Thieme chemistry journal awardees-where are they now? bridgehead lithiated 9-oxabispidines

Article abstract of DOI:10.1055/s-0029-1217999

Bi- and tricyclic 9-oxabispidines are smoothly deprotonated at -78C by s-BuLi at one of the bridgehead carbon atoms to give -lithio ethers, which were trapped with electrophiles in good yields. Rearrangements to ring-contracted N,O-acetals occurred upon w

Full text of DOI:10.1055/s-0029-1217999

LETTER
2749
Thieme Chemistry Journal Awardees – Where Are They Now?
Bridgehead Lithiated 9-Oxabispidines
Bridgehead Lithiated
9
a
-Oxabispid
t
ines thias Breuning,* Melanie Steiner, David Hein, Christian Hörl, Philipp Maier
Universität Würzburg, Institut für Organische Chemie, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884755; E-mail: breuning@chemie.uni-wuerzburg.de
Received 1 July 2009
Abstract: Bi- and tricyclic 9-oxabispidines are smoothly deproto-
nated at –78 °C by s-BuLi at one of the bridgehead carbon atoms to
give a-lithio ethers, which were trapped with electrophiles in good
yields. Rearrangements to ring-contracted N,O-acetals occurred
upon warming in the absence of an electrophile. The a-lithio ether
intermediates are presumably stabilized by negative hyperconjuga-
tion.
Key words: 9-oxabispidines, carbanions, rearrangements, lithia-
tion, bicyclic compounds
Matthias Breuning studied chemistry at the University of Würzburg,
Germany, and obtained his PhD degree in 1999 under the guidance of
Prof. G. Bringmann working on the atroposelective synthesis of axi-
ally chiral biaryls. After postdoctoral studies on enantioselective qui-
none Diels–Alder reactions with Prof. E. J. Corey at Harvard
University in Cambridge, MA, USA, he joined the Bayer HealthCare
AG in Wuppertal, Germany, as a senior research scientist in medi-
cinal chemistry. His independent career began in 2002 as a group lea-
der at the Institute of Organic Chemistry at the University of
Würzburg. Dr. Breuning’s main research interests include the de-
velopment of novel chiral catalysts and auxiliaries, with particular
emphasis on bicyclic diamines and organocatalysts, and their applica-
tion in natural product synthesis. His research activities were recogni-
zed with the Emmy-Noether young investigator award (2002) and the
Thieme Journal Award (2004).
The natural alkaloid (–)-sparteine (1, Figure 1)1 and the
(–)-cytisine derived (+)-sparteine surrogate 22 are the aux-
iliaries of choice for almost all s-BuLi-mediated asym-
metric deprotonation–electrophilic trapping reactions.3
The enantioselective total synthesis of such chiral bis-
pidines {3,7-diazabicyclo[3.3.1]nonanes}, however, is
still a time-consuming challenge severely hampering an
efficient design of derivatives.3 We therefore investigated
the closely related bi- and tricyclic 9-oxabispidines of
types 3 and 4, which are more easily accessible due to the
ether bridge.4–6 These diamines, in particular 4, possess
high potential as chiral ligands in transition-metal-cata-
lyzed transformations: The complex [(4)PdBr2] was suc-
cessfully used in the oxidative kinetic resolution of
secondary alcohols,5 and [(4)CuCl2] provided up to 98%
ee in enantioselective Henry reactions.6 Deprotonations
with s-BuLi in the presence of 3 or 4, however, failed,
probably because the 9-oxabispidines are lithiated at one
of the bridgehead carbon atoms.
tions, whereas THF gets readily deprotonated (t1/2,
35 °C = 10 min).8,10 The resulting a-lithio ethers are usually
highly reactive intermediates11 that undergo fast consecu-
tive reactions like fragmentations,12 [1,2]-alkyl shifts,11a,13
or [2,3]-sigmatropic Wittig rearrangements.11a,13a,b,14
The intermolecular trapping of nonstabilized a-lithio
ethers was as yet only realized with epoxides.15,16 Well
studied is the enantioselective deprotonation of cyclo-
octene oxide (5, Scheme 1) with s-BuLi at –90 °C in the
presence of the chiral auxiliary (–)-sparteine (1).15
Quench of the resulting anion with electrophiles delivered
the a-substituted derivatives 6 in good yields and enantio-
selectivities. The lithiation of 9-oxabicyclo[3.3.1]nona-
2,6-diene (7) with t-BuLi–TMEDA is the only example
for a deprotonation of an oxygen-bridged bicyclic com-
pound.17,18 This process, however, is facilitated by the for-
mation of a stabilized allyl anion intermediate, as obvious
from the regioisomeric products 8A and 8B obtained upon
addition of an electrophile.17
NMe
N
NMe
N
NMe
N
N
O
O
NMe
R
(–)-sparteine (1)
2
3
4
(R = H, alkyl, Ph)
Figure 1
The stability of nonactivated7 ethers against strong organo-
lithium bases such as s-BuLi widely differs. Et2O, for
example, is relatively inert (t1/2, 35 °C = 31 h)8,9 and there-
fore it is often used as the solvent for deprotonation reac-
In this letter we report on the deprotonation of the 9-oxa-
bispidines 3 and 4 with s-BuLi at –78 °C leading to stable
a-lithio ethers that were trapped with electrophiles in
SYNLETT 2009, No. 17, pp 2749–2754
Advanced online publication: 30.09.2009
DOI: 10.1055/s-0029-1217999; Art ID: S07609ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2750
M. Breuning et al.
LETTER
s-BuLi (1.25 equiv), 1 (1.3 equiv),
pidines themselves autocatalytically activate the organo-
lithium base by complexation, thus facilitating an
intermolecular proton abstraction (vide supra).
