Chiral 2-endo-substituted 9-oxabispidines: Novel ligands for enantioselective copper(ii)-catalyzed henry reactions

Article abstract of DOI:10.1002/chem.200901789

A flexible approach, applicable on a gram scale, to chiral 2-endosubstituted 9-oxabispidines was developed. The key intermediate, a cis-configured 6-aminomethylmorpholine-2carbonitrile, was prepared from (R)-3aminopropane-1,2-diol and 2-chloroacrylonitril

Full text of DOI:10.1002/chem.200901789

DOI: 10.1002/chem.200901789
Chiral 2-endo-Substituted 9-Oxabispidines: Novel Ligands for
Enantioselective Copper(II)-Catalyzed Henry Reactions
Matthias Breuning,*[a] David Hein,[a] Melanie Steiner,[a] Viktoria H. Gessner,[b] and
Carsten Strohmann[b]
Abstract: A flexible approach, applica-
ble on a gram scale, to chiral 2-endo-
substituted 9-oxabispidines was devel-
oped. The key intermediate, a cis-con-
figured 6-aminomethylmorpholine-2-
carbonitrile, was prepared from (R)-3-
aminopropane-1,2-diol and 2-chloro-
thus furnishing the enantiomerically
pure bi- and tricyclic 9-oxabispidines in
19–59% yield. The CuCl2 complex of
the tricyclic 9-oxabispidine, which car-
ries an 2-endo,N-anellated piperidine
ring, is an excellent catalyst for enan-
tioselective Henry reactions giving the
S-configured b-nitro alcohols in 91–
98% ee (13 examples). Surprisingly, the
analogous copper complexes of the bi-
cyclic 9-oxabispidines delivered the
Keywords: aldol reaction · asym-
metric synthesis · enantioselective
catalysis · nitrogen heterocycles ·
oxabispidines
A
enantiocomplementary
R-configured
was introduced by Grignard addition,
cyclization, and exo-selective reduction,
products in 33–57% ee. The respective
transition states were discussed.
Introduction
growing number of transition-metal-catalyzed asymmetric
transformations.[4–7] The restricted accessibility of synthetic
bispidines, however, seriously hampers structural modifica-
tions.[6] The few known total syntheses[8] are time-consuming
and do not permit facile variations, in particular the stereo-
chemically decisive endo-annelated rings in 1 and 2.[6,9] To
address this problem, we investigated the structurally closely
related bi- and tricyclic 9-oxabispidines of types 3 and 4.
The formal substitution of the methylene bridge by an ether
function offered new synthetic options as previously shown
in the preparation of some derivatives.[10,11] In addition, the
high potential of 4 as a chiral ligand was recently proven in
the PdII-catalyzed oxidative kinetic resolution of secondary
alcohols.[11] Herein we report on a novel and efficient ap-
proach to chiral 9-oxabispidines that allows a flexible late-
stage introduction of a 2-endo substituent or an annelated
ring. Upon application of these diamines in CuII-catalyzed
Henry reactions, they provide excellent enantiomeric excess-
es of up to 98%.
The two most prominent chiral bispidines (3,7-diazabicyclo-
[3.3.1]nonanes) are the alkaloid (ꢀ)-sparteine (1) and the
truncated (+)-sparteine surrogate 2 derived from the natural
product (ꢀ)-cytisine.[1] Both diamines are powerful chiral li-
gands successfully used in numerous enantioselective depro-
tonation–electrophilic trapping reactions[1–3] and a steadily
[a] Dr. M. Breuning, D. Hein, M. Steiner
Institut fꢀr Organische Chemie
Universitꢁt Wꢀrzburg
Am Hubland, 97074 Wꢀrzburg (Germany)
Fax : (+49)931-888-4755
E-mail: breuning@chemie.uni-wuerzburg.de
Results and Discussion
[b] V. H. Gessner, Prof. Dr. C. Strohmann
Institut fꢀr Anorganische Chemie
The stereoselective synthesis of the key intermediate, the
cis-configured 2-cyanomorpholine (cis-7; Scheme 1), was
achieved in five steps and 30% overall yield or seven steps
and 46% overall yield starting with the commercially avail-
able chiral aminodiol 5, which was converted into the diami-
Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Supporting information for this article, including general methods
and further reactions, is available on the WWW under http://
dx.doi.org/10.1002/chem.200901789.
