Asymmetric synthesis of α-substituted β-formyl δ-lactones via a Michael addition/α-alkylation protocol

Article abstract of DOI:10.1055/s-1999-2665

An efficient trans-diastereo- and enantioselective synthesis of α- substituted β-formyl δ-lactones 5 (de ≥98%, ee = 80 - 95%) is described, employing formaldehyde-SAMP-hydrazone (1) as a neutral formyl anion equivalent. The new procedure involves the Michael addition of 1 to 5,6- dihydro-2H-pyran-2-one (2) followed by trans-selective α-alkylation and subsequent oxidative cleavage of the auxiliary.

Full text of DOI:10.1055/s-1999-2665

LETTER
629
Asymmetric Synthesis of a-Substituted b-Formyl d-Lactones via a Michael
Addition/a-Alkylation Protocol
D. Enders*, J. Vázquez
Institut für Organische Chemie, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax: +49 (241) 8888127; E-mail: enders@RWTH-Aachen.de
Received 28 January 1998
acid in order to activate the a,b-unsaturated lactone 2.
Various Lewis acids (AlCl3, BF3◊Et2O, TiCl4, ZnCl2, etc)
were tested, but as was previously observed with enones,9
only trialkylsilyl (TBS or TMS) triflates as promoters
Abstract: An efficient trans-diastereo- and enantioselective syn-
thesis of a-substituted b-formyl d-lactones 5 (de ≥98%, ee = 80 -
95%) is described, employing formaldehyde-SAMP-hydrazone (1)
as a neutral formyl anion equivalent. The new procedure involves
the Michael addition of 1 to 5,6-dihydro-2H-pyran-2-one (2) fol- gave rise to the formation of the desired Michael adduct
lowed by trans-selective a-alkylation and subsequent oxidative
(S,R)-3 in acceptable yield (54%) and good diastereomer-
ic excess (de = 80%). It should be mentioned that attempts
to isolate the corresponding silylketene acetal were not
successful. The reaction was therefore quenched with pH
7 buffer or Et3N to neutralize the triflic acid generated.11
It was also observed that tetrahydrofuran instead of
dichloromethane as solvent gave rise to undesired byprod-
ucts. In addition, it was necessary to use dilute conditions
to avoid the byproducts resulting from both the electro-
philic and the nucleophilic nature of (S)-1. Initially, the re-
action is quite fast, but an optimum time is about 30 h after
which no improvement of the yield was observed. Related
1,4-additions of 1 to 2-butenolide gave poor yields but ex-
cellent diastereoselectivities.
cleavage of the auxiliary.
Key words: SAMP-hydrazone, formyl anion equivalent, alkylation
of lactones, Michael addition, asymmetric synthesis
Lactones1 and their derivatives feature as important sub-
units in many natural products, such as sesquiterpenes,2 a-
methylene lactones3 and macrolides.4 In addition, they
show various biological properties, such as in semiochem-
icals, flavours and fragances, antibiotics or cytostatics.
Therefore the efficient and flexible asymmetric synthesis
of lactone building blocks is of great interest.5
The previously demonstrated utility of formaldehyde
SAMP-hydrazone (S)-1 as a neutral chiral formyl anion
and cyanide equivalent6 for nucleophilic additions to ni-
troalkenes,7 sugar aldehydes,8 a,b-unsaturated ketones9
and trifluoromethylketones10 should allow the introduc-
tion of the formyl group at the b-position of lactones via
1,4-addition. To the best of our knowledge, asymmetric
nucleophilic formylation of a,b-unsaturated lactones has
not been reported yet. Additionally, a subsequent alkyla-
tion should introduce further complexity at the a-centre.
Thus, the retrosynthetic analysis of the d-lactones A leads
to the synthons B and C and 2-pentenolide 2 as the
Michael acceptor (Figure).
