Vinyl sulfoxides as stereochemical controllers in intermolecular Pauson-Khand reactions: Applications to the enantioselective synthesis of natural cyclopentanoids

Article abstract of DOI:10.1002/chem.200400443

The use of sulfoxides as chiral auxiliaries in asymmetric intermolecular Pauson-Khand reactions is described. After screening a wide variety of substituents on the sulfur atom in α,β-unsaturated sulfoxides, the readily available o-(N,N-dimethylamino)phenyl vinyl sulfoxide (1i) has proved to be highly reactive with substituted terminal alkynes under N-oxide-promoted conditions (CH₃CN, 0°C). In addition, these Pauson-Khand reactions occurred with complete regioselectivity and very high diastereoselectivity (de = 86→96%, (S,R_S) diastereomer). Experimental studies suggest that the high reactivity exhibited by the vinyl sulfoxide 1i relies on the ability of the amine group to act as a soft ligand on the alkyne dicobalt complex prior to the generation of the cobaltacycle intermediate. On the other hand, both theoretical and experimental studies show that the high stereoselectivity of the process is due to the easy thermodynamic epimerization at the C₅ center in the resulting 5-sulfinyl-2- cyclopentenone adducts. When it is taken into account that the known asymmetric intermolecular Pauson-Khand reactions are limited to the use of highly reactive bicyclic alkenes, mainly norbornene and norbornadiene, this novel procedure constitutes the first asymmetric version with unstrained acyclic alkenes. As a demonstration of the synthetic interest of this sulfoxide-based methodology in the enantioselective preparation of stereochemically complex cyclopentanoids, we have developed very short and efficient syntheses of the antibiotic (-)-pentenomycin I and the (-)-aminocyclopentitol moiety of a hopane triterpenoid.

Full text of DOI:10.1002/chem.200400443

FULL PAPER
Vinyl Sulfoxides as Stereochemical Controllers in Intermolecular Pauson–
Khand Reactions: Applications to the Enantioselective Synthesis of Natural
Cyclopentanoids
Marta Rodríguez Rivero, InØs Alonso, and Juan C. Carretero*[a]
Abstract: The use of sulfoxides as
chiral auxiliaries in asymmetric inter-
molecular Pauson–Khand reactions is
described. After screening a wide vari-
ety of substituents on the sulfur atom
in a,b-unsaturated sulfoxides, the read-
ily available o-(N,N-dimethylamino)-
phenyl vinyl sulfoxide (1i) has proved
to be highly reactive with substituted
terminal alkynes under N-oxide-pro-
moted conditions (CH3CN, 0 8C). In ad-
dition, these Pauson–Khand reactions
occurred with complete regioselectivity
and very high diastereoselectivity (de=
86–>96%, (S,RS) diastereomer). Ex-
perimental studies suggest that the
high reactivity exhibited by the vinyl
sulfoxide 1i relies on the ability of the
amine group to act as a soft ligand on
the alkyne dicobalt complex prior to
the generation of the cobaltacycle in-
termediate. On the other hand, both
theoretical and experimental studies
show that the high stereoselectivity of
the process is due to the easy thermo-
dynamic epimerization at the C5 center
in the resulting 5-sulfinyl-2-cyclopente-
none adducts. When it is taken into ac-
count that the known asymmetric inter-
molecular Pauson–Khand reactions are
limited to the use of highly reactive bi-
cyclic alkenes, mainly norbornene and
norbornadiene, this novel procedure
constitutes the first asymmetric version
with unstrained acyclic alkenes. As a
demonstration of the synthetic interest
of this sulfoxide-based methodology in
the enantioselective preparation of
stereochemically complex cyclopenta-
noids, we have developed very short
and efficient syntheses of the antibiotic
(À)-pentenomycin I and the (À)-ami-
nocyclopentitol moiety of a hopane tri-
terpenoid.
Keywords: asymmetric synthesis ·
cyclopentenones · natural products ·
Pauson–Khand reactions
sulfoxides
· vinyl
Introduction
were described in the early 1970s as involving heating stoi-
chiometric amounts of dicobaltoctacarbonyl, alkyne, and
alkene,[3] huge progress has been made. Among the key ad-
vances in this reaction, those worthy of notice are the dis-
covery of efficient promoters that allow the process to be
performed under mild conditions (for instance, tertiary
amine N-oxides,[4] secondary amines,[5] thioethers,[6] silica
gel,[7] and molecular sieves[8]), the development of catalytic
cobalt procedures,[9] the extension of the reaction to other
metal mediators, such as rhodium,[10] ruthenium,[11] titani-
um[12] and iridium,[13] the application of the reaction to the
synthesis of complex natural products,[2,14] the deep theoreti-
cal study of the mechanistic aspects of the reaction,[15] and
the development of highly efficient diastereoselective and
asymmetric versions of PK reactions.[16]
Despite this impressive progress, however, some impor-
tant limitations still remain. One is that these improvements
deal mainly with the intramolecular version of the PK reac-
tion, essentially the cyclization of 1,6- and 1,7-enynes to pro-
vide bicyclic [3.3.0]- and [4.3.0]-fused cyclopentenones, while
the thermodynamically less favorable intermolecular process
has been left out of most of these advances. If we focus on
the asymmetric version of the PK reaction,[2,16] as far as we
Over the last two decades, transition-metal-mediated reac-
tions have acquired a prominent and ever-increasing role in
improving organic synthesis efficiency.[1] One such emblem-
atic reaction is the cobalt-mediated formal [2+2+1] cycload-
dition of an alkyne, an alkene, and CO, known as the
Pauson–Khand (PK) reaction, which involves the formation
À
of three C Cbonds in a single step. Due to this inherent
synthetic efficiency, it is hardly surprising that the PK reac-
tion has become one of the most powerful tools in current
cyclopentenone synthesis.[2] Since the first PK reactions
[a] M. Rodríguez Rivero, I. Alonso, Prof. J. C. Carretero
Departamento de Química Orgµnica
Facultad de Ciencias
Universidad Autónoma de Madrid, 28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: juancarlos.carretero@uam.es
Supporting information for this article (containing experimental pro-
cedures and characterization data of all starting vinyl sulfoxides,
NMR spectra (PDF) and Cartesian coordinates of all optimized struc-
tures described in the article) is available on the WWW under http://
www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 5443 – 5459
DOI: 10.1002/chem.200400443
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FULL PAPER
are aware, all the reported studies on intermolecular proc-
esses are limited to the use of a few highly reactive strained
bicyclic alkenes, specifically norbornene, norbornadiene, and
bicyclo[3.2.0]hept-6-ene. This important drawback can be
easily understood by considering the low reactivity and re-
gioselectivity usually displayed by simple unstrained alkenes.
For instance, the reaction of 1-octene with the dicobalthexa-
carbonyl complex of phenylacetylene in refluxing toluene
gives a 1:1 mixture of the 2,4- and 2,5-disubstituted cyclo-
pentenone PK adducts in a poor yield of 18%.[17] Among
the most remarkable results described up to now in asym-
metric intermolecular PK reactions are the studies of Peri-
càs and co-workers with either a chiral auxiliary bonded to
the alkyne[18] (for example, the Oppolzerꢁs sultam[18a] in
Scheme 1) or a chiral ligand on the cobalt,[19] and with nor-
bornadiene or norbornene as the reactive alkene. By also
using norbornene, Shibata et al. have recently reported the
first example of a catalytic asymmetric intermolecular PK
reaction, with an iridium-promoted procedure applied in
this case [13a] (Scheme 2).
Scheme 2. Catalytic iridium-promoted asymmetric intermolecular PK re-
actions reported by Shibata et al.
Therefore, paradoxically, the direct enantioselective syn-
thesis of a simple chiral nonfused cyclopentenone remains a
challenging target in this field. Taking into account our pre-
vious work on the behavior of the tert-butylsulfinyl group as
an efficient chiral auxiliary in intramolecular PK reactions
of 1,6-enynes (Scheme 3),[20] and keeping in mind the results
described first by Krafft et al. (Scheme 4)[21] and more re-
cently by Yoshida and co-workers (Scheme 5)[11c] regarding
Scheme 1. Relevant example of an asymmetric intermolecular PK reac-
tion with a chiral auxiliary bonded to the alkyne, reported by Pericàs
et al.
Scheme 3. The tert-butylsulfinyl group as an efficient chiral auxiliary in
intramolecular PK reactions of 1,6-enynes. BOC=tert-butoxycarbonyl.
Abstract in Spanish: Se ha estudiado la utilización de sulfó-
xidos como auxiliares quirales en reacciones de Pauson–
Khand intermoleculares. Tras considerar una amplia varie-
dad de vinil sulfóxidos diferentemente sustituidos en el µtomo
de azufre, se ha encontrado que el o-(N,N-dimetilamino)fenil
sulfóxido (1i) presenta una elevada reactividad frente a al-
quinos terminales en reacciones de Pauson–Khand. Ademµs,
estas reacciones transcurren con regioselectividades comple-
tas y diastereoselectividades muy elevadas (ed=86–>96%).
Estudios teóricos y experimentales sugieren que la gran reac-
tividad mostrada por el vinil sulfóxido 1i se debe a la capaci-
dad del grupo amino para coordinarse al complejo de dico-
balto del alquino, favoreciendo así la posterior formación del
cobaltaciclo intermedio. Por otro lado, estudios tanto teóricos
como experimentales han demostrado que la elevada diaste-
reoselectividad del proceso es consecuencia de la fµcil epime-
rización termodinµmica en la posición C-5 de las 5-sulfinil-2-
ciclopentenonas finales. Teniendo en cuenta que hasta el mo-
mento la reacción de Pauson–Khand intermolecular estaba li-
mitada al empleo de alquenos bicíclicos muy reactivos, prin-
cipalmente norborneno y norbornadieno, este nuevo procedi-
miento constituye la primera versión asimØtrica con alquenos
acíclicos no tensionados. Como demostración de la utilidad
sintØtica de esta nueva metodología en la preparación enan-
tioselectiva de sistemas ciclopentµnicos complejos, se han de-
sarrollado síntesis muy eficaces del antibiótico (À)-penteno-
micina I y de la unidad de aminociclopentitol de un triperpe-
noide.
Scheme 4. Relevant examples of regioselective intermolecular PK reac-
tions reported by Krafft et al.[21]
Scheme 5. Relevant examples of regioselective intermolecular PK reac-
tions reported by Yoshida et al.[11c]
the use of achiral alkenes with nitrogen- or sulfur-tethered
substituents as controlling metal-chelating groups in regiose-
lective intermolecular PK reactions, we envisaged that a
possible alternative to the asymmetric synthesis of substitut-
ed nonfused cyclopentenones could rely on the use of ap-
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
propriately substituted vinyl sulfoxides as unstrained chiral
alkene partners. Particularly, we thought that by using a suit-
able potentially cobalt-coordinating group tethered to the
sulfoxide, thereby giving a pseudointramolecular character
to the reaction, the sulfinyl chiral auxiliary group could si-
multaneously improve the reactivity and control the regiose-
lectivity and stereoselectivity of the process. In addition, as
illustrated in Scheme 6, the chemical versatility offered by
tronic environments around the sulfur atom were synthe-
sized. The racemic sulfoxides 1a–i were readily prepared by
one of the following straightforward methods (Scheme 8):
Scheme 6. Proposed enantioselective synthesis of substituted cyclopenta-
noids based on the intermolecular asymmetric PK reaction of vinyl sulf-
oxides.
the enone moiety and the sulfinyl group in the expected 5-
sulfinyl-2-cyclopentenone product (I) turns this type of PK
adduct into a very appealing synthetic intermediate for
asymmetric synthesis, especially for the enantioselective syn-
thesis of stereochemically complex cyclopentanoids. Herein,
we describe in detail the scope and limitations of sulfoxides
as stereochemical controllers in intermolecular PK reac-
tions[22] and the application of this new methodology to the
efficient enantioselective synthesis of two natural cyclopen-
tanols: the antibiotic (À)-pentenomycin I and the (À)-ami-
nocyclopentitol moiety of the hopanoid of Zymomonas mo-
bilis (II, Scheme 7).
Scheme 8. Synthesis of compounds of type 1. THF=tetrahydrofuran,
MCPBA=meta-chloroperoxybenzoic acid, Tol=tolyl, Py=pyridyl,
LDA=lithium diisopropylamide, Ms=mesyl=methane sulfonyl, DBU=
1,8-diazabicyclo[5.4.0]undec-7-ene.
a) reaction of vinyl magnesium bromide with the corre-
sponding disulfide and further MCPBA oxidation; b) con-
densation of the starting methyl sulfoxide with formalde-
hyde, followed by mesylation (Et3N/MsCl) and basic elimi-
nation with DBU; or c) direct sulfinylation of vinyl magnesi-
um bromide with tert-butylthiosulfinate (for the synthesis of
the tert-butylsulfoxide 1e).
PK reaction of vinyl sulfoxides 1a–i with the dicobalthexa-
carbonyl complex of 1-hexyne: In the pioneering study of
Khand and Pauson on the thermal reaction of alkyne dico-
balt complexes with electron-deficient alkenes,[23] such as
ethyl acrylate or acrylonitrile, it was reported that this type
of alkenes afforded the 1,3-diene product, instead of the ex-
pected cyclopentenone PK adduct, as a result of a competi-
tive fast b-H elimination step after formation of the key co-
baltacycle intermediate. These early results are most likely
the origin of the extensive belief of the unsuitability of elec-
tron-deficient olefins in PK reactions. In contrast to this gen-
eral assumption, Cazes and co-workers reported in 1999 that
certain sterically uncongested electron-poor alkenes, such as
methyl acrylate and phenyl vinyl sulfone, gave good yields
Scheme 7. Structure of the natural product pentenomycin I and the ami-
nocyclopentitol moiety of the hopanoid of Zymomonas mobilis.
Results and Discussion
Synthesis of the racemic sulfoxides: First, to check the via-
bility of vinyl sulfoxides as alkenes in intermolecular PK re-
actions, a variety of substrates with different steric and elec-
Chem. Eur. J. 2004, 10, 5443 – 5459
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J. C. Carretero et al.