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Chem. Eur. J. 2009, 15, 12764 – 12769

FULL PAPER
Addition of a Grignard reagent RMgX afforded the amino
ketones 10, which were deprotected at the nitrogen atom
and cyclized by filtration through basic alumina to give the
imines 11. Reduction of the double bond with sodium boro-
hydride occurred highly stereoselectively from the less-hin-
dered exo side, thus establishing the required endo orienta-
tion of R in 12. Direct N-methylation of 12a,d (R=Ph, Et)
or, as in the case of the derivatives 12b,c (R=iPr, Cy) that
are carrying more sterically encumbering substituents, acyla-
tion–reduction provided 3a–d[14] in 19–59% overall yield
from cis-7.
The tricyclic 9-oxabispidine 4[14] was prepared similarly
(Scheme 2). After addition of 4-chlorobutyl magnesium bro-
mide to cis-7, the resulting ketone 13 was N-deprotected.
Simple filtration through basic alumina induced a twofold
cyclization to the iminium salt 14, which was reduced to
give 4 in just three steps and 51% overall yield.
Scheme 1. Synthesis of the key intermediate cis-7 (Boc=tert-butoxycar-
bonyl, Ts=tosyl, TFAA=trifluoroacetic anhydride).
no alcohol 6 in analogy to a known sequence (67%
yield).[12] Michael addition of 6 to 2-chloroacrylonitrile and
subsequent KOtBu-mediated cyclization furnished an easily
separable 42:58 mixture of trans-7 and cis-7. The unwanted
minor diastereomer trans-7 was epimerized to cis-7 using a
two-step protocol: Treatment with KOtBu in warm anhy-
drous tBuOH afforded the cis-amide 9, which was dehydrat-
ed with TFAA providing cis-7 in 62% yield. The unexpected
formation of 9 is probably the result of an addition of
tBuOH to the nitrile function of trans-7, isomerization to
give 8, and b elimination.[13]
Scheme 2. Final steps to the tricyclic 9-oxabispidine 4 (TFA=trifluoro-
acetic acid).
Many efficient catalysts are known for enantioselective
Henry reactions,[15,16] among them, Maheswaranꢃs complex
[CuCl2{(ꢀ)-sparteine}],[4] which delivered good to excellent
79–96% ee in the addition of nitromethane to several alde-
hydes. The promising results prompted us to choose this
transformation as the model reaction for an evaluation of
the potential of the 9-oxabispidines. The required CuCl2
complexes 15a–d and 16 were obtained as greenish solids by
simple treatment of 3a–d and 4 with CuCl2 in methanol.
The further conversion of the intermediate cis-7 into the
bicyclic 9-oxabispidines 3a–d was straightforward (Table 1):
Table 1. Final steps to the bicyclic 9-oxabispidines 3a–d.
3, 10–12
R
10
11
12
3
Yield [%]
Yield [%]
Yield [%]
Yield [%]
a
b
c
Et
96
68
56
81
99
99
94
99
82
67
58[a]
42
In the crystal structure of catalyst 16 (Figure 1),[17,18] the
highly distorted geometry at the central copper atom is
striking. With an angle of 62.58 between the CuCl2 and the
CuN2 plane, the copper atom adopts an intermediate ar-
iPr
Cy
Ph
76[a]
92
d
80
[a] Overall yield from 11.
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12765

M. Breuning et al.
Table 3. Enantioselective Henry reactions catalyzed by 16.[19]
Entry 17, 18
R
t [h] Yield [%][a] ee [%][b] Configuration
1
2
3
4
5
6
7
8
a
c
d
e
f
b
g
h
i
j
k
l
m
a
a
4-O2N-Ph
3-O2N-Ph
2-O2N-Ph
4-MeO-Ph
3-MeO-Ph
2-MeO-Ph
4-Cl-Ph
18 95
18 95
18 94
99 81
99 92
18 91
99 81
18 92
144[c] 82
168 85
95
92
97
91
96
97
95
98
95
93
94
92
96
95
94
S
S
S
S
S
S
S
S
Figure 1. Crystal structure of 16.[17]
2-Cl-Ph
Ph
9
S
10
11
12
13
14[e]
15[f]
2-furyl
R[d]
S
PhACTHNGUTERNNUG
(CH2)2 144[c] 81
rangement between a square-planar geometry, as it would
be expected for a d10 Cu complex, and a tetrahedral one,
thus showing the strong impact of the chiral diamine 4 on
the coordination sphere.
iBu
nOct
4-O2N-Ph
4-O2N-Ph
168[c] 45
168[c] 44
18 95
S
S
S
S
18 95
The results of the additions of nitromethane to 4-nitro-
benzaldehyde (17a) and 2-methoxybenzaldehyde (17b) in
the presence of 15a–d (20 mol% each) are summarized in
Table 2.[19] All reactions were performed at ꢀ108C with
[a] Isolated yields. [b] Determined by HPLC on the chiral phase. [c] Re-
actions run at RT. [d] Formal inversion of the stereodescriptor due to the
Cahn–Ingold–Prelog (CIP) notation. [e] 10 mol% of 16 and 1.5 mol% of
NEt3 were used. [f] 5 mol% of 16 and 0.75 mol% of NEt3 were used.
