One-pot organocatalytic direct asymmetric synthesis of γ-amino alcohol derivatives

Article abstract of DOI:10.1055/s-2003-41423

This report describes the unprecedented use of unmodified aldehydes as donors in catalytic three component one-pot asymmetric Mannich reactions. The Mannich-type reactions were also readily performed for the first time with both in situ generated and pref

Full text of DOI:10.1055/s-2003-41423

LETTER
1651
One-Pot Organocatalytic Direct Asymmetric Synthesis of g-Amino Alcohol
Derivatives
O
A
ne-Pot
O
rganoca
r
talytic
D
m
irect Asymmetric
S
a
ynthesis of
n
g
-Amino A
l
d
cohol
D
eriva
o
tives Córdova*1
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
E-mail: acordova1a@netscape.net
Received 21 May 2003
unmodified aldehydes and N-PMP-protected a-imino eth-
yl glyoxylate affording a-amino and b-amino acid deriva-
Abstract: This report describes the unprecedented use of unmodi-
fied aldehydes as donors in catalytic three component one-pot
asymmetric Mannich reactions. The Mannich-type reactions were
1
0
tives. However, we were unable to use other preformed
also readily performed for the first time with both in situ generated imines as electrophiles, which significantly limited the
and preformed N-PMP protected aromatic aldimines. The proline- generality of the reaction. In this context, reactions with
catalyzed reactions provided an efficient and very mild entry to ei-
aromatic imines would have been highly attractive since
ther enantiomer of g-amino alcohol derivatives in high yield and
they open a novel route for synthesis of g-amino alcohol
stereoselectivity.
and b-amino acid derivatives that are used as chiral syn-
2a
Key words: asymmetric synthesis, asymmetric catalysis, Mannich
reactions, aldehydes, imines
thons for enzyme inhibitors and cancer drugs. Moreover,
there is no report of a catalytic asymmetric three compo-
nent Mannich reaction with unmodified aldehydes as do-
nors.11 We therefore embarked on the search for a
g-Amino alcohols and b-amino acids are present in sever- catalytic asymmetric three-component one-pot Mannich
al molecules of pharmaceutical and biological interest.2 process that would involve aldehydes for both nuchleo-
Among the plethora of methods that exist for their con- phile and electrophile generation. Herein, we disclose the
3
,4
struction, the Mannich reaction is one of the most attrac-
first direct three component one-pot asymmetric Mannich
reactions with aldehydes that provide a new entry for
the synthesis of either enantiomer of g-amino alcohol
derivatives with excellent enantioselectivities.
5
tive carbon-carbon bond forming routes. Retrosynthetic
analysis suggests that the most efficient Mannich process
would be
a three component one-pot operation
(
Scheme 1). However, these transformations are very dif-
In initial experiments, propionaldehyde, N-PMP-protect-
ed a-imino p-nitrophenyl (0.1 M) and L-proline (30
mol%) were reacted under different conditions. After sev-
eral attempts, we discovered that the corresponding Man-
nich adduct 1 could be obtained if the aldehyde was added
in small portions to the reaction mixture. We decided to
ficult to control and could result in unwanted side-reac-
tions. Therefore, b-amino acid derivatives are synthesized
via asymmetric Mannich-reactions involving carbon-car-
bon bond formation between preformed ester enolate
equivalents and imines. Initially, chiral auxiliaries were
used with the disadvantage that they have to be removed
in additional steps. Recent advances in catalytic asym-
metric Mannich-type reactions have led to excellent pro-
tocols for the preparation of b-amino acid derivatives.
reduce 3-amino substituted propanal 1 with excess NaBH4
6
to g-amino alcohol 2 prior to isolation and ee determina-
tion, due to epimerization and racemization of 1 during
7
1
2
work-up and purification. We found that slow addition
of the propionaldehyde (1 M) in DMF at 4 °C afforded
the highest conversion providing g-amino alcohol 2 in
However, these catalytic systems are also indirect and
require formation of the starting materials prior to the
reaction.
8
(
1% yield and 99% ee as a predominant diastereomer
Scheme 2).1
3,14
Scheme 1 Retrosynthetic analysis of b-amino acid and g-amino
alcohol derivatives based on the one-pot three component Mannich
reaction with unmodified aldehydes.
Based on our research program on amine-catalyzed asym-
8
9
metric synthesis, we demonstrated that L-proline and its
derivatives can catalyze Mannich-type reactions between
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1651,1654,ftx,en;D11403ST.pdf.
