Asymmetric hetero Diels-Alder route to quaternary carbon centers: Synthesis of (-)-malyngolide

Article abstract of DOI:10.1016/S0040-4039(01)01227-8

Conformationally constrained chiral bis(oxazoline)-metal complex catalyzed asymmetric hetero Diels-Alder reactions of Danishefsky's diene and a variety of α-keto esters constructed quaternary carbon centers enantioselectively. The reaction was utilized in

Full text of DOI:10.1016/S0040-4039(01)01227-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6231–6233
Asymmetric hetero Diels–Alder route to quaternary carbon
centers: synthesis of (−)-malyngolide
Arun K. Ghosh* and Michio Shirai
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 8 May 2001; accepted 5 July 2001
Abstract—Conformationally constrained chiral bis(oxazoline)-metal complex catalyzed asymmetric hetero Diels–Alder reactions
of Danishefsky’s diene and a variety of a-keto esters constructed quaternary carbon centers enantioselectively. The reaction was
utilized in the synthesis of (−)-malyngolide. © 2001 Elsevier Science Ltd. All rights reserved.
Development of effective catalytic processes for the
enantioselective hetero Diels–Alder reactions of alde-
hydes and dienes is of significant interest in organic
synthesis.1 The potential of chiral bis(oxazoline)-metal
complexes as versatile catalysts for a variety of asym-
metric transformations has been documented.2 We
recently reported conformationally constrained chiral
bis(oxazoline)-metal complex catalyzed asymmetric het-
ero Diels–Alder reactions of Danishefsky’s diene and
various bidentate aldehydes including glyoxalate esters
and benzyloxyacetaldehyde to form the respective
cycloadduct enantioselectively.3 The reaction proceeded
through a Mukaiyama aldol reaction followed by an
acid-catalyzed cyclization to provide the hetero Diels–
Alder product (Fig. 1). Jørgensen and co-workers have
also demonstrated that the corresponding reaction with
alkyl pyruvates and Danishefsky’s diene can proceed
with high enantioselectivities and isolated yields.4 The
resulting cycloadduct provided important enantioselec-
tive access to quaternary chiral centers. Enantioselective
synthesis of such quaternary centers is of significant
interest in organic synthesis.5 As per our continuing
interest in the development of effective methodologies
for quaternary chiral centers, we subsequently investi-
gated catalytic hetero Diels–Alder reactions of a variety
of a-keto esters utilizing cis-aminoindan-2-ol derived
conformationally constrained inda-box-metal com-
plexes.6,7 One of the main advantages of inda-box-
derived catalysts is that both enantiomers are
commercially available or can be readily synthesized,
providing convenient access to either enantiomer of the
cycloadduct in a stereopredictable fashion.7 Herein, we
report that the inda-box derived ligand–metal com-
plexes are effective catalysts for hetero Diels–Alder
reactions of Danishefsky’s diene and a number of a-
keto esters. The methodology was utilized in the syn-
thesis of the marine natural product (−)-malyngolide,
an antibiotic with significant activity against Strepto-
coccus pyogenes and Mycobacterium smegmatis.8 Since
the first synthesis by Mukaiyama,9 a number of other
syntheses of (−)-malyngolide have been reported.10
However, only a few them utilize asymmetric catalytic
methodology.11
As described previously, the ligand–metal complexes
were prepared by reaction of an equimolar mixture of
bis(oxazoline) ligand and Cu(OTf)2 in dry CH2Cl2 at
23°C under a nitrogen atmosphere.2 The resulting chiral
catalyst (5–20 mol% to ketone) was cooled to −78°C
and representative a-keto ester followed by 1.2–2 equiv.
of Danishefsky’s diene were added. The reaction mix-
ture was stirred at −78°C for 12 h. After this period, the
formation of the respective Mukaiyama aldol product
as well as pyranone derivative 5 can be observed by
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01227-8

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A. K. Ghosh, M. Shirai / Tetrahedron Letters 42 (2001) 6231–6233
TLC. The reaction mixture was treated with an excess of
trifluoroacetic acid in CH2Cl2 and the resulting mixture
was warmed to 0°C. During a 4–8 h period, the aldol
product is converted to cyclocondensation product 5.
The enantiomeric excess of various hetero Diels–Alder
cycloadducts was determined by chiral HPLC analysis
(using a Daicel OD column, 10% isopropanol/hexane as
the eluent) of the cycloadducts or the derived secondary
alcohol after reduction of the a,b-unsaturated ketone as
well as by comparison of optical rotation with the
authentic material.
furnished cycloadduct 5d in 73% isolated yield and 56%
e.e. with ligand ent-3 derived catalyst (entry 6).13 In
contrast, the reaction with ligand 4 derived catalyst
afforded 5d in lower enantioselectivity (47% e.e.). Inter-
estingly, the reaction of 1 with benzyloxy-2-undecanone
did not provide any cycloadduct.
To corroborate the stereochemical assignment of the
cycloadduct derived from ethyl 2-oxoundecanate (entry
6), pyranone derivative 5d was utilized in the synthesis
of (−)-malyngolide. Reduction of 5d with NaBH4 in the
presence of cerium chloride heptahydrate followed by
treatment of the resulting 1,2-reduction product with
K-10 and methanol furnished the Ferrier rearrangement
product 6 as a 1:1 mixture of diastereomer (Scheme 1).
Ethyl ester 6 was then converted to benzyl ether 7 in a
three-step sequence involving: (1) LiAlH4 reduction of
the ester to a primary alcohol in ether at 0°C, (2)
hydrogenation of the olefin with 10% Pd–C in CH3OH
and (3) protection of the free alcohol as benzyl ether by
treatment with sodium hydride and benzyl bromide.
Methyl acetal 7 was isolated in 56% overall yield (from
6) after silica gel chromatography. Exposure of 7 to
Jones’ reagent in acetone at 23°C furnished d-lactone 8
directly in 60% isolated yield. Methylation of 8 was
accomplished by a modified Mukaiyama procedure.9
Deprotonation of 8 with LHMDS and HMPA at −78°C
The results of various hetero Diels–Alder reactions are
summarized in Table 1. As can be seen, both the choice
of ligand and the size of alkyl groups in the keto ester
have relevance on the observed enantioselectivity. The
reaction of methyl pyruvate and diene 1 with 10 mol%
chiral catalyst derived from conformationally con-
strained bis(oxazoline) 3 provided near quantitative yield
of cycloadduct 5a in 87% e.e. The corresponding reaction
with ethyl pyruvate furnished 5b in 96% e.e.; however,
the reaction yield was moderate. In comparison, reaction
of ethyl pyruvate with ent-3 ligand derived catalyst
furnished ent-5b (entry 4) in 62% yield and 99% e.e.
Ligand 4 derived catalyst has exhibited similar results
(entry 3). The reaction of ketone containing a propenyl
side chain gave 83% e.e. with ligand 3-derived catalyst.12
The keto ester containing a large nonyl side chain
Table 1. Hetero Diels–Alder reaction of a-ketoesters and diene 1

