Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide

Article abstract of DOI:10.1002/anie.201400928

β-Hydroxy-α-amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β-hydroxy- α-amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one-flask protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L- or D-threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes. On aldol: Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide (LiHMDS) in the presence of LiCl followed by addition of either an aldehyde or ketone substrate affords aldol addition products which are stereochemically homologous with L- or D-threonine, respectively. These products can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction.

Full text of DOI:10.1002/anie.201400928

Angewandte
Chemie
DOI: 10.1002/anie.201400928
Synthetic Methods
Stereocontrolled Synthesis of syn-b-Hydroxy-a-Amino Acids by Direct
Aldolization of Pseudoephenamine Glycinamide**
Ian B. Seiple, Jaron A. M. Mercer, Robin J. Sussman, Ziyang Zhang, and Andrew G. Myers*
Abstract: b-Hydroxy-a-amino acids figure prominently as
chiral building blocks in chemical synthesis and serve as
precursors to numerous important medicines. Reported herein
is a method for the synthesis of b-hydroxy-a-amino acid
derivatives by aldolization of pseudoephenamine glycinamide,
which can be prepared from pseudoephenamine in a one-flask
protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine
glycinamide with lithium hexamethyldisilazide in the presence
of LiCl followed by addition of an aldehyde or ketone
substrate affords aldol addition products that are stereochem-
ically homologous with l- or d-threonine, respectively. These
products, which are typically solids, can be obtained in
stereoisomerically pure form in yields of 55–98%, and are
readily transformed into b-hydroxy-a-amino acids by mild
hydrolysis or into 2-amino-1,3-diols by reduction with sodium
borohydride. This new chemistry greatly facilitates the con-
struction of novel antibiotics of several different classes.
enantiomeric forms on multigram scale from the appropriate
enantiomer of pseudoephenamine[2] and N-Boc glycine using
either one- or two-step protocols (the yields are effectively
the same; Scheme 1). The compound 1 is conveniently
recrystallized from absolute ethanol and forms a free flowing,
A
s part of a program to develop practical synthetic
chemistry for the discovery of new antibiotics we investigated,
and herein report, a two-step method for the constructive
assembly of enantiomerically pure syn-b-hydroxy-a-amino
acids from simple starting materials. These products figure
prominently as chemical precursors to a number of important
medicines, most notably antibiotics, as evidenced by the fact
that five of the compounds prepared in this study have been
transformed into antibiotics from four different structural
classes: amphenicols, monobactams, vancomycins, and mac-
rolides. The chemistry we describe offers a number of
practical advantages relative to existing methodology, which
we discuss after presentation of our results.
Scheme 1. Synthesis of pseudoephenamine glycinamide (1). Boc=tert-
butoxycarbonyl, Piv=pivaloyl, TFA=trifluoroacetic acid.
white crystalline solid (mp 168–1708C, 78% overall yield
employing the one-flask protocol followed by recrystalliza-
tion, 30-g scale). X-ray crystallographic analysis reveals that
the crystalline lattice is free of any solvent or water molecules.
Furthermore, unlike pseudoephedrine glycinamide,[3] in crys-
talline form 1 shows little or no propensity to hydrate upon
exposure to the air and thus is easily weighed and transferred
in the laboratory.
The basis of the new methodology stems from the
discovery that pseudoephenamine glycinamide (1) undergoes
efficient and diastereoselective syn aldolization with both
aldehyde and (remarkably) ketone substrates.[1] The key
precursor in this transformation, 1, is readily available in both
Enolization/syn-aldolization of 1 was readily achieved by
the following general protocol. Freshly (flame) dried anhy-
drous lithium chloride (saturating, ca. 7.8 equiv)[4] and
1 (1.3 equiv)[5] were combined at 238C in anhydrous THF
(ca. 0.15m in 1) and the resulting suspension was stirred at
238C until 1 dissolved; a portion of the excess LiCl did not
dissolve. The resulting suspension was cooled to ꢀ788C
whereupon a freshly prepared solution of lithium hexame-
thyldisilazide in THF (1m, 2.5 equiv) was added by syringe.
After stirring at ꢀ788C for 5 minutes, the reaction flask was
transferred to an ice-water bath for 25 minutes, then was re-
cooled to ꢀ788C where a solution of an aldehyde or ketone
substrate in THF (1m, 1 equiv) was added. The progress of the
aldol addition was conveniently monitored by TLC analysis.
