A concise synthesis of (S)-N-ethoxycarbonyl-α-methylvaline

Article abstract of DOI:10.1021/jo7012862

(Chemical Equation Presented) A practical and efficient protocol for the three-step synthesis of (S)-N-emoxycarbonyl-α-methylvaline 3 is described which utilizes readily available commercial starting materials. The key transformations involve resolution-crystallization of tartrate salt 6 followed by a one-pot procedure for the preparation of 3 which is isolated as the dicyclohexylamine salt in 45% overall yield and in 91-95% ee.

Full text of DOI:10.1021/jo7012862

range of both medicinal4 and herbicidal agents (Figure 1).5 While
the asymmetric syntheses of 1 and 2 have been reported,6 each
pose formidable challenges due to starting material availability,
length of synthesis, and low-yielding transformations which are
most likely due to the sterically hindered nature of 1. Classical
resolution strategies have also been reported;7 however, com-
plete procedures are scarce since racemic 1 is not readily
available and many procedures are only found in published
patents which are often difficult to interpret and often lack
complete accounts of experimental details. In this paper, we
document a full description of an experimentally simplified
protocol for the three-step preparation of (S)-N-ethoxycarbonyl-
R-methylvaline 3 which is amenable to large scale and offers
significant advantages over currently available methodologies.
A Concise Synthesis of
(S)-N-Ethoxycarbonyl-r-methylvaline
Jeffrey T. Kuethe,* Donald R. Gauthier, Jr.,
Gregory L. Beutner, and Nobuyoshi Yasuda
Department of Process Research, Merck & Co., Inc., P.O. Box
2000, Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
ReceiVed June 18, 2007
A practical and efficient protocol for the three-step synthesis
of (S)-N-ethoxycarbonyl-R-methylvaline 3 is described which
utilizes readily available commercial starting materials. The
key transformations involve resolution-crystallization of
tartrate salt 6 followed by a one-pot procedure for the
preparation of 3 which is isolated as the dicyclohexylamine
salt in 45% overall yield and in 91-95% ee.
FIGURE 1. Methylvaline and derivatives.
The synthesis of 3 began with the Strecker reaction of
3-methyl-2-butanone 4 (Scheme 1). Reaction of 4 with 0.95
equiv of NaCN in the presence of 0.5 equiv of NH4Cl and 0.5
equiv of MgSO4 in 7 M NH3 in MeOH (3.0 equiv) at 30 °C
The preparation of R-methyl-R-substituted amino acids as
unnatural amino acid analogues has received considerable
interest due to restricted conformational freedom and the
tendency to induce 310-, R-helical, and â-turn-type conforma-
tions when incorporated in peptide chains,1 and these compounds
have been incorporated into marketed pharmaceuticals such as
Aldomet (L-R-methylDOPA).2 Since R-methyl-R-substituted
amino acids are unable to undergo racemization, these nonpro-
teinogenic building blocks can impart significant changes in
biological activities and have found applications in enzyme
mimetics and in de novo design of proteins.3 As R-methyl-R-
substituted amino acids are rarely found in nature, the prepara-
tion of these increasingly important building blocks in high yield
and enantiopure form, by methods that are also amenable to
large scale, underscores the importance of developing new
methodologies. In particular, R-methylvaline 1 and its amide
derivative 2 have been used extensively in the preparation of a
(4) For leading references, see: (a) Fitch, D. M.; Evans, K. A.; Chai,
D.; Duffy, K. J. Org. Lett. 2005, 7, 5521. (b) Shen, D.-M.; Shu, M.;
Willoughby, C. A.; Shah, S.; Lynch, C. L.; Hale, J. J.; Mills, S. G.;
Chapman, K. T.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Lyons, K.; Pivnichny, J. V.; Kwei, G. Y.; Carella,
A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.;
Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A. Bioorg. Med. Chem.