A. K. Ghosh, M. Shirai / Tetrahedron Letters 42 (2001) 6231–6233
6233
Scheme 1. (a) NaBH4, CeCl3·7H2O, EtOH/H2O, 0°C; (b) K-10, CH3OH, 0–23°C (56%); (c) LiAlH4, Et2O, 0°C; (d) H2, Pd–C,
CH3OH, 23°C; (e) BnBr, NaH, DMF, 0°C (56%, three steps); (f) Jones’ reagent, acetone, 23°C (60%); (g) LHMDS, HMPA, CH3I,
THF, −78°C (96%).
followed by reaction with methyl iodide provided alky-
lation product 9 as a 1.5:1 mixture of diastereomers in
96% yield. The removal of the benzyl group by hydro-
genation with 10% Pd–C afforded a mixture (1.5:1) of
(−)-malyngolide 10 and its epimer which were easily
separated by flash column chromatography over silica
gel (30% EtOAc/hexane). Spectral data (1H and 13C
NMR) for synthetic 10 ([h]2D3 −7.3° (c 1.1, CHCl3), lit.
[h]2D3 −13° (c 2, CHCl3) are in full agreement with that
reported in the literature.9 Thus, (−)-malyngolide 10 has
been synthesized in enantiomerically enriched form.14
Cappiello, J.; Krishnan, K. Tetrahedron: Asymmetry 1996,
7, 2615.
4. (a) Johannsen, M.; Yao, S.; Jørgensen, K. A. Chem.
Commun. 1997, 2169; (b) Yao, S.; Johannsen, M.; Audrain,
H.; Hazell, R. G.; Jorgensen, K. A. J. Am. Chem. Soc. 1998,
120, 8599.
5. For excellent reviews on quaternary carbon centers with
four carbon substituents, see: (a) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. Engl. 1996, 37, 388; (b)
Fuji, K. Chem. Rev. 1993, 93, 2037 and references cited
therein.
6. Ghosh, A. K.; Kawahama, R.; Wink, D. Tetrahedron Lett.
2000, 41, 8425.
In conclusion, cis-aminoindan-2-ol-derived conforma-
tionally constrained bis(oxazoline) complexed with
Cu(OTf)2 is a very effective catalyst for the hetero
Diels–Alder reaction of Danishefsky’s diene and alkyl
2-oxoalkanoate containing a small alkyl group. The
resulting cycloadduct provided an important access to
quaternary carbon centers enantioselectively. The
methodology was applied to the synthesis of (−)-malyn-
golide. Further studies aimed at improving enantiose-
lectivity and exploring reaction scope are in progress.
7. (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetra-
hedron: Asymmetry 1997, 8, 1; (b) Ghosh, A. K.; Fidanze,
S.; Senanayake, C. H. Synthesis 1998, 937.
8. Cardllina, II, J. H.; Moore, R. E.; Arnold, E. V.; Clardy,
J. J. Org. Chem. 1979, 44, 4039.
9. (a) Mukaiyama, T. Tetrahedron 1981, 37, 4111; (b) Sakito,
Y.; Tanaka, S.; Asami, M.; Mukaiyama, T. Chem. Lett.
1980, 1223.
10. For recent syntheses, see: (a) Enders, D.; Knopp, M.
Tetrahedron 1996, 52, 5805; (b) Maezaki, N.; Matsumori,
Y.; Shogaki, T.; Soejima, M.; Tanaka, T.; Ohishi, H.; Iwata,
C. Chem. Commun. 1997, 1755; (c) Winter, E.; Hoppe, D.
Tetrahedron 1998, 54, 10329; (d) Matsuo, K.; Matsumoto,
T.; Nishiwaki, K. Heterocycles 1998, 48, 1213; (e) Maezaki,
N.; Matsumori, Y.; Shogaki, T.; Soejima, M.; Ohishi, H.;
Tanaka, T.; Iwata, C. Tetrahedron 1998, 54, 13087; (f)
Ohira, S.; Ida, T.; Moritani, M.; Hasegawa, T. J. Chem.
Soc., Perkin Trans. 1 1998, 293; (g) Carda, M.; Castillo,
E.; Rodriguez, S.; Marco, J. A. Tetrahedron Lett. 2000, 41,
5511; (h) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000,
122, 10470 and references cited therein.
Acknowledgements
Financial support for this work was provided by the
National Institutes of Health (GM 55600). We thank
Professor David Crich for helpful discussions.
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