Synthesis of highly functionalized azabicycles via 2-alkenyl sulfoximines

Article abstract of DOI:10.1055/s-2006-942427

Functionalized cycloalkanones have been converted into enantiomerically pure endocyclic 2-alkenyl sulfoximines. Titanated derivatives thereof undergo highly diastereoselective γ-hydroxyalkylation reactions with various amino aldehydes yielding isomerically pure vinyl sulfoximines, which can be cyclized by N-deprotection. The resulting heterobicyclic systems are expected to be interesting scaffolds for the synthesis of topological mimetics of peptides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942427

2224
PAPER
Synthesis of Highly Functionalized Azabicycles via 2-Alkenyl Sulfoximines
H
ighly Functionalize
d
i
A
zabic
c
ycles via
2
h
a
foximines el Reggelin,*a Jochen Kühl,a Jan Philipp Kaiser,a Philipp Bühleb
a
Fax +49(6151)165531; E-mail: re@punk.oc.chemie.tu-darmstadt.de
Merck KGaA, PLS R&D Cosmetics, Frankfurter Str. 250, 64293 Darmstadt, Germany
b
Received 31 May 2006
Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday
duced by us in 1992.6 The synthesis of these valuable sul-
fur(VI) electrophiles has been developed further in 19957
and since 2001 a large-scale (several 100 g) procedure is
available.8 Lithiation of 2 by n-BuLi in toluene at –78 °C
Abstract: Functionalized cycloalkanones have been converted into
enantiomerically pure endocyclic 2-alkenyl sulfoximines. Titanated
derivatives thereof undergo highly diastereoselective g-hydroxy-
alkylation reactions with various amino aldehydes yielding isomer-
ically pure vinyl sulfoximines, which can be cyclized by N- followed by transmetallation with chlorotris(isopro-
deprotection. The resulting heterobicyclic systems are expected to
poxy)titanium delivers a 2-alkenyl titanium species which
be interesting scaffolds for the synthesis of topological mimetics of
appears to be uniformly configured and configurationally
peptides.
stable on the timescale of the subsequent g-hydroxyalky-
lation reaction effected by the addition of an aldehyde 3.5
Key words: amino aldehydes, asymmetric synthesis, bicyclic com-
pounds, metallation, sulfoximines
This results in the generation of isomerically pure g-hy-
droxy vinylsulfoximines such as 7 (Scheme 2) which can
be used as Michael acceptors in the final cyclization reac-
tion initiated by X-deprotection (Scheme 1 and, for select-
ed examples, Scheme 2).
In a recent publication we motivated the synthesis of high-
ly substituted aza(poly)cyclic ring systems as topological
mimetics for b-turn structures.1 As a structural variable to
connect the peptide with the non-peptide world we pro-
posed the pseudo torsional angle b which has been intro-
duced by Ball et al. as an alternative means to classify b-
turns.2 From these reflections the necessity was derived to
develop a synthetic protocol flexible enough to allow for
the synthesis of a broad range of nitrogen heterocycles
with maximum control of their relative and absolute con-
figuration.
OH
a) n-BuLi, –78 °C
H
Z
O
S
b) ClTi(Oi-Pr)3, –78 °C to 0 °C
Z
c)
O
0 °C, toluene
p-Tol
N
Phth
N
H
6
OTBS
1aS
5
PhthN
7
S1a
hydrazine
–78 °C to r.t.
OH
H
The method developed is based on metallated 2-alkenyl
sulfoximines3 derived from 2 which may be open chain or
cyclic (Scheme 1).4,5 These in turn are prepared from
commercially available cyclic sulfonimidates 4 intro-
Z
Z = CH2: 84% (10 g scale)
single isomer
N
H
1aS
8
O
OH
H
Z
a) n-BuLi, –78 °C
b) ClTi(Oi-Pr)3, –78 °C to 0 °C
S
p-Tol
Z
Ph
N
Ph
c)
0 °C, toluene
OTBS
N
H
H
9
FMOCN
1aS
H
O
d) piperidine, (NH4)2CO3
Z = CH2:
10 (77%, one-pot)
S1a
Scheme 2 Examples of 2-azabicyclo[4.4.0]decanes 8 and 2-azabi-
cyclo[3.3.0]octanes 10 from 2-alkenyl sulfoximines 5 and 9, respec-
tively
Whereas early work focussed on the synthesis of oxygen
heterocycles (X = O),9,10 the recognition of the biological
activity of some azacyclic derivatives11 (X = N) made us
change our synthetic goals.1,12 Although we succeeded to
synthesize all possible structural realizations of 1 (23 = 8
ring combinations) including two ring sizes for the central
Scheme 1 General outline of the method
SYNTHESIS 2006, No. 13, pp 2224–2232
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-942427; Art ID: C03406SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

PAPER
Highly Functionalized Azabicycles via 2-Alkenyl Sulfoximines
2225
ring (n = 0, 1) in the meantime, all compounds synthe- protocol, it turned out that increasing the reaction temper-
sized so far were unfunctionalized in ring 1. On the other ature in the g-hydroxyalkylation step was not accompa-
hand, this missing functionalization represents a severe nied by an erosion of stereoselectivity.1 Therefore, we
drawback for the application of these compounds as topo- repeated the reaction sequence (Scheme 4; e–gb, h), but
logical mimetics for b-turn structures. As a strategic posi- this time aldehyde 6 was added at 0 °C. We were pleased
tion (Z, Scheme 2) for this necessary widening of the to note that under these modified conditions the expected
constitutional scope of the reaction, the marked position, bicyclic acetal 8b was formed as a single isomer in 50%
three bonds apart from the carbinol carbon, was deduced yield without isolation of intermediates. Despite this suc-
from the analysis of b-turns by Ball.2
cess, the moderate yield raises questions about the origin
of the observed stereoselectivity and the material loss. To
address these issues, we repeated the sequence again but
this time omitting the final cyclization step. This led to the
formation of vinylsulfoximine 15, again as a single isomer
in good 81% yield. This is in contradiction to the possibil-
ity of a diastereomer-differentiating cyclization leading to
isomerically pure 8b via a faster reacting diastereomer of
15. If one furthermore takes into account that 20% of the
starting material 5b was recovered after the one-pot cy-
clization to 8b, it seems plausible to assume a certain
amount of retroaddition to be responsible for the reduced
yield.
In the 2-azabicyclo[4.4.0] series, we envisaged the syn-
thesis of 8-aza- (Z = NR in 8) and 8-oxo (Z = C=O in 8)
derivatives. The starting sulfoximine 5a for the 2,8-di-
azabicyclodecane 8a was prepared from commercially
available hydrate 11, which was, after Boc-protection,
treated with lithiated methyl sulfoximine 13 (Scheme 3).
O
HO OH
Boc2O, KHCO3,
CHCl3, r.t.
95%
N
N
Cl
Boc
H
H
11
12
O
S
O
O
O
TBSO
OH
a, b
Me
N
H
(ds > 98%)
c, d
p-Tol
13
N
H
OH
O
15
NBoc
S1a
N
Boc
e–h
59% (one-pot)
1aS
e–gb, i
81%
O
N
H
5a (83%)
O
1aS
O
S
8a
O
TBSO
+
a–d
76%
1aS
Me
N
Scheme 3 Synthesis of 2,8-diazabicyclo[4.4.0]octane 8a. Reagents
and conditions: (a) n-BuLi, –78 °C, THF; (b) 12, –78 °C; (c) TMSCl,
EtMe2N, CH2Cl2; (d) KOt-Bu, n-BuLi, –78 °C to r.t.; (e) n-BuLi,
–78 °C, toluene; (f) ClTi(Oi-Pr)3, –78 °C to 0 °C; (g) 6, 0 °C; (h) hy-
drazine, –78 °C to r.t.
p-Tol
O
O
13
5b
50%
(with gb
conditions)
e–ga, h
14
OH
OH
H
The alcohol thus generated was silylated and delivered,
after base treatment, the target sulfoximine 5a by elimina-
tion and isomerization with an overall yield of 83% (Ad-
dition–Elimination–Isomerization: AEI sequence).3,13 To
our delight this compound behaves as expected in the
lithiation, transmetallation, g-hydroxyalkylation sequence
(e–h in Scheme 3), furnishing the intermediate vinyl sulf-
oximine (not shown) as a single isomer (judged from the
H
O
O
p-TsOH
O
acetone, r.t.
56%
N
H
N
H
1cS
8c
1aS
8b
Scheme 4 Synthesis of ketone 8c. Reagents and conditions:
(a) n-BuLi, –78 °C, THF; (b) 14, –78 °C; (c) TMSCl, EtMe2N,
CH2Cl2; (d) KOt-Bu, n-BuLi, –78 °C to r.t.; (e) n-BuLi, –78 °C, to-
luene; (f) ClTi(Oi-Pr)3, –78 °C to 0 °C; (ga) 6, –78 °C; (gb) 6, 0 °C;
(h) hydrazine, –78 °C to r.t.; (i) (NH4)2CO3.