Table 2. Enantioselective Henry reactions catalyzed by 15a–d.
which reacted slowly even at RT, the isolated yields of 18
were high (81–95%). The S-configured products (S)-18 were
preferentially formed with 16 in all cases. This is in sharp
contrast to the Henry reactions catalyzed by the bicyclic
copper complexes 15a–d (see Table 2), which preferentially
delivered the enantiocomplementary b-nitro alcohols (R)-
18.
Furthermore, the enantio- and diastereoselective addition
of nitroethane to 17a (Scheme 3) furnished the anti-adduct
19 in a good anti/syn ratio of 80:20 and in high 94% ee
(95% yield).
Entry 17, 18 Cat. t [h] Yield [%][a] ee [%][b] Configuration
1
2
3
4
5
6
7
a
a
a
a
b
b
b
15a
15b
15c
15d
15b
15c
15d
18
36
39
22
36
42
24
96
91
91
93
86
88
90
36
33
39
56
38
46
57
R
R
R
R
R
R
R
[a] Isolated yields. [b] Determined by HPLC on the chiral phase.
3 mol% of triethylamine as an additional base in a nitrome-
thane/methanol solvent system to afford the R-configured b-
nitro alcohols (R)-18a and (R)-18b in good yields of 86–
96%, albeit with low 33–57% ee. The observed stereoselec-
tivities slightly improved with an increased steric demand of
the substituent R (EtꢁiPr<Cy<Ph).
Scheme 3. Addition of nitroethane to 17a catalyzed by 16.
Catalyst 16, which possesses the tricyclic 9-oxabispidine 4
as the chiral ligand, was evaluated next (Table 3).[19] Excel-
lent enantiomeric excesses in the range of 91–98% were ob-
tained with all of the aromatic (17a–i), heteroaromatic
(17j), and aliphatic (17k–m) aldehydes tested. Thus, catalyst
16 gave distinctly better asymmetric inductions than the
complexes 15a–d and the known complex [CuCl2{(ꢀ)-spar-
teine}].[4] A reduction of the amount of catalyst did not lead
to any significant loss in enantioselectivity, as demonstrated
on 17a as the model substrate. The b-nitro alcohol 18a was
obtained in 94–95% ee with 20, 10, and 5 mol% of 16 (en-
tries 1, 14, and 15). With the exception of 17l and 17m,
The unexpected opposite stereochemical behavior of 15a–
d and 16 might be explained by the transition states 20 and
21 (Scheme 4). Based on known models,[15,20] we propose a
Scheme 4. Proposed transition states 20 and 21.
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9-Oxabispidines
FULL PAPER
(100 MHz, CDCl3): d=28.3 (CMe3), 42.6 (6-CH2), 45.6 (NMe), 56.0 (C-
5), 56.5 (C-3), 64.3 (C-2), 75.9 (C-6), 79.7 (CMe3), 116.4 (CN), 155.9 ppm
(CO2); IR (film): v˜ =3360, 2978, 2941, 2810, 2252, 1710, 1519, 1459, 1366,
1253, 1172, 1113 cmꢀ1; HRMS (ESI+): m/z: calcd for C12H21N3NaO3
[M+Na]+: 278.1475; found: 278.1474; elemental analysis calcd (%) for
C12H21N3O3 (255.31): C 56.45, H 8.29, N 16.46; found: C 56.13, H 8.25, N
16.17.
pentavalent copper species in which the nitronate is posi-
tioned perpendicular to the ligand plane, while two nonequi-
valent equatorial sites are available for the coordination of
the aldehyde. In the transition state 20, the aldehyde is
probably bound to the more easily accessible northern posi-
tion, thus leading to the observed R-configured b-nitro alco-
hols. By contrast, a complexation at the southern position
might occur in 21, which would result in the formation of
the S-configured products. Most likely, the latter alignment
is energetically strongly favored since it avoids the otherwise
larger steric repulsion between the chloride ligand and the
annelated piperidine ring of the chiral diamine 4, which
reaches deeply into the active site.
