Asymmetric synthesis of fused bicyclic α-amino acids having a hexahydro-cyclopenta[c]pyridine skeleton via intramolecular Pauson-Khand reaction of 1-sulfonimidoyl-substituted 5-azaoct-1-en-7-ynes

Article abstract of DOI:10.1021/jo030171x

An asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine skeleton and carrying besides an enone structural element a substituent at the β-position is described. The key steps of the synthesis are a highly selective al

Full text of DOI:10.1021/jo030171x

Asym m etr ic Syn th esis of F u sed Bicyclic r-Am in o Acid s Ha vin g a
Hexa h yd r o-cyclop en ta [c]p yr id in e Sk eleton via In tr a m olecu la r
P a u son -Kh a n d Rea ction of 1-Su lfon im id oyl-Su bstitu ted
5-Aza oct-1-en -7-yn es
Markus Gu¨nter and Hans-J oachim Gais*
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule (RWTH) Aachen,
Professor-Pirlet-Strasse 1, D-52056 Aachen, Germany
gais@rwth-aachen.de
Received May 19, 2003
An asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine
skeleton and carrying besides an enone structural element a substituent at the â-position is
described. The key steps of the synthesis are a highly selective allylation of N-tert-butylsulfonyl
imino ester with bis(allylsulfoximine)titanium complexes and a highly diastereoselective Pauson-
Khand cycloaddition of sulfonimidoyl-substituted γ,δ-unsaturated R-amino acid esters carrying a
substituent at the â-position and a propargyl group at the N-atom. The cyclization is accompanied
by a reductive cleavage of the sulfoximine group of the primary cyclization product. Surprisingly,
the removal of the sulfoximine group proceeds with inversion of the configuration at the S-atom
and gives N-methyl-phenylsulfinamide with g98% ee. Deprotection of the bicyclic N-tert-butylsul-
fonyl-protected amino acid ester was accomplished through treatment with CF3SO3H under
anhydrous conditions. The enantio- and diastereomerically pure sulfoximine-substituted γ,δ-
unsaturated R-amino acid esters used as starting material were obtained through a highly regio-
and diastereoselective allylation of N-tert-butylsulfonyl imino ester with acyclic bis(allylsulfoximine)-
titanium complexes, described previously.
In tr od u ction
in the asymmetric synthesis of the bicyclic amino acid
esters 1, which contain a hexahydro-cyclopenta[c]pyridine
skeleton and carry besides an enone structural element
a substituent at the â-position (Scheme 1). Because of
the cyclopentenone ring of 1, synthesis of a large number
of highly substituted analogues can be envisioned. With
the exception of the N-tosyl-substituted parent compound
(R ) H),5 amino acids of type 1 were not known up to
now. The bicyclic amino acid esters 1 and their deriva-
tives should be interesting building blocks for the syn-
The synthesis of conformationally constrained R-amino
acids and their incorporation into peptides are currently
topics of high interest.1,2 The restricted conformational
flexibility of such peptidomimetics can have large effects
on their biological activity and metabolic stability.2 Much
sought after are fused bicyclic R-amino acids having the
N-atom incorporated into a ring system.3 Many of these
amino acids display interesting pharmacological activi-
ties,4 and they have served as building blocks for the
synthesis of peptidomimetics.1 We have been interested
(3) (a) Waid, P. P.; Flynn, G. A.; Huber, E. W.; Sabol, J . S.
Tetrahedron Lett. 1996, 37, 4091. (b) Hamper, B. C.; Dukesherer, D.
R.; South, M. S. Tetrahedron Lett. 1996, 37, 3671. (c) Witulski, B.;
Go¨ssmann, M. Chem. Commun. 1999, 1879. (d) Bergmeier, S. C.;
Fundy, S. L.; Seth, P. P. Tetrahedron 1999, 55, 8025. (e) Conti, P.;
Dallanonce, C.; De Amici, M.; De Micheli, C.; Fruttero, R. Tetrahedron
1999, 55, 5623. (f) Czombos, J .; Aelterman, W.; Tkachev, A.; Martins,
J . C.; Tourwe´, D.; Pe´ter, A.; To´th, G.; Fu¨lo¨p, F.; De Kimpe, N. J . Org.
