5-substituted derivatives of the tricyclic (+)-sparteine surrogate in the enantioselective lithiation/stannylation of an O-alkyl carbamate

Article abstract of DOI:10.1002/ejoc.201300987

5-Mono- and 5,5-disubstituted tricyclic bispidines, derivatives of the known (+)-sparteine surrogate, have been synthesized in four-to-six steps from the natural alkaloid (-)-cytisine and evaluated as chiral ligands in the enantioselective lithiation/stannylation of an O-alkyl carbamate. Structure-selectivity studies revealed that a small 5-endo substituent is tolerated, whereas larger 5-endo substituents and even small 5-exo substituents lead to significantly reduced levels of chirality transfer. Novel tricyclic bispidines have been synthesized from the readily available alkaloid (-)-cytisine and evaluated in the enantioselective lithiation/stannylation of an O-alkyl carbamate. Structure-selectivity studies revealed that an increased steric demand at the 5-endo position is not favorable.

Full text of DOI:10.1002/ejoc.201300987

FULL PAPER
DOI: 10.1002/ejoc.201300987
5-Substituted Derivatives of the Tricyclic (+)-Sparteine Surrogate in the
Enantioselective Lithiation/Stannylation of an O-Alkyl Carbamate
Matthias Breuning*[a] and David Hein[b]
Keywords: Asymmetric synthesis / Ligand effects / Enantioselectivity / Amines / Alkaloids
5-Mono- and 5,5-disubstituted tricyclic bispidines, deriva- selectivity studies revealed that a small 5-endo substituent is
tives of the known (+)-sparteine surrogate, have been syn-
thesized in four-to-six steps from the natural alkaloid (–)-cyt-
isine and evaluated as chiral ligands in the enantioselective
lithiation/stannylation of an O-alkyl carbamate. Structure–
tolerated, whereas larger 5-endo substituents and even small
5-exo substituents lead to significantly reduced levels of
chirality transfer.
the reactivity of 3 relative to that of 4,[21] 3) substituents
larger than the N-methyl group in 4 result in lower yields
and enantioselectivities,[13] and 4) the rigidity of the 2-en-
do,3N-fused piperidine ring seems to be beneficial because
none of the bicyclic bispidines tested so far, for example, 6
(35% ee)[12] and 7 (75% ee),[7] reached the excellent asym-
metric inductions achieved with 3 and 4.
Introduction
The natural tetracyclic bispidine (3,7-diazabicyclo[3.3.1]-
nonane) (–)-sparteine (3, Scheme 1) is the ligand of choice
for various asymmetric transformations,[1] in particular, for
sBuLi-mediated enantioselective lithiation/electrophilic
trapping reactions, including the recently developed enan-
tioselective homologation of boronic esters.[2] The broad
success of 3, however, has been hampered by the restricted
accessibility of its enantiomer, (+)-sparteine (ent-3),[3] which
has triggered an intense search for modified and simplified
derivatives,[4–14] finally culminating in the development of
the tricyclic (+)-sparteine surrogate 4 by O’Brien and co-
workers.[5,6,15,16] The stereodiscriminating power of bispid-
ines has largely been investigated through studies of the
enantioselective lithiation/silylation of N-Boc-pyrrolidine
(1) discovered by Kerrick and Beak.[17] They revealed that
the bispidine framework is superior to all other diamine
structures tested,[7–10,18,19] and that the excellent 95–97% ee
values obtained with (–)-sparteine (3) are still un-
rivalled.[10–13,17,20] In addition, these studies also provided
some important information about the minimum structural
requirements of a highly stereoselective bispidine, which
showed that 1) the endo-fused piperidine ring of 3 plays a
decisive role in chirality transfer, as is evident from the high
asymmetric induction achieved with the (+)-sparteine sur-
rogate 4 (90% ee)[6,9,13] and as supported by DFT calcula-
tions,[12,13] 2) the exo-fused ring of 3 is only of minor impor-
tance for chirality transfer (cf. 5: 21% ee),[11] but it reduces
Scheme 1. Chiral bispidines 3–7 in the enantioselective lithiation/
silylation of N-Boc-pyrrolidine (1) and the targeted, modified (+)-
sparteine surrogates 8.
Surprisingly, the endo-fused piperidine ring in the (+)-
sparteine surrogate 4 has not yet been modified,[22] despite
its obviously decisive role in chirality transfer. In particular,
substitutions at C-5 should be rewarding because they will
significantly enhance the steric demand at the outermost
carbon atom, which might exert a strong effect on the
asymmetric induction. In this full paper we present the syn-
thesis of the novel 5-mono- and 5,5-disubstituted deriva-
[a] Organic Chemistry Laboratory, University of Bayreuth,
Universitätsstraße 30, 95447 Bayreuth, Germany
E-mail: Matthias.Breuning@uni-bayreuth.de
http://www.neu.uni-bayreuth.de/de/Uni_Bayreuth/Fakultaeten/
2_Biologie_Chemie_und_Geowissenschaften/chemie/
oci-breuning/de/
[b] Institute of Organic Chemistry, University of Würzburg,
Am Hubland, 97074 Würzburg, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300987.
Eur. J. Org. Chem. 2013, 7575–7582
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Breuning, D. Hein
FULL PAPER
tives 8 of the tricyclic bispidine 4 and their application as (Scheme 3). Transformation of 11dA into the tetracyclic
chiral ligands in the enantioselective lithiation/stannylation spiro compound 12c required two steps, base-induced elimi-
of an O-alkyl carbamate.
nation of methanol to give the alkene 13 and cyclopropan-
ation of the double bond. Under Corey–Chaykovsky condi-
tions with Me3SO+I–/NaH in DMSO, the product 12c was
obtained in a low yield of 17% as a result of decomposition
of the starting material. Simmons–Smith cyclopropanation
of 13 with CH2I2/Et2Zn provided only partial conversion to
12c, even in the presence of a large excess of CH2I2/Et2Zn.
Because all attempts to separate 12c from 13 were unsuc-
cessful, the resulting mixture of 12c/13 was twice re-sub-
jected to these cyclopropanation conditions. This procedure
ensured complete consumption of 13, although the isolated
yield of 45% was 12c was low.
Results and Discussion
Synthesis of the Bispidines 8
The synthesis of the 5-substituted bispidines 8 was
straightforward from the natural alkaloid (–)-cytisine (9,
Scheme 2), which can be isolated in good quantities from
the seeds of the Golden Rain tree, Laburnum anagyroides.[15]
Protection of the secondary amino group and hydrogen-
ation of the annulated pyridone according to a known pro-
tocol[15] afforded the key intermediate, the lactam 10. The
required substituents at the 5-position were introduced by
deprotonation of 10 with LDA and subsequent electrophilic
trapping of the amide enolate with MeI, iPrI, NSFI [N-
fluorobis(phenylsulfonyl)amide], or MOMCl (meth-
oxymethyl chloride). The attack occurred preferentially
from the sterically less hindered exo side, thus leading to
diastereomeric mixtures with the exo isomer 11A[23] pre-
vailing over the endo isomer 11B (11A:11B Ͼ 90:10, except
for 11a: 11aA/11aB = 75:25). The major diastereomers 11A
were obtained in analytically pure form by column
chromatography; in the case of 11aA/11aB, both diamines
could be isolated. Larger quantities of 11aB, the minor endo
product of the methylation of 10, were accessible by epi-
merization of 11aA by deprotonation and reprotonation
with BHT (2,6-di-tert-butyl-4-methylphenol) as a sterically
demanding proton source, giving a 47:53 mixture of 11aA
and 11aB.