Compound 9: The nitrile trans-7 (8.77 g, 34.4 mmol) was dissolved in an-
hydrous tBuOH (750 mL), and KOtBu (3.86 g, 34.4 mmol) was added.
The reaction mixture was stirred for 16 h at 558C, quenched with saturat-
ed aqueous NH4Cl (600 mL), and extracted with EtOAc (4ꢄ200 mL).
The combined organic layers were washed with brine (200 mL), dried
over MgSO4, and evaporated to give the amide 9 (5.92 g, 21.7 mmol,
63%) as a colorless oil. M.p. 548C; [a]2D1 =+8.75 (c=0.09 in MeOH);
1H NMR (400 MHz, CDCl3): d=1.44 (s, 9H; CMe3), 1.80 (t, J=10.9 Hz,
1H; 5-Hax), 1.88 (t, J=11.2 Hz, 1H; 3-Hax), 2.30 (s, 1H; NMe), 2.71 (d,
J=11.4 Hz, 1H; 5-Heq), 3.15 (d, J=11.2 Hz, 1H; 3-Heq), 3.20–3.37 (m,
2H; 6-CH2), 3.69 (m, 1H; 6-H), 4.10 (dd, J=10.8, 2.7 Hz, 1H; 2-Hax),
4.89 (brs, 1H; BocNH), 5.82 (brs, 1H; NHH), 6.64 ppm (brs, 1H;
NHH); 13C NMR (100 MHz, CDCl3): d=28.3 (CMe3), 43.0 (6-CH2), 45.9
(NMe), 56.3 (C-3), 56.7 (C-5), 75.3 (C-2), 75.4 (C-6), 79.6 (CMe3), 156.0
(CO2), 172.5 ppm (CONH2); IR (KBr): v˜ =3384, 2978, 2941, 2877, 2802,
1694, 1533, 1366, 1253, 1173, 1118 cmꢀ1; HRMS (ESI+): m/z: calcd for
C12H24N3O4 [M+H]+: 274.1761; found: 274.1761.
Conclusion
In summary, we have developed a novel and highly flexible
approach to chiral 9-oxabispidines of types 3 and 4. The
CuCl2 complex 16 with the tricyclic diamine 4 is an efficient
catalyst for asymmetric Henry reactions delivering the b-
nitro alcohols in excellent 91–98% ee. Surprisingly, the
enantiocomplementary products were obtained with the
analogous complexes 15a–d derived from the bicyclic 9-oxa-
bispidines 3. Further investigations on this issue are in prog-
ress.
Dehydration of 9 to cis-7: A solution of 9 (3.86 g, 14.1 mmol) in anhy-
drous THF (280 mL) was cooled to ꢀ208C and NEt3 (3.96 mL, 2.85 g,
28.2 mmol) was added. TFAA (1.96 mL, 2.97 g, 14.1 mmol) was slowly in-
troduced. The reaction was warmed to RT overnight and the solvent was
removed in vacuo. Column chromatographic purification (silica gel, n-
pentane/EtOAc 1:1!0:1) delivered the nitrile cis-7 (3.57 g, 14.0 mmol,
99%) as a brownish oil.
Compound 13: tBuLi (60.5 mL, 1.7m in n-pentane, 103 mmol) was added
dropwise at ꢀ788C to a solution of 1-chloro-4-iodobutane (5.81 mL,
10.4 g, 47.5 mmol) in anhydrous Et2O (60 mL). MgBr2·OEt2 (12.8 g,
49.7 mmol) was added after 2.5 h at ꢀ788C. Stirring was continued for
1 h at ꢀ788C and for 1 h at 08C. A solution of cis-7 (4.04 g, 15.8 mmol)
in anhydrous THF (50 mL) was introduced dropwise within 1 h. After 7 h
at 08C, the reaction mixture was carefully quenched with saturated aque-
ous NH4Cl (250 mL) and extracted with EtOAc (5ꢄ200 mL). The com-
bined organic layers were washed with brine (200 mL), dried over
MgSO4, and evaporated. Column chromatography (silica gel, n-pentane/
EtOAc/MeOH 2:1:0!0:0:1) of the residue gave 13 (3.92 g, 11.2 mmol,
71%) as a yellowish oil. The spectroscopic data of 13 were fully identical
to those given in ref. [11].
