Asymmetric Intermolecular Pauson-Khand Reactions of Unstrained Olefins: The (o-Dimethylamino)phenylsulfinyl Group as an Efficient Chiral Auxiliary

Article abstract of DOI:10.1021/ja038491l

The first asymmetric version of intermolecular Pauson?Khand reactions of unstrained alkenes is described. Generally simple acyclic alkenes exhibit low reactivity and regioselectivity in intermolecular Pauson?Khand reactions; however, o-(dimethylamino)phen

Full text of DOI:10.1021/ja038491l

Published on Web 11/14/2003
Asymmetric Intermolecular Pauson-Khand Reactions of Unstrained Olefins:
The (o-Dimethylamino)phenylsulfinyl Group as an Efficient Chiral Auxiliary
Marta Rodr´ıguez Rivero, Juan Carlos de la Rosa, and Juan Carlos Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
Received September 12, 2003; E-mail: juancarlos.carretero@uam.es
Table 1. N-Oxide-Promoted Intermolecular PKR of 1-Hexyne
Dicobalt Complex with Racemic Vinyl Sulfoxides 1
Since its discovery three decades ago, the Co2(CO)8-mediated
cocyclization of an alkene, an alkyne, and carbon monoxide, known
as the Pauson-Khand reaction (PKR), has become one of the most
efficient methods for the synthesis of cyclopentanoid systems.1
However, despite impressive recent advances in this field, such as
the development of the first versions of both catalytic and
asymmetric intramolecular PKR,2 some important limitations still
remain. One of these is the lack of asymmetric intermolecular
versions of PKR for unstrained olefins, which would open a
synthetically quite general access to the enantioselective synthesis
of substituted nonfused cyclopentenones from simple alkenes and
alkynes. Up to now, to the best of our knowledge, all the reported
examples of asymmetric intermolecular PKR are limited to the use
of highly reactive strained cyclic alkenes, such as norbornene,
norbornadiene, and bicyclo[3.2.0]hept-6-ene.1,3
Herein we report that vinyl sulfoxides, in particular the potentially
cobalt-coordinating4,5 2-(N,N-dimethylamino)phenyl vinyl sulf-
oxide, react with a wide variety of alkyne dicobalt complexes under
mild conditions and with exceptionally high levels of regio- and
stereocontrol. In addition, the chemical versatility of the result-
ing 5-sulfinyl-2-cyclopentenones makes this type of PK adducts
very appealing intermediates in organic synthesis, as illustrated
here by a highly efficient four-step enantioselective synthesis of
(-)-pentenomycin I antibiotic.6
Having demonstrated previously that 1-tert-butylsulfinyl-1,6-
enynes were suitable substrates for stereoselective intramolecular
PKR,7,8 we decided to explore the ability of sulfoxide-based chiral
auxiliaries in the much less thermodynamically favorable intermo-
lecular processes. First, to check the viability of this hypothesis a
series of racemic vinyl sulfoxides (1a-f), displaying different steric
and electronic environments around the sulfur atom, were prepared
by straightforward methods and treated with the dicobalt complex
of 1-hexyne under a variety of reaction conditions. In accordance
with the usual low reactivity of unstrained alkenes in intermolecular
PKR,1 we only found metal decomplexation and formation of side
products under thermal conditions (toluene or CH3CN at 80 °C),
while a sluggish reaction was observed at room temperature using
amine N-oxides as promoters in low polar solvents (e.g., toluene
or CH2Cl2). Pleasingly, a faster and cleaner reaction was observed
using N-methylmorpholine N-oxide (NMO) in acetonitrile (Table
1).
Some important conclusions are drawn from the data of Table
1. Unlike the low regioselectivity usually observed in the PKR of
simple monosubstituted alkenes with terminal alkynes,9 the PKR
of all vinyl sulfoxides 1 was completely regioselective, leading
exclusively to the 2,5-disubstituted cyclopentenones 2. In contrast,
both the reactivity and the stereoselectivity proved to be strongly
dependent on the substitution at sulfur. Thus, a low conversion
(although very high stereoselectivity) was observed in the case of
the bulky sulfoxides 1d,e (entries 4 and 5), even in the presence of
entrya
R
alkene
t (h)
adduct
A/B ratiob
yield (%)c
1
p-Tol
o-Tol
o-BrC6H4
2,4,6-(i-Pr)3C6H2
t-Bu
o-(Me2N)C6H4
o-(Me2N)C6H4
1a
1b
1c
1d
1e
1f
2
24
24
24
24
1
2a
2b
2c
2d
2e
2f
74:26
90:10
86:14
94:6
>98:<2
92:8
68
28
30
24
20
63
74
2d
3d
4d
5d
6
7e
1f
4
2f
93:7
a
Reaction conditions: dicobalt complex (1.5 equiv), alkene 1 (1.0 equiv),
b
1
NMO (6.0 equiv), CH3CN, rt. By H NMR on the crude mixtures after
filtration of the cobalt byproducts. In pure adducts after chromatography.