Lett. 2004, 14, 941. (c) Tice, C. M.; Hormann, R. E.; Thompson, C. S.;
Friz, J. L.; Cavanaugh, C. K.; Michelotti, E. L.; Garcia, J.; Nicolas, E.;
Albericio, F. Bioorg. Med. Chem. Lett. 2003, 13, 475.
(5) (a) Los, M. US Patent 4554013, 1985. (b) Orwick, P. L.; Templeton,
A. R. US Patent 4404012, 1983. (c) Los, M. US Patent 4017510, 1977. (d)
Gastrock, W. H.; Wepplo, P. J. US Patent 4683324, 1987. (e) Eur. Patent
0,123.830, 1984.
(6) (a) Seebach, D.; Aebi, J. D.; Naef, R.; Weber, T. HelV. Chim. Acta
1985, 68, 144. (b) Obrecht, D.; Spiegler, C.; Scho¨nholzer, P.; Mu¨ller, K.
HelV. Chim. Acta 1992, 75, 1666. (c) Obrecht, D.; Bohdal, U.; Broger, C.;
Bur, D.; Lehmann, C.; Ruffieuz, R.; Scho¨nholzer, P.; Spiegler, C.; Mu¨ller,
K. HelV. Chem. Acta 1995, 78, 563. (d) Cativiela, C.; D´ıaz-de-Villegas, M.
D.; Ga´lvez, J. A.; Lapen˜a, Y. Tetrahedron 1995, 51, 5921. (e) Cooper, T.
S.; Laurent, P.; Moody, C. J.; Takle, A. K. Org. Biomol. Chem. 2004, 2,
265.
(7) (a) Turk, J.; Panse, G. T.; Marshall, G. R. J. Org. Chem. 1975, 40,
953. (b) Kruizinga, W. H.; Bolster, J.; Kellogg, R. M.; Kamphuis, J.;
Boesten, W. H. J.; Meijer, E. M.; Schoemaker, H. E. J. Org. Chem. 1988,
53, 1826. (c) Boesten, W. H. J.; Peters, P. J. H. Eur. Patent 150854, 1984.
(d) Sonke, T.; Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.;
Schoemaker, W. H. J.; Kamphuis, J.; Formaggio, F.; Toniolo, C.; Rutjes,
N. In StereoselectiVe Biocatalysis; Patel, R. M., Ed.; Dekker: New York,
2000; pp 23-58. (e) Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.;
Peters, P. J. H.; Schoemaker, H. E.; Kamphuis, J. Tetrahedron: Asymmetry
1993, 4, 1113. (f) Kaptein, B.; Broxterman, Q. B.; Schoemaker, H. E.;
Rutjes, F. P. J. T.; Veerman, J. J. N.; Kamphuis, J.; Peggion, C.; Formaggio,
F.; Toniolo, C. Tetrahedron 2001, 57, 6567.
(1) For leading references, see: (a) Formaggio, F.; Barazza, A.; Bertocco,
A.; Toniolo, C.; Broxterman, Q. B.; Kaptein, B.; Brasola, E.; Pengo, P.;
Pasquato, L.; Scrimin, P. J. Org. Chem. 2004, 69, 3849 and references cited
therein. (b) Pengo, P.; Broxtermen, Q. B.; Kaptein, B.; Pasquato, L.; Scrimin,
P. Langmuir 2003, 19, 2521. (c) Karle, I. L.; Balaram, P. Biochemistry
1990, 29, 6747. (d) Mutter, M. Angew Chem. 1985, 97, 639.
(2) Reinhold, D. F.; Firestone, R. A.; Gaines, W. A.; Chemerda, J. M.;
Sletzinger, M. J. Org. Chem. 1968, 33, 1209 and references cited therein.
(3) For recent reviews, see: (a) Andrews, M. J. I.; Tabor, A. B.