Experimental Section
Compounds cis-7 and trans-7: 2-Chloroacrylonitrile (5.46 g, 4.98 mL,
62.4 mmol) was added to a solution of 6 (12.4 g, 60.5 mmol) in anhydrous
THF (80 mL). The mixture was stirred for 16 h at RT and cooled to
ꢀ158C. A solution of KOtBu (7.47 g, 66.6 mmol) in anhydrous THF
(250 mL) was slowly dropped in and stirring was continued for 1 h at
ꢀ158C and 2 h at RT. The reaction mixture was quenched with saturated
aqueous NH4Cl (750 mL) and extracted with EtOAc (3ꢄ500 mL). The
organic layers were combined, washed with brine (200 mL), and dried
over MgSO4. The solvent was removed under reduced pressure to give a
42:58 mixture of trans-7 and cis-7. Column chromatographic separation
(silica gel, n-pentane/EtOAc 1:1!0:1) delivered trans-7 (6.02 g,
23.6 mmol, 39%) and cis-7 (6.95 g, 27.2 mmol, 45%) as brownish oils.
The nitrile trans-7 crystallized upon standing.
Compound 14: TFA (95 mL) was slowly added at ꢀ158C to a solution of
13 (6.47 g, 18.5 mmol) in anhydrous CH2Cl2 (75 mL). The reaction mix-
ture was warmed to RT within 16 h and concentrated in vacuo. The resi-
due was co-evaporated three times with CH2Cl2 (15 mL) to quantitatively
give the TFA salt of the N-deprotected amino ketone as a colorless oil.
1H NMR (400 MHz, CD3OD): d=1.68–1.83 (m, 4H; 3’-H, 4’-H), 2.75 (dt,
J=19.1, 7.0 Hz, 1H; 2’-H), 2.85 (dt, J=19.1, 7.0 Hz, 1H; 2’-H), 2.95 (dd,
J=12.2, 11.4 Hz, 1H; 5-Hax), 2.98 (s, 3H; NMe), 3.02 (dd, J=12.7,
11.5 Hz, 1H; 3-Hax), 3.12 (dd, J=13.6, 9.3 Hz, 1H; 6-CHH), 3.31 (m, 1H;
6-CHH), 3.58 (t, J=6.4 Hz, 2H; 5’-H), 3.59 (m, 1H; 5-Heq), 3.82 (ddd,
J=12.7, 2.5, 1.8 Hz, 1H; 3-Heq), 4.28 (ddt, J=11.2, 9.3, 2.6 Hz, 1H; 6-H),
4.50 ppm (dd, J=11.4, 2.7 Hz, 1H; 2-H); 13C NMR (100 MHz, CD3OD):
d=21.0 (C-3’), 33.0 (C-4’), 38.6 (C-2’), 41.6 (6-CH2), 44.2 (NMe), 45.4 (C-
5’), 53.8 (C-3), 54.6 (C-5), 72.0 (C-6), 78.7 (C-2), 205.8 ppm (C=O). Upon
column chromatography (basic alumina (act. V), EtOAc/MeOH 1:0!
9:1), a twofold cyclization to the iminium salt 14 (3.92 g, 17.0 mmol,
92%, violet oil) occurred. The spectroscopic data of 14 were fully identi-
cal to those given in ref. [11].
Compound trans-7: M.p. 758C; [a]2D2 =+23.8 (c=0.15 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=1.44 (s, 9H; CMe3), 1.90 (t, J=11.0 Hz,
1H; 5-Hax), 2.30 (dd, J=11.9, 3.7 Hz, 1H; 3-Hax), 2.31 (s, 3H; NMe), 2.78
(d, J=11.6 Hz, 1H; 5-Heq), 2.84 (d, J=12.0 Hz, 1H; 3-Heq), 3.16 (dt, J=
14.2, 6.1 Hz, 1H; 6-CHH), 3.35 (m, 1H; 6-CHH), 4.00 (m, 1H; 6-H), 4.74
(dd, J=3.5, 1.4 Hz, 1H; 2-Heq), 4.76 ppm (brs, 1H; NH); 13C NMR
(100 MHz, CDCl3): d=28.3 (CMe3), 42.4 (6-CH2), 45.8 (NMe), 55.7 (C-
3), 56.6 (C-5), 64.1 (C-2), 72.8 (C-6), 79.5 (CMe3), 117.2 (CN), 155.8 ppm
(CO2); IR (KBr): v˜ =3360, 2978, 2944, 2807, 2246, 1705, 1518, 1458, 1366,
1272, 1252, 1171, 1115, 737 cmꢀ1
;
HRMS (ESI+): m/z: calcd for
C12H22N3O3 [M+H]+: 256.1656; found: 256.1652; elemental analysis calcd
(%) for C12H21N3O3 (255.31): C 56.45, H 8.29, N 16.46; found: C 56.10, H
8.06, N 16.75.