DOI: 10.1055/s-2003-41423
Scheme 2 One-pot direct asymmetric synthesis of 3-amino alde-
hyde 1 and alcohol 2. Ar = p-NO C H , PMP = p-methoxyphenyl.
2
6
4
©
Georg Thieme Verlag Stuttgart · New York

1
652
A. Córdova
LETTER
To broaden the scope of this transformation, a set of dif- yield with dr of >10:1 and 81% ee (entry 7). As compared
ferent aromatic N-PMP-protected imines were reacted to the reactions with preformed imines the yields were
with propionaldehyde to afford aromatic g-amino alcohol slightly decreased. Nevertheless, the ee was not signifi-
derivatives 2–7a (Table 1). In most cases, the reaction cantly affected. Furthermore, electron-deficient acceptor
proceeded smoothly with excellent enantioselectivities. In aldehydes were also efficiently converted with only 2
addition, Mannich reactions with other aldehydes besides equivalents of propionaldehyde and 10 mol% proline.
propanal were also catalyzed by proline under the set
Table 2 One-Pot Direct Three Component Asymmetric Proline-
Catalyzed Mannich Reactions with Unmodified Aldehydes
reaction conditions. For example, heptanal reacted with
N-PMP-protected a-imino p-nitrophenyl to provide the
corresponding Mannich product in 60% yield and dr>19:1
1
5
and 90% ee. The reactions were readily performed on 10
mmol scale with no detrimental effect on yield or enantio-
selectivity.
Table 1 Products from the Proline-Catalyzed Mannich-Reaction of
a
Unmodified Aldehydes with N-PMP-Protected a-Imino Aryls
Entry
R
Yielda
75%
65%
81%
65%
62%
77%
55%
drb
eec
Product
1
2
3
4
5
6
7
p-NO C H
4
>10:1
5:1
99%
93%
91%
93%
75%
97%
81
2
3
4
5
6
7
8
2
6
p-CNC H
6
4
p-BrC H
10:1
6:1
6
4
Entry
R
Yieldb
81%
72%
57%
81%
81%
89%
75%
drc
eed
Product
p-ClC H
6
4
1
2
3
4
5
6
p-NO C H
>10:1
7:1
99%
98%
95%
93%
81%
96%
55%
2
2
6
4
C H
4:1
6
5
3
6
p-CNC H4
m-BrC H
4:1
6
4
6:1
4
6
p-BrC H4
Et
>10:1
p-ClC H4
>10:1
4:1
5
6
a
Isolated yields of pure product after column chromatography.
Dr = syn/anti as determined by NMR after column chromatography.
The ee’s of products 2–8 were determined by chiral-phase HPLC
b
c
C H
6
6
5
m-BrC H4
3:1
7
analysis.
6
7
p-MeOC H4
2:1
7a
6
The stereochemistry of the reaction was determined by
synthesis and determined to be (2S,3S) based on NMR
a
PMP = p-methoxyphenyl.
b
c
d
Isolated yields of pure product after column chromatography.
Dr = syn/anti as determined by NMR after column chromatography.
The ee’s of products 2–7a were determined by chiral-phase HPLC
analysis and chiral-phase HPLC analysis of g-amino alco-
17,18
hols 6 and 9 (Scheme 3).
Hence, L-proline provides
analysis.
syn b-amino aldehyde derivatives with S absolute stere-
ochemistry. The stereochemical outcome is explained by
L-proline directing a si-facial attack of the imines by the
si-face of the enamine intermediates (Figure 1).
Thereafter, we addressed the more challenging task of
performing the transformations as three component one-
pot operations. We believed that we would be able to di-
rect the role of the aldehyde components of the reaction by
adding the donor slowly to the reaction mixture. Hence,
slow addition of the propionaldehyde (1 M) to the reaction
mixture containing p-methoxyaniline (0.1 M), p-nitroben-
zaldehyde (0.1 M) and L-proline followed by in situ re-
duction with NaBH afforded g-amino alcohol 2 in 75%
4
1
6
yield and 95% ee (Table 2, entry 1). Furthermore, per-
forming the one-pot procedure with other aromatic alde-
hydes as acceptors afforded b-amino alcohol derivatives
Scheme 3 Determination of absolute configuration of amino alco-
hol product 6 and its deprotection.
