Enantioselective nucleophilic formylation and cyanation of conjugated enones via Michael addition of formaldehyde SAMP-hydrazone

Full text of DOI:10.1021/ja9610500

7002
J. Am. Chem. Soc. 1996, 118, 7002-7003
Scheme 1
Enantioselective Nucleophilic Formylation and
Cyanation of Conjugated Enones Wia Michael
Addition of Formaldehyde SAMP-Hydrazone
Jose-Mar´ıa Lassaletta,* Rosario Ferna´ndez,
Elo´ısa Mart´ın-Zamora, and Elena D´ıez
Departamento de Qu´ımica Orga´nica
Facultad de Qu´ımica, UniVersidad de SeVilla
Apartado de Correos No. 553
E-41071, SeVille, Spain
ReceiVed April 1, 1996
The Michael addition of carbon nucleophiles to conjugated
enones is one of the most powerful methods for carbon-carbon
bond formation. Due to its relevance in the synthesis of
biologically active compounds, much effort has centered on
carrying out this reaction in a stereoselective way.1 The
asymmetric introduction of nonfunctionalized fragments has
been satisfactorily solved by addition of organometallics.2
Likewise, chiral 5-oxocarbonyl compounds have been com-
monly synthesized from enones by asymmetric addition of silyl
enol ethers,3 enamines,4 imines,5 malonates,6 aminocarbene
complex anions,7 and other enolate and aza-enolate equivalents.
Many fewer possibilities can be found for asymmetric acylations
(f1,4 diketones), a good approach being the addition of
metalated aminonitriles.8 To complete this scenario, a good
methodology for the asymmetric addition of a formyl anion
equivalent (f4-oxoaldehydes) should be of great interest.9
Taking advantage of their aza-enamine character, we have
recently reported on the use of formaldehyde dimethyl-10 and
SAMP-hydrazones11 as neutral formyl anion and cyanide
equivalents in their Michael additions to conjugated nitroalkenes.
We now report the dimethylthexylsilyl (TDS) triflate-promoted12
regio- and diastereoselective addition of formaldehyde SAMP-
hydrazone [(S)-1] to prochiral cyclic and acyclic conjugated
enones (2a-g) (Scheme 1). The reaction proceeds in few
minutes at -78 °C in THF, and both the silyl enol ethers 3,
primary products of the reaction, and the corresponding depro-
tected ketones 4 can be isolated in good yields and with excellent
de’s (85-g98%). The results of these additions are collected
in Table 1.
Emphasis should be given to the fact that quaternary
stereogenic centers14 (entries b and e) are easily created with
high diasteroselections and with the highest yields within the
series. Interestingly, the reaction takes place in the presence
of Et3N with similar results.15 The diastereoselectivities
observed, which are highly dependent on temperature, are not
much affected when reaction mixtures are allowed to warm up
before quenching. Thus, the process is essentially irreversible,
and kinetically controlled products are obtained. Experiments
changing the order of addition of the reagents demonstrated that
hydrazone-TDSOTf complexes are irreversibly formed and that
the precomplexed ketone is the reactive species. Racemization-
free cleavage of the chiral auxiliary to yield the desired
4-oxoaldehydes 5 has been performed in good yields by either
ozonolysis16 or HCl-mediated hydrolysis. High-yielding oxida-
tive cleavage of adducts 4 to 4-oxonitriles 6 has also been easily
achieved by treatment with magnesium monoperoxyphtalate
hexahydrate (MMPP‚6H2O),17 giving additional worth to this
methodology. The results of the synthesis of compounds 5 and
6 are summarized in Table 2.
(1) Recent reviews: (a) Oare, D. A.; Heathcock, C. H. Top. Stereochem.
1989, 20, 87-170. (b) Oare, D. A.; Heathcock, C. H. Top. Stereochem.
1989, 20, 227-407.
(2) Review: Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-
806. Recent examples: Wang. Y.; Gladysz J. A. J. Org. Chem. 1995, 60,
903-909 and references cited therein.
(3) Lohray, B. B.; Zimbiniski, R. Tetrahedron Lett. 1990, 31, 7273-
7276.
