Asymmetric synthesis of succinic semialdehyde derivatives

Article abstract of DOI:10.1021/jo026557+

The nucleophilic Michael addition of 2-(diphenylmethoxymethyl)-1-methyleneamino pyrrolidine 1D to prochiral aliphatic and aromatic alkylidene malonates 2 takes place in the presence of MgI₂ to afford the corresponding Michael adducts 3 in excel

Full text of DOI:10.1021/jo026557+

Asym m etr ic Syn th esis of Su ccin ic Sem ia ld eh yd e Der iva tives
J ose´ M. Lassaletta,*,† J uan Va´zquez,‡ Auxiliadora Prieto,‡ Rosario Ferna´ndez,‡
Gerhard Raabe,§ and Dieter Enders§
Instituto de Investigaciones Quı´micas (CSIC-USe), Isla de la Cartuja, Americo Vespucio s/ n,
E-41092 Seville, Spain, Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de
Sevilla, Apartado de Correos 553, E-41071 Seville, Spain, and RWTH-Aachen, Professor Pirlet Strasse,
1, D-52074 Aachen, Germany
jmlassa@cica.es
Received October 11, 2002
The nucleophilic Michael addition of 2-(diphenylmethoxymethyl)-1-methyleneamino pyrrolidine 1D
to prochiral aliphatic and aromatic alkylidene malonates 2 takes place in the presence of MgI2 to
afford the corresponding Michael adducts 3 in excellent yields and good selectivities. In the aromatic
series, optically pure (de > 98%) major diastereomers (S,S)-3 were isolated in good yields (77-93%)
after chromatographic separation. Direct, racemization-free BF3‚OEt2-catalyzed thiolysis of com-
pounds 3 afforded dithioacetals 7. These compounds were transformed into malonates 8 and succinic
semialdehyde derivatives 9 by Raney Nickel mediated desulfuration or decarboxylation, respectively.
In tr od u ction
dene malonates have been reported. The asymmetric
addition of simple aliphatic or aromatic rests has been
accomplished by using dialkylzinc and trialkylaluminum
reagents in the presence of Cu(OTf)2 and chiral phos-
phorus ligands.2 The addition of optically enriched alle-
nyltitanium reagents allows the introduction of a versa-
tile silylacetylene moiety.3 The addition of lithiated
benzylic and allylic amine derivatives in the presence of
(-)-sparteine has been successfully used for the synthesis
of nitrogenated adducts.4 Other bifunctional compounds
also have been synthesized with use of this strategy.
Thus, Box-type ligands were used in the Cu(II)-catalyzed
asymmetric aza-Michael addition of hydroxylamine to
several alkylidene malonates,5 while the phospha-
Michael addition of TADDOL-derived phosphites to these
compounds affords phosphonomalonates with high dia-
stereoselectivities.6
The asymmetric synthesis of several 1,5-dicarbonyl
compounds also has been accomplished from alkylidene
malonates as the Michael acceptors with use of several
enolates7 and enolate equivalents as silylketene acetals,8
enamines,9 lithioenamines,10 and aza-enolates from hy-
drazones,11 while the direct addition of ketones also has
been developed by using proline as the catalyst.12 In a
The asymmetric Michael addition of nucleophiles to
conjugated carbonyl compounds is one of the most power-
ful methods for carbon-carbon bond formation.1 Thus,
a wide range of compounds can be synthesized by using
this tool, depending on the variability of nucleophiles and
types of acceptor used. Among the latter, alkylidene
malonates appear as a suitable class of substrates
presenting interesting characteristics: (1) they are easily
available through Knoevenagel condensation of mal-
onates and different carbonyl compounds; (2) for the most
common type of malonates, the presence of two identical
carboxyl groups at the same olephinic carbon eliminates
the Z/E isomerism, which constitutes a problem in other
classes of substrates; (3) the enhanced electrophilic
reactivity provided by the geminal carboxylate functions
allows addition reactions to be carried out with poorer
nucleophiles and/or under milder conditions with respect
to other Michael acceptors; and (4) the presence of two
geminal carbonyl groups provides chelating ability to
these substrates, which is an essential tool for the control
of the stereochemistry for metal-promoted or catalyzed
additions.
These properties have been exploited for the synthesis
of a variety of compounds. In particular, many examples
of the asymmetric Michael addition to prochiral alkyli-
(2) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001, 12,
1151.
(3) Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543.
(4) Curtis, M. D.; Beak, P. J . Org. Chem. 1999, 64, 2996.
(5) (a) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Kim, H.; Perci-
accante, R.; Tolomelli, A. Tetrahedron: Asymmetry 2001, 12, 2395. (b)
Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Gianotti, M.; Perciaccante,
R.; Tolomelli, A. Tetrahedron: Asymmetry 2002, 13, 1407.
