One-step highly diastereoselective synthesis of γ-aminoalkyl-substituted γ-butyrolactones by an asymmetric samarium-mediated ketyl-alkene coupling reaction

Article abstract of DOI:10.1021/jo020574h

The samarium(II) iodide mediated reaction of N,N-dibenzyl-protected (S)-α-amino aldehydes with (1S,2R)-N-methylephedrinyl acrylate gave the (4R, 1′S)-γ-(aminoalkyl)-γ-butyrolactones in good yields with high diastereoselectivities (up to 80% de); (4R, 1′S)γ-amino-(2-phenylethyl)-γ-butyrolactone (6a), which should be a potent precursor for γ-secretase inhibitors, was obtained with high de value.

Full text of DOI:10.1021/jo020574h

On e-Step High ly Dia ster eoselective
Syn th esis of γ-Am in oa lk yl-Su bstitu ted
γ-Bu tyr ola cton es by a n Asym m etr ic
Sa m a r iu m -Med ia ted Ketyl-Alk en e
Cou p lin g Rea ction
Shin-ichi Fukuzawa,* Manabu Miura, and
Takahide Saitoh
Department of Applied Chemistry, Institute of Science and
Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku,
Tokyo 112-8551, J apan
fukuzawa@chem.chuo-u.ac.jp
Received August 29, 2002
Abstr a ct: The samarium(II) iodide mediated reaction of
N,N-dibenzyl-protected (S)-R-amino aldehydes with (1S,2R)-
N-methylephedrinyl acrylate gave the (4R,1′S)-γ-(aminoalkyl)-
γ-butyrolactones in good yields with high diastereoselectiv-
ities (up to 80% de); (4R,1′S)-γ-amino-(2-phenylethyl)-γ-
butyrolactone (6a ), which should be a potent precursor for
γ-secretase inhibitors, was obtained with high de value.
F IGURE 1.
de).2f The indium-mediated allylation of amino aldehydes
has been recently reported and affords R-methylene-γ-
(aminoalkyl)-γ-butyrolactones in good yields, but the
problem of unsatisfactory selectivities (30-70% de) re-
mains.3 Recently, Nadin et al. reported the stereoselective
synthesis of (4R,1′S)-γ-(protected-amino)-γ-butyrolac-
tones via protected R-amino epoxides.2a Aguilar et al.
reported the synthetic methods of (4S,1′S)-γ-(protected-
amino)-γ-butyrolactones via protected R-amino epoxides,
in which the key step is the Sharpless oxidation of allylic
alcohols.2g These methods seem to be useful for obtaining
diastereomerically pure amino lactones but require sev-
eral steps and their overall yields are not satisfactory
(30% from a chiral R-amino ester and 14% from a chiral
epoxy alcohol). Thus, the synthetic methods so far
reported have the drawback of an unsatisfactory stereo-
selectivity or multistep procedure. We wish to report here
the one-step, highly stereoselective synthesis of (4R,1′S)-
γ-(aminoalkyl)-γ-butyrolactones by the samarium(II) io-
dide methodology:4 this method can provide the potent
precursor of γ-secretase inhibitors where the alkyl group
is 2-phenylethyl.
Hydroxyethylene dipeptide isosteres, i.e., the δ-amino-
γ-hydroxy acids 1 (Figure 1), are pharmaceutically
important compounds with structures basic for HIV
protease inhibitors and γ-secretase inhibitors which are
potential curatives for Alzheimers disease, especially
when R1 and R2 are benzyl (Bn).1 γ-(Aminoalkyl)-γ-
butyrolactones should be useful starting compounds for
the preparation of 1 if the R-substituent (R2) can be
introduced stereoselectively.1b,c Then, the stereocontrolled
syntheses of γ-(aminoalkyl)-γ-butyrolactones have been
intensively studied and most of the methods employ
chiral amino aldehydes or esters as starting compounds.2
The allylation of amino aldehydes with allylsilane may
be the simplest way, which requires only a few steps to
access the γ-(aminoalkyl)-γ-butyrolactones, but the
stereoselectivity is not satisfactory in some cases (70%
(1) For example: (a) Myers, A. G.; Barbay, J . K.; Zohng, B. J . Am.
