Catalytic asymmetric desymmetrization of meso-diamide derivatives through enantioselective N-allylation with a chiral π-allyl Pd catalyst: Improvement and reversal of the enantioselectivity

Article abstract of DOI:10.1021/jo052488y

In the presence of the Trost ligands-Pd catalysts, N-monoallylation of bis(2,4,6-triisopropylbenzne)sulfonylamides derived from meio-1,2-diamines proceeds with good to excellent enantioselectivity (85-96% ee) to give asymmetric desymmetrization products.

Full text of DOI:10.1021/jo052488y

1,2-diamine bistrisylamides 1 using a chiral π-allyl Pd catalyst
Catalytic Asymmetric Desymmetrization of
meso-Diamide Derivatives through
(eq 1).4,5 This reaction proceeded in the presence of (allyl-Pd-
Enantioselective N-Allylation with a Chiral
π-Allyl Pd Catalyst: Improvement and Reversal
of the Enantioselectivity
Osamu Kitagawa, Shinichi Matsuo, Kanako Yotsumoto, and
Takeo Taguchi*
Tokyo UniVersity of Pharmacy and Life Science, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan
taguchi@ps.toyaku.ac.jp; kitagawa@ps.toyaku.ac.jp
ReceiVed December 2, 2005
Cl)2 and (R,R)-Trost ligand to give N-monoallylated (asymmetric
desymmetrization) products 2 in 71-90% ee. We also succeeded
in the conversion of asymmetric desymmetrization product 2a
[R ) R ) (CH2)4] to σ-receptor agonist 3 (eq 1).3a The present
reaction is the first example of asymmetric desymmetrization
with meso-diamine derivatives.6,7 In addition, it should be
noteworthy that among transition metal-catalyzed N-C bond-
forming reactions, this reaction is a rare example of asymmetric
induction at the nitrogen nucleophile site (enantiocontrol of
prochiral nitrogen nucleophile).8 In this paper, we report the
improvement of the enantioselectivity by screening the Trost
In the presence of the Trost ligands-Pd catalysts, N-
monoallylation of bis(2,4,6-triisopropylbenzne)sulfonyl-
amides derived from meso-1,2-diamines proceeds with good
to excellent enantioselectivity (85-96% ee) to give asym-
metric desymmetrization products. Under the same condi-
tions, in the reaction with meso-bistolunesulfonylamide
derivatives, reversal of the enantioselectivity is observed.
(3) (a) Radesca, L.; Bowen, W. D.; Paolo, L. D.; De Costa, B. R. J.
Med. Chem. 1991, 34, 3058. (b) De Costa, B. R.; Dominguez, C.; He, X.;
Williams, W.; Radesca, L.; Bowen, W. J. Med. Chem. 1992, 35, 4334. (c)
Novakova, M.; Ela, C.; Bowen, W. D.; Hasin, Y.; Eilam, Y. Eur. J.
Pharmacol. 1998, 353, 315. (d) Hong, W.; Werling, L. L. Eur. J. Pharmacol.
2002, 436, 35. (e) Govindaraju, T.; Gonnade, R. G.; Bhadbhade, M. M.;
Kumar, V. A.; Ganesh, K. N. Org. Lett. 2003, 5, 3013. (f) Govindaraju, T.;
Kumar, V. A.; Ganesh, K. N. J. Org. Chem. 2004, 69, 5725. (g) Govindaraju,
T.; Kumar, V. A.; Ganesh, K. N. J. Am. Chem. Soc. 2005, 127, 4144.
(4) Kitagawa, O.; Yotsumoto, K.; Kohriyama, M.; Dobashi, Y.; Taguchi,
T. Org. Lett. 2004, 6, 3605.
(5) For reviews on catalytic asymmetric allylation with a chiral π-al-
lylpalladium complex see: (a) Hayashi, T. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1994; pp 325-
365. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(6) To the best of our knowledge, there has been no report on asymmetric
desymmetrization of meso-diamine derivatives. In the reaction with diamine
substrates, the enantiocontrol may be difficult because of high nucleophilicity
of the amino group and the strong ability to chelate with transition metal,
which may result in dissociation of the chiral ligand from the catalytic center
and deactivation of the catalyst.
(7) In contrast to diamine derivatives, catalytic asymmetric desymme-
trization of meso-diols has been well-known. (a) Vedejs, E.; Daugulis, O.;
Diver, S. T. J. Org. Chem. 1996, 61, 430. (b) Oriyama, T.; Imai, K.; Sano,
T.; Hosoya, T. Tetrahedron Lett. 1998, 39, 397. (c) Kawabata, T.; Stragies,
R.; Fukuya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron Lett. 2003,
44, 1545. (d) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am.
Chem. Soc. 2003, 125, 2052. (e) Trost, B. M.; Mino, T. J. Am. Chem. Soc.
2003, 125, 2410. (f) Shimizu, H.; Katsuki, T. Chem. Lett. 2003, 32, 480.
(g) Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I. Angew. Chem.,
Int. Ed. 2003, 42, 3383. (h) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.;
Sigman, M. S. J. Org. Chem. 2003, 68, 4600. (i) Mizuta, S.; Tsuzuki, T.;
Fujimoto, T.; Yamamoto, I. Org. Lett. 2005, 7, 3633. (j) For a review see:
Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765.
Organic compounds possessing a diamine functionality have
played an important role in the field of medicinal and synthetic
chemistry.1 Various optically active synthetic diamine deriva-
tives have been employed as chemotherapeutic agents or as
chiral ligands for asymmetric reaction.1 Accordingly, numerous
synthetic methods for optically active diamine derivatives have
been developed,1 while the asymmetric synthesis of these
diamine derivatives through a catalytic enantioselective reaction
has been limited to only a few examples.2 Especially, until now
catalytic asymmetric synthesis of chiral cyclic syn-diamines such
as unsymmetrical cis-1,2-diaminocycloalkanes has been uncom-
mon. It is also noted that chiral compounds possessing a cis-
1,2-diaminocyclohexane and -cyclopentane skeleton have re-
ceived attention as potent medicinal agents.3
Recently, we found a new method for the preparation of
optically active unsymmetrical cis-1,2-diaminocycloalkane de-
rivatives through enantioselective N-monoallylation of meso-
* Address correspondence to this author. FAX and phone: +81-426-76-3257.
(1) (a) Michalson, E. T.; Szmuszkovicz, J. Prog. Drug Res. 1989, 33,
135. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
(2) (a) Li, Z.; Ferna´ndez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611.
(b) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001, 980. (c) Ooi, T.;
Sakai, D.; Takeuchi, M.; Tayama, E.; Maruoka, K. Angew. Chem., Int. Ed.
2003, 42, 5868. (d) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003,
125, 11836. (e) Chune, D.; Alper, H. Tetrahedron: Asymmetry 2004, 15,
1537.
(8) (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002,
67, 8682. (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003,
14, 587. (c) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J.
Am. Chem. Soc. 2005, 127, 3676.
10.1021/jo052488y CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/18/2006
2524
J. Org. Chem. 2006, 71, 2524-2527

