Practical enantioselective synthesis of β-substituted-β-amino esters

Article abstract of DOI:10.1021/jo050177h

A practical, large-scale synthesis of a β-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the

Full text of DOI:10.1021/jo050177h

Practical Enantioselective Synthesis of â-Substituted-â-amino
Esters
Alok K. Awasthi,* Mark L. Boys, Kimberly J. Cain-Janicki, Pierre-Jean Colson,
Wendel W. Doubleday, Joseph E. Duran, and Payman N. Farid
Pfizer Global Research & Development, Pfizer Inc., Ann Arbor, Michigan 48105
alok.k.awasthi@pfizer.com
Received January 27, 2005
A practical, large-scale synthesis of a â-amino ester 1 was developed. A chiral imine derived from
(S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with
high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue
of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of
methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the
imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with
p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the
amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and
hydrochloride salt formation in a one-pot process. The method was successfully applied toward the
synthesis of a wide variety of â-amino esters.
Introduction
tedious for a manufacturing synthesis of 1. Alternatively,
1 could be prepared also by transformation of aspartic
acid5 or by an enzymatic resolution method.6 Our strategy
The development of enantioselective syntheses of â-
amino acids is of constant interest in organic chemistry1
due to the importance of this subunit in biologically active
compounds. Our interest in this field stemmed from the
need of an efficient scaleable synthesis of the alkyne
derivative 1, a key intermediate in the preparation of
Xemilofiban, a platelet aggregation inhibitor.2
(1) (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3. (c) Cardillo,
G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117. (d) Davis, F. A.; Zhou,
P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13. (e) Juaristi, E. Enantio-
selective Synthesis of â-Amino Acid; Wiley-VCH Inc.: New York, 1997.
(f) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983. (g)
Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem.
1999, 6, 955. (h) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1, 1.
(i) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(2) Boys, M. L.; Cain-Janicki, K. J.; Doubleday, W. W.; Farid, P. N.;
Kar, M.; Nugent, S. T.; Behling, J. R.; Pilipauskas, D. R. Org. Process
Res. Dev. 1997, 1, 233.
(3) Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams,
K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjoeng, F. S.; Lindmark,
R. J.; Toth, M.; Zupec, M.; McMackins, D. E.; Adams, S. P.; Miyano,
M.; Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacquin, P.;
Nicholson, N.; Panzer-Knodle, S. G.; Haas, N. F.; Page, J. D.; Szalony,
J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen,
L. P. J. Med. Chem. 1995, 38, 2378.
(4) Babiak, K.; Babu, S.; Behling, J. R.; Boys, M. L.; Cain-Janicki,
K. J.; Doubleday, W. W.; Farid, P.; Hagen, T. J.; Hallinan, E. A.;
Hansen, D. W., Jr.; Korte, D. E.; McLaughlin, K. T.; Medich, J. R.;
Nugent, S. T.; Orlovski, V.; Park, J. M.; Peterson, K. B.; Pilipauskas,
D. R.; Pitzele, B. S.; Tsymbalov, S.; Stahl, G. L. U.S. Patent 5536869,
July 16, 1996.
Early routes to 1 involved the synthesis of a racemic
precursor followed by either formation of a Mandelate
ester and chromatographic separation2,3 or a resolution
with Mandelic acid.4 However, the inefficient resolution
associated largely with the difficulty of recycling the
undesired enantiomer made the method expensive and
(5) Boys, M. L. Tetrahedron Lett. 1998, 39, 3449.
(6) (a) Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D.
Biorg. Med. Chem. Lett. 1997, 7, 1699. (b) Topgi, R.; Ng, J. S.; Landis,
B.; Wang, P. T.; Behling, J. R. J. Biorg. Med. Chem. 1999, 7, 2221. (c)
Landis, B.; Mullins, P. B.; Mullins K. E.; Wang, P. T. Org. Process Res.
Dev. 2002, 6, 539.
* Corresponding author. Phone: 734-622-7215. Fax: 734-622-5165.
10.1021/jo050177h CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/03/2005
J. Org. Chem. 2005, 70, 5387-5397
5387

Awasthi et al.
SCHEME 1
SCHEME 2
TABLE 1. Ratio of Isomer anti-2/syn-2/oxa-2a in
involved the diastereoselective 1,2 addition of an organo-
metallic reagent to a chiral imine as shown in Scheme
1.
Solution
entry
R
1H NMR solvent/T anti-2/syn-2 oxa-2a (%)
The 1,2-addition of organometallic reagents to chiral
imine for the preparation of enantioenriched amines has
received considerable attention.7 While this methodology
has been mostly used to generate chiral amines, it has
also been used in the preparation â-amino esters.8 To our
knowledge, only a few examples of alkynyl â-amino ester
preparation have been reported.8f-h Similarly, there are
few examples of the application of this methodology to
prepare chiral propargylic amines.9 Among the methods
of interest for the synthesis of â-amino acids, the addition
of Reformatsky-type reagents to chiral imines or oxa-
zolidines derived from phenylglycinol8a-d or to chiral
sulfonyl imines1d,10 is very attractive due to the high
stereoselectivity often observed. Drawbacks of these
methodologies are that the methods described usually
involve conditions or reagents generally not suitable for
large-scale synthesis or are incompatible with the alkyne
functionality. Herein, we report the development of a
practical and scalable synthesis using the Reformatsky
reaction methodology and its generalization to a wide
variety of â-amino esters.
1
2
3
4
6
CH2OH
CDCl3/25 °C
THF-d8/25 °C
NMP-d9/25 °C
NMP-d9/-10 °C
CDCl3
2/1
20
4/1
traces
traces
traces
NAa
94/6
96/4
3/2
CH3
a NA: not applicable.
dependent equilibrium is typical for aryl-imines derived
from amino alcohols.11 Noteworthy is that the imines of
3-trimethylsilylpropynal and (S)-valine methyl ester12 or
R-methylbenzylamine13 were reported as a mixture of
anti and syn isomers. The imine 2b derived from R-
methylbenzylamine was prepared and used as a reference
to compare with the imine 2a. As described in the
literature13 the imine 2b was obtained as a mixture of
isomers (anti/syn, 3/2 in CDCl3) and the major isomer
was confirmed as an anti isomer via a nOe study (see
the Experimental Section), 1H NMR, and 13C NMR.14 The
conformation of the major isomer in 2a was assumed to
be anti based on this study.
To study the preparation of 4a from imine 2a, the
reagent of choice appeared to us to be the Reformatsky
reagent 3 (BrZnCH2CO2tBu‚THF), as it was reported to
be a reasonably stable isolable well-characterize solid as
a dimer form.15 While this reagent was easily prepared
on a gram scale and was well characterized, a multi-
kilogram preparation had not been described. We re-
investigated this synthesis to optimize the preparation
and isolation conditions. Activation of zinc was performed
in situ in THF with dibromoethane at reflux temper-
ature16a or with trimethylsilyl chloride16b at 22 °C. The
reagent was then formed at 50 °C by the controlled
addition of tert-butyl bromoacetate to a stirred suspension
of the activated zinc. Such conditions led to higher yield
and adequate exothermic control of the reaction upon
Results and Discussion
The imine 2a was prepared from phenylglycinol and
3-trimethylsilyl-2-propynal in THF in the presence of
MgSO4 or in toluene followed by the azeotropic removal
of water by distillation. The imine was isolated by
precipitation with heptane. It is interesting to note that
the imine in solution presented variable syn/anti ratios
of isomers in equilibrium with a mixture of oxazolidines
isomers depending on the nature of the solvent used for
NMR. In a slightly acidic solvent such as CDCl3, the syn/
anti ratio was 2/1 with up to 20% of oxazolidine isomers
detectable. The anti form is increased in a nonacidic
solvent like THF or in polar solvents such as NMP. The
anti/syn ratios were 4/1 at 20 °C in THF-d8 or 94/6 at 20
°C (96/4 at -10 °C) in NMP-d9. Only traces of oxa-
zolidines were then observed. This type of solvent-
(11) (a) Miao, C. K.; Sorcek, R.; Jones, P.-J. Tetrahedron Lett. 1993,
34, 2259. (b) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron
Lett. 1992, 33, 235.
(12) Van Maanen, H. L.; Kleijn, H.; Jastrzebski, J. T. B. H.; Verweiz,
J.; Kieboom, A. P. G.; van Koten, G. J. Org. Chem. 1995, 60, 4331.
(13) Van der Steen, F. H.; Kleijn, H.; Britovsek, G. J. P.; Jastrzebski,
J. T. B. H.; van Koten, G. J. Org. Chem. 1992, 57, 3906. Imine 2b was
reported to be a 70/30 mixture of anti/syn isomers. See also ref 8g. We
prepared the imine 2b and reconfirmed the stereochemistry by nOe
experiments. See experimental detail.
(7) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895. (b) Bloch, R. Chem. Rev. 1998, 98, 1407. (c) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069 (d) Ellman, J. A.; Owens, T.
D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(8) (a) Mokhallalati, M. K.; Wu, M. J.; Pridgen, L. N. Tetrahedron
Lett. 1993, 34, 47. (b) Wu, M. J.; Pridgen, L. N. Synlett 1990, 636. (c)
Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883. (d) Andre´s, C.;
Gonza´lez, A.; Pedrosa, R.; Pe´rez-Encabo, A. Tetrahedron Let. 1992, 33,
2895. (e) Marcotte, S.; Pannecoucke, X.; Feason, C.; Quirion, J.-C. J.
Org. Chem. 1999, 64, 8461. (f) Rico, J. G.; Lindmark, R. J.; Rodgers T.
E.; Bovy, P. R. J. Org. Chem. 1993, 58, 7948. (g) Hattori, K.; Yamamoto,
H. Synlett 1993, 2, 129. (h) Tang, T. P.; Ellman, J. A. J. Org. Chem.
2002, 67, 7819.
(14) Alvaro, G.; Savoia, D.; Valentinetti, M. R. Tetrahedron 1996,
38, 12571.
(15) (a) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron 1984, 40,
2781. (b) Dekker, J.; Budzelaar, P. H. M.; Boersma, J.; van de Kerk,
G. J. M.; Spek, A. L. Organometallics 1984, 3, 1403. (c) Dekker, J.;
Schouten, A.; Budzelaar, P. H. M.; boersma, J.; Van Der Kerk, G. J.
M.; Spek, A. L.; Duisenberg, A. J. M. J. Organomet. Chem. 1987, 320,
1.
(9) Enders, D.; Schankat, J. Helv. Chim. Acta 1995, 78, 970. Hattori,
K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 1151.
(10) Robinson, A. J.; Wyatt, P. B. Tetrahedron 1993, 49, 11329.
(16) (a) Erdik, E. Tetrahedron 1987, 43, 2203. (b) Picotin, G.;
Miginiac, P. J. Org. Chem. 1987, 52, 4796.
