The Direct Organocatalytic Asymmetric Mannich Reaction: Unmodified Aldehydes as Nucleophiles

Article abstract of DOI:10.1021/jo0347359

The unprecedented application of unmodified aldehydes as nucleophilic donors in direct catalytic asymmetric Mannich-type reactions is disclosed in a full account. Our efforts in broadening the applicability of chiral pyrrolidine-based catalysts in direct

Full text of DOI:10.1021/jo0347359

Th e Dir ect Or ga n oca ta lytic Asym m etr ic Ma n n ich Rea ction :
Un m od ified Ald eh yd es a s Nu cleop h iles
Wolfgang Notz, Fujie Tanaka, Shin-ichi Watanabe, Naidu S. Chowdari, J ames M. Turner,
Rajeswari Thayumanavan, and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La J olla, California 92037
carlos@scripps.edu
Received May 29, 2003
The unprecedented application of unmodified aldehydes as nucleophilic donors in direct catalytic
asymmetric Mannich-type reactions is disclosed in a full account. Our efforts in broadening the
applicability of chiral pyrrolidine-based catalysts in direct asymmetric Mannich-type reactions led
to the highly diastereo- and enantioselective and concise synthesis of functionalized R- and â-amino
acids, â-lactams, and amino alcohols.
In tr od u ction
applicability, it is surprising that, unlike the parent aldol
reaction, modern asymmetric Mannich-type reactions
have emerged only in the past few years. These variants
typically involve the addition of preformed enolate equiva-
lents to preformed imines, and both stoichiometric5 and
catalytic6 amounts of chiral controller have been em-
ployed.
Originally founded in the area of catalytic antibodies
designed to operate with imine and enamine reaction
mechanisms,7 research in our laboratories has recently
focused on translating these concepts to small molecule
catalysis. These efforts have led to the development of
amine-catalyzed direct asymmetric aldol,8 Michael,9
Diels-Alder,10 and Mannich-type reactions.11,12 The com-
mon feature of these reactions is the use of unmodified
nucleophilic donors,13 which, upon activation by inter-
mediate enamine formation, add stereoselectively to the
corresponding acceptors under very mild conditions.
In 1912, Carl Mannich disclosed his systematic studies
of the three-component reaction between an enolizable
CH-acidic substrate, an amine component, and an alde-
hyde to form a â-amino carbonyl compound.1 It is gener-
ally assumed that, in a preequilibrium, the aldehyde and
the amine form an imine (or an iminium salt thereof),
which is subsequently attacked by the nucleophilic enol
tautomer of the CH-acidic component. In this reac-
tion, the proper choice of reaction conditions as well as
reaction partners is key to successfully effect an amino-
alkylation in a selective manner. Not only are the
aldehyde and CH-acidic substrate both capable of forming
the reactive iminium ion and serving as nucleophiles at
the same time, but subsequent eliminations or competi-
tive aldol reactions might diminish the efficiency of the
reaction. To overcome these intricate problems of selec-
tivity that could impose severe limitations on an other-
wise powerful transformation, enormous efforts have
been directed toward the development of new methodolo-
gies and variants, which today allow for the deliberate
steering of this reaction toward a uniform product
formation. These approaches include the use of preformed
electrophiles (imines, hydrazones, iminium salts), nu-
cleophiles (enolates, enol ethers, enamines), or both, and
in many cases a catalyst is involved.2 Hence, it became
possible to assign a defined role to each reactant in the
reaction mixture and the formation of byproducts can
consequently be minimized.
(2) For comprehensive reviews, see: (a) Arend, M.; Westermann,
B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044 and references
therein. See also: (b) Hart, D. J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
(c) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: New York, 1991;
Vol. 2, pp 893-951. (d) Overman, L. E.; Ricca, D. J . In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon Press: New York, 1991; Vol. 2, p 1007. (e) Denmark, S. E.;
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E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, Germany,
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99, 1069. (g) Risch, N.; Arend, M. In Stereoselective Synthesis, Methods
of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoffman, R.,
Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart, Germany, 1996;
Vol. E21/b, pp 1833-1929. (h) Cole, D. C. Tetrahedron 1994, 50, 9517.
(i) Brown, M. J . Heterocycles 1989, 29, 2225.
Two key features render the Mannich-reaction and its
products very attractive: (a) the reaction tolerates a large
diversity of reactants3 and (b) the â-amino carbonyl
products are valuable synthons for natural product
synthesis4 and can be readily converted to derivatives
that possess useful applications in paint and polymer
chemistry, plant protection, and particularly medicine
and the pharmaceutical industry. In light of this wide
(3) Ammonia and primary and secondary aliphatic as well as
aromatic amines can be used, and the active hydrogen component may
be
a ketone, ester, nitrile, nitro compound, an R-alkyl pyridine,
hydrogen cyanide, or a thiol, as well as an electron-rich heterocyclic
or aromatic systems.
(4) Mannich reactions have been involved in the key steps of natural
product syntheses. Illustrative examples include the following: (a)
Robinson’s landmark synthesis of tropinone; see: Robinson, R. J .
Chem. Soc. 1917, 111, 762. (b) Corey’s synthesis of porantherine; see:
Corey, E. J .; Balanson, R. D. J . Am. Chem. Soc. 1974, 96, 6516. (c)
Overman’s synthesis of strychnine; see: Knight, S. D.; Overman, L.
E.; Pairaudeau, G. J . Am. Chem. Soc. 1993, 115, 9293.
(1) Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647.
10.1021/jo0347359 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/13/2003
9624
J . Org. Chem. 2003, 68, 9624-9634

Direct Catalytic Asymmetric Mannich Reactions
Herein, we disclose a full account of our efforts in the
synthesis of functionalized R- and â-amino acids, â-lac-
tams, and amino alcohols using unmodified aldehydes as
nucleophilic donors and chiral pyrrolidine-based catalysts
in the direct asymmetric catalytic Mannich-type reaction.
Resu lts a n d Discu ssion
In recent years, optically active nonproteinogenic
amino acids have gained increased importance mainly
due to their implementation into peptide mimics and
isosteres, their utility as versatile chiral synthetic inter-
mediates, and due to the interest of pharmaceutical,
agrochemical, and food industries in these compounds.14
We deemed our proline-catalyzed Mannich-type reactions
a suitable strategy to accomplish a stereoselective entry
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unsaturated carbonyl compounds are activated as dienophiles in a
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J . Org. Chem, Vol. 68, No. 25, 2003 9625

Notz et al.
SCHEME 1. Retr osyn th etic An a lysis of â-Am in o
Ca r bon yl Com p ou n d s Ba sed on Ma n n ich
Rea ction s of Un m od ified Ald eh yd es w ith Im in es
affording functionalized R-amino acids with excellent
diastereo- and enantioselectivities, the extension of this
approach to aldehyde donors presented itself as a sig-
nificant objective. We became interested in whether
enamine intermediates formed from aliphatic alde-
hydes might serve as nucleophiles in a stereoselective,
amino acid-catalyzed Mannich-type addition to imines.
To evaluate this possibility, a mixture of isovaleraldehyde
(2 equiv), L-proline (10 mol %), and N-PMP-protected
R-imino ethyl glyoxylate (0.1 M) was stirred in DMSO
at room temperature. We observed the formation of a
single product, which could be isolated in 80% yield after
8 h and characterized as the â-formyl-substituted leucine
derivative 1. This constitutes the first example of an
unmodified aldehyde being successfully used in a catalytic
asymmetric Mannich-type reaction. Most significantly, 1
was isolated as the predominant diastereomer (dr > 10:
1) with an ee of 87% (eq 1).19
to both functionalized R- and â-amino acids and their
derivatives.15,16 As outlined in Scheme 1, the use of
aldehydes as nucleophilic donors17,18 offers a particularly
attractive entry to functionalized â-amino acids and their
derivatives including â-lactams and amino alcohols.
