Lewis acid promoted highly diastereoselective petasis borono-mannich reaction: Efficient synthesis of optically active β,γ -unsaturated α-amino acids

Article abstract of DOI:10.1021/ol300581n

An efficient and straightforward method for the preparation of highly enantiomerically enriched β,γ -unsaturated α-amino acid derivatives by a Lewis acid promoted diastereoselective Petasis reaction of vinylboronic acid, N-tert-butanesulfinamide, and glyoxylic acid has been developed. The synthetic utilities of the approach were demonstrated by the rapid and convenient construction of challenging cyclopenta[c]proline derivatives.

Full text of DOI:10.1021/ol300581n

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2062–2065
Lewis Acid Promoted Highly
Diastereoselective Petasis Borono-
Mannich Reaction: Efficient Synthesis
of Optically Active β,γ-Unsaturated
r-Amino Acids
Yi Li and Ming-Hua Xu*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, China
xumh@mail.shcnc.ac.cn
Received March 7, 2012
ABSTRACT
An efficient and straightforward method for the preparation of highly enantiomerically enriched β,γ-unsaturated R-amino acid derivatives by a
Lewis acid promoted diastereoselective Petasis reaction of vinylboronic acid, N-tert-butanesulfinamide, and glyoxylic acid has been developed.
The synthetic utilities of the approach were demonstrated by the rapid and convenient construction of challenging cyclopenta[c]proline
derivatives.
Optically pure nonproteinogenic amino acids are fasci-
nating in the field of biological and medicinal chemistry
and are also utilized as versatile building blocks in modern
organic synthesis and new drug discovery.1 An interesting
class of these compounds is β,γ-unsaturated R-amino acids
and their derivatives, which are important structural mo-
tifs present in many biologically active natural products
and pharmaceutical compounds.2 In the past decade, a
great number of methods have been developed to access
these valuable compounds.2a,3,4 Among them, the asym-
metric Petasis borono-Mannich reaction represents a
(3) For representative examples, see: (a) Ma, J.-A. Angew. Chem.,
Int. Ed. 2003, 42, 4290. (b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103,
ꢀ
3013. (c) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584. (d)
Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2000, 122, 2657. (e) Zhou, G.; Zheng, W.;
Wang, D.; Zhang, P.; Pan, Y. Helv. Chim. Acta 2006, 89, 520. (f)
(1) For reviews, see: (a) Amino Acids, Peptides, and Proteins in
Organic Chemistry; Hughes, A. B., Ed.; Wiley-VCH: Weinheim, 2009;
Vols. 1 and 2. (b) Meierhenrich, U. Amino Acids and the Asymmetry of
Life; Springer-Verlag: Heidelberg, 2008. (c) Barrett, G. C.; Elmore, D. T.
Amino Acids and Peptides; Cambridge University Press: Cambridge, 1998.
(d) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc., Perkin
Trans. 1 2000, 4197.
(2) For representative examples, see: (a) Berkowitz, D. B.; Charette,
B. D.; Karukurichi, K. R.; McFadden, J. M. Tetrahedron: Asymmetry
2006, 17, 869. (b) Rando, R. R. Acc. Chem. Res. 1975, 8, 281. (c)
Berkowitz., D. B.; Jahng, W.-J.; Pedersen, M. L. Bioorg. Med. Chem.
Lett. 1996, 6, 2151. (d) Feng, L.; Kirsch, J. F. Biochemistry 2000, 39,
2436. (e) Soper, T. S.; Manning, J. M.; Marcotte, P. A.; Walsh, C. T.
J. Biol. Chem. 1977, 252, 1571. (f) Sahm, U.; Knobloch, G.; Wagner, F.
J. Antibiot. 1973, 26, 389. (g) Pruess, D. L.; Scannell, J. P.; Kellett, M.;
Ax, H. A.; Janecek, J.; Williams, T. H.; Stempel, A.; Berger, J.
J. Antibiot. 1974, 27, 229. (h) Kuroda, Y.; Okuhara, M.; Goto, T.;
Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1980, 33, 132.
^
Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett.
1992, 33, 4313. (g) Berkowitz, D. B.; Pumphrey, J. A.; Shen, Q.