We found that the enantioselectivity can be improved by
further survey of the Trost ligands (A-C, Figure 1).9 That is,
the reaction of cyclohexanediamide 1a with Trost ligand B
having a phosphinonaphthyl group gave N-monoallylated prod-
uct 2a in higher enantioselectivity (93% ee, entry 2 in Table
1), while in the case of ligand C possessing a 1,2-diphenyleth-
ylenediamine skeleton, a considerable decrease in the enantio-
selectivity was observed (71% ee, entry 3). The improvement
of the enantioselectivity by using Trost ligand B was also
realized in the reaction with other meso-1,2-diamide derivatives
1b and 1c (entry 4 vs 5, entry 6 vs 7). In these reactions, the
products 2b and 2c were obtained in 85% ee and 96% ee,
respectively (entries 5 and 7). Although the ee was not high
with cyclohexane-1,3-diamide 1d (57% ee, entry 9), the increase
in the enantioselectivity was clearly remarkable (entry 8 vs 9).
Unfortunately, in the reaction of 2-siloxy-1,3-diaminopropane
1e, the use of Trost ligand B was not effective. In this case, in
comparison with Trost ligand A, a slight decrease in the
enantioselectivity was observed (entry 11 vs 12). Since the
enantioselectivity was strongly influenced by the reaction
temperature, the temperature control shown in Table 1 was
required.
FIGURE 1. Several types of Trost ligand.
TABLE 1. Asymmetric Desymmetrization of Various
meso-Diamides through Catalytic Enantioselective N-Allylation
Next, we investigated the reversal of the enantioselectivity
by a sulfonyl substituent on a nitrogen atom. The N-monoal-
lylaion of bistrisylamides 1a-1c with (R,R)-Trost ligands A-C
gave (1R,2S)-2a-c as major enantiomers (entries 1-7 in Table
1). Contrary to these, under similar conditions with (R,R)-Trost
ligand A, in the reaction of 4-tosylamide 1f and 2-nosylamide
1g, (1S,2R)-isomeres of 2f and 2g were obtained as the major
enantiomers (2f 52% ee, 2g 69% ee, entries 1 and 4 in Table
2).4 To elucidate the origin of the difference of the enantio-
selectivity by the sulfonyl substituent, the reactions with several
sulfonylamide derivatives were further examined with (R,R)-
Trost ligand A (entries 6, 8, and 10 in Table 2). The reaction of
benznensulfonylamide 1h gave the product 2h with the same
enantioselectivity (1S,2R) and similar ee (50% ee) as in the case
of 4-tosyl derivative 1f (entry 6). With 2-tosyl derivative 1i,
(1S,2R)-2i was obtained in poor enantioselectivity (7% ee, entry
8). The reaction of mesityl derivative 1j proceeded in the
opposite enantioselectivity from those of 1f-i (same enantio-
selectivity as that of trisyl derivative 1a) to give (1R,2S)-2j in
26% ee (entry 10). Although the effect of the 2-nosyl group in
the reaction of 1g is still obscure, these results may indicate
the importance of an o-alkyl substituent for (1R,2S)-selectivity.
a Isolated yield. b The ee was determined by HPLC analysis with use of
a chiral column. c CH2Cl2 was used as a solvent. d The absolute configu-
ration of the major enantiomer was not determined. e The ee and the
chemical yield of a hydroxy derivative that was obtained after removal of
the TBS group are shown.
The best (1S,2R)-selectivity was obtained through the reaction
of 4-tosyl derivative 1f with Trost ligand B (entry 2 in Table
2). In this case, the desymmetrization product (1S,2R)-2f was
obtained in 73% ee (at room temperature). Furthermore, when
the reaction was conducted at lower temperature (-15 to -10
°C), the ee of the desymmetrization product 2f increased to 85%
(eq 2). Both trisyl-product 2a and tosyl-product 2f can be
converted to optically active N-allyl-1,2-diaminocyclohexane 4
(Scheme 1) by desulfonylation with use of Birch reduction.4,10
Therefore, both enantiomers of 4 with high enantioselectivity
(93% ee and 85% ee) can be obtained through the reaction of
1a and 1f with use of the same chiral ligand (avoiding the use
of both enantiomers of the chiral ligand).11 Such reversal of
ligands, and the reversal of the enantioselectivity by a sulfonyl
substituent on a nitrogen atom.
As described in our previous paper,4 the use of Trost ligand
as a chiral phosphine and trisyl (2,4,6-triisopropylbenznesulfonyl
) Trs) group as a sulfonyl substituent on a nitrogen atom was
essential for the achievement of good enantioselectivity. For
example, in the presence of the standard Trost ligand (0.073
equiv, Trost ligand A in Figure 1), (allyl-PdCl)2 (0.036 equiv),
allyl acetate (1 equiv), and t-BuOK (1 equiv), the reaction with
bistrisylamides 1a and 1c of meso-1,2-diaminocyclohexane and
meso-1,2-diphenylethylenediamine gave the desymmetrization
products 2a and 2c with good enantioselectivity (both 90% ee,
entries 1 and 6 in Table 1).4 On the other hand, under the same
conditions, with 1,2-diaminocyclopentane 1b and 1,3-diamine
derivatives 1d and 1e, moderate or poor enantioselectivity was
observed (2b 71% ee, 2d 18% ee, 2e 27% ee, entries 4, 8, and
11 in Table 1).4
(9) (a) Trost, B. M.; Vranken, D. L. V.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327. (b) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew.
Chem., Int. Ed. 2002, 41, 3492.
(10) Neipp, C. E.; Humphrey, J. M.; Martin, S. F. J. Org. Chem. 2001,
66, 531.
J. Org. Chem, Vol. 71, No. 6, 2006 2525