Moreover, not only does this strategy involve the creation
of two contiguous stereocenters upon carbon-carbon
bond formation but it also provides for ready structural
and functional diversity.
On the basis of our previous research results concern-
ing the addition of ketones to R-imino ethyl glyoxylate11b
(15) For reviews concerning the synthesis of R-amino acids, see: (a)
Williams, R. M., Synthesis of Optically Active R-Amino Acids, in The
Organic Chemistry Series, Baldwin, J . E., Ed., Pergamon Press:
Oxford, 1989. (b) Williams, R. M.; Hendrix, J . A. Chem. Rev. 1992, 92,
889. (c) Williams, R. M. Aldrichim. Acta 1992, 25, 11. (d) Duthaler, R.
O. Tetrahedron 1994, 50, 1539. (e) Williams, R. M. In Advances in
Asymmetric Synthesis; Hassner, A., Ed.; J AI Press: Stamford, CT,
1995; Vol. 1, pp 45-94. (f) Arend, M. Angew. Chem., Int. Ed. Engl.
1999, 38, 2873. For recent reviews about nonproteinogenic amino acids,
see ref 2h, 5k and the following: (g) J uaristi, E.; Quintana, D.;
Escalante, J . Aldrichim. Acta 1994, 27, 3.
We then performed an extensive screen of structurally
diverse amine catalysts (Table 1). Although some of them
have proven very useful in our earlier studies,9,10a in the
reaction of heptanal with N-PMP-protected R-imino ethyl
glyoxylate, only proline, hydroxyproline, and its tert-butyl
ether derivative exhibited catalytic activity that affords
the desired Mannich product in acceptable yield and very
high stereoselectivities (entries 1-5). These results sug-
gest that hydroxyproline should be suitable for im-
mobilization through the hydroxy functionality for stud-
ies aimed at the construction of continuous-flow reaction
systems or to aid in catalyst recovery and recycling.
Compared to proline, amine catalysts with other substi-
tution patterns of the ring system, catalysts containing
additional heteroatoms in the ring system, and catalysts
lacking the carboxylate functionality all compromised the
chemical yield or stereoselectivity of the reaction, in many
cases both.
A solvent survey, using isovaleraldehyde as donor,
revealed the suitability of many commonly used solvents
(Table 2) with 1,4-dioxane providing the best results in
terms of yield (81%) and stereoselectivities (dr > 10:1,
93% ee). Interestingly, the ionic liquid [bmim]BF4 is also
a suitable solvent for this reaction, providing the desired
Mannich product, albeit with diminished diastereoselec-
tivity, with excellent enantiomeric excess at a signifi-
cantly accelerated reaction rate. Moreover, using 1,4-
dioxane as solvent, we established that the use of 1.5
equiv of isovaleraldehyde and 5 mol % of proline is
sufficient to afford the desired Mannich product 1 in a
very clean reaction, which almost completely suppressed
the competing self-aldolization of the aldehyde donor.
Given the significance of aqueous reaction conditions
in process chemistry, we next investigated the influence
of water on the Mannich reaction of preformed R-imino
ethyl glyoxylate with linear aldehydes. To our surprise,
(16) For R-amino acids, several strategically different approaches
are conceivable. Asymmetric Strecker reaction: (a) Enders, D.; Shil-
vock, J . P. Chem. Soc. Rev. 2000, 29, 359. (b) Davis, F. A.; Kee, S.;
Zhang, H.; Fanelli, D. L. J . Org. Chem. 2000, 65, 8704. (c) Kunz, H. In
Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J .,
Schaumann, E., Eds.; Houben-Weyl: Stuttgart, Germany; 1995; Vol.
E21b, p 1931. For an account comprising the important work on
catalytic versions by Corey, Hoveyda, J acobsen, Kobayashi, Lipton,
and Shibasaki, see: (d) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875.
(e) Nogami, H.; Kanai, M.; Shibasaki, M Tetrahedron Lett. 2001, 42,
279. Addition of electrophiles to glycine enolate derivatives: (f)
Seebach, D.; Hoffmann, M. Eur. J . Org. Chem. 1998, 1337, 7. (g)
Aoyagi, Y.; J ain, R. P.; Williams, R. M. J . Am. Chem. Soc. 2001, 123,
3472 and references therein. (h) Scho¨llkopf, U. Tetrahedron 1983, 39,
2085. (i) Scho¨llkopf, U. In Topics in Current Chemistry; Boschke, F.
L., Ed.; Springer-Verlag: Berlin, Germany, 1983; Vol. 109, pp 45-85.
Addition of nucleophiles to electrophilic glycine templates: (j) Knudsen,
K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; J ørgensen, K. A. J .
Am. Chem. Soc. 2001, 123, 5943. (k) O’Donnell, M. J .; Delgado, F.;
Drew, M. D.; Pottorf, R. S.; Zhou, C.; Scott, W. L. Tetrahedron Lett.
1999, 40, 5831 and references cited therein. (l) Williams, R. M.;
Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem. Soc. 1988, 110, 1547.
(m) Thompson, K. A.; Hall, D. G. Chem. Commun. 2000, 23, 2379. (n)
Kobayashi, S.; Kitagawa, H.; Matsubara, R. J . Comb. Chem. 2001, 3,
401. See also refs 6m and 13a,b,d. For the use of imino glyoxylates in
catalytic aza-Diels-Alder reactions, see: (o) Yao, S.; Saaby, S.; Hazell,
R. G.; J ørgensen, K. A. Chem. Eur. J . 2000, 6, 2435. For â-amino acid
synthesis, see ref 5k and the following examples of alternative catalytic
asymmetric synthesis of â-amino acid derivatives: (p) Sibi, M. P.; Shay,
J . J .; Liu, M.; J asperese, C. P. J . Am. Chem. Soc. 1998, 120, 6615. (q)
Myers, J . K.; J acobsen, E. N. J . Am. Chem. Soc. 1999, 121, 8959. (r)
Nelson, S.; Spencer, K. L. Angew. Chem., Int. Ed. 2000, 39, 1323. (s)
Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002,
41, 2197. (t) Hodous, B. L.; Fu, G. C. J . Am. Chem. Soc. 2002, 124,
1578.
(17) Noncatalytic diastereoselective Mannich-type reactions of enam-
ines derived from aldehydes have been reported earlier. See: Risch,
N.; Arend, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2422.
(18) Originally, only ketones were used successfully as donors in
our proline-catalyzed aldol and Mannich-type reactions. See ref 8d.
Recently, for the first time, we also used aldehydes successfully as
donors in amine-catalyzed asymmetric Michael-type, aldol, and here
Mannich-type reactions. See refs 9b, 8d, and 11c. Following these
reports, several other groups described the successful use of unmodified
aldehydes as nucleophiles. See: (a) Bøgevig, A.; J uhl, K.; Kumaragu-
rubaran, N.; J ørgensen, K. A. Chem. Commun. 2002, 620. (b) Bøgevig,
A.; Kumaragurubaran, N.; Zhuang, W.; J ørgensen, 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.
(19) For a preliminary account of these results, see ref 11c.
