Camphoric acid derived sulfur containing bicyclic carboxylic acids as chiral auxiliaries in N-acyliminium ion chemistry

Article abstract of DOI:10.1016/j.tet.2010.07.009

Three novel sulfur containing chiral bicyclic carboxylic acids were synthesized from d-camphoric acid. Two of these compounds were briefly evaluated for their potency as chiral auxiliaries in Asymmetric Electrophilic α-Amidoalkylation (AEαA) reactions.

Full text of DOI:10.1016/j.tet.2010.07.009

Tetrahedron 66 (2010) 7279e7287
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journal homepage: www.elsevier.com/locate/tet
Camphoric acid derived sulfur containing bicyclic carboxylic acids as chiral
auxiliaries in N-acyliminium ion chemistry
a
b
c
c
b,
*
€
J. Brackow , J. Pabel , P. Mayer , K. Polborn , K.T. Wanner
a Carbogen Amcis AG, Neulandweg 5, CH-5502 Hunzenschwil, Switzerland
Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universitat München, Butenandtstr. 7, Haus C, D-81377 München, Germany
Department Chemie, Ludwig-Maximilians-Universitat München, Butenandtstr. 9, Haus D, D-81377 München, Germany
b
€
c
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2010
Received in revised form 1 July 2010
Accepted 2 July 2010
Available online 30 July 2010
Three novel sulfur containing chiral bicyclic carboxylic acids were synthesized from D-camphoric acid.
Two of these compounds were briefly evaluated for their potency as chiral auxiliaries in Asymmetric
Electrophilic -Amidoalkylation (AE A) reactions.
a
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Acyliminium salt
Asymmetric synthesis
Asymmetric electrophilic
(AE A)
a-amidoalkylation
a
Thioanhydride
Thiolactone
1. Introduction
presence of trimethylsilyl triflate (TMS-OTf).3e7 Especially the
generation of chiral N-acyliminium salts with the potential to give
rise to high levels of asymmetric induction in trapping reactions
with appropriate nucleophiles has attracted our attention. As part
of our studies, we have developed the bicyclic lactone carboxylic
acid 1 (Fig. 1) derived from camphoric acid as an easily accessible
The development of methodologies that allow efficient and
variable access to common and potentially bioactive structural
units is a challenging and ongoing task in modern organic chem-
istry. The number of general synthetic tools for the construction of
such chiral core structures is still rather limited. N-Heterocycles are
an important structural motif frequently found for bioactive sub-
stances. Among these, substituted and often chiral piperidines are
of particular interest in both academia and industry. A common
approach, which is widely applied and of high flexibility to con-
struct this type of compounds is based on trapping reactions of
N-acyliminium salts,1 which can often be prepared in situ from
readily available starting materials, such as pyridine and carboxylic
acid derivatives. Especially the use of pyridines as precursors for the
generation of N-acyliminium salts2 appears to be very attractive
since the repertoire for the synthesis of functionalized pyridines is
well established in the literature, giving rapid access to almost all
kinds of substituted piperidine derivatives.
auxiliary for asymmetric electrophilic a-amidoalkylation (AEa
A)8
reactions in the past. The asymmetric induction observed in
We and others have previously reported efficient protocols for
the in situ formation of N-acyliminium salts derived from activated
carboxylic acid moieties, such as acyl chlorides and pyridines in the
* Corresponding author. Tel.: þ49 89 2180 77249; fax: þ49 89 2180 77247; e-mail
address: Klaus.wanner@cup.uni-muenchen.de (K.T. Wanner).
Figure 1.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.009

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
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trapping reactions of N-acyliminium ions derived from 1 with
amphiphilic nucleophiles is assumed to be the result of
a coordination complex that might form between the organo-
metallic reagent and the lactone function of the chiral auxiliary
1.9 The auxiliary allows excellent stereocontrol in many exam-
ples.10e13 In continuation of our efforts to develop new and efficient
methyl ether had been required. Similar to the oxo analogue14
and the corresponding N-phenylimide16,17 of 6, treatment of 6
with base, a substoichiometric amount of sodium methanolate,
resulted in a ring contraction yielding thiocamphanic acid methyl
ester 11. Interestingly, in line with the results observed for rear-
rangement reactions of the aforementioned compounds, the nu-
chiral auxiliaries for AEaA reactions, we became interested in
cleophile had exclusively added to the a-bromo substituted
thiocamphanic acid 2, sulfenamide 3 and sultame 4. In this paper we
present the successful syntheses of these so far unknown com-
pounds as well as preliminary results regarding the use of carboxylic
acid 2 and 4 as chiral auxiliaries in asymmetric electrophilic
carbonyl group resulting in the formation of thiolactone 11. The
lactone that would form upon attack on the opposite carbonyl
group in 6, could not be detected. Finally, saponification of 11
with potassium hydroxide in THF/H2O provided thiolactone 2,
a thio analogue of camphanic acid. The yield for this step was
quantitative, as for the subsequent transformation of 2 into the
acid chloride 12 by treatment with oxalyl chloride/DMFcat.
(Scheme 1).
a-amidoalkylation (AEaA) reactions.
2. Results and discussion
Thioanhydride 6 appeared to be a suitable starting material for
the preparation of sulfenamide derivative 10, as well. When thio-
anhydride 6 was treated with an excess of sodium methoxide, in
contrast to the reaction with substoichiometric amounts of base,
which had led to 11, the mercapto carboxylic acid ester 7 was
obtained (85%). Presumably, in this case the thiolactone 11 is
formed as well, but cleaved to 7 by the excess of base now present
in the reaction mixture. To bring along the transformation of 7
into the sulfenamide derivative 8, compound 7 was treated with
N-chlorosuccinimide in liquid ammonia providing 8 in a clean
reaction in 90% yield.18,19 Acid catalyzed cyclization of 8 led to the
For the synthesis of thiocamphanic acid 2, a thio analogue of
camphanic acid, a long known and widely used chiral derivatiz-
ing reagent, a procedure published by Gerlach and Kappes14 and
Müller and Boléa15 for the preparation of this compound was
followed. Accordingly,
D
-camphoric acid
5 was subjected to
a HelleVolhardeZelinsky reaction for
a-bromination and sub-
sequently treated with hydrogen sulfide in the presence of pyr-
idine as a base to give thioanhydride 6. The yield for 6 still
amounted to 31%, though the synthetic sequence consisted of
three steps and for the purification of the crude product in
addition to column chromatography, crystallization from tert-butyl
Scheme 1.

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
7281
bicyclic sulfenamide derivative 9, which represents a rare ex-
ample of this class of compounds. However, extensive side re-
actions had reduced the yield to 39%. Finally, N-methylation
employing LDA and methyl iodide completed the synthesis of the
bicyclic ester 10 (yield 70%). Interestingly, sulfenamide 10 is also
accessible from thiolactone 11, a transformation that can be
performed in a single synthetic step only. Thus, treatment of
thiolactone 11 with sulfuryl chloride and methylamine gives rise
to sulfenamide 10 in 50% yield. To the best of our knowledge, this
type of reaction representing a formal nitrogen insertion into the
sulfurecarbon bond of a thiolactone moiety is unprecedented so
far. This transformation may be rationalized by an oxidative
cleavage reaction of the thiolactone unit by sulfuryl chloride
leading to an intermediate with an activated thiol and carboxylic
acid moiety. Aminolysis of these functions should establish the
final N-acyl sulfenamide group.
