Synthesis and synthetic applications of α,β-dideuterio-α- amino esters promoted by samarium diiodide

Article abstract of DOI:10.1055/s-2008-1032063

A new, easy, and high-yielded route to isotopically labeled amino acid derivatives is reported. This process takes place through a SmI ₂-promoted 1,4-reduction of a variety of dehydroamino esters in the presence of D₂O. The dideuteri

Full text of DOI:10.1055/s-2008-1032063

402
LETTER
Synthesis and Synthetic Applications of a,b-Dideuterio-a-amino Esters Promo-
ted by Samarium Diiodide
Synthesis
o
of
α
,
β
-Dideu
s
terio-
α
-am
é
inoEsters M. Concellón,* Humberto Rodríguez-Solla,* Carmen Concellón, Paula Tuya
Departamento Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
E-mail: jmcg@uniovi.es
Received 11 October 2007
O
O
O
Abstract: A new, easy, and high-yielded route to isotopically la-
beled amino acid derivatives is reported. This process takes place
through a SmI2-promoted 1,4-reduction of a variety of dehydro-
amino esters in the presence of D2O. The dideuterio amino esters
were transformed into other dideuterated compounds such as α-
amino acids and 1,2-amino alcohols. A mechanism to explain the
1,4-reduction process is also proposed.
TMSCl
MeOH
NBS
CCl4
Br
OH
OMe
OMe
NHAc
NHAc
NHAc
1
2
3
P(OMe)3
Key words: amino acids, deuteration, reductions, samarium
O
O
P
O
tetramethylguanidine
RCH=O
MeO
MeO
Isotopically labeled compounds are very useful to estab-
lish the mechanism of organic reactions and the biosyn-
thesis of many natural compounds.1 The incorporation of
isotopically labeled α-amino acid residues into proteins
has become a vital tool in the determination of protein
structure by NMR techniques. The indiscriminate incor-
poration of the NMR active isotopes 15N and 13C enables
the effective employment of heteronuclear correlation ex-
periments, while the incorporation of deuterium simpli-
fies the assignment of the residual 1H resonances,
facilitating structural determination through the interpre-
tation of NOE data. In this context, the incorporation of
deuterated α-amino acids into polypeptides is a powerful
tool in the structural determination of large biomolecules.2
In addition, α-amino acids isotopically labeled on the
side-chain have also found utility as valuable probes into
biosynthetic pathways.3
Pioneered by Kagan in 1977,4 samarium diiodide has rap-
idly become an important reagent in organic chemistry be-
cause of its versatility in one- and two-electron-transfer
reactions. Since then, SmI2 has emerged as one of the
more useful reducing agents in synthetic organic chemis-
try. As a consequence of its increasing importance, sever-
al reviews have appeared that focus the utility of
samarium diiodide to promote C–C bond-formation reac-
tions,5 and different reduction processes6 including the re-
duction of multiple bonds.6c
R
OMe
OMe
NHAc
NHAc
5
4
Scheme 1 Synthesis of starting materials 5
deuterio-2-hydroxyamides,10 and 2,2,3,3-tetradeuterio es-
ters, amides, and acids.11
As part of our program concerned with the development
of new reduction processes mediated by SmI2, towards the
synthesis of various deuterated compounds we wish to re-
port herein a new and easy route to access α,β-dideuterio-
α-amino esters, by treatment of dehydroamino acids me-
diated by a SmI2 and D2O system, in high yields. A mech-
anism to explain this process is also proposed.
The starting (Z)-N-acetyldehydroamino esters 5 were eas-
ily prepared in four steps from commercially available N-
acetylglycine (1) after an esterification, bromination, and
a Horner–Wadsworth–Emmons protocol (Scheme 1).12
The reaction of various (Z)-N-acetyldehydroamino esters
5 in THF with SmI2 and D2O13 at room temperature for 30
minutes afforded the corresponding dideuterio amino es-
ters 6 in moderate or high yields (Table1).14
This proposed methodology for obtaining isotopically la-
beled α-amino acid derivatives is general and the R group
can be varied. Thus, aliphatic (linear, branched, or cyclic),
unsaturated, or aromatic aldehydes may be used to intro-
duce different R groups. It is noteworthy that the deutera-
tion of the C–C double bond was completely
chemoselective. Thus, employing compound 5f (Table1,
entry 6), only the C=C conjugated with the carbonyl group
was deuterated remaining the nonconjugated C–C double
bond unaltered.