Tetrahedron 1999, 55, 11711. (b) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. ReV. 2001, 101, 3131. (c) Licini, G.; Prins, L.; Scrimin,
P. Eur. J. Org. Chem. 2005, 969. (d) Ohfune, Y.; Shinada, T. Eur. J. Org.
Chem. 2005, 5127. (e) Cativiela, C.; D´ıaz-de-Villega, M. D. Tetrahedron:
Asymmetry 2007, 18, 569. (f) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007,
5, 406.
10.1021/jo7012862 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/22/2007
J. Org. Chem. 2007, 72, 7469-7472
7469

afforded quantitative conversion to crude racemic 5.8 The use
of an excess of ketone 4 ensured that complete consumption of
NaCN occurred. The choice of workup conditions for this
reaction was found to be crucial for conversion to enantioen-
riched 5 (vide infra). The optimal conditions involved concen-
tration of nearly all the NH3/MeOH from the reaction mixture
under reduced pressure and temperature, dilution with MTBE,
and filtration of the inorganic solids. This procedure allowed
for the complete removal of all inorganic salts without an
aqueous workup and provided a means of drying crude 5 by
azeotropic distillation under reduced pressure to a KF (by Karl
Fisher titration) of <400 µg/mL of water. Crude 5 was then
solvent switched back to MeOH by distillation prior to utilization
in the next reaction. Initial experiments employed an aqueous
workup after filtration of the inorganic salts and were followed
by extraction with MTBE. However, difficulties were encoun-
tered upon concentration since azeotropic drying of MeOH
under reduced pressure, after complete removal of MTBE, was
nearly impossible leaving a MeOH solution of 5 which was
particularly “wet” with water.9 In addition, the low boiling point
of 5 resulted in significant losses during removal of MeOH when
the concentration was conducted at elevated temperatures.10
The preparation of enantioenriched 5 involved a resolution-
crystallization protocol with L-tartaric acid.5d The conversion
of racemic 5 to enantioenriched 6 involved the formation of
imine 7 and HCN, where upon equilibration, the desired salt 6
was isolated in high enantiopurity. It was discovered through
extensive experimentation that careful attention to detail was
necessary for the success of this resolution. For example, initial
experiments which employed an aqueous workup of crude 5
from the Strecker reaction of 4 led to the formation of significant
amounts of ammonium tartrate. In certain cases where the water
content of the reaction was high (>1000 µg/mL), ammonium
tartrate became the only isolated product. On the other hand,
when the optimal conditions for workup of 5 described above
were utilized, little ammonium tartrate was formed and good
conversion to 6 was observed in excellent enantiopurity and
good chemical yield. Successful conditions for conversion to 6
involved addition of crude 5 in MeOH (KF < 400 µg/mL) to
a solution of a slight excess (1-1.3 equiv) of L-tartaric acid in
MeOH followed by stirring at rt for 48-72 h. In order to
minimize loss of HCN during the resolution, the reaction mixture
was sealed and vented to an oil bubbler followed by a caustic
scrubber which trapped any escaping HCN. The course of the
reaction could be monitored by filtration of a small sample,
conversion to benzamide 8, and analyzing by chiral super critical
fluid chromatography (SFC). After 24 h, the enantiopurity of 6
was typically 80% ee, and after 48 h, >91% ee was achieved.
After filtration, tartrate salt 6 was isolated in 61-65% overall
yield for the two-step procedure and in 92-95% ee.
SCHEME 1
carbamate to serve as an easily removable protecting group.
Due to severe steric interactions, basic hydrolysis of amino
nitrile 5 is sluggish and low conversion to amide intermediate
2 or the corresponding amino acid 1 is observed. The conversion
of 6 to amide 2 has been described5d and involves conversion
of 6 to the free amino nitrile 5 followed by hydrolysis in conc.
H2SO4; however, conversion of 6 to (S)-methylvaline 1 or any
of its other derivatives has not been described. It was envisioned
that acid hydrolysis of 5 under more forcing conditions followed
by conversion to ethyl carbamate 3 could be effected in a one-
pot procedure after conversion of 6 to free aminonitrile 5.
