Enantioselective allylation of nitro group-stabilized carbanions catalyzed by chiral crown ether phosphine-palladium complexes

Article abstract of DOI:10.1021/jo961343b

Enantioselective allylations of α-nitro ketones (3) and α-nitro esters (15) with allyl acetate were carried out in the presence of 2 equiv of alkali metal fluorides (KF, RbF, CsF) and 1 mol % of palladium catalysts prepared in situ from Pd₂(dba)₃·CHCl₃ and chiral phosphine ligands. Moderate enantioselectivities were observed in the reaction of nitro ketones 3, giving products 4 (4a, 49% ee; 4b, 58% ee; 4c, 44% ee) when rubidium fluoride and ferrocenylphosphine ligands bearing monoaza-15-crown-5 (1b) or monoaza-18-crown-6 (1c) moieties were used as a base and a chiral ligand, respectively. Optically active allylation product 4a was converted into 1-methyl-1-azaspiro[4.5]-decan-10-amine (13), a precursor to opioid receptor binding agents. Enantioselectivity in the reaction of nitro esters 15 increased in accord with increasing steric demand of the ester alkyl group (Me < Et < t-Bu). The highest selectivity (80% ee) for the reaction of tert-butyl ester 15c was observed when the reaction was carried out at -40 °C in the presence of the palladium catalyst with the ligand (1c) bearing a monoaza-18-crown-6 moiety, RbF (2 equiv), and RbClO₄ (1 equiv). The pronounced effect of the crown ether moiety for both enantioselection and rate acceleration can be explained by assuming the formation of a ternary complex involving the crown ether, rubidium cation, and enolate anion at the stereodifferentiating transition state. Optically active nitro ester (R)-16c was converted into (R)-α-methylglutamic acid (20).

Full text of DOI:10.1021/jo961343b

9090
J . Org. Chem. 1996, 61, 9090-9096
En a n tioselective Allyla tion of Nitr o Gr ou p -Sta bilized Ca r ba n ion s
Ca ta lyzed by Ch ir a l Cr ow n Eth er P h osp h in e-P a lla d iu m
Com p lexes
Masaya Sawamura,*,† Yuki Nakayama,‡ Wen-Ming Tang,‡,§ and Yoshihiko Ito*,‡
Department of Chemistry, School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113, J apan, and Department of Synthetic Chemistry and Biological Chemistry,
Faculty of Engineering, Kyoto University, Kyoto 606-01, J apan
Received J uly 15, 1996X
Enantioselective allylations of R-nitro ketones (3) and R-nitro esters (15) with allyl acetate were
carried out in the presence of 2 equiv of alkali metal fluorides (KF, RbF, CsF) and 1 mol % of
palladium catalysts prepared in situ from Pd2(dba)3‚CHCl3 and chiral phosphine ligands. Moderate
enantioselectivities were observed in the reaction of nitro ketones 3, giving products 4 (4a , 49% ee;
4b, 58% ee; 4c, 44% ee) when rubidium fluoride and ferrocenylphosphine ligands bearing monoaza-
15-crown-5 (1b) or monoaza-18-crown-6 (1c) moieties were used as a base and a chiral ligand,
respectively. Optically active allylation product 4a was converted into 1-methyl-1-azaspiro[4.5]-
decan-10-amine (13), a precursor to opioid receptor binding agents. Enantioselectivity in the reaction
of nitro esters 15 increased in accord with increasing steric demand of the ester alkyl group (Me <
Et < t-Bu). The highest selectivity (80% ee) for the reaction of tert-butyl ester 15c was observed
when the reaction was carried out at -40 °C in the presence of the palladium catalyst with the
ligand (1c) bearing a monoaza-18-crown-6 moiety, RbF (2 equiv), and RbClO4 (1 equiv). The
pronounced effect of the crown ether moiety for both enantioselection and rate acceleration can be
explained by assuming the formation of a ternary complex involving the crown ether, rubidium
cation, and enolate anion at the stereodifferentiating transition state. Optically active nitro ester
(R)-16c was converted into (R)-R-methylglutamic acid (20).
In tr od u ction
and limitations of this type of reaction but also to achieve
the highest enantioselectivity possible. In this context,
we examined several nitro compounds such as R-nitro
ketones (3a -c) and R-nitro esters (15a -c) as a new class
of substrates for the enantioselective palladium-catalyzed
allylation.7 Since the nitro group can be easily converted
Stereocontrol by a chiral catalyst in the palladium-
catalyzed enantioselective allylation of prochiral stabi-
lized carbanions is an extremely difficult task because a
chiral ligand is located far from the prochiral nucleophile
attacking the π-allyl carbon of the (π-allyl)palladium(II)
intermediate and the nucleophile does not interact with
the palladium atom directly at the stereodifferentiating
transition state.1,2 We have previously reported that
reasonably high enantioselectivity can be obtained in the
allylation of â-diketone enolates by employing properly
designed chiral phosphines bearing an aza crown ether
moiety as ligands of the palladium catalysts.3,4 The
crown ether phosphines were designed so as to have a
secondary interaction with the reacting substrate5,6 by
forming a crown ether-metal enolate inclusion complex.
However, the mechanism of stereocontrol remains to be
clarified. In order to gain a deeper insight into the
stereocontrol by means of the secondary ligand-substrate
interaction, it is important not only to expand the scope
(3) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J . Am. Chem.
Soc. 1992, 114, 2586.
(4) Reexamination of the enantiomeric excesses of the allylation
product of 2-acetylcyclohexanone by GLC analysis with Chiraldex G-TA
(0.25 mm × 30 m, 120 °C, base-line separation) revealed that the
reported ee values in refs 1c and 3, which had been determined by 1H
NMR analyses with a chiral shift reagent and by optical rotations of
the allylation product, respectively, had been overestimated by aproxi-
mately 15%. The highest ee values for this allylation product reported
in ref 1c (81% ee) and ref 3 (75% ee) should be revised to 70% ee and
65% ee, respectively. The ee value (65% ee) for the allylation product
of 2-acetylcyclopentanone reported in ref 3, which had been determined
by 1H NMR analysis with a chiral shift reagent, was confirmed to be
correct by GLC analysis with Chiraldex G-TA (120 °C, base-line
separation). Separation of the allylation product of 2-methyl-1-phen-
ylbutane-1,3-dione by chiral GLC was not successful.
(5) For a review, see: Sawamura, M.; Ito, Y. Chem. Rev. 1992, 92,
857.
(6) For recent papers in accord with this concept, see: (a) Sawamura,
M.; Kitayama, K.; Ito, Y. Tetrahedron: Asymmetry 1993, 4, 1829. (b)
Ward, J .; Bo¨rner, A.; Kagan, H. B. Tetrahedron: Asymmetry 1992, 3,
849. (c) Bo¨rner, A.; Holz, J .; Kless, A.; Heller, D.; Berens, U.
Tetrahedron Lett. 1994, 35, 6071. (d) Bo¨rner, A.; Ward, J .; Ruth, W.;
Holz, J .; Kless, A.; Heller, D.; Kagan, H. B. Tetrahedron 1994, 50,
10419. (e) Holz, J .; Bo¨rner, A.; Kless, A.; Borns, S.; Trinkhaus, S.; Selke,
R.; Heller, D. Tetrahedron: Asymmetry 1995, 6, 1973. (f) Bo¨rner, A.;
Kless, A.; Kempe, R.; Heller, D.; Holz, J .; Baumann, W. Chem. Ber.