Dicobalt complex (3 equiv) was used. Reaction run at 0 °C.
c
d
e
a large excess of the alkyne dicobalt complex (3-fold excess) and
under prolonged reaction times. On the opposite end, the PKR of
the less hindered p-tolylsulfoxide 1a was complete in 2 h, although
with poor stereocontrol (entry 1). An intermediate result with regard
to reactivity and stereoselectivity was obtained in the case of the
o-substituted arylsulfoxides 1b,c (entries 2 and 3). HoweVer, the
ortho-amino-substituted sulfoxide 1f afforded by far the most
synthetically interesting result: not only was 1f the most reactiVe
alkene, but the reaction was also highly diastereoselectiVe10 (entry
6). This remarkable reactivity, which may be tentatively ascribed
to the prior coordination of the Me2N moiety to the cobalt
complex,4,5 allowed it to carry out the process at 0 °C (entry 7),
affording 2f as a 93:7 mixture of A/B epimers11 in 74% yield.
Next, to explore the structural scope of the PKR of the optimal
vinyl sulfoxide 1f, a variety of alkyne dicobalt complexes were
subjected to the same reaction conditions (NMO, CH3CN, 0 °C).
The results are collected in Table 2.
Gratifyingly, reasonable yields of isolated adducts (49-74%),
complete regioselectivities, and very high diastereoselectivities11
(de ) 86 to >96%) were obtained from all terminal alkynes,
including primary-, benzyl-, and tertiary alkyl-substituted ones
(entries 1-3), aryl acetylenes (entry 4), and functionalized alkynes
(entries 5-7). It is worth noting that the reaction conditions are so
mild that even alkynes having a primary bromoalkyl chain can be
successfully used (entry 7). However, no reaction at all occurred
in the case of internal alkynes, as 2-butyne (entry 8). This drawback
was partially solved by performing the reaction at high pressure
(10 Kbar) at room temperature, affording the adducts 9 in 33%
yield and high stereoselectivity (entry 9).12
To apply these highly diastereoselective PKR in asymmetric
synthesis, enantiopure vinyl sulfoxide 1f was required. The prepara-
tion of (R)-1f was readily achieved in two steps from the sulfinyl
9
14992
J. AM. CHEM. SOC. 2003, 125, 14992-14993
10.1021/ja038491l CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. PKR of Vinyl Sulfoxide 1f with Differently Substituted
Alkynes
In conclusion, the first asymmetric version of intermolecular PKR
of acyclic alkenes, relying on the use of sulfoxides as chiral
auxiliaries, has been developed. o-(Dimethylamino)phenyl vinyl
sulfoxide (1f), readily available in both racemic and enantiopure
forms, reacts under very mild conditions with terminal alkynes in
a completely regioselective and highly stereoselective manner. The
resulting enantiopure 5-sulfinyl-2-cyclopentenones are versatile
intermediates in asymmetric synthesis since the five positions at
the ring can be easily functionalized by straightforward carbonyl-
or sulfoxide-based reactions. Further studies on the mechanistic
behavior of 1f, as well as the application of the PK adducts in
enantioselective synthesis of cyclopentanoids are underway.
entrya
R
R′
t (h)
adduct
A/B ratiob
yield (%)c
1
n-Bu
t-Bu
Bn
p-Tol
TMS
CH2CH2OTIPS
CH2CH2CH2Br
Me
H
H
H
H
H
H
H
Me
Me
4
26
14
12
16
7
6
24
48
2f
3
4
5
6
7
8
9
9
93:7
>98:<2
93:7
74
55
58
49
59
66
68
nr
2d,e
3d
4
93:7
5e
6
7
>98:<2
>98:<2
>98:<2
Acknowledgment. Financial support of this work by the MCYT
is gratefully acknowledged (Project BQU2000-0226). M.R.R. thanks
the MEC for a predoctoral fellowship.