The sulfenamide derivative 10 was, in addition, used for the
preparation of the carboxylic acid 3 and the carboxylic acid chloride
13. Saponification of 10 with potassium hydroxide in aqueous
MeOH gave carboxylic acid 3 (77%) and treatment with oxalyl
chloride/DMFcat. provided acid chloride 13.
To evaluate the potency of the acid chlorides 12 and 15 as chiral
auxiliaries in Asymmetric Electrophilic
a-Amidoalkylation re-
actions, some trapping reactions of N-acylpyridinium ions gener-
ated from these compounds were performed.
N-Acyliminium ions derived from pyridine derivatives are
commonly generated in an equilibrium reaction by treating the
pyridine derivative with an appropriate acid chloride. Trapping
reactions, however, may fail when the equilibrium is too far on the
left side, which is often the case for reactants in which the reaction
centres are sterically hindered. But, in general, the situation is
distinctly improved when 1 equiv of a silyl triflate, like TMS-OTf, is
added as this effects a shift of the equilibrium towards the side of
the products as reported by us.7
Based on this result, 1 equiv of TMS-OTf was employed for the
generation of the N-acyliminium ion 17 from 16 and the carboxylic
acid chloride 12 whose potency as a chiral auxiliary should be
studied. For the asymmetric amidoalkylation reaction, 4-phenyl-
pyridine (16), acid chloride 12 and TMS-OTf were mixed at room
temperature and after 1 h cooled to ꢀ78 ꢁC before PhMgBr
(3.0 equiv) was added to trap the thus generated N-acyliminium ion
17. As expected, the diastereomeric dihydropyridines 18 and 19 were
obtained, butthoughtheyieldwasstillacceptable(50%),thereaction
was practically devoid of any diastereoselection (Scheme 3). For
The sulfenamide derivative 10 was finally used for the prepa-
ration of the carboxylic acid derivative 15 exhibiting a sultame
moiety, the compound to be tested as chiral auxiliary in Asym-
metric Electrophilic a-Amidoalkylation reactions. Fortunately, the
sulfenamide derivative 10 underwent a clean oxidation reaction to
give sultame derivative 14 when treated with m-chloroperbenzoic
acid in dichloromethane, the yield for this step amounting to 92%
(Scheme 2). The subsequent saponification of ester 14 with LiOH in
aqueous THF provided carboxylic acid 4, but in reduced yield, as
decomposition reactions occurred (62%). Finally, when 4 was
treated with oxalyl chloride/DMFcat. the desired carboxylic acid
halide 15 was obtained in quantitative yield.
Scheme 2.
Scheme 3.

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
7282
compound 18, for which suitable crystals had been obtained, an X-
ray analysis was performed, which revealed that compound 18
possesses (R)-configuration at the newly created stereocentre (see
Fig. 2). As any significant asymmetric induction was lacking, further
experiments with chiral auxiliary 12 were abandoned.
by employing a large excess of 4-methoxypyridine (20, 10 equiv).
Then upon addition of EtMgI (at ꢀ78 ꢁC), the desired dia-
stereomeric dihydropyridones 22 and 23 were formed in reason-
able yield (74%) (Scheme 4). With a diastereomeric ratio of 91/9 (22/
23), also the diastereoselectivity had been quite pleasing, but sig-
nificantly dropped to 61/39 (24 and 25), when PhMgBr was used for
the trapping reaction of the N-acyliminium ion 21, though the yield
remained almost unchanged (74%). The major diastereomer
resulting from the EtMgBr addition, 22, was found by X-ray analysis
to be (S)-configured at the newly created stereocenter (Fig. 3). For
diastereomers 24 and 25 no efforts to determine the configuration
were made.
Figure 2. Crystal structure of the dihydropyridine 18.
Figure 3. Crystal structure of the dihydropyridine 22.
Further experiments were performed to test the potency of the
sultame derivative 15 as a chiral auxiliary. This time 4-methoxy-
pyridine was used as a precursor for the generation of the
N-acyliminium ion. Under common conditions similar to those
described above and unaffected whether TMS-OTf had been
employed or not, either no addition products or only very small
quantities were formed. A reasonable conversion was finally
effected when the N-acyliminium ion 21 (Scheme 4) was generated
3. Conclusion
In summary, we have performed the synthesis of the new sulfur
containing chiral bicyclic carboxylic acids 2, 3 and 4 and their car-
boxylic acid chlorides. The acid chlorides 12 and 15 were evaluated
for their potency as chiral auxiliaries in Asymmetric Electrophilic
a-Amidoalkylation (AEaA) reactions. But though these were only
Scheme 4.

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
7283
preliminary studies, the potency for asymmetric induction of these
compounds appears to be low.
n
¼2970 cmꢀ1, 1709, 1681. C10H13BrO2S (277.18): calcd. C 43.33, H
4.73; S 11.57; found C 43.58, H 4.73, S 11.72.
4. Experimental section
4.1. General experimental
4.4. Methyl (1S,4R)-4,7,7-trimethyl-3-oxo-2-thiabicyclo[2.2.1]
heptane-1-carboxylate (11)
To a solution of 6 (2.76 g, 9.97 mmol) in anhyd THF (5 mL) at
ꢀ50 ꢁC a NaOMe solution (5.4 M in MeOH,1.75 mL, 9.45 mmol) was
carefully added. The mixture was warmed to 0 ꢁC over night (at
ꢀ33 ꢁC a precipitate is formed). After removing the solvent, the
residue was dissolved in 2 M HCl and extracted with CH2Cl2
(4ꢂ20 mL). After drying over MgSO4, the solvent was removed in
vacuo and the resulting residue purified by CC (PE/EtOAc¼8:2).
All reactions were performed using flame-dried glassware un-
der argon atmosphere. All solvents were freshly dried using stan-
dard procedures.20 As petroleum ether (PE) the fraction 40e80 ꢁC
was used. 1H and 13C NMR spectra were recorded on a JNMR-GX
400 (Joel, 400 MHz) or a JNMR-GX 500 (Joel, 500 MHz) spectrom-
eter, respectively. The nature of the carbon substitution deduced
from DEPT and HMQC spectra are expressed as multiplicity that
would have been observed in a proton coupled carbon NMR spec-
trum. Infrared spectra were obtained on a PerkineElmer Model
1600 FT-IR spectrometer. Microanalytical data for carbon, hydrogen
and nitrogen were determined on a Heraeus Rapid Analyser and on
an Elementar Vario EL Analyser. Flash chromatography (CC) was
performed with 40e63 mesh silica gel.