1
7
3
–7 with excellent enantioselectivities. The reactions pro-
ceeded with superb chemo-selectivity with no formation
of cross-aldol products or self-Mannich adducts. In fact, In conclusion, for the first time unmodified aldehydes
proline was able to catalyze the two-component direct were successfully used in catalytic three component one-
asymmetric Mannich reaction between propionaldehyde pot asymmetric Mannich reactions. We demonstrated that
and p-anisidine affording self-Mannich adduct 8 in 55% proline-catalyzed reactions provide a highly enantioselec-
tive multigram entry to either enantiomer of amino alco-
Synlett 2003, No. 11, 1651–1654 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
One-Pot Organocatalytic Direct Asymmetric Synthesis of g-Amino Alcohol Derivatives
1653
Vol. 2; Jacobsen, E. N.; Pfaltz, A.; Yamomoto, H., Eds.;
Springer: Berlin, 1999, 93.
(
6) (a) Palomo, C.; Oiarbide, M.; Gonzales-Rego, M. C.;
Sharma, A. K.; Garcia, J. M.; Landa, C.; Linden, A. Angew.
Chem. Int. Ed. 2000, 39, 1063. (b) Corey, E. J.; Decicco, C.
P.; Newbold, R. C. Tetrahedron Lett. 1991, 39, 5287.
(
1
c) Seebach, D.; Betschart, C.; Schiess, M. Helv. Chim. Acta
984, 67, 1593. (d) Evans, D. A.; Urpi, F.; Somers, T. C.;
Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112,
215.
8
(7) For recent catalytic asymmetric examples, see: (a) Ishitani,
H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180. (b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org.
Lett. 2002, 4, 143. (c) Wenzel, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 12964. (d) Xue, S.; Yu, S.; Deng, Y.;
Wulff, W. D. Angew. Chem. Int. Ed. 2001, 40, 2271.
Figure 1 Potential transition state.
(
8) (a) Córdova, A.; Notz, W.; Barbas, C. F. III J. Org. Chem.
2
002, 67, 301. (b) Córdova, A.; Notz, W.; Barbas, C. F. III
hol derivatives and the corresponding products 2–8 were
obtained in high yields and excellent enantioselectivities.
Moreover, our methodology starts with achiral, readily
available and inexpensive materials and was performed
under operationally simple conditions. Further research
addressing the scope and applicability of this methodolo-
gy is currently under investigation.
Chem. Commun. 2002, 3024. (c) Watanabe, S.-i.; Córdova,
A.; Tanaka, F.; Barbas, C. F. III Org. Lett. 2002, 4, 4519.
(
4
d) Córdova, A.; Barbas, C. F. III Tetrahedron Lett. 2003,
4, 1923.
(9) For other L-proline catalyzed aldehyde addition reactions,
see: (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.;
Jørgensen, K. A. Chem. Commun. 2002, 620. (b) Bøgevig,
A.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2002, 41, 1790. (c) List, B. J. Am.
Chem. Soc. 2002, 124, 5656. (d) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.
10) (a) Córdova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.;
Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1866.
Acknowledgment
This study was supported in part by the Wennergren Foundation.
The author would like to thank Prof. Kim D. Janda for valuable
discussions.
(
(
(
4
b) Córdova, A.; Barbas, C. F. III Tetrahedron Lett. 2002,
3, 7749.
11) There are reports of direct asymmetric Mannich reactions
with unmodified ketones, see: (a) Notz, W.; Sakthivel, K.;
Bui, T.; Zhong, G.; Barbas, C. F. III Tetrahedron Lett. 2001,
42, 199. (b) Juhl, K.; Gathergood, N.; Jørgensen, K. A.
Angew Chem. Int. Ed. 2001, 40, 2995. (c) Yamasaki, S.;
Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857.
(d) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
References
(
1) Current address: Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University, SE-10691
Stockholm, Sweden. Fax: +46(8)154908
(
2) (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: Weinheim, 1997. (b) Kleinmann, E. F. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Flemming, I., Eds.; Pergamon Press: New York, 1991,
Chap. 4.1. (c) Seebach, D.; Matthews, J. L. Chem. Commun.
(e) Córdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1842.
(f) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125,
338. (g) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 4712.
1997, 2015. (d) Knapp, S. Chem. Rev. 1995, 95, 1859.
(
e) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am.
Chem. Soc. 1982, 104, 6465.
(12) We observed that Mannich product 1 was unstable and
racemized if stored at room temperature or subjected to silica
gel column chromatography. In addition, 1 is prone to
epimerization that decreases the diastereomeric ratio.