Tetrahedron Lett. 1994, 35, 8743. (h) Rose, N. G. W.; Blaskovich,
M. A.; Wong, A.; Lajoie, G. A. Tetrahedron 2001, 57, 1497. (i) Fadnavis,
N. W.; Seo, S.-H.; Seo, J.-H.; Kim, B.-G. Tetrahedron: Asymmetry 2006,
17, 2199. (j) Hang, J. F.; Deng, L. Bioorg. Med. Chem. Lett. 2009, 19,
3856. (k) Armstrong, A.; Challinor, L.; Moir, J. H. Angew. Chem., Int.
Ed. 2007, 46, 5369. (l) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am.
Chem. Soc. 2005, 127, 11269. (m) Armstrong, A.; Challinor, L.; Cooke,
R. S.; Moir, J. H.; Treweeke, N. R. J. Org. Chem. 2006, 71, 4028. (n)
Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org. Chem. 2000, 65,
2907. (o) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2003, 5, 2449. (p)
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r
10.1021/ol300581n
Published on Web 04/05/2012
2012 American Chemical Society

powerful and most direct approach for the stereoselective
preparation of β,γ-unsaturated R-amino acids.4 To our
knowledge, despite the fact that the strategies involving
chiral amines,4c,l chiral boronate esters,4l,m and chiral
organocatalysts4n have been employed, the results are
far from satisfactory. Excellent stereoselectivities are only
obtained in some cases of using chiral amines such as
2-phenylglycinol4e and R-methylbenzylamine;4j however,
the hydrogenolytic conditions for removal of these N-
benzylic groups also reduce the olefin functionalities lead-
ing to the corresponding saturated derivatives. From this
point of view, a practical synthesis of β,γ-unsaturated R-
amino acids via asymmetric Petasis reaction with great
stereocontrol still remains a challenge.
N-tert-Butanesulfinamide hasbeenproventobea highly
efficient chiral auxiliary in the asymmetric synthesis
of various chiral amines by virtue of its excellent diaste-
reocontrol and easy cleavage under mild conditions.5,6
In 2003, Naskar and co-workers reported the first use of
(S)-N-tert-butanesulfinamide in a Petasis reaction with
arylboronic acids to generate arylglycines, but the results
were disappointing, giving racemic diastereomers in low to
moderate yields.4k In our earlier work,6 we successfully
demonstrated the use of chiral N-tert-butanesulfinylimino
ester as a chiral glycine cation equivalent for the asymmetric
synthesis of synthetically uesful diverse amino acids such
as D-allylglycine,6g β-vinyl-R-arylalanines,6j R-(3-indolyl)-
glycines,6l R-allenylglycines,6m and R-arylglycines.6n Taking
into account these successes and the mechanistic proposal of
the Petasis reaction,4a,7 we envisaged that the possibility of
an asymmetric Petasis reaction of vinylboronic acids
with chiral N-tert-butanesulfinamide and glyoxylic acid
might be expected if a proper Lewis acid is presented in
the reaction system. The chelation of a Lewis acid with
a N-sulfinyl imine intermediate should direct the intra-
molecular transfer of a vinyl group in a highly stereo-
selective manner, thus leading to the optically active
β,γ-unsaturated R-amino acid products. Interestingly,
during the course of our studies, a recent work disclosed
that a Petasis reaction of styrenylboronic acids and
glyoxylic acid with (S)-tert-butylsulfinamide can actu-
ally proceed with high stereoselectivities (10:1À20:1 dr)
under similar Naskar4k conditions to further produce
optically active β,γ-dehydrohomoarylalanine deriva-
tives, but the reactions of alkenyl boronic acids all
showed a low degree of diastereoselectivity (85:15 and
89:11 dr).4g Herein, we report our efforts to develop an
efficient and convenient method for an asymmetric
Petasis reaction of vinylboronic acid, tert-butylsulfina-
mide, and glyoxylic acid using a Lewis acid mediated
coordination protocol. The method produces chiral
β,γ-unsaturated R-amino acid derivatives with excellent
disatereoselectivities (96À99% de) under practical
conditions.
Table 1. Screening of Lewis Acids for Diastereoselective Petasis
Reactiona
(4) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois,
P. M. P. Chem. Rev. 2010, 110, 6169. (b) Petasis, N. A. Aust. J. Chem.
€
2007, 60, 795. (c) Churches, Q. I.; Stewart, H. E.; Cohen, S. B.; Shroder,
A.; Turner, P.; Hutton, C. A. Pure Appl. Chem. 2008, 80, 687. (d)
Churches, Q. I.; Johnson, J. K.; Fifer, N. L.; Hutton, C. A. Aust. J.
