A new synthesis of β-amino acids by use of ketene diethyl acetal as enolate equivalent

Article abstract of DOI:10.1016/j.tetlet.2005.01.114

Reaction of phenylsulfonyl formamides, readily available in a single step from an aromatic aldehyde and sodium phenylsulfinate, with ketene diethyl acetal under basic conditions gives N-formyl β-amino acid esters in good yield, which can be kinetically resolved with a lipase.

Full text of DOI:10.1016/j.tetlet.2005.01.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1819–1821
A new synthesis of b-amino acids by use of ketene diethyl
acetal as enolate equivalent
Kai Rossen,a,* Pavol Jakubec,a Michael Kieselb and Matthias Janikb
aDegussa AG, EC-EX-R&D-WO, Rodenbacher Chaussee 4, 63457 Hanau, Germany
bDegussa AG, Aqura NMR Department, Rodenbacher Chaussee 4, 63457 Hanau, Germany
Received 17 November 2004; revised 20 January2005; accepted 24 January2005
Abstract—Reaction of phenylsulfonyl formamides, readily available in a single step from an aromatic aldehyde and sodium phenyl-
sulfinate, with ketene diethyl acetal under basic conditions gives N-formyl b-amino acid esters in good yield, which can be kinetically
resolved with a lipase.
Ó 2005 Elsevier Ltd. All rights reserved.
While some b-amino acids are found in nature, it is pri-
marilythe more recent work of Seebach and Gellmann
that pointed out to the organic communitytheir impor-
tance.1 The abilityof even small b-amino acid peptides
to form stable secondarystructures is remarkable. Re-
cently, a significant number of drug candidates in clini-
cal development incorporate b-amino acids, highlighting
the need for an efficient synthetic access.2 Just as the
classical Strecker a-amino acid synthesis consists of
the addition of a carboxylate anion equivalent (cyanide)
to an imine, b-amino acids are frequentlyprepared by
adding an ester enolate equivalent to an imine. The clas-
sical example is the Rodionov reaction, wherebysimply
heating a mixture of an aromatic aldehyde, ammonium
acetate and malonic acid leads directlyto b-amino acid,
typically in less than 60% yield. Mechanistically, the key
step of this reaction is the addition of malonate to the in
situ formed imine.3 Recently, asymmetric versions of
this reaction are reported, some with impressive ee val-
ues. In these reactions TMS enolethers are added to ani-
line derived imines or Boc imines using Lewis acid
catalysis.4 Unfortunately, the need to remove the aniline
oxidativelywith CAN and the expense in preparing the
TMS-enolether impose a limit on the practical applica-
bilityof this approach.
While TMS-ketene acetals and TMS-ketenethio acetals
are generallyused as acetate anion equivalents, we are
unaware of similar uses of the readilyavailable and sta-
ble ketene diethyl acetal 2. We now report on the suc-
cessful addition of ketene diethyl acetal 2 into an in
situ prepared acyl imine 3 for the synthesis of b-amino
acid derivates 4 (Scheme 1, Table 1).5 Indeed, N-formyl
imines 3 are easilygenerated in situ from phenylsulfonyl
formamides 1 using the chemistrydescribed originally
byDutch workers and recentlyelegantlyapplied by
the Merck and the Braese groups.6
Gratifyingly, combining 1 with 2 equiv of 2 led to the
clean formation of 4 using 6 equiv of Et3N in CH2Cl2
(Scheme 1). Optimization of reaction conditions showed
that the reaction performs well in toluene and CH3CN,
but gave complex reaction mixtures in THF, MeOH and
AcOEt. For R = Ph, optimization of bases byreplacing
Et3N with the more basic DBU led to an increase of the
rate of the reaction, albeit at the expense of reduced
yields (Table 1). The optimum base for this reaction
is Cs2CO3, which resulted in a veryclean conversion
in 24 h to give 4 in a gratifying 90% yield. More
O
O
O
OEt
OEt
HN
N
HN
base
2
COOEt
R
SO2Tol
R
R
Keywords: b-Amino acid; Ketene diethylacetal; Acyl imine; Acetate
enolate; Enzymic kinetic resolution.
4
1
3
*
Scheme 1. Synthesis of b-aminoesters using ketene diethyl acetal as
enolate equivalent.
Corresponding author. Tel.: +49 6181 594296; fax: +49 6181
594312; e-mail: kai.rossen@degussa.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.114

