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Diastereoselective Three-Center Michael Addition of -Ketoesters to Prostereogenic -Unsaturated Carbonyl Compounds Catalyzed by K2CO3 or Cs2CO3.

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[I51 K D. King, J. Phys. Chem. 1980. H4. 2517.
1161 H. Hopf, Cheni. Ber. 1971, 104, 3087: R. J. Bushby, Q. R E V .Chem. Sac.
1970, 24. 585: D. A. Ben-Efraim, F. Sondheimer. Terruhrdron 1969, 25,
2837.
[17] A H. Alberts, H. Wynberg, J: Clirm. Soc. Chem. Commun. 1988, 748.
[I81 ( M , =168.24): T=173K.spacegroupC2/c,u = 29.285(4).h = 6.2398(8),
c = 11.4790(23)A,
E = 90.0,
= 101.245(14),
7 = 90.0".
V=
~ ; colorless, coffin-shaped
2057.4(10) A3, Z = 8, rrcalc =1.09 g ~ m - clear,
crystals (0.22 x 0.50 x 0.55 mm3) were obtained by isotropic distillation of
pentane into a solution of 6 in chloroform. Enraf-Nonius CAD-4 fourcircle diffraclometer, 29,,, = 52 2015 symmetry-independent reflectiona, of which 1286 with FZ> 3u(F2) were used for the refinement
(SHELXS): 166 refined parameters. R = 0.033, R, = 0.041, M.-' =
uZ(F,). Further details of the crystal structure investigation may be obtained from the Fachinformationszentrum Kdrlsruhe. Gesellschaft fur
wissenschaftlich-technische Information GmbH, D-W-7514 EggensteinLeopoldshafen 2 (FRG) on quoting the depository number CSD-56676,
the names of the authors, and the journal citation.
[I91 J. L. Hencher in The Climnistrj.of the FuncrionulGroups, The Chemistry of'
rhr Curhon Crrrhon Triple Bond, Purr I (Ed.: S. Patai). Wiley. New York,
1978. p. 57.
Chrm[20] L. Brandsma. H. Verkruijsse, Prepurume Polar Or~unome~ullic
hrr:1. i. 1st ed.. Springer, Berlin, 1987, p. 21.2
a
Table
Compounds 3 arise in a reaction with lk relative
topicity"'] via a cyclic synclinal transition state Pb]
(Scheme 2).
Table 1. Michael addition of 1 to 2 in the presence of 0.5 equivalent of K,CO, or
CS,CO,.
Entry
1
2
R'
R2
Conditlons [a]
O,
Diastereoselective Three-Center Michael Addition
of P-Ketoesters to Prostereogenic a$-Unsaturated
Carbonyl Compounds Catalyzed by K 2 C 0 3
or Cs2C03**
Isolated
yields
3:4 [c]
["/.I
1
2
3
a
a
a
a
a
4
b
b
b
b
5
6
7
8
9
10
11
12
c
b
Me
Me
Me
tBu
tBu
Bz
rBu
rBu
tBu
rBu
Bz
b
a
IBu
b
c
b
b
b
b
b
b
b
b
b
Me
Me
H
H
H
H
H
H
H
H
H
Me
K,C0,,40"C, 6 h
K,C03,20"C, 7 d
K,CO3.2O'C, 1 5 h
K,CO,, 20"C, 15 h
K,C03, 5 7 ° C 3 h
K,CO,. 20% 15 h
Cs,CO,, -30°C. 5 h
K,CO, [d], -3O"C, 5 h
Cs,CO, [el, -50°C 7 h
K,CO, [f], -2O"C, 5 h
K,CO,[f], -2O"C, 5 h
K,CO,[fl, -20'C,72h
[bl
52
78
65
67
65
70
X4
30
58
56
87
70:30
80:20
X5:15
>95:5
77:23
>95:5
>95:5
15:85
35:65
20:80
15:85
<5:95
[a] Reactions for entries 1-9 were carried out in dry acetone. [b] Quantitative by gas
chromatography with a 20m SE-30 column. [c] Determined by 'H NMR spectroscopy
(200 or 400 MHz). [d] 0.25 Equiv [18]crown-6. [el 0.25 Equiv dihenzo-[24]crown-8.
