Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric mannich reaction of N -protected aminoacetaldehydes: Formal synthesis of (-)-agelastatin A

Article abstract of DOI:10.1021/ja301120z

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.

Full text of DOI:10.1021/ja301120z

Article
pubs.acs.org/JACS
Stereocontrolled Synthesis of Vicinal Diamines by Organocatalytic
Asymmetric Mannich Reaction of N-Protected Aminoacetaldehydes:
Formal Synthesis of (−)-Agelastatin A
Taichi Kano,† Ryu Sakamoto,† Matsujiro Akakura,‡ and Keiji Maruoka*,†
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡Department of Chemistry, Aichi University of Education, Igaya-cho, Kariya, Aichi 448-8542, Japan
S
* Supporting Information
ABSTRACT: The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological
activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is
still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich
reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino
sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected
aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically
active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (−)-agelastatin A.
Scheme 1. Amine-Catalyzed Reaction of
Aminoacetaldehydes
INTRODUCTION
■
Chiral vicinal diamines constitute important structural motifs
which are found in a broad variety of natural products, biologi-
cally active compounds, and chiral catalysts in various asym-
metric reactions.1 Despite their extensive utility, the develop-
ment of new methods for the efficient preparation of vicinal
diamines remains a significant and important challenge.2,3 Vari-
ous catalytic asymmetric Mannich-type reactions of carbonyl
compounds having an α-nitrogen functional group have been
employed for the synthesis of such chiral diamines;4,5 however,
the efficient method for the highly diastereoselective synthesis
of both syn- and anti-diamines from the same set of reactants by
simply replacing the catalyst has rarely been reported.4f,k,l In
enamine catalysis, while both syn- and anti-selective asymmetric
Mannich reactions of simple aliphatic aldehydes have been
developed,6 diastereo- and enantioselective synthesis of vicinal
diamines by a Mannich approach using an α-nitrogen func-
tionalized aldehyde as a nucleophile has not been reported to
date. Here, an α-nitrogen functionality of aldehyde might
promote the undesired side reaction through path b as shown
in Scheme 1,7 and to the best of our knowledge, use of amino-
acetaldehyde 1 or 2 having a common and easily removable
N-protecting group,8 such as Z (benzyloxycarbonyl) and Boc
(t-butoxycarbonyl), has not been reported so far in enamine
catalysis. In this context, we have become interested in the
possibility of asymmetric Mannich reaction of aminoacetaldehydes
1 and 2 as an efficient method for the stereocontrolled synthesis
of vicinal diamines (Scheme 2). Here we report both syn- and
anti-selective asymmetric Mannich reaction using Z- or Boc-
protected aminoacetaldehyde as new entry of α-nitrogen
functionalized aldehyde nucleophile in enamine catalysis.
RESULTS AND DISCUSSION
■
We first examined the Mannich reaction between N-Z-
protected aminoacetaldehyde 19 and N-Boc-protected imine
Received: February 3, 2012
Published: April 9, 2012
© 2012 American Chemical Society
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We have previously designed the axially chiral amino sul-
fonamide catalyst (S)-3,11,12 which has the advantage of giving
mainly anti-products in the direct asymmetric Mannich reac-
tion, while proline and the related catalysts show the oppo-
site syn-selectivity.6k,12 To develop an efficient method for the
preparation of anti-vicinal diamines, we then examined (S)-3
as catalyst in the reaction between N-Z-protected amino-
acetaldehyde 1 and N-Boc-protected imine derived from 4-
methoxybenzaldehyde (Table 2). When the reaction was
Scheme 2. Diastereo- and Enantioselective Synthesis of
Vicinal Diamines
Table 2. anti-Selective Mannich Reaction between
derived from benzaldehyde in the presence of 30 mol % of
L-proline in acetonitrile at 0 °C.6k Fortunately, the reaction
proceeded smoothly to give the desired syn-Mannich product,
which was a syn-vicinal diamine protected by Z and Boc groups,
in virtually perfect enantioselectivity without forming by-
products (Table 1, entry 1).10 This result suggested that the
N-Z-Aminoacetaldehyde 1 and a N-Boc Imine Catalyzed
a
by (S)-3
Table 1. syn-Selective Mannich Reaction between
N-Z-Aminoacetaldehyde 1 and N-Boc Imines Catalyzed
by L-Proline
b
c
d
entry
solvent
yield (%)
anti/syn
ee (%)
a
1
2
3
4
5
6
CH3CN
THF
65
81
41
63
76
76
0
2.0/1
1.8/1
1.9/1
2.4/1
4.5/1
5.3/1
−
94
99
97
91
92
98
−
dioxane
CH2Cl2
DMF
NMP
e
7
NMP
8
HMPA
DMSO
75
90
4.7/1
81
f
9
5.4/1
97
a
The reaction of 1 (0.375 mmol) with an N-Boc imine (0.125 mmol)
was carried out in the presence of (S)-3 (0.0063 mmol) in a solvent
(250 μL) at room temperature. The N-Boc imine was added using a
b
syringe pump over 4 h. Stirring was then continued for 3 h. Isolated
c
d
yield of diastereomeric mixture. Determined by 1H NMR. The ee of
e
anti-product was determined by HPLC using chiral column. The
reaction was performed at 0 °C. Use of 375 μL of DMSO.