FULL PAPER
Table 1. N-Oxide-promoted intermolecular PK reactions of 1-hexyne dicobalt complex with racemic vinyl sulf-
oxides 1.
of PK adducts when the reac-
tions were carried out in the
presence of NMO as the pro-
moter.[24] Our recent work on 1-
sulfinyl-1,6-enynes[20] and 1-sul-
fonyl-1,6-enynes[25] in intramo-
lecular PK reactions proved
that, under appropriate experi-
mental conditions, both a,b-un-
saturated sulfoxides and a,b-un-
saturated sulfones can be excel-
lent substrates in this kind of
process.[26]
Entry[a]
R
1
t [h]
Conversion
2
A:B ratio[b]
Yield [%][c]
1
p-Tol
o-Tol
o-BrC6H4
2,4,6-(iPr)3C6H2
tBu
o-MeSC6H4
o-Py
o-(H2N)C6H4
o-(Me2N)C6H4
o-(Me2N)C6H4
1a
1b
1c
1d
1e
1 f
1g
1h
1i
2
24
24
24
24
24
1
24
1
4
>99
70
73
60
65
<1
>99
>99
>99
>99
2a
2b
2c
2d
2e
2 f
2g
2h
2i
74:26
90:10
86:14
94:6
68
28
30
24
20
–
19
-
63
74
2[d]
3[d]
4[d]
5[d]
6[d]
7
>98:<2
–
73:27
-
92:8
8[d]
9
Taking into account all these
precedents, we first explored
the thermal reaction of vinyl
10[e]
1i
2i
93:7
sulfoxides
1 with the cobalt
[a] Reaction conditions: cobalt complex (1.5 equiv), alkene 1 (1.0 equiv), NMO·H2O (6.0 equiv), CH3CN, RT.
[b] Determined by 1H NMR spectroscopy on the crude mixtures after filtration of the cobalt byproducts.
[c] Pure adducts after chromatography. [d] 3 equivalents of dicobalt complex were used. [e] Reaction run at
08C.
complex of 1-hexyne. However,
regardless of the substrate (1a
or 1i) and solvent used (toluene
or acetonitrile at 808C), we ob-
tained a complex mixture of
products in which neither the PK cyclopentenone nor the
1,3-diene could be detected. A similar result was also ob-
served when the reaction was carried out in the presence of
cyclohexylamine as the promoter[5] in toluene at 908C . As
these disappointing results could be due, at least partially, to
the low thermal stability of the sulfinyl group, we turned to
PK reactions promoted by amine N-oxides, which usually in-
volve the use of very mild reaction conditions (usually 08C
or room temperature). However, under the conditions re-
ported by Cazes and co-workers (excess of NMO, CH2Cl2/
THF, RT),[24,27] a sluggish reaction was observed, with the
slow metal decomplexation of the alkyne dicobalt complex
and recovery of the starting vinyl sulfoxide being the main
result. To our delight a much faster reaction occurred when
acetonitrile was used as the solvent. The reaction of 1a with
the dicobalt complex of 1-hexyne under these conditions
(6 equivalents of NMO·H2O,[28] acetonitrile, RT) was com-
pleted within 2 h and occurred with complete chemoselectiv-
ity (the possible competitive formation of the 1,3-diene
product was not detected) and regioselectivity (only the 2,5-
disubstituted cyclopentenone was formed). After filtration
of the cobalt byproducts and standard silica gel purification,
the cyclopentenone 2a was isolated in 68% yield as a 74:26
mixture of diastereomers.
The most relevant results obtained by using the set of
vinyl sulfoxides 1 in the PK reactions with 1-hexyne, under
these optimized experimental conditions, are shown in
Table 1.
In contrast to the very high alkyne regioselectivity but
low alkene regioselectivity usually described in the PK reac-
tions of monosubstituted unfunctionalized alkenes with ter-
minal alkynes,[17,29] in the case of vinyl sulfoxides 1 all of the
reactions were completely regioselective with regard to both
alkyne and alkene components, thereby affording exclusive-
ly the 2,5-disubstituted cyclopentenones. The same type of
PK regioisomer has been previously reported from ethyl ac-
rylate, acrylonitrile, and phenyl vinyl sulfone,[24] a fact sug-
gesting that this 2,5-regioselectivity is a general trend for
electron-deficient alkenes.[30]
Interestingly, both the reactivity and the stereoselectivity
proved to be highly dependent on the substitution at the
sulfur center. In the series of noncoordinating sulfoxides
(1a–e) a correlation between the steric bulk of the sulfoxide
and the reactivity was observed. Thus, in contrast to the rel-
atively high reactivity of the p-tolyl sulfoxide 1a (entry 1),
whose PK reaction was completed in less than 2 h, the
ortho-substituted sulfoxides 1b and 1c (entries 2 and 3) and,
particularly, the very bulky triisopropylphenylsulfoxide 1d
(entry 4) and tert-butylsulfoxide 1e (entry 5), gave incom-
plete conversions after 24 h, even in the presence of a large
excess of the cobalt complex (3-fold excess). Consequently,
from these hindered substrates, the corresponding cyclopen-
tenones were isolated in poor yields (20–30%). With regard
to the stereoselectivity of the reaction, a qualitative correla-
tion with the bulkiness of the sulfoxide may also be deduced
from the data of Table 1: the greater the steric bulk of the
sulfoxide, the higher the stereoselectivity, with complete
stereocontrol reached in the case of the tert-butylsulfoxide
1e (A:B ratio: >98:<2, entry 5).
A much more varied outcome was observed in the case of
the potentially cobalt-coordinating sulfoxides 1 f–i. Thus, un-
expectedly, the methyl thioether 1 f did not react at all[31]
(entry 6), whereas the ortho-aminophenyl derivative 1h
(entry 8) evolved completely but with formation of a com-
plex mixture of products.[32] In the case of the pyridinyl sulf-
oxide 1g (entry 7), the PK adduct 2g could be isolated after
purification, albeit in only 19% yield. This poor yield is in
contrast with the good results described by Yoshida and co-
workers in intermolecular ruthenium-catalyzed PK reactions
of a,b-unsaturated pyridinylsilanes.[11c] In our series of vinyl
sulfoxides, the most synthetically interesting result was, by
far, the one obtained from the ortho-dimethylaminophenyl
sulfoxide 1i, which was the most reactive alkene and afford-
ed the PK adduct 2i with high diastereoselectivity (entry 9).
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
This unstrained alkene is reactive enough to perform the re-
action at 08C, thereby giving rise to the cyclopentenone 2i
in 74% yield as a 93:7 mixture of diastereomers (entry 10).
At this point it is important to mention that in our previ-
ously reported studies on asymmetric Heck reactions with
sulfoxides as stereochemical controllers, the o-dimethylami-
nophenylsulfinyl group also provided the best results in
terms of reactivity and stereoselectivity,[33] a result suggest-
ing the broad applicability of this sulfoxide-based chiral aux-
iliary in transition-metal-mediated reactions.
high sensitivity of the process to the steric environment
À
around the C Ctriple bond, no reaction at all occurred in
the case of an internal alkyne such as 2-butyne (entry 9).
This drawback could be partially solved by performing the
reaction at high pressure[34] (10 Kbar) and room temperature
for 48 h. Under these conditions the reaction occurred
cleanly, albeit with incomplete conversion (30% of 1i was
recovered), to afford the adducts 10 with high stereoselec-
tivity (entry 10) and in 33% yield (47% in converted
product).
Scope of the reaction: Having found a highly reactive and
stereoselective vinyl sulfoxide for the model PK reaction,
we next explored the structural scope of this process with
regard to the substitution at the alkyne. The results obtained
in the PK reactions of the optimal vinyl sulfoxide 1i with a
variety of alkyne dicobalt complexes under the optimized
N-oxide-promoted conditions (NMO·H2O, CH3CN, 0 8C) are
summarized in Table 2.
Configurational assignment of the PK adducts and mecha-
nistic considerations: In the case of the p-tolylsulfoxide 2a
*
the (S*,RS ) configuration of the major diastereomer A and,
consequently, the (R*,RS ) configuration of the minor dia-
*
stereomer B were assigned by comparison of the NMR
spectroscopy data with those previously reported for struc-
turally very similar p-tolylsulfinyl cyclopentenones (for ex-
ample, 3-ethoxy-5-(p-tolylsulfinyl)cyclopent-2-en-1-one).[35]
To support this tentative stereochemical assignment, we ob-
tained suitable crystals of the 2-tert-butylcyclopentenone
3A, which was one of the few solid PK adducts among
Table 2. PK reaction of vinyl sulfoxide 1i with substituted alkynes.
those depicted in Tables 1 and 2. The unequivocal (S*,RS )
*
configuration of this compound is shown in Figure 1. With
Entry[a]
R
R’ t [h] Adduct A:B ratio[b] Yield [%][c]
1
nBu
tBu
Bn
p-Tol
TMS
2OTIPS H
2CH2OHTIPS
2CH2CH2Br
Me
H
H
H
H
H
H
H
H
4
26
14
12
16
2
2i
3
4
5
6
7
8
9
10
10
93:7
>98:<2
93:7
93:7
>98:<2
93:7
>98:<2
>98:<2
–
74
55
58
49
59
62
66
68
–
2[d][e]
3[d]
4
5[e]
6
7
C
C
C
7
6
8
9
Me 24
Me 48
10[f]
Me
92:8
33
Figure 1. X-ray crystal structure of 3A.
[a] Reaction conditions: dicobalt complex (1.5 equiv), alkene
1
(1.0 equiv), NMO·H2O (6.0 equiv), CH3CN, 0 8C. [b] Determined by
1H NMR spectroscopy on the crude mixtures after filtration of the cobalt
byproducts. [c] Pure adducts after chromatography. [d] 3 equivalents of
dicobalt complex were used. [e] Reaction run at RT. [f] Reaction run at
10 Kbar.
À
regard to the conformation around the C S bond in the
crystal, it is interesting to note that the sulfinylic oxygen
atom and the aryl group are oriented in such a way as to
minimize the steric and electronic interactions with the cy-
5
1
À À
À
clopentenone ring (dihedral angles: O S C C =74.77(10)8
5
1
À À
À
Interestingly, reasonable yields of isolated pure adducts
(49–74%), complete regioselectivities, and high to complete
diastereoselectivities (de=86–>96%) were obtained from
all terminal alkynes, including primary, benzyl, and tertiary
alkyl substituted ones (entries 1–3), aryl acetylenes
(entry 4), silylated acetylenes (entry 5), and functionalized
alkynes (entries 6–8). Interestingly, the reaction conditions
are so mild that even alkynes with a primary bromoalkyl
chain can be successfully used (entry 8). As expected, the al-
kynes substituted with the bulkiest groups, especially tert-
butyl and TMS (entries 2 and 5), reacted more slowly. In
these cases the temperature of the reaction was raised to
room temperature and an excess of the alkyne dicobalt com-
plex was used (3-fold excess) in order to assure complete
conversion of the starting alkene. In agreement with the
and C(aryl) S C C =À176.44(9)8). Related to this confor-
mational preference, we noticed a general trend in the
chemical shifts of the H5 and Me2N signals in the H NMR
1
spectra of the diastereomers A and B. Thus, both the H5
atom and the Me2N group always appear significantly more
deshielded in the dominant isomer A than in the minor
isomer B (Scheme 9). This very simple spectroscopic criteria
can be used for the stereochemical assignment of all the PK
adducts obtained from the optimal vinyl sulfoxide 1i.
Since the keto–enol tautomerism in the sulfinyl cyclopen-
tenones 2 is expected to be a very favorable process because
of the acidity of the hydrogen atom at the C5 position, we
wondered if the stereoselectivity of the PK reaction would
not simply reflect the thermodynamic equilibria between
the A and B epimers. As described below, both theoretical
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FULL PAPER
1
Scheme 9. Significant H NMR spectroscopy data of diastereomers A and
B (in CDCl3).
Figure 2. B3LYP/6-31G* optimized structures for cyclopentenones 2i’A
and 2i’B.
and experimental studies unequivocally proved that this
thermodynamic factor is indeed the origin of the stereose-
lectivity.
First, we found an excellent agreement between the ob-
served stereoselectivity of the PK reactions and the differ-
ence in energy content of both A and B epimers calculated
by theoretical methods. In the interest of time economy, cal-
culations were made with a methyl group located on the
double bond of the cyclopentenone ring instead of an n-
butyl one. Conformation analyses of these 2,5-disubstituted
cyclopentenones were performed by using the semiempirical
PM3(tm)[36] procedure, as implemented in Hyper-
Chem 6.02.[37] Then, the low-energy structures were reopti-
mized by using hybrid DFT (B3LYP)[38] and the 6-31G*[39]
basis set, as implemented in the Gaussian 03[40] program
package. Frequencies were also computed at the same level
of theory/basis and zero-point energy (ZPE) correction was
included. The results are summarized in Table 3. The final
optimized structures for the modeled A and B cyclopente-
none epimers with the o-(N,N-dimethylamino)phenyl sub-
stituent (2i’) are shown in Figure 2.
spectra for these epimers (Scheme 9) could be associated to
the anisotropic effect exerted by the carbonyl group, which
causes a shielding in that proton in diastereomer B with re-
1
5
5
À
À À
spect to A (dihedral angles: A: O C
C
H =À57.5338; B:
1
5
5
À
À À
O C
C H =39.7658). This effect can be extended to the
Me2N group, which is nearer to the carbonyl group in dia-
stereomer B (distance: CO···H3CN=2.586 ꢂ) than in dia-
stereomer A (distance: CO···H3CN=4.067 ꢂ).
Among the experimental evidence on the easy epimeriza-
tion process at the C5 position, we observed that an NMR
spectroscopy sample of pure 7A (obtained from the initial
93:7 diastereomeric mixture by trituration with cold hexane)
isomerized again to the 93:7 isomeric ratio in 16 h in
[D6]acetone, in 3 h in CD3CN (the solvent of the PK reac-
tion), and instantaneously in [D6]DMSO or CD3OD. This
fast thermodynamic equilibration in polar solvents, even in
the absence of any added base, could explain why we failed
in all our attempts to separate the A/B mixtures by silica gel
chromatography.
Table 3. Theoretical calculations on the relative stability of the A and B
As a third piece of evidence, the behavior of the disubsti-
tuted a,b-unsaturated sulfoxides cis-11 and trans-11 was also
conclusive. These compounds were readily prepared by reac-
tion of a cis/trans mixture of propenyl lithium (generated in
situ by treatment of 1-bromo-1-propene with tBuLi) with o-
dimethylaminophenyl disulfide, sulfide-to-sulfoxide oxida-
tion with MCPBA, and final silica gel separation of both iso-
mers. In this way, trans-11 and cis-11 were isolated in 11%
and 56% overall yields, respectively (Scheme 10). Unlike
epimers.