1
500 MHz H NMR spectrum of the crude reaction mix-
ture). Moreover, the hydrazine-induced cyclization pro-
ceeded smoothly to the target compound 8a with 59%
yield in a one-pot procedure.
Finally, the liberation of the ketone was achieved with p-
toluenesulfonic acid in acetone, accompanied by a simul-
taneous desilylation of the auxiliary (OTBS in S1a → OH
in S1c, see Scheme 2 for the encoding of the auxiliary).
Unfortunately we were unable to obtain a correct elemen-
tal analysis of 8c due to the presence of minor amounts of
impurities. This, and the impossibility to remove the ace-
tal without concomitant loss of the silyl protecting group
prompted us to develop an alternative route to the ketone
The synthesis of the 8-oxo derivative, ketone 8c, turned
out to be a little bit more difficult (Scheme 4). Although
the synthesis of the functionalized 2-alkenyl sulfoximine
5b from commercially available monoacetal 14 via the
standard AEI route posed no special problems (76% over-
all yield), initial attempts to apply the one-pot protocol
(Scheme 4; e–ga, h) to prepare the protected bicycle 8b
failed. Fortunately, in the course of our efforts to adapt the
reaction sequence to the requirements of a polymer-bound
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

2226
M. Reggelin et al.
PAPER
(Scheme 5). The idea was to keep the acetal functionality reaction mixtures we observed two protons at d = 6.02
to be as close as possible to the working procedure by re- ppm and d = 6.30 ppm coupled by a 10 Hz coupling con-
placing the dioxolane moiety by a benzodioxepane which stant that we assign to the endocyclic double bond of di-
should be sensitive to hydrogenolysis.14 The best method ene 22 which may be an elimination product of ether 21.
for the synthesis of the hitherto unknown monoacetal 18 The g-hydroxyalkylation–Michael addition sequence (g–
we found was the extractive acetalization developed by j) with 5c as starting material proceeded smoothly deliv-
Babler and Spina.15 To our surprise, the standard AEI pro- ering the protected bicycle 8d as a single isomer in 63%
tocol for the synthesis of the endocyclic sulfoximine 5c yield without isolation of intermediates.
delivered a mixture of compounds containing various
To our great surprise and disappointment we were unable
amounts of the sulfinic acid amide 20. After considerable
to obtain the desired ketone 8e (8c with the silylated side
experimentation we found it useful to eliminate the si-
chain in the auxiliary) by hydrogenolysis. Neither the
lylether formed after step (d) to the vinyl sulfoximine 19
and using n-BuLi alone instead of combining this step
with the isomerization by application of a KOt-Bu/n-BuLi
mixture.
original procedure (H2/PdO/0.5h/r.t.),14 nor various mod-
ifications (H2 pressure up to 150 bar, catalyst loading up
to 15%, Pd/C instead of PdO and prolonged reaction
times) were successful.
O
HO
OH
OH
+
O
H
H
HO
O
O
H2/cat.
16
17
O
various cond.
N
H
N
H
a
55%
1aS
8d
1aS
O
O
8e
b–e
O
O
Scheme 6 Unsuccessful attempts to hydrogenolyze 8d
1aS
13
+
quant.
O
18
19
Finally, our suspicion that this failure must be somehow
related to the presence of the sulfoximine moiety was ap-
proved by hydrogenation experiments of benzylated com-
pounds before and after adding stoichiometric amounts of
a sulfoximine. These experiments clearly showed that
transition-metal-catalyzed hydrogenation reactions are in-
hibited by sulfoximines. As a consequence the deprotec-
tion step has to be postponed to a later stage after removal
of the auxiliary.1,3,4,10,12
f
72%
OH
O
O
H
g–j
O
1aS
O
63%
N
5c
H
1aS
8d
+
For the synthesis of the 2,7-diazabicyclo[3.3.0]octanes
(Scheme 2, Z = NBn) the functionalized sulfoximine 9a
was needed (Scheme 7).
H
O
O
O
S
H
O
+
+
p-Tol
OTBS
O
O
N
The application of the AEI sequence, employing the com-
mercially available ketone 23 and the methyl sulfoximine
13, led to the formation of the desired 2-alkenyl sulfox-
imine 9a albeit in a rather low yield of 31%. This com-
H
20 (16%)
22 ?
21 ?
Scheme 5 Synthesis of bicycle 8d. Reagents and conditions: (a)
0.04 M H2SO4, hexane, liquid-liquid extractor; (b) n-BuLi, –78 °C, pound turned out to be a quite unstable species, highly
THF; (c) 18, –78 °C; (d) TMSCl, EtMe2N, CH2Cl2; (e) n-BuLi,
–78 °C; (f) n-BuLi/KOt-Bu, –78 °C to r.t.; (g) n-BuLi, –78 °C, tolue-
ne; (h) ClTi(Oi-Pr)3, 0 °C; (i) 6, 0 °C; (j) hydrazine, –78 °C to r.t.
prone to decomposition generating sulfinic acid amide 20
(Scheme 5) as one decomposition product. Column chro-
matographic purification without base conditioning accel-
erates this undesired behavior. We therefore suspect the
This indeed led to a quantitative formation of 19, which
was isomerized under carefully controlled conditions
(only 1 equiv of KOt-Bu, starting at –78 °C) yielding 72%
of the target sulfoximine 5c accompanied by 16% of
sulfinic acid amide 20. From these experiments it is obvi-
ous that the generation of the latter byproduct is associat-
ed with the presence of the KOt-Bu needed to initiate the
isomerization. This in turn makes us believe that its for-
mation is a consequence of a SN2¢ attack of the tert-bu-
tanolate onto 5c with allylic ether 21 as a plausible
substitution product.16 In the 1H NMR spectra of the crude
decomposition to be initiated by intramolecular attack of
the ring nitrogen in a SN2¢ reaction onto the double bond
followed by sulfinamide extrusion. Nevertheless, we tried
to convert 9a into the target heterobicycles 10a,b. For that
purpose the sulfoximine was metallated as described be-
fore and treated with the serine-derived aldehyde 24 and
protected phenyl alaninal 25, respectively. In situ cycliza-
tion of the resulting g-hydroxyalkylation products with
hydrazine (in case of 24) or piperidine (in case of 25) de-
livered the target compounds 10a,b, respectively. Both
compounds could be isolated as pure isomers in moderate
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Azabicycles via 2-Alkenyl Sulfoximines
2227
Synthesis of 2-Alkenyl Sulfoximines; General Procedure 1 (GP-
1)
OH
H
32% (one-pot)
To a stirred solution of methyl sulfoximine 13 (1.0 equiv) in THF
(3 mL/mmol), a solution of n-BuLi (1.2 equiv, 2.5 M in n-hexane)
was added dropwise via syringe at –78 °C. After stirring the mixture
for 15 min, the corresponding ketone (1.3–2.5 equiv) was added.
The resulting mixture was stirred for 10 min at –78 °C, followed by
30 min at r.t. and then quenched by pouring it into a solution of
NH4Cl (3 mL/mmol). The layers were separated and the aqueous
phase was extracted with Et2O (5 mL/mmol). After drying the com-
bined organic layers over Na2SO4 the solvents were removed under
reduced pressure. The crude product was taken up in CH2Cl2 (4 mL/
mmol), and 4-dimethylaminopyridine (0.2 equiv), Me2NEt
(2.0 equiv) and TMSCl (1.5 equiv) were added successively at
0 °C. The mixture was stirred at r.t. until complete silylation (con-
trolled by TLC). Then the reaction was quenched by pouring the so-
lution into vigorously stirred ice water (5 mL/mmol). The layers
were separated and the aqueous phase was extracted with Et2O
(5 mL/mmol). The combined organic layers were dried over
Na2SO4 and the solvents were removed under reduced pressure, fur-
nishing the crude silyl ether, which was used without further purifi-
cation.
BnN
e, f
O
N
Ot-Bu
H
ga)
1aS
H
Ot-Bu
NPhth
10a
24
ha
O
O
S
NBn
a–d
31%
Me
N
NBn
1aS
+
p-Tol
TBSO
9a
23
13
e, f
Ph
O
gb)
H
OH
NHFMOC
25
H
hb
BnN
1aS
44% (one-pot)
N
Ph
H
10b
Scheme
7
Synthesis of highly functionalized 2,7-diazabi-
To a suspension of KOt-Bu (1.0 equiv) in toluene (5 mL/mmol) was
added dropwise a solution of n-BuLi (2.0 equiv, 2.5 M in n-hexane)
under vigorous stirring at –78 °C. After 30 min a solution of the
crude silyl ether in toluene (1.5 mL/mmol) was injected via syringe.
