Expedient Synthesis of Large-Ring trans-Enamide Macrolides by CuI-Mediated Intramolecular Coupling of Vinyl Iodide with Amide: Total Synthesis of Palmyrolide A

Article abstract of DOI:10.1002/ejoc.201600325

An efficient and improved procedure for copper-catalyzed coupling of vinyl iodide with amide in an intramolecular fashion is described. The protocol utilizes a combination of copper iodide, CsF and (±)-1,2-diaminocyclohexane as ligand. The vinyl iodide couples efficiently with the amide to generate an enamide macrolide without any alteration in the double -bond geometry. The developed method was applied in the synthesis of several large-ring enamide macrolides, and for the total synthesis of natural product palmyrolide A and homologated sanctolide A.

Full text of DOI:10.1002/ejoc.201600325

DOI: 10.1002/ejoc.201600325
Full Paper
Natural Product Synthesis
Expedient Synthesis of Large-Ring trans-Enamide Macrolides by
CuI-Mediated Intramolecular Coupling of Vinyl Iodide with
Amide: Total Synthesis of Palmyrolide A
Jhillu Singh Yadav,*[a,b] Borra Suresh,[a,b] and Pabbaraja Srihari*[a]
Abstract: An efficient and improved procedure for copper-cat- enamide macrolide without any alteration in the double -bond
alyzed coupling of vinyl iodide with amide in an intramolecular geometry. The developed method was applied in the synthesis
fashion is described. The protocol utilizes a combination of cop- of several large-ring enamide macrolides, and for the total syn-
per iodide, CsF and ( )-1,2-diaminocyclohexane as ligand. The thesis of natural product palmyrolide A and homologated sanc-
vinyl iodide couples efficiently with the amide to generate an tolide A.
Introduction
al.[13] used a similar protocol (Maio's conditions) under micro-
wave irradiation with trans-vinyl iodide and observed the for-
Enamides are important structural components of many natural
products exhibiting impressive biological properties such as
anti-inflammatory,[1] cytotoxic,[2] neuroactive,[3] and sedative[4]
activities, and protease inhibition.[5] Enamides are also well
known for their utility in the preparation of heterocycles[6] and
in the asymmetric synthesis of amides and amino acids.[7] Cop-
per-catalyzed coupling[8] reaction between aryl halides and het-
eroatomic nucleophiles, as a complement over the existing,
more investigated palladium-catalyzed processes, has attracted
significant attention because of the high stability and low cost
of copper. Although intermolecular coupling reaction of vinyl
halides with amides is well practiced, the intramolecular cou-
pling of vinyl halides with amides is less well explored. For the
first time Li et al.[9] demonstrated that copper iodide in the
presence of N,N′-dimethylethylenediamine as ligand efficiently
catalyzes an intramolecular vinylation of amides to produce
five- to- seven-membered lactams (Figure 1). The second report
was from Evano et al.,[10] wherein cis-vinyl iodide was coupled
with amide by employing Buchwald's conditions[11] [i.e.,
copper(I) iodide/cesium carbonate] for the total synthesis of
paliurine F, and the third report came from Maio et al.,[12] who
described the formation of a trans-N–H enamide macrocylce in
moderate yield towards the total synthesis of palmyrolide A by
diluted/modified Buchwald conditions. Later, Srinivas Reddy et
[a] Division of Natural Products Chemistry,
CSIR – Indian Institute of Chemical Technology,
Hyderabad 500007, India
E-mail: yadavpub@gmail.com
srihari@iict.res.in
http://www.iictindia.org/staff/jsy/index.html
http://www.iictindia.org/staffprofiles/staffprofile.aspx?emp_id=IICT1725
[b] Academy of Scientific and Innovative Research (AcSIR),
Anusandhan Bhawan,
2 Rafi Marg, New Delhi 110001, India
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600325.
Figure 1. Approaches to enamide formation by intramolecular vinylation of
amides.
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mation of the cis-enamide. The limited number of reports on macrolides. The transformation progressed well, yielding several
intramolecular enamide formation reaction and on the selectiv- large-ring (12-, 14-, 15-, and 16-membered) enamide macrolides
ity for the end product generated under microwave conditions from the corresponding precursors in good yields (Table 2).
prompted us to explore this reaction further in an effort to
Table 2. Synthesis of large-ring macrolide enamide lactams.
improve the yield and to apply the approach to the synthesis
of large-ring macrolides. We herein report the results of our
studies on the intramolecular vinylation of amides with an im-
provement in yields and its application to the versatile synthesis
of large-ring enamide macrolides.