Yield 1.72 g (76%), colourless crystals, mp 72e75 ꢁC. TLC Rf¼0.38
20
(PE/EtOAc¼8:2). [
a
]
þ80.5 (c 1.01, CH2Cl2). 1H NMR (500 MHz,
D
CDCl3)
d
¼1.09 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.15 (s, 3H, CH3),
1.75e1.87 (m, 2H, CH3CCH2), 2.30 (ddd, J¼13.4/9.2/4.1 Hz, 1H, CH2),
2.75 (ddd, J¼13.4/10.5/5.5 Hz, 1H, CH2), 3.81 (s, 3H, OCH3). 13C NMR
(125 MHz, CDCl3)
d
¼11.7 (q, CH3), 18.7 (q, CH3), 18.7 (q, CH3), 30.1 (t,
CH2), 34.8 (t, CH2), 52.7 (q, OCH3), 55.6 (s), 62.8 (s), 69.9 (s), 169.5 (s,
COOCH3), 207.4 (s, COSR). MS (CI, CHþ5 ): m/z (%)¼229 (32) [Mþ1]þ,
4.2. General procedure for the synthesis of carboxylic acid
halides (GP 1)
223 (35), 187 (876), 167 (39), 159 (100). IR:
n
¼2977 cmꢀ1, 2363,
1734. HRMS (70 eV): [M]þ calcd for C11H16O3S (228.0820), found
228.0833.
The carboxylic acid was dissolved in 2 mL of anhyd CH2Cl2. After
addition of one drop anhyd DMF (1:10 in CH2Cl2), it was treated
with stated quantity of C2O2Cl2. The solvent was removed in high
vacuum after 2 h, and a solution was generated from residue in
specified concentration.
4.5. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-thiabicyclo[2.2.1]
heptane-1-carboxylic acid (2)
A solution of 11 (124.8 mg, 0.547 mmol) and KOH (92.0 mg,
1.64 mmol) in a THF/H2O (5:1) mixture (1.0 mL) was stirred at room
temperature for 12 h. After removing the solvent in vacuo 2 M HCl
was added to the resulting residue and the aqueous layer was
extracted with CH2Cl2 (5ꢂ). The combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The free
carboxylic acid 2 was obtained as colourless crystals.
4.3. (1R,5R)-1-Bromo-5,8,8-trimethyl-3-thiabicyclo[3.2.1]
octane-2,4-dione (6)
PCl5 (20.5 g, 100 mmol) in petroleum ether (40 mL) was sus-
pended in a dry Schlenk flask. Camphoric acid (10.0 g, 50 mmol)
was added to this suspension while cooling with ice. The mixture
was stirred for 2 h at 0 ꢁC, and for 3 h at room temperature. After
the solvent was removed in high vacuum, a reflux condenser was
added to the Schlenk flask. Bromine (1.71 mL, 33 mmol) was added
dropwise and the resulting mixture was heated to 55 ꢁC. Further
bromine was added after 2 h (1.50 mL, 29 mmol) and 8 h (1.00 mL,
20 mmol). Excess bromine was removed in high vacuum after 16 h,
and the product was distilled in vacuo (4.2ꢂ10ꢀ1 mbar, 130 ꢁC). The
resulting, pale yellow coloured oil was immediately used without
further purification.
Yield 117.3 mg (quant.), colourless crystals, mp 238e240 ꢁC.
20
TLC Rf¼0.31 (PE/EtOAc/HOAc¼69:30:1).
[
a
]
þ93.9 (c 1.00,
D
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
¼1.11 (s, 3H, CH3), 1.15 (s, 3H,
CH3), 1.21 (s, 3H, CH3), 1.61 (m, 2H, CH2), 2.37 (ddd, J¼13.3/9.1/
4.2 Hz, 1H, CH2), 2.78 (ddd, J¼13.3/10.6/5.2 Hz, 1H, CH2), 2.51 (ddd,
J¼13.6/10.6/4.2 Hz, 1H, CH2). 13C NMR (100 MHz, CDCl3)
¼11.7 (q,
d
CH3), 16.7 (q, CH3), 16.7 (q, CH3), 30.4 (t, CH2), 34.7 (t, CH2), 55.8 (s),
63.0 (s), 69.7 (s), 174.2 (C]O), 207.0 (C]O). MS (FABþ): m/z (%)¼
215 [Mþ1]þ. HRMS (FABþ): [MþH]þ calcd for C10H15O3S
(215.0742), found 215.0781. IR:
n
¼2970 cmꢀ1, 2682, 1707. Anal.
Hydrogen sulfide gas was introduced into a solution of pyridine
(38.6 mL, 10 equiv) in anhyd THF (80 mL) at ꢀ78 ꢁC and the crude
product from the first step dissolved in anhyd THF (10 mL) was
slowly added dropwise. The mixture was warmed to room tem-
perature over night. The resulting, colourless precipitation was
filtrated and washed with THF. The filtrate was treated with 2 M
HCl (saturated with NaCl). The aqueous layer was extracted with
THF (3ꢂ300 mL). The combined organic layers were dried over
MgSO4, filtered and the solvent was removed in vacuum. The
resulting residue was purified from pyridine and other polar side
products by CC with a short column (PE/EtOAc¼9:1). Crystallization
from tert-butyl methyl ether resulted 6.
Calcd for C10H14O3S (214.29): C 56.05, H 6.59, S 14.96. Found C
55.80, H 6.45, S 14.81.
4.6. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-thiabicyclo[2.2.1]
heptane-1-carbonyl chloride (12)
According to GP 1 from oxalyl chloride (8.9 mg, 71
mmol, 6.0 ml)
and 2 (10 mg, 47 mol). The residue was dissolved in anhyd CDCl3
m
(0.7 mL), transferred in a NMR sample tube under inert gas and
employed for NMR-experiments. The carboxylic acid chloride was
obtained in quantitative yield.
1H NMR (500 MHz, CDCl3):
d
¼1.00 (s, 3H, CH3), 1.16 (s, 3H, CH3),
Yield 4.30 g (31%), colourless crystals, mp 249e253 ꢁC. TLC
1.23 (s, 3H, CH3), 1.65 (ddd, J¼13.2/9.4/4.1 Hz, 1H, CH2), 2.01 (ddd,
J¼13.2/10.8/4.7 Hz, 1H, CH2), 2.22 (ddd, J¼13.7/9.4/4.7 Hz, 1H, CH2),
2.66 (ddd, J¼13.7/10.8/4.1 Hz, 1H, CH2).
20
Rf¼0.42 (PE/EtOAc¼8:2). [
a]
ꢀ2.0 (c 1.01, CH2Cl2). 1H NMR
D
(500 MHz, CDCl3)
d
¼1.16 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.37 (s, 3H,
CH3), 2.11 (ddd, J¼14.8/11.8/5.0 Hz, 1H, CH2), 2.25 (ddd, J¼14.8/9.6/
5.7 Hz, 1H, CH2), 2.66 (ddd, J¼15.1./9.6/5.0 Hz, 1H, CH2), 2.74 (ddd,
4.7. Dimethyl (1S,3R)-1-mercapto-2,2,3-
trimethylcyclopentane-1,3-dicarboxylate (7)
J¼15.1/11.8/5.7 Hz, 1H, CH2). 13C NMR (125 MHz, CDCl3)
d
¼17.4 (q,
CH3), 17.5 (q, CH3), 25.0 (q, CH3), 33.8 (t, CH2), 37.5 (t, CH2), 51.8 (s),
61.8 (s), 83.7 (s), 192.2 (s, CO), 199.6 (s, CO). MS (CI, CHþ5 ): m/z (%)¼
279 (98) [Mþ1]þ, 277 (100) [Mþ1]þ, 199 (10), 197 (17). IR:
Compound 6 (4.11 g, 14.8 mmol) in anhyd THF (10 mL) was
cooled to ꢀ50 ꢁC and
a NaOMe solution (5.4 M in MeOH,

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7284
74.0 mmol, 13.7 mL) was added. The reaction mixture was warmed
to room temperature. After16 h, it was acidified with 30 mL 2 M HCl
and the aqueous layer was extracted with CH2Cl2 (5ꢂ100 ml). Rests
of methanol in the aqueous layer were removed in vacuo and the
resulting aqueous layer was saturated with NaCl. After extracting
with CH2Cl2 (2ꢂ) the combined organic layers were dried over
MgSO4 and the solvent was removed in vacuo. The raw product was
purified by CC (PE/EtOAc¼9:1).
