Organocatalytic sequential α-amination-Horner-Wadsworth-Emmons olefination of aldehydes: Enantioselective synthesis of γ-amino-α, β-unsaturated esters

Article abstract of DOI:10.1021/ol063012j

(Chemical Equation Presented) A novel and highly enantioselective method for the synthesis of γ-amino-α,β-unsaturated esters via tandem α-amination-Horner-Wadsworth-Emmons (HWE) olefination of aldehydes is described. The one-pot assembly has been demonstr

Full text of DOI:10.1021/ol063012j

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1001-1004
Organocatalytic Sequential
-Amination Horner Wadsworth−Emmons
Olefination of Aldehydes:
r
−
−
Enantioselective Synthesis of
γ
-Amino-r,â-Unsaturated Esters
Shriram P. Kotkar, Vilas B. Chavan, and Arumugam Sudalai*
Chemical Engineering and Process DeVelopment DiVision, National Chemical
Laboratory, Pashan Road, Pune 411 008, India
a.sudalai@ncl.res.in
Received December 13, 2006
ABSTRACT
A novel and highly enantioselective method for the synthesis of γ-amino-r,â-unsaturated esters via tandem r-amination−Horner−Wadsworth−
Emmons (HWE) olefination of aldehydes is described. The one-pot assembly has been demonstrated for the construction of functionalized
chiral 2-pyrrolidones, subunits present in several alkaloids.
Chiral allylic amines, particularly γ-amino-R,â-unsaturated
esters 3, are the key structural elements present in a variety
of important naturally occurring molecules1 and are among
the most versatile synthetic intermediates for peptide deriva-
tives,2 iminosugars,3 glutamate receptors,4 amino acids,5
alkaloids,6 carbohydrate derivatives,7 etc., possessing various
biological activities such as enzyme inhibitors.1a,7 Moreover,
they are readily functionalized to aminodiols,8amino epoxy
esters,9 etc. Few general methods of synthesis are described
in the literature to obtain enantiomerically pure γ-amino-
R,â-unsaturated esters,10,11 and most of them employ Wittig
olefination of R-amino aldehydes that are usually prepared
from naturally occurring R-amino acids. However, these
methods are limited by the possibility that racemization may
(1) (a) Fusetani, N.; Matsunaga, S.; Matsumoto, H.; Takebayashi, Y. J.
Am. Chem. Soc. 1990, 112, 7053. (b) Coleman, J. E.; de Silva, E. D.; Kong,
F.; Andersen, R. J.; Allen, T. M. Tetrahedron 1995, 51, 10653.
(2) (a) Thoen, J. C.; Morales-Ramos, A. I.; Lipton, M. A. Org. Lett.
2002, 4, 4455. (b) Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden,
A. J. Org. Chem. 2001, 66, 4180. (c) Broady, S. D.; Rexhausen, J. E.;
Thomas E. J. J. Chem. Soc., Perkin Trans. 1 1999, 1083.
(3) Hulme, A. N.; Montgomery, C. H. Tetrahedron Lett. 2003, 44, 7649.
(4) (a) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron 2002, 58, 9359.
(b) Dauban, P.; Saint-Fuscien, C. D.; Acher, F.; Prezeau, L.; Brabet, I.;
Pin, J.; Dodd, R. H. Bioorg. Med. Chem. Lett. 2000, 10, 129. (c) Dauban,
P.; Saint-Fuscien, C. D.; Dodd, R. H. Tetrahedron 1999, 55, 7589.
(5) (a) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.;
Yanagi, K. J. Am. Chem. Soc. 1989, 111, 6301. (b) Jumnah, R.; Williams,
J. M. J.; Williams, A. C. Tetrahedron Lett. 1993, 34, 6619. (c) Bower, J.
F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J. Chem. Soc., Perkin
Trans. 1 1997, 1411. (d) Burgess, K.; Liu, L. T.; Pal, B. J. Org. Chem.
1993, 58, 4758.
(6) (a) Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta, W. B.
Tetrahedron 1995, 51, 11087. (b) Trost, B. M. Angew. Chem., Int. Ed. 1989,
28, 1173.
(7) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115,
444.
(8) (a) Oh, J. S.; Jeon, J.; Park, D. Y.; Kim, Y. G. Chem. Commun.
2005, 770. (b) Reetz, M. T.; Strack, T. J.; Mutulis, F.; Goddard, R.
Tetrahedron Lett. 1996, 37, 9293.
(9) Yoo, D.; Kim, H.; Kim, Y. G. Synlett 2005, 1707.
(10) (a) Wei, Z-Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569. (b) Wei,
Z.-Y.; Knaus, E. E. Tetrahedron Lett. 1994, 35, 2305. (c) Rubsam, F.; Evers,
A. M.; Michel, C.; Giannis, A. Tetrahedron 1997, 53, 1707. (d) Thoen, J.
C.; Morales-Ramos, A. I.; Lipton, M. A. Org. Lett. 2002, 4, 4455. (e)
Koskinen, A. M. P.; Otsomaa, L. A. Tetrahedron 1997, 53, 6473.
(11) (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149. (b)
Gryko, D.; Chalko, J.; Jurczak, J. Chirality 2003, 514 and references cited
therein.
10.1021/ol063012j CCC: $37.00
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Published on Web 02/13/2007