9626 J . Org. Chem., Vol. 68, No. 25, 2003

Direct Catalytic Asymmetric Mannich Reactions
TABLE 1. Ca ta lyst Scr een for th e Ma n n ich -Typ e Rea ction of Hep ta n a l w ith r-Im in o Eth yl Glyoxyla tea
a
PMP ) p-methoxyphenyl. A mixture of heptanal (0.375 mmol), imine (0.25 mmol), and catalyst (0.05 mmol, 20 mol %) was stirred in
DMSO (2.5 mL) at room temperature unless noted otherwise. Isolated yield. c For entries 1-5, the dr and ee values were determined
b
by chiral-phase HPLC of the extracted reaction mixture. For entries 6-18, these values were determined by chiral-phase HPLC of purified
d
products. The major enantiomer for the syn product possessed (S,S)-configuration unless noted otherwise. The major enantiomer for
the syn product possessed (R,R)-configuration. e See ref 24. f (+)-CSA ) (1S)-(+)-10-camphorsulfonic acid. Reaction performed in THF.
g
and in sharp contrast to the related aldol reaction,8a we
found that the reaction with n-heptanal as donor toler-
ated substantial amounts of water in the reaction mix-
ture without eroding the enantioselectivity (Table 3).
Whereas the presence of water did, however, affect the
chemical yield of this reaction, the syn diastereoselec-
tivity was not compromised and remained very high for
all entries, typically being >19:1.20
(Table 4). In all cases, the desired Mannich products were
formed with excellent enantioselectivities. The diastereo-
selectivities obtained are dependent on the chain length
as well as the bulkiness of the substituents of the
aldehyde donors. Typically, aldehydes with a chain length
longer than five carbon atoms afforded products, e.g. 5-9,
with excellent diastereoselectivities of dr > 19:1 (Table
4, entries 5-9), and higher diastereoselectivities were
achieved with increased chain length in the order of R )
Me < Et < i-Pr < n-Pent. Under these conditions, the
sterically more demanding 3,3-dimethylbutyraldehyde
did not undergo reaction to form the corresponding
Mannich product. Similar observations were made, if
acceptors other than preformed R-imino glyoxylates were
employed under these conditions. For example, N-PMP
aldimines preformed from benzaldehyde or p-nitro-
benzaldehyde did not afford Mannich products in reac-
tions with unmodified aldehydes as donors. However, we
Thus, anhydrous dioxane was selected as solvent of
choice, and using these conditions a set of aldehydes was
reacted with N-PMP-protected R-imino ethyl glyoxylate
(20) The application of aqueous reaction media allowed for the
development of a novel one-pot Mannich/indium-promoted allylation
tandem reaction affording γ-lactones, thus providing novel R-amino-
γ-lactones with three contiguous stereocenters. See: Co´rdova, A.;
Barbas, C. F., III Tetrahedron Lett. 2003, 44, 1923. For a complete
study of the organocatalytic Mannich reaction in ionic liquids see:
Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III Synlett 2003,
1906.
J . Org. Chem, Vol. 68, No. 25, 2003 9627

Notz et al.
TABLE 2. Solven t Scr een for th e Ma n n ich -Typ e
Rea ction of Isova ler a ld eh yd e w ith r-Im in o Eth yl
Glyoxyla te
The development of methodologies that provide for the
direct and deliberate synthesis of all possible stereo-
isomers is an important task in asymmetric catalysis and
is still required for direct Mannich-type reactions. For
example, our proline-catalyzed asymmetric Mannich-type
reactions with unmodified ketones and aldehydes have
been limited in that, upon carbon-carbon bond forma-
tion, two new stereocenters could only be created with
high syn diastereoselectivity without the option of pro-
viding for the corresponding â-amino carbonyl compounds
with similarly high anti diastereoselectivity in a direct
manner.11,12 To address this issue, we reinvestigated a
number of chiral pyrrolidine derivatives that have proven
superior to proline in our earlier studies concerning
organocatalysis with amines.8a,b,e,9 In particular, we
focused on pyrrolidine derivatives lacking the stereo-
directing carboxylate functionality of proline and recently
found that the commercially available (S)-2-methoxy-
methylpyrrolidine (SMP)23 effected the desired transfor-
mation best.24,25 When using DMSO as a solvent and 2
equiv of linear or branched aliphatic aldehyde, SMP
catalysis afforded the corresponding â-formyl-function-
alized amino acid derivatives with high anti diastereo-
selectivities (typically dr > 10:1, in many cases dr >19:
1) and the enantiomeric excesses ranging from ee 74%
to 92% (eq 2).
yield (%)
of 1
ee (%)
solvent
DMSO
of 1a
81
70
62
75
79
75
81
82
90
87
80
74
88
88
92b
93
96b
93
Et2O
CHCl3
EtOAc
THF
dioxane
[bmim]BF4
a
dr >10:1 for all solvents, except for [bmim]BF4 (dr ) 5:1).
Reaction performed at 4 °C.
b
TABLE 3. Effect of Wa ter on th e Ma n n ich -Typ e
Rea ction of n -Hep ta n a l w ith r-Im in o Eth yl Glyoxyla tea
entry
dioxane:H2O
yieldb (%)
eec (%)
1
2
3
4
5
6
7
100:0
99:1
98:2
>82
>70
>75
>59
>60
>52
44
>99
>99
>99
>99
>99
>99
>99
95:5
90:10
85:15
80:20
The absolute and relative configuration of the products
obtained by SMP catalysis was established by careful
imidazole-promoted anti f syn isomerization26 of the anti
products produced by SMP and its enantiomer RMP,
respectively. Thus, SMP catalysis provides functionalized
R-L-amino acid derivatives with anti stereochemistry.24
To date, only preformed R-imino ethyl glyoxylate was
used as acceptor in our direct Mannich-type reactions
employing unmodified aliphatic aldehydes as donors,
which constituted a significant limitation of the general-
ity of the reaction. It would be desirable to extend the
scope of this reaction to other preformed imines as
electrophiles and, as depicted in Scheme 1, eventually
apply them under a more general and efficient one-pot
three-component protocol. However, these transforma-
tions are very difficult to control, mainly due to the
challenge of assigning a specific role to each reaction
a
PMP ) p-methoxyphenyl. A mixture of n-heptanal (0.75
mmol), R-imino ethyl glyoxylate (0.5 mmol), and l-proline (0.05
mmol) was stirred in the indicated dioxane-H2O mixture (5 mL)
b
at room temperature for 16-24 h. Isolated yield after column
chromatography. c The ee of syn-5 was determined by chiral-phase
HPLC.
established different reaction conditions that allowed for
this reaction to succeed (vide infra). An interesting
example is provided by (S)-citronellal adduct 7 (Table 4,
entry 7), which was formed with complete stereocontrol.
When the (R)-enantiomer of citronellal was used, again
only a single diastereomer was obtained. Thus, the ab-
solute stereochemistry of the two newly formed stereo-
genic centers seems to be controlled by the catalyst
proline to a very high degree independent of another
chiral center present in the donor.
(21) Whereas these products and the Mannich products described
herein in general epimerize and racemize, respectively, when stored
neatly at room temperature, they can be stored at -25 °C in solution
(EtOAc) without decomposition, epimerization, and loss of ee.
(22) Typically, the syn/anti isomers are an inseparable mixture by
preparative column chromatography. However, both the syn and anti
isomers could be resolved by analytical HPLC.
