The preparation of single enantiomer 2-naphthylalanine derivatives using rhodium-methyl BoPhoz-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/op050026g

The single enantiomers of 2-naphthylalanine and N-tert-butoxycarbonyl 2-naphthylalanine were prepared from 2-naphthaldehyde. The sequence has been optimized and run on multikilogram scale, with the key step the asymmetric hydrogenation of methyl 2-acetamido-3-(2-naphthyl)propenoate using the rhodium complex of the methyl BoPhoz ligand, which proceeded smoothly at scale with 97.9% ee. Enhancement to >99.5% ee was achieved by crystallization of the methyl 2-amino-3-(2-naphthyl)propanoate methanesulfonic acid addition salt, the product of acidic deacylation of the hydrogenation product. This protocol for enantiomeric purity enhancement appears to be general for these types of amino acid derivatives. Subsequent transformations did not effect the enantiomeric purity, affording the desired products in >99.5% ee.

Full text of DOI:10.1021/op050026g

Organic Process Research & Development 2005, 9, 472−478
The Preparation of Single Enantiomer 2-Naphthylalanine Derivatives Using
Rhodium-Methyl BoPhoz-catalyzed Asymmetric Hydrogenation
Neil W. Boaz,* Shannon E. Large, James A. Ponasik, Jr., Mary K. Moore, Theresa Barnette, and W. Dell Nottingham
Research Laboratories, Eastman Chemical Company, Kingsport, Tennessee 37662, U.S.A.
Abstract:
variety of pharmaceutically active materials. Of particular
interest are 2-naphthylalanine (2-amino-3-[2-naphthyl]pro-
panoic acid, 1) and especially the N-tert-butoxycarbonyl (N-
Boc) derivative 2. These materials, particularly 2 as it has
advantages for solid-phase peptide synthesis, have found
extensive use in the synthesis of a number of pharmaceuti-
cally useful agents, including luteinizing hormone-releasing
factors,4 somatostatin analogues,5 growth hormone release
stimulators,6 advanced glycated end product (AGE) receptor
modulators,7 and NK1 tachykinin receptor antagonists.8
The single enantiomers of 2-naphthylalanine and N-tert-bu-
toxycarbonyl 2-naphthylalanine were prepared from 2-naph-
thaldehyde. The sequence has been optimized and run on
multikilogram scale, with the key step the asymmetric hydro-
genation of methyl 2-acetamido-3-(2-naphthyl)propenoate using
the rhodium complex of the methyl BoPhoz ligand, which
proceeded smoothly at scale with 97.9% ee. Enhancement to
>99.5% ee was achieved by crystallization of the methyl
2-amino-3-(2-naphthyl)propanoate methanesulfonic acid addi-
tion salt, the product of acidic deacylation of the hydrogenation
product. This protocol for enantiomeric purity enhancement
appears to be general for these types of amino acid derivatives.
Subsequent transformations did not effect the enantiomeric
purity, affording the desired products in >99.5% ee.
There have been a number of preparations of enantio-
merically enriched N-Boc-2-naphthylalanine (as well as the
parent amino acid), utilizing strategies involving enzymatic
resolution,4a-c,9 alkylation of a chiral enolate,10 chiral phase-
transfer alkylation,11 and asymmetric hydrogenation.12 The
Introduction
Asymmetric hydrogenation is an efficient and attractive
approach to single enantiomer materials, largely due to the
ability to transform inexpensive achiral starting materials
such as olefins or ketones into higher-value products with
high enantioselectivity. The area of asymmetric hydrogena-
tion, and in particular the design and synthesis of novel
ligands for these transformations, has been under intense
investigation.1 Although there are a number of materials
available via asymmetric hydrogenation, the preparation of
amino acid derivatives using this technology has long been
of particular interest. Indeed, the first commercial application
of asymmetric hydrogenation was the preparation of L-DOPA
by Knowles and co-workers.2 We have recently reported the
synthesis and utility of a new class of phosphine-amino-
phosphine ligands (BoPhoz ligands) that show exceedingly
high enantioselectivities and activities for the asymmetric
hydrogenation of dehydro-R-amino acid and itaconate de-
rivatives, as well as high enantioselectivities and activities
for the asymmetric hydrogenation of R-ketoesters.3 We chose
to demonstrate the scale-up potential of these ligands for the
preparation of an unnatural amino acid.
(3) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E. Org.
Lett. 2002, 4, 2421-2424. (b) Boaz, N. W.; Debenham, S. D.; Large, S.
E.; Moore, M. K. Tetrahedron: Asymmetry 2003, 14, 3575-3580. (c) Boaz,
N. W.; Mackenzie, E. B.; Debenham, S. D.; Large, S. E.; Ponasik, J. A., Jr.
J. Org. Chem. 2005, 70, 1872-1880.
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(b) Nestor, J. J.; Jones, G. H.; Vickery, B. H. U.S. Patent 4,341,767, 1982.