Scheme 3. Synthesis of the 5,5-disubstituted tricyclic bispidine lact-
ams 12a–c.
Final reduction of the bispidine lactams 11aA, 11aB,
11bA, and 12a–c with LiAlH4 in THF at reflux afforded the
target bispidines 8a–8f in good-to-high yields (Scheme 4).
Scheme 4. Reduction of the bispidine lactams to the bispidines 8a–
f.
Enantioselective Deprotonation Reactions
Among the enantioselective deprotonation/electrophilic
trapping reactions of O-alkyl carbamates, which were
pioneered and developed by Hoppe and co-workers,[1,24] the
lithiation/stannylation of 14 (Table 1) serves as a model reac-
tion for the evaluation of new chiral diamines. This reaction
is known to proceed under virtually complete stereocontrol
(97–98% ee) in the presence of (–)-sparteine (3),[10,16,25,26]
Scheme 2. Synthesis of the 5-monosubstituted tricyclic bispidin-
ones 11a–11d [NSFI = N-fluorobis(phenylsulfonyl)amide, MOMCl
=
methoxymethyl chloride, BHT
= 2,6-di-tert-butyl-4-meth-
ylphenol].
The 5,5-disubstituted bispidine lactams 12a (R = Me) and provides high ee values of 90–92% with the (+)-sparte-
and 12b (R = F) were prepared from the corresponding 5- ine surrogate 4.[6,25] Typically, the chiral bispidine–sBuLi
monosubstituted derivatives 11aA and 11cA by a sub- adduct is formed first by mixing equimolar amounts of the
sequent deprotonation/electrophilic trapping sequence bispidine and sBuLi at –78 °C in Et2O, then the substrate
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Lithiation/Stannylation of an O-Alkyl Carbamate
14 is added and, after 4 h, the electrophile Bu3SnCl, which mand at the active site. Thus, the real steric requisite of the
traps the generated chiral α-lithio-carbamate.
methyl group in 8c would lie in between that of an equato-
rial one (as in 8a) and a truly axially one (as in 8d), which
is in good agreement with the experimentally observed de-
crease in the asymmetric inductions.
Table 1. Lithiation/stannylation of the carbamate 14 in the presence
of chiral bispidines.
Entry
Bispidine Yield [%][a]
ee [%][b]
Configuration
1[c]
2[d]
3
4
5
6
7
8
3
68–73
84
66
64
70
71
66
68
97–98
90–92
92
51
79
34
40
65
S
R
R
R
R
R
R
R
4
Figure 1. Proposed conformations of the fused piperidine ring in
the prelithiation complexes 16A and 16B.
8a
8b
8c
8d
8e
8f
Conclusions
[a] Isolated yields. [b] Determined by HPLC analysis on a chiral
phase. [c] Data from ref.[6,14,25,26] [d] Data from ref.[6,25]
The novel 5-mono- and 5,5-disubstituted tricyclic bispid-
ines 8a–f, derivatives of the well-known (+)-sparteine surro-
gate 4, have been prepared in four-to-six simple steps from
the natural product (–)-cytisine (9) and their potential as
chiral diamines evaluated in the enantioselective lithiation/
stannylation of O-alkyl carbamate 14. An excellent 92% ee
was reached with the 5-exo-methyl-substituted bispidine 8a,
but larger 5-exo substituents, as in 8b, and even small 5-
endo substituents, as in 8c–f, cause a strong decrease in
enantioselectivity. Consequently, the unsubstituted methyl-
ene group, as present in the (+)-sparteine surrogate 4, is
confirmed as being crucial for high asymmetric inductions.
We tested our modified tricyclic bispidines first by using
the 5-exo-methyl derivative 8a,[23] which afforded (R)-15
with an excellent 92% ee and good 66% yield. Because the
stereodiscrimination is identical to that obtained with the
known (+)-sparteine surrogate 4, we initially assumed that
a 5-exo substituent exerts only a minor effect on chirality
transfer because it points away from the active sBuLi bind-
ing site between the two nitrogen atoms. The mediocre 51%
ee reached with the 5-exo-isopropyl derivative 8b,[23] how-
ever, contradicts this; a bulkier substituent at the 5-exo-po-
sition does have a significant and negative impact on the ee.
A clear trend can be seen for the 5-endo-substituted bispid-
ines 8c–f: The enantiomeric excess of 15 rapidly drops with Experimental Section
increasing size of the substituent and even small atoms such
General: All reactions with moisture-sensitive reagents and dry sol-
as fluorine in 8e or the spiro-fused cyclopropyl group in 8f
result in significantly lower enantioselectivities (40 and 65%
ee, respectively). Thus, the sterically least demanding CH2
group as found in the (+)-sparteine surrogate (4) seems to
vents were performed under argon in flame-dried glassware. An-
hydrous THF, Et2O, CH2Cl2, and DMSO were prepared by using
standard procedures.[30] Commercially available reagents (highest
quality available) were used as received. The bispidine lactam 10
be optimal; any substitution at this position is unfavorable was prepared according to ref.[15] from the natural alkaloid (–)-
cytisine (9), which was isolated from the seeds of Laburnum anagy-
roides.[15] All reactions were monitored by TLC on precoated silica
gel (Merck F254); spots were visualized by UV light (254 nm) or
by staining with aqueous KMnO4. Silica gel (Merck, particle size
63–200 μm) was used for column chromatography.
with respect to chirality transfer.
The large difference in the asymmetric inductions
achieved with the 5,5-dimethylated bispidine 8d (34% ee)
and the 5-endo-monomethylated derivative 8c (79% ee) is
surprising because both bispidines carry the same methyl
substituent at the 5-endo position. However, it might be ex-
plained by the conformation of the fused piperidine ring
in the pre-lithiation complex 16 (bispidine·sBuLi·complex,
Figure 1),[27,28] which precedes the decisive lithiation step.
For 8d (and also for all other 5,5-di- and 5-exo-monosubsti-
tuted bispidines), it is very likely that this ring adopts the
usual chair conformation (or a slightly distorted one) as
shown in 16A, whereas a twist-boat geometry of the fused
Melting points were measured with a Reichert–Kofler Heiztisch
microscope. Optical rotations ([α]TD) were recorded with a Jasco P-
1020 polarimeter (10 cm cell). NMR spectra were recorded with a
Bruker Avance 400 instrument and calibrated by using residual
non-deuteriated solvent as internal reference. The peak assignments
in the 1H and 13C NMR spectra were made on the basis of 2D
NMR experiments (COSY, HSQC, HMBC). IR spectra were re-
corded with a Jasco FT-IR-3410 spectrometer and HRMS with a
Bruker Daltonics micrOTOF focus mass spectrometer using ESI
piperidine ring as in 16B might be energetically favorable in (electronspray ionization).
the case of the 5-endo-methyl-substituted bispidine 8c (R =
General Procedure (GP1) for the Substitution of the Bispidine Lact-
ams at the 5-Position: LDA (2.3 equiv.) was freshly prepared by
deprotonation of iPr2NH (2.5 equiv.) in dry THF (1 mL/
Me, RЈ = H in 16)[29] because this conformation allows the
otherwise axially oriented methyl group to slip into a
pseudo-equatorial position, which also reduces its steric de- mmoliPr2NH) with nBuLi (2.3 equiv.) at –78 °C and room temp.
