Reactions of azidoacetate enolates with aromatic aldehydes: Preparation of N-BOC 3-arylserines

Article abstract of DOI:10.1055/s-1999-2854

Azidoacetates undergo aldol-like reaction with aromaticaldehydes in the presence of sub-stoichiometric amounts of NaOEt. The product azido alcohols (2a)-(2q) may be directly converted to N-BOC phenyl serine analogues.

Full text of DOI:10.1055/s-1999-2854

1444
LETTER
Reactions of Azidoacetate Enolates with Aromatic Aldehydes: Preparation of
N-BOC 3-Arylserines
Graham Geen,1 Christopher J. Shaw#, J. B. Sweeney#*
1SB Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW
#Department of Chemistry, University of Reading, Reading, RG6 6AD
Received 1 June 1999
Table 1 Preparation of 2-Azido-3-Hydroxyesters via Azidoaldol
reaction
Abstract: Azidoacetates undergo aldol-like reaction with aromati-
caldehydes in the presence of sub-stoichiometric amounts of
NaOEt. Theproduct azido alcohols (2a)-(2q) may be directly con-
verted to N-BOC phenyl serine analogues
Keywords: aminoacids, arylserines
As part of a program of research concerning incorporation
of non-proteinogenic aminoacids into polypeptides, we
required a new entry to a range of 2-amino-3-hydroxyes-
ters.1 We thought that such compounds would be avail-
able from the corresponding azidoalcohols, and that if
such compounds could be prepared via an aldol-like reac-
tion, this would represent a useful addition to the armoury
of synthetic chemistry. We here report the preliminary re-
sults wehave obtained from study of such reactions.
Scheme 1
The reaction of aryl aldehydes with ethylazidoacetate is
well-known to give good yields of 2-azidocinnamates (1),
through the intermediacy of hydroxyazide (2) (Scheme 1),
the reaction forming the basis of the Hemetsberger-Knit-
telsynthesis of indoles.2 Very littlework has been reported
concerning the interception of the reaction to allow isola-
tion of these hydroxyazides,3 and our synthetic studies
commenced here. Thus, reaction of benzaldehyde with
ethylazidoacetate in the presence of one equivalent of so-
dium ethoxide in ethanol at room temperature overnight
gave, as expected, a good yield of azidocinnamate (1a).
We then repeated the reaction at low temperature, this
time using a hindered base (LDA) and an aprotic solvent
(THF): we isolated only starting materials from the reac-
tion. Using a variety of strong bases, a similar lack of suc-
cess was observed. When the original, protic reaction was
repeated using a sub-stoichiometric amountof base
(0.1eq.), rather than a full equivalent, no azidocinnamate
tained from such reactions when reaction temperatures
were considerably lower than ambient (ca. -40°C).3 Thus,
(2a) was obtained as a 2:1 mixture of diastereoisomers, in
1
favour of the syn-isomer (as judged from analysis of H
nmr data);4 the isomers were not separable using standard
column chromatography.
When (2a) was resubjected to the dipolar, aprotic reaction
conditions previously examined, (LHMDS base, THF sol-
vent,-78°C), retro-aldol reaction occurred and only ethyl
azidoacetate andbenzaldehyde were isolated from the re-
was observed and hydroxyazide (2a) was isolated as the
only product of the reaction, in 46% yield (Scheme2).
This observation is at odds with that previously described,
which concluded that azidoalcohols could only be ob-
Synlett 1999, No. 9, 1444–1446 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Reactions of Azidoacetate Enolates with Aromatic Aldehydes: Preparation of N-BOC 3-Arylserines
1445
Table 2 Effect of base on Azidoaldolreaction
Scheme 2
action, thereby giving a clue as to the reason for poor re-
action under those conditions. Using five other aromatic
aldehydes, the ’azidoaldol’reaction proved to be a general
one (Table 1),5 although in all cases, the diastereoselectiv-
ity of the reaction was mediocre (3.3:1-1:1, always in
favour of syn-isomers) even when a bulkier ester group
was employed. The greatest selectivity was observed in-
the reaction of t-butyl azidoacetate and ortho-anisalde-
hyde. Table 2 shows the variation of yield and
diastereoselectivityof the reaction with change in the base
employed. Note that, in all the reactions examples, the use
of strong bases under aprotic conditions led topoor yields
of hydroxy azides, although in some cases the diastereo-
selectivity was improved. Some of these hydroxyazides
were then converted to the corresponding N-BOC ar-
ylserines, in acceptable yields (Table 3).6 Separation of Thus, we have shown that aldol-like reactions of azidoac-
the anti- and syn-isomers could not be accomplished using etates havepotential in synthesis; the optimization and
usual flash chromatographic techniques.
augmentation of thepreliminary results presented above is
a focus of our present research.
Table 3 Preparation of N-BOC-Arylserines
Synlett 1999, No. 9, 1444–1446 ISSN 0936-5214 © Thieme Stuttgart · New York