(6) Tedeschi, L.; Enders, D. Org. Lett. 2001, 3, 3515.
(7) (a) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38,
3531. (b) Kanemasa, S.; Tatsukawa, A.; Wada, E. J . Org. Chem. 1991,
56, 2875.
(8) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J . S. J .
Am. Chem. Soc. 1999, 121, 1994. (b) Evans, D. A.; Rovis, T.; Kozlowski,
M. C.; Downey, C. W.; Tedrow, J . S. J . Am. Chem. Soc. 2000, 122,
9134.
* To whom correspondence should be addressed. Fax: +34 95
4460565.
† Instituto de Investigaciones Qu´ımicas.
‡ Departamento de Qu´ımica Orga´nica.
§ RWTH-Aachen.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, UK, 1992. (b) Lee, V. J . In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 4, Chapters 1.2 and 1.3. (c) Kozlowski, J . A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4, Chapter 1.4. (d) Leonard, J .; Diez-
Barra, E.; Merino, S. Eur. J . Org. Chem. 1998, 2051.
10.1021/jo026557+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003
2698
J . Org. Chem. 2003, 68, 2698-2703

Asymmetric Synthesis of Succinic Semialdehyde Derivatives
SCHEME 1
similar way, the asymmetric addition of acyl (formyl)
anion equivalents would open access to less accessible
1,4-dicarbonyl compounds. A few reports have been
described for such a reaction in racemic fashion,13 but to
the best of our knowledge, the asymmetric acylation of
alkylidene malonates has not been reported so far.14 On
the other hand, SAMP-derived formaldehyde hydrazone
1A had been successfully used as a neutral formyl anion
equivalent15 for the asymmetric formylation of enones16
and R,â-unsaturated lactones,17 but the extension of this
methodology to acyclic R,â-unsaturated esters was un-
successfully investigated. The precedent of the addition
of 1A to nitroalkenes,18 which exhibit similar levels of
reactivity to that of alkylidene malonates,19 suggested
that the addition of formaldehyde N,N-dialkylhydrazones
to the latter should also be possible under non-catalyzed
conditions, or, at least, under mild conditions compatible
with the hydrazone moiety. Results collected on the basis
of this hypothesis are given herein.20
SCHEME 2
Resu lts a n d Discu ssion
The initial experiments were carried out with formal-
dehyde SAMP-hydrazone 1A and several easily available,
prochiral dimethyl alkylidene malonates 2.21 To our
surprise, no reaction was observed under a variety of
uncatalized conditions. Therefore, we decided to activate
the substrates 2 by means of a Lewis acid as the catalyst
or promoter. Taking into account the chelating ability of
1A, the reaction was expected to proceed after establish-
ment of an equilibrium between metal-hydrazone and
metal-malonate complexes (Scheme 1).
The selection of a suitable catalyst, however, presented
some difficulties. For instance, it was found that common
Lewis acids, such as ZnCl2, AlCl3, Ti(OiPr)4, or trialkyl-
silyl triflates, either in catalytic or stoichiometric amounts,
afforded the expected hydrazono dicarboxylates 3 in low
yields, due to the formation of variable amounts of glyoxal
bis-hydrazone 4 as an undesired byproduct (Scheme 2).
The formation of this product is consistent with an
activation of the reagent 1A by the Lewis acid, followed
by nucleophilic attack of a second molecule of free reagent
to the electrophilic complex formed. Air oxidation of the
resulting R-hydrazinohydrazone finally affords the un-
desired product 4.22 In the case of the aromatic substrate
2e (R ) Ph), benzaldehyde SAMP-hydrazone 5 was also
isolated as a byproduct, even in dry media. Its formation
can be explained by a [2+2] cycloaddition23 of the
hydrazone to the activated alkylidene malonate followed
by a retrocycloaddition to the observed highly conjugated
byproduct 5 (Scheme 3), along with dimethyl methylidene
malonate, unstable against polymerization.
Finally, it was found that use of catalytic amounts of
MgI2 or MgBr2 in methylene chloride as the solvent
minimized the side reactions mentioned above and led
to the almost exclusive formation of compounds 3,
presumably due to the establishment of the equilibrium
shown in Scheme 1. Use of other solvents including THF,
Et2O, MeOH, or toluene resulted in lower yields of the
desired adducts. These conditions allowed the isolation
of adducts 3 in good yields, but unfortunately, the
observed diastereoselectivities were disappointing in all
cases. In the light of these results, formaldehyde hydra-
zones 1B-H were synthesized24 and used in a second
screening performed to analyze the effect of the modified
(9) (a) Blarer, S. J .; Seebach, D. Chem. Ber. 1983, 116, 2250. (b)
Martens, J .; Lu¨bben, S. Tetrahedron 1991, 47, 1205. Recently, a related
Friedel-Crafts addition of several aromatic heterocycles has also been
reported: (c) Zhuang, W.; Hansen, T.; J ørgensen, K. A. Chem.
