Aziridinium from N,N-dibenzyl serine methyl ester: Synthesis of enantiomerically pure β-amino and α,β-diamino esters

Article abstract of DOI:10.1021/ol060700u

Reaction of N,N-dibenzyl-O-methylsulfonyl serine methyl ester with a variety of heteronucleophiles (sodium azide, sodium phthalimide, amines, thiols) and carbanions (sodium malonate) gave, via an aziridinium intermediate, the corresponding β-amino or α,β-

Full text of DOI:10.1021/ol060700u

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2183-2186
Aziridinium from N,N-Dibenzyl Serine
Methyl Ester: Synthesis of
Enantiomerically Pure
-Diamino Esters
â-Amino and
r,â
Ce´dric Couturier,† Je´rome Blanchet,† Thierry Schlama,‡ and Jieping Zhu*,†
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France, and
Socie´te´ Rhodia, Centres de Recherche de Lyon, 69192 Saint-Fons Cedex, France
zhu@icsn.cnrs-gif.fr
Received March 22, 2006
ABSTRACT
Reaction of N,N-dibenzyl-O-methylsulfonyl serine methyl ester with a variety of heteronucleophiles (sodium azide, sodium phthalimide, amines,
thiols) and carbanions (sodium malonate) gave, via an aziridinium intermediate, the corresponding -amino or -diamino ester in good to
excellent yield. A short synthesis of orthogonally protected and enantiomerically pure 2,3-diamino propionate (Dap) is described.
â
r,â
The high density of functionalization associated with its ready
availability in both enantiomerically pure forms have made
serine an ideal starting material in organic synthesis.1 Several
versatile serine-based synthons have been developed allowing
regio- and stereoselective introduction of functional groups
into the molecule. Among them, Garner’s aldehyde2 and
Jackson’s â-alanyl anion synthon3 are notable examples and
have been widely applied in the synthesis of complex natural
products. On the other hand, earlier efforts aimed at
synthesizing â-alanyl cation synthons for direct functional-
ization of serine have met with only limited success due to
the competitive â-elimination process leading to racemic
adducts (Scheme 1).4 To avoid this undesired reaction, serine
Scheme 1 â-Alanyl Cation Equivalent, Problem of
â-Elimination
† Institut de Chimie des Substances Naturelles.
derivatives with reduced R-CH acidity have been synthesized.
Indeed, by using the bulky electron-donating N-protecting
groups such as N-phenylfluorenyl5 and N-trityl6 or by
converting the carboxylic acid to the Weinreb amide,7 the
undesired â-elimination process can be effectively mini-
mized.8 However, the application scope of these synthons is
still limited.
‡ Socie´te´ Rhodia, Centres de Recherche de Lyon.
(1) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction
of Chiral Molecules Using Amino Acids; John Wiley & Sons: New York,
1987.
(2) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364. (b)
Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979-2984. (c) Garner,
P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395-4398. (d)
Angrick, M. Montash. Chem. 1985, 116, 645-649. (e) Campbell, A. D.;
Raynham, T. M.; Taylor, R. J. K. Synthesis, 1998, 1707-1709. (f) For a
review, see: Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans.
I 2001, 2136-2157.
(3) (a) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S. J. Org. Chem.
1998, 63, 7875-7884. (b) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S.
J. Org. Chem. 1998, 63, 7875-7884. (c) Tabanella, S.; Valancogne, I.;
Jacskon, R. F. W. Org. Biomol. Chem. 2003, 1, 4254-4261
(4) (a) Photaki, I. J. Am. Chem. Soc. 1963, 85, 1123-1126. (b) Olsen,
R. K. J. Org. Chem. 1970, 35, 1912-1915. (c) Boggs, N. T., III; Goldsmith,
B.; Gawley, R. E.; Koehler, K. A.; Hiskey, R. G. J. Org. Chem. 1979, 44,
2262-2269. (d) Bajgrowicz, J. A.; El Hallaoui, A.; Jacquier, R.; Pigiere,
C.; Viallefont, P. Tetrahedron 1985, 41, 1833-1843.
10.1021/ol060700u CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/19/2006