(23) This proline-derived amine was developed by Enders et al. as
a chiral auxiliary and is commercially available in both enantiomeric
forms. For an excellent review of its use in asymmetric synthesis, see:
Enders, D.; Klatt, E. Synthesis 2001, 1403.
(24) Co´rdova, A.; Barbas, C. F., III Tetrahedron Lett. 2002, 43, 7749.
(25) SMP has been reported earlier to be an effective chiral auxiliary
in Mannich-type reactions involving preformed SMP-enamines derived
from ketones. See ref 5v. In these studies, SMP also directed the
predominant formation of the anti diastereomer.
Whereas the reaction of propionaldehyde and butyr-
aldehyde provided almost equal amounts of diastereo-
mers (Table 4, entries 2 and 3) after their chromato-
graphic isolation, we found that, in the cases of 1-4
(Table 4, entries 1-4), the diastereomeric ratio is sig-
nificantly higher if determined directly after aqueous
workup rather than after column chromatography. This
indicates that compounds 1-4 are prone to epimerization
during workup and purification on silica gel, which in
turn provided the anti diastereomer in excellent ee values
as observed for 1 (ee > 98%).21,22
(26) Ward, D. E.; Sales, M.; Sasmal, P. K. Org. Lett. 2001, 3, 3671.
9628 J . Org. Chem., Vol. 68, No. 25, 2003

Direct Catalytic Asymmetric Mannich Reactions
TABLE 4. Un m od ified Ald eh yd es a s Don or s in th e Syn th esis of â-F or m yl-Su bstitu ted r-Am in o Acid Der iva tives
a
b
PMP ) p-methoxyphenyl. Yields of isolated pure product after column chromatography. c dr ) syn/anti as determined by NMR
after column chromatography. The ee values were determined by chiral-phase HPLC analysis. e dr ) syn/anti as determined by NMR
d
of the crude product after extractive workup. f Enantiomers could not be resolved completely by HPLC. Results for (R)-citronellal as
g
donor.
partner to avoid the formation of undesired side products,
particularly those arising from aldol-type side reactions.
Moreover, there is no report of a catalytic asymmetric
three-component Mannich reaction with unmodified al-
dehydes as donors.27 We therefore embarked on the
search for a catalytic asymmetric one-pot three-compo-
nent Mannich process that would involve aldehydes for
both nucleophile and electrophile generation. Unlike
traditional mixed Mannich-type reactions involving ke-
tone nucleophiles and aldehyde-derived electrophiles, the
exclusive use of aldehydes as both nucleophiles and
electrophilic constituents in this reaction poses additional
and significant obstacles.
To minimize potential side reactions, we initially fo-
cused on Mannich-type reactions with preformed imines.
In this context, aromatic imines are especially attractive
since they are readily accessible and furthermore provide
for a novel route for the synthesis of â-amino alcohol and
acid derivatives that are used as chiral synthons for en-
zyme inhibitors and cancer drugs.5k We chose propion-
aldehyde as an aldehyde donor, N-(p-nitrobenzylidene)-
p-anisidine as the preformed imine component, and
L-proline (30 mol %) as the catalyst. In initial experi-
ments, we varied the concentration of the imine (0.1-
0.5 M) as well as the amount of propionaldehyde used
(2-10 equiv) and found that lower concentration and
fewer equivalents of propionaldehyde provided better
yields of the desired Mannich product and less self-aldol
product of propionaldehyde. We found that, to obtain the
corresponding Mannich adduct 10 in a clean reaction, it
was crucial that the propionaldehyde be added very
slowly to the reaction mixture. Similar observations were
made by others in related aldol reactions.18d The best
results were obtained when performing the reaction in
DMF at 4 °C28 and adding the propionaldehyde (2 equiv)
as a cold (4 °C) 1 M solution in DMF over 14 h via syringe
pump addition. These conditions afforded the highest
conversion and, upon in situ NaBH4 reduction29 of
Mannich product 10, provided â-amino alcohol 11 pre-
dominantly as one diastereomer in 81% yield and 99% ee
(eq 3).
As in the case of the reaction of n-heptanal with
N-PMP-protected R-imino ethyl glyoxylate (Table 3), we
again assessed the impact of the presence of water on
the reaction profile of the Mannich-type reaction of
(27) Following submission of this paper concerning one-pot three-
component Mannich reactions involving aldehydes, Hayashi et al.
reported similar results also obtained with proline catalysis: Hayashi,
Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem., Int. Ed. 2003, 42, 3677.
J . Org. Chem, Vol. 68, No. 25, 2003 9629

Notz et al.
TABLE 5. Effect of Wa ter on th e Ma n n ich -Typ e
Rea ction of P r op ion a ld eh yd e w ith P r efor m ed Ar om a tic
Ald im in es
TABLE 7. Dir ect Asym m etr ic P r olin e-Ca ta lyzed
Ma n n ich -Typ e Rea ction s of Un m od ified Ald eh yd es w ith
P r efor m ed Ar om a tic Im in es
entry
R
R′
product yieldb (%)
drc
eed (%)
entry
DMF:H2O
yieldb (%)
eec (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
p-NO2C6H4
p-CNC6H4
p-BrC6H4
p-ClC6H4
Ph
11
12
13
14
15
16
17
81
72
57
81
65
89
60
>10:1
7:1
99
98
95
93
93
96
90
1
2d
3
4
5
6
7
8
100:0
100:0
99:1
98:2
95:5
90:10
85:15
80:20
>92
>85
>92
>88
>96
>90
73
>97
>99
>99
>97
>99
>99
>97
97
6:1
>10:1
4:1
3:1
m-BrC6H4
Pent p-NO2C6H4
>19:1
a
b
75
PMP ) p-methoxyphenyl. Isolated yields of pure product
after column chromatography. c dr ) syn/anti as determined by
NMR after column chromatography. The ee values of products
11-17 were determined by chiral-phase HPLC analysis.
a
PMP ) p-methoxyphenyl. For this reaction, a solution of
d
propionaldehyde (2.5 mmol) in the indicated DMF-H2O mixture
(2 mL) was slowly added to a mixture of imine (0.5 mmol) and
L-proline (0.15 mmol) in the indicated DMF-H2O mixture (3 mL)
over 5 h at 0 °C and the mixture was stirred for 1 h at the same
cosolvent. Whereas in DMF as solvent lowering the
temperature to -15 °C exhibited no marked improvement
compared to 4 °C (Table 6, entries 1 and 2), in the
presence of water at -15 °C (entry 5), both the yield and
diastereoselectivity of the reaction were increased sig-
nificantly, while the ee was slightly diminished. The
addition of methanol as cosolvent proved unsuccessful
in improving the reaction results, affording the corre-
sponding Mannich product in both diminished dia-
stereoselectivity and enantiomeric excess (entry 3).
To broaden the scope of this transformation, a set of
different p-anisidine-derived aromatic imines were re-
acted with propionaldehyde to afford aromatic â-amino
alcohol derivatives 11-17 (Table 7). In all cases, the
reaction proceeded in a clean manner affording amino
alcohols 11-17 with very high enantioselectivities (ee
93-99%).30 As in the cases of R-imino ethyl glyoxylate
as acceptor, an increase of the diastereoselectivity was
again observed with increasing chain length of the
aliphatic aldehyde. For example, n-heptanal as a donor
reacted smoothly with N-(p-nitrobenzylidene)-p-anisidine
providing the corresponding amino alcohol 17 (Table 7,
entry 7) in 60% yield with excellent diastereoselectivity
of dr > 19:1 and enantioselectivity of 90% ee.
