Facile approach to optically active α-Alkylidene-β-amino esters by thermal overman rearrangement

Article abstract of DOI:10.1021/ol1011746

(Figure Presented) A convenient synthetic method for enantioenriched (E)-α-alkylidene-β-amino esters has been developed through thermal Overman rearrangement. Readily accessible (Z)-β-branched Morita-Baylis-Hillman esters serve as chiral pool precursors. Thermal rearrangement proceeded through a concerted pseudopericyclic transition state to produce (E)-stereoselective products. We expanded the synthetic utilities of α-alkylidene-β-amino esters via preparation of α-alkylidene- β-lactam derivatives.

Full text of DOI:10.1021/ol1011746

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3234-3237
Facile Approach to Optically Active
r-Alkylidene-ꢀ-amino Esters by Thermal
Overman Rearrangement
Sung Il Lee,† Soon Young Moon,† Geum-Sook Hwang,*,‡ and Do Hyun Ryu*,†
Department of Chemistry, Sungkyunkwan UniVersity, Suwon 440-746, Korea, and
Korea Basic Science Institute and Graduate School of Analytical Science and
Technology, Chungnam National UniVersity, Seoul, 136-713, Korea
dhryu@skku.edu; gshwang@kbsi.re.kr
Received May 21, 2010
ABSTRACT
A convenient synthetic method for enantioenriched (E)-r-alkylidene-ꢀ-amino esters has been developed through thermal Overman rearrangement.
Readily accessible (Z)-ꢀ-branched Morita-Baylis-Hillman esters serve as chiral pool precursors. Thermal rearrangement proceeded through
a concerted pseudopericyclic transition state to produce (E)-stereoselective products. We expanded the synthetic utilities of r-alkylidene-ꢀ-
amino esters via preparation of r-alkylidene-ꢀ-lactam derivatives.
The transformation of readily available allylic alcohols to
relatively inaccessible allylic amines through [3,3]-sigmatropic
rearrangement has been the focus of numerous investigations
over the past few decades, beginning with the first report by
Overman.1,2 This reaction can be accomplished at either
elevated temperature or at room temperature catalyzed by
Hg(II) or Pd(II) complexes. [3,3]-Sigmatropic rearrangement
has been employed as a pivotal step in the syntheses of
alkaloids, antibiotics, unnatural amino acids, and other
complex natural products.3 Among these targets, preparation
of ꢀ-amino acids is of particular interest to medicinal and
bioorganic chemists, as various ꢀ-amino acid moieties can
be found in HIV-protease inhibitors, ꢀ-lactam antibiotics,
and peptidomimetics.4
Recently, we reported a highly enantioselective and (Z)-
stereocontrolled three-component coupling reaction of R,ꢀ-
acetylenic esters, aldehydes, and trimethylsilyl iodide (TMSI)
using chiral cationic oxazaborolidinium catalysts.5 The reaction
provides optically active (Z)-ꢀ-iodo Morita-Baylis-Hillman
(MBH) esters with good to excellent yield and enantioselectivity
in a straightforward manner.6,7 In addition, the subsequent
metal-catalyzed cross-coupling of these esters are performed
directly to access the ꢀ-branched MBH esters in a single
step (Scheme 1).8
† Sungkyunkwan University.
‡ Korea Basic Science Institute and Chungnam National University.
(1) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. (b) Overman,
L. E. Acc. Chem. Res. 1980, 13, 218. (c) Overman, L. E. Angew. Chem.,
Int. Ed. 1984, 23, 579. (d) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M.
J. Org. Chem. 1998, 63, 188. (e) Galeazzi, R.; Martelli, G.; Orena, M.;
Rinaldi, S. Synthesis 2004, 15, 2560. (f) Chen, B.; Mapp, A. K. J. Am.
Chem. Soc. 2005, 127, 6712. (g) Lee, E. E.; Batey, R. A. J. Am. Chem.