The salt-break of 6 to 5 in the presence of either NaOH or
NH4OH has been studied,4d,11 and solutions of 5 in certain
solvents are chemically stable for prolonged periods of time
without any loss of enantiopurity.10a Armed with this data,
slurrying 6 in CH2Cl2 followed by the addition of 3.2 equiv of
5 N NaOH provided a homogeneous biphasic solution (Scheme
1
2). Separation of the layers and analyzing both layers by H
NMR revealed that quantitative extraction of 5 into the organic
layer had occurred and all the tartrate remained in the aqueous
layer. Although the organic layer could be concentrated under
reduced pressure and used without further purification, simple
extraction of the organic extract with 50% v/v H2SO4 (6 equiv)
was also quantitative, leaving virtually no detectable amounts
1
Having identified optimal conditions for the preparation of
enantioenriched 6, our attention turned to the preparation of (S)-
methylvaline 1 and suitable conditions for isolation. Since 1 is
highly soluble in water, efforts were focused on the preparation
of ethyl carbamate 3 which would not only facilitate its isolation
by extraction into an organic solvent but also allow the ethyl
of 5a in the organic layer as revealed by H NMR analysis of
each layer. Hydrolysis of 5a in 50% H2SO4 was conducted at
100 °C for 18-24 h to provide a crude aqueous solution of
R-methylvaline 1.12 Attempts to use this crude hydrolysis
mixture for the direct conversion to 3 by adjusting the pH to
8.5-9.0 and addition of 1.2 equiv of ethyl chloroformate
resulted in the formation of at least three products of which 3
was the major component (80%). Interestingly, urethane 9 was
identified as a significant reaction product which suggested that
(8) (a) Deng, S. L.; Liu, D. Z. Synthesis 2001, 2445. (b) Christjohannes,
J.; Heimgartner, H. HelV. Chim. Acta 1986, 69, 374. (c) Piper, J. R.;
Stringfellow, C. R.; Johnston, T. P., Jr. J. Med. Chem. 1966, 9, 911.
(9) Horsley, L. H. Azeotropic Data III; American Chemical Society:
Washington, DC, 1973.
(10) The reported bp of 5 is 71 °C/13 mmHg (see ref 7c) and 43-47
°C/3 mmHg (see ref 7a).
(11) (a) Gastrock, W. H.; Wepplo, P. J.; Kremer, K. A. M.; Drabb, T.
W. Eur. Patent 1050529B1. (b) Kremer, K. A. M. International Patent WO
01/47856A1.
7470 J. Org. Chem., Vol. 72, No. 19, 2007

SCHEME 2
pure form as the dicyclohexylamine (DCH) salt in 70% overall
yield from 6 and in 92-95% ee. The final ee determination of
3 was conducted by conversion to benzhydryl ester 11 with
diphenyldiazomethane17 and analyzing by chiral SFC.
In conclusion, we have established a rapid, practical, and
efficient method for the three-step preparation of (S)-N-
ethoxycarbonyl-R-methylvaline 3 which proceeds in 45% overall
yield from readily available bulk chemicals, requires no
chromatographic separations, and provides 3 in 92-95% ee. A
clear understanding of the reaction parameters, which can greatly
affect the outcome of each transformation, allows for successful
preparation of 3. The formation of tartrate salt 6 under anhydrous
conditions and removal of ammonia prior to formation of
carbamate 3 were necessary in order to obtain reproducible
yields. The use of D-tartaric acid would also provide access to
the enantiomer of 3 using the present methodology. Application
of this methodology for the preparation of other R,R-disubsti-
tuted amino acids may be possible and could aid in the discovery
and development of a wide range of structurally intriguing
compounds.
competitive reaction of ammonia, liberated during the hydrolysis
of amide intermediate 2, with ethyl chloroformate was occurring.