Chem. Soc. 2001, 123, 7207. (b) Li, Y.-M.; Xu, M.; Lai, M. T.; Huang,
Q.; Castro, J . L.; DiMuzio-Mower, J .; Harrison, T.; Lellis, C.; Nadin,
A.; Neduvelil, J . G.; Register, R. B.; Sardana, M. K.; Shearman, M. S.;
Smith, A. L.; Shi, X. P.; Yin, K.-C.; Shafer, J . A.; Gardell, S. J . Nature
2000, 405, 689. (c) Shearman, M. S.; Beher, D.; Clarke, E. E.; Lewis,
H. D.; Harrison, T.; Hunt, P.; Nadin, A.; Smith, A. L.; Stevenson, G.;
Castro, J . L. Biochemistry 2000, 39, 8698. (d) Ghosh, A. K.; McKee, S.
P.; Thompson, W. J .; Darke, P. L.; Zugay, J . C. J . Org. Chem. 1993,
58, 1025. (e) Kempf, D. J .; Lara, E.; Stein, H. H.; Cohen, J .; Egan, D.
A.; Plattner, J . J . J . Med. Chem. 1990, 33, 371.
(2) For 4R,1′S amino lactones: (a) Nadin, A.; Lopez, J . M. S.;
Neduvelil, J . G.; Thomas, S. R. Tetrahedron 2001, 57, 1861. (b)
Benedetti, F.; Maman, P.; Norbedo, S. Tetrahedron Lett. 2000, 41,
10075. (c) Kano, S.; Yokomatsu, T.; Shibuya, S. Tetrahedron Lett. 1991,
32, 233. (d) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 547.
(e) Hormuth, S.; Reissig, H.-U.; Dorsch, D. Angew. Chem., Int. Ed. Engl.
1993, 32, 1449. For 4S,1′S amino lactones: (f) Ghosh, A. K.; Fidanze,
S. J . Org. Chem. 1998, 63, 6146. (g) Aguilar, N.; Moyano, N. A.; Pericas,
M. A.; Riera, A. J . Org. Chem. 1998, 63, 3560. (h) Dondoni, A.; Perrone,
D.; Semola, M. T. J . Org. Chem. 1995, 60, 7927. (i) Hanessian, S.; Park,
H.; Yang, R.-Y. Synlett 1997, 353. (j) Vara Prasad, J . V. N.; Rich, D.
H. Tetrahedron Lett. 1990, 31, 1803. (k) Fray, A. H.; Kaye, R. L.;
Kleinman, E. F. J . Org. Chem. 1986, 51, 4828. (l) Decamp, A. E.;
Kawaguchi, A. T.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1991,
32, 1867.
Upon treatment of the mixture of the 2S dibenzylated
amino aldehyde 2a (R ) Bn) and ethyl acrylate 3 with a
THF solution of SmI2 in the presence of t-BuOH at 0 °C
for 2 h, the corresponding γ-aminoalkyl γ-butyrolactone
was obtained as a mixture of diastereomers 6a and 7a
in 50% yield. To determine the configuration of the ether
carbon, the amino lactone was converted into the corre-
sponding 1,4-diol (8) by reduction with LiAlH4. The
(3) (a) Steurer, S.; Podlech, J . Eur. J . Org. Chem. 2002, 899. (b)
Steurer, S.; Podlech, J . Org. Lett. 1999, 1, 481. (c) Steurer, S.; Podlech,
J . Eur. J . Org. Chem. 1999, 1551.
(4) Matsuda et al. reported the diastereoselective coupling reaction
between the R-Z-protected amino ketones and crotonic esters: (a)
Matsuda, F.; Kawatsura, M.; Dekura, F.; Shirahama, H. J . Chem. Soc.,
Perkin Trans. 1 1999, 2371. (b) Kawatsura, M.; Dekura, F.; Shirahama,
H.; Matsuda, F. Synlett 1996, 373.
