Highly stereoselective intramolecular Michael addition using α-sulfinyl vinyllithium as an unprecedented Michael donor

Article abstract of DOI:10.1021/ol006697a

(equation presented) The first example of an asymmetric intramolecular Michael addition reaction using α-lithiated vinylic sulfoxide as a Michael donor is reported. Michael addition of the α-lithiated vinylic sulfoxide to (Z)-enoates proceeds with high di

Full text of DOI:10.1021/ol006697a

ORGANIC
LETTERS
2001
Vol. 3, No. 1
29-31
Highly Stereoselective Intramolecular
Michael Addition Using r-Sulfinyl
Vinyllithium as an Unprecedented
Michael Donor
Naoyoshi Maezaki, Sachiko Yuyama, Hiroaki Sawamoto, Tomoko Suzuki,
Mayuko Izumi, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received October 5, 2000
ABSTRACT
The first example of an asymmetric intramolecular Michael addition reaction using r-lithiated vinylic sulfoxide as a Michael donor is reported.
Michael addition of the r-lithiated vinylic sulfoxide to (Z)-enoates proceeds with high diastereoselectivity to give the adducts having a stereogenic
center with (R)-configuration at the â-position of the ester in the cyclopentene ring formation. The selectivity was reversed in the six-membered
ring formation. On the other hand, the corresponding (E)-enoates provided Michael adducts with poor diastereoselectivity.
Vinylic sulfoxides are well-known chiral Michael acceptors,
and the efficacy of the sulfoxide to differentiate the diaste-
reotopic face of double bonds has made this reaction an
attractive subject for study.1,2 In contrast, the use of vinylic
sulfoxide as a “Michael donor” has remained unexplored.
Recently, we have reported a novel intramolecular alkylation
of a vinylic lithium species generated by R-deprotonation
of vinylic sulfoxides with LDA.3 Next, we turned our
attention to Michael addition reactions of the R-lithiated
vinylic sulfoxides to enoates, since the addition of the chiral
carbanions to the prochiral Michael acceptor should proceed
diastereoselectively, thereby creating a stereogenic center at
the â-position of the ester. Although asymmetric reaction
by means of the chiral R-sulfinyl vinylic carbanions has been
extensively examined on the intermolecular nucleophilic
addition to aldehydes4 or ketones,5 this type of reaction
generally proceeds with moderate to poor diastereoselectivity,
except for one example.6 Furthermore, to the best of our
knowledge, there is no report regarding the order of acidity
between the R-proton of the vinylic sulfoxide and the R,â-
or γ-protons of the enoate, which can be abstracted by a
strong base such as LDA.7 In addition, this reaction provides
a convenient access to functionalized cyclohexene and
cyclopentene derivatives, which would be functionalized
diastereoselectively.1,2 In this paper, we report a highly
diastereoselective intramolecular Michael addition reaction
of the vinylic sulfoxides with (Z)-enoates.
The required four geometric isomers of methyl 7-sulfinyl-
(4) Fawcett, J.; House, S.; Jenkins, P. R.; Lawrence, N. J.; Russell, D.
R. J. Chem. Soc., Perkin Trans. 1 1993, 67-73 and references therein.
(5) Haynes, R. K.; Katsifis, A. G. Aust. J. Chem. 1989, 42, 1473-1483.
Haynes, R. K.; Katsifis, A. G. J. Chem. Soc., Chem. Commun. 1987, 340-
342.
(1) For a review, see: Carren˜o, M. C. Chem. ReV. 1995, 95, 1717-
1760.
(2) Priego, J.; Carretero, J. C. Synlett 1999, 1603-1605.
(3) (a) Maezaki, N.; Izumi, M.; Yuyama, S.; Sawamoto, H.; Iwata, C.;
Tanaka, T Tetrahedron 2000, 56, 7927-7945. (b) Maezaki, N.; Izumi, M.;
Yuyama, S.; Iwata, C.; Tanaka, T. Chem. Commun. 1999, 1825-1826.