5388 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Substituted-â-amino Esters
SCHEME 3
SCHEME 4
choice for this reaction. Finally, optimal conditions were
identified when the reagent was added to the imine 2a
in NMP at -10 °C as shown in Scheme 4. Diastereo-
selectivity of 95-98% was then achieved.
TABLE 2. Selectivity of the Coupling
The selectivity in this type of reaction is often ex-
plained by the formation of an organometallic chelate
giving a conformationally rigid structure and allowing
for the addition of the organometallic reagent on the less
hindered face.7 We were able to isolate such an interme-
diate by taking advantage of the poor reactivity in THF.
Thus after reaction of 1 equiv of reagent 3 and imine 2a
in THF, no reaction was observed and it was possible to
isolate the chelate 5 after precipitation with heptane. IR
spectra of compound 5 showed a clear difference from the
imine 2a with a shift of the imine band from 1709 to 1720
cm-1 and a disappearance of the OH band. Broad peaks
characterized 1H NMR of 5 in THF-d8 although 1H NMR
in NMP-d9 or DMF-d7 showed similar spectra to the
imine 2a. Reaction of this isolated chelate with an
additional equivalent of reagent 3 in NMP provided
compounds 4a/4b with selectivity comparable to previous
reactions starting from imine 2a and isolated reagent 3
in NMP.
entry
solvents
conditions T (°C) t (h)
% de
1
2
THF
DMF
DMF/THF 20%
DMF/THF 40%
DMSO
DMSO/THF 20%
NMP
NMP
NMP/THF 25%
DMAc
1,4-dioxane
Aa
A
A
A
A
A
A
Bb
A
B
A
20
-5
0
5
1
1
1
1
1
1
1
60-80
96
3
80
4
0
70
5
10
0
97
6
79
7
-10
-10
-10
20
95
8
95 to 98c
8
0.5 80d
9
7
20
70
90
10
20
a Condition A: a solution of imine 2a (1 equiv) was added to a
solution of 3 (2 equiv) at the given temperature. Reaction were
quenched with a solution of NH4Cl and HCl. b Condition B: solid
3 (2 equiv) was added to the solution of imine 2a at the given
temperature. Reactions were quenched with a solution of NH4Cl
and HCl. c Yield for 4a-SS isomer isolated by chromatography on
silica gel was 84%. d Yield determined by GC quantitation with
an external standard of 90%.
As stated above, the reaction performed in THF did
not proceeded with the addition of 1 equiv of reagent 3
and proceeded slowly upon the addition of another
equivalent of 3 with low selectivity (Figure 1). In contrast,
when the reaction was performed in NMP, after the
addition of 1 equiv of reagent, the reaction was 50%
complete with high diastereoselectivity and was complete
after the addition of the second equivalent of 3 (Figure
2). Mixing the sequence as shown in Scheme 4 (i.e. adding
the first equivalent of 3 in THF and the second equivalent
of 3 in NMP) gave comparable selectivity. This suggests
that the intermediate was the same in either solvent. One
equivalent of reagent 3 was necessary to consume the
hydroxyl proton in both cases to yield the intermediate
5. This had greater reactivity in NMP and reacted
spontaneously with a second equivalent of the reagent
3. The origin of the difference in selectivity and reactivity
when the reaction is performed in a polar solvent like
NMP vs THF may be speculated. One explanation is the
scale-up. Compound 3 was then isolated as a solid after
precipitation from the reaction mixture upon cooling. The
solid reagent could be stored at -20 °C and was found
to be stable at that temperature for at least 6 months.
Alternatively, THF was removed under reduced pressure
or by decantation and replaced with the coupling reaction
solvent (NMP, DMF, or DMSO) and use directly in
solution. The solution of the reagent was found to be less
stable and could only be stored for several hours at
subzero temperatures.
Coupling reactions were performed initially in THF
with excess of the solid Reformatsky reagent 3. Results
showed that the reaction proceeded with medium to low
selectivity, long reaction times (over 5 h at 22 °C), and
incomplete conversion (Table 2, entry 1) to give a mixture
of diastereoisomers 4a/4b.
Polar solvents were then screened in an attempt to
increase the solubility of the reagent and to enhance the
rate and the selectivity of the reaction. When the reaction
was performed in polar aprotic solvents such as DMF,
DMSO, or NMP, the reaction was found to proceed in a
dose controlled manner with a higher diastereoselectivity.
Surprisingly when the reaction was performed in a
mixture of those polar solvents with THF, the selectivity
dropped significantly. DMF was found to react readily
with the Reformatsky reagent while NMP reacted only
slowly at room temperature and insignificantly at low
temperatures (below 0 °C).17 Elimination to form an ene-
yne byproduct was observed to a great extent in DMSO
due to the higher operating temperature associated with
this solvent.18 NMP, therefore, became the solvent of
(17) The Reformatsky reagent was found to react with DMF and
NMP as shown below. This side reaction is, however, avoided in NMP
at temperatures below 0 °C.
(18) This was also observed in the reaction of zinc enolate with
imine: Van Maanen, H. L.; Johan, H. K.; Jastrzebski, J. T. B. H.; van
Koten, G. Recl. Trav. Chim. Pays-Bas 1994, 113, 567.
J. Org. Chem, Vol. 70, No. 14, 2005 5389

Awasthi et al.
SCHEME 5
SCHEME 6a
FIGURE 1. Formation of 4a/4b in THF. Imine 2a (1 equiv)
and reagent 3 (2 equiv) were mixed together in THF.
a Reagents and conditions: (a) PTSA (1 equiv), THF, heptane,
(94%); (b) (1) PTSA, ethanol, reflux, (2) NaHCO3, MTBE, (3)
NaOEt, ethanol, rt, 1.5 h, (4) precipitation with HCl, (5) recrys-
tallization ACN, MTBE (77.7% overall yield).
supports the idea that an imino-alcohol residue was
critical for the formation of a chelate in order to obtain
good selectivity and good reactivity.
FIGURE 2. Formation of 4a in NMP. Reagent 3 (2 equiv)
was added in portions at -10 °C to imine 2a (1 equiv).
The presence of the alcohol residue offers the advan-
tage of a removal of the auxiliary by oxidative cleavage.
The presence of the alkynyl group precludes hydro-
genolysis as a cleavage method. Oxidative cleavage
protocols described in the literature usually involve the
use of lead tetraacetate in dichloromethane or methanol.
This reagent due to its toxicity and the need to dispose
of the lead containing waste stream is generally avoided
in a pharmaceutical manufacturing setting. There are
few reports of the oxidative cleavage of amino-alcohol
with periodic acid20 or sodium periodate,11 usually with
low yield for the latter.
The oxidative cleavage with periodate and periodic acid
was studied with a mixture of4a/4b. Periodic acid gave
typically a very complicated reaction mixture in our
hands, so our attention focused on the use of sodium
periodate. As previously described in the literature when
using periodic acid,20 we quickly identified the need for
using a formaldehyde scavenger such as methylamine to
avoid the formation of an oxazolidine as a major byprod-
uct (reaction of the amino alcohol residue in 4a/4b with
benzaldehyde, the byproduct of the cleavage). As shown
in Scheme 5, the reaction was performed by reacting a
mixture of isomers 4a/4b (80-90/20-10) with sodium
periodate in the presence of methylamine in ethanol/
water. To our surprise we found that the major isomer
(SR)-4a reacted preferentially under the reaction condi-
tions and the minor isomer (RR)-4b was left intact (or
partially consumed) in solution. The oxidative cleavage
proceeded therefore as a kinetic resolution. The imine 6
and the sodium iodate salts cocrystallized as the reaction
proceeded and the product was isolated as a mixture of
inorganic salts and 6 and the unreacted diastereoisomer
4b was washed out in the mother liquor. The imine 6
was then separated from the salts by dissolution in THF
and removal of the salts by filtration. Imine 6 was
preponderance of the anti conformer in NMP (Table 1).
The syn conformation of the imine would lead to the (SR)-
4b isomer (minor) assuming a rigid structure for the
chelate, whereas the anti isomer would lead to the major
isomer (SS)-4a. Higher selectivity should therefore be
observed in NMP, where mostly the anti form of the
imine 2a was observed. Another probable factor is the
change in the reagent structure, from a dimeric form in
THF to a monomeric form in a polar aprotic solvent, as
proposed in the literature.15b This could explain the
increased reactivity observed in such solvents as the
monomeric species has been demonstrated by calculation
to be the likely reactive species for a simple Reformatsky
coupling.19
The stereochemistry of the new asymmetric center was
determined by comparison of the final compound 1 with
material prepared by transformation of aspartic acid.5
The SS selectivity is in good agreement with similar
transformations of chiral imines by an organometallic
reagent.7
The effect of the chiral auxiliary was briefly studied.
When the coupling was performed with imine 2b derived
from methylbenzylamine, poor selectivity reactivity with
the reagent 3 in THF or NMP was observed. This result
(19) (a) Mainz, J.; Arrieta, A.; Lopez, X.; Ugalde, J. M.; Cossio, F.
P.; Lecea, B. Tetrahedron Lett. 1993, 34, 6111. (b) Dewar, M. J. S.;
Merz, K. M., Jr. J. Am. Chem. Soc. 1987, 109, 6553.
(20) Chang, Z.-Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3475.
5390 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Substituted-â-amino Esters
SCHEME 7a
a Reagents and conditions: (i) (S)-phenylglycinol, MgSO4, toluene; (ii) 3 (2 equiv), NMP/THF, -5 °C (9a to 9d) or DMSO, rt (9e and 9f);
(iii) NaIO4, MeOH, MeNH2 for 10a to 10d and Pb(OAc)4 for 10e and 10f, MeOH; (iv) pTSA, EA.
SCHEME 8a
TABLE 3.
entry
R
9
10
12a
1
2
3
4
5
6
a
b
c
d
e
f
88.9%b
not isolated
not isolated
70.5% (isolated)
not isolated
not isolated
85%*
63%
49%
55%
65%
43%
NA
Not isolated
91.4%b
93.3%b
not isolated
not isolated
a Overall isolated yield from imines 9 (3 steps) or aldehyde 8.
b Isolated from heptane slurry.
obtained with ee > 99% and a yield of 91% based on the
major isomer 4a.
