 is susceptible to dissolving metal
reduction. We are examining alternative procedures for
removing the ephedrine portion in 15.
In addition to the epoxide-based routes described above,
we have also examined the utility of the alkylidene mor-
pholinone 2 for the preparation of functionalized dienes. Prins
reaction11 of 2 with formaldehyde provided the spirodioxane
17 as a single diastereomer12 (Scheme 5). Treatment of 17
with excess allyltrimethylsilane/BF3 etherate provided dia-
stereomerically pure bisallylation product 18 (76%). Ring
closure of 18 (74%) and subsequent removal of the chiral
controller provided the nine-membered oxacycle 19 (89%,
99% ee, Scheme 5). The bisallylation of 17 augurs well for
the employment of functionalized allylsilanes and allylmetal
reagents in the acetal opening to provide functionalized
oxonines. Also, alkylidene morpholinones related to 2 with
varying substitution on the double bond undergo the Prins
reaction readily. For example, we have prepared analogues
of 17 in which the methyl group is replaced by other alkyl
or aryl groups.13 We are currently examining the allylation
reactions of these substrates.
Acknowledgment. These investigations were supported
by the Natural Sciences and Engineering Research Council
of Canada and the Canada Foundation for Innovation. We
thank Ms. Julie Collins, Centre for Chemical Analysis,
Research and Training, Memorial University, for the X-ray
structure of epoxide 3.
The diene 18 was also employed in the synthesis of a
functionalized eight-membered ring 20 (Scheme 5). At this
Supporting Information Available: Experimental meth-
(11) For reviews on the Prins reaction, see: (a) Snyder, B. B. Compr.
Org. Synth. 1991, 2, 527. (b) Adams, D. R.; Bhatnagar, S. P. Synthesis
1977, 661.
(12) The stereochemistry of 17 was assigned by analogy to similar
spirodioxanes prepared by us earlier: Jain, R. P. Ph.D. thesis, University
of Pune, 2002 and ref 5b.
1
ods, spectroscopic data with assignments, H and 13C data
for all compounds, and the crystallographic information for
epoxide 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Adsool, V. A., unpublished results. Also see ref 5b for disubstituted
analogues of 17.
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