Aldehyde reactants were typically completely consumed
within 30 minutes at ꢀ788C, whereas reactions with ketone
substrates proceeded more slowly and in certain cases
required warming to 08C to achieve complete conversion
(see Table 1 and the Supporting Information). In all cases
[*] Dr. I. B. Seiple, J. A. M. Mercer, R. J. Sussman, Z. Zhang,
Prof. Dr. A. G. Myers
Department of Chemistry and Chemical Biology
Harvard University, Cambridge, MA 02138 (USA)
E-mail: myers@chemistry.harvard.edu
[**] We gratefully acknowledge the NSF for partial financial support. We
express our gratitude to Dr. Shao-Liang Zheng for his exceptional
work in conducting X-Ray crystallographic analyses. J.A.M.M.
acknowledges Pfizer for financial support through the ACS SURF
program. I.B.S. acknowledges postdoctoral fellowship support from
the National Institutes of Health (F32M099233). Z.Z. is a Howard
Hughes Medical Institute International Student Research fellow.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400928.
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Table 1: Aldolization of pseudoephenamine glycinamide (1) with alde-
hyde and ketone substrates.
chemistries of the syn-aldol adducts 8 and 9 (from para-
nitrobenzaldehyde and para-methanesulfonylbenzaldehyde,
respectively) were rigorously established to form a homochi-
ral series with 4 on the basis of their successful conversion into
the active antibiotics chloramphenicol and thiamphenicol,
respectively (see below). Stereochemical assignments of the
remaining aldehyde addition products from Table 1 were
made by analogy. The stereochemistry of these products
conforms with the diastereofacial preferences for alkylation
reactions of pseudoephenamine amide enolates, provided
that a Z enolate (with the a-amino group and enolate oxygen
atom cis) is invoked, which seems to us to be quite
reasonable.[2b] The syn stereochemistry presumably arises
from a Zimmerman—Traxler transition structure.[8]
In addition to its general, efficient, and stereoselective
reactions with aldehyde substrates (linear, branched, and a-
tetrasubstituted aliphatic, aromatic, a-oxygenated, and a,b-
unsaturated), 1 also serves as an exceptional substrate for
aldolization with ketone substrates, thus providing aldol
adducts with fully substituted b-centers, as illustrated by the
seven examples (13–19) in Table 1. The stereochemistry of the
aldol adduct 16 (from methyl isopropyl ketone) was estab-
lished unambiguously by X-ray analysis of its crystalline
hydrate. Not surprisingly, it was found to be fully consistent
with the stereochemistry of the aldehyde aldol adducts (the
methyl group acts as the “small” group). We also rigorously
established the stereochemistry of the aldol adduct 18 by X-
ray analysis of a crystalline derivative, and this conformed to
that of the other aldol products. This product appears to
represent a case of stereochemical matching, where the
diastereofacial preferences of the enolate and the chiral
ketone substrate (the latter consistent with a Felkin–Anh
trajectory)[9] are reinforcing, thus accounting for the extra-
ordinarily high stereoselectivity and yield of this particular
transformation. The product 19 (55% yield upon isolation),
from methyl styryl ketone, was formed least efficiently, and
we believe it to be a consequence of competitive conjugate
addition (ca. 15%).
[a] Xf+ =(R,R)-pseudoephenamine. Reactions were run at a final con-
centration of 0.1m (electrophile) and were performed on at least
a 1 mmol scale. Yields of major isolated diastereomers are reported.
Diastereomeric ratios can be found in the Supporting Information.
[b] Reaction was run on a 20-g scale. Enolization was conducted at 08C,
and the final concentration of electrophile was 0.05m. HMDS=hex-
amethyldisilazide, TBDPS=tert-butyldiphenylsilyl, TIPS=triisopropyl-
silyl.
As a seemingly minor point, we note that careful analysis
1
of the H NMR spectra of the majority of the purified aldol
adducts from Table 1 reveals that in addition to the two
rotameric forms of the expected syn-aldol diastereomers,
trace (ꢁ 5%) amounts of an impurity corresponding to the
N!O-acyl transfer product, a b-amino ester, are present.[10]
This data reveals that the latter constitutional isomer is only
slightly higher in energy than the tertiary amide form, thus
providing a rationale for the remarkable facility of the
subsequent transformations of the direct aldol products,
namely their hydrolysis and reduction.