occur during the Wittig reaction.12 For these reasons, a
general synthetic process which employs readily available
starting materials and overcomes the above difficulties is still
desirable for obtaining chiral γ-amino-R,â-unsaturated esters,
3.
Scheme 1. In Situ Trapping of R-Amino Aldehydes with
Triethyl Phosphonoacetate
Organocatalysis is a rapidly growing research field in
organic synthesis and has the advantage of being highly
selective and reducing synthetic manipulations.13 It is often
associated with mild and simple reaction conditions that are
appealing because of the easy handling, cost, and safety
issues. In recent years, proline has been employed in a variety
of asymmetric reactions including aldol,14 Diels-Alder,15
Michael addition,16 and R-functionalization17 among many
others.13b,18 Particularly, proline-catalyzed direct R-amination
of aldehydes has emerged as a reliable method for the
enantioselective synthesis of R-amino acid derivatives.19
In proline-catalyzed direct R-amination of aldehydes, the
reactive intermediate 2, generated in situ, was transformed
into several functionalized organic derivatives: for instance,
it was reduced to 1,2-aminoalcohol,19a cyclized by intramo-
lecular Wittig olefination to 3,6-dihydropyridazines,20a or
condensed under aldol conditions to form functionalized
â-amino alcohols.20b As part of our research program directed
toward asymmetric synthesis of biologically active molecules
using organocatalysts,21 we designed experiments in trapping
the intermediate 2 with triethyl phosphonoacetate to obtain
the corresponding chiral γ-amino-R,â-unsaturated esters 3
(Scheme 1). In this communication, we describe a one-pot
procedure for obtaining highly enantioselective synthesis of
γ-amino-R,â-unsaturated esters 3 using tandem R-amina-
tion-Horner-Wadsworth-Emmons (HWE) olefination of
aldehydes 1 (Scheme 1).
In the preliminary study, R-amination of n-butyraldehyde
was conducted following List’s protocol19a to obtain R-amino
aldehyde 2 in situ. Because these R-amino aldehydes are
prone to racemization,12 we performed several experiments
to identify the most effective and suitable base for HWE
olefination. First, the in situ olefination of 2 was carried out
by the addition of triethyl phosphonoacetate (1.5 equiv) and
Cs2CO322 (1 equiv) that produced 3a in 80% yield with low
enantioselectivity (22% ee), probably due to racemization
caused by the base. However, improvements in ee’s (88%)
were achieved by screening of other bases, particularly DBU
(Masamune-Roush protocol)23 (Table 1, entries 2 and 3).
Table 1. Proline-Catalyzed R-Amination/HWE Olefination of
n-Butyraldehyde
entry
basea
temp (°C) time (min) yieldb (%) eec (%)
(12) R-Amino aldehydes are often susceptible to racemization: (a)
Fehrentz, J. A.; Castro, B. Synthesis 1983, 676. (b) Rettle, K. E.; Homnick,
C. F.; Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47, 3016. (c)
Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110, 7447.
(13) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c)
Houk, K. N.; List, B. Acc.Chem. Res. 2004, 37, 487. (d) List, B., Bolm, C.,
Eds. AdV. Synth. Catal. 2004, 346. (e) List, B.; Seayad, J. Org. Biomol.
Chem. 2005, 3, 719.
1
2
3
4
Cs2CO3
Ba(OH)2
DBU
25
25
25
5
120
120
120
45
80
78
87
84
22
67
88
99
DBU
a
b
LiCl (1.5 equiv) was used in the case of DBU. Yield of isolated
product after column chromatography. c Enantiomeric excess was determined
by chiral HPLC analysis (Chiracel OD-H, hexane/2-propanol ) 96:4).
(14) (a) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A.
Angew. Chem., Int. Ed. 2005, 44, 1343. (b) List, B.; Lerner, R. A.; Barbas,
C. F., III J. Am. Chem. Soc. 2000, 122, 2395.
(15) (a) Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. AdV. Synth.
Catal. 2005, 347, 1353. (b) Ramachary, D. B.; Chowdari, N. S.; Barbas,
C. F., III Synlett 2003, 1910.
(16) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
43, 3958.
(17) For R-functionalization reviews: (a) Franzen, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296. (b) Guillena, G.; Ramon, D. J. Tetrahedron:
Asymmetry 2006, 17, 1465.
Because of the epimerizable nature of R-amino aldehydes,
we believed that a shorter reaction time and lower temper-
ature should prevent racemization without compromising on
the yields. Expectedly, by performing the reaction at 5 °C
for 45 min, 3a was indeed obtained in 84% yield with
excellent enantioselectivity (99% ee) (Table 1).
We examined the scope of several aldehydes bearing
different functionalities under the optimized reaction condi-
tions.24 In all cases studied, the desired γ-amino-R,â-
unsaturated esters 3a-f were obtained in excellent yields
(80-88%) and enantioselectivities (92-99%) (Table 2).
However, use of other solvents such as THF and CH2Cl2
for the tandem protocol resulted in a sluggish reaction with
poor yields (<50%).
(18) (a) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785. (b) Fonseca, M. T. H.; List, B. Angew. Chem., Int.
Ed. 2004, 43, 3958. (c) For a review of proline-catalyzed asymmetric
reactions, see: List, B. Tetrahedron 2002, 58, 5573.
(19) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (b) Bogevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790. (c) Kumaragurubaran, N.; Juhl, K.; Zhuang,
W.; Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (d)
Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448.
(20) (a) Oelke, A. J.; Kumarn, S.; Longbottom, D. A.; Ley, S. V. Synlett
2006, 2548. (b) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III Org.
Lett. 2003, 5, 1685.
(21) (a) Kotkar, S. P.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6813. (b)
Narina, S. V.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6799. (c) Kotkar, S.
P.; Sudalai, A. Tetrahedron: Asymmetry 2006, 17, 1738.
(22) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637.
(23) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
1002
Org. Lett., Vol. 9, No. 6, 2007

