Asymmetric Pauson-Khand cyclizations of 1-sulfinylenynes

Article abstract of DOI:10.1055/s-2001-17511

The use of sulfoxides as chiral auxiliaries in intramolecular Pauson-Khand (PK) reactions is described. In particular, the tert-butylsulfinyl group acts as a very efficient chiral auxiliary in intramolecular PK reactions of 1-sulfinyl- 1,6-enynes. As the

Full text of DOI:10.1055/s-2001-17511

1888
FEATURE ARTICLE
Asymmetric Pauson–Khand Cyclizations of 1-Sulfinylenynes
A
symmetr
u
ic Pauson–K
a
hand
C
ycli
n
zations of 1-Sulfin
Cylenynes arlos Carretero,* Javier Adrio
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Fax +34(9)13973925; E-mail: juancarlos.carretero@uam.es
Received 21 May 2001
stereomers, and further two-step dehydration by mesyla-
Abstract: The use of sulfoxides as chiral auxiliaries in intramolec-
tion (MsCl, Et3N) and basic elimination (DBU, CH2Cl2).
The a,b-unsaturated sulfoxides 2a and 2b were obtained
in high yields as 3–4:1 mixtures of trans/cis isomers,
ular Pauson–Khand (PK) reactions is described. In particular, the
tert-butylsulfinyl group acts as a very efficient chiral auxiliary in in-
tramolecular PK reactions of 1-sulfinyl-1,6-enynes. As the starting
enynes are readily available in optically pure form and the final des- readily separable by simple flash chromatography. Unex-
ulfinylation step is high yielding, this procedure constitutes an effi-
cient alternative to the synthesis of enantiomerically pure
bicyclo[3.3.0]oct-1-en-3-ones.
pectedly, this method failed in the case of the tert-butyl-
sulfinyl derivative 2c, since the final treatment of the
mesylate derivative of 1c with different bases afforded a
Key words: sulfoxides, Pauson–Khand reaction, asymmetric syn-
mixture of a,b- and b,g-unsaturated sulfoxides among
thesis, enynes, bicyclo[3.3.0]octenones
other products. Alternatively, 2c was efficiently prepared
(81% yield, Scheme 1) by direct Wadsworth–Emmons
olefination of 5-hexynal with diethyl (tert-butylsulfi-
nyl)methylphosphonate (3). This reaction afforded a near-
ly equimolecular mixture of trans+cis isomers 2c, which
were separated by chromatography.
The cobalt-mediated formal cycloaddition of alkynes, alk-
enes and carbon monoxide, a process known as Pauson–
Khand (PK) reaction, is nowadays one of the most conver-
gent and useful methods for cyclopentenone synthesis.1
Parallel to the current interest in the search of highly effi-
cient asymmetric versions of the most important organic
reactions, a great effort has been devoted to the develop-
ment of asymmetric PK reactions. Despite some interest-
ing results recently described using chiral ligands,2 to the
present the use of chiral auxiliaries covalently attached to
either the alkyne or the alkene component has been the
most studied approach, especially in the former case.1d,3
O
O
R
S
R
S
CH2 Li+
-
R
i) MsCl, Et3N
S
H
OH
O
ii) DBU, rt
THF, –78 °C
O
2a, 70%, trans/cis = 80/20
2b, 78%, trans/cis =75/25
R= p-Tol, 1a, 78%
R= o-(Me2N)C6H4, 1b, 74%
R= t-Bu, 1c, 80%
2c,
Sulfoxides have been widely used as stereochemical con-
trollers in important reactions such as Diels–Alder reac-
tions, 1,3-dipolar cycloadditions and nucleophilic
additions.4 However, precedents of the use of a,b-unsatur-
ated sulfoxides in transition metal-catalyzed reactions are
very scarce.5,6 Here, we describe that 1-sulfinyl-1,6-
enynes are not only suitable substrates in intramolecular
PK reactions, but that in the case of 1-tert-butylsulfinyl-
1,6-enynes their cyclizations occur with complete diaste-
reocontrol.7
i) n-BuLi,
THF, –78 °C
O
S
t-Bu
O
P
S
EtO
EtO
O
ii)
O
t-Bu
3
H
2c, 81%, trans/cis = 56/44
Scheme 1
With the 1,6-enynes 2 in hand we explored their reactivity
under typical PK reaction conditions. The alkyne dicobalt
complexes of enynes 2, readily formed by treatment of 2
with Co2(CO)8 (CH2Cl2, r.t.), reacted under both thermal
(CH3CN, 80 ºC; conditions I) and amine N-oxide-promot-
ed conditions [6 equiv of N-methylmorpholine N-oxide
(NMO), CH2Cl2, r.t.; conditions II] to give the PK adducts
4 as the main products. The results are summarized in
Table 1.
First, to explore the reactivity of 1-sulfinyl-1,6-enynes in
PK reactions and the dependence of the stereoselectivity
of the process with the substitution at sulfur, three differ-
ent racemic 1-sulfinylhept-1-en-6-ynes were prepared
from 5-hexynal:8 the p-tolylsulfinyl enyne 2a, the poten-
tially cobalt-chelating o-(N,N-dimethylamino)phenyl-
sulfinyl9 enyne 2b, and the bulky tert-butylsulfinyl enyne
2c (Scheme 1). Both aromatic 1-sulfinylenynes (2a,b)
were obtained by initial condensation of the carbanion of
the corresponding methyl aryl sulfoxide with 5-hexynal,
to give the b-hydroxysulfoxides 1a,b as mixtures of dia-
Regardless of the starting enyne 2 and the experimental
conditions (entries 1–6, yields 46–55%), very similar
yields of products 4 were obtained after chromatographic
purification. However, the most interesting outcome con-
cerns the stereoselectivity of the process: while the cy-
clizations of the aromatic sulfoxides 2a and 2b were
moderately stereoselective, leading to a ª3:1 mixture of A
and B diastereomers (entries 1–4), the PK cyclization of
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
1437-210X,E;2001,0,12,1888,1896,ftx,en;E03701ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

FEATURE ARTICLE
Asymmetric Pauson–Khand Cyclizations of 1-Sulfinylenynes
1889
Table 1 PK Reactions of Enynes ( ) trans-2
nation of NMR (mainly values of J4,5 and d5) and chemical
correlations (MCPBA oxidation of the A+B mixtures to
the same sulfone), and unequivocally confirmed in the
case of 4cA by X-ray diffraction.10
O
H
R
O
H
S
R
S
i. Co2(CO)8,
CH2Cl2, rt
H
R
H
S
4
5
O
+
O
To demonstrate the usefulness of the tert-butylsulfinyl
group as an efficient chiral auxiliary in intramolecular
asymmetric PK reactions, three issues had to be ad-
dressed: the synthesis of enantiopure 1-tert-butylsulfi-
nylenynes, the determination of the structural scope of
this type of PK cyclization, and the final elimination of the
chiral auxiliary.