Chem. 2011, 64, 62. (e) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc.
1997, 119, 445. (f) Jiang, B.; Xu, M. Org. Lett. 2002, 4, 4077. (g)
Churches, Q. I.; White, J. M.; Hutton, C. A. Org. Lett. 2011, 13, 2900.
(h) Shevchuk, M. V.; Sorochinsky, A. E.; Khilya, V. P.; Romanenko,
V. D.; Kukhar, V. P. Synlett 2010, 1, 73. (i) Petasis, N. A.; Patel, Z. D.
Tetrahedron Lett. 2000, 41, 9607. (j) Jiang, B.; Yang, C.-G.; Gu, X.-H.
Tetrahedron Lett. 2001, 42, 2545. (k) Naskar, D.; Roy, A.; Seibei, W. L.;
Portlock, D. E. Tetrahedron Lett. 2003, 44, 8865. (l) Southwood, T. J.;
Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236. (m) Koolmeister,
time
(h)
yield
(%)b
de
entry
catalyst
(%)c
1
À
8
12
12
8
87
64
60
71
70
61
84
51
53
77
43
42
71
82
92
90
90
93
93
90
98
98
69
97
96
92
2
In(OTf)3
Yb(OTf)3
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
InCl3
3
4
5
8
6
12
8
€
T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969. (n) Lou,
S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
7
8
InBr3
12
24
8
(5) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
ꢀ
110, 3600. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A.
9
InBr3
Chem. Soc. Rev. 2009, 38, 1162. (c) Senanayake, C. H.; Krishnamurthy,
D.; Lu, Z.-H.; Han, Z.; Gallon, E. Aldrichimica Acta 2005, 38, 93.
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Res. 2008, 41, 831. (b) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett.
2004, 6, 3953. (c) Zhong, Y.-W.; Isumi, K.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2004, 6, 4747. (d) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Isumi, K.;
Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2005, 127, 11956. (e) Sun,
X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979. (f) Liu, R.-H.;
Fang, K.; Wang, B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307.
(g) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1259.
(h) Wang, R.; Fang, K.; Sun, B.-F.; Xu, M.-H.; Lin, G.-Q. Synlett 2009,
2301. (i) Liu, M.; Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Chem.;Eur. J.
2009, 15, 10217. (j) Liu, M.; Shen, A.; Sun, X.-W.; Deng, F.; Xu, M.-H.;
Lin, G.-Q. Chem. Commun. 2010, 46, 8460. (k) Shen, A.; Liu, M.; Jia,
Z.-S.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5154. (l) Ji, D.-M.; Xu,
M.-H. Chem. Commun. 2010, 46, 1550. (m) Jin, S.-S.; Xu, M.-H. Adv.
Synth. Catal. 2010, 352, 3136. (n) Li, Y.; Ji, D.-M.; Xu, M.-H. Org.
Biomol. Chem. 2011, 9, 8452.
10
11
12
13
AgCOCF3
FeCl3
24
24
8
FeBr3
FeCl2
a The reaction was performed with 10 mol % of catalyst, (E)-
styrylboronic acid 1a (0.30 mmol), (R)-N-tert-butanesulfinamide 2
(0.25 mmol), and glyoxylic acid 3 (0.25 mmol) in dry CH2Cl2 (1 mL)
at room temperature. b Isolated yield. c The diastereoselectivity of the
product was determined by LC-MS analysis.
Our initial investigation commenced with the reaction
of (E)-styrylboronic acid 1a with (R)-N-tert-butanesulfi-
namide 2 and glyoxylic acid 3 in CH2Cl2 at ambient
temperature (Table 1). In the absence of any Lewis acid
catalyst, the reaction can proceed well and afford the
(7) (a) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000,
ꢀ
56, 10023. (b) Candeias, N. R.; Cal, P. M. S. D.; Andre, V.; Duarte, T.;
Veiros, L.; Gois, P. M. P. Tetrahedron 2010, 66, 2736.