[a]
R
DEAB
Calculated A/B
ratio[b] (R’=Me)
Experimental A/B
ratio (R’=nBu)
p-Tol
tBu
o-(Me2N)C6H4
0.7
2.5
1.9
77:23
99:1
96:4
74:26
>98:<2
92:8
[a] DE B3LYP/6–31G*+ZPE [kcalmolÀ1]. [b] At 258C.
Structure A in Figure 2 shows a conformation (dihedral
5
1
5
1
À À
À
À À À
angles: O S C C =84.6358 and C(Ar) S C C =
À166.7418) quite similar to the one adopted by 3A in the
solid state (see Figure 1). In the minor diastereomer B the
sulfinylic oxygen atom and the aryl group are again oriented
in a way that minimizes the steric and electronic interactions
with the cyclopentenone ring. The relative orientation be-
tween the H5 atom and the sulfinyl group is almost anti in
Scheme 10. Synthesis of disubstituted a,b-unsaturated sulfoxides trans-11
and cis-11.
the behavior of the parent vinyl sulfoxide 1i, the sterically
more demanding disubstituted alkenes cis-11 and trans-11
failed to react with the dicobalt complex of 1-hexyne under
the standard N-oxide-promoted conditions. Gratifyingly, as
5
5
À À
À
both diastereomers (dihedral angles: A: O S C H =
5
5
À À
À
À158.3848; B: O S C H =166.1148). Thus, the observed
trend in the chemical shifts of the H5 signals in the H NMR
1
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
in the case of the PK reaction of disubstituted alkynes, the
reaction occurred cleanly under high-pressure conditions
(10 Kbar), albeit with incomplete conversions (40–55% of
starting alkene 11 was recovered), to provide the expected
regioisomer 12 in 22–31% yield after chromatography (49–
52% yield in converted product). This reaction is stereo-
chemically quite relevant because the same 70:30 mixture of
trans-12A and trans-12B isomers was isolated regardless of
the starting cis or trans configuration of the alkene 11
(Scheme 11). This stereochemical convergence can only be
Scheme 12. Competitive kinetic experiment involving two very different
ortho-substituted phenyl sulfoxides.
complex; this coordination is supposed to be the rate-deter-
mining step in the PK reaction.[15]
To gain more insight into the subtle contribution of both
steric and coordinating effects to the reactivity of vinyl sulf-
oxide 1i in the PK reactions, we performed a second com-
petitive experiment with two similar amino-substituted teth-
ered sulfoxides: the optimal o-dimethylamino substrate 1i
and the somewhat bulkier o-diethylamino derivative 1j (pre-
pared by following the same method described for 1i). Equi-
molecular amounts of 1i, 1j, and the dicobaltcarbonyl com-
plex were treated as usual (NMO, CH3CN, 0 8C, 60 min) and
gave rise to an 85:15 mixture of the corresponding PK ad-
ducts 2i and 2j (Scheme 13). This sizeable selectivity indi-
Scheme 11. PK reactions of isomers trans-11 and cis-11 under high pres-
sure.
explained by assuming an easy epimerization at the C5
center. The trans relative configuration at C4/C5 in both 12
products was assigned from the low value of the J4,5 coupling
constant (2.4 and 2.8 Hz for trans-12A and trans-12B, re-
spectively), which is in full agreement with typical values in
known related trans-cyclopentenones.[41] On the other hand,
the relative configuration at the sulfur and C5 centers was
established following the spectroscopic rule shown in
Scheme 9.
Another very relevant issue of the PK reactions of the
vinyl sulfoxides 1 is the mechanistic origin of the high reac-
tivity exhibited by the o-dimethylaminophenyl derivative 1i.
To estimate more accurately the magnitude of this effect, we
carried out the competitive kinetic experiment shown in
Scheme 12, involving two very different ortho-substituted
phenyl sulfoxides. The reaction of equimolecular amounts of
Scheme 13. Competitive kinetic experiment involving two similar ortho-
o-tolylsulfoxide 1b, o-(dimethylamino)phenyl sulfoxide 1i,
and the dicobaltcarbonyl complex of 1-hexyne under the op-
timal PK reaction conditions (NMO, CH3CN, 0 8C, 60 min)
led to an 11:89 mixture of the corresponding PK adducts 2b
and 2i. This result clearly shows that substrate 1i, despite
the higher steric bulk of the o-dimethylamino group relative
to the methyl group in 1b, is nearly one order of magnitude
more reactive than 1b. The higher reactivity of 1i suggests
that the o-dimethylamino group could be acting as a het-
eroatomic coordinating group at the cobalt center, thus
favoring the further coordination of the alkene to the cobalt
substituted phenyl sulfoxides.
cates that a moderate increase in the steric environment
around the nitrogen atom has a deeply detrimental effect on
the reactivity; this result is in full agreement with the pre-
sumed role of the nitrogen atom as a cobalt-coordinating
heteroatom in the formation of the key sterically congested
alkene–dicobalt complex intermediate III (Scheme 14).
À
When the four-bond separation between the C Cdouble
bond and the amine moiety is taken into account, it is ex-
Chem. Eur. J. 2004, 10, 5443 – 5459
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J. C. Carretero et al.
FULL PAPER
Scheme 14. Presumed intermediates III and IV in the formation of 2i.
pected that both groups will coordinate the same cobalt
atom on the dicobalt complex. A similar kind of coordina-
tion has been proposed in the case of PK reactions of achi-
ral tethered aminoalkenes.[21]
Figure 3. Optimized calculated structures for olefin complexes III and
their cobaltacycles IV.
To shed some light to this point, we performed some theo-
retical calculations by using, as simplified substrates, the o-
aminophenyl vinyl sulfoxide as an olefin model and propyne
as an alkyne model. In the elucidation of the possible com-
petence of homonuclear coordination (nitrogen and olefin
coordinating the same cobalt atom) versus binuclear coordi-
nation (nitrogen and olefin coordinating different cobalt
atoms), we decided to analyze the relative stability of the
starting olefin complexes III and their resulting products IV.
Complexes III and cobaltacycles IV were fully optimized by
semiempirical (PM3[36]) and DFT (B3LYP[38]) methods. In
this case, the effective core potential LANL2DZ[42] was used
for Co and S, and the STO-3G*[43] basis set was used for C,
H, N, and O. Frequencies were calculated at the same level
of theory/basis and ZPE correction was included. The opti-
mized structures found for homonuclear (IIIa) and binuclear
(IIIb) complexes and their corresponding cobaltacycles are
shown in Figure 3. Distances and energy differences are col-
lected in Table 4.
Table 4. Significant distances [ꢂ] in complexes III, relative energies
(DErelat
)
between IIIa and IIIb [KcalmolÀ1], and energy differences
(DEreact) between complexes III and cobaltacycles IV [KcalmolÀ1].
IIIa IIIb
2.121
2.050
2.129
1.418
2.625
0.0
À
Co(1) C(1)
2.179
2.100
2.077
1.414
2.762
3.6
À
Co(1) C(2)
À
Co N
À
C(1) C(2)
À
C(1) C(3)
[a]
DErelat
[a]
DEreact
À31.5
À22.6
[a] ZPE correction included.
chiral sulfoxides developed by Kagan and co-workers
(Scheme 15).[45] The ring opening of the commercially avail-
able enantiopure sulfite 13 with o-(N,N-dimethylamino)phen-
As can be seen in Table 4, there are significant differences
1
À
in the optimized interatomic distances. For instance, the C
C3 distance is shorter in IIIa than in IIIb but the opposite is
observed for the Co N distances. However, the most in-
[44]
À
teresting outcome of this theoretical study concerns the rela-
tive optimized energies: not only is the homonuclear com-
plex IIIa more stable than IIIb (DErelat) but its reaction is
much more exothermic (DEreact), a fact strongly supporting
the theory that the homonuclear coordination is the prefer-
red path for this step.
Applications in enantioselective synthesis: Any application
of the synthetic potential of this regio- and diastereoselec-
tive intermolecular PK methodology to the enantioselective
synthesis of polysubstituted cyclopentanoids required, first,
the preparation of enantiomerically pure vinyl sulfoxide 1i.
Initially, we applied the sulfite-based method of synthesis of
Scheme 15. Synthesis of chiral sulfoxide (R)-1i. Ts=tosyl=toluene-4-sul-
fonyl.
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
yllithium (generated in situ by treatment of the correspond-
ing iodide with nBuLi) in THF at À788Cgave the diastereo-
merically pure sulfinate 14 as the major regioisomer (61%
yield). Disappointingly, the further reaction of 14 with mag-
nesium vinyl bromide (2 equivalents) under the same reac-
tion conditions (THF, À788C) provided the expected vinyl
sulfoxide (R)-1i in low yield (21%) and with incomplete
enantioselectivity (95.5% ee, as determined by HPLCwith a
Chiralcel OD column). The use of a higher amount of the
Grignard reagent (4 equivalents) resulted in a more severely
detrimental effect on the enantioselectivity (77% ee), there-
by showing that this sulfinylation reaction occurs with par-
tial racemization at the sulfur center.
Scheme 16. Synthesis of (À)-pentenomycin. a) NMO, CH3CN, 0 8C;
b) OsO4, TMEDA, CH2Cl2, À788C; c) toluene, reflux; d) 2 m HCl, RT.
TIPS=triisopropylsilyl,
mine.
TMEDA=N,N,N’,N’-tetramethylethylenedia-
Next, we turned out to the asymmetric synthesis of sulfox-
ides recently reported by Senanayake and co-workers.[46]
The initial enantiopure sulfinylating reagent, the N-tosyl-
1,2,3-oxathiazolidine 15, was prepared in one step from the
readily available and inexpensive (1R,2S)-N-tosylnorephe-
drine. The reaction of 15 with a stoichiometric amount of o-
(N,N-dimethylamino)phenyl magnesium iodide occurred
under mild conditions in THF at À788Cwith selective cleav-
vinyl sulfoxide (>99% ee, as determined by HPLCwith a
Chiralcel OD column), thereby proving that the PK reaction
took place without any racemization at the sulfur center.[50]
This is an interesting point since it has been reported that
the intermolecular PK reaction of norbornene with acetylen-
ic sulfoxides occurs with partial racemization at the sulfur
atom.[18d] Since the dihydroxylation of (S,RS)-7 with OsO4
under normal catalytic conditions (3 mol% OsO4, NMO,
CH2Cl2, 08C) gave a mixture of stereoisomers, we turned to
the procedure of Donohoe et al. for dihydroxylation of al-
kenes with the stoichiometric pair OsO4/TMEDA under ex-
tremely mild reaction conditions.[51] In CH2Cl2 at À788Cthe
reaction was highly stereoselective in favor of dihydroxyla-
tion on the expectedly less hindered face of the double
bond, that opposite to the sulfinyl group at the C5 atom.
This reaction provided the stable osmate diester 17 in 81%
yield; the (2S,3S,5S) configuration of the product could be
established by NOESY experiments (see the Supporting In-
formation for details). Compound 17 suffered a clean sulfox-
ide pyrolysis in refluxing toluene to afford the enone–
osmate diester 18 in 72% yield. Final acid hydrolysis of the
hydroxy-protecting groups (2m HCl) provided the natural
(À)-(2S,3S)-pentenomycin I (19), whose absolute rotary
power was in full agreement with literature data ([a]D =À32
(c=0.2, EtOH); literature value:[42] [a]D =À32 (c=0.3,
EtOH)). Alternatively, its very high optical purity was un-
equivocally confirmed by HPLCanalysis of the triacetate
derivative (>99% e.e, as determined by HPLCwith a Chir-
alpak AD column).
À
age of the S N bond to give rise to sulfinate 16, which re-
sults from the inversion of configuration at the sulfur atom,
in nearly quantitative yield (99%). To our delight, the reac-
tion of 16 with vinyl magnesium bromide (3 equivalents) in
THF at À788Cprovided the desired sulfoxide ( R)-1i in
66% yield and with complete enantioselectivity
(Scheme 15), thereby demonstrating that this second substi-
tution at the sulfur atom also took place with complete in-
version of configuration.
To highlight the synthetic interest of our novel asymmet-
ric intermolecular version of the PK reaction, we selected
two natural cyclopentanoids as synthetic objectives: the anti-
biotic (À)-pentenomycin I, with a 4,5,5-trisubstituted cyclo-
pentenone structure, and the (À)-aminocyclopentitol moiety
of the hopanoid of Zymomonas mobilis, which displays a
stereochemically complex 1,1,2,3,4,5-hexasubstituted cyclo-
pentane framework (Scheme 7).
(À)-Pentenomycin I was isolated in 1973 from the culture
broths of Streptomyces eurythermus[47] and has proved to be
moderately active against Gram-positive and Gram-negative
bacteria.[48] To the best of our knowledge, five asymmetric
syntheses of this compound have been reported to date,[49]
with four of them requiring carbohydrates as starting mate-
rials; this implies the use of long and lineal synthetic se-
quences (10–20 chemical steps). A very efficient enantiose-
lective four-step synthesis of (À)-pentenomycin I from the
vinyl sulfoxide (R)-1i, taking advantage of the convergent
formation of the cyclopentenone ring by a PK reaction, is
shown in Scheme 16. After the PK reaction, the rest of the
synthetic steps are straightforward: dihydroxylation of the
Bacteriohopanetetrol ether II (Scheme 7) is an abundant
triterpenoid of the hopane family, found in the membrane
of several bacteria, such as Methylobacterium organophy-
lum, Rhodopseudomonas acidophila, and Zymomonas mobi-
lis.[52] To our knowledge, to date, only a total synthesis of its
aminocyclopentitol unit has been reported, which required
d-glucosamine as a commercially available starting materi-
al.[53] An eight-step stereodirected synthesis of the (À) enan-
tiomer of this aminocyclopentitol, from the same PK adduct
(S,RS)-7A, is shown in Scheme 17.
À
C Cdouble bond, generation of the enone moiety by sulf-
oxide pyrolysis, and deprotection of the hydroxy groups.