E
Et2O, –90 °C, 4 h
O
O
then E-X, –78 °C → r.t., 5 h
58–80%, 74–86% ee
6
5
The further lithiation–CD3OD-trapping of 10A/B solely
afforded the dideuterated 9-oxabispidine 11 in 79% yield
(Scheme 2).19 The observed quantitative H/D exchange
implies a highly selective deprotonation–deuteration se-
quence, since any competing dedeuteration–redeuteration
processes would lead to the recovery of formally un-
changed starting material. Consequently, the kinetic iso-
tope effect causing this selectivity must be large;20,21 a kH/
kD value of >94:6 = 15.7 was calculated under the as-
sumption that the lower detection limits of 10A and 10B
in the 1H NMR spectrum of 11 are <3%. If no bridgehead
proton was available, dedeuteration occurred, as found in
the lithiation–protonation of 11 giving a 48:38:14 mixture
of 10A, 10B, and 11 in 87% yield.
E-X: RCHO, RCONMe2, Et2CO, EtOCOCl, R3SnCl, TMSCl
t-BuLi (4.5 equiv),
TMEDA, n-hexane,
–90 °C → –30 °C
O
O
+
O
then E-X, –78 °C
22–96%
H
E
E
7
8A
8B
E-X: TMSOTf, Me3SnCl, Me3PbCl
Scheme 1
good yields. At higher temperatures, rearrangements oc-
curred.
In order to prove the instability of the 9-oxabispidines to-
wards strong organolithium bases we used a deprotona-
tion–deuteration sequence (Table 1). And indeed,
treatment of 3a–c and 4 with an excess of s-BuLi at
–78 °C in Et2O followed by quench with CD3OD deliv-
ered the monodeuterated derivatives 9A/B and 10A/B in
good isolated yields (75–89%) and with high deuterium
incorporation (73–100%).19 Thus, these 9-oxabispidines
are the first examples of nonstabilized7 and nonoxiranyl-
derived ethers that undergo smooth deprotonation at low
temperatures to give a-lithio ether intermediates which
can be trapped by external electrophiles.
s-BuLi (2.0 equiv),
NMe
N
NMe
N
NMe
N
D
O
D
O
D
Et2O, –78 °C, 1.5 h
O
D
+
then CD3OD,
–78 °C → r.t., 2 h
10A
10B
79%
11
s-BuLi (2.0 equiv), Et2O, –78 °C, 1.5 h
then MeOH, –78 °C → r.t., 4 h
87%, 10A/10B/11 = 48:38:14
Scheme 2
The exclusive formation of the regioisomers 9bA and 9cA
from the unsymmetric bicyclic 9-oxabispidines 3b and 3c
indicates a strong steric shielding of the bridgehead proton
at C1 by the substituents R. In contrast to that, no signifi-
cant differentiation was observed in the deprotonation–
deuteration of the tricyclic diamine 4 possessing the anne-
lated piperidine ring. The regioisomeric products 10A and
10B were obtained in a 55:45 ratio. It should be noted that
the use of s-BuLi is essential since no reaction occurred at
–78 °C with the weaker base n-BuLi; an external activa-
tion of s-BuLi by chelating ligands such as 1, 2, or
TMEDA is not required. It is very likely that the 9-oxabis-
Other electrophiles such as MeI, TMSCl, and BzCl were
also suited for trapping the a-lithiated 9-oxabispidines, as
demonstrated on 4 as the model substrate (Table 2). The
products 12A/B, 13A/B, and 14A/B were obtained in 43–
78% yield and with an improved regioselectivity of up to
73:27 for the sterically more demanding electrophiles
TMSCl and BzCl.19
The attempted further methylation of 12A/B to give the
9-oxabispidine 15, however, failed (Scheme 3). After
deprotonation with s-BuLi, no reaction was observed with
MeI as the electrophile, while stronger methylating agents
Table 1 Deprotonation–Deuteration of the 9-Oxabispidines 3a–c and 4
s-BuLi (1.5–3.0 equiv),
NMe
NMe
D
O
NMe
H
O
H
Et2O, –78 °C, 1.5–2 h
+
O
D
then CD3OD,
–78 °C → r.t., 5–16 h
N
N
N
1
1R2
R1
1R2
R
R2
R
3, 4
9A, 10A
9B, 10B
Entry
Starting material R1
R2
Product
Isolated yield (%) D incorporation (%)a A/Ba
b
1
3a
3b
3c
4
H
Me
Me
Me
9a
9b
9cc
89
86
75
85
100
85
–
2
Et
Ph
100:0
100:0
55:45
3
73
4d
-(CH2)4-
10
100
a Determined by 1H NMR.
b 9aA = 9aB.
c According to 1H NMR spectroscopy and mass spectrometry, some deuteration at the phenyl group had occurred, too.
d No reaction was observed with n-BuLi as the base.