Scheme 2. Stereoselective Synthesis of Enantiomerically Pure
â-Amino or R,â-Diamino Esters
Scheme 3. Synthesis of (S)-R-Azido-â-N,N-dibenzylamino
Propionate 5a
The ability of the N,N-dibenzyl group to shield the R-CH
of R-amino acid from deprotection has been amply demon-
strated9 and a variety of N,N-dibenzyl amino aldehydes,
including serinal,10 have been synthesized. We document
herein that N,N-dibenzyl-O-methylsulfonyl serine methyl
ester (4) is a stable R,â-alanyl double cation synthon. It reacts
with a variety of heteronucleophiles (NaN3, sodium phthal-
imide, amine, thiol) and carbanions (sodium malonate) to
afford, via an aziridinium intermediate, the corresponding
â-amino ester or R,â-diamino ester (5) in good to excellent
yield (Scheme 2).
Compound D-4 was obtained in 80% isolated yield by
mesylation of the readily available D-N,N-dibenzyl serine
methyl ester (6)10b under classic conditions (MsCl, Et3N, CH2-
Cl2, rt, Scheme 3). We stress that formation of the chloro
amine resulting from the attack of the chloride ion on the
mesylate 4 was not observed.11 Compound D-4 in its pure
form is stable at room temperature and can be stored for
weeks in a refrigerator without detectable degradation.12 This
highly desirable stability can be ascribed to the bulky
N-protecting group that protects the compound from the
â-elimination as well as from the formation of aziridinium.13
As a prototypical transformation, reaction of 4 with sodium
azide was first examined (Scheme 3). Under optimized
conditions (MeCN/DMF ) 4/1, 60 °C), a single product was
isolated in 90% yield whose structure was determined to be
(S)-methyl R-azido-â-N,N-dibenzyl propionate (5a). Methyl
N,N-dibenzyl-â-azido alanate (7a) resulting from the formal
direct nucleophilic substitution of mesylate by azide was not
detected in the crude product by 1H NMR analysis (Scheme
3). The formation of N,N-dibenzyl aziridinium-2-carboxylate
8 followed by regioselective ring opening by an SN2 process
could explain the formation of 5a.
The structure of 5a was determined by its transformation
to the known compound 11 (Scheme 4). Staudinger reduction
Scheme 4. Structural Determination of Compound 5a
(5) (a) Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544-2546.
(b) Lu, H. S. M.; Volk, M.; Kholodenko, Y.; Gooding, E.; Hochstrasser,
R. M.; DeGrado, W. F. J. Am. Chem. Soc. 1997, 119, 7173-7180. See
also: (c) Koskinen, A. M. P.; Rapoport, H. J. Org. Chem. 1989, 54, 1859-
1866. (d) Atfani, M.; Lubell, W. D. J. Org. Chem. 1995, 60, 3184-3188.
(6) (a) Dugave, C.; Menez, A. J. Org. Chem. 1996, 61, 6067-6070. (b)
Dugave, C.; Menez, A. Tetrahedron: Asymmetry 1997, 8, 1453-1465. (c)
Mustapa, M. F. M.; Harris, R.; Bulic-Subanovic; Elliott, S. L.; Bregant, S.;
Groussier, M. F. A.; Mould, J.; Schutz, D.; Chubb, N. A. L.; Gaffney, P.
R. J.; Driscoll, P. C.; Tabor, A. B. J. Org. Chem. 2003, 68, 8185-8192.
(d) Bregant, S.; Tabor, A. B. J. Org. Chem. 2005, 70, 2430-2438.
(7) Panda, G.; Rao, N. V. Synlett 2004, 714-716.
(8) Other â-alanyl cation synthons: Serine â-lactone: (a) Arnold, L. D.;
May, R. G.; Vederas, J. C. J. Am. Chem. Soc. 1988, 110, 2237-2241. Cyclic
sulfamidates, see: (b) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.
Tetrahedron: Asymmetry 1990, 1, 881-884. Aziridine 2-carboxylate, for
selected examples see: (c) Nakajima, K.; Tanaka, T.; Morita, K.; Okawa,
K. Bull. Chem. Soc. 1980, 53, 283-284. (d) Baldwin, J. E.; Adlington, R.
M.; O’Neil, I. A.; Schofield, C.; Spivey, A. C.; Sweeney, J. B. J. Chem.
Soc. Chem. Chem. 1989, 1852-1854. (e) Dauban, P.; Dubois, L.; Tran
Huu Dau, M. E.; Dodd, R. H. J. Org. Chem. 1995, 60, 2035-2043. For
recent reviews on the aziridine chemistry, see: (f) McCoull, W.; Davis, F.
A. Synthesis 2000, 10, 1347-1365. (g) Hu, X. E. Tetrahedron 2004, 60,
2701-2743. (h) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-
619. (i) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247-258.
of azide gave the diamine 9 in 83% yield. Protection of the
resulting primary amine as tert-butyloxycarbamate gave 10.
The observed NH-CHR correlation in the COSY spectrum
of 10 is in accord with the structure of 5a. Finally, removal
of the N-benzyl group under hydrogenolysis conditions
afforded the known (S)-NR-Boc â-amino-alanine methyl ester.
To further confirm the assignment of the stereochemistry of
5a, both (S)- and (R)-O-methylmandelic acid derivatives 12
and 13 were synthesized. The calculated chemical shift
(9) Reetz, M. T. Chem. ReV. 1999, 99, 1121-1162.
(10) (a) Laib, T.; Chastanet, J.; Zhu, J. Tetrahedron Lett. 1997, 38, 1771-
1772. (b) Laib, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63, 1709-
1713. (c) Andre´s, J. M.; Pedrosa, R. Tetrahedron 1998, 54, 5607-5616.
(d) East, S. P.; Shao, F.; Williams, F.; Jouille´, M. M. Tetrahedron 1998,
54, 13371-13390.
(11) See for example: (a) Gmeiner, P.; Junge, D.; Ka¨rtner, A. J. Org.
Chem. 1994, 59, 6766-6776. (b) Chuang, T.-H.; Sharpless, K. B. Org.
Lett. 2000, 2, 3555-3557. (c) Chuang, T.-H.; Sharpless, K. B. Org. Lett.
1999, 1, 1435-1437.
(12) Certain mesylates derived from N,N-dibenzyl amino alcohol can
be purified by low-temperature flash chromatography, see: Thomas, C.;
Orecher, F.; Gmeiner, P. Synthesis 1998, 1491-1496.
differences [∆δArCH NBn (12-13)) ) -0.09 ppm; ∆δCO2Me(12-13)
)
2
2
0.04 ppmp] were indicative of the S configuration of
(13) (a) Lubell, W.; Rapoport, H. J. Org. Chem. 1989, 54, 3824-2831.
(b) Temal-la¨ıb, T.; Chastanet, J.; Zhu, J. J. Am. Chem. Soc. 2002, 124,
583-590.
2184
Org. Lett., Vol. 8, No. 10, 2006