Results and Discussion
From a review of the reports on macrocyclic molecules with
enamide functionality embedded in a 14–16-membered ring,
several molecules such as sanctolide A,[14] laingolide, laingol-
ide A and B,[15] palmyrolide A,[3] and madangolide[16] with bio-
logical activities were identified. We wanted to develop a proce-
dure for constructing a 15-membered enamide macrolide with
a view to extending the strategy to other macrolides. Thus, we
began our studies with the coupling reaction of vinyl iodide
and amide in an intramolecular fashion towards the formation
of a 15-membered enamide macrolide (Scheme 1). Accordingly,
when 1[17] was subjected to a coupling reaction under Buch-
wald's conditions at 90 °C in N,N-dimethylformamide (DMF)/
dimethyl sulfoxide (DMSO), the reaction did not succeed even
after 36 h (Table 1, Entry 1). However, changing the solvent
from DMF or DMSO to tetrahydrofuran (THF), the reaction was
successful but proceeded with a low yield (Entry 7). While inves-
tigating several other reaction conditions by varying the base/
ligand/solvent as shown in Table 1, it was observed that the
reaction proceeded with low conversion when Cs2CO3 or CsF
were used as the base in the presence of N,N′-dimethylethyl-
enediamine as ligand with THF as solvent. Finally, substituting
the ligand N,N′-dimethylethylenediamine with ( )-trans-1,2-di-
aminocyclohexane, with CsF as base, and shifting the solvent
from THF to the nonpolar solvent toluene, the reaction pro-
ceeded with 70 % yield, providing the 15-membered enamide
lactam 1aa.
[a] Yield of isolated product after column chromatography.
The primary enamides were less stable, therefore these cou-
pled products were immediately subjected to N-methylation to
obtain the stable N-methylated products.[18] Notably, all en-
Scheme 1. Intramolecular coupling of vinyl iodide with amide.
amides retained the geometry of the vinyl iodide precursor.
With the optimized result, we proceeded to investigate the Compound 6 (Table 2, Entry 6), with an ester moiety, also
scope of this reaction for the syntheses of other large-ring formed the trans-enamide (desmethyl palmyrolide) exclusively.
Table 1. Optimization of intramolecular coupling of vinyl iodide with amide.[a]
Entry
Base
Ligand
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
CsF
Cs2CO3
CsF
N,N′-dimethylethylenediamine
( )-1,2-diaminocyclohexane
N,N′-dimethylethylenediamine
N,N′-dimethylethylenediamine
( )-1,2-diaminocyclohexane
( )-1,2-diaminocyclohexane
N,N′-dimethylethylenediamine
N,N′-dimethylethylenediamine
( )-1,2-diaminocyclohexane
DMF
DMF
DMSO
1,4-dioxane
DMF
1,4-dioxane
THF
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
30
THF
toluene
20
70
CsF
[a] All the reactions were performed in a sealed tube at 90 °C for 24 h.
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With the successful synthesis of variable large-ring enamide
macrolides, and in a continuation of our efforts on the total
synthesis of natural macrolides,[19] we applied the developed
protocol for the total synthesis of neuroactive natural product
palmyrolide A.[3] Retrosynthetically, palmyrolide A (7) was envis-
aged to be synthesized from 8 through an intramolecular cou-
pling reaction forming an enamide lactam as the key step fol-
lowed by N-methylation. A convergent approach was designed
wherein two key fragments, 9 and 10, are coupled together by
using the Yamaguchi protocol to generate the precursor ester
8 (Scheme 2). Compounds 9 and 10 can be obtained from the
known alcohol 11.
Scheme 3. Synthesis of fragment 9.
by treatment with zirconocene dichloride[24] and diisobutyl-
aluminum hydride (DIBAL-H) in the presence of N-iodosuccin-
imide afforded vinyl iodide 18. MOM deprotection in 18 was
achieved under acidic conditions (4
M HCl), and the resulting
alcohol was further oxidized in a two-step sequence to furnish
Scheme 2. Retrosynthesis for palmyrolide A (7).
the second key fragment 10 (Scheme 4).