Synlett 2009, No. 17, 2749–2754 © Thieme Stuttgart · New York

LETTER
Bridgehead Lithiated 9-Oxabispidines
2751
s-BuLi (2.0 equiv), Et2O,
Table 2 Deprotonation–Electrophilic Trapping of 4
NMe
NMe
NMe
Me
O
H
O
–78 °C → r.t., 16 h
s-BuLi (3.0 equiv),
NMe
N
NMe
NMe
N
H
O
H
E
O
44%
Et2O, –78 °C, 1.5 h
NMe
+
O
E
then E-X (5.0 equiv),
–78 °C → r.t., 16 h
rac-17
3a
N
4
12A–14A
12B–14B
base (3.0 equiv), Et2O,
NMe
N
Me
O
–78 °C → r.t., 16 h
NMe
N
A/Ba
+
O
Me
Entry
EX
Product
E
Yield (%)
78
then H2O
1
2
3
MeI
12
Me
56:44
64:36
73:27
18A
18B
52 (65)b
43 (56)b
NMe
N
H
O
H
TMSCl
BzCl
13
TMS
Bz
s-BuLi: 46%, 18A/18B = 58:42
n-BuLi: 36%, 18A/18B = 63:37
8
14
NMe
a Determined by 1H NMR.
b Based on recovered starting material.
4
DH2C
O
NMe
+
O
N
DH2C
N
s-BuLi (3.0 equiv), Et2O,
–78 °C → r.t., 16 h
such as MeOTf afforded complex product mixtures hint-
ing at N-methylated oxabispidinium salts. With the depro-
tonation–deuteration of 12A/B resulting in a 64:36
mixture of the deuterated 9-oxabispidines 16A/B (ratio
41:59) and 12A/B, the electrophilic trapping of the a-
lithio ethers of 12A/B with MeI and MeOTf must have
failed for unknown reasons.
19A
19B
then D2O
NMe
NMe
DH2C
O
DH2C
O
44%,
19A/19B/19C/19D
= 32:29:29:10
+
D
N
N
D
19C
19D
Scheme 4
s-BuLi (3.0 equiv),
10
8
11
NMe
11
NMe
NMe
N
NMe
N
Me
O
Me
NMe
Et2O, –78 °C, 3 h
Me
O
9
NMe
H
O
H
Li
O
s-BuLi
O
Me
+
12
+ O
Li
7
N
7
N
N
then MeI (6.0 equiv),
–78 °C → r.t., 16 h
1
N
2
12A
12B
15
4
20A
20B
s-BuLi (3.0 equiv),
Et2O, –78 °C, 1.5 h
NMe
NMe
N
Me
O
D
D
O
Me
Li
Li
Li
+
NMe
N
then CD3OD,
–78 °C → r.t., 4 h
NMe
N
NMe
Li
+
NMe
N
O
+
O
O
O
H
N
16A
16B
86%, 64% deuteration
16A/16B = 41:59
8
N
H
2
21A
22A
21B
22B
Scheme 3
D2O
19A
D2O
19B
s-BuLi
If the unsubstituted 9-oxabispidine 3a was lithiated at
–78 °C and slowly warmed to room temperature in the ab-
sence of an electrophile, a rearrangement to the ring-
contracted N,O-acetal rac-17 occurred (44% yield,
Scheme 4).19 The analogous deprotonation–rearrange-
ment of the unsymmetric tricyclic 9-oxabispidine 4 deliv-
ered the regioisomers 18A/B in a 58:42 ratio and 46%
yield.22 A similar result (18A/18B = 63:37, 36% yield)
was obtained by using n-BuLi as the base, which is appar-
ently capable of lithiating 4 at higher temperatures, but not
at –78 °C (cf. Table 1, footnote d). Quenching the crude
Li
Li
NMe
Li
Li
NMe
D2O
O
O
19C, 19D
N
N
23A
23B
Scheme 5
upon warming to give the lithium amides 21A/B under
cleavage of the C10–N11 and the C12–N11 bond, respec-
tively.24 Products arising from a competing breakage of
reaction mixture with D2O instead of water furnished, ac- the C8–N7 or C2–N7 bond in the southern morpholine
cording to in-depth NMR and HRMS investigations, a moiety were not detected. Intramolecular addition of the
32:29:29:10 mixture of four compounds, the two expected amide group in 21A/B to the enol ether furnished the in-
termediates 22A/B,25 which were deuterated upon workup
to give 19A/B. The latter cyclization, in which a lithium
amide is converted into a primary carbanion, is probably
facilitated by an intramolecular chelation of the lithium
atom with the nitrogen atom in b-position. In contrast to
21B, which seems to be resistant towards further lithia-
tion, the intermediate 21A was again partly deprotonated
at C8 giving the stabilized allylic anion 23A. Twofold
monodeuterated N,O-acetals 19A and 19B, and, in addi-
tion, the two 19A-derived dideuterated species 19C and
19D, in which a further H–D exchange at C8 had oc-
curred.23
The latter result can be explained by the following mech-
anism (Scheme 5): Initial unselective deprotonation of 4
at one of the bridgehead carbon atoms C9 and C1 afforded
the a-lithio ethers 20A/B, which underwent b-elimination
Synlett 2009, No. 17, 2749–2754 © Thieme Stuttgart · New York

2752
M. Breuning et al.
LETTER
s-BuLi (3.0 equiv),
additive
Et2O, –78 °C, 2 h
deuteration and ring closure of 23A finally led to the dia-
stereomers 19C and 19D.
