Toward the total synthesis of divergolides C and D

Article abstract of DOI:10.1055/s-0033-1338974

The divergolides are a family of structurally unprecedented ansa macrocycles. We describe a synthetic strategy toward divergolides C and D that hinges on the biomimetic diversification of a common intermediate. An advanced precursor that incorporates all the carbon atoms of divergolide C and D is presented, and atropisomerism in a sterically crowded acyl naphthalene is studied.

Full text of DOI:10.1055/s-0033-1338974

LETTER
▌A
letter
Toward the Total Synthesis of Divergolides C and D
Toward Divergolides C and D
Anastasia Hager, Christian A. Kuttruff, Dominik Hager, Daniel W. Terwilliger, Dirk Trauner*
Fakultät für Chemie und Pharmazie, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science,
Butenandtstrasse 5-13, 81377 München, Germany
E-mail: dirk.trauner@lmu.de
Received: 16.06.2013; Accepted: 25.06.2013
OH
O
Abstract: The divergolides are a family of structurally unprece-
H
dented ansa macrocycles. We describe a synthetic strategy toward
divergolides C and D that hinges on the biomimetic diversification
of a common intermediate. An advanced precursor that incorporates
all the carbon atoms of divergolide C and D is presented, and atrop-
isomerism in a sterically crowded acyl naphthalene is studied.
O
OH
O
O
HN
O
O
O
N
H
O
Key words: natural products, ansamycins, macrolides, divergent
synthesis, atropisomerism
O
HO
O
O
OH
Divergent synthesis is an attempt to employ a common in-
termediate that can be readily diversified to reach several
related targets.1 Such an approach can be justified on bio-
synthetic grounds, since the variation of a metabolite is
frequently found in nature. A case in point are the diver-
golides, a small family of ansa macrolides that have been
recently reported (Figure 1).2
divergolide A (1)
divergolide B (2)
OH
O
H
O
1
N
4'
1''
O
A
B
C
4''
H
O
3'
3
HO
OH
HO
C
NH
5
O
OH
D
O
A
B
The divergolides were isolated by Hertweck and co-work-
ers from Streptomyces sp. HKI0576 that was derived from
the stem of Bruguiera gymnorrhiza, a Chinese mangrove
tree.2 Divergolides A–D (1–4) inhibit the growth of sever-
al types of bacteria and were found to be toxic to a variety
of cancer cell lines.2 In addition to their promising biolog-
ical activities, the divergolides are marked by very attrac-
tive molecular architectures. As such, they have spurred
significant interest in the community resulting in several
synthetic approaches which recently surfaced in the liter-
ature.3 One of them utilized a key intermediate,3b the syn-
thesis of which we published earlier as a part of a PhD
thesis.4 Motivated by these reports, we now disclose our
own efforts toward the synthesis of divergolides C and D.
O
HO
10
8
D
11
O
12
9
O
OH
divergolide C (3)
divergolide D (4)
Figure 1 The recently isolated divergolides A–D (1–4)
Hertweck et al. proposed that biosynthesis of the diver-
golides involves 3-amino-5-hydroxybenzoic acid
(AHBA, 6) as a starter unit and several extender units that
include malonyl-CoA, methylmalonyl-CoA, and the un-
usual ethylmalonyl-CoA and isobutyrylmalonyl-CoA.2,5
Assembly of these components on a polyketide synthase
could afford a common macrocyclic intermediate 5,
which may subsequently be diversified to reach both di-
vergolides C and D (Scheme 1). According to this biosyn-
thetic scheme, the seven-membered lactam ring in
divergolide C (3) could be formed via conjugate addition
of an enolate formed by deprotonation of the pentenedioic
acid derived moiety in the ‘northeastern’ sector onto the
naphthoquinone portion (path a in Scheme 1). By contrast,
acyl shift, followed by aldol addition of an analogous eno-
late to a carbonyl of the naphthoquinone would give rise
to divergolide D (path b in Scheme 1). It is possible that
the acyl migration proposed for the formation of 4 takes
place after the cyclization process. Based on these consid-
erations, it is conceivable that the macrocyclic precursor 5
is a natural product itself and could possibly be isolated.6
Structurally, divergolides C and D (3 and 4) differ from
the other two newly isolated family members. They both
exhibit a macrolactone that contains four stereocenters.
Divergolide C (3) features a naphthohydroquinone that is
fused to a seven-membered lactam, whereas divergolide
D (4) possesses a butyrolactam adjacent to a naphthalene-
1-(4H)-one with a tertiary alcohol at one of the fusion
points. Due to their strained 15- and 19-membered macro-
cycles, the ansa chains of divergolides C and D, respec-
tively, could also represent stereogenic elements.
SYNLETT 2013, 24, 000A–000F
Advanced online publication: 21.08.2013
DOI: 10.1055/s-0033-1338974; Art ID: ST-2013-B0557-L
© Georg Thieme Verlag Stuttgart · New York
We found it worthwhile to test this biosynthetic hypothe-
sis and explore whether both natural products could be
made from one common intermediate in the laboratory.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