Chem. 2000, 65, 5469. (g) Chinchilla, R.; Falvello, L. R.; Galindo, N.;
Na´jera, C. J . Org. Chem. 2000, 65, 3034. (h) Valls, N.; Lo´pez-Canet,
M.; Vallribera, M.; Bonjoch, J . Chem. Eur. J . 2001, 7, 3446. (i)
Tanimori, S.; Fukubayashi, K.; Kirihata, M. Tetrahedron Lett. 2001,
42, 4013. (j) Kotha, S.; Sreenivasachary, N. Eur. J . Org. Chem. 2001,
3375. (k) Millet, R.; Domarkas, J .; Rombaux, P.; Rigo, B.; Houssin, R.;
He´nichart, J .-P. Tetrahedron Lett. 2002, 43, 5087. (l) Maison, W.;
Adiwidjaja, G. Tetrahedron Lett. 2002, 43, 5957. (m) Zhang, J .; Xiong,
C.; Wang, W.; Ying, J .; Hruby, V. J . Org. Lett. 2002, 4, 4029. (n) Valls,
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Hattori, K.; Grossman, R. B. J . Org. Chem. 2003, 68, 1409.
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Sundermann, B., Eds.; Wiley-VCH: Weinheim, Germany, 2002.
(5) Bolton, G. L.; Hodges, J . C.; Rubin, J . R. Tetrahedron 1997, 53,
6611.
* To whom correspondence should be addressed.
(1) (a) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon: Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539. (c) Rutjes, F. P. J . T.; Wolf, L. B.; Schoemaker, H. E. J . Chem.
Soc., Perkin Trans. 1 2000, 4197. (d) Barrett, G. C.; Davies, J . S. Amino
Acids, Peptides, and Proteins; The Royal Society of Chemistry: Cam-
bridge, UK, 2002; Vol. 33, p 1.
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Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303; Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244. (c) Adang, A. E. P.; Hermkens, P. H. H.;
Linders, J . T. M.; Ottenheijm, H. C. J .; van Staveren, C. J . Recl. Trav.
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10.1021/jo030171x CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003
J . Org. Chem. 2003, 68, 8037-8041
8037

Gu¨nter and Gais
SCHEME 2. γ-Am in o Alk yla tion of Allylic
Su lfoxim in es 5
F IGURE 1. Tecomanine and potential analogues.
SCHEME 1. Retr osyn th etic An a lysis of Bicyclic
Am in o Acid Der iva tives 1
TABLE 1. Asym m etr ic Syn th esis of th e Am in o Acid
Der iva tives 4a -d
allylic
sulfoximine
amino acid
derivative
chemical
yield (%)
isolated
yield (%)
dr
5a
5b
5c
5d
4a
4b
4c
4d
90
93
92
96
67
85
77
82
g99:1
g99:1
g99:1
g99:1
amendable to a [2+2+1]-cycloaddition. N-Methyl sulfox-
imines are Lewis bases,11 a feature that could perhaps
prevent cobalt complexes of 3 from undergoing such a
cycloaddition. In the final step of the synthesis of 1 it
was planned to remove the sulfonimidoyl group of 2
reductively.12
thesis of peptidomimetics, and they could exhibit inter-
esting biological activities as bicyclic analogues of pipecolic
acid.6 Besides these applications, amino acid esters 1
could perhaps also serve as starting materials for the
synthesis of analogues of the alkaloid tecomanine, which
shows a strong hypoglycemic activity (Figure 1).7 We
envisioned a synthesis of 1 through a Pauson-Khand
cycloaddition8 of the sulfonimidoyl-substituted enynes 3,
derived from the (syn,E)-configured γ,δ-unsaturated R-ami-
no acid esters 4. We have recently described a flexible
asymmetric synthesis of 4 through a highly regio- and
diastereoselective allylation of N-tert-butylsulfonyl imino
ester with acyclic bis(allylsulfoximine)titanium com-
plexes.9 Support for the feasibility of a Pauson-Khand
cycloaddition of enynes 3 came from the work of Bolton
et al., who showed that the cycloaddition of the parent
N-tosyl-substituted enyne (R ) H) being devoid, however,
of a substituent at the δ-position, proceeded with high
diastereoselectivity to give the corresponding bicyclic
N-tosyl amino acid.5 Although intramolecular Pauson-
Khand reactions involving sulfonyl- and sulfinyl-substi-
tuted alkenes have been described,10 it remained to be
seen whether alkenyl sulfoximines of type 3 are also
Resu lts a n d Discu ssion
Syn th esis of th e En yn es. The enantio- and diaste-
reomerically pure R-amino acid derivatives 4a -d were
obtained in good yields (Scheme 2, Table 1) through the
successive treatment of the allylic sulfoximines 5a -d 13
with n-BuLi, 2 equiv of ClTi(Oi-Pr)3, and the N-tert-
butylsulfonyl R-imino ester 6 in THF at -78 °C.9 Because
of the much more facile cleavage of N-tert-butylsulfon-
ylamines as compared to N-tosylamines,14 the amino
alkylation of 5a -d was carried out with 6, whose
synthesis we have reported recently,9 and not with the
corresponding N-tosyl analogue.15 Treatment of sulfona-
mides 4a -d with propargyl bromide in DMF in the
presence of Cs2CO3 afforded the enynes 3a -d , respec-
tively (Scheme 3, Table 2) in high yields.