recovery
of 24
additive
none
D
O
H
O
80%
94%
The unexpected stability of the bridgehead lithiated 9-oxa-
bispidines at –78 °C is supposedly a consequence of two
effects (Scheme 6): Firstly, the destabilizing interaction
between the s-orbital of the electron-rich C–Li bond and
the free electron pair of the neighboring oxygen atom,
which causes the high reactivity of ‘normal’ a-lithio
ethers,11 should be less pronounced. Assuming that the
lithiated 9-oxabispidines preferentially adopt a double
chair conformation, as known from their nonlithiated
counterparts and from the structurally closely related bis-
pidines,26 the orbitals should be locked in an unfavorable
gauche orientation which minimizes the destabilizing in-
teraction (illustration A). Secondly, the nitrogen atoms in
b-position probably exert a strong stabilizing effect by a
twofold negative hyperconjugation.27 As depicted in illus-
tration B, the required overlap between the electron-rich
s-orbital of the C–Li bond and the two energetically low-
lying s*-orbitals of the two adjacent C–N bonds should be
optimal due to the antiparallel orientation of these orbitals
in the double chair conformation.26 The resulting reduc-
tion of electron density in the C–Li bond in combination
with the addition of some p-character to the s(C–C)-
bonds can also be expressed by the mesomeric structures
C and D.
then CD3OD,
–78 °C → r.t., 8 h
TMEDA
(3.0 equiv)
25
24
Scheme 7
vate s-BuLi by complexation, but also facilitate the depro-
tonation due to the formation of a-lithio ethers which are
stabilized by negative hyperconjugation.
In conclusion, the deprotonation of the 9-oxabispidines 3
and 4 with s-BuLi at –78 °C afforded a-lithio ethers,
which are presumably stabilized by negative hyperconju-
gation. Trapping of these intermediates at –78 °C with
electrophiles afforded bridgehead-substituted 9-oxabis-
pidines in good yields, while rearrangements to ring-con-
tracted N,O-acetals occurred in the absence of an
electrophile upon warming.
Acknowledgment
We thank Dr. M. Grüne and Dr. M. Büchner for performing the
NMR and mass spectroscopy experiments and Chemetall for a ge-
nerous gift of s-BuLi.
References and Notes
(1) (a) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens,
H.; Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri,
W.; Kolczewksi, S.; Hense, T.; Hoppe, I. Pure Appl. Chem.
1994, 66, 1479. (b) Hoppe, D.; Hense, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2282. (c) Clayden, J. Organolithiums:
Selectivity for Synthesis; Pergamon: New York, 2002.
(d) Hodgson, D. M. Topics in Organometallic Chemistry,
Vol. 5; Springer: Berlin, 2003. (e) Gawley, R. E.; Coldham,
I. In The Chemistry of Organolithium Compounds;
Rappoport, Z.; Marek, I., Eds.; Wiley: Chichester, 2004,
997. (f) Hoppe, D.; Christoph, G. In The Chemistry of
Organolithium Compounds; Rappoport, Z.; Marek, I., Eds.;
Wiley: Chichester, 2004, 1055. (g) Chuzel, O.; Riant, O. In
Topics in Organometallic Chemistry, Vol. 15; Lemaire, M.;
Mangeney, P., Eds.; Springer: Berlin, 2005, 592.
(h) Hoppe, D. Synthesis 2009, 43.
destabilizing interaction σ(C1–Li) – np(O)
60°
60°
2
Li
O
Li
O
NMe
NMe
•
•
•
•
8
1
5
C8
C2
A
C5
stabilizing interactions σ(C1–Li) – σ*(C2–N3) and σ(C1–Li) – σ*(C8–N7)
(negative hyperconjugation)
Me
Li
Li
2
N
NMe
NMe
NMe
NMe
Li
O
1
3
O
8
O
7
N
B
Me
C
D
Scheme 6
(2) (a) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org. Synth.
2006, 83, 141. (b) O’Brien, P. Chem. Commun. 2008, 655.
(3) (a) Breuning, M.; Steiner, M. Synthesis 2008, 2841.
(b) Lesma, G.; Sacchetti, A.; Silvani, A.; Danieli, B. In
New Methods for the Asymmetric Synthesis of Nitrogen
Heterocycles; Vicario, J. L.; Badía, D.; Carrillo, L., Eds.;
Research Signpost: Kerala, 2005, 334.
(4) (a) Breuning, M.; Steiner, M. Synthesis 2007, 1702.
(b) Breuning, M.; Steiner, M. Tetrahedron: Asymmetry
2008, 19, 1978.
The close structural relationship between D and the pro-
posed intermediates 21A/B in the rearrangements of 3a
(see Scheme 5) strongly implies that negative hyperconju-
gation also plays an important role in initiating the latter
process.