O
ii. Conditions
I or II
A (4R*, 5S*, SS*)
B (4S*, 5R*, SS*)
Entry R
Enyne Condi- Adduct A:B
Yield
(%)c
tionsa
Ratiob
1
2
3
4
5
6
p-Tol
p-Tol
2a
2a
I
4a
4a
4b
4b
4c
4c
75:25
73:27
71:29
70:30
52
49
55
46
II
I
As starting compounds for the Wadworth–Emmons olefi-
nation a variety of substituted alkynyl aldehydes (com-
pounds 5–8) were readily prepared following reported
procedures11 or straightforward methods (Scheme 2). On
the other hand, the synthesis of both enantiomers of tert-
butylsulfinylmethyl phosphonates 3 was achieved by one-
step sulfinylation of the anion of dialkyl methylphospho-
nates with known enantiomerically pure sulfinates and
thiosulfinates (Scheme 3). Thus, the reaction of the anion
of dimethyl methylphosphonate with (S)-tert-butanesulfi-
nate of diaceton-D-glucose12 afforded (S)-3’ in 37% yield,
whereas the sulfinylation of the anion of diethyl meth-
ylphosphonate with (R)-tert-butyl tert-butanethio-
sulfinate13 gave (R)-3 in good yield (70%) and excellent
optical purity (ee = 98.5%, HPLC, Chiralpak AS). Reac-
tions of ( )-3 or (R)-3 with the corresponding alkynyl al-
dehyde afforded the racemic or enantiomerically pure (S
configuration) enynes 2c and 9–12 in high yields (77–
89%; Table 2), respectively. In all cases the major trans
isomer was readily separated by simple flash chromatog-
raphy. Additionally, the enyne trans-13, bearing a phenyl
o-Me2NC6H4 2b
o-Me2NC6H4 2b
II
I
t-Bu
t-Bu
2c
2c
>98:<2 50
>98:<2 46
II
a Conditions I: CH3CN, 80 °C; Conditions II: NMO◊H2O (6 equiv),
CH2Cl2, r.t.
b Obtained from 1H NMR on the crude mixtures after filtration of the
cobalt byproducts.
c In pure PK products. Isomers A and B were separated by flash
chromatography.
the tert-butylsulfinyl derivative 2c was completely stere-
oselective, affording almost exclusively the A isomer (en-
tries 5 and 6).
The stereochemical assignment of A (4R*,5S*,SS*) and B
(4S*,5R*,3S*) isomers was first established by a combi-
Biographical Sketches
Juan Carlos Carretero postdoctoral fellow with mainly sulfoxides and sul-
was born in Madrid, Spain, Prof. Léon Ghosez. He sub- fones, and their application
in 1960. He studied chemis- sequently joined the Depart- to the synthesis of natural
try at the Universidad Au- ment of Organic Chemistry products and pharmacologi-
tónoma de Madrid (B.S. of the Universidad Autóno- cally active compounds.
degree in 1982) and ob- ma de Madrid, where he be- One of his research interests
tained his PhD in 1985 un- came Associate Professor in deals with the use of enanti-
der the supervision of Prof. 1988 and full Professor in omerically pure sulfur com-
José L. García Ruano. He 2000. He has been involved pounds as stereochemical
spent two and a half years at in the development of high- controllers in transition met-
the Université Catholique ly stereoselective methods al-catalyzed reactions.
de Louvain, Belgium, as a from sulfur compounds,
Javier Adrio was born in carried out his PhD thesis at clizations and Pauson–
Madrid, Spain in 1968. He the same university, under Khand reactions. He is cur-
studied chemistry at the the supervision of Prof. Juan rently working as a synthet-
Universidad Autónoma de C. Carretero working in new ic chemist in the research
Madrid, where he received synthetic applications of laboratory of a pharmaceuti-
his BSc and MSc degrees in functionalized a,b-unsatur- cal company.
1992 and 1994, respective- ated sulfoxides and sulfones
ly. From 1995 to 2000 he in intramolecular radical cy-
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

1890
J. C. Carretero, J. Adrio
FEATURE ARTICLE
figuration 2c and 9–13 under thermal conditions
(conditions I). Remarkably, with all the terminal alkynes
(entries 1–5) the reactions took place with complete stere-
oselectivity in favor of the A adduct (A:B ratio >98:<2),
showing the powerful and general stereochemical control
exerted by the tert-butylsulfinyl group in the PK cycliza-
tions of 1-sulfinylenynes. Regarding the efficiency of the
process, it is to be noted that the yields were somewhat
higher from the 4,4-disubstituted 1,6-enynes 9 and 10
(65% and 60%, entries 2 and 3, respectively) than in the
case of the unsubstituted model substrate 2c (50%, entry
1), likely due to the entropically favorable gem-dialkyl ef-
fect. The procedure can also be applied to the synthesis of
enantiomerically pure azabicyclo[3.3.0]octenones as it is
shown by the reaction of the aza-enyne 12 (60%, entry 5).
O
O
i) Ph3P=CHOMe
ii) HCl, THF
NaOH
n-Bu4N+I-
H
H
H
O
CH2Cl2/H2O
5, 35%*
Br
i) NaH, THF
Br
OR
O
i) NaEtO, EtOH
EtO2C
EtO2C
EtO2C
EtO2C
H
n
EtO2C
EtO2C
n
ii)
OR
OR
ii) pTsOH
OR
Br
acetone/H2O
n = 1, 6, 44%*
n = 2, 7, 54%*
R = Me or Et
n
i)
Br
PCC
O
H2N
OH
BOCN
BOCN
OH
ii) (BOC)2O
CH2Cl2
CH2Cl2
H
8, 39%*
* Overall yield
The cyclization was also completely stereoselective, but
much less efficient, in the case of the homologous 1,7-
enyne 11 (entry 4, 30%). Disappointingly, no reaction at
all was observed from nonterminal alkynes, such as 13
(entry 6). This lack of reactivity could be ascribed to the
great increase in steric hindrance due to the bulky substit-
uents at both ends of the enyne.
Scheme 2
substituent at the alkyne terminus, was prepared by Sono-
gashira reaction of trans-9 with iodobenzene [Pd(OAc)2,
CuI, PPh3, Et3N, C6H6; 73% yield].
O
O
i) n-BuLi, THF, -78 °C
Table 3 Thermal PK Reactions of (S)-trans-Enynes 2c and 9–13
O
(MeO)
2P
S
(MeO)2PCH3
t-Bu
O
O
ii)
O
S
O
S
t-Bu
H
t-Bu
S
t-Bu
S
H
i. Co2(CO)8,
CH2Cl2, rt
H
(S)-3', 37%
t-Bu
ODAG
H
n
n
n
X
X
O
+ X
O
O
(EtO)2P
R
ii. CH3CN, ∆
O
O
i) n-BuLi, THF, -100 °C
S
trans
R
(EtO)2PCH3
R
t-Bu
A (4R, 5S, SS)
O
B (4S, 5R, SS)
ii)
S
t-Bu
t-Bu
(R)-3, 70%
S
Entry Enyne
X
n
R
Product A:B
Ratioa
Yield
(%)b
Scheme 3
1
2
3
4
5
6
(S)-2c CH2
1
1
1
2
1
1
H
H
H
H
H
Ph
4c
14
>98: <2 50
>98: <2 65
>98: <2 60
>98: <2 30
>98: <2 60
Table 3 summarizes the results obtained in the PK reac-
tions of the dicobalt complexes of the enynes of trans con-
(S)-9
CMe2
(S)-10 C(CO2Et)2
(S)-11 C(CO2Et)2
(S)-12 NBOC
(S)-13 CMe2
15
16
17
-
Table 2 Synthesis of Enantiomerically Pure (S)-1-tert-Butylsulfi-
nylenynes
O
O
O
i) n-BuLi, THF, -78 °C
t-Bu
S
S
n
(EtO)2P
-
-
X
O
t-Bu
ii)
X
5-8
(R)-3
H
a Determined by 1H NMR on the crude mixtures.
n
(S)-9-12
b Pure A adduct after flash chromatography.