Eur. J. Org. Chem. 2013, 7575–7582
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M. Breuning, D. Hein
FULL PAPER
(30 min each). A solution of the lactam (1.0 equiv.) in dry THF
(10 mL/mmol lactam) was added at –78 °C and, after 1–2 h of stir-
ring, the electrophile (2.0–3.0 equiv.). The reaction mixture was
warmed to room temp. over 16 h, quenched with water (25 mL/
mmol lactam), and extracted with EtOAc (5ϫ 25 mL/mmol lact-
am). The combined organic layers were washed with brine (25 mL/
–124.0 (MeOH, c = 0.52). IR (ATR): ν = 2952, 2866, 1691, 1628,
˜
1
1443, 1234, 765 cm–1. H NMR (400 MHz, CDCl3, 83:17 mixture
of rotamers): δ = 4.79 (d, J = 14.0 Hz, 1 H, 8-H), 4.59 (d, J =
14.0 Hz, 0.83 H, 12-Hrot1), 4.38–4.22 (m, 0.34 H, 10-Hrot2, 12-
Hrot2), 4.19 (d, J = 13.4 Hz, 0.83 H, 10-Hrot1), 3.66 (s, 0.51 H,
OMerot2), 3.59 (s, 2.49 H, OMerot1), 3.44 (dt, J = 11.2, 3.2 Hz, 1
mmol lactam), dried with MgSO4, and the solvents evaporated. H, 2-H), 3.07 (br. d, J = 13.4 Hz, 0.83 H, 10-Hrot1), 3.02–2.88 (m,
Column chromatography (silica gel, EtOAc/MeOH, 100:0Ǟ 90:10)
delivered the 5-substituted bispidine lactam.
0.34 H, 10-Hrot2, 12-Hrot2), 2.85 (dd, J = 14.0, 1.9 Hz, 0.83 H, 12-
Hrot1), 2.78 (d, J = 13.8 Hz, 1 H, 8-H), 2.55 (m, 1 H, CHMe2), 2.26
(m, 1 H, 5-Hax), 2.16 (m, 1 H, 3-H), 1.76 (m, 5 H, 3-H, 4-H, 9-H,
13-H2), 1.64 (br. s, 1 H, 1-H), 1.42 (br. q, J ≈ 13 Hz, 1 H, 4-Hax),
0.92 (d, J = 7.1 Hz, 3 H, CHMe), 0.75 (d, J = 6.8 Hz, 3 H,
CHMe) ppm. 13C NMR (100 MHz, CDCl3, only signals of the
major rotamer given): δ = 171.6 (C-6), 156.0 (CO2), 59.4 (C-2), 52.6
(OMe), 49.1 (C-10), 47.3 (C-5), 45.8 (C-8), 44.3 (C-12), 33.3 (C-1),
33.1 (C-13), 27.84 (C-9), 27.80 (CHMe2), 27.4 (C-3), 20.3 (CHMe),
19.7 (C-4), 17.8 (CHMe) ppm. HRMS (ESI): calcd. for
C16H26N2NaO3 [M + Na]+ 317.1836; found 317.1835.
Methyl (1R,2S,5R,9R)-5-Methyl-6-oxo-7,11-diazatricyclo[7.3.1.02,7]-
tridecane-11-carboxylate (11aA) and Methyl (1R,2S,5S,9R)-5-
Methyl-6-oxo-7,11-diazatricyclo[7.3.1.02,7]tridecane-11-carboxylate
(11aB): According to the general procedure GP1, bispidine lactam
10 (3.08 g, 12.2 mmol) was methylated with MeI (2.29 mL, 5.20 g,
36.6 mmol) to give the 5-endo-methylated bispidine 11aB (faster
eluting, 455 mg, 1.71 mmol, 14%) and the 5-exo-methylated bispid-
ine 11aA (slower eluting, 1.92 g, 7.20 mmol, 59%) as yellowish sol-
ids. The initial dr 11aA/11aB, determined by 1H NMR of the crude
product, was 75:25.
The 1H NMR splitting pattern of the proton 4-Hax includes a large
quartet (J ≈ 13 Hz), which must originate from a geminal coupling
with 4-Heq, a 1,3-diaxial coupling with 3-Hax, and a 1,3-diaxial
coupling with 5-Hax. The latter relation proves the equatorial and
thus exo orientation of the 5-isopropyl group.
11aA: M.p. 69 °C. [α]2D1 = –114.2 (MeOH, c = 0.27). IR (ATR): ν
˜
= 2933, 2856, 1687, 1631, 1434, 1411, 1227, 1011, 764, 734 cm–1.
1H NMR (400 MHz, CDCl3, 83:17 mixture of rotamers): δ = 4.67
(d, J = 13.8 Hz, 1 H, 8-H), 4.53 (d, J = 13.9 Hz, 0.83 H, 12-Hrot1),
4.30 (br. d, J = 13.8 Hz, 0.17 H, 12-Hrot2), 4.18 (br. d, J = 12.8 Hz,
0.17 H, 10-Hrot2), 4.10 (d, J = 13.3 Hz, 0.83 H, 10-Hrot1), 3.58 (s,
0.5 H, OMerot2), 3.50 (s, 2.5 H, OMerot1), 3.40 (br. d, J = 11.8 Hz,
1 H, 2-H), 2.99 (d, J = 13.4 Hz, 0.83 H, 10-H), 2.96–2.81 (m, 0.34
H, 10-Hrot2, 12-Hrot2), 2.78 (dd, J = 13.9, 2.0 Hz, 0.83 H, 12-Hrot1),
2.70 (d, J = 13.7 Hz, 1 H, 8-H), 2.31 (m, 1 H, 5-Hax), 2.15 (qd, J
= 12.8, 2.9 Hz, 1 H, 3-H), 1.90–1.65 (m, 5 H, 3-H, 4-H, 9-H, 13-
H2), 1.55 (br. s, 1 H, 1-H), 1.33 (qd, J = 13.0, 2.6 Hz, 1 H, 4-Hax),
1.06 (d, J = 7.0 Hz, 3 H, 5-Me) ppm. 13C NMR (100 MHz, CDCl3,
only signals of the major rotamer given): δ = 172.8 (C-6), 155.9
(CO2), 59.9 (C-2), 52.4 (OMe), 48.9 (C-10), 46.0 (C-8), 44.1 (C-12),
36.6 (C-5), 33.05 (C-1), 33.03 (C-13), 28.8 (C-4), 27.7 (C-9), 27.5
(C-3), 17.0 (5-Me) ppm. HRMS (ESI): calcd. for C14H22N2NaO3
[M + Na]+ 289.1523; found 289.1523.
