Synthesis of angiolam A

Article abstract of DOI:10.1021/ol403423r

The first total synthesis of angiolam A has been accomplished in 18 steps. Key steps include vinylogous Mukaiyama aldol reactions of aldehydederived dienol ethers, conjugate reduction of the resulting double bond followed by diastereoselective protonation

Full text of DOI:10.1021/ol403423r

Letter
pubs.acs.org/OrgLett
Synthesis of Angiolam A
Marc Timo Gieseler and Markus Kalesse*
Institute for Organic Chemistry and Centre of Biomolecular Drug Research (BMWZ), Leibniz Universitat Hannover, Schneiderberg
̈
1B, 30167 Hannover, Germany
Helmholtz Centre for Infection Research, Inhoffenstrasse 7, Braunschweig, Germany
S
* Supporting Information
ABSTRACT: The first total synthesis of angiolam A has been accomplished in
18 steps. Key steps include vinylogous Mukaiyama aldol reactions of aldehyde-
derived dienol ethers, conjugate reduction of the resulting double bond
followed by diastereoselective protonation and the Witzeman protocol for
macrolactamization. Comparison of the optical rotation of the synthesized
material with the isolation data established that the absolute configuration of
angiolam A is opposite from the proposed structure.
n 1985, Hofle and Reichenbach reported on the isolation
and structural elucidation of angiolam A (Scheme 1), a new
The eastern fragment can be constructed from dithiane 3 and
iodide 4. The four chiral centers of segment 2 are generated by
two identical sequences of vinylogous Mukaiyama aldol
reaction of an aldehyde-derived silyl enol ether followed by
direct reduction of the α,β-unsaturated aldehyde with Stryker’s
reagent to generate the corresponding enolate which is
protonated by the previously established secondary alcohol to
generate the desired 1,4-anti relationship (Scheme 1).
The synthesis commenced with a stereoselective vinylogous
Mukaiyama aldol reaction using OXB15as the chiral Lewis acid,
aldehyde 10 and the aldehyde-derived dienol ether 11 to yield
alcohol 12 with an enantiomeric access of 91% (Scheme 2).
The VMAR was directly followed by Stille coupling (13), 1,4-
reduction and α-protonation using Stryker’s reagent.6
This transformation is believed to occur through conjugate
reduction followed by intramolecular protonation by the
secondary alcohol (6−9, Scheme 1). The resulting aldehyde
forms hemiacetal 14, which can be directly converted to the
corresponding unsaturated ester through an olefination with
the tributylphosphine-derived Wittig reagent 15.7 Other
olefination strategies such as HWE-olefination only yielded
the corresponding oxa-Michael product or resulted in
diminished yields. Established oxidation state changes gave
access to aldehyde 16, which was subjected again to a sequence
of vinylogous aldol reaction (OXB2, 17)5 followed by Stryker
reduction and stereoselective protonation which proceeds with
a diastereomeric ratio of >20:1. Here, it should be pointed out
that the two VMA reactions proceed with different selectivities
and different catalysts were used. We realized that the addition
̈
I
antibiotic from Angiococcus disciformis.1 However, there was
uncertainty about the C2−C3 double bond geometry and
additionally, the absolute configuration was not determined.
Angiolam A exhibits notable antibacterial activity against Gram-
positive bacteria (MIC 0.78 μg/mL) with no acute toxicity in
mice with concentrations of up to 300 mg/kg. So far, there are
no reports on the synthesis or biology of angiolam A. Our
interest in this natural product originated from the possibility to
construct the 1,4-anti relationship (5) of hydroxyl and methyl
groups through enolate protonation generated by 1,4-reduction
of unsaturated aldehydes (Scheme 1).2 This highly selective
process occurs with diastereomeric ratios of up to 20:1 and
provides the product as its hemiacetal which serves to protect
the α-position from epimerization. The corresponding
precursors for such asymmetric protonations are easily
accessible by vinylogous Mukaiyama aldol reactions
(VMAR).3 We recently developed a protocol which takes
advantage of silyldienol ether 11 as a redoxeconomic4 reagent
to access δ-hydroxy-α,β-unsaturated aldehydes with high
enantioselectivites in one step (Scheme 1).5
The synthesis presented herein demonstrates the practic-
ability of the vinylogous Mukaiyama aldol reaction followed by
internal protonation to construct complex polyketides. It
additionally confirms the C2−C3 double bond of angiolam to
be E-configured. Our retrosynthetic analysis disconnects
angiolam into three fragments (Scheme 1).
Fragment 2 contains the phosphonium salt required for
olefination to the northern segment, 3. As we will point out
below, our initial strategy to establish the macrocyclization
through ester formation failed and we therefore decided to use
