Addition of diethylzinc to dicobalt hexacarbonyl complexes of α,β-acetylenic aldehydes with virtually complete enantioselectivity. A formal synthesis of (+)-incrustoporin

Article abstract of DOI:10.1021/ol0260268

(Matrix presented) The addition of diethylzinc to dicobalt hexacarbonyl complexes of acetylenes mediated by (R)-2-piperidino-1,1,2-triphenylethanol takes place with very high enantioselectivity (96-99% ee) to afford the S enantiomers of dicobalt hexacarbo

Full text of DOI:10.1021/ol0260268

ORGANIC
LETTERS
2
002
Vol. 4, No. 14
381-2383
Addition of Diethylzinc to Dicobalt
Hexacarbonyl Complexes of
2
r,â-Acetylenic Aldehydes with Virtually
Complete Enantioselectivity. A Formal
Synthesis of (+)-Incrustoporin
Montserrat Fontes, Xavier Verdaguer, Llu ´ı s Sol a` , Anton Vidal-Ferran,
Katamreddy Subba Reddy, Antoni Riera, and Miquel A. Peric a` s*
Unitat de Recerca en S ´ı ntesi Asim e` trica (URSA-PCB), Parc Cient ´ı fic de Barcelona and
Departament de Qu ´ı mica Org a` nica, UniVersitat de Barcelona, c/Josep Samitier,
1-5, E-08028 Barcelona, Spain
mapericas@pcb.ub.es
Received May 3, 2002
ABSTRACT
The addition of diethylzinc to dicobalt hexacarbonyl complexes of acetylenes mediated by (R)-2-piperidino-1,1,2-triphenylethanol takes place
with very high enantioselectivity (96−99% ee) to afford the S enantiomers of dicobalt hexacarbonyl complexes of 1-alkynyl-1-propanols. The
utility of this process is exemplified by the development of a short, highly enantioselective (99% ee) synthesis of unnatural incrustoporin.
The secondary carbynol moiety is present in the structures
of many natural products. Accordingly, a great deal of
synthetic effort has been devoted to its enantiocontrolled
formation. Additions to carbonyl groups (either reduction
of prochiral ketones or nucleophilic alkylation of aldehydes)
are key to this purpose, the current emphasis being on
catalytic enantioselective processes.1
Achievement of enantioselectivity in these reactions
normally relies on the successful preferential recognition of
one of the enantiotopic faces of the carbonyl substrate by a
chiral ligand/metal assembly. Accordingly, the existence of
a significant difference in steric bulk between the carbonyl
substituents is key for success in this endeavor.
diethylzinc to benzaldehydes, while the corresponding ad-
ditions to substrates unsubstituted at the R and â carbons
2
constitute a less well-solved problem.
Dialkylzinc addition to R,â-acetylenic aldehydes (1) could
provide a convenient entry to the synthetically useful
3
enantiopure propargyl alcohols (2). However, despite con-
siderable effort dedicated to the study of this problem,
enantioselectivities reported so far are generally not satisfac-
4
tory, and just one report describes a highly enantioselective
(ee > 95%) addition of diethylzinc to 3-phenylpropanal (1a)
by a process involving a titanium-based catalyst.5
(2) (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem.
ReV. 2000, 100, 2159-2231. (b) Soai, K.; Shibata, T. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. II, pp 911-961. (c) Pu, L.; Yu, H.-B. Chem.
ReV. 2001, 101, 757, 824.
(3) Other approaches have been devised for the enantiocontrolled
preparation of this structural motif; see: (a) El-Sayed, E.; Anand, N. K.;
Carreira, E. M. Org. Lett. 2001, 3, 3017-3020. (b) Anand, N. K.; Carreira,
E. K. J. Am. Chem. Soc. 2001, 123. (c) L u¨ tjens, H.; Nowotny, S.; Knochel,
P. Tetrahedron: Asymmetry 1995, 6, 2675-2678.
When we center our attention on the enantioselective
addition of dialkylzincs to aldehydes, many different ligands
ensure nearly complete enantiocontrol over the addition of
(
1) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asym-
metric Catalysis; Springer: Berlin, 1999.
1
0.1021/ol0260268 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/17/2002

