Enantiopure β3-neopentylglycine: synthesis and resolution

Article abstract of DOI:10.1016/j.tetasy.2009.01.018

A procedure has been developed for the large scale synthesis of enantiopure β³-neopentylglycine and its Cbz-protected derivative. The synthetic route developed in our laboratory features Cbz-protection of the racemic β-amino acid followed by resolution with l-norephedrine and provides the enantiomerically pure Cbz-β-neopentylglycine in good yield and excellent enantiopurity. No toxic or dangerous chemicals are used, allowing the scale-up of this procedure without major safety concerns.

Full text of DOI:10.1016/j.tetasy.2009.01.018

Tetrahedron: Asymmetry 20 (2009) 478–482
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiopure b3-neopentylglycine: synthesis and resolution
a
b
a
b
Matthijs K. J. ter Wiel a, , Mirjam Arnold , Sandra Peter , Ingo Troltsch , Stefan Merget ,
Florian Glaser b, Michael Schwarm a, Harjinder S. Bhatti c, Biju Kuriakose c, Suryakant S. Pol c,
Mohanasundaram Balamurugan c, Viral V. Joshi c
*
a Evonik Degussa GmbH, R&D Exclusive Synthesis and Amino Acids, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
b AQura GmbH, Organic Analysis and Chromatography, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany
c Evonik Degussa India Pvt. Ltd, Krislon House, Saki Vihar Road, Saki Naka, Mumbai 400072, India
a r t i c l e i n f o
a b s t r a c t
A procedure has been developed for the large scale synthesis of enantiopure b3-neopentylglycine and its
Cbz-protected derivative. The synthetic route developed in our laboratory features Cbz-protection of the
racemic b-amino acid followed by resolution with L-norephedrine and provides the enantiomerically pure
Cbz-b-neopentylglycine in good yield and excellent enantiopurity. No toxic or dangerous chemicals are
used, allowing the scale-up of this procedure without major safety concerns.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 7 January 2009
Accepted 21 January 2009
Available online 13 February 2009
1. Introduction
literature concerning large-scale preparative procedures. Histori-
cally, many of the b-amino acids have been prepared by the
a
-Amino acids dominate life on a molecular level, as they are
Arndt–Eistert homologation sequence using the highly toxic and
dangerous diazomethane. Since then, a large number of different
approaches have been established for the synthesis of enantiome-
rically pure b-amino acids, the most successful being the asym-
metric hydrogenation of dehydroamino acid derivatives,5–9 the
asymmetric conjugate addition of nitrogen nucleophiles10 and
the enzymatic resolution of ester-11,12 or amide-derivatives.13
Furthermore, over the past few years, organocatalysed reactions
have become increasingly successful, and a number of reports
describing approaches towards b-amino carbonyl compounds
have appeared.14–19 Although organocatalysis sometimes suffers
from relatively inaccessible ligands, long reaction times and dilute
conditions, it is becoming more attractive and efficient. More
‘classical’ approaches towards b-amino acids and their derivatives
involve syntheses with, for example, chiral Lewis acids and chiral
auxiliaries.20–29 The majority of these routes suffer from long syn-
thetic sequences, expensive chemicals, long reaction times and
protecting groups that are difficult to remove. Despite all efforts,
there have until now been no general routes found for large-scale
preparations of b-amino acids. We became interested in b3-
neopentylglycine, which we considered useful as a potential
building block for physiologically active compounds due to its
sterically demanding and lipophilic tert-butyl substituent. How-
ever, the lipase resolution protocol, which has been found to be
very useful for the resolution and large-scale manufacture of aro-
matic b3-amino acids, could not be applied to the synthesis of b3-
neopentylglycine as attempted enzymatic resolution afforded
only racemic material. We therefore concentrated our efforts on
the synthesis of this aliphatic b3-amino acid via the formation
of diastereomeric salts.
the basic structural components of enzymes and proteins. On a
macroscopic scale,
industry on enormous scales and are of immense economic impor-
tance; for example, as food supplements, feed additives and build-
ing blocks for active pharmaceutical ingredients.
a-amino acids are produced by the chemical
Compared to
a-amino acids, the use of b-amino acids is very
low. However, interest in b-amino acids is steadily increasing, as
can be seen from the large number of investigations concerning
the chemistry and properties of b-amino acids, b-peptides and
their derivatives.1,2 In Nature, b-amino acids and b-peptides are
not uncommon compounds. In fact, some b-amino acids, such as
b-alanine, occur relatively often in naturally occurring peptides.