P a u son -Kh a n d R ea ct ion . Treatment of enynes
3a -d with 1.1 equiv of Co2(CO)8 for 30 min in THF led
to their complete conversion to the cobalt complexes 7a -
d , which were isolated by chromatography but not
further characterized (vide infra). We were pleased to see
that complexes 7a -d gave upon treatment with 6 equiv
of N-morpholine-N-oxide (NMO) in two portions over a
period of 4 h at -78 °C and warming the reaction mixture
to room temperature directly the sulfonimidoyl-free bi-
cyclic amino acid derivatives 9a -d in approximately 95%
purity. The bicyclic amino acid derivatives were generally
obtained as single diastereomers (1H NMR) (Table 3,
entries 1-4), except in the case of the phenyl-substituted
(6) (a) Couty, F. Amino Acids 1999, 16, 297. (b) Tjen, K. C. M. F.;
Kinderman, S. S.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J . T.
Chem. Comunn. 2000, 699. (c) Barluenga, J .; Ferna´ndez, M. A.; Aznar,
F.; Valde´s, C. Tetrahedron Lett. 2002, 43, 8159. (d) Carbonnel, S.; Troin,
Y. Heterocycles 2002, 57, 1807. (e) Huang, H.; Spande, T. F.; Panek, J .
S. J . Am. Chem. Soc. 2003, 125, 626. (f) Partogyan-Halim, K.; Besson,
L.; Aitken, D. J .; Husson, H.-P. Eur. J . Org. Chem. 2003, 268.
(7) (a) Hammouda, Y.; Rashid, A. K.; Amer, M. S. J . Pharm.
Pharmacol. 1964, 16, 833. (b) Lins, A. P.; Felicio, J . D. Phytochemistry
1993, 34, 876. (c) Vidari, G.; Tripolini, M.; Novella, P.; Allegrucci, P.;
Garlaschelli, L. Tetrahedron: Asymmetry 1997, 8, 2893. (d) Kemp, M.
I.; Whitby, R. J .; Coote, S. J . Synthesis 1998, 552.
(8) (a) Pauson, P. L. Organometallics in Organic Synthesis; de
Meijere, A., Tom Dieck, H., Eds.; Springer: Berlin, Germany, 1988; p
233. (b) Schore, N. E. Org. React. 1991, 40, 1. (c) Brummond, K. M.;
Kent, J . L. Tetrahedron 2000, 56, 3263. (d) Geis, O.; Schmalz, H.-G.
Angew. Chem. 1998, 110, 995; Angew. Chem., Int. Ed. 1998, 37, 911.
(9) Schleusner, M.; Gais, H.-J .; Koep, S.; Raabe, G. J . Am. Chem.
Soc. 2002, 124, 7789.
(11) For reviews on sulfoximines, see: (a) Pyne, S. G. Sulfur Rep.
1999, 21, 281. (b) Reggelin, M.; Zur, C. Synthesis 2000, 1, 1.
(12) J ohnson, C. R.; J onsson, E. U.; Wambsgans, A. J . Org. Chem.
1979, 44, 2061.
(13) Gais, H.-J .; Hainz, R.; Mu¨ller, H.; Bruns, P.; Giesen, N.; Raabe,
G.; Runsink, J .; Nienstedt, S.; Decker, J .; Schleusner, M.; Hachtel, J .;
Loo, R.; Woo, C.-W.; Das, P. Eur. J . Org. Chem. 2000, 3973.
(14) Tschaen, D. H.; Turos, E.; Weinreb, S. M. J . Org. Chem. 1984,
49, 5058.