The synthesis of fragment 9 commenced with the known
alcohol[20] 11, which was converted into nitrile 12 in a two-
step process; namely, bromination with triphenylphosphine and
CBr4, followed by nucleophilic substitution reaction with NaCN
in DMSO. Nitrile 12 was converted into the corresponding acid
in a two-step sequence (DIBAL reduction followed by further
oxidation to acid 13) in 84 % yield. Acid 13 was coupled with
Weinreb salt to afford the Weinreb amide and then treated with
tBuLi in diethyl ether to obtain the corresponding tert-butyl
ketone 14. Stereoselective reduction of the keto moiety with
(S)-CBS reagent[21] gave the chiral secondary alcohol 15 by ap-
plying a reported procedure.[20c] Compound 15, on debenzyl-
ation with Pd/C followed by oxidation with 2,2,6,6-tetramethyl-
piperidine 1-oxyl (TEMPO) and bis(acetoxy)iodobenzene
(BAIB),[22] gave an acid that was further activated by treatment
with ethyl chloroformate in the presence of triethylamine and
exposed to aq. NH4OH to furnish the key fragment amide 9 in
97 % yield (Scheme 3).
Scheme 4. Synthesis of fragment 10.
The second fragment, 10, was also synthesized from known
alcohol 11. Accordingly, alcohol 11 was protected as the corre-
The two key fragments 9 and 10 were coupled by applying
sponding MOM ether with chloromethyl methyl ether in the a modification of Yamaguchi's protocol[12] to yield the ester
presence of DIPEA, and the benzyl ether was cleaved by treat- compound 8. The latter was subjected to intramolecular cou-
ment with Pd/C (10 %) to provide alcohol 16 in excellent yield. pling reaction according to our optimized reaction conditions
The resulting primary alcohol 16 was oxidized under 2-iodoxy- to provide the enamide precursor for palmyrolide A, which was
benzoic acid (IBX) conditions and treated with Br2 and triphenyl immediately N-methylated with CH3I in the presence of NaH to
phosphite[23] to yield the corresponding dibromo compound give the natural product palmyrolide A (7) in 90 % yield
17. Exposure of the latter to potassium tert-butoxide followed (Scheme 5). Notably, the substrate for the coupling reaction was
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completely consumed within 24 h, and no isomerization was iodide precursor,[25] with one methylene group between vinyl
observed.
iodide and ester functionality, by applying a strategy similar to
that used to obtain the product vinyl iodide 18 from alcohol
16 in Scheme 4, was not fruitful from precursor alcohol 22.
Hence, we proceeded to synthesize 23 with an extra methylene
group that can be used for the synthesis of homologated sanc-
tolide A (20). The synthesis commenced with the known com-
pound 21, which was utilized earlier by our group for the total
synthesis of sanctolide A.[19a] Benzyl deprotection in 21 was
easily achieved with Pd/C, and the resulting alcohol was
oxidized to the aldehyde under Dess–Martin conditions and fur-
ther subjected to Takai olefination to provide vinyl iodide 23.
Silyl (TBDPS) deprotection of 23 with tetrabutylammonium
fluoride (TBAF) followed by oxidation of the resulting alcohol
under BAIB and TEMPO conditions provided acid 24. The result-
ing acid was activated with ethyl chloroformate in the presence
of triethylamine and treated with NH4OH to furnish the precur-
sor 19 for the coupling reaction (Scheme 6). Compound 19 was
exposed to our optimized reaction conditions to furnish the
enamide macrolide, which was N-methylated to provide the sta-
ble homologated sanctolide A (20).
Scheme 5. Total synthesis of palmyrolide A (7).
After accomplishing the total synthesis of natural product
palmyrolide A, we envisaged applying same methodology to
synthesize sanctolide A. However, our attempts to obtain vinyl
Conclusions
We have successfully demonstrated the intramolecular coupling
of vinyl iodide with amide to yield large-ring enamide macrol-
ides with improved selectivity and yield over existing proce-
dures. The methodology was utilized for the synthesis of natural
product palmyrolide A, desmethyl palmyrolide A, and homolo-
gated sanctolide A (15-membered macrolides). Further studies
with the current protocol towards its application in the total
synthesis of natural products and their analogues and investiga-
tion of their biological properties are being pursued.
Supporting Information (see footnote on the first page of this
article): Experimental details, compound data, and copies of NMR
spectra of new compounds.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for funding from the XII Five Year Plan
project ORIGIN (under budget head CSC-0108). J. S. Y. thanks
the CSIR, New Delhi for a Bhatnagar Fellowship. B. S. thanks the
CSIR, New Delhi for financial support in the form of a fellowship.
Keywords: Macrcycles · Natural products · Enamides ·
Esterification · Intramolecular coupling · Copper
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Received: March 16, 2016
Published Online: April 24, 2016
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