Stereoselective Synthesis of Dysoxylactam A

Article abstract of DOI:10.1021/acs.orglett.9b04426

The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of the fatty acid chain are created by utilizing Merck-Carreira and Marshall's propargylation reaction, Evans' alkylation methodology, and Noyor

Full text of DOI:10.1021/acs.orglett.9b04426

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Synthesis of Dysoxylactam A
Somnath S. Chandankar*,†,‡ and Sadagopan Raghavan†,‡
†Department of Organic Synthesis & Process Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
S
* Supporting Information
ABSTRACT: The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of
the fatty acid chain are created by utilizing Merck-Carreira and Marshall’s propargylation reaction, Evans’ alkylation
methodology, and Noyori’s transfer hydrogenation protocol.
Scheme 1. Retrosynthetic Disconnection of Dysoxylactam A
ysoxylactam A (1) (Figure 1) is a 17-membered
Dmacrocyclic lipid isolated from the bark of the plant
Dysoxylum hongkongense.1 The relative configuration of
dysoxylactam was determined by extensive NMR studies, and
its absolute configuration was established by X-ray diffraction
of the p-bromobenzoate derivative. Dysoxylactam A is shown
to reverse P-glycoprotein (P-gp) mediated multidrug resistance
of chemotherapeutic agents in vitro. It brings about its action
through inhibition of the transport function of P-gp protein. It
exhibits weak antiproliferative activity against K 562, MCF 7,
and KB tumor cell lines. Structurally it is characterized by the
presence of the long dihydroxy acid chain possessing five
stereogenic centers linked to L-valine via an ester and amide
bond.
Herein, we disclose the first stereoselective synthesis of
dysoxylactam A by taking advantage of Merck-Carreira and
Marshall’s asymmetric propargylation protocol, Evans’ meth-
odology, and Noyori’s transfer hydrogenation protocol. The
retrosynthetic disconnection is depicted in Scheme 1. The
target was envisioned to be obtained by esterification followed
by amide bond formation between compound 3 and Boc-Val-
OH (2) and subsequent removal of the C9 hydroxy protecting
group. The triol derivative 3 might be obtained from 7-octyn-
1-ol derivative 4 and Weinreb amide 5 followed by
stereoselective hydrogenation. Compound 5 was surmised to
be obtained from propargylic ether 6 utilizing Evans’
methodology to introduce the C10 stereocenter. We proposed
synthesis of alkyne 6 from aldehyde 7 and mesylate 8 following
Marshall’s protocol.
The synthesis of mesylate 8, Scheme 2, began by subjecting
acetaldehyde 9 to the Merck-Carreira propargylation protocol2
Received: December 10, 2019
Figure 1. Dysoxylactam A isolated from Dysoxylum hongkongense.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Mesylate 8
Scheme 5. Synthesis of Dysoxylactam A
Scheme 3. Synthesis of Weinreb Amide 5
The aldehyde 7 was subjected to Marshall’s propargylation5
with mesylate 8 to furnish homopropargylic alcohol 12 in 86%
yield (92:8 ds)6 Scheme 3. The hydroxyl was protected as its
TBS ether 6 under standard conditions. Reduction over Pd/C
under an atmosphere of hydrogen yielded the alcohol 13 which
upon oxidation using TEMPO and hypervalent iodine reagent7
afforded the acid 14. Imide 16 was obtained8 via reaction of
the mixed anhydride, derived from acid 14 and pivaloyl
chloride, with oxazolidinone 15. Methylation using NaHMDS
proceeded diastereoselectively to furnish compound 17 which
on hydrolysis afforded the acid 18. Weinreb amide formation
proceeded without incident to afford compound 5.
Scheme 4. Synthesis of C1−C16 Subunit 26
Lithium acetylide derived from alkyne 4 on reaction with
Weinreb amide 5 cleanly afforded the propargylic ketone 19,
Scheme 4. Transfer hydrogenation using (R,R)-TSDPEN-
[RuCl(cymene)] in aqueous media9 afforded propargylic
alcohol 2010 in 92% yield (>95% ds). Protection of hydroxy
group as its TBDPS ether under standard conditions furnished
compound 21. The stage was now set for coupling the fatty
acid derivative with the L-valine derivative. Toward this end,
the C13 hydroxy was selectively deprotected by removal of the
TBS ether using PPTS in methanol to afford alcohol 3.
Attempted esterification of compound 3 with Boc-Val-OH
proved nontrivial, with no product being obtained using DCC,
HOBT11/EDCI, HOBT12/HATU, Hunig’s base13/BOP-Cl,
Hunig’s base14 and cyanuric chloride, and Hunig’s base.15 The
reaction proceeded with DCC in the presence of an equivalent
amount of DMAP16 to afford an epimeric mixture of ester 22
that could not be separated, Scheme 4. The diasteroselectively
could not be ascertained by examination of 1H NMR spectrum
of the ester 22 due to the presence of rotamers. Attempted
coupling of alcohol 3 with Fmoc-Val-Cl in the absence17 or in
the presence of 20 mol % of DMAP18 failed to afford any ester
even when run at 60 °C overnight.
Going forward, reduction of the epimeric mixture of ester 22
under hydrogen atmosphere furnished the saturated alcohol 23
as an inseparable mixture, which on oxidation using TEMPO
and PhI(OAc)2 yielded acid 24. Deprotection of the carbamate
using TFA furnished the trifluoroacetate salt which on
using benzyl ether 10 to furnish alcohol 11 in 90% yield (96%
ee).3 Mesylation following the standard procedure yielded
mesylate 8. Aldehyde 7 was obtained following a reported
procedure using Evans’ methodology.4
B
DOI: 10.1021/acs.orglett.9b04426
Org. Lett. XXXX, XXX, XXX−XXX

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using HF/pyridine19 yielded target 1 in 95% yield with
physical characteristics in excellent agreement with the
reported data (Scheme 5).
In conclusion, the first synthesis of macrocyclic lipid
dysoxylactam 1 is disclosed. The C9 carbinol stereocenter
was created using Noyori’s transfer hydrogenation and the C12
and C13 stereocenters using Marshall’s propargylation
protocol. The C10 and C14 methyl groups were introduced
using Evans’ protocol. Esterification of C13 hydroxy with Boc-
Val-OH proceeded in the presence of an equivalent amount of
DMAP to furnish the ester and its epimer. The total synthesis
was accomplished in 16 steps with an overall yield of 22.2%.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04426.
1
Experimental procedures; H and 13C NMR spectro-
scopic characterization data (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*Email: somnathchandankar3@gmail.com.
ORCID
Somnath S. Chandankar: 0000-0001-6800-0718
Sadagopan Raghavan: 0000-0003-1984-2366
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.C. is thankful to the Council of Scientific and Industrial
Research (CSIR) New Delhi for a fellowship. S.R. is grateful to
CSIR, New Delhi, for funding under the XII five year plan
programme entitled ORIGIN (CSC-108). Manuscript Com-
munication No. IICT/Pubs./2019/422.
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(3) The absolute configuration of the alcohol as depicted was
unambiguously established by comparison of the 1H NMR spectra of
the derived (R)- and (S)-mandelate esters.
C
DOI: 10.1021/acs.orglett.9b04426
Org. Lett. XXXX, XXX, XXX−XXX