10.1021/jo020574h CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/04/2003
2042
J . Org. Chem. 2003, 68, 2042-2044

TABLE 1. Sm I2-Med ia ted Rea ction of Am in o Ald eh yd e
w ith Acr ylic Ester sa
entry
ester
amino aldehyde
yield, %b
6:7c
1
2
3
3
3
3
3
3
4
4
4
4
4
5
5
5
5
5
2a
2b
2c
2d
2a
2a
2b
2c
2d
2a
2a
2b
2c
2d
2a
50
27
66
36
22
60
40
83
32
30
46
22
63
22
13
62:38
53:47
51:49
52:48
60:40
92:8
84:16
89:11
90:10
68:32
35:65
42:58
54:46
65:35
64:36
4
5d
6
7
8
9
10d
11
12
13
14
15d
F IGURE 2. Transition state of the SmI2-mediated coupling
reaction of the R-amino aldehyde with the chiral acrylic ester.
TABLE 2. Sm I2-Med ia ted Rea ction of (R)-2a w ith
a
Conditions: SmI2 (1.5 mmol), (S)-2 (0.5 mmol), ester (0.6
Acr ylic Ester sa
b
mmol), t-BuOH (0.6 mmol), 0 °C, 2 h. Isolated yield of a mixture
of 6 and 7. c Determined by 1H NMR and/or HPLC. HMPA (6
d
entry
ester
yield, %b
9:10c
mmol) was added.
1
2
3
3
4
5
56
45
59
58:42
38:62
92:8
stereochemistry of 8a was established by comparison of
their H NMR spectra with those separately prepared by
1
a
Conditions: SmI2 (1.5 mmol), (R)-2a (0.5 mmol), ester (0.6
b
the stereoselective allylation of 2a with allyl organo-
metallic compounds followed by hydroboration.2c,5a The
chiral HPLC analysis (Chiralpack AD) of the amino
lactone and 8 further demonstrated that the 4R,1′S
isomer 6a was preferably formed in the ratio 6a :7a )
62:38. The reaction with other amino aldehydes 2b-d
(R ) i-Bu, i-Pr, Me) gave the corresponding lactones as
mixtures of almost 1:1 diastereomers in moderate yields.
These results are summarized in Table 1 (entries 1-4).
The chiral center of the amino aldehyde 2 poorly con-
trolled the stereochemistry of the coupling reaction.
The use of the chiral acrylic ester derived from (1S,2R)-
N-methylephedrine 4 instead of 3 produced a dramatic
enhancement in the diastereoselectivity for the 4R,1′S
amino lactones 6. The reaction of each of the amino
aldehydes 2a -d with 4 afforded 6a -d as the major
products in high diastereomeric excess (up to 84% de)
(Table 1, entries 6-9).6 Compared to Nadin’s 4R,1′S
amino lactone synthesis, which involves a three-step
transformation and separation of a diastereomeric mix-
ture of the precursor, this samarium iodide method is
much simpler and more efficient in accessing the 4R,1′S
amino lactone with good yield and selectivity.2a As 4R,1′S
isomers of amino lactones were obtained in one-step
reactions in high diastereoselectivity, we next tried to
prepare the 4S,1′S isomer by using (1R,2S)-N-methyl-
ephedrinyl acrylate 5, which is an enantiomer of 4.
Although the reaction of 2a with 5 afforded the 4S,1′S
isomer 7a as a major isomer, the diastereoselectivity was
low (30% de) (Table 1, entry 11). The observed stereo-
chemistry of the product seemed to be dependent on the
alkyl substituent of the amino aldehydes 2a -d ; with the
benzyl and isobutyl derivatives, the 4S,1′S isomer was
preferably produced, while with the isopropyl and the
methyl derivatives, the 4R,1′S isomer was preferably
mmol), t-BuOH (0.6 mmol), 0 °C, 2 h. Isolated yield of a mixture
of 9 and 10. c Determined by 1H NMR and/or HPLC.
F IGURE 3.
obtained. In any event, the diastereoselectivities in the
reaction with 5 were lower than those with 4.