In contrast to reaction conditions typical for hydrolysis of
tertiary amides, hydrolysis of the aldol adducts of Table 1
proceeds under remarkably mild conditions, and are more
consistent with saponification of an ester than hydrolysis of
a tertiary amide (Table 2). For example, hydrolysis of 4 was
complete within 4 hours at 238C in the presence of 1 equiv-
alent of sodium hydroxide in 1:1 THF/methanol. Once
hydrolysis was complete, pseudoephenamine was recovered
by extraction with dichloromethane in quantitative yield (ꢂ
95% purity), and the alkaline aqueous solution was lyophi-
only one of the four possible diastereomeric aldol addition
products predominated (Table 1), and this product was
typically readily isolated in diastereomerically pure form by
flash column chromatography (55–98% yield of purified
product). The minor diastereomeric aldol addition product(s)
typically constituted less than 15% of the product mixture.[6,7]
As shown in Table 1, many different aldehydes and
ketones were found to be effective substrates. We observed
that the majority of the purified primary aldol products were
solids. In the case of the product 4 (from isobutyraldehyde)
crystals suitable for X-ray analysis were obtained. The solid-
state structure of 4 derived from (R,R)-1 revealed it to be the
syn-aldol product that is stereochemically homologous with
l-threonine. In addition, the absolute and relative stereo-
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Table 2: Mild alkaline hydrolysis of aldol adducts.[a]
Scheme 2. Esterification and N-Boc protection of amino carboxylates.
Alkaline hydrolysis conditions were not uniformly suc-
cessful with every substrate. In certain cases retroaldol
fragmentation was faster than hydrolysis, even when employ-
ing our optimal protocol. For example, treatment of the
ketone aldol adduct 17 with 1 equivalent of sodium hydroxide
in 1:1 methanol/water at 238C provided primarily three
products: acetophenone, pseudoephenamine, and sodium
glycinate (the latter two products presumably result from
hydrolytic cleavage of 1). None of the desired b-hydroxy-a-
amino sodium carboxylate was observed.[13] We envisioned
that retroaldol fragmentation would be avoided if the b-
hydroxy substituent were shielded, and for this purpose we
chose a cyclic carbamate, which can easily be introduced and
removed[14] under very mild reaction conditions and has the
added benefit of protecting the a-amino function. Treatment
of the aldol adduct 17 with phosgene (1.1 equiv) and
diisopropylethylamine (3 equiv) at ꢀ788C in dichlorome-
thane formed, within 30 minutes, the cyclic carbamate 28,
which was isolated in pure form by simple biphasic extraction
(Scheme 3). Although 28 was resistant to alkaline hydrolysis
[a] (R,R)-Pseudoephenamine was recovered in ꢂ90% yield in each case
in high purity. Yields are those of the isolated product. Enantiomeric
purity was determined by 1H NMR analysis of the (R)- and (S)-MTPA
amides. For experimental details, see the Supporting Information.
lized to provide the b-hydroxy-a-amino sodium carboxylate
22 in 92% yield and greater than 98% ee (Table 2). The
inclusion of methanol was critical to avoid retroaldol frag-
mentation during the hydrolysis, which was otherwise facile,
especially with aromatic aldol addition products. In a note-
worthy example, use of the THF/methanol/sodium hydroxide
protocol with substrate 10 afforded the aromatic aldolate 25
in 94% yield and greater than 98% ee (auxiliary recovery:
97% yield). A protected form of the latter a-amino acid
served as a key starting material in the synthesis of
vancomycin as reported by the Nicolaou group.[11]
Interestingly, the present hydrolysis conditions are much
milder than those required for hydrolysis of pseudoephe-
drine[10] and pseudoephenamine[2b] amide alkylation products,
thus suggesting that the b-hydroxy group of the aldol adducts
may facilitate N!O-acyl transfer. In this regard, it is notable
(though not surprising) that X-ray crystallographic analysis
(structures 4 and 16) reveals an internal hydrogen bond
between the amide carbonyl groups and their b-hydroxy
functions. We believe that facile hydrolysis (and reduction) of
pseudoephenamine amide aldol products occurs by rapid N!
O-acyl transfer and subsequent saponification (reduction) of
the resulting b-amino ester, as we have previously proposed
for alkaline hydrolyses of pseudoephedrine amides.[10]
Scheme 3. Cyclic carbamate formation followed by hydrolysis under
neutral conditions affords protected a-amino acid derivatives.