B
A. Hager et al.
LETTER
Retrosynthetically, macrocycle 5 can arise from three al protection of acid 14 provided compound 15. Hydroly-
building blocks that represent the ‘northwestern’ naphtha- sis under mild conditions gave rise to the free acid 16,
lene moiety 7, the ‘eastern’ flank including an ester bond, which was then combined with secondary alcohol 12 us-
compound 8, and the ‘southwestern’ zone that features an ing Yamaguchi conditions. Subsequent deprotection of 17
unusual ethyl side chain 9.
using TBAF gave access to alcohol 18, which was oxi-
dized to the free acid 8 under Jones conditions. Other ox-
idation protocols, such as DMP, TPAP/NMO/H2O or
TPAP/BAIB/H2O led to decomposition of the starting
material.
Our synthetic efforts started with the assembly of the
‘eastern’ part 8, which was accessible in a short sequence
from alcohol 12 and acid 16 (Scheme 2). First, the two ad-
jacent stereocenters in 12 were set by a diastereo- and en-
antioselective Brown allylation7 of 3-methylcroton The synthesis of the ‘southwestern’ chain 9 started with
aldehyde 11 and vinyl methyl methoxy ether 107b,8 that the acylation of Koga’s auxiliary10 19 with activated
gave the product as a single diastereoisomer with an enan- trans-2-pentenoic acid (Scheme 3). Subsequent conjugate
tiomeric ratio of 92:8. Next, acid 14 was procured from addition of divinyl magnesiocuprate to 20 proceeded
known ethyl ester 13.9 Hydrolysis of 13 followed by glob- smoothly, and the corresponding alkene 21 could be pre-
OH
O
O
H
N
O
H
O
HO
OH
HO
NH
O
OH
O
O
HO
O
O
OH
a
b
divergolide C (3)
divergolide D (4)
O
O
H
N
O
b
HO
a
O
O
HO
b
O
5
O
H2N
OH
O
COOH
CoAS
COOH
CoAS
COOH
AHBA (6)
1 x ethylmalonyl-CoA
1 x isobutyrylmalonyl-CoA
COOH
O
O
CoAS
COOH
CoAS
3 x malonyl-CoA
2 x methylmalonyl-CoA
amide bond formation
OMe
OMe
O
H
NHBoc
N
O
MOMO
COOH
HO
O
O
H
O
O
7
9
HO
O
alkylation
O
O
Br
ring-closing
metathesis
OMOM
8
5
Scheme 1 Proposed biogenesis of divergolides C and D (3 and 4) and retrosynthetic analysis of the key intermediate 5
Synlett 2013, 24, A–F
© Georg Thieme Verlag Stuttgart · New York

LETTER
Toward Divergolides C and D
C
s-BuLi, then
(+)-B(Ipc)2OMe,
then BF3⋅OEt2
OH
OMOM
10
then
OHC
OMOM
12, er 92:8
11 68%
OTBS
KOH,
MeOH–H2O
TBSOTf,
2,6-lutidine
OH
OH
98%
O
TBSO
COOEt
COOH
15
13
14
OTBS
OTBS
then K2CO3,
MeOH
TCBC, Et3N, then 12
quant.
O
O
78%
COOH
16
OMOM
COOH
17
OH
TBAF
84%
Jones reagent
92%
O
O
O
O
OMOM
18
OMOM
8
Scheme 2 Synthesis of the ‘eastern’ chain 8. TCBC = 2,4,6-trichlorobenzoyl chloride.
pared on a gram scale. The desired stereochemical out- and LiAlH4 gave alcohol 23, which was converted into the
come of the reaction was secured by single-crystal X-ray volatile bromide 9 using Appel-type conditions.
analysis of 21 and related compound 22.11
The synthesis of formyl naphthalene 7 was achieved in
Cleavage of the auxiliary group proved more difficult than five steps starting from known Danishefsky-type diene
anticipated. Lithium methoxide only delivered undesired 2412 and p-benzoquinone 2513 (Scheme 4).14 Diels–Alder
amide 22. However, a combination of lithium methoxide reaction of the two compounds under optimized condi-
Scheme 3 Assembly of the ‘southwestern’ chain 9
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, A–F