The resulting mixture was stirred for 2 h at –78 °C, then warmed to
r.t. and stirred until complete conversion (controlled by TLC). The
mixture was poured into a solution of NH4Cl (4 mL/mmol), the lay-
ers were separated and the aqueous phase was extracted with Et2O
(5 mL/mmol). The combined organic layers were dried over
Na2SO4 and the solvents were removed under reduced pressure. The
residue was purified by flash chromatography or crystallized from
n-heptane furnishing the 2-alkenyl sulfoximines as colorless or
light-yellow solids.
cyclo[3.3.0]octanes. Reagents and conditions: (a) n-BuLi, –78 °C,
THF; (b) 23, –78 °C; (c) TMSCl, EtMe2N, CH2Cl2; (d) KOt-Bu,
n-BuLi, –78 °C to r.t.; (e) n-BuLi, –78 °C, toluene; (f) ClTi(Oi-Pr)3,
–78 °C to 0 °C; (ga) 24, 0 °C; (gb) 25, 0 °C; (ha) hydrazine, –78 °C to
r.t.; (hb) piperidine, 0 °C.
yields. The latter fact can be traced back, at least in part,
to the delicate properties of the starting sulfoximine as de-
scribed above. We think that the yields would improve
considerably after changing the N-protecting group to an
electron acceptor.
In summary we have shown that functionalized cyclic 2-
alkenyl sulfoximines are available from monoprotected
cycloalkanones, piperidinones and pyrrolidinones via an
Addition–Elimination–Isomerisation (AEI) sequence.
These new allylic sulfoximines are suitable starting mate-
rials for the g-hydroxyalkylation–Michael addition proce-
dure developed earlier for unfunctionalized sulfoximines.
The resulting highly substituted, enantiomerically pure bi-
cyclic ring systems can be regarded as promising scaf-
folds for the preparation of biologically active type-III
mimetics17 for g-turn structures. Work along these lines is
currently underway.
(+)-[SS,N(1S)]-N-{1-[tert-Butyl(dimethyl)silanyloxymethyl)]-2-
methyl-propyl}-4-(p-tolyl-sulfonimidoylmethyl)-3,6-dihydro-
2H-pyridine-1-carboxylic Acid tert-Butyl Ester (5a)
Following GP-1: with methyl sulfoximine 13 (5.37 g, 14.53 mmol,
1 equiv), n-BuLi (6.9 mL, 15.98 mmol, 1.1 equiv), N-Boc-piperidi-
none 12 (3.76 g, 18.89 mmol, 1.3 equiv), TMSCl (4.74 g,
43.58 mmol, 3 equiv), EtMe2N (7.4 g, 101.70 mmol, 7 equiv),
KOt-Bu (1.78 g, 14.53 mmol, 1 equiv) and n-BuLi (13.4 mL,
29.06 mmol, 2 equiv). 2-Alkenyl sulfoximine 5a (6.83 g, 83.0%)
was obtained after flash column chromatography (hexane–Et2O,
8:1–1:1) as a colorless solid.
[a]D20 +1.3 (c 1, CH2Cl2); Rf = 0.31 (hexane–Et2O, 1:1).
1H NMR (500 MHz, CDCl3): d = –0.052 [s, 6 H, Si(CH3)2], 0.827
[s, 9 H, SiC(CH3)3], 0.876 (d, J3,4 = 6.8 Hz, 3 H, H-4), 0.952 (d,
All solvents used were dried over appropriate drying agents and dis-
tilled under argon prior to use. Moisture-sensitive steps were carried
out under an argon atmosphere, using flame-dried glassware and sy-
ringe/Schlenk techniques. Unless specified otherwise all solutions
of NaHCO3, NH4Cl, (NH4)2CO3 and NaCl were saturated aqueous
solutions. TLC was performed on SilG/UV254 (Macherey Nagel &
Co.). Chromatographic separations were carried out on Merck silica
gel 60 (15–40 mm) at 2–3 bar. Melting points were determined on a
Gallenkamp apparatus and are uncorrected. Specific optical rota-
tions were determined on a Perkin-Elmer Polarimeter 241 with
Haake D8 thermostat in 1 dm cuvettes. NMR spectra were mea-
sured on Bruker AC 300 or DRX 500 spectrometers using TMS as
internal reference (for atom numbering see Figure 1). Mass spectra
were run on a Bruker-Franzen Esquire LC mass spectrometer (ESI-
MS) and on a double-focusing spectrometer MAT 95 (EI-MS). El-
emental analyses were done on a Vario EL by Elementar.
J
3,4¢ = 6.8 Hz, 3 H, H-4¢), 1.431 (s, 9 H, H-16), 1.965 (m, 1 H, H-3),
2.036 (m, 1 H, H-12), 2.323 (m, 1 H, H-12¢), 2.405 (s, 3 H, H-9),
3.066 (m, 1 H, H-2), 3.315 (m, 1 H, H-13), 3.412 (m, 1 H, H-13¢),
3.457 (dd, J1,1¢ = 10.1 Hz, J1,2 = 6.1 Hz, 1 H, H-1), 3.519 (dd,
J1¢,2 = 7.6 Hz, J1,1¢ = 10.1 Hz, 1 H, H-1¢), 3.652 (d, J10,10¢ = 12.8 Hz,
1 H, H-10), 3.668 (m, 1 H, H-17), 3.802 (m, 1 H, H-17¢), 3.855 (d,
J
10,10¢ = 12.8 Hz, 1 H, H-10¢), 5.256 (s, 1 H, H-18), 7.264 (d,
J6,7 = 8.0 Hz, 2 H, H-7), 7.738 (d, J6,7 = 8.0 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = –5.29, –5.22, 16.88, 18.40, 20.08,
21.58, 26.09, 28.53, 28.98, 30.10, 40.41, 43.55, 61.26, 64.25, 65.80,
79.72, 126.39, 128.52, 129.49, 129.69, 136.31, 143.43, 154.82.
Anal. Calcd for C29H50N2O4SSi: C, 63.23; H, 9.15; N, 5.09. Found:
C, 63.29; H, 9.25; N, 5.01.
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

2228
M. Reggelin et al.
PAPER
O
17
O
16
12
18
15
14
15
O
N
O
16
17
10
O
S
14
6
O
7
6
10
S
5
6
7
13
O
5
5
11
1
8
13
7
8
3
2
11
12
4
1
O
N
2
8
N
2
OTBS
1
9
OTBS
O
9
3
4
3
4
18
5a
5b
21
O
O
18
O
O
12
6
13
25
15
7
O
7
19
N
8
6
5
S
17
16
H
16 17
20
9
15
8
O
S
11
22
23 24
14
N
10
4
2
14
10
3
5
9
O
N
6
1
18
5
10
2
7
13
11
1
O
OH
11
2
1
O
12
19
4
OTBS
8
N
3
S
17
16
OTBS
9
N
12
18
19
9a
15
3
OTBS
4
5c
13
20
14
15
O
OH
OH
H
22
O
H
OH
6
9
4
21
O
21 N7
O
H
6
3
2
4
24
5
23
7
8
3
2
5
10
O
10
8
4
6
1
22
3
2
7
5
23
1
21
9
N
O
10
11
N
8
11
1
H
11
9
O
H
O
N
S
17
16
H
S
O
17
16
12
18
19
N
S
17
16
18
19
N
12
13
15
OTBS
15
OTBS
18
19
N
12
13
15
OTBS
20
13
14
20
14
8a
20
14
8b
8d
23
23
OH
H
22
O
22
OH
4
3
6
7
H
OH
H
5
21 20
8
9
2
21 20
10
5
3
1
5
3
4
8
1
N
H
24
26
4
8
24
6
2
N
O
6
2
N
O
19
19
7
1
11
25
7
25
26
27
O
N
O
N
H
9
H
S
9
17
16
S
S
15
14
15
14
18
19
N
12
15
28
N
10
OH
16
17
N
10
16
13
13
OTBS
OTBS
17
18
20
13
14
18
11
11
12
8c
12
10a
10b
Figure 1
(+)-[SS,N(1S)]-N-{1-[tert-Butyl(dimethyl)silanyloxymethyl]-2-
methyl-propyl}-8-(p-tolyl-sulfonimidoylmethyl)-1,4-dioxa-
spiro[4.5]dec-7-ene (5b)
J1,1 = 10.0 Hz, 1 H, H-1¢), 3.645 (d, J10,10¢ = 13.4 Hz, 1 H, H-10),
3.837 (d, J10,10 = 13.4 Hz, 1 H, H-10¢), 3.929 (‘s’, 4 H, H-15), 5.168
(s, 1 H, H-17), 7.299 (d, J6,7 = 8.2 Hz, 2 H, H-7), 7.756 (d,
J6,7 = 8.2 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = –5.27, –5.19, 16.83, 18.50, 20.12,
21.61, 26.12, 27.93, 30.04, 31.23, 36.20, 61.21, 64.08, 64.49, 65.86,
107.32, 127.30, 129.28, 129.85, 129.36, 136.30, 143.22.
