Synthesis of chiral vicinal diamines by highly diastereoselective three-component phenolic Mannich reaction: Temperature-dependent stereodivergency

Article abstract of DOI:10.1021/ol050334z

(Chemical Equation Presented) A diastereoselective three-component synthesis of chiral o-1,2-diaminoalkyl phenols from an electron-rich phenol, an amine, and a chiral α-N,N-dibenzylamino aldehyde is developed. The diastereoselectivity of this phenolic Man

Full text of DOI:10.1021/ol050334z

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1641-1644
Synthesis of Chiral Vicinal Diamines by
Highly Diastereoselective
Three-Component Phenolic Mannich
Reaction: Temperature-Dependent
Stereodivergency
Christophe Rondot and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received February 17, 2005
ABSTRACT
A diastereoselective three-component synthesis of chiral o-1,2-diaminoalkyl phenols from an electron-rich phenol, an amine, and a chiral
-N,N-dibenzylamino aldehyde is developed. The diastereoselectivity of this phenolic Mannich reaction is temperature-dependent,and either
anti or syn diastereomer can be prepared by controlling the reaction conditions. Low reaction temperature ( 20 C) favors the formation of
anti adduct 1, whereas higher temperature (60 C) under otherwise identical conditions produces mainly the syn isomer.
r
−
°
°
Chiral vicinal diamines are frequently found as a subunit in
a large number of bioactive natural products, biotin (vitamin
H) and penicillins being notable examples.1 This functionality
can also be found in various medicinally relevant compounds
including anticancer drugs such as 1,2-diaminoplatinum
complexes.2 In addition, the 1,2-diamine is also considered
as a privileged structural element3 in the search for chiral
catalysts.1,4
since the starting materials are readily available.5,6 A variety
of organometallic reagents have been successfully used, and
the diastereoselective Strecker reaction5 and Mannich reac-
tion5,7 have also been developed to reach a diverse set of
functionalized chiral diamines. Interestingly, while asym-
metric phenolic aldol reaction between chiral R-amino
aldehyde and phenol is well-known,8 the asymmetric phe-
nolic Mannich reaction or imino Friedel-Crafts reaction of
Many elegant synthetic routes have been developed to
obtain the chiral 1,2-diamine unit.1 Among them, nucleophilic
addition to R-N,N-dibenzylamino aldimine, amino oxime,
amino nitrone, and amino hydrazone is particularly attractive
(5) Reetz, M. T. Chem. ReV. 1999, 99, 1121-1162.
(6) For recent general reviews on the nucleophilic adition to imine, see:
(a) Enders, D.; Reinhold, U. Tetrahedon: Asymmetry 1997, 8, 1895-1946.
(b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. (c) Bloch,
R. Chem. ReV. 1998, 98, 1407-1438. (d) Alvaro, G.; Savoia, D. Synlett
2002, 651-673.
(1) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580-2627.
(7) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1045-1070.
(2) Reedijk, J. J. Chem. Soc., Chem. Commun. 1996, 801-806.
(3) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
(4) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, 2000; Vols. 1 and 2.
(8) (a) Casiraghi, G.; Cornia, M.; Rassu, G. J. Org. Chem. 1988, 53,
4919-4922. (b) De Paolis, M.; Blankenstein, J.; Bois-Choussy, M.; Zhu,
J. Org. Lett. 2002, 4, 1235-1238. (c) De Paolis, M.; Chiaroni, A.; Zhu, J.
J. Chem. Soc., Chem. Commun. 2003, 2896-2897.
10.1021/ol050334z CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