(6) Solladie´, G.; Moine, G. J. Am. Chem. Soc. 1984, 106, 6097-6098.
(7) Selected references, see: Jeyaraj, D. A.; Kapoor, K. K.; Yadav, V.
K.; Gauniyal, H. M.; Parvez, M. J. Org. Chem. 1998, 63, 287-294. Ihara,
M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans.
1 1993, 2251-2258. Feit, B. A.; Melamed, U.; Schmidt, R. R.; Speer, H.
J. Chem Soc., Perkin Trans. 1 1981, 1329-1338.
10.1021/ol006697a CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/05/2000

1,6-heptadienoates (2a) were prepared from the known
4-(tetrahydro-2H-pyran-2-yloxy)butanal8 as shown in Scheme
1.
Table 1. Intramolecular Michael Addition of Vinylic
Sulfoxides 2aa
yield (%)b
entry substrate enoate vinylic sulfoxide 3a
3b de (%)
Scheme 1
1
2
3
4
(2E,6E)-2a
(2Z,6E)-2a
(2E,6Z)-2a
(2Z,6Z)-2a
E
Z
E
Z
E
E
Z
Z
44
71
12
19
40
0
10
0
5
100
9
100
a All reactions were carried out using LDA (1.5 equiv) in THF at -78
°C. b Isolated yield.
thermodynamically stable (E)-vinylic sulfoxide.3,13 Upon
treatment of the (E)-enoate (2E,6E)-2a with 1.5 equiv of
LDA in THF at -78 °C, intramolecular Michael addition
reaction proceeded promptly to give the cyclic sulfoxides
3a and 3b in good yield, but without selectivity (entry 1).
In contrast, cyclization of the corresponding (Z)-enoate
exclusively afforded 3a having a stereogenic center with the
(R)-configuration at the â-position of the ester (entry 2). (Z)-
Vinylic sulfoxides (2E,6Z)- and (2Z,6Z)-2a also afforded
cyclized products via base-promoted isomerization of the
vinylic sulfoxide moiety. Although the predominant forma-
tion of the (R)-diastereomeric isomer in (Z)-enoate (2Z,6Z)-
2a was the same as that of (2Z,6E)-2a, the yields were
lowered, presumably as a result of the low reactivity of the
(Z)-vinylic sulfoxide, which has to be isomerized prior to
cyclization (entries 3 and 4). It should be noted that products
arising from deprotonation at the R,â- or γ-positions of the
enoates were not detected at all. Moreover, treatment of the
cyclized products 3a and 3b, respectively, with 1.5 equiv of
LDA at -78 °C for 30 min followed by reprotonation
resulted in complete recovery of the starting materials,
wherein neither the retro-Michael product 2a nor a mixture
of 3a and 3b formed by recyclization was produced.
Consequently, this cyclization is apparently irreversible.
When the reaction of (2Z,6E)-2a was carried out in the
presence of an additive, such as TMEDA and HMPA, both
the yield and the diastereoselectivity were lowered depending
on the amount of addition (Table 2).
a Reagents and conditions: (a) (MeO)2P(O)CH2S(O)Tol, n-BuLi,
THF, rt [(E)-1, 33%; (Z)-1, 45%]; (b) p-TsOH‚H2O, THF, rt; (c)
Dess-Martin periodinane, CH2Cl2, rt; (d) (MeO)2P(O)CH2CO2Me,
NaH, THF, -20 °C [(2E,6E)-2a; 62% in three steps, (2E,6Z)-2a;
48% in three steps]; (e) (CF3CH2O)2P(O)CH2CO2Me, KHMDS, 18-
crown-6, THF, -20 °C [(2Z,6E)-2a; 64% in three steps, (2Z,6Z)-
2a: 45% in three steps].