(3) (a) Hama, N.; Matsuda, T.; Sato, T.; Chida, N. Org. Lett. 2009, 11,
2687. (b) Imaoka, T.; Iwamoto, O.; Noguchi, K.-I.; Nagasawa, K. Angew.
Chem., Int. Ed. 2009, 48, 3799. (c) Matveenko, M.; Banwell, M. G.; Willis,
A. C. Org. Lett. 2008, 10, 4693.
Soc. 2005, 127, 14887
.
(2) For catalytic enantioselective rearrangement of imidate, see: (a)
Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org.
Chem. 1997, 62, 1449. (b) Anderson, C. E.; Overman, L. E. J. Am. Chem.
Soc. 2003, 125, 12412. (c) Kirsch, S. F.; Overman, L. E.; Watson, M. P. J.
Org. Chem. 2004, 69, 8101. (d) Watson, M. P.; Overman, L. E.; Bergman,
(4) (a) Hamada, Y.; Matsumoto, H.; Yamaguchi, S.; Kimura, T.;
Hayashi, Y.; Kiso, Y. Bioorg. Med. Chem. 2004, 12, 159. (b) Hansen, T.;
Alst, T.; Havelkova, M.; Strøm, M. B. J. Med. Chem. 2010, 53, 595. (c)
Sadowsky, J. D.; Murray, J. K.; Tomita, Y.; Gellman, S. H. ChemBioChem
2007, 8, 903.
R. G. J. Am. Chem. Soc. 2007, 129, 5031
.
10.1021/ol1011746  2010 American Chemical Society
Published on Web 06/21/2010

Scheme 1
.
Asymmetric Synthesis of (Z)-ꢀ-Iodo
Scheme 2
.
Overman Rearrangement of Allylic
Trichloroacetimidate
Morita-Baylis-Hillman Esters
We anticipated that the optically active (Z)-ꢀ-branched
MBH ester could be useful for producing chiral R-alkylidene-
ꢀ-amino esters through an Overman rearrangement. In this
paper, we demonstrate that a series of (Z)-ꢀ-branched MBH
esters can be an excellent precursor for enantioenriched (E)-
R-alkylidene-ꢀ-amino esters.9
The ꢀ-phenyl-ꢀ′-pentyl substituted substrate 1 was
selected for our initial optimization (Scheme 2). The allylic
trichloroacetimidate 2 of this substrate was prepared in
quantitative yields using the DBU-catalyzed addition of
allylic alcohol to trichloroacetonitrile (5.0 equiv)1e in
MeCN media.
Initial attempts with mercury(II) and palladium(II)
catalyst were unsatisfactory. Specifically, although the
mercury(II)-catalyzed reaction provided the desired [3,3]-
rearranged compound, undesired mixtures of five- and six-
membered cyclized compounds and a γ-proton eliminated
compound (4, 5, and 6, respectively; Scheme 2) were also
present. Screening a variety of Pd(II) complexes for the
desired Overman rearrangement proved to be similarly
unsuccessful.
We next changed our focus to thermal [3,3]-sigmatropic
rearrangement. At the outset, crude trichloroacetimidate 2
was refluxed under various solvents. As a result, formations
of five- and six-membered cyclized products were avoided;
however, the remaining DBU and polar basic solvent induced
γ-proton elimination. Trichloroacetimidate 2 cannot be
purified through chromatography on silica gel in either acidic
or basic conditions. Further, acidic workup cannot completely
remove DBU. Fortunately, short path silica gel filtration was
successful. Crude trichloroacetimidate 2 was promptly passed
through the minimum amount of silica gel to produce base-
free pure trichloroacetimidate 2 in a quantitative yield.
Heating of 2 for 1 h in toluene furnished allylic trichloro-
acetamide 3 in an 84% yield and a 9/1 (E)-stereoselectivity.
To evaluate the substrate scope of this methodology, we
investigated the thermal Overman rearrangements of various
R1 and R2 under optimized conditions (Tables 1 and 2).