O
OCH3
O
R
O
N
O
+
N
H
H
H
O
(R,S)-5
(S)-1
2
de > 98%
ee = 80 - 95%
CH2Cl2, − 78°C
O3, CH2Cl2
− 78°C
54%
50 - 70%
TBSOTf
O
O
O
R
N
O
O
O
OCH3
H
H
N
1. LDA, THF, − 78°C
2. RX/HMPA, − 78°C
R
C
R
O
O
*
N
H
O
N
N
N
B* ≡
H
44 - 90%
H
*
H
OCH3
OCH3
2
A
O
B
(S)-1
(S,R)-3
de = 80%
(S,R,S)-4
de = 80 - >98%
*
Figure
Scheme
We now describe the trans-diastereo- and enantioselec-
tive synthesis of the title a-substituted b-formyl d-lac-
tones via Michael addition of formaldehyde SAMP-
hydrazone (S)-1 to 2-pentenolide 2 as the key step. As is
depicted in the Scheme, it was necessary to use a Lewis
Unfortunately, the mixture of b-epimers 3 was only sepa-
rable by HPLC on chiral stationary phases and therefore
this mixture was directly used in the subsequent deproto-
Synlett 1999, No. 5, 629–631 ISSN 0936-5214 © Thieme Stuttgart · New York

630
D. Enders, J. Vázquez
LETTER
nation / a-alkylation step. After metalation of the lactone (4c,d) and thus it was possible to use the diastereomerical-
3 with lithium diisopropylamide (LDA) at – 78 °C in ly enriched lactone hydrazones 4 in the following oxida-
THF, HMPA (2.5 - 5 equivalents) and the requisite alkyl- tion step. This hydrazone cleavage to remove the auxi-
ating agents were added stepwise to afford the a-substitut- liary was carried out by ozonolysis14 at –78 °C in dichlo-
ed lactone hydrazones 4 in medium to excellent yields (44 romethane affording the title aldehyde d-lactones (R,S)-5
- 90%) and diastereomeric excesses of de = 80 – ≥98% in acceptable yields (50 - 70%) and high diastereo- and
(Table 1).12 The optimum alkylating temperature concern- enantiomeric excesses (de ≥98%, ee = 80 - 95%, Table 1).
ing yield and stereoselectivity turned out to be – 78 °C for
more reactive electrophiles and – 35 °C in the case of less
reactive halides.
The a-substituted b-formyl d-lactones 5 are not very sta-
ble and their purification required special silica gel (parti-
cle size 0.063 - 0.10 mm) to avoid partial decomposition.
Upon prolonged standing they tend to decompose and
should therefore be stored as their corresponding acetals15
or should be prepared directly before use in further reac-
tions.
In summary, our Michael addition / a-alkylation protocol
employing formaldehyde SAMP-hydrazone as a neutral
chiral formyl anion equivalent in the 1,4-addition to 2-
pentenolide opens a stereoselective entry to 3-substituted
2-oxo-tetrahydro-2H-4-pyrancarbaldehydes, which are
useful building blocks for the asymmetric synthesis of
bioactive compounds.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz prize, Sonderforschungsbereich 380) and the Fonds der
Chemischen Industrie. We thank the Ministerio de Educación y
Cultura for a postdoctoral fellowship to J.V. We also thank Degussa
AG, BASF AG, Bayer AG and former Hoechst AG for the donation
of chemicals.
a) Yield after flash chromatography. b) Determined by HPLC on chiral
stationary phases [ chiralpak AD (4.6 x 250 mm), (S,S)-Whelk-O 1
References and Notes
(4 x 250 mm), chiralcel OJ (4.6 x 250 mm)] after HPLC separation.
Figures in brackets refer to the de values of the alkylation reactions. c)
(1) For general reviews on lactones see: a) Pielartzik, H.; Irmisch-
e)
5a decomposes during ozonolysis. d) After flash chromatography.