Also identified in the crude reaction mixture was oxazolinone
10.13 The formation of 10 could be explained by acylation of
both the nitrogen atom and the carboxylate ion followed by
intramolecular cyclization to 10 and represents an unusual case
of formation of an oxazolinone under Schotten-Baumann
reaction conditions.14 After extensive examination of all of the
reaction parameters, it was discovered that optimal conditions
for the one-pot conversion of 5a to 3 required heating in 50%
H2SO4 (6 equiv) at 100 °C for 18-24 h followed by adjusting
the pH to 12 by the addition of 10 N NaOH (12 equiv). In
order to effectively remove ammonia from the reaction mixture
and eliminate the competitive formation of urethane 9, distil-
lation of ammonia from the crude mixture was conducted at
100-104 °C at atmospheric pressure.15 The removal of ap-
proximately 1/4 of the total reaction volume was required to
completely remove ammonia from the reaction mixture.16 Once
the distillation was complete, the reaction mixture was cooled
to 20-25 °C, 0.90 equiv of ethyl chloroformate was added,
and the pH of the mixture was maintained around 10.0 by the
portionwise addition of 10 N NaOH over 1-2 h. These
conditions also suppressed the formation of 10 and resulted in
an extremely clean reaction profile. Finally, the pH of the
reaction mixture was readjusted to 2.2 with conc. HCl and the
mixture was filtered to remove the precipitated Na2SO4 formed
during the neutralization of H2SO4 with NaOH. After extraction
with MTBE and drying, carbamate 3 was isolated in analytically
Experimental Section
Caution: The potential for HCN release is present. These
reactions should be effectively scrubbed with either a caustic or
bleach scrubber, and adequate protective equipment should be worn
at all times to prevent exposure.
Preparation of (S)-2-Amino-2,3-dimethylbutyronitrile (2R,3R)-
Tartrate (6). In a 75 L round-bottom flask equipped with a
mechanical stirrer, condenser, and thermocouple was added 2.79
kg (23.2 mol) of MgSO4, 1.24 kg (23.2 mol) of NH4Cl, and 2.16
kg (44.1 mol) of NaCN. The solids were slurried in 26.5 L (185.6
mol) of 7 M NH3 in MeOH and cooled to -5 to -10 °C. The
internal temperature of the slurry was -5 °C and rose to 8 °C after
stirring for 10 min as some of the solids dissolved. To the resulting
suspension was added in one portion (4.00 kg, 46.4 mol) of
3-methyl-2-butanone 4. The internal temperature slowly rose from
8 to 35 °C over the course of 1 h, at which point it slowly decreased
to 30 °C and was held at this temperature for 3 h (total reaction
time 4 h). The reaction was judged complete by GC analysis at
this point. The solvent was then removed under reduced pressure
(∼ 30 mmHg) while maintaining the internal temperature <30 °C
until nearly all of the MeOH and ammonia were removed. The
resulting slurry of inorganic salts and the product was diluted with
30 L of MTBE, stirred at rt for 30 min, and filtered. The inorganic
wet cake was washed with 4 L of MTBE. The filtrate was then
charged to a 75 L round-bottom flask equipped with a thermocouple,
mechanical stirrer, and a vacuum distillation apparatus. The solvent
was concentrated under reduced pressure (∼30 mmHg) while
maintaining the internal temperature <20 °C and solvent switched
to a final volume of 20 L of MeOH for use in the next step without
further purification. The KF of the solution was 373 µg/mL of water,
(12) Hydrolysis of 5 with 6 N HCl at 100 °C to R-methylvaline 1 required
heating for 24-36 h and 1 could be isolated in ∼80 % yield after
concentration under reduced pressure. Unfortunately, isolated amino acid
1 was contaminated with significant amounts of ammonium chloride.
Attempts to convert crude aqueous solutions of 1 to 3 by the method describe
above were complicated by the formation of numerous unidentified
byproducts.
