A general, enantioselective synthesis of 1-azabicyclo[m.n.0]alkane ring systems

Article abstract of DOI:10.1016/j.tetlet.2013.01.041

In this Letter, we describe a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr, which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields and, for many systems, the only enantioselective preparation reported to date.

Full text of DOI:10.1016/j.tetlet.2013.01.041

Tetrahedron Letters 54 (2013) 1645–1648
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Tetrahedron Letters
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A general, enantioselective synthesis of 1-azabicyclo[m.n.0]alkane ring systems
Timothy J. Senter a, Michael L. Schulte a, Leah C. Konkol a,b, Tyler E. Wadzinski b, Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center,
Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe a novel approach for the general and enantioselective synthesis of a diverse
array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further
functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated
allylation of an Ellman sulfinimine in greater than 9:1 dr, which is readily separable by column chroma-
tography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabi-
cyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent
overall yields and, for many systems, the only enantioselective preparation reported to date.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 19 December 2012
Revised 2 January 2013
Accepted 4 January 2013
Available online 24 January 2013
Keywords:
Azabicycle
Olefin metathesis
Enantioselective
Allylation
Alkaloid
Natural products and pharmaceutical compositions that possess
azabicyclic ring systems 1–9 are very common; however, synthetic
approaches to access these 1-azabicyclo[m.n.0]alkane systems
(Fig. 1) are limited.1–8 In general, the existing strategies for the con-
struction of azabicyclic ring systems rely on Staudinger–aza-Wittig
c
-chloro N-(tert-butanesulfinyl)ketimines 13,11 and Brown and
co-workers employed a related strategy for the total synthesis of
(ꢀ)-tashiromine 17 and (ꢀ)-epilupinine 18 (Scheme 2, Eq 1).21
Inspired by these results and our internal efforts, we envisioned
a protocol that would subject various chloroalkyl N-(tert-butane-
sulfinyl)aldehydes 19 to an asymmetric allylation reaction to pro-
vide 20 in high diastereomeric ratio (dr).18,22,23 Deprotection and
alkylation of the pyrrolidine would provide azocines 21, substrates
approaches,9
7-exo-tet-cyclizations,10,11cycloadditions
([5+2],
[4+2], and [2+2+2]),12 ring-closing metathesis (RCM) strategies,13
Mitsunobu approaches,14 and rearrangements (nitrone and intra-
molecular Schmidt rearrangements)15,16 For the larger azabicyclic
ring systems, routes are very rare, and those reported lack
stereocontrol.8,17
1
, m = 1, 1-azabicyclo[4.3.0]nonane
(indolizine)
N
H
Toward the development of an enantioselective toolbox of syn-
thetic routes to access these valuable azaheterocycles, we recently
reported a novel six step approach for the rapid and enantioselec-
tive synthesis of azabicyclic systems such as 1–3 (Scheme 1).18
Here, an indium-mediated allylation of a chiral aldimine substrate
10, N-alkylation to afford 11, ring-closing metathesis (RCM) to pro-
vide 12, and finally a one-pot deprotection/acetal hydrolysis reduc-
tive amination sequence afforded enantiopure azabicyclic ring
systems 1–3.18 This methodology was then employed for the enan-
tioselective total syntheses of (+)-grandisine D,18 cremastrine,19
and amabiline.20
2, m = 2, 1-azabicyclo[5.3.0]decane
(octahydro-1H-pyrrolo[1,2-a]azepine)
3
m
m
, m = 3, 1-azabicyclo[6.3.0]undecane
(decahydropyrrolo[1,2-a]azocine)
4
, m = 1, 1-azabicyclo[4.4.0]dodecane
(quinolizidine)
N
H
5, m = 2, 1-azabicyclo[5.4.0]tridecane
(decahydropyrido[1,2-a]azepine)
6
, m = 3, 1-azabicyclo[6.4.0]tetradecane
(decahydro-1H-pyrido[1,2-a]azocine)
7
, m = 1, 1-azabicyclo[5.4.0]tridecane
While this was a notable advance, we also wanted to develop a
streamlined route to access the higher homologs 4–9 in an enan-
tioselective manner. De Kimpe and co-workers recently demon-
strated the asymmetric synthesis of 2-arylpyrrolidines 15 from
N
H
(decahydropyrido[1,2-a]azepine)
8, m = 2, 1-azabicyclo[5.5.0]tetradecane
(decahydro-1H-azepino[1,2-a]azepine)
9, m = 3, 1-azabicyclo[6.5.0]pentadecane
(dodecahydroazepino[1,2-a]azocine)
m
Figure 1. Representative 1-azabicyclo[m.n.0]alkane ring systems, including their
alternative IUPAC nomenclature, of interest in both natural product synthesis and
drug discovery.