1446
G. Geen et al.
LETTER
(5) The experimental procedure for the preparation of ethyl 2-
Acknowledgement
azido-3-hydroxy-3-(2-chlorophenyl)propanoate (2a) is
representative:sodium (10.9 mg, 0.47 mmol, 0.1 eq) was
added to dry ethanol (6 mL), followed sequentially by ethyl
azidoacetate (0.550 g, 4.26 mmol, 1 eq) and benzaldehyde
(0.458 g, 4.32 mmol, 1 eq) and the reaction was stirred
overnight. after which time 2M HCl (5 mL) was added. The
solution was extracted with ethyl acetate (2 x10 mL) and the
combined extracts dried (MgSO4) and concentrated in vacuo
to yield the crude product as a yellow oil. After column
chromatography, acolourless oil (0.46 g, 46%) was obtained;
Rf 0.13(petrol:ether (7:1)); νmax (neat) / cm-1 3481, 2984,
2114, 1734; dH (400 MHz, CDCl3) 1.24 (3H, m), 3.98 &
4.09(total 1H, 2 x d, J 4.6 & 6.9), 4.24 (2H, m), 4.99 & 5.15
(total 1H, 2 x d,J 6.9 & 4.6), 7.35 (5H, m); dC (100 MHz,
CDCl3) 13.9, 62.1, 66.7, 67.6, 74.0, 74.4, 139.1, 128.8, 126.4,
126.2, 168.5;m/z (CI) (%) 51.03 (6), 79.05 (44), 107.04
We acknowledge the financial support of the EPSRC (studentship
to CJS), SBPharmaceuticals (CASE support to CJS and the Univer-
sity of Reading) the Nuffield Foundation, and ZENECA (for an
award from the Strategic Research Fund to JBS).
References and Notes
(1) For recent syntheses of such aminoacid derivatives,see:
Adams, Z.M.; Jackson, R.F.W.; Palmer, N.J.;Rami, H.K.;
Wythes, M.J.; J. Chem.Soc., Perkin Trans. 1, 1999, 937;
Enders, D.; Thomas, C.R.; Raabe, G.; Runsink, J.; Helv.
Chim. Acta, 1998, 81, 1329; Liu, J.Q.; Ito, S.; Dairi, T.; Itoh,
N.; Shimizu, S.; Yamada, H.;App. Microbiol. Biotech., 1998,
49, 702; deRooij, B.M.; Commandeur, J.N.M.; Hommes,
J.W.; Aalbers, T.; Groot,E.J.; Vermeulen, N.P.E.; Chem. Res.
Toxicology, 1998,11, 111; Liu, J.Q.; Dairi, T.; Itoh, N.;
Kataoka,M.; Shimizu, S.; Yamada, H.; Euro.J. Biochem.,
1998, 255, 220- 226; Carda, M.; Murga, J.; Rodriguez,
S.;Gonzalez, F.; Castillo, E.; Marco, J.A.; Tetrahedron:
Asymmetry, 1998, 9,1703; Liu, J.Q.; Ito, S.; Dairi, T.;Itoh, N.;
Kataoka, M.; Shimizu, S.; Yamada, H.; Appl.Env. Microbiol.,
1998, 64, 549; Talwar, R.; Jagath, J.R,Datta, A.; Prakash, V.;
Savithri, H.S.; Rao, N.A.; ActaBiochim. Polonica, 1997, 44,
679; Delle Fratte,S.; White, R.H.; Maras, B.; Bossa, F.;
Schirch, V.; J. Bacteriology,1997, 179, 7456; Jagath, J.R.;
Appaji Rao,N.; Savithri, H.S.; Biochem. J.,1997, 327, 877;
Lociuro, S.; Tavecchia, P.; Marzorati, E.; Landini, P.;
Goldstein,B.P.; Denaro, M.; Ciabatti, R.; J.Antibiot., 1997, 50,
344; Jagath, J.R.;Sharma, B.; Appaji Rao, N.; Savithri, H.S.;
J. Biol. Chem., 1997, 272,24355; Kataoka, M.; Ikemi, M.;
Morikawa, T.; Miyoshi, T.; Nishi, K.; Wada,M.; Yamada, H.;
Shimizu, S.; Euro.J. Biochem., 1997, 248, 385; Marco,J.A.;
Carda, M.; Murga, J.; Gonzalez, F.; Falomir, E.; Tetrahedron
Lett., 1997, 38,1841; Bycroft, M.; Herbert, R.B.; Ellames,