chiral R-amino aldimine was unknown.9,10 Indeed, the
reduced electrophilicity of imine in conjunction with its
higher tendency to undergo imine-enamine tautomerization
leading to racemization made this transformation particularly
challenging. In this regard, the elegant three-component
synthesis of chiral Betti base from phenol, aldehyde, and
chiral amine developed by the Chan group is a notable
exception.11,12 However, in this case, the chirality was
induced by the chiral amine, which is less prone to
racemization upon formation of iminium intermediate. We
report herein the first examples of diastereoselective three-
component synthesis of chiral o-1,2-diaminoalkyl phenols
(1, 2) from an amine (3), a chiral R-N,N-dibenzylamino
aldehyde (4), and a phenol (5) and document that both syn
and anti diastereomers are readily accessible in a stereose-
(OTf)3, BF3‚OEt2),17 additives (Na2SO4, tertiary amines,
molecular sieves 4 Å), and solvents (MeCN, CH2Cl2,
dichloroethane), the best conditions we found consisted of
performing the reaction in dichloromethane in the presence
of a catalytic amount of Yb(OTf)3 (0.1 equiv) and sodium
sulfate (Scheme 2). It is noteworthy that the same reaction
Scheme 2. Three-Component Synthesis of Diamino Phenol
lective fashion by simply changing the reaction temperature
13-15
(Scheme 1).
Diamines of type 1 and 2 are subunits of
Scheme 1. Stereoselective and Stereodivergent Syntheses of
Chiral o-1,2-Diaminoalkyl Phenols by a Three-Component
Phenolic Mannich Reaction
took place even in the absence of Lewis acid, albeit with a
longer reaction time and lower yield.18 Interestingly, the
diastereoselectivity was found to be temperature-dependent
(Table 1). At -20 °C, the reaction produced mainly the anti
Table 1. Three-Component Reaction of R-Naphthol,
Benzylamine, and L-R-N,N-Dibenzylaminophenylalaninal:
Temperature-Dependent Stereodivergencya
entry
T (°C)
reaction time (h)
yieldb (%)
1a/2ac
1
2
3
4
5
-20
0
20
20
60d
20
20
5
16
4
88
79
75
84
44
14/1
9/1
7/1
1/1
1/18
a Reaction was run in dichloromethane (concentration: 0.5 M) in the
presence of ytterbium triflate (0.1 equiv) and sodium sulfate. b Isolated yield
of major isomer. c Determined by analysis of 1H NMR spectrum. d The
reaction was performed in 1,2-dichloroethane.
a number of natural products such as cyanocycline C.16
The three-component condensation of benzylamine (3a),
L-R-N,N-dibenzylaminophenylalaninal (4a), and R-naphthol
(5a) was used as a model for the survey of reaction
conditions. After screening of catalysts (InCl3, Yb(OTf)3, Sc-
diastereomer (1a, entry 1, vide supra for the stereochemical
issue), the diastereoselectivity decreased as the temperature
went from -20 to 0 °C and to 20 °C. The reaction became
syn-selective when the same reaction was run at 60 °C (syn/
anti ) 18/1, entry 5). Carefully monitoring the reaction
course indicated that the anti/syn ratio is changing gradually
in favor of the syn adduct at 20 °C (entries 3 vs 4).
Furthermore, the control experiment shows that syn adduct
(2a) was produced by simply heating a CDCl3 solution of
diastereomerically pure anti adduct (1a). We thus speculated
that the temperature-dependent stereodivergency did not
(9) Diastereoselective Passerini reaction with chiral N,N-dibenzylamino
aldehyde: Cuny, G.; Gamez-Montano, R.; Zhu, J. Tetrahedron 2004, 60,
4879-4885.
(10) For a recent review, see: Bandini, M.; Melloni, A.; Umani-Ronchi,
A. Angew. Chem., Int. Ed. 2004, 43, 550-556.
(11) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem.
2003, 68, 1589-90.
(12) Phenolic Mannich reaction of phenol, formaldehyde, and racemic
amino acid has also been reported; see: Short, J. H.; Ours, C. W. J.
Heterocycl. Chem. 1975, 12, 869-876.
(13) Petasis, N. A. In Multicomponent Reactions with Organoboron
Compounds in Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 199-223.
(14) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Asymmetric Isocyanide-
based MCRs. In Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 1-32.
(17) (a) Kobayashi, S. Chem. Soc. ReV. 1999, 28, 1-15. (b) Kobayashi,
S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV. 2002, 102,
2227-2302.
(18) Scandium triflate-catalyzed three-component imino Friedel-Crafts
reaction: Huang, T.; Li, C.-J. Tetrahedron Lett. 2000, 41, 6715-6719.
(15) Seayad, J.; List, B. Catalytic Asymmetric Multicomponent Reactions
in Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, 2005; pp 277-299.
(16) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669-1730.
1642
Org. Lett., Vol. 7, No. 8, 2005