Treatment of the cobalt complex of the TIPS derivative of
propargylic alcohol with enantiopure (R)-1i (NMO, CH3CN,
08C) afforded the adduct 7 in a 93:7 isomer ratio (62%
yield). Trituration of this mixture with cold hexane provided
the pure major diastereomer (S,RS)-7A. The optical purity
of this compound proved to be as high as that of the starting
Stereoselective hydride reduction of the ketone 7A with
DIBALH in THF at À788Cprovided a single alcohol, which
was protected as the TBDMS derivative 20 (TBDMSCl, imi-
dazole, CH3CN; 95% overall yield from 7). The trans ster-
Chem. Eur. J. 2004, 10, 5443 – 5459
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J. C. Carretero et al.
FULL PAPER
proving unequivocally the (1R,2R,3S,4S,5R) configuration
and, therefore, the stereochemistry of its synthetic precur-
sors.
Conclusion
We have demonstrated that, under appropriate conditions,
a,b-unsaturated sulfoxides behave as efficient acyclic olefin-
ic partners in asymmetric intermolecular PK reactions, to
provide substituted 5-sulfinyl-2-cyclopentenones with com-
plete regiocontrol and high stereoselectivity. Among the va-
riety of screened sulfoxides, the cobalt-chelating o-(N,N-di-
methylamino)phenyl vinyl sulfoxide (1i) gave the best re-
sults in terms of reactivity and stereoselectivity with a wide
variety of substituted terminal alkynes. With the readily
available sulfoxide (R)-1i, this methodology opens a new
access to the enantioselective synthesis of cyclopentanoids.
This synthetic interest has been illustrated by developing ef-
ficient stereoselective syntheses of (À)-pentenomycin I and
a stereochemically complex aminocyclopentitol. Efforts to
further apply the metal-coordinating ability of the o-dime-
thylaminophenyl sulfinyl group as a chiral auxiliary in other
stereoselective transition-metal-mediated reactions are un-
derway.
Scheme 17. Synthesis of the (À)-aminocyclopentitol moiety. a) DIBALH,
THF, À788C; b) TBDMSCl, imidazole, CH3CN, RT; c) OsO4, NMO,
THF/H2O 10:1, RT; d) NaHCO3, toluene, reflux, then SiO2 purification;
e) MCPBA, CH2Cl2, RT; f) NaN3, NH4Cl, DMF, 1008C ; g) H, Pd/C
2
(10%), MeOH; h) HCl/MeOH, RT. TBDMS=tert-butyldimethylsilyl,
DIBALH=diisobutylaluminum hydride, DMF=N,N-dimethylforma-
mide.
Experimental Section
General: All reagents were obtained from commercial suppliers and
were used without further purification except NMO·H2O, which was puri-
fied by precipitation from acetone before use. THF, Et2O, and CH2Cl2
were dried over microwave-activated 4 ꢂ molecular sieves. Reactions
were monitored by thin-layer chromatography carried out on 0.25 mm
Merck silica gel plates (Merck-60 230–400 mesh). Merck-60 230–
400 mesh silica gel was used for flash column chromatography. NMR
spectra were recorded on Bruker AC-200 or AC-300 instruments in
CDCl3 (calibrated at d=7.26 and 77.0 ppm for 1H and 13Cexperiments,
respectively), CD3OD (d=3.31 and 49.0 ppm) or D2O (d=4.70 ppm).
Mass spectra and high-resolution mass spectra were determined on a
Hewlett–Packard HP-5985 mass spectrometer at 70 eV ionising voltage
(EI) or under fast atom bombardment (FAB) conditions. Melting points
were determined in open-end capillary tubes on a GallenKamp appara-
tus. Optical rotations were measured on a Perkin-Elmer 241Cpolarime-
ter. HPLCwas conducted on an Agilent 1100 instrument, with Daicel
Chiralpak AD and Chiralcel OD columns. High-pressure reactions were
conducted under 10 Kbar pressure by using a Hofer HP 14 apparatus.
eochemistry of 20 was inferred from the well-known stereo-
chemical behavior of b-ketosulfoxides with reducing hydride
reagents.[35] The dihydroxylation of 20 under standard OsO4
catalytic conditions (3 mol% OsO4, NMO, THF/H2O, RT)
occurred mainly from the alkene face opposite to the bulky
allylic substituent, thereby providing an inseparable 90:10
mixture of both cis-diols 21 and 21’ (83% yield). Sulfoxide
pyrolysis of this mixture by heating in toluene at 1108Cand
further silica gel chromatographic separation afforded the
cyclopentenediol 22 in 78% yield, along with 8% of its dia-
stereomer 22’.[54] As expected from both steric and hydro-
gen-bond considerations, the epoxidation of 22 with
MCPBA (CH2Cl2, RT) was completely stereoselective and
occurred on the same side of the allylic hydroxy group (op-
posite face to the bulky silylated ether) to give a single ep-
oxide 23. Due to the very different steric environment of
both epoxidic carbon atoms, the trans opening of 23 with
NaN3 in DMF at 1008Cwas completely regioselective in
favor of attack at the least hindered position (C3) to provide
exclusively the azide 24 (76% yield). Once the configuration
of the five stereogenic carbon centers had been controlled,
the final hydrogenation of the azide moiety (H2, Pd/C), fol-
lowed by hydroxy deprotection in acid media (HCl,
MeOH), afforded the (À)-aminocyclopentitol 25 ([a]D =À6
(c=0.3, MeOH); literature value for the enantiomer:[53]
[a]D =+6.2 (c=1.2, MeOH)). The 1H and 13CNMR spectro-
scopy data of this compound were identical to those descri-
bed in the literature for the (+) enantiomer,[53] thereby
2-n-Butyl-5-(p-tolylsulfinyl)-2-cyclopentenone (2a):
A solution of 1-
hexyne (26 mL, 0.23 mmol) and [Co2(CO)8] (77 mg, 0.23 mmol) in
CH3CN (1 mL) was stirred at RT under an argon atmosphere. After 1 h,
N-methylmorpholine N-oxide (106 mg, 0.90 mmol) and a solution of 1a
(25 mg, 0.15 mmol) in CH3CN (1 mL) were added and the resulting so-
lution was stirred for 2 h. The reaction mixture was diluted with CH2Cl2,
treated with trimethylamine N-oxide (50 mg) to remove the remaining
cobalt complex and stirred for 10 min at RT. After removal of the sol-
vent, the crude product was dissolved in diethyl ether and filtered
through a pad of celite, which was washed with diethyl ether. The com-
bined organic solvents were evaporated and the residue was purified by
chromatography (hexane/ethyl acetate 3:1) to afford 2aA and 2aB as a
74:26 diastereomeric mixture (28 mg, 68%, colorless oil). A: 1H NMR
(300 MHz, CDCl3): d=7.52–7.21 (m, 5H; Ar, H-3), 3.49 (dd, J=2.2,
6.5 Hz, 1H; H-5), 3.04–2.89 (m, 1H; H-4), 2.41 (s, 3H; ArCH3), 2.40–2.26
(m, 1H; H-4), 2.18 (m, 2H; H-1’), 1.51–1.09 (m, 4H; H-2’, H-3’),
0.88 ppm (t, J=7.0 Hz, 3H; H-4’); 13C NMR (75 MHz, CDCl3): d=201.7,
201.0, 157.7, 156.9, 147.0, 146.8, 142.1, 141.6, 139.1, 135.4, 129.9, 129.5,
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
125.0, 124.0, 68.1, 66.0, 29.6, 29.5, 29.3, 25.5, 24.7, 24.2, 23.9, 22.3, 22.1,
2-n-Butyl-5-(tert-butylsulfinyl)-2-cyclopentenone (2e): A solution of 1-
hexyne (39 mL, 0.34 mmol) and [Co2(CO)8] (116 mg, 0.34 mmol) in
CH3CN (1 mL) was stirred under an argon atmosphere at RT. After 1 h,
N-methylmorpholine N-oxide (162 mg, 1.38 mmol) and a solution of 1e
(30 mg, 0.23 mmol) in CH3CN (1 mL) were added. After 12 h at RT, an-
other 1.5 equivalents of the cobalt complex were added and the resulting
solution was stirred for 12 h. The reaction mixture was diluted with
CH2Cl2, treated with trimethylamine N-oxide (150 mg), and stirred for
10 min at RT. After removal of the solvent, the crude product was dis-
solved in diethyl ether and filtered through a pad of celite. The combined
organic solvents were evaporated and the residue was purified by chro-
matography (hexane/ethyl acetate 3:2) to afford 2eA (10 mg, 20%, color-
less oil). 1H NMR (300 MHz, CDCl3): d=7.38 (m, 1H; H-3), 4.29 (dd,
J=2.0, 6.9 Hz, 1H; H-5), 3.25 (m, 1H; H-4), 2.54 (m, 1H; H-4), 2.18 (m,
2H; H-1’), 1.45 (m, 2H; H-2’), 1.31 (m, 2H; H-3’), 1.27 (s, 9H; C(CH3)3),
0.89 ppm (t, J=7.3 Hz, 3H; H-4’); 13C NMR (75 MHz, CDCl3): d=204.7,
158.2, 145.9, 58.1, 55.1, 29.5, 24.6, 23.7, 23.4, 22.3, 13.8 ppm; HRMS
(EI+): calcd for (C9H14O2S) [MÀtBu]+: 186.0715; found: 186.0717.
2-n-Butyl-5-(2-pyridylsulfinyl)-2-cyclopentenone (2g): A solution of 1-
hexyne (29 mL, 0.25 mmol) and [Co2(CO)8] (87 mg, 0.25 mmol) in
CH3CN (1 mL) was stirred under an argon atmosphere at RT. After 1 h,
N-methylmorpholine N-oxide (138 mg, 1.17 mmol) and a solution of 1g
(30 mg, 0.20 mmol) in CH3CN (1 mL) were added and the resulting so-
lution was stirred for 1 h. The reaction mixture was diluted with CH2Cl2,
treated with trimethylamine N-oxide, and stirred for 10 min at RT. After
removal of the solvent, the crude product was dissolved in diethyl ether
and filtered through a pad of celite. The combined organic solvents were
evaporated and the residue was purified by chromatography (aluminum
oxide neutral; hexane/ethyl acetate 2:1) to afford 2gA and 2gB as a
73:27 diastereomeric mixture (10 mg, 19%, colorless oil). A: 1H NMR
(200 MHz, CDCl3): d=8.63 (m, 1H; Ar), 7.95 (m, 2H; Ar), 7.45–7.26 (m,
2H; Ar, H-3), 4.09 (dd, J=2.7, 6.5 Hz, 1H; H-5), 2.90–2.61 (m, 1H; H-
4), 2.48–2.26 (m, 1H; H-4), 2.21 (m, 2H; H-1’), 1.54–1.18 (m, 4H; H-2’,
H-3’), 0.90 ppm (t, J=7.0 Hz, 3H; H-4’); 13C NMR (75 MHz, CDCl3): d=
202.0, 199.8, 163.4, 161.8, 157.4, 155.5, 149.7, 149.3, 148.0, 147.1, 137.9,
137.5, 124.7, 121.3, 120.6, 65.6, 62.8, 29.5, 29.1, 24.7, 24.6, 23.7, 22.3, 13.8,
13.7 ppm; HRMS (FAB+): calcd for (C14H17NO2S) [M]+: 263.0980;
found: 263.0975; B: 1H NMR (200 MHz, CDCl3; significant signals): d=
4.08 (m, 1H; H-5), 3.09 (m, 1H; H-4), 2.61 (m, 1H; H-4), 2.09 ppm (m,
2H; H-1’).
21.4, 13.8, 13.7 ppm; HRMS (FAB+): calcd for (C16H20O2S) [M]+:
1
276.1184; found: 276.1177; B: H NMR (300 MHz, CDCl3; significant sig-
nals): d=7.03 (m, 1H; H-3), 4.20 (dd, J=2.2, 6.5 Hz, 1H; H-5), 2.85–2.70
(m, 1H; H-4), 2.36 (s, 3H; ArCH3), 1.91 ppm (m, 2H; H-1’).
2-n-Butyl-5-(o-tolylsulfinyl)-2-cyclopentenone (2b):
A solution of 1-
hexyne (52 mL, 0.45 mmol) and [Co2(CO)8] (154 mg, 0.45 mmol) in
CH3CN (2 mL) was stirred under an argon atmosphere at RT. After 1 h,
N-methylmorpholine N-oxide (211 mg, 1.80 mmol) and a solution of 1b
(50 mg, 0.30 mmol) in CH3CN (2 mL) were added. After 10 h at RT, an-
other 1.5 equivalents of the cobalt complex were added and the resulting
solution was stirred for 14 h at RT. The reaction mixture was diluted with
CH2Cl2, treated with trimethylamine N-oxide (200 mg), and stirred for
10 min at RT. After removal of the solvent, the crude product was dis-
solved in diethyl ether and filtered through a pad of celite. The combined
organic solvents were evaporated and the residue was purified by chro-
matography (hexane/ethyl acetate 5:1) to afford 2bA and 2bB as a 90:10
diastereomeric mixture (23 mg, 28%, colorless oil). A: 1H NMR
(300 MHz, CDCl3): d=7.82 (dd, J=2.8, 7.3 Hz, 1H; Ar), 7.44–7.35 (m,
3H; Ar, H-3), 7.21 (dd, J=2.4, 6.1 Hz, 1H; Ar), 3.53 (dd, J=2.4, 6.9 Hz,
1H; H-5), 3.06–2.97 (m, 1H; H-4), 2.42 (s, 3H; ArCH3), 2.33–2.17 (m,
3H; H-4, H-1’), 1.51–1.23 (m, 4H; H-2’, H-3’), 0.89 ppm (t, J=7.3 Hz,
3H; H-4’); 13C NMR (75 MHz, CDCl3): d=202.0, 158.0, 155.9, 146.9,
140.4, 134.2, 130.9, 126.9, 124.1, 65.0, 29.5, 24.7, 23.2, 22.3, 18.0, 13.7 ppm;
HRMS (EI+): calcd for (C16H20O2S) [M]+: 276.1184; found: 276.1182;