G.J.; J. Chem. Soc., Perkin Trans. 1, 1996, 2439; Streefland,
L.; Blandamer, M.J.; Engberts, J.B.F.N.; J. Am.Chem. Soc.,
1996, 118, 9539; Hawes,J.W.; Harper, E.T.; Crabb, D.W.;
Harris, R.A.; FEBS Lett.; 1996, 389, 263; Tavecchia, P.; Kurz,
M.; Colombo, L.;Bonfichi, R.; Selva, E.; Lociuro, S.;
Marzorati, E.; Ciabatti, R; Tetrahedron, 1996, 52, 8763;
Okuda, H.;Nagata, S.; Misono, H.; J. Biochem., 1996, 119,
690; Davis, F.A.; Liu, H.; Reddy, G.V.; Tetrahedron
Lett.,1996, 37, 5473; Hayashi, H.; Inoue, K.; Mizuguchi, H.;
Kagamiyama, H.;Biochem., 1996, 35, 6754; Takagi, H.;
Harima, A.; Euro.Neuropsychopharm., 1996, 6, 43.
+
(100),163.08 (28), 253.10 (14) [M++NH4 ]C11H13N3O3
requires 253.1301; found 253.1310. When tert-butyl esters
were employed, distilled tert-butanol replacedethanol in the
above procedure.
(6) The experimental procedure for the preparation ofethyl 2-(N-
BOC)-3-hydroxy-3-(2-chlorophenyl)propanoate (3b)
isrepresentative: palladium on carbon (0.052 g, 0.1 eq) was
stirred in ethylacetate (4 mL) under a hydrogen atmosphere
until hydrogen uptake ceased. Ethyl 2-azido-3-hydroxy-3-(2-
chlorophenyl)propanoate (0.500 g, 1.86 mmol) anddi-tert-
butyl dicarbonate (0.618 g, 2.83 mmol, 1.5 eq) were then
added simultaneously, as a solution in ethyl acetate (1 mL). To
the reaction wasthen added Celite¨ and the mixture was
filtered through a Celite¨pad; this pad was then washed with
ethyl acetate and the filtrate concentrated in vacuo, to yield the
crude product as an oil, which was purified by column
chromatography, to give (3b) as a colourless oil(0.393 g,
61%); Rf 0.43 (Petrol:ether (2:3)); νmax (neat) / cm-1 3441,
2981, 2935, 1730, 1716; dH (400MHz, CDCl3) 1.00-1.44 (3H,
br. m), 4.17 (2H, m), 4.63 (1H, d, J 9.5), 5.22 (1H, s),5.34 (1H,
d, J 9.5), 5.51-5.56 (1H, br. m), 7.13-7.46; dC (100 MHz,
CDCl3) 14.0, 14.4, 27.6, 28.3, 57.3, 58.2 (CNH), 61.9, 62.0,
71.0, 71.8, 85.5, 126.3, 126.8, 127.2, 128.1, 128.3,128.4,
128.5, 128.6, 129.1, 129.3, 129.4, 129.5, 132.0, 132.3,
137.5,137.8, 155.8, 156.0, 170.4, 171.1; m/z (CI) (%) 57.05
(26), 104.02 (59), 147.04 (100), 169.99 (9), 210.09
(20),243.94 (65), 288.02 (32), 344.13 (3) [M+H+]
C16H22ClNO5 requires 344.1265; found 344.1278. It should
be noted that, especially for (3g-3l), many of the 1H nmr
resonances were broadened by the presence of different
rotameric forms.
(2) Hemetsberger, H.; Knittel, D.; Monatsch. Chem., 1970, 101,
161; idem., ibid., 1969, 100, 1599.
(3) Murakami, Y; Watanabe, T; Suzuki, H; Kotake, N;Takahashi,
T; Toyonari, K; Ohno, M; Takase K; Suzuki, T; Kondo, K;
Chem. Pharm. Bull., 1997, 45, 1739.
Article Identifier:
1437-2096,E;1999,0,09,1444,1446,ftx,en;L09899ST.pdf
(4) Ko, S.Y.; J. Org. Chem.,1995, 60, 6250.
There is an erratum or addendum to this paper.
Please check www.thieme.de/chemistry/synthesis/index.html.
Synlett 1999, No. 9, 1444–1446 ISSN 0936-5214 © Thieme Stuttgart · New York