Aldehyde
X
n
Enyne trans/cisa
Yield (%)b
[trans]c
We also confirmed that the PK cyclizations occurred
without any racemization at the sulfur atom. For instance,
the enantiomeric purity of adducts 4cA and 14A was
proved to be higher than 96% [1H NMR, Eu(hfc)3]. As the
last step of these asymmetric PK cyclizations stereocon-
trolled by sulfoxides, the reductive cleavage of the sulfi-
nyl group was efficiently carried out by simple treatment
with activated zinc14 (sat. NH4Cl, THF, r.t.), not affecting
the enone moiety at all (Table 4). The desulfinylation of
the enantiomerically pure adducts 4cA, 14A and 15A af-
forded the corresponding virtually enantiopure bicyc-
5-hexynal CH2
1
1
1
2
1
2c
9
56/44
>98/<2
75/25
65/35
60/40
81 [45]
89 [89]
85 [64]
84 [55]
77 [46]
5
6
7
8
CMe2
C(CO2Et)2
C(CO2Et)2
NBOC
10
11
12
a Determined by 1H NMR on the crude mixture.
b In pure olefins after flash chromatography.
c Yield of the pure trans isomer.
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Pauson–Khand Cyclizations of 1-Sulfinylenynes
1891
Table 4 Synthesis of (R)-Bicyclo[3.3.0]oct-1-en-3-ones by Des-
ulfinylation of the PK Adducts
O
S
R
t-Bu
R
R = H, trans-2c; 50%
i, ii
R = CO2Et, trans-10; 60%
t-Bu
O
S
O
O
S
H
t-Bu
H
S
R
R
R
t-Bu
i, ii
R
i, ii
O
R
b
R
PK Adduct
4cA
R
Product Yield (%)a [a]D
4cA
15A
R = H, 2c, trans/cis = 55:45; 44%
R = H, cis-2c; 41%
H
18
19
20
92
+41 (c = 0.6)
+139 (c = 0.6)c
+88 (c = 0.4)
R = CO2Et, 10, trans/cis = 75:25; 57%
R = CO2Et, cis-10; 56%
14A
Me
CO2Et
96
i. Co2(CO)8, CH2Cl2, rt; ii. CH3CN, 800 C.
15A
95d
Scheme 4
a Pure isolated enone.
b Values in CHCl3.
urated sulfoxides the s-cis conformation is the most stable
one (conformer C, dihedral angle C=C–S–O of approxi-
mately 0º). Thus, complexation of the dicobalt hexacarbo-
nyl moiety to the least hindered face of the double bond,
opposite to the bulky tert-butyl group (Cb-re face), would
lead to the complex D, which would evolve by a C–Co in-
sertion step to produce the key cobaltacycle E, containing
the final stereogenic carbons at positions C-4 and C-5. Ac-
cording to the assumed mechanism of the PK reaction,1
the evolution of E by CO insertion, reductive elimination
and cobalt decomplexation steps would yield the observed
A adduct.
c [a]D (S)-19 = –141 (c = 0.2, CHCl3) Ref.15.
d ee = 96.5% (HPLC, Chiralpak AS).
lo[3.3.0]oct-1-en-3-ones (R)-18, (R)-19 and (R)-20 in
excellent yields (92–96%) and very high enantiomeric ex-
cesses [ee = 96.5% for (R)-20, HPLC, chiralpack AS]. On
the other hand, since enantiomerically pure enone 19 was
a known compound,15 this desulfinylation reaction al-
lowed us to confirm the configurational assignment of the
A adducts previously established by 1H NMR and X-ray
diffraction.
On the other hand, both computational studies16a and ex-
perimental evidence17 indicate that in cis a,b-unsaturated
sulfoxides the most stable conformer around the C–S
bond is that in which the 1,3-parallel interaction between
the alkyl substitution at b-position and the substituents at
the sulfoxide is minimized (conformation F, C=C–S–O
dihedral angle of approximately 134º). Interestingly, in
such conformation F the least hindered face is again the
Cb-re face (the one opposite to the tert-butyl group) as in
the case of conformer C in trans a,b-unsaturated sulfox-
ides. Thus, alkene complexation would lead to the p-com-
plex G and further C–Co insertion would give the
cobaltacycle H, showing the same relative configuration
at sulfur and C-5 than cobaltacycle E. Further evolution of
H should lead to the bicyclo[3.3.0]octenone I, which
bears the bulky tert-butylsulfinyl group on the hindered
endo face of the bicyclic structure. A presumed final ther-
modynamic epimerization of the activated enolic C-4 po-
sition, under the experimental reaction conditions of the
PK reaction, would convert I into the observed A adduct18
(Scheme 5).
Once it was demonstrated that the PK reactions of trans-
1-tert-butylsufinyl-1,6-enynes occurred in a very highly
stereoselective manner, we explored the behavior of the
tert-butylsulfinylenynes of cis configuration, (isolated in
substantial amounts in the initial Wadsworth–Emmons
olefination step, Table 2).
Gratifyingly, the thermal PK reactions of the dicobalt
complexes of the tert-butylsulfoxides cis-2c and cis-10
were also completely stereoselective affording the same
cyclopentenones 4cA (41% yield) and 15 (56% yield) ob-
tained from the diastereomeric enynes trans-2c and trans-
10. From a practical point of view this unexpected lack of
stereospecificity, but complete stereoselectivity in favor
of the A isomer, is particularly interesting because it
would indicate that the PK cyclizations could be carried
out using the cis+trans mixtures of enynes isolated in the
Wadsworth–Emmons olefination step. Thus, the PK reac-
tions of a 55:45 mixture of trans/cis-2c and a 75:25 mix-
ture of trans/cis-10 afforded the adducts 4cA and 15,
respectively, as the only isolated products in similar yields
to those obtained from the corresponding pure trans
enynes (Scheme 4).
In summary, we have demonstrated that a,b-unsaturated
sulfoxides are suitable substrates in intramolecular asym-
metric PK reactions. Complete diastereoselections were
obtained using the tert-butylsulfinyl group as a chiral aux-
iliary in the PK cyclization of 1-sulfinyl-1,6-enynes. Re-
markably, trans+cis mixtures of 1-sulfinyl-1,6-enynes
can be used directly since both isomers display the same
stereoselectivity in their PK reactions. A final straightfor-
A plausible explanation for the fact that both diastere-
omers, cis and trans enynes, exhibit the same p-facial se-
lectivity in the stereochemically determinant olefin
insertion step could rely on the presumed conformational
preferences around the C–S bond in the starting dicobalt
sulfinylenyne complexes (Scheme 5). It has been well es-
tablished by theoretical calculations16 and experimental
results in other types of reactions17 that in trans a,b-unsat-
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

1892
J. C. Carretero, J. Adrio
FEATURE ARTICLE
matography (hexane–EtOAc, 4:1) to give trans-2a (251 mg, 55%)
and cis-2a (70 mg, 15%).
trans-1,6-enyne
cis-1,6-enyne
tBu
O
O
S
Co2(CO)6
β
S
tBu
β
(OC)6Co2
X
trans-2a
1H NMR: d = 7.51–7.48 (m, 2 H), 7.32–7.28 (m, 2 H), 6.61 (dt,
J = 6.8, 15.2 Hz, 1 H), 6.24 (dt, J = 1.2, 15.1 Hz, 1 H), 2.41 (s, 3 H),
2.38 (m, 2 H), 2.30 (dt, J = 2.2, 6.7 Hz, 2 H), 1.96 (t, J = 2.2 Hz, 1
H), 1.70 (m, 2 H).