(4) Hickmott, P. W. In The Chemistry of Enamines; Patai, S., Rappoport
Z., Eds.; John Wiley & Sons: New York, 1994; pp 727-871.
(5) (a) Desmae¨le, D.; Pain, G.; d’Angelo, J. Tetrahedron: Asymmetry
1992, 3, 863-866. (b) For a recent review, see: d’Angelo, J.; Desmae¨le,
D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459-505.
(6) (a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116,
1571-1572. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1176-1178. (c) Kawara, A.; Taguchi, T.
Tetrahedron Lett. 1994, 35, 8805-8808.
(7) Anderson, B. A.; Wulff, W. D.; Rahm, A. J. Am. Chem. Soc. 1993,
115, 4602-4611.
(8) Enders, D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995,
659-666 and references cited therein.
(9) The only precedent to our knowledge consists of addition of a chiral
oxidized dithioacetal derived reagent which, upon a complicated two-step
deprotection sequence, gave poor yields and ee’s of the desired products:
(a) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. Synthesis 1981,
74-76. (b) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. J. Chem.
Soc., Perkin Trans. 1 1981, 1284-1286.
(10) Lassaletta, J. M.; Ferna´ndez, R. Tetrahedron Lett. 1992, 33, 3691-
3694.
(11) (a) Ferna´ndez, F.; Gasch, C.; Lassaletta, J. M.; Llera, J. M.
Tetrahedron Lett. 1994, 35, 471-472. (b) Enders, D.; Syrig, R.; Raabe,
G.; Ferna´ndez, R.; Gasch, C.; Lassaletta, J. M.; Llera, J. M. Synthesis 1996,
48-52.
(12) Attempts to carry out the reaction under the same conditions as for
conjugated nitroalkenes (i.e., rt, no catalyst) failed. Other Lewis acids (ZnCl2,
TiCl4, etc.) were also unsuccessfully tested. The use of trialkylsilyl triflates
as promoters for the addition of soft nucleophiles to enones has recently
been reported: Kim, S.; Park, J. H. Synlett 1995, 163-164.
(13) The cis stereochemistry was assigned by comparison of the derived
nitrile (R)-6c (vide infra) with the known racemic form: Cocker, W.;
Grayson, D. H.; Shannon, P.V. R. J. Chem. Soc., Perkin Trans. 1 1995,
1153-1162.
The absolute configuration of the adduct (R,S)-4f was
determined by X-ray structure analysis,18 and that corresponding
(14) The asymmetric creation of quaternary carbon centers has recently
been reviewed: Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
(15) This should allow the choice of Lewis acid-sensitive starting
materials, although such possibility has not been tested.
(16) After ozonolysis, the chiral auxiliary SAMP can be recycled: Enders,
D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933-2960.
(17) Ferna´ndez, F.; Gasch, C.; Lassaletta, J. M.; Llera, J. M.; Va´zquez,
J. Tetrahedron Lett. 1993, 34, 141-144.
(18) Complete crystallographic details for this compound will be
published separately: Dia´nez, M. J.; Estrada, M. D.; Lo´pez-Castro, A.;
Pe´rez-Garrido, S. Dpto. F´ısica Materia Condensada, Apartado de Correos
1065, E-41080 Seville, Spain.
(19) Jones oxidation of the volatile aldehyde (R)-5a gave the known (R)-
3-oxocyclopentanecarboxylic acid [(R)-7, 84% from (R,S)-4a]. (R)-7 had
[R]21 +21.8° (c 1.9, CH3OH). The maximum reported value for this
D
compound is [R]21D +22.1° (c 1.9, CH3OH): (a) Toki, K. Bull. Chem. Soc.
Jpn. 1958, 31, 333. (b) Sato, Y.; Nishioka, S.; Yonemitsu, O.; Ban, T. Chem.
Pharm. Bull. 1963, 11, 829-834.