(10) Rivero, M. R.; Adrio, J .; Carretero, J . C. Eur. J . Org. Chem.
2002, 2881.
(15) Sun, P.; Weinreb, S. M.; Shang, M. J . Org. Chem. 1997, 62,
8604.
8038 J . Org. Chem., Vol. 68, No. 21, 2003

Asymmetric Synthesis of Fused Bicyclic R-Amino Acids
SCHEME 3. Syn th esis a n d P a u son -Kh a n d
Cycloa d d ition of En yn es 3
F IGURE 2. Observed NOE’s of amino acid derivative 9b.
F IGURE 3. Transition state model for the Pauson-Khand
cycloaddition of eynes 3.
of their trans relationship. According to the magnitudes
of the vicinal coupling constants J 4-H,4a-H ) 12.4 Hz and
J 3-H,4-H ) 5.2 Hz of 9b in CDCl3, its six-membered ring
adopts in solution preferentially a chairlike conformation
in which the ester group is in a pseudoaxial and the R
substituent in a pseudoequatorial position. This was
supported by the magnitudes of the vicinal coupling
constants of 1d (vide infra). Because of similar chemical
shifts and magnitudes of coupling constants, the same
configuration was assigned to 9a , 9c, and 9d .
The highly diastereoselective formation of 9a -d could
be rationalized by assuming that the intramolecular
addition of the C-Co bond to the double bond occurs via
the transition state TS in which the ester group is placed
in a pseudoaxial position while the substituent at the
â-position, the double bond, and the tert-butylsulfonyl
group are placed in pseudoequatorial positions (Figure
3).
TABLE 2. Syn th esis of En yn es 3a -d
amino acid
derivative
enyne
yield (%)
4a
4b
4c
4d
3a
3b
3c
3d
95
94
91
96
TABLE 3. P a u son -Kh a n d Cycloa d d ition of En yn es
3a -d
sulfinamide 8
condi- amino acid yield
yield
(%)
eec
(%)
entry enyne tionsa derivative (%)
drb
1
2
3
4
5
6
3a
3b
3c
3d
3b
3b
I
I
I
I
II
III
9a
9b
9c
9d
9b
9b
49 g98:2
51 g98:2
55 g98:2
60
35
30
70
68
66
71
d
g98
g98
g98
g98
e
93:7
85:15
66:34
We were surprised to see that the Pauson-Khand
reaction of 3a -d was accompanied by a reductive cleav-
age of the sulfonimidoyl group of 2a -d , which ought to
be the primary cyclization products (cf. Scheme 1). In all
cases the (R)-configured sulfinamide 812,16 with g98% ee
was isolated as a second reaction product in similar yields
as 9a -d . Thus, the reductive cleavage of the sulfonim-
idoyl group of 2a -d had occurred under inversion of
configuration at the S-atom. It is interesting to note in
this context that intramolecular Pauson-Khand reac-
tions involving alkenyl sulfones and alkenyl sulfoxides
are apparently not accompanied by a desulfurization of
the corresponding R-sulfonyl- and R-sulfinyl-substituted
cyclopentenone derivatives.10 To see whether the de-
sulfurization is caused in some way by NMO, the Pau-
son-Khand reaction of 3b was carried out in boiling
MeCN by omitting NMO (Table 3, entry 6). Under these
conditions the sulfonimidoyl free amino acid derivative
9b was also obtained, albeit with a much lower diaste-
reoselectivity and yield. Finally the structure of the cobalt
complexes 7a -d was probed by chemical means to
evaluate whether it is the complex formation that causes
the reductive removal of the sulfonimidoyl group. Treat-
d
e
a
I: THF, -78 °C, 3 equiv of NMO, 1 h, rt, 1 h, -78 °C, 3 equiv
of NMO. II: CH2Cl2, 0 °C, 3 equiv of NMO, 1 h, rt, 1 h, 0 °C, 3
equiv of NMO. III: MeCN, 81 °C, 2 h. Determined by 1H NMR
b
spectroscopy. c Determined by GC on chiral stationary phase. Not
d
isolated. e Not determined.