C
X
F
coordination Cβ-re
coordination Cβ-re
face
face
O
tBu
S
tBu
H
H
H
X
13C NMR: d = 141.1, 140.6, 138.6, 135.5, 129.7, 124.2, 83.2, 68.9,
30.4, 26.4, 21.1, 17.4.
MS: m/z (%) = 232 (M+, 0.5), 203 (22), 183 (21), 169 (69), 156,
X
O
S
H
Co
Co
Co
Co
D
G
(44), 141 (39), 124 (81), 91 (100), 77 (49).
HRMS (m/z): calcd for M+ 232.0923; found 232.0921.
Insertion
O
Insertion
O
tBu
tBu
H
S
cis-2a
H
S
H
1H NMR: d = 7.49–7.46 (m, 2 H), 7.28–7.24 (m, 2 H), 6.13 (m, 2
H), 2.66 (m, 2 H), 2.34 (s, 3 H), 2.17 (dt, J = 2.1, 6.9 Hz, 2 H), 1.94
(t, J = 2.2 Hz, 1 H), 1.57 (m, 2 H).
X
X
H
Co
Co
E
H
Co
13C NMR: d = 140.7, 140.6, 139.9, 137.3, 129.5, 123.5, 82.7, 69.1,
31.1, 27.6, 27.1, 20.8, 17.3.
MS: m/z (%) = 232 (M+,0.9), 215 (72), 193 (42), 163 (19), 140 (20),
124 (49), 109 (15), 91 (100), 77 (40), 65 (45).
Co
O
tBu
S
O
tBu
O
S
H
H
HRMS (m/z): calcd for M+ 232.0923; found 232.0922.
Epimerization at C-4
4
5
O
X
X
( )-1-[2-(N,N-Dimethylamino)phenylsulfinyl]-1-hepten-6-yne
(2b)
I
A
By a similar procedure to that described for the synthesis of 2a, 2-
(N,N-dimethylamino)phenyl methyl sulfoxide (246 mg, 1.34 mmol)
was converted into trans-2b (150 mg, 43%) and cis-2b (49 mg,
14%)
Scheme 5
ward reductive desulfinylation step affords enantiopure
bicyclo[3.3.0]oct-1-en-3-ones in excellent yields.
trans-2b
NMR spectra were obtained in CDCl3 at room temperature on a
Bruker AC-200 instrument [1H (200 MHz), 13C (50 MHz)]. Mass
spectra (MS) and high-resolution mass spectra (HRMS) were deter-
mined at an ionising voltage of 70 eV (EI) on a Hewlett-Packard
HP-5985 mass spectrometer. All reagents were obtained from com-
mercial suppliers and were used without further purification. THF
was distilled from sodium/benzophenone, CH2Cl2 was distilled
from P2O5. All reactions involving the use of n-BuLi, LDA and
Co2(CO)8 (Strem Company) were carried out in flame- or oven-
dried glassware under inert argon atmosphere, in these cases anhy-
drous solvents were used. Chromatography was carried out using
Merck 60 230–400 mesh silica gel. (R)-tert-Butyl tert-
butanethiosulfinate13 and the starting aldehydes were prepared as
described in the literature.11
1H NMR: d = 7.75 (dd, J = 2.5, 7.9 Hz, 1 H), 7.38 (m, 1 H), 7.24 (m,
1 H), 7.14 (dd, J = 2.3, 8.1 Hz, 1 H), 6.42 (m, 2 H), 2.73 (s, 6 H),
2.28 (m, 2 H), 2.14 (dt, J = 3.1, 7.9 Hz, 2 H), 1.92 (t, J = 3.0 Hz, 1
H), 1.63 (m, 2 H).
13C NMR: d = 152.0, 139.6, 136.2, 134.1, 131.2, 124.8, 124.1,
120.0, 83.0, 68.8, 44.8, 30.5, 26.9, 17.6.
MS: m/z (%) = 261 (M+, 8), 244 (92), 163 (32), 150 (100), 136 (45),
91 (41), 77 (36).
HRMS (m/z): calcd for M+ 261.1184; found 261.1187.
cis-2b
1H NMR: d = 7.86 (m, 1 H), 7.39 (m, 1 H), 7.26 (t, J = 7.49 Hz, 1
H), 7.13 (m, 1 H), 6.05 (m, 2 H), 2.78 (m, 1 H), 2.65 (m, 6 H), 2.56
(m, 1 H), 2.26 (m, 2 H), 1.97 (t, J = 3.4 Hz, 1 H), 1.70 (m, 2 H).
13C NMR: d = 151.2, 139.6, 139.4, 137.3, 131.4, 125.1, 124.7,
120.4, 83.4, 69.0, 44.9, 28.3, 27.7, 18.0.
( )-1-(p-Tolylsulfinyl)-1-hepten-6-yne (2a)
A solution of methyl p-tolyl sulfoxide (2.0 g, 12.9 mmol) in THF
(20 mL), at –78 °C, was treated with LDA (5.8 mL, 8.7 mmol, 1.5
M in THF), stirred for 30 min, and treated dropwise with a solution
of 5-hexynal (1.53 g, 15.9 mmol) in THF (10 mL). After being
stirred for 1 h at –78 °C, a sat. aq solution of NH4Cl (10 mL) was
added. The mixture was extracted with CH2Cl2 (2 ¥ 15 mL) and the
combined organic layers were dried (Na2SO4) and evaporated. The
residue was purified by flash chromatography (hexane–EtOAc, 1:1)
to give 1-(p-tolylsulfinyl)-6-heptyn-2-ol (1a) (2.53 g, 78%). A solu-
tion of this alcohol (0.5 g, 2.0 mmol) in anhyd CH2Cl2 (10 mL), at
0 °C, was treated with Et3N (2.76 mL, 19.9 mmol) and mesyl chlo-
ride (0.17 mL, 2.28 mmol), stirred for 30 min at r.t., and treated
dropwise with DBU (1.7 mL, 11.4 mmol). After being stirred at r.t.
for 4 h, the reaction mixture was quenched with a sat. aq solution of
NH4Cl (10 mL) and extracted with CH2Cl2 (2 ¥ 30 mL). The com-
bined organic layers were dried (Na2SO4) and evaporated, to afford
a 80:20 mixture of trans/cis-2a, which was separated by flash chro-
(R)-Diethyl (tert-Butylsulfinyl)methylphosphonate [(R)-3]
A solution of diethyl methylphosphonate (0.50 g, 3.28 mmol) in
THF (25 mL), at –100 °C [at higher temperatures a little racemiza-
tion was observed (1–3%)], was treated with n-BuLi (2.3 M in hex-
anes, 1.43 mL, 3.28 mmol) stirred for 10 min, and added dropwise
to a solution of (R)-tert-butyl tert-butanethiosulfinate13 (0.31 g, 1.64
mmol; ee = 98.5%) in THF (25 mL). After being stirred for 30 min
at –100 °C, a sat. aq NH4Cl solution (10 mL) was added. The mix-
ture was extracted with CH2Cl2 (2 ¥ 20 mL) and the combined or-
ganic layers were dried (Na2SO4) and evaporated. The residue was
purified by flash chromatography (ethyl acetate) to afford (R)-3
(0.29 g, 70%).