177.4 (s, CONS). MS (CI, CHþ5 ): m/z (%)¼244 (100) [Mþ1]þ, 212 (6).
IR:
n
¼3110 cmꢀ1, 2976, 2810, 1719, 1638. Anal. Calcd for C11H17NO3S
(243.33): C 54.30, H 7.04, N 5.76, S 13.18. Found C 54.22, H 6.87, N
5.62, S 13.30.
4.10. Methyl (1S,5R)-3,5,8,8-tetramethyl-4-oxo-2-thia-3-
azabicyclo[3.2.1]octane-1-carboxylate (10)
Yield 3.29 g (85%), colourless oil. TLC Rf¼0.36 (PE/EtOAc¼8:2).
Procedure A: At ꢀ78 ꢁC a lithium diisopropylamide solution
20
[
a]
þ18.2 (c 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d¼0.97 (s,
(2.0 M THF/n-heptane, 950 mmol, 475 ml) was added to 9 (0.19 g,
D
3H, CH3), 1.06 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.57 (ddd, J¼13.7/10.4/
7.3 Hz, 1H, H3CCCH2), 1.90 (dddd, J¼14.8/9.5/7.3/1.4 Hz, 1H,
HSCCH2), 2.43 (t, J¼1.4 Hz, 1H, SH), 2.65 (ddd, J¼13.7/9.5/4.4 Hz, 1H,
H3CCCH2), 2.89 (dddd, J¼14.8/10.4/4.4/1.4 Hz, 1H, HSCCH2), 3.68 (s,
3H, HSCCO2CH3), 3.74 (s, 3H, CO2CH3). 13C NMR (100 MHz, CDCl3)
0.79 mmol) in anhyd THF (5 mL). The mixture was allowed to warm
to room temperature for some minutes, then again cooled to
ꢀ78 ꢁC, and treated with CH3I (561 mg, 3.95 mmol, 246
mL). After
stirring over night at room temperature, 5 mL of 2 M HCl were
added. The aqueous layer was extracted with CH2Cl2 (5ꢂ20 mL).
The combined organic layers were washed with a Na2SO3 solution,
dried over MgSO4 and the solvent was removed in vacuo. Purifi-
cation was effected by CC (PE/EtOAc¼8:2).
d
¼21.9 (q, CH3), 22.1 (q, CH3), 22.5 (q, CH3), 32.2 (t, CH2), 34.1 (t,
CH2), 50.8 (s), 51.7 (q, OCH3), 52.5 (q, OCH3), 54.9 (s), 62.2 (s), 173.6
(s, COOCH3), 177.0 (s, COOCH3). MS (CI, CHþ5 ): m/z (%)¼261 (8)
[Mþ1]þ, 229 (100), 201 (13), 197 (12). IR:
n
¼3449 cmꢀ1, 2969, 2361,
Yield 142.1 mg (70%), colourless crystals, mp 82e85 ꢁC. TLC
20
2341. Anal. Calcd for C12H20O4S (260.35): C 55.36, H 7.74; S 12.32.
Found. C 55.71, H 7.58, 12.39.
Rf¼0.25 (PE/EtOAc¼8:2). [
a]
ꢀ180.1 (c 0.455, CH2Cl2). 1H NMR
D
(500 MHz, CDCl3)
d
¼1.04 (s, 3H, CH3), 1.22 (s, 3H, NCOCH3), 1.28 (s,
3H, CH3), 1.87 (ddd, J¼14.2/12.3/5.2 Hz, 1H, CH2CH2CCO2CH3), 2.17
(ddd, J¼14.2/9.8/5.0 Hz, 1H, CH2CH2CCO2CH3), 2.58 (ddd, J¼14.8/
9.8/5.2 Hz, 1H, CH2CCO2CH3), 2.90 (s, 3H, NCH3), 3.09 (ddd, J¼14.8/
12.3/5.0 Hz, 1H, CH2CCO2CH3), 3.78 (s, 3H, OCH3). 13C NMR
4.8. Dimethyl (1S,3R)-1-aminosulfanyl-2,2,3-trimethylcy-
clopentane-1,3-dicarboxylate (8)
N-Chlorosuccinimide (3.29 g, 24.6 mmol) in anhyd THF (10 mL)
was filled in a flame-dried two-neck Schlenk flask with dry ice
cooler. Ammonia was condensed at ꢀ78 ꢁC (150 mL). Compound 7
(3.21 g, 12.3 mmol) in anhyd THF (10 mL) was dropped to this
mixture. The mixture was slowly warmed to ꢀ30 ꢁC and stirred
until the ammonia was completely vaporized (e8 h). Phosphate
buffer (c¼1.0 M, pH 7, 30 mL) was added to the residue and the
aqueous phase extracted with CH2Cl2 (5ꢂ). The combined organic
layers were dried over MgSO4 and the solvent was removed in
vacuo. The resulting raw product was purified by CC (PE/
EtOAc¼8:2).
(125 MHz, CDCl3)
d
¼15.6 (q, CH3), 20.2 (q, CH3), 21.7 (q, CH3), 34.9
(q, NCH3), 36.8 (t, CH2), 37.7 (t, CH2), 48.4 (s), 52.9 (q, OCH3), 54.8
(s), 68.2 (s, CS), 169.2 (s, COOCH3), 175.0 (s, CONS). MS (CI, CHþ5 ): m/z
(%)¼258 (100) [Mþ1]þ. IR:
n
¼2980 cmꢀ1, 1709, 1630, 1290. Anal.
Calcd for C12H19NO3S (257.35): C 56.01, H 7.44, N 5.44, S 12.46.
Found C 56.10, H 7.28, N 5.28, S 12.68.
Procedure B: At ꢀ20 ꢁC 11 (20 mg, 0.089 mmol) in anhyd CH2Cl2
(2 mL) was treated with SO2Cl2 (74 mg, 0.44 mmol, 36 mL). The
mixture was warmed to room temperature and the solvent was
removed in high vacuo. The residue was dissolved in anhyd CH2Cl2
(2 mL) and the solution was treated with methylamine (2.0 M in
Yield 3.05 g (90%), pale yellow oil. TLC Rf¼0.15 (PE/EtOAc¼8:2).