Table 2. Stereodivergent Three-Component Synthesis of Chiral o-1,2-Diaminoalkylphenols 1 and 2
entry 1
phenol
amine
R2 ) Bn (3a)
3a
3a
3a
3a
R-amino aldehyde
R1 ) CH2Ph (4a)
T (°C)
yielda (%)
anti/syn
1
2
3
4
5
6
7
8
R-naphthol (5a)
-20
60
-20
20
-20
-20
-20
-20
-20
-20
60
88
48
52
100
31
95
64
51
43
70
25
0
1a/2a ) 14/1
1a/2a ) 1/18
1b/2b ) 17/1
1b/2b ) 0/100
1c/2c ) 6/1
1d/2d ) 100/0
1e/2e ) 6/1
1f/2f ) 100/0b
1g/2g ) 6/1
5a
5a
5a
5a
5a
5a
4a
R1 ) Me (4b)
4b
R1 ) CH2OTBS (4c)
R1 ) CH2Ph (4a)
4a
4a
4a
4a
R2 ) TBSOCH2CH2 (3b)
R2 ) 4-MeO-phenyl (3c)
â-naphthol (5b)
4-MeO-1-naphthol (5c)
sesamol (5d)
3a
3a
3a
3a
3a
9
10
11
12
1h/2h ) 12/1
1h/2h ) 0/100
5d
5d
4a
N-Boc-phenylalaninal (4d)
rt
a Isolated yield of major diastereomer. b Addition occurred at C-1 position.
result from the change of the facile selectivity during the
nuclephilic addition of phenol to imine19 but was a conse-
quence of equilibrium of these two isomers.
level of N-substitution. The coupling constant (JH4-H5 ) 8.5
Hz)21 together with the observation of a NOE cross-peak
between the protons H-4 and H-5 of 7 and 8 indicated the
cis relationship of these two protons and, hence, the anti
stereochemistry of 1h. Similarly, the stereochemistry of 2h
(syn) was deduced from imidazolidinones 9 and 10 whose
The scope of this three-component phenolic Mannich
reaction is examined with various inputs including four
phenols, three amines, and four protected amino aldehydes
derived from phenylalanine, alanine, and serine, respec-
tively.20 As is seen from Table 2, the reaction was quite
general and gave either syn or anti adduct, depending on
the reaction temperature, in good chemical yield and good
to excellent diastereoselectivity. Functionalized amines such
as â-amino alcohol (3b) as well as 4-methoxyaniline (3c)
took part in this reaction. However, secondary amine failed
to produce the desired phenolic Mannich base (data not
shown). As expected, only electron-rich phenol can partici-
pate in this reaction to afford the desired adduct. While N,N-
dibenzylamino aldehyde was initially selected on the basis
of the diastereoselectivity issue, it turns out that the N-
protective group played a decisive role for the present
Mannich reaction since no reaction took place with L-N-Boc
phenylalanal (4d, entry 12) under otherwise identical condi-
tions.
Scheme 3. Determination of Relative Stereochemistry and
Enantiomeric Purity of Adducts 1h and 2h
The stereochemistry of the syn and anti adducts was
determined by their conversion to the rigid imidazolidinones
(Scheme 3). Thus, treatment of 1h with triphosgene in the
presence of triethylamine produced the cyclic carbamate 6.
Interestingly, when 6 was submitted to hydrogenolysis
conditions (H2, Pd(OH)2, MeOH), a sequence of partial
debenzylation followed by transacylation occurred to afford
directly two imidazolidinones 7 and 8, differing only in the
(19) Yb(OTf)3 may coordinate to imino nitrogen. However, we surmised
that five-membered chelate was not formed under our reaction conditions.
(20) Synthesized following literature precedents: (a) Beaulieu, P. L.;
Wernic, D.; J. Org. Chem. 1996, 61, 3635-3645. (b) La¨ıb, T.; Chastanet,
J.; Zhu, J. J. Org. Chem. 1998, 63, 1709-1713.
(21) Cortes, S.; Kohn, H. J. Org. Chem. 1983, 48, 2246-2254.
Org. Lett., Vol. 7, No. 8, 2005
1643