The imine was hydrolyzed in the presence of p-
toluenesulfonic acid (PTSA) monohydrate and the amine
7 was isolated as the PTSA salt by precipitation from
THF/heptane. Thus mixing a solution of 6 in THF with
PTSA (1 equiv) followed by addition of heptane led
quickly to the precipitation of 7, which was isolated by
filtration in quantitative yield. Compound 1 was then
obtained by successive treatment of 7 with an excess of
PTSA in EtOH, neutralization followed by reaction with
sodium ethoxide in ethanol, and precipitation of 1 with
HCl and recrystallization from acetonitrile. This succes-
sion of transformations was performed without isolation
and achieves sequentially the transesterification and the
desilylation followed by formation and isolation of the
hydrochloride salt as shown in Scheme 6. The title
compound 1 was obtained in 77.7% yield.
a Reagents and conditions: (i) K2CO3, DMF, MEMCl; (ii) (S)-
phenylglycinol, MgSO4, toluene; (iii) 3 (2 equiv), NMP/THF, -5
°C; (iv) Pb(OAc)4‚MeOH; (v) (1) pTSA, EtOH, (2) THF/heptane
precipitation.
periodate and methylamine in ethanol followed by forma-
tion of the corresponding pTSA salt with p-toluene-
sulfonic acid monohydrate.
The transformation of alkyl imines 9e and 9f to their
corresponding â-amino esters proved to be more delicate.
The corresponding imines were found to be less reactive
than previously encountered for unsaturated derivative.
Higher temperature (room temperature vs -5 °C), longer
reaction time (over 20 h), and an excess of reagent 3 were
required. DMSO was chosen as preferred solvent as to
avoid reaction of NMP with 3.17 Thus, using DMSO as
solvent, in both cases studied, the selectivity of the
coupling was very high. In addition, the sodium periodate
procedure did not perform efficiently for the oxidative
cleavage in the case of the tert-butyl derivative and was
not attempted in the case of 10f. Lead tetraacetate in
MeOH was used successfully replacing sodium periodate
in the preparation of 12e. It could be noted that in the
case of the alkyl derivatives, hydrogenolysis could be used
rather than the oxidative method.
After demonstrating the generality of the Reformatsky
coupling method with aryl, alkynyl, and alkyl derivatives,
our attention focuses on the preparation of 3-amino-3-
(3,5-dihalo-2-hydroxyphenyl)propionic acid ethyl ester 18
as shown in Scheme 8. Our interest in that material
stemmed from a need of multigram to kilogram quanti-
ties of that type of â-amino acid for the development of
novel API acting as RVâ3 integrin inhibitors.21
With that background in hand, the preparations of
several â-amino acids were demonstrated and are sum-
1
marized in Scheme 7 and in Table 3. H NMR of the
products of the Reformatsky coupling 10 determined the
diastereoselectivities of the syntheses. The stereochem-
istry of the final products was assigned by similarity with
the alkynyl derivative.
The imines 9a-f were easily prepared from the cor-
responding aryl, heterocyclic, and alkyl aldehydes 8a-f
by reaction with (S)-phenylglycinol in toluene in the
presence of MgSO4. The coupling of aryl imines 9a and
9b or heterocyclic imines 9c and 9d with 3 to the
corresponding adducts 10a-d proceeded with high yields
and high diastereoselectivities in NMP/THF at -5 °C (no
1
diastereoisomers were detected by H NMR). Interest-
ingly, while in the case of the alkynyl derivative a
mixture of diastereoisomers was obtained when using a
solution of reagent 3 in NMP/THF, in the aromatic
derivative, no loss of selectivity was observed. The
â-amino esters 12a-d were then prepared with sodium
(21) Holzemann, G. IDrugs 2001, 4, 72.
J. Org. Chem, Vol. 70, No. 14, 2005 5391

Awasthi et al.
TABLE 4.
observed. We also demonstrated that the method is fairly
general for the preparation of a wide range of â-amino
esters 12 and 18. The method was easily applied to
various derivatives without excessive optimization and
changes in the process with good overall yield. The
â-amino esters 12 and 18 were obtained with high purity
and high ee from the corresponding aldehyde without
purification of the intermediates.
X, Y
14
18a
a
b
c
89%
88%
95%
49%
45%, >99% eeb
33%, >99% eeb
a Overall yield from 14. b Determined by Chiral LC.
The obvious starting materials were commercially
available 3,5-dihalosalicyladehydes. Initially the imine
derived from 3,5-dichlorosalicyladehyde and phenyl-
glycinol was prepared and tested. However, as expected,
reaction of that imine with reagent 3 failed to give any
product.
Experimental Section
3-(Trimethylsilyl)-2-propynal was obtained by custom syn-
thesis neat or as a solution in MTBE in 96% purity. The other
reagents were obtained from commercial sources and used
without purification. The solvents MTBE, EA, toluene, THF,
and ethanol 2B (denatured with 5% toluene) were used as
technical grade without purification. NMP (HPLC grade) was
purchased and used without further drying. 1H and 13C NMR
spectra were recorded on a 400 MHz spectrometer. DSC
(Differential Scan Calorimetry) was run in a closed pan from
room temperature to 300 °C (at 10 °C/min). GCs were obtained
with use of a HP1 column 10 m × 0.53 mm i.d. 2.65 µm film
(detector temperature 260 °C; injector temperature 240 °C,
FID detection; 50 °C, 5 min hold time; ramp to 250 °C at 15
°C/min, hold 10 min). Chiral LC’s were obtained on a chiracel
OF column with a mobile phase of hexane/n-butanol (99/1) at
a flow rate of 1.0 mL/min and UV detection at 210 nm.
Reactions were performed under an atmosphere of dry nitro-
gen unless otherwise stated.
The MEM group was chosen as the phenol-protecting
group of choice throughout the syntheses based on the
potential ease of removal under acidic condition.22 The
MEM derivative 14a-c of 3,5-dihalosalicylaldehydes
13a-c were easily prepared with MEMCl and K2CO3 in
DMF. The use of K2CO3 instead of NaH typically used
for this kind of protection allowed us to have an easily
scalable process. The imines 15a-c were prepared fol-
lowing the typical procedure from (S)-phenylglycinol.
Addition of 2 equiv of Reformatsky reagent 3 to imine
15 in NMP at -5 °C led to the coupling product with high
diastereoselectivity to give the corresponding products
16a-c. The oxidative cleavage of the amino-alcohol
residue in the coupled products 16a-c with the standard
sodium periodate procedure, while giving the desired
product,23 proved to be more difficult than previously
encounter to carry through the final â-amino acids. Lead
acetate in methanol was, however, used successfully to
afford accordingly the corresponding imines 17a-c.
Last, having to prepare the ethyl ester, a one-step
process was devised to allow the MEM deprotection, the
imine hydrolysis, and the transesterification and the
crystallization of the final product to occur simulta-
neously. These transformations were achieved by reflux-
ing the crude imines isolated from the oxidative cleavage
in ethanol in the presence of p-toluenesulfonic acid
monohydrate. The resulting deprotected ethyl esters were
then precipitated out of solution and isolated as pTSA
salts 18a-c with high purity and high ee (Table 4). As
for the examples 12a-e described above, the â-amino
esters 18a-c were prepared in high overall yields and
high chiral purity without isolation and purification of
intermediates.
(RS)-[[3-(Trimethylsilyl)-2-propynylidene]amino]ben-
zeneethanol (2a). To a slurry of l-phenylglycinol (10.00 g,
72.9 mmol) in toluene (55 mL), at ambient temperature, was
added 1.05 equiv of 3-(trimethylsilyl)-2-propynal (9.66 g, 76.5
mmol) at such a rate as to keep the temperature below 30 °C.
The mixture was stirred at ambient temperature for 1 h. The
water was azeotropically removed with toluene under reduced
pressure to a final weight of 28.2 g (1.5 × the expected yield).
At room temperature and with stirring heptane (75 mL) was
added and the mixture was cooled to -10 °C for 8 h. Filtration
of the solids by suction followed by a heptane rinse of the cake
and air-drying produced the solid imine 2a in 80% yield (15.00
g) in 4:1 ratio of anti to syn isomers (as determined by 1H NMR
in THF-d8) or 94/6 ratio of anti to syn isomer (as determined
by 1H NMR in NMP-d9). Mp 78-80 °C; 1H NMR (THF-d8) anti-
isomer, δ 0.20 (s, 9H), 3.61 (t, J ) 6.3 Hz, 1H), 3.95 (t, J ) 6.3
Hz, 1H), 4.18 (t, J ) 6.3 Hz, 1H), 7.17 (tt, J ) 7.3 and 1.4 Hz,
1H), 7.25 (complex t, J ) 7.3 Hz, 2H), 7.35 (complex d, J )
7.3 Hz, 2H), 7.57 (s, 1H); 1H NMR (THF-d8) syn-isomer, δ 0.22
(s, 9H), 3.63-3.76 (complex band, 3H), 5.01 (m, 1H), 7.16 (tt,
J ) 7.3 and 1.4 Hz, 1H), 7.23 (complex t, J ) 7.3 Hz, 2H),
7.33 (complex d, J ) 7.3 Hz, 2H), 7.56 (d, 1H); 1H NMR (NMP-
d9) anti-isomer, δ 0.20 (s, 9H), 3.56-3.69 (m, 2H), 4.33 (dd,
1H), 5.15 (broad, 1H), 7.23-7.28 (m, 1H), 7.31-7.40 (m, 4H),
7.72 (s, 1H); 1H NMR (NMP-d9) syn-isomer, δ 0.22 (s, 9H), 7.67
(s, 1H), 5.0-5.1 (m, 1H), other signals are overlapped by the
anti-isomer; 13C NMR (THF-d8) anti-isomer, δ -0.3, 67.9, 79.3,
96.5, 103.5, 127.9, 128.2, 129, 141.9, 145.4; 13C NMR (THF-
d8) syn-isomer, δ -0.4, 68.6, 73.2, 98.2, 103.6, 127.7, 128.6,
The process for the preparation of 18b was further
optimized for pilot plant scale-up and was reported in a
separate paper.24
Conclusions
128.9, 142.4, 143.3: IR 1610, 2370, 2340, 3390, 3610 cm-1
Anal. Calcd for C14 H19NOSi: C, 68.52; H, 7.80; N, 5.71.
Found: C, 68.59; H, 7.52; N, 5.71.
.
We have demonstrated a highly stereoselective and
scalable method to prepare the â-alkynyl-â-amino acid
ester 1. An unusual stereodifferentiation during an
oxidative cleavage of a mixture of diastereoisomers was
(R)-r-Methyl-N-[3-(trimethylsilyl)-2-propylidene]ben-
zenemethanamine (2b). To a solution of (R)-methylbenzyl-
amine (1.28 mL, 10.0 mmol) in toluene (8 mL), at ambient
temperature, was added 3-(trimethylsilyl)-2-propynal (1.27 g,
10 mmol) at such a rate as to keep the temperature below 35
°C. The mixture was stirred at ambient temperature for 0.5
h. MgSO4 (1 g) was added to the solution and the slurry was
stirred at 22 °C for 2 h, filtered, and concentrated under
reduced pressure to afford an oil (2.21 g, 96.5% yield) contain-
ing imine 2b in 3:2 ratio of anti to syn isomers (as determined
(22) Green, T. W.; Wuts, P. G. Protective Group in Organic Synthesis,
3rd ed.; Wiley: New York, 1999; pp 41 and 268 for the MEM group.