amino acid 9d , which, under the conditions used, was
contaminated with a small amount of its diastereomer
(entry 4). Preparative HPLC of 9a -c afforded the pure
bicyclic enones in medium to good overall yields, based
on 3a -c. Surprisingly, treatment of 3b with NMO in
CH2Cl2 at 0 °C gave 9b with lower diastereoselectivity
and yield (Table 3, entry 5). The 1H NMR spectra of 9a -d
in [D6]-benzene at room temperature showed an overlap
and a line broadening of the signals of 1-H and 3-H. We
tentatively ascribe the line broadening to a restricted
rotation around the N-S bond. The configuration of 9b
1
was assigned by H NOE experiments in [D6]-benzene
at 50 °C. Recording the spectra at the higher temperature
resulted in a better line separation and a sharpening of
the signals of 1-H and 3-H. The NOE experiment
revealed strong NOE’s between 3-H and 4-H, 4-H and
5-HR, and 4a-H and 5-Hâ, respectively, which proved
their cis relationship (Figure 2). The lack of NOE’s
between 4-H and 4a-H, and 4a-H and 5-HR is indicative
(16) Bund, J .; Gais, H.-J .; Schmitz, E.; Erdelmeier, I.; Raabe, G. Eur.
J . Org. Chem. 1998, 1319.
J . Org. Chem, Vol. 68, No. 21, 2003 8039

Gu¨nter and Gais
SCHEME 4. Dep r otection of th e Am in o Gr ou p
In concluding the asymmetric synthesis of amino acid
esters of type 1, the amino acid derivative 9d was treated
with 3 equiv of CF3SO3H in CH2Cl2 for 30 min, which
afforded the amino acid ester 1d in 85% yield (Scheme
1
4). In contrast to the H NMR spectra of the N-sulfonyl
derivatives 9a -d the 1H NMR spectrum of the amino
acid derivative 1d exhibited sharp signals, which allowed
an analysis. According to the magnitudes of the coupling
constants J 3-H,4-H ) 5.3 Hz and J 4-H,4a-H ) 12.4 of 1d
the amino acid derivative adopts in solution a chairlike
conformation similar to that of 9a -d .
F IGURE 4. Putative substitution of the sulfonimidoyl group
of the keto sulfoximines with inversion at the S-atom and
model experiments.
ment of complex 7a with (NH4)2Ce(NO3)6 in acetone17 led
to a quantitative recovery of sulfoximine 3a (cf. Scheme
3). Therefore we conclude that the desulfurization occurs
after the Pauson-Khand process at the stage of 2a -d .
Reductive defunctionalizations during Pauson-Khand
reactions have been described previously for R-halo
cyclopentenone derivatives.18 It has been suggested that
an allylic hydridocobalt complex,19 derived from the
alkyne cobalt complex, is responsible for the reduction
of the R-halo ketone.18b The formation of sulfinamide 8
with inversion of configuration would lend support to the
notion that the reduction of 2a -d may be caused at least
in part by an allylic hydridocobalt complex derived from
7a -d , since the alternative reduction of 2a -d by a single
electron-transfer mechanism should proceed under reten-
tion of configuration at the S-atom (Figure 4).11,12 Thus,
reaction of 2a -d with such a hydridocobalt species could
give enolates 10a -d and the S-H sulfoximine 11a .
Protonation of the former during workup and isomeriza-
tion of the latter compound would afford 9a -d and 8,
respectively. However, we have not been able to isolate
reaction products, which might have given information
as to the intermediate formation of such hydridocobalt
complexes, nor did we carry out experiments to trap such
putative allylic cobalt complexes derived from 7a -d .
Besides the hydridocobalt mechanism, a substitution of
the sulfonimidoyl group of 2a -d with nucleophilic cobalt
compounds could also be envisioned,20 which might be
present in the reaction mixture, with formation of a
cobalt-sulfinamide complex 11b, which upon workup
could deliver 8. Two simple test reactions were carried
out with the ketosulfoximine 1221 as a model compound
for 2a -d . However, treatment of 12 with either Co2(CO)8
or HCo(CO)4, which was prepared from Co2(CO)8 and
hydrogen as an equilibrium mixture,22 did not lead to
cleavage of the starting material, which was recovered
in almost quantitative yield.