1995, 128, 767. (g) Bo¨rner, A.; Holz, J .; Ward, J .; Kagan, H. B. J . Org.
Chem. 1993, 58, 6814. (h) Bo¨rner, A.; Kless, A.; Holz, J .; Baumann,
W.; Tillack, A.; Kadyrov, R. J . Organomet. Chem. 1995, 490, 213. (i)
Kless, A.; Kadyrov, R.; Bo¨rner, A.; Holz, J .; Kagan, H. B. Tetrahedron
Lett. 1995, 36, 4601. (j) Fields, L. B.; J acobsen, E. N. Tetrahedron:
Asymmetry 1993, 4, 2229. (k) Yamazaki, A.; Morimoto, T.; Achiwa, K.
Tetrahedron: Asymmetry 1993, 4, 2287. (l) Yamazaki, A.; Achiwa, K.
Tetrahedron: Asymmetry 1995, 6, 51. (m) Spencer, J .; Gramlich, V.;
Ha¨usel, R.; Togni, A. Tetrahedron: Asymmetry 1996, 7, 41. (n)
MacFarland, D. K.; Landis, C. R. Organometallics 1996, 15, 483. (o)
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J . Am. Chem.
Soc. 1995, 117, 6194. (p) Kimmich, B. F. M.; Landis, C. R.; Powell, D.
R. Organometallics 1996, 15, 4141.
† The University of Tokyo.
‡ Kyoto University.
§ On leave from Department of Chemistry, Guizhou Teachers
University, China.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) (a) Fiaud, J .-C.; Hibon De Gournary, A.; Larcheveque, M. Kagan,
H. B. J . Organomet. Chem. 1978, 154, 175. (b) Hayashi, T.; Kanehira,
K.; Tsuchiya, H.; Kumada, M. J . Chem. Soc., Chem. Commun. 1982,
1162. (c) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J . Org.
Chem. 1988, 53, 113. (d) Ito, Y.; Sawamura, M.; Matsuoka, M.;
Matsumoto, Y.; Hayashi, T. Tetrahedron Lett. 1987, 28, 4849. (e) Genet,
J .-P.; Ferroud, D.; J uge, S.; Montes, J . R. Tetrahedron Lett. 1986, 27,
4573. (f) Genet, J .-P.; J uge, S.; Montes, J . R.; Gaudin, J . M. J . Chem.
Soc., Chem. Commun. 1988, 718. (g) Genet, J .-P.; J uge, S.; Achi, S.;
Mallart, S.; Montes, J . R.; Levif, G. Tetrahedron 1988, 44, 5263.
(2) Exceptionally high selectivities have been reported in the enan-
tioselective allylation of 2-cyanopropionate promoted by a palladium-
rhodium two-component catalyst system: Sawamura, M.; Sudoh, M.;
Ito, Y. J . Am. Chem. Soc. 1996, 118, 3309.
S0022-3263(96)01343-6 CCC: $12.00 © 1996 American Chemical Society

Allylation of Nitro Group-Stabilized Carbanions
J . Org. Chem., Vol. 61, No. 26, 1996 9091
Ta ble 1. En a n tioselective Allyla tion of
2-Nitr ocycloh exa n on e (3a ) w ith Allyl Aceta te in th e
P r esen ce of P d -(S)-(R)-1c Ca ta lysta
Sch em e 1
4a
concn, M yield,b % ee,c % (confign)
3a
entry base
solvent
1
2
3
4
5
6
7
8
KF
KF
KF
KF
mesitylene
toluene
THF
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
40
47
66
33
50
57
28
31
14 (R)
19 (R)
25 (R)
25 (R)
29 (R)
38 (R)
42 (R)
31 (R)
CH2Cl2
RbF THF
RbF CH2Cl2
RbF CH2Cl2
CsF CH2Cl2
a
Reaction was carried out in 2 mL of solvent at -25 °C for 40
h. 3a (1 mmol):allyl acetate:base:Pd2(dba)3‚CHCl3:(S)-(R)-1c )
1:1.5:2.0:0.005:0.0105. Isolated yield by PTLC. c Determined by
b
GLC analysis of 4a with Chiraldex G-TA (150 °C, base-line
separation).
Ta ble 2. Liga n d Effect in th e P a lla d iu m -Ca ta lyzed
En a n tioselective Allyla tion of 2-Nitr ocycloh exa n on e (3a )
w ith Allyl Aceta tea
4a
concn, M yield,b % ee,c % (confign)
3a
entry
chiral ligand
(S)-(R)-1a
(S)-(R)-1b
(S)-(R)-1c
(S)-(R)-1d
(S)-(R)-1e
(S)-(R)-1f
(S)-(R)-2a
(S)-(R)-2b
(S)-(R)-2c
(R)-BINAP
(S,S)-CHIRAPHOS
(R)-DIOP
into an amino group, these reactions may be regarded
as equivalents of enantioselective allylations of R-amino
ketones and R-amino esters (acids), respectively.8
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
1.0
0.5
0.7
0.7
0.7
0.5
0.5
0.5
9
27
28
48
40
11
8
22
17
18
2
4 (R)
41 (R)
42 (R)
39 (R)
17 (R)
31 (R)
2 (R)
2 (S)
Resu lts a n d Discu ssion
En a n tioselective Allyla tion of r-Nitr o Keton es
(Scheme 1, Tables 1-3). The reaction of 2-nitrocyclo-
hexanone (3a ) with allyl acetate was carried out at -25
°C in the presence of alkali metal fluorides (MF, 2 equiv;
M ) K, Rb, Cs) and the palladium catalysts (1 mol %)
prepared in situ from Pd2(dba)3‚CHCl3 and chiral phos-
phine ligands.
6 (R)
15 (R)
<1
10
11
12
14
<1
a
Reaction was carried out in CH2Cl2 (2 mL) at -25 °C for 40 h.
RbF was used for base. 3a (1 mmol):allyl acetate:RbF:Pd2(dba)3‚
b
CHCl3:chiral ligand ) 1:1.5:2.0:0.005:0.0105. Isolated yield by
PTLC. c Determined by GLC analysis of 4a with Chiraldex G-TA
(150 °C, base-line separation).
after 40 h in order to compare the reactivity. Allylation
product 4a was isolated by PTLC, and enantiomeric
excesses were determined by GLC analysis with chiral
stationary phase column Chiraldex G-TA (0.25 mm × 30
m, 150 °C, base-line separation). The reaction conditions
employed for asymmetric allylation of â-diketones, which
use KF and mesitylene for a base and a solvent, respec-
tively, gave the product (4a ) with only 14% ee (R) (Table
1, entry 1). Slightly higher selectivities were obtained
in toluene, THF, and CH2Cl2 (Table 1, entries 2-4). As
shown in entries 5 and 6 (Table 1), RbF was found to be
a better base, giving (R)-4a with 29% ee and 38% ee in
THF and CH2Cl2, respectively. The later selectivity was
further improved to 42% by carrying out the reaction at
a slightly lower concentration (ca. 0.5 M) (Table 1, entry
7). CsF was less effective in both reactivity and selectiv-
ity (Table 1, entry 8).