(13) Fiammengo, R.; Licini, G.; Nicotra, A.; Modena, G.; Pasquato, L.;
Scrimin, P.; Broxterman, Q. B.; Kaptein, B. J. Org. Chem. 2001, 66, 5905.
(14) The individual components of the crude reaction mixture were
identified by analysis of the crude NMR and were not separated from one
another.
(15) Removal of ammonia from water is most effectively accomplished
at the boiling point of water, see: Perry’s Chemical Engineers’ Handbook,
6th ed.; McGraw Hill Book Co.: New York, 1984.
(16) The course of the ammonia distillation was monitored by acidifica-
tion of a small sample, dilution with DMSO-d6, and analysis for the
ammonium triplet at 7.3-7.6 ppm.
1
and the final H NMR assay was 4.3 kg of 5 (87%).
In a separate 100 L round-bottom flask equipped with a
thermocouple and mechanical was added 6.79 kg (46.4 mol) of
L-tartaric acid and 45 L of MeOH. The resulting homogeneous
solution was cooled to an internal temperature of 8 °C, and the
above crude solution of amino nitrile 5 in MeOH was added over
45 min. After approximately 2 L of the crude amino nitrile solution
was added, the solution was seeded with 100 g of 6 which was
95% ee. The reaction mixture should not be placed under a positive
pressure of nitrogen as this will remove HCN from the reaction
mixture and only ammonium tartrate will be isolated. The reaction
mixture was sealed and vented only to an oil bubbler followed by
(17) Kumar, S.; Murray, R. W. J. Am. Chem. Soc. 1984, 106, 1041.
J. Org. Chem, Vol. 72, No. 19, 2007 7471

a caustic solution. The resulting slurry was stirred at rt for 72 h, at
which point, after conversion to the benzamide 8, the ee of 6 was
found to be 92%. The reaction slurry was filtered, and the wet cake
was washed with 10 L of MTBE and dried under vacuum/N2 sweep
for 3 h to give 8.66 kg (82 wt %, 61% overall yield) of 6 as a
MeOH solvate and a white solid which was sufficiently pure for
use in the next reaction without further purification:18 1H NMR
(DMSO-d6, 400 MHz) δ 0.90 (d, 3H, J ) 6.8 Hz), 0.92 (d, 3H, J
) 6.8 Hz), 1.27 (s, 3H), 1.69 (m, 1H), 3.13 (s, MeOH), 4.23 (s,
2H), 6.42 (br s, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 17.6, 17.7,
24.5, 37.1, 49.0 (MeOH), 54.4, 72.6, 124.6, 173.8.
1.96 kg (18.1 mol) of ethyl chloroformate was added over the course
of 1 h. After the addition of ethyl chloroformate, the pH of the
reaction mixture was maintained between 9.8 and 10.2 by the
portionwise addition of ∼1.5 L of 10 N NaOH. After 2.5 h, the
pH of the reaction mixture stabilized at 10 and the reaction was
complete. The reaction mixture was diluted with 12 L of MTBE,
and the pH of the reaction mixture was back adjusted to 2.2 by the
addition of 2.65 L of conc. HCl. The resulting biphasic slurry was
filtered and the inorganic wet cake washed with 10 L of MTBE.
The biphasic filtrate was transferred to a 100 L extractor, and the
layers were allowed to separate. The aqueous layer was back
extracted with 10 L of MTBE. The combined MTBE extracts were
dried over 600 g of MgSO4 for 1.5 h, filtered, and added to a 50
L round-bottom flask equipped with a mechanical stirrer, thermo-
couple, and a vacuum distillation apparatus. The solvent was
concentrated to a final volume of 12-13 L under reduced pressure
(∼30 mmHg) while maintaining the internal temperature <20 °C.