(23) The sodium periodate process was later successfully optimized
for 15b and was reported in ref 24.
(24) Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-
J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable, C. M.; Lantz,
M. K.; Moore, C. M. V.; Murphy, J. B.; Rogers, T. E.; Ruminski, P. G.;
Shah, A. S.; Storer, N.; Wise, B. E. Org. Process Res. Dev. 2004, 8, 51.
5392 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Substituted-â-amino Esters
by 1H NMR and NOE experiments in CDCl3); 1H NMR (CDCl3)
amount of remaining benzaldehyde )
concentration of sample (g/L) × 50 × 5/2
anti-isomer, δ 0.22 (s, 9H), 1.55 (d, 3H, J ) 7.7 Hz), 4.41 (dt,
1
1H, J ) 6.6 Hz), 7.57 (d, 1H, J ) 0.6 Hz); H NMR (CDCl3)
syn-isomer, δ 0.26 (s, 1H), 1.51 (d, 3H, J ) 6.6 Hz), 5.12 (dt,
titer (mol/L) ) (preweighed amount of benzaldehyde -
1
1H, J ) 5.3 Hz), 7.51 (d, 1H, J ) 1.4 Hz); H NMR (CDCl3)
amount remaining)/106
anti/syn-isomer, δ 7.22 to 7.40 (m, overlapping peaks); 13C
NMR (CDCl3) anti-isomer, δ 0.0, 24.1, 70.6, 98.3, 101.1, 126.7,
127.2, 128.5, 143.7; 13C NMR (CDCl3) syn-isomer, δ 0.0, 24.1,
64.4, 96.5, 104.4, 126.8, 127, 128.4, 144.5; IR 1610, 2370, 2340,
3390, 3610 cm-1. Anal. Calcd for C14H19NSi: C, 73.30; H, 8.35;
N, 6.11; Found: C, 73.29; H, 8.81; N, 5.95.
yield ) mol/L × (total volume of solution/
theoretical 100% yield)
Method B: Preparation of Solid Reagent (3). Zn metal
(176.0 g, 2.69 mol, 30-100 mesh) and THF (1.25 L) were
charged into a l L, three-necked, round-bottomed flask that
was fitted with a condenser, temperature probe, and mechan-
ical stirrer. With stirring, trimethylsilyl chloride (3.25 mL,
0.060 mol) was added to the vessel via syringe. The suspension
of zinc in THF was stirred at room temperature for 1 h. tert-
Butyl bromoacetate (500 g, 2.56 mol) was then added dropwise
to bring the temperature to 50 °C and maintain that temper-
ature (5 °C with cooling over a 1 h time period. Controlled
reagent addition was performed with a 50 mL syringe and
syringe pump. The reaction mixture was allowed to stir at 50
°C for 40 min after the addition was complete. The reaction
mixture was allowed to cool to 10 °C to precipitate the reagent
as a white solid. The reagent was colleted by filtration with
use of a pressure filter (extra coarse). The cake was washed
three times with THF (3 × 200 mL) and dried on the filter
with a stream of N2 to afford 3 as a white powder (690 g, 81%
yield). Analyses of 3 were consistent with literature data.15b
1,1-Dimethylethyl (3S)-[(2-Hydroxy-(1S)-phenylethyl)-
amino]-5-(trimethylsilyl)-4-pentynoate (4a). Method A.
A solution of the product of 3 in NMP/THF (2.6/1, 1.5 L, 1.57
M, 2.4 mol), prepared as above, was charged in a 4 L flask
(jacketed, 4 ports fitted with mechanical stirrer, Teflon coated
temperature probe, and addition funnel). The solution was
cooled to -10 °C and a solution of imine of 2a (220.0 g, 0.96
mol) in NMP (0.250 L) was added after 30 min while the
temperature was maintained at -3 °C. After total conversion
(less than 1% of starting material), a mixture of ammonium
chloride aqueous solution (1.0 L, 29 wt %) and 2 N HCl (0.5
L) was added in 15 min from -10 to 13 °C. The mixture was
warmed to 25 °C and MTBE (1.0 L) was added. The mixture
was stirred for 30 min and the layers were separated. The
aqueous layer was extracted with MTBE (0.5 L). The organic
layers were combined and washed successively with a solution
of NH4Cl (29 wt %, 0.5 L), H2O (0.5 L), and a saturated solution
of NaCl (0.5 L) and were concentrated under reduced pressure
to afford an orange oil (366 g) containing the title compound
4a (84 wt. %, 91% yield determined by GC quantitation) and
1,1-dimethylethyl (3R)-[(2-hydroxy-(1S)-phenylethyl)amino]-
5-(trimethylsilyl)-4-pentynoate (4b) mixture obtained with 80%
de as determined by chiral HPLC. Samples of the two isomers
were separated by preparative chiral HPLC for analytical
purposes.
BrZnCH2CO2t-Bu‚THF (3). Method A: Preparation of
a Solution in NMP/THF. Step A: A 4 L jacketed flask, fitted
with a condenser, temperature probe, and a mechanical stirrer,
was charged with Zn metal (180.0 g, 2.77 mol, 30-100 mesh)
and THF (1.25 L). With stirring, 1,2-dibromoethane (4.74 mL,
0.055 mol) was added to the vessel via a syringe. The
suspension of zinc in THF was heated to reflux (65 °C) and
maintained at this temperature for 1 h. The mixture was
cooled to 50 °C before charging the tert-butyl bromoacetate
(488.0 g, 369 mL, 2.5 mol) over a 1.5 h time period. Controlled
reagent addition was performed with a 50 mL syringe and
syringe pump (addition rate set at 4.1 mL/min). A temperature
of 50 ( 5 °C was maintained during the addition (self-heating).
It is important to determine that the formation of the reagent
is initiated to avoid any accumulation of unreacted tert-butyl
bromoacetate, leading potentially to a strong exotherm and
foaming of THF. The reaction mixture was allowed to stir at
50 °C for 1 h after the addition was complete. The reaction
mixture was allowed to cool to 25 °C, and the agitation was
turned off to allow the precipitate to settle (the product
precipitates from THF solution at 31 °C). The THF mother
liquor was removed by decantation into a 2 L round-bottom
flask under partial vacuum (20 mmHg) with a dip tube (coarse
fritted glass filter). This removed 65% of THF from the vessel,
then 800 mL of NMP was added and agitation was resumed
for 5 min at 25 °C. The reaction mixture was transferred to
another vessel by filtration to remove the remaining zinc to
afford about 1.5 L of green/orange solution. The titer of the
solution was found to be 1.57 M with a molar yield of 94% of
3 (see below for titration method).
Step B: Titration Method. A 1.0 mL aliquot of the
Reformatsky-NMP/THF solution was removed from the reac-
tion mixture via syringe and added to a 25 mL round-bottom
flask that contained a preweighed amount of benzaldehyde
(250-300 mg) and a magnetic stir bar, under a nitrogen
atmosphere. The reaction mixture was stirred for 30 min at
room temperature. To the flask were added aqueous NH4Cl
(29 wt %, 5.0 mL) and methyl tert-butyl ether (5.0 mL). The
resulting mixture was stirred for 5 min at room temperature.
The agitation was stopped and the layers were allowed to
separate over 5 min. A 1.0 mL aliquot of the organic layer was
removed and diluted to 25 mL with MTBE in a volumetric
flask. This solution was subjected to gas chromatography (GC)
analysis with use of a HP-1 10 m column. Standard solutions
of benzaldehyde in MTBE at concentrations of 0.04, 0.01, and
0.002 M are co-injected with the sample. The sample concen-
tration was determined from the linearity plot of the standard
solutions and the sample GC peak area. The concentration of
the Reformatsky solution was determined by using the fol-
lowing calculation:
Data for 4b: 1H NMR (CDCl3, TMS) δ 0.16 (s, 9H), 1.45 (s,
9H), 2.52 (dd (AB), J ) 15.3 and 5.6 Hz, 1H), 2.56 (dd (AB), J
) 15.3 and 5.6 Hz, 1H), 3.55 (dd, J ) 7.7 and 5.6 Hz, 1H),
3.59 (dd, J ) 10.7 and 8.5 Hz, 1H), 3.74 (dd, J ) 10.8 and 4.5
Hz, 1H), 4.15 (dd, J ) 8.4 and 4.5 Hz, 1H), 7.27-7.34 (m, 5H);
13C NMR (CDCl3) δ 0.1, 28.1, 42.2, 44.9, 67.2, 67.5, 80.9, 88.6,
105.0, 127.7, 128.5, 139.7, 170.1; DSC 79.68 °C (endo 71.68
J/g), 237.33 °C (exo 169.0 J/g); [R]25 +179.3 (c 0.36, CHCl3);
D
IR (MIR) 2167, 1735 cm-1; UV max (nm) 204 (abs 0.37).
Microanal. Calcd for C20 H31NO3Si: C, 66.44; H, 8.64; N, 3.87.
Found: C, 66.34; H, 8.88; N, 3.89.
Data for 4a: 1H NMR (CDCl3, TMS) δ 0.09 (s, 9H), 1.46 (s,
9H), 2.49 (dd (AB), J ) 15.6 and 8.6 Hz, 1H), 2.59 (dd (AB), J
) 15.6 and 5.1 Hz, 1H), 3.59 (dd, J ) 11.1 and 6.5 Hz, 1H),
3.77 (dd, J ) 11.1 and 4.5 Hz, 1H), 3.89 (dd, J ) 8.7 and 5.1
Hz, 1H), 3.97 (dd, J ) 8.7 and 5.1 Hz, 1H), 7.24-7.36 (m, 5H);
13C NMR (CDCl3) δ -0.1, 28.1, 42.3, 46.2, 62.1, 65.5, 81.2, 88.3,
105.9, 127.3; DSC 252.27 °C (exo 342.3 J/g); [R]25 -5.6 (c
D
1.024, CHCl3); IR (neat) 2167, 1735 cm-1; UV max (nm) 205
J. Org. Chem, Vol. 70, No. 14, 2005 5393

Awasthi et al.
(abs 0.33). Microanal. Calcd for C20 H31NO3Si: C, 66.44; H,
8.64; N, 3.87. Found: C, 66.22; H, 8.82; N, 3.85.
was cooled to 3 °C and held at this temperature for 3 h. The
mixture was filtered on an ace-glass pressure filter (extra
coarse, 600 mL) and the cake was dried for 3.5 h under a N2
vacuum (Karl-Fisher analysis showed 5.60% H2O remaining).
