One-pot stereoselective synthesis of 1,2-amino alcohol derivatives

Article abstract of DOI:10.1021/ol201173a

Common β-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-pot decarboxylation-alkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl gro

Full text of DOI:10.1021/ol201173a

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3426–3429
One-Pot Stereoselective Synthesis of
1,2-Amino Alcohol Derivatives
ꢀ
Alicia Boto* and Ivan Romero-Estudillo
´ ´ ꢀ
Instituto de Productos Naturales y Agrobiologıa CSIC, Avda. Astrofısico Fco. Sanchez 3,
38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es
Received May 3, 2011
ABSTRACT
Common β-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-
pot decarboxylationꢀalkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl groups, generally in high yields. A
variation of the process (decarboxylationꢀDielsꢀAlder) allows the formation of bi- and polycyclic systems, which are useful precursors of
alkaloid cores or iminosugars.
The synthesis of chiral 1,2-amino alcohols and 1,2-
diamines has elicited much interest, since these compounds
are present in chiral ligand or catalysts1 and also in
Scheme 1
bioactive products, such as alkaloids,2 iminosugars,3 and
synthetic drugs.4
We reasoned that a diversity of these compounds could
be built in two steps from simple glycine derivatives
(Scheme 1). Thus, the desired amino alcohol or diamine
compounds 1 could be formed from the amino acids 2 by
one-pot decarboxylationꢀalkylation (or arylation).5
(1) (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650–1667. (b)
The amino acids 2 can be formed in good yields and high
stereoselectivities by different methodologies,6,7 such as
the reaction of aldehydes (X = O) or imines 3 (X = N-
alkyl) with glycine enolates, generated from glycine deri-
vatives 4 under phase-transfer conditions.6
With these two processes, a variety of alkyl or aryl
groups R and R2 could be introduced. This communica-
tion describes the preliminary studies of this strategy,
which allowed the conversion of threonine derivative 2a8
(R = Me, X = O, Scheme 2) into 1,2-amino alcohols 1a
(R2 = alkyl, aryl) in good yields and high optical purity.
Fache, F.; Schultz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
2000, 100, 2159–2231. (c) See also: Alcaide, B.; Almendros, P. Eur.
J. Org. Chem. 2002, 1595–1601. (d) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033–8061.
(2) (a) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957–5978. (b)
See also: Felpin, F-X; Lebreton, J. Tetrahedron 2004, 60, 10127–10153.
(3) (a) Davis, B. G. Tetrahedron: Asymmetry 2009, 20, 652–671. (b)
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Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur.
J. Org. Chem. 2005, 2159–2191. (c) Afarinkia, K.; Bahar, A. Tetrahe-
dron: Asymmetry 2005, 16, 1239–1297. (d) Lillelund, V. H.; Jensen,
H. H.; Laing, X.; Bols, M. Chem. Rev. 2002, 102, 515–553. (e) Asano, N.;
Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680. (f) See also: Kumar, A.; Rawal, G. K.; Vankar,
Y. D. Tetrahedron 2008, 64, 2379–2390.
€
€
(4) (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601–
635. (b) Beck, G. Synlett 2002, 837–850.
(5) For previous results from our scissionꢀaddition of nucleophiles
methodologies, see: (a) Boto, A.; Hernandez, R.; Saavedra, C. Synlett
2010, 659–663. (b) Saavedra, C.; Hernandez, R.; Boto, A.; Alvarez, E.
(6) (a) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656–5682. (b) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007,
46, 4222–4266. (c) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37,
518–525.
ꢀ
ꢀ
J. Org. Chem. 2009, 74, 4655–4665. (c) Boto, A.; Hernandez, D.; Hernandez,
R. Tetrahedron Lett. 2009, 50, 3974–3977. (d) Boto, A.; Gallardo, J. A.;
ꢀ
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Hernandez, D.; Hernandez, R. J. Org. Chem. 2007, 72, 7260–7269.
r
10.1021/ol201173a
Published on Web 05/26/2011
2011 American Chemical Society