B: 1H NMR (300 MHz, CDCl3; significant signals): d=3.94 (dd, J=1.6,
6.9 Hz, 1H; H-5), 2.36 ppm (s, 3H; ArCH3).
2-n-Butyl-5-(2-bromophenylsulfinyl)-2-cyclopentenone (2c): A solution
of 1-hexyne (22 mL, 0.19 mmol) and [Co2(CO)8] (67 mg, 0.19 mmol) in
CH3CN (1 mL) was stirred under an argon atmosphere at RT. After 1 h,
N-methylmorpholine N-oxide (91 mg, 0.78 mmol) and a solution of 1c
(30 mg, 0.13 mmol) in CH3CN (1 mL) were added. After 12 h at RT, an-
other 1.5 equivalents of the cobalt complex were added and the resulting
solution was stirred for 12 h at RT. The reaction mixture was diluted with
CH2Cl2, treated with trimethylamine N-oxide (90 mg), and stirred for
10 min at RT. After removal of the solvent, the crude product was dis-
solved in diethyl ether and filtered through a pad of celite. The combined
organic solvents were evaporated and the residue was purified by chro-
matography (hexane/ethyl acetate 3:1) to afford 2cA and 2cB as an
86:14 diastereomeric mixture (15 mg, 30%, colorless oil). A: 1H NMR
(300 MHz, CDCl3): d=7.82 (dd, J=1.6, 7.5 Hz, 1H; Ar), 7.57 (t, J=
7.5 Hz, 2H; Ar), 7.39 (m, 2H; H-3, Ar), 4.09 (dd, J=2.7, 7.0 Hz, 1H; H-
5), 2.89 (m, 1H; H-4), 2.21 (m, 3H; H-1’, H-4), 1.56–1.21 (m, 4H; H-2’,
H-3’), 0.90 ppm (t, J=7.0 Hz, 3H; H-4’); 13C NMR (75 MHz, CDCl3): d=
201.7, 157.7, 147.1, 141.6, 133.2, 132.5, 128.3, 127.1, 118.7, 63.9, 29.5, 24.8,
23.3, 22.4, 13.8 ppm; HRMS (EI+): calcd for (C15H17O2SBr) [M]+:
2-n-Butyl-5-[2-(N,N-dimethylamino)phenylsulfinyl]-2-cyclopentenone
(2i): A solution of 1-hexyne (23 mL, 0.20 mmol) and [Co2(CO)8] (68 mg,
0.20 mmol) in CH3CN (1 mL) was stirred under an argon atmosphere at
RT. After 1 h, N-methylmorpholine N-oxide (108 mg, 0.92 mmol) and a
solution of 1i (30 mg, 0.15 mmol) in CH3CN (1 mL) were added at 08C
and the resulting solution was stirred for 4 h at this temperature. The re-
action mixture was diluted with CH2Cl2, treated with trimethylamine N-
oxide (50 mg), and stirred for 10 min at RT. After removal of the solvent,
the crude product was dissolved in diethyl ether and filtered through a
pad of celite. The combined organic solvents were evaporated and the
residue was purified by chromatography (Et3N-pretreated SiO2; hexane/
ethyl acetate 3:1) to afford 2iA and 2iB as a 93:7 diastereomeric mixture
1
340.0133; found: 340.0132; B: H NMR (300 MHz, CDCl3; significant sig-
nals): d=3.97 (m, 1H; H-5), 3.19 ppm (m, 1H; H-4).
2-n-Butyl-5-(2,4,6-triisopropylphenylsulfinyl)-2-cyclopentenone (2d):
A
solution of 1-hexyne (19 mL, 0.16 mmol) and [Co2(CO)8] (55 mg,
0.16 mmol) in CH3CN (1 mL) was stirred under an argon atmosphere at
RT. After 1 h, N-methylmorpholine N-oxide (76 mg, 0.65 mmol) and a
solution of 1d (30 mg, 0.11 mmol) in CH3CN (1 mL) were added. After
12 h at RT, another 1.5 equivalents of the cobalt complex were added
and the resulting solution was stirred for 12 h. The reaction mixture was
diluted with CH2Cl2, treated with trimethylamine N-oxide (70 mg), and
stirred for 10 min at RT. After removal of the solvent, the crude product
was dissolved in diethyl ether and filtered through a pad of celite. The
combined organic solvents were evaporated and the residue was purified
by chromatography (hexane/ethyl acetate 5:1) to afford 2dA and 2dB as
a 94:6 diastereomeric mixture (10 mg, 24%, colorless oil). A: 1H NMR
(300 MHz, CDCl3): d=7.41 (m, 1H; H-3), 7.08 (s, 2H; Ar), 4.18 (dd, J=
1.6, 6.5 Hz, 1H; H-5), 3.73 (m, 2H; CH(CH3)2), 3.39 (m, 1H; H-4), 2.95
(m, 1H; H-4), 2.90 (m, 1H; CH(CH3)2), 2.16 (m, 2H; H-1’), 1.51–1.20
(m, 22H; H-2’, H-3’, CH(CH3)2), 0.89 ppm (t, J=7.3 Hz, 3H; H-4’);
13C NMR (75 MHz, CDCl3): d=201.6, 156.1, 152.7, 150.1, 146.4, 134.0,
123.0, 66.3, 34.3, 29.6, 28.3, 28.1, 24.6, 23.7, 23.6, 22.3, 13.7 ppm; HRMS
(EI+): calcd for (C24H36O2S) [M]+: 388.2436; found: 388.2438; B:
1H NMR (300 MHz, CDCl3; significant signal): d=4.12 ppm (m, 1H;
H-5).
1
(34 mg, 74%, colorless oil). A: H NMR (200 MHz, CDCl3): d=7.79 (dd,
J=1.6, 7.7 Hz, 1H; Ar), 7.42 (dt, J=1.6, 7.7 Hz, 1H; Ar), 7.30 (m, 1H;
H-3), 7.24 (dt, J=1.2, 7.3 Hz, 1H; Ar), 7.09 (dd, J=1.2, 8.1 Hz, 1H; Ar),
4.29 (dd, J=2.4, 6.9 Hz, 1H; H-5), 2.77 (s, 6H; N(CH3)2), 2.63 (m, 1H;
H-4), 2.18 (m, 2H; H-1’), 2.03 (m, 1H; H-4), 1.50–1.24 (m, 4H; H-2’, H-
3’), 0.88 ppm (t, J=7.3 Hz, 3H; H-4’); 13CNMR (75 MHz, CDCl 3): d=
203.2, 158.0, 150.3, 146.9, 135.4, 131.6, 125.6, 123.7, 119.3, 63.0, 44.6, 29.5,
24.7, 23.6, 22.3, 13.8 ppm; HRMS (FAB+): calcd for (C17H24NO2S)
[M+H]+: 306.1528; found: 306.1532; B: 1H NMR (200 MHz, CDCl3; sig-
nificant signals): d=4.05 (m, 1H; H-5), 2.68 ppm (s, 6H; N(CH3)2).
2-tert-Butyl-5-[2-(N,N-dimethylamino)phenylsulfinyl]-2-cyclopentenone
(3):
A solution of 3,3-dimethyl-1-butyne (28 mL, 0.23 mmol) and
[Co2(CO)8] (79 mg, 0.23 mmol) in CH3CN (1 mL) was stirred under an
argon atmosphere at RT. After 1 h, N-methylmorpholine N-oxide
(108 mg, 0.92 mmol) and a solution of 1i (30 mg, 0.15 mmol) in CH3CN
(1 mL) were added at RT. After 12 h, another 1.5 equivalents of the
cobalt complex were added and the resulting solution was stirred for
14 h. The reaction mixture was diluted with CH2Cl2, treated with trime-
thylamine N-oxide (100 mg), and stirred for 10 min at RT. After removal
Chem. Eur. J. 2004, 10, 5443 – 5459
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5453

J. C. Carretero et al.
FULL PAPER
of the solvent, the crude product was dissolved in diethyl ether and fil-
tered through a pad of celite. The combined organic solvents were evapo-
rated and the residue was purified by chromatography (Et3N-pretreated
SiO2; hexane/ethyl acetate 4:1) to afford 3A (26 mg, 55%, white solid).
M.p. 133–1368C; 1H NMR (300 MHz, CDCl3): d=7.80 (dd, J=1.6,
7.7 Hz, 1H; Ar), 7.43 (dt, J=1.6, 7.3 Hz, 1H; Ar), 7.30 (t, J=2.8 Hz, 1H;
H-3), 7.25 (dt, J=1.2, 7.7 Hz, 1H; Ar), 7.10 (dd, J=1.2, 8.1 Hz, 1H; Ar),
4.27 (dd, J=2.4, 6.9 Hz, 1H; H-5), 2.78 (s, 6H; N(CH3)2), 2.60 (td, J=
2.8, 19.0 Hz, 1H; H-4), 1.99 (ddd, J=2.8, 6.9, 19.4 Hz, 1H; H-4),
1.19 ppm (s, 9H; C(CH3)3); 13CNMR (75 MHz, CDCl 3): d=202.5, 156.6,
154.4, 150.4, 135.5, 131.6, 125.7, 123.7, 119.2, 64.1, 44.6, 32.1, 28.1,
22.8 ppm; HRMS (FAB+): calcd for (C17H24NO2S) [M+H]+: 306.1528;
found: 306.1536.
solid). M.p. 133–1358C; 1H NMR (300 MHz, CDCl3): d=7.82–7.79 (m,
2H; Ar, H-3), 7.44 (dt, J=1.6, 7.3 Hz, 1H; Ar), 7.26 (t, J=1.2, 7.7 Hz,
1H; Ar), 7.10 (dt, J=1.2, 7.7 Hz, 1H; Ar), 4.28 (dd, J=2.8, 6.9 Hz, 1H;
H-5), 2.81 (dt, J=3.2, 19.4 Hz, 1H; H-4), 2.79 (s, 6H; N(CH3)2), 2.16
(ddd, J=2.4, 6.9, 19.8 Hz, 1H; H-4), 0.19 ppm (s, 9H; Si(CH3)3);
13C NMR (75 MHz, CDCl3): d=206.8, 172.6, 150.3, 147.7, 135.7, 131.6,
125.5, 123.7, 119.2, 63.6, 44.5, 27.2, À2.0 ppm; HRMS (EI+): calcd for
(C16H23NO2SiS) [M]+: 321.1219; found: 321.1221.
5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2-(triisopropylsilyloxy)methyl-
2-cyclopentenone (7): A solution of 3-(triisopropylsilyloxy)-1-propyne
(244 mg, 1.15 mmol) and [Co2(CO)8] (394 mg, 1.15 mmol) in CH3CN
(3 mL) was stirred under an argon atmosphere at RT. After 1 h, N-meth-
ylmorpholine N-oxide (540 mg, 4.61 mmol) and a solution of 1i (150 mg,
0.77 mmol) in CH3CN (2 mL) were added at 08Cand the resulting so-
lution was stirred for 2 h at this temperature. The reaction mixture was
diluted with CH2Cl2, treated with trimethylamine N-oxide (250 mg), and
stirred for 10 min at RT. After removal of the solvent, the crude product
was dissolved in diethyl ether and filtered through a pad of celite. The
combined organic solvents were evaporated and the residue was purified
by chromatography (Et3N-pretreated SiO2; hexane/ethyl acetate 6:1) to
afford 7A and 7B (207 mg, 62%, white solid) as a 93:7 diastereomeric
mixture. The mixture was triturated with cold hexane to afford diastereo-
merically pure 7A (176 mg, 53% overall yield). A: M.p. 87–888C;
1H NMR (300 MHz, CDCl3): d=7.83 (dd, J=1.6, 7.7 Hz, 1H; Ar), 7.60
(m, 1H; H-3), 7.45 (dt, J=1.6, 7.7 Hz, 1H; Ar), 7.27 (dt, J=1.2, 7.7 Hz,
1H; Ar), 7.11 (dd, J=1.2, 8.1 Hz, 1H; Ar), 4.47 (m, 2H; H-1’), 4.36 (dd,
J=2.4, 6.9 Hz, 1H; H-5), 2.78 (s, 6H; N(CH3)2), 2.78–2.67 (m, 1H; H-4),
2.17–2.04 (m, 1H; H-4), 1.05 ppm (m, 21H; TIPS); 13CNMR (75 MHz,
CDCl3): d=201.6, 158.5, 150.4, 147.0, 135.4, 131.7, 125.7, 123.8, 119.3,
64.0, 58.5, 44.6, 23.9, 17.9, 11.8 ppm; HRMS (FAB+): calcd for
(C23H38NO3SiS) [M+H]+: 436.2342; found: 436.2338; B: 1H NMR
(300 MHz, CDCl3; significant signals): d=4.11 (dd, J=4.0, 4.9 Hz, 1H;
H-5), 2.68 ppm (s, 6H; N(CH3)2).
2-Benzyl-5-[2-(N,N-dimethylamino)phenylsulfinyl]-2-cyclopentenone (4):
A solution of 3-phenyl-1-propyne (19 mL, 0.15 mmol) and [Co2(CO)8]
(53 mg, 0.15 mmol) in CH3CN (1 mL) was stirred under an argon atmos-
phere at RT. After 1 h, N-methylmorpholine N-oxide (72 mg, 0.61 mmol)
and a solution of 1i (20 mg, 0.10 mmol) in CH3CN (1 mL) were added at
08C. After 5 h, another 1.5 equivalents of the cobalt complex were added
and the resulting solution was stirred for 9 h at 08C. The reaction mixture
was diluted with CH2Cl2, treated with trimethylamine N-oxide (70 mg),
and stirred for 10 min at RT. After removal of the solvent, the crude
product was dissolved in diethyl ether and filtered through a pad of
celite. The combined organic solvents were evaporated and the residue
was purified by chromatography (Et3N-pretreated SiO2; hexane/ethyl
acetate 4:1) to afford 4A and 4B as a 93:7 diastereomeric mixture
1
(20 mg, 58%, colorless oil). A: H NMR (200 MHz, CDCl3): d=7.81 (dd,
J=1.6, 7.5 Hz, 1H; Ar), 7.44 (dt, J=1.6, 7.5 Hz, 1H; Ar), 7.34–7.07 (m,
8H; H-3, Ar), 4.36 (dd, J=2.7, 7.0 Hz, 1H; H-5), 3.53 (m, 2H; CH2),
2.78 (s, 6H; N(CH3)2), 2.66 (m, 1H; H-4), 2.01 ppm (m, 1H; H-4);
13C NMR (75 MHz, CDCl3): d=202.4, 159.4, 150.4, 146.4, 138.1, 135.4,
131.7, 129.0, 128.5, 126.4, 125.7, 123.8, 119.3, 63.2, 44.6, 31.5, 23.6 ppm;
HRMS (FAB+): calcd for (C20H22NO2S) [M+H]+: 340.1371; found:
1
340.1376; B: H NMR (200 MHz, CDCl3; significant signals): d=4.11 (m,
Compound (5S, SR)-7A was obtained from (R)-1i: [a]D =+470 (c=0.2,
CHCl3); HPLC: ee>99% (Daicel Chiralcel OD column, hexane/isopro-
1H; H-5), 2.70 ppm (s, 6H; N(CH3)2).
panol 98:2 at 0.5 mLminÀ1
, l=220 nm; tR =24.2 min (5S,SR) and
5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2-p-tolyl-2-cyclopentenone (5):
A
solution of 4-ethynyltoluene (29 mL, 0.23 mmol) and [Co2(CO)8]
30.1 min (5R,SS)).