Methyl (1R,2S,5R,9R)-5-Fluoro-6-oxo-7,11-diazatricyclo[7.3.1.02,7]-
tridecane-11-carboxylate (11cA): According to the general pro-
cedure GP1, bispidine lactam 10 (1.00 g, 3.96 mmol) was fluori-
nated with NFSI (2.50 g, 7.92 mmol) to give bispidine 11cA
(824 mg, 3.05 mmol, 77%) as a yellowish solid, m.p. 132 °C. [α]2D1
= –103.6 (MeOH, c = 0.25). IR (ATR): ν = 2928, 2863, 1679, 1643,
˜
1443, 1238, 1074, 760 cm–1. 1H NMR (400 MHz, CDCl3, 88:12
mixture of rotamers): δ = 4.86 (ddd, J = 47.9, 11.6, 5.9 Hz, 0.88
H, 5-Hax,rot1), 4.58 (d, J = 13.9 Hz, 1 H, 8-H), 4.70–4.53 (m, 0.12
H, 5-Hax,rot2), 4.51 (d, J = 14.1 Hz, 0.88 H, 12-Hrot1), 4.38–4.19
(m, 0.24 H, 10-Hrot2, 12-Hrot2), 4.14 (d, J = 12.4 Hz, 0.88 H, 10-
Hrot1), 3.59 (s, 0.36 H, OMerot2), 3.54 (s, 2.64 H, OMerot1), 3.45
(br. d, J = 10.9 Hz, 1 H, 2-H), 3.03 (d, J = 13.5 Hz, 1 H, 10-H),
2.95–2.75 (m, 2 H, 8-H, 12-H), 2.38–2.10 (m, 2 H, 3-H, 4-H), 1.99–
1.66 (m, 5 H, 3-H, 4-H, 9-H, 13-H2), 1.59 (s, 1 H, 1-H) ppm. 13C
NMR (100 MHz, CDCl3, only signals of the major rotamer given):
δ = 166.9 (d, J = 20.0 Hz, C-6), 156.1 (CO2), 85.8 (d, J = 180 Hz,
C-5), 59.2 (C-2), 52.6 (OMe), 49.1 (C-10), 46.0 (C-8), 44.1 (C-12),
32.9 (C-13), 32.8 (C-1), 27.3 (C-9), 26.8 (d, J = 20.0 Hz, 4-C), 23.8
The 1H NMR splitting pattern of the proton 4-Hax includes a large
quartet (J = 13.0 Hz), which must originate from a geminal cou-
pling with 4-Heq, a 1,3-diaxial coupling with 3-Hax, and a 1,3-diax-
ial coupling with 5-Hax. The latter relation proves the equatorial
and thus exo orientation of the 5-methyl group.
(d,
J
=
11.9 Hz, 3-C) ppm. HRMS (ESI): calcd. for
11aB: M.p. 73 °C. [α]2D1 = –96.9 (MeOH, c = 0.26). IR (ATR): ν =
˜
C13H19FN2NaO3 [M + Na]+ 293.1272; found 293.1272.
1
2862, 1689, 1608, 1429, 1231, 935, 762 cm–1. H NMR (400 MHz,
1
The H NMR splitting pattern of the proton 5-Hax,rot1 includes a
CDCl3, 79:21 mixture of rotamers): δ = 4.64 (br. d, J = 13.7 Hz, 1
H, 8-H), 4.53 (d, J = 14.0 Hz, 0.79 H, 12-Hrot1), 4.33 (d, J =
14.0 Hz, 0.21 H, 12-Hrot2), 4.11 (d, J = 13.4 Hz, 1 H, 10-H), 3.61
(s, 0.63 H, OMerot2), 3.57 (s, 2.37 H, OMerot1), 3.40 (br. d, J =
10.1 Hz, 1 H, 2-H), 3.02 (d, J = 13.1 Hz, 1 H, 10-H), 2.80 (m, 1
H, 12-H), 2.77 (dt, J = 13.7, 2.7 Hz, 1 H, 8-H), 2.45 (m, 1 H, 5-
H), 2.16 (m, 1 H, 3-H), 1.93–1.72 (m, 4 H, 4-H, 9-H, 13-H2), 1.69–
1.56 (m, 3 H, 1-H, 3-H, 4-H), 1.20 (d, J = 7.4 Hz, 3 H, 5-Me) ppm.
13C NMR (100 MHz, CDCl3, only signals of the major rotamer
given): δ = 173.8 (C-6), 155.4 (CO2), 59.3 (C-2), 52.4 (OMe), 48.6
(C-10), 46.2 (C-8), 44.1 (C-12), 36.1 (C-5), 33.1 (C-1), 32.7 (C-13),
27.7 (C-9), 26.6 (C-4), 23.5 (C-3), 18.7 (5-Me) ppm. HRMS (ESI):
calcd. for C14H22N2NaO3 [M + Na]+ 289.1523; found 289.1521.
doublet with J = 11.6 Hz, which must originate from a 1,3-diaxial
coupling with 4-Hax. This relation proves the equatorial and thus
exo orientation of the 5-fluoride substituent.
Methyl (1R,2S,5S,9R)-5-(Methoxymethyl)-6-oxo-7,11-diazatricyclo-
[7.3.1.02,7]tridecane-11-carboxylate (11dA): Bispidine lactam 10
(1.50 g, 5.94 mmol) was treated with MOMCl (1.3 mL, 1.20 g,
14.9 mmol) according to the general procedure GP1, affording bi-
spidine 11dA (1.28 g, 4.32 mmol, 73%) as a yellowish oil. [α]2D1
=
–108.7 (MeOH, c = 0.26). IR (ATR): ν = 2862, 1689, 1622, 1443,
˜
1
1235, 1103, 765 cm–1. H NMR (400 MHz, CDCl3, 76:24 mixture
of rotamers): δ = 4.76 (d, J = 13.9 Hz, 0.76 H, 8-Hrot1), 4.69 (br.
d, J = 13.2 Hz, 0.24 H, 8-Hrot2), 4.60 (d, J = 14.0 Hz, 0.76 H, 12-
Hrot1), 4.54 (br. d, J = 14.5 Hz, 0.24 H, 12-Hrot2), 4.19 (br. d, J =
14.7 Hz, 1 H, 10-H), 3.71 (dd, J = 8.9, 6.3 Hz, 1 H, CHHOMe),
Methyl
(1R,2S,5S,9R)-5-Isopropyl-6-oxo-7,11-diazatricyclo-
[7.3.1.02,7]tridecane-11-carboxylate (11bA): Bispidine lactam 10
(500 mg, 1.98 mmol) was treated with iPrI (594 μL, 1.01 g, 3.68–3.54 (m, 4 H, CHHOMe, CO2Me), 3.48 (m, 1 H, 2-H), 3.36
5.94 mmol) according to the general procedure GP1, yielding bispi-
(s, 0.72 H, CH2OMerot2), 3.32 (s, 2.28 H, CH2OMerot1), 3.06 (m, 1
H, 10-H), 2.97–2.76 (m, 2 H, 8-H, 12-H), 2.70 (m, 0.24 H, 5-
dine 11bA (297 mg, 1.01 mmol, 51%) as a colorless oil. [α]2D1
=
7578
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7575–7582

Lithiation/Stannylation of an O-Alkyl Carbamate
Hax,rot2), 2.53 (m, 0.76 H, 5-Hax,rot1), 2.22 (m, 1 H, 3-H), 2.09–1.78 9), 23.3 (d, J = 9.3 Hz, C-3) ppm. HRMS (ESI): calcd. for
(m, 5 H, 3-H, 4-H, 9-H, 13-H2), 1.75–1.57 (m, 2 H, 1-H, 4-
Hax) ppm. 13C NMR (100 MHz, CDCl3, only signals of the major
rotamer given): δ = 170.0 (C-6), 156.1 (CO2), 73.0 (OCH2), 59.6
(C-2), 58.9 (CH2OMe), 52.6 (CO2Me), 49.2 (C-10), 45.9 (C-8), 44.3
(C-12), 42.3 (C-5), 33.3 (C-1), 33.2 (C-13), 27.9 (C-9), 27.3 (C-3),
23.7 (C-4) ppm. HRMS (ESI): calcd. for C15H24N2NaO4 [M +
Na]+ 319.1628; found 319.1628.
C13H18F2N2NaO3 [M + Na]+ 311.1178; found 311.1178.
Methyl
(1R,2S,9R)-5-Methylene-6-oxo-7,11-diazatricyclo-
[7.3.1.02,7]tridecane-11-carboxylate (13): A solution of lactam 11dA
(600 mg, 2.02 mmol) in dry THF (8 mL) was treated with KOtBu
(274 mg, 2.43 mmol) at –78 °C. The reaction mixture was warmed
to room temp. over 16 h and the solvents evaporated. Colum
chromatography (silica gel, EtOAc/MeOH, 100:0Ǟ 90:10) deliv-
ered alkene 13 (385 mg, 1.46 mmol, 72%) as a yellowish solid, m.p.
