Organic Letters
Letter
optimal counteracid. Lowering the temperature to −30 °C had
no effect on er, but the conversion fell dramatically.
Interestingly, when water was excluded from the reaction, an
er of 95:5 was achieved (Table S1, entries 10 and 11,
Supporting Information). Unfortunately, the reaction never
reached completion, thus making these conditions unprac-
tical.21
In the alternative, ultimately successful route (Scheme 3),
aldehyde 27 was subjected to an organocatalytic α-chlorination
reaction, using perchlorinated quinone 31 as the Cl+ source
and the MacMillan imidazolidinone TFA-salt 14 as the
catalyst.25,26 Instead of 31, N-chlorosuccinimide was also
tested in this reaction, but it afforded lower conversions than
quinone 31.27 The intermediate α-chloroaldehyde was directly
oxidized in the same pot to the corresponding carboxylic acid
32.28 The crude acid was then methylated with MeI under
basic conditions, yielding the diester 33 in 71% yield over two
steps. It was noteworthy that this two-step sequence could not
be carried out with unsaturated aldehyde (+)-7; a complex
mixture of compounds was obtained under the same reaction
conditions. The diester 33 was then converted into the
corresponding azide via SN2 reaction with NaN3, yielding the
azide 34 in 84% yield. The azide group was then converted to
the Boc-protected amino group via hydrogenolysis in the
presence of Boc2O. To our delight, the diastereomers were
separable chromatographically at this stage, giving the desired
full-protected natural product 35 in 74% yield, alongside with
4-epi-35 (9%, 86:14 diastereomeric purity).
With these conditions at hand, we continued with the total
synthesis. The entire route is shown in Scheme 3 starting from
Scheme 3. Total Synthesis Route
With diastereomerically pure 35, the final stages were then
explored. Saponification under basic conditions led to
epimerization of the labile C2 stereocenter. In contrast,
refluxing the compound 35 in 6 M HCl smoothly removed
the Boc and ester protecting groups, and after neutralization of
the hydrochloride salt by an ion exchange column, crude (+)-1
was obtained. In order to get analytically pure samples and to
remove the hydroxy acid 36, the crude product was
recrystallized twice from water giving us pure (+)-1 in 28%
yield. It was noteworthy that 36 could not be transformed to
the lactone by dehydration (e.g., benzene, reflux) since these
conditions resulted in the formation of several side products.
In summary, we have developed an enantioselective
organocatalytic total synthesis route for (+)-lycoperdic acid
without using a chiral pool approach. As the key trans-
formation, iminium-catalyzed Mukaiyama−Michael reaction
between silyloxyfuran 4 and acrolein (6) using a specifically
optimized catalyst 20 successfully installed the key C4 tertiary
stereogenic center. Efforts to synthesize derivatives of (+)-1 as
well as wider studies of the developed Mukaiyama−Michael
reaction are underway.
ASSOCIATED CONTENT
* Supporting Information
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sı
The Supporting Information is available free of charge at
Experimental details and characterization data (PDF)
Copies of H and 13C NMR spectra (PDF)
1
the known silyloxyfuran 4 (see also the Supporting
Information).22,23 In gram scale, the enantioselective Mukaiya-
ma−Michael reaction afforded the aldehyde (+)-7 in 47% yield
and er 94:6. (+)-7 was then reduced to 27 with an 86% yield
after chromatographic purification. In both of these trans-
formations, the sensitivity of acrolein, (+)-7, or 27 to
polymerization were found to hamper the yields.
In our initial route, aldehyde 27 was first α-aminated with
DBAD (28) using List’s protocol,16 and the resulting amino
aldehyde 29 was oxidized to the corresponding carboxylic acid
30. Unfortunately, this relatively straightforward route to
(+)-lycoperdic acid had to be abandoned since the subsequent
N−N bond cleavage could not be reliably achieved (Scheme
3).24
Accession Codes
CCDC 1972521 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
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Petri M. Pihko − Department of Chemistry and NanoScience
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Center, University of Jyvaskyla 40520 Jyvaskyla, Finland;
C
Org. Lett. XXXX, XXX, XXX−XXX