For aromatic aldehydes, substitution by an electron-
withdrawing group in the para position increased either the
chemical yield or the (E)-stereoselectivity (Table 1, entries
2-6 and Table 2, entries 2, 6, 7, and 9). Moreover, a more
sterically hindered R1 enhanced (E)-selectivity (Table 1,
entries 10 and 11).
The DBU-catalyzed preparation of trichloroacetimidate
was good for the ꢀ-MBH esters derived from aromatic
aldehydes (R1 ) Ar, 7a-7k, 7n-7q, and 7s-7y). To our
surprise, the same conditions did not provide the desired
products with aliphatic aldehydes (7l, 7m, and 7r).
To produce the desired trichlroacetimidate, DBU was
exchanged with the stronger base NaH in order to generate
the allylic alkoxide. The reaction of alkyl chained MBH
esters (R1 ) alkyl) with 2.0 equiv of NaH in dichloromethane
provided a corresponding imidate, and sequential rearrange-
ment afforded 8l, 8m, and 8r in excellent yield with moderate
E/Z selectivity (Table 1, entries 12, 13 and Table 2, entry
5).
(5) For a recent reports on cationic oxazaborolidinium, see: (a) Ryu,
D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106. (b) Sim, J. Y.;
Hwang, G.-S.; Kim, K. H.; Ko, E. M.; Ryu, D. H. Chem. Commun. 2007,
5064. (c) Lee, M. Y.; Kim, K. H.; Jiang, S.; Jung, Y. H.; Sim, J. Y; Hwang,
G.-S.; Ryu, D. H. Tetrahedron lett. 2008, 49, 1965. (d) Corey, E. J. Angew.
Chem., Int. Ed. 2009, 48, 2100. (e) Gao, L.; Hwang, G.-S.; Lee, M. Y.;
Ryu, D. H. Chem. Commun. 2009, 5460.
(6) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem.,
Int. Ed. 2009, 48, 4398.
(7) For a review on (Z)- ꢀ-halo MBH ester synthesis, see :(a) Li, G.;
Hook, J.; Wei, H.-X. In Recent Research DeVeropments in Organic &
Bioorganic Chemistry; Transword Research Network: Trivandrum, India,
2001; Vol. 4, pp 49-61. (b) Li, G.; Wei, H.-X.; Caputo, T. D. Tetrahedron
Lett. 2000, 41, 1. (c) Li, G.; Gao, J.; Wei, H.-X.; Enright, M. Org. Lett.
2000, 2, 617. (d) Timmons, C.; Kattuboina, A.; Banerjee, S.; Li, G.
Tetrahedron 2006, 47, 7151. (e) Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Synlett
2007, 59.
(8) For other routes to ꢀ-branched MBH products, see: (a) Kataoka, T.;
Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S. Angew. Chem.,
Int. Ed. 2000, 39, 2358. (b) Ramachandran, P. V.; Rudd, M. T.; Burghardt,
T. E.; Reddy, M. V. R. J. Org. Chem. 2003, 68, 9310. (c) Reynolds, T. E.;
Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 15382. (d)
Reynolds, T. E.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 7806. (e)
Tarsis, E.; Gromova, A.; Lim, D.; Zhou, G.; Coltart, D. M. Org. Lett. 2008,
10, 4819. (f) Mueller, A. J.; Jennings, M. P. Org. Lett. 2008, 10, 1649. (g)
Lee, S. I.; Hwang, G.-S.; Shin, S. C.; Lee, T. G.; Jo, R. H.; Ryu, D. H.
Org. Lett. 2007, 9, 5087.
Transposition of the enantioenriched (R)-ꢀ-branched MBH
ester 7a produced (R)-trichloroacetamide 8a with clean
transfer of chirality. Similarly, 7c, 7o, and 7s were rearranged
in excellent yields to furnish only the corresponding (R)-
enantiomers 8c, 8o, and 8s, respectively (Table 3).