THF, 0.444 mmol, 222
m
l) at ꢀ20 ꢁC. The mixture was allowed to
[
a
]
20 þ2.0 (c 1.16, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
d
¼1.02 (s, 3H,
warm to room temperature and the reaction was interrupted after
12 h adding phosphate buffer (c¼1.0, pH 7). CC on silica gel (PE/
EtOAc¼8:2) yielded 11.4 mg (50%) of 10.
D
CH3), 1.13 (s, 3H, CH3O2CCCH3), 1.22 (s, 3H, CH3), 1.54 (ddd, J¼13.8/
10.6/6.1 Hz, 1H, SCCH2CH2), 1.86 (ddd, J¼16.0/9.6/6.1 Hz, 1H,
SCCH2), 2.44e2.56 (m, 2H, CH2), 2.60 (br s, 2H, NH2), 3.62 (s, 3H,
H3CCCO2CH3), 3.70 (s, 3H, SCCO2CH3). 13C NMR (100 MHz, CDCl3):
4.11. (1S,5R)-3,5,8,8-Tetramethyl-2,2,4-trioxo-2
azabicyclo[3.2.1]octane-1-carbonyl chloride (15)
l
6-thia-3-
d
¼20.7 (q, CH3), 21.3 (q, CH3), 22.9 (q, CH3), 27.7 (t, CH2CSNH2), 32.0
(t, CH2), 51.2 (s), 51.5 (q, H3CCCOOCH3), 51.9 (OCH3), 55.6 (s), 69.2 (s,
CSNH2), 172.7 (s, H2NSCCOOCH3), 176.8 (s, H3CCCOOCH3). MS (EI,
70 eV): m/z (%)¼275 (12) [Mþ], 195 (19), 167 (62), 94 (100). IR:
According to GP 1 from 4 (4.0 mg, 15
(22 mg, 0.18 mmol, 15 l). The obtained residue was dissolved in
mmol) and oxalyl chloride
m
n
¼3405 cmꢀ1
,
2950, 1718, 1204. Anal. Calcd for C12H21NO4S
anhyd CDCl3 (0.7 mL), transferred in a NMR sample tube under
inert gas and employed for NMR-experiments. The carboxylic acid
chloride was obtained in quantitative yield.
(275.37): C 52.34, H 7.69, N 5.09, S 11.64. Found C 52.19, H 7.51, N
5.20, S 11.92.
1H NMR (400 MHz, CDCl3)
d¼1.17 (s, 3H, CH3), 1.28 (s, 3H,
4.9. Methyl (1S,5R)-5,8,8-trimethyl-4-oxo-2-thia-3-azabicyclo
[3.2.1]octane-1-carboxylate (9)
NCOCCH3), 1.42 (s, 3H, CH3), 1.91 (ddd, J¼14.8/12.1/4.4 Hz, 1H,
CH2CH2CCOCl), 2.03 (ddd, J¼14.8/9.6/5.6 Hz, 1H, CH2CH2CCOCl),
2.82 (ddd, J¼15.7/12.1/5.6 Hz, 1H, CH2CCOCl), 3.10e3.18 (m, 1H,
A mixture of 8 (3.01 g, 10.9 mmol) in anhyd CH3CN (40 mL) and
TFA (1.37 g, 12.0 mmol, 0.92 mL) was heated under reflux for 12 h.
After removing the solvent, crude 8 was purified by CC on silica gel
(PE/EtOAc/HOAc¼68:30:2).
CH2CCOCl), 3.16 (s, 3H, NCH3). IR:
n
¼2989 cmꢀ1, 1782, 1698.
4.12. (1S,5R)-3,5,8,8-Tetramethyl-2,2,4-trioxo-2l
6-thia-3-
azabicyclo[3.2.1]octane-1-carboxylic acid (4)
Yield 1.02 g (39%), yellow crystal, mp 131e133 ꢁC. TLC Rf¼0.15
20
(PE/EtOAc¼8:2). [
a
]
ꢀ206.6 (c 1.04, CH2Cl2). 1H NMR (500 MHz,
A solution of 14 (215 mg, 0.744 mmol) in THF/H2O 4:1 (10 mL)
was treated with LiOH (156 mg, 3.71 mmol). The mixture was
stirred over night and 5 mL of 2 M HCl were added. The aqueous
layer was extracted with CH2Cl2 (5ꢂ30 mL). The combined organic
layers were dried over MgSO4, and the solvent was removed in
vacuo. CC (PE/EtOAc/HOAc¼67:30:3) yielded 4.
D
CDCl3)
d
¼1.05 (s, 3H, CH3), 1.20 (s, 3H, NOCCH3), 1.38 (s, 3H, CH3),
1.92 (ddd, J¼13.8/12.4/5.8 Hz, 1H, CH2CH2CCO2CH3), 2.26 (ddd,
J¼13.8/10.1/4.4 Hz, 1H, CH2CH2CCO2CH3), 2.64 (ddd, J¼15.1/10.1/
5.8 Hz, 1H, CH2CCO2CH3), 3.15 (ddd, J¼15.1/12.4/4.4 Hz, 1H,
CH2CCO2CH3), 3.78 (s, 3H, OCH3). 13C NMR (125 MHz, CDCl3):
d
¼14.7 (q, CH3), 20.5 (q, CH3), 21.5 (q, CH3), 37.1 (t, CH2), 37.6 (t,
Yield 125.7 mg (61%), colourless crystals, mp 149 ꢁC decomp.
20
CH2), 48.1 (s), 53.0 (q, OCH3), 55.2 (s), 67.1 (s, CS), 169.5 (s, CO2CH3),
TLC Rf¼0.1 (PE/EtOAc/HOAc¼67:30:3). [
a
]
ꢀ6.8 (c 0.65, CH2Cl2).
D

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
7285
1H NMR (500 MHz, CDCl3)
d
¼1.17 (s, 3H, CH3), 1.28 (s, 3H,
HRMS (70 eV): [M]þ calcd for C18H26N2O5S (382.1562), found
382.1553.
NCOCCH3), 1.42 (s, 3H, CH3), 1.91 (ddd, J¼14.6/12.0/5.0 Hz, 1H,
CH2CH2CCO2H), 2.03 (ddd, J¼14.6/9.8/5.4 Hz, 1H, CH2CH2CCO2H),
2.81 (ddd, J¼16.2/12.0/5.4 Hz, 1H, CH2CCO2H), 2.96 (ddd, J¼16.2/
9.8/5.0 Hz, 1H, CH2CCO2H), 3.14 (s, 3H, NCH3). 13C NMR (125 MHz,
4.14. (1S,5R)-3,5,8,8-Tetramethyl-2,2-dioxo-1-[((R)-4-oxo-2-
phenyl-3,4-dihydropyridin-1(2H)-yl)carbonyl]-2l
6-thia-3-
CDCl3):
d
¼15.8 (q, COCCH3), 19.4 (q, CH3), 21.7 (q, CH3), 25.2 (q,
azabicyclo[3.2.1]octane-4-on (24) and (1S,5R)-3,5,8,8-
Tetramethyl-2,2-dioxo-1-[((S)-4-oxo-2-phenyl-3,4-
NCH3), 28.8 (t, CH2), 32.1 (t, CH2), 48.0 (s), 55.1 (s), 80.7 (s, CS), 167.8
(s, COOH), 172.8 (s, CONCH3). MS (ESI): m/z (%)¼276 [Mþ1]þ, 298
dihydropyridin-1(2H)-yl)carbonyl]-2l
6-thia-3-azabicyclo
(MþNaþ). IR:
n
¼3543 cmꢀ1, 3474, 2973, 2783, 2623, 1742, 1683.