(c) Rivier, J. E.; Porter, J.; Rivier, C. L.; Perrin, M.; Corrigan, A.; Hook,
W. A.; Siraganian, R. P.; Vale, W. W. J. Med. Chem. 1986, 29, 1846-
1851. (d) Rasmussen, J. H.; Rasmussen, P. H.; Wachs, W. O.; Hansen, S.;
Fomsgaard, J. PCT Intl. Appl. WO 2003055902, 2003. (e) Janaky, T.;
Juhasz, A.; Bajusz, S.; Schally, A. V. U.S. Patent 6,214,969, 2001. (f) Haviv,
F.; Dwight, W. J.; Nichols, C. J.; Greer, J. PCT Intl. Appl. WO 2000009544,
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The continuing interest in unnatural amino acids is driven
by their extensive use as key building blocks for a large
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10.1021/op050026g CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/24/2005

high enantioselectivities and activities for the asymmetric
hydrogenation of dehydroamino acid derivatives using the
rhodium complexes of the phosphine-aminophosphine (Bo-
Phoz) ligands 3 suggested that a sequence incorporating this
type of asymmetric hydrogenation might be a viable approach
to prepare N-Boc-2-naphthylalanine (and also the native
amino acid) efficiently and in absolute enantiomeric purity.
particularly toward acidic media, suggested that its use might
limit the options for downstream chemistry. In addition, the
relatively expensive nature of the Boc anhydride reagent and
the cumbersome nature of the preparation of the dehy-
droamino acid derivative14 suggested that converting to this
derivative at a late stage of the synthesis would be advanta-
geous.
Although the initial preparation of the substrates 6 utilized
rapid and versatile phosphonate chemistry as shown below,15
the lengthy preparation of the phosphonate reagent and its
atom inefficiency indicate that it is not advantaged for larger-
scale preparation of any particular dehydroamino acid.
Results and Discussion
The rhodium complexes of a number of ligands (including
3) have been reported to afford 2-naphthylalanine derivatives
in high enantioselectivities under screening conditions.12,13
In selecting a particular ligand for preparative purposes,
scalability factors can become very important, particularly
if high enantioselectivity is routinely obtained and ee
enhancement is possible. We chose to utilize the BoPhoz
ligands 3 for our investigations, as in addition to high
enantioselectivities, the ligand synthesis is readily scaled
(either enantiomer), they have long shelf stability, are easy
to use, and afford high turnover numbers and exceedingly
high turnover frequencies.3 Reaction screening with the
rhodium complex of 3 indicated that either the N-acetyl or
N-Boc substrates 6a or 6b, respectively, afforded the
hydrogenation product 7 in high enantiomeric purity (7a,
98.1% ee; 7b, 97.4% ee). The product stereochemistry was
as expected, with ligand R,S-3 affording the S enantiomers
of the amino acids.3 The sensitivity of the Boc derivative,
The preparative synthesis of the single enantiomers of 1
and 2 instead used a classical approach as shown in Scheme
1. This synthesis is described for the preparation of the R
enantiomers of 1 and 2 using the rhodium complex of S,R-
3, but the other enantiomers are equally available by using
R,S-3.
The first step utilized the classical Erlenmeyer condensa-
tion, in general the most efficient preparative method for
aryl-substituted dehydroamino acids.16 In this case the
chemistry involved the condensation of 2-naphthaldehyde
with N-acetyl glycine using acetic anhydride as solvent and
dehydrating agent (the excess was used to afford a fluid
reaction mixture and minimize by-product formation) and
sodium acetate as base at 100 °C to form the oxazol-5(4H)-
one (azlactone) product 5 along with some highly colored
impurities. Removal of these by-products was effected by
trituration of the crude product with methanol (5 is largely
insoluble) at ambient temperature, affording the desired
azlactone 5 as a pale-yellow solid in about 65% overall yield.
The use of methanol for this re-slurry also avoids the
necessity for complete drying of the product, as methanol is
used as solvent for the next step.
(9) (a) Lankiewicz, L.; Kasprzykowski, F.; Grzonka, Z.; Kettmann, U.; Herman,
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Ann. Chem. 1989, 1215-1232.
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Larionov, O. V.; Harutyunyan, S. R.; Vyskocˇil, Sˇ; North, M.; Kagan, H.
Angew. Chem., Int. Ed. 2001, 40, 1948-1951. (b) Belokon, Y. N.;
Bespalova, N. B.; Churkina, T. D.; Cisarˇova´s, I.; Ezernitskaya, M. G.;
Harutyunyan, S. R.; Hrdina, R.; Kagan, H.; Kocˇovsky´, P.; Kochetkov, K.
A.; Ikonnikov, N. S.; Larionov, O. V.; Lyssenko, K. A.; North, M.; Polasˇek,
M.; Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskocˇil, Sˇ. J. Am. Chem. Soc.
2003, 125, 12860-12871.
(12) Krause, H. W.; Kreuzfeld, H.-J.; Schmidt, U.; Dobler, Ch.; Michalik, M.;
Taudien, S.; Fisher, Ch. Chirality 1996, 8, 173-188.
(13) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125-10138. (b) RajanBabu, T. V.; Ayers, T. A.; Halliday,
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(c) Almena Perea, J. J.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry
1999, 10, 375-384. (d) Yonehara, K.; Hashizume, T.; Mori. K.; Ohe, K.;
Uemura, S. J. Org. Chem. 1999, 64, 5593-5598. (e) Yonehara, K.; Ohe,
K.; Uemura, S. J. Org. Chem. 1999, 64, 9381-9385. (f) Li, W.; Zhang, Z.;
Xiao, D.; Zhang, X. J. Org. Chem. 2000, 65, 3489-3496. (g) Liu, D.; Li,
W.; Zhang, X. Org. Lett. 2002, 4, 4471-4474. (h) Tang, W.; Zhang, X.