At this point, we were confident of succeeding in the
development of a one-pot three-component protocol for
the challenging task of directing the role of the aldehyde
components. We were delighted to find that, as in the
case of preformed imines, slow addition of propionalde-
hyde as 1 M solution in DMF to a mixture of p-anisidine
(0.1 M), p-nitrobenzaldehyde (0.1 M), and L-proline (30
mol %) in DMF at 4 °C afforded, after in situ NaBH4
reduction, â-amino alcohol 11 in 85% yield, >99% ee, and
in a diastereomeric ratio of dr > 10:1 (Table 8, entry 1).
Similar results were obtained when applying this protocol
to other substituted aromatic aldehydes, which led to the
formation of â-amino alcohol derivatives 12-17 with
excellent enantioselectivities of 93-98% ee (Table 8,
entries 2-6). In the case of the more reactive p-nitro-
benzaldehyde, reduced amounts of propionaldehyde (2
temperature. Isolated yield after column chromatography. c The
b
d
ee of syn-11 was determined by chiral-phase HPLC. The reaction
mixture was stirred at 4 °C for 18 h after slow addition of
propionaldehyde.
TABLE 6. Tem p er a tu r e Effect on th e Ma n n ich -Typ e
Rea ction w ith P r efor m ed Ald im in es
entry
solvent
temp (°C) yield (%)
dr
4:1
ee (%)
1
2
3
4
5
DMF
DMF
4
-15
4
4
-15
65
58
72
75
94
93
94
51
84
87
4:1
3:1
12:1
DMF/MeOH (95:5)
DMF/H2O(95:5)
DMF/H2O(95:5)
>19:1
aldehydes with preformed aromatic aldimines (Table 5)
and found that also this reaction tolerates significant
amounts of water present in the reaction mixture without
compromising the excellent enantiomeric excess obtained
for Mannich product 11. Furthermore, under all condi-
tions the formation of the corresponding syn diastereomer
was favored, with dr typically being >8:1. As can be
inferred from entries 7 and 8, the presence of higher
amounts of water does, however, have a detrimental
effect on the chemical yield presumably due to partial
hydrolysis of the imine.
We then probed the effect of the reaction temperature
in an attempt to further optimize this reaction (Table 6).
Thus, we performed the Mannich reaction of propion-
aldehyde with benzaldehyde-derived aldimine at lower
temperatures in DMF as well as in the presence of a
(28) The reaction also proceeded well in other solvents. Dioxane (at
23 °C): 65% yield; dr > 10:1; 99% ee. THF (at 23 °C): 51% yield; dr >
10:1; 99% ee. Ether (at 23 °C): 40% yield; dr > 10:1; 99% ee. THF (at
4 °C): 36% yield; dr > 10:1; >99% ee. Dioxane (at 4 °C): 62% yield; dr
> 10:1; 99% ee.
(29) We observed that Mannich product 15 was configurationally
unstable if stored at room temperature or subjected to silica gel column
chromatography. We therefore decided to reduce the aldehyde func-
tionality of 15 with excess NaBH4 prior to isolation and determination
of ee.
(30) These reactions can be readily performed on a 10 mmol scale
with no detrimental effect on yield or enantioselectivity as demon-
strated for amino alcohol 16.
9630 J . Org. Chem., Vol. 68, No. 25, 2003

Direct Catalytic Asymmetric Mannich Reactions
TABLE 8. Dir ect On e-P ot Th r ee-Com p on en t Asym m etr ic P r olin e-Ca ta lyzed Ma n n ich -Typ e Rea ction s
4 °C in DMF
-20 °C in DMF
-20 °C in DMF-H2O (95:5)
entry
R
X
product
yieldb (%)
drc
eec (%)
yieldb (%)
drc
eec (%)
yieldb (%)
drc
eec (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
n-Pent
p-NO2
p-CN
p-Br
p-Cl
H
m-Br
p-NO2
11
12
13
14
15
16
17
85
65
81
65
65
77
73e
>10:1
5:1
10:1
6:1
>99
93
91
93
93
87
83
77
92
82
86
87
65:1
65:1
16:1
12:1
4:1
98
99
89
90
79
80
88
89
83
85
25:1
21:1
29:1
6:1
24:1
17:1
11:1
99
97
93
76
88
87
>99
84
4:1
94
4:1
97
11:1
138:1
90d
>99
4:1e
75d,e
a
b
PMP ) p-methoxyphenyl. Isolated yields of pure product after column chromatography. c The dr and ee values were determined by
d
chiral-phase HPLC of the extracted mixture unless noted otherwise; dr ) syn/anti. The ee value was determined by chiral-phase HPLC
after column chromatography. e The reaction was performed at 4 °C for 7 h.
TABLE 9. F or m a tion of Self-Ma n n ich P r od u cts
equiv) and L-proline (10 mol %) were sufficient to afford
11 in similar yield and stereoselectivities (80%, dr 12:1,
99% ee). When performed at lower temperatures and
with water as a cosolvent, respectively, in the cases of
electron-deficient aromatic systems an increase in dia-
stereoselectivity and enantiomeric excess can be observed
(Table 8, entries 1, 2, and 7), whereas in the cases of
entry
R
product
yieldb
syn:antic
eed (%)
halogen-substituted aromatic systems the results are
inconclusive.31 We sought to extend these reactions to the
SMP-catalyzed Mannich-type reaction. Application of
conditions at Table 7, entry 1 to the same reaction except
with the use of SMP as the catalyst produced a slow
reaction and the yield of product 11 was very low after
24 h (<5%). When the same reaction was performed in
DMF/H2O (95:5) for 24 h, the yield was significantly
improved (68%); however, the dr was 1:1 and the ee of
the products was low (syn and anti were 11% and 39%
ee, respectively).
It is important to note that these reactions typically
proceeded with minimal formation of cross-aldol products
or self-Mannich adducts being observed. However, when
adding a DMF solution of propionaldehyde (5 equiv) to a
solution of p-anisidine (1 equiv) and proline (20 mol %)
in DMF in the absence of any other aldehyde, proline did
catalyze the direct asymmetric self-Mannich reaction
with propionaldehyde both as donor and acceptor com-
ponent, which furnished self-Mannich adduct 18 in 85%
yield with dr 4:1 and 82% ee (Table 9, entry 1). In a
similar fashion, self-Mannich products 19-22 were ob-
tained when hexanal, decanal, 4-pentenal, and isovaler-
aldehyde were used as the only aldehyde component
present in the reaction mixture (Table 9, entries 2-5).