The rearrangement of trichloroacetimidate proceeded in a
highly (E)-stereoselective manner. The (E)-stereochemistry
of the resulting R-alkylidene-ꢀ-amino esters were assigned
(9) For other methods to R-alkylidene-ꢀ-amino esters, see: (a) Benfatti,
F.; Cardillo, G.; Gentilucci, L.; Mosconi, E.; Tolomelli, A. Org. Lett. 2008,
10, 2425. (b) Davis, F. A.; Qiu, H.; Song, M.; Gaddiraju, N. V. J. Org.
Chem. 2009, 74, 2798.
Org. Lett., Vol. 12, No. 14, 2010
3235

Table 1. Result of Synthesis of Various R-Alkylidene-ꢀ-amino
Esters from Racemic (Z)-ꢀ-Branched MBH Esters
Table 3. Clean Transfer of Chirality of Enantioenriched
(R)-(Z)-ꢀ-Branched MBH Esters
entry
R1
R2
7 ee %
8 ee %
1
2
3
4
a
c
o
s
Ph
Me
Me
n-C5H13
Et
89
80
97
95
89
79
97
96
(4-CN)C6H4
(4-F)C6H4
(4-F)C6H4
entry
R1
E/Zb
yielda (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Ph
92/8
>99/1
>99/1
91/9
92/8
92/8
77/23
89/11
79/21
93/7
>99/1
61/39
70/30
86
80
87
97
100
78
99
72
50
70
(4-F)C6H4
(4-CN)C6H4
(4-CF3)C6H4
(4-Br)C6H4
(4-Cl)C6H4
(2-F)C6H4
o-tol
9
p-tol
Figure 1. NOE correlation of R-alkylidene-ꢀ-amino esters.
10c
11
12
13
j
k
l
1-Naph
2-Naph
Et
iPr
72
100
86
m
transition state B, transition state A is favored, thereby
producing mainly the (E)-isomer.11
a Combined yield of E/Z isomers. b Determined by column chromatog-
raphy separation. c Reaction time is 2 h.
To highlight its chemical utility, we applied this novel
synthetic method to the construction of optically active
ꢀ-lactams. Besides their significance as bioactive agents, the
importance of ꢀ-lactams as chiral building blocks has been
widely recognized in the field of organic synthesis.12 For
the synthesis of optically active ꢀ-lactams, we utilized
R-alkylidene-ꢀ-amino esters, which were envisioned as
suitable precursors for the preparation of various enantio-
merically enriched R-alkylidene-ꢀ-lactams.
Table 2. Result of Synthesis of Various R-Alkylidene-ꢀ-amino
Esters from Racemic (Z)-ꢀ-Branched MBH Esters
Trichloroacetamide 8a underwent basic hydrolysis under
H2O/EtOH reflux to produce the unnatural ꢀ-amino acid 9a.
The resulting ꢀ-amino acid was treated with 2,2′-dipyridyld-
entry
R1
R2
E/Zb
yielda (%)
13
1
n
o
p
q
r
Ph
n-C5H13
n-C5H13
n-C5H13
n-C5H13
n-C5H13
Et
90/10
90/10
82/18
92/8
74/26
93/7
84
96
97
82
94
70
96
88
91
88
42
67
isulfide/PPh3 to give R-alkylidene-ꢀ-lactam 10a in two
2
(4-F)C6H4
(2-Br)C6H4
o-tol
steps, with a 85% yield. Similarly, 8u was converted to the
corresponding ꢀ-lactam in good yield (Scheme 3).