Angew. Chem., Int. Ed. 2002, 41, 1612-1614. (i) Zhou, Y.-G.; Zhang, X.
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Zhang, X. Tetrahedron: Asymmetry 2004, 15, 2173-2175. (k) Wu, S.; He,
M.; Zhang, X. Tetrahedron: Asymmetry 2004, 15, 2177-2180.
(14) (a) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054-7057. (b) Flynn,
D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48, 2424-2426. (c)
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Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold,
R.; Meyer, R.; Riedl, B. Synthesis 1992, 487-490. (c) Schmidt, U.;
Lieberknecht, A.; Wild, J. Synthesis 1988, 159-172.
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A. H., Ed.; John Wiley: New York, 1943; Coll. Vol. 2; p 1.
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473

Scheme 1. Synthetic sequence for the preparation of N-Boc
R-2-naphthylalanine
Table 1. Solvent screening for the asymmetric
hydrogenation of 6a to R-7a using the rhodium complex of
S,R-3a
substrate
entry
solvent
concentration (M) ee (%) conversion (%)
1
2
3
4
5
6
7
8
9
methanol
methanol
acetone
acetone
toluene
0.19b
0.37
0.19b
0.37
0.19
0.37
0.19
0.37
0.19
0.37
97.2
94.8
97.0
97.0
97.8
97.4
97.2
97.2
97.6
97.4
99.6
87.9
99.3
100
100
100
100
100
99.9
99.7
toluene
ethyl acetate
ethyl acetate
TCEc
10 TCEc
a All reactions were run at S:C molar ratio of 250:1 for 1 h at ambient
temperature and were initially slurries (except where indicated) that became
homogeneous as the reaction progressed. b Initial reaction mixture was homo-
geneous. c TCE is tetrachloroethylene.
The (in)solubility characteristics of 6a caused concern for
the ability to perform an efficient asymmetric hydrogenation
reaction at reasonable concentration. Thus, the hydrogenation
was screened using the rhodium complex of S,R-3 in a variety
of solvents at two concentrations. The results are shown in
Table 1 and indicate that a number of solvents performed
well for this reaction, despite the limited solubility of the
substrate. Toluene was chosen as the solvent for further
investigation, as it afforded the best overall results.
Further optimization of this hydrogenation in toluene
indicated a rapid and highly enantioselective reaction with
a turnover frequency of up to 19 200 catalyst turnovers per
hour. The reaction was complete well within 1 h and afforded
up to 98.3% ee at a catalyst loading of 0.04 mol % (S:C,
2500:1). The hydrogenation was scaled up to 22-L scale in
toluene using 0.05 mol % loading (S:C, 2000:1) of the
rhodium complex of S,R-3, and resulted in smooth hydro-
genation, affording the desired product R-7a with complete
conversion and high enantioselectivity (97.9% ee). The initial
run required extended reaction time, but eventually afforded
complete conversion with a moderate exotherm to about 33
°C. Modifying the equipment in subsequent runs to allow
subsurface hydrogen addition greatly increased the reaction
rate (the exotherm remained the same), indicating that mass
transfer limitations were the cause of the slow rate of the
first run.
The hydrogenation product R-7a can be isolated in 96%
yield (and the ee enhanced) by crystallization from a toluene/
heptane mixture. This afforded R-7a with >99% ee that
possessed a negative optical rotation, indicating that it was
the R enantiomer based on literature data.13a,17 Unfortunately,
R-7a tends to solidify into large masses rather than crystal-
lize, resulting in material that would be difficult to isolate
on large scale. Instead, the solvent was removed, and the
crude product was submitted directly to the next step.
The fourth step of the sequence involved removal of the
N-acetyl group. Both this step and the ester hydrolysis are
performed under acidic conditions and in principle could be
run concurrently. However, amine salt R-8, the product of
Conversion of the azlactone to the methyl ester 6a was
most conveniently performed using a catalytic amount of
sodium methoxide in methanol. This reaction was very rapid,
as evidenced by the conversion of a slurry of 5 in methanol
to a homogeneous solution upon the addition of the catalyst.
The methyl ester product partially precipitated from solution,
and the addition of water completed the solid formation,
affording the ester 6a in 91% yield as a tan solid.
Although this material appeared quite pure by NMR and
GC, there were small amounts of impurities present that were
anathema for the asymmetric hydrogenation reaction using
the rhodium complex of ligand 3. When industrially useful
low loadings of catalyst were used, these impurities resulted
in virtually complete catalyst inactivation and no reaction.
The offending impurities were readily removed by charcoal
treatment in acetone at ambient temperature, although it
required a large amount of both acetone (10 mL/g of crude
6a) and carbon (0.75 g/g of crude 6a) for effective impurity
removal and product recovery. Purified 6a was most ef-
ficiently recovered by distillation of the majority of the
acetone from the filtrate (resulting in a slurry of purified
6a) and dilution of this reduced solution with approximately
three volumes of water. The product 6a was obtained with
up to 91% recovery on laboratory scale using this protocol,
resulting in an overall yield of 6a from 4 of 54%. The
recoveries were slightly lower at kilo-scale, affording an
overall yield to 6a of 42%.
(17) Pattabiraman, T. N.; Lawson, W. B. Biochem. J. 1972, 126, 659-665.