Then, the effect of the ring size of crown ether and the
length of tether were examined for reactivity and enan-
tioselectivity using RbF in CH2Cl2 (Table 2). The ligand
(1a ) tethered to monoaza-12-crown-4 with a dimethylene
group gave almost racemic product in only 9% yield
(Table 2, entry 1). The ligand (1b) tethered to monoaza-
15-crown-5 was found to be as effective as 1c in both
reactivity and selectivity (Table 2, entry 2). The highest
yield was obtained with the ligand bearing 1,10-diaza-
18-crown-6 1d , while the enantioselectivity was slightly
lower than that obtained using 1b and 1c (Table 2, entry
4). The enantioselectivity drastically decreased with the
Table 1 summarizes the results with the ferroce-
nylphosphine ligand tethered to monoaza-18-crown-6
with dimethylene group 1c. The reaction was quenched
(7) For the palladium-catalyzed allylic alkylations of nitro group-
stabilized carbanions, see the following. For R-nitro ketones: (a)
Ognyanov, V.; Hesse, M. Synthesis 1985, 645. For R-nitro esters: (b)
Genet, J . P.; Ferroud, D. Tetrahedron Lett. 1984, 25, 3579. (c) Genet,
J . P.; Grisoni, S. Tetrahedron Lett. 1986, 27, 4165. (d) Lalonde, J . J .;
Bergbreiter, D. E.; Wong, C.-H. J . Org. Chem. 1988, 53, 2323. For
nitroalkanes: (e) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura,
T.; Takahashi, K. J . Org. Chem. 1985, 50, 1523. (f) Deardorff, D. R.;
Savin, K. A.; J ustman, C. J .; Karanjawala, Z. E.; Sheppeck, J . E., II;
Hager, D. C.; Aydin, N. J . Org. Chem. 1996, 61, 3616.
(8) For the use of 2-nitropropionates for the preparation of R-
methylated R-amino acids, see: Robinson, B.; Shepherd, D. M. J . Chem.
Soc. 1961, 5037. See also ref 7d.

9092 J . Org. Chem., Vol. 61, No. 26, 1996
Sawamura et al.
Ta ble 3. P a lla d iu m -Ca ta lyzed En a n tioselective
Sch em e 2
Allyla tion of r-Nitr o Keton es (3a -c) w ith Allyl Aceta tea
3
entry
2
chiral ligand time, h yield,b % ee,c % (confign)
1
2
3
2a
2b
2c
(S)-(R)-1b
(S)-(R)-1c
(S)-(R)-1b
120
260
94
74 (3a )
95 (3b)
95 (3c)
49 (R)
58 (R)
44 (R)
a
Reaction was carried out in CH2Cl2 (2 mL) at -25 °C. RbF
was used for base. 3 (1 mmol):allyl acetate:RbF:Pd2(dba)3‚CHCl3:
b
chiral ligand ) 1:1.5:2.0:0.005:0.0105. Isolated yield by PTLC.
c Determined by GLC analysis of 4 with Chiraldex G-TA (150 °C,
base-line separation).
ligand-bearing monoaza-21-crown-7 1e (Table 2, entry 5).
The ligand (1f) tethered to monoaza-18-crown-6 by tri-
methylene group gave (R)-4a with lower enantiomeric
excess (31%) in only 11% yield (Table 2, entry 6). The
ferrocenylphosphines lacking the crown ether moiety
(2a -c)1c,9 and other nonfunctionalized chiral ligands such
as BINAP,10 CHIRAPHOS,11 and DIOP12 were much less
effective in both reactivity and selectivity, most of them
giving almost racemic product (Table 2, entries 7-12),
showing the crucial importance of the ligand crown ether
moiety.
The results of the palladium-catalyzed asymmetric
allylation of R-nitro ketones 3a -c in the optimized
reaction conditions are summarized in Table 3. The
reaction of 3a in the presence of the palladium catalyst
with 1b was led to completion in 120 h to give (R)-4a in
74% yield (Table 3, entry 1). It should be noted that the
product enantiomeric excess (49% ee) is also significantly
improved as compared with that in Table 2, entry 2 (41%
ee). Higher enantioselectivity (58% ee) with the same
chiral sense was observed for the reaction of 6,6-dimethyl-
2-nitrocyclohexanone (3b) (Table 3, entry 2). 2-Nitrocy-
cloheptanone (3c) was allylated more selectively with
ligand 1b (44% ee, Table 3, entry 3) rather than with 1c
(31% ee).
Sch em e 3
In order to determine the absolute configuration and
to show a synthetic utility, allylation product 4a was
converted into 1-methyl-1-azaspiro[4.5]decan-10-amine
(13),13 whose N-acyl derivatives are reported to show
potent opioid receptor binding activity (Scheme 2). The
carbonyl group of nitro ketone 4a with rotation [R]20
D
+47.8 (CHCl3) (36% ee) was protected as acetal, and then
the vinyl group of acetal 5 was converted to carboxylic
acid by sequential oxidation with 9-BBN/H2O2 and PDC.
Esterification of the carboxylic acid gave nitro ester 7.
The nitro group of 7 was hydrogenated in the presence
of Raney Ni to form an amino ester, which underwent
ring closure during the hydrogenation to give spiro
lactam 8. The lactam was then reduced to secondary
amine 9 with LiAlH4 and converted into carbamate 10.
The hydrolysis of acetal followed by condensation with
O-methylhydroxylamine gave N-methoxyimine 12. Di-
determined to be R by X-ray crystal structure analysis
of the major diastereomer of amide 14, which was
obtained by the condensation with (R)-O-methylmandelic
acid.
The absolute configuration of 4b was determined by
comparing its CD spectrum with that of 4a (see the
supporting information). The configuration of 4c was
assigned on the basis of the comparison of the sign of
the optical rotations and the pattern of GLC (Chiraldex
G-TA) separation with those of 4a and 4b.
E n a n t ioselect ive Allyla t ion of r-Nit r o E st er s
(Scheme 3, Table 4). The enantioselective allylation of
2-nitro-2-propionates (15a -c) with different ester alkyl
groups were first carried out in CH2Cl2 at -25 °C in the
13
astereoselective reduction of 12 with LiAlH4 gave
desired diamine 13 (100% de), whose configuration was
(9) (a) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Na-
gashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.;
Yamamoto, K.; Kumada, M. Bull. Chem. Soc. J pn. 1980, 53, 1138. (b)
Hayashi, T.; Yamazaki, A. J . Organomet. Chem. 1991, 413, 295.
(10) (R)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl: Takaya, H.;
Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.;
Akutagawa, S.; Noyori, R. J . Org. Chem. 1986, 51, 629.
(11) (S,S)-1,2-Bis(diphenylphosphino)butane: Fryzuk, M. D.; Bos-
nich, B. J . Am. Chem. Soc. 1977, 99, 6262.
(12) (S,S)-2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino)butane: Kagan, H. B.; Dang, T. P. J . Am. Chem. Soc. 1972, 94,
6429.
(13) Fujimoto, R. A.; Boxer, J .; J ackson, R. H.; Simke, J . P.; Neale,
R. F.; Snowhill, E. W.; Barbaz, B. J .; Williams, M.; Sills, M. A. J . Med.
Chem. 1989, 32, 1259.