Org. Lett., Vol. 14, No. 8, 2012
2063

expected product in 87% yield and, surprisingly, with 82%
de, unlike in reported cases of arylboronic acids4k (Table 1,
entry 1). Encouraged by this result, we attempted to
employ a Lewis acid as the catalyst to promote the
reaction. As expected, when the reaction was performed
in the presence of 10 mol % of In(OTf)3, a considerable
increase in product diastereomeric excess (92% de vs
82% de) was observed, but a slightly diminished yield
was also obtained simultaneously (Table 1, entry 2). To
achieve better results, a series of transition-metal-based
Lewis acids were carefully screened. As sumarized in
Table 1, the Lewis acid indeed plays an important role
in reaction stereocontrol. In almost all cases, increased
diastereoselectivities were attained, albeit with moder-
ate yields which are due to incomplete conversion.
With 10 mol % of InBr3, the reaction gave the desired
product 4a in 51% yield with the best de of 98% after 12
h (entry 8). Prolonging the reaction time to 24 h did not
lead to an increased yield (53%, entry 9). Notably, an
equally high level of diastereocontrol (97% de) can be
achieved when rather cheap FeCl3 was used as a Lewis
acid (entry 11).
reaction yield and diastereomeric excess (entry 7).
Interestingly, the reaction yield was found to be sensitive
to concentration (entries 8À9).8 When the reaction was
carried out at the concentration 0.3 M, 4a could be
isolated in an optimal yield of 65% without any loss in
diastereoselectivity (entry 8).
Table 3. Diastereoselective Petasis Reaction of Boronic Acids
with N-tert-Butanesulfinamide 2 and Glyoxylic Acid 3a
Table 2. Optimization of the Reaction Conditions Using InBr3
as Catalysta
time
(h)
yield
(%)b
de
(%)c
entry
mol %
solvent
1
10
10
10
10
10
5
CH2Cl2
toluene
THF
12
24
24
12
8
51
43
6
98
97
88
96
À
2
a The reaction was performed with boronic acid 1 (0.36 mmol),
(R)-N-tert-butanesulfinamide 2 (0.30 mmol), and glyoxylic acid 3
(0.30 mmol) in the presence of 10 mol % of InBr3 in dry CH2Cl2 (1 mL)
for 12 h at room temperature. b Isolated yield. c The diastereoselectivity was
determined by LC-MS analysis; see Supporting Information for details.
3
4
Cl(CH2)2Cl
HMPA
53
d
5
À
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
71
50
65
56
95
98
98
98
7
20
10
10
12
12
12
8e
9f
Having identified the optimal reaction conditions, we
sought to evaluate the scope and generality of the reaction.
As presented in Table 3, a wide range of vinylboronic
acids bearing different substituents were successfully re-
acted with glyoxylic acid and (R)-tert-butylsulfinamide
(Table 3), giving the corresponding β,γ-unsaturated
R-amino acid products 4 with excellent diastereoselectiv-
ities (93À99% de) in all cases. Generally, (E)-styrylboronic
acids containing either electron-donating or -withdrawing
groups underwent the Petasis reaction in moderate to good
yields with high selectivities (entries 1À8). However, it is
likely that the para-CF3 substituent on the phenyl ring of
the styrylboronic acid has little effect on the reaction
stereoselectivity (entry 7). Gratifyingly, when differently
a The reaction was performed with (E)-styrylboronic acid 1a (0.30
mmol), (R)-N-tert-butanesulfinamide 2 (0.25 mmol), and glyoxylic acid
3 (0.25 mmol) in dry CH2Cl2 (1 mL) for 12 h at room temperature.
b Isolated yield. c The diastereoselectivity was determined by LC-MS
analysis. d No product. e The reaction was conducted at 0.3 M. f The
reaction was conducted at 0.4 M.
Encouraged by these preliminary results, we decided to
further explore the study to improve the reaction yield. As
revealed in Table 2, the investigation of various solvents
suggested that the use of CH2Cl2 was the best choice
(entries 1 and 5). With lower catalyst loading (5 mol %),
an increase in both the reaction rate and yield was ob-
served, but the diastereoselectivity dropped to 95% de
(entry 6). On the other hand, enhancing the loading
amount of InBr3 to 20 mol % had little effect on the
(8) See Supporting Information for details.