Con clu sion a n d Su m m a r y
We have demonstrated that the Pauson-Khand cy-
cloaddition of 1-sulfonimidoyl-substituted 5-azaoct-1-en-
7-ynes carrying an ester group at C-4 and a substituent
at C-3 provides a highly diastereoselective access to
fused bicyclic amino acids containing the hexahydro-
cyclopenta[c]pyridine skeleton. The starting materials for
the synthesis of the 5-azaoct-1-en-7-ynes were obtained
enantio- and diastereomerically pure through a highly
selective allylation of N-tert-butylsulfonyl imino ester
with enantiomerically pure bis(allylsulfoximine)titanium
complexes. A notable feature of this Pauson-Khand cy-
clization involving alkenyl sulfoximines is the concomi-
tant reductive cleavage of the sulfonimidoyl group of the
cyclization products, which, remarkably, proceeds under
inversion of configuration at the S-atom. The mechanism
of this transformation is not known at present and
further investigations are required for a better under-
standing.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of Su lfon im id -
oyl-Su bstitu ted N-P r op a r gyl Am in o Acid Ester s 3 (GP 1).
To a solution of the amino acid ester 4 (1 mmol) in DMF (5
mL) was added Cs2CO3 (1.2 mmol). After the suspension had
been stirred for 15 min at room temperature, it was cooled in
an ice bath to 0 °C. Propargyl bromide was added (2.0 mmol,
80% in toluene) and the mixture was allowed to warm to room
temperature and stirred overnight. Then DMF was removed
in vacuo and aqueous NH4Cl (10 mL) was added to the residue.
The aqueous layer was extracted with EtOAc (3 × 10 mL).
The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. Flash chromatography (EtOAc) gave 3
as a light yellow oil.
Gen er a l P r oced u r e for th e P a u son -Kh a n d Rea ction
(GP 2). To a solution of ester 3 (1 mmol) in THF (100 mL) was
added Co2(CO)8 (1.1 mmol). The brown solution was stirred
until TLC indicated complete conversion of the starting
material (30 min). The solution was cooled to -78 °C and NMO
was added (3 mmol). After the mixture had been stirred for 1
h at -78 °C, it was warmed to room temperature within 1 h
and then cooled to -78 °C. An additional portion of NMO (3
mmol) was added and the mixture was stirred first for 1 h at
-78 °C and then for 1 h at room temperature. Then the
mixture was filtered through a pad of Celite, which was
subsequently washed with EtOAc. Concentration of the organic
phase in vacuo and flash chromatography (EtOAc) of the
(17) Ganesh, P.; Nicholas, K. M. J . Org. Chem. 1997, 62, 1737.
(18) (a) Ishizaki, M.; Suzuki, D.; Hoshino, O. J . Fluorine Chem. 2001,
111, 81. (b) Arjona, O.; Csa´ky, A. G.; Murcia, M. C.; Plumet, J . J . Org.
Chem. 1999, 64, 7338.
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M.; Moyano, A.; Pericas, M. A.; Serratosa, F. Tetrahedron 1985, 41,
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Ungvary, F. J . Organomet. Chem. 1999, 586, 54.
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(22) Bor, G. Pure Appl. Chem. 1986, 58, 543.
8040 J . Org. Chem., Vol. 68, No. 21, 2003

Asymmetric Synthesis of Fused Bicyclic R-Amino Acids
residue afforded 9 of 95% purity and sulfinamide 8 as a white
solid. The ee value of sulfinamide 8 was determined by GC:
heptakis-(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-â-cyclo-
dextrin (Hydrodex-â-6-TBDM, Macherey & Nagel), 25 m, 0.25
mm, 100 kPa, T ) 120 °C, 2 min; 5 K/min 160 °C, 5 min; 5
K/min 200 °C, 30 min. Rt(S) ) 21.2 min; Rt(R) ) 23.5 min.
(+)-(E,SS,2S,3R)-5-[N-Meth yl-S-p h en ylsu lfon im id oyl]-
3-m eth yl-2-[(2-m eth yl-p r op a n e-2-su lfon yl)-p r op -2-yn yl-
a m in o]-p en t-4-en oic Acid Eth yl Ester (3a ). Following GP1,
reaction of sulfoximine 4a (1.0 g, 2.32 mmol) with Cs2CO3 (983
mg, 2.78 mmol) and propargyl bromide (0.52 mL, 4.64 mmol,
80% in toluene) afforded the N-propargyl amino ester deriva-
tive 3a (1.03 g, 95%) as a light yellow oil. [R]D +46.4 (c 1.33,
mmol) in dry acetone (10 mL) was added Co2(CO)8 (83 mg, 0.24
mmol) and the mixture was stirred at room temperature. After
1 h TLC showed the complete consumption of 3a and the
mixture was cooled to -78 °C. A solution of (NH4)2Ce(NO3)6
(0.84 g, 1.54 mmol) in dry acetone (20 mL) was added. After
the mixture had been stirred for 2 h at -78 °C, it was warmed
to room temperature and stirred for an additional hour. Then
the mixture was poured into brine (20 mL) and extracted with
diethyl ether (5 × 10 mL). The combined organic layers were
washed with brine and dried (MgSO4). Concentration in vacuo
gave 3a (99 mg, 96%) as a light yellow oil.