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methanolic methanesulfonic acid acetyl solvolysis of 7a, is
a highly tractable solid that could be readily recrystallized
to absolute enantiomeric purity. This type of behavior was
also observed for several other species similar to 8 that we
have investigated. The initial recrystallization protocol used
refluxing n-propanol as the solvent, and under laboratory
conditions afforded R-8 with >99.5% ee in 70% yield. Under
the extended reflux that would occur upon scale-up of the
recrystallization it was noted that there was significant
transesterification of the methyl ester to the n-propyl ester,
which caused difficulties during the crystallization. Instead,
the product was isolated by diluting the cooled methanolic
reaction mixture with two volumes each of 2-propanol and
heptane to afford R-8 in 90% yield with >99% ee. This
material was recrystallized under a similar protocol from
refluxing methanol (2 mL/g of 6) by cooling to ambient
temperature and dilution with two volumes each of 2-pro-
panol and heptane, resulting in 92% recovery of R-8 (83%
overall yield) with >99.5% ee.
Conversion of the methyl ester of 8 to the native amino
acid 1 could be performed under either acidic or basic
hydrolysis conditions. Basic hydrolysis was a much faster
reaction, but resulted in a small but unacceptably significant
amount of racemization (ca. 1% loss of ee). Acidic hydrolysis
of R-8 in dilute hydrochloric acid left the chiral center
untouched. Neutralization afforded the amino acid R-1 as a
highly pure white precipitate in 98% yield and >99.5% ee.
Subsequent conversion to the Boc derivative under literature
reaction conditions (triethylamine, methanol, sodium hy-
droxide)18 afforded the desired product R-2 as an intractable
thick oil, which only grudgingly crystallized in an overall
75% yield (two steps).
In the hopes of obtaining higher overall efficiency and
better morphology for 2, these last two steps were telescoped
into one pot. Thus, after acidic hydrolysis to afford R-1,
excess sodium hydroxide was added followed by di-tert-butyl
dicarbonate to form the N-Boc derivative R-2 under Schot-
ten-Baumann conditions. This reaction proceeded exceed-
ingly well, and acidification of the reaction mixture afforded
R-2 as a free-flowing white solid that precipitated directly
from the reaction mixture. It was generally advisable to re-
slurry this material in water to remove small amounts of
water-soluble salts that were occluded in the product cake.
Filtration and drying afforded R-2 in 97% overall yield for
the two steps in the lab and 93% upon scale-up.
Analysis of this final product for chemical purity was
performed by reverse-phase HPLC, and afforded >98%
purity (area percent) in all cases. The enantiomeric purity
was assessed by conversion of R-2 to N-Boc-2-naphthyla-
lanine methyl ester (R-9) under nucleophilic conditions
(CH3I, KHCO3, acetone, 50 °C, quantitative yield) and chiral
HPLC analysis. All batches prepared afforded >99.5% ee
for R-2, indicating no loss of enantiomeric purity during the
functional group transformations from R-8.
Conclusions
The single enantiomers of 2-naphthylalanine and N-tert-
butoxycarbonyl 2-naphthylalanine were prepared using a
rhodium-methyl BoPhoz-catalyzed hydrogenation of dehy-
droamino acid derivative 6a as the key stereoselective step.
The asymmetric hydrogenation proceeded particularly
smoothly during scale-up with a commercially relevant high
substrate-to-catalyst ratio as a result of the ease of use and
stability of the ligand 3 and complexes prepared from it. This
hydrogenation rapidly afforded the desired product with
complete conversion, high yield, and excellent enantiose-
lectivity due to the high turnover frequency and stereose-
lectivity of the methyl BoPhoz-rhodium complex. The
downstream chemistry proceeded smoothly to the desired
products, with enhancement to absolute enantiomeric purity
conveniently afforded by simple recrystallization of am-
monium methanesulfonate intermediate 8. Subsequent con-
version to the desired products proceeded without loss of
enantiomeric purity.
Experimental Section
General Methods. All solvents were used as received
from Burdick and Jackson except where indicated. All
reagents were used as received from Aldrich Chemical Co.
except where indicated. Bis(1,5-cyclooctadiene)rhodium tri-
1
fluoromethanesulfonate was obtained from Alfa Aesar. H
NMR (300 MHz) and 13C NMR (75.5 MHz) spectra were
obtained on a Varian Gemini-300 spectrometer. Mass spectral
data were collected on a Micromass Autospec magnetic
double focusing mass spectrometer using field desorption
ionization techniques. High-resolution mass spectra were run
by positive ion electrospray on a Waters Model LCT time-
of-flight mass spectrometer in positive ion mode. Gas
chromatography was performed on a Hewlett-Packard 6890
gas chromatograph with flame ionization detection. Chiral
HPLC was performed on a Hewlett-Packard 1050 HPLC
with UV detection. Reverse-phase HPLC was performed on
a Hewlett-Packard 1100 HPLC with UV detection. Optical
rotations were determined on a Rudolph Research Autopol
III polarimeter. Melting points are uncorrected.