[a]D = –103 (c = 0.2, CHCl3); ee = 98.5% (HPLC, Daicel Chiralpak
AS column).
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Pauson–Khand Cyclizations of 1-Sulfinylenynes
1893
1H NMR: d = 4.61 (m, 4 H), 2.90 (m, 2 H), 1.46 (t, J = 12 Hz, 6 H),
1.23 (s, 9 H).
(S)-trans-10
[a]D = –93 (c = 1, CHCl3).
13C NMR: d = 62.7, 54.6, 54.4, 44.7, 41.9, 22.1, 16.0, 15.9.
1H NMR: d = 6.21 (m, 2 H), 4.25 (q, J = 7.1 Hz, 4 H), 2.96 (d,
J = 6.3 Hz, 2 H), 2.73 (d, J = 2.6 Hz, 2 H), 2.00 (t, J = 2.5 Hz, 1 H),
1.19 (t, J = 7.1 Hz, 6 H), 1.15 (s, 9 H).
13C NMR: d = 168.9, 134.6, 133.0, 71.9, 61.8, 56.1, 54.6, 34.6, 22.8,
22.7, 13.8.
Preparation of (S)-(tert-Butylsulfinyl)enynes; Typical
Procedure
(S)-1-(tert-Butylsulfinyl)-1-hepten-6-yne [(S)-2c]
A solution of (R)-3 (0.20 g, 0.78 mmol) in THF (7 mL), at –78 °C,
was treated with n-BuLi (2.5 M in hexanes, 0.34 mL, 0.85 mmol),
stirred for 10 min, and treated dropwise with 5-hexynal (112 mg,
1.17 mmol). The solution was stirred for 1 h at –78 °C and quenched
with sat. aq NH4Cl (5 mL). The mixture was extracted with CH2Cl2
(2 ¥ 15 mL) and the combined organic layers were dried (Na2SO4)
and evaporated to give a 55:45 crude mixture of trans+cis-2c. Fur-
ther purification by flash chromatography (hexane–EtOAc, 4:1) af-
forded (S)-trans-2c (69 mg, 45%) and (S)-cis-2c (56 mg, 36%).
MS: m/z (%) = 342 (M+, 0.58), 286 (23), 268 (10), 223 (20), 195
(35), 163 (24), 139 (21), 123 (40), 57 (100).
(S)-cis-10
[a]D = +40 (c = 1.8, CHCl3).
1H NMR: d = 6.11 (m, 2 H), 4.16 (q, J = 7.1 Hz, 4 H), 3.24 (m, 1
H), 2.91 (m, 1 H), 2.76 (d, J = 2.4 Hz, 2 H), 2.02 (t, J = 2.5 Hz, 1
H), 1.20 (t, J = 7.1 Hz, 6 H), 1.18 (s, 9 H).
13C NMR: d = 169.1, 136.9, 134.5, 72.1, 61.9, 56.1, 54.8, 31.9, 23.0,
(S)-trans-2c
22.4, 13.8.
1
[a]D = +72.6 (c = 1, CHCl3); ee = 96% by H NMR [Yt(hfc)3, 0.4
equiv].
MS: m/z (%) = 342 (M+, 0.5), 326 (1.5), 286 (23), 223 (23), 195
(39), 170 (24), 123 (39), 57 (100).
1H NMR: d = 6.41 (dt, J = 6.6, 14.9 Hz, 1 H), 6.13 (dt, J = 1.2, 15.1
Hz, 1 H), 2.40 (m, 2 H), 2.30 (dt, J = 2.1, 6.7 Hz, 2 H), 1.96 (t,
J = 2.1 Hz, 1 H), 1.71 (m, 2 H), 1.24 (m, 9 H).
13C NMR: d = 141.1, 128.8, 83.5, 69.0, 54.4, 30.9, 26.9, 22.8, 17.7.
MS: m/z (%) = 142 (M+ – t-Bu), 125 (66), 97 (15), 79 (18), 67 (6),
57 (100).
(S)-Diethyl 2-(2-Propynyl)-2-[4-(tert-butylsulfinyl)-3-
butenyl]malonate [(S)-11]
Following the typical procedure, the olefination of 711a (315 mg,
1.24 mmol) with (R)-3 (213 mg, 0.83 mmol) afforded a 65:35 mix-
ture of (S)-trans+cis-11. Further separation by flash chromatogra-
phy (hexane–EtOAc, 5:1) gave (S)-trans-11 (157 mg, 55%) and (S)-
cis-11 (83 mg, 29%).
HRMS: m/z calcd for M+ – t-Bu 142.0447; found 142.0452.
(S)-cis-2c
[a]D = +181 (c = 1, CHCl3).
1H NMR: d = 6.27 (m, 1 H), 6.05 (m, 1 H), 2.57 (m, 1 H), 2.41 (m,
1 H), 2.23 (m, 2 H), 1.97 (t, J = 2.0 Hz, 1 H), 1.65 (m, 2 H), 1.23 (s,
9 H).
13C NMR: d = 143.1, 131.2, 84.5, 69.1, 55.0, 28.7, 27.6, 22.6, 17.9.
(S)-trans-11
[a]D = –64.6 (c = 1.5, CHCl3).
1H NMR: d = 6.41 (m, 1 H), 6.15 (m, 1 H), 4.21 (q, J = 7.2 Hz, 4
H), 2.83 (d, J = 2.7 Hz, 2 H), 2.20 (m, 4 H), 2.01 (t, J = 1.8 Hz, 1
H), 1.24 (t, J = 7.2 Hz, 6 H), 1.20 (s, 9 H).
13C NMR: d = 169.8, 140.6, 128.7, 78.5, 71.6, 61.7, 58.1, 54.4, 31.0,
30.6, 26.9, 22.8, 21.0, 14.1.
MS: m/z (%) = 198 (M+, 0.07), 142 (7), 125 (38), 97 (12), 79 (16),
57 (100).
MS: m/z (%) = 356 (M+, 0.5), 300 (14), 255 (12), 198 (34), 171 (19),
135 (48), 85 (14).
HRMS: m/z calcd for M+ 198.1072; found 198.1078.
HRMS: m/z calcd for M+ 356.1657; found 356.1660.
(S)-1-(tert-Butylsulfinyl)-4,4-dimethyl-1-hepten-6-yne [(S)-9]
Following the typical procedure the olefination of 511b (236 mg,
1.55 mmol) with (R)-3 (324 mg, 1.26 mmol) afforded after flash
chromatography (hexane–EtOAc, 5:1) (S)-trans-9 (221 mg, 89%).
(S)-cis-11
[a]D = +20.5 (c = 1.5, CHCl3).
1H NMR: d = 6.28 (m, 1 H), 6.04 (m, 1 H), 4.13 (q, J = 7.3 Hz, 4
H), 2.82 (d, J = 2.7 Hz, 2 H), 2.32 (m, 2 H), 2.16 (m, 2 H), 2.01 (t,
J = 2.1 Hz, 1 H), 1.21 (m, 15 H).