Upon treatment with (R)-dimethylphosphorylmethyl p-tolyl
sulfoxide,9 the aldehyde afforded (E)- and (Z)-isomers of R,â-
unsaturated sulfoxides 1 in 33% and 45% yields, respec-
tively.10 Then, both isomers were converted into the (E)- and
(Z)-enoates 2a by sequential reactions: (1) hydrolysis of the
THP ether with p-TsOH in MeOH; (2) oxidation of the
resulting alcohol with Dess-Martin periodinane; (3) Hor-
ner-Wadsworth-Emmons reaction11 or Still and Gennari’s
method.12 Thus, the four geometric isomers of 2a were
obtained in satisfactory yields (45-64% in three steps).
With all the geometric isomers in hand, we examined the
intramolecular Michael addition reaction (Scheme 2, Table
1).
Scheme 2
Table 2. Effects of Additives on Intramolecular Michael
Additiona
yield (%)b
entry
additive (equiv)
3a
3b
de (%)
Diastereoselectivity of the Michael addition reactions was
remarkably affected by the geometry of the “enoate” but not
that of the “vinylic sulfoxide”, whose geometry is labile
under the reaction conditions and rapidly isomerizes to the
1
2
3
4
5
71
52
33
21
51
0
8
7
11
7
100
73
65
31
76
HMPA (0.2)
HMPA (1)
HMPA (5)
TMEDA (1)
(8) Amanda, J.; Murphy, J. A.; Sherburn, M. S. Tetrahedron 1989, 45,
7835-7858.
(9) Mikolajczyk, M.; Midura, W.; Grzejszczak, S.; Zatorski, A.; Chefc-
zynska, A. J. Org. Chem. 1978, 43, 473-478. Mikolajczyk, M.; Grzejszczak,
S.; Zatorski, A. J. Org. Chem. 1975, 40, 1979-1984.
a All reactions were carried out using LDA (1.5 equiv) in THF at -78
°C. b Isolated yield.
30
Org. Lett., Vol. 3, No. 1, 2001

Scheme 3
Scheme 4
The size of the ester moiety in the (Z)-enoates 2b-d14
showed significant effects on the yield of intramolecular
Michael addition reactions (Scheme 3, Table 3, entries 1-4).
spectroscopic data of 8 and 9 revealed that all amides were
optically pure and no loss of optical purity resulted from
cyclization. The absolute configurations of the â,â-disub-
stituted propionates were established by the PGME method
recently developed by Yabuuchi and Kusumi.16
This assignment of the absolute configuration was con-
sistent with that determined by transformation of 3b and 7b
into known compounds 10 and 11, respectively, via oxidation
of the sulfoxide to the sulfone (m-CPBA, CH2Cl2) followed
by desulfurization (Na-Hg, NaH2PO4, MeOH) as shown in
Scheme 5.17,18
Table 3. Intramolecular Michael Addition of Vinylic
Sulfoxides 2a-ea
yield (%)c
entry substrateb enoate
R
n
product
a
b
1
2
3
4
5
6
(2Z,6E)-2a
(2Z,6E)-2b
(2Z,6E)-2c
(2Z,6E)-2d
(2E,7E)-2e
(2Z,7E)-2e
Z
Z
Z
Z
E
Z
Me
Et
i-Pr
t-Bu
Me
Me
1
1
1
1
2
2
3
71
54
45
0
0
tr
tr
4d
5d
6
0
Scheme 5
7
7
38
tr
40
60
a All reactions were carried out using LDA (1.5 equiv) in THF at -78
°C. b The substrates 2b-e were prepared in a similar manner for (2Z,6E)-
c
2a. Isolated yield. d The absolute configuration of 4a and 5a was
determined by comparing the 1H NMR spectral data of the PGME amides
from 4a and 5a with that from 3a.
Replacement of the methyl ester in (2Z,6E)-2a with other
esters (Et, i-Pr, and t-Bu) caused decrease of the yield in
the order Me > Et > i-Pr . t-Bu. and the selectivities are
also slightly reduced. Cyclohexene ring formations using
(2E,7E)- and (2Z,7E)-2e15 also proceeded in a fashion similar
to the cyclopentene ring formation. The diastereoselectivity
of the Michael addition to the (Z)-enoate is higher than that
of the corresponding (E)-enoate. Interestingly, the selectivity
was reversed completely (entries 5 and 6).
