Stereoselective total synthesis of palmyrolide A via intramolecular trans N-methyl enamide formation

Article abstract of DOI:10.1016/j.tetlet.2016.08.054

The stereoselective total synthesis of palmyrolide A was accomplished through macrocyclization reaction involving trans enamide formation by coupling of vinyl iodide with secondary amide in an intramolecular fashion. The two coupling partners, vinyl iodide 4 and secondary amide 3 were synthesized from the same intermediate alcohol 5. Yamaguchi esterification and CBS-reduction are the other key steps involved in the synthesis.

Full text of DOI:10.1016/j.tetlet.2016.08.054

Accepted Manuscript
Stereoselective total synthesis of palmyrolide A via intramolecular trans N-
methyl enamide formation
Suresh Borra, Sravanth Kumar Amrutapu, Srihari Pabbaraja, Yadav Jhillu Singh
PII:
S0040-4039(16)31081-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.054
TETL 48025
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 April 2016
15 August 2016
17 August 2016
Please cite this article as: Borra, S., Amrutapu, S.K., Pabbaraja, S., Singh, Y.J., Stereoselective total synthesis of
palmyrolide A via intramolecular trans N-methyl enamide formation, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.08.054
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Graphical Abstract
Stereoselective total synthesis of palmyrolide
A via intramolecular trans N-methyl
enamide formation
Leave this area blank for abstract info.
B. Suresh, A. Sravanth Kumar, P. Srihari and J. S. Yadav

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Stereoselective total synthesis of palmyrolide A via intramolecular trans N-methyl
enamide formation
Suresh Borraa,b, Sravanth Kumar Amrutapua,b, Srihari Pabbarajaa, ∗ and Yadav Jhillu Singha,b ∗
aAcademyof Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110001, India.
bDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
The stereoselective total synthesis of palmyrolide A was accomplished through macrocyclization
reaction involving trans enamide formation by coupling of vinyl iodide with secondary amide in
an intramolecular fashion. The two coupling partners, vinyl iodide 4 and secondary amide 3
were synthesized from the same intermediate alcohol 5. Yamaguchi esterification and CBS-
reduction are the other key steps involved in the synthesis.
Received in revised form
Accepted
Available online
Keywords:
enamide
macrolide
Yamaguchi esterification
neuroactive
secondary amide
Secondary metabolites produced by cyanobacteria attract
significant attention due to their interesting biological properties
like antitumor, antiviral, antibiotic, antimalarial, CNS and
immunosuppressive activities.1,2 The screening efforts from
Gerwick et al had resulted in isolation and identification of the
15-membered macrocycle palmyrolide A as a potent neuroactive
compound from two genera Leptolyngbya cf and Oscillatoria
species.3 This compound was also found to display sodium
channel blocking activity in neuro-2a cell (IC50 = 5.2 µM) and
functioned as VGSC antagonist to block veratridine-induced
sodium influx.4 The absolute structure of palmyrolide A with a
rare N-methyl enamide and an intriguing t-butyl branch was
confirmed only after its total synthesis.5a
methodology for the synthesis of several large ring macrocycles
including palmyrolide A.8 The procedure has now been extended
to the coupling reaction of vinyl iodide with secondary amide to
generate the corresponding N-substituted enamide and utilized
for the total synthesis of palmyrolide A. The results pertaining to
these investigations are presented herein.
Retrosynthesis
To begin with, our retrosynthetic analysis for palmyrolide A
(Scheme 1) revealed two key fragments 3 and 4 which can be
coupled together in a convergent fashion initially through a
Yamaguchi esterification reaction to result in an ester 2 and later
subjected to an intramolecular coupling reaction between vinyl
iodide and secondary amide resulting in the formation of the
target molecule 1. The key intermediates 3 and 4 can be
synthesized following a divergent approach from the common
intermediate 5, which in turn can be easily accessible from chiral
epoxy alcohol 6 in four steps. The chiral epoxy alcohol can be
easily synthesized from commercially available inexpensive 1, 5-
pentanediol.
Intrigued by the structural and biological properties displayed
by enamide containing natural products,6 we became interested in
this class of compounds7 and have targeted neuroactive
palmyrolide A for the total synthesis. Of the five earlier
contributions for palmyrolide A, Maio et al5a,b and Srinivas
Reddy et al5c have used primary amide as the precursor for
enamide formation and later methylated (N-methlyation) the
enamide. Brimble and co-workers5d have reported the total
synthesis involving the sequential ring closing metathesis/olefin
isomerization reaction. Sudhakar et al5e have utilized an
intramolecular dehydrative cyclization to form the trans-
enamide. We have recently reported an improved procedure for
the coupling of vinyl iodide and primary amide to generate an
e—na—mid—e macrocycle in an intramolecular fashion and utilized the
∗ Corresponding author. Tel.: 914027191895; fax: +914027160512; e-mail: yadavpub@gmail.com
∗ Corresponding author. Tel.: +914027191815; fax: +914027160512; e-mail: srihari@iict.res.in