[3.2.1]octane-4-on (25)
Anal. Calcd for C11H17NO5S (275.33): C 47.99, H 6.22, N 5.09, S 11.65.
Found C 47.72, H 6.08, N 4.97, S 11.61.
According to GP 1 from 4 (12 mg, 0.043 mmol) and Oxalyl
chloride (30 mg, 0.23 mmol) under DMF-catalysis 15 was prepared.
The residue was dissolved in CH2Cl2 (2 mL) and 4-methoxypyridine
(46 mg, 0.42 mmol) was added. To the resulting mixture PhMgBr
4.13. (1S,5R)-1-[((S)-2-Ethyl-4-oxo-3,4-dihydropyridin- 1(2H)-
yl)carbonyl]-3,5,8,8-tetramethyl-2,2-dioxo-2l
6-thia-3-
azabicyclo[3.2.1]octane-4-on (22) and (1S,5R)-1-[((R)-2-Ethyl-
4-oxo-3,4-dihydropyridin-1(2H)-yl)carbonyl]-3,5,8,8-
tetramethyl-2,2-dioxo-2
on (23)
(3 M in Et2O, 0.051 mmol, 17
m
l,) was added at ꢀ78 ꢁC. After 12 h
the mixture was stirred for further 15 min at room temperature and
quenched with 2 M HCl (2 mL). After extracting with CH2Cl2 the
combined organic layers were dried over MgSO4 and the solvent
was removed in vacuo. The two diastereomers could be separated
by CC (iPr2O/EtOAc¼7:3). The relative stereochemistry of the two
diastereomeres could not be assigned (selectivity according their
order of elution: 39/61; determined from the raw product).
l
6-thia-3-azabicyclo[3.2.1]octane-4-
According to GP 1 from 4 (14 mg, 0.05 mmol) and oxalyl chloride
(22 mg, 0.18 mmol) under DMF-catalysis acid chloride 15 was
prepared. The residue was dissolved in CH2Cl2 (2 mL) and
4-methoxypyridine (55 mg, 0.50 mmol) was added. To the result-
Minor isomer: Yield 4.4 mg (24%), colourless crystals, mp 118 ꢁC
20
ing mixture EtMgI (2.74 M in Et2O, 0.052 mmol, 19
ml,) was added at
(decomp.). TLC Rf¼0.27 (iPr2O/EtOAc¼7:3). [
a]
D
þ65.4 (c 0.15,
ꢀ78 ꢁC. After 12 h the mixture was stirred for further 15 min at
room temperature and quenched with 2 M HCl (2 mL). After
extracting with CH2Cl2 the combined organic layers were dried
over MgSO4 and the solvent was removed in vacuo. CC (iPr2O/
EtOAc¼6:4) yielded 14.2 mg (74%) of a diastereomeric mixture of
22 and 23. The separation of isomers occurred by prep. HPLC (iPr2O/
EtOAc¼70:30): tR¼17.3 min; tR¼24.0 min. HPLC analysis of the raw
CH2Cl2). 1H NMR (500 MHz, CD2Cl2):
d
¼0.85 (s, 3H, CH3), 1.22 (s, 3H,
CH3), 1.45 (s, 3H, CH3), 1.94 (ddd, J¼14.3/11.8/5.0 Hz, 1H, CH2), 2.10
(ddd, J¼14.3/9.9/5.0 Hz, 1H, CH2), 2.58 (ddd, J¼14.8/11.8/4.7 Hz, 1H,
CH2), 2.78 (ddd, J¼16.5/2.8/1.1 Hz, 1H, CH2¼O), 3.08e3.14 (m, 2H,
CH2; CH2CO), 3.12 (s, 3H, NCH3), 5.41 (dd, J¼8.8/1.1 Hz,1H, NCH]CH),
6.08 (dd, J¼7.4/2.5 Hz, 1H, NCHPh), 7.23e7.42 (m, 2H, Har), 7.27e7.34
(m, 3H, Har), 8.15 (d, J¼8.8 Hz, 1H, NCH]CH). 13C NMR (100 MHz,
i
product (Si 60, Pr2O/EtOAc¼6:4, 1 mL/min): 23 tR¼9.6 min, 8.6%;
CD2Cl2):
d
¼15.9 (q, CH3), 20.1 (q, CH3), 21.0 (q, CH3), 25.4 (q, NCH3),
22 tR¼13.3 min, 91.4%. The relative configuration of 22 was de-
30.0 (t, CH2), 32.8 (t, CH2), 42.0 (CH2CO), 52.0 (s), 54.0 (s), 56.6 (d,
NCHPh), 81.0 (s), 108.0 (NCH]CH), 126.1 (d, Car.), 128.2 (d, Car.), 129.0
(d, Car.), 139.3 (d, NCH]CH), 141.5 (s, Car.), 163.0 (s, NCO), 172.2 (s,
CH3NCO), 191.3 (s, CH2CO). MS (CI, CHþ5 ): m/z (%)¼431 (33) [Mþ1]þ,
termined by X-ray structure analysis.
4.13.1. Compound 22. Yield 10.0 mg (52%), colourless crystals, mp
20
218 ꢁC (decomp.). TLC Rf¼0.14 (iPr2O/EtOAc¼6:4). [
a
]
þ352.0 (c
367 (100). IR:
n
¼2950 cmꢀ1, 1672, 1600, 1320, 1294, 1209. HRMS
D
0.29, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
¼0.95 (t, J¼7.5 Hz, 3H,
(70 eV): [M]þ calcd for C22H26N2O5S (430.1562), found 430.1529.