2064
Org. Lett., Vol. 14, No. 8, 2012

substituted linear substrate (E)-alkenyl boronic acids
were employed, the reactions also proceeded smoothly
and gave products 4iÀk in 57%À62% yields with up
to 99% de (entries 9À11). Moreover, it is worth noting
that benzofuran-2-boronic acid (1l) and benzothiophen-
2-boronic acid (1m) are also found to be suitable sub-
strates, as they exhibited high reactivity and led to the
formation of highly optically active R-(2-benzofuranyl)-
glycine 4l and R-(2-benzothiophenyl)glycine 4m (99%
and 96% de, respectively, entries 12 and 13). These results
are among the best in the asymmetric Petasis reaction of
vinylboronic acid.
possible working model was proposed (Figure 1). As
shown in Figure 1, imine nitrogen and carbonyl oxygen
of the quaternary boronate complex coordinated to a
Lewis acidic metal to form a five-membered ring chelation.
Since the uncoordinated N-sufinyl group adopts an ap-
proximately synperiplanar configuration,10 the styryl group
prefers to migrate from the Re face rather than the Si face
of the imine CdN bond because the latter is strongly
shielded by the bulky tert-butyl group, resulting in the R-
configured product.
To understand the stereochemical outcome of the reac-
tion, the chiral free R-styrylglycine was readily obtained by
removal of the N-sulfinyl group under acidic conditions.
Its absolute configuration was unambiguously determined
to be (R) by comparison of the optical rotation with that of
the known compound.3i,8
While the reactions are efficient to produce highly
optically active β,γ-unsaturated R-amino acid products,
we next turned our attention toward demonstrating
the synthetic utility of these compounds. As illustrated in
Scheme 1, treatment of the N-sulfinyl unsaturated amino
acid 4a with thionyl chloride in methanol followed by
concomitant esterification led to removal of the sulfinyl
group and gave methyl ester 5a. Subsequently, reduc-
tive amination of 5a with 3-phenyl-2-propynal or 3-(4-
methoxyphenyl)-2-propynal provided the key inter-
mediate 6a or 6b. Finally, under typical PausonÀKhand
reaction conditions, the corresponding cyclopenta-
[c]proline derivatives 7a and 7b were obtained in mod-
erate yields with high diastereoselectivities (96:4 dr
and >99:1 dr) and enantioselectivities. The stereochemistry
of 7a was determined by NOE experimentation. It has
been well-known that the cyclopenta[c]proline and its
derivatives, which contain a chiral bicyclic core structure
of 3-azabicyclo[3,3,0]octane, have attracted a great deal
of interest9 and should be useful as a highly tunable
chiral material.
Figure 1. Mechanistic proposals for stereocontrol.
In summary, we have developed an extremely mild
and practical approach for the asymmetric synthesis of
β,γ-unsaturated R-amino acids through a Lewis acid pro-
moted highly diastereoselective Petasis borono-Mannich
three-component reaction of N-tert-butanesulfinamide
with glyoxylic acid and vinylboronic acid. The reaction is
general and efficient with respect to substrate scope and
stereocontrol. It provides straightforward access to var-
ious enantiomerically enriched β,γ-unsaturated R-amino
acids (up to 99% de) that are widely useful in medicinal
chemistry and asymmetric synthesis. Further applica-
tions of the methodology are currently underway in our
laboratory.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21021063), the
State Key Laboratory of Drug Research, SIMM, and
National Science & Technology Major Project is greatly
acknowledged.
Scheme 1. Synthetic Applicability of β,γ-Unsaturated R-Amino
Acids
Supporting Information Available. Experimental de-
tails including characterization data, copies of 1H and 13
C
NMR and HPLC/LC-MS spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(9) (a) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1.
(b) Jiang, B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43, 2543. (c) Koep, S.;
Gais, H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243. (d) Tang, Y.;
Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett. 2005, 7,
1657.
(10) For related crystal structures and theoretical calculations: (a)
Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 1539. (b) Owens, T. D.; Souers, A. J.; Ellman, J. A.
J. Org. Chem. 2003, 68, 3. (c) Schenkel, L. B.; Ellman, J. A. Org. Lett.
2003, 5, 545. (d) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998,
1629. (e) Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc.,
Perkin Trans. 2 2000, 43.
Based on the observed diastereofacial selectivity and our
previous studies on metal chelation to N-sulfinyl imines, a
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2065