On the other hand, the addition of propionaldehyde to
a solution of p-anisidine (1 equiv), proline (20 mol %),
1
2
3
4
5
Me
18
19
20
21
22
85
51
90
92
64
4:1
5:1
4:1
5:1
2:1
82
85
81
87
18
n-Bu
n-Octyl
allyl
i-Pr
a
b
PMP ) p-methoxyphenyl. Isolated yields of pure product
after column chromatography. c Determined by NMR after column
d
chromatography. Determined by chiral-phase HPLC analysis.
and isovaleraldehyde in DMF resulted in a complex
reaction mixture consisting of cross-aldol and self-aldol
products together with a number of unidentified side-
products. If the sterically more hindered cyclohexane-
carboxaldehyde is chosen as a potential aldimine com-
ponent instead of isovaleraldehyde, again only self-
Mannich adduct 18 is formed. These results clearly
demonstrate that, using aliphatic aldehydes as nucleo-
philes, the careful choice of reaction partners as well as
reaction conditions is key to a successful one-pot three-
component Mannich reaction. Although the yields were
slightly decreased in this three-component protocol as
compared to the reactions with preformed imines, the
diastereo- and enantioselectivities were not significantly
affected. Regardless of the protocol applied, the absolute
stereochemical outcome of the reaction was identical. The
absolute stereochemistry of the products 11-22 was
assigned to be (2S,3S) on the basis of NMR analysis and
chiral-phase HPLC analysis of â-amino alcohol 15. This
product obtained by L-proline catalysis had the same
retention time as known (2S,3S)-15 synthesized inde-
pendently earlier via known procedures.32a,b Furthermore,
the NMR data of the major diastereomer of PMP-
deprotected 15 were identical with those of the previously
reported syn diastereomer.32c This stereochemical out-
come is in full accord with the preceding results origi-
nating from L-proline catalysis and is explained best
(31) It is noteworthy that in some cases the ee as well as the syn/
anti ratios are to some extent dependent on the workup procedure
applied and workup times. For example, we found that, prior to the
NaBH4 reduction, in some cases extraction and drying of the organic
phase (MgSO4) resulted in improved syn/anti ratios and enantiomeric
excesses compared to a direct one-pot reduction protocol. Furthermore,
we showed that the Mannich products bearing an aldehyde functional-
ity are slightly prone to epimerization, thus diminishing the syn/anti
ratio. This might explain some of the lower selectivities observed (e.g.
Table 8, entries 4 and 6).
J . Org. Chem, Vol. 68, No. 25, 2003 9631

Notz et al.
SCHEME 2. Syn th esis of Asp a r tic Acid
Der iva tives a n d â-La cta m sa
F IGURE 1. (Left) Chairlike Transition State for the proline-
catalyzed direct asymmetric Mannich reaction. (Right) Possible
transition state for the SMP-catalyzed direct asymmetric
Mannich reaction.
invoking previously reported chairlike six-membered
transition states (Figure 1, left) with L-proline directing
a nucleophilic si-facial attack of the imine by the si-face
of an assumed aldehyde derived enamine intermedi-
ate.11a,33
Lacking the stereodirecting carboxylate of proline, the
topicity of the transition state for the SMP-catalyzed
reaction is altered (Figure 1, right). The si-face of the
imine is selectively attacked by the re-face of the enamine
drawing the ethereal oxygen closer to the imine nitrogen,
which if protonated, may provide for a favorable Cou-
lombic interaction.34 This attractive force could com-
pensate for potential steric interactions between the
pyrrolidine group of SMP and the PMP protecting group
of the imine.
Common to all the Mannich products described above
is the aldehyde functionality, which offers an attrac-
tive and versatile reaction site for further transforma-
tions. For example, we have recently demonstrated that
Mannich products 1-9 (Table 4) from the reaction of
unmodified linear and branched aliphatic aldehydes with
N-PMP-protected R-imino ethyl glyoxylate can be further
transformed by subsequent treatment with Et2AlCN in
toluene/THF mixtures at low temperatures. This pro-
vided â-cyanohydroxymethyl R-amino acid derivatives
with three contiguous stereogenic centers in a one-pot
fashion and in a highly diastereo- and enantioselective
manner (eq 4).35
a
Reagents and conditions: (a) (i) NaClO2, KH2PO4, 2-methyl-
2-butene, t-BuOH/H2O; (ii) CH2N2, Et2O, 89% (2 steps). (b)
LHMDS, THF, -20 °C, 96%. (c) (i) LiOH, dioxane/H2O; (ii) CH2N2,
Et2O, 92% (2 steps). (d) CAN, MeCN/H2O, 0 °C, 87%. (e) LiAlH4,
THF, 0 °C, 88%.
Most importantly, however, base-promoted cyclization36
of 23 by means of LHMDS furnished the known car-
bapenem antibiotic PS-6 precursor 2437 in excellent yield.
1H NMR analysis of 24 and 25 confirmed the cis relation-
ship of the vicinal methine protons at C-3 and C-4 based
on their vicinal coupling constant J 3,4 ≈ 5.9 Hz.37 As
3
shown for Mannich product 1, the absolute stereochem-
istry was determined to be (3S,4S) on the basis of
correlation by synthesis of known R-alkyl-â-lactam 2538
via oxidation and an efficient hydrolysis/esterification
protocol and comparison to the data reported (Scheme
2). The absolute stereochemistry of products 2-9 was
assigned accordingly based on the unique stereodirection
during this reaction. Thus, our methodology of proline
catalysis provides an alternative mild, facile, and stereo-
selective route to functionalized â-lactams with syn
stereochemistry with L-proline catalyzing the formation
of L-amino acids.
As in the cases reported previously, the N-PMP group
in â-lactam 25 could be removed oxidatively. This was
easily accomplished by treatment of 25 with CAN in
MeCN/H2O at 0 °C, which afforded 2639 in 87% yield.
Alternatively, as exemplified for 1, both the aldehyde and
the ester functionality can be simultaneously reduced.
Treatment of 1 with LiAlH4 afforded diol 27 in 88% yield
(Scheme 2). Such 3-alkyl-substituted-2-aminobutane-1,4-
diols are ideal starting materials for the synthesis of
chiral pyrrolidines, which, for example, have been em-
ployed as versatile and useful intermediates for the
synthesis of antibacterial quinolinecarboxylic acids as
medical bactericides.40
The aldehyde functionality present in the R-amino
acids derived from aldehyde donors (Table 4) can be
further oxidized providing a straightforward entry to
functionalized aspartic acids. As demonstrated for 1, the
aldehyde group was readily oxidized (NaClO2) and sub-
sequently esterified (CH2N2) to afford the aspartic acid
derivative 23 without loss of the ee and dr (Scheme 2).
Unnatural amino acids that contain carbonyl groups
have been shown to be useful as distinctively reactive
(32) (a) Vicario, J . L.; Bad´ıa, D.; Carrillo, L. J . Org. Chem. 2001,
66, 9030. (b)Vicario, J . L.; Bad´ıa, D.; Carrillo, L. Org. Lett. 2001, 3,
773. (c) J aeger, V.; Buss, V.; Schwab, W. Liebigs Ann. Chem. 1980,
122. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH ) 99:1, flow rate
1.0 mL/min, λ ) 254 nm): tR ) 14.02 min.
(33) Very recently, calculations confirmed this stereochemical out-
come. See: Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249.
(34) Electrostatic interactions have been observed in noncatalytic
asymmetric Mannich-type reactions with preformed SMP enamines.
See ref 2a and: Vinkovic, V.; Sunjic, V. Tetrahedron 1997, 53, 689.
(35) Watanabe, S.; Co´rdova, A.; Tanaka, F.; Barbas, C. F., III Org.
Lett. 2002, 4, 4519.
(36) (a) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987,
28, 4331. (b) Gennari, C.; Venturini, I.; Gislon, G.; Schimperna, G.
Tetrahedron Lett. 1987, 28, 227.
(37) (a) Manhas, M. S.; Ghosh, M.; Bose, A. K. J . Org. Chem. 1990,
55, 575. (b) Greff, Z.; Horvath, Z.; Nyitrai, J .; Kajtar-Peredy, M.; Brlik,
J . J . Chem. Res. 1990, S, 170. (c) Greff, Z.; Horvath, Z.; Nyitrai, J .;
Kajtar-Peredy, M.; Brlik, J . J . Chem. Res. 1990, M, 1201.