Commun. 2001, 347.
(10) (a) Tomioka, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986,
27, 4611. (b) Enders, D.; Demir, A. S.; Puff, H.; Franken, S. Tetrahedron
Lett. 1987, 28, 3795.
(11) Enders, D.; Demir, A. S.; Renderbach, B. E. M. Chem. Ber. 1987,
120, 1731.
(12) Betancort, J . M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C.
F., III Tetrahedron Lett. 2001, 42, 4441.
(13) (a) Stetter, H.; J onas, F. Chem. Ber. 1981, 114, 564. (b)
Cerfontain, H.; van Noort, P. C. M. Synthesis 1980, 490.
(14) For the alternative asymmetric acylation of simple enoates
see: (a) Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int. Ed.
Engl. 1990, 29, 179. (b) Enders, D.; Shilvock, J . P.; Raabe, G. J . Chem.
Soc., Perkin Trans. 1 1999, 1617.
(15) Ferna´ndez, R.; Lassaletta, J . M. Synlett 2000, 1228.
(16) (a) Lassaletta, J . M.; Ferna´ndez, R.; Mart´ın-Zamora, E.; D´ıez
E. J . Am. Chem. Soc. 1996, 118, 7002. (b) D´ıez, E.; Ferna´ndez, R.;
Gasch, C.; Lassaletta, J . M.; Llera, J . M.; Martı´n-Zamora, E.; Va´zquez,
J . J . Org. Chem. 1997, 62, 5144.
(17) (a) Enders, D.; Va´zquez, J . Synlett 1999, 629. (b) Enders, D.;
Va´zquez, J .; Raabe, G. Chem. Commun. 1999, 701. (c) Enders, D.;
Va´zquez, J .; Raabe, G. Eur. J . Org. Chem. 2000, 893.
(18) Enders, D.; Syrig, R.; Raabe, G.; Ferna´ndez, R.; Gasch, C.;
Lassaletta, J . M.; Llera, J . M. Synthesis 1996, 48.
(19) As discussed in ref 4a, the electrophilic reactivity of nitroalkenes
and malonates can be a priori correlated with the pK values in
nonaqueous solvent of the anions generated upon addition. See also:
Olmstead, W. N.; Bordwell, F. G. J . Org. Chem. 1980, 45, 3299.
(20) Preliminary communication: Va´zquez, J .; Prieto, A.; Ferna´ndez,
R.; Enders, D.; Lassaletta, J . M. Chem. Commun. 2002, 498.
(21) Lehnert, W. Tetrahedron Lett. 1970, 54, 4723.
(22) A similar explanation has been offered for the dimerization of
formaldehyde dimethylhydrazone promoted by Brønsted acids: Con-
don, F. E.; Farcasiu, D. J . Am. Chem. Soc. 1970, 92, 6625.
(23) For a related Lewis acid-catalized polar [2+2] cycloaddition
see: Gautier, A.; Renault, J .; Fauran, C. Bull. Soc. Chim. Fr. 1963,
2738.
J . Org. Chem, Vol. 68, No. 7, 2003 2699

Lassaletta et al.
SCHEME 3
of 3b in 95% yield as a 84:16 mixture of diastereomers.
The optimized conditions and auxiliary were then ex-
tended to the addition of reagent 1D to alkylidene
malonates 2a -i with the results collected in Table 2.
As deduced from these results, a high reactivity was
found for both aliphatic and aromatic substrates, though
the optimized experimental conditions were different for
the two groups of substrates. In the case of aliphatic
substrates, higher yields and cleaner reaction mixtures
were observed for reactions performed by adding the
hydrazone reagent to the MgI2-precomplexed malonates
(see the Experimental Section). Surprisingly, when these
conditions were applied to aromatic compounds 2e-i
clean but incomplete reactions were observed. In these
cases, better results (higher conversions) were achieved
by addition of MgI2 to a solution containing the alkylidene
malonate and the hydrazone 1D. Additionally, optimal
reaction temperatures of -78 and 0 °C were applied to
the addition to aliphatic and aromatic substrates, re-
spectively. In the former case, high yields and moderate
stereoselectivities [de 68-78%, major (S,R)-isomer] were
observed with the only exception of the more hindered
substrate 2c (R ) isopropyl): at -78 °C, this compound
afforded adduct 3c in 94% yield, but with a very low (de
10%) and reversed [major (S,S)-isomer] selectivity, while
the reaction carried out at 0 °C gave (R,S)-3c as the major
isomer (de 16%). Better inductions (de 78-90%) were ob-
served in the aromatic series, even at the higher reaction
temperature (0 °C) applied to maintain high yields of
adducts. At this point it is important to stress that the
resolving properties of the selected diphenylmethoxy-
methyl pyrrolidine as the auxiliary allowed an easy chro-
matographic separation for many of the diasteromeric
mixtures obtained,26 and that this behavior proved to be
uniform for the aromatic adducts investigated. In this
way, good yields (77-93%) of optically pure (de > 98%)
adducts 3e-i were obtained in a single reaction step.