In order to prove the pivotal role of the nitrogen atoms of
the 9-oxabispidines in the deprotonation reactions, two
control experiments were done with the ether 24,28 which
possesses the same bicyclic skeleton, but lacks the two ni-
trogen atoms (Scheme 7): Treatment of 24 with s-BuLi
and, subsequently, with CD3OD did not lead to the mono-
deuterated ether 25 or any decomposition products; even
in the presence of activating diamine TMEDA, only un-
changed starting material was recovered in 94% yield.
The reluctance of 24 towards lithiation clearly shows that
the nitrogen atoms of the 9-oxabispidines not only acti-
(5) Breuning, M.; Steiner, M.; Mehler, C.; Paasche, A.; Hein, D.
J. Org. Chem. 2009, 74, 1407.
(6) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.;
Strohmann, C. Chem. Eur. J. 2009, in press.
(7) The term ‘nonactivated ethers’ refers to ethers that do not
form benzyl-, allyl-, or vinyl-stabilized a-lithio ethers upon
deprotonation.
(8) Gilman, H.; Gaj, B. J. J. Org. Chem. 1957, 22, 1165.
(9) Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem.
1992, 57, 6833.
Synlett 2009, No. 17, 2749–2754 © Thieme Stuttgart · New York

LETTER
Bridgehead Lithiated 9-Oxabispidines
2753
(10) Gilman, H.; Haubein, A. H.; Hartzfeld, H. J. Org. Chem.
1954, 19, 1034.
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Compounds; Rappoport, Z.; Marek, I., Eds.; Wiley:
Chichester, 2004, 749. (b) See ref. 1c, page 12.
(12) Lithiated THF, for example, fragments by [3+2]-
cycloreversion: (a) Jung, M. E.; Blum, R. B. Tetrahedron
Lett. 1972, 18, 3791. (b) Bates, R. B.; Kroposki, L. M.;
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S. C. J. Organomet. Chem. 1971, 29, 1.
(13) (a) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann./
Recl. 1997, 1275. (b) Marshall, J. A. In Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M.; Fleming, I.;
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(c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1979, 18,
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MHz, CDCl3): d = 1.36 (m, 3 H, CH2), 1.56 (m, 1 H, CH2),
1.77 (m, 3 H, CH2, 6-H), 2.19 (s, 3 H, 11-Me), 2.24 (d,
J = 11.6 Hz, 1 H, 12-H), 2.26 (m, 1 H, 2-H), 2.39 (dd,
J = 11.4, 1.3 Hz, 1 H, 10-H), 2.55 (dd, J = 11.6, 1.4 Hz, 1 H,
8-H), 2.81 (d, J = 11.6 Hz, 1 H, 8-H¢), 2.89 (m, 1 H, 6-H¢),
2.91 (d, J = 11.7 Hz, 1 H, 10-H¢), 2.92 (m, 1 H, 12-H¢). 13
C
NMR (100 MHz, CDCl3): d = 24.8 (CH2), 25.3 (CH2), 28.3
(CH2), 47.5 (11-Me), 54.5 (C-12), 57.3 (C-6), 57.9 (C-8),
58.4 (C-10), 64.9 (C-2), 68.4 (t, J = 22.1 Hz, C-9), 71.6 (t,
J = 22.2 Hz, C-1). IR (ATR): n = 2931, 2754, 1438, 1352,
1288, 1276, 1176, 1135, 1076, 1056, 1023, 788, 752, 721,
699 cm–1 HRMS (ESI+): m/z calcd for C11H18D2N2O [M +
H]+: 199.1774; found: 199.1774.
Compound 12A/B (ratio A/B = 56:44): 1H NMR (400 MHz,
CDCl3): d = 1.05 (s, 3 H B, 1-Me), 1.10 (s, 3 H A, 9-Me),
1.27–1.86 (m, 7 H A, 8 H B, CH2, 12-H B), 1.91 (br d,
J = 10.5 Hz, 1 H, 2-H B), 2.00 (dd, J = 11.4, 2.4 Hz, 1 H,
10-H A), 2.11–2.18 (m, 3 H, 2-H A, 8-H A, 12-H A), 2.15 (s,
3 H, 11-Me), 2.16 (s, 3 H, 11-Me), 2.29 (ddd, J = 11.5, 4.1,
1.7 Hz, 1 H, 10-H B), 2.55 (ddd, J = 11.5, 4.3, 1.8 Hz, 1 H,
8-H B), 2.80 (m, 2 H, 8-H¢ A, 8-H¢ B), 2.84–2.93 (m, 3 H A,
3 H B, 6-H¢, 10-H¢, 12-H¢), 3.54 (t, J = 3.7 Hz, 1 H, 1-H A),
3.88 (t, J = 4.3 Hz, 1 H, 9-H B). 13C NMR (100 MHz,
CDCl3): d = 24.8 (CH2), 25.16 (CH2), 25.24 (2 × CH2), 25.7
(1-Me B), 26.2 (1-Me A), 27.2 (CH2), 28.1 (CH2), 47.32 (11-
Me), 47.34 (11-Me), 53.8 (C-12 A), 57.3 (C-6 A), 57.58 (C-
6 B or C-10 B), 57.62 (C-6 B or C-10 B), 58.0 (C-8 B), 60.6
(C-12 B), 63.9 (C-8 A), 64.2 (C-2 A), 64.3 (C-10 A), 69.1
(C-9 B), 70.1 (C-9 A), 70.8 (C-2 B), 72.0 (C-1 B), 73.1 (C-1
A). IR (ATR): n = 2930, 2854, 2758, 1457, 1357, 1286,
1260, 1102, 1055, 812 cm–1. HRMS (ESI+): m/z calcd for
C12H22N2O [M + H]+: 211.1805; found: 211.1805.