S0002-7863(96)01050-5 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 29, 1996 7003
Table 1. Asymmetric Michael Additions of (S)-1 to Enones 2
Table 2. Synthesis of 4-Oxoaldehydes 5 and 4-Oxonitriles 6
product 5 (7)
product 6
yield
(%)
yield
(%)
educt
[R]22
ee
[R]22
ee
conf
D
D
4a
4b
4c
4d
4e
4f
(84)a (-21.8)a
(99)a
g98c
97c
95e
85c
g
90
98
70d
83
87
95
91
+35.3
93b (R)
87
94
78
69
79
88
-22.0
+82.3
+34.3
+5.5
-54.2 g98c (R)
+63.6
-11.7
-24.3
97c (R,R)
94b (S)
84b (R)
-55.6f
-39.7f
+15.3 >98h (R)
4g
g
+8.1
96h (R)
a Characterized as its corresponding acid 7 (see ref 19). b Determined
as de of its (2R,3R)-2,3-butanediol derived ketal. c Determined as de
of compounds 4. d Yield of pure (2R,3R)-isomer (see ref 13). e Deter-
mined by shift experiments using (R)-1-(9-antryl)-2,2,2-trifluoroethanol
f
as cosolvent. Maximum values measured for freshly obtained products.
g Racemization occurs during ee determination with Eu(hfc)3. h Deter-
mined by shift experiments using Eu(hfc)3 in CDCl3.
important chiral building blocks, some of them bearing qua-
ternary stereogenic centers. In our opinion, the excellent
enantioselectivity and predictable absolute configuration will
prove to have many applications in the field of natural product
synthesis.
Acknowledgment. We thank the Direccio´n General de Investiga-
cio´n Cient´ıfica y Te´cnica for financial support (Grant PB 94/1429).
We also thank the Ministerio de Educacio´n y Ciencia for a doctoral
fellowship to E.D. and a postdoctoral fellowship to E.M.-Z.
Supporting Information Available: Full experimental details,
spectral and analytical data for compounds 3a-f, 4a-g, 5b-g, 6a-g,
and 7, ORTEP figure and tables containing bond lengths and angles
for compound 4f, detailed experiments for the determination of the
absolute configuration of compounds 6d and 6e (11 pages). See any
current masthead page for ordering and Internet access instructions.
a Determined by 13C- and/or 1H-NMR spectroscopy. b 95:5 Mixture
of cis and trans isomers.13 c Unstable compound.
to 4a has been assigned (R,S) by comparison of the optical
rotation of the derived (+)-(R)-3-oxocyclopentanecarboxylic
acid [(R)-7] with literature data.19 Additionally, the empirical
rule developed by Lemie`re et al.20 was used to assign the 3S
and 3R configuration to the (2R,3R)-2,3-butanediol-derived
ketals of compounds 6d and 6e, respectively. Assuming
uniform reaction pathways, the stereochemistry of b, c, and g
series compounds has been assigned by analogy. Summarizing,
the nucleophilic attack always occurs to the same face of the
enone, irrespective of its stereochemistry.21
JA9610500
(21) A chairlike geometry for the approach of the reactants is proposed.
Thus, the steric repulsion between the CH2OMe group and both the bulky
TDS+-chelated oxygen atom and the substituent R1 should result in a much
higher energy for B than for A, according to the absolute configuration
and the high induction observed. Such geometries, stabilized by secondary
orbital interactions, have been demonstrated to be operative for closely
related systems: Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J. Org. Chem.
1995, 60, 1143-1147.
In conclusion, this paper describes a new simple and efficient
methodology for the highly diastereoselective asymmetric
Michael addition of a neutral masked formyl anion and cyanide
equivalent to prochiral conjugated enones. The chiral formal-
dehyde SAMP-hydrazone and its enantiomeric RAMP-hydra-
zone11b,22 can be used for the enantioselective synthesis of
(20) Lemie`re, G. L.; Dommisse, R. A.; Lepoivre, F. C.; Alderweireldt,
F. C.; Hiemstra, H.; Wynberg, H.; Jones, J. B.; Toone, E. J. J. Am. Chem.
Soc. 1987, 107, 1363-1370. See supporting information for details.
(22) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173-182.