Z-2-Methyl-4-(naphthalen-2-ylmethylene)oxazol-5(4H)-
one (5). Acetic anhydride (17.275 L, 183 mol, 10 equiv)
was added to a 50-L round-bottom flask with mechanical
stirrer, condenser, and thermowell. N-acetylglycine (4.304
kg, 36.7 mol, 2 equiv), anhydrous sodium acetate (3.014 kg,
36.7 mol, 2 equiv), and 2-naphthaldehyde (4, 2.87 kg, 18.4
mol) were added. The mixture was heated to 100 °C (no
exotherm noted) to afford a homogeneous solution and was
held for 12 h to consume 99.3% of 4 (GC analysis). The
mixture was allowed to cool to 87 °C and transferred while
hot to a 72-L round-bottom flask with a mechanical stirrer,
addition funnel, and a thermowell in an ice-water cooling
bath. The mixture was cooled to below 30 °C, and water
(2.3 L) was added slowly in portions over 4 h such that the
temperature of the reaction mixture remained below 40 °C
(maximum observed temperature was 28 °C). At this point
22 L of water was added rapidly, resulting in an exotherm
to 38 °C. The mixture was cooled to below 30 °C and then
stirred for 1 h. The solid was isolated by filtration and washed
(18) Ponnusamy, E.; Fotodar, U.; Spisni, A.; Fiat, D. Synthesis 1986, 48-49.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
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475

with 30 L of water followed by 5 L of methanol. The
resulting solid was dried on the nutsche for 8 h, then dried
in a vacuum oven at ambient temperature under a nitrogen
were each cooled to below 30 °C, filtered onto a single
nutsche, and washed with 20 L of water. The solids were
dried on the nutsche for 12 h, then dried in a vacuum oven
with nitrogen purge at 45 °C for 2.5 days (until there was
no residual moisture) to afford 2.062 kg (66% recovery, 42%
overall yield from 4) of 6a as a white powder, mp 153-154
1
purge to afford 6.045 kg of crude 5. H NMR (CDCl3) δ
8.404 (s, 1H); 8.38-8.34 (m, 1H); 7.94-7.83 (m, 3H); 7.59-
7.50 (m, 2H); 7.307 (s, 1H); 2.449 (s, 3H). 13C NMR (CDCl3)
δ 168.0; 166.1; 134.5; 133.9; 133.3; 132.8; 131.6; 131.1;
129.3; 128.7; 128.2; 127.9; 127.8; 126.8; 15.8. HRMS m/z
calcd for C15H12NO2 (M + H+) 238.0868, found 238.0865.
GC (Chirasil L-Valine [Varian] 25 m × 0.25 mm i.d., film
thickness 0.12 µm, 100 °C, 5 min; 100-175 °C, 10°/min;
175 °C, 17.5 min): tR (4) 8.9 min, tR (5) 26.4 min.
1
°C. H NMR (DMSO-d6) δ 9.773 (s, 1H); 8.170 (s, 1H);
7.95-7.91 (m, 3H); 7.779 (d, 1H, J ) 8.79 Hz); 7.58-7.55
(m, 2H); 7.335 (s, 1H); 3.738 (s, 3H); 2.051 (s, 3H).13C NMR
(DMSO-d6) δ 169.5; 165.6; 133.0; 131.1; 130.9; 130.1;
128.4; 128.0; 127.5; 127.1; 126.9; 126.6; 126.4; 52.2; 22.5.
HRMS m/z calcd for C16H16NO3 (M + H+) 270.1130, found
270.1133. Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61;
N, 5.20. Found: C, 71.59; H, 5.92; N, 5.11. GC (Chirasil
L-Valine [Varian] 25 m × 0.25 mm i.d., film thickness 0.12
µm, 200 °C isothermal): tR (6a) 23.3 min.
Methyl 2-Acetamido-3-(2-naphthyl)propenoate (6a).
Methanol (17 L) was charged to a 50-L round-bottom flask,
and crude 5 (6.045 kg, 18.4 mol maximum) prepared above
was added. The mixture was stirred for 30 min, filtered on
a nutsche, and washed two times with 4 L of methanol. The
solids were dried on the nutsche for 3 h and then added to
12 L of methanol cooled to 15 °C in a 72-L round-bottom
flask with a mechanical stirrer, a thermowell, and an addition
funnel. A 25% solution of sodium methoxide in methanol
(160 mL, 0.70 mol mmol, 0.04 equiv based on 2) was added
to the slurry of 5 slowly over 1 h such that the temperature
remained below 30 °C (maximum observed 27 °C). A
homogeneous solution was observed after the addition. The
reaction mixture was allowed to stir at 21 °C for 1 h at which
point TLC analysis (1:4 ethyl acetate:heptane) indicated a
small amount of residual 5. Additional 25% sodium meth-
oxide (25 mL, 0.004 mol, 0.0002 equiv) was added, and the
mixture was stirred at 23-25 °C for 1 h to complete the
reaction (TLC analysis). The stirrer was slowed to minimum
speed, and the reaction mixture was cooled to 15 °C. Cold
water (24 L, prepared by mixing 16 L of water with 8 kg of
ice) was added over 4 h to maintain the temperature below
20 °C (maximum observed 17.2 °C) resulting in a large
amount of tan precipitate. The mixture was cooled to 15 °C
and stirred for 1 h, and the solid was collected by filtration
on a nutsche and washed with 8 L of water. The solid was
dried on the filter for 12 h and then in a vacuum oven at 40
°C under a nitrogen purge for 1 day to afford 3.108 kg (63%
from 4) of crude 6a as a tan powder. Acetone (35 L) was
charged to a 50-L round-bottom flask with a mechanical
stirrer and condenser. The crude 6a (3.108 kg) was added,
and the mixture was heated to 50 °C and stirred until a
homogeneous solution was obtained. Activated carbon
(Darco; 2.33 kg, 0.75 g/g of 6a) was added, and the mixture
was heated to reflux (54 °C) and stirred for 1 h. The mixture
was cooled to below 30 °C, and the charcoal was removed
by vacuum filtration into a 72-L flask with a mechanical
stirrer and a distillation head. The carbon was washed with
15 L of acetone, and the cake was pulled dry. The solution
was distilled at atmospheric pressure (head temperature ca.