SCHEME 4
TABLE 1. Ad d ition to Hyd r a zon es 1A-H to 2ba
reagent
1A
1B
1C
1D
1E
1F
1G
1H
deb
30
28
-
52
43
-
45
-
c
c
c
Regeneration of the formyl group to obtain aldehydes
6 was accomplished by ozonolytic cleavage of the hydra-
zone CdN double bond in moderate yields (55-74%)
(Scheme 5). Unfortunately, condensation of aldehyde 6e
[obtained from optically pure hydrazone (S,S)-3e] with
(S)-1-amino-2-(diphenylmethoxymethyl)pyrrolidine, con-
ducted for the determination of its enantiomeric excess,
afforded 3e as a near 50:50 mixture of (S,S)-3e and (S,R)-
3e. As the mild conditions used for the ozonolytic cleav-
age of hydrazones usually keep the stereogenic centers
untouched, this result suggests that extensive racemiza-
tion of this sensitive aldehyde 6e takes place during the
chromatographic purification. A much higher stability
was expected for the aliphatic series, but starting from
3a or 3c, a 5-20% of racemization was also observed
after chromatography of the resulting aldehydes. Even
though the crude products were obtained with a reason-
able purity and could be eventually used without puri-
fication at this step, alternative removals of the auxiliary
were also investigated. Fortunately, it was found that the
a
b
In CH2Cl2 at -78 °C in the presence of 10% MgI2. Deter-
mined by 1H NMR analysis of the crude reaction mixtures. c No
reaction.
auxiliaries in the stereochemical outcome of the conjugate
addition (Scheme 4).
To keep the reactivity of the reagent as high as pos-
sible, the pyrrolidine ring was maintained as a common
characteristic in these reagents, as we had previously
noticed that this structural motif confers a high nucleo-
philicity to the aza-enamine system.25 The results of the
reactions of 1A-H with ethylidene derivative 2b as a
model substrate are collected in Table 1.
From this study, 1-methyleneamino-2-(1-methoxydi-
phenylmethyl)pyrrolidine 1D emerged as the most con-
venient reagent, affording the corresponding adduct 3b
in 78% yield as a 76:24 mixture of diastereomers. Further
improvement of this result was observed by using a
stoichiometric amount of MgI2, which promoted formation
(24) 1B: Syrig, R. Ph.D. Thesis, RWTH Aachen, 1996. 1C, 1D, 1H:
Pareja, C.; Mart´ın-Zamora, E.; Ferna´ndez, R.; Lassaletta, J . M. J . Org.
Chem. 1999, 64, 8846. 1E, 1F , 1G: Bolkenius, M. Ph.D. Thesis, RWTH
Aachen, 1999.
(25) A similar behavior has been reported for related enamines:
Ha¨felinger, G.; Mack, H.-G. In The Chemistry of Enamines; Patai, S.,
Rappoport, Z., Eds.; J ohn Wiley & Sons: New York, 1994; pp 1-85.
(26) Such a behavior has also been observed in the addition of 1D
to reactive aldehydes and ketones: (a) Ferna´ndez, R.; Mart´ın-Zamora,
E.; Pareja, C.; Va´zquez, J .; D´ıez, E.; Monge, A.; Lassaletta, J . M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 3428. (b) Ferna´ndez, R.; Mart´ın-
Zamora, E.; Pareja, C.; Alcarazo, M.; Mart´ın, J .; Lassaletta, J . M.
Synlett 2001, 1158.
2700 J . Org. Chem., Vol. 68, No. 7, 2003

Asymmetric Synthesis of Succinic Semialdehyde Derivatives
TABLE 2. Ad d ition of 1D to Alip h a tic a n d Ar om a tic Alk ylid en e Ma lon a tes 2a -i
a
b
Isolated yield. If applicable, given as a sum of individual yields of diastereomers. Determined by 1H NMR analysis of the crude
reaction mixtures. c Determined by 1H NMR of the purified major isomer. Addition of 1D to precomplexed 2. e Inseparable mixture of
d
diastereoisomers. f Addition of MgI2 to a solution containing 2 and 1D. The minor (S,R) isomer decomposed upon chromatographic
g
purification.