SCHEME 2. Determination of Absolute Configuration of 2ka
TABLE 2. Substituent Effect of the Sulfonyl Group on the
Nitrogen Atom
a Reagents and conditions: (a) CF3COOH, CH2Cl2, rt; (b) Ts-Cl, Et3N,
THF, rt, 63% (2 steps); (c) 10% Pd-C/H2, CH3OH, rt; (d) allyl bromide,
K2CO3, THF, 60 °C; (e) Ts-Cl, Et3N, THF, 60 °C, 25% (3 steps).
SCHEME 3. Determination of Absolute Configuration of 2ba
a Reagents and conditions: (f) Na, liquid NH3; (g) Ts-Cl, Et3N, THF,
60 °C, 16% (2 steps).
SCHEME 4. Determination of Absolute Configuration of 2ca
a Isolated yield. b The ee was determined by HPLC analysis with use of
a chiral column.
a Reagents and conditions: (a) Trs-Cl, Et3N, THF, rt, 75%; (b) NaH,
Ms-Cl, THF, rt, 69%; (c) TMS-N3, TBAF, THF, 50 °C, 97%; (d) t-BuOK,
(allyl-Pd-Cl)2, dppe, allyl acetate, toluene-dioxane, 0 °C, 72%; (e) Ph3P,
H2O, THF, rt, 36%; (f) Trs-Cl, Et3N, dioxane, 100 °C, 26%.
tosyl derivative 2f (Scheme 1).12 Those of cyclopentane deriva-
tives 2b and 2k and 1,2-diphenylethylenediamine derivative 2c
were confirmed by the direct comparison with authentic samples
prepared from the known azide alcohol 5 and amino alcohol 8,
respectively (Schemes 2,3f 3,12 and 4).
In conclusion, we have succeeded in the improvement of the
enantioselectivity in the catalytic asymmetric N-monoallylation
of meso-bissulfonamides by screening the Trost ligands. Fur-
thermore, we found a remarkable reversal of the enantioselec-
tivity by the sulfonyl substituent on the nitrogen atom. The
present reaction should provide a new methodology for the
preparation of optically active unsymmetrical cis-1,2-diami-
nocycloalkane derivatives. In addition, the present reaction
should be notable as a rare example of asymmetric induction
at the nitrogen nucleophile site in transition metal-catalyzed
SCHEME 1. Determination of Absolute Configuration of
2h-2ja
a Reagents and conditions: (a) Na, liquid NH3; (b) Ts-Cl, Et3N, THF,
60 °C, 9-21% (2 steps).
the enantioselectivity was also observed in the reaction with
1,2-diaminocyclopentane derivatives. That is, the reaction of
1b and 1k with (R,R)-Trost ligand B gave (1R,2S)-2b and
(1S,2R)-2k in 85% ee and 43% ee, respectively (entry 5 in Table
1, eq 2), while the ee values are lower than those of cyclohexane
derivatives 2a and 2f. Unfortunately, the reaction with bis-
tosylamide of 1,2-diphenylethylenediamine failed because of
its extremely low solubility in various organic solvents.
The stereochemical assignment of the products 2a, 2f, and
2g was already described in the previous paper.4 The absolute
configurations of 2h-j were determined by the conversion to
(11) For recent examples in relation to the switch of enantioselectivity
by the use of the same chiral ligand, see: (a) Sibi, M. P.; Shay, J. J.; Liu,
M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (b) Kobayashi, S.;
Kusakabe, K.; Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220.
(c) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908.
(d) Wilkinson, J. A.; Rossington, S. B.; Leonard, J.; Hussein, N. Tetrahedron
Lett. 2004, 45, 1191. (e) Du, D.; Lu, S.; Fang, T.; Xu, J. J. Org. Chem.
2005, 70, 3712. (f) Desimoni, G.; Faita, G.; Guala, M.; Laurenti, A.; Mella,
M. Chem. Eur. J. 2005, 11, 3816.
(12) The reaction conditions in the conversion of Schemes 1 and 3 were
not optimized, while as described in our previous paper,4 similar conversion
with trisyl derivative 2a gave 4f in 46% yield.
2526 J. Org. Chem., Vol. 71, No. 6, 2006