The cake containing a mixture of the title compound and iodate
salt was charged into a 500 mL flask and toluene (THF can
also be used) (130 mL) was added. After 30 min of stirring at
30 °C, the mixture was filtered. The cake was washed twice
with toluene (THF can also be used) (2 × 50 mL). The three
fractions were combined and partially concentrated to a weight
of 161 g containing 53.3 wt % of the title compound (deter-
mined by GC quantitation) with a yield of 92% and a chiral
purity of 99.9% (determined by chiral HPLC). A sample was
isolated for full characterization by concentration of the
solution: 1H NMR (CDCl3, TMS) δ 0.20 (s, 9H), 1.45 (s, 9H),
2.66 (dd (AB), J ) 15.0 and 7.0 Hz, 1H), 2.80 (dd (AB), J )
15.0 and 7.7 Hz, 1H), 4.83 (dt, J ) 7.6 and 1.7 Hz, 1H), 7.38-
Method B. Reformatsky reagent 3 (60.0 g, 0.18 mmol) was
added in 10 portions to a solution of imine 2a (21.0 g, 0.086
mol) in NMP (100.0 mL) at -10 °C while maintaining an
internal temperature of 7.5 ( 2.5 °C. The reaction was
monitored by GC. After addition the mixture was stirred 2 h
at -10 °C. A mixture of a saturated solution of ammonium
chloride (75 mL) and HCl 37% (6.0 mL) was added to the
solution at -10 °C and the mixture was warmed up to 22 °C.
The mixture was extracted with MTBE (2 × 100.0 mL). The
organic layers were combined and washed successively with
a saturated solution of Ammonium hydroxide (100.0 mL),
water (100.0 mL), and a saturated solution of NaCl (100.0 mL),
dried with Na2SO4, filtered, and concentrated under reduce
pressure to afford an orange oil containing a mixture of isomer
4a/4b (30.92 g, 97.6/2.4) as determined by GC. The crude
reaction mixture was purified by chromatography on silica gel
(250 g, elution withheptane 80%/ethyl acetate 20%) to afford
4a (25.91 g, 83.7%) as a pale yellow oil. Analyses were
consistent with the above description for 4a. Microanal. Calcd
for C20 H31NO3Si: C, 66.44; H, 8.64; N, 3.87. Found: C, 66.2;
H, 8.64; N, 3.70.
Preparation of Zinc Chelate (5). Reagent 3 solid (3.32
g, 10.0 mmol) was added in 2 min to a solution of imine 2a
(2.45 g, 10 mmol) in THF (30.0 mL), which was then cooled to
0 °C to form an homogeneous orange solution. The mixture
was stirred at 0 °C for 30 min and heptane was added.
Precipitation occurred and the slurry was stirred at 0 °C for
20 min. The solids were filtered off under N2 and washed with
heptane (20 mL) and dried in a pressure filter under N2 (2
Psi) and vacuum to afford 5 (2.13 g, 55%) as a pale orange
solid. GC trace analysis of a sample quenched with ammonium
chloride showed only imine 2. DSC 262.33 °C (exo 402.1 J/g);
IR (MIR) 1720 cm-1. Microanal. Calcd for C14H18BrNOSiZn:
C, 43.15; H, 4.68; N, 3.59; Br, 20.51. Found: C, 42.93; H, 4.68;
N, 3.61; Br, 20.86.
Formation of 4 from 2 through the Isolation of Zinc
Chelate (5). The Reformatsky reagent 3 (16.6 g, 50.0 mmol)
was added to a solution of imine 2a (12.25 g, 50.0 mmol) in
THF (100.0 mL) at 0 °C. After 5 min, the reaction mixture
was held to 22 °C. Additional THF (100 mL) was added and
the solution was filtered through a coarse sintered glass filter
and the filtrate was concentrated under reduced pressure to
afford an orange solid (22.3 g) containing 5. The residue was
taken up in NMP (100 mL). The solution was cooled to -10
°C and a second equivalent of 3 (16.6 g, 50.0 mmol) was added
as a solid by portions while maintaining the temperature at
-7.5((2.5) °C. The mixture was stirred at -10 °C for 2.5 h
and held at 5 °C for 1 h. An additional 1.5 g of reagent 3 was
added and after 20 min, a solution of NH4Cl (20 wt % in water,
100 mL) was added while maintaining a temperature of 5((5)
°C followed by MTBE (100 mL). The layers were separated
and the aqueous layer was extracted with MTBE (100 mL).
The combined MTBE layers were washed with a solution of
NH4Cl (20 wt %), water, and brine, dried with Na2SO4, filtered,
and concentrated under reduced pressure to afford an orange
oil containing a mixture of 4a/4b (16.7 g, ratio of 97.4/2.6) and
a trace of recovered imine 2a (2%) as determined by GC.
1,1-Dimethyl (3S)-[(Phenylmethylene)amino-5-trimeth-
ylsilyl]-4-pentynoate (6). NaIO4 (77.0 g, 0.36 mol) was
charged into a 500 mL flask followed by water (330 mL) and
the mixture was stirred for 30 min at 25 °C. A solution of 1,1-
dimethyl (3S)-[(2-hydroxy-(1S)-phenylethyl)amino]-5-(trimethyl-
silyl)-4-pentynoate (4a) (116.3 g, 86 wt %, 0.277 mol) in ethanol
(520 mL) was charged into a 1 L flask (4 ports, jacketed, fitted
with mechanical stirrer and Teflon coated temperature probe)
purged with N2, followed by addition of a solution of methyl-
amine (40 wt %, 24 mL, 0.278 mol). After 5 min of stirring at
25 °C, a slurry of NaIO4 in water was added portion wise while
maintaining a temperature below 35 °C (32 ( 2 °C). After
complete addition, conversion was complete and the mixture
7.44 (m, 3H), 7.74-7.77 (m, 2H), 8.56 (d, J ) 1.5 Hz, 1H); 13
C
NMR (CDCl3) δ 0.1, 28.1, 43.2, 56.5, 80.8, 92.5, 103.2, 128.5,
128.6, 130.9, 135.9, 161.8, 169.6; DSC: 72.22 °C (endo 112.4
J/g); [R]25 -35.5 (c 1.16, CHCl3); IR (MIR) 2174, 1728, 1641
D
cm-1; UV max (nm) 205 (abs 1.004), 248 (abs 0.655). Microanal.
Calcd for C19 H27NO2Si: C, 68.75; H, 8.65; N, 4.33. Found: C,
69.10; H, 8.43; N, 4.33.
1,1-Dimethylethyl (3S)-Amino-5-(trimethylsilyl)-4-pen-
tynoate 4-Methylphenylsulfonate Salt (7). A solution of 6
(123.3 g, 0.374 mol) in dry THF (350 mL) was prepared.
p-Toluenesulfonic acid monohydrate (71.2 g, 0.374 mol) was
charged to a 4 L jacketed reaction vessel under nitrogen. An
overhead stirrer with a 10 cm Teflon stir blade was attached.
A thermocouple thermometer was put in place. The reactor
jacket was cooled to 0 °C. The solution of 6 was added via an
addition funnel over 5 min with stirring at 250 rpm. The
reaction temperature rose to 10 °C. The addition funnel was
rinsed with THF (300 mL). After stirring for 15 min the
mixture became homogeneous. The stirring rate was increased
to 350 rpm. Heptane (1360 mL) was added over 5 min. The
product crystallized and the agitation was increased to 540
rpm. The solvent was distilled from the reactor under vacuum
under the following conditions. An oil pump connected to a
vacuum regulator was used to adjust the vacuum to 45 mmHg.
The jacket temperature was set to 20 °C and a dry ice/2-
propanol condenser with a 2 L receiving flask was used to
collect the distillate. The distillate collected was 900 mL. The
reactor was placed under a nitrogen atmosphere and additional
heptane (900 mL) was added. The slurry was cooled to 2 °C.
The solids were collected on a 10 cm coarse glass fritted filter
with a vacuum. The reaction vessel was rinsed by adding
heptane (500 mL) and THF (50 mL) with stirring. The reaction
mixture was cooled to 10 °C and added to the filter. The cake
was washed with heptane (3 × 300 mL) and dried by using a
combination of vacuum and nitrogen flow for 4.5 h to produce
7 (145.9 g, 94%); mp 142 °C; 1H NMR (CDCl3, 400 MHz) δ
8.32 (br, s, 3H), 7.79 (d, J ) 8.0 Hz, 2H), 7.15 (d, J ) 8.0 Hz,
2H), 4.40 (dd, J ) 8.0 and 6.0 Hz, 1H), 2.89 (dd, J ) 17.0 and
8.0 Hz, 1H), 2.76 (dd, J ) 17.0 and 5.0 Hz, 1H), 2.36 (s, 3H),
1.41 (s, 9H), 0.10 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 168.6,
141.6, 140.2, 128.8 (2C), 126.1 (2C), 98.5, 92.7, 82.0, 40.6, 38.6,
27.9 (3C), 21.3, -0.5 (3C). Anal. Calcd for C19 H31NO5SSi: C,
55.17; H, 7.55; N, 3.39. Found: C, 55.27; H, 7.27; N, 3.34.
Ethyl (3S)-Amino-5-(trimethylsilyl)-4-pentynoate Hy-
drochloride Salt (1). A solution of 7 (500.0 g, 1.21 mol) and
p-toluenesulfonic acid monohydrate (69.5 g, 0.365 mol) in
ethanol 2B (930 mL) was heated to reflux and held for 4 h.
Reaction completion was determined by GC. The reaction
mixture was concentrated under reduced pressure. MTBE
(1200 mL) was charged to the concentrate with stirring to
complete dissolution. A 26 wt/wt % of potassium bicarbonate
aqueous solution (1387.0 g) was added to the MTBE solution.
The biphasic mixture was stirred for 15 min. The aqueous
layer was back-extracted with MTBE (700 mL). The combined
organic layers were extracted a second time with a 26 wt/wt
5394 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Substituted-â-amino Esters
% of potassium bicarbonate aqueous solution (306.0 g). The
organic layer was concentrated under reduce pressure. Water
was removed azeotropically with ethanol 2B (900 mL) under
reduced pressure. An 87.3% yield of the desired silyl protected
ethyl ester free amine is typically obtained (1.06 mol in this
experiment). To the concentrate was charged ethanol 2B (600
mL), followed by 21 wt % of sodium ethoxide (in ethanol
denatured with 5% toluene) (39.6 mL, 0.106 mol, 0.1 equiv
sodium ethoxide). The reaction solution was allowed to cool
to room temperature and stirred for 1.5 h. Desilylation
completion was determined by GC. In a separate vessel was
charged ethanol 2B (720 mL), followed by acetyl chloride (81.6
mL, 1.15 mol, 1.1 equiv). This addition was carried out over
20 min, not allowing the temperature to rise above 45 °C. The
solution was then cooled to 20-25 °C. The resulting hydrogen
chloride/ethyl acetate/ethanol solution was charged to the
desilylation reaction mixture. A 5 °C exotherm was observed.
The reaction was cooled to 25 °C with stirring over a 30 min
period and then stirred at 25 °C for an additional 30 min. The
reaction mixture was concentrated under reduced pressure.