Allylation of Nitro Group-Stabilized Carbanions
J . Org. Chem., Vol. 61, No. 26, 1996 9093
Ta ble 4. P a lla d iu m -Ca ta lyzed En a n tioselective Allyla tion of 2-Nitr op r op ion a tes (15) w ith Allyl Aceta tea
16
entry
R (15)
chiral ligand
base
additiveb
T, °C
yield,c %
ee,d % (confign)
1
2
3
4
5
Me (15a )
Et (15b)
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1c
(S)-(R)-1b
(S)-(R)-1b
(S)-(R)-1d
(S)-(R)-1e
(S)-(R)-2a
(S)-(R)-2c
KF
KF
KF
-25
-25
-25
-25
-25
-25
-25
-40
-25
-25
-25
-25
-25
-25
43 (16a )
44 (16b)
95 (16c)
95 (16c)
91 (16c)
88 (16c)
98 (16c)
92 (16c)
95 (16c)
91 (16c)
60 (16c)
89 (16c)
72 (16c)
14 (16c)
23 (R)
37 (R)
51 (R)
60 (R)
34 (R)
64 (R)
69 (R)
80 (R)
20 (R)
18 (R)
51 (R)
11 (R)
12 (S)
1 (S)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
t-Bu (15c)
RbF
CsF
RbF
RbF
RbF
KF
RbF
RbF
RbF
RbF
RbF
6e
7e
8e,f
9
RbClO4
RbClO4
10
11
12
13
14
a
Reaction was carried out in CH2Cl2 (2 mL) for 40 h unless otherwise noted. 15 (1 mmol):allyl acetate:MF:Pd2(dba)3‚CHCl3:chiral
ligand ) 1:1.5:2.0:0.005:0.0105. 15:RbClO4 ) 1:1. c Isolated yield by PTLC. Determined by GLC analysis of the products with Chiraldex
G-TA (90 °C) for 16a ,b and by HPLC analysis of 17 (see Scheme 3 and Experimental Section for the transformation) with SUMICHIRAL
OA-4400 (hexane:ClCH2CH2Cl:EtOH ) 225:20:1) for 16c (base-line separation except for 16a ). e Reaction was carried out in 6 mL of
CH2Cl2. f Reaction time was 70 h.
b
d
Sch em e 4
presence of 2 equiv of KF and 1 mol % of the palladium
catalyst containing the ferrocenylphosphine ligand (1c)
tethered to 18-crown-6 by a dimethylene group, and the
rates of reactions were compared on the basis of isolated
yields (PTLC) of allylation products 16a -c (Table 4,
entries 1-3). The enantioselectivity for the R-isomer
increased continuously from 23% to 51% with increasing
steric demand of the ester alkyl group (Me < Et < t-Bu).
The observed reactivities were not expected; i.e., while
methyl (15a ) and ethyl ester (15b) gave only 43% and
44% yields, complete conversion was observed for the
reaction of the sterically most demanding tert-butyl ester
(15c). Aggregation of enolates in the cases of the
sterically less demanding nitro esters might be respon-
sible for the unexpected reactivities. As in the cases of
the reaction of nitro ketone 3a , the enantioselectivity was
dependent on the counter cations of metal fluoride bases
(Table 4, entries 3-5), and the highest selectivity was
again observed with RbF (60% ee). The selectivity was
improved by using a large amount of CH2Cl2 solvent (64%
ee, Table 4, entry 6) with RbClO4 (69% ee, Table 4, entry
7) and then further improved to 80% ee (92% yield) by
carrying out the reaction at -40 °C for 70 h (Table 4,
entry 8).14 We speculate that the added RbClO4 might
have increased a ratio of Rb+-bound ligand to free
ligand.15 When the ligand (1b) tethered to monoaza-15-
crown-5 was used, the reactions proceeded smoothly but
the selectivities were only 20% ee and 18% ee with KF
and RbF, respectively (Table 4, entries 9 and 10). The
ligands bearing 1,10-diaza-18-crown-6 (1d ) were less
efficient in terms of both catalytic activity and enantio-
selectivity compared with 1c (Table 4, entry 11). As
shown in entries 12-14 (Table 4), the reactions using of
the ligand bearing a monoaza-21-crown-7 moiety (1e) and
the ferrocenylphosphines (2a ,c) lacking a crown ether
moiety gave almost racemic product.
product (R)-16d (64% ee) was subjected to hydrobora-
tion-oxidation (9-BBN/H2O2) to give alcohol 18. The
alcohol was then oxidized to carboxylic acid 19 with PDC.
The reduction of nitro group by catalytic transfer hydro-
genation (Pd/C, HCO2NH4)18 followed by hydrolysis of
tert-butyl ester with CF3CO2H gave, after treatment with
an ion-exchange column, optically active R-methylglutam-
ic acid 20. The absolute configuration of 16d was
determined by comparing the optical rotation of this
amino acid with the reported value.17
Mech a n ism of En a n tioselection . Unlike the enan-
tioselective allylation of â-diketones,3 relatively high
enantioselectivities were obtained with rubidium fluoride
rather than potassium fluoride in the reaction of both
nitro ketones and nitro esters. It is obvious that rela-
tively high reactivity and enantioselectivity were ob-
served when a ferrocenylphosphine bearing a proper
crown ether moiety was employed as a chiral ligand of
palladium catalyst. The ligand bearing a monoaza-18-
crown-6 moiety (1c), whose ring size is complementary
with the size of rubidium cation, generally gave good
results in terms of both reactivity and selectivity, while
the ligand bearing the crown ether moiety of smaller ring
size (1b) showed the comparable enantioselectivities only
Since the nitro group can be easily converted into an
amino group, the allylation product thus obtained is
considered to be useful synthetic intermediate for opti-
cally active R-methylated R-amino acids.16 For example,
the conversion of (R)-16d to R-methylglutamic acid (20)17
was carried out as shown in Scheme 4. The allylation
(16) For the synthesis and biological activity of optically active
R-alkylated amino acids, see: Moon, S.-H.; Ohfune, Y. J . Am. Chem.
Soc. 1994, 116, 7405 and references cited therein.
(17) (a) Izumi, Y.; Tatsumi, S.; Imaida, M.; Fukuda, Y.; Akabori, S.
Bull. Chem. Soc. J pn. 1965, 38, 1338. (b) Abei, J . D.; Seebach, D. Helv.
Chim. Acta 1985, 68, 1507. (c) Colson, P.-J .; Hegedus, L. S. J . Org.
Chem. 1993, 58, 5918.
(14) The ee was not further improved by lowering the reaction
temperature to -50 °C; 7 days, 77% yield, 79% ee.
(15) No effect of RbClO4 was observed in the enantioselective
allylation of nitro ketone 3a .
(18) Ram, S.; Ehrenkaufer, R. E. Synthesis 1986, 133.

9094 J . Org. Chem., Vol. 61, No. 26, 1996
Sawamura et al.
prepacked C.I.G. (Kusano) column. The chiral stationary
phase columns Chiraldex G-TA (for GLC, 0.25 mm × 30 m)
and Sumichiral OA-4400 (for HPLC) were purchased from
Advanced Separation Technologies, Inc., and Sumitomo Chemi-
cal Co., respectively.