[f] Mixture of hexamethylphosphoric triamide (HMPA)/CH,CI, (5/1) as solvent
(Krypand 0.25equiv 4,7,13,16,21,24-hexaoxa-1,10-diazahicyclo[8.8.8]hexacosane
tofix 222).
By Nicole Ouvrard, Jean Rodriguez,* and Maurice Santelli
In our investigations['] on the synthesis of the PrelogDjerassi lactoner2]it appeared that another attractive and
direct way for the preparation of the key intermediate would
be the Michael additionL3]of a 8-ketoester to an a,p-unsaturated carbonyl compound. The (2S,3R)$-ketoesters I [41
serve as a model compounds for our study (Scheme 1). The
correct (2R,3S) enantiomer can be formed from readily
available (S)-(-)-pulegone."]
1
3
II, Z = C0,R'
4
Scheme 2. Possible cyclic transition states 1 and 11.
-
3
la,
R1 = M e
lb, R ' = f E u
2a, R 2 = Me
2b, R 2 = H
lC, R ' = B z
4
a, R 1 R 2 - Me
b, R: Bu,R2 = H
I
=BZ,R~=H
d, R ' - Bu,R 2 = Me
C,R
Scheme I . Michael addition of a-ketoesters to %,P-unsaturatedcompounds
The diastereoselective Michael addition has been studied
extensively in recent years and constitutes one of the most
useful methods for carbon-carbon bond formation.[51We
wish to report here on the highly diastereoselective, threecenter Michael additionr6]of simple chirdl 8-ketoesters with
a prostereogenic cc,B-unsaturated carbonyl compound; this
provides a stereocontrolled route to compounds with three
contiguous stereogenic centers."]
The K,CO, or Cs,CO, catalyzed reaction of 1 with
Michael acceptors 2 in acetone provides 3,['] one of the four
possible diastereomers, with high selectivity (entries 1 - 7,
[*] Dr. J. Rodriguez, N. Ouvrard. Prof. Dr. M. Santelli
Laboratoire de Synthese Organique associe au CNRS Centre de St-JkrBme
[**I
boite D12. F-13397 Marseille Cedex 13 (France)
This work was supported by Rhdne-Poulenc-Rorer (Vitry). We are grateful to Dr. J. C . Barriere (Rhdne-Poulenc-Rorer) for helpful discussions.
A n g w C h m . lnt. Ed. Engl. 1992, 3f. No. 12
Examination of molecular models shows that in transition
state I1 there is substantial nonbonding interaction between
the alkoxycarbonyl group of the Michael donor and the
carbonyl part of the a,B-unsaturated function (Scheme 2).
This finding is supported by the observed effect of R' and RZ
on the diastereoselectivity of the reaction at room temperature or below. The ratio 3:4 is only 85:15 for R' = Me,
R2 = H (entry 3), while 3 is obtained almost exclusively
when R' = tBu or Bz, R2 = H (entries 4, 6, and 7).
In all cases, the diastereofacial control is total; this is probably a consequence of the almost planar structure of the
enolate derived from 1. By analogy with related systems, one
can expect that this endocyclic enolate will be attacked exclusively from the face opposite to the methyl substituent."
The highest diastereoselectivity is obtained with K,CO, at
room temperature (entries 4 and 6) or at -30°C when
Cs2C0, is used as catalyst (entry 7). It is of interest to note
that poor or no stereoselectivity was reported previously for
the addition of simple cyclic or acyclic @-ketoestersto methyl
ethylidenemalonate with K,CO, as base.r7a1To our knowledge, our results constitute the first example of three-center
($> VCH Verlugsgesellschuft mhH, W-6940 M'einheim, 1992
0570-0833~92jl212-I651$3.50+,2510
1651
diastereoselectivity for five-membered carbocyclic ring syst e m ~ . [6l~ ~ .