Table 1. One-Pot ScissionꢀAlkylation
Scheme 2
I2
Nu
yield
(%)b
entry
(equiv)a
t1 °C f t2 °C
(equiv)
1
2
3
4
5
1.0
1.0
0.5
0.5
0.5
0 f 25
ꢀ78 f ꢀ10
0 f 25
3
35
36
51
42
78
3
3
0 f 25
3c
5
0 f 25
a DIB (2 equiv), I2, hν, 25 °C, 3 h; then t1 °C, CH2dC(OTMS)Ph and
BF3•OEt2 (2 equiv), t1 °C f t2 °C, 3 h. b The yields are given for products
purified by chromatography on silica gel. c Boron trifluoride was added
before the nucleophile.
Moreover, the choice of compound 2a as the substrate
would highlight whether a small-sized R group can induce
good stereoselectivities in the alkylation step.
The one-pot decarboxylationꢀalkylation couples radi-
cal and ionic processes and takes place under mild condi-
tions. Thus, when compound 2a (Scheme 2) is treated with
(diacetoxyiodo)benzene (DIB) and iodine, in the presence
of visible light (sunlight or 80 W tungsten-filament lamps),
a carboxyl radical is formed which undergoes scission to
give a C-radical 5.9 The radical reacts with iodine, to give
the unstable R-iodoamide 6, which reacts with acetate ions
from DIB to give the N,O-acetal 7. In the presence of a
Lewis acid, the acyliminium ion 8 is formed, which can be
trapped by carbon nucleophiles,10 affording the aminoal-
cohols 1a.
The best conditions for the one-pot scissionꢀalkylation
process were studied using the conversion 2af9 (Table 1).
The different temperatures tried (entries 1 and 2) gave
similar results. However, the amount of iodine was im-
portant (entries 1 and 3), and the best yields were obtained
with substoichiometric amounts. The order of addition
was studied as well (entries 3 and 4) and the amount of
nucleophile (entries 3 and 5). The optimized conditions are
given in entry 5. Remarkably, an excellent stereoselectivity
was obtained (dr >99:1).
ꢀ
(7) (a) For other recent works on chiral amino alcohols, see: Metro,
T. X.; Gomez-Pardo, D.; Cossy, J. J. Org. Chem. 2007, 72, 6556–6561.
(b) Lombardo, M.; Mosconi, E.; Pasi, F.; Petrini, M.; Trombini, C.
J. Org. Chem. 2007, 72, 1834–183. (c) Menche, D.; Arikan, F.; Li, J.;
Rudolph, S. Org. Lett. 2007, 9, 267–270. (d) Fustero, S.; Albert, L.;
The application of this reaction to the synthesis of chiral
nitrogen heterocycles is shown in Scheme 3. Thus, the
scissionꢀallylation reaction gave the allyl derivatives
~
Acena, J. L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett. 2008, 10, 605–
~
ꢀ
608. (e) Ona-Burgos, P.; Fernandez, I.; Iglesias, M. J.; Garcıa-Granda,
´
ꢀ
S.; Lopez-Ortiz, F. Org. Lett. 2008, 10, 537–540. (f) Tellam, J. P.;
€
Kociok-Kohn, G.; Carbery, D. R. Org. Lett. 2008, 10, 5199–5202. (g)
Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73,
9619–9626. (h) Wang, B.; Wang, Y.-J. Org. Lett. 2009, 11, 3410–3413. (i)
Jha, V.; Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762–2765. (j)
Qian, Y.; Xu, X.; Jiang, L.; Prajapati, D.; Hu, W. J. Org. Chem. 2010, 75,
7483–7486. (k) Pizzirani, D.; Kaya, T.; Clemons, P. A.; Schreiber, S. L.
Org. Lett. 2010, 12, 2822–2825.
Scheme 3
(8) Although substrate 2a can be prepared from glycine enolates, it
was prepared from commercial L-threonine, following standard proce-
dures: Zietlow, A.; Steckhan, E. J. Org. Chem. 1994, 59, 5658–5661.
(9) (a) The decarboxylation of amino acids can also be induced
electrochemically: Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1986, 25, 843–844. (b) Seebach, D.; Charczuk, R.; Gerber, C.; Renaud,
P.; Berner, H.; Schneider, H. Helv. Chim. Acta 1989, 72, 401–425. (c)
Herborn, C.; Zietlow, A.; Steckhan, E. Angew. Chem., Int. Ed. Engl.
1989, 28, 1399–1401. (d) Matsumura, Y.; Shirakawa, Y.; Satoh, Y.;
Umino, M.; Tanaka, T.; Maki, T.; Onomura, O. Org. Lett. 2000, 2,
1689–1691. (e) For reviews on the subject, see: Utley, J. Chem. Soc. Rev.
1997, 26, 157–167. (f) Moeller, K. D. Tetrahedron 2000, 56, 9527–9554.
(10) (a) For the addition of nucleophiles to iminium ions, see: Yazici,
A.; Pyne, S. G. Synthesis 2009, 339–368 (part I). (b) Yazici, A.; Pyne,
S. G. Synthesis 2009, 513–541 (part 2). (c) Ferraris, D. Tetrahedron 2007,
63, 9581–9597. (d) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63,
2541–2569. (e) Schaus, S. E.; Ting, A. Eur. J. Org. Chem. 2007, 5797–
5815. (f) Petrini, M.; Torregiani, E. Synthesis 2007, 159–186. (g) Petrini,
M. Chem. Rev. 2005, 105, 3949–3977. (h) Royer, J.; Bonin, M.; Micouin,
L. Chem. Rev. 2004, 104, 2311–2352. (i) Maryanoff, B. E.; Zhang, H. C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–
1628.
Org. Lett., Vol. 13, No. 13, 2011
3427

