Total Synthesis of Macrocyclic Dysoxylactam A

Article abstract of DOI:10.1002/asia.202000482

The total synthesis of dysoxylactam A, a novel 17-membered macrolactam with potent multi-drug-resistant reversing activities, has been achieved, starting from 4-pentene-1-al in a longest linear sequence of 17 steps and 9.5percent overall yield. The key transformations consist of iterative aldol and ring-closing metathesis reactions for the construction of the stereochemically enriched polypropionate scaffold and the macrocycle, respectively.

Full text of DOI:10.1002/asia.202000482

DOI: 10.1002/asia.202000482
Communication
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Total Synthesis of Macrocyclic Dysoxylactam A
D. Prabhakar Reddy[a, b] and Biao Yu*[b, c]
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Abstract: The total synthesis of dysoxylactam A, a novel 17-
membered macrolactam with potent multi-drug-resistant
reversing activities, has been achieved, starting from 4-
pentene-1-al in a longest linear sequence of 17 steps and
9.5% overall yield. The key transformations consist of
iterative aldol and ring-closing metathesis reactions for the
construction of the stereochemically enriched polypropio-
nate scaffold and the macrocycle, respectively.
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A persistent effort has been given to the chemical and
biological studies of various parts of Dysoxylum species, given
its folkloric background.[1,2] The leaves of this Chinese herbal
plant have been used for treatment of malaria and the twigs for
production of Hangkonoides[2] which are used as an anticancer
agent.[3] In 2019, Yue and coworkers isolated a novel macro-
lactam, namely dysoxylactam A (1, Scheme 1), from the bark of
Dysoxylum hongkongense.[4] Significantly, dysoxylactam A, com-
prising a stereochemically enriched fatty acid skeleton and a
valine residue, represents the first example of a 17-membered
cyclolipolactam. Moreover, this molecule has been shown to be
able to reverse multidrug resistance in cancer cells with the
fold-reversals ranging from 28.4 to 1039.7 at a non-cytotoxic
concentration of 10 μM. Further studies revealed that it could
inhibit the function of P-glycoprotein, a key mediator in the
multidrug resistance. The chemical architecture of dysoxylactam
A was assigned based on residual dipolar coupling (RDC)-based
NMR analysis and validated by X-ray diffraction analysis of its 9-
O-p-bromobenzoate derivative.[4]
Scheme 1. Dysoxylactam A (1) and its retrosynthetic analysis.
Chandankar and Raghavan.[5] The synthesis employed Merck-
Carreira and Marshall’s propargylation, Evans’ alkylation, and
Noyori’s transfer hydrogenation protocols to create the stereo-
centers presenting in the fatty acid chain, and utilized Steglich
esterification and HATU mediated macrolactamization to elabo-
rate the macrocycle. Shortly, Ye et al. disclosed an alternative
approach to the synthesis of dysoxylactam A.[6] Their synthesis
took advantage of Aggarwal and Matteson homologations,
diastereoselective Brown crotylation, and Krische allylation to
build up the stereochemically enriched fatty acid fragment and
a cross-metathesis reaction (at C6-C7) to construct the macro-
cycle. Independently and in line with our long interest in
macrocyclic natural products,[7] we completed a total synthesis
of dysoxylactam A, and herein we report our synthetic
approach.
Given the polypropionate pattern of the stereochemically
crowded region in dysoxylactam A (1), we envisioned a
straightforward synthetic approach capitalizing mainly on aldol
reactions, which has been reliably applied in the synthesis of
polyketide natural products, such as deoxyerythronolide B and
(À )-pironetin.[8] Thus, the cyclic target compound 1 could be
accessible by a Ru-mediated ring-closing metathesis of the
linear diene 2 followed by saturation of the resulting double
bond (at C5–C6) (Scheme 1). The preparation of diene 2 would
involve esterification of the functionalized alcohol 3 with N-Boc-
valine followed by amide formation with 5-hexenoic acid. The
polypropionate fragment 3, a major focus of the synthesis,
could be synthesized in a stereocontrolled manner by using
sequential Evans aldol reactions starting from commercially
available 4-pentene-1-al (4).