The configurations of 3 and 4 were confirmed by chemical
correlation with the known y,h-unsaturated ketone 6.[l2l
Preparation of 6 from 3b was straightforward (Scheme 3):
selective reduction of the aldehyde functionality (NaBH,,
iPrOH, room temperature, 57
was followed by decarboxylation and selenoxide elimination (o-nitrophenylselenocyanate, Bu,P, CH,Cl,; 15% pTsOH, C,H6, reflux, then
H,O,, THF, 72% overallr'*''). The spectroscopic and ana-
----
The diastereoselectivity increases significantly when
R2 = Me instead of RZ = H (cf. entries 10 and 12).
The results presented here are in accord with a cyclic transition state characterized by a chelate complex between the
enolate and the carbonyl functions; this is an important requisite for stereocontrol under kinetic conditions. This proposition is supported by the observed effect of a specific complexing agent which causes the reaction to proceed through
a nonchelated antiperiplanar transition state giving rise to a
reverse diastereoselectivity. The base-catalyzed Michael addition of the P-ketoesters 1 to a prostereogenic a$-unsaturated carbonyl compound 2 has high diastereoselectivity and
offers a synthetically attractive approach to the optically
active Prelog-Djerassi lactone and related compounds.
56 %
Received: June 17. 1992 [Z 5412 IE]
German version: Angew. Chem. 1992, 104,1658
6
3b
Scheme 3. Preparation of ketone 6.
lytical data of 6 prepared in this way were identical to those
of a sample synthesized previously by a different route.['21
A slight increase in temperature affects the diastereoselectivity; the reaction then most likely proceeds to a certain
extent via transition state 11. The other explanation, equilibration of the products, can be ruled out. A mixture of 3a
and 4a in the ratio 60:40 did not equilibrate when treated
with K,CO, in acetone for seven days (compare entries 1
and 2, 4 and 5). A specific complexing agent has a greater
effect on the diastereoselectivity. Indeed, the complexation
of the metal ion by either a crown ether (entries 8 and 9) or
by Kryptofix 222 (entries 10-12) results in a reverse
diastereoselectivity ;4, arising from the ul relative topicity, is
obtained with high selectivity. Under these conditions lower
temperature is required because of the enhanced basicity and
potential side reactions. The ratio 3:4 is independent of the
reaction time, indicating that the Michael addition remains
under kinetic control. These results['31 provide evidence for
the participation of the metal ion in the stabilization of the
cyclic transition state I (Scheme 2). The results can be best
explained by assuming that in the presence of a complexing
agent, the bulky complex formed by the specific cryptand
and the cation (M' in Scheme 4) favors the ion pair dissocia t i ~ n [ ' and
~ ] suppresses the coordination between the enolate and the a$-unsaturated compound. These two facts are
in agreement with an open antiperiplanar transition state[''l
IV rather than 111 in which the nonbonding interaction between the ester group of the Michael donor and the carbonyl
part of the a$-unsaturated function is present (Scheme 4).
R2
lk
0
3
rn
CAS Registry numbers:
l a , 80796-76-5; 1 b, 144320-35-4; l c , 144407-31-8; 2a.625-33-2; 2b,4170-30-3;
3 (R' = Me, R2 = H), 144320-37-6; 3 a , 144320-36-5; 3b, 144320-38-7; 3c,
144320-39-8;4(R1= Me,R2 = H), 144407-33-0;4a,144407-32-9;4b,
14440734-1; 4c, 144407-35-2; 4d. 144320-40-1.
[I] S. Hacini. M. Santelli, Ztruhedron 1989, 45, 6449; ibid. 1990, 46. 7787.
(21 For a recent review, see: S. F. Martin, D. E. Guinn, Synthesis 1991, 245.