(79 mg, 0.23 mmol) in CH3CN (1 mL) was stirred under an argon atmos-
phere at RT. After 1 h, N-methylmorpholine N-oxide (108 mg,
0.92 mmol) and a solution of 1i (30 mg, 0.15 mmol) in CH3CN (1 mL)
were added at 08Cand the resulting solution was stirred for 12 h at this
temperature. The reaction mixture was diluted with CH2Cl2, treated with
trimethylamine N-oxide (50 mg), and stirred for 10 min at RT. After re-
moval of the solvent, the crude product was dissolved in diethyl ether
and filtered through a pad of celite. The combined organic solvents were
evaporated and the residue was purified by chromatography (Et3N-pre-
treated SiO2; hexane/ethyl acetate 3:1) to afford 5A and 5B as a 93:7 di-
5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2-[2-(triisopropylsilyloxy)eth-
yl)]-2-cyclopentenone (8): A solution of 4-(triisopropylsilyloxy)-1-butyne
(35 mg, 0.15 mmol) and [Co2(CO)8] (53 mg, 0.15 mmol) in CH3CN
(1 mL) was stirred under an argon atmosphere at RT. After 1 h, N-meth-
ylmorpholine N-oxide (72 mg, 0.61 mmol) and a solution of 1i (20 mg,
0.10 mmol) in CH3CN (1 mL) were added at 08Cand the resulting so-
lution was stirred for 7 h at this temperature. The reaction mixture was
diluted with CH2Cl2, treated with trimethylamine N-oxide (40 mg), and
stirred for 10 min at RT. After removal of the solvent, the crude product
was dissolved in diethyl ether and filtered through a pad of celite. The
combined organic solvents were evaporated and the residue was purified
by chromatography (Et3N-pretreated SiO2; hexane/ethyl acetate 5:1) to
1
astereomeric mixture (26 mg, 49%, colorless oil). A: H NMR (300 MHz,
CDCl3): d=7.85 (dd, J=1.6, 7.7 Hz, 1H; Ar), 7.80 (t, J=2.8 Hz, 1H; H-
3), 7.62 (d, J=8.1 Hz, 2H; p-Tol), 7.46 (dt, J=1.6, 7.7 Hz, 1H; Ar), 7.30
(dd, J=1.2, 7.3 Hz, 1H; Ar), 7.18 (d, J=8.5 Hz, 2H; p-Tol), 7.13 (dd, J=
1.2, 8.1 Hz, 1H; Ar), 4.48 (dd, J=2.8, 6.7 Hz, 1H; H-5), 2.83 (td, J=3.2,
19.8 Hz, 1H; H-4), 2.81 (s, 6H; N(CH3)2), 2.35 (s, 3H; ArCH3), 2.19 ppm
(ddd, J=2.8, 6.9, 19.8 Hz, 1H; H-4); 13CNMR (75 MHz, CDCl 3): d=
201.3, 158.3, 150.4, 143.5, 138.6, 135.4, 131.7, 129.1, 128.1, 126.9, 125.7,
123.8, 119.3, 64.4, 44.6, 23.2, 21.3 ppm; HRMS (EI+): calcd for
(C20H21NO2S) [M]+: 339.1293; found: 339.1302; B: 1H NMR (300 MHz,
CDCl3; significant signals): d=4.24 (dd, J=2.4, 6.1 Hz, 1H; H-5), 2.59 (s,
6H; N(CH3)2), 2.32 ppm (s, 3H; ArCH3).
1
afford 8A (30 mg, 66%, white solid). M.p. 82–838C; H NMR (200 MHz,
CDCl3): d=7.81 (dd, J=1.6, 7.7 Hz, 1H; Ar), 7.49 (m, 1H; H-3), 7.44
(dt, J=1.6, 7.7 Hz, 1H; Ar), 7.26 (dt, J=1.2, 7.7 Hz, 1H; Ar), 7.11 (dd,
J=1.2, 7.7 Hz, 1H; Ar), 4.30 (dd, J=2.8, 6.9 Hz, 1H; H-5), 3.80 (m, 2H;
H-2’), 2.78 (s, 6H; N(CH3)2), 2.70 (m, 1H; H-4), 2.47 (m, 2H; H-1’), 2.05
(m, 1H; H-4), 1.03 ppm (m, 21H; TIPS); 13C NMR (75 MHz, CDCl3):
d=203.0, 160.1, 150.4, 143.8, 135.6, 131.6, 125.7, 123.8, 119.3, 63.0, 61.2,
44.6, 28.7, 23.8, 18.0, 11.9 ppm; HRMS (FAB+): calcd for
(C24H40NO3SiS) [M+H]+: 450.2498; found: 450.2497.
Compound (5S,SR)-8A was obtained from (R)-1i: [a]D =+290 (c=0.3,
CHCl3); HPLC: ee>99% (Daicel Chiralcel OD column, hexane/isopro-
5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2-trimethylsilyl-2-cyclopente-
none (6): A solution of trimethylsilylacetylene (43 mL, 0.31 mmol) and
[Co2(CO)8] (105 mg, 0.31 mmol) in CH3CN (1 mL) was stirred under an
argon atmosphere at RT. After 1 h, N-methylmorpholine N-oxide (72 mg,
0.62 mmol) and a solution of 1i (30 mg, 0.15 mmol) in CH3CN (1 mL)
were added at RT and the resulting solution was stirred for 16 h at this
temperature. The reaction mixture was diluted with CH2Cl2, treated with
trimethylamine N-oxide (70 mg), and stirred for 10 min at RT. After re-
moval of the solvent, the crude product was dissolved in diethyl ether
and filtered through a pad of celite. The combined organic solvents were
evaporated and the residue was purified by chromatography (Et3N-pre-
treated SiO2; hexane/ethyl acetate 4:1) to afford 6A (29 mg, 59%, white
panol 98:2 at 0.5 mLminÀ1
, l=230 nm; tR =39.8 min (5S,SR) and
53.4 min (5R,SS)).
2-(3-Bromopropyl)-5-[2-(N,N-dimethylamino)phenylsulfinyl]-2-cyclopen-
tenone (9): A solution of 5-bromo-1-pentyne (79 mg, 0.54 mmol) and
[Co2(CO)8] (184 mg, 0.54 mmol) in CH3CN (3 mL) was stirred under an
argon atmosphere at RT. After 1 h, N-methylmorpholine N-oxide
(252 mg, 2.15 mmol) and a solution of 1i (70 mg, 0.36 mmol) in CH3CN
(2 mL) were added at 08Cand the resulting solution was stirred for 6 h
at this temperature. The reaction mixture was diluted with CH2Cl2, treat-
ed with trimethylamine N-oxide (120 mg), and stirred for 10 min at RT.
5454
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 5443 – 5459

Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
After removal of the solvent, the crude product was dissolved in diethyl
ether and filtered through a pad of celite. The combined organic solvents
were evaporated and the residue was purified by chromatography (Et3N-
pretreated SiO2; hexane/ethyl acetate 3:1) to afford 9A (90 mg, 68%,
white solid). M.p. 97–998C; 1H NMR (300 MHz, CDCl3): d=7.81 (dd,
J=1.6, 7.7 Hz, 1H; Ar), 7.45 (dt, J=1.6, 7.6 Hz, 1H; Ar), 7.41 (m, 1H;
H-3), 7.27 (dt, J=1.2, 7.7 Hz, 1H; Ar), 7.11 (dd, J=1.2, 7.7 Hz, 1H; Ar),
4.33 (dd, J=2.4, 6.9 Hz, 1H; H-5), 3.39 (t, J=6.9 Hz, 2H; H-3’), 2.79 (s,
6H; N(CH3)2), 2.67 (m, 1H; H-4), 2.40 (m, 2H; H-1’), 2.13–2.00 ppm (m,
3H; H-4, H-2’); 13CNMR (50 MHz, CDCl 3): d=202.8, 159.2, 150.3,
144.7, 135.2, 131.6, 125.5, 123.7, 119.3, 62.9, 44.5, 32.8, 30.0, 23.7,
23.6 ppm; HRMS (FAB+): calcd for (C16H21NO2SBr) [M+H]+:
370.0476; found: 370.0470.
2-n-Butyl-5-[2-(N,N-diethylamino)phenylsulfinyl]-2-cyclopentenone (2j):
A: 1H NMR (200 MHz, CDCl3): d=7.82 (dd, J=1.6, 7.5 Hz, 1H; Ar),
7.43 (dt, J=1.6, 7.5 Hz, 1H; Ar), 7.30 (m, 2H; H-3, Ar), 7.12 (dd, J=1.6,
7.5 Hz, 1H; Ar), 4.47 (dd, J=2.7, 7.0 Hz, 1H; H-5), 3.10 (q, J=7.0 Hz,
4H; N(CH2CH3)2), 2.75–2.60 (m, 1H; H-4), 2.17 (m, 2H; H-1’), 2.12–1.94
(m, 1H; H-4), 1.60–1.22 (m, 4H; H-2’, H-3’), 1.06 (t, J=7.0 Hz, 6H;
N(CH2CH3)2), 0.90 ppm (t, J=7.0 Hz, 3H; H-4’); 13CNMR (75 MHz,
CDCl3): d=203.1, 157.9, 147.8, 147.1, 137.6, 131.1, 125.9, 124.2, 122.0,
62.9, 47.7, 29.6, 24.7, 23.7, 22.4, 13.8, 12.1 ppm; HRMS (MALDI-TOF):
calcd for C19H28NO2S [M+H]+: 334.1835; found: 334.1827; B: 1H NMR
(200 MHz, CDCl3; significant signal): d=4.15 ppm (dd, J=2.7, 7.0 Hz,
1H; H-5).
(1R,2S)-2-(p-Tolylsulfonylamino)-1-phenylpropyl (S)-2-(N,N-dimethyla-
mino)phenyl sulfinate (16): A solution of N,N-dimethyl-2-iodoaniline
(1.02 g, 4.13 mmol) and I2 in dry Et2O (4 mL) was added to a flask con-
taining Mg (150 mg, 6.19 mmol) at RT under an argon atmosphere. The
reaction mixture was heated until complete formation of the magnesium
iodide. It was then diluted with dry THF (15 mL) and cooled to À788C.
A solution of 15[46] (725 mg, 2.06 mmol) in dry THF (10 mL) was added.
The solution was stirred at À788Cfor 1 h and saturated aqueous NH 4Cl
(20 mL) was then added. The mixture was extracted with ethyl acetate
(2ꢃ15 mL) and the combined organic layers were dried (Na2SO4) and
evaporated. The crude product was purified by flash chromatography
(hexane/ethyl acetate 4:1) to afford 16 (975 mg, 99%, colorless oil).
[a]D =À147 (c=1.2, CHCl3); 1H NMR (200 MHz, CDCl3): d=7.99 (dd,
J=1.6, 8.1 Hz, 1H; Ar), 7.83 (d, J=8.1 Hz, 2H; Ar), 7.51 (dt, J=1.6,
7.5 Hz, 1H; Ar), 7.35–7.20 (m, 6H; Ar), 7.09 (m, 3H; Ar), 5.70 (d, J=
9.7 Hz, 1H; H-1), 5.11 (d, J=2.7 Hz, 1H; NH), 3.64 (m, 1H; H-2), 2.62
(s, 6H; N(CH3)2), 2.43 (s, 3H; ArCH3), 0.93 ppm (d, J=7.0 Hz, 3H; H-
3); 13CNMR (75 MHz, CDCl 3): d=152.4, 143.2, 138.6, 138.3, 137.5, 133.5,
129.6, 128.2, 127.9, 127.1, 125.9, 125.0, 123.2, 119.7, 84.1, 54.3, 45.1, 21.5,
14.7 ppm; HRMS (FAB+): calcd for (C24H29N2O4S2) [M+H]+: 473.1569;
found: 473.1573.
2,3-Dimethyl-5-[2-(N,N-dimethylamino)phenylsulfinyl]-2-cyclopentenone
(10): A solution of 2-butyne (18 mL, 0.23 mmol) and [Co2(CO)8] (79 mg,
0.23 mmol) in CH3CN (1 mL) was stirred under an argon atmosphere at
08C. After 1 h, N-methylmorpholine N-oxide (54 mg, 0.46 mmol) and a
solution of 1i (15 mg, 0.08 mmol) in CH3CN (0.5 mL) were added at 08C.
The solution was placed in a teflon reaction vessel and allowed to react
at 10 Kbar and RT for 48 h. The reaction mixture was diluted with
CH2Cl2, treated with trimethylamine N-oxide (50 mg), and stirred for
10 min at RT. After removal of the solvent, the crude product was dis-
solved in diethyl ether and filtered through a pad of celite. The combined
organic solvents were evaporated and the residue was purified by chro-
matography (Et3N-pretreated SiO2; hexane/ethyl acetate 2:1) to afford
10A and 10B as a 92:8 diastereomeric mixture (7 mg, 33%, conversion=
70%, colorless oil). A: 1H NMR (200 MHz, CDCl3): d=7.81 (dd, J=1.6,
7.7 Hz, 1H; Ar), 7.43 (dt, J=1.6, 7.3 Hz, 1H; Ar), 7.26 (t, J=7.7 Hz, 1H;
Ar), 7.10 (d, J=8.1 Hz, 1H; Ar), 4.28 (dd, J=2.8, 7.3 Hz, 1H; H-5), 2.78
(s, 6H; N(CH3)2), 2.65–2.56 (m, 1H; H-4), 2.01 (s, 3H; CH3), 1.97–1.81
(m, 1H; H-4), 1.72 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=
202.6, 171.1, 150.4, 137.0, 135.7, 131.5, 125.7, 123.7, 119.2, 62.8, 44.6, 28.2,
17.3, 8.1 ppm; HRMS (EI+): calcd for (C15H19NO2S) [M]+: 277.1137;
found: 277.1150; B: 1H NMR (200 MHz, CDCl3; significant signals): d=
4.06 (dd, J=3.2, 4.9 Hz, 1H; H-5), 2.68 ppm (s, 6H; N(CH3)2).