(hexane/AcOEt ) 30) gave 2a (175 mg, 85%). The ee (93% ee) of
2a was determined by HPLC analysis, using a CHIRALCEL OD-H
column [25 cm × 0.46 cm i.d.; 1% i-PrOH in hexane; flow rate,
0.5 mL/min; (+)-2a (minor), tR ) 11.8 min; (-)-2a (major), tR )
N-C coupling and as the first example of asymmetric desym-
metrization with meso-diamine derivative.
Experimental Section
1
14.4 min]. H NMR data for 2a coincided with those reported in
our previous paper.4
General Procedure of Catalytic Asymmetric N-Allylation
with (R,R)-Trost Ligand-Pd Catalyst. Under Ar atmosphere, to
a suspension of t-BuOK (34 mg, 0.3 mmol) in toluene (1.5 mL)
was added diamide 1a (194 mg, 0.3 mmol). After the solution was
stirred for 5 min at room temperature, allylpalladium chloride dimer
(4 mg, 0.011 mmol), (R,R)-Trost ligand B (17 mg, 0.022 mmol),
and allyl acetate (33 µL, 0.3 mmol) in 1,4-dioxane (1.5 mL) were
added to the mixture at -15 °C, and then the reaction mixture was
stirred for 14 h from -15 to -10 °C. The mixture was poured into
2% HCl solution and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
Acknowledgment. We are grateful to Prof. Barry M. Trost
for helpful suggestions regarding the Trost ligands.
Supporting Information Available: Experimental procedures
and spectral data for all new compounds; 1H and 13C NMR spectra
of new compounds (2j, 2k, 7) with no elemental analysis. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052488Y
J. Org. Chem, Vol. 71, No. 6, 2006 2527