The stereochemistry of the amino lactone 6a can be
explained by the nonchelation control in the reaction with
3; the amino nitrogen does not coordinate to the sa-
marium atom.5 This diastereoselection is similar to the
samarium(II) iodide mediated iodomethylation of a chiral
amino aldehyde; the stereocenter of (S)-2 produces R
stereochemistry to the ether carbon of the lactone ring.7
The enhanced stereoselectivity in the reaction with the
1S,2R acrylate 4 may be explained by matching the
stereoselection of the S chiral center of the amino carbon
and the S chiral center of the ester carbon, as illustrated
in Figure 2; chelation of the ester carbonyl oxygen to
samarium should be involved in the high diastereoselec-
tion. This conformation should be the most preferable,
thus leading to the R stereochemistry of the lactone ring.
On the other hand, mismatching of the two chiral centers
between the S amino carbon and the R ester carbon
resulted in low diastereoselection. In the reaction of (R)-
2a , the use of the 1R,2S acrylate 5 afforded enhanced
diastereoselectivity leading to the S chiral center (9) to
the lactone ring, while the 1S,2R ester 4 afforded low R
selectivity due to the mismatched stereochemistry (Table
2, Figure 3).
(5) (a) Reez, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem. 1987,
99, 1186. (b) Laib, T.; Chastanet, J .; Zhu, J . J . Org. Chem. 1998, 63,
1709.
The addition of HMPA to the reaction mixture of (S)-
2a with acrylic esters 3-5 always gave the 4R,1′S isomer
(6) (a) Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J . Am.
Chem. Soc. 1997, 119, 1482. (b) Fukuzawa, S.; Nakanishi, A.; Fujinami,
T.; Sakai, S. J . Chem. Soc., Perkin Trans. 1 1988, 1669.
(7) Cocellon, J . M.; Bernad, P. L.; Pe`rez-Andre`s, J . A. J . Org. Chem.
1997, 62, 8902.
J . Org. Chem, Vol. 68, No. 5, 2003 2043

(5R,1′S)-5-(1′-(Diben zyla m in o)-2′-p h en yleth yl)d ih yd r o-
6a as a major isomer, independent of the stereochemistry
of the acrylic ester with almost the same diastereoselec-
tivity (6a :7a ) (60:40)-(68:32)) (Table 1, entries, 5, 10,
and 15). Since HMPA can strongly coordinate to the
samarium atom and prevent organic molecules from
chelating to the samarium atom,8 the coupling reaction
seemed to proceed without any chelation of samarium
in the presence of HMPA; neither the amino nitrogen nor
the carbonyl oxygen chelate to samarium.
fu r a n -2(3H)-on e (6a ). [R]25 ) -6.5° (c ) 0.46, CHCl3) (lit.2c
D
+0.2°). 1H NMR (300 MHz, CDCl3): δH 1.8-1.9 (m, 1H), 2.2-
2.5 (m, 3H), 2.9-3.1 (m, 3H, including CHN and CH2Ph), 3.70
(s, 4H), 4.65-4.75 (m, 1H), 7.1-7.4 (m, 15 H), 13C NMR: δC 26.4,
28.1, 32.4, 54.3, 62.3, 80.8, 126.1, 126.9, 128.1, 128.2, 128.6,
128.7, 129.1, 129.5, 139.1, 139.9, 177.1. Anal. Calcd for C26H27
-
NO2: C, 81.01; H, 7.06; N, 3.63. Found: C, 80.98; H, 7.36; N,
3.57. Data for the minor isomer (5S,1′S)-5-(1′-(dibenzylamino)-
2′-phenylethyl)dihydrofuran-2(3H)-one (7a ) are as follows. 1H
NMR (300 MHz, CDCl3): δH 2.3-2.6 (m, 4H), 2.8-3.2 (m, 3H,
including CHN and CH2Ph), 3.64 (d, 2H, J ) 13.5 Hz), 4.05 (d,
2H, J ) 13.5 Hz), 4.4-4.5 (m, 1H), 7.1-7.3 (m, 15H).