(14) (a) Nakai, T.; Mikami, M. Chem. Rev. 1986, 86, 885.
(b) Nakai, T.; Mikami, M. Org. React. 1994, 46, 105.
(15) Hodgson, D. M.; Buxton, T. J.; Cameron, I. D.; Gras, E.;
Kirton, E. H. M. Org. Biomol. Chem. 2003, 1, 4293.
(16) For nonstereoselective deprotonation–electrophilic trapping
reactions of epoxides, see: (a) Hodgson, D. M.; Norsikian,
S. L. M. Org. Lett. 2001, 3, 461. (b) Yamauchi, Y.;
Katagiri, T.; Uneyama, K. Org. Lett. 2002, 4, 173.
(17) Bassioni, G.; Köhler, F. H. Eur. J. Org. Chem. 2006, 2795.
(18) For the related deprotonation–stannylation of 8-methyl-8-
azabicyclo[3.2.1]oct-2-ene, see: (a) Lavoie, G. G.;
Bergmann, R. G. Angew. Chem., Int. Ed. Engl. 1997, 36,
2450. (b) Skoog, S. J.; Mateo, C.; Lavoie, G. G.; Hollander,
F.; Bergmann, R. G. Organometallics 2000, 19, 1406 . For
the bridgehead lithiation of bridged ketones and other
derivatives, see: (c) Hayes, C. J.; Simpkins, N. S.; Kirk,
D. T.; Mitchell, L.; Baudoux, J.; Blake, A. J.; Wilson, C.
J. Am. Chem. Soc. 2009, 131, 8196.
Compound 14A/B (ratio A/B = 73:27): 1H NMR (400 MHz,
CDCl3): d = 1.10–1.65 (m, 4 H A, 4 H B, CH2), 1.70–1.95
(m, 3 H A, 3 H B, CH2, 6-H), 2.10–2.45 (m, 5 H, 2-H A, 10-
H A, 12-H A, 10-H B, 12-H B,), 2.25 (s, 3 H, 11-Me A), 2.27
(s, 3 H, 11-Me B), 2.56 (dd, J = 11.7, 2.0 Hz, 1 H, 8-H A),
2.59 (br d, J = 10.7 Hz, 1 H, 2-H B), 2.82 (ddd, J = 11.7, 4.3,
1.6 Hz, 1 H, 8-H B), 2.95 (m, 5 H, 6-H¢ A, 12-H¢ A, 6-H¢ B,
8-H¢ B, 10-H B), 3.20 (d, J = 11.7 Hz, 1 H, 8-H¢ A), 3.30 (d,
J = 11.5 Hz, 1 H, 10-H¢ A), 3.46 (d, J = 12.2 Hz, 1 H, 12-H¢
B), 3.79 (t, J = 4.1 Hz, 1 H, 1-H A), 4.14 (t, J = 4.2 Hz, 1 H,
9-H B), 7.43 (m, 2 H A, 2 H B, PhH), 7.55 (m, 1 H A, 1 H
(19) All new compounds have been characterized by 1H NMR
and 13C NMR spectroscopy as well as HRMS spectrometry.
Compounds 9b, 9c, and 13A/B could not be separated from
the starting materials.
Spectroscopic Data for Selected Compounds
Compound 9a: mp 70 °C. 1H NMR (400 MHz, CDCl3):
d = 2.21 (s, 6 H, 3-Me, 6-Me), 2.41 (d, J = 11.1 Hz, 2 H, 6-
H, 8-H), 2.42 (dd, J = 11.1, 4.4 Hz, 2 H, 4-H, 6-H), 2.89 (d,
J = 11.1 Hz, 4 H, 2-H¢, 4-H¢, 6-H¢, 8-H¢), 3.85 (t, J = 4.3 Hz,
1 H, 5-H). 13C NMR (100 MHz, CDCl3): d = 47.8 (3-Me, 6-
Me), 58.4 (NCH2), 58.5 (NCH2), 68.0 (t, J = 21.8 Hz, C-1),
68.4 (C-5). HRMS (ESI+): m/z calcd for C8H16DN2O [M +
H]+: 158.1398; found: 158.1398.
B, PhH), 8.17 (m, 2 H A, PhH), 8.25 (m, 2 H B, PhH). 13
C
NMR (100 MHz, CDCl3): d = 24.67 (CH2 B), 24.70 (CH2
A), 25.1 (CH2 B), 25.2 (CH2 A), 26.5 (CH2 B), 27.8 (CH2 A),
47.2 (11-Me A), 47.3 (11-Me B), 53.6 (C-12 A), 56.6 (C-12
B), 57.1 (C-6 A), 57.4 (C-10 B), 57.7 (C-8 B), 57.9 (C-6 B),
59.6 (C-8 A), 59.8 (C-10 A), 64.0 (C-2 A), 65.5 (C-2 B),
69.3 (C-9 B), 72.9 (C-1 A), 80.5 (C-9 A), 81.9 (C-1 B), 127.9
(PhH A), 128.0 (PhH B), 130.3 (PhH A), 130.6 (PhH B),
132.7 (PhH A), 132.8 (PhH B), 135.2 (PhH A), 135.5 (PhH
B), 199.1 (C=O B), 200.7 (C=O A). IR (ATR): n = 2934,
2852, 2763, 1674, 1446, 1266, 1099, 1054, 708, 689, 665
cm–1. HRMS (ESI+): m/z calcd for C18H25N2O2 [M + H]+:
301.1911; found: 301.1910.