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 345 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.041

1646
T. J. Senter et al. / Tetrahedron Letters 54 (2013) 1645–1648
S
O
S
OR
OR
O
S
OR
OR
N
H
N
O
OR
OR
N
N
2
2
n
n
n
10
11
12
1, n = 1
2
3
, n = 2
, n = 3
Scheme 1. First generation rapid, enantioselective synthesis of azabicyclic ring systems 1–3.
for a ring closing metathesis reaction24 to provide general, enantio-
selective access to 1-azabicyclo[m.n.0]alkane cores 1–9 with an
S
S
1. KOH
2. HCl
HN
O
N
embedded olefin as
(Scheme 3).
a handle for further functionalization
O
NH
NaBH4
(1)
(2)
Cl
Cl
Ar
Ar
Ar
The requisite chloroalkyl N-(tert-butanesulfinyl)aldehydes 19
were easily prepared in 92–94% yields by condensing the
corresponding chloroaldehydes 22 with the Ellman (S)-tert-
butanesulfinamide 23 employing CuSO4 in DCM.25,26 A subsequent
indium-mediated allylation reaction affords the anticipated (R)-
anti-adducts 20 in >9:1 diastereoselectivity and up to 86%
yield.18,22,23 After column chromatography, single diasteromers of
analogs 20 resulted, which were carried forward. Following modi-
fication of the known protocols,11,21 acid-mediated deprotection
and base-induced, microwave-assisted cyclization and alkylation
with the required allyl, butenyl, and pentenyl bromides smoothly
afforded the chiral N-alkyl azocines 21 in 63–83% yields for the
three step, one-pot reaction sequence (Scheme 4).27 To enable
the one-pot sequence, a number of bases, solvents, and tempera-
tures were evaluated; however, K2CO3 and NaI in DMF under
microwave irradiation (120 °C, 15 min) proved to be general for
all substrates, even the larger 7-azocine rings.
With all of the chiral N-alkyl azocines 21 in hand, we focused on
the RCM to provide the 1-azabicyclo[m.n.0]alkane systems 1–9.
Initial attempt following several known reaction conditions with
Grubbs II18,20,24,28,29 failed to provide the desired unsaturated 1-
azabicyclo[5.4.0]tridecane core of 7. A perusal of the literature
regarding RCM methods with tertiary amines, suggested that ‘pro-
tection’ of the amine by in situ generation of ammonium salts en-
abled facile ring-closing.29–31 Thus, treatment of 21c1 with 1.1
equivalent of camphor sulfonic acid (CSA) in 0.05 M toluene,
followed by the addition of 10 mol % of Grubbs II and micro-
wave heating for 1 hour at 100 °C, provided the unsaturated
13
14
15
O
n
1. HCl
2. NaHCO3
S
HN
N
PhOOC
Cl
Cl
n
H
3. LiAlH4
OH
16
17
18
(-)-tashiromine (n = 1)
(-)-epilupinine (n = 2)
Scheme 2. Application of
pyrroles and azabicyclic systems in high enantioselectivity.
c-chloro N-(tert-butanesulfinyl)ketimines to access
In(0), sat. NaBr
Br
S
H
S
1. HCl
2. Base
3.