We disclose in the present paper a convenient solution to
this problem that allows the ethylation of diversely substi-
tuted R,â-acetylenic aldehydes with virtually complete enan-
tioselectivity.
Over the last few years, we have been involved in a
research program devoted to the synthesis of modular ligands
for a variety of catalytic enantioselective processes from
purely synthetic yet enantiopure epoxides. As a result of lead
identification and structural refining processes, we have
developed the new ligands 3-6 that, besides a great structural
simplicity, depict very high catalytic activity and enantio-
control in the addition of diethylzinc to aldehydes of many
different structural types.6
the amino alcohol ligands encountered difficulties in ef-
ficiently differentiating between the rather similar substituents
of the aldehyde in the space near the reaction center.
In view of these results, we decided to submit the substrate
aldehyde to a reversible modification that could increase the
difference in steric bulk between the carbonyl branches and,
hence, favor stereodifferentiation in the attack. The formation
of the dicobalt hexacarbonyl complex of 1a was designed
for this purpose: this robust class of alkyne complexes,
7
widely used for protection of the triple bond, has also found
application for enhanced stereodifferentiation in the ox-
azaborolidine-mediated borane reduction of ketones.8
Complex 7a was prepared in essentially quantitative yield,
As a first step in our research and with the purpose of
determining the optimal ligand for these reactions, we studied
the use of 3-6 in the addition of diethylzinc to 3-phenyl-
propynal (1a). The reactions were performed at 0 °C for 3
h with 6 mol % ligand, and the results are summarized in
Table 1. As it can be seen, all four studied ligands exhibited
2
and the addition of Et Zn in the presence of ligands 3-6
was next studied. While the increase in enantioselectivity
was spectacular from the first moment, the reaction condi-
tions required optimization. At room temperature, reaction
yields were not satisfactory. Carbonyl groups within the
dicobalt complex may compete with the aldehyde for
coordination with the active catalyst, thus diminishing total
conversion.
A thorough examination of reaction conditions led to the
following set of optimal parameters: 20% mol ligand, 2.0
2
Table 1. Ligand Evaluation for the Enantioselective Et Zn
Addition to Phenylpropynal (1a) and Its Dicobalt Hexacarbonyl
Complex (7a)
equiv Et Zn, toluene as the solvent, 4 h reaction at -10 °C.
2
Use of 3-6 under these conditions led to the results shown
in Table 1. Simultaneous consideration of yields and enan-
tioselectivities led us to select ligand 4 for the continuation
9
of our study. Thus, 4 was used for the ethylation of an array
of dicobalt hexacarbonyl complexes of alkynals that covers
a range of substitutions (primary, secondary, or tertiary) and
natures (alkyl, vinyl, or aryl) at the carbon directly bonded
to the triple bond, as shown in Table 2. Starting complexes
ligand
2a from 1a ee [%]a
8a from 7a ee [%]b
Table 2. Enantioselective Ethylation of Dicobalt Hexacarbonyl
Complexes of R,â-Acetylenic Aldehydes Mediated by
(R)-2-Piperidino-1,1,2-triphenylethanol (4)
3
4
5
6
38
43
31
51
88
99
79
98
a
Enantiomeric excesses were determined by GC analysis. b Enantiomeric
excesses were determined by HPLC analysis.
alcohol 8
poor behavior in the reaction. This result was particularly
surprising, since 3-6 have been previously shown to induce
the addition of diethylzinc to R-unsubstituted saturated and
R,â-unsaturated aldehydes with enantioselectivities in the
entry
R
yield [%]
ee [%]
a
b
c
d
Ph
n-C5H11
t-C4H9
63
82
51
83
99
99
96
98
85-95% range. We interpreted these results to indicate that
1-cyclohexen-1-yl
(
4) (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-
9
1
1
43. (b) Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn.
997, 70, 207-217. (c) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem.
998, 63, 1364-1365.
(7a,b) were readily available from complexation of com-
mercial aldehydes or by formylation and complexation of
(5) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron
1
0
the corresponding alkynes (7c,d).
1
994, 50, 4363-4384.
(
6) (a) Vidal-Ferran, A.; Moyano, A.; Peric a` s, M. A.; Riera, A.
Under the optimized conditions, the ethylation reactions
took place, as a general trend, at elevated conversions
Tetrahedron Lett. 1997, 38, 8773-8776. (b) Sol a` , L.; Reddy, K. S.; Vidal-
Ferran, A.; Moyano, A.; Peric a` s, M. A.; Riera, A.; Alvarez-Larena, A.;
Piniella, J. F. J. Org. Chem. 1998, 63, 7078-7082. (c) Vidal-Ferran, A.;
Moyano, A.; Peric a` s, M. A.; Riera, A. J. Org. Chem. 1997, 62, 4970-
(7) Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 37, 3475-3478.
(8) (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153-9156.
(b) Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org.
Chem. 1996, 61, 9021-9025.
4
982. (d) Reddy, K. S.; Sola, L.; Moyano, A.; Peric a` s, M. A.; Riera, A.
Synthesis 2000, 165-176. (e) Reddy, K. S.; Sola, L.; Moyano, A.; Peric a` s,
M. A.; Riera, A. J. Org. Chem. 1999, 64, 3969-3974.
2382
Org. Lett., Vol. 4, No. 14, 2002