(R)-2-(N,N-Dimethylamino)phenyl vinyl sulfoxide [(R)-1i]: Vinyl magne-
sium bromide (1m in THF, 5.24 mL, 5.24 mmol) was added to a solution
of sulfinate 16 (825 mg, 1.75 mmol) in THF (15 mL) at À788C. The so-
lution was stirred at À788Cfor 2 h and saturated aqueous NH 4Cl
(20 mL) was then added. The mixture was extracted with ethyl acetate
(2ꢃ15 mL) and the combined organic layers were dried (Na2SO4) and
evaporated. The crude product was purified by flash chromatography
(hexane/diethyl ether 1:1) to afford the sulfoxide (R)-1i (225 mg, 66%,
colorless oil). The spectral data were identical to those described for
(Æ)-1i. [a]D =+551 (c=1.0, CHCl3); HPLC: ee>99% (Daicel Chiralpak
AD column, hexane/isopropanol 95:5 at 0.5 mLminÀ1, l=254 nm; tR =
19.5 min (S) and 21.4 min (R)).
2-n-Butyl-5-[2-(N,N-dimethylamino)phenylsulfinyl]-4-methyl-2-cyclopen-
tenone (12): A solution of 1-hexyne (33 mL, 0.29 mmol) and [Co2(CO)8]
(98 mg, 0.29 mmol) in CH3CN (1.5 mL) was stirred under an argon at-
mosphere at RT. After 1 h, N-methylmorpholine N-oxide (67 mg,
0.57 mmol) and a solution of (Z)-11 (20 mg, 0.10 mmol) in CH3CN
(1 mL) were added. The solution was placed in a teflon reaction vessel
and allowed to react at 10 Kbar and RT for 48 h. The reaction mixture
was diluted with CH2Cl2, treated with trimethylamine N-oxide (50 mg),
and stirred for 10 min at RT. After removal of the solvent, the crude
product was dissolved in diethyl ether and filtered through a pad of
celite. The combined organic solvents were evaporated and the residue
was purified by chromatography (Et3N-pretreated SiO2; hexane/ethyl
acetate 5:1) to afford trans-12A (7 mg, 22%, conversion=60%, colorless
oil) and trans-12B (3 mg, 9%, colorless oil).
(2S,3S,5S,SR)-[5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2,3-osmadioxy-
2-(triisopropylsilyloxy)methylcyclopentan-1-one]-[N,N,N’,N’-tetramethy-
lethylenediamine] osmate diester (17):
A solution of OsO4 (71 mg,
0.28 mmol) in CH2Cl2 (2 mL) was added to a solution of cyclopentenone
(5S,SR)-7A (110 mg, 0.25 mmol) and TMEDA (42 mL, 0.28 mmol) in
CH2Cl2 (3 mL) cooled to À788Cunder an argon atmosphere. After being
stirred at À788Cfor 1 h, the reaction mixture was treated with saturated
aqueous Na2SO3 (5 mL) and stirred for 2 h at RT. The mixture was ex-
tracted with AcOEt (5ꢃ10 mL) and the combined organic layers were
dried (Na2SO4) and evaporated. The crude product was triturated with
hexane and filtered to afford 17 (165 mg, 81%, brown solid). M.p. >
By following the same procedure, (E)-11 (20 mg, 0.10 mmol) afforded
trans-12A (5 mg, 16%, conversion=45%) and trans-12B (2 mg, 6%).
1
trans-12A: H NMR (300 MHz, CDCl3): d=7.85 (dd, J=1.6, 7.7 Hz, 1H;
Ar), 7.45 (dt, J=1.6, 7.3 Hz, 1H; Ar), 7.28 (dt, J=1.2, 7.7 Hz, 1H; Ar),
7.13 (m, 1H; H-3), 7.09 (dd, J=1.2, 7.7 Hz, 1H; Ar), 3.92 (d, J=2.8 Hz,
1H; H-5), 2.92 (m, 1H; H-4), 2.78 (s, 6H; N(CH3)2), 2.18 (m, 2H; H-1’),
1.50–1.24 (m, 4H; H-2’, H-3’), 0.89 (t, J=7.3 Hz, 3H; H-4’), 0.44 ppm (d,
J=7.3 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=203.0, 163.2, 150.6,
145.7, 135.0, 131.6, 125.6, 124.0, 118.9, 69.7, 44.6, 30.7, 29.5, 24.5, 22.4,
18.6, 13.8 ppm; HRMS (EI+): calcd for C18H25NO2S [M]+: 319.1606;
found: 319.1620.
trans-12B: 1H NMR (300 MHz, CDCl3): d=7.81 (dd, J=1.6, 7.7 Hz, 1H;
Ar), 7.49 (dt, J=1.6, 7.3 Hz, 1H; Ar), 7.33 (dt, J=1.2, 7.7 Hz, 1H; Ar),
7.18 (dd, J=1.2, 7.7 Hz, 1H; Ar), 7.16 (m, 1H; H-3), 3.65 (d, J=2.4 Hz,
1H; H-5), 3.37 (m, 1H; H-4), 2.71 (s, 6H; N(CH3)2), 2.09 (m, 2H; H-1’),
1.50–1.24 (m, 4H; H-2’, H-3’), 1.30 (d, J=7.3 Hz, 3H; CH3), 0.87 ppm (t,
J=7.3 Hz, 3H; H-4’); 13CNMR (75 MHz, CDCl 3): d=199.6, 160.1, 150.8,
146.8, 135.0, 131.8, 126.5, 124.4, 119.6, 69.5, 44.8, 37.1, 29.6, 24.4, 22.4,
19.9, 13.8 ppm; HRMS (EI+): calcd for C18H25NO2S [M]+: 319.1606;
found: 319.1617.
1408C(decomp);
[
a]D =À99 (c=0.2, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.83 (dd, J=1.6, 7.7 Hz, 1H; Ar), 7.39 (dt, J=1.6, 7.7 Hz,
1H; Ar), 7.25 (dt, J=1.2, 7.3 Hz, 1H; Ar), 7.06 (dd, J=1.2, 7.7 Hz, 1H;
Ar), 5.03 (dd, J=1.6, 4.4 Hz, 1H; H-3), 4.36 (dd, J=8.9, 11.3 Hz, 1H; H-
5), 4.23/4.02 (AB system, J=10.9 Hz, 2H; H-1’), 3.02 (m, 4H;
NCH2CH2N), 2.84 (s, 3H; N(CH3)2), 2.83 (s, 3H; N(CH3)2), 2.82 (m, 1H;
H-4), 2.80 (s, 3H; N(CH3)2), 2.73 (s, 3H; N(CH3)2), 2.68 (s, 6H;
N(CH3)2), 1.76 (m, 1H; H-4), 1.13 ppm (m, 21H; TIPS); 13CNMR
(75 MHz, CDCl3): d=212.5, 150.3, 136.5, 131.0, 125.7, 123.8, 119.3, 99.7,
88.7, 65.7, 64.3, 64.0, 61.8, 51.7, 51.4, 51.3, 46.0, 44.5, 23.8, 17.9, 11.8 ppm;
HRMS (FAB+): calcd for (C29H54N3O7SiSOs) [M+H]+: 808.3067;
found: 808.3066.
(2S,3S)-[2,3-Osmadioxy-2-(triisopropylsilyloxy)methyl-4-cyclopente-
none]-[N,N,N’,N’-tetramethylethylenediamine] osmate diester (18): A so-
lution of sulfoxide 17 (110 mg, 0.14 mmol) in toluene (5 mL) was heated
Chem. Eur. J. 2004, 10, 5443 – 5459
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5455

J. C. Carretero et al.
FULL PAPER
to reflux for 1 h. The mixture was then cooled to RT, the solvent was
evaporated under reduced pressure, and the residue was purified by chro-
matography (CH3CN) to afford 18 (64 mg, 72%, brown solid). M.p.
>2008C(decomp); [ a]D =+245 (c=0.1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.61 (dd, J=2.0, 5.7 Hz, 1H; H-3), 6.26 (dd, J=1.2, 6.1 Hz,
1H; H-2), 5.58 (dd, J=1.2, 2.4 Hz, 1H; H-4), 4.23/4.00 (AB system, J=
8.9 Hz, 2H; H-1’), 3.05 (m, 4H; NCH2CH2N), 2.86 (s, 3H; N(CH3)2), 2.84
(s, 3H; N(CH3)2), 2.83 (s, 3H; N(CH3)2), 2.75 (s, 3H; N(CH3)2), 1.02 ppm
(m, 21H; TIPS); 13CNMR (50 MHz, CDCl 3): d=206.7, 162.9, 133.2, 94.1,
64.4, 62.3, 52.1, 51.6, 17.9, 11.9 ppm; HRMS (FAB+): calcd for
(C21H43N2O6SiOs) [M+H]+: 639.2505; found: 639.2487.
(À)-Pentenomycin I (19):[48] A solution of cyclopentenone 18 (64 mg,
0.10 mmol) in 2m HCl (4 mL) was stirred at RT for 6 h. The mixture was
washed with CH2Cl2 (3ꢃ5 mL) and the aqueous layer was concentrated.
The residue was purified by chromatography (ethyl acetate/methanol
10:1) to afford (À)-(2S,3S)-pentenomycin (11 mg, 76%, colorless oil).
[a]D =À32 (c=0.2, EtOH) (natural product:[48] [a]D21 =À32 (c=0.3,
EtOH)); 1H NMR (300 MHz, D2O): d=7.78 (dd, J=2.4, 6.1 Hz, 1H; H-
3), 6.39 (dd, J=1.2, 6.1 Hz, 1H; H-2), 4.78 (dd, J=1.2, 2.8 Hz, 1H; H-4),
3.77/3.71 ppm (AB system, J=11.3 Hz, 2H; H-6); 13CNMR (75 MHz,
D2O): d=213.3, 168.0, 136.9, 79.8, 75.1, 66.8 ppm.
H-4), 1.75–1.60 (m, 1H; H-4), 1.05 (m, 21H; TIPS), 0.95 (s, 9H; tBuSi),
0.26 (s, 3H; CH3Si), 0.17 ppm (s, 3H; CH3Si); 13CNMR (75 MHz,
CDCl3): d=150.8, 144.9, 137.4, 131.3, 125.6, 124.5, 124.4, 119.9, 77.6, 67.9,
60.7, 45.0, 25.7, 18.0, 11.9, À4.4, À4.6 ppm; HRMS (MALDI-TOF): calcd
for C29H54NO3Si2S [M+H]+: 552.3358; found: 552.3373; HPLC: ee>99%
(Daicel Chiralcel OD column, hexane/isopropanol 99.3:0.7 at
0.5 mLminÀ1
,
l=245 nm; tR =18.3 min (2S,3S,SR) and 22.2 min
(2R,3R,SS)).
3-(tert-Butyldimethylsilyloxy)-4-[2-(N,N-dimethylamino)phenylsulfinyl]-
2-(triisopropylsilyloxy)methyl-1,2-cyclopentanediol (21 and 21’): OsO4
(2.5% in tBuOH, 126 mL, 0.01 mmol) was added to a solution of 20
(230 mg, 0.42 mmol) and NMO (98 mg, 0.83 mmol) in THF/H2O 10:1
(22 mL). After being stirred at RT for 7 h, the reaction mixture was treat-
ed with saturated aqueous Na2SO3 (10 mL) and stirred for 30 min at RT.
The organic layer was separated, the aqueous layer was extracted with
AcOEt (4ꢃ10 mL), and the combined organic layers were dried
(Na2SO4) and evaporated. The residue was purified by flash chromatog-
raphy (Et3N-pretreated SiO2; hexane/ethyl acetate 6:1) to afford
(1R,2S,3S,4S,SR)-21 and (1S,2S,3S,4S,SR)-21’ as an inseparable mixture
(90:10) (203 mg, 83%, colorless oil). (1R,2S,3S,4S,SR)-21: 1H NMR
(300 MHz, CDCl3): d=7.74 (dd, J=1.6, 7.7 Hz, 1H; Ar), 7.42 (dt, J=1.6,
7.7 Hz, 1H; Ar), 7.28 (dt, J=1.2, 7.3 Hz, 1H; Ar), 7.14 (dd, J=1.2,
7.7 Hz, 1H; Ar), 4.45 (dd, J=5.3 Hz, 1H; H-2), 3.96–3.91 (m, 1H; H-3),
3.81 (s, 2H; H-1’), 3.54 (ddd, J=4.9, 9.7, 12.1 Hz, 1H; H-5), 3.50 (s, 1H;
OH), 3.06 (d, J=12.9 Hz, 1H; OH), 2.68 (s, 6H; N(CH3)2), 1.87 (ddd, J=
5.7, 10.5, 15.8 Hz, 1H; H-4), 1.64 (ddd, J=3.2, 4.9, 15.4 Hz, 1H; H-4),
1.04 (m, 21H; TIPS), 0.94 (s, 9H; tBuSi), 0.22 (s, 3H; CH3Si), 0.19 ppm
(s, 3H; CH3Si); 13CNMR (75 MHz, CDCl 3): d=151.0, 135.5, 131.9, 126.2,
124.8, 120.1, 82.8, 79.6, 72.6, 65.3, 64.7, 45.0, 27.1, 25.7, 18.0, 11.9, À4.4,
À4.9 ppm; HRMS (MALDI-TOF): calcd for C29H56NO5Si2S [M+H]+:
586.3412; found: 586.3402; (1S,2S,3S,4S,SR)-21’: 1H NMR (300 MHz,
CDCl3; significant signals): d=4.49 (d, J=7.7 Hz, 1H; H-2), 2.66 ppm (s,
6H; N(CH3)2).