to produce the corresponding aminodiol 4 (92% yield), which
was hydrogenated over Raney nickel, thus affording either
the cyclized dihydroxy pyrrolidone 5 (dr ) 1:5, 65% yield)
or its triacetate derivative 7, a building block found in
sphingosines,28 depending upon the reaction conditions
(Scheme 2).
Table 2. Proline-Catalyzed Asymmetric Tandem R-Amination/
HWE Olefinationa
Scheme 2. Synthesis of 2-Pyrrolidone 5 and Triacetate 7
a
Reaction conditions: aldehyde (1.2 equiv), DBAD (1 equiv), L-proline
(10 mol %), triethyl phosphonoacetate (1.5 equiv), LiCl (1.5 equiv), DBU
The stereochemistry in 5 is assigned unambiguously on
the basis of COSY and NOESY studies29 and X-ray
crystallographic analysis (Figure 1) of its triacetate 6 as well
as by the literature precedence.19a The single-step transforma-
tion of 3c under hydrogenation conditions (Raney nickel,
H2, 60 psig) to obtain 2-pyrrolidone 8 (70% yield, 91% ee)
constitutes another application of this methodology (Scheme
3).
(1 equiv), and CH3CN were used. b Yields of isolated product after column
c
chromatography. Enantiomeric excess was determined by chiral HPLC
analysis (Chiracel OD-H).
The absolute configuration of the newly generated amine
center was assigned on the basis of the previously established
configuration of R-amino aldehyde,19a which was also
confirmed by matching the sign of the optical rotation of
pyrrolidone 825 as well as by X-ray crystallographic analysis
of triacetate 6 (Figure 1).
In summary, we have reported, for the first time, a novel,
one-pot procedure of sequential R-amination-HWE olefi-
(24) General experimental procedure: To a cooled solution of dibenzyl
azodicarboxylate (DBAD) (328 mg, 1 mmol) and L-proline (11.5 mg, 10
mol %) in dry CH3CN (10 mL) at 0 °C was added n-butyraldehyde (87
mg, 1.2 mmol), and the mixture was stirred for 2 h at 0 °C and further at
10 °C for 1 h. This was followed by addition of lithium bromide (130 mg,
1.5 mmol), triethyl phosphonoacetate (336 mg, 1.5 mmol), and DBU (152
mg, 1 mmol) in that sequence, and the whole mixture was stirred at 5 °C
for 45 min. It was then quenched by the addition of aqueous ammonium
chloride solution and extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give the crude product
3a, which was then purified by flash column chromatography (packed with
silica gel 60-120 mesh) using petroleum ether and ethyl acetate as eluents
to afford the pure product 3a. Viscous liquid: yield, 84%; HPLC, Chiracel
OD-H column (2-propanol/n-hexane ) 4:96, flow rate 1.0 mL/min, λ )
260 nm). Retention time (min): 40.15 (major) and 54.95 (minor). The
racemic standard was prepared in the same way with DL-proline as catalyst
[99% ee, [R]25 +10 (c 1.0, CHCl3)]. IR (CHCl3) ν 3389, 3020, 2926,
D
2852, 1758, 1715, 1289, 1215, 1041, 757 cm-1. 1H NMR (200 MHz, CDCl3)