f
performed in acetonitrile, the desired anti-Mannich product
was obtained in moderate yield, albeit with low diastereose-
lectivity (entry 1). After screening a variety of solvents, DMSO
was found to be the among best in terms of both yield and
stereoselectivity (entry 9).
With the optimal reaction conditions, the anti-selective and
enantioselective direct Mannich reaction of N-Z-protected amino-
acetaldehyde 1 with several other N-Boc imines was examined,
and the results are summarized in Table 3. All reactions examined
proceeded to give anti-Mannich products with excellent enantio-
selectivity (entries 1−8). The N-Boc-protected aminoacetalde-
hyde 213 was also applicable to the present Mannich reaction, thus
giving the N,N′-di-Boc protected anti-vicinal diamine (entry 9).
The absolute configuration of both syn- and anti-Mannich
products was determined by conversion to the known cyclic
ureas14 and comparison of the optical rotations (see Supporting
Information). The L-proline-catalyzed Mannich reaction of 1
was found to give a syn-vicinal diamine having (1R,2S) con-
figuration. On the other hand, the absolute configuration of an
anti-vicinal diamine obtained in the reaction catalyzed by (S)-3
was determined to be (1R,2R). Based on the observed stereo-
chemistry, transition-state models can be proposed as shown in
Figure 1. In the case of the L-proline-catalyzed reaction, the si
face of N-Boc-protected imine approaches the Si face of the domi-
nant E-s-trans-enamine (TS1) over the sterically congested E-s-
cis-enamine (TS2). While both E-s-trans- and E-s-cis-enamine
a
The reaction of 1 (0.375 mmol) with an N-Boc imine (0.125 mmol)
was carried out in the presence of L-proline (0.0375 mmol) in CH3CN
b
(1.0 mL) at 0 °C for 4 h. Isolated yield of diastereomeric mixture.
c
d
Determined by 1H NMR. The ee of syn-product was determined by
e
HPLC using chiral column. The N-Boc imine was added using a
syringe pump over 4 h. Stirring was then continued for 3 h. The
Mannich adduct was isolated before reduction with NaBH4.
f
Z group was sufficient to suppress undesired side reactions
(path b in Scheme 1) caused by the nucleophilic character of
the α-nitrogen. With several other N-Boc imines, almost
optically pure syn-Mannich products were obtained in moderate
to good yield (entries 2−5). The reactive imine derived from 4-
chlorobenzaldehyde was added slowly using a syringe pump to
prevent catalyst deactivation by the undesired addition of
proline to the imine (entry 3).
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Table 3. anti-Selective Mannich Reaction between
N-Protected Aminoacetaldehydes and N-Boc Imines
a
Catalyzed by (S)-3
Figure 1. Transition-state models for the asymmetric Mannich
reaction catalyzed by L-proline and (S)-3.
a
The reaction of an N-protected aminoacetaldehyde (0.375 mmol)
with an N-Boc imine (0.125 mmol) was carried out in the presence of
(S)-3 (0.0063 mmol) in DMSO (250 μL) at room temperature. The
N-Boc imine was added using a syringe pump over 4 h. Stirring was
b
then continued for 3 h. Isolated yield of diastereomeric mixture.
c
d
Determined by 1H NMR. The ee of anti-product was determined by
e
f
Figure 2. B3LYP/6-31G* optimized transition-state structure of the
reaction.
HPLC using chiral column. Use of 375 μL of DMSO. The reaction
was performed at 50 °C.