Exp er im en ta l Section
(5R,1′S)-5-(1′-(Diben zyla m in o)-3′-m eth ylbu tyl)d ih yd r o-
Gen er a l Con sid er a tion s. 1H (400 MHz) and 13C NMR
spectra were recorded in CDCl3, and the chemical shifts are
reported in δ units downfield from tetramethylsilane, used as
the internal standard. HPLC analyses were performed on Daicel
Chiralcel OD and AD columns (0.46 mm, 25 cm), with with
2-propanol/n-hexane ((10:90)-(1:99)) as eluent, or on an ODS
(Kanto Chemicals Ltd., Mightysil RP-18) column. Elemental
analyses were carried out in the Microanalytical Laboratory at
Chuo University. Column chromatography was performed using
Merck silica gel 60.
Ma ter ia ls. Commercial dry THF was used without further
purification. (1S,2R)- and (1R,2S)-N-methylephedrinyl acrylates
5 and 6 were prepared by the reaction of commercial acryloyl
chloride with N-methylephedrine.6a Enantiomerically pure (2S)-
N,N-dibenzylamino aldehydes are prepared by the reported
method.9
fu r a n -2(3H)-on e (6b). [R]25 ) -42.2° (c ) 0.38, CHCl3) (lit.2c
D
-43.9°). 1H NMR (300 MHz, CDCl3): δH 0.61 (d, 3H, J ) 6.4
Hz), 0.83 (d, 3H, J ) 6.4 Hz), 1.1-1,3 (m, 1H), 1.5-2.0 (m, 4H),
2.2-2.55 (m, 2H), 2.6-2.7 (m, 1H), 3.55 (d, 2H, J ) 13.8 Hz),
3.75 (d, 2H, J ) 13.8 Hz), 4.6-4.7 (m, 1H), 7.1-7.3 (m, 10H).
13C NMR: δC 22.2, 23.4, 24.7, 26.5, 28.2, 35.4, 54.4, 58.1, 80.4,
127.0, 128.2, 128.9, 139.6, 177.4. HRMS: m/z calcd for C23H29
-
NO2 352.2277 [M + H], found 352.2185. Data for the minor
isomer (5S,1′S)-5-(1′-(dibenzylamino)-3′-methylbutyl)dihydro-
furan-2(3H)-one (7b ) are as follows. 1H NMR (300 MHz,
CDCl3): δH (distinguished signals) 0.47 (d, 3H, J ) 6.45 Hz),
0.80 (d, 3H, J ) 6.45 Hz), 3.64 (d, 2H, J ) 13.18 Hz), 3.69 (d,
2H, J ) 13.18 Hz), 4.55 (dt, 1H, J ) 7.32, 7.92 Hz).
(5R,1′S)-5-(1′-(Dib en zyla m in o)-2′-m et h ylp r op yl)-d ih y-
d r ofu r a n -2(3H)-on e (6c). [R]25 ) -12.8° (c ) 0.46, CHCl3).
D
1H NMR (300 MHz, CDCl3): δH 1.06 (d, 3H, J ) 7.03 Hz), 1.10
(d, 3H, J ) 7.0 Hz), 1.95-2.05 (m, 1H), 2.2-2.3 (m, 4H), 2.4-
2.5 (m, 1H), 3.59 (d, 2H, J ) 13.4 Hz), 3.71 (d, 2H, J ) 13.4 Hz),
4,76 (dt, 1H, J ) 7.6, 6.8 Hz). 13C NMR: δC 19.2, 23.1, 25.1,
27.1, 27.8, 54.5, 64.2, 79.2, 127.0, 128.2, 129.2, 139.2, 177.3. Anal.
Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C, 78.52;
H, 8.36; N, 4.27. Data for the minor isomer (5S,1′S)-5-(1′-
(dibenzylamino)-2′-methylpropyl)dihydrofuran-2(3H)-one (7c) are
as follows. 1H NMR (300 MHz, CDCl3): δH 0.87 (d, 3H, J ) 6.81
Hz), 1.03 (d, 3H, 7.03 Hz), 1.5-1.6 (m, 1H), 1.9-2.1 (m, 3H),
2.5-2.6 (m, 3H, including CHN), 3.82 (d, 2H, J ) 13.18 Hz),
3.89 (d, 2H, J ) 13.4 Hz), 4.81 (dt, 1H, J ) 8.4, 6.8 Hz).