Previously, we have reported the use of samarium diio-
dide in a range of practical methods for the synthesis of
various deuterated compounds such as 2,3-dideuterio es-
ters,7 amides7 or acids,8 2-deuterio-3-hydroxyesters,7 (E)-
α,δ-dideuterio-β,γ-unsaturated esters9 or acids,8 3-aryl-3-
1
The position of deuteration was established by H NMR
SYNLETT 2008, No. 3, pp 0402–0404
Advanced online publication: 23.01.2008
x
x.
x
x.
2
0
0
8
and 13C NMR spectroscopy of compounds 6, while the
DOI: 10.1055/s-2008-1032063; Art ID: G31007ST
© Georg Thieme Verlag Stuttgart · New York
complete deuterium incorporation (>99%) was verified

LETTER
Synthesis of α,β-Dideuterio-α-amino Esters
403
O
OSmI2
O
Table 1 Synthesis of Isotopically Labeled α-Amino Esters 6
O
D
O
SmI2
D O–THF
2
R
OMe
R
OMe
R
OMe
SmI2, D2O
THF
N
N
N
R
OMe
R
OMe
H
D
D
D
NHAc
NHAc
O
D
O
O
5
7
8
5
6
Entry
6
R
Yield (%)a
1
2
3
4
5
6
7
6a
n-C7H15
82
72
80
65
85
65
75
SmI2
O
O
O
1) D2O
SmI2
6b
6c
6d
6e
6f
PhCH2CH2
i-Pr
R
OMe
N SmI2
R
OMe
R
OMe
N SmI2
2) H3O+
D
D
NHAc
D
Ac
Ac
6
10
9
s-Bu
Scheme 2 Mechanistic proposal for the conversion of 5 into 6
Cy
D
O
(Z)-EtCH=CH(CH2)5
OH
NH3Cl
6g
Phb
D
concd HCl
reflux, 12 h
D
O
a Isolated yield of pure compounds 6 after column chromatography
based on compounds 5.
11e quantitative yield
OMe
NHAc
b In this case the reaction was performed on the ethyl ester rather than
the methyl ester.
D
D
6e
LiAlH4
by mass spectrometry.15 These α,β-dideuterio-α-amino
acid derivatives were isolated as mixtures of stereoiso-
mers (approx. 1:1 by 1H NMR spectroscopy and GC-MS)
this fact being in agreement with the observed results of
the SmI2 and D2O promoted synthesis of other deuterated
compounds.7–9
OH
NHAc
D
12e 86% yield
Scheme 3 Conversion of 6e into 11e and 12e
It is noteworthy that D2O is the cheapest deuteration re-
agent available for obtaining organic compounds isotopi-
cally labeled with deuterium.
Acknowledgment
We thank the Ministerio de Educación y Ciencia (CTQ2004-1191/
BQU) for financial support. J.M.C. thanks Carmen Fernández-
Flórez for her time. H.R.S. thanks the Ministerio de Educación y
Ciencia for a Ramón y Cajal Contract (Fondo Social Europeo). Our
thanks to Euan C. Goddard for his revision of the English.
The synthesis of products 6 might be explained by assum-
ing that the SmI2-promoted 1,4-reduction of 5 is initiated
by single-electron transfer of SmI2 to generate the enolate
8; this radical is then hydrolyzed by the acidic deuterium
from the N–D bond and afford the corresponding radical
9. After a second electron transfer from SmI2 the radical
generated the dianion 10, this being hydrolyzed by D2O to
afford the corresponding compound 6 (Scheme 2). When
the starting compounds 5 were not pretreated with D2O, a
competitive hydrolysis of 8 and 10 produced by the acidic
proton of the N–H amide group and D2O afforded a mix-
ture of mono-, di-, and nondeuterated compounds.16
References and Notes
(1) Mann, J. In Secondary Metabolism; Oxford University
Press: Oxford, 1991, Chap. 3, 417.
(2) For a review on the application of isotopic labeling in
protein-structure determination, see: Lian, L.-Y.; Middleton,
D. A. Prog. Nucl. Magn. Reson. Spectrosc. 2001, 39, 171.
(3) For example, see: (a) Baldwin, J. E.; Adlington, R. M.;
Marquess, D. G.; Pitt, A. R.; Porter, M. J.; Russell, A. T.