6,6-Dim eth yl-2-n itr ocycloh exa n on e (3b) was prepared
from 9.8 g (77 mmol) of 6,6-dimethylcyclohexanone22 according
to the literature procedure20 for the preparation of 3a as
colorless crystals in 40% yield: mp 98.5-100 °C; 1H NMR (200
MHz, CDCl3, TMS) δ 1.16 (s, 3H), 1.27 (s, 3H), 1.58-1.99 (m,
4H), 2.27-2.61 (m, 2H), 5.53 (dd, J ) 12.8, 6.3 Hz, 1H); 13C-
{1H} NMR (100 MHz, CDCl3, TMS) δ 18.81, 24.20, 24.97,
31.99, 40.21, 46.31, 89.67, 202.86. Anal. Calcd for C8H13
-
NO3: C, 56.12; H, 7.65; N, 8.18. Found: C, 55.98; H, 7.88; N,
8.02.
Gen er al P r ocedu r e for th e P alladiu m -Catalyzed En an -
tioselective Allyla tion s of r-Nitr o Keton es 3 a n d r-Nitr o
Ester s 15. In a small glass vessel, chiral ligand (0.0105 mmol)
and Pd2(dba)3‚CHCl3 (0.0050 mmol) were dissolved in 1 mL of
reaction solvent. After being stirred for 1 h at rt, the solution
was transferred to a 20-mL Schlenk tube containing metal
fluoride (2.0 mmol) by using 1 mL of solvent (in the case of
Table 4, entries 6-8, 4 mL more of solvent was added here).
The nitro compound (3 or 15, 1.00 mmol) was added to the
suspension at rt, and the mixture was cooled to a given
reaction temperature before addition of allyl acetate (1.5
mmol). The reaction mixture was kept for a given reaction
time at the same temperature. The reaction was quenched
with 5% hydrochloric acid and extracted with ether four times.
The combined organic phases were washed with saturated
aqueous NaHCO3, dried over MgSO4, and concentrated under
reduced pressure. The allylation product (4 or 16) was isolated
by PTLC on silica gel.
2-Allyl-2-n itr ocycloh exa n on e (4a ):7a [R]25D +54.5 (c 1.35,
CHCl3) (41% ee); 1H NMR (200 MHz, CDCl3, TMS) δ 1.55-
1.91 (m, 4H), 1.91-2.16 (m, 1H), 2.47-2.71 (m, 3H), 2.71-
2.95 (m, 2H), 5.05-5.25 (m, 2H), 5.59-5.82 (m, 1H); 13C{1H}
NMR (50 MHz, CDCl3, TMS) δ 21.2, 26.7, 36.0, 39.6, 39.8, 96.7,
120.7, 130.1, 200.1. Anal. Calcd for C9H13NO3: C, 59.00; H,
7.15; N, 7.65. Found: C, 59.27; H, 7.30; N, 7.69.
F igu r e 1. Illustration of possible nucleophilic attack of the
rubidium enolate of 15 (or 3) to the π-allylpalladium(II)
complex bearing chiral ligand (S,R)-1c.
in the case of the reaction of nitro ketones (3). Even
though more work is needed to understand the role of
the rubidium cation and monoaza crown ether, the
pronounced effect of the monoaza crown ether suggests
that this metal cation-binding site interacts with the
rubidium enolate attaking the π-allylpalladium complex
and that such an interaction plays an important role for
the enantioselection as well as the rate acceleration. On
the basis of the absolute configuration of products, we
speculate that enolate anion of the nitro compound
attacks one of the terminal π-allyl carbon atom in such
a way that a bulky substituent (R1 for 3, OR for 15) can
avoid the steric repulsion against one of the ligand phenyl
groups as visualized in Figure 1.19
Con clu sion
We presented a new example of enantioselective reac-
tion in which a secondary interaction between a chiral
ligand and a substrate plays an important role for the
stereocontrol. An enantioselectivity as high as 80% was
achieved in the palladium-catalyzed asymmetric allyla-
tion of nitro ester with a bulky ester alkyl group (15c)
through the modification of chiral phosphine ligand with
metal cation-binding crown ether moiety while the
selectivity was moderate for the reaction of nitro ketones
(3). We believe that the results presented here may be
helpful for future mechanistic studies of palladium-
catalyzed enantioselective allylic alkylation and that our
chiral crown ether phosphine ligands are potentially
applicable to other enantioselective catalytic processes
involving main group metal ion species such as metal
enolates, alkoxides and acetylides.
2-Allyl-6,6-d im eth yl-2-n itr ocycloh exa n on e (4b): [R]25
D
+55.0 (c 1.30, CHCl3) (57% ee); 1H NMR (200 MHz, CDCl3,
TMS) δ 1.12 (s, 3H), 1.15 (s, 3H), 1.58-2.09 (m, 5H), 2.63 (dd,
J ) 13.0, 7.0 Hz, 1H), 2.78-2.99 (m, 2H), 5.07-5.22 (m, 2H),
5.52-5.73 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3, TMS) δ
17.31, 25.90, 26.91, 34.13, 39.44, 41.72, 46.93, 94.41, 120.97,
130.33, 203.80. Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11;
N, 6.63. Found: C, 62.84; H, 8.25; N, 6.65.
2-Allyl-2-n itr ocycloh ep ta n on e (4c): [R]25D +11.1 (c 1.51,
CHCl3) (43% ee); 1H NMR (200 MHz, CDCl3, TMS) δ 1.40-
2.06 (m, 7H), 2.36-2.80 (m, 4H), 3.02 (dd, J ) 14.2, 6.7 Hz,
1H), 5.10-5.22 (m, 2H), 5.59-5.80 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3, TMS) δ 24.37, 25.39, 29.27, 33.64, 41.21(2C),
99.15, 121.11, 130.16, 202.15. Anal. Calcd for C10H15NO3: C,
60.84; H, 7.67; N, 7.10. Found: C, 60.95; H, 7.80; N, 7.13.
(R)-6-Nitr o-6-(2′-pr open yl)-1,4-dioxaspir o[4.5]decan e (5).
A solution of (R)-3a (2.27 g, 12.4 mmol, 36% ee), p-TsOH‚H2O
(180 mg, 0.95 mmol), and ethylene glycol (14 mL, 251 mmol)
in 70 mL of benzene was refluxed for 7 days. Saturated
aqueous NaHCO3 was added and extracted with ether four
times. The combined organic phases were washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
The residue was distilled (108-109 °C/0.5 mmHg) and purified
by preparative HPLC (YMC-SH 543-5, hexane:AcOEt ) 14:
1) to afford 1.01 g (36%) of (R)-5: [R]25D +14.5 (c 1.78, CHCl3);
1H NMR (200 MHz, CDCl3, TMS) δ 1.21-1.50 (m, 1H), 1.58-
1.82 (m, 5H), 2.08 (dt, J ) 14.5, 4.3 Hz, 1H), 2.39 (td, J )
13.1, 3.2 Hz, 1H), 2.59 (dd, J ) 14.4, 8.0 Hz, 1H), 3.36 (dd, J
) 14.7, 6.4 Hz, 1H), 3.87-4.01 (m, 4H), 5.11-5.21 (m, 2H),
5.42-5.63 (m, 1H); 13C{1H} NMR (50 MHz, CDCl3, TMS) δ
21.5, 22.4, 29.4, 33.6, 35.8, 65.2, 94.6, 109.6, 120.4, 130.3.
Anal. Calcd for C11H17NO4: C, 58.13; H, 7.54; N, 6.19.
Found: C, 58.38; H, 7.50; N, 6.19.