the described olefination to join both segments.
Received: November 26, 2013
© XXXX American Chemical Society
A
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Letter
Scheme 1. Originally Proposed Configuration of Angiolam A
Scheme 2
and Retrosynthetic Disconnection
displacement with sodium azide. In order to allow conjunction
of fragments through the above-mentioned Wittig olefination,
the primary TBS group in compound 27 was removed and the
alcohol oxidized to aldehyde 28 (Scheme 3).
8
of B(OMe)3 as competitor for binding of the product to the
chiral Lewis acid led to improved turnover numbers.
Even though we proposed that the secondary alcohol
generated during the vinylogous Mukaiyama aldol only serves
as intramolecular proton source, it is additionally required for
the activation of the Stryker’s reagent. Experiments with
protected alcohols did not perform the conjugate addition at all.
This parallels the observation that transformations with
Stryker’s reagent usually require catalytic quantities of water.
The synthesis continues with oxidation of hemiacetal 18 and
addition of t-butyl acetate in a Claisen condensation to generate
As shown in Scheme 4, the endgame starts with a Wittig
olefination between compounds 2 and 28. It should be pointed
out that this reaction proved to be a challenging transformation
that failed when other olefination conditions were employed.
For instance, the use of triphenylphosphine for the
construction of the Wittig reaction as well as Horner−
Wadsworth−Emmons conditions failed to generate any
detectable product in the subsequent olefination reaction.
Furthermore, all attempts to introduce the entire northern
segment through an ester formation failed as well. The
difficulties associated with this transformation became apparent
by the fact that the α-stereocenter at C4 exhibited substantial
epimerization (1:1) during the olefination reaction. Fortu-
nately, we were able to separate these isomers during the
purification of the final product.
With 29 in hand, the Staudinger reaction liberated the amine
and upon heating in toluene in the presence of DMAP the
desired macrocyclization product 30 was obtained in 63% yield.
The cyclization is believed to occur according to the Witzeman
protocol11 via an acylketene intermediate which is liberated
from the t-butyl ester and then trapped by the free amine. The
dithiane could be removed with AgNO3 and NCS12 and finally
Et3N·3HF at elevated temperature removed both TBS groups
1
19. Although by H NMR only the cyclic acetal of 19 can be
detected it is possible to esterify the secondary alcohol with
bromopropionic acid under Steglich conditions,9 which was a
prerequisite for its further functionalization. Substitution of
bromide by tributylphosphane established segment 2 that was
the pivotal segment for the construction of angiolam A
(Scheme 2).
The synthesis of the northern fragment started with Roche
ester-derived aldehyde 20, which was converted to aldehyde 22
using reagent 21 in an Evans aldol reaction. Transformation of
this aldehyde to its corresponding dithiane (3) and subsequent
alkylation with 24,10 provided the desired product (26). After
removal of the PMB group and transformation of the resulting
alcohol to its mesylate the azide was introduced through
B
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Letter
we therefore conclude that authentic angiolam A is the opposite
enantiomer with respect to our synthetic material (authentic:
+24.8; synthetic: −25.0).
Scheme 3
In summary, we have developed a sequence of stereoselective
vinylogous Mukaiyama aldol reaction and subsequent conjugate
reduction followed by stereoselective protonation to provide
rapid access to polyketides with two new stereocenters. Here,
all four configurations of the southern fragment are constructed
in this way, and we see the synthesis of angiolam A as prime
example of the construction of this particular motif found in
polyketides. Additionally, the Witzeman protocol was estab-
lished for the macrolactamization. The synthetic material also
established that the absolute configuration of angiolam A is
opposite from the proposed structure and confirms the C2−C3
double bond to be E-configured (Figure 1).
Figure 1. Configuration of authentic angiolam A.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4
■
S
Detailed synthetic information as well as spectroscopic
characterization of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: markus.kalesse@oci.uni-hannover.de.
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENTS
■
We thank Dr. R. Jansen, Helmholtz Centre for Infection
Research (HZI), for providing authentic angiolam A. This work
was supported by the DFG (Ka 913/21-1).
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