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formed into more than 100 novel macrolide antibiotics in
ongoing research in our laboratory.[15] Hydrolysis of 30
provided the acid 31 in 94% yield (90% recovered pseudo-
ephenamine).
less asymmetric aminohydroxylation of certain alkenyl
esters,[22] multistep transformations of Garner aldehyde-type
intermediates,[23] asymmetric hydrogenation of 2-amino-b-
ketoesters,[24] as well as other strategies.[14f,25]
To apply our new aldol methodology to synthesize
chloramphenicol and thiamphenicol, antibiotics which are
on the essential medicine list published by the World Health
Organization[16] and play critical roles in the treatment of
infectious disease, especially in developing countries,[17] we
investigated reductive cleavage of the auxiliary to produce 2-
amino-1,3-diols. Remarkably, treatment of the aldol adduct 8
with the mild reducing agent sodium borohydride (5.0 equiv)
in ethanol at 408C provided the 2-amino-1,3-diol 32 in 80%
yield (Scheme 4), and the auxiliary was recovered quantita-
Constructive syntheses are generally more powerfully
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simplifying, for they enable retrosynthetic targeting of the C
C bond linking the stereogenic, heteroatom-bearing centers.
The pioneering advances of the Schçllkopf group, employing
bis(lactim) ethers,[26] and the Seebach group, employing
masked glycine-derived heterocycles,[27] as substrates in
diastereoselective aldol additions remain important enabling
methodologies. To reveal the parent b-hydroxy-a-amino acids
or esters, however, strongly acidic conditions are required and
auxiliary-derived byproducts can complicate isolation of the
products.[26e,f] Evans and Weber developed a-isothiocyanato
acyl oxazolidinones as substrates in their diastereoselective
tin-mediated aldol chemistry,[28] and notable advances have
been recorded by the groups of Willis,[29] Feng,[30] and Seidel[31]
to transform this method into processes mediated by chiral
catalysts. These a-isothiocyanate methodologies afford thio-
carbamate heterocycles as products, which conveniently serve
to protect the amine and alcohol functionalities of the aldol
adducts, but require a three-step procedure to reveal the
embedded a-amino acids. Methods employing chiral glycine
enolate equivalents have also been reported by the groups of
Bold,[32] Iwanowicz,[33] Caddick,[34] and Franck.[35] Hydroxy-
methylations of alanine equivalents to form a-alkyl serine
derivatives have also been reported.[36]
Another notable approach employs Schiff bases of glycine
tert-butyl esters in aldol reactions with aldehyde substrates to
provide aldol addition products which are then treated with
acid to reveal the embedded b-hydroxy-a-amino esters.
Advances in this area were reported by the groups of
Mukaiyama,[37] Belokon,[38] Miller,[39] and Corey,[40] and sub-
sequently several modifications have emerged and provide
both syn[41] and anti[42] products. While these methods are
convenient because of the facile enolization of glycine Schiff
bases and the direct conversion of the aldol products into b-
hydroxy-a-amino esters, they often suffer from poor diaste-
reoselectivities, narrow substrate scope, and frequently
require further functionalization to permit separation of syn
and anti aldol addition products.
Ito, Hayashi, and co-workers employed a-isocyano esters
and amides in aldol reactions catalyzed by chiral gold(I)
complexes, thus providing oxazoline-4-carboxylate products
which can be converted into b-hydroxy-a-amino acids upon
treatment with strong acid.[43] Oxazoline-4-carboxylates have
also been constructed by the addition of 5-alkoxyoxazoles to
aldehydes catalyzed by chiral aluminum catalysts, as demon-
strated by Suga and Ibata[44] and the Evans group.[45] These
systems were found to be highly effective only with aromatic
aldehyde substrates, and conversion of the oxazoline products
into b-hydroxy-a-amino acids requires three steps and harshly
acidic conditions. Barbas, Tanaka, and co-workers reported
a method for the aldolization of phthalimidoacetaldehyde
catalyzed by proline that achieved high enantio- and diaste-
reoselectivities, but only with a-branched aldehyde sub-
strates.[46] The Wong group has developed methodology for
chemoenzymatic aldolization of glycine catalyzed by threo-
Scheme 4. Mild reductive cleavage of aldol adducts applied to the
syntheses of chloramphenicol and thiamphenicol.
tively in pure form. We are aware of only one previous report
of the reduction of tertiary amides (a-hydroxy morpholina-
mides) to the corresponding alcohols with sodium borohy-
dride.[18] Reduction of pseudoephedrine and pseudoephen-
amine amides to the corresponding primary alcohols has
historically been achieved using lithium amidotrihydroborate
(LAB),[2b,3b,10] a much more reactive hydride donor that we
introduced in 1996.[19] Again, we believe that the facile
reduction with sodium borohydride we observe is due to
intramolecular N!O-acyl transfer followed by reduction of
the resulting a-amino ester.[20] The synthesis of chloramphe-
nicol was completed by acylation of 32 with methyl dichlor-
oacetate (Scheme 4), thus providing the antibiotic in excellent
yield in just three steps from (R,R)-pseudoephenamine
glycinamide (1) and para-nitrobenzaldehyde. Thiamphenicol
was synthesized by an identical two-step sequence from the
aldol adduct 9. In contrast to the three-step routes to
chloramphenicol and thiamphenicol reported here, the com-
mercial routes to these substances require about six linear
steps, including a resolution.[21]
Commensurate with their importance in medicine, chem-
ists have developed an extraordinarily diverse array of
methods to synthesize enantiomerically enriched b-hydroxy-
a-amino acids. These may be divided into two broad
categories: constructive syntheses (as in the present work)
and nonconstructive syntheses. The latter include the Sharp-
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
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