spectroscopic property (JH4-H5 ) 5.5 Hz, NOE: H-4/H-6)
is in accord with the trans stereochemistry. The enantio-
merical purity of 7, hence that of 1h, was determined to be
higher than 93% by its transformation to the diastereomeric
mandelates 11 and 12.22 This result demonstrated that little,
if any, racemization occurred during the present phenolic
Mannich and subsequent transformations.
While the nucleophilic addition of phenol onto the N,N-
dibenzylaminoaldimine leading predominantly to the anti
adduct is readily explained on the basis of the Felkin-Ahn
model,23 the facile isomerization of anti to syn adduct is
intriguing. Two crossover experiments were performed in
order to probe the mechanism of epimerization (Scheme 4).
responsible for the therml isomerization of 1 to 2. On the
other hand, heating a DCE solution of 1a and 4-methoxy-
benzylamine (3d, 2 equiv) led not only to the formation of
syn adduct 2a but also to 2i in which the 4-methoxybenzy-
lamine was incorporated (Scheme 4). On the basis of this
observation, the following mechanistic hypothesis was
advanced to account for thermal isomerization: 1,4-elimina-
tion of the benzylic amine assisted by the neighboring
phenoxyl group and possibly the basicity of the benzylamino
function that may act as an internal base would provide the
o-quinone methide intermediate 13. Michael addition of
available amine onto 1324 according, once again, to the
Felkin-Ahn model would give the observed syn adduct 2.
In summary, we reported a three-component synthesis of
chiral o-1,2-diaminoalkylphenol from readily available start-
ing materials. The synthesis is diastereoselective and ste-
reodivergent allowing the access to four possible enantiomers
by simply changing the absolute configuration of the amino
aldehyde and reaction temperature. It represents one of the
shortest routes to access this type of chiral entity.
Scheme 4. Mechanistic Hypothesis for the Thermal
Isomerization of Anti Adduct 1 to Syn Adduct 2
Acknowledgment. Financial support from CNRS and a
doctoral fellowship from this institute to C.R. are gratefully
acknowledged.
Supporting Information Available: Experimental details
and physical data for compounds 1-12. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050334Z
(22) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59,
4202-4205. (b) Helmchen, G.; Ott, R.; Sauber, K. Tetrahedron Lett. 1972,
3873-3878.
(23) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205-
2208.
(24) Recent examples of formation/trapping of ortho-quinone methide:
(a) Van de Water, R. W.; Magdziak, D. J.; Chau, J. N. C.; Pettus, T. R. R.
J. Am. Chem. Soc. 2000, 122, 6502-6503. (b) Lindsley, C. W.; Chan, L.
K.; Goess, B. C.; Joseph, R.; Shair, M. D. J. Am. Chem. Soc. 2000, 122,
422-423. (c) Pande, P.; Shearer, J.; Yang, J.; Greenberg, W. A.; Rokita,
S. E. J. Am. Chem. Soc. 1999, 121, 6773-6779. (d) Angle, S. R.; Rainier,
J. D.; Woytowicz, C. J. Org. Chem. 1997, 62, 5884-5892.
Heating a 1,2-dichloroethane (DCE) solution of anti adduct
(1a) and sesamol (5d) to 60 °C afforded only the anti isomer
2a without concurrent formation of 1h or 2h indicating that
retro-Mannich reaction did not take place and was not
1644
Org. Lett., Vol. 7, No. 8, 2005