Well known classes of natural products, which are important be-
cause of their antibiotic activity, are the penicillins and the cepha-
losporins, both contain a b-lactam ring in their structures. Another
natural compound containing a b-amino acid moiety is the anti-
cancer drug Taxol.
Apart from the naturally occurring substances, the pharmaceu-
tical industry has investigated and developed a number of physio-
logically active compounds which incorporate a b-amino acid
residue. Examples include Sitagliptin phosphate3 (JanuviaTM
,
Merck & Co.) for treatment of type 2 diabetes and the peptide
deformylase inhibitor LBM415 (Novartis).4
Despite the increased interest in b-amino acids, b-peptides and
their derivatives, only limited information can be found in the
* Corresponding author. Tel.: +49 62218653685; fax: +49 6221869706.
E-mail address: matthijs.ter.wiel@evonik.com (M.K.J. ter Wiel).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.018

M. K. J. ter Wiel et al. / Tetrahedron: Asymmetry 20 (2009) 478–482
479
bility to form diastereomerically pure salts. Relatively early on, it
became clear that the best results were obtained using commer-
2. Results and discussion
cially available
L
-(ꢀ)-norephedrine and (R)-phenylethylamine.
For a synthesis to be applied on an industrial scale, the chemis-
try of choice should be safe, easy to perform and not involve any
hazardous or toxic chemicals. Moreover, raw materials should be
cost-attractive and readily available, and the number of steps and
isolations should be limited as much as possible. With these con-
siderations in mind, we started our investigations towards the syn-
thesis of enantiomerically pure b3-neopentylglycine via
diastereomeric resolution.30
There are many good reasons to opt for diastereomeric resolu-
tion. Diastereomeric resolutions can be performed on a large scale
and are generally robust and safe processes. The resolving agent
can, after re-isolation and purification, be used for new resolutions
and does not need to be discarded. Moreover, the undesired enan-
tiomer can often be racemised after the resolution and resolved
again, if economically attractive.
The resolution of diastereomers has become a well known
method since the first resolution experiments by Pasteur,31 and
has been used many times for a large number of compounds.32
Although commonly used in practice, such resolutions have re-
ceived considerably less attention in the literature. Detailed inves-
tigations to find the rationale behind diastereomeric resolutions
were undertaken by Collet in the 1980’s.33,34 Nevertheless, the
development of new methodologies for diastereoselective salt for-
mation has remained a topic of considerable interest, as shown by
the work on ‘Dutch resolution’ by Kellogg et al.35 For the investiga-
tions presented herein, we also deviated slightly from the ‘classical’
conditions by using only half an equivalent of the resolving agent
for economic reasons.
Compared with other frequently used resolving agents, these bases
offer the additional advantages that they have relatively low
molecular weights (compared with e.g., quinine), are non-toxic
(compared with e.g., strychnine and brucine) and that both enanti-
omers are readily available.
It should be noted that in almost all cases, no salt formation oc-
curred in polar solvents such as water, ethanol, iso-propanol or
acetone. We therefore concentrated on apolar solvents such as tol-
uene, ethers and esters. In order to have a closer look at the phys-
ical properties of the salts, experiments were performed using
10.0 g of rac-Cbz-b3-neopentylglycine. The results of these experi-
ments using half an equivalent of (R)-phenylethylamine in various
solvents are depicted in Table 1.38
Table 1
Results of the resolution of rac-Cbz-b3-neopentylglycine with (R)-phenylethylamine
Solvent
Yielda
Yieldb
Ratio (R):(S)
Diastereomeric excess
S-factor
n-BuOAc
EtOAc
Toluene
MiBK
IPAc
MTBE
THF
57.7
78.7
69.1
80.3
83.1
97.4
74.6
26.9
39.4
34.6
40.2
41.6
48.8
37.3
85.2
85.7
87.7
81.9
84.4
73.0
86.4
14.8
14.4
12.4
18.2
15.6
27.0
13.6
70.4
71.3
75.3
63.7
68.8
46.0
72.8
0.41
0.56
0.52
0.51
0.57
0.45
0.54
a
Yields based on (R)-phenylethylamine.