Following GP-1: with methyl sulfoximine 13 (2.00 g, 5.42 mmol,
1 equiv), n-BuLi (2.60 mL, 5.96 mmol, 1.1 equiv), 1,4-cyclohexan-
dione-monoethylenketal 14 (1.10 g, 7.05 mmol, 1.3 equiv), TMSCl
(2.94 g, 27.1 mmol, 5 equiv), EtMe2N (2.38 g, 32.52 mmol,
6 equiv), KOt-Bu (662 mg, 5.42 mmol, 1 equiv) and n-BuLi
(4.70 mL, 10.84 mmol, 2 equiv). 2-Alkenyl sulfoximine 5b (2.09 g,
75.9%) was obtained after flash column chromatography (hexane–
Et2O, 8:1–1:1) as colorless oil.
Anal. Calcd for C27H45NO4SSi: C, 63.86; H, 8.93; N, 2.76. Found:
C, 63.78; H, 8.93; N, 2.68.
Benzo-7,12-dioxa-spiro[5.6]dodecan-3-one (18)
[a]D20 +0.3 (c 1, CH2Cl2); Rf = 0.32 (hexane–Et2O, 1:1).
In a 500-mL liquid-liquid extractor, equipped with NaHCO3
(1.50 g) as acid scavenger in the overflow flask, to a solution of 1,2-
dihydroxymethyl benzene 17 (18.83 g, 136.28 mmol, 2 equiv) in
H2SO4 (300 mL, 0.04 M) 1,4-cyclohexadione 16 (7.64 g,
68.14 mmol, 1 equiv) and n-hexane (200 mL) were added. This
mixture was extracted continuously with n-hexane (150 mL) for
8 d, changing the n-hexane overflow flask every two days. After re-
1H NMR (500 MHz, CDCl3): d = –0.050, 0.038 [2 s, 6 H, Si(CH3)2],
0.834 [s, 9 H, SiC(CH3)3], 0.896 (d, J3,4 = 6.9 Hz, 3 H, H-4), 0.964
(d, J3,4¢ = 6.9 Hz, 3 H, H-4¢), 1.983 (m, 1 H, H-3), 2.128 (m, 2 H, H-
16), 2.180 (m, 1 H, H-12), 2.407 (s, 3 H, H-9), 2.506 (m, 1 H, H-
12¢), 1.660 (m, 2 H, H-13), 3.078 (m, 1 H, H-2), 3.476 (dd,
J1,1¢ = 10.0 Hz, J1,2 = 5.9 Hz, 1 H, H-1), 3.532 (dd, J1¢,2 = 7.8 Hz,
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Azabicycles via 2-Alkenyl Sulfoximines
2229
moving all volatiles under reduced pressure, the residue was tritu-
rated with Et2O (100 mL). Insoluble materials were filtered off. The
solvent was removed from the filtrate under reduced pressure and
the residue was purified by flash column chromatography
(hexanes–Et2O, 8:1–3:1) or crystallization from TBME furnishing
8.70 g 18 (55%) as a colorless solid.
101.38, 126.51, 127.11, 127.73, 128.86, 129.63, 130.15, 136.60,
138.47, 143.48.
Anal. Calcd for C33H49NO4SSi: C, 67.88; H, 8.46; N, 2.40. Found:
C, 67.87; H, 8.51; N, 2.30.
(–)-[SS,N(1S)]-N-{1-[tert-Butyl(dimethyl)silanyloxymethyl]-2-
methyl-propyl}-1-benzyl-3-(p-tolyl-sulfonimidoylmethyl)-2,5-
dihydro-1H-pyrrole (9a)
Mp 26 °C; Rf = 0.64 (hexanes–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.209 (t, J2,3 = 6.9 Hz, 4 H, H-3),
2.495 (t, J2,3 = 6.9 Hz, 4 H, H-2), 4.945 (s, 4 H, H-5), 7.105 (m, 2 H,
H-8), 7.213 (m, 2 H, H-7).
13C NMR (75 MHz, CDCl3): d = 31.20, 37.56, 65.09, 100.96,
126.29, 127.06, 137.77, 210.66.
To a stirred solution of methyl sulfoximine 13 (4.60 g, 12.45 mmol,
1 equiv) in THF (40 mL) a solution of n-BuLi (1.492 g, 2.5 M in
hexane, 13.07 mmol, 1.05 equiv) was added dropwise via syringe at
–78 °C and the mixture was stirred for 30 min. Then this solution
was added dropwise at –78 °C to a stirred solution of N-benzylpyr-
rolidin-3-one 23 (2.456 g, 13.74 mmol, 1.1 equiv) in THF (60 mL)
within 2 h. The resulting mixture was stirred for another 50 min and
then quenched at the same temperature by addition of a solution of
NaHCO3 (100 mL) with rapid stirring. After warming to r.t., the lay-
ers were separated and the aqueous phase was extracted Et2O
(3 × 10 mL/mmol). The combined organic layers were dried over
Na2SO4 and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (hexane–
Et2O, 3:1–1:2 + 1% Me2NEt) furnishing 4.117 g of the epimeric
g-hydroxyalkylation products (61%) as yellow oil in a diastereo-
meric ratio of 3.37:1. To a stirred solution of this mixture
(7.56 mmol, 1 equiv) in CH2Cl2 (75 mL) was added 4-dimethylami-
nopyridine (46 mg, 0.38 mmol, 0.05 equiv) and Me2NEt (884 mg,
12.09 mmol, 1.6 equiv) at r.t. TMSCl (1.038 g, 9.55 mmol,
1.26 equiv) was added dropwise at 0 °C and stirred for 16 h at r.t.
The reaction was quenched by pouring the solution into vigorously
stirred ice water (75 mL), the layers were separated and the aqueous
phase was extracted with Et2O (3 × 50 mL). The combined organic
layers were dried over Na2SO4 and the solvents were removed under
reduced pressure furnishing 4.00 g of the crude silyl ether as light
brown oil, which was used without further purification. To a solu-
tion of n-BuLi (1.958 g, 2.5 M in hexane, 6.81 mmol, 1.05 equiv) in
toluene (20 mL) a solution of the crude silyl ether in toluene (20
mL) was added dropwise at –78 °C under an argon atmosphere. Af-
ter 50 min, this solution was added at –78 °C to a suspension of
KOt-Bu (774 mg, 6.48 mmol, 1.0 equiv) in toluene (30 mL) and n-
BuLi (1.958 g, 2.5 M in hexane, 6.81 mmol, 1.05 equiv). The re-
sulting mixture was stirred for 15 min at –78 °C, and for another
3.5 h at r.t. at which point a solution of NaHCO3 (70 mL) was add-
ed. The layers were separated and the aqueous phase was extracted
with Et2O (3 × 50 mL). The combined organic phases were dried
over Na2SO4 and the solvents were removed under reduced pres-
sure. The residue was purified by flash column chromatography
(hexanes–Et2O, 1:2 + 1% EtNMe2), furnishing 9a (2.079 g, 52%) as
yellow oil, which crystallizes after days to a light-yellow solid.
Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.22; H,
6.99.
(–)-[SS,N(1S)]-N-{1-[tert-Butyl(dimethyl)silanyloxymethyl]-2-
methyl-propyl}-3-(p-tolyl-sulfonimidoylmethyl)benzo-7,12-
dioxa-spiro[5.6]dodec-2-ene (5c)
Following GP-1: with methyl sulfoximine 13 (3.67 g, 10 mmol,
1 equiv), n-BuLi (3.67 g, 11 mmol, 1.1 equiv), monoketal 18
(2.56 g, 11 mmol, 1.1 equiv), TMSCl (3.48 g, 30 mmol, 3 equiv)
and EtMe2N (4.30 mL, 2.93 g, 40 mmol, 4 equiv) the crude O-
TMS-protected alcohol was obtained in quantitative yield. Deviat-
ing from GP-1, the preparation of 5c was continued as follows: To
a solution of the crude silyl ether (6.30 g, 8.58 mmol, 1 equiv) in
toluene (86 mL) a solution of n-BuLi (5.67 g, 17.16 mmol, 2 equiv)
was added dropwise at –78 °C. After stirring for 3 h at –78 °C the
reaction was quenched by addition of a solution of NH4Cl
(100 mL). Then the layers were separated, the aqueous phase was
extracted with Et2O (30 mL), the combined organic phases were
washed with NaCl solution (50 mL) and the aqueous phase was ex-
tracted again with Et2O (30 mL). The combined organic phases
were dried over Na2SO4 and the solvents were removed under re-
duced pressure, furnishing vinyl sulfoximine 19 (5.36 g, quant.),
which was used for the next transformation without purification. To
a vigorously stirred suspension of KOt-Bu (963 mg, 8.58 mmol,
1 equiv) in toluene (50 mL) was added a solution of n-BuLi (2.83 g,
8.58 mmol, 1 equiv) at –78 °C. After 30 min, a solution of the
vinyl sulfoximine 19 in toluene (100 mL) was added dropwise. The
mixture was stirred at r.t. for additional 16 h and then quenched by
pouring it into a solution of NH4Cl (100 mL). The layers were sep-
arated, the aqueous phase was extracted with Et2O (30 mL), and the
combined organic phases were washed with a solution of NaCl
(50 mL). Then the aqueous phase was extracted again with Et2O
(30 mL). The combined organic phases were dried over Na2SO4 and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (hexanes–Et2O, 5:1) fur-
nishing 2-alkenylsulfoximine 5c (3.59 g, 72%) as a colorless oil.