The concentrate was cooled to room temperature and toluene
(920 mL) was added. The mixture was stirred for 20 min and
then concentrated under reduced pressure. Toluene (920 mL)
was added to the concentrate and the solution was stirred for
20 min. Solids were collected by filtration and dried to afford
crude 1 (184.94 g, 86.1% yield).
A portion of the crude 1 (80.0 g) was recrystallized from
acetonitrile/MTBE. To crude 1 (80 g) was added acetonitrile
(400 mL). The mixture was heated to reflux and the resulting
heated opaque yellow solution was filtered through Celite (20
g, Celite had been washed with hot acetonitrile). The filtrate
was concentrated under vacuum to remove 195 mL of solvent.
The concentrated solution was cooled to 45 °C. To the solution
was added MTBE (195 mL). The resulting opaque mixture was
then heated to reflux, cooled to 50 °C, and then stirred for 15
min. The mixture was then cooled to 40 °C and then held for
15 min. The mixture was then allowed to cool to 22 °C and
filtered. The resulting solids were dried on the filter for 10
min, then under high vacuum for 2 h, providing 1 (72.18 g).
1H NMR (d6-DMSO) δ 1.21 (t, J ) 7 Hz, 3H), 2.84 (dd, J )
16 and 9 Hz, 1H), 3.03 (dd, J ) 16 and 5 Hz, 1H), 3.70 (d, J )
2 Hz, 1H), 4.13 (q, J ) 7 Hz, 2H), 4.31 (m, 1H), 8.82 (s, 3H);
13C NMR (d6-DMSO) δ 13.9, 37.6, 38.4, 60.7, 77.9, 78.6, 168.4;
DSC 125-131 °C (endo 107.2 J/g); [R]25D -6.7; IR (MIR) 3252,
2128, 1726 cm-1. Microanal. Calcd for C7H12NO2Cl: C, 47.33;
H, 6.81; N, 7.89; Cl, 19.96. Found: C, 47.15; H, 6.84; N, 7.99;
Cl, 19.55.
General Method A (Imine Preparation). (S)-Phenyl-
glycinol (1 equiv) was then added at once (endothermic
reaction) to a solution of aldehyde (1 equiv) in toluene or THF
(10 mL/g of (S)-phenylglycinol) at room temperature. After 30
min at 22 °C, MgSO4 was added. The mixture was stirred for
2 h at 22 °C then filtered on a coarse fritted filter and the
cake was washed with toluene or THF. The filtrate and washes
were concentrated under reduce pressure to afford a crude
containing the desired imine. The crude was used directly in
the coupling reaction except when specified.
washed successively with a saturated solution of NH4Cl (1
mL/g of 3), DI water (1 mL/g of 3), and saturated sodium
chloride solution (1 mL/g of 3). The organic layer was dried
with MgSO4, filtered, and concentrated to afford a crude oil
containing the desired product 10 (from 9) or 16 (from 15) as
a single diastereoisomer. The material was used directly in
the oxidative cleavage (general method C or D) except when
specified.
General Method C (Oxidative Cleavage with Sodium
Periodate). Methylamine (40 wt % in water, 1.1 to 1.2 equiv)
was added to a solution of crude ester 10 in ethanol (4 mL/g
of crude ester 10). A slurry of NaIO4 (1.2-1.3 equiv) in water
(2 mL/g of crude ester 10) was then added by portion while
maintaining the temperature below 30 °C. An additional
portion of NaIO4 could be added as specified if the reaction
did not complete and the mixture was heated to 30 °C for 0.5
h. The mixture was cooled to 25 °C, concentrated under reduce
pressure, and taken up in MTBE (as needed) and the residual
solids were filtered off. The layers were separated and the
organic layer was washed with water, dried with MgSO4,
filtered, and concentrated to afford an oil that was used
directly in the salt formation.
General Method D (Oxidative Cleavage with Lead
Acetate). Lead tetraacetate (1 equiv) was added in one portion
to a solution of crude ester 10 or 16 (1 equiv) in methanol (15
mL/g of crude ester 10 or 16) at 0 °C. Addition was exothermic
and the temperature goes up to 4 °C. The reaction mixture
was stirred for 3 h at 0 °C and then 15% aqueous NaOH (1.5
mL/g of crude ester) was added to the reaction mixture while
maintaining the temperature below 5 °C. Methanol was
removed under reduced pressure on rotovap. An additional
portion of 15% aqueous NaOH (60 mL/g of crude ester 10 or
16) was added and the reaction mixture was extracted 3× with
ethyl acetate (3 mL/g of crude ester 10 or 16) and washed 2×
with DI water (2 mL/g of crude ester 10 or 16) and 2× with a
saturated NaCl solution (1 mL/g of crude ester 10 or 16) then
dried over anhydrous MgSO4. It was then filtered over Celite
and concentrated under reduced pressure to give an oil
containing the desired product 11 or 17.
General Procedure E (Isolated pTSA Tbutyl Ester
Salts 12). A solution of p-toluenesulfonic acid monohydrate
(calcd 1 equiv vs crude imine 11) in THF (1.5 mL/g of pTSA‚
H2O) was added to a solution of crude imine 11 in THF (2.5
mL/g of crude imine 11). After 5 min, heptane (5 mL/g of crude
imine) was added and after a few minutes heavy salt precipi-
tation occurred. Additional heptane was added if needed and
the slurry was stirred for 0.5 h after precipitation then the
salt was filtered off and the cake was washed twice with
heptane/THF 20 to 30 vol % (5 mL/g of crude imine). The solids
were then dried under vacuum/nitrogen flow as needed and
collected to afford the desired â-amino ester 12 as a pTSA salt.
General Procedure F (Isolated pTSA Ethyl Ester Salts
18). p-Toluenesulfonic acid monohydrate (1.3 equiv) was added
to a solution of crude 17 (1 equiv) in absolute ethanol (2 mL/g
of crude 17). The reaction mixture was then heated to reflux
for 8 h after which solvent was removed under reduced
pressure. Residual solid was taken up in THF (1 mL/g of crude
17) and THF was then stripped off under reduced pressure.
Residue was dissolved in fresh THF (1 mL/g of crude 17) and
dissolved on warming to 40 °C. Heptane, ethyl acetate ,or THF
as specified was added and reaction mixture was cooled to 30
°C. A thick slurry precipitated out and was filtered with the
aid of a THF/heptane solution. Solid was washed with acetone
or a mixture of THF 30%/heptane and dried under vacuum at
40 psi under a blanket of nitrogen at 48-49 °C for 16 h to
afford 18 as a white solid.
General Method B (Reformatsky Coupling Reaction).
A solution of crude imine 9 or 15 in NMP was prepared under
nitrogen and then added in 30 min to a solution of reagent 1
(2.2 equiv) in NMP/THF (when 3 was prepared and used as a
titrated solution), NMP or DMSO (when the reagent 3 was
used as solid, 2 mL/g of 3) at -10 °C while the temperature
was maintained at -5 °C. The mixture was stirred for 3 h at
-8((3) °C or until the reaction was complete and then cooled
to -10 °C. A mixture of 2 N HCl solution/saturated solution
of NH4Cl (1/2 v/v, 2.4 mL/g of 1) was added in 10 min
(exothermic, temperature typically rose from -10 to 7 °C).
MTBE (2-2.4 mL/g of 1) was added and the mixture was
stirred for 30 min at 23 °C. Stirring was stopped and the layers
were separated. The aqueous layer was extracted with MTBE
(1 mL/g of 1). The two organic layers were combined and
(3S)-3-Amino-3-phenylpropionic Acid tert-Butyl Ester
p-Toluene-4-sulfonic Acid (12a). Following the general
procedure A, crude 9a was prepared (40.07 g, 88.9%) from (S)-
phenylglycinol (27.44 g, 0.20 mol) and benzaldehyde 2a (21.75
g, 0.205 mol).
J. Org. Chem, Vol. 70, No. 14, 2005 5395

Awasthi et al.
Following the general procedure B, crude 10a (33.24 g,
1H NMR (CDCl3, TMS) δ 1.32 (s, 9H), 2.35 (s, 3H), 2.96 (m,
2H), 4.72 (m (br), 1 H), 6.22 (dd, 1H, J ) 3.3, 1.8 Hz), 7.12 (d,
2 H, J ) 8 Hz), 7.22-7.23 (m, 1H), 7.67 (d, 2H, J ) 8.1 Hz),
8.23 (s (broad), 3H); 13C NMR (d6-DMSO, TMS) (ppm) 21.3,
27.8, 36.8, 45.7, 81.7, 109.5, 110.6, 126.1, 128.8, 140.2, 141.5,
142.9, 148.6, 168.8. Microanal. Calcd for C18H25NO6S: C, 56.30;
H, 6.57; N, 3.65. Found: C, 55.08; H, 5.69; N, 3.83.
(3S)-3-Amino-3-pyridin-3-ylpropionic Acid tert-Butyl
Ester p-Toluene-4-sulfonic Acid Salt (12d). Following the
general procedure A, 9d was prepared as crude (42.25 g, white
solid, 93.3%) from (S)-phenylglycinol (27.96 g, 0.2 mol) and
3-pyridinecarbixaldehyde (8d) (21.96 g, 0.205 mol) followed by
slurry with heptane (100 mL), filtration, and drying under
vacuum.
Following the general procedure B, crude 10d (27.85 g) was
prepared as an orange oil as a single diastereoisomer as
determined by 1H NMR and 13C NMR from 3 (121 mL of 1.36
M solution in NMP/THF (3/2), 0.164 mol) and a portion of
crude imine 10d (17.00 g, calcd 0.075 mol). In that example,
additional back extractions after regular extractions were
performed. A saturated solution of NH4Cl (50 mL) was added
to the aqueous layer followed by extraction with MTBE and
the layers were separated. This was repeated a second time
and the MTBE layers were combined, dried with MgSO4,
filtered, and concentrated
Following general procedures C and E, 12d (19.28 g) was
isolated as an ivory solid from crude 10d, NaIO4 (19.57 g, 0.091
mol), MeNH2 (40 wt % aqueous solution, 5.56 mL, 0.077 mol),
and pTSA‚H2O (10.72 g, 0.057 mol) with heptane as non-
solvent.