3c
4
5
6
7
8
iPr
As illustrated in Scheme 3, selective deprotection of the
trichloroacetamide of R-alkylidene-ꢀ-amino ester 8a with
Cs2CO3 in DMSO delivered the corresponding free ꢀ-amino
ester 11a. This free amine can then be converted to other
useful functionalized amine groups. As an example, tosyla-
tion under standard reaction conditions furnished 12a in two
steps, with a 72% yield.
s
t
(4-F)C6H4
(4-CF3)C6H4
Ph
(4-F)C6H4
(4-CF3)C6H4
o-tol
Et
93/7
u
v
w
x
y
iPr
iPr
Ph
Ph
90/10
89/11
86/14
70/30
88/12
9
10
11
12
Ph
CCPh
The stereochemistries of the R-alkylidene-ꢀ-amino esters
were determined by preparing authentic samples via non-
equivalent routes (Scheme 4). Synthesis of ꢀ-lactam 13a can
be accomplished from (S)-(-)-1-phenylethylamine in three
steps,14 showing a rotation at the Na line of -35.5. On the
other hand, R-alkylidene-ꢀ-lactam 10a was subjected to
a Combined yield of E/Z isomers. b Determined by column chromatog-
raphy separation. c Reaction time is 5 h.
on the basis of the chemical shift values of vinyl protons in
1
the H NMR and NOE NMR spectral analyses. The NOE
of (E)-ꢀ-amino esters revealed strong correlations between
the allylic protons and the phenyl protons. Otherwise, (Z)-
ꢀ-amino esters exhibited strong correlations between the
vinylic protons and allylic protons (Figure 1).
(10) (a) Birney, D. M.; Xu, X.; Ham, S. Angew. Chem., Int. Ed. 1999,
38, 189. (b) de Lera, A. R.; Alvarez, R.; Lecea, B.; Torrado, A.; Coss´ıo,
F. P. Angew. Chem., Int. Ed. 2001, 40, 557. (c) C¸ elebi-Olc¸u¨m, N.; Aviyente,
¨
V.; Houk, K. N. J. Org. Chem. 2009, 74, 6944.
(11) The Overman rearrangement of (E)-stereoisomer of 7a provided
8a in lower E/Z-ratio (∼2.5/1) and 73% yield.
(12) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107,
4437.
These results could be explained by a pseudopericyclic
transition state, as illustrated in Figure 2.10 Because a serious
steric interaction between R1 and ethyl ester is obvious in
(13) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71,
4706.
3236
Org. Lett., Vol. 12, No. 14, 2010

exhibited a rotation at the Na line of -35.0, established the
(R)-absolute stereocenter for the major enantiomer of 8a
produced in the thermal rearrangement.
Scheme 4
.
Determination of Absolute Configuration of
R-Alkylidene-ꢀ-amino Esters
Figure 2
. Proposed transition state for thermal [3,3]-sigmatropic
rearrangement of ꢀ-branched MBH ester.
Scheme 3. Application of R-Alkylidene-ꢀ-amino Esters to
Synthesis of Optically Active ꢀ-Lactams
In conclusion, we have developed a convenient synthetic
method for the production of (E)-R-alkylidene-ꢀ-amino esters
through thermal Overman rearrangement. We demonstrated
that optically active (Z)-ꢀ-branched MBH esters can serve
as chiral precursors to produce the corresponding rearranged
products without loss of optical purity. Moreover, various
R-alkylidene-ꢀ-lactam derivatives were successfully prepared
using hydrolysis-intramolecular cyclization. Thus, the method
described in this paper is valuable to the field of synthetic
organic chemistry.
Acknowledgment. This work was supported by grants
NRF-20090094024 (Priority Research Centers Program), NRF-
20080058667 (Basic Science Research Program) and NRF-
20090076108 (Basic Science Research Program).
catalytic heterogeneous hydrogenation15 to form the 1:1
mixture of cis- and trans- isomers. The trans 13a, which
Supporting Information Available: Experimental details
and chracterization data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach, D. J. Org.
Chem. 1992, 57, 2396. (b) McNeil, A. J.; Toombes, G. E. S.; Gruner, S. M.;
Lobkovsky, E.; Collum, D. B.; Chandramouli, S. V.; Vanasse, B. J.; Ayers,
T. A. J. Am. Chem. Soc. 2004, 126, 16559.
(15) Legeay, J.-C.; Langlois, N. J. Org. Chem. 2007, 72, 10108.
OL1011746
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