Tetrahedron 1996, 52, 2515. (b) Church, N. J.; Young, D.
W. J. Chem. Soc., Perkin Trans. 1 1998, 52, 1475.
(c) Pirrung, M. C. Acc. Chem. Res. 1999, 32, 711.
(4) (a) Namy, J.-L.; Girard, P.; Kagan, H. B. New J. Chem.
1977, 1, 5. (b) Girard, P.; Namy, J.-L.; Kagan, H. B. J. Am.
Chem. Soc. 1980, 102, 2693.
(5) (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(b) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
3321. (c) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745.
(d) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727.
(e) Kagan, H. B. Tetrahedron 2003, 59, 10351.
To demonstrate some synthetic applications of the ob-
tained α-amino esters 6, a selected example was readily
transformed into isotopically labeled α-amino acids2,3 11
and dideuterated 1,2-amino alcohols 1217 (Scheme 3).18
These reactions took place in very high yields and no loss
of the deuterium atoms were observed in both cases.
In conclusion, we have described a general synthesis of
isotopically labeled α-amino acid derivatives in good
yields through a SmI2-promoted 1,4-reduction process on
readily available dehydroamino esters. Other different
isotopically labeled compounds such as α-amino acids
and 1,2-amino alcohols were accessed.
(f) Concellón, J. M.; Rodríguez-Solla, H. Chem. Soc. Rev.
2004, 33, 599.
Synlett 2008, No. 3, 402–404 © Thieme Stuttgart · New York

404
J. M. Concellón et al.
LETTER
(6) (a) Molander, G. A. In Organic Reactions, Vol. 46; Paquette,
L. A., Ed.; John Wiley: New York, 1994, 211. (b) Dahlén,
A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393.
(c) Concellón, J. M.; Rodríguez-Solla, H. Eur. J. Org. Chem.
2006, 1613.
(7) Concellón, J. M.; Rodríguez-Solla, H. Chem. Eur. J. 2001,
7, 4266.
(8) Concellón, J. M.; Rodríguez-Solla, H. Chem. Eur. J. 2002,
8, 4493.
(9) Concellón, J. M.; Bernad, P. L.; Rodríguez-Solla, H. Angew.
Chem. Int. Ed. 2001, 40, 3897.
(10) Concellón, J. M.; Bardales, E.; Gómez, C. Tetrahedron Lett.
2003, 44, 5323.
(11) Concellón, J. M.; Rodríguez-Solla, H.; Concellón, C.
Tetrahedron Lett. 2004, 45, 2129.
(16) However, the deuteration of 8 to give 9 produced by D2O
could not be rejected.
(17) β-Amino alkanols are important building blocks and have
been used to prepare a large number of biologically active
natural and synthetic compounds, including unnatural amino
acids: (a) Corey, E. J.; Zhang, F. Angew. Chem. Int. Ed.
1999, 38, 1931. (b) O’Brien, P. Angew. Chem. Int. Ed. 1999,
38, 326. (c) Johannes, C. W.; Visser, M. S.; Weatherhead, G.
S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340.
(d) Chang, B. L.; Ganesan, A. Bioorg. Med. Chem. Lett.
1997, 7, 1511. (e) Li, G.; Chang, H. T.; Sharpless, K. B.
Angew. Chem. Int. Ed. 1996, 35, 451. (f) Rogers, G. A.;
Parsons, S. M.; Anderson, D. S.; Nilson, L. M.; Bahr, B. A.;
Kornreich, W. D.; Kaufman, R.; Jacobs, R. S.; Kirtman, B.
J. Med. Chem. 1989, 32, 1217.
(12) (a) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K.
R. J. Am. Chem. Soc. 2003, 125, 3534. (b) Daumas, M.; Vo-
Quang, L.; Le Goffic, F. Synth. Commun. 1990, 20, 3395.
(c) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984,
20, 53.
(13) The solution of SmI2 in THF was rapidly obtained by
reaction of diiodomethane with samarium powder in the
presence of sonic waves: Concellón, J. M.; Rodríguez-Solla,
H.; Bardales, E.; Huerta, M. Eur. J. Org. Chem. 2003, 1775.