Table 1. Synthesis of â-Amino Ester and R,â-Diamino Estera
Scheme 5. Synthesis of Dipeptide 14
dibenzyl aziridinium precursors,16,17 it is interesting to note
that compound 4 was notably absent from these literature
reports.18 Encouraged by these results, the reaction of 4 with
morpholine was next examined. Gratifyingly, simply heating
an acetonitrile solution of morpholine with 4 to 80 °C
afforded 5b in 92% yield (Table 1). The structure of 5b was
determined by its transformation to the dipeptide 14 (Scheme
5). The NH-CHâ correlation in the COSY spectrum of 14
clearly indicated the structural identity of 5b. Moreover, the
de of 14, hence the ee of 5b, was determined to be higher
than 95%.
The reaction of 4 with other amines was next examined
as a means for the syntheses of diversely substituted chiral
diamines.19 Although the degree of regioselectivity is sensi-
tive to the nature of nucleophiles, the reaction is uniformly
R-selective with a variety of cyclic as well as acyclic amines
providing compound 5 as the major regioisomer (Table 1).
Whereas tert-butylamine reacted with 4 to afford 5i as a sole
isolable regioisomer in moderate yield, other sterically less
encumbered primary amines were poor substrates for this
reaction due to the occurrence of a double alkylation reaction
(results not shown). Imidazole also participated in this
reaction to afford two regioisomers in a one-to-one ratio.
Reaction of 4 with phthalimide anion worked under the
identical conditions to provide the corresponding R-regio-
isomer 5k in 56% yield. Thiols are also suitable nucleophiles.
Thus reaction of 4 with methyl thioglycolate or the potassium
salt of thiolacetic acid (MeCN, 80 °C) afforded 5l and 5m
in yields of 42% and 50%, respectively. Due to the inherent
1
a Isolated yield. b Not observed in the H NMR spectrum of the crude
product. c Determined from the 1H NMR spectrum of the crude product.
d Inseparable mixture of two diastereoisomers.
compound 5a.14 Thus the configuration of the R-center was
reversed in the course of this reaction. In addition, analysis
of 1H NMR spectra of compounds 12 and 13 indicated that
the de of 12 and 13, and hence the ee of their precursor 5a,
was higher than 95%. It is interesting to note that the
transformation shown in Scheme 4 represents a new synthesis
of selectively protected 2,3-diamino propionate (Dap), which
is a key structural subunit in a number of natural products.
Besides being shorter than other recently reported routes,
the advantage of the present synthesis is the ready access to
D-Dap from the cheaper L-serine.15
(16) (a) Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717-5720. (b) Dieter,
R. K.; Deo, N.; Lagu, B.; Dieter, J. W. J. Org. Chem, 1992, 57, 1663-
1671. (c) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem. 1999,
1693-1699. (d) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2,
647-649. (e) O’Brien, P.; Towers, T. D. J. Org. Chem. 2002, 67, 304-
307. (f) Graham, M. A.; Wadsworth, A. H.; Zahid, A.; Rayner, C. M. Org.
Biomol. Chem. 2003, 1, 834-849. (g) McKay, C.; Wilson, R. J.; Rayner,
C. M. Chem. Commun. 2004, 1080-1081. (h) Couty, F.; Evano, G.; Prim,
D. Tetrahedron Lett. 2005, 46, 2253-2257.
(17) For interesting examples of ring opening of aziridine by a vicinal
tertiary amine leading to aziridinium, see: (a) Concello´n, J. M.; Riego, E.
J. Org. Chem. 2003, 68, 6407-6410. (b) Concello´n, J. M.; Riego, E.; Rivero,
I. A.; Ochoa, A. J. Org. Chem. 2004, 69, 6244-6248. (b) Concello´n, J.
M.; Riego, E.; Sua´rez, J. R.; Garcia-Granda, S.; Diaz, M. R. Org. Lett.
2004, 6, 4499-4501.
(18) Compound 6 has been converted to the corresponding R-fluoro and
R-bromo derivatives via an aziridinium intermediate, see: (a) Somekh, L.;
Shanzer, A. J. Am. Chem. Soc. 1982, 104, 5836-5837. (b) Nagle, A. S.;
Salvatore, R. N.; Chong, B.-D.; Jung, K. W. Tetrahedron Lett. 2000, 41,
3011-3014.
(19) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580-2627. (b) Rondot, C.; Zhu, J. Org. Lett. 2005, 7, 1641-
1644. (c) Cabello, N.; Kizirian, J.-C.; Gille, S.; Alexakis, A.; Bernardinelli,
G.; Pinchard, L.; Caille, J.-C. Eur. J. Org. Chem. 2005, 4835-4842. (d)
Mosse´, S.; Alexakis, A. Org. Lett. 2005, 7, 4361-4364 and references
therein.
Whereas a number of N,N-dibenzyl amino alcohols have
previously been synthesized and elegantly exploited as N,N-
(14) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59,
4202-4205.
(15) Recent synthesis, see: (a) Otsuka, M.; Kittaka, A.; Iiomori, T.;
Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33,
509-514. (b) Batt, D. G.; Houghton, G. C.; Daneker, W. F.; Jadhav, P. K.
J. Org. Chem. 2000, 65, 8100-8104. (c) Englund, E. A.; Gopi, H. N.;
Appella, D. H. Org. Lett. 2004, 6, 213-215. Ring opening of 2-carboxylate
azirdine: (d) Kim, Y.; Ha, H.-J.; Han, K.; Ko, S. W.; Yun, H.; Yoon, H.
J.; Kim, M. S.; Lee, W. K. Tetrahedron Lett. 2005, 46, 4407-4409.
Org. Lett., Vol. 8, No. 10, 2006
2185