(-)-(3S,4R,4a R)-2,3,4,4a ,5,6-Hexa h yd r o-6-oxo-4-p h en yl-
1H-cyclop en ta [c]-p yr id in e-3-ca r boxylic Acid Eth yl Ester
(1d ). To a solution of 9d (137 mg, 0.33 mmol) in CH2Cl2 (15
mL) was added a 0.25 M solution of F3CSO3H in CH2Cl2 (4
mL) at room temperature. The mixture was stirred 1 h and 2
M NaOH (1 mL) was added. After 5 min the mixture was
diluted with aqueous NH4Cl (10 mL). Then it was extracted
with CH2Cl2 (3 × 5 mL) and the combined organic phases were
dried (MgSO4). Flash chromatography (EtOH:n-hexane, 2:1)
gave 1d (82 mg, 85%) as a yellow liquid that turned brown
upon standing in air. [R]D -2.5 (c 0.61, CH2Cl2). 1H NMR (C6D6,
400 MHz) δ 0.64 (t, J ) 7.1 Hz, 3 H), 1.22 (br s, 1 H), 1.60 (dd,
J ) 18.4, J ) 2.8 Hz, 1 H), 2.23 (dd, J ) 18.4, 6.6 Hz, 1 H),
2.28 (dd, J ) 5.3, 12.4 Hz, 1 H), 3.21 (d, J ) 14.3 Hz, 1 H),
3.53 (d, J ) 5.3 Hz, 1 H), 3.60-3.70 (m, 3 H), 4.00 (d, J ) 14.3
Hz), 5.73 (t, J ) 1.5 Hz), 6.92-6.95 (m, 2 H), 6.99-7.09 (m, 3
H). 13C NMR (C6D6, 100 MHz,) δ 13.8 (d), 39.2 (d), 41.3 (u),
43.4 (u), 53.5 (d), 59.7 (u), 60.9 (d), 126.8 (d), 127.1 (d), 127.4
(d), 128.4 (d), 139.3 (u), 171.2 (u), 176.8 (u), 205.3 (u). IR
(CHCl3) ν˜ 3324 (m), 3062 (m), 2983 (s), 2935 (m), 1725 (s), 1628
(m), 1545 (m), 1497 (w), 1449 (m), 1377 (m), 1190 (s), 1076
(w), 1030 (s), 934 (w), 901 (w), 856 (m) cm-1. MS (EI, 70 eV)
m/z (rel intensity, %) 285 [M+] (2), 212 (100), 184 (15), 167
(8), 155 (7), 141 (11), 128 (11), 118 (12), 117 (20), 115 (32), 103
(11), 94 (14), 91 (80), 80 (10), 78 (14), 77 (30). HRMS (EI,
70 eV) calcd for C18H19NO3 285.136493, found 285.136329.
1
CH2Cl2). H NMR (CDCl3, 400 MHz) δ 1.13 (t, J ) 6.9 Hz, 3
H), 1.32 (d, J ) 6.7 Hz, 3 H), 1.41 (s, 9 H), 2.26 (t, J ) 1.7 Hz,
1 H), 2.74 (s, 3 H), 3.18 (m, 1 H), 3.76 (dq, J ) 10.9, 7.2 Hz, 1
H), 3.97 (dq, J ) 10.9, 7.2 Hz, 1 H), 4.08-4.20 (br m, 1 H),
4.25 (d, J ) 9.9 Hz, 1 H), 4.40 (br d, J ) 19.3 Hz, 1 H), 6.48 (d,
J ) 14.8 Hz, 1 H), 6.79 (dd, J ) 14.8, 8.9 Hz, 1 H), 7.50-7.60
(m, 3 H), 7.83-7.89 (m, 2 H). 13C NMR (CDCl3, 75 MHz) δ
13.9 (d), 17.8 (d), 24.6 (d), 29.2 (d), 35.3 (u), 37.1 (d), 61.4 (u),
62.6 (u), 64.2 (d), 72.7 (u), 80.0 (u), 128.7 (d), 129.4 (d), 131.7
(d), 132.8 (d), 138.8 (u), 146.0 (d), 169.8 (u). IR (CHCl3) ν˜ 3302
(w), 3272 (w), 2980 (m), 2938 (m), 2877 (w), 2805 (w), 1737
(s), 1630 (w), 1447 (m), 1383 (w), 1323 (s), 1247 (s), 1132 (s),
1080 (w), 1024 (m), 973 (w), 868 (m), 814 (w) cm-1. MS (EI, 70
eV) m/z (rel intensity, %) 467 [M+ - 1] (3), 347 (21), 271 (14),
223 (30), 209 (17), 194 (16), 182 (12), 163 (12), 149 (17), 140
(40), 131 (20), 125 (54), 120 (19), 107 (16), 82 (16), 77 (13), 57
(100). Anal. Calcd for C22H32N2O5S2 (468.63): C, 56.38; H, 6.88;
N, 5.98. Found: C, 56.73; H, 6.71; N, 5.81.