N
O
HN
n
O
Cl
Cl
n
Br
m
19
20
N
N
H
m
Grubbs II
n
n
m
21
1-9
Scheme 3. Envisioned route to employ chloroalkyl N-(tert-butanesulfinyl)alde-
hydes, an asymmetric allylation and subsequent RCM to access diverse 1-
azabicyclo[m.n.0]alkane cores in high enantioselectivity.
a
S
In(0), sat. NaBr
S
H
H2N
O
O
N
O
23
Br
Cl
Cl
19a
H
n
n
>9:1 dr
CuSO4, rt, 16 h
separable by
22a
22b
, n = 1
, n = 2
22c, n = 3
, n = 1, 93%
, n = 2, 92%
19c, n = 3, 94%
chromatogrpahy
19b
21a1
21a2
, n = 1, m = 1, 67%
, n = 1, m = 2, 64%
1. 4 M HCl/dioxane
2. K2CO3, NaI, DMF
mw, 120 oC, 15 min
S
21a3, n = 1, m = 3, 74%
HN
n
O
N
m
21b1
21b2
, n = 2, m = 1, 83%
, n = 2, m = 2, 68%
Cl
n
3. K2CO3,
Br
m
21b3, n = 2, m = 3, 73%
21c1
, n = 3, m = 1, 65%
21c2
, n = 3, m = 2, 63%
20a
20b
, n = 1, 85%
, n = 2, 85%
21c3, n = 3, m = 3, 69%
20c, n = 3, 86%
Scheme 4. Enantioselective synthesis of N-alkyl azocines 24.

T. J. Senter et al. / Tetrahedron Letters 54 (2013) 1645–1648
1647
1. TFA (1.1 equiv.)
2. 10 mol %Grubbs II
0.05 M toluene
mw, 100 oC, 1 h
68%
and, for many systems, the only enantioselective preparation re-
ported to date.
Grubbs II
N
H
N
DCM, refux
N
H
or
Grubbs II
toluene, mw
Acknowledgments
-7
unsat
21c1
-7
unsat
The authors gratefully acknowledge funding from the Depart-
ment of Pharmacology, Vanderbilt University Medical Center and
the Warren Family & Foundation for funding the William K.
Warren, Jr. Chair in Medicine. Vanderbilt houses the Vanderbilt
Specialized Chemistry Center of the MLPCN and we acknowledge
MLPCN support (U54MH084659).
Scheme 5. RCM approaches to access the 1-azabicyclo[m.n.0]alkane cores.
1. TFA (1.1 equiv.)
N
m
N
H
n
= 1-3
m = 1-3
2. 10 mol %Grubbs II
0.05 M toluene
n
References and notes
n
m
mw, 100 oC, 1 h
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22
Scheme 6. Optimal RCM conditions for the enantioselective synthesis of the
unsaturated 1-azabicyclo[m.n.0]alkane cores 22 of 1–9.
1-azabicyclo[5.4.0]tridecane core of
7 in 70% isolated yield
(Scheme 5).27 An evaluation of additional acids led to the use of tri-
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olefin handle for further functionalization. The stereochemistry is
established via a highly diastereoselective indium-mediated allyla-
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ily separable by column chromatography to afford
a single
diastereomer. This methodology allows for the rapid preparation
of 1-azabicyclo[m.n.0]alkane ring systems that are not readily
accessible through any other chemistry in excellent overall yields
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N
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N
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22a1
22a2
22a3
, 34%
, 29%
, 32%
N
H
N
H
N
H
22b1
, 59%
22b2
22b3
, 39%
, 30%
14. De Kimpe, N.; Stanoeva, E.; Georgieva, A.; Keppens, M.; Kulinkovich, O. Org.
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N
H
N
N
H
H
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22c1
22c2
22c3
, 34%
, 36%
, 33%
8067.