The highly promising bioactivity and novel chemical
structure of dysoxylactam A have attracted attention from
synthetic and medicinal chemists. The first report on the total
synthesis of dysoxylactam
A was published recently by
[a] D. Prabhakar Reddy
Innovation Research Institute of Traditional Chinese Medicine
Shanghai University of Traditional Chinese Medicine
1200 Cai Lun Road, Shanghai 201203 (China)
[b] D. Prabhakar Reddy, B. Yu
State Key Laboratory of Bio-organic and Natural Products Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: byu@sioc.ac.cn
[c] B. Yu
School of Chemistry and Materials Science
Hangzhou Institute for Advanced Study
University of Chinese Academy of Sciences
1 Sub-lane Xiangshan, Hangzhou 310024 (China)
Thus, the aldol reaction of 4-pentene-1-al (4) with the Evans
propionate 5[9] mediated by dibutylboron triflate led to the
known aldol adduct 6[10] in 89% yield as a single diastereomer,
thus establishing the required stereocenter at C9 and C10
(Scheme 2). Reductive removal of the auxiliary under Soai’s
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202000482
This manuscript is part of a special collection for the 20th Anniversary of the
Tateshina Conference.
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with acid 16 did not take place at all to provide the desired
ester 2 (Scheme 3).
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Alternatively, we tried the esterification of 3 with N-Boc-L-
valine instead of amide acid 16 (Scheme 4). Indeed, the
condesation of 3 and N-Boc-L-valine proceeded smoothly in
presence of EDCI and an excess amount of DMAP (5 eq.) in
CH2Cl2.[22] However, epimerization at the valine residue took
place simultaneously, resulting in an inseparable epimeric
mixture of the esters. Attampts to avoid the epimerization
under various conditions were not successul. In addition, it was
also found difficult to calculate the exact ratio of the two
diastereomers due to rotameric nature of the amino acid
derivatives.[23] To move forward, the Boc-protected esters were
treated with TFA in dichloromethane to give the free amines as
their TFA salts, which were then allowed to react with 5-
hexenoic acid in the presence of HATU and Hunig’s base[24] to
furnish the desired bis-olefin amides 2 in 79% yield (3 steps).
The two epimers were still inseparable.
Nevertheless, the final stage was set for the total synthesis,
i.e., ring closing metathesis and hydrogenation to complete the
macrolactam. Thus, the epimeric mixture of dienes 2 was
treated with 20 mole% of grubbs 2nd generation catalyst[25,26] in
refluxing dichlomethane; the macrocycles were formed as a
inseparable diastereomeric mixture. As the geometry of the
newly formed double bond at C5-C6 was of no consequence for
the total synthesis of dysoxylactam A (1), the resulting macro-
cyclic olefins were used for the next step without further
purification and analysis. In fact, these two steps were carried
out in one pot. Subjection of the olefins to hydrogenation in
the presence of Pd/C under 1 atm H2 led to the separable
natural product dysoxylactam A (1) along with its C-2‘ epimer
17 in a 3:2 ratio. The spectral and analytical data of the
synthetic 1 were in full agreement with those previously
reported for the natural and synthetic dysoxylactam A (1).[27]
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Scheme 2. Synthesis of polypropionate fragment 3.
conditions[11] (LiBH4, Et2O/MeOH) furnished the corresponding
1,3-diol, which was subsequently protected with benzaldehyde
acetal to give acetal 7 in 84% yield over two steps; the
diastereoisomer was not detected with 1H NMR analysis.
Regioselective cleavage of the benzylidene acetal at the less
hindered oxygen with DIBAL-H afforded primary alcohol 8 in
93% yield.[12] Treatment of the resultant alcohol with I2 in the
presence of imidazole and Ph3P led to the desired iodoalkane 9,
which was found instable and thus was used immediately for
the subsequent alkylation reaction.