SCHEME 5. Syn th esis of Com p ou n d s 6, 7, 8, a n d 9
using Eu(hfc)3 as the shift reagent (see the Experimental
Section). These data demonstrated that the dithioketa-
lation proceeds without racemization, even for the more
sensitive aromatic derivatives. Compounds 7a -i are
versatile intermediates, which can also be transformed
into other useful derivatives by making use of the
chemistry of the dithioketal moiety. As an illustrative
example, ultrasound-assisted Ra-Ni mediated desulfu-
ration of 7b and 7g was effected to afford known
malonates 8b28 (75%) and 8g29 (71%), respectively. As the
overall result, reagent 1D has been used as a chiral
reagent for the asymmetric nucleophilic methylation of
alkylidene malonates, being the racemization-free direct
dithioketalation the key step in this process. Other useful
compounds can also be obtained upon typical transfor-
mation of the malonate terminus. For instance, optically
pure adducts 7d ,f,h ,i readily undergo decarboxylation
under Krapcho conditions30 (NaCl, wet DMSO, 150 °C)
to afford succinic semialdehyde derivatives 9d ,f,h ,i in
moderate-to-good yields (63-81%) as an interesting class
of differentiated 1,4-dicarbonyl compounds.
The absolute configuration of malonate 8g was deter-
mined by comparison of its optical rotation with literature
data: 8g had [R]21 +44.3 (c 0.7, MeOH) [lit.29 [R]24
D
D
+45.0 (c 1, MeOH)]. As the transformations 3 f 7 and 7
f 8 are assumed to proceed with retention of configu-
ration in neighbor stereogenic centers, the (3S) configu-
rations of 3g and 7g were deduced thereof. The absolute
configurations of 3a ,b,d -f,h ,i and 7a ,b,d -f,h ,i were
assigned by analogy. In the case of adduct 3c, however,
the abnormal low selectivity observed does not allow
assigning the absolute configuration in this way. Fortu-
direct dithioketalation of the hydrazone moiety27 was a
suitable reaction to this aim. Thus, treatment of adducts
3a -i with ethanedithiol in the presence of an excess of
BF3‚OEt2 (2.5-5 equiv) as the promoter afforded the
desired dithioketals 7a -i (Scheme 5, Table 3).
The enantiomeric purity of compounds 7 was indepen-
1
dently measured by HPLC or H NMR LIS experiments,
(28) Mori, K.; Kamada, A.; Kido, M. Liebigs Ann. Chem. 1991, 775.
(29) Legros, J .-Y.; Toffano, M.; Fiaud, J .-C. Tetrahedron 1995, 51,
3235.
(27) D´ıez, E.; Lo´pez, A. M.; Pareja, C.; Mart´ın-Zamora, E.; Ferna´n-
dez, R.; Lassaletta, J . M. Tetrahedron Lett. 1998, 39, 7955. This
procedure allows recovery of the chiral hydrazine in 70-75% yield.
(30) Krapcho, A. P. Synthesis 1982, 805.
J . Org. Chem, Vol. 68, No. 7, 2003 2701

Lassaletta et al.
TABLE 3. Syn th esis of Dith iok eta ls 7
a
b
1
Isolated yield. Determined by HPLC, using a chiral stationary phase column (Daicel Chiralpak AD). c Determined by H NMR shift
d
experiments, using Eu(hfc)3. From (S,R)-3c.
(1 mmol) under an argon atmosphere. The mixture was then
treated as described above. Representative spectral and ana-
lytical data for compounds 3a and 3e are as follows:
nately, the (S,R)-3c isomer could be crystallized and its
absolute configuration was established by X-ray diffrac-
tion analysis.
3a . Flash chromatography (Et2O-PE 1:6, 1% Et3N) gave
412 mg (91%) of 3a as a 89:11 mixture of diastereoisomers.
(S,R)-3a : 1H NMR (300 MHz, CDCl3) δ 0.11-0.22 (m, 1H),
1.05 (d, 3H, J ) 6.95 Hz), 1.37-1.40 (m, 1H), 1.79-2.03 (m,
2H), 2.52-2.58 (m, 1H), 2.79-2.85 (m, 1H), 3.03 (s, 3H), 3.04-
3.14 (m, 1H), 3.50 (d, 1H, J ) 9.4 Hz), 3.74 (s, 3H), 3.75 (s,
3H), 4.68 (dd, 1H, J ) 8.9 Hz, J ) 2.0 Hz), 6.38 (d, 1H, J )
4.4 Hz), 7.22-7.43 (m, 10H). 13C NMR (75 MHz, CDCl3) δ 16.5,
22.0, 25.8, 36.6, 50.2, 51.2, 52.0, 52.2, 56.1, 67.2, 85.6, 126.7,
126.8, 127.0, 129.4, 130.1, 133.5, 140.8, 141.7, 168.9, 169.2.