trans-10 and cis-109c in good overall yield, witha dr of16:1.
Both isomers could be readily separated.
Table 2. One-Pot Scissionꢀaza-DielsꢀAlder
The lower stereoselectivity with respect to the previous
process was probably due to the smaller size of the
nucleophile, which allowed its addition to the acyliminium
ion 8 from the most hindered face. The product trans-10
was N-alkylated, and the resultant diolefin 11 underwent a
metathesis reaction to give compound 12 in very good
yield.
The processcan be alsoappliedtoelectron-rich aromatic
rings, such as furan derivatives (Scheme 4). In this case, a
lower temperature (ꢀ78 °C) and a different Lewis acid
(TMSOTf) were required to obtain the furan derivatives
139c or 14 in good yields. The furan ring can be easily
derivatized (reduction, Achmatowitz oxidation, ozonoly-
sis, DielsꢀAlder, etc.),11 allowing the formation of many
different 1,2-amino alcohols.
Lewis acid
entry
t1 °C f t2 °C
(equiv)a
yield (%)b
1
2
3
4
5
6
7
ꢀ78 f ꢀ10
0 f 25
BF3•OEt2 (2)
BF3•OEt2 (2)
TMSOTf (4)
TMSOTf (4)
Cu(OTf)2 (2)
Cu(OTf)2 (2)
TiCl4 (2)
49
31
71
51
21
36
20
ꢀ78 f ꢀ10
0 f 25
ꢀ78 f ꢀ10
0 f 25
ꢀ78 f ꢀ10
a DIB (2 equiv), I2 (0.5 equiv), hν, 25 °C, 3 h; then t1 °C, 2,3-
dimethylbutadiene and the Lewis acid, t1 °C f t2 °C, 3 h. b The yields
are given for products purified by chromatography on silica gel.
Scheme 4
isomer was formed, it was isolated as a mixture of epimers
at 10-C.13
Scheme 5
A variation of the scissionꢀalkylation process al-
lowed us to obtain chiral bicyclic and polycyclic sys-
tems. In this variation, the decarboxylation was coupled
to an aza-DielsꢀAlder cyclization.12 The optimization
of the reaction conditions is shown in Table 2, using 2,3-
dimethyl-1,3-butadiene as the diene, to give the bicyclic
product 15. The best conditions were obtained with
t1 = ꢀ78 °C and TMSOTf as the Lewis acid (entry 3,
71% yield). Product 15 was formed with excellent
stereoselectivity (dr >99:1).
Using the same conditions, 1,3-cyclohexadiene afforded
the tricyclic product 16 (Scheme 5), also in good yield
(70%) and excellent dr (>99:1).
With 1,3-cyclooctadiene, however, the DielsꢀAlder re-
action was replaced by an alkylation reaction, giving the
diene 17 as the major product. Although only the trans
The best conditions could vary according to the
diene. In the case of electron-rich dienes such as
Danishefsky’s diene or 1-trimethylsilyloxy-1,3-buta-
diene (Scheme 6), the best results were obtained with
ZnI2 at 0 °C.
When Danishefsky’s diene was used, the piperidinone
18 was obtained in good yield as the exclusive product.
In the case of 1-trimethylsilyloxy-1,3-butadiene, the
initially formed cycloaddition product 19 underwent
elimination to the acyliminium ion 20, which was
trapped by an excess of nucleophile, to give the addi-
tion compound 21. Considering the number of steps
involved in the addition, each step has proceeded in
(11) Boto, A.; Alvarez, L. Furan and its derivatives. In Heterocycles
in Natural Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.;
Wiley-VCH: 2011; Chapter 4, ISBN: 978-3-527-32706-5.
(12) (a) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57, 6099–
6138. (b) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558–3588.
(c) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (d) See also: Boto, A.;
ꢀ
ꢀ
Leon, Y.; Gallardo, J. A.; Hernandez, R. Eur. J. Org. Chem. 2005, 3461–
3468.
(13) Compound 17 was probably formed from a 10-oxazolidinyl-40-
halo (or acyl)-20-cyclooctene, by elimination of the leaving group. This
intermediate, in turn, was formed by addition of the cyclooctadiene to
the acyliminium ion 8, followed by addition of a heteroatomic nucleo-
phile at the 40-position.
3428
Org. Lett., Vol. 13, No. 13, 2011

