Asymmetric total synthesis of (+)-fumimycin via 1,2-addition to ketimines

Article abstract of DOI:10.1039/c0cc03399e

The first asymmetric total synthesis of fumimycin was accomplished. As a key step, a 1,2-addition of methyl Grignard reagents to ketimines with quinine as additive was employed. The absolute configuration of (+)-fumimycin was determined by CD-spectroscopy

Full text of DOI:10.1039/c0cc03399e

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Asymmetric total synthesis of (+)-fumimycin via 1,2-addition
to ketiminesw
a
b
c
a
¨
Patrick J. Gross, Filipp Furche, Martin Nieger and Stefan Brase*
Received 22nd August 2010, Accepted 5th October 2010
DOI: 10.1039/c0cc03399e
The first asymmetric total synthesis of fumimycin was
accomplished. As a key step, a 1,2-addition of methyl Grignard
reagents to ketimines with quinine as additive was employed.
The absolute configuration of (+)-fumimycin was determined
by CD-spectroscopy combined with time-dependent density
functional calculations.
There are only few methods for the stereocontrolled synthesis
of a-trisubstituted amines by 1,2-addition to ketimines. The
catalytic enantioselective 1,2-addition to ketimines is described
in two examples, both employing a different substrate class.6
Most stereocontrolled methods use chiral auxiliaries con-
nected to the ketimine-nitrogen7 or adjacent to the ketimine
function.8 These diastereoselective methods require a removal
step of the attached auxiliary. More advantageous is the use of
non-covalently-bound chiral additives. This strategy avoids
the extra step of auxiliary removal and allows in principle a
direct recovery and reuse of the unchanged chiral reagent.
The enantioselective 1,2-addition to ketimines by using
chiral additives is described once by Huffman et al. They
employed amino alcohol quinine to control the addition of
lithium alkynylides to cyclic N-acyl ketimines.9
The mycotoxin1 fumimycin (1), isolated from Aspergillus
fumisynnematus F746, displays promising antibacterial activity.2
It is a potent inhibitor of peptide deformylase (PDF), an
enzyme essential for prokaryotic growth, but not for mammalian
cells.3 Therefore, fumimycin may represent a lead structure to a
class of novel antibacterials. It displays optical activity, yet its
absolute configuration was unknown.
Recently, we succeeded in accomplishing the first total
synthesis of racemic fumimycin.4 Key step for the formation
of the a-trisubstituted amine 2 was the 1,2-addition of a
Grignard reagent to ketimine 3 (Scheme 1).5 Here, we report
our systematic development of an enantioselective method for
the 1,2-addition to ketimines resulting in the first asymmetric
synthesis of (+)-fumimycin. Finally, the absolute configura-
tion of fumimycin was elucidated by using CD-spectroscopy.
We envisioned a related approach for the addition of methyl
organometallic reagents to acyclic N-phosphoryl ketimines 3.
Following Huffman et al., we chose quinine as additive, which
is readily available and inexpensive. Due to its amino function,
quinine can be separated from the product mixture by a
simple workup with NH4Cl-solution. To generate the opposite
enantiomer, we planned to use quinidine, which represents the
pseudo-enantiomer of quinine. For the elaboration of such a
method, we used ketimine 4 as simplified model system,
yielding a-trisubstituted amine 5. In general, we employed a
solution of 5 equivalents of quinine, to which the organo-
metallic reagent was added, followed by a solution of ketimine 4.
Initial tests with lithium, magnesium and zinc reagents showed
good conversion, albeit no selectivity (Table 1, entries 1–3). It
was expected that deprotonation of the alcohol function of
quinine prior to the addition of the organometallic reagent
might influence the selectivity. Indeed, by treating quinine with
Table 1 Screening of different organometallic reagentsa
Scheme 1 Retrosynthetic strategy for fumimycin with 1,2-addition to
ketimine 3 as key step. TBS = tert-butyldimethylsilyl.
a Institute of Organic Chemistry, Karlsruhe Institute of Technology
(KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany.
E-mail: braese@kit.edu; Fax: +49 721-608-8581
Entry (Base); reagent Temp/1C Solvent Conversion (%) ee (%)
1
2
3
4
5
6
MeLi
MeMgBr
ZnMe2
MeLi; MeMgCl ꢀ40
MeLi; MeMgBr ꢀ40
MeLi; MeMgI ꢀ40
0
0
20
THF
THF
Toluene 60
THF
THF
THF
91
95
ꢀ7
b University of California, Irvine, Department of Chemistry,
1102 Natural Sciences II, Irvine, CA 92697-2025, USA.
E-mail: filipp.furche@uci.edu; Fax: +1 949 824-8571
c Laboratory of Inorganic Chemistry, University of Helsinki,
00014 University of Helsinki, Finland
o5
ꢀ10
o5
ꢀ44
ꢀ16
86
98
76
w Electronic supplementary information (ESI) available: Experimental
details. Crystal structure data of 4, 7, 8, 8-iPrOH and 9. CCDC 786071
(4), 786072 (7), 786073 (8), 786074 (8-iPrOH) and 786075 (9). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc03399e
a
Conditions: organometallic reagent (6.3 eq.) or base (5.0 eq.) and
then organometallic reagent (1.3 eq.). The yields based on conversion
are 490%.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9215–9217 9215