Mp 59 °C; [a]D20 –11.2 (c 1, CH2Cl2); Rf = 0.10 (hexane–Et2O,
1:2 + 1% Me2NEt).
[a]D20 –8.2 (c 0.8, CH2Cl2); Rf = 0.30 (hexanes–Et2O, 2:1).
1H NMR (500 MHz, CDCl3): d = –0.045, –0.034 [2 s, 6 H,
Si(CH3)2], 0.841 [s, 9 H, SiC(CH3)3], 0.895 (d, J3,4 = 6.8 Hz, 3 H,
H-4), 0.971 (d, J3,4¢ = 7.0 Hz, 3 H, H-4¢), 1.981 (m, 1 H, H-3), 2.422
(s, 3 H, H-9), 3.077 (m, 1 H, H-2), 3.339 (d, J14,14¢ = 10.0 Hz, 1 H,
H-14), 3.358 (m, 1 H, H-13), 3.423 (m, 1 H, H-13¢), 3.460 (dd,
1H NMR (500 MHz, CDCl3): d = –0.032, –0.020 [2 s, 6 H,
Si(CH3)2], 0.851 [s, 9 H, SiC(CH3)3], 0.920 (d, J3,4 = 6.9 Hz, 3 H,
H-4), 0.992 (d, J3,4¢ = 6.9 Hz, 3 H, H-4¢), 1.895 (m, 2 H, H-13),
2.009 (m, 1 H, H-3), 2.132 (m, 1 H, H-12), 2.284 (‘d’,
J19,19¢ = 6.9 Hz, 1 H, H-19), 2.396 (‘d’, J19,19¢ = 6.9 Hz, 1 H, H-19¢),
J
1,1¢ = 10.0 Hz, J1,2 = 5.9 Hz, 1 H, H-1), 3.516 (d, J14,14¢ = 10.0 Hz,
2.425 (s, 3 H, H-9), 2.464 (m, 1 H, H-12¢), 3.107 (m, 1 H, H-2),
3.499 (dd, J1,1¢ = 10.1 Hz, J1,2 = 6.0 Hz, 1 H, H-1), 3.554 (dd,
J1¢,2 = 7.9 Hz, J1,1¢ = 10.1 Hz, 1 H, H-1¢), 3.679 (d, J10,10¢ = 12.8 Hz,
1 H, H-10), 3.872 (d, J10,10¢ = 12.8 Hz, 1 H, H-10¢), 4.844 (m, 4 H,
H-15), 5.184 (‘s’, 1 H, H-20), 7.061 (m, 2 H, H-18), 7.172 (m, 2 H,
H-17), 7.281 (d, J6,7 = 8.1 Hz, 2 H, H-7), 7.778 (d, J6,7 = 8.1 Hz,
2 H, H-6).
1 H, H-14¢), 3.523 (dd, J1¢,2 = 7.6 Hz, J2,3 = 3.2 Hz, 1 H, H-1¢),
3.710 (d, J15,15¢ = 2.1 Hz, 2 H, H-15, H-15¢), 3.822 (d, J10,10¢ = 13.9,
1 H, H-10), 4.007 (d, J10,10¢ = 13.9 Hz, 1 H, H-10¢), 5.474 (br ‘s’,
1 H, H-12), 7.224 (m, 1 H, H-19), 7.280 (m, 4 H, H-17, H-18),
7.279 (d, J6,7 = 8.2 Hz, 2 H, H-7), 7.772 (d, J6,7 = 8.2 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = –5.27, –5.19, 16.81, 18.49, 20.19,
21.62, 26.12, 30.05, 57.82, 60.07, 60.40, 61.30, 61.82, 65.83,
127.05, 128.40, 128.71, 129.49, 129.56, 130.28, 131.01, 136.59,
139.41, 143.38.
13C NMR (125 MHz, CDCl3): d = –4.98, –4.91, 17.08, 18.78, 20.46,
21.90, 26.40, 27.70, 28.87, 30.30, 35.11, 61.45, 64.40, 64.92, 66.16,
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

2230
M. Reggelin et al.
PAPER
HRMS (EI): m/z [M]+ calcd for C30H46N2O2SSi: 526.3049; found:
526.3027.
64.50, 64.60, 65.20, 69.40, 107.40, 128.99, 129.20, 129.80, 132.49,
133.81, 134.20, 138.17, 143.45, 155.70, 168.43.
Anal. Calcd for C30H46N2O2SSi: C, 68.39; H, 8.80; N, 5.32. Found:
C, 68.01; H, 8.72; N, 5.21.
Anal. Calcd for C38H54N2O7SSi: C, 64.19; H, 7.66; N, 3.97. Found:
C, 64.93; H, 7.51; N, 3.96.
Synthesis of Aza(poly)cycles; General Procedures 2 (GP-2)
g-Hydroxyalkylation (GP-2.1)
(+)-[SS,N(1S),4S,4aR,8aS]-N-{1-[tert-Butyl(dimethyl)silanyl-
oxymethyl]-2-methyl-propyl}-4-hydroxy-8a-(p-tolyl-sulfon-
imidoylmethyl)octahydro[1,6]naphthyridine-6-carboxylic Acid
tert-Butyl Ester (8a)
Following GP-2.1 and GP-2.3: with 2-alkenyl sulfoximine 5a
(5.29 g, 9.60 mmol, 1 equiv) and aminoaldehyde 6 (1.95 g,
9.60 mmol, 1 equiv) 8a (3.55 g, 59%) was obtained as colorless
foam after chromatographic workup (hexane–EtOAc, 1:1–1:3).
To a stirred solution of 2-alkenyl sulfoximine (5a, 5b, 5c, 9a;
1 equiv) in toluene (5 mL/mmol) a solution of n-BuLi (2.5 M in
hexane, 1.1 equiv) was injected dropwise via syringe at –78 °C. Af-
ter the solution was stirred for 15 min, ClTi(Oi-Pr)3 (1 M in hexane,
1.2 equiv) was added dropwise. The mixture was stirred for another
15 min at this temperature and then for 60 min at r.t. Then, aminoal-
dehyde (1.30 equiv) dissolved in THF (1 mL/mmol or less) was
added at 0 °C and the mixture was stirred for 1–3 h. The progress of
the reaction was monitored by TLC.
[a]D20 +34.6 (c 1, CH2Cl2); Rf = 0.17 (hexane–EtOAc, 1:5).
1H NMR (500 MHz, CDCl3): d = –0.079, –0.053 [2 s, 6 H,
Si(CH3)2], 0.827 [s, 9 H, SiC(CH3)3], 0.866 (d, J14,13 = 6.9 Hz, 3 H,
H-14), 0.942 (d, J13,14¢ = 6.9 Hz, 3 H, H-14¢), 1.440 (s, 9 H, H-23),
1.682 (br s, 1 H, H-8), 1.690 (br s, 2 H, H-3), 1.953 (m, 1 H, H-13),
1.970 (br s, 1 H, H-5), 2.409 (br s, 1 H, H-8¢), 2.427 (s, 3 H, H-20),
2.450 (br s, 1 H, H-2), 2.784 (br s, 1 H, H-9), 2.932 (m, 1 H, H-12),
2.950 (br s, 1 H, H-2¢), 2.974 (br s, 1 H, H-9¢), 3.123 (d,
Work-up with (NH4)2CO3 (GP-2.2)
After warming to r.t. the mixture was poured into a rapidly stirred
solution of (NH4)2CO3 (30 mL/mmol). After stirring for 30 min the
layers were separated and the aqueous layer was extracted with
Et2O (3 × 10 mL/mmol). The organic phases were dried over
Na2SO4 and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (conditions
given in the description of the individual compounds), furnishing
the 4-hydroxyvinyl sulfoximines as oils or solids.