δ 0.94 (m, 3H), 1.25 (t, J ) 7 Hz, 3H), 1.62 (m, 2H), 4.13 (q, J ) 7.3 Hz,
2H), 4.64 (m, 1H), 5.11 (m, 4H), 5.85 (d, J ) 15.6 Hz, 1H), 6.86 (m, 2H),
7.28 (m, 10H). 13C NMR (50 MHz, CDCl3) δ 10.42, 13.90, 23.88, 60.32,
64.70, 67.45, 68.01, 122.25, 127.48, 127.87, 128.25, 144.77, 155.53, 156.56,
166.09. Anal. calcd C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C,
65.25; H, 6.28; N, 6.59%.
(25) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656.
(26) For examples, see: (a) Elbein, A.; Molyneux, R. I. In Alkaloids,
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; John Wiley:
New York, 1990. (b) The Alkaloids: Chemistry and Biology; Cordell, G.
A., Ed.; Academic Press: San Diego, 2000; Vol. 54.
Figure 1. ORTEP diagram of triacetate 6.
Among the potential applications of this methodology, a
short asymmetric synthesis of substituted 2-pyrrolidone
derivatives 5 and 8, common subunits present in a variety
of alkaloids,26 seemed attractive to us due to their chemo-
therapeutic utilities such as anti-HIV and anticancer agents.27
For the synthesis of 5, amino olefinic ester 3e underwent
Os-catalyzed dihydroxylation in a diastereoselective manner8
(27) (a) Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045. (b)
Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67,
4630.
(28) Raghavan, S.; Rajender, A. J. Org. Chem. 2003, 68, 7094.
Org. Lett., Vol. 9, No. 6, 2007
1003

been demonstrated by its easy and efficient incorporation in
the synthesis of important optically active 2-pyrrolidinone
derivatives 5 and 8 in good yields and by the great substrate
generality. We hope that this method will find tremendous
applications in the synthesis of various biologically active
organic molecules due to its salient features such as (1) easy
availability of starting materials, (2) simple environmentally
friendly procedure, and (3) availability of proline in both
enantiomeric forms.
Scheme 3. Synthesis of (S)-5-Isopropylpyrrolidin-2-one (8)
nation of aldehydes that leads to enantioselective synthesis
of γ-amino-R,â-unsaturated esters 3 with excellent yields and
high enantioselectivities. The potential of this reaction has
Acknowledgment. S.P.K. thanks CSIR, New Delhi, for
the award of a fellowship. The authors are thankful to Dr.
B. D. Kulkarni, Deputy Director, National Chemical Labora-
tory, Pune, for his constant encouragement.
(29) The relative stereochemistry of 5 was confirmed by COSY and
NOESY studies. A significant NOESY correlation was observed between
H4 and H5. There was no observed correlation between H3-H4 and H3-H5
confirming a syn relationship between H4 and H5.
Supporting Information Available: Spectral data for all
the compounds are given. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 9, No. 6, 2007