(14) General Procedure for Compound 6a
(18) General Procedure for the Synthesis of Compound 11e
2-Acetylamino-3-cyclohexyl-2,3-dideuteriopropanoic acid
methyl ester (6e, 100 mg, 0.43 mmol) was refluxed in concd
HCl for 12 h. Then, aq HCl was evaporated at low pressure
and 2-amino-3-cyclohexyl-2,3-dideuteriopropanoic acid
hydrochloride was recovered as a colorless solid; quant.
yield. 1H NMR (300 MHz, D2O): δ = 1.68 (d, J = 7.9 Hz, 1
H), 1.63–1.40 (m, 5 H), 1.35–1.21 (m, 1 H), 1.10–1.01 (m, 3
H), 0.98–0.72 (m, 2 H). 13C NMR (75 MHz, D2O): δ = 175.3
(C), 52.8 (CD, J = 20.5 Hz), 39.3 (CHD, J = 19.0 Hz), 35.2
(CH), 34.9 (CH2), 34.1 (CH2), 28.1 (CH2), 27.8 (CH2), 27.7
Under nitrogen, a solution of SmI2 (1.2 mmol) in THF (15
mL) was added dropwise to a stirred solution of the starting
material 5a in D2O (2 mL) and THF (2 mL) at r.t. The
reaction mixture was stirred for 30 min and then treated with
0.1 M aq HCl (5 mL). Standard workup afforded the crude
2,3-dideuterio-2-amino ester 6a, which was purified by flash
column chromatography on SiO2 (hexane–EtOAc, 5:1):
Methyl 2-Acetylamino-2,3-dideuteriodecanoate (6a)
Rf = 0.26 (hexane–EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 6.16 (br s, 1 H), 3.70 (s, 3 H), 1.99 (s, 3 H),
1.65–1.51 (m, 1 H), 1.33–1.10 (m, 12 H), 0.84 (t, J = 6.7 Hz,
3 H). 13C NMR (75 MHz, CDCl3): δ = 173.2 (C), 169.8 (C),
52.1 (CH3), 51.7 (t, J = 21.8 Hz, CD), 31.8 (t, J = 19.6 Hz,
CHD), 31.6 (CH2), 29.2 (CH2), 29.0 (2 × CH2), 24.9 (CH2),
22.9 (CH3), 22.5 (CH2), 13.9 (CH3). MS (70 eV): m/z (%) =
245 (5) [M+], 186 (55), 144 (100). HRMS: m/z calcd for
C13H23D2NO3: 245.1960; found: 245.1944. IR (neat): 3263,
3063, 2922, 1742, 1652, 1374 cm–1.
(CH2). IR (neat): = 3425, 2926, 1652, 1265 cm–1
.
General Procedure for the Synthesis of Compound 12e
To a solution of 2-acetylamino-3-cyclohexyl-2,3-
dideuteriopropanoic acid methyl ester (6e, 57 mg, 0.25
mmol) in THF (5 mL), a 1.0 M in THF solution of LiAlH4
(0.28 mL, 0.28 mmol) was added dropwise at 0 °C under
nitrogen. The resulting solution was stirred at r.t. for 12 h,
then quenched with ice water and filtered through a pad of
Celite®. The aqueous layer was extracted with Et2O, dried
over Na2SO4 and finally the solvents were removed under
vacuum, to afford 2-acetylamino-3-cyclohexyl-2,3-
dideuteriopropan-1-ol as a white solid; 83% yield. 1H NMR
(300 MHz, CDCl3): δ = 5.63 (br s, 1 H), 3.66 (d, J = 11.1 Hz,
1 H), 3.50 (d, J = 11.1 Hz, 1 H), 2.01 (s, 3 H), 1.79–0.84 (m,
12 H). 13C NMR (75 MHz, CDCl3): δ = 171.1 (C), 66.3
(CH2), 49.1 (t, J = 20.0 Hz, CD), 38.2 (t, J = 19.5 Hz, CHD),
34.1 (CH), 33.6 (CH2), 32.8 (CH2), 26.3 (CH2), 26.1 (CH2),
26.0 (CH2), 23.4 (CH3). IR (neat): 1653, 1636, 1558, 1540
cm–1.
(15) In the mass spectra (MS and HRMS) of deuterated
compounds 6a,c,e,g, the [M]+ peaks of the corresponding
nondeuterated compounds are either absent or very weak,
indicating that these species are present to an extent of <2%.
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