Pielartzik, B.; Eicher, T. In Houben-Weyl, 4th ed., Vol. E5,
Diastereoisomers were not separable by HPLC. f) Determined as de of
part 1; Falbe, J., Ed.; Thieme: Stuttgart 1985; p 715. b) Boyd,
G.V. In The Chemistry of Acid Derivatives, The Chemistry of
Functional Groups; Patai, S., Ed.; Wiley: Chichester 1979; p
492; 1992; p 548. c) Mulzer, J. In Comprehensive Organic
the corresponding acetal derived from (R,R)-2,3-butanediol by GC on
chiral stationary phases (Lipodex E 25m). g) Determined as de of the
corresponding acetal by HPLC on chiral stationary phases [(S,S)-
whelk-O 1 (4 x 250 mm)] h) Determined by shift experiments using
Synthesis, Vol. 6; Trost, B. M.; Fleming, I.; Winterfeldt, E.;
(R)-1-(9-anthryl)-2,2,2-trifluoroethanol as co-solvent. i) Determined
Eds.; Pergamon: Oxford 1991; p 323. d) Collins, I. J. Chem.
as de of the corresponding hydrazone 4.
Soc., Perkin Trans. 1 1998, 1869-1888 and references cited
therein.
(2) Yoshioka, H.; Mabry, T. J.; Timmermann, B. N.
The trans-configuration of the a,b-disubstituted d-lac-
Sesquiterpene Lactones; University of Tokyo Press: Tokyo
1973.
tones 4 was determined by 1H NMR spectroscopy through
the trans-diaxial coupling constants (9.5 - 10.7 Hz) of the
methine hydrogens at the two new stereogenic centres.
NOE experiments on compound 4b (R = Me) confirmed
this relative configuration. The absolute configuration of
the minor diastereomer (R,R)-4b was determined by X-
ray structure analysis, the configuration of the major iso-
mer therefore being (3S,4R). In addition, we have recently
obtained the crystal structure of the major trans-diastere-
omer of (R,S)-4c.13 Assuming a uniform reaction pathway
for all cases, the relative topicity for the nucleophilic at-
tack of 1 to the a,b-unsaturated d-lactone 2 is the same as
previously reported for 1,4-additions to enones.9
(3) For reviews see: a) Grieco, P. A. Synthesis 1975, 67. b) Hoff-
mann, H. M. R.; Rabe, J. Angew. Chem. 1985, 97, 96; Angew.
Chem. Int. Ed. Engl. 1985, 24, 94. c) Petragnani, N.; Ferraz,
H. M. C.; Silva, G. V. J. Synthesis 1986, 157. d) Sarma, J. C.;
Sharma, R. P. Heterocycles 1986, 441. e) Ito, M. Pure Appl.
Chem. 1991, 63, 13.
(4) For reviews see: a) Nicolaou, K. C. Tetrahedron 1977, 33,
683. b) Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew.
Chem. 1977, 89, 602; Angew. Chem. Int. Ed. Engl 1977, 16,
587. c) Rossa, L.; Vögtle, F. Top. Curr. Chem. 1983, 113, 1.
d) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.
e) Boeckmann Jr., R. K.; Goldstein, S. W. In The Total Synthe-
sis of Natural Products, Vol. 7; ApSimon, J., Ed.; Wiley: New
York 1988; p1.
In some cases the diastereomers of the d-lactones 4 were
separable by flash chromatography (4b) or by HPLC
(5) For alternative asymmetric syntheses of d-lactones developed
in our group see: a) Enders, D.; Rendenbach, B. E. M. Chem.
Ber. 1987, 120, 1223. b) Enders, D.; Gröbner, R.; Runsink, J.
Synlett 1999, No. 5, 629–631 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of a-Substituted b-Formyl d-Lactones via a Michael Addition
631
Synthesis 1995, 947. c) Enders, D.; Kaiser, A. Heterocycles
1997, 46, 631. d) Enders, D.; Teschner, P.; Gröbner, R.;
Raabe, G. Synthesis 1999, 237.