13C NMR: d = 169.8, 142.4, 131.6, 78.4, 71.7, 61.8, 56.3, 54.3, 31.0,
29.6, 24.7, 22.8, 22.6, 14.5.
MS: m/z (%) = 356 (M+, 0.6), 300 (12), 255 (6), 199 (33), 198 (23),
135 (54), 91 (46), 77 (22).
1
[a]D = –87 (c = 1, CHCl3). ee = 96% by H NMR [Yt(hfc)3, 0.4
equiv].
1H NMR: d = 6.41 (dt, J = 7.8, 15.2 Hz, 1 H), 6.17 (d, J = 15.1 Hz,
1 H), 2.31 (m, 2 H), 2.07 (d, J = 2.2 Hz, 2 H), 2.01 (t, J = 2.2 Hz, 1
H), 1.21 (s, 9 H), 1.01 (s, 6 H).
13C NMR: d = 138.5, 130.7, 81.7, 70.5, 54.4, 43.5, 34.1, 31.4, 26.7,
24.0, 22.9.
HRMS: m/z calcd for M+ 356.1657; found 356.1645.
MS: m/z (%) = 170 (M+, 5), 153 (44), 131 (7), 107 (11), 97 (15), 89
(17), 81 (20), 57 (100).
HRMS: m/z calcd for M+ 170.0769; found 170.0765.
(S)-N-(tert-Butoxycarbonyl)-N-[(3-tert-butylsulfinyl)-2-
propenyl]-2-propynylamine [(S)-12]
Following the typical procedure, the olefination of 8 (335 mg, 1.71
mmol) with (R)-3 (292 mg, 1.14 mmol) afforded a 60:40 mixture of
(S)-trans+cis-12. Further separation by flash chromatography (hex-
ane–EtOAc, 4:1) gave (S)-trans-12 (157 mg, 46%) and (S)-cis-12
(106 mg, 31%).
(S)-Diethyl 2-(2-Propynyl)-2-[3-(tert-butylsulfinyl)-2-
propenyl]malonate [(S)-10]
Following the typical procedure, the olefination of 611a (670 mg,
2.79 mmol) with (R)-3 (474 g, 1.85 mmol) afforded a 75:25 mixture
of (S)-trans+cis-10. Further separation by flash chromatography
(hexane–EtOAc, 4:1) gave (S)-trans-10 (405 mg, 64%) and (S)-cis-
10 (133 mg, 21%).
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

1894
J. C. Carretero, J. Adrio
FEATURE ARTICLE
(S)-trans-12
[a]D = –147 (c = 1, CHCl3).
( )-4-[2-(N,N-Dimethylamino)phenylsulfinyl]bicyclo[3.3.0]oct-
1-en-3-one (4bA and 4bB); Method A
The reaction of Co2(CO)8 (157 mg, 0.46 mmol) and ( )-trans-2b
(91 mg, 0.35 mmol) afforded after flash chromatography (hexane–
EtOAc, 4:1) 4bA (41 mg, 41%) and 4bB (14 mg, 14%).
1H NMR: d = 6.4 (dt, J = 2.5, 7.1 Hz, 1 H), 6.32 (m, 1 H), 4.18 (d,
J = 2.6 Hz, 2 H), 4.03 (m, 2 H), 2.23 (t, J = 2.5 Hz, 1 H), 1.49 (s, 9
H), 1.24 (s, 9 H).
13C NMR: d = 154.3, 135.9, 132.1, 106.9, 80.7, 78.8, 72.0, 54.8,
4bA
1H NMR: d = 7.90 (dd, J = 1.7, 8.0 Hz, 1 H), 7.43 (m, 1 H), 7.33 (m,
1 H), 7.12 (m, 1 H), 5.84 (m, 1 H), 3.74 (d, J = 5.6, 7.8 Hz, 1 H),
3.05 (m, 1 H), 2.64 (s, 6 H), 2.51 (m, 2 H), 2.16 (m, 2 H), 1.25 (m,
2 H).
53.8, 47.1, 43.8, 36.5, 35.9, 28.1, 22.8.
MS: m/z (%) = 284 (M+ – CH3, 1), 243 (10), 187 (28), 138 (7), 126
(8), 94 (21), 57 (100).
HRMS: m/z calcd for M+ – CH3 284.1318; found 284.1320.
13C NMR: d = 202.1, 188.1, 151.0, 135.7, 131.7, 126.4, 125.0,
124.4, 119.6, 71.0, 48.4, 44.6, 30.0, 26.0, 25.2.
(S)-cis-12
[a]D = +84 (c = 1, CHCl3).
1H NMR: d = 6.25 (m, 2 H), 4.11 (m, 4 H), 2.25 (t, J = 2.7 Hz, 1 H),
1.62 (s, 9 H), 1.23 (s, 9 H).
4bB
1H NMR: d = 7.86 (dd, J = 1.7, 8.6 Hz, 1 H), 7.44 (m, 1 H), 7.34 (m,
1 H), 7.11 (dd, J = 1.3, 7.9 Hz, 1 H), 5.91 (m, 1 H), 4.17 (d, J = 4.0
Hz, 1 H), 3.02 (m, 1 H), 2.74 (s, 6 H), 2.45 (m, 2 H), 1.81 (m, 2 H),
0.75 (m, 2 H).
13C NMR: d = 154.5, 139.6, 132.0, 97.8, 82.1, 81.0, 78.7, 78.1, 71.9,
71.1 55.1, 53.2, 48.2, 28.1, 28.0, 22.9, 22.5.
MS: m/z (%) = 242 (M+ – t-Bu, 10), 226 (28), 187 (11), 143 (7), 126
(11), 94 (15), 57 (100).
13C NMR: d = 203.6, 191.9, 150.3, 136.0, 131.3, 125.4, 124.1,
123.9, 119.0, 71.1, 44.5, 42.5, 28.9, 26.5, 25.3.
HRMS: m/z calcd for M+ – t-Bu 242.0855; found 242.0850.
(4R,5S,SS)-4-(tert-Butylsulfinyl)bicyclo[3.3.0]oct-1-en-3-one
(4cA)
Pauson–Khand Reactions; Typical Procedures
( )-4-(p-Tolylsulfinyl)bicyclo[3.3.0]oct-1-en-3-one (4aA and
4aB)
Method A: The reaction of Co2(CO)8 (194 mg 0.56 mmol) and (S)-
trans-2c (100 mg, 0.50 mmol) afforded the PK product 4cA (57 mg,
50%, eluent: hexane–EtOAc, 4:1). Method B: The reaction of
Co2(CO)8 (100 mg, 0.29 mmol) and (S)-trans-2c (51 mg, 0.26
mmol) afforded 4cA (27 mg, 46%).
Method A: Thermal Reaction
To a stirred solution of Co2(CO)8 (150 mg, 0.44 mmol) in CH2Cl2
(5 mL), at r.t., was added dropwise a solution of enyne ( )-trans-2a
(79 mg, 0.34 mmol) in CH2Cl2 (5 mL). The solution was stirred for
10 min and the solvent was evaporated. The residue was dissolved
in CH3CN (10 mL) and heated at reflux for 15 min. The reaction
mixture was cooled to r.t. and filtered through celite, which was
washed with CH2Cl2 (30 mL). The combined solvents were evapo-
rated and the residue was purified by flash chromatography (hex-
ane–EtOAc, 4:1) to afford 4aA (34 mg, 38%) and 4aB (12 mg,
14%).