1H NMR (CDCl3, TMS) δ 1.24 (s, 9H), 2.35 (s, 3H), 2.90 (dd,
1H, J ) 8.87, 16.6 Hz), 3.09 (dd, 1H, J ) 5.8, 16.6 Hz), 4.71
(dd, 1 H, J ) 6.0, 8.9 Hz), 7.09 (d, 1H, J ) 7.9 Hz), 7.19 (d, 2
H, J ) 4.9, 7.9 Hz), 7.57 (d, 2H, J ) 8.1 Hz), 7.99 (dd, 1H, J
) 1.7, 8.1 Hz), 8.46 (dd, 1H, J ) 1.4, 5.0 Hz), 8.70 (d, 1H, 1.9
Hz); 13C NMR (CDCl3, TMS) (ppm) 21.3, 27.7, 48.9, 49.9, 81.9,
124.2, 125.8, 128.9, 132.5, 137.2, 140.5, 141.2, 148.3, 148.6,
168.3; [R]25D -1.5 (c 0.998, CHCl3); IR (MIR) (cm-1) 2116, 1721,
1540. Anal. Calcd for C14H26N2O5S: C, 57.15; H, 6.46; N, 6.44;
S, 8.38. Found: C, 57.85; H, 6.64; N, 7.10; S, 8.13.
(3S)-3-Amino-4,4-dimethylpentanoic Acid tert-Butyl
Ester p-Toluene-4-sulfonic Acid Salt (12e). Following the
general procedure A, 9e was prepared as crude (14.41 g, clear
oil) from (S)-phenylglycinol (10.00 g, 0.073 mol) and trimethyl-
acetaldehyde (8e) (6.59 g, 0.076 mol).
97.3%) was prepared as a yellow oil solidifying on standing as
1
a single diastereoisomer as determined by H NMR and 13C
NMR from 1 (160 mL of 1.378 M solution in NMP/THF, 3/2))
and a portion of crude imine 9a (22.53 g, 0.1 mol).
Following general procedures C and E, 12a (19.28 g) was
isolated as a white solid from a portion of crude 10a (27.37 g,
calcd 0.075 mol), NaIO4 (19.57 g, 0.091 mol), MeNH2 (40 wt %
aqueous solution, 5.56 mL, 0.077 mol), and pTSA‚H2O (10.72
g, 0.057 mol) with heptane as a nonsolvent. 1H NMR (d6-
DMSO, TMS) δ 1.26 (s, 9H), 2.29 (s, 3H), 2.81 (dd, 1H, J )
9.2, 15.6 Hz), 2.99 (dd, J ) 5.8, 15.8 Hz), 4.55 (m, 1 Hz), 7.11
(d, 2H, J ) 8.1 Hz), 7.38 to 7.49 (m, 8H), 8.31 (s (broad), 3H);
13C NMR (d6-DMSO, TMS) (ppm) 20.8, 27.5, 51.2, 80.8, 125.5,
127.7, 128.2, 128.6, 128.9, 136.4, 138.0, 145.0, 168.1; [R]25D -2.5
(c 0.91, CHCl3); IR (MIR) (cm-1) 1725. Microanal. Calcd for
C20H27NO5S: C, 61.05; H, 6.92; N, 3.56; S, 8.15. Found: C,
60.13; H, 7.03; N, 3.53; S, 8.46.
(3S)-3-Amino-3-(3,5-dichlorophenyl)propionic Acid tert-
Butyl Ester p-Toluene-4-sulfonic Acid Salt (12b). Follow-
ing the general procedure A, 9b was prepared as crude (27.00
g, pale yellow oil) from (S)-phenylglycinol (11.44 g, 0.086 mol)
and 3,5-dichlorobenzaldehyde (8b) (15.0 g, 0.086 mol).
Following the general procedure B, crude 10b (35.2 g) was
prepared as an orange oil solidifying on standing as a single
diastereoisomer as determined by 1H NMR and 13C NMR from
3 (165 mL of 1.15 M solution in NMP/THF (3/2), 0.189 mol)
and a portion of crude imine 9b (25.39 g, calcd 0.086 mol).
Following general procedures C and E, 12b (25.1 g) was
isolated as a ivory solid from crude 10b, NaIO4 (25.92 g, 0.112
mol and 2 portions of 6.0 g, 0.026 mol), MeNH2 (40 wt %
aqueous solution, 8.9 mL, 0.1 mol), and pTSA‚H2O (13.6 g,
0.072 mol) with heptane as nonsolvent.
1H NMR (CDCl3, TMS) δ 1.26 (s, 9H), 2.37 (s, 3H), 2.84 (dd,
1H, J ) 9.5, 16.3 Hz), 2.98 (dd, J ) 5.1, 16.2 Hz), 4.53 (m, 1
Hz), 7.14 (d, 2H, J ) 7.9 Hz), 7.19 (t ) 1 H, J ) 1.8 Hz), 7.32
(d, 2H, J ) 8.1 Hz), 7.56 (d, 2H, J ) 8.1 Hz), 8.43 (s (broad),
3H); 13C NMR (d6-DMSO, TMS) (ppm) 21.4, 27.8, 39.5, 51.4,
81.9, 125.8, 126.4, 129.1, 129.1, 135.2, 139.1, 140.6, 140.7,
168.1; [R]25 +37.4 (c 0.147, CHCl3); IR (MIR) (cm-1) 1726,
D
1587, 1567. Microanal. Calcd for C20H25Cl2NO5S: C, 51.95; H,
5.64; N, 3.01; Cl, 15.33; S, 7.02. Found: C, 51.65; H, 5.64; N,
3.01; Cl, 15.13; S, 7.02.
(3S)-3-Amino-3-furan-2-ylpropionic Acid tert-Butyl Es-
ter p-Toluene-4-sulfonic Acid Salt (12c). Following the
general procedure A, 9c was prepared as crude (54.72 g, yellow
solid, 91.4%) from (S)-phenylglycinol (38.16 g, 0.278 mol) and
freshly distilled 3-furaldehyde (8c) (26.73 g, 0.278 mol) fol-
lowed by slurry with heptane (100 mL), filtration, and drying
under vacuum.
Following the general procedure B, crude 10e (18.11 g) was
prepared as a yellow oil as a single diastereoisomer as
1
determined by H NMR and 13C NMR from 3 (57.50 g, 0.173
mol) and crude imine 9e in DMSO at room temperature for
20 h.
Following the general procedure B, crude 10c (7.3 g) was
prepared as an orange oil solidifying on standing as a single
diastereoisomer as determined by 1H NMR and 13C NMR from
3 (43 mL of 1.36 M solution in NMP/THF (3/2), 0.058 mol)
and a portion of crude imine 9c (5.00 g, calcd 0.023 mol). The
crude was purified by chromatography on silica gel, eluting
with heptane/MTBE (2:1) to yield the desired product 10c (5.43
g, 70.5%).
Following general procedures D and E, 12e (11.83 g) was
isolated as a white solid from crude 12e, Pb(OAc)4 (23.40 g,
0.054 mol), and pTSA‚H2O (8.24 g, 0.043 mol). The pTSA salt
was prepared from MTBE/heptane.
1H NMR (CDCl3, TMS) δ 1.01 (s, 9H), 1.41 (s, 1H), 2.35 (s,
3H), 2.55 (dd, 1H, J ) 4.0, 17.7 Hz), 2.66 (dd, 1H, J ) (0.0,
17.6 Hz), 3.28 (m, 1H), 7.15 (d, 2H), 7.75 (d, 2H), 7.80 (s (broad),
3H); 13C NMR (CDCl3, TMS) (ppm) 21.3, 26, 27.9, 33.2, 33.8,
1H NMR (CDCl3, TMS) δ (ppm) 1.44 (s, 9H), 2.71-2.65 (m,
2H), 3.55 (dd, 1H, J ) 12.0, 7.9 Hz), 3.79-3.75 (m, 2H), 4.25
(dd, 1 H, J ) 7.7, 6.2 Hz), 6.07 (d, 1H, J ) 3.2 Hz), 6.21 (dd,
1 H, J ) 3.2, 1.8 Hz), 7.29-7.19 (m, 6H); 13C NMR (CDCl3,
TMS) δ (ppm) 28.1, 40.7, 51.4, 61.7, 66.1, 81, 106.3, 109.9,
57.4, 82.1, 126.1, 139.9, 141.9, 170.9; [R]25 -24.7 (c 0.777,
D
CHCl3); IR (MIR) (cm-1) 1718. Anal. Calcd for C18H31NO5S:
C, 57.64; H, 8.37; N, 3.58; S, 8.80. Found: C, 57.88; H, 8.37;
N, 3.75; S, 8.58.
127.08, 127.4, 128.4, 141.4, 141.6, 155.3, 170.9; [R]25 +7.6 (c
(3S)-3-(2-Hydroxy-(1S)-phenylethylamino)methylhex-
anoic Acid tert-Butyl Ester (10f). Following the general
procedure A, 9f was prepared as crude (15.14 g, clear oil) from
(S)-phenylglycinol (10.00 g, 0.073 mol) and isobutyraldehyde
(8f) (6.59 g, 0.076 mol).
D
0.983, CHCl3); IR (MIR) (cm-1) 3427, 2974, 2929, 2870, 1720,
1452, 1365, 1147. Microanal. Calcd for C19H25NO4: C, 67.80;
H, 7.86; N, 3.84 Found: C, 68.86; H, 7.60; N, 3.23.
Following general procedures C and E, 12c (4.39 g, 78%) as
a pale yellow solid was isolated from 10c, NaIO4 (3.55 g, 0.017
mol), MeNH2 (40 wt % aqueous solution, 1.30 mL, 0.015 mol),
and pTSA‚H2O (2.35 g, 0.0123 mol) with heptane as non-
solvent.
Following the general procedure B, crude 10f (19.4 g) was
prepared as a yellow oil as a single diastereoisomer as
1
determined by H NMR and 13C NMR from 3 (57.50 g, 0.173
mol) and crude imine 9f in DMSO at room temperature for 20
5396 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Substituted-â-amino Esters
h. Additional reagent 3 (11.47 g, 0.035 mol) was added and
the mixture was stirred for an additional 20 h.
A portion of the crude (3 g) was purified by silica gel (elution
heptane, 30% ethyl acetate) to afford the desired product 10f
(2.31 g) as a pale yellow oil.
Following general procedures D and F, 18a (7.40 g) was
isolated as a salt containing 0.25 equiv of THF from a portion
of crude 15a (17.40 g, calcd 0.033 mol), Pb(OAc)4 (15 g, 0.033
Mol), and pTSA‚H2O (6.3 g, 0.033 mol).
1H NMR (d6-DMSO, TMS) δ 1.12 (t, 3H, J ) 7.1 Hz), 2.29
(s, 3H), 2.97 (dd, 1H, J ) 7.4, 16.5 Hz), 3.04 (dd, J ) 7.0, 16.5
Hz), 7.44 (d, 2H, J ) 7.1 Hz), 7.48 (d, 2h, J ) 8.1 Hz), 7.58
(2H, d, J ) 2.5 Hz), 8.15 (s (broad), 3H) and THF 1.76 (m,
0.25 × 4H), 3.60 (m, 0.25 × 4H); 13C NMR (CDCl3, TMS) (ppm)
13.9, 21.4, 25.6, 36.3, 49.3, 61.4, 67.9, 123.5, 125.2, 125.5, 125.8,
128.9, 129.9, 140.6, 140.6, 149.2, 170.2 and THF 25.6,
67.9; [R]25D +6.7 (c 1.063, CHCl3); IR (MIR) (cm-1) 3146, 2981,
2904, 1724, 1596, 1472. Microanal. Calcd for C18H21Cl2O6S‚
0.25C4H8O: C, 48.73; H, 4.95; N, 2.99; Cl, 15.14. Found: C,
48.91; H, 4.95; N, 2.90; Cl, 14.95.