process can be further functionalized to give iminosugars
and polycyclic systems, among others.
Sincethetransisomers canbeeasilytransformedintothe
cis diastereomers using Mitsunobo14 or other related
methodologies, this process could allow the preparation
of a variety of chiral amino alcohols.
Scheme 6
In summary, the one-pot decarboxylationꢀalkylation
process and its variation, the decarboxylationꢀaza-Dielsꢀ
Alder reaction, allow the efficient conversion of cyclic
carbamates of β-hydroxy amino acids into chiral 1,2-
disubstituted-1,2-amino alcohols. The process takes place
under mild conditions, generally in good yields and high
stereoselectivities. The application of this process to the
syntheses of other amino alcohols and chiral diamines will
be reported in due course.
Acknowledgment. This work was supported by the Re-
search Program CTQ2009-07109 of the Plan Nacional de
ꢀ
ꢀ
Investigacion Cientıfica, Desarrollo e Innovacion Tec-
´
ꢀ
ꢀ
nologica, Ministerio de Ciencia e Innovacion, Spain. We
also acknowledge financial support from FEDER funds. I.
R.E. thanks CSIC for a predoctoral JAE fellowship.
high yield to account for the final result. These bicyclic
products obtained during the scissionꢀaza-DielsꢀAlder
Supporting Information Available. Procedures for the
synthesis of compounds 9ꢀ18 and 21, and their 1H and
13C NMR spectra; COSY or/and NOESY experiments
for compounds 9 and 18. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) (a) But, T. Y. S.; Toy, P. H. Chem.;Asian J. 2007, 2, 1340–1355.
(b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Pavan Kumar,
K. V. P. Chem. Rev. 2009, 109, 2551–2651.
Org. Lett., Vol. 13, No. 13, 2011
3429