(S,S)-3a : 1H NMR (300 MHz, CDCl3) δ 0.11-0.22 (m, 1H), 1.10
(d, 3H, J ) 6.95 Hz, CH3), 1.37-1.40 (m, 1H), 1.79-2.03 (m,
2H), 2.52-2.58 (m, 1H), 2.79-2.85 (m, 1H), 3.02 (s, 3H),
3.04-3.14 (m, 1H), 3.56 (d, 1H, J ) 8.3 Hz), 3.69 (s, 3H), 3.75-
(s, 3H), 4.71 (dd, 1H, J ) 7.9 Hz, J ) 2.1 Hz), 6.44 (d, 1H, J
) 4.5 Hz), 7.22-7.43 (m, 10H). 13C NMR (75 MHz, CDCl3) δ
16.4, 21.9, 26.0, 36.3, 50.2, 51.1, 52.0, 52.2, 55.7, 66.8, 85.6,
126.7, 126.8, 127.0, 129.4, 130.0, 130.1, 133.6, 141.0, 141.8,
168.9, 169.2. IR (film, cm-1) 2949, 1736, 1597. MS (CI) m/z
453 (11, M+ + 1), 421 (28), 188 (100). Anal. Calcd for
Con clu sion s
In summary, the conjugate addition of chiral formal-
dehyde hydrazone 1D, acting as a neutral d1 reagent, to
alkylidene malonates 2 appears as a new entry to 1,4-
dicarbonyl derivatives as are compounds 3, 7, and 9.
Though good inductions were observed in general, the
method is particularly useful in the aromatic (e-i) series,
where the resolving properties of the chosen auxiliary
led to good yields of optically pure adducts in a single
step. Extension of this methodology to related substrates
bearing two different electron-withdrawing groups on the
same carbon of olefinic substrates is a current object of
study in our laboratories.
Exp er im en ta l Section
Melting points were determined by using a metal block and
are uncorrected. Optical rotations were measured at room
temperature. 1H and 13C NMR spectra were obtained in CDCl3
with either TMS (0.00 ppm 1H, 0.00 ppm 13C) or CDCl3 (7.26
C
26H32O5N2: C, 69.00; H, 7.13; N, 6.19. Found: C, 68.53; H,
7.31; N, 6.16.
3e. Flash chromatography (Et2O-PE 1:7, 1% Et3N) gave 398
1
ppm H, 77.00 ppm 13C) as an internal reference or C6D6 with
mg (77%) of (S,S)-3e and 54 mg (11%) of (S,R)-3e as oils. (S,S)-
1
3e: [R]25 +16.9 (c 0.9, CH2Cl2). H NMR (300 MHz, C6D6) δ
either TMS (0.00 ppm 1H, 0.00 ppm 13C) or C6D6 (7.15 ppm
1H, 128.0 ppm 13C) as an internal reference. FT-IR spectra
were recorded for KBr pellets or films. EI-mass spectra were
recorded at 70 eV, using an ionizing current of 100 µA, an
accelerating voltage of 4 kV, and a resolution of 1000 or 10000
(10% valley definition). The reactions were monitored by TLC.
Purification of the products was carried out by chromatography
(silica gel). The light petroleum ether used had a boiling range
40-65 °C. Enantiomeric mixtures of compounds 7 were used
as references for the ee determination of the purified com-
pounds by HPLC or 1H NMR.
D
0.10-0.24 (m, 1H), 0.90-1.17 (m, 1H), 1.65-1.79 (m, 1H),
1.96-2.03 (m, 1H), 2.29-2.38 (m, 1H), 2.60-2.66 (m, 1H), 3.09
(s, 3H), 3.11 (s, 3H), 3.51 (s, 3H), 4.55 (d, 1H, J ) 11.6 Hz),
4.64 (dd, 1H, J ) 11.6 Hz, J ) 3.6), 4.90 (dd, 1H, J ) 9.4 Hz,
J ) 1.5 Hz), 6.44 (d, 1H, J ) 3.6 Hz), 7.04-7.86 (m, 15H); 13
C
NMR (75 MHz, C6D6) δ 22.4, 25.9, 48.7, 50.2, 51.6, 51.7, 51.9,
56.5, 68.8, 86.2, 127.1, 127.3, 127.4, 127.4, 128.7, 129.4, 130.0,
131.3, 132.3, 139.8, 140.7, 141.6, 168.7, 168.8. IR (film, cm-1
)
3059, 2949, 1757, 1600. EM (CI) m/z 515 (39, M+ + 1), 483
(100). Anal. Calcd for C31H34O5N2: C, 72.35; H, 6.66; N, 5.44.