1H NMR (CDCl3, TMS) δ 0.68 (d, 3H, J ) 6.5 Hz), 0.83 (d,
3H, J ) 6.5 Hz), 1.19 (m, 1H), 1.32 (m, 1H), 1.46 (s, 9H), 1.61
(s, 1H), 2.26 (dd, 1H, J ) 5.70, 14.62 Hz), 2.38 (dd, 1H, J )
5.71, 14.57 Hz), 2.92 (m, 1H), 3.51 (dd, 1H, J ) 10.75, 8.54
Hz), 3.69 (dd, 1H, 4.32, 10/72 Hz), 3.84 (dd, 1H, J ) 8.49, 4.44
Hz), 7.23 to 7.35 (m, 5H); 13C NMR (CDCl3, TMS) (ppm) 22.3,
24.7, 28.1, 40.4, 44.9, 50.5, 61.8, 67.0, 80.6, 127.3, 127.5, 128.5,
141.5, 171.9; [R]25D +49 (c 1.005, CHCl3); IR (MIR) (cm-1) 3428,
3331, 1721. Anal. Calcd for C19H31NO3: C, 70.99; H, 9.72; N,
4.36. Found: C, 69.29; H, 9.75; N, 4.08.
3,5-Dichloro-2-(2-methoxyethoxymethoxy)benzalde-
hyde (14a). Potassium carbonate (powder, oven dried at 100
°C under vacuum, 8.28 g, 0.06 mol) was added to a solution of
3,5-dichlorosalicylaldehyde (13a) (11.46 g, 0.06 mol) in DMF
(40 mL) at room temperature to give a bright yellow slurry.
MEMCl (neat, 7.64 g, 0.061 mol) was then added while
maintaining the bath temperature at 20 °C. Gas evolution is
observe during the addition. The mixture was then stirred at
22 °C for 3 h and additional MEMCl (neat, 0.3 g) was added.
The mixture was then stirred for an extra 0.5 h and poured
into 200 mL of cold water to precipitate the product. The slurry
was filtered on a pressure filter and the cake was washed with
DI water (2 × 50 mL) and then dried under N2/vacuum to
afford 14a (14.94 g, 89%) as a pale yellow solid. 1H NMR
(CDCl3, TMS) δ 3.37 (s, 3H), 3.54 to 3.56 (m, 2H), 3.91 to 3.93
(m, 2H), 5.30 (s, 2H), 7.63 (d, 1H, J ) 2.6 Hz), 7.73 (d, 1H, J
) 2.6 Hz), 10.30 (s, 1H); 13C NMR (CDCl3, TMS) δ (ppm) 59.1,
70.1, 99.6, 126.6, 129.6, 130.8, 132.1, 135.4, 154.7, 188.3; DSC
31.17 °C (endo 83.12 J/g). Microanal. Calcd for C11H12Cl2O4:
C, 47.34; H, 4.33; Cl, 25.40. Found: C, 47.15; H, 4.26; Cl, 25.16.
3-Bromo-5-chloro-2-(2-methoxyethoxymethoxy)benz-
aldehyde (14b). Following the procedure for 14a, 14b (182.4.0
g, 88%, off white solid) was prepared from potassium carbonate
(powder, oven dried at 100 °C under vacuum, 94.1 g, 0.685
mol) and 3-chloro-5-bromosalicylaldehyde (13b) (150.0 g, 0.64
mol) and MEMCl (neat, 107.14 g, 0.86 mol) in DMF (750 mL).
1H NMR (CDCl3, TMS) δ (ppm) 3.38 (s, 3H), 3.55 to 3.57 (m,
2H), 3.92 to 3.94 (m, 2H), 5.30 (d, 2H), 7.79 (d, 1H, J ) 2.68
Hz), 7.82 (d, 1H, J ) 2.68 Hz); 13C NMR (CDCl3, TMS) δ (ppm)
59.1, 70.2, 71.5, 99.8, 118.9, 127.3, 131.3, 132.1, 138.3, 155.8,
188.5. Microanal. Calcd for C11H12BrClO4: C, 40.82; H, 3.74;
Br, 24.69; Cl, 10.95. Found: C, 40.53; H, 3.74; Br 23.60; Cl,
10.96.
5-Bromo-3-chloro-2-(2-methoxyethoxymethoxy)benz-
aldehyde (14c). Following the procedure for 14a, 14c (46.0
g, 95%, off white solid) was prepared from potassium carbonate
(powder, oven dried at 100 °C under vacuum, 22.1 g, 0.16 mol)
and 3-chloro-5-bromosalicylaldehyde (13c) (35.0 g, 0.15 mol)
and MEMCl (neat, 25.0 g, 0.2 mol) in DMF (175 mL). 1H NMR
(CDCl3, TMS) δ 3.35 (s, 3H), 3.54 to 3.56 (m, 2H), 3.91 to 3.93
(m, 2H), 5.30 (s, 2H), 7.77 (d, 1H), 7.85 (d, 1H), 10.30 (s, 1H);
13C NMR (CDCl3, TMS) δ (ppm) 59.1, 70.1, 71.5, 99.5, 117.9,
129.7, 129.8, 132.4, 138.1, 155.1, 188.2. Microanal. Calcd for
C11H12BrClO4: C, 40.82; H, 3.74; Br, 24.69; Cl, 10.95. Found:
C, 40.64; H, 3.48; Br 24.67; Cl, 10.99.
(3S)-3-Amino-3-(3,5-dichloro-2-hydroxyphenyl)propi-
onic Acid Ethyl Ester p-Toluene-4-sulfonic Acid Salt
(18a). Following the general procedure A, 15a was prepared
as crude from (S)-phenylglycinol (17.20 g, 0.125 mol) and
aldehyde 14a (35 g, 0.125 mol).
(3S)-3-Amino-3-(3-bromo-5-chloro-2-hydroxyphenyl)-
propionic Acid Ethyl Ester p-Toluene-4-sulfonic Acid
(18b). Following the general procedure A, 15b was prepared
as crude from (S)-phenylglycinol (54.86 g, 0.4 mol) and
aldehyde 14b (129.42 g, 0.4 mol).
Following the general procedure B, crude 16b (221.0 g) was
prepared as an orange oil as a single diastereoisomer as
determined by 1H NMR and 13C NMR from 3 (332.0 g, 0.8 mol,
solid) in NMP and crude imine 15b in NMP.
Following general procedures D and F, 18b (55 g as a white
solid) was isolated as a salt containing 0.25 equiv of THF from
a portion of crude 16b (∼111.0 g, calcd 0.2 mol), Pb(OAc)4
(88.67 g, 0.2 mol), and pTSA‚H2O (50 0.0 g, 0.26 mol).
1H NMR (d6-DMSO, TMS) (ppm) 1.14 (t, 3H), 2.29 (s, 3H),
3.0 (m, 2H), 4.05 (q, 2H), 4.9 (t, 1H), 7.11 (d, 2H), 7.48 (dd,
3H), 7.70 (d, 1H), 8.35 (br s, 3H); 13C NMR (DMSO, TMS)
(ppm) 13.8, 20.8, 37.2, 45.8, 60.6, 112.5, 124.1, 125.5, 127.2,
127.6, 128.1, 132.2, 137.9, 145.2, 150.7, 168.98; DSC 146.19
°C (endo), 178.15 °C (endo, 68.66 J/g), 210.63 °C (exo); [R]25
D
+6.3 (c 1.110, MeOH); IR (MIR) (cm-1) 3036, 2980, 2903, 2857,
1722, 1595, 1486, 1467, 1419, 1376. Microanal. Calcd for
C18H21BrClNO6S: C, 43.69; H, 4.27; N, 2.83; Br, 16.15; Cl, 7.16;
S, 6.48. Found: C, 44.47; H, 4.46; N, 2.66; Br, 15.15; Cl, 7.05;
S, 6.52.
(3S)-3-Amino-3-(5-bromo-3-chloro-2-hydroxyphenyl)-
propionic Acid Ethyl Ester p-Toluene-4-sulfonic Acid
(18c). Following the general procedure A 15c (48.0 g) was
prepared as a pale yellow oil from (S)-phenylglycinol (13.71 g,
0.1 mol) and aldehyde 14c (32.35 g, 0.1 mol).
Following the general procedure B, crude 16c (228.0 g) was
prepared as an orange oil as a single diastereoisomer as
determined by 1H NMR and 13C NMR from 3 (332.0 g, 0.8 mol,
solid) in NMP and crude imine 15c in NMP.
Following general procedures D and F, 18c (38 g) was
prepared as a white solid from a portion of crude ester 16c
(calcd 111.0 g, corrected for 0.2 mol), Pb(OAc)4 (88.67 g, 0.2
mol), and pTSA‚H2O (50.0 g, 0.26 mol).
1H NMR (DMSO, TMS) (ppm) 1.12 (t, 3H), 2.29 (s, 3H), 3.0
(m, 2H), 4.05 (q, 2H), 4.88 (t, 1H), 7.11 (d, 2H), 7.48 (d, 2H),
7.55 (d, 1H), 7.68 (1H, d), 8.35 (br s, 3H); 13C NMR (DMSO,
TMS) (ppm) 13.8, 20.8, 37.1, 45.6, 60.6, 110.6, 122.5, 125.4,
127.9, 128.1, 129.5, 131.9, 137.8, 145.3, 150.1, 168.9; [R]25D +4.2
(c 0.960, MeOH); IR (MIR) (cm-1) 2922, 1726, 1621, 1591, 1494,
1471, 1413, 1376, 1324, 1286, 1237, 1207. Microanal. Calcd
for C18H21BrClNO6S: C, 43.69; H, 4.27; N, 2.83; Br, 16.15; Cl,
7.16; S, 6.48. Found: C, 43.40; H, 4.24; N, 2.73; Br, 16.40; Cl,
7.20; S 6.54.
Acknowledgment. The authors thank Teddy
Albano, Daniel L. Sweeney, Patricia M. Finnegan, and
the Physical Methodology Department for their analyti-
cal support.
Following the general procedure B, crude 16a (66.26 g) was
prepared as an orange oil solidifying on standing as a single
diastereoisomer as determined by 1H NMR and 13C NMR from
3 (91.3 g, solid, 0.275 mol) in NMP and crude imine 15a.
JO050177H
J. Org. Chem, Vol. 70, No. 14, 2005 5397