CH2CH3), 1.16 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.59 (s, 3H, CH3),
1.66e1.82 (m, 2H, CH2), 1.94e2.02 (m, 1H, CH2), 2.07e2.14 (m, 1H,
CH2), 2.59e2.64 (m, 2H, CH2, CH2CO), 2.76 (dd, J¼16.9/6.0 Hz, 1H,
CH2C]O), 3.04 (ddd, J¼15.0/9.9/5.0 Hz, 1H, CH2), 3.17 (s, 3H,
NCH3), 4.75e4.82 (m, 1H, NCHEt), 5.45 (dd, J¼8.4/1.3 Hz, 1H,
NCH]CH), 8.10 (dd, J¼8.4/1.5 Hz, 1H, NCH]CH). 13C NMR
Major isomer: Yield 9.0 mg (50%), colourless crystals, mp
20
249e253 ꢁC. TLC Rf¼0.06 (iPr2O/EtOAc¼7:3). [
a]
þ277.3 (c 0.29,
D
CH2Cl2). 1H NMR (500 MHz, C2D2Cl4, 80 ꢁC):
d
¼1.22 (s, 3H, CH3),1.33
(s, 3H, CH3), 1.60 (s, 3H, CH3), 1.95e2.03 (m, 1H, CH2), 2.09e2.16 (m,
1H, CH2), 2.60e2.68 (m, 1H, CH2), 3.01e3.17 (m, 3H, CH2C]O, CH2),
3.21 (s, 3H, NCH3), 5.49 (d, J¼8.4 Hz, 1H, NCH]CH), 6.12 (br s, 1H,
NCHPh), 7.19e7.22 (m, 2H, Har), 7.29e7.40 (m, 3H, Har), 8.31 (d,
(125 MHz, CDCl3):
d
¼10.2 (q, CH2CH3), 16.1 (q, CH3NCOCCH3), 20.5
(q, CH3), 21.4 (q, CH3), 22.9 (t, CH2), 25.4 (q, NCH3), 30.7 (t, CH2),
33.0 (t, CH3NCOCCH2), 40.3 (t, CH2CO), 51.9 (s), 54.0 (s), 56.8 (d,
NCHEt), 80.7 (s), 109.5 (d, NCH]CH), 141.0 (d, NCH]CH), 163.0 (s,
NCO), 172.3 (CH3NCO), 192.7 (CH2CO). MS (CI, CHþ5 ): m/z (%)¼383
J¼8.4 Hz,1H, NCH]CH). 13C NMR (125 MHz, C2D2Cl4, 80 ꢁC):
¼16.1
d
(q, CH3), 20.5 (q, CH3), 21.6 (q, CH3), 25.4 (q, NCH3), 30.6 (t, CH2), 33.2
(t, CH2), 42.9 (CH2CO), 52.0 (s), 54.2 (s), 57.7 (d, NCHPh), 81.3 (s),
111.1 (NCH]CH), 126.1 (d, Car.), 128.0 (d, Car.), 129.0 (d, Car.), 136.5 (d,
NCH]CH), 141.5 (s, Car.), 163.3 (s, NCO), 172.3 (s, CH3NCO), 191.3 (s,
CH2CO). MS (CI, CHþ5 ): m/z (%)¼431 (92) [Mþ1]þ, 367 (100), 327 (53).
(100) [Mþ1]þ, 319 (37). IR:
n
¼2925 cmꢀ1, 1697, 1664, 1598, 1319.
HRMS (70 eV): [M]þ calcd for C18H26N2O5S (382.1562), found
382.1575.
IR:
n
¼2977 cmꢀ1, 1697, 1667, 1602, 1320, 1292, 1207, 1158. HRMS
(70 eV): [M]þ calcd for C22H26N2O5S (430.1562), found 430.1532.
4.13.2. Compound 23. Yield 1.4 mg (7%), colourless crystals. TLC
Rf¼0.12 (iPr2O/EtOAc¼6:4). 1H NMR (500 MHz, CDCl3)
d
¼0.89 (t,
4.15. (1S, 4R)-1-[(R)-2,4-Diphenyl-1,2-
J¼7.4 Hz, 3H), 1.20 (s, 3H), 1.29 (s, 3H), 1.49e1.72 (m, 5H),
1.91e2.02 (m, 1H), 2.11 (ddd, J¼14.3/9.9/4.7 Hz, 1H), 2.48e2.61
(m, 2H), 2.82 (dd, J¼16.6/6.5 Hz, 1H), 3.08 (ddd, J¼14.8/10.0/
4.9 Hz, 1H), 3.14 (s, 3H), 5.03 (q, J¼6.7 Hz, 1H), 5.34 (dd, J¼8.5/
1.4 Hz, 1H), 7.90 (dd, J¼8.5/1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
dihydropyridylcarbonyl]-4,7,7-trimethyl-2-thiabicyclo[2.2.1]
heptane-3-on (18) and (1S,4R)-1-[(S)-2,4-diphenyl-1,2-
dihydropyridylcarbonyl]-4,7,7-trimethyl-2-thiabicyclo[2.2.1]
heptane-3-on (19)
d
¼10.4 (q, CH2CH3), 16.2 (q, CH3NCOCCH3), 20.2 (q, CH3), 21.6
To
a
solution of 12 (70 mg, 0.30 mmol) and 16 (47 mg,
l)
(q, CH3), 24.6 (t, CH2), 25.6 (q, NCH3), 30.1 (t, CH2), 32.9 (t,
CH3NCOCCH2), 39.1 (t, CH2CO), 51.9 (s), 53.8 (s), 54.9 (d, NCHEt),
80.1 (s), 107.8 (d, NCH]CH), 140.3 (d, NCH]CH), 162.1 (s, NCO),
172.2 (s, CH3NCO), 192.9 (s, CH2CO). MS (CI, CHþ5 ): m/z (%)¼383
0.30 mmol) in CH2Cl2 (3 mL) TMS-OTf (67 mg, 0.30 mmol, 54
m
was added. The resulting solution was cooled to ꢀ78 ꢁC and
PhMgBr (3.0 M in Et2O, 0.9 mmol, 0.3 ml) was added. The mixture
was stirred for 12 h and quenched with phosphate buffer (c¼1.0 M,
pH 7, 2 mL). After extracting with CH2Cl2 the combined organic
(100) [Mþ1]þ, 319 (32), 242 (18). IR:
n
¼2928 cmꢀ1, 1669, 1598.

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J. Brackow et al. / Tetrahedron 66 (2010) 7279e7287
7286
layers were dried over MgSO4 and the solvent was removed in
vacuo. CC (PE/EtOAc¼9:1) yielded a diastereomeric mixture of 18
and 19. The separation of isomers occurred by prep. HPLC (n-hep-
tane/EtOAc¼92:8) 18: tR¼17.3 min; 19: tR¼24.0 min. HPLC analysis
of the raw product (Si 60, n-heptane/EtOAc¼95:5): 18 tR¼19.3 min,
50.5%; 19 tR¼23.4 min, 49.5%. The relative configuration of 18 was
determined through X-ray structure analysis.
in high vacuum after 2 h. The residue was dissolved in anhyd CDCl3
(1.0 mL), transferred in a NMR sample tube under inert gas, and
employed for NMR experiments. The carboxylic acid chloride was
obtained in quantitative yield.
1HNMR(400 MHz,CDCl3)
d
¼1.15(s, 3H, CH3),1.23(s, 3H, CH3),1.31
(s, 3H, CH3),1.87 (ddd, J¼14.2/12.0/4.5 Hz,1H, CH2CH2CCO2CH3), 2.25
(ddd, J¼14.2/9.8/5.7 Hz, 1H, CH2CH2CCO2CH3), 2.72 (ddd, J¼14.3/9.8/
4.5 Hz, 1H, CH2CCO2CH3), 2.96 (s, 3H, NCH3), 3.04 (ddd, J¼14.3/12.0/
4.15.1. Compound 18. Yield 19.2 mg (15%), colourless crystals, mp
83 ꢁC (decomp.). TLC Rf¼0.45 (PE/EtOAc¼8:2). 1H NMR (500 MHz,
5.7 Hz, 1H, CH2CCO2CH3). IR:
n
¼2972 cmꢀ1, 1727, 1601.