(13) The reaction proceeded in other solvents as well at 23 °C:
Dioxane: 65% yield, dr>10:1, 99% ee; THF: 51% yield,
(
(
(
3) For examples of alternative asymmetric synthesis of 1,3-
amino alcohols, see: (a) Kochi, T.; Tang, T. P.; Ellman, J. A.
J. Am. Chem. Soc. 2002, 124, 6518. (b) Yamamoto, Y.;
Kornatsu, T.; Maryama, K. J. Chem. Soc., Chem. Commun.
1985, 814. (c) Toujas, J.-L.; Toupet, L.; Vaultier, M.
Tetrahedron 2000, 56, 2665. (d) Barluenga, J.; Fernandez-
Marí, F.; Viado, A. L.; Aguilar, E.; Olano, B. J. Org. Chem.
dr>10:1, 99% ee; Et O: 40% yield, dr>10:1, 99% ee; and at
2
4 °C: THF: 36% yield, dr>10:1, >99% ee; dioxane: 62%
yield, dr>10:1, 99% ee.
1996, 61, 5659.
4) For examples of alternative catalytic asymmetric synthesis
of b-amino acid derivatives, see: (a) Sibi, M. P.; Shay, J. J.;
Liu, M.; Jasperese, C. P. J. Am. Chem. Soc. 1998, 120, 6615.
(14) Anhydrous DMF (3 mL) was added to a vial containing the
aldimine (0.5 mmol) and proline (30 mol%) and placed in a
4 °C cold room. The reaction was initiated by slow addition
(0.2 mL/min) of a pree-cooled mixture of propionaldehyde
(5.0 mmol) in anhyd DMF (2 mL) with syringe pump at 4
°C. After 15 h the reaction mixture was diluted with anhyd
(b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959. (c) Nelson, S.; Spencer, K. L. Angew. Chem. Int.
Ed. 2000, 39, 1323. (d) Davies, H. M. L.; Venkataramani, C.
Angew. Chem. Int. Ed. 2002, 41, 2197. (e) Hodous, B. L.;
Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578.
Et
followed by reduction with NaBH
Next, the reaction mixture was poured into a vigorously
stirred bi-phaseic solution of Et O and 1 M aq HCl. The
O (2 mL) and the temperature decreased to at 0 °C
2
(400 mg) for 10 min.
4
5) For review, see: (a) Arend, M.; Westerman, B.; Risch, N.
Angew. Chem. Int. Ed. 1998, 37, 1044. (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069. (c) Denmark, S.;
Nicaise, O. J.-C. In Comprehensive Asymmetric Catalysis,
2
organic layer was separated and the aq phase was extracted
thoroughly with EtOAc. The combined organic phases were
dried (MgSO ), concentrated, and purified by flash column
4
Synlett 2003, No. 11, 1651–1654 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
654
A. Córdova
LETTER
chromatography (silica gel, mixtures of hexanes/EtOAc) to
was poured into a vigorously stirred bi-phaseic solution of
afford 2. (2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-
Et O and 1 M aq HCl. The organic layer was separated and
the aqueous phase was extracted thoroughly with EtOAc.
The combined organic phases were dried (MgSO4),
concentrated, and purified by flash column chromatography
(silica gel, mixtures of hexanes/EtOAc) to afford 2.
2
1
(
4-nitrophenyl)-propan-1-ol (2): H NMR (CDCl ):
3
d = 0.91 (d, 3 H, J = 7.0 Hz), 2.21 (m, 1 H), 3.64 (m, 2 H),
.67 (s, 3 H, OMe), 4.65 (d, 1 H, J = 4.0 Hz), 6.42 (d, 2 H,
J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8 Hz), 7.51 (d, 2 H, J = 8.8
3
1
3
Hz), 8.17 (d, 2 H, J = 8.8 Hz). C NMR: d = 11.9, 41.6,
(17) (a) NMR-data of the major diastereomer of PMP-
deprotected 6 was identical to the previously reported syn-
diastereomer, see: Jaeger, V.; Buss, V.; Schwab, W. Liebigs
56.0, 60.8, 66.0; 115.0, 115.1, 123.9, 128.3, 141.0, 147.3,
150.6, 152.6. HPLC (Daicel Chiralpak AD, hexanes/i-
PrOH = 99:1, flow rate 1.0 mL/min, l = 254 nm): major
Ann. Chem. 1980, 122. (b) (2S,3S)-3-Amino-2-methyl-3-
1
isomer: t = 36.10 min; minor isomer: t = 21.49 min;
phenylpropan-1-ol (9): H NMR (CD OD): d = 1.10 (d, 3
R
R
3
[
[
a] = –65.2 (c 0.2, MeOH). HRMS: 317.1496; C H N O
4
H, J = 4.4 Hz), 2.35 (m, 1 H), 3.44 (d, 1 H, J = 5.14 Hz),
3.48 (d, 1 H, J = 6.6 Hz), 4.35 (d, 1 H, J = 6.6 Hz), 7.54 (m,
D
17 20
2
+
(M + H ): calcd 317.1496]; C H N O (316.1423).