Compound cis-7: [a]2D2 =+41.0 (c=0.20 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=1.41 (s, 9H; CMe3), 1.86 (dd, J=11.5, 10.4 Hz, 1H; 5-Hax),
2.24 (t, J=11.2 Hz, 1H; 3-Hax), 2.27 (s, 3H; NMe), 2.66 (d, J=11.6 Hz,
1H; 5-Heq), 2.88 (d, J=10.6 Hz, 1H; 3-Heq), 3.10 (ddd, J=14.3, 6.8,
5.4 Hz, 1H; 6-CHH), 3.33 (m, 1H; 6-CHH), 3.61 (m, 1H; 6-H), 4.41 (dd,
J=10.9, 2.7 Hz, 1H; 2-Hax), 5.00 ppm (brs, 1H; NH); 13C NMR
Compound 4: NaBH4 (691 mg, 18.3 mmol) was added at ꢀ108C to a solu-
tion of 14 (3.92 g, 17.0 mmol) in anhydrous MeOH (350 mL). The reac-
tion mixture was stirred for 4 h at 08C and then evaporated. MeOH
(50 mL) was added and all volatiles were removed in vacuo. After addi-
tion of 1n HCl (500 mL), the reaction mixture was extracted with
CH2Cl2 (3ꢄ250 mL). The organic layers were discarded. The aqueous
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M. Breuning et al.
layer was made basic (pH>10) with 6n NaOH (125 mL) and extracted
with CHCl3 (12ꢄ200 mL). The combined organic layers were washed
with brine (800 mL), dried over MgSO4, and concentrated in vacuo.
Column chromatography afforded the tricyclic 9-oxabispidine 4 (2.65 g,
13.5 mmol, 79%) as a low-melting colorless solid. Alternatively, purifica-
tion of crude 4 by distillation (60–708C/0.1 mbar) is possible. The spectro-
scopic and analytical data of 4 were in agreement with those reported in
ref [10a].
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[4] For enantioselective Henry reactions catalyzed by the complex
[CuCl2{(ꢀ)-sparteine}], see: H. Maheswaran, K. L. Prasant, G. G.
Krishna, K. Ravikumar, B. Sridhar, M. L. Kantam, Chem. Commun.
2006, 4066–4068.
Copper complex 16: CuCl2 (274 mg, 2.04 mmol) was added at RT to a so-
lution of the 9-oxabispidine 4 (400 mg, 2.04 mmol) in anhydrous MeOH
(4 mL). After 5 h at RT, the green precipitate formed was collected by
filtration through a sintered glass funnel and dried under reduced pres-
sure. Recrystallization from hot MeOH afforded 16 (374 mg, 1.13 mmol,
55%) as fine green needles.
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General procedure for the enantioselective Henry reactions catalyzed by
the copper complex 16: The aldehyde 17 (271 mmol) was added at ꢀ108C
or RT to a solution of the catalyst 16 (17.9 mg, 54.0 mmol, 20 mol%) in
anhydrous MeNO2 (1.5 mL). NEt3 (8.13 mmol, 150 mL of a 54.2 mm solu-
tion in anhydrous MeOH, 3 mol%) was added after 30 min. Stirring was
continued at ꢀ108C or RT for 18–168 h. The reaction mixture was dilut-
ed with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc
(3ꢄ20 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Column chromatographic purification (silica gel,
n-pentane/EtOAc 100:0!5:1) delivered the known b-nitro alcohols 18.[21]
The enantiomeric excess was determined by HPLC on the chiral phase;
the absolute configuration of the major enantiomer was assigned by com-
parison with the literature-known retention times on chiral HPLC or by
the sign of the optical rotation.[21]
CCDC-726133 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
(Emmy-Noether fellowship to M.B.), Bayer HealthCare, and Chemetall.
We thank Priv.-Doz. Fink for helpful discussions.
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Chem. Eur. J. 2009, 15, 12764 – 12769

9-Oxabispidines
FULL PAPER
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Received: June 29, 2009
Published online: October 15, 2009
Chem. Eur. J. 2009, 15, 12764 – 12769
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12769