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methyl lithium as base and subsequent addition of methyl
magnesium bromide, a-trisubstituted amine 5 was obtained in
44% ee (entry 5).
With methyl magnesium bromide as organometallic reagent,
we tested other bases for the deprotonation (Table 2). In terms
of selectivity and reactivity, methyl lithium proved to be the
reagent of choice (entry 2).
Employing methyl magnesium bromide and methyl lithium,
several b-amino alcohols were screened for their ability to
induce selectivity (Table 3). Quinine and quinidine yielded
the highest enantioselectivities (entries 1 and 2), and both
enantiomers of amine 5 could be obtained (yet with unknown
absolute configuration).
Fig.
2
Eyring plot for the determination of the isoinversion
Screening of a variety of solvents indicated that polar solvents
lead to better selectivity. The best results were obtained
with THF.
temperature.
an unselective pathway. By plotting the data of both temperature
ranges as Eyring plot, two linear slopes are obtained (Fig. 2).
The intersection marks the isoinversion temperature Tinv
(ꢀ69 1C), at which the highest selectivity can be obtained.
Finally we investigated the influence of concentration on the
selectivity. Higher concentration improved the selectivity,
until solubility limited further increase of concentration. Thus,
amine 5 could be finally obtained in 65% ee and 57% isolated
yield. After the optimisation of organometallic reagent, base,
amino alcohol, solvent, temperature and concentration the
optimised conditions were used for the 1,2-addition to ketimine
3, a precursor of fumimycin (Scheme 2). Amine 2 could be
obtained in 59% ee. This material was transformed to lactone
6 in three steps, according to our previously described
work towards racemic fumimycin.4 Intermediate 6 could be
enantioenriched: one single recrystallisation furnished 6 in
90% ee in the mother liquor. This material was further
functionalised,4 finally giving rise to (+)-fumimycin (ent-1).
Thus the first asymmetric synthesis of fumimycin could be
accomplished, in 18 steps, 90% ee and 1.6% overall yield. The
optical rotation of the synthesized (+)-fumimycin ([a]D:+109)
was contrary to the optical rotation reported for the natural
product ([a]D: ꢀ11.9) (see ESIw). (+)-Fumimycin represents
Next we investigated the temperature dependency of the
selectivity (Fig. 1). By lowering the reaction temperature to
ꢀ70 1C the selectivity increased up to 61% ee. Interestingly,
the selectivity decreased in the temperature range below
ꢀ70 1C. This might be explained by the principle of isoinversion.10
Below a certain temperature, the reaction proceeds partly via
Table 2 Screening of different basesa
Entry
Base
Conversion (%)
ee (%)
1
2
3
4
5
6
nBuLi
MeLi
LiHMDS
NaHMDS
NaH
76
498
87
88
86
ꢀ42
ꢀ44
ꢀ30
ꢀ49
ꢀ19
ꢀ25
KHMDS
82
a
Conditions: quinine (5.0 eq.), base (5.0 eq.), THF, ꢀ40 1C; MeMgBr
(1.3 eq.). The yields based on conversion are 490%.
Table 3 Screening of different chiral amino alcoholsa
Entry
Amino alcohol
Conversion (%)
ee (%)
1
2
4
3
5
Quinine
Quinidine
Cinchonidine
(+)-N-Methyl-norephedrine
(S)-N-Ethylprolinol
98
52
22
35
76
ꢀ44
+51
ꢀ17
+28
o5
a
Conditions: amino alcohol (5.0 eq.), MeLi (5.0 eq.), THF, ꢀ40 1C;
MeMgBr (1.3 eq.). The yields based on conversion are 490%.
Scheme 2 Enantioselective 1,2-addition to ketimine 3, enantio-
enrichment by recrystallisation and final conversion to (+)-fumimycin
(ent-1).
Fig. 1 Temperature dependency of the enantioselecivity.
9216 Chem. Commun., 2010, 46, 9215–9217
c
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Finally we used CD-spectroscopy to elucidate the absolute
configuration. The CD-spectra of fumimycin was simulated
using time-dependent density functional theory (TDDFT)11 as
12
implemented in TURBOMOLE. z The characteristic strong band
at 255 nm arises from an n - p* transition in the fumaric
acid side chain which is chirally perturbed by the lactone
carbonyl chromophore (see ESIw). The simulated curve of
the (R)-enantiomer matches with the measured CD-curve of
the synthesized (+)-fumimycin (Fig. 3). It can be concluded
that the natural (ꢀ)-fumimycin bears (S)-configuration.
The enantioselective 1,2-addition of methyl Grignard reagents,
employing quinine as chiral additive, yielded a-trisubstituted
amines in up to 65% ee. This novel methodology13 and enantio-
enrichment by recrystallisation enabled the first asymmetric
synthesis of (+)-fumimycin in 90% ee. The absolute configu-
ration of (+)-fumimycin was assigned to be (R) using
CD-spectroscopy and TDDFT-calculations.
Scheme 3 Precursors of fumimycin, whose structures were confirmed
by X-ray analysis.
therefore the unnatural enantiomer. The natural enantiomer
should be accessible by employing quinidine instead of quinine
as additive (see Table 3). To determine the absolute configu-
ration, crystallisation of several intermediates were attempted.
Thus, the structures of the ketimines 4 and 7 could be
confirmed, as well as the structures of the a-trisubstituted
amines 8 and 9 (Scheme 3). However, enantioenriched samples
of 8 and 9 furnished only racemic monocrystals (see ESIw).
P.G. acknowledges a scholarship of the German Business
Foundation, F.F. acknowledges support by the NSF, grant
no. CHE-0840513.
Notes and references
z The PBE0 hybrid functional was used with SVPD-basic sets, the
structure was optimized using PBE0/TZVP. Solvent effects were
treated by the COSMO continuum solvation model. See ESIw for
further details.
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Fig. 3 Simulated CD-curve of (R)-fumimycin (upper panel) and
measured CD-curve of (+)-fumimycin (lower panel).
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9215–9217 9217