1
7
20
2
4
1
3
(
15) (1S,2S)-1-(4-Methoxyphenylamino)-1-(4-nitrophenyl)-2-
5 H). C NMR: d = 12.0, 40.9, 59.1, 66.2, 126.9, 127.1,
128.2, 143.9. (c) L-Proline derived 6 had the same retention
time as (2S,3S)-6 that had been synthesized via known
procedures, see: Vicario, J. L.; Badía, D.; Carrillo, L. J. Org.
Chem. 2001, 66, 9030. (d) See also: Vicario, J. L.; Badía,
D.; Carrillo, L. Org. Lett. 2001, 3, 773; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/
1
hydroxymethylheptane: H NMR (CD OD): d = 0.83 (t, 3
3
H, J = 7.0 Hz), 1.22–1.55 (m, 8 H), 2.08 (m, 1 H), 3.54 (d, 1
H, J = 3.3 Hz), 3.68 (s, 3 H, OMe), 3.73 (d, J = 3.3 Hz), 4.71
(
d, J = 3.3 Hz), 6.48 (d, 2 H, J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8
1
3
Hz). C NMR: d = 14.4, 22.9, 27.8, 29.7, 46.4, 56.1, 63.9,
9
6.6, 115.3, 124.1, 128.7, 147.5. HPLC (Daicel Chiralpak
AD, hexanes/i-PrOH = 90:10, flow rate 1.0 mL/min,
min, l = 254 nm): t = 14.02 min.
R
l = 254 nm): major isomer: t = 17.79 min; minor isomer:
(18) (2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-
R
1
t = 7.43 min; [a] = –24.7 (c 0.2, MeOH). HRMS:
phenylpropan-1-ol (6): H NMR (CD OD): d = 0.95 (d, 3
R
D
3
+
373.2120; C H N O [(M + H ): calcd 373.2122);
H, J = 7.0 Hz), 2.05 (m, 1 H), 3.38 (dd, 1 H), 3.56 (dd, 1 H),
3.62 (s, 3 H, OMe), 4.43 (d, 1 H, J = 4.0 Hz), 6.38 (d, 2 H,
J = 8.8 Hz), 6.50 (d, 2 H, J = 8.8 Hz), 7.12 (m, 1 H), 7.24 (m,
21
28
2
4
C H N O (372.2048968).
21
28
2
4
(
16) Anhydrous DMF (3 mL) was added to a vial containing p-
nitrobenzaldehyde (0.5 mmol), p-anisidine (0.5 mmol) and
proline (30 mol%) and placed in a 4 °C cold room. The
reaction was initiated by slow addition (0.2 mL/min) of a
pree-cooled mixture of propionaldehyde (5.0 mmol) in
anhyd DMF (2 mL) with syringe pump at 4 °C. After 16 h of
total reaction time the temperature was decreased to 0 °C
1
3
2 H); 7.31 (d, 2 H, J = 7.7 Hz). C NMR: d = 12.8, 43.7,
56.3, 61.4, 66.0, 115.7, 116.0, 127.7, 128.6, 129.3, 143.9,
144.6, 151.9, 153.1, 157.7. HPLC (Daicel Chiralpak AD,
hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, l = 254 nm):
major isomer: t = 14.02 min; minor isomer: t = 12.18;
R
R
[a] = –6.2. (c 1, MeOH). HRMS: 272.1647; C H NO
D
17 21
2
+
followed by dilution with anhyd Et O (2 mL) and reduction
[(M + H ): calcd 272.1645); C H NO (271.172206).
17 21 2
2
with NaBH (400 mg) for 10 min. Next, the reaction mixture
4
Synlett 2003, No. 11, 1651–1654 ISSN 1234-567-89 © Thieme Stuttgart · New York