Yields based on Cbz-b3-neopentylglycine.
b
Although these results appeared to be quite promising, a subse-
quent recrystallisation of the diastereomerically enriched salt
would probably not be sufficient to give diastereomerically pure
material. Furthermore, it was noticed that the salt pair formed with
(R)-phenylethylamine was difficult to filter and wash and, there-
fore, was likely to give problems during centrifugation on a large
scale.
In the first step of our synthesis, we condensed malonic acid,
pivaldehyde and ammonium acetate in ethanol to give the racemic
b-amino acid according to the so-called Rodionov synthesis, as de-
picted in Scheme 1.36
O
NH2 O
NH4OAc
+
Similarly, experiments using
L
-(ꢀ)-norephedrine as the resolv-
HO2C
CO2H
OH
ing base were performed using 10.0 g of rac-Cbz-b3-neopentylgly-
cine. Although the product was similarly fluffy, it was more
easily filtered and could be washed without problems. However,
it required extended drying times at 50 °C. The results of these res-
olution experiments are shown in Table 2.38
EtOH, 36%
O
Cbz-Cl, toluene
O
NH
O
water, NaOH, 78%
OH
Table 2
Results of the resolution of rac-Cbz-b3-neopentylglycine with L-(ꢀ)-norephedrine
Scheme 1. Synthesis of racemic, Cbz-protected b3-neopentylglycine.
Solvent
Yielda
Yieldb
Ratio (R):(S)
Diastereomeric excess
S-factor
Theyieldof 36%wassomewhatlow, due tothetediousseparation
of the b-amino acid from acetate, malonate and ammonium salts.
Once pure, the racemic b-amino acid was protected with Cbz-chlo-
ride under Schotten–Baumann conditions in 78% yield. The Cbz-
groupwas chosenas theprotectivegroup forthe aminefunctionality
asitcanberemovedeasilybycatalytichydrogenationandaftercom-
pletion of the reaction and separation of the catalyst no undesired
by-products remain in the reaction mixture. Moreover, the Cbz-
group is a good chromophore, which facilitates analysis by HPLC
and provides an analytical handle for the molecule. Both the synthe-
sis of rac-b3-neopentylglycine and its Cbz-protection were con-
ducted on multi-kilogram scales. Having protected the amine
moiety, the carboxylic acid functionality can be used for the forma-
tion of diastereomeric salts with a chiral base. For the assignment of
the correct stereochemistry, we prepared enantiopure (R)-b3-
Toluene
MTBE
IPAc
EtOAc
MiBK
75.4
84.5
62.2
61.6
51.3
60.7
37.8
42.3
31.1
30.8
25.7
32.6
4.3
23.0
3.7
4.9
4.9
95.7
77.0
96.3
95.1
95.1
93.8
91.4
54.0
92.6
90.3
90.3
87.7
0.69
0.46
0.58
0.56
0.46
0.53
nBuOAc
6.2
a
Yields based on
L
-(ꢀ)-norephedrine.
b
Yields based on rac-Cbz-b3-neopentylglycine.
As the experiments using
L
-(ꢀ)-norephedrine and toluene gave
the best overall results, with respect to yields and purities, it was
decided to focus on this particular combination of reagent and sol-
vent. Various experiments performed on larger scales afforded the
salt pair in around 74% yield and with diastereomeric ratios (R):(S)
ca. 2.5:97.5 and S-factors of around 0.70–0.74. Yields could be im-
proved further by addition of 0.55 equiv of
L
-(ꢀ)-norephedrine in-
neopentylglycine from Cbz-L-tert-leucine through an Arndt–Eistert
stead of 0.5 equiv. Based on the amount of rac-Cbz-b-
neopentylglycine employed, yields improved from 37% to 41%,
while the diastereoselectivity of the salt formation remained
unchanged. Although various other experiments were performed
homologation sequence to function as a reference with defined ste-
reochemistry during our resolution experiments.37
In an initial screening, various chiral amines (e.g., b-amino alco-
hols, phenylethylamines, norephedrine) were tested for their capa-

480
M. K. J. ter Wiel et al. / Tetrahedron: Asymmetry 20 (2009) 478–482
O
O
OH
OH
see Table 2
O
NH
O
O
NH
O
+
for results
NH2
NH3
OH
O
O
NH2
O
Pd/C, H2,
extraction
95.9%
O
NH
O
OH
ethanol, water,
94.1%
OH
Scheme 2. Resolution of racemic Cbz-b3-neopentylglycine and hydrogenation of the enantiomerically pure derivative to obtain enantiomerically pure (S)-b3-
neopentylglycine.