(12) a) Posner, G. H.; Loomis, G. L. J. Chem. Soc., Chem.
Commun. 1972, 892. b) Herrmann, J. L.; Schlessinger, R. H. J
Chem. Soc., Chem. Commun. 1973, 711.
(6) Enders, D.; Bolkenius, M.; Vázquez, J.; Lassaletta, J. M.;
Fernández, R. J. Prakt. Chem. 1998, 340, 281.
c) General procedure for the a-alkylation: A solution of the
1,4-adduct 3 (2 mmol) in THF (4 ml) cooled at – 78 °C was
treated with a solution of LDA (2.2 mmol) in THF (4 ml) at –
78 °C. After stirring for 3h, HMPA (0.87 ml or 1.74 ml) was
added dropwise. The mixture was then treated with the alkyl
halide (2.6 mmol) and kept at – 78 °C or warmed up to – 35 °C
until consumption of the starting material was detected by
TLC. After hydrolysis with saturated NH4Cl solution the
aqueous phase was extracted with Et2O and the combined
organic phase was extracted with water and dried (MgSO4).
The crude material was purified by flash chromatography
(SiO2, Et2O/pentane).
(7) a) Lassaletta, J. M.; Fernández, R. Tetrahedron Lett. 1992, 33,
3691-3694. b) Fernández, R.; Gasch, C.; Lassaletta, J. M.;
Llera, J. M. Tetrahedron Lett. 1994, 35, 471. c) Enders, D.;
Syrig, R.; Raabe, G.; Fernández, R.; Gasch, C.; Lassaletta, J.
M.; Llera, J. M. Synthesis 1996, 48. d) Lassaletta, J. M.;
Fernández, R.; Gasch, C.; Vázquez, J. Tetrahedron 1996, 52,
9143.
(8) Lassaletta, J. M.; Fernández, R.; Martín-Zamora, E.; Pareja,
C. Tetrahedron Lett. 1996, 37, 5787.
(9) a) Lassaletta, J. M.; Fernández, R.; Martín-Zamora, E.; Díez,
E. J. Am. Chem. Soc. 1996, 118, 7002. b) Díez, E.; Fernández,
R.; Gasch, C.; Lassaletta, J. M.; Llera, J. M.; Martín-Zamora,
E.; Vázquez, J. J. Org. Chem. 1997, 62, 5144.
(10) Fernández, R.; Martín-Zamora, E.; Pareja, C.; Vázquez, J.;
Díez, E.; Monge, A.; Lassaletta, J. M. Angew. Chem. 1998,
110, 3598; Angew. Chem. Int. Ed. Engl. 1998, 37, 3428.
(11) General procedure for the Michael addition: To a cooled (–
78 °C) solution of 2-pentenolide 2 (10 mmol) and (S)-1 (20
mmol) in CH2Cl2 (80 ml) was added dropwise TBS triflate (12
mmol) pre-cooled at – 30 °C. The mixture was stirred for 30
h, neutralized with Et3N at – 78 °C and allowed to warm to
0 °C. The mixture was washed with water, dried (MgSO4) and
purified by flash chromatography (SiO2, Et2O/pentane
3:1ÆEt2O).
(13) Complete crystallographic details for compounds (R,R)-4b
and (R,S)-4c will be published in a full paper in due course.
(14) Typical procedure for ozonolysis: Ozone was bubbled
through a solution of 4 (1 mmol) in dry CH2Cl2 (25 ml) at
–78 °C until the mixture retained its initial colour (TLC
control). Me2S (1.1 mmol) was added and the mixture was
allowed to warm to room temperature, concentrated in vacuo,
and the residue purified by flash chromatography (SiO2,
0.063-0.100 mm, Et2O/pentane).
(15) a) Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 2183.
b) Enders, D.; Whitehouse, D.L. Synthesis 1996, 621.
Article Identifier:
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Synlett 1999, No. 5, 629–631 ISSN 0936-5214 © Thieme Stuttgart · New York