D
A. Hager et al.
LETTER
tions provided Boc-protected naphthoquinone 26 as a sin- tions. Lithiation of bromide 9 using excess of t-BuLi fol-
gle isomer, the structure of which was unambiguously lowed by addition of naphthyl aldehyde 7, aqueous
confirmed through X-ray crystallography. Treatment of workup, and immediate Dess–Martin oxidation, reliably
26 with N-bromosuccinimide cleanly yielded the mono- provided the desired ketone 29 in 67% over two steps. In-
brominated naphthalene 27,15 which was then trans- terestingly, the 1H NMR spectrum of 29 at room tempera-
formed into hydroquinone dimethyl ether 28 by MOM ture showed two different sets of signals as soon as any
protection and reductive etherification. Deprotonation of side chain was attached to the carbonyl group (Scheme 4,
the amide, followed by lithiation of 28 and quenching of bottom). Since we do not observe Boc rotamers on bro-
the resulting dianion with DMF provided aldehyde 7 in monaphthalene 28 and naphthaldehyde 7, we attribute this
good yield of 86%.
observation to a hindered rotation around the axis between
the carbonyl group and the naphthalene moiety. As a re-
sult, compound 29 exists at room temperature as a mixture
of two atropisomers 29a and 29b (Scheme 4). In order to
show that these diastereomers can be interconverted, we
The stage was now set to bring the three building blocks
together (Scheme 4). In order to attach the southwestern
chain 9, we had to carefully optimize the reaction condi-
Scheme 4 Synthesis of the naphthalene building block 7 and attachment of the ‘southwestern’ chain (top); high-temperature 1H NMR exper-
iments of compound 29 (bottom)
Synlett 2013, 24, A–F
© Georg Thieme Verlag Stuttgart · New York

LETTER
Toward Divergolides C and D
E
OMe
H
OMe
OMe
N
O
NH2
HO
HO
8, EDC, HOBt
HCl, MeOH
quant.
29
OMe
O
O
64%
O
MOMO
O
30
31
O
H
N
O
divergolide C (3)
and
1) RCM
2) oxidation
HO
O
O
O
MOMO
divergolide D (4)
O
5
Scheme 5 Completion of the assembly of precursor 31
1
performed variable-temperature H NMR experiments.
Indeed, at 60 °C the signals of the two diastereomers co-
alesce to one set of peaks, as it is illustrated for the meth-
oxy protons of the MOM group.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental details, spectroscopic and analytical data for all new
compounds (including X-ray data for 20, 21 and 22, as well as for
26 and 27). SnuIofigop
m
r
t
ioarnStungIpionmf
rorat
t
Next, removal of both protecting groups in 29 under acid-
ic conditions using a solution of HCl in MeOH gave free
aminonaphthalene 30 in quantitative yield (Scheme 5). It
is worth noting, that due to the absence of the MOM group
in 30, free rotation around the axis is enabled, which is re-
flected in the NMR spectra. Finally, amide coupling of
free amine 30 and carboxylic acid 8 with EDC and HOBt
gave ring-closing-metathesis precursor 31 in 64% yield.
So far, our attempts to oxidize and cyclize this compound
via olefin metathesis to reach key intermediate 5 have
been unsuccessful and have only yielded dimeric com-
pounds. A solution to this problem could involve substitu-
tions that ensure that the s-cis conformation of the amide
conducive to cyclization is energetically attainable.
References
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precursor for divergolides C and D that possesses all car-
bon atoms of the natural products. Our synthetic study al-
lowed for detailed investigations of atropisomerism in
sterically crowded acyl naphthalenes, an issue that needs
to be addressed in the final synthesis of the molecules.
Our efforts to complete the synthesis of the divergolides
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Acknowledgment
The authors would like to acknowledge D. Hog (LMU, München)
and Dr. J. Lefranc (LMU, München) for helpful discussions, as well
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, A–F

F
A. Hager et al.
LETTER
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Synlett 2013, 24, A–F
© Georg Thieme Verlag Stuttgart · New York