using different concentrations of the amino acid or amounts of the
resolving agent, these did not result in substantial further improve-
ments with respect to the selectivity of the salt formation or the
yield of the product. Diastereomerically pure material was there-
fore obtained by recrystallisation of the salt, for which a mixture
of toluene and ethanol proved to be best. During the recrystallisa-
tion, a small amount of the material was lost, ranging typically
from 5% to 10% of the initially isolated material.
nium acetate (6.60 kg, 85.7 mol). The reaction mixture was heated
for 16 h at 80 °C and cooled to room temperature. Filtration of the
reaction mixture and washing of the cake with a small amount of
ethanol (0.8 l) were followed by the removal of the volatiles by dis-
tillation under reduced pressure at 80 °C. The subsequent residue
was slurried in ethyl acetate (76 l), filtered and washed with a sec-
ond amount of ethyl acetate (11.5 l). The cake was reslurried in
acetone (52 l) and filtered. The residue was then dissolved in a
hot (75 °C) mixture of ethanol (18.3 l) and water (4.8 l). After cool-
ing to room temperature, the solids were isolated to give a first
crop of crude product (3.2 kg). The filtrate was concentrated under
reduced pressure and cooled to give a second crop (0.45 kg). At this
point, the crude products still contained some malonic acid. There-
fore, the whole was taken up in hot ethanol. After cooling, the solid
was isolated by filtration and was dried to give 3-amino-4,4-dim-
ethylpentanoic acid (2.77 kg, 18.6 mol, 36.1%) as a white crystal-
line solid. A small sample was recrystallised from a mixture of
acetone, ethanol and water for analytical purposes; 1H NMR
(500 MHz, DMSO-d6 + HCl) d: 0.91 (s, 9H, t-Bu), 2.44 (dd; J = 17.7,
The (S)-Cbz-b-neopentylglycine was liberated from its salt by
extraction of the
while the amino acid derivative was taken up in ethyl acetate. This
step proceeded without any significant loss. Re-isolation of
-(ꢀ)-
L-(ꢀ)-norephedrine into an acidic water layer
L
norephedrine was not investigated at this point. Subsequent cleav-
age of the Cbz-group using a Pd–C catalyst under a hydrogen atmo-
sphere was achieved without any problems, as is depicted in
Scheme 2. The free enantiomerically pure b-amino acid was iso-
lated as a white solid in high yields and in high enantiomeric pur-
ity, and no racemisation of the chiral centre was observed, as
determined by GC.38
0
7.7 Hz; 1H; H2), 2.64 (dd, J = 17.7, 4.4 Hz, 1H, H2 ), 3.18–3.25 (m,
1H, H3), 7.98 (s, 3H, NH3þ); 13C NMR (125 MHz, DMSO-d6 + HCl) d:
26.1 (q), 33.4 (t), 34.0 (s), 56.5 (d), 172.6 (s); IR (KBr), kꢀ1 (cmꢀ1):
3398, 2960, 1582, 1559, 1396.
3. Conclusion
Herein, we have demonstrated that enantiomerically pure (S)-b-
neopentylglycine can be obtained efficiently by resolution of its Cbz-
derivative with
easy access to both enantiomers of b-neopentylglycine, as both
(+)- and
-(ꢀ)-norephedrine are commercially available. Although
L
-(ꢀ)-norephedrine. This methodology allows for
4.2. rac-3-Benzyloxycarbonylamino-4,4-dimethylpentanoic
acid; rac-Cbz-b3-neopentylglycine
D-
L
the emphasis has been on synthesis of the enantiomerically pure
b-amino acids, the (S)-Cbz-b-neopentylglycine itself, obtained after
the resolution, could be of even more interest. As its amine function-
ality is already protected, it could serve directly as a building block
for the construction of new b3-peptides or other pharmaceutically
active compounds using well-established peptide chemistry.