To the concentrated solution was added 3.28 kg (18.1 mol) of
dicyclohexylamine over the course of 2 h while maintaining the
internal temperature <30 °C, and the slurry was stirred overnight
at rt. The slurry was diluted with 12 L of heptane, stirred for 45
min, and filtered. The wet cake was washed with 5 L of heptane
and dried under vacuum/N2 sweep for 6 h to give 5.044 kg (73%,
92%ee) of 3 as an analytically pure colorless solid: mp 129-
Preparation of (S)-2-Ethoxycarbonylamino-2,3-dimethylbu-
tyric Acid Dicyclohexylamine Salt (3). In a 100 L cylindrical
extractor was added 25 L of CH2Cl2 followed by 7.32 kg of 82 wt
% (6.00 kg by assay, 22.9 mol) of 6. The sides of the extractor
were rinsed with 5 L of CH2Cl2. To the slurry of 6 was added 14.5
L (73.3 mol) of 5 N NaOH. Within 15 min, a biphasic homogeneous
solution formed and the layers were allowed to separate. The bottom
organic layer was separated, and the top aqueous layer was
discarded. The extractor was washed with water, and the organic
layer was added back into the extractor. To the organic layer was
added 15.0 L (26.9 mol) of 50% v/v of H2SO4, and the layers were
well mixed for 15 min and allowed to settle. The bottom aqueous
layer was separated and placed into a 100 L round-bottom flask
equipped with a thermocouple, mechanical stirrer, and reflux
condenser. The reaction mixture was then heated to 100 °C for
18-20 h. The reaction mixture was allowed to cool to rt, and the
pH was adjusted to 12 by the addition of 27.5 L (275 mol) of 10
N NaOH while keeping the internal temperature <100 °C. After
all the NaOH was added, the internal temperature was increased
to 103-104 °C, and the distillate containing aqueous ammonia was
collected. This atmospheric distillation was also conducted with
effective scrubbing to a 5 N HCl solution in order to prevent release
1
130 °C; H NMR (CDCl3, 400 MHz) δ 0.90 (d, 3H, J ) 6.8 Hz),
0.97 (d, 3H, J ) 6.8 Hz), 1.21 (m, 9H), 1.45 (q, 4H, J ) 11.5 Hz),
1.61 (m, 5H), 1.76 (m, 4H), 1.97 (m, 4H), 2.32 (m, 1H), 2.92 (m,
2H), 4.04 (m, 2H), 6.44 (s, 1H), 9.50 (br s, 2H); 13C NMR (CDCl3,
100 MHz) δ 14.8, 18.3, 18.6, 21.3, 24.8, 25.3, 28.9, 34.6, 52.4,
59.6, 63.3, 155.1, 177.4. Anal. Calcd for C21H40N2O4: C, 65.59;
H, 10.48; N, 7.28. Found: C, 65.60; H, 10.62; N, 7.12.
Acknowledgment. We thank Mirlinda Biba of Merck & Co.,
Inc., for assistance with chiral HPLC analysis and Dr. Robert
A. Reamer for valuable NMR assistance.
1
of ammonia. A total of 5.5 L of distillate was collected, and H
NMR analysis of a small sample of the reaction mixture, re-acidified
with H2SO4, revealed that all the ammonia was removed. Charac-
teristic ammonium peaks in the 1H NMR of DMSO-d6 appear as a
triplet at ∼7.3-7.6 ppm. After the distillation of ammonia was
complete the reaction mixture was allowed to cool to 25 °C, and
Supporting Information Available: Experimental details for
the preparation of 8 and 11, analytical details for ee determination
of 6 and 3, as well as copies of 1H NMR and 13C NMR spectra for
compounds 6, 8, 3, and 11. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Satisfactory elemental analysis could not be obtained for tartrate
salt 6 due to the presence of MeOH and trace amounts of ammonium tartrate
present in the isolated solid.
JO7012862
7472 J. Org. Chem., Vol. 72, No. 19, 2007