1
In the H–1H COSY NMR spectrum, the cross peak 4-Hax/5-Hax
shows a quartet with a coupling constant of J = 13.1 Hz for 4-Hax.
This quartet must originate from a geminal coupling with 4-Heq, a
1,3-diaxial coupling with 3-Hax, and a 1,3-diaxial coupling with 5-
Hax. The latter relation proves the equatorial and thus exo orienta-
tion of the 5-methoxymethyl group.
100 °C. [α]2D3 = –103.6 (MeOH, c = 0.29). IR (ATR): ν = 2911,
˜
2855, 1690, 1605, 1429, 1310, 1231, 934, 761 cm–1. 1H NMR
(400 MHz, CDCl3, 75:25 mixture of rotamers): δ = 6.05 (s, 1 H,
C=CH), 5.20 (s, 1 H, C=CH), 4.80 (d, J = 13.8 Hz, 1 H, 8-H), 4.53
(d, J = 13.9 Hz, 0.75 H, 12-Hrot1), 4.33 (br. d, J = 13.8 Hz, 0.5 H,
10-Hrot2 12-Hrot2), 4.18 (d, J = 13.4 Hz, 0.75 H, 10-Hrot1), 3.56 (s,
3 H, OMe), 3.55 (m, 1 H, 2-H), 3.06 (br. d, J = 13.3 Hz, 0.75 H,
10-Hrot1), 2.99 (br. d, J = 13.9 Hz, 0.25 H, 10-Hrot2), 2.89 (br. d, J
= 14.0 Hz, 1 H, 8-H), 2.83 (dd, J = 14.0, 2.0 Hz, 1 H, 12-H), 2.63
(dt, J = 14.1, 3.2 Hz, 1 H, 4-H), 2.36 (m, 1 H, 4-H), 2.22 (m, 1 H,
3-H), 2.09–1.77 (m, 4 H, 3-H, 9-H, 13-H2), 1.68 (br. s, 0.75 H, 1-
Hrot1), 1.63 (br. s, 0.25 H, 1-Hrot2) ppm. 13C NMR (100 MHz,
CDCl3, only signals of the major rotamer given): δ = 164.2 (C-6),
155.9 (CO2), 138.2 (C=CH2), 120.5 (C=CH2), 59.4 (C-2), 52.6
(OMe), 49.0 (C-10), 46.3 (C-8), 44.4 (C-12), 33.5 (C-1), 32.8 (C-
13), 29.0 (C-4), 27.9 (C-9), 27.7 (C-3) ppm. HRMS (ESI): calcd.
for C14H20N2NaO3 [M + Na]+ 287.1366; found 287.1366.
Epimerization of 11aA: According to the general procedure GP1,
bispidine lactam 11aA (1.80 g, 6.76 mmol) was deprotonated and
re-protonated with BHT (3.72 g, 16.9 mmol) to give the 5-endo-
methylated bispidine 11aB (faster eluting, 756 mg, 2.84 mmol,
42%) and the 5-exo-methylated bispidine 11aA (slower eluting,
846 mg, 3.18 mmol, 47%) as slightly brownish solids. The initial dr
11aA/11aB, determined by 1H NMR of the crude product, was
47:53.
Methyl
(1R,2S,9R)-5,5-Dimethyl-6-oxo-7,11-diazatricyclo-
[7.3.1.02,7]tridecane-11-carboxylate (12a): Bispidine lactam 11aA
(900 mg, 3.38 mmol) was methylated with MeI (633 μL, 1.44 g,
10.1 mmol) according to the general procedure GP1, delivering bi-
Methyl
decane-5,1Ј-cyclopropane]-11-carboxylate (12c)
(1R,2S,9R)-6-Oxo-7,11-diazaspiro[tricyclo[7.3.1.02,7]tri-
spidine 12a (777 mg, 2.77 mmol, 82%) as a yellowish oil. [α]2D1
=
–77.3 (MeOH, c = 0.60). IR (ATR): ν = 2921, 2860, 1691, 1626,
˜
1445, 1235, 1141, 766 cm–1. 1H NMR (400 MHz, CDCl3, 80:20 Method A Corey–Chaykovsky Cyclopropanation: Me3SO+I–
mixture of rotamers): δ = 4.63 (d, J = 13.7 Hz, 1 H, 8-H), 4.56 (br. (83.3 mg, 378 μmol) in dry DMSO (500 μL) was deprotonated with
Ϫ
d, J = 14.0 Hz, 0.80 H, 12-Hrot1), 4.56 (br. d, J = 12.8 Hz, 0.20 H, NaH (9.0 mg, 378 μmol) at room temp. for 1 h. Alkene 13 (50 mg,
12-Hrot2), 4.17 (m, 0.20 H, 10-Hrot2), 4.11 (d, J = 13.1 Hz, 0.80 H, 189 μmol) was added and stirring at room temp. was continued for
10-Hrot1), 3.62 (s, 0.60 H, OMerot2), 3.58 (s, 2.40 H, OMerot1), 3.43 15 h. The reaction mixture was quenched with saturated aqueous
(br. d, J = 11.3 Hz, 1 H, 2-H), 3.03 (br. d, J = 13.1 Hz, 1 H, 10-
H), 2.84 (d, J = 13.9 Hz, 1 H, 12-H), 2.78 (dm, J = 13.8 Hz, 1 H, with MgSO4 and column chromatography (silica gel, EtOAc/
8-H), 2.20 (m, 1 H, 3-H), 2.04–1.78 (m, 3 H, 9-H, 13-H2), 1.72– MeOH, 100:0Ǟ 90:10) afforded the spirocyclic product 12c
NH4Cl (10 mL) and extracted with CH2Cl2 (4ϫ 15 mL). Drying
1.56 (m, 4 H, 1-H, 3-H, 4-H2), 1.17 (s, 2.4 H, 5-Merot1), 1.14 (s, 3 (9.0 mg, 32.3 μmol, 17%) as a yellowish oil.
H, 5-Me), 1.12 (s, 0.6 H, 5-Merot2) ppm. 13C NMR (100 MHz,
Method B Ϫ Simmons–Smith Cyclopropanation: Alkene 13 (195 mg,
CDCl3, only signals of the major rotamer given): δ = 176.3 (C-6),
155.6 (CO2), 59.8 (C-2), 52.5 (OMe), 48.8 (C-10), 46.6 (C-8), 44.2
(C-12), 38.4 (C-5), 35.0 (C-4), 33.3 (C-1), 32.5 (C-13), 28.3 (5-Me),
27.9 (C-9), 27.3 (5-Me), 24.4 (C-3) ppm. HRMS (ESI): calcd. for
C15H25N2O3 [M + H]+ 281.1860; found 281.1860.