Exp er im en ta l Section
Ma ter ia ls. Unless otherwise noted, materials were ob-
tained from commercial suppliers and used without further
purification. R-Nitro ketones 3a ,c,20 Pd2(dba)3‚CHCl3,21 and
ferrocenylphosphines 1a -f3 and 2a -c1c,9 were prepared ac-
cording to the literature procedures. 2-Nitropropionates 15a ,b
were distilled before use. Preparative medium-pressure liquid
chromatography (MPLC) was performed with a silica gel
(19) For other examples of proposed ternary complexes involving
crown ether, metal cation, and enolate anion, see: (a) Cram, D. J .;
Sogah, D. Y. J . Chem. Soc., Chem. Commun. 1981, 625. (b) De Vries,
E. F. J .; Ploeg, L.; Colao, M.; Brussee, J .; Van der Gen, A. Tetrahe-
dron: Asymmetry 1995, 6, 1123.
(20) (a) Fischer, R. H.; Weitz, H. M. Synthesis 1980, 261. (b) Bischoff,
C.; Schro¨der, E. J . Prakt. Chem. 1972, 314, 891.
(21) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J . J .; Ibers, J . A. J .
Organomet. Chem. 1974, 65, 253.
(22) Bailey, W. J .; Madoff, M. J . Am. Chem. Soc. 1954, 76, 2707.

Allylation of Nitro Group-Stabilized Carbanions
J . Org. Chem., Vol. 61, No. 26, 1996 9095
(R)-6-(3′-H yd r oxyp r op yl)-6-n it r o-1,4-d ioxa sp ir o[4.5]-
d eca n e (6). A solution of (R)-5 (1.01 g, 4.44 mmol) in 5 mL
of THF was added to a solution of 9-BBN (2.17 g, 8.89 mmol)
in 10 mL of THF at 0 °C. The mixture was stirred for 3.5 h at
0 °C and for 1 h at rt and then treated with 0.1 mL of water.
After the mixture was cooled to 0 °C, 3 N NaOH (2.6 mL) and
30% H2O2 (3.65 mL) was carefully added in this order. Water
was added and extracted with AcOEt three times. The
combined organic phases were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (hexane/
211.1207, found 211.1196. Anal. Calcd for C11H19NO2: C,
66.97; H,9.71; N, 7.10. Found: C, 66.71; H, 10.00; N, 6.97.
(R)-1,3-Dioxola n e-2-sp ir ocycloh exa n e-2′-sp ir o-2′′-1′′-
(eth oxyca r bon yl)a za cyclop en ta n e (10). A solution of ethyl
chloroformate (603 mg, 5.56 mmol) in 3 mL of CH2Cl2 was
slowly added to a solution of (R)-9 (182.2 mg, 0.92 mmol) in
1.3 mL of Et3N. After 1 h of stirring at rt, the mixture was
combined with water and extracted with AcOEt three times.
The combined organic phases were dried over MgSO4 and
concentrated under reduced pressure. The residue was puri-
fied by bulb-to-bulb distillation (180 °C/0.2 mmHg) to afford
224.9 mg (90%) of (R)-10: [R]25D +7.0 (c 1.46, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS) δ 1.19-2.84 (m, 9H), 1.25 (t, 3H),
1.91-2.15 (m, 1H), 2.21-2.37(m, 1H), 3.12-3.34 (m, 1H),
3.35-3.66 (m, 2H), 3.76-3.96 (m, 4H), 4.02-4.23 (m, 2H); 13C-
{1H} NMR (50 MHz, CDCl3, TMS) δ 14.8, 21.6, 23.3, 23.5, 34.4,
35.1, 36.6, 49.6, 65.0, 65.1, 66.2, 70.0, 113.0, 155.4; HRMS (EI)
calcd for C14H23NO4 (M+) 269.1626, found 269.1625. Anal.
Calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C,
61.65; H, 8.45; N, 5.27.
AcOEt) to afford 1.04 g (95%) of (R)-6: [R]25 -3.9 (c 1.71,
D
CHCl3); 1H NMR (200 MHz, CDCl3, TMS) δ 1.10-1.14 (m, 4H),
1.14-1.85 (m, 5H), 1.92-2.15 (m, 2H), 2.44 (dddd, J ) 9.9,
9.9, 3.8, 1.2 Hz, 1H), 3.52-3.80 (m, 2H), 3.86-4.02 (m, 4H)
(OH not detected); 13C{1H} NMR (50 MHz, CDCl3, TMS) δ 21.6,
22.4, 26.2, 27.7, 29.3, 33.6, 62.2, 65.1, 65.2, 95.0, 109.9. Anal.
Calcd for C11H19NO5: C, 53.86; H, 7.80; N, 5.74. Found: C,
54.08; H, 8.00; N, 5.55.
(R)-6-[2′-(Met h oxyca r b on yl)et h yl]-6-n it r o-1,4-d ioxa -
sp ir o[4.5]d eca n e (7). PDC (5.57 g, 14.79 mmol) was added
to a solution of (R)-6 (1.04 g, 4.23 mmol) in 11 mL and stirred
at rt for 36 h. The mixture was diluted with ether, passed
through a pad of Celite, and concentrated by heating at 45 °C
under a reduced pressure. This procedure was repeated once
more to give crude carboxylic acid (961 mg). For esterification,
the carboxylic acid was dissolved in 5 mL of THF and 10 mL
of ether and treated with a solution of CH2N2 in ether. The
excess CH2N2 was decomposed with AcOH. The mixture was
washed with saturated aqueous NaHCO3, extracted with ether
three times, dried over MgSO4, and concentrated under
reduced pressure. Purification of the residue by MPLC (silica
(R)-6-Oxo-1-(et h oxyca r b on yl)-1-a za sp ir o[4.5]d eca n e
(11). A solution of (R)-10 (224.9 mg, 0.84 mmol) in 0.5 mL of
CH2Cl2 was treated with 22 mL of 10% hydrochloric acid and
stirred for 19 h at rt. The mixture was extracted with AcOEt
three times, and the combined organic phases were washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by MPLC (silica gel,
hexane:AcOEt ) 1:1) followed by bulb-to-bulb distillation to
afford 132 mg (70%) of (R)-11: [R]25 -10.2 (c 1.14, CHCl3);
D
1H NMR (200 MHz, CDCl3, TMS) δ 1.23 (dt, J ) 14.2, 7.2 Hz,
3H), 1.47-2.17 (m, 9H), 2.23-2.45 (m, 1H), 2.46-2.80 (m, 2H),
3.46-3.67 (m, 2H), 4.03-4.22 (m, 2H); 13C{1H} NMR (50 MHz,
CDCl3, TMS) δ 14.0 and 14.7 (2 s), 22.3 and 22.9 (2 s), 23.3
and 23.5 (2 s), 24.6 and 24.7 (2 s), 35.6 and 36.7 (2 s), 37.1
and 38.2 (2 s), 39.8 (s), 47.8 and 48.4 (2 s), 60.77 and 60.85 (2
s), 71.1 and 71.5 (2 s), 154.5 and 154.9 (2 s), 208.0 and 208.3
(2 s). Anal. Calcd for C12H19NO3: C, 63.98; H, 8.50; N, 6.22.