4.18. Methyl (1S,5R)-3,5,8,8-tetramethyl-2,2,4-trioxo-2l6
-
CD2Cl2)
d
¼1.07 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.87
(br s, 2H, CH2), 2.63 (br s, 2H, CH2), 5.84 (m, 1H, NCH]CH), 6.16 (m,
1H, NCHPhCH), 6.33 (m, 1H, NCHPhCH), 7.22e7.40 (m, 9H, Har,
NCH]CH), 7.44e7.47 (m, 2H, Har). 13C NMR (125 MHz, CDCl3)
thia-3-aza-bicyclo[3.2.1]octane-1-carboxylate (14)
To a solution of 10 (362 mg, 1.40 mmol) in CHCl3 (15 mL)
MCPBA (517.1 mg, 3.0 mmol) was added at 0 ꢁC. The mixture was
slowly warmed to room temperature and stirred for 24 h. The
organic layer was diluted with CH2Cl2 (100 mL) and extracted with
NaHCO3 (2ꢂ). The organic layer was dried over MgSO4 and the
solvent was removed. Purification was effected by CC (PE/
EtOAc¼8:2).
d
¼11.7 (q, CH3), 18.5 (q, CH3), 19.0 (q, CH3), 31.0 (q, CH2), 34.2 (t,
CH2), 54.8 (d, NCHPhCH), 56.8 (s), 61.6 (s), 67.8 (s), 108.5 (d, NCH]
CH), 120.2 (d, NCHPhCH), 125.6 (d, CH), 126.7 (d, CH), 126.8 (d, CH),
127.8 (d, CH), 128.0 (d, CH), 128.6 (d, CH), 128.7 (d, CH), 132.8 (s),
138.0 (s), 140.6 (s), 167.5 (C]O), 206.6 (s, SC]O). MS (CI, CHþ5 ): m/z
(%)¼291 (2) [Mþ1]þ, 197 (100), 169 (29). IR:
n
¼2977 cmꢀ1, 1701,
1654, 1651, 1334. HRMS (70 eV): [M]þ calcd for C27H27NO2S
(429.1762), found 429.1757.
Yield 373.4 mg (92%), colourless crystal, mp 127e128 ꢁC. TLC
20
Rf¼0.18 (PE/EtOAc¼8:2). [
a
]
ꢀ9.6 (c 0.56, CH2Cl2). 1H NMR
D
(500 MHz, CDCl3)
d
¼1.10 (s, 3H, CH3), 1.27 (s, 3H, NCOCCH3), 1.42
4.15.2. Compound 19. Yield 10.2 mg (8%), yellow crystals, mp 83 ꢁC
(decomp.). TLC: Rf¼0.42 (PE/EtOAc¼8:2). 1H NMR (500 MHz, CDCl3)
(s, 3H, CH3), 1.87 (ddd, J¼14.2/12.0/4.8 Hz, 1H, CH2CH2CCO2CH3),
2.02 (ddd, J¼14.2/9.8/5.4 Hz, 1H, CH2CH2CCO2CH3), 2.73 (ddd,
J¼16.0/12.0/5.4 Hz, 1H, CH2CCO2CH3), 2.95 (ddd, J¼16.0/9.8/
d
¼1.08 (s, 3H, CH3), 1.23 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.81e1.93 (m,
4.8 Hz, 1H, CH2CCO2CH3), 3.13 (s, 3H, NCH3), 3.91 (s, 3H, OCH3). 13
C
2H, CH2), 2.44e2.45 (m, 2H, CH2), 5.84 (m, 1H, NCH]CH), 6.06 (m,
1H, NCHPhCH), 6.35 (m, 1H, NCHPhCH), 7.08 (m, 1H, NCH]CH),
7.25e7.45 (m, 8H, Har), 7.58e7.60 (m, 2H, Har). 13C NMR (125 MHz,
NMR (125 MHz, CDCl3)
d
¼15.8 (q, COCCH3), 19.4 (q, CH3), 21.6 (q,
CH3), 25.2 (q, NCH3), 28.9 (t, CH2), 32.1 (t, CH2), 47.8 (s), 53.8 (q,
OCH3), 55.1 (s), 80.8 (s, CS), 164.3 (s, COOCH3), 172.8 (s, CONCH3).
MS (CI, CHþ5 ): m/z (%)¼290 (100) [Mþ1]þ, 232 (63). IR:
CD2Cl2)
d
¼11.1 (q, CH3), 18.1 (q, CH3), 18.8 (q, CH3), 30.9 (q, CH2),
33.4 (t, CH2), 54.7 (d, NCHPhCH), 57.0 (s), 61.2 (s), 67.9 (s), 108.0 (d,
NCH]CH),119.7 (d, NCHPhCH),125.1 (d, CH),125.4 (d, CH),126.3 (d,
CH),127.4 (d, CH),127.5 (d, CH), 128.2 (d, CH),128.4 (d, CH), 132.1 (s),
n
¼2980 cmꢀ1, 2956, 1743, 1696. Anal. Calcd for C12H19NO5S
(289.35): C 49.81, H 6.62, N 4.84, S 11.08. Found C 49.80, H 6.22, N
4.80, S 11.13.
137.6 (s), 140.4 (s), 166.0 (C]O), 206.5 (s, SC]O). IR:
n
¼2959 cmꢀ1
,
1717, 1653, 1329. HRMS (FABþ): [M]þ calcd for C27H28NO3S
(430.1850), found 430.1864.
4.19. X-ray crystallographic data
4.16. (1S,5R)-3,5,8,8-Tetramethyl-4-oxo-2-thia-3-aza-bicyclo
[3.2.1]octane-1-carboxylic acid (3)
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 769427 and nos. CCDC 743814. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44 1223336033 or e-mail: depos-
it@ccdc.cam.ac.uk).
KOH (279 mg, 4.98 mmol) was added to a solution of 10
(428 mg, 1.66 mmol) in MeOH/water (4:1) (10 mL) and the mixture
was stirred for 28 h at room temperature. After removing of MeOH
in vacuo CH2Cl2 (10 mL) was added and the aqueous layer was
acidified with 2 M HCl. The aqueous layer was extracted with
CH2Cl2 (5ꢂ), the combined organic layers were dried over MgSO4
and after removing the solvent the remaining residue was purified
by CC (PE/EtOAc/HOAc¼78:2:2).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.07.009.
Yield 310 mg (77%), colourless crystals, mp 224 ꢁC. TLC Rf¼0.12
20
(PE/EtOAc/HOAc¼78:20:2). [
a
]
ꢀ187.8 (c 1.03, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3)
d
¼1.10 (s, 3H, CH3), 1.22 (s, 3H, NCOCH3), 1.30 (s,
References and notes
3H, CH3), 1.87 (ddd, J¼14.0/12.4/5.2 Hz, 1H, CH2CH2CCO2CH3), 2.19
(ddd, J¼14.0/9.9/5.0 Hz, 1H, CH2CH2CCO2CH3), 2.60 (ddd, J¼14.8/9.9/
5.2 Hz, 1H, CH2CCO2CH3), 2.91 (s, 3H, NCH3), 3.07 (ddd, J¼14.8/12.4/
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rahedron 2001, 57, 109.
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€
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€
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[3.2.1]octane-1-carbonyl chloride (13)
According to GP1 from 3 (4.3 mg, 0.018 mmol, 22
mmol) and
oxalyl chloride (5 mg, 0.06 mmol, 5 L). The solvent was removed
m
12. Ludwig, M.; Polborn, K.; Wanner, K. T. Heterocycles 2003, 61, 299.

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