1820
K. Rossen et al. / Tetrahedron Letters 46 (2005) 1819–1821
Table 1.
O
O
H
EntryR
Base
Et3N
Yield (%)
Conditions
O
2
N
TolSO2K
a
b
a
a
a
a
a
N
OEt
OEt
4a
4a
4a
4d
4e
4f
Ph
Ph
80
48
90
77
67
62
55
HN
Ph
OEt
OEt
DBU
Ph
Ph
Ph
Cs2CO3
Et3N
Et3N
3
11
9
4-NO2Ph
4-MeOPh
4-OHPh
3-Thiophenyl
3
Et3N
Cs2CO3
O
4g
O
O
S
a 6 equiv of base, 24 h, reflux.
b 2 equiv of base, 24 h, rt.
O
HN
O
O
+
HN
O
OEt
Ph
Ph
OEt
Ph
10
rac-8
4a
O
O
Scheme 4. Proposal mechanism of formation of rac-8.
HN
HN
NH2
i
ii,iii
R
COOH
SO2Tol
Et3N, the initial addition product 9 will react with a
nucleophile to lead directlyto the the b-amino ester
4a. It is likely that triethylammonium phenylsulfinate
acts as the nucleophile, as we have managed to isolate
10 from a reaction mixture. With K2CO3 as base, it is
expected that the potassium phenylsulfinate is less solu-
ble and an alternative stabilization of the intermediate 9
7
5
6a,b
Scheme 2. Reagents and conditions: (i) Et3N, DCHM, 24 h, 60%; (ii)
Et3N, ketene diethyl acetal, DCHM; (iii) concd. HCl, 50 °C, 5 h, 35%
after two steps.
+
bythe elimination of H can become competitive. The
importantly, the classical Rodionov reaction is poor for
both nitro- and hydroxy-substituted benzaldehydes (15–
25% yield for 4-NO2, no reaction for 4-OH). In contrast,
our new reaction system works well for these substrates
(Table 1). As expected, phenylsulfonyl imines derived
from aliphatic aldehydes 6a (R = H, Scheme 2) undergo
elimination of phenylsulfinate to give formyl enamines 5
in about 60% yield. An exception is the pivaldehyde de-
rived 6b (R = Me), which gives rise to the b-amino acid
analogue of tert-leucine 7, albeit onlyin an unoptimized
35%.
resulting ketene acetal 11 can undergo a subsequent
reaction with formyl imine 3 to give 8. This condensa-
tion is novel in that this complex, and to the best of
our knowledge unprecedented, heterocyclic structure is
prepared in a 2 + 1 multicomponent condensation.
In order to explore the chemistryfurther and elucidate
the relative stereochemistryof the three adjacent chiral
centers, the molecule was heated with ethanolic HCl
(Scheme 5). After neutralization the cyclic aminidine
12 was obtained in as a 6:4 mixture of diastereomers
12a and 12b in 93% yield, apparently resulting from
the epimerization of the chiral center adjacent to the
ethyl carboxylate group. Together with the coupling
constant measured in 8, it is possible to assign the rela-
tive stereochemistryto 8 as given. Clearly, the ease of
formation of 8 and 12 and the multitude of reactions
possible with these highlyfunctionalized novel scaffold
make them a promising starting material for further
studies. While the chemistryconstitutes an alternative
to both the classical Rodionov reaction and newer meth-
ods for the preparation of b-amino acids, an enantiose-
lective approach into this class of compounds would
clearlybe highlydesirable.
An interesting insight into the mechanism of the reac-
tion was obtained when K2CO3 was used as a base
(Scheme 3).7 In addition to the expected b-amino ester
4a (10%), the major product of the reaction was 8, iso-
lated in 38% yield. The novel structure was elucidated
bya combination of NMR methods and MS and is sur-
prisinglypresent as a single diastereomer. The large cou-
pling constant of 9.14 Hz between both ring methines is
indicative of the expected diequatorial arrangement of
the side chains. The conformation in the side chain is
determined bya transformation to a simpler ssytem
(vide infra).
Unexpected as it maybe, the formation of 8 is neverthe-
less mechanisticallyquite reasonable ( Scheme 4). When
the reaction is performed with a soluble base such as
While initial attempts to induce chiralityhave met with
verylimited success, an enzymatic resolution of the for-
O
O
O
O
O
N
HN
O
N
HN
O
O
O
O
N
N
N
N
i
+
HN
Ph
HN
Ph
Ph
Ph
i
COOEt
Ph
Ph
COOEt
rac 12a
+
Ph
Ph
COOEt
rac 12b
SO2Tol
Ph
Ph
1a
4a
rac-8
rac-8
Scheme 3. Reagents and conditions: (i) ketene diethyl acetal, K2CO3,
DCHM, 24 h, reflux, 10% 4a, 38% 8.
Scheme 5. Reagents and conditions: (i) EtOH, concd. HCl, 1.5 h,
100 °C, 93%, dr 12a:12b 60:40.