Found: C, 63.82; H, 8.65; N, 6.03.
gel, hexane:AcOEt ) 2:1) afforded 597 mg (52%) of (R)-7: [R]25
D
-5.8 (c 0.92, CHCl3); 1H NMR (200 MHz, CDCl3, TMS) δ 1.17-
1.47 (m, 1H), 1.47-1.82 (m, 5H), 1.97 (dtd, J ) 13.8, 4.0, 1.7
Hz, 1H), 2.10-2.34 (m, 3H), 2.46 (dddd, J ) 15.9, 12.3, 3.8,
1.1 Hz, 1H), 2.91 (dddd, J ) 17.5, 11.6, 3.1, 1.4 Hz, 1H), 3.68
(s, 3H), 3.86-4.02 (m, 4H); 13C{1H} NMR (50 MHz, CDCl3,
TMS) δ 21.6, 22.3, 26.5, 28.2, 29.5, 33.5, 51.8, 65.2, 94.3, 109.7,
172.6. Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N, 5.13.
Found: C, 52.75; H, 7.15; N, 5.06.
(R)-1-(Eth oxyca r bon yl)-6-(m eth oxyim in o)-1-a za sp ir o-
[4.5]d eca n e (12). A solution of (R)-11 (122 mg, 0.54 mmol)
in 1.3 mL of pyridine was treated with H2NOMe‚HCl (301 mg,
3.60 mmol) and stirred for 23 h at rt. The reaction mixture
was diluted with 3 mL of water, made alkaline with 3 N
NaOH, and extracted with CH2Cl2 three times. The combined
organic phases were washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was
purified by PTLC (silica gel, hexane:AcOEt ) 1:1) to afford
120 mg (87%) of (R)-12: [R]25D +16.7 (c 1.44, CHCl3); 1H NMR
(200 MHz, CDCl3, TMS) δ 1.24 (dt, J ) 6.7, 6.7 Hz, 3H), 1.30-
1.97 (m, 9H), 2.02-2.16 (m, 1H), 2.48-2.68 and 2.84-3.03 (m,
1H + 1H′), 3.18-3.25 and 3.25-3.32 (m, 1H + 1H′), 3.36-
(R)-1,3-Dioxola n e-2-sp ir ocycloh exa n e-2′-sp ir o-5′′-2′′-
p yr r olid in on e (8). Raney Ni (W7) (ca. 200 mg) was added
to a solution of (R)-7 (113 mg, 0.413 mmol) in MeOH (2 mL),
and the mixture was stirred in an autoclave at 30 °C at a
hydrogen pressure of 100 atm. After the mixture was stirred
for 2 d, progress of the reaction was checked by TLC, which
indicated the remains of the starting material. Raney Ni (ca.
200 mg) was added, and the mixture was again subjected to
the hydrogenation for 4 d. After the completion of reaction
was confirmed by TLC, the mixture was passed through a pad
of Celite and evaporated. The residue was then purified by
chromatography on silica gel (hexane:AcOEt, Et2NH) followed
by bulb-to-bulb distillation (200 °C/0.2 mmHg) to afford 52 mg
(60%) of (R)-8: [R]25D -9.6 (c 1.07, CHCl3); 1H NMR (200 MHz,
CDCl3, TMS) δ 1.18-1.93 (m, 9H), 2.22-2.40 (m, 2H), 2.44-
2.65 (m, 1H), 3.83-4.10 (m, 4H), 5.64 (br s, 1H); 13C{1H} NMR
(50 MHz, CDCl3, TMS) δ 21.7, 22.9, 28.5, 30.5, 32.0, 37.5, 64.5,
65.3, 65.7, 111.0, 177.9; HRMS (EI) calcd for C11H17NO3 (M+)
211.1207, found 211.1196. Anal. Calcd for C11H17NO3: C,
62.53; H, 8.16; N, 6.66. Found: C, 61.97; H, 8.24; N, 6.59.
(R)-1,3-Dioxola n e-2-sp ir ocycloh exa n e-2′-sp ir o-2′′-p yr -
r olid in e (9). LiAlH4 (168 mg, 4.42 mmol) was added at 0 °C
to a solution of (R)-8 (232.6 mg, 1.10 mmol) in 5 mL of THF.
The mixture was then refluxed for 40 h and quenched at 0 °C
by sequential additions of water (168 µL), 15% NaOH (168 µL),
and water (504 µL). After the mixture was stirred at rt for 30
min, the aluminum salts were filtered off with a pad of Celite
and washed with THF. The filtrate and washings were
combined and concentrated under reduced pressure. The
residue was then purified by bulb-to-bulb distillation (120 °C/
0.2 mmHg) to afford 182 mg (84%) of (R)-9: [R]25D -0.9 (c 0.86,
CHCl3); 1H NMR (200 MHz, CDCl3, TMS) δ 1.22-1.98 (m,
13H), 2.83-3.04 (m, 2H), 3.92-4.11 (m, 4H); 13C{1H} NMR
(50 MHz, CDCl3, TMS) δ 22.7, 23.1, 26.1, 32.2, 32.3, 37.3, 46.7,
64.8, 65.0, 67.0, 112.3; HRMS (EI) calcd for C11H19NO3 (M+)
3.50 (m, 1H), 3.77 (s, 3H), 3.96-4.27 (m, 2H);
13C{1H} NMR
(50 MHz, CDCl3, TMS) δ 14.7 and 14.9 (2 s), 21.2 and 21.4 (2
s), 23.1 and 23.2 (2 s), 23.36 and 23.43 (2 s), 23.9 (s), 36.2 and
37.1 (2 s), 38.5 and 39.6 (2 s), 47.9 and 48.5 (2 s), 60.2 and
60.4 (2 s), 61.6 (s), 65.7 and 66.4 (2 s), 154.4 and 155.7 (2 s),
157.3 and 157.9 (2 s). Anal. Calcd for C13H22N2O3: C, 61.39;
H, 8.72; N, 11.01. Found: C, 61.11; H, 8.95; N, 10.89.
(R)-1-Meth yl-1-a za sp ir o[4.5]d eca n -6-a m in e (13).13 Li-
AlH4 (170 mg, 4.47 mmol) was added to a solution of (R)-12
(105 mg, 0.414 mmol) in 4.5 mL of THF at 0 °C. After 7 h of
stirring at rt, the mixture was diluted with 5 mL of ether and
cooled to 0 °C before being quenched by sequential additions
of water (170 µL), 15% NaOH (170 µL), and water (510 µL).
The mixture was stirred for 1 h at rt, and aluminum salts were
filtered off with a pad of Celite and washed with THF. The
combined filtrate and washings were concentrated under
reduced pressure. The residue was purified by bulb-to-bulb
distillation (180 °C/16 mmHg) to afford 65 mg (93%) of (R)-
1
13: [R]25 -1.20 (c 1.25, CHCl3); H NMR (200 MHz, CDCl3,
D
TMS) δ 1.10-1.95 (m, 14H), 2.23 (s, 3H), 2.46-2.67 (m, 2H),
2.87-2.98 (m, 1H).