(31 E. D. Bergmann, D. Ginsburg, R. Pappo, Org. React. 1959, 10, 179.
[4] For the preparation of l a from (R)-(+)-pulegone see: J. N. Marx, L. R.
Norman. J. Org. Chem. 1975,40, 1602; compounds 1 b,c were prepared by
esterification of pulegenic acid following the literature procedure: C . F.
Murphy. R. E. Koehler, J. Org. Chem. 1970, 35, 2429.
[5] For reviews see: a) K. Tomioka, K. Koga in As-vmmelrir Svnthesis, Vul. 2
(Ed.: J. D. Morrison), Academic Press, New York, 1983. p. 201; b) D. A.
Oare, C . H. Heathcock, Top. Stereochem. 1989, 19, 227; c) ibid. 1991. 20,
87.
[6] For the first report of the diastereoselective three-center Michael addition
with b-lactone enolates, see: J. Mulzer, A. Chucholowski, 0. Lammer, I.
Jibril, G. Huttuer, J. Chem. SOC.Chrm. Commun. 1983, 869.
[7j For recent reports on the construction of contiguous quaternary and tertiary carbon centers, see: a) K. Tomioka, K. Yasuda, K. Koga, J1 Chem.
SOC.Chem. Cumnrun. 1987, 1345; b) J. C. Gilbert, T. A. Kelly, Tetrahedron
1988, 44, 7587; c) T. Kitahara, H. Kurata, K. Mori, ibfd. 1988, 44, 4339;
d) M. C . Pirrung, W L. Brown, S. Rege, P. Laughton, J! Am. Chem. So<.
1991. 113?8561.
[8] All new compounds gave satisfactory analytical and/or spectral data. For
example 3c: colorless oil: R, = 0.40, ether/pentane ( l / l ) ; [z]L]:&
+ 98.4
(CHCI,, C = 2); IR (neat): v=3040, 2970, 2730, 1750, 1725, 1220,
1160 c m - '; ' H NMR (400 MHz, CDCI,): 6 = 0.97 (d, J = 6.8 Hz, 3H),
1.03 (d, J = 6.8 Hz, 3 H), 1.62-1.80 (m,1 H), 1.98-2.05 (m, 1 H), 2.082.19(m,1H),2.28(ddd,J=16.8,10.2,2.7Hz,lH),2.34(m,lH),2.44
(dd, J=18.4, 6.8Hz, IH), 2.78 (dq d, J = 1 6 . 8 , 6.8, 2.7Hz), 2.99 (d,
J =16.8.2.7 Hz, 1 H), 5 . 0 7 ( d , J = 12.3 Hz, l H ) , 5.14(d,J=12.3 Hz, 1 H),
7.19 (m, SH), 9.69 (d. J = 2.6 Hz, 1 H); I3C NMR (100 MHz. CDCI,):
6 =16.05 (q), 17.09 (4). 28.79 (t), 30.68 (d), 37.67 (d), 39.33 (t), 46.96 ( t ) ,
65.04(s),66.71 (t). 128.26(d), 128.43(d). 128.61 (d). 135.17(s), 169.94(s),
201.49 (d), 207.57 (s); high-resolution MS Cdkd. for C,,H,,O,: 302.1518;
found: 302.1513.
[9] A. Barco, S. Benetti, G. P. Pollini. Synthesis 1973, 316.
[lo] a) Seebach-Prelog nomenclature: D. Seebach, V. Prelog, Angew. Chem.
1982,94,696; Angebi. Chem. Int. Ed. Engl. 1982,2I, 654. b) For a topological rule for C-C bond formingprocesses between prochiral centers, see: D.
Seebach, J. Golinski, He/v. Chirn. Aelu 1981.64, 1413, and references cited
therein.