Mp 149–150 °C.
1
[a]D = +35.5 (c = 1, CHCl3); ee ≥ 96% by H NMR [Eu(hfc)3, 0.4
equiv].
1H NMR: d = 5.91 (m, 1 H), 3.56 (m, 1 H), 5.25 (d, J = 3.2 Hz, 1 H),
2.68 (m, 1 H), 2.25 (m, 1 H), 2.11 (m, 2 H), 1.35 (m, 2 H), 1.33 (s,
9 H).
13C NMR: d = 205.3, 192.2, 123.3, 65.4, 54.2, 42.1, 30.1, 26.5, 24.9,
23.3.
MS: m/z (%) = 226 (M+, 0.2), 210 (0.5), 170 (34), 152 (6), 1222
(100), 107 (13), 91 (20), 77 (15).
HRMS: m/z calcd for M+ 226.1027; found 226.1022.
Method B: N-Oxide-Promoted Reaction
To a stirred solution of Co2(CO)8 (150 mg, 0.44 mmol) in CH2Cl2
(5 mL), at r.t., was added dropwise a solution of enyne ( )-trans-2a
(80 mg, 0.34 mmol) in CH2Cl2 (5 mL). The solution was stirred for
10 min and N-methylmorpholine N-oxide (309 mg, 2.64 mmol) was
added in one portion. The resulting solution was stirred for 1 h at
r.t., filtered through celite, which was washed with CH2Cl2 (30 mL).
The combined solvents were evaporated and the residue was puri-
fied by flash chromatography (hexane–EtOAc, 4:1) to afford 4aA
(33 mg, 37%) and 4aB (10 mg, 12%).
(4R,5S,SS)-7,7-Dimethyl-4-(tert-butylsulfinyl)bicyclo[3.3.0]oct-
1-en-3-one (14A)
Method A: The reaction of Co2(CO)8 (98 mg, 0.28 mmol) and (S)-
trans-9 (50 mg, 0.22 mmol) afforded the PK product 14A (37 mg,
65%, eluent: hexane–EtOAc, 5:1).
Mp 131–132 °C.
[a]D = +83.9 (c = 0.7, CHCl3); ee ≥ 96% by 1H NMR [Eu(hfc)3, 0.4
equiv].
1H NMR: d = 5.86 (m, 1 H), 3.81 (m, 1 H), 3.20 (d, J = 3.1 Hz, 1
H), 2.47 (m, 2 H), 2.01 (dd, J = 8.3, 11.9 Hz, 2 H), 1.27 (s, 9 H),
1.25 (s, 3 H), 1.12 (s, 3 H).
13C NMR: d = 204.8, 191.3, 123.3, 66.0, 54.2, 45.1, 42.3, 40.7, 40.6,
30.9, 30.6, 23.3.
4aA
Mp 92-93 °C.
1H NMR: d = 7.47–7.44 (m, 2 H), 7.31–7.28 (m, 2 H), 5.89 (m, 1
H), 3.32 (m, 1 H), 3.25 (d, J = 3.6 Hz, 1 H), 2.52 (m, 2 H), 2.36 (s,
3 H), 1.88 (m, 2 H), 1.13 (m, 1 H), 0.89 (m, 1 H).
13C NMR: d = 202.2, 192.5, 141.1, 138.6, 129.8, 123.6, 123.4, 75.8,
42.05, 29.1, 26.4, 25.2, 21.2.
4aB
Anal. Calcd for C14H22O2S: C, 66.10; H, 8.72. Found: C, 65.65; H,
8.94.
Mp 120–121 °C.
1H NMR: d = 7.48–7.44 (m, 2 H), 7.27–7.25 (m, 2 H), 5.64 (m, 1
H), 3.91 (d, J = 3.2 Hz, 1 H), 2.89 (m, 1 H), 2.36 (m, 2 H), 2.34 (s,
3 H), 2.11 (m, 1 H), 1.89 (m, 2 H), 1.12 (m, 1 H).
13C NMR: d = 201.9, 191.1, 141.8, 138.1, 129.6, 125.3, 124.6, 73.8,
45.9, 30.4, 26.2, 25.2, 21.4.
(4R,5S,SS)-7,7-Bis(ethoxycarbonyl)-4-(tert-butylsulfinyl)bi-
cyclo[3.3.0]oct-1-en-3-one (15A)
Method A: The reaction of Co2(CO)8 (110 mg, 0.32 mmol) and (S)-
trans-10 (82 mg, 0.24 mmol) afforded the PK product 15A (55 mg,
60%, eluent: hexane–EtOAc, 4:1).
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Pauson–Khand Cyclizations of 1-Sulfinylenynes
[a]D = +41 (c = 0.6, CHCl3).
1895
Mp 139–140 °C.
[a]D = +76 (c = 1, CHCl3).
The spectral data were identical to those described for ( )-18.19
1H NMR: d = 5.86 (m, 1 H), 2.87 (m, 1 H), 2.60 (m, 3 H), 2.18 (m,
1 H), 2.04 (m, 3 H), 1.17 (m, 1 H).
1H NMR: d = 5.96 (m, 1 H), 4.24 (m, 4 H), 3.74 (m, 1 H), 3.32 (m,
2 H), 2.87 (d, J = 8.0, 12.5 Hz, 1 H), 1.97 (m, 2 H), 1.30 (s, 9 H),
1.25 (m, 6 H).
(R)-7,7-Bis(ethoxycarbonyl)bicyclo[3.3.0]oct-1-en-3-one [(R)-
20]
Following the typical procedure, adduct 15A (30 mg, 0.08 mmol)
afforded after flash chromatography (hexane–EtOAc, 6:1) (R)-20
(20 mg, 95%).
13C NMR: d = 201.1, 186.15, 170.58, 124.15, 65.7, 62.4, 62.2, 60.4,
54.4, 40.6, 37.2, 35.5, 23.4, 13.9.
(4R,5S,SS)-8,8-Bis(ethoxycarbonyl)-4-(tert-butylsulfinyl)bi-
cyclo-[4.3.0]non-1-en-3-one (16A)
Method A: The reaction of Co2(CO)8 (51 mg, 0.15 mmol) and
enyne (S)-trans-11 (39 mg, 0.11 mmol) afforded the PK product
16A (13 mg, 30%, eluent: hexane–EtOAc, 4:1).
[a]D = +88 (c = 0.4, CHCl3); ee = 96.5% (HPLC, Daicel Chiralpak
AS column).
The spectral data were identical to those described for ( )-20.20
Mp 161–163 °C.
1H NMR: d = 5.96 (m, 1 H), 4.21 (m, 4 H), 3.32 (m, 2 H), 3.12 (m,
1 H), 2.85 (dd, J = 4.6, 7.1 Hz, 1 H), 2.66 (dd, J = 4.1, 9.7 Hz, 1 H),
2.12 (dd, J = 2.4, 9.8 Hz, 1 H), 1.75 (m, 1 H), 1.26 (m, 6 H).
[a]D = +55 (c = 0.6, CHCl3).
1H NMR: d = 6.01 (m, 1 H), 4.18 (m, 4 H), 3.56 (m, 1 H), 3.21 (m,
1 H), 2.78 (m, 1 H), 2.51 (m, 1 H), 2.29 (m, 1 H), 2.01 (m, 1 H), 1.69
(m, 1 H), 1.48 (m, 1 H), 1.31 (s, 9 H), 1.29 (m, 6 H).