738 μmol) was dissolved in dry CH2Cl2 (10 mL) and ZnEt2 (1.0 m
in n-hexane, 2.21 mL, 2.21 mmol) and CH2I2 (298 μL, 988 mg,
3.69 mmol) were added at 0 °C. After 16 h at room temp., a further
batch of ZnEt2 (1.0 m in n-hexane, 2.21 mL, 2.21 mmol) and CH2I2
(298 μL, 988 mg, 3.69 mmol) was added at 0 °C. The reaction mix-
ture was stirred for 16 h at room temp., quenched with HCl (1 n,
20 mL), basified with NaOH (1 n), and extracted with CH2Cl2 (3ϫ
30 mL). The combined organic layers were washed with brine
Methyl (1R,2S,9R)-5,5-Difluoro-6-oxo-7,11-diazatricyclo[7.3.1.02,7]-
tridecane-11-carboxylate (12b): According to the general procedure
GP1, bispidine lactam 11cA (750 mg, 2.77 mmol) was fluorinated
with NFSI (1.75 g, 5.55 mmol) to give bispidine 12b (567 mg, (20 mL) and dried with MgSO4. The solvent was removed under
1.97 mmol, 71%) as a yellowish solid, m.p. 105 °C. [α]2D1 = –83.6
reduced pressure to give a mixture of alkene 13 and product 12c,
(MeOH, c = 0.25). IR (ATR): ν = 2923, 2865, 1692, 1660, 1445, which was purified by column chromatography (silica gel, EtOAc/
˜
1
1236, 1125, 751 cm–1. H NMR (400 MHz, CDCl3, 68:32 mixture
MeOH, 100:0Ǟ 90:10). Because 13 and 12c could not be separated
of rotamers): δ = 4.61 (d, J = 13.8 Hz, 1 H, 8-H), 4.55 (d, J = by chromatography, the cyclopropanation procedure described
14.0 Hz, 0.68 H, 12-Hrot1), 4.37 (d, J = 14.2 Hz, 0.32 H, 12-Hrot2),
4.32 (d, J = 13.9 Hz, 0.32 H, 10-Hrot2), 4.17 (d, J = 13.3 Hz, 0.68
H, 10-Hrot1), 3.63 (s, 0.96 H, OMerot2), 3.60 (s, 2.04 H, OMerot1),
3.55 (m, 1 H, 2-H), 3.08 (d, J = 13.2 Hz, 1 H, 10-Hrot1), 2.93 (d, J
= 13.7 Hz, 1 H, 8-Hrot1), 3.03–2.89 (m, 0.64 H, 8-Hrot2, 10-Hrot2),
2.87 (d, J = 13.9 Hz, 1 H, 12-H), 2.54–2.18 (m, 2 H, 3-H, 4-H),
above was repeated twice, until no more alkene 13 was left. The
pure product 12c (92.4 mg, 332 μmol, 45%) was obtained as a
slightly yellowish oil. [α]2D1 = –31.1 (MeOH, c = 0.25). IR (ATR):
ν = 2930, 2862, 1694, 1626, 1444, 1236, 766 cm–1. 1H NMR
˜
(400 MHz, CDCl3, 76:24 mixture of rotamers): δ = 4.78 (dt, J =
13.6, 2.0 Hz, 1 H, 8-H), 4.61 (br. d, J = 13.7 Hz, 0.76 H, 12-Hrot1),
2.14–1.80 (m, 5 H, 3-H, 4-H, 9-H, 13-H2), 1.74 (m, 1 H, 1-H) ppm. 4.61 (br. d, J = 14.9 Hz, 0.24 H, 12-Hrot2), 4.19 (br. d, J = 12.4 Hz,
13C NMR (100 MHz, CDCl3, only signals of the major rotamer
1 H, 10-H), 3.69 (s, 0.72 H, OMerot2), 3.58 (s, 3.28 H, 2-H,
given): δ = 161.7 (t, J = 29.7 Hz, C-6), 155.5 (CO2), 112.2 (t, J =
OMerot1), 3.07 (br. d, J = 13.2 Hz, 1 H, 10-H), 2.96–2.78 (m, 2 H,
244 Hz, C-5), 58.8 (C-2), 52.7 (OMe), 48.6 (C-10), 46.8 (C-8), 44.2 8-H, 12-H), 2.37 (m, 1 H, 4-H), 2.07 (m, 1 H, 3-H), 1.99–1.84 (m,
(C-12), 33.1 (C-1), 32.3 (C-13), 30.7 (t, J = 23.0 Hz, C-4), 27.4 (C- 3 H, 9-H, 13-H2), 1.79 (m, 1 H, 4-H), 1.70 (br. s, 1 H, 1-H), 1.43
Eur. J. Org. Chem. 2013, 7575–7582
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7579

M. Breuning, D. Hein
(m, 1 H, Hcyclopropyl), 1.25 (m, 1 H, 3-H), 0.94 (m, 1 H, Hcyclopropyl), HRMS (ESI): calcd. for C15H29N2 [M + H]+ 237.2325; found
FULL PAPER
0.57 (m, 1 H, Hcyclopropyl), 0.49 (m, 1 H, Hcyclopropyl) ppm. 13C
NMR (100 MHz, CDCl3, only signals of the major rotamer given):
δ = 172.4 (C-6), 155.6 (CO2), 59.9 (C-2), 52.5 (OMe), 48.9 (C-10),
46.4 (C-8), 44.3 (C-12), 33.4 (C-1), 33.0 (C-13), 30.2 (C-4), 27.9 (C-
9), 27.4 (C-3), 21.3 (C-5), 18.6 (Ccyclopropyl), 13.6 (Ccyclopropyl) ppm.
HRMS (ESI): calcd. for C15H23N2O3 [M + H]+ 279.1703; found
279.1703.
237.2326.
The 1H NMR splitting pattern of the proton 4-Hax includes a large
quartet (J = 12.7 Hz), which must originate from a geminal cou-
pling with 4-Heq, a 1,3-diaxial coupling with 3-Hax, and a 1,3-diax-
ial coupling with 5-Hax. The latter relation proves the equatorial
and thus exo orientation of the 5-isopropyl group.
(1R,2S,5S,9S)-5,11-Dimethyl-7,11-diazatricyclo[7.3.1.02,7]tridecane
(8c): Reduction of 11aB (1.20 g, 4.51 mmol) according to the gene-
ral procedure GP2 afforded bispidine 8c (741 mg, 3.56 mmol, 79%)
as a slightly yellowish oil. [α]2D3 = –4.7 (MeOH, c = 0.59). IR (ATR):
General Procedure (GP2) for the Reduction of the Bispidine Lact-
ams: The lactam (1.0 equiv.) was dissolved in dry THF (7–9 mL/
mmol lactam) and slowly added at 0 °C to a suspension of LiAlH4
(6 equiv.) in dry THF (4–7 mL/mmollactam). The reaction mixture
was allowed to slowly warm to room temp., heated at reflux over-
night, cooled to 0 °C, and diluted with Et2O. Saturated aqueous
Na2SO4 was added dropwise until effervescence ceased. The solids
were removed by filtration through a small pad of Celite and the
filter cake was exhaustively washed with CH2Cl2/MeOH (90:10).
The filtrate was dried with MgSO4 and evaporated under reduced
pressure to give bispidine 8.
ν = 2935, 1654, 1447, 1039, 739 cm–1 1H NMR (400 MHz,
.
˜
CD3OD): δ = 2.94 (br. d, J = 11.6 Hz, 1 H, 12-H), 2.78 (br. d, J =
11.0 Hz, 1 H, 10-H), 2.74 (dt, J = 11.2, 2.3 Hz, 1 H, 8-H), 2.57 (dt,
J = 11.2, 1.8 Hz, 1 H, 6-H), 2.42 (dd, J = 11.1, 5.1 Hz, 1 H, 10-
H), 2.28 (dd, J = 11.5, 5.2 Hz, 1 H, 12-H), 2.18 (s, 3 H, 11-Me),
2.16 (m, 1 H, 8-H), 2.06 (dd, J = 11.2, 3.6 Hz, 1 H, 6-H), 1.92 (m,
2 H, 2-H, 9-H), 1.85 (m, 1 H, 5-Heq), 1.78 (m, 1 H, 3-H), 1.72 (m,
1 H, 13-H), 1.66–1.51 (m, 3 H, 1-H, 4-H2), 1.48 (m, 1 H, 13-H),
1.16 (d, J = 7.1 Hz, 3 H, 5-Me), 1.14 (m, 1 H, 3-H) ppm. 13C NMR
(100 MHz, CD3OD): δ = 68.3 (C-2), 63.3 (C-6), 62.3 (C-8), 60.8
(C-10), 56.6 (C-12), 47.0 (11-Me), 35.9 (C-1), 33.4 (C-13), 31.6 (C-
4), 31.4 (C-9), 29.8 (C-5), 26.1 (C-3), 18.7 (5-Me) ppm. HRMS
(ESI): calcd. for C13H25N2 [M + H]+ 209.2012; found 209.2012.