56 °C) until 36 L of acetone was removed. The reaction
mixture was cooled to 38 °C, and half of the mixture was
transferred to the original (cleaned) 50-L flask, and each
portion was cooled to below 30 °C. The product was
precipitated by adding 35 L of water to each flask, resulting
in an exotherm (heat of mixing) to about 35 °C. The mixtures
Methyl R-2-Acetamido-3-(2-naphthyl)propionate (R-
7a). To a 22-L drop-bottom pressure vessel with an addition
port and a gas inlet dip tube was charged 16.5 L of toluene.
Purified 6a (2.062 kg, 7.66 mol) was added slowly with
stirring to avoid clumping of the solid. The resulting slurry
was degassed with argon for 30 min using the dip tube.
During this time a catalyst solution was prepared by
combining ligand S,R-3 (2.81 g, 4.6 mmol, 0.0006 equiv)
and bis(1,5-cyclooctadiene)rhodium(I) trifluoromethane-
sulfonate (1.79 g, 3.8 mmol, 0.0005 equiv) in 50 mL of
argon-degassed methanol. After the degassing of the reaction
mixture was complete, the headspace of the vessel was
pressurized with 15 psig of argon and vented three times.
The headspace was pressurized with 2 psig of argon, and
the catalyst solution was added via a gastight syringe. The
vessel was then pressurized to 15 psig with hydrogen, vented,
and then held under a constant 15 psig hydrogen pressure
with subsurface hydrogen introduction (via the dip tube) and
the reaction was followed by hydrogen uptake using a mass
flowmeter. After about 1.5 h the mixture became homoge-
neous during which time an exotherm to 33 °C was noted.
The reaction was stirred under hydrogen for a total of about
6 h. Chiral GC analysis of the reaction mixture indicated
>99.9% conversion to R-7a with 97.9% ee. The resulting
solution of R-7a was taken directly to the next step. On small
scale, the product could be isolated by solvent removal and
recrystallized from toluene/heptane to afford R-7a in >95%
1
yield with >99% ee, mp 95-96 °C. H NMR (CDCl3) δ
7.85-7.75 (m, 3H); 7.553 (s, 1H); 7.47 (m, 2H); 7.218 (d,
1H, J ) 8.52 Hz); 6.01 (br s, 1H); 4.966 (q, 1H, J ) 6.04
Hz); 3.727 (s, 3H); 3.314 (dd, 1H, J ) 5.77, 13.74 Hz); 3.244
(dd, 1H, J ) 6.04, 14.01 Hz); 1.973 (s, 3H). 13C NMR
(CDCl3) δ 172.3; 169.9; 133.6; 133.5; 132.5; 128.3; 128.1;
127.7; 127.6; 127.3; 126.3; 125.8; 53.3; 52.4; 38.1; 23.0.
HRMS m/z calcd for C16H18NO3 (M + H+) 272.1287, found
272.1283. Chiral GC (Chirasil L-Valine [Varian] 25 m ×
0.25 mm i.d., film thickness 0.12 µm, 185 °C isothermal,
15 psig He): tR(R-7a) 15.5 min, tR(S-7a) 16.0 min. Chiral
HPLC (250 × 4.6 mm Chiralpak AD-H, 90:10 hexane:2-
propanol, 1 mL/min, λ ) 254 nm): tR (R-7a) 13.2 min, tR
(S-7a) 16.2 min. [R]24D ) -35.3 (c 1.00, ethanol); [R]24
)
D
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-104.7 (c 0.99, CHCl3), indicating the R enantiomer of
7a.13a,17
according to TLC analysis (neutralized sample, triethylamine-
deactivated plate, 2:1 ethyl acetate:heptane). The reaction
mixture was cooled to ambient temperature, and sodium
hydroxide (2 M, 4.6 mL, 9.2 mmol, 3 equiv) was added to
afford a solution with a small amount of precipitate. The
pH of the mixture was found to be ca. 12, and it was acidified
to pH 6 by the addition of 86 µL (1.5 mmol) of acetic acid,
resulting in the precipitation of a large amount of white solid.
The reaction mixture was stirred at ambient temperature for
2 h, filtered, and washed with water. The resulting white
solid was dried in a vacuum oven at ambient temperature
with a nitrogen purge to afford 650 mg (98%) of R-1 which
was 99.8% ee (determined by sequential conversion to R-2
and R-9 as indicated below and analysis by chiral HPLC).