All reactions have been performed on a multi-gram, while at
other times early in the synthetic sequence, on a multi-kilogram
scale. No particularly dangerous, unstable or toxic chemicals were
used, which allows a safe transfer of this procedure to production
scale. All chemicals used in this synthesis are readily available in
commercial quantities.
Racemic b-neopentylglycine (3.5 kg, 24.1 mol) was dissolved in
water (18.2 l) and the pH of the solution was adjusted to 11 with con-
centrated NaOH (50% in water). At 0 °C, a 50% solution of Cbz-chloride
(9.6 kg, 28.2 mol) in toluene was added while maintaining the pH of
the solution between 10.5 and 11.5 with 50% sodium hydroxide. After
the reaction was complete, the toluene layer was separated and the
aqueous layer was washed with toluene (3 ꢁ 6 l). Acidification of
the aqueous layer with aq. HCl (32%, 4.0 l) to pH 2 resulted in the sep-
aration of some solids that were extracted with two portions of tolu-
ene (17 and 14 l). The organic layer was isolated, and toluene was
removed under reduced pressure. Water (25 l) was added to the res-
idue and heating was continued to distill off all toluene. The cake iso-
lated after cooling of the mixture was reslurried in water (20 l) and
stirred for 6 h. The final product (5.23 kg, 18.7 mol, 77.6%) was ob-
tained as a white solid after drying at 80 °C under reduced pressure;
1H NMR (500 MHz, DMSO-d6) d: 0.83 (s, 9H, t-Bu), 2.18 (dd, J = 15.3,
This resolution represents, to the best of our knowledge, the
only example of a resolution of an aliphatic b-amino acid reported
in the literature.
4. Experimental
0
10.7 Hz, 1H, H2), 2.46 (dd, J = 15.3, 3.0 Hz, 1H, H2 ), 3.72–3.82 (m,
1H, H3), 4.99 (d, J = 12.7 Hz, 1H, Hbenzyl), 5.03 (d, J = 12.7 Hz, 1H,
4.1. rac-3-Amino-4,4-dimethylpentanoic acid; rac-b-
neopentylglycine
0
Hbenzyl ), 6.80 (d, J = 9.6 Hz, 1H, NHminor rotamer), 7.14 (d, J = 9.6 Hz,
1H, NHmajor rotamer), 7.25–7.39 (m, 5H, arom.); 13C NMR (125 MHz,
DMSO-d6) d 26.6 (q), 35.2 (t), 35.8 (s), 56.7 (d), 65.3 (t), 127.8 (d),
128.0 (d), 128.7 (d), 137.8 (s), 156.4 (s), 173.5 (s); IR (KBr), kꢀ1
(cmꢀ1): 3320, 2966, 1730, 1697, 1544, 1260, 1058, 697.
A 50 l vessel was charged with ethanol (33.8 l), malonic acid
(5.55 kg, 53.3 mol), pivaldehyde (4.56 kg, 52.9 mol) and ammo-

M. K. J. ter Wiel et al. / Tetrahedron: Asymmetry 20 (2009) 478–482
481
4.3. (S)-3-Benzyloxycarbonylamino-4,4-dimethylpentanoic
acid,
-(ꢀ)-Norephedrine salt
(160 ml) and water (40 ml) and filled into an autoclave. Palladium
on carbon (1.0 g, 5%) was added, and the mixture was flushed three
times with hydrogen. The reaction mixture was left to stir at 50 °C
for 24 h under 10 bar hydrogen. The catalyst was removed by fil-
tration, leaving a colourless solution. Removal of all volatiles left
the enantiomerically pure amino acid as a white solid (9.77 g,
67.4 mmol, 94.1%); The shifts in the 1H and 13C NMR spectra were
L
Racemic Cbz-protected b-neopentylglycine (150 g, 537 mmol)
was suspended in toluene (1.5 l). This mixture was heated to 80–
90 °C and
L-(ꢀ)-norephedrine (44.7 g, 296 mmol, 0.55 equiv) was
added to the slightly turbid solution as a solid. The resulting solu-
tion was allowed to reach room temperature in 4 h and was then
cooled in an ice bath for 1 h. The solids were filtered off, washed
with cold toluene (2 ꢁ 100 ml) and dried at 50 °C under reduced
pressure. It should be noted that complete removal of all the tolu-
ene can take up to 2 days. The dried solid was weighed (95.3 g,
221 mmol, 41.2%) and analysed by HPLC (ratio (R):(S) = 2.8:97.2).