J11,11¢ = 14.1 Hz, 1 H, H-11), 3.298 (br s, 1 H, OH), 3.358 (br s, 1 H,
H-6), 3.366 (dd, J15,15¢ = 9.9 Hz, J12,15 = 6.3 Hz, 1 H, H-15), 3.497
(dd, J15,15¢ = 9.9 Hz, J12,15¢ = 7.3 Hz, 1 H, H-15¢), 3.562 (br s, 1 H, H-
6¢), 3.681 (d, J11,11¢ = 14.1 Hz, 1 H, H-11¢), 3.887 (br s, 1 H, NH),
4.101 (m, 1 H, H-4), 7.306 (d, J18,17 = 8.1 Hz, 2 H, H-18), 7.824 (d,
J17,18 = 8.1 Hz, 2 H, H-17).
Hydrazine-Induced Cyclization (GP-2.3)
13C NMR (125 MHz, CDCl3): d = –5.33, –5.29, 17.34, 18.46, 19.75,
21.60, 26.10, 28.59, 30.00, 30.28, 36.13, 38.71, 39.61, 43.43, 44.64,
57.99, 60.36, 61.51, 65.49, 67.74, 79.78, 128.84, 129.88, 139.44,
143.49, 155.18.
To the solution of the vinyl sulfoximine obtained by GP-2.1 a mix-
ture of aq hydrazine hydrate (80%, 9.0–10.1 equiv) and EtOH
(1 mL/mL hydrazine hydrate solution) was added at –78 °C. The re-
sulting mixture was allowed to reach r.t. and was stirred for 6–16 h
until complete consumption of the vinyl sulfoximine (monitored by
TLC). After the addition of Et2O (10 mL/mmol) the precipitate was
filtered off and washed with Et2O (3 ×, 1 mL/mmol). The filtrate
was concentrated in vacuo and the residue was purified by flash col-
umn chromatography (conditions given in the description of the in-
dividual compounds), furnishing the aza(poly)cycles as oils or
solids.
Anal. Calcd for C32H57N3O5SSi: C, 61.60; H, 9.21; N, 6.73. Found:
C, 61.70; H, 9.24; N, 6.65.
(+)-[SS,N(1S),4S,4aR,8aS]-N-{1-[tert-Butyl(dimethyl)silanyl-
oxymethyl]-2-methyl-propyl}-4-hydroxy-8a-(p-tolyl-sulfon-
imidoylmethyl)octahydro-quinolin-6-one-ethylene-ketal (8b)
Following GP-2.1 and GP-2.3: with 2-alkenyl sulfoximine 5b
(400 mg, 0.788 mmol, 1 equiv) and amino aldehyde 6 (208 mg,
1.02 mmol, 1.3 equiv) 8b (230 mg, 50%) was obtained as colorless
foam.
(–)-[SS,N(1S),3S,7R]-N-{1-[tert-Butyl(dimethyl)silanyloxymeth-
yl]-2-methyl-propyl}-2-(3-hydroxy-3-{8-[1-(p-tolyl-sulfonimi-
doyl)meth-(Z)-ylidene]-1,4-dioxa-spiro[4.5]dec-7-yl}propyl)-
isoindole-1,3-dione (15)
Following GP-2.1 and GP-2.2: with 2-alkenyl sulfoximine 5b
(400 mg, 0.79 mmol, 1 equiv) and amino aldehyde 6 (208 mg,
1.02 mmol, 1.3 equiv) 4-hydroxyvinyl sulfoximine 15 (455 mg,
81%) was obtained as a colorless foam after chromatographic work-
up (hexane–EtOAc, 2:1–1:1).
[a]D20 –92.0 (c 1, CH2Cl2); Rf = 0.20 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = –0.142, –0.107 [2 s, 6 H,
Si(CH3)2], 0.786 [s, 9 H, SiC(CH3)3], 0.900 (d, J13,14 = 6.9 Hz, 3 H,
[a]D20 +37.5 (c 1, CH2Cl2); Rf = 0.53 (CH2Cl2–MeOH–concd aq
NH3, 90:10:1).
1H NMR (500 MHz, C6D6, 330 K): d = –0.005, 0.018 [2 s, 6 H,
Si(CH3)2], 0.922 [s, 9 H, SiC(CH3)3], 1.103 (d, J14,13 = 6.9 Hz, 3 H,
H-14), 1.219 (d, J14¢,13 = 6.9 Hz, 3 H, H-14¢), 1.306 (m, 1 H, H-3),
1.622 (m, 1 H, H-3¢), 1.652 (m, 1 H, H-8), 1.947 (m, 1 H, H-6),
2.016 (s, 3 H, H-20), 2.104 (m, 1 H, H-6¢), 2.128 (m, 1 H, H-5),
2.225 (m, 1 H, H-8¢), 2.253 (m, 1 H, H-9), 2.283 (m, 1 H, H-13),
2.707 (m, 1 H, H-9¢), 2.758 (m, 2 H, H-2), 3.181 (d,
J11,11¢ = 14.1 Hz, 1 H, H-11), 3.255 (m, 1 H, H-12), 3.567 (m, 4 H,
H-14), 0.960 (d,
J13,14¢ = 6.9 Hz, 3 H, H-14¢), 1.498 (dd,
H-21), 3.589 (m, 1 H, H-15), 3.593 (d, J11,11¢ = 14.1 Hz, 1 H, H-11¢),
3.716 (dd, J15,15¢ = 10.0 Hz, J15¢,12 = 7.5 Hz, 1 H, H-15¢), 3.674 (m,
1 H, H-4), 6.979 (d, J18,17 = 8.1 Hz, 2 H, H-18), 7.881 (d,
J17,18 = 8.1 Hz, 2 H, H-17).
J5,6 = 6.0 Hz, J6,6' = 14.4 Hz, 1 H, H-6), 1.554 (m, 1 H, H-8), 1.660
(m, 1 H, H-3), 1.750 (m, 1 H, H-6), 1.780 (m, 1 H, H-8¢), 1.970 (m,
1 H, H-13), 2.080 (m, 1 H, H-9), 2.140 (m, 1 H, H-3¢), 2.404 (s, 3 H,
H-20), 2.750 (m, 1 H, H-9¢), 2.830 (m, 1 H, H-12), 3.260 (dd,
The two heteroatom-bound protons are too broad to assign!
J
J
15,15¢ = 10.1 Hz, J12,15 = 5.7 Hz, 1 H, H-15), 3.450 (dd,
15,15¢ = 10.1 Hz, J12,15¢ = 8.3 Hz, 1 H, H-15¢), 3.760 (m, 1 H, H-5),
13C NMR (125 MHz, C6D6, 330 K): d = –5.18, –5.09, 17.40, 18.62,
20.33, 21.14, 26.27, 29.68, 30.22, 30.57, 30.68, 36.06, 39.94, 44.30,
57.64, 61.26, 61.93, 64.31, 66.13, 67.08, 109.65, 129.05, 129.78,
141.51, 142.83.
3.780 (m, 4 H, H-21), 3.950 (m, 2 H, H-2), 4.100 (m, 1 H, H-4),
4.560 (br s, 1 H, OH), 6.430 (s, 1 H, H-11), 7.284 (d, J17,18 = 8.2 Hz,
2 H, H-18), 7.682 (m, 2 H, 25-H), 7.766 (d, J17,18 = 8.2 Hz, 2 H, H-
17), 7.828 (m, 2 H, 24-H).
Anal. Calcd for C30H52N2O5SSi: C, 62.03; H, 9.02; N, 4.82. Found:
C, 61.84; H, 9.06; N, 4.76.
13C NMR (125 MHz, CDCl3): d = –5.40, –5.34, 17.26, 18.39, 20.04,
21.56, 26.04, 29.75, 30.80, 34.70, 35.20, 35.70, 35.80, 43.70, 61.70,
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Azabicycles via 2-Alkenyl Sulfoximines
2231
(+)-[SS,N(1S),4S,4aR,8aS]-N-{1-[tert-Butyl(dimethyl)silanyl-
oxymethyl]-2-methyl-propyl}-4-hydroxy-8a-(p-tolyl-sulfon-
imidoylmethyl)octahydro-quinolin-6-one-o-xylyl-ketal (8d)
Following GP-2.1 (deviating from GP-2.1, ClTi(Oi-Pr)3 was added
at 0 °C!) and GP-2.3: with 2-alkenyl sulfoximine 5c (1.00 g,
1.73 mmol, 1 equiv) and aminoaldehyde 6 (456 mg, 2.24 mmol,
1.3 equiv) 8d (716 mg, 63%) was obtained as colorless oil after
chromatographic workup (hexanes–EtOAc, 1:1–3:1).