1H NMR (NaOD/D2O) δ 7.86-7.81 (m, 3H); 7.683 (s, 1H);
7.54-7.45 (m, 2H); 7.390 (d, 1H, J ) 8.52 Hz); 3.60-3.55
(m, 1H); 3.159 (dd, 1H, J ) 5.49, 13.73 Hz); 2.938 (dd,
1H, J ) 7.97, 13.46 Hz). 13C NMR (NaOD/D2O) δ 185.0;
138.9; 135.9; 134.7; 130.7; 130.6; 130.4; 130.4; 130.3; 129.1;
128.5; 60.1; 43.9. HRMS m/z calcd for C13H14NO2 (M +
H+) 216.1025, found 216.1037. [R]25D ) +14.9 (c 0.43, 0.04
M HCl). The positive rotation indicates the R enantiomer of
1.17
N-Boc-R-2-naphthylalanine (R-2). Water (14.89 L) was
added to a 50-L round-bottom flask with a mechanical stirrer,
thermowell, and condenser. Aqueous hydrochloric acid (3
M, 4.27 L, 12.8 mol, 2.0 equiv) was added. Methanesulfonate
salt R-8 (2.082 kg, 6.4 mol) was added, and the mixture was
stirred to afford a homogeneous solution. The mixture was
heated to 95 °C for 12 h at which point 1H NMR analysis of
an aliquot indicated >99% conversion of 8 to 1.21 The
reaction mixture was cooled to 40 °C and transferred to a
72-L round-bottom flask (in a cooling bath) equipped with
a mechanical stirrer, thermowell, addition funnel, and
condenser. The mixture was cooled to 33 °C, and 50%
sodium hydroxide (2.66 kg, 33.25 mol, 5.2 equiv) was added
over 2 h. Di-tert-butyl dicarbonate (Boc anhydride; 1.676
kg, 7.7 mol, 1.2 equiv) was added over 1 h such that the
temperature remained below 35 °C (maximum observed 34.9
°C). The reaction mixture was cooled to below 30 °C, the
cooling was removed, and the mixture was stirred for 6 h
and then analyzed by 1H NMR to indicate >99% conversion
of 1 to 2.22 HCl (3 M, 4.685 L, 14.1 mol, 2.2 equiv) was
added slowly over 6 h, resulting in the precipitation of a
solid (but not much observable gas evolution). The mixture
was stirred for 1 h and was checked and found to be acidic
(pH 1-2). The solid was isolated by filtration, washed with
1.1 L of water, and dried on the nutsche for 12 h. Water
(12.5 L) was added to the flask and the contents of the
nutsche were added. The heterogeneous mixture was stirred
for 30 min and filtered, and the product cake was washed
Methyl R-2-Amino-3-(2-naphthyl)propionate Meth-
anesulfonic Acid Addition Salt (R-8). The toluene solution
of crude R-7a (7.66 mol maximum) was added to a 50-L
flask with a mechanical stirrer, stripping head, and addition
funnel. The solvent was stripped at 60 mm vacuum by
heating in stages from 50 to 114 °C until no further distillate
was removed. The residual material was cooled to 40 °C at
which point it solidified. Methanol (3.85 L) was added and
the material was dissolved by stirring while slowly lowering
the stirrer paddle from the top of the liquid. Methanesulfonic
acid (1.103 kg, 11.5 mol, 1.5 equiv) was added over 50 min
so that the temperature of the solution remained below 60
°C. The mixture was heated to reflux (68 °C) for 72 h to
afford complete consumption of 7a by TLC analysis (2:1
ethyl acetate:heptane).19 The reaction mixture was cooled
to 31 °C, and 2-propanol (7.685 L) and heptane (7.685 L)
were added to complete the precipitation. The mixture was
stirred while cooling to below 28 °C, at which point the solid
was isolated by filtration and washed with 2 L of 2-propanol
and 2 L of heptane. The product was air-dried on the nutsche
for 6 h, then added to 4 L of methanol in a 50-L flask with
a mechanical stirrer, thermowell, and condenser, and washed
in with 200 mL of methanol. The mixture was heated to
reflux for 15 min to afford a homogeneous solution and then
cooled to 33 °C. 2-Propanol (9 L) and heptane (9 L) were
added to complete the precipitation of 8, and the mixture
was cooled to 30 °C and stirred for 1 h. The solid was
isolated by filtration and washed sequentially with 1 L of
2-propanol and 1 L of heptane. The solid was air-dried for
2 h on the nutsche and then dried in a vacuum oven at
ambient temperature under a nitrogen purge to afford 2.082
kg (84% overall from 6a) of R-8a, mp 197-198 °C, that
possessed 99.9% ee as determined by conversion to the
corresponding acetamide 7a and chiral GC analysis.20 1H
NMR (DMSO-d6) δ 8.442 (br s, 3H); 7.93-7.86 (m, 3H);
7.758 (s, 1H); 7.53-7.51 (m, 2H); 7.381 (dd, 1H, J ) 1.37,
8.52 Hz); 4.437 (t, 1H, J ) 6.59 Hz); 3.699 (s, 3H); 3.276
(d, 2H, J ) 6.59 Hz); 2.324 (s, 3H). 13C NMR (DMSO-d6)
δ 169.4; 133.0; 132.3; 128.2; 128.2; 127.6; 127.5; 127.4;
126.2; 126.0; 53.3; 52.7; 39.7; 36.1. HRMS m/z calcd for
C14H16NO2 (M-CH3SO3) 230.1181, found 230.1187. Anal.
Calcd for C15H19NO5S: C, 55.37; H, 5.89; N, 4.30. Found:
C, 55.63; H, 5.92; N, 4.19. [R]25 ) +2.2 (c 1.03, H2O).