K. Rossen et al. / Tetrahedron Letters 46 (2005) 1819–1821
Table 2. Resolution of b-aminoester 4a with different enzymes
1821
Supplementary data
Enzyme
Ee (%)
Conversion (%)
s-Value
The supplementarydata is available online with the pa-
per in ScienceDirect. Supplementarydata associated
with this article can be found, in the online version, at
10.1016/j.tetlet.2005.01.114.
Esterase from hog liver
Chiro CLEC-CAB
NOVOZYM 525 L
SP 525
18
16
40
58
30
48
30
41
3
2
74
20
References and notes
O
O
O
1. (a) Hintermann, T.; Seebach, D. Chimia 1997, 50, 244–247;
(b) Seebach, D.; Mattthews, J. L. Chem. Commun. 1997,
2015–2022; (c) Gellman, S. H. Acc. Chem. Res. 1998, 31,
173–180.
2. (a) Ikemoto, N.; Tellers, D. M.; Spencer, D.; Liu, J.;
Huang, A.; Rivera, N. R.; Njolito, E.; Hsiao, Y.; Mc-
Williams, C. J.; Armstrong, J. M.; Armstrong, J. D.; Sun,
Y.; Mathre, D. J.; Grabowski, E. J. J.; Tillyer, R. D. J. Am.
Chem. Soc. 2004, 126, 3048–3049; (b) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991–8035; (c) Cordova, A. Acc.
Chem. Res. 2004, 37, 102–112.
HN
HN
HN
Ph
(3S)-4a, 95% ee, 43%
i
COOEt
COOH
COOEt
+
Ph
rac-4a
Ph
13
ii
NH2
COOH
Ph
3. (a) Rodionov, V. M.; Dudinskaya, A. A. Zhurnal Obshchei
Khimii 1958, 28, 2242–2246; (b) Tan, C. Y. K.; Weaver, D.
F. Tetrahedron 2002, 58, 7449–7461.
4. (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 12964–12965; (b) Ishitani, H.; Ueno, M.; Kobayashi,
S. J. Am. Chem. Soc. 2000, 124, 12964–12965; Kobayashi,
S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143–
145.
5. To a solution of 1a (0.0150 mol) in dichloromethane
(70 mL) was added triethylamine (0.0900 mol, 12.5 mL)
followed bydiethyl ketene acetal (0.0300 mol, 3.9 mL). The
resulting suspension was refluxed for 24 h. After cooling to
room temperature the solution was extracted with water
(two times 20 mL). The organic layer was dried over
MgSO4, concentrated under vacuum and the residue was
(3R)-14, 80%ee, 30%
Scheme 6. Reagents and conditions: (i) NOVOZYM 525L, 78 h,
phosphate buffer, 27 °C, pH = 7; (ii) concd. HCl, 2.5 h, 75 °C.
myl b-amino esters should be feasible. As expected, 4a is
no substrate for the acylase, but a screen of various lip-
ases revealed partial conversion.8 Measurement of the ee
value obtained at partial conversion allowed the calcula-
tion of the s-values, thus giving a quick and objective
comparison of the enantio-differentiating abilityof the
different enzymes (Table 2). The results showed that
NOVOZYM 525 L, a Candida antarctica lipase B, is
the best one found with s-values of about 70. A subse-
quent preparative run at 27 °C went to 54% conversion
giving an isolated yield of 43% of (3S)-4a with 95% ee
and (3R)-14 with 30% unoptimized isolated yield of
80% ee (Scheme 6).
purified bySiO column chromatography(hexane/AcOEt
2
1:1) to afford 4a as a yellowish oil, 80%. 1H NMR
(500 MHz, CDCl3, major rotamer) d 8.22 (s, 1H, formyl),
7.28 (m, 5H, phenyl), 6.77 (br, 1H, amide), 5.52 (m, 1H,
H3),4.08 (q, J = 7.1 Hz, OCH2), 2.89 (m, 2H, H2), 1.17 (t, J
7.1 Hz, 3H, CH3); 13C NMR (CDCl3, 126 MHz) d 171.1
(C1), 160.3 (formyl), 140.0 (C10), 128.8 (C30), 127.8 (C40),
126.3 (C20), 60.9 (OCH2), 48.3 (C3), 40.0 (C2), 14.1 (CH3).
6. (a) Olijnsma, T.; Engberts, J. B. F. N.; Strating, J. Rec.
Travaux Chim. Pays-Bas 1972, 91, 209–212; (b) Dahmen, S.;
Braese, S.; Braese, S. J. J. Am. Chem. Soc. 2002, 124, 5940–
5941; (c) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001,
123, 9696–9697; (d) Sisko, J.; Mellimger, M.; Sheldrake, P.
W.; Baine, N. H. Org. Synth. 2000, 77, 198–205.
In summary, we have shown that ketene diethyl acetal
can serve as an acetate enolate equivalent in a novel
and apparentlyquite versatile formyl b-amino ester syn-
thesis. We have demonstrated that a kinetic enzymatic
resolution of this substrate is possible, thus extending
this approach to the synthesis of valuable enantiomeri-
callypure b-amino acid derivatives. Additionally, a
complex 2 + 1 multicomponent reaction product is ob-
tained in a highlydiastereoselective manner bysimply
changing the reaction conditions.
7. For other uses of 2 in condensation and hetero Diels Alder
reactions: (a) Avenoza, A.; Busto, J. H.; Canal, N.;
Peregrina, J. M. Chem. Commun. 2003, 1376–1377; (b)
Zaitseva, G. S.; Livantsova, L. I.; Novikova, O. P. Zhurnal
Obshchei Khimii 1994, 64, 1750–1751; (c) Audrain, H.;
Jorgensen, K. A. J. Am. Chem. Soc. 2000, 122, 11543–
11544.
Acknowledgements
8. Faulconbridge, S. J.; Holt, K. E.; Sevillano, L. G.; Lock, C.
J.; Tiffin, P. D.; Tremayne, N.; Winter, S. Tetrahedron Lett.
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We thank S. Merget for developing and performing the
chiral assays.