(2R,5′R)-N-(1′-Meth yl-1′-a za sp ir o[4.5]d ec-6′-yl)-2-m eth -
oxy-2-p h en yla ceta m id e (14). A solution of (R)-13 (6.5 mg,
38.5 µmol) in 150 µL of CH2Cl2 was added to a mixture of (R)-
R-methoxy-R-phenylacetic acid (13 mg, 78.2 µmol), DCC (15.7

9096 J . Org. Chem., Vol. 61, No. 26, 1996
Sawamura et al.
mg, 76.1 µmol), and CH2Cl2 (100 µL) and stirred for 23 h at
rt. The mixture was filtered and concentrated under reduced
pressure. The residue was treated with AcOEt and cooled to
0 °C. The precipitates were filtered off, and the filtrate was
concentrated under reduced pressure. The 1H NMR spectrum
of the residue indicated that the diastereomer ratio is in the
range of 2:1 to 3:1. From this mixture, the major isomer (5.5
mg) was isolated by PTLC (silica gel, AcOEt, Et2NH): 1H NMR
(200 MHz, CDCl3, TMS) δ 1.12-1.48 (m, 5H), 1.57-1.88 (m,
6H), 2.12 (s, 3H), 2.16-2.30 (m, 1H), 2.52-2.70 (m, 1H), 2.82-
2.96 (m, 1H), 3.37 (s, 3H), 3.61-3.74 (m, 1H), 4.57 (s, 1H), 6.84
(br d, J ) ca. 5 Hz, 1 H), 7.27-7.48 (m, 5H).
The configuration of the major isomer was determined to
be (2R,5′R) by X-ray structure analysis of a single crystal
obtained from a ligroin solution by slow evaporation of the
solvent.
ter t-Bu tyl 2-n itr op r op ion a te (15c) was prepared in 72%
yield according to the literature procedure23 for the preparation
of a related compound (MPLC): 1H NMR (200 MHz, CDCl3,
TMS) δ 1.49 (s, 9H), 1.75 (d, J ) 7.1 Hz, 3H), 5.11 (q, J ) 7.0
Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3, TMS) δ 15.6, 27.6,
83.9, 84.4, 164.0.
30 min at 0 °C and for 2.5 h at rt and then treated with 0.12
mL of water. After the mixture was cooled to 0 °C, 3 N NaOH
(2.8 mL) and 30% H2O2 (4.1 mL) were carefully added in this
order. The mixture was stirred at rt for 1.5 h. Water was
then added and the mixture extracted with AcOEt three times.
The combined organic phases were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (hexane/
AcOEt) to afford 0.892 g (77%) of (R)-18: [R]25 +4.1 (c 1.39,
D
CHCl3); 1H NMR (200 MHz, CDCl3, TMS) δ 1.48 (s, 9H), 1.43-
1.71 (m, 2H), 1.76 (s, 3H), 2.10-2.40 (m, 2H), 3.67 (t, J ) 6.5
Hz, 2H) (OH not detected); 13C{1H} NMR (50 MHz, CDCl3,
TMS) δ 21.2, 26.8, 27.5, 32.9, 61.8, 84.0, 93.0, 166.2. Anal.
Calcd for C10H19NO5: C, 51.49; H, 8.21; N, 6.00. Found: C,
51.48; H, 8.39; N, 5.84.
(R)-4-(ter t-Bu toxycar bon yl)-4-n itr open tan oic Acid (19).
PDC (4.42 g, 11.74 mmol) was added to a solution of (R)-18
(783 mg, 3.36 mmol) in 9.2 mL and the resulting mixture
stirred for 3 h at 0 °C and then for 12 h at rt. The mixture
was diluted with ether, passed through a pad of Celite, and
concentrated by heating at 45 °C under reduced pressure. The
residue was purified by chromatography on silica gel (hexane/
AcOEt/MeOH) to afford crude (R)-19, which was used without
further purification: 1H NMR (200 MHz, CDCl3, TMS) δ 1.48
(s, 9H), 1.76 (s, 3H), 2.38-2.55 (m, 4H) 8.03 (s, 1H).
Meth yl (R)-2-m eth yl-2-n itr o-4-p en ten oa te (16a ):7d [R]25
D
+4.7 (c 1.00, CHCl3) (12% ee); 1H NMR (200 MHz, CDCl3,
TMS) δ 1.77 (s, 3H), 2.88 (dd, J ) 14.2, 7.3 Hz, 1H), 3.00 (dd,
J ) 14.2, 7.2 Hz, 1H), 3.28 (s, 3H), 5.14-5.27 (m, 2H), 5.56-
5.77 (m, 1H).
(R)-2-Meth ylglu ta m ic Acid (20). To a solution of (R)-19
(605 mg, 2.45 mmol) in 16 mL of MeOH were successively
added 10% Pd/C (302 mg) and HCO2NH4 (1.76 g, 28 mmol).
After 32 h of stirring at rt, the mixture was filtered through a
pad of Celite and concentrated under reduced pressure. The
residual colorless solid was dissolved in 5 mL of CF3CO2H and
stirred overnight. After evaporation of CF3CO2H, the residue
was subjected to an ion-exchange column (Amberlite IR-120B
H+ form). The column was washed with water. Elution with
5% aqueous NH4OH followed by evaporation gave crude amino
acid 20, which was then recrystallized from a mixture of ether
Eth yl (R)-2-m eth yl-2-n itr o-4-p en ten oa te (16b): [R]25
D
+9.4 (c 1.11, CHCl3) (35% ee); 1H NMR (200 MHz, CDCl3,
TMS) δ 1.29 (t, J ) 7.2 Hz, 3H), 1.76 (s, 3H), 2.87 (dd, J )
14.1, 7.5 Hz, 1H), 2.99 (dd, J ) 14.1, 7.3 Hz, 1H), 4.27 (q, J )
7.1 Hz, 2H), 5.16-5.28 (m, 2H), 5.56-5.77 (m, 1H); 13C{1H}
NMR (50 MHz, CDCl3, TMS) δ 13.8, 21.0, 40.8, 62.8, 92.0,
121.5, 129.6, 167.0. Anal. Calcd for C8H13NO4: C, 51.33; H,
7.00; N, 7.48. Found: C, 51.46; H, 7.14; N, 7.54.
ter t-Bu tyl (R)-2-m eth yl-2-n itr o-4-pen ten oate (16c): [R]25
D
+12.5 (c 1.26, CHCl3) (66.0% ee); 1H NMR (200 MHz, CDCl3,
TMS) δ 1.47 (s, 9H), 1.72 (s, 3H), 2.83 (dd, J ) 14.1, 7.3 Hz,
1H), 2.95 (dd, J ) 14.1 Hz, 7.1 Hz, 1H), 5.15-5.27 (m, 2H),
5.56-5.77 (m, 1H); 13C{1H} NMR (50 MHz, CDCl3, TMS) δ
21.0, 27.6, 40.9, 84.0, 92.5, 121.2, 129.8, 165.8. Anal. Calcd
for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.79;
H, 8.22; N, 6.42.
and MeOH to afford 201 mg (51%) of colorless crystals: [R]25
D
-4.6 (c 2.02, 6 N HCl) [lit.16a [R]rtD -12.1 (c 4, 6 N HCl) for (R)
1
isomer]; H NMR (200 MHz, D2O, TPS) δ 1.49 (s, 3H), 1.97-
2.09 (m, 2H), 2.23-2.34 (m, 2H).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 8 and 10 and CD spectra of 4a ,b (5 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
ter t-Bu tyl (R)-5-Hyd r oxy-2-m eth yl-2-n itr op en ta n oa te
(18). A solution of (R)-16c (1.07 g, 4.95 mmol, 64% ee) in 10
mL of THF was added to a solution of 9-BBN (1.22 g, 10.0
mmol) in 10 mL of THF at 0 °C. The mixture was stirred for
(23) Kornblum, N.; Blackwood, R. K. Organic Syntheses; J ohn Wiley
& Sons: New York, 1963; Collect. Vol. 4, p 454.
J O961343B