D
R-2-Naphthylalanine (R-1). Methanesulfonate salt R-8
(>99.7% ee; 1.00 g, 3.07 mmol) was combined with 3 M
HCl (2.05 mL, 6.14 mmol, 2.0 equiv). The mixture was
heated to 95 °C for 22 h to consume virtually all of 8
(19) The reaction time can be signficantly shortened by performing the reaction
under pressure above the boiling point of the solvent (reaction times as
short as 40 min have been observed using a microwave reactor at 115 °C).
These types of facilities were unavailable to us during scale-up.
(20) Methanesulfonate 8 (8.1 mg, 0.025 mmol) was slurried in 1 mL of
dichloromethane, and triethylamine (11 µL, 0.079 mmol, 3.1 equiv) was
added to afford a homogeneous solution. Acetic anhydride (6 mL, 0.064
mmol, 2.5 equiv) was added and the mixture was allowed to sit for 1 h.
The mixture was diluted with 3 mL of ethyl acetate, then washed with 3 M
HCl (1 mL) and saturated sodium bicarbonate (1 mL). The solution of 7a
thus generated was dried (magnesium sulfate) and analyzed directly by either
chiral GC or HPLC to determine the ee.
(21) A sample of the reaction mixture (150 µL) was concentrated at reduced
pressure, dissolved in D2O, and concentrated once more. The resulting
material was analyzed by 1H NMR in D2O by comparing the integration of
the product peak (one proton) at 4.37 ppm with the starting material peak
(three protons) at 3.75 ppm to determine the conversion.
(22) A sample of the reaction mixture (0.20 mL) was concentrated at reduced
pressure, dissolved in D2O, and concentrated once more. The resulting
material was analyzed by 1H NMR in D2O by comparing the integration of
the product peak (one proton) at 4.25 ppm with the starting material peak
(one proton) at 3.55 ppm to determine the conversion.
Vol. 9, No. 4, 2005 / Organic Process Research & Development
•
477

with 2 L portions of water until the pH of the wash was
above 3 (total 5 washes). The product was air-dried on the
nutsche for 2 h and then dried at 50 °C in a vacuum oven
with nitrogen purge until no moisture remained to afford
1.868 kg (93%) of R-2 which was >99% chemically pure
and >99.5% ee as determined by conversion to the methyl
ester R-9 and chiral HPLC analysis (see below), mp 91-93
°C. The NMR spectrum indicates two isomers, syn and anti
rotamers of the carbamate. 1H NMR (CDCl3) major isomer
δ 7.82-7.86 (m, 3H); 7.631 (s, 1H); 7.47-7.44 (m, 2H);
7.319 (d, 1H, J ) 8.52 Hz); 5.018 (br d, 1H, J ) 7.42 Hz);
4.663 (br q, 1H, J ) 7.14 Hz); 3.39-3.33 (m, 1H); 3.24-
3.17 (m, 1H); 1.381 (br s, 9H). minor isomer δ 7.82-7.86
(m, 3H); 7.631 (s, 1H); 7.47-7.44 (m, 2H); 7.319 (d, 1H, J
) 8.52 Hz); 6.42 (m, 1H); 4.66 (m, 1H); 3.1-3.0 (m, 2H);
1.177 (br s, 9H). 13C NMR (DMSO-d6) δ 173.6; 155.4;
135.7; 133.0; 131.8; 127.6; 127.5; 127.4; 127.4; 127.3; 125.9;
125.4; 78.0; 55.1; 36.7; 28.1. FDMS: m/z 314.109 (M -
H+). HRMS m/z calcd for C18H22NO4 (M + H+) 316.1549,
found 316.1568. HPLC (150 × 4.6 mm Aquasil C18, 5 µ,
70:30 0.1% aqueous H3PO4:acetonitrile; 20 min, 5:95 0.1%
aqueous H3PO4:acetonitrile, 10 min, 1.0 mL/min, λ ) 225
nm): tR 10.4 min. [R]25 ) -17.3 (c 1.04, CHCl3).
D
Methyl N-Boc-R-2-naphthylalanine (R-9). N-Boc-R-2-
naphthylalanine (R-2) (100 mg, 0.32 mmol) was dissolved
in 2 mL of acetone. Potassium hydrogen carbonate (50 mg,
0.50 mmol, 1.6 equiv) was added followed by iodomethane
(50 µL, 0.80 mmol, 2.5 equiv). The mixture was heated to
reflux for 12 h, then cooled to ambient temperature. The
reaction mixture was diluted with ethyl acetate, washed with
aqueous sodium bicarbonate (10 mL), 2 M sodium thiosulfate
(5 mL), and water (10 mL). The organic layer was dried
with magnesium sulfate and concentrated to afford 0.11 g
of R-9 (99%) which was 99.7% ee by chiral HPLC analysis.
1H NMR (CDCl3) δ 7.80 (m, 3H); 7.586 (s, 1H); 7.45 (m,
2H); 7.26 (m, 1H); 5.000 (br d, 1H, J ) 7.14 Hz); 4.677 (q,
1H, J ) 6.87 Hz); 3.713 (s, 3H); 3.35-3.15 (m, 2H); 1.399
(s, 9H). Chiral HPLC (250 mm × 4.6 mm Chiralpak AD-H,
97:3 hexane:2-propanol, 1 mL/min, λ ) 254 nm): tR (R-9)
34.0 min, tR (S-9) 36.8 min.
Received for review February 23, 2005.
OP050026G
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