91
5
Diastereoselective
and Enantioselective
Syntheses
Most of the syntheses presented in Chapters 1–4 generated achiral amino acids or
chiral, racemic amino acids. A few chiral, nonracemic amino acids were prepared,
but the purpose was to illustrate some specic point of a synthesis. Preparation of
non-α-amino acids using methods that proceed with high diastereoselectivity or
enantioselectivity is very important since any biological activity usually resides in a
single diastereomer, if not a single enantiomer (see Chapter 6 for biologically active
amino acids). The enantioselective methods presented will include the use of chiral
auxiliaries, chiral catalysts, or chiral templates (as dened by Hanessian).
1
5.1 α-AMINO ACID TEMPLATES
Chiral, nonracemic α-amino acids will be manipulated to produce chiral, nonra-
cemic non-α-amino acids. The fundamental premise was introduced in Chapter 1,
Section 1.4.1. Indeed, several of the synthetic methods discussed in previous chapters
will be used here, but the emphasis is on diastereoselectivity and enantioselectivity.
In many cases, the carboxyl portion of the amino acid starting material is con-
verted to an aldehyde, allowing subsequent reactions that are not available to carbox-
ylic acids. An example of this approach is the conversion of N-Boc alanine to N-Boc
alanol (1)
2
via conversion to the ester and reduction with lithium borohydride. The
next step will be a common feature of this and succeeding chapters. Oxidation of
the alcohol moiety in 1 to an aldehyde, in this case using SO
3
•pyridine in dimethyl
sulfoxide (DMSO),
3
allowed condensation with sodium cyanide to give a cyanohy-
drin. Hydrolysis of the nitrile moiety gave the N-Boc-protected corresponding amino
carboxylic acid, 2-hydroxy-3-aminobutanoic acid (2). Similarly, Boc-glycine led to
ethyl 2-hydroxy-3-aminobutanoate in about 84% yield.
2
1
(a) Hanessian, S. Total Synthesis of Natural Products: The “Chiron” Approach. Pergamon, 1983; (b)
Hanessian, S. Acc. Chem. Res. 1979, 12, 159; (c) Hanessian, S.; Franco, J.; Larouche, B. Pure Appl.
Chem. 1990, 62, 1887.
2
Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.; Etoh, Y.; Shimaoka, I.; Tsubaki, A.;
Murakami, M.; Yamaguchi, T.; Iyobe, A.; Umeyama, H.; Kiso, Y. Chem. Pharm. Bull. 1990, 38, 2487.
3
See Parikh, J.R.; von E. Doering, W. J. Am. Chem. Soc. 1967, 89, 5505.
92
Methods of Non-α-Amino Acid Synthesis, Second Edition
BocHN
CO
2
H
Me
BocHN
Me
BocHN
Me
CO
2
H
OH
OH
1. MeI, KHCO
3
DMF
2. NaBH
4
, LiCl
THF-Et
3
O
1. Py•SO
3
, DMSO
toluene
2. NaCN; HCl
3. HCl
12
70%
Olenation is another important reaction made possible by the presence of the
aldehyde moiety, and it extends the chain. With proper choice of the ylid in a Wittig
type reaction,
4,5
a new carboxyl moiety can be incorporated. A Horner-Wadsworth-
Emmons olenation
6,7
of N-Cbz alanal (3), for example, gave methyl 4-(N-Cbz
amino)pent-2-enoate (4) as a mixture of cis:trans isomers (>30:1).
8
A number of
other derivatives were prepared by using different amino acid starting materials.
CHO
CO
2
Me
NHCbzNHCbz
P
O
F
3
CH
2
CO
F
3
CH
2
CO
CO
2
Me
(Me
3
Si)
2
NK, –78°C
MeCN/THF, 18-crown-6
34
86%
A different synthetic route converted alanine to the diastereomeric mixture of
oxazolidin-2-ones, 5 and 6.
9
After separation of these diastereomers, oxidative cleav-
age of the alkene moiety in 5 (with RuCl
3
and NaIO
4
) led to 7 and basic hydrolysis
gave D-isothreonine (9).
10
L-Allo-threonine (10) was formed in a similar manner
from diastereomer 6, via 8.
CO
2
H
Me
H
2
N
Ph
N
O
O
H
Me
Ph
N
O
O
H
Me
HO
2
C
N
O
O
H
Me
HO
2
C
N
O
O
H
Me
HO
2
C
NH
2
Me
HO
2
C
NH
2
Me
OH
OH
+
RuCl
3
, NaIO
4
aq. MeOH
RuCl
3
, NaIO
4
aq. MeOH
5
6
7
8
9
10
KOH
KOH
4
(a) Wittig, G.; Rieber, M. Annalen 1949, 562, 187; (b) Wittig, G.; Geissler, G. Annalen 1953, 580, 44;
(c) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 87, 1318; (d) Gensler, W.J. Chem. Rev. 1957, 57, 191 (see
p. 218).
5
See (a) Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/London,
England, 2010, pp. 729–739; (b) Smith, M.B. March’s Advanced Organic Chemistry, 7th ed. John
Wiley & Sons, Hoboken, NJ, 2013, pp. 1165–1173.
6
(a) Horner, L.; Hoffmann, H.; Wippel, J.H.; Klahre, G. Ber. 1959, 92, 2499; (b) Wadsworth, W.S., Jr.;
Emmons, W.D. J. Am. Chem. Soc. 1961, 83, 1733; (c) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87.
7
See (a) Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/London,
England, 2010, pp. 739–744; (b) Smith, M.B. March’s Advanced Organic Chemistry, 7th ed. John
Wiley & Sons, Hoboken, NJ, 2013, pp. 1169–1170.
8
Kogen, H.; Nishi,T. J. Chem. Soc. Chem. Commun. 1987, 311.
9
Wolf, J.-P.; Pfander, H. Helv. Chim. Acta, 1986, 69, 918.
10
Wolf, J.-P.; Pfander, H. Helv. Chim. Acta, 1987, 70, 116.

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