(1R,2S,5R,9S)-5,11-Dimethyl-7,11-diazatricyclo[7.3.1.02,7]tridecane
(8a): Reduction of 11aA (1.20 g, 4.51 mmol) according to the gene-
ral procedure GP2 delivered bispidine 8a (657 mg, 3.16 mmol,
70%) as a colorless oil. [α]2D3 = +10.6 (MeOH, c = 0.21). IR (ATR):
ν = 2917, 1659, 1443, 1266, 1142, 1047, 891, 785, 743 cm–1. 1H
˜
NMR (400 MHz, CD3OD): δ = 3.04 (d, J = 11.4 Hz, 1 H, 12-H),
2.93 (d, J = 11.1 Hz, 1 H, 10-H), 2.87 (dt, J = 11.2, 2.0 Hz, 1 H,
8-H), 2.73 (ddd, J = 11.1, 3.7, 2.0 Hz, 1 H, 6-H), 2.27 (m, 2 H, 8-
H, 10-H), 2.14 (s, 3 H, 11-Me), 2.09 (dd, J = 11.5, 2.6 Hz, 1 H, 12-
H), 1.97 (d, J = 11.3 Hz, 1 H, 2-H), 1.88–1.73 (m, 3 H, 4-H, 5-Hax,
9-H), 1.67–1.54 (m, 4 H, 1-H, 3-H, 13-H2), 1.47 (t, J = 11.1 Hz, 1
H, 6-Hax), 1.42 (m, 1 H, 3-H), 0.99 (qd, J = 13.0, 3.8 Hz, 1 H, 4-
Hax), 0.84 (d, J = 6.4 Hz, 3 H, 5-Me) ppm. 13C NMR (100 MHz,
CD3OD): δ = 66.9 (C-2), 66.3 (C-6), 61.6 (C-8), 61.5 (C-10), 57.1
(C-12), 47.4 (11-Me), 36.1 (C-1), 34.9 (C-4 or C-13), 34.8 (C-4 or
C-13), 31.9 (C-5), 31.50 (C-3), 31.48 (C-9), 20.0 (5-Me) ppm.
HRMS (ESI): calcd. for C13H25N2 [M + H]+ 209.2012; found
209.2012.
1
In the H NMR spectrum, the two protons 6-Hax and 6-Heq pos-
sess, in addition to their large geminal coupling with J = 11.2 Hz,
only a small doublet (J Ͻ 4 Hz), which excludes a 1,3-diaxial rela-
tionship between 6-H and 5-H. Therefore 5-H must be equatorial,
which proves an axial and thus endo orientation of the 5-methyl
group.
(1R,2S,9S)-5,5,11-Trimethyl-7,11-diazatricyclo[7.3.1.02,7]tridecane
(8d): According to the general procedure GP2, lactam 12a (640 mg,
2.28 mmol) was reduced to give bispidine 8d (457 mg, 2.05 mmol,
90%) as a yellowish oil. [α]2D1 = –12.8 (MeOH, c = 0.46). IR (ATR):
ν = 2930, 2777, 1654, 1445, 1032 cm–1 1H NMR (400 MHz,
.
˜
CD3OD): δ = 2.96 (d, J = 11.6 Hz, 1 H, 12-H), 2.79 (m, 1 H, 8-H,
10-H), 2.47 (dd, J = 11.1, 5.1 Hz, 1 H, 10-H), 2.39 (dd, J = 11.1,
2.3 Hz, 1 H, 6-H), 2.34 (dd, J = 11.5, 5.2 Hz, 1 H, 12-H), 2.20 (s,
3 H, 11-Me), 2.19 (m, 1 H, 8-H), 1.91 (m, 2 H, 2-H, 9-H), 1.76 (m,
2 H, 3-H, 13-H), 1.68 (m, 2 H, 1-H, 6-H), 1.52–1.41 (m, 2 H, 4-H,
13-H), 1.22 (m, 2 H, 3-H, 4-H), 1.08 (s, 3 H, 5-Me), 0.86 (s, 3 H,
5-Me) ppm. 13C NMR (100 MHz, CD3OD): δ = 69.6 (C-6), 67.9
(C-2), 62.2 (C-8), 60.8 (C-10), 56.7 (C-12), 46.8 (11-Me), 39.0 (C-
4), 35.5 (C-1), 33.2 (C-13), 31.6 (C-5), 31.2 (C-9), 30.5 (5-Me), 27.7
(C-3), 25.5 (5-Me) ppm. HRMS (ESI): calcd. for C14H27N2 [M +
H]+ 223.2169; found 223.2173.
In the 1H NMR spectrum, the proton 6-Hax appears as a large
triplet (J = 11.1 Hz), which must originate from a geminal coupling
with 6-Heq and a 1,3-diaxial coupling with 5-Hax. Furthermore, the
large quartet of the proton 4-Hax (J = 13.0 Hz) must originate from
a geminal coupling with 4-Heq, a 1,3-diaxial coupling with 3-Hax,
and a 1,3-diaxial coupling with 5-Hax. Both relations prove the
equatorial and thus exo orientation of the 5-methyl group.
(1R,2S,5S,9S)-5-Isopropyl-11-methyl-7,11-diazatricyclo[7.3.1.02,7]-
tridecane (8b): According to the general procedure GP2, lactam
11bA (260 mg, 883 μmol) was reduced to give bispidine 8b (194 mg,
821 μmol, 93%) as a colorless oil. [α]2D2 = +13.7 (MeOH, c = 0.23).
(1R,2S,9S)-5,5-Difluoro-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tri-
decane (8e): Reduction of 12b (342 mg, 1.19 mmol) according to
the general procedure GP2 delivered bispidine 8e (195 mg,
IR (ATR): ν = 2930, 2871, 1660, 1465, 1443, 1065, 1039, 740 cm–1.