Found: C, 72.33; H, 6.93; N, 5.42. (S,R)-3e: [R]23 -65.6 (c
Syn th esis of Ad d u cts 3. Gen er a l P r oced u r e: Meth od
A. To a stirred, cooled solution of 2a -d (1 mmol) (-78 °C for
2a ,b,d ; 0 °C for 2c) and MgI2 (1 mmol) in dry CH2Cl2 (1 mL)
was added a solution of hydrazone 1D (1.5 mmol) in CH2Cl2
(1 mL) under an argon atmosphere. The mixture was stirred
until completion of the reaction (TLC), washed with H2O, dried
(MgSO4), and purified by flash chromatography. Meth od B.
To a stirred, cooled (0 °C) solution of 2e-i (1 mmol) and
hydrazone 1D (2 mmol) in dry CH2Cl2 (1 mL) was added MgI2
D
1
1.0, CH2Cl2). H NMR (300 MHz, C6D6) δ 0.25-0.36 (m, 1H),
0.95-1.08 (m, 1H), 1.67-1.86 (m, 2H), 2.27-2.36 (m, 1H),
2.61-2.67 (m, 1H), 3.13 (s, 6H), 3.43 (s, 3H), 4.57 (d, 1H, J )
11.3 Hz), 4.68 (dd, 1H, J ) 11.3 Hz, J ) 4.4 Hz), 4.79 (dd, 1H,
J ) 9.4 Hz, J ) 2.3 Hz), 6.66 (d, 1H, J ) 4.6 Hz), 7.05-7.80
(m, 15H). 13C NMR (75 MHz, C6D6) δ 22.0, 26.5, 48.1, 50.2,
51.1, 51.6, 52.0, 56.2, 66.5, 86.1, 127.3, 127.3, 127.5, 128.6,
129.3, 130.1, 130.4, 133.1, 140.1, 141.9, 142.9, 168.6, 168.9.
2702 J . Org. Chem., Vol. 68, No. 7, 2003

Asymmetric Synthesis of Succinic Semialdehyde Derivatives
MS (CI) m/z 515 (16, M+ + 1), 483 (100, M+ - OCH3). HRMS
m/z calcd for C31H35N2O5 515.2546, found 515. 2547.
Hz, H-1), 3.74 (s, 3H), 3.75 (s, 3H), 9.71 (s, 1H). 13C NMR (75
MHz, CDCl3) δ 11.3, 45.2, 52.1, 52.4, 53.8, 168.2, 168.2, 200.7.
IR (film, cm-1) 2959, 2851, 1738, 1397, 1092. MS (CI): m/z
189 (35%, M+ + 1), 157 (100, M+ - OCH3), 143 (17), 128 (19).
HRMS m/z calcd for C8H12O5 189.0763, found 189.0763.
Syn th esis of Dith iok eta ls 7a -i. Gen er a l P r oced u r e. To
a cooled (0 °C) solution of 3 (1 mmol) in dry CH2Cl2 (5 mL)
was added 1,2-ethanedithiol (126 µL, 1.5 mmol) and then BF3‚
Et2O (2.5 mmol for 3a ,b,e,f and 5 mmol for 3c,d ,g-i) under
an argon atmosphere. The mixture was allowed to warm to
room temperature and stirred until TLC indicated consump-
tion of the starting material. The mixture was then washed
with saturated NaHCO3 solution (2 × 10 mL), dried (MgSO4),
concentrated, and the resulting residue was purified by column
chromatography. Representative spectral and analytical data
for compounds 7a and 7e are as follows:
Syn th esis of Ca r boxyla tes 9. Gen er a l P r oced u r e. To a
solution of dithioketals 7 (1 mmol) in DMSO (20 mL) was
added H2O (1 mmol, 18 µL) and NaCl (1.2 mmol, 70 mg). The
mixture was heated at 150 °C until total consumption of
starting material (tlc control, 2-3 h). The mixture of the
reaction was washed with water (2 × 200 mL), and the water
layer was extracted with ether (4 × 100 mL). The organic layer
was dried (Na2SO4) and concentrated, and the residue was
purified by column chromatography (Et2O-PE 1:4). Repre-
sentative spectral and analytical data for compound 9d are
as follows:
7a . Flash chromatography (AcOEt-PE 1:10) gave 230 mg
(87%) of 7a as an oil: 78% ee by HPLC (Chiralpak AD,
2-propanol-hexane 5:95, 0.5 mL/min, 25 °C), R isomer 6.3 min,
S isomer 6.9 min. [R]25 +5.1 (c 1.1, CH2Cl2). 1H NMR (300
D
1
9d : 240 mg (81%, oil). [R]26 +2.7 (c 1.1, CH2Cl2). H NMR
D
MHz, CDCl3) δ 1.14 (d, 3H, J ) 6.8 Hz), 2.52 (m, 1H), 3.16-
3.18 (m, 4H), 3.69 (d, 1H, J ) 6.6 Hz), 3.72 (s, 3H), 3.73 (s,
3H), 4.62 (d, 1H, J ) 6.9 Hz). 13C NMR (75 MHz, C6D6) δ 14.9,
38.5, 38.7, 41.5, 51.7, 51.9, 55.9, 57.8, 168.4, 168.9. IR (film,
cm-1) 3053, 2847, 1732. MS (CI) m/z 265 (6, M+ + 1), 233 (100).