(-)-(3S,4R,4a R)-2,3,4,4a ,5,6-Hexa h yd r o-4-m eth yl-2-(2-
m eth yl-p r op a n e-2-su lfon yl)-6-oxo-1H-cyclop en ta [c]p yr i-
d in e-3-ca r boxylic Acid Eth yl Ester (9a ). Following GP2,
reaction of 3a (262 mg, 0.56 mmol) with Co2(CO)8 (210 mg,
0.61 mmol) and NMO (392 mg, 3.36 mmol) gave 9a (94 mg,
49%) as a white solid and 8 (61 mg, 70%) of g98% ee as a
white solid.
8: [R]D -168.3 (c 0.91, acetone).
Ack n ow led gm en t. Financial support of this work
by the Deutsche Forschungsgemeinschaft (Collaborative
Research Center “Asymmetric Synthesis with Chemical
and Biological Methods” SFB 380 and Graduate Pro-
gram “Methods in Asymmetric Synthesis” GK 440) and
the Gru¨nenthal GmbH, Aachen, is gratefully acknowl-
edged. We thank Dr. J an Runsink for the NOE mea-
surements and Cornelia Vermeeren for the HPLC
separations.
9a : mp 112 °C; [R]D -44.2 (c 1.82, CH2Cl2). 1H NMR (C6D6,
300 MHz) δ 0.63 (d, J ) 6.9 Hz, 3 H), 0.92 (t, J ) 7.2 Hz, 3 H),
1.12 (s, 9 H), 1.35 (m, 1 H), 1.53 (dd, J ) 18.3, 3.0 Hz, 1 H),
2.11 (dd, J ) 18.3, 6.7 Hz, 1 H), 2.36 (br m, 1 H), 3.91 (q, J )
6.9 Hz, 2 H), 4.35-4.67 (br m, 3 H), 5.65 (s, 1 H). 13C NMR
(C6D6, 75 MHz) δ 14.1 (d), 16.4 (d), 24.1 (d), 39.8 (u), 40.7 (d),
41.7 (d), 45.8 (u), 60.9 (u), 61.0 (d), 61.4 (u), 129.0 (d), 170.6
(u), 171.8 (u), 204.9 (u). IR (KBr) ν˜ 3677 (w), 3443 (m), 2980
(m), 2937 (m), 1732 (s), 1708 (s), 1636 (s), 1479 (m), 1452 (m),
1384 (m), 1320 (s), 1260 (m), 1209 (s), 1175 (s), 1125 (s), 1064
(w), 1024 (m), 1002 (m), 953 (m), 916 (m), 898 (m), 861 (w),
834 (w), 808 (w) cm-1. MS (CI, methane) m/z (rel intensity, %)
344 [M+ + 1] (28), 252 (11), 224 (100). HRMS (EI, 70 eV, M+-
[C4H9SO2]) calcd for C12H16NO3 222.113018, found 222.113145.
P r ep a r a tion of th e Dicoba lt Ca r bon yl Alk yn e Com -
p lex 7a a n d Its Oxid a tive Dem eta la tion w ith Cer ic
Am m on iu m Nitr a te. To a stirred solution of 3a (103 mg, 0.22
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, experimental details and characterization of com-
pounds not described in the experimental part, and 1H and
13C NMR spectra of 1d and of 9a -d . This material is available
free of charge via the Internet at http://pubs.acs.org.
J O030171X
J . Org. Chem, Vol. 68, No. 21, 2003 8041