13C NMR: d = 202.8, 180.2, 169.5, 128.2, 64.6, 62.0, 61.7, 61.3,
56.4, 37.9, 35.6, 30.6, 29.7, 23.1, 22.9, 14.0.
Acknowledgement
Financial support of this work by the Ministerio de Ciencia y Tec-
nología (project BQU2000-0226) is gratefully acknowledged.
MS: m/z (%) = 384 (M+, 0.1), 328 (28), 310 (31), 280 (100), 237
(36), 206 (76), 183 (23), 133 (53), 91 (22).
References
HRMS: m/z calcd for M+ 384.1606; found 384.1604.
(1) Recent reviews: (a) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (b) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297. (c) Jeong, N. In Transition
Metals for Organic Synthesis; Beller, M.; Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998, 560. (d) Marco-Contelles,
J.; Ingate, S. T. Org. Prep. Proc. Int. 1998, 30, 121.
(e) Geis, O.; Schmalz, H.-G.Angew. Chem. Int. Ed. 1998, 37,
911. (f) For a recent theoretical mechanistic study see:
Yamanka, M.; Nakamura, E. J. Am. Chem. Soc. 2001, 123,
1703.
(2) (a) Castro, J.; Moyano, A.; Pericás, M. A.; Riera, A.;
Alvarez-Larena, A.; Piniella, J. F. J. Am. Chem. Soc. 2000,
122, 7944. (b) Hiroi, K.; Watanabe, T.; Kabagishi, R.; Abe,
I. Tetrahedron Lett. 2000, 41, 891. (c) Hicks, F. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 7026.
(3) (a) Fonquerna, S.; Moyano, A.; Pericàs, M. A.; Riera, A. J.
Am. Chem. Soc. 1997, 119, 10225; and references therein.
(b) Castro, J.; Sörensen, H.; Riera, A.; Morin, C.; Moyano,
A.; Pericàs, M. A.; Greene, A. E. J. Am. Chem. Soc. 1990,
112, 9388.
(4) Carreño, C. Chem. Rev. 1995, 95, 1717.
(5) Díaz-Buezo, N.; García-Mancheño, O.; Carretero, J. C. Org.
Lett. 2000, 2, 1451; and references therein.
(6) For the use of alkynyl p-tolyl sulfoxides in intermolecular
PK reactions, see: Montenegro, E.; Moyano, A.; Pericàs, M.
A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F.
Tetrahedron: Asymmetry 1999, 10, 457.
(7) Previous communication: Adrio, J.; Carretero, J. C. J. Am.
Chem. Soc. 1999, 121, 7411.
(4R,5S,SS)-7-(tert-Butoxycarbonyl)-4-(tert-butylsulfinyl)-7-
azabicyclo[3.3.0]oct-1-en-3-one (17A)
Method A: The reaction of Co2(CO)8 (88 mg, 0.26 mmol) and (S)-
trans-12 (60 mg, 0.20 mmol) afforded the PK product 17A (39 mg,
60%, eluent: hexane–EtOAc, 3:1).
Mp 178–179 °C.
[a]D = +41 (c = 1, CHCl3).
1H NMR: d = 6.07 (m, 1 H), 4.30 (m, 2 H), 4.09 (m, 2 H), 3.35 (m,
1 H), 3.06 (m, 1 H), 1.55 (s, 9 H), 1.28 (s, 9 H).
13C NMR: d = 181.6, 180.9, 153.9, 123.6, 80.6, 64.1, 63.7, 54.4,
49.7, 49.1, 46.8, 46.4, 40.2, 38.7, 28.3, 23.2, 23.0.
Anal. Calcd for C16H25NO4S: C, 58.29; H, 7.70; N, 4.28. Found: C,
58.23; H, 7.60, N, 4.28.
Reductive Desulfinylation; Typical Procedure
(R)-7,7-Dimethyl-bicyclo[3.3.0]oct-1-en-3-one [(R)-19]
To a vigorously stirred suspension of powered activated Zn (422
mg, 6.45 mmol) in THF (7 mL) were sequentially added a sat. aq
NH4Cl solution (7 mL) and a solution of 14A (25 mg, 0.1 mmol) in
THF (3 mL). The resulting mixture was stirred at r.t. for 1 h. The
mixture was filtered through celite, which was washed with CH2Cl2.
The combined solvents were evaporated, and the residue was puri-
fied by flash chromatography (hexane–EtOAc, 6:1) to afford (R)-19
(14 mg, 96%).
[a]D = +139 (c = 0.6, CHCl3); {[a]D (S)-1915 = –141 (c = 0.2,
CHCl3)}.
(8) For the synthesis of a,b-unsaturated sulfoxides, see for
instance: Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P.
Chiral Sulfur Reagents. Applications in Asymmetric and
Stereoselective Synthesis; CRC Press: Boca Raton, 1997.
(9) The o-(N,N-dimethylamino)phenylsulfinyl group has been
used as an efficient chiral auxiliary in asymmetric Heck
reactions, see ref.5.
(10) The crystallographic data of compound 4cA have been
deposited at the Cambridge Crystallographic Data Centre
(supplementary publication nº CCDC 133957); see also
ref.7.
The spectroscopic data were identical to those described for (S)-
19.15
1H NMR: d = 5.83 (m, 1 H), 3.18 (m, 1 H), 2.60 (dd, J = 6.4, 17.8
Hz, 2 H), 2.44 (m, 2 H), 2.05 (dd, J = 3.3, 17.8 Hz, 1 H), 1.94 (dd,
J = 8.1, 12.2 Hz, 1 H), 1.20 (s, 3 H), 1.12 (s, 3 H).
(R)-Bicyclo[3.3.0]oct-1-en-3-one [(R)-18]
Following the typical procedure, adduct 4cA (22 mg, 0.1 mmol) af-
forded after flash chromatography (hexane–EtOAc, 6:1) (R)-18 (12
mg, 93%).
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York

1896
J. C. Carretero, J. Adrio
FEATURE ARTICLE
(15) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3836.
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Am. Chem. Soc. 1986, 108, 7399.
(17) Arai, Y.; Takayama, H.; Koizumi, T. Tetrahedron Lett.
1987, 28, 3689.
(18) For a related epimerization at C-4 in PK reactions, see:
Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968.
(19) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46,
5436.
(11) (a) Chantani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J.
Am. Chem. Soc. 1998, 120, 5335. (b) Oppolzer, W.; Xu, J.
Z.; Stone, C. Helv. Chim. Acta 1991, 74, 465.
(12) Khiar, N.; Fernández, I.; Alcudia, F. Tetrahedron Lett. 1994,
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(13) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011.
(14) Unsuccessful results were obtained using other
desulfinylating reagents, such as Al(Hg), Na(Hg)or Raney
Ni. For the use of activated zinc in C–S reductive cleavages,
see: Holton, R. A.; Kennedy, R. M.; Kim, H.-B.; Krafft, M.
E. J. Am. Chem. Soc. 1987, 109, 1597.
(20) Morimoto, T.; Chatani, N.; Ban, H.; Fukumoto, Y.; Murai,
S. J. Org. Chem 1997, 62, 3762.
Synthesis 2001, No. 12, 1888–1896 ISSN 0039-7881 © Thieme Stuttgart · New York