˜
1H NMR (400 MHz, CD3OD): δ = 3.05 (d, J = 11.6 Hz, 1 H, 12- 847 μmol, 71%) as a slightly yellowish oil. [α]2D2 = –17.9 (MeOH, c
H), 2.94 (d, J = 11.2 Hz, 1 H, 10-H), 2.90 (dt, J = 11.2, 2 Hz, 1 H,
8-H), 2.85 (ddd, J = 10.6, 3.2, 2.0 Hz, 1 H, 6-H), 2.34 (ddd, J =
11.2, 3.2, 1.9 Hz, 1 H, 8-H), 2.26 (ddd, J = 11.1, 3.5, 1.9 Hz, 1 H,
10-H), 2.14 (s, 3 H, 11-Me), 2.11 (dd, J = 11.6, 2.7 Hz, 1 H, 12-
H), 2.00 (d, J = 11.3 Hz, 1 H, 2-H), 1.86 (m, 2 H, 4-H, 9-H), 1.67–
1.44 (m, 7 H, 1-H, 3-H2, 5-Hax, 6-H, 13-H2), 1.38 (oct., J = 6.7 Hz,
1 H, CHMe2), 1.05 (qd, J = 12.7, 4.0 Hz, 1 H, 4-Hax), 0.90 (d, J =
6.8 Hz, 6 H, CHMe2) ppm. 13C NMR (100 MHz, CD3OD): δ =
= 0.10). IR (ATR): ν = 2917, 1660, 1442, 1284, 1099, 1052,
˜
1
1000 cm–1. H NMR (400 MHz, CD3OD): δ = 3.01 (m, 2 H, 6-H,
12-H), 2.86 (m, 2 H, 8-H, 10-H), 2.37–2.25 (m, 2 H, 8-H, 10-H),
2.15 (s, 3 H, 11-Me), 2.20–2.02 (m, 4 H, 2-H, 4-H, 6-H, 12-H), 1.89
(m, 2 H, 9-H), 1.84–1.63 (m, 4 H, 1-H, 3-H, 4-H, 13-H), 1.55 (m,
2 H, 3-H, 13-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 121.1
(dd, J = 244, 237 Hz, C-5), 65.5 (C-2), 62.2 (dd, J = 31.2, 24.6 Hz,
C-6), 61.0 (C-8), 60.8 (C-10), 56.8 (C-12), 47.1 (11-Me), 35.3 (C-
67.3 (C-2), 62.2 (C-6), 61.8 (C-8), 61.5 (C-10), 57.1 (C-12), 47.2 1), 34.1 (C-13), 33.7 (dd, J = 25.1, 21.5 Hz, 3-C), 31.3 (C-9), 28.0
(11-Me), 42.8 (C-5), 36.0 (C-1), 34.7 (C-13), 32.6 (CHMe2), 31.8 (d, J = 10.7 Hz, 4-C) ppm. HRMS (ESI): calcd. for C12H21F2N2
(C-9), 31.4 (C-3), 29.5 (C-4), 20.6 (CHMe), 20.3 (CHMe) ppm. [M + H]+: 231.1667; found 231.1667.
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Eur. J. Org. Chem. 2013, 7575–7582

Lithiation/Stannylation of an O-Alkyl Carbamate
(1R,2S,9S)-11-Methyl-7,11-diazaspiro[tricyclo[7.3.1.02,7]tridecane-
5,1Ј-cyclopropane] (8f): According to the general procedure GP2,
lactam 12c (205 mg, 736 μmol) was reduced to give bispidine 8f
(137 mg, 622 μmol, 84%) as a yellowish oil. [α]2D2 = +8.3 (MeOH,
I. Marek), Wiley, Chichester, UK, 2004, vol. 2, p. 1055–1164;
h) R. E. Gawley, I. Coldham, in: The Chemistry of Organo-
lithium Compounds (Eds.: Z. Rappoport, I. Marek), Wiley,
Chichester, 2004, p. 997–1053; i) D. M. Hodgson, Topics in Or-
ganometallic Chemistry, Springer, Berlin, 2003; j) J. Clayden,
Organolithiums: Selectivity for Synthesis Pergamon Press, New
York, 2002; k) I. Marek, J. Chem. Soc. Perkin Trans. 1 1999,
535–544; l) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2282–2316; m) D.
Hoppe, F. Hintze, P. Tebben, M. Paetow, H. Ahrens, J.
Schwerdtfeger, P. Sommerfeld, J. Haller, W. Guarnieri, S. Kol-
czewski, T. Hense, I. Hoppe, Pure Appl. Chem. 1994, 66, 1479–
1486.
c = 0.25). IR (ATR): ν = 2923, 2820, 2770, 1441, 1110, 1038,
˜
859 cm–1. 1H NMR (400 MHz, CD3OD): δ = 3.12 (d, J = 10.8 Hz,
1 H, 14-H), 2.96 (d, J = 11.0 Hz, 1 H, 12-H), 2.88 (br. d, J =
11.1 Hz, 1 H, 10-H), 2.34 (m, 3 H, 6-H, 8-H, 12-H), 2.21 (s, 3 H,
13-Me), 2.26–2.16 (m, 2 H, 2-H, 10-H), 2.02 (br. d, J = 11.5 Hz, 1
H, 6-H), 1.95–1.75 (m, 3 H, 1-H, 3-H, 4-H), 1.74–1.54 (m, 3 H, 9-
H, 13-H2), 1.49 (m, 1 H, 3-H), 1.00 (m, 1 H, 4-H), 0.67 (m, 1 H,
H
cyclopropyl), 0.37 (m, 1 H, Hcyclopropyl), 0.27 (m, 2 H,
[2]
Hcyclopropyl) ppm. 13C NMR (100 MHz, CD3OD): δ = 67.4 (C-2),
66.0 (C-6), 61.4 (C-8), 61.2 (C-12), 57.2 (C-10), 47.0 (11-Me), 36.0
(C-9), 35.2 (C-4), 34.3 (C-13), 31.5 (C-1), 30.8 (C-3), 18.6 (C-5),
14.8 (Ccyclopropyl), 9.9 (Ccyclopropyl) ppm. HRMS (ESI): calcd. for
C14H25N2 [M + H]+ 221.2012; found 221.2014.
For recent work on enantioselective deprotonations in the pres-
ence of 3 or 4, see: a) P. J. Rayner, P. O’Brien, R. A. J. Horan,
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General Procedure for the Lithiation/Stannylation of the O-Alkyl
Carbamate 14: All reactions were performed as described in ref.[6]
,
with carbamate 14 (400–700 μmol). The bispidines 8 were bulb-to-
bulb distilled (0.8 mbar, 100–150 °C) from CaH2 prior to use. A
solution of bispidine 8 (1.3 equiv.) in dry Et2O (2 mL/mmol14) was
added dropwise to a solution of sBuLi (1.4 m in cyclohexane,
1.3 equiv.) in dry Et2O (2 mL/mmol14) at –78 °C. After 30 min,
carbamate 14 (1.0 equiv.) was added dropwise through a cannula
over 10 min and stirring was continued for 4–6 h. Bu3SnCl
(1.5 equiv.) was added dropwise and the reaction mixture was
warmed to room temp. over 16 h. The reaction mixture was
quenched with HCl (1 n, 40 mL/mmol14) and extracted with Et2O
(3ϫ 40 mL/mmol14). The combined organic layers were washed
with saturated aqueous KF (40 mL/mmol14), dried with MgSO4,
and the solvents evaporated. Column chromatography (silica gel,
n-pentane/EtOAc, 100:0Ǟ 97:3) afforded carbamate 15 in analyti-
cally pure form. The spectroscopic data of 15 are consistent with
those reported in ref.[26] The enantiomeric excess of product 15 was
determined in accord with ref.[6] by HPLC: Daicel Chiralcel OD-
H, n-hexane/iPrOH, 600:1, 0.5 mL/min, 226 nm, retention times:
9.1 min [(S)-15] and 10.7 min [(R)-15]. The chiral bispidine 8 was
recovered from the acidic aqueous phase by addition of NaOH
(80 mL/mmol14) and extraction with CHCl3 (5ϫ 40 mL/mmol14).
The combined organic layers were dried with MgSO4 and the sol-
vent removed under reduced pressure. Bulb-to-bulb distillation
(0.8 mbar, 100–150 °C) delivered the pure bispidine 8 (Ͼ50% recov-
ery).
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all intermediates and final prod-
ucts.
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Acknowledgments
The authors gratefully acknowledge the financial support of the
Deutsche Forschungsgemeinschaft (DFG) (DFG, BR2015/5-1).
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M. Breuning, D. Hein
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Received: July 3, 2013
Published Online: October 2, 2013
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Eur. J. Org. Chem. 2013, 7575–7582