(+)-[SS,N(1S),2S,3R,3aR,6aR)]-N-{1-[tert-Butyl(dimethyl)sila-
nyloxymethyl]-2-methyl-propyl}-5-benzyl-2-tert-butoxymeth-
yl-6a-(p-tolyl-sulfonimidoylmethyl)octahydro-pyrrolo[3,4-
b]pyrrol-3-ol (10a)
Following GP-2.1 and GP-2.3: with 9a (352 mg, 0.66 mmol,
1 equiv), n-BuLi (240 mg, 2.5 M in hexane, 0.84 mmol,
1.24 equiv), ClTi(Oi-Pr)3 (0.91 mL, 1 M in hexane, 0.92 mmol,
1.35 equiv), aldehyde 24 (252 mg, 0.92 mmol, 1.35 equiv) and
aqueous hydrazine hydrate (80%, 0.42 mL, 6.83 mmol, 10.1 equiv)
10a (145 mg, 32%) was obtained as a colorless foam after chro-
matographic workup (hexanes–Et2O–1% EtNMe2, 1:1–1:3).
[a]D20 +31.9 (c 1, CH2Cl2); Rf = 0.13 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = –0.068, –0.044 [2 s, 6 H,
Si(CH3)2], 0.839 [s, 9 H, SiC(CH3)3], 0.883 (d, J14,13 = 6.9 Hz, 3 H,
H-14), 0.964 (d, J14¢,13 = 6.9 Hz, 3 H, H-14¢), 1.576 (m, 1 H, H-3),
1.676 (m, 1 H, H-3¢), 1.872 (m, 1 H, H-9), 1.926 (m, 3 H, H-6, H-
8), 1.972 (m, 1 H, H-13), 1.994 (m, 1 H, H-5), 2.182 (m, 1 H, H-8¢),
2.414 (m, 1 H, H-9¢), 2.425 (s, 3 H, H-20), 2.760 (m, 1 H, H-2),
2.903 (m, 1 H, H-2¢), 2.963 (m, 1 H, H-12), 3.180 (d,
[a]D20 +30.7 (c = 0.75, CH2Cl2), Rf = 0.10 (hexane–Et2O, 1:2 + 1%
Me2NEt).
1H NMR (500 MHz, CDCl3): d = –0.075, –0.054 [2 s, 6 H,
Si(CH3)2], 0.831 [s, 9 H, SiC(CH3)3], 0.868 (d, J12,11 = 6.9 Hz, 3 H,
H-12), 0.938 (d, J12¢,11 = 6.9 Hz, 3 H, H-12¢), 1.107 (s, 9 H, H-26),
1.948 (m, 1 H, H-11), 2.321 (dd, J5,5¢ = 9.6 Hz, J5,4 = 6.5 Hz, 1 H,
H-5), 2.419 (s, 3 H, H-18), 2.563 (d, J7,7¢ = 10.4 Hz, 1 H, H-7),
2.671 (ddd, J4,5 = 6.5 Hz, J4,3 = 7.6 Hz, J4,5¢ = 2.6 Hz, 1 H, H-4),
2.884 (d, J7¢,7 = 10.4 Hz, 1 H, H-7¢), 2.920 (ddd, J10,11 = 2.9 Hz,
J10,13 = 5.9 Hz, J10,13¢ = 7.7 Hz, 1 H, H-10), 2.961 (dd, J5¢,5 = 9.6 Hz,
J5¢,4 = 2.6 Hz, 1 H, H-5¢), 3.180 (dd, J24,24¢ = 8.5 Hz, J24,2 = 6.0 Hz,
1 H, H-24), 3.256 (ddd, J2,3 = 4.7 Hz, J2,24 = 6.0 Hz, J2,24¢ = 4.7 Hz,
1 H, H-2), 3.354 (dd, J24¢,24 = 8.5 Hz, J24',2 = 4.7 Hz, 1 H, H-24¢),
3.377 (dd, J13,13¢ = 10.0 Hz, J10,13 = 5.9 Hz, 1 H, H-13), 3.488 (dd,
J13¢,13 = 10.0 Hz, J13¢,10 = 7.7 Hz, 1 H, H-13¢), 3.531 (br s, 2 H, H-
19), 3.552 (d, J9,9¢ = 13.9 Hz, 1 H, H-9), 3.606 (d, J9¢,9 = 13.9 Hz,
1 H, H-9¢), 3.964 (dd, J3,4 = 7.6 Hz, J3,2 = 4.7 Hz, 1 H, H-3), 7.278
(d, J16,15 = 8.3 Hz, 2 H, H-16), 7.285 (m, 5 H, H-21, H-22, H-23),
7.789 (d, J15,16 = 8.3 Hz, 2 H, H-15).
J11,11¢ = 14.4 Hz, 1 H, H-11), 3.393 (dd,
J15,15¢ = 9.9 Hz,
J15,12 = 6.3 Hz, 1 H, H-15), 3.517 (dd, J15¢,15 = 9.9 Hz,
J15¢,12 = 7.3 Hz, 1 H, H-15¢), 3.698 (d, J11,11¢ = 14.4 Hz, 1 H, H-11¢),
3.966 (m, 1 H, H-4), 4.796 (br s, 2 H, H-21), 4.843 (d,
J
21¢,21¢¢ = 15.1 Hz, 1 H, H-21¢), 4.927 (d, J21¢,21¢¢ = 15.1 Hz, 1 H, H-
21¢¢), 7.034 (m, 2 H, H-24), 7.140 (m, 2 H, H-23), 7.297 (d,
J18,17 = 8.2 Hz, 2 H, H-18), 7.838 (d, J17,18 = 8.2 Hz, 2 H, H-17).
The two heteroatom-bound protons are too broad to assign!
13C NMR (125 MHz, CDCl3): d = –5.31, –5.26, 17.31, 18.47, 19.67,
21.58, 26.61, 26.87, 27.62, 29.16, 30.36, 30.45, 34.31, 43.19, 57.36,
60.52, 61.36, 65.38, 66.99, 67.10, 102.47, 126.14, 126.26, 126.75,
128.85, 129.82, 138.20, 138.32, 139.83, 143.27, 127.59, 127.71,
129.58, 129.64, 134.24, 134.64, 135.86, 135.89.
Anal. Calcd for C36H56N2O5SSi: C, 65.81; H, 8.59; N, 4.26. Found:
C, 65.91; H, 8.66; N, 4.07.
The two heteroatom-bound protons are too broad to assign!
13C NMR (125 MHz, CDCl3): d = –5.28, –5.22, 17.12, 18.48, 19.92,
21.58, 26.11, 27.49, 29.99, 51.65, 53.86, 59.82, 61.24, 64.73, 65.56,
65.84, 66.42, 68.21, 70.22, 73.16, 76.76, 127.22, 128.44, 128.88,
129.33, 129.65, 138.37, 138.59, 143.26.
[SS,N(1S),4S,4aR,8aS]-N-[1-hydroxymethyl-2-methyl-propyl]-
4-hydroxy-8a-(p-tolyl-sulfonimidoylmethyl)octahydro-
quinolin-6-one (8c)
To a solution of azabicycle 8b (3.0 g, 5.16 mmol, 1 equiv) in ace-
tone (10 mL) was added p-toluenesulfonic acid monohydrate
(1.96 g, 10.23 mmol, 2 equiv). After the solution was stirred for
40 h at r.t. the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography (CH2Cl2–
MeOH–concd aq NH3, 200:15:1–200:40:4), furnishing ketone 8c
(1.22 g, 56%), slightly contaminated with unknown impurities, as a
colorless foam.
ESI-MS (CHCl3, CH3OH): m/z (%) = 710.5 (8, [M + K]+), 694.5
(100, [M + Na]+), 317.4 (9, [C19H29N2O2]+).
HRMS (EI): m/z [M]+ calcd for C37H61N3O4SSi: 671.4152; found:
671.4145.
Anal. Calcd for C37H61N3O4SSi: C, 66.13; H, 9.15; N, 6.25. Found:
C, 66.20; H, 9.09; N, 6.20.
(+)-[SS,N(1S),2S,3R,3aR,6aR)]-N-{1-[tert-Butyl(dimethyl)sila-
nyloxymethyl]-2-methyl-propyl}-2,5-dibenzyl-6a-(p-tolyl-sul-
fonimidoylmethyl)octahydro-pyrrolo[3,4-b]pyrrol-3-ol (10b)
Following GP-2.1, 9a (352 mg, 0.66 mmol, 1 equiv) was treated
with a solution of n-BuLi (244 mg, 2.5 M in hexane, 0.84 mmol,
1.24 equiv), ClTi(Oi-Pr)3 (0.89 mL, 1 M in hexane, 0.92 mmol,
1.35 equiv) and aldehyde 25 (332 mg, 0.89 mmol, 1.35 equiv). Af-
ter 2 h at 0 °C piperidine (564 mg, 6.62 mmol, 10 equiv) was added
to induce the cyclization. The mixture was stirred at r.t. for 14 h,
then Et2O (20 mL) was added and the mixture was poured into a
rapidly stirred solution of (NH4)2CO3 (30 mL). After stirring for
35 min the layers were separated and the aqueous layer was extract-
ed with Et2O (3 × 15 mL). The combined organic phases were
washed with a solution of NH4Cl (30 mL) and the aqueous layer
was extracted back with Et2O (2 × 25 mL). The organic phases were
dried over Na2SO4 and the solvents were removed under reduced
pressure. The residue was dissolved in hot MeOH (8 mL) and re-
crystallized at r.t. After filtration of the white precipitate, which was
washed with a small quantity of MeOH, the solvent was removed
under reduced pressure. Purification of the residue by flash column
chromatography (hexane–Et2O, 1:2–1:8 + 1% Me2NEt) gave 10b
(196 mg, 44%) as light-yellow foam.