HRMS m/z calcd for C10H17O4S2 265.0568, found 265.0544.
7e. Flash chromatography (Et2O-PE 1:6) gave 199 mg
(61%) of 7e as an oil: >98% ee by 1H NMR [25% Eu(hfc)3].
[R]20D +8.6 (c 1.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 2.53-
2.63 (m, 1H), 2.79-2.89 (m, 1H), 2.97-3.05 (m, 2H), 3.44 (s,
3H), 3.78 (dd, 1H), 3.77 (s, 3H), 4.07 (d, 1H, J ) 9.7 Hz), 4.99
(d, 1H, J ) 6.5 Hz), 7.25-7.37 (m, 5H). 13C NMR (75 MHz,
CDCl3) δ 37.7, 38.7, 51.9, 52.3, 52.7, 56.0, 56.4, 127.5, 127.7,
129.6, 137.2, 167.6, 168.5. IR (film, cm-1) 2845, 1736. MS (CI)
m/z 327 (33, M+ + 1), 295 (77), 105 (100). HRMS m/z calcd for
(500 MHz, CDCl3) δ 1.79-1.86 (m, 2H), 2.33-2.35 (m, 1H),
2.47 (dd, 1H, J ) 15.7 Hz, J ) 7.2 Hz), 2.67 (t, 2H, J ) 8.2
Hz), 2.73 (dd, 1H, J ) 15.7 Hz, J ) 5.3 Hz), 3.17-3.23 (m,
4H), 3.68 (s, 3H), 4.80 (d, 1H, J ) 5.3 Hz), 7.18-7.30 (m, 5H).
13C NMR (125 MHz, CDCl3) δ 33.1, 35.3, 36.2, 38.6, 38.8, 41.1,
51.6, 57.5, 125.9, 128.3, 128.4, 141.6, 173.3. IR (film, cm-1
)
2924, 2855, 1736, 1435, 1092. MS (FAB) m/z 319 (15%, M+
+
23), 295 (40, M+ - 1), 265 (100). Anal. Calcd for C15H20O2S2:
C, 60.77; H, 6.80. Found: C, 60.96; H, 6.86.
Ack n ow led gm en t. We thank the MCYT (Grants
BQU2001-2376 and PPQ2000-1341; fellowship to A.P.),
and the Fonds der Chemischen Industrie for financial
support. The donation of chemicals by Degussa AG,
BASF AG, and Bayer AG is gratefully acknowledged.
C
15H19O4S2 327.0725, found 327.0716.
Syn th esis of Ald eh yd es 6. Gen er a l P r oced u r e. Ozone
was bubbled through a solution of 3 (1 mmol) in dry CH2Cl2
(6 mL) at -78 °C until the appearance of a permanent blue
color (5-10 min). Me2S (5 mmol) was added. The mixture was
allowed to warm to room temperature and concentrated, and
the resulting residue was purified by column chromatography.
Representative spectral and analytical data for compound 6a
are as follows:
6a . Flash chromatography (AcOEt-PE 1:10) gave 117 mg
(62%) of 6a as an oil. 1H NMR (300 MHz, CDCl3) δ 1.21 (d,
3H, J ) 7.5 Hz, CH3), 3.12-3.22 (m, 1H), 3.73 (d, 1H, J ) 7.1
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 3b-d ,f-i, 6c,e, 7b-d ,f-i, and 9f,h ,i, 13
C
NMR spectra for compounds (S,R)-3e, (S,R)-3f, (S,S)-3g, (S,R)-
3g, (S,R)-3h , (S,R)-3e, (S,S)-3i, 6a ,c,e, 7a ,c,e, and 9f, and
ORTEP drawing and X-ray data for compound (S,R)-3c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026557+
J . Org. Chem, Vol. 68, No. 7, 2003 2703