[ l l ] For preferred (runs alkylation of related endocyclic enolates with an asymmetric center at the 3/ position, see inter alia: D. A. Evans in Asymmetric
Synthesis, Vol. 3 (Ed.: J. D. Morrison), Academic Press, New York, 1984,
p. I ; K. Tomioka, K. Yasuda, H. Kawasaki, K. Koga. Tefruhedron Lett.
1986, 26, 3247; see also refs. [6] and [7c].
[12] a) N. Ouvrard, Ph. D. Thesis, University of Marseilles, 1992. Ketone 6 has
been prepared independently by another route and fully characterized by
its spectral and analytical data. Its configuration was confirmed by an
X-ray structure determination of the corresponding carboxylic acid arising
from an oxidative cleavage o f the double bond. These results will he
reported in due course. 6 : colorless oil; R, = 0.42, ether/pentane (119);
,:IX[
128.8 (CHCI,, c = 2); IR (CCI,): Y = 3080, 2960. 1745, 1640.
920cm-'; ' H NMR (400 MHz, CDCI,): 6 = 0.98 (d, J =7.1 Hz. 3H),
1.02(d,J=6.0Hz,3H),1.26(m,lH),1.63(dm,J=10.3Hz.1H),1.96
(m. 3H), 2.19 (dd, J=16.4. 7.1Hz. l H ) , 2.59 (m. 1H). 4.89 (d,
J=lO.OHz, l H ) , 4.92 (d, J = 1 7 . 1 Hz, lH), 5.71 (ddd, J=17.1, 10.0,
7.3 HZ, 1 H); "C-NMR (50.33 MHz, CDCI,): S = 16.28, 20.24, 29.58,
+
4
0
IV
Scheme 4. Possible acyclic transition states 111 and IV
1652
8 VCH
VerlugsgeseNschufj mbH. W-4940 Weinheim, 1992
0570-083319211212-1652 $3.50+ ,2510
Angew. Chem. In[.Ed. EngI. 1992, 31. Nu. 12
33.68, 36.42, 38.77, 60.88, 114.00, 141.69,219.74; satisfactory C, H analysis, b) C. S . Sell, Ausr. J. Chem. 1975, 28, 1383; c) K. B. Sharpless, M. W.
Young, J. Org. Chrm. 1975, 40, 947; P. A. Grieco, S . Gilman, M.
Nishizawa. ibid. 1976, 41. 1485.
[13] For similar effects of crown ethers, see: R. S. Glass, D. R. Deardorff, K.
Henegar, Terrahedron Left. 1980, 21, 2467; T. Takeda, T. Hoshiko, T.
Mukaiyama, Chem. Lett. 1981, 797; L. Viteva, Y Stefanovsky, Tetrahedron Lrrr. 1989, 30, 4565; L. Viteva, Y Stefanovsky, C. H. R. Tsvetanov,
L. Gorrichon, J. Ph.ys. Org. Chem. 1990, 3, 205.
[14] C. L. Liotta, H. P. Harris, J. A m . Chern. SOC.1974.96,2250, and references
cited therein.
[i5] For previously invoked acyclic transition state, see, inter aka: C. H.
Heathcock. D. A. Oare, J. Org( Chem. 1985, 50, 3022; Y Yamamoto. S.
Nishii. ibid. 1988. 53. 3597, and references cited therein.
rneta-Phenylene Units as Conjugation Barriers
in Phenylenevinylene Chains
By Heike Gregorius, Martin Baumgarten. Ronald Reuter,
Nikolai Tyutyulkov, and Klaus Miillen*
Dedicated to Professor Emanuel Vogel on the occasion
of his 65 th birthday
The incorporation of meta-phenylene units into conjugated oligomers and polymers has wide-reaching effects on their
properties. Alongside the commonly observed increase in
solubility‘’] is the formation of “non-Kekule” structures,
which hinder the spin pairing in potential high-spin systems
such as l.[’] In compounds with singlet states, meta systems
such as 2 and 3 are expected at first glance to display extend-
ed n: conjugation just like the “para” analogues (for example,
4). We can, however, now show that for the neutral and ionic
(doped) derivatives of 2 and 3 the rneta-phenylene unit interrupts the conjugative interaction and induces charge localization. As a result, intervalence bands appear in the absorption spectra of the charged species at extremely high
wavelengths in the near-IR region.