In order to obtain a diastereomerically pure product, the product
was recrystallised from a mixture of toluene (720 ml) and ethanol
(190 ml). The salt dissolved at close to 100 °C in the solvent mix-
ture and was heated at reflux for 20 min. On cooling to room tem-
perature over ca. 3 h, a fluffy solid formed. After further cooling in
an ice bath and stirring for an additional hour, the solids were iso-
lated by filtration and then dried at 50 °C to give the diastereomer-
ically pure product as a fluffy solid (83.9 g, 194 mmol, 36.1%); 1H
NMR (500 MHz, DMSO-d6) d: 0.83 (s, 9H, t-Bu, b-AA), 0.86 (d,
identical to those reported for the racemate above; ½a D20
¼ ꢀ67:7 (c
ꢂ
1, H2O). The determination of the enantiomeric purity was per-
formed by GC using a Chirasil Dex CB column. Sample preparation:
2.5 mg of the sample was treated with 500 ll 3 M hydrochloric
acid in ethanol (prepared by mixing 37 ml of ethanol and 10 ml
of acetyl chloride) for 45 min at 110 °C. All solvents were removed
in a nitrogen stream and the residue was subsequently treated
with a mixture of 200
tic acid anhydride for 10 min at 110 °C. After removal of all vola-
tiles, the remaining material was dissolved in 150 l of toluene
ll dichloromethane and 200 ll trifluoroace-
l
and analysed. Temperature program: 70 °C for 1 min then an in-
crease of 3 °C minꢀ1 until 160 °C; then at 160 °C for 1 min; sample
volume 0.2 ll; hydrogen gas as mobile phase; split 70:1; The enan-
tiomeric purity of the sample proved to be 99.9% for the (S)-enan-
tiomer; IR (KBr), kꢀ1 (cmꢀ1): 2966, 1639, 1494, 1464, 1387, 1146.
J = 6.5 Hz, 3H, Me,
L
-nor.), 2.13 (dd, J = 15.0, 9.6 Hz, 1H, H2, b-AA),
0
2.34 (dd, J = 15.0, 3.5 Hz, 1H, H2 , b-AA), 3.02–3.12 (m, 1H, H2,
nor.), 3.68–3.82 (m, 1H, H3, b-AA), 4.56 (d, J = 4.2 Hz, 1H, H1,
L
-
-
References
L
nor.), 4.95 (d, J = 12.7 Hz, 1 H, Hbenzyl, b-AA), 5.02 (d, J = 12.7 Hz,
1. For an excellent review the reader is referred to: Juaristi, E.; Soloshonok, V. A.
In Enantioselective Synthesis of b-Amino Acids; Wiley-Interscience: New Jersey,
ISBN 0-471-46738-3, 2005.
2. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219–
3232.
3. Kim, D.; Kowalchick, J. E.; Brockunier, L. L.; Parnee, E. R.; Eiermann, G. J.; Fisher,
M. H.; He, H.; Leiting, B.; Lyons, K.; Scapin, G.; Patel, S. B.; Petrov, A.; Pryor, K.
D.; Roy, R. S.; Wu, J. K.; Zhang, X.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.;
Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2008, 51, 589–602.