To show the potential of the present method, we have
developed a highly efficient enantioselective synthesis of (S)-
incrustoporin (10), the enantiomer of the antifungal antibiotic
isolated from the basidiomycete Incrustoporia carneola
Scheme 1. Formal Enantioselective Synthesis of
S)-(-)-Incrustoporin (10)
(
1
4
(Scheme 1).
p-Tolylacetylene (9) was formulated with DMF via its
bromomagnesium derivative, and the crude aldehyde was
treated with octacarbonyl dicobalt in toluene to afford the
aldehyde complex 7e in 68% overall yield. Ethylation of this
aldehyde under the optimized conditions previously used for
7
a-d afforded the propargyl alcohol complex 8e in >99%
ee and 72% yield. A subsequent oxidative decomplexation
with cerium ammonium nitrate (CAN) in methanol led to
propargyl alcohol (S)-(-)-2f in 87% yield with no loss of
optical purity as ascertained by chiral HPLC. Since this
alcohol had been previously converted to incrustoporin by a
Pd-catalyzed cyclocarbonylation taking place with retention
15
of configuration, the formation of enantiopure 2f completes
a formal enantioselective synthesis of unnatural incrustoporin
that takes place with a very high level of enantiocontrol.
(>90%), and the target propargyl alcohol complexes could
be isolated in good purity after acidic workup. It is worth
noting that enantioselectivities are outstanding in all cases
Figure 1. Modular ligands for the highly enantioselective addition
of diethylzinc to aldehydes.
(>96% ee) and virtually complete for 8a and 8b (>99%
ee).
The enantiomeric purities of the resulting complexes were
determined by HPLC.11 Comparison of optical rotation and
Acknowledgment. We thank DGESIC (PB98-1246) and
CIRIT (2001SGR-00050) for financial support. X.V. thanks
MCYT for a Ramon y Cajal research contract. K.S.R. thanks
MEC for a fellowship under the program “Estancias Tem-
porales de Cient ´ı ficos y Tecn o´ logos Extranjeros en Espa n˜ a”.
retention times of 2a obtained by decomplexation of 8a with
literature values allowed the configurational assignment of
12
the formed alcohol complex as S. This is in agreement with
Noyori’s empirical rule and with previous experience with
the same ligand.13 On this basis and taking into account the
regularity of the elution behavior in HPLC, the configurations
of 8b-d were also assigned as S.
Supporting Information Available: Full characterization
and experimental details for the synthesis of dicobalthexa-
carbonyl-alkynal complexes and their corresponding dieth-
ylzinc addition products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
(
9) Ligand 4 is commercially available in both enantiomeric forms.
10) Jones, E. R. H.; Skattebol, L.; Whiting, M. C. J. Chem. Soc. 1958,
1
054-1059.
OL0260268
(11) Ethylation product mixtures were compared with racemic samples
prepared by addition of ethylmagenesium bromide to the starting aldehydes
in ether.
(14) Zapf, S.; Anke, T.; Sterner, O. Acta Chem. Scand. 1995, 49, 233-
234.
(15) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron:
Asymmetry 1999, 10, 1163-1172.
(
12) Soai, K.; Niwa, S. Chem. Lett. 1989, 481-484.
(13) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley &
Sons: New York, 1994.
Org. Lett., Vol. 4, No. 14, 2002
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