Figure 2. Mono-unsaturated 1-azabicyclo[m.n.0]alkane ring systems 22 synthe-
sized that encompass all of the key azabicyclic ring systems 1–9. Yields are overall
from commercial aldehydes 22, and ranged from 29–59%.
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1648
T. J. Senter et al. / Tetrahedron Letters 54 (2013) 1645–1648
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J2 = 10.4 Hz, 2H); 1.763 (quint., J = 6.5 Hz, 2H); 1.53–1.32 (m, 5H). 13C NMR
(100.6 MHz, CDCl3) d (ppm): 134.23, 119.14, 55.92, 54.83, 45.08, 40.56, 34.91,
32.60, 26.88, 24.92, 22.79. HRMS (TOF, ES+) C13H27NOSCl [M+H]+ calcd 280.1502,
found 280.1504.
N
H
26. Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883–8904.
27. Representative experimental:
(S)-1,2-diallylazepane 21c1: A 4 N solution of HCl/dioxanes (14.92 ml) was cooled
to 0 °C and slowly added to a microwave vial containing sulfinamide 20c (2.0 g,
7.15 mmol). Solution was then brought to ambient temperature and stirred for an
additional 45 min, and concentrated in vacuo to afford the deprotected amine as
the HCl salt in quantitative yield. The amine was dissolved in DMF (35.9 mL), then
K2CO3 (1.98 g, 14.34 mmol) and NaI (1.18 g, 7.89 mmol) were added in a single
batch. The vial was sealed and submitted to microwave irradiation at 120 °C for
15 min. LC/MS analysis showed full consumption of starting material to the
cyclized secondary amine. Allyl bromide (0.954 g, 7.89 mmol) and an additional
equivalent of K2CO3 (0.99 g, 7.15 mmol) was then added to the pale yellow
solution at ambient temperature, and stirring was continued for 4 h. Mixture was
dissolved in 5% LiCl solution and extracted with Et2O (5 ꢂ 40 mL). Organic
fractions were combined, washed with brine, dried over Na2SO4, and concen-
trated in vacuo to yield a pale yellow crude oil. Purification by flash chromatog-
raphy (1:1 hex/EtOAc) afforded the desired product as a clear oil (0.82 g, 64%).
H
S O
N
Cl
(S,E)-N-(6-Chlorohexylidene)-2-methylpropane-2-sulfinamide 19c: To a solution of
6-chlorohexanal (7.37 g, 54.79 mmol) in DCM (219 ml) at ambient temperature
was added CuSO4 (20.11 g, 126.02 mmol) and (S)-2-methylpropane-2-sulfinam-
ide (7.64 g, 63.01 mmol) in a single batch. The reaction was stirred for 12 h, at
which point the starting material was fully consumed by TLC analysis (4:1 hex/
EtOAc, Rf = 0.35). The heterogeneous mixture was filtered through a silica pad and
20
½ꢀꢁD ꢀ5.0° (c 0.9, MeOH). 1H NMR (400.1 MHz, CDCl3) d (ppm): 5.82 (m, 2H);
concentrated in vacuo to yield
a viscous oil, which was purified by flash
chromatography (4:1 hex/EtOAc) to afford the desired product as a clear oil
5.19–4.93 (m, 4H); 3.22 (m, 2H); 2.85 (m, 1H); 2.70 (m, 2H); 2.26 (m, 1H); 2.06
(m, 1H); 1.75 (m, 1H); 1.66–1.38 (m, 7H). 13C NMR (100.6 MHz, CDCl3) d (ppm):
137.98, 137.51, 115.99, 115.66, 62.45, 55.71, 49.83, 39.34, 32.65, 28.88, 27.53,
25.78. HRMS (TOF, ES+) C12H22N [M+H]+ calcd 180.1752, found 180.1751.
20
(12.34 g, 94%). ½ꢀꢁD +157.9° (c 1.5, MeOH). 1H NMR (400.1 MHz, CDCl3) d (ppm):
8.05 (t, J = 4.5 Hz, 1H); 3.52 (t, J = 6.5 Hz, 2H); 2.53 (m, 2H); 1.79 (m, 2H); 1.66 (m,
2H); 1.51 (m, 2H); 1.18 (s, 9H). 13C NMR (100.6 MHz, CDCl3) d (ppm): 169.26,
56.64, 44.82, 35.96, 32.37, 26.56, 24.78, 22.42. HRMS (TOF, ES+) C10H21NOSCl
[M+H]+ calcd 238.1032, found 238.1034.