4. Slade, J.; Parker, D.; Girgis, M.; Mueller, M.; Vivelo, J.; Liu, H.; Bajwa, J.; Chen, G.-
P.; Carosi, J.; Lee, P.; Chaudhary, A.; Wambser, D.; Prasad, K.; Bracken, K.; Dean,
0
1H, Hbenzyl , b-AA), 6.83 (d, J = 9.6 Hz, 1H, NHminor rotamer, b-AA),
7.20–7.38 (m, 11H, arom., 5H b-AA, 5H
13C NMR (125 MHz, DMSO-d6) d: 16.1 (q,
35.4 (t, b-AA), 37.0 (s, b-AA), 50.2 (d, -nor.), 57.0 (d, b-AA), 65.2
(t, b-AA), 75.4 (d, -nor.), 126.7 (d, -nor.), 127.1 (d, -nor.), 127.8
(d, b-AA), 127.9 (d, b-AA), 128.2 (d, -nor.), 128.6 (d, b-AA), 137.9
L-nor., 1H NHmajor rotamer);
L
-nor.), 26.7 (q, b-AA),
L
L
L
L
L
(s, b-AA), 143.3 (s,
L-nor.), 156.4 (s, b-AA), 174.8 (s, b-AA);
½
a 2D0
ꢂ
¼ ꢀ6:4 (c 1, EtOH); IR (KBr), kꢀ1 (cmꢀ1): 3369, 2965, 1692,
ˇ
K.; Boehnke, H.; Repic, O.; Blacklock, T. Org. Process Res. Dev. 2006, 10, 78–93.
1543, 1401, 1259, 1062, 738, 700.
5. Enthaler, S.; Erre, G.; Junge, K.; Holz, J.; Börner, A.; Alberico, E.; Nieddu, I.;
Gladiali, S.; Beller, M. Org. Process Res. Dev. 2007, 11, 568–577. and references
cited therein.
6. Peña, D.; Minnard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124,
14552–14553.
4.4. (S)-3-Benzyloxycarbonylamino-4,4-dimethylpentanoic
acid; (S)-Cbz-b-neopentylglycine
7. Hansen, K. B.; Rosner, T.; Kybryk, M.; Dormer, P. G.; Armstrong, J. D., III Org. Lett.
2005, 7, 4935–4938.
8. Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419–422.
9. Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.;
Heller, D. Org. Process Res. Dev. 2003, 7, 355–361.
10. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–
2891.
11. Gröger, H.; May, O.; Hüsken, H.; Georgeon, S.; Drauz, K.; Landfester, K. Angew.
Chem. 2006, 118, 1676–1679; . Angew. Chem., Int. Ed. 2006, 45, 1645–1648.
12. Forró, E.; Fülöp, F. Chem. Eur. J. 2007, 13, 6397–6401.
13. Gedey, S.; Liljeblad, A.; Lázár, L.; Fülöp, F.; Kanerva, L. T. Tetrahedron:
Asymmetry 2001, 12, 105–110.
The
L
-(ꢀ)-norephedrine salt of (S)-3-benzyloxycarbonylamino-
4,4-dimethylpentanoic acid (83.4 g, 194 mmol) was added to a mix-
ture of ethyl acetate (300 ml) and water (250 ml) in a three-necked
flask. The pH was adjusted to 2 by the dropwise addition of hydro-
chloric acid (32%, 22 ml), while the mixture was vigorously stirred.
The water phase was separated and extracted twice with ethyl ace-
tate (2 ꢁ 100 ml). The combined organic layers were washed with
brine (8%, 200 ml) and dried over sodium sulfate. Removal of the sol-
vent afforded the protected amino acid as a white solid (51.9 g,
186 mmol, 95.9%); The shifts in the 1H and 13C NMR spectra were
identical to those reported for the racemate above; Elemental Anal.
Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.34; H,
14. Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452,
453–455.
15.
Yang, J. W.; Stadler, M.; List, B. Angew. Chem. 2007, 119, 615–617; . Angew.
Chem., Int. Ed. 2007, 46, 609–611.
16. Yang, J. W.; Stadler, M.; List, B. Nature Protocols 2007, 2, 1937–1942.
17. Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem. 2005, 117, 7632–7635;
. Angew. Chem., Int. Ed. 2005, 44, 7466–7469.
18. Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Córdova, A. Angew. Chem. 2007, 119,
792–795; . Angew. Chem., Int. Ed. 2007, 46, 778–781.
19. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964–12965.
20. Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 500–501.
21. MacNevin, C. J.; Moore, R. L.; Liotta, D. C. J. Org. Chem. 2008, 73, 1264–1269.
22. Díaz-Sánchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Fernández, R.; Juaristi, E.
J. Org. Chem. 2007, 72, 4822–4825.
23. Sakai, T.; Kawamoto, Y.; Tamioka, K. J. Org. Chem. 2006, 71, 4906–4909.
24. Etxebarria, J.; Vicario, J. L.; Badia, D.; Carillo, L.; Ruiz, N. J. Org. Chem. 2005, 70,
8790–8800.