(38) Palomo, C.; Aizpurua, J . M.; Gracenea, J . J .; Garcia-Granada,
S.; Pertierra, P. Eur. J . Org. Chem. 1998, 2201, 1. [R]D -95 (c 0.5,
CH2Cl2) {lit. [R]D -108.7 (c 1.0, CH2Cl2)}.
(39) Palomo, C.; Aizpurua, J . M.; Ontoria, J . M.; Iturburu, M.
Tetrahedron Lett. 1992, 33, 4823.
9632 J . Org. Chem., Vol. 68, No. 25, 2003

Direct Catalytic Asymmetric Mannich Reactions
handles that provide for the facile modification of proteins
and peptides.41 As such they are key synthons in their
own right and provide for facile diversification. For
example, we found that the carbonyl group of these
aldehyde donor derived amino acids is readily converted
to the corresponding oxime under mild conditions without
epimerization. Thus, in the reaction with isovaleralde-
hyde or heptanal as donor, O-benzylhydroxylamine hy-
drochloride and pyridine were added directly to the
reaction mixture after complete consumption of the imino
glyoxylate. Within 2 h, the formation of oxime 28 and
29, respectively, as the only stereoisomer was complete
(eq 5).
performed on a multigram scale under operationally
simple conditions. Most significantly, however, we de-
veloped a one-pot three-component protocol, which ap-
plies aliphatic aldehydes as nucleophilic donors and
affords the corresponding Mannich products in a highly
enantioselective manner with good syn diastereoselec-
tivity and exceptional chemoselectivity. We demonstrated
that an individual fine-tuning of the reaction parameters
for a given combination of reactants allows for the
optimization of yield and stereoselectivities. The number
of different functionalities present in these Mannich
products allows for a large variety of further chemical
modifications. In particular, we exploited the presence
of the aldehyde functionality and developed two novel
asymmetric one-pot tandem reactions. The Mannich
hydrocyanation reaction afforded â-cyanohydroxymethyl
R-amino acid derivatives with three contiguous stereo-
centers as single diastereomers. Additionally, simple
reaction of â-formyl-substituted-R-amino acid esters with
substituted hydroxylamines can provide for the rapid
generation of large families of oxime-containing amino
acids, a testament to the versatility of the aldehyde
functionality common to our Mannich products.
Considering the number of consecutive mechanistic
events required for the one-pot, three-component Man-
nich reaction to occur without preactivation of compo-
nents, the small amino acid proline possesses the re-
markable ability to catalyze an in situ enamine formation,
to form and activate the aldimine, which in the cases of
enolizable aldehydes occurred without isomerization, to
enhance the nucleophilicity of the donors by enamine
formation, and finally to transfer its inherent chiral
information to the products in a highly efficient manner.
Proline is not unique with respect to its potential to
mediate catalytic asymmetric reactions involving alde-
hyde donors. Indeed, the first account of an efficient
reaction of this type involved the use of chiral diamines
such as (S)-2-(morpholinomethyl)-pyrrolidine as catalysts9b
of asymmetric Michael reactions where proline itself
proved to be a poor catalyst of aldehyde addition. Proline,
however, has proven to be the most versatile of organo-
catalysts in asymmetric aldehyde addition reactions
working effectively in aldol, Mannich, and more recently
amination reaction manifolds. Our account reported here
reflects the advancement in the field of direct proline-
catalyzed enantioselective carbon-carbon bond forma-
tion, and the results further underscore the value of
proline catalysis in particular and organocatalysis in
general. The unveiling potential of these strategies
should continue to be an intriguing and rewarding
endeavor for some time to come.
Oximes of this type were recently integrated into
glycopeptide analogues containing unnatural sugar-
peptide linkages.42 Thus, reaction of these aldehyde-
containing amino acids with a variety of hydroxylamines
can provide for the synthesis of a diverse family of D- or
L-amino acids with oxime-containing side chains. These
oxime-containing amino acids can now be considered as
building blocks in combinatorial syntheses.
Con clu sion
In conclusion, for the first time unmodified aldehydes
were successfully used as donors in catalytic asymmetric
Mannich-type reactions. We showed that the proline-
catalyzed reaction of N-PMP-protected R-imino ethyl
glyoxylate with aldehydes provides a highly enantio-
selective entry to functional amino acids, â-lactam anti-
biotics, and serine protease inhibitors.43 The correspond-
ing products were obtained in high yields and excellent
syn diastereoselectivities. Notably, by switching to (S)-
2-methoxymethylpyrrolidine (SMP) as catalyst, we ac-
complished the highly diastereoselective synthesis of the
corresponding anti diastereomers in a direct manner.
Thus, all four possible stereoisomers of functionalized R-
and â-amino acids are now accessible with very high
stereocontrol from achiral, readily available, and inex-
pensive starting materials and catalysts. Moreover, our
methodology does not require separate preactivation of
substrates nor Lewis-acidic heavy metals and can be
(40) (a) Yoshida, T.; Takeshita, M.; Orita, H.; Kado, N.; Yasuda, S.;
Kato, H.; Itoh, Y. Chem. Pharm. Bull. 1996, 44, 1128. (b) Ito, Y.; Kato,
H.; Yasuda, S.; Kato, N.; Yoshida, T.; Takeshita, M. J P Patent
09059228, Mar 4, 1997. (c) Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.;
Yoshida, T.; Yamamoto, Y. Int. Patent WO 9622988, Aug 1, 1996. (d)
Hirabayashi, S.; Ike, K.; Zanka, A.; Kawakami, T.; Ichihara, M. Int.
Patent WO 9220652, Nov 26, 1992.
Exp er im en ta l Section
Typ ica l P r oced u r e for t h e Ca t a lyt ic Asym m et r ic
Ma n n ich -Typ e Rea ction w ith P r op ion a ld eh yd e a n d P r e-
for m ed Ald im in es: F or m a tion of 11-17. Anhydrous DMF
(3 mL) was added to a vial containing the corresponding
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
µL/min) of a precooled mixture of propionaldehyde (5.0 mmol)
in anhydrous DMF (2 mL) with a syringe pump at 4 °C. After
14-15 h of total reaction time the reaction mixture was diluted
with anhydrous Et2O (2 mL) and the temperature decreased
to 0 °C followed by reduction with NaBH4 (400 mg) for 10 min.
(41) For example, see: Cornish, V. W.; Hahn, K. M.; Schultz, P. G.
J . Am. Chem. Soc. 1996, 118, 8150.
(42) Carbohydrate-based oximes derived from γ-keto amino acids
were recently applied to the synthesis of glycopeptides with clustered
oxime-linked glycans. See: Marcaurelle, L. A.; Shin, Y.; Goon, S.;
Bertozzi, C. R. Org. Lett. 2001, 3, 3691 and references therein.
(43) Although the p-methoxyphenyl group (PMP) was used as the
nitrogen protective group throughout our studies, other nitrogen
protective groups are also conceivable, particularly in the case of
glyoxylate imines. For an example, see: Nakamura, Y.; Matsubara,
R.; Kiyohara, H.; Kobayashi, S. Org. Lett. 2003, 5; 2481. Hayashi, Y.;
Tsuboi, W.; Shoji, M.; Suzuki, N. J . Am. Chem. Soc. 2003, 125, 11208.
J . Org. Chem, Vol. 68, No. 25, 2003 9633

Notz et al.