Xf+ =(R,R)-pseudoephenamine. [a] Product contained ꢁ8% TBDPS-
OH after aqueous extraction.
The a-amino sodium carboxylates obtained upon alkaline
hydrolysis can be converted into a-amino acid methyl esters
upon exposure to acidic methanol (e.g., 20!26; Scheme 2).
Alternatively, treatment of the same substrates with di-tert-
butyldicarbonate affords N-Boc-protected amino acids in
high yield (e.g., 23!27; Scheme 2). The N-Boc a-amino acid
27 is noteworthy for it serves as precursor to the fully
synthetic monobactam antibiotic BAL30072, which is cur-
rently in phase I clinical trials as an anticipated treatment for
infections caused by Gram-negative bacteria.[12]
(presumably because of the acidity of the carbamate function)
we found that heating a solution of 28 in a 1:1 mixture of 1,4-
dioxane and pure water at reflux for 24 hours effected clean
hydrolysis of the auxiliary. Straightforward acid-base extrac-
tion then provided the acid 29 in 85% yield (and, separately,
pseudoephenamine in 97% yield). By an analogous sequence,
treatment of 18 with phosgene provided the carbamate 30
(the stereochemistry of which was rigorously established by
X-ray crystallography). This intermediate has been trans-
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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
ꢀ
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-
4
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[5] Pseudoephenamine glycinamide (1) can also be used as the
nine aldolases which, while highly stereoselective for certain
aldehyde substrates, is limited in scope.[47]
limiting reagent, with a moderate decrease in yield: aldolization
of 1 (1.0 equiv) with benzaldehyde (1.2 equiv) provided pure 7 in
65% yield (standard conditions provided the product in 80%
yield).
Aldolization of pseudoephenamine glycinamide offers
a number of advantages. Enolization of 1 proceeds under very
mild conditions (LiHMDS, LiCl) without metal additives, and
the syn-aldol products are readily obtained in stereoisomeri-
cally pure form by column chromatography. A broad
selection of electrophiles, including alkyl and aryl aldehydes
and ketones, undergo efficient aldolization with 1, whereas
many other glycine equivalents react efficiently only with aryl
or alkyl aldehydes, and very few are reported to react
efficiently with ketones.[48] With the exception of chemo-
enzymatic approaches,[47] the aforementioned glycine equiv-
alents all require shielding of the a-amino group, but this is
not necessary with our method. Hydrolysis of the aldol
adducts of 1 proceeds under unusually mild reaction con-
ditions compared to other glycine equivalents, and both the
product and the auxiliary can be isolated by straightforward
biphasic extraction. Additionally, reduction of pseudoephen-
amine glycinamide aldol adducts to the corresponding
primary alcohols can be accomplished with the mild reducing
agent sodium borohydride. We believe pseudoephenamine
glycinamide (1) is an exceedingly practical reagent for the
synthesis of b-hydroxy-a-amino acids and chiral 2-amino-1,3-
diols, and anticipate the methods reported herein will have
broad applicability in chemical synthesis.
[6] These minor products were not readily separated and therefore
were not carefully studied, with the exception of the minor
adducts from symmetric ketone substrates (13–15). See the
Supporting Information for further details.
[7] Interestingly, we observed that aldol addition reactions of
pseudoephedrine glycinamide (Ref. [3]) were inferior to those
of pseudoephenamine glycinamide (1). For example, the yield of
the isoalted major syn-aldol adduct of pseudoephedrine glyci-
namide and benzaldehyde was just 57% (d.r. 72% desired:28%
sum of minor isomers) whereas the parallel transformation with
1 gave an 80% yield of pure syn-aldol product (dr 85%
desired:15% sum of minor isomers).
[8] a) H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
1920 – 1923; b) D. A. Evans, Aldrichimica Acta 1982, 15, 23 – 32.
[9] By contrast, the mismatched combination of the enolate from
(S,S)-1 and the same chiral ketone that led to 18 was poorly
selective, thus affording a 52:25:15:8 mixture of diastereomeric
aldol adducts which was not characterized in detail.
[10] We have previously proposed N!O-acyl transfer products as
important intermediates in both acidic and alkaline hydrolyses
of pseudoephedrine amides. See Ref. [3b] and the following
paper: A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J.
Kopecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496 – 6511.