7.61;N, 5.28;½a D20
¼ þ13:4(c1.4, CHCl3);determinationoftheenan-
ꢂ
tiomeric purity was performed by HPLC using a Chiralcel AD Column
as the stationary phase and a mixture of i-hexane/i-propanol/triflu-
oroacetic acid = 850:150:1 as the eluent using a flow of 1 ml minꢀ1
at 30 °C. The separations were performed using ca. 10 mg of the sub-
stance, dissolved in 10 ml of the eluent. The detection was per-
formed at 215 nm; the enantiomeric purity of the sample proved
to be 99.9% for the (S)-enantiomer; IR (KBr), kꢀ1 (cmꢀ1): 3419,
3092, 2967, 1723, 1668, 1541, 1255, 756, 625, 546.
25. Chi, Y.; English, E. P.; Pomerantz, W. C.; Horne, W. S.; Joyce, L. A.; Alexander, L.
R.; Fleming, W. S.; Hopkins, E. A.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129,
6050–6055.
26. Periasamy, M.; Suresh, S.; Ganesn, S. S. Tetrahedron: Asymmetry 2006, 17, 1323–
1331.
4.5. (S)-3-Amino-4,4-dimethylpentanoic acid; (S)-b-
neopentylglycine
(S)-3-Benzyloxycarbonylamino-4,4-dimethylpentanoic
acid
27. Paloma, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gómez-Bengoa, E.; Garcia, J. M.
(20.0 g, 71.6 mmol) was dissolved in mixture of ethanol
a
J. Am. Chem. Soc. 2004, 126,
9188–9189.

482
M. K. J. ter Wiel et al. / Tetrahedron: Asymmetry 20 (2009) 478–482
28. Tessier, A.; Lahmar, N.; Pytkowicz, J.; Bigaud, T. J. Org. Chem. 2008, 73, 3970–3973.
29. Shin, D.-Y.; Jung, J.-K.; Seo, S.-Y.; Lee, Y.-S.; Paek, S.-M.; Chung, Y. K.; Shin, D.
M.; Suh, Y.-G. Org. Lett. 2003, 5, 3635–3638.
30. A search performed on the 5th of January 2009 in the SciFinder database
revealed that no procedure involving a resolution was known for the presently
presented amino acid or one of its derivatives.
35. Vries, T. R.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.; Kellogg, R. M.;
Broxtermann, Q. B.; Minnaard, A.; Kaptein, B.; van der Sluis, S.; Hulshof, L. A.;
Kooistra, J. Angew. Chem. 1998, 110, 2491–2496; . Angew. Chem., Int. Ed. 1998,
37, 2349–2354.
36. Lázár, L.; Martinek, T.; Bernáth, G.; Fülöp, F. Synth. Commun. 1998, 28, 219–
224.
31. Pasteur, L. C.R. Acad. Sci. 1848, 26, 535.
32. Sheldon, R. A. Chirotechnology: Industrial Synthesis of Optically Active
Compounds, 2nd ed.; Marcel Dekker: New York, 1993.
33. Jacques, J.; Collet, A.; Wilen, S. H.. In Enantiomers, Racemates, and Resolution;
John Wiley & Sons: New York, ISBN 0-471-08058-6, 1981.
34. Collet, A.; Brienne, M.-J.; Jacques, J. Chem. Rev. 1980, 80, 215–230.
37. This compound has been reported in the literature: Koch, K.; Podlech, J. Synth.
Commun. 2005, 38, 2789–2794. An ½
a 2D0
ꢂ ¼ ꢀ11:2 (c 1.4, CHCl3) has been
provided for (R)-Cbz-b3-neopentylglycine. For (R)-Cbz-b3-neopentylglycine
synthesised in our laboratories, we determined ½a D20
¼ ꢀ13:7 (c 1.4, CHCl3).
ꢂ
38. The absolute configuration of the resolved Cbz-b3-amino acid was assigned by
comparison with a reference sample of (R)-Cbz-b3-neopentylglycine.