Scheme 6. Reaction of Malonate Anion with 4
Scheme 7. One-Pot Synthesis of 5 from Alcohol 6
The yield of this one-pot process was actually higher than
the overall yield of the two-step process.
In summary, we demonstrated that optically pure N,N-
dibenzyl-O-methylsulfonyl serine methyl ester (4) is a stable
precursor of N,N-dibenzyl aziridinium-2-carboxylate (8). It
reacts with a variety of heteronucleophiles (NaN3, sodium
phthalimide, amine, thiol) and carbanions (sodium malonate)
to afford the corresponding â-amino ester or R,â-diamino
ester (5) in good to excellent yield. Ring opening occurred
preferentially at the sterically more hindered CR position with
inversion of configuration. A short synthesis of an important
nonproteinogenic amino acid, the NR-Boc-2,3-diamino pro-
pionate (Dap), has been developed.
basicity of the malonate anion, its reaction with â-alanyl
cation synthon usually led to the formation of racemic adduct
via a sequence of â-elimination/Michael addition.20 We were
thus glad to observe that the reaction of 4 with sodium
dimethyl malonate (DMF, 100 °C) provided cleanly the
R-substituted product 5n in 67% yield. The structure of 5n
was fully established by detailed spectroscopic studies and
its chemical transformation to pyrrolidinone 15. It is interest-
ing to note that the lactamization displayed high group
selectivity21 to afford the 3,4 trans isomer as the only isolable
product.
Finally, we found that 5 could be synthesized in a one-
pot fashion from N,N-dibenzyl serine methyl ester without
isolation of the mesylate 4. Thus mesylation of 6 with Ms2O
in MeCN in the presence of Et3N at room temperature
followed by addition of NaN3 and heating to 60 °C afforded
5a in 74% isolated yield (Scheme 7). Similary, 5b was
prepared in 77% yield by using morpholine as a nucleophile.
Acknowledgment. Financial support from Rhodia and
this institute is gratefully acknowledged. C.C. is a recipient
of a doctoral fellowship jointly funded by Rhodia and CNRS.
Supporting Information Available: Experimental de-
1
tails, physical data, and copies of H and 13C NMR spectra
of compounds 4, 6, 5a-n, 9-13, and 15. This material is
(20) Wei, L.; Lubell, W. D. Org. Lett. 2000, 2, 2595-2598 and references
therein.
available free of charge via the Internet at http://pubs.acs.org.
(21) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17.
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