N
H
S
O
NH
(S)-Octahydropyrido[1,2-a]azepine unsat-7: To a solution of diene 21c1 (106 mg,
0.59 mmol) in toluene (11.8 mL) was added trifluoroacetic acid (71 mg,
0.62 mmol), and Grubbs 2nd generation catalyst (49 mg, 0.06 mmol). Solution
was submitted to microwave irradiation for 1 h at 100 °C. The toluene was
removed in vacuo, and the crude residue purified to afford the desired product as
Cl
20
the TFA salt (105 mg, 68%). ½ꢀꢁD +45.2° (c 1.25, MeOH). 1H NMR (400.1 MHz,
(S)-N-((R)-9-Chloronon-1-en-4-yl)-2-methylpropane-2-sulfinamide 20c: NaBr
(380 g) was dissolved in 841 mL of deionized H2O. To this fully dissolved
saturated NaBr solution was added aldimine 19c (10.00 g, 42.05 mmol) and
indium powder (19.31 g, 168.2 mmol). The mixture was stirred vigorously for
5 min., then allyl bromide was (20.35 g, 168.2 mmol) added in a single batch.
Vigorous stirring was continued for 9 h, at which point the starting material was
consumed by TLC analysis (1:1 hex/EtOAc, Rf = 0.34). The mixture was quenched
with NaHCO3 and extracted ꢂ5 with EtOAc. The organic fractions were combined,
washed with brine, dried over Na2SO4, and concentrated in vacuo to yield crude
CDCl3) d (ppm): 5.88 (m, 1H); 5.64 (m, 1H); 3.94 (m, 1H); 3.57 (m, 2H); 3.18–3.04
(m, 2H); 2.73 (t, 1H); 2.25 (m, 1H); 2.24–1.92 (m, 3H); 1.89–1.72 (m, 3H); 1.58
(m, 2H). 13C NMR (100.6 MHz, CDCl3) d (ppm): 126.83, 120.24, 63.64, 55.70,
54.32, 31.93, 30.59, 27.21, 26.00, 21.96. HRMS (TOF, ES+) C10H18N [M+H]+ calcd
152.1439, found 152.1440.
28. Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8, 4541–4543.
29. Merino, P.; Tejero, T.; Greco, G.; Marca, E.; Delso, I.; Gomez-SanJuan, A.;
Matute, R. Heterocycles 2012, 84, 75–100.
30. Woodward, C. P.; Spiccia, N. D.; Jackson, W. R.; Robinson, A. J. Chem. Commun.
2011, 47, 779–781.
oil. Purification by flash chromatography (1:1 hex/EtOAc) afforded the desired
20
clear oil (10.10 g, 86%). ½ꢀꢁD +25.7° (c 1.5, MeOH). 1H NMR
product as
a
(400.1 MHz, CDCl3) d (ppm): 5.77 (m, 1H);5.15 (m, 2H); 3.52 (t, J = 6.5 Hz, 2H);
3.30 (sextet, J = 6.1 Hz, 1H); 3.21 (br d, J = 6.1 Hz, 1H); 2.35 (dp, J1 = 6.5 Hz,
31. Verhelst, S. H. L.; Martinez, B. P.; Timmer, M. S. M.; Lodder, G.; van der Marel, G.
A.; Overkleeft, H. S.; van Boom, J. H. J. Org. Chem. 2003, 68, 9598–9603.