Compound 10A/B (ratio A/B = 55:45): mp 35 °C. 1H NMR
(400 MHz, CDCl3): d = 1.36 (m, 3 H A, 3 H B, CH2), 1.56
(m, 1 H A, 1 H B, CH2), 1.70–1.87 (m, 3 H A, 3 H B, CH2,
6-H), 2.19 (s, 3 H A, 3 H B, 11-Me), 2.25 (m, 2 H A, 2 H B,
2-H, 12-H), 2.39 (dd, J = 11.7, 1.3 Hz, 1 H, 10-H A), 2.40
(ddd, J = 11.6, 4.2, 1.6 Hz, 1 H, 10-H B), 2.55 (dd, J = 11.6,
1.5 Hz, 1 H, 8-H A), 2.56 (ddd, J = 11.6, 4.5, 1.7 Hz, 1 H, 8-
H B), 2.78–2.95 (m, 4 H A, 4-H B, 6-H¢, 8-H¢, 10-H¢, 12-H¢),
3.47 (t, J = 3.5 Hz, 1 H, 1-H A), 3.85 (t, J = 4.1 Hz, 1 H, 9-
H B). 13C NMR (100 MHz, CDCl3): d = 24.6 (CH2 A, B),
25.1 (CH2 A, B), 28.2 (CH2 A, B), 47.4 (11-Me A, B), 54.4
(C-12), 54.5 (C-12), 57.2 (C-6 A, B), 57.8 (C-8), 57.9 (C-8),
58.2 (C-10), 58.3 (C-10), 64.9 (C-2), 65.0 (C-2), 68.3 (t,
J = 19.8 Hz, C-9 A), 68.7 (C-9 B), 71.4 (t, J = 21.6 Hz, C-1
B), 71.8 (C-1 A). IR (ATR): n = 2929, 2853, 2784, 1458,
1354, 1283, 1199, 1161, 1119, 1069, 973, 815, 722 cm–1.
HRMS (ESI+): m/z calcd for C11H19DN2O [M + H]+:
198.1711; found: 198.1711.
Compound rac-17: 1H NMR (400 MHz, CDCl3): d = 1.26 (s,
3 H, 5-Me), 2.06 (d, J = 11.1 Hz, 1 H, 4-H), 2.21 (s, 3 H, 3-
Me), 2.25 (dd, J = 11.0, 1.8 Hz, 1 H, 2-H), 2.42 (s, 3 H, 6-
Me), 2.54 (dd, J = 11.1, 1.8 Hz, 1 H, 2-H¢), 2.76 (d, J = 11.1
Hz, 1 H, 4-H¢), 3.03 (dd, J = 8.3, 1.7 Hz, 1 H, 7-H), 3.05 (dd,
J = 8.3, 5.4 Hz, 1 H, 7-H¢), 4.32 (dq, J = 5.4, 1.8 Hz, 1 H, 1-
H). 13C NMR (100 MHz, CDCl3): d = 20.2 (5-Me), 37.1 (6-
Me), 45.0 (3-Me), 57.8 (C-7), 58.2 (C-2), 62.3 (C-4), 73.0
(C-1), 92.7 (C-5). IR (ATR): n = 2925, 2853, 1662, 1456,
1258, 1015, 854, 793 cm–1. HRMS (ESI+): m/z calcd for
C8H17N2O [M + H]+: 157.1335; found: 157.1335.
Compound 11: [a]D22 +14.9 (c 0.22, MeOH). 1H NMR (400
Synlett 2009, No. 17, 2749–2754 © Thieme Stuttgart · New York

2754
M. Breuning et al.
LETTER
(20) A dilithiation of 10A/B followed by dideuteration, which
would also explain the quantitative formation of 11, but
without relying on a high kinetic isotope effect, can be
excluded since otherwise 11 should also had been formed in
the lithiation–deuteration of 4.
(21) For high kinetic isotope effects in (–)-sparteine(1)-mediated
asymmetric deprotonations, see for example: (a) Hoppe, D.;
Paetow, M.; Hintze, F. Angew. Chem., Int. Ed. Engl. 1993,
32, 394. (b) Gallager, D. J.; Beak, P. J. Org. Chem. 1995, 60,
7092.
A), 58.8 (C-8 B), 60.1 (C-10 B), 62.3 (C-8 A), 63.3 (C-2 A),
71.4 (C-2 B), 72.2 (C-9 B), 76.9 (C-1 A), 93.5 (C-9 A), 96.0
(C-1 B). IR (ATR): n = 2925, 2852, 2793, 1730, 1442, 1377,
1331, 1258, 1181, 1132, 823, 719, 607 cm–1 HRMS (ESI+):
m/z calcd for C11H21N2O [M + H]+: 197.1648; found:
197.1648.