In conclusion, we have developed a novel route for the
synthesis of fuctionalized five- and six-membered ring
cycloalkenyl sulfoxides via unprecedented asymmetric in-
tramolecular Michael addition reaction of the R-sulfinyl
carbanion with the enoate. Deprotonation with LDA under-
went at the R-sulfinyl position rather than at the enoate part
to give 2-[2-(p-tolylsulfinyl)-2-cycloalkenyl]acetate. Stereo-
selectivity of the intramolecular Michael addition was
dependent on the geometry of the enoate, and very high
diastereoselectivity was observed when the (Z)-enoate was
used as a Michael acceptor. Further work is in progress to
explore the full scope of this methodology.
To determine the optical purity and absolute configuration,
the products 3-7 were converted into the amides 8 and 9
with optically pure phenylglycine methyl ester (PGME) via
hydrolysis of esters (LiOH in aqueous MeOH) followed by
condensation with (R)- or (S)-PGME (PyBOP, HOBT, and
Supporting Information Available: Experimental pro-
cedure for intramolecular Michael addition and spectral data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006697A
1
N-methylmorphorine) as shown in Scheme 4. H NMR
(10) Selective synthesis of (E)- and (Z)-1 is also possible; see: ref 3a
and Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org.
Chem. 1987, 52, 1078-1082.
(11) Horner, L.; Hoffmann, H.; Klink, W.; Ertel, H.; Toscano, V. G.
Chem. Ber. 1962, 95, 581-601. Wadsworth, W. S., Jr.; Emmons, W. D. J.
Am. Chem. Soc. 1961, 83, 1733-1738.
(12) Still, W. C.; Gennari, C. Tetrahedon Lett. 1983, 24, 4405-4408.
(13) (a) Posner, G. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1983; Vol. 2A, pp 225-241. (b) Schmidt, R.
R.; Speer, H.; Schmid, B. Tetrahedron Lett. 1979, 4277-7280. (c) Posner,
G. H.; Tang, P.-W.; Mallamo, J. P. Tetrahedron Lett. 1978, 42, 3995-
3998. (d) Okamura, H.; Mitsuhira, Y.; Miura, M.; Takei, H. Chem. Lett.
1978, 517-520.
(15) The substrates (2E,7E)- and (2Z,7E)-2e were synthesized by a
procedure similar to that for 2a using 5-(tetrahydro-2H-pyran-2-yloxy)-
pentanal as a starting material.
(16) Yabuuchi, T.; Kusumi, T. J. Org. Chem. 2000, 65, 397-404.
(17) Takano, S.; Yamada, O.; Iida, H.; Ogasawara, K. Synthesis 1994,
592-596. In the case of compound 10, considerable loss of optical purity
during derivatization was observed presumably as a result of strong alkaline
conditions in the desulfurization reaction [10: [R]26 +78.0 (lit. [R]30
D
D
+107.4), 11: [R]26 +81.9 (lit. [R]30 +84.4)].
D
D
(14) The esters (2Z,6E)-2b-d were selectively synthesized from (E)-1
by a procedure similar to that for 2a except that Ando’s protocol (Ando,
K. J. Org. Chem. 1999, 64, 8406-8408) was used for construction of the
(Z)-enoate moiety.
(18) The compound 10 was used as a starting material of (+)-hirsutic
acid (Nishida, M.; Iseki, K.; Shibasaki, M.; Ikegami, S. Chem. Pharm. Bull.
1991, 38, 3230-3237) and chaulmoogric acid (Mislow, K.; Steinberg, I.
V. J. Am. Chem. Soc. 1955, 77, 3807-3810).
Org. Lett., Vol. 3, No. 1, 2001
31