We began by preparing several L-phenylalanine deriva-
tives, 21ꢀ22 and 23a, from 2-bromopropionyl bromide
using standard procedures and then examined the ensuing
cyclizations mediated by samarium iodide (SmI2) (Table 1).
Reactions of the unprotected amide 21 failed to give any
of the desired adduct under various conditions and re-
turned the corresponding des-bromo material (entry 1).
Much to our surprise, a variety of conditions employing
corresponding NH-protected para-methoxybenzyl (PMB)
derivative 22 also failed to afford the desired tetramic acid
and resultedinsteadinthe aniline 24from anunanticipated
cleavage(Table 1, inset). Preliminary studies with the PMB
protected glycine derivative (not shown) also failed to
produce the corresponding tetramic acid and led to the
amide 24 upon SmI2 treatment. We were therefore grati-
fied to find the NH protected benzyloxycarbonyl (Cbz)
bromide 23a gave the desired tetramic acid 25a, albeit in a
paltry 14% yield (entry 3) upon exposure to a freshly
prepared SmI2 solution (3.5 equiv, 0.1 M in THF) followed
by aqueous workup and exposure to diazomethane (8.0
equiv, 0.4 M in Et2O). Use of Fe(acac)313b (0.1 equiv) led to
a slight improvement (18% yield, entry 4), whereas addi-
tion of HMPA13a (10 equiv) increased the yield even
further to 31% (Table 2, entry 5). Lowering the tempera-
ture of the reaction to either ꢀ10 or ꢀ40 °C thwarted
product formation (entries 6ꢀ7). Switching the additive to
DMPU and raising the temperature to 0 °C afforded a
slight gain (entry 8).13c,d Upon reinvestigation of HMPA,
we found 0 °C with 5ꢀ10 equiv of the additive at 0 °C to
provide the optimum yield (entries 9ꢀ10).
Table 2. Scope of SmI2-Mediated Cyclization to Construct
3-Methyl-4-O-methylated Tetramic Acids 25
We therefore turned our attention toward retention of
the enantiomeric integrity within compound 25a and other
derivatives emerging from this method (Table 2). The
starting R-bromides 23aꢀf for these experiments were
prepared from their respective nonracemic amino esters
in yields ranging from 41 to 60% for the two-step trans-
formation, one chromatography sequence. On the other
hand, the proline derivative 23g was prepared from L-
proline methyl ester hydrochloride and 2-bromopropionyl
bromide in an 87% yield. Each of these epimeric bromides
was then individually subjected to samarium iodide. Treat-
ment of the respective optically active cyclization adducts
(25aꢀd, 25f) with KOt-Bu (potassium tert-butoxide, 2.0
equiv) provided the corresponding racemic product in
a Isolated two-step yield of 25. b Enantiomeric ratios (er) were
determined by HPLC.
under a minute for subsequent comparative HPLC
studies.7a This process underscores the challenge of devis-
ing a base mediated cyclization protocol that retains the
enantiomeric integrity of the starting amino acid.14 Stan-
dards for 25e and 25g, which proved difficult toracemizein
this manner, were prepared from the corresponding race-
mic amino acid.
The 92:8 er measured by HPLC for adduct 25a indicated
a slight loss of integrity during the course of the cyclization
process (Table 2, entry 1).13a,b Concerned about the effect
of HMPA on the basicity of the reaction, we halved its
equivalents. This change led to a sluggish reaction display-
ing a comparable ratio. We theorized that perhaps
SmI2OMe formed during the course of the reaction might
beresponsible forthelossofintegrity and, therefore, added
ethylacetate inthe hopesofconsumingit. Whileimproving
the er, this modification lowered the yield. We therefore
(10) (a) Komodo, T.; Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.;
Hirota, A. Tetrahedron Lett. 2003, 44, 1659. (b) Komodo, T.; Sugiyama,
Y.; Abe, N.; Imachi, M.; Hirota, H.; Koshino, H.; Hirota, A. Tetra-
hedron Lett. 2003, 44, 7417. (c) Komoda, T.; Kishi, M.; Abe, N.;
Sugiyama, Y.; Hirota, A. Biosci. Biotechnol. Biochem. 2004, 68, 903.
(11) Lan, H.-Q.; Ruan, Y.-P.; Huang, P.-Q. Chem. Commun. 2010,
46, 5319.
(12) Jones, R. C. F.; Bates, A. D. Tetrahedron Lett. 1986, 27, 5285.
(13) (a) Molander, G. A.; Mckie, J. A. J. Org. Chem. 1992, 57, 3132.
(b) Molander, G. A.; Mckie, J. A. J. Org. Chem. 1993, 58, 7216. For
reviews on SmI2 catalyzed reactions, see: (c) Kagan, H. B. Tetrahedron
2003, 59, 10351. (d) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem.
Rev. 2004, 104, 3371.
(14) During the preparation of this manuscript we learned of a
telluride-mediated Dieckmann cyclization of N-benzyl protected R-
bromoacyl amides. However, the enantiomeric integrities of products
were not determined: Dittmer, D. C.; Avilov, D. V.; Kandula, V. S.;
Purzycki, M. T.; Martens, Z. J.; Hohn, E. B.; Bacler, M. W. ARKIVOC
2010, vi, 61.
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