Next, the reaction mixture was poured into a vigorously stirred
biphasic solution of Et2O and saturated aqueous NH4Cl
solution (or alternatively sodium phosphate buffer pH 7.2). The
organic layer was separated and the aqueous phase was
extracted thoroughly with ethyl acetate. The combined organic
phases were dried (MgSO4), concentrated, and purified by flash
column chromatography (silica gel, mixtures of hexanes/ethyl
acetate) to afford the desired â-amino alcohols. The enantio-
meric excesses of the products were determined by HPLC
analysis with use of chiral stationary phases.
Typ ica l Th r ee-Com p on en t, On e-P ot P r oced u r e for th e
Ca ta lytic Asym m etr ic Ma n n ich -Typ e Rea ction of Ald e-
h yd es a n d p-An isid in e: F or m a tion of 11-17. To a vial
containing the acceptor aldehyde (0.5 mmol), p-anisidine (0.5
mmol), proline (30 mol %), and anhydrous DMF (3 mL) was
added the corresponding donor aldehyde (5.0 mmol) in anhy-
drous DMF (2 mL) at 4 °C with a syringe pump. After 15-16
h of total reaction time the temperature was decreased to 0
°C followed by dilution with anhydrous Et2O (2 mL) and
reduction with NaBH4 (400 mg) for 10 min. Next, the reaction
mixture was poured into a vigorously stirred biphasic solution
of Et2O and saturated aqueous NH4Cl solution (or alternatively
sodium phosphate buffer pH 7.2). The organic layer was
separated and the aqueous phase was extracted thoroughly
with ethyl acetate. The combined organic phases were dried
(MgSO4), concentrated, and purified by flash column chroma-
tography (silica gel, mixtures of hexanes/ethyl acetate) to
afford the desired â-amino alcohols. The enantiomeric excesses
of the products were determined by HPLC analysis with use
of chiral stationary phases.
Typ ica l P r oced u r e for th e F or m a tion of Self-Ma n n ich
P r od u cts 18-22. To a vial containing p-anisidine (0.5 mmol)
and L-proline (30 mol %) in DMF (5 mL) was added aldehyde
(4 mmol) at - 15 °C and the solution was stirred for 7 h. After
completion of the reaction the mixture was diluted with ether
(2 mL) and treated with NaBH4 (400 mg) at 0 °C for 10 min.
The reaction mixture was poured into a half- saturated NH4Cl
solution and ether under vigorous stirring, the layers were
separated, and the aqueous phase was extracted thoroughly
with ether. The combined organic phases were dried (Na2SO4),
concentrated, and purified by flash column chromatography
(silica gel, mixtures of hexanes/ethyl acetate) to afford the
desired amino alcohols.
123.9, 128.3, 141.0, 147.3, 150.6, 152.6; HPLC (Daicel Chiral-
pak AD, hexanes/i-PrOH 99:1, flow rate 1.0 mL/min, λ ) 254
nm): major isomer tR ) 36.10 min, minor isomer tR ) 21.49
min; [R]D -65.2 (c 0.2, MeOH); HR-MS 317.1496; C17H20NO2
(M + H+) calcd 317.1496.
a n ti/syn -11 (fr om SMP r ea ction ): HPLC (Daicel Chiral-
pak OD-H, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, 254
nm) 28.0 min ((S,S)-11), 31.4 min ((R,R)-11), 35.6 min (anti),
50.0 min (anti); 1H NMR (400 MHz, CDCl3) (syn:anti ) 1:1, *
donates the anti diastereomer) δ 0.89 (d, J ) 7.0 Hz, 3H* ×
1
1
1/2), 0.90 (d, J ) 7.0 Hz, 3H × /2), 2.12 (m, 1H* × /2), 2.21 (m,
1
1H × /2), 3.67 (s, 3H), 3.63-3.74 (m, 2H), 4.38 (d, J ) 7.0 Hz,
1
1
1H* × /2), 4.65 (d, J ) 3.8 Hz, 1H × /2), 6.43 (d, J ) 8.8 Hz,
1
1
2H × /2), 6.44 (d, J ) 8.8 Hz, 2H* × /2), 6.67 (d, J ) 8.8 Hz,
1
1
2H* × /2), 6.68 (d, J ) 8.8 Hz, 2H × /2), 7.48 (d, J ) 8.8 Hz,
1
1
2H* × /2), 7.51 (d, J ) 8.8 Hz, 2H × /2), 8.16 (d, J ) 8.8 Hz,
2H* × /2), 8.17 (d, J ) 8.8 Hz, 2H × /2); 13C (100 MHz, CDCl3)
(syn:anti ) 1:1) 11.6, 14.4, 41.0, 55.6, 60.4, 65.6, 66.2, 114.6,
114.7, 115.3, 123.6, 123.7, 128.0, 140.5, 140.7, 146.9, 147.0,
150.4, 152.2, 152.5.
1
1
(2S,3S)-2-Meth yl-3-(4-m eth oxyp h en yla m in o)-3-(4-br o-
m op h en yl)-p r op a n -1-ol (18): 1H NMR (CD3OD) δ 0.94 (d,
3H, J ) 7.3 Hz), 2.03 (m, 1H), 3.37 (dd, 1H), 3.55 (dd, 1H),
3.62 (s, 3H, OMe), 4.43 (d, 1H, J ) 5.1 Hz), 6.47 (d, 2H, J )
9.2 Hz), 6.61 (d, 2H, J ) 8.8 Hz), 7.25 (d, 2H, J ) 8.4 Hz),
7.40 (d, 2H, J ) 8.4 Hz); 13C NMR (CD3OD) δ 12.7, 43.6, 56.3,
60.8, 65.8; 115.7, 115.9, 130.6, 132.3, 143.7, 144.1, 153.2; HPLC
(Daicel Chiralpak AD, hexanes/i-PrOH 99:1, flow rate 1.0 mL/
min, λ ) 254 nm) major isomer tR ) 14.00 min, minor isomer
tR ) 10.14 min; [R]D -38.9 (c 0.6, CHCl3); HR-MS 350.0753,
C
17H20BrNO2 (M
+
H+) calcd 350.0753, C17H20BrNO2
349.067732.
Ack n ow led gm en t. This study was supported in
part by the NIH (CA27489) and The Skaggs Institute
for Chemical Biology. The authors thank Armando
Co´rdova for technical contributions.
Note Ad d ed a fter ASAP P ostin g. There was an
error in the product structure in Table 3 in the version
posted ASAP November 13, 2003; the corrected version
was posted November 18, 2003.
(2S ,3S )-2-Me t h y l-3-(4-m e t h o x y p h e n y la m in o )-3-(4-
1
n itr op h en yl)p r op a n -1-ol (11): H NMR (CDCl3) δ 0.91 (d,
Su p p or tin g In for m a tion Ava ila ble: For new compounds,
a complete set of analytical data is provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
3H, J ) 7.0 Hz), 2.21 (m, 1H), 3.64 (m, 2H), 3.67 (s, 3H, OMe),
4.65 (d, 1H, J ) 4.0 Hz), 6.42 (d, 2H, J ) 8.8 Hz), 6.68 (d, 2H,
J ) 8.8 Hz), 7.51 (d, 2H, J ) 8.8 Hz), 8.17 (d, 2H, J ) 8.8 Hz);
13C NMR (CD3OD) δ 11.9, 41.6, 56.0, 60.8, 66.0; 115.0, 115.1,
J O0347359
9634 J . Org. Chem., Vol. 68, No. 25, 2003