(À)-Pentenomycin I triacetate:[55] Acetic anhydride (101 mL, 1.07 mmol)
was added to a solution of pentenomycin (11 mg, 0.08 mmol) in ice-cold
pyridine (204 mL, 2.52 mmol) under an argon atmosphere. After 24 h at
RT, water (5 mL) was added and the mixture was extracted with ethyl
acetate (3ꢃ5 mL). The combined organic solvents were evaporated and
the residue was purified by chromatography (hexane/ethyl acetate 2:1) to
afford (À)-pentenomycin triacetate (13 mg, 63%, white solid). M.p. 111–
[55]
1128C(literature value:
m.p. 112–1148C); [a]D =À8 (c=0.2, EtOH)
(literature value:[55] [a]D =À8 (c=0.5, EtOH)); 1H NMR (300 MHz,
CDCl3): d=7.45 (dd, J=2.8, 6.1 Hz, 1H; H-3), 6.51 (dd, J=1.6, 6.5 Hz,
1H; H-2), 5.81 (dd, J=1.6, 2.8 Hz, 1H; H-4), 4.36 (s, 2H; H-6), 2.10 (s,
3H; Ac), 2.08 (s, 3H; Ac), 2.05 ppm (s, 3H; Ac); 13CNMR (75 MHz,
CDCl3): d=199.7, 170.0, 169.5, 168.6, 154.3, 135.8, 77.2, 72.1, 64.3, 20.6,
20.4, 20.1 ppm; HPLC: ee>99% (Daicel Chiralpak AD column, hexane/
isopropanol 95:5 at 0.5 mLminÀ1, l=220 nm; tR =33.0 min (2S,3S) and
36.5 min (2R,3R)).
5-(tert-Butyldimethylsilyloxy)-1-(triisopropylsilyloxy)methyl-3-cyclopen-
tene-1,2-diol (22): A two-necked round-bottomed flask, equipped with a
stirrer and
a reflux condenser and containing NaHCO3 (1.15 g,
13.65 mmol), was flame-dried in an argon stream. A solution of the sulf-
oxides 21 and 21’ (200 mg, 0.34 mmol) in toluene (8 mL) was added
through a cannula and the mixture was stirred vigorously and heated at
reflux for 16 h. The mixture was cooled to RT and filtered over celite.
The residue was purified by flash chromatography (Et3N-pretreated
SiO2; hexane/ethyl acetate 10:1) to afford (1R,2R,5R)-22 (111 mg, 78%,
colorless oil) and (1S,2S,5R)-22’ (11 mg, 8%, colorless oil). (1R,2R,5R)-
(1S,5S,SR)-5-[2-(N,N-Dimethylamino)phenylsulfinyl]-2-(triisopropylsily-
loxy)methyl-2-cyclopenten-1-ol: DIBALH (1.0m in THF, 1.89 mL,
1.89 mmol) was added to
a solution of cyclopentenone (5S,SR)-7A
(275 mg, 0.63 mmol) in dry THF (10 mL) cooled to À788Cunder argon
atmosphere. After being stirred at this temperature for 1 h, the mixture
was poured into an Erlenmeyer flask containing saturated aqueous potas-
sium–sodium tartrate (25 mL) and AcOEt (25 mL). The two layers were
stirred at RT for 30 min and separated. The aqueous layer was extracted
with AcOEt (4ꢃ15 mL) and the combined organic layers were dried
(Na2SO4) and evaporated. The residue was purified by flash chromatog-
raphy (Et3N-pretreated SiO2; hexane/ethyl acetate 3:1) to afford the al-
cohol (265 mg, 96%, colorless oil). [a]D =+250 (c=1.0, CHCl3);
1H NMR (200 MHz, CDCl3): d=7.80 (d, J=8.1 Hz, 1H; Ar), 7.41 (t, J=
7.5 Hz, 1H; Ar), 7.23 (t, J=7.5 Hz, 1H; Ar), 7.10 (d, J=8.1 Hz, 1H;
Ar), 5.63 (s, 1H; H-3), 5.37 (m, 1H; H-1), 4.44 (m, 2H; H-1’), 3.84 (m,
1H; H-5), 3.47 (d, J=2.7 Hz, 1H; OH), 2.75 (s, 6H; N(CH3)2), 2.56–2.42
(m, 1H; H-4), 1.90 (dd, J=8.6, 17.8 Hz, 1H; H-4), 1.08 ppm (m, 21H;
TIPS); 13C NMR (50 MHz, CDCl3): d=150.6, 142.9, 136.1, 131.3, 126.8,
125.5, 123.7, 119.3, 78.6, 66.4, 61.9, 44.5, 26.5, 17.9, 11.7 ppm; HRMS
(FAB+): calcd for C23H40NO3SiS [M+H]+: 438.2498; found: 438.2487.
1
22: [a]D =À84 (c=1.0, CHCl3); H NMR (200 MHz, CDCl3): d=5.93 (m,
1H; H-3), 5.86 (m, 1H; H-4), 4.69 (s, 1H; H-5), 4.63 (m, 1H; H-2), 3.97/
3.74 (AB system, J=9.7 Hz, 2H; H-1’), 3.22 (s, 1H; OH), 2.56 (d, J=
5.4 Hz, 1H; OH), 1.09 (m, 21H; TIPS), 0.87 (s, 9H; tBuSi), 0.08 (s, 3H;
CH3Si), 0.06 ppm (s, 3H; CH3Si); 13CNMR (50 MHz, CDCl 3): d=135.8,
134.5, 80.9, 79.9, 77.3, 65.5, 25.8, 17.9, 11.9, À4.6, À4.9 ppm; HRMS
(MALDI-TOF): calcd for C21H44O4Si2Na [M+Na]+: 439.2670; found:
439.2674; (1S,2S,5R)-22’: [a]D =+3 (c=1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.88 (dt, J=1.6, 6.1 Hz, 1H; H-3), 5.65 (dt, J=1.6, 6.1 Hz,
1H; H-4), 4.78 (c, J=1.6 Hz, 1H; H-5), 4.55 (dq, J=1.6, 10.1 Hz, 1H; H-
2), 3.78/3.60 (AB system, J=9.7 Hz, 2H; H-1’), 3.56 (s, 1H; OH), 2.89 (d,
J=9.7 Hz, 1H; OH), 1.06 (m, 21H; TIPS), 0.92 (s, 9H; tBuSi), 0.15 (s,
3H; CH Si), 0.14 ppm (s, 3H; CH3Si); 13CNMR (75 MHz, CDCl 3): d=
3
135.9, 132.0, 79.4, 75.2, 74.8, 63.3, 25.7, 18.0, 12.0, À4.4, À4.8 ppm.
(1S,2R,3R,4R,5S)-4-(tert-Butyldimethylsilyloxy)-3-(triisopropylsilyloxy)-
methyl-6-oxabicyclo[3.1.0]hexane-2,3-diol (23): A solution of MCPBA
(70%, 222 mg, 0.90 mmol) in CH2Cl2 (10 mL) was added to a solution of
22 (125 mg, 0.30 mmol) in CH2Cl2 (5 mL). After 3 days at RT, saturated
aqueous Na2SO3 (5 mL) was added, followed by saturated aqueous
NaHCO3 (20 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2ꢃ10 mL). The combined organic
layers were dried (Na2SO4) and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate 4:1) to afford 23 (120 mg,
92%, colorless oil). [a]D =À49 (c=1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d=4.25 (m, 1H; H-2), 4.07 (s, 1H; H-4), 3.85/3.78 (AB system,
J=9.7 Hz, 2H; H-1’), 3.66 (m, 1H; H-1), 3.37 (d, J=2.7 Hz, 1H; H-5),
2.96 (brs, 1H; OH), 2.73 (brs, 1H; OH), 1.05 (m, 21H; TIPS), 0.87 (s,
9H; tBuSi), 0.10 (s, 3H; CH3Si), 0.08 ppm (s, 3H; CH3Si); 13CNMR
(3S,4S,SR)-3-(tert-Butyldimethylsilyloxy)-4-[2-(N,N-dimethylamino)phe-
nylsulfinyl]-2-(triisopropylsilyloxy)methylcyclopentene (20): TBDMSCl
(456 mg, 3.03 mmol) was added to a solution of the alcohol (265 mg,
0.61 mmol) and imidazole (124 mg, 1.82 mmol) in dry CH3CN (8 mL)
under an argon atmosphere. After 14 h at RT, water (5 mL) was added.
The organic layer was separated, the aqueous layer was extracted with
AcOEt (2ꢃ10 mL), and the combined organic layers were dried
(Na2SO4) and evaporated. The residue was purified by flash chromatog-
raphy (Et3N-pretreated SiO2; hexane/ethyl acetate 8:1) to afford 20
(330 mg, 99%, white solid). M.p. 78–808C ; [a]D =+166 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.80 (dd, J=1.6, 7.5 Hz, 1H; Ar), 7.44
(dt, J=1.6, 7.5 Hz, 1H; Ar), 7.25 (dt, J=1.6, 7.5 Hz, 1H; Ar), 7.15 (dd,
J=1.1, 7.5 Hz, 1H; Ar), 5.66 (m, 1H; H-5), 5.23 (m, 1H; H-2), 4.26 (m,
2H; H-1’), 3.76 (m, 1H; H-3), 2.69 (s, 6H; N(CH3)2), 2.55–2.41 (m, 1H;
5456
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
(75 MHz, CDCl3): d=78.0, 76.2, 74.8, 66.7, 58.8, 56.2, 25.6, 17.9, 11.8,
À4.8, À5.2 ppm; HRMS (MALDI-TOF): calcd for C21H44O5NaSi2
[M+Na]+: 445.2619; found: 445.2612.
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32–42.
(1R,2R,3S,4S,5R)-3-Azido-5-(tert-butyldimethylsilyloxy)-1-(triisopropylsi-
lyloxy)methyl-1,2,4-cyclopentanetriol (24):
A solution of epoxide 23
(70 mg, 0.16 mmol) in DMF (7 mL) was added to a mixture of NH4Cl
(104 mg, 1.94 mmol) and NaN3 (126 mg, 1.94 mmol) in DMF (7 mL)
under an argon atmosphere. The reaction mixture was stirred at 1008C
for 20 h and water (10 mL) was then added. The organic layer was sepa-
rated and the aqueous layer was extracted with AcOEt (2ꢃ10 mL). The
combined organic layers were dried (Na2SO4) and evaporated. The resi-
due was purified by flash chromatography (hexane/ethyl acetate 10:1) to
afford 24 (58 mg, 76%, white solid). M.p. 49–508C ; a[ ]D =À12 (c=1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d=4.01 (dd, J=4.5, 7.7 Hz, 1H;
H-2), 3.87 (m, 1H; H-5), 3.86/3.82 (AB system, J=10.1 Hz, 2H; H-1’),
3.71 (m, 1H; H-3), 3.67 (m, 1H; H-4), 3.35 (s, 1H; OH), 2.67 (d, J=
4.5 Hz, 1H; OH), 2.46 (d, J=7.7 Hz, 1H; OH), 1.08 (m, 21H; TIPS),
0.88 (s, 9H; tBuSi), 0.11 (s, 3H; CH3Si), 0.09 ppm (s, 3H; CH3Si);
13C NMR (75 MHz, CDCl3): d=80.9, 80.6, 78.8, 78.0, 71.5, 66.9, 25.6,
17.9, 11.7, À4.6, À5.1 ppm; HRMS (MALDI-TOF): calcd for C21H45N3O5-
Si2Na [M+Na]+: 498.2790; found: 498.2805.
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(1R,2R,3S,4S,5R)-3-Amino-5-(tert-butyldimethylsilyloxy)-1-(triisopropyl-
silyloxy)methyl-1,2,4-cyclopentanetriol: 10% Pd/C(7 mg) was added to a
solution of azide 24 (35 mg, 0.07 mmol) in MeOH (3 mL) and the result-
ing suspension was stirred under an H2 atmosphere for 1 h. The solution
was filtered over celite, the filter cake was rinsed with methanol, and the
combined filtrate was evaporated to afford the amine (33 mg, 99%, col-
orless oil). [a]D =+1 (c=0.8, CH3OH); 1H NMR (300 MHz, CD3OD):
d=3.82 (d, J=7.3 Hz, 1H; H-5), 3.77 (s, 2H; H-1’), 3.67 (d, J=8.5 Hz,
1H; H-2), 3.39 (dd, J=7.3, 8.3 Hz, 1H; H-4), 2.85 (t, J=8.9 Hz, 1H; H-
3), 1.12 (m, 21H; TIPS), 0.92 (s, 9H; tBuSi), 0.13 ppm (s, 6H; CH3Si);
13CNMR (75 MHz, CD 3OD): d=84.9, 80.6, 78.0, 77.8, 68.9, 61.7, 26.5,
18.6, 13.2, À4.2, À4.6 ppm; HRMS (MALDI-TOF): calcd for
C21H48NO5Si2 [M+H]+: 450.3066; found: 450.3074.
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(1R,2R,3S,4S,5R)-4-Amino-1-hydroxymethyl-1,2,3,5-cyclopentanetetrol
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MeOH/HCl (1 mL) was stirred at RT for 4 h. The solvent was evaporated
and the resulting residue was washed with dry diethyl ether to afford 25
as a highly hygroscopic white solid (14 mg, 97%). [a]D =À6 (c=0.3,
CH3OH) (literature value for the enantiomer:[53] [a]D =+6.2 (c=1.2,
CH3OH)); 1H NMR (300 MHz, CD3OD): d=3.94 (d, J=9.7 Hz, 1H; H-
5), 3.81 (d, J=6.1 Hz, 1H; H-2), 3.71 (dd, J=6.1, 8.9 Hz, 1H; H-3), 3.67/
3.56 (AB system, J=10.9 Hz, 2H; H-1’), 3.22 ppm (t, J=9.3 Hz, 1H; H-
4); 13CNMR (75 MHz, CD 3OD): d=84.1, 78.2, 77.5, 72.7, 64.7, 60.9 ppm.
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Acknowledgment
Financial support of this work by the McyT (Ministerio de Ciencia y Tec-
nologia) is gratefully acknowledged (Projects: BQU2000-0226 and
BQU2003-0508). M.R.R. thanks the MEC(Ministerio de Aducación) for
a predoctoral fellowship. We also thank J. C. de la Rosa for some experi-
mental work, the Centro de Computación Científica (Universidad Autón-
oma de Madrid) for computation time, and Dr. M. Alcamí (Universidad
Autónoma de Madrid) for helpful discussions.
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Chem. Eur. J. 2004, 10, 5443 – 5459
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J. C. Carretero et al.
FULL PAPER
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5458
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www.chemeurj.org
Chem. Eur. J. 2004, 10, 5443 – 5459

Stereochemical Control in Intermolecular Pauson–Khand Reactions
5443 – 5459
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Received: May 6, 2004
Published online: September 23, 2004
Chem. Eur. J. 2004, 10, 5443 – 5459
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5459