8
9f
Me
92:8
33
Supporting Information Available: Experimental procedures,
characterization data of all new compounds, X-ray diffraction data of
3A, and NMR spectra (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions: dicobalt complex (1.5 equiv), alkene 1 (1.0 equiv),
NMO (6.0 equiv), CH3CN, 0 °C. b,c,d As in Table 1. e Reaction run at room
temperature. f Reaction run at 10 Kbar.
Scheme 1
References
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(3) Using this type of alkenes, Perica`s et al. have reported outstanding results.
See, for instance: (a) Fonquerna, S.; Moyano, A.; Perica`s, M. A.; Riera,
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Scheme 2
(4) Krafft et al. demonstrated that sulfur and nitrogen coordination to cobalt
improves the reactivity and regioselectivity in intermolecular PKR of
unstrained alkenes: Krafft, M. E.; Juliano, C. A.; Scott, I. A.; Wright,
C.; McEachin, M. D. J. Am. Chem. Soc. 1991, 113, 1693-1703.
(5) For the use of pyridylsilyl as directing group in the intermolecular Ru-
catalyzed PKR, see: Itami, K.; Mitsudo, K.; Yoshida, J. Angew. Chem.,
Int. Ed. 2002, 41, 3481-3484.
(a) NMO, CH3CN, 0 °C. (b) OsO4, TMEDA, CH2Cl2, -78 °C. (c)
Toluene, reflux. (d) HCl 2M, rt.
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1233-1238.
(7) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7411-7412.
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M.; Adrio, J.; Carretero, J. C. Eur. J. Org. Chem. 2002, 2881-2889.
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In contrast, the intermolecular PKR of electron-poor alkenes, such as
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derivative of norephedrine 10 following the recently reported
Senanayake’s procedure.13 Reaction of 10 with o-(dimethylamino)-
phenylmagnesium iodide (THF, -78 °C) and further treatment with
vinylmagnesium bromide afforded (R)-1f in 66% overall yield and
in very high optical purity (ee > 99%, HPLC), showing that both
displacement reactions at sulfur occur with complete inversion of
configuration (Scheme 1).
Finally, to highlight the synthetic potential of these sulfinylated
PK products, we accomplished the shortest reported synthesis of
the antibiotic (-)-pentenomycin I14 (Scheme 2). Treatment of cobalt
complex 11 with (R)-1f under the optimized PKR conditions
afforded the adduct 12 (62% yield) in a 93:7 isomer ratio. Simple
precipitation with cold hexane gave pure 12A, whose excellent
optical purity (ee > 99%, HPLC) proved that, as expected, the PKR
took place without racemization at sulfur.15,16 The stereoselective
dihydroxylation of 12A with OsO4/TMEDA furnished the remark-
ably stable osmate diester 13 (81% yield). Sulfoxide pyrolysis in
refluxing toluene gave the hydroxyl-protected enone 14 (72%),
which after acidic hydrolysis afforded the natural (-)-(2S,3S)-
pentenomycin I (ee > 99%, determined by HPLC on its triacetate
derivative).14
(10) For the use of the o-(dimethylamino)phenylsulfinyl group as chiral
auxiliary in asymmetric Heck reactions, see: D´ıaz Buezo, N.; Alonso, I.;
Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129-7130.
(11) The stereochemical assignment of the diastereomers 2-9 (A + B) was
first tentatively established by NMR and unequivocally confirmed in the
case of 3A by X-ray diffraction.
(12) For a review on the use of high pressure on organometallic reactions,
see: Reiser, O. In High-Pressure Chemistry; Van Eldik, R., Klaerner,
F.-G., Eds.; Wiley-VCH: Weinheim, Germany, 2002; pp 223-238.
(13) Han, Z.; Krishnamurthy, D.; Grover, P.; Wilkinson, H. S.; Fang, Q. K.;
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(14) Gallos, J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron Lett. 2001,
42, 5769-5771 and references therein.
(15) As a second example of the lack of racemization at sulfur in the asymmetric
version of this PKR, adduct (5S,SR)-7A was obtained in >99% ee from
enantiopure vinyl sulfoxide (R)-1f.
(16) In contrast, the PKR of sulfinylacetylenes takes place with partial
racemization at sulfur: Montenegro, E.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Alvarez-Larena, A.; Piniella, J. F. Tetrahedron: Asymmetry 1999,
10, 457-471.
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