(23) 13C NMR and HRMS also indicate the formation of a small
amount of a trideuterated species, the structure of which is
unknown.
(24) The proposed b-elimination of 20A/B to 21A/B is
comparable to the fragmentation of lithiated TMEDA, which
provides LiNMe2 and N,N-dimethylaminoethylene as
intermediates, see: Köhler, F. H.; Hertkorn, N.; Blümel, J.
Chem. Ber. 1987, 120, 2081.
(25) The proposed cyclization of 21A/B to 22A/B is similar to the
LiHMDS/TMEDA-catalyzed hydroamination of electron-
rich C–C double bonds, see: Horillo-Martinez, P.; Hultsch,
K. C.; Gil, A.; Branchadell, V. Eur. J. Org. Chem. 2007,
3311.
(26) According to preliminary quantum chemical calculations,
the double chair conformation is highly favored for 2-endo-
substituted 9-oxabispidines such as 3 and 4. The same
preference was found for the bispidines, see: (a) Galasso,
V.; Goto, K.; Miyahara, Y.; Kovač, B.; Klasinc, L. Chem.
Phys. 2002, 277, 229. (b) Galasso, V.; Asaro, F.; Berti, F.;
Kovač, B.; Habuš, I.; Sacchetti, A. Chem. Phys. 2003, 294,
155.
(27) (a) Hoffmann, R.; Radom, L.; Pople, J. A.; Schleyer, P.v.R.;
Hehre, W. J.; Salem, L. J. Am. Chem. Soc. 1972, 94, 6221.
(b) Schleyer, P.v.R.; Kos, A. J. Tetrahedron 1983, 39, 1141.
(c) Petillo, P. A.; Lerner, L. E. ACS Symp. Ser. 1993, 539,
156. (d) Lill, S. O. N.; Rauhaut, G.; Anders, E. Chem. Eur.
J. 2003, 9, 3143; and references cited therein. (e)Karni, M.;
Bernaconi, C. F.; Rappoport, Z. J. Org. Chem. 2008, 73,
2980; and references cited therein.
(22) The Following Procedure is Representative:
Rearrangement of Compound 4
s-BuLi (3.30 mL, 4.59 mmol, 1.39 M in cyclohexane) was
added at –78 °C to a solution of 4 (300 mg, 1.52 mmol) in
anhyd Et2O (10 mL). The reaction mixture was warmed to
r.t. within 16 h, quenched with H2O (30 mL), and extracted
with CH2Cl2 (10 × 30 mL). The combined organic layers
were dried over MgSO4 and evaporated. Column chroma-
tography (basic alumina, activity V, n-pentane–EtOAc =
6:1) delivered an inseparable 58:42 mixture of 18A and 18B
(137 mg, 698 mmol, 46%) as a colorless oil. 1H NMR (400
MHz, CDCl3): d = 1.07 (m, 1 H, 3-H A), 1.18–1.40 (m, 4 H,
3-H¢ A, 3-H B, 4-H A, 4-H B), 1.26 (s, 3 H, 1-Me B), 1.29
(s, 3 H, 9-Me A), 1.46–1.60 (m, 4 H, 3-H¢ B, 5-H A, 5-H¢ A,
5-H B), 1.66 (m, 1 H, 5-H¢ B), 1.77 (m, 2 H, 4-H¢ A, 4-H¢ B),
1.88 (dd, J = 10.9, 2.3 Hz, 1 H, 2-H B), 2.03 (m, 1 H, 6-H A,
6-H B), 2.11 (dt, J = 11.7, 2.0 Hz, 1 H, 2-H A), 2.17 (d,
J = 11.2 Hz, 1 H, 8-H A), 2.38 (dd, J = 11.4, 1.8 Hz, 1 H, 8-
H B), 2.40 (s, 3 H, 11-Me B), 2.44 (s, 3 H, 10-Me A), 2.53
(dd, J = 11.1, 2.0 Hz, 1 H, 8-H¢ B), 2.62 (dd, J = 8.9, 6.5 Hz,
1 H, 10-H B), 2.68 (d, J = 11.2 Hz, 1 H, 8-H¢ A), 2.70 (m, 2
H, 6-H¢ A, 6-H¢ B), 2.91 (dd, J = 8.7, 6.4 Hz, 1 H, 11-H A),
3.15 (d, J = 8.8 Hz, 1 H, 11-H¢ A), 3.41 (d, J = 9.0 Hz, 1 H,
10-H¢ B), 3.97 (d, J = 6.5 Hz, 1 H, 1-H A), 4.27 (dt, J = 6.5,
2.0 Hz, 1 H, 9-H B). 13C NMR (100 MHz, CDCl3): d = 18.3
(1-Me B), 19.8 (9-Me A), 24.1 (C-4 A), 24.2 (C-4 B), 24.9
(C-5 B), 25.4 (C-5 A), 26.3 (C-3 B), 26.7 (C-3 A), 37.5 (10-
Me A), 40.7 (11-Me B), 54.3 (C-6 A), 55.16 (C-6 B, C-11
(28) Compound 24 was prepared from cycloocta-1,5-diene
according to: Bordwell, F. G.; Douglass, M. L. J. Am. Chem.
Soc. 1966, 88, 993.
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