To demonstrate the synthetic utility of this asymmetric
transformation, the optically enriched anti-Mannich product was
converted to the corresponding α,β-diamino ester and β-lactam,
which are key structural motifs in many biologically active
compounds (Scheme 3).1b Thus, the anti-Mannich product,
which was obtained from the reaction between 1 and N-
Boc-protected imine derived from benzaldehyde, was converted to
the protected anti-α,β-diamino ester 4 by oxidation with NaClO2
followed by esterification with TMSCHN2 (60% yield over three
steps). Subsequent N-Boc deprotection and treatment of the
resulting β-amino ester 5 with TMSCl, triethylamine, and then
might be formed in the reaction catalyzed by (S)-3, the reaction of
E-s-cis-enamine with the activated N-Boc-protected imine at the
appropriate position (TS4) is faster than that of E-s-trans-
enamine with N-Boc-protected imine (TS3), giving the anti-
vicinal diamine predominantly.11,12
DFT calculations at the B3LYP/6-31G* level were also done
to address the observed stereoselectivities.15 The most favor-
able transition state is in accord with our previously mentioned
transition-state model TS4 for the Mannich reaction of 1
catalyzed by (S)-3 (Figure 2).16
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alkaloid, (−)-agelastatin A,18 which has a potent antitumor
activity, as shown in Scheme 5. Mannich product 8 was
converted to diene 9 by Nozaki−Hiyama−Takai−Kishi coupl-
ing with (E)-1-bromoprop-1-ene.19 After deprotection of the
Boc group of 9, amide 11 was formed under standard coupling
conditions. Treatment of 11 with Hoveyda−Grubbs second-
generation catalyst20 cleanly afforded cyclopentene 12,21 which
was converted in one pot to cyclopentanone 14 by 2-iodoxy-
benzoic acid (IBX) oxidation and the subsequent intra-
molecular conjugate addition of the pyrrole moiety.18g Since 14
was an intermediate in previous total synthesis of (−)-agelastatin
A by Ichikawa’s group,18g this work contributes to its formal
synthesis.
Scheme 3. Synthesis of α,β-Diamino Ester 4 and β-Lactam 6
In summary, we have developed a diastereo- and enantio-
selective direct Mannich reaction of N-protected amino-
acetaldehydes with N-Boc-protected imines catalyzed by
proline and the axially chiral amino sulfonamide (S)-3. This
organocatalytic process represents the first example of Mannich
reaction using Z or Boc-protected aminoacetaldehyde as new
entry of α-nitrogen functionalized aldehyde nucleophile in
enamine catalysis. The obtained optically active vicinal diamines
are useful chiral synthons as exemplified by the formal synthesis
of (−)-agelastatin A. Further investigations to expand the scope
of this and related reactions are currently underway.
t-BuMgCl gave β-lactam 6 (51% yield over two steps).17 In
addition, the anti-Mannich product was readily converted to α,β,γ-
triamine 7 with three different protecting groups by reductive
amination (Scheme 4).
Scheme 4. Synthesis of α,β,γ-Triamine 7
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure and spectral data for all new
compounds and computational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 5. Formal Total Synthesis of (−)-Agelastatin A
AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. R.S. thanks the Japan Society for
the Promotion of Science for Young Scientists for Research
Fellowships. We thank the Research Center for Computational
Science, Okazaki (Japan) for the use of their facility in our
computational studies.
REFERENCES
■
(1) (a) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 3161. (b) Viso,
A.; de la Pradilla, R. F.; García, A.; Flores, A. Chem. Rev 2005, 105,
3167. (c) Gonzal
2009, 38, 1916.
(2) For reviews on catalytic asymmetric diamination of aklenes, see:
́
ez-Sabín, J.; Rebolledo, F.; Gotor, V. Chem. Soc. Rev.
(a) Muniz, K. New J. Chem. 2005, 29, 1371. (b) Cardona, F.; Goti, A.
̃
Nat. Chem. 2009, 1, 269. (c) de Figueiredo, R. M. Angew. Chem., Int.
Ed. 2009, 48, 1190.
(3) For reviews on the synthesis of α,β-diamino acids, see:
(a) Gomez Arrayas, R.; Carretero, J. C. Chem. Soc. Rev. 2009, 38,
́ ́
1940. for a general review on the catalytic asymmetric synthesis of β-
amino acids, see: (b) Weiner, B.; Szymanski, W.; Janssen, D. B.;
Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656 ; see also
ref 1b.