Rf = 0.24 (CH2Cl2–MeOH–concd aq NH3, 90:10:1).
1H NMR (500 MHz, CDCl3): d = 0.901 (d, J(14,14¢),13 = 6.9 Hz, 6 H,
H-14, H-14¢), 1.743 (m, 1 H, H-13), 2.021 (m, 1 H, H-2), 2.041 (m,
1 H, H-3), 2.161 (m, 1 H, H-3¢), 2.244 (m, 1 H, H-8), 2.440 (s, 3 H,
H-20), 2.460 (m, 1 H, H-8¢), 2.515 (m, 1 H, H-6), 2.809 (m, 1 H, H-
11), 2.896 (m, 1 H, H-6¢), 3.173 (m, 1 H, H-2¢), 3.375 (m, 1 H, H-
9), 3.542 (m, 1 H, H-5), 3.590 (m, 1 H, H-9¢), 3.599 (m, 2 H, H-15),
3.681 (m, 1 H, H-11), 4.283 (m, 1 H, H-11¢), 4.305 (m, 1 H, H-4),
7.423 (d, J18,17 = 8.2 Hz, 2 H, H-18), 8.007 (d, J17,18 = 8.2 Hz, 2 H,
H-17).
All heteroatom-bound protons (2 × OH, 1 × NH) are too broad to
assign!
13C NMR (125 MHz, CDCl3): d = 19.41, 21.78, 30.17, 31.70, 34.08,
35.91, 39.98, 41.86, 57.86, 59.47, 63.15, 64.05, 66.80, 129.80,
129.90, 139.80, 145.71, 206.01.
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York

2232
M. Reggelin et al.
PAPER
[a]D20 +34.0 (c 1, CH2Cl2); Rf = 0.12 (hexane–Et2O, 1:5 + 1%
Me2NEt).
Acknowledgment
We thank the Fonds der Chemischen Industrie (Kekulé Fellowship
for P.B.) and Solvay Pharmaceuticals (Hannover, Germany) for ge-
nerous financial support.
1H NMR (500 MHz, CDCl3): d = –0.077, –0.052 [2 s, 6 H,
Si(CH3)2], 0.831 [s, 9 H, SiC(CH3)3], 0.870 (d, J12,11 = 6.9 Hz, 3 H,
H-12), 0.924 (d, J12¢,11 = 6.9 Hz, 3 H, H-12¢), 1.940 (m, 1 H, H-11),
2.334 (dd, J5,5¢ = 9.7 Hz, J5,4 = 6.2 Hz, 1 H, H-5), 2.437 (s, 3 H, H-
18), 2.535 (dd, J24,24¢ = 13.7 Hz, J24,2 = 7.8 Hz, 1 H, H-24), 2.651 (d,
References
J7,7¢ = 10.5 Hz, 1 H, H-7), 2.700 (ddd, J4,5 = 6.2 Hz, J4,5¢ = 2.3 Hz,
(1) Reggelin, M.; Junker, B.; Heinrich, T.; Slavik, S.; Bühle, P.
J. Am. Chem. Soc. 2006, 128, 4023.
(2) Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467.
(3) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(4) Reggelin, M.; Weinberger, H.; Gerlach, M.; Welcker, R. J.
Am. Chem. Soc. 1996, 118, 4765.
(5) Reggelin, M.; Weinberger, H. Angew. Chem., Int. Ed. Engl.
1994, 33, 444.
(6) Reggelin, M.; Weinberger, H. Tetrahedron Lett. 1992, 33,
6959.
(7) Reggelin, M.; Welcker, R. Tetrahedron Lett. 1995, 36, 5885.
(8) Reggelin, M.; Junker, B. Chem.–Eur. J. 2001, 7, 1232.
(9) Reggelin, M.; Weinberger, H.; Heinrich, T. Liebigs Ann.
Recl. 1997, 1881.
J4,3 = 7.9 Hz, 1 H, H-4), 2.776 (dd, J24,24¢ = 13.7 Hz, J24¢,2 = 6.4 Hz,
1 H, H-24¢), 2.860 (d, J7¢,7 = 10.5 Hz, 1 H, H-7¢), 2.895 (ddd,
J10,11 = 3.0 Hz, J10,13 = 6.1 Hz, J10,13¢ = 7.6 Hz, 1 H, H-10), 2.924
(dd, J5¢,5 = 9.7 Hz, J5¢,4 = 2.3 Hz, 1 H, H-5¢), 3.321 (ddd,
J2,3 = 5.2 Hz, J2,24 = 7.8 Hz, J2,24¢ = 6.4 Hz, 1 H, H-2), 3.373 (dd,
J
J
13,13¢ = 10.1 Hz, J13,10 = 6.1 Hz, 1 H, H-13), 3.380 (d,
9,9¢ = 13.9 Hz, 1 H, H-9), 3.496 (dd, J13,13 = 10.1 Hz,
J13¢,10 = 7.6 Hz, 1 H, H-13¢), 3.503 (d, J19,19¢ = 12.8 Hz, 1 H, H-19),
3.556 (d, J19¢,19 = 12.8 Hz, 1 H, H-19¢), 3.670 (d, J9¢,9 = 13.9 Hz,
1 H, H-9¢), 3.900 (dd, J3,4 = 7.9 Hz, J3,2 = 5.2 Hz, 1 H, H-3), 7.105
(d, J26,27 = 8.3 Hz, 2 H, H-26), 7.194 (m, 1 H, H-28), 7.259 (m,
J27,28 = 7.4 Hz, 6 H, H-21, H-22, H-27), 7.291 (d, J16,15 = 8.3 Hz,
2 H, H-16), 7.242 (m, 1 H, H-23), 7.755 (d, J15,16 = 8.3 Hz, 2 H, H-
15).
The two heteroatom-bound protons are too broad to assign!
(10) Reggelin, M.; Gerlach, M.; Vogt, M. Eur. J. Org. Chem.
13C NMR (125 MHz, CDCl3): d = –5.26, –5.21, 17.17, 18.50, 19.92,
21.64, 26.11, 29.97, 40.37, 50.77, 53.73, 59.78, 61.38, 65.55, 66.88,
67.87, 68.16, 69.39, 76.67, 126.32, 127.29, 128.51, 128.61, 128.75,
129.00, 129.27, 129.77, 138.31, 138.37, 139.51, 143.40.
1999, 1011.
(11) Reggelin, M.; Heinrich, T.; Junker, B.; Antel, J.; Preuschoff,
U. Solvay Pharmaceuticals GmbH, Germany Application
WO 99/58500, 72, 1999.
(12) Reggelin, M.; Heinrich, T. Angew. Chem. Int. Ed. 1998, 37,
ESI-MS (CHCl3, CH3OH): m/z (%) = 714.4 (13, [M + K]+), 698.4
2883.
(100, [M + Na]+), 676.4 (11, [M]+), 321.4 (99, [C21H25N2O]+).
(13) Bund, J.; Gais, H. J.; Erdelmeier, I. J. Am. Chem. Soc. 1991,
113, 1442.
(14) Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1989, 30,
4165.
MS (EI, 70 eV): m/z (%) = 674.9 (100, [M – H]+), 660.7 (5, [M –
CH3]+), 584.0 (4, [M – C7H7]+).
HRMS (EI): m/z [M – CH3]+ calcd for C38H54N3O3SSi: 660.3655;
(15) Babler, J. H.; Spina, K. P. Synth. Commun. 1984, 14, 39.
(16) For SN2¢ reactions of 2-alkenyl sulfoximines with C-
nucleophiles, see: Gais, H.-J.; Müller, H.; Bund, J.;
Scommoda, M.; Brandt, J.; Raabe, G. J. Am. Chem. Soc.
1995, 117, 2453.
found: 660.3643.
Anal. Calcd for C39H57N3O3SSi: C, 69.29; H, 8.50; N, 6.22. Found:
C, 69.47; H, 8.44; N, 6.25.
(17) Rich, D. H.; Ripka, A. S. Curr. Opin. Chem. Biol. 1998, 2,
441.
Synthesis 2006, No. 13, 2224–2232 © Thieme Stuttgart · New York