(5R,1′S)-5-(1′-(Diben zyla m in o)eth yl)d ih ydr ofu r a n -2(3H)-
R ea ct ion of (1S,2R)-N-Met h ylep h ed r in yl Acr yla t e
4
w ith (2S)-N,N-Diben zyl-3-p h en ylp r op a n a l (2a ). Under a
nitrogen atmosphere, samarium powder (99.9%; 225 mg, 1.5
mmol) was placed in a 50 mL Schlenk tube equipped with a
magnetic stirring bar. A dry THF (10 mL) solution of diiodo-
methane (400 mg, 1.5 mmol) was added using a syringe through
a septum. The mixture was then stirred for 2 h at room
temperature, and the samarium(II) iodide solution was obtained
as a deep green solution. The Schlenk tube was cooled in a ice
bath, and a mixture of 4 (140 mg, 0.6 mmol), 2a (165 mg, 0.5
mmol), and t-BuOH (42 mg, 0.6 mmol) in THF (1 mL) was slowly
injected over a period of 5 min. The resulting solution is stirred
at 0 °C for 2 h, during which time the deep green color of the
solution faded. The solution was hydrolyzed with 20 mL of
saturated ammonium chloride. Passing it through Celite filtered
off the insoluble part, and the aqueous phase was extracted with
three 20 mL portions of ethyl acetate. The organic phase was
washed with brine and then dried over magnesium sulfate. The
solvent was removed under reduced pressure to give the crude
product as a pale yellow oil. 1H NMR measurement of the crude
product revealed that the product was obtained as a mixture of
diastereomers in the ratio 6a :7a ) 92:8. The product was
isolated by preparative TLC on silica gel (2:1 hexane/ethyl
acetate as eluent) to afford the pure (5R,1′S)-5-(1′-(dibenzyl-
amino)-2′-phenylethyl)dihydrofuran-2(3H)-one (6a ) as a pale
yellow liquid (108 mg, 0.28 mmol, 56% yield based on 2a ). The
82% diastereomeric excess of the product was further confirmed
by conversion to the corresponding diol 8a by HPLC using a
chiral column (Chiralpack AD).
on e (6d ). [R]25 ) +20.7° (c ) 0.34, CHCl3) (lit.2c +24.0°). 1H
D
NMR (300 MHz, CDCl3): δH 1.20 (d, 3H, J ) 6.8 Hz), 1.9-2.1
(m, 1H), 2.2-2.4 (m, 3H), 2.69 (quint, 1H, J ) 7.0 Hz), 3.44 (d,
2H, J ) 13.8 Hz), 3.72, (d, 2H, J ) 13.8 Hz), 4.42 (dt, 1H, J )
7.0, 7.3 Hz), 7.2-7.4 (m, 10H). 13C NMR: δC 8.8, 26.1, 28.1, 54.2,
56.3, 82.6, 127.0, 128.3, 128.8, 139.4, 177.3. HRMS: m/z calcd
for C20H23NO2 310.1807 [M + H], found 310.1580. Data for the
minor isomer (5S,1′S)-5-(1′-(dibenzylamino)ethyl)-dihydrofuran-
2(3H)-one (7d ) are as follows. 1H NMR (300 MHz, CDCl3): δH
(distinguished signals) 4.1-4.2 (m, 1H).
Ack n ow led gm en t. We wish to thank the Institute
of Science and Engineering, Chuo University, for finan-
cial support.
Su p p or tin g In for m a tion Ava ila ble: Figures giving 1H
and 13C NMR spectra of the major products 6a -d . This
material is available free of charge via the Internet at
http/pubs.acs.org.
(8) Hou, Z.; Wakatsuki, Y. J . Chem. Soc., Chem. Commun. 1994,
1205.
(9) Reez, T.; Drewes, M. W.; Schwickardi, R. Org. Synth. 1998, 76,
110.
J O020574H
2044 J . Org. Chem., Vol. 68, No. 5, 2003