[11] K. C. Nicolaou, C. N. C. Boddy, H. Li, A. E. Koumbis, R.
Hughes, S. Natarajan, N. F. Jain, J. M. Ramanjulu, S. Brase,
M. E. Solomon, Chem. Eur. J. 1999, 5, 2602 – 2621.
Received: January 27, 2014
[12] M. Hornsey, L. Phee, W. Stubbings, D. W. Wareham, Int. J.
Antimicrob. Agents 2013, 42, 343 – 346.
Published online: && &&, &&&&
[13] Attempts to hydrolize substrate 17 with alkaline hydrogen
peroxide or under acidic conditions were not successful.
[14] a) M. E. Jung, Y. H. Jung, Tetrahedron Lett. 1989, 30, 6637 –
6640; b) G. M. C. Di, D. Misiti, G. Zappia, M. G. Delle,
Tetrahedron 1993, 49, 11321 – 11328; c) L. Williams, Z. Zhang,
X. Ding, M. M. Joullie, Tetrahedron Lett. 1995, 36, 7031 – 7034;
d) M. G. Delle, G. M. C. Di, D. Misiti, G. Zappia, Tetrahedron:
Asymmetry 1997, 8, 231 – 243; e) T. Laꢁb, J. Chastanet, J. Zhu,
Tetrahedron Lett. 1997, 38, 1771 – 1772; f) C. Tomasini, A.
Vecchione, Org. Lett. 1999, 1, 2153 – 2156.
Keywords: aldol reaction · amino acids · asymmetric synthesis ·
chiral auxiliaries · synthetic methods
.
[1] Aldol addition reactions of pseudoephedrine amides (but not
glycine amides) are well precedented. See: a) J. L. Vicario, D.
Badꢀa, E. Domꢀnguez, M. Rodrꢀguez, L. Carrillo, J. Org. Chem.
2000, 65, 3754 – 3760; b) J. L. Vicario, M. Rodrꢀguez, D. Badꢀa, L.
Carrillo, E. Reyes, Org. Lett. 2004, 6, 3171 – 3174; c) M.
Rodrꢀguez, J. L. Vicario, D. Badꢀa, L. Carrillo, Org. Biomol.
Chem. 2005, 3, 2026 – 2030; d) M. Ocejo, L. Carrillo, J. S. Vicario,
D. Badꢀa, E. Reyes, J. Org. Chem. 2011, 76, 460 – 470; e) B. R.
Kusuma, G. E. L. Brandt, B. S. J. Blagg, Org. Lett. 2012, 14,
6242 – 6245.
[2] a) For practical, scalable syntheses of (R,R)- and (S,S)-pseudoe-
phenamine, see: K. T. Mellem, A. G. Myers, Org. Lett. 2013, 15,
5594 – 5597; b) For the alkylation of pseudoephenamine amides,
see: M. R. Morales, K. T. Mellem, A. G. Myers, Angew. Chem.
2012, 124, 4646 – 4649; Angew. Chem. Int. Ed. 2012, 51, 4568 –
4571; c) For the synthesis and alkylation of pseudoephenamine
alaninamide pivaldimine, see: C. L. Hugelshofer, K. T. Mellem,
A. G. Myers, Org. Lett. 2013, 15, 3134 – 3137.
[15] I. B. Seiple, Z. Zhang, A. Langlois, K. Yabu, P. M. Wright, M.
´
Condakes, F. Szczypinski, A. G. Myers, unpublished results.
[16] Word Health Organization Model List of Essential Medicines,
18th
edition:
http://www.who.int/medicines/publications/
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6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
I. B. Seiple, J. A. M. Mercer,
R. J. Sussman, Z. Zhang,
A. G. Myers*
&&&& — &&&&
Stereocontrolled Synthesis of syn-b-
Hydroxy-a-Amino Acids by Direct
Aldolization of Pseudoephenamine
Glycinamide
On aldol: Enolization of (R,R)- or (S,S)-
pseudoephenamine glycinamide with
lithium hexamethyldisilazide (LiHMDS)
in the presence of LiCl followed by
addition of either an aldehyde or ketone
substrate affords aldol addition products
which are stereochemically homologous
with l- or d-threonine, respectively. These
products can be obtained in stereoiso-
merically pure form in yields of 55–98%,
and are readily transformed into b-hy-
droxy-a-amino acids by mild hydrolysis or
into 2-amino-1,3-diols by reduction.
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!