Our next task was to generate the C12-methyl stereocenter
which was anti to the C10-methyl group. Fortunately, Evans
et al. have developed an effective protocol to geneate such
alkyl stereocenters using chiral amide enolates derived from
prolinol derivatives.[13] Hence, iodoalkane 9 was allowed to react
with a lithium enonlate generated from D-prolinol N-propiona-
mide 10 by using LDA, furnishing dimethyl amide 11 in 82%
yield; the corresponding diastereoisomer was not detected with
1H NMR analysis. Amide 11 was subjected to hydrolysis with 1 N
HCl to yield the corresponding acid, which was then allowed to
react with lithium aluminumhydride to give primary alcohol 12
(95% over two steps). The resutling primary alcohol was
oxidized under DessÀ Martin periodinane[14] conditions to give
the corresponding aldehyde, which was used in the next aldol
reaction without further purification.
Indeed, applying Evans‘ syn aldol reaction conditions used
for the previous addition of 5 and 4, the reaction of the newly
prepared aldehyde and 5 in the presence of dibutylboron
triflate afforded the desired adduct 13 in >20:1 d.r. and 78%
yield. Reductive cleavage of the oxazolidinone in amide 13 with
lithium borohydride (Soai’s conditions) gave 1,3-diol 14 in 87%
yield. Regioselecetive tosylation of the primary hydroxyl group
was achieved with TsCl in the presence of Bu2SnO and Et3N,
leading to tosylate 15. Treatment of 15 with an excess amount
of methyllithium in the presence of CuI provided the required
polyketide fragment 3 in 76% yield over two steps.[15]
Having the key fragment (3) in hand, we set out to couple
alcohol 3 with acid fragment 16, which was easily prepared in
two steps from L–Val-OMe.[16] Surprisingly, under various
esterification conditions, including with such classical condensa-
tion reagents as DCC/DMAP,[17] EDCI/HOBT/DMAP,[18] BOPCl,[19]
TCBA/Et3N/DMAP,[20] and MNBA,[21] the reaction of alcohol 3
Scheme 3. Attempted esterification of 3 for the synthesis of ester 2.
Scheme 4. Syntheis of dysoxylactam A (1) and its epimer (17).
Chem Asian J. 2020, 15, 1–4
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[4] C. P. Liu, C. Y. Xie, J. X. Zhao, K. L. Ji, X. X. Lei, H. Sun, L. G. Lou, J. M. Yue,
J. Am. Chem. Soc. 2019, 141, 6812.
In summary, we have developed an efficient approach to
the total synthesis of dysoxylactam A (1), in that a longest linear
sequence of 17 steps with 9.5% overall yield is registered. The
synthesis takes advantage of the iterative Evans aldol reaction
sequence to construct the stereochemically crowded polypropi-
onate skeleton and the ring-closing metathesis reaction to
elaborate the macrocycle. Application of the present approach
to the synthesis of dysoxylactam A derivatives and structure-
activity-relationship studies on this novel type of 17-membered
macrolactam with multi-drug-resistant reversing activities are
currently underway and the results will be reported in due
course.
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Acknowledgements
This work is financially supported by the National Key Research &
Development Program of China (2018YFA0507602), the National
Natural Science Foundation of China (21621002), the Key Research
Program of Frontier Sciences of the Chinese Academy of Sciences
(ZDBS-LY-SLH030), and the Strategic Priority Research Program of
the Chinese Academy of Sciences (XDB20020000).
Conflict of Interest
The authors declare no conflict of interest.
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Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
Germany, 2003; pp 296–322 and references therein.
Keywords: Dysoxylactam A · macrocyclolipopeptide · multi-
drug-resistant agent · Aldol reaction · ring-closing metathesis
[26] D. P. Reddy, N. Zhang, Z. Yu, Z. Wang, Y. He, J. Org. Chem. 2017, 82,
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[27] A detailed comparison of the 1H and 13C NMR data between the natural
and synthetic dysoxylactam A is provided in the Supporting Informa-
tion.
Manuscript received: April 15, 2020
Revised manuscript received: May 12, 2020
Version of record online: ■■■, ■■■■
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
COMMUNICATION
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The total synthesis of dysoxylactam
A, a 17-membered macrolactam with
multi-drug-resistant reversing activ-
ities, has been achieved with a
longest linear sequence of 17 steps
in 9.5% overall yield.
D. Prabhakar Reddy, B. Yu*
1 – 4
Total Synthesis of Macrocyclic Dys-
oxylactam A
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