The meta-distyrylbenzene 3a (= 2 b) and the homologous
oligo(meta-phenyleneviny1ene)s 3 b 3 d were each synthesized by Wittig olefination. In this process the use of 3,5-ditert-butylphenyl terminal groups to increase the solubility
(as in the preparation of the para analogues 4) was invaluable.[31A Wittig reaction with 514] and 3-methylbenzaldehyde yields the one styryl unit longer 3,5-di-tert-butyl-3‘methylstilbene, which on bromination with N-bromosuccinimide affords both the phosphonium salt 6 and the
corresponding aldehyde 8 formed in a Sommelet reaction.
Oligomers with even n (3b and 3d) arise in the reaction of
stilbene-3,3’-bis(methyltriphosphoniumbromide)[’] with the
aldehydes 7L61and 8, respectively, whereas those with uneven
n (3a and 3c) are formed from isoterephthaldialdehyde and
the phosphonium salts 5 and 6, respectively. Subsequent isomerization with iodine yields the corresponding all-trans
compounds 3 ad.[’]
5: R=CH2P+Ph3 Br-
7: R=CHO
6: R=CH2P+Ph3Er-
o.J&A)
‘/
\
\
\
8: R=CHO
‘ /
tt
bb
tt
la
The new hydrocarbons were electrochemically and chemically (with alkali metals) reduced. The electron-transfer
products were characterized by cyclic voltammetry, electron
absorption spectroscopy (Table 1, Fig. I), and ESR and
NMR spectroscopy.
Ib
R
R
a: R = H
b: R=feft-butyl.
n=l
R
Table 1. Absorption maxima A,,
phenylenevinylenefs.
2
[nm] of neutral and charged oligo(mefa-
Compound
1, (neutral)
(CHCI,. T = 300 K)
stilbene
3a
3b
3c
3d
309
240
239
240
242
A,, (monoanion)
(THF/K+, T = 300 K)
R=teft-butyl
a: n.1
b: n-2
c: n-3
d: n=4
R
R
306
306
312
312
496
476
493
487
484
699
636
653
661
685
1810
1864
1984
1983
3
R
R=tert-butyl
a: n-1
R
K
b: n=Z
c: n = 3
d: n=4
e: n=5
4
[*I
Prof. Dr. K. Miillen. H. Gregorius, Dr. M. Baumgarten, R. Reuter
Max-Planck-Institut fur Polymerforschung
Ackermannweg 10, D-W-6500 Mainz (FRG)
Prof. Dr. N. Tyutyulkov
Acadamy of Science, Sofia (Bulgaria)
AngrM,. Chem. Int. Ed. Engl 1992. 31, No. 12
0 VCH
The meta-distyrylbenzene 3a has a distinctly higher redox
activity than para-distyrylbenzene 4a: whereas 4a is reduced
by alkali metals only to the dianion,”] 3a yields the tetraanion, which can be detected chemically by trapping it with
dimethyls~lfate;[~I
in a well-resolved ‘H NMR spectrum the
signals of the olefinic protons appear at very high field
(6 = 2.5-3.5).
The cyclic voltammetry shows that the first reduction potential of 3a-3d is almost independent of the number of
repeating units (3a: -2.41, 3b: -2.29, 3c: -2.29, 3d:
-2.34V). These values are similar to those for stilbene,
Verlags~esellschajimbH. W-6940 Weinheim, 1992
#57#-#833/92/1212-1653 $3.50+.25/0
1653
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k2co3, carbonyl, ketoesters, compounds, michael, unsaturated, prostereogenic, three, cs2co3, catalyzed, diastereoselective, additional, center
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