2
Tetrahedron Letters
Scheme 3. Reagents and conditions: (i) PPh3, CBr4, CH2Cl2, 0
o
oC- rt, 6h, 95%; (ii) NaCN, DMSO, 120 C, 3 h, 92%; (iii) (a)
DIBAL-H, CH2Cl2, -78 oC, 0.5 h; (b) NaClO2, NaH2PO4.H2O, 2-
methyl-2-butene, t-BuOH:H2O (3:1), 0 oC-rt, 8 h, 84% (for 2
steps); (iv) CDI, NMeHOMe.HCl, CH2Cl2, 0 oC-rt, 8 h, 91%; (v)
t-BuLi, Diethyl ether, -78 C, 0.5 h, 79%; (vi) (S)-CBS 1.0 M in
toluene, BH3.DMS, toluene, 0 oC-rt, 8 h, 90%, 97.3% de; (vii) H2,
I
I
O
O
O
N
NH
NH
OH
o
O
O
+
O
O
O
OH
Pd-C (10%), MeOH,
8 h, 98%; (viii) TEMPO, BAIB,
3
4
acetonitrile, rt, 8 h, 94%; (ix) Ethyl chloroformate, Et3N, 20%
MeNH2 in H2O, CH2Cl2, 0 oC-rt, 0.5 h, 98%.
1
2
O
The alcohol 5 obtained in good quantities was also utilized for
the synthesis of second key fragment
OH
BnO
1,5-Pentanediol
BnO
4 (Scheme 4).
Accordingly, alcohol was initially protected as the
6
5
OH
5
corresponding MOM ether and subjected to debenzylation with
Pd-C (10%) to yield the alcohol 16 in quantitative yield. 16 on
oxidation with IBX followed by treatment with bromine in
presence of triphenyl phosphite provided the gem-dibromide 17.
Elimination reaction occurred smoothly with an exposure of 17
to t-BuOK in the presence of 18-crown-6 to provide the alkyne
18.12 The terminal free acetylene 18 was converted to trans-vinyl
iodide following Negishi’s protocol13 employing Schwartz
reagent (generated in situ from zirconocene dichloride and
DIBAL-H) followed by iodination with NIS to furnish 19 in 81%
yield. MOM deprotection followed by oxidation of the resulting
primary alcohol 20 provided the key acid fragment 4 with a vinyl
iodide moiety (Scheme 4).
Scheme 1. Retrosynthesis of palmyrolide A
Our synthesis for the common intermediate 5 commenced
with a ring opening reaction9 of epoxide 6 that was synthesized in
four steps following literature procedures starting from 1,5-
pentanediol10 to provide the mixture of 7 and 7a in 93% yield.
The mixture of diols was directly treated with NaIO4 and the
resulting crude aldehyde was further reduced with NaBH4 to
yield alcohol 5 along with easily separable unreacted 7a (Scheme
2).
Scheme 2. Reagents and conditions: (i) Me3Al, Hexanes, 0 oC,
1 h, 83%; (ii) (a) NaIO4, THF:H2O (3:1), 0 oC- rt, 1h; (b) NaBH4,
THF, rt, 0.5 h, 72% (for 2 steps)
Alcohol 5 was treated with triphenylphosphine (TPP) and
carbon tetrabromide (CBr4) to yield the corresponding bromide 8
and subjected to nucleophilic displacement reaction with NaCN
to furnish the nitrile 9. Compound 9 was converted to acid in
two-step procedure and then coupled with Weinreb salt to
provide Weinreb amide 11 (Scheme 3) which upon treatment
Scheme 4. Reagents and conditions: (i) (a) MOM-Cl, DIPEA,
CH2Cl2, 0 oC-rt, 8 h, 98%; (b) H2, Pd-C (10%), MeOH, 8 h, 95%;
(ii) (a) IBX, DMSO, CH2Cl2, rt, 1 h; (b) P(OPh)3, Br2, TEA,
CH2Cl2, -78 oC, 1 h, 90% (for 2 steps); (iii) t-BuOK, 18-crown-6,
Hexanes, reflux, 8 h, 95%; (iv) Cp2ZrCl2, DIBAL-H, NIS,
t
o
with BuLi in diethyl ether at -78 C provided the corresponding
tert-butyl ketone 12 in 79% yield. Stereoselective reduction of
ketone 12 with (S)-CBS11 catalyst furnished the desired chiral
alcohol 13 in 90% yield with 97% de. Compound 13 on
debenzylation with Pd-C (10%) followed by oxidation of the
resulting primary alcohol 14 with TEMPO and [bis(acetoxy)-
iodo]benzene (BAIB) afforded the acid 15, which was activated
by ethyl chloroformate in presence of triethylamine and then
treated with aq. 20% MeNH2 to furnish the key fragment N-
methyl amide7a 3 in 98% yield (Scheme 3)
o
CH2Cl2, 50 C, 1 h, 75%; (v) Dioxane.HCl 4M, THF, rt, 6 h,
90%; (vi) (a) IBX, DMSO, CH2Cl2, rt, 1 h; (b) NaClO2,
o
NaH2PO4.H2O, 2-methyl-2-butene, t-BuOH:H2O (3:1), 0 C-rt, 8
h, 88% (for 2 steps)
With the two key fragments 3 and 4 in hand, the stage was set
to proceed further for the target synthesis. As planned earlier, the
final step for target synthesis would be a secondary enamide
formation reaction. Thus, we proceeded initially with the
coupling of two fragments 3 and 4 following Yamaguchi’s
protocol14 to yield the ester 2 in 81% yield (Scheme 5). Although
the coupling reaction of vinyl iodide with primary amide to get
the corresponding enamide in an intramolecular fashion is well
reported,15,5a to the best of our knowledge the same with
secondary amide in an intramolecular fashion is not reported. It
was also observed that the resulting primary enamides
synthesized were existing in rotameric forms and sometimes tend
to isomerize to get cis and trans isomers and hence have to be
protected/N-methylated to get the stable products. This feature
has made us to focus on N-methylated enamide formation
reaction directly through the coupling of vinyl iodide with N-

3
methyl amide. Our initial attempts for intramolecular coupling
reaction for enamide formation with substrate 2 following
Buchwald’s condition using CuI as catalyst, Cs2CO3 as base, N,
N-dimethylethylenediamine as ligand and THF as solvent ended
up with recovery of starting material. However, from our recent
procedure with an improvement in selectivity and yield for the
coupling reaction of vinyl iodide with primary amide,8 we
planned to investigate the same with secondary amide, since this
would end up