an anomeric carbon leads to two attractive disconnections.
These scissions would allow for the convergent assembly
of 1 by coupling a derivative of the central core unit 3 with
two excised enantiomerically pure fragments, alcohol 2 and
piperidine 4 (Scheme 1). Chiral alcohol 2 could be obtained
or aryloxy group should not significantly prohibit a substitu-
tion reaction of the fully elaborated electrophile.
Toward this end, tosylate (R)-13, an orthogonally protected
butane triol, was targeted. The first step of this synthesis
was accomplished by alkylation of 3-butene-1-ol with BnCl
under solvent-free phase transfer catalysis conditions (NaOH/
BnCl/Bu4NHSO4)10 to afford benzyl ether 9 (Scheme 3).11
Scheme 1. Retrosynthetic Analysis
Scheme 3. HKR Synthesis of Epoxide (R)-10
A small amount of the symmetric ether (BnOBn) was formed
in this process, which was suppressed by using more
concentrated NaOH.
from the asymmetric reduction of the corresponding ketone,7
and the quaternary substituted piperidine 4 potentially could
be derived from ethyl nipecotate.
Treatment of alkene 9 with m-chloroperbenzoic acid
cleanly afforded racemic epoxide 10,12 which readily un-
derwent a salen-mediated (1.5 mol % catalyst, 50 mol %
H2O) hydrolytic kinetic resolution.13 The desired epoxide (R)-
1014 was conveniently separated from the newly formed diol
antipode (S)-11 by distillation. Chiral SFC indicated that
the enantiomeric ratio of the isolated epoxide 10 was >99:1
(R:S). Subsequent oxirane ring opening was accomplished
with 4-methoxyphenol (PMP-OH) and K2CO3, which proved
to be much cleaner than the similar openings with sodium
and potassium alkoxides of aliphatic alcohols (Scheme 2).15
One possible asymmetric approach to lactone 3 hinged
on the stereospecific displacement of a leaving group from
a secondary center of electrophile 5 with the enolate of a
phenylacetate derivative (Scheme 1).8 Although 2-arylal-
kanoic acids have recently been prepared by the alkylation
of carboxylate enolates with tosylates,9 it was not apparent
whether enantiomerically pure, R-alkoxy secondary tosylates
would enter into this protocol; concerns included low
substrate reactivity, stereocenter scrambling, and elimination.
To investigate the effect of the neighboring alkoxyl group
on the electrophile, tosylate 7 was synthesized from 1,2-
epoxyhexene (Scheme 2). The lithium dianion of phenyl-
acetic acid cleanly displaced the tosyl group of 7 to afford
the desired R-phenyl-â-alkoxymethyl carboxylic acid 8 in
an 82% isolated yield. This indicated that an adjacent alkoxy
(7) Hansen, K. B.; Chilenski, J. R.; Desmond, R.; Devine, P. N.;
Grabowski, E. J. J.; Heid, R.; Kubryk, M.; Mathre, D. J.; Varsolona, R.
Tetrahedron: Asymmetry 2003, 14, 3581.
(8) For recently developed alternative asymmetric methodology for the
preparation of 3-aryl-δ-lactones, see: (a) Smitrovich, J. H.; Boice, G. N.;
Qu, C.; DiMichele, L.; Nelson, T. D.; Huffman, M. A.; Murry, J.;
McNamara, J.; Reider, P. J. Org. Lett. 2002, 4, 1963. (b) Smitrovich, J. H.;
DiMichele, L.; Qu, C.; Boice, G. N.; Nelson, T. D.; Huffman, M. A.; Murry,
J. J. Org. Chem. 2004, 69, 1903.
(9) Kusumoto, T.; Ichikawa, S.; Asaka, K.; Sato, K.-i.; Hiyama, T.;
Tetrahedron Lett. 1995, 36, 1071.
(10) (a) Freedman, H. H.; Dubois, R. A. Tetrahedron Lett. 1975, 16,
3251. (b) Burgstahler, A. W.; Weigel, L. O.; Sanders, M. E.; Shaefer, C.
G.; Bell, W. J.; Vuturo, S. B. J. Org. Chem. 1977, 42, 566.
Scheme 2. R-Alkoxy Sulfonate Displacement
(11) For alternative preparations of 4-benzyloxy-1-butene (9), see: (a)
Westwell, A. D.; Williams, J. M. J. Tetrahedron 1997, 53, 13063. (b)
Berranger, T.; Langlois, Y. J. Org. Chem. 1995, 60, 1720.
(12) (a) Muehlbacher, M.; Poulter, C. D. J. Org. Chem. 1988, 53, 1026.
(13) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307. (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
(14) For an alternative synthesis of (R)-10, see: Frick, J. A.; Klassen, J.
B.; Bathe, A.; Abramson, J. M.; Rapoport, H. Synthesis 1992, 621.
(15) We synthesized and utilized other orthogonally substituted triols;
however, these strategies suffered from either poor epoxide opening yields,
low downstream yields, or significant problems relating to acetal decom-
postion during subsequent deprotection. The use of the PMP protecting
group for the primary alcohol successfully overcame these issues. Fukuyama,
T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985, 26, 6291.
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Org. Lett., Vol. 7, No. 1, 2005