(4) Representative catalytic asymmetric synthesis of vicinal diamines
and related compounds: (a) Nishiwaki, N.; Knudsen, K. R.; Gothelf,
K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992.
(b) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Further synthetic utility of the present Mannich reaction was
successfully demonstrated in the formal synthesis of a marine
7519
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Journal of the American Chemical Society
Article
Chem. 2003, 68, 2583. (c) Salter, M. M.; Kobayashi, J.; Shimizu, Y.;
Kobayashi, S. Org. Lett. 2006, 8, 3533. (d) Cutting, G. A.; Stainforth,
Hoboken, NJ, 2007. (b) Kumar, G. B.; Shah, A. C.; Pilati, T.
Tetrahedron Lett. 1997, 38, 3297.
(9) (a) Driguez, H.; Vermes, J.-P.; Lessard, J. Can. J. Chem. 1978, 56,
119. (b) Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org. Chem. 1988, 53,
3457.
N. E.; John, M. P.; Kociok-Kohn, G.; Willis, M. C. J. Am. Chem. Soc.
̈
2007, 129, 10632. (e) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (f) Yan, X.-X.; Peng,
Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc.
(10) To prevent isomerization, the Mannich product was treated
with NaBH4 in one pot and converted to the corresponding alcohol.
(11) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408.
́ ́ ́
2008, 130, 14362. (g) Hernandez-Toribio, J.; Gomez Arrayas, R.;
Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 16150. (h) Shang, D.; Liu,
Y.; Zhou, X.; Liu, X.; Feng, X. Chem.Eur. J. 2009, 15, 3678.
(i) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am.
(12) (a) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem., Int. Ed.
2009, 48, 1838. (b) Kano, T.; Yamaguchi, Y.; Maruoka, K. Chem.
Eur. J. 2009, 15, 6678. (c) Kano, T.; Song, S.; Kubota, Y.; Maruoka, K.
Angew. Chem., Int. Ed. 2012, 51, 1191.
(13) (a) Hanzlik, R. P.; Thompson, S. A. J. Med. Chem. 1984, 27, 711.
(b) Aboul-Fadl, T.; Rajeev, G.; Broom, A. D. J. Heterocyclic Chem.
2008, 45, 445.
(14) Lee, S.-H.; Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron 2001,
57, 2139.
(15) Frisch, M. J. et al. Gaussian 03, revision E.01; Gaussian Inc.:
Wallingford, CT, 2004.
Chem. Soc. 2010, 132, 4925. (j) Hernan
́ ́
dez-Toribio, J.; Gomez
Arrayas
́
, R.; Carretero, J. C. Chem.Eur. J. 2010, 16, 1153. (k) Lu, G.;
Yoshino, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2011, 50, 4382. (l) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren,
B.-Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am.
Chem. Soc. 2011, 133, 8428.
(5) Representative organocatalytic synthesis of vicinal diamines and
related compounds: (a) Ooi, T.; Kameda, M.; Fujii, J.; Maruoka, K.
Org. Lett. 2004, 6, 2397. (b) Okada, A.; Shibuguchi, T.; Ohshima, T.;
Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005,
44, 4564. (c) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.;
Shibasaki, M. Chem. Asian. J. 2007, 2, 794. (d) Singh, A.; Yoder, R. A.;
Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466.
(e) Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731.
(f) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866.
(g) Kobayashi, S.; Yazaki, R.; Seki, K.; Yamashita, Y. Angew. Chem., Int.
Ed. 2008, 47, 5613. (h) Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am.
Chem. Soc. 2008, 130, 10878. (i) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am.
Chem. Soc. 2008, 130, 14088. (j) Zhang, H.; Syed, S.; Barbas, C. F., III
Org. Lett. 2010, 12, 708. (k) Davis, T. A.; Wilt, J. C.; Johnston, J. N. J.
Am. Chem. Soc. 2010, 129, 2880. (l) Davis, T. A.; Johnston, J. N. Chem.
Sci. 2011, 1076.
(16) Some of the substrate functionalities have been omitted to
simplify the calculations. Other transition-state structures and
calculation data bearing on the reaction are described in the
Supporting Information.
(17) (a) Lynch, J. K.; Holladay, M. W.; Ryther, K. B.; Bai, H.; Hsiao,
C.-N.; Morton, H. E.; Dickman, D. A.; Arnold, W.; King, S. A.
Tetrahedron: Asymmetry 1998, 9, 2791. (b) De Risi, C.; Pollini, G. P.;
Veronese, A. C.; Bertolasi, V. Tetrahedron 2001, 57, 10155.
(18) Representative synthesis of agelastatin A: (a) Stien, D.;
Anderson, G. T.; Chase, C. E.; Koh, Y.-H.; Weinreb, S. M. J. Am.
Chem. Soc. 1999, 121, 9574. (b) Feldman, K. S.; Saunders, J. C. J. Am.
Chem. Soc. 2002, 124, 9060. (c) Hale, K. J.; Domostoj, M. M.; Tocher,
D. A.; Irving, E.; Scheinmann, F. Org. Lett. 2003, 5, 2927.
(d) Domostoj, M. M.; Irving, E.; Scheinmann, F.; Hale, K. J. Org.
Lett. 2004, 6, 2615. (e) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621.
(f) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(g) Ichikawa, Y.; Yamaoka, T.; Nakano, K.; Kotsuki, H. Org. Lett.
2007, 9, 2989. (h) Yoshimitsu, T.; Ino, T.; Tanaka, T. Org. Lett. 2008,
10, 5457. (i) Dickson, D. P.; Wardrop, D. J. Org. Lett. 2009, 11, 1341.
(j) Wehn, P. M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 3802.
(k) Hama, N.; Matsuda, T.; Sato, T.; Chida, N. Org. Lett. 2009, 11,
2687. (l) Movassaghi, M.; Siegel, D. S.; Han, S. Chem. Sci. 2010, 561.
(m) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. 2011,
13, 5744.
(19) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Jin, H.; Uenishi, J.; Christ, W. J.;
Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (c) Takai, K.; Tagashira,
M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc.
1986, 108, 6048.
(20) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(21) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973.
(6) Representative amine-catalyzed Mannich reactions of aldimines
or their analogues: (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(b) Cor
III J. Am. Chem. Soc. 2002, 124, 1842. (c) Cor
Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124,
1866. (d) Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem., Ind. Ed.
2004, 43, 6528. (e) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G.
Angew. Chem., Int. Ed. 2005, 44, 4079. (f) Franzen, J.; Marigo, M.;
́
dova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F.,
́
dova, A.; Watanabe, S.-I.;
́
́
Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296. (g) Mitsumori, S.; Zhang, H.; Cheong, P.
H.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006,
́
128, 1040. (h) Ibrahem, I.; Cordova, A. Chem. Commun. 2006, 1760.
(i) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
(j) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III J. Am. Chem.
Soc. 2006, 128, 9630. (k) Yang, J. W.; Stadler, M.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 609. (l) Cheng, L.; Han, X.; Huang, H.;
Wong, M. W.; Lu, Y. Chem. Commun. 2007, 4143. (m) Yang, J. W.;
Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453.
(n) Gianelli, C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2008, 47, 8700. (o) Hayashi, Y.; Okano, T.;
Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int.
Ed. 2008, 47, 9053. (p) Hahn, B. T.; Frohlich, R.; Harms, K.; Glorius,
̈
F. Angew. Chem., Int. Ed. 2008, 47, 9985 ; see also refs 12 and 13.
(7) A less electron-donating phthalimidoacetaldehyde has been
utilized as an aldehyde nucleophile having an α-nitrogen functional
group in the chiral amine-catalyzed aldol reaction and Michael
addition. See: (a) Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III
Org. Lett. 2004, 6, 3541. (b) Urushima, T.; Yasui, Y.; Ishikawa, H.;
Hayashi, Y. Org. Lett. 2010, 12, 2966. (c) Albertshofer, K.;
Thayumanavan, R.; Utsumi, N.; Tanaka, F.; Barbas, C. F., III
Tetrahedron Lett. 2007, 48, 693 ; see also ref 8.
(8) Phthalimido group is quite sensitive to nucleophilic reagents. For
instance, the phthalimido group of Mannich product obtained from
phthalimidoacetaldehyde and N-Boc protected imine was readily
reduced with NaBH4 to the corresponding hemiaminal. See
Supporting Information for detail and also: (a) Wuts, P. G. M.;
Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; Wiley:
7520
dx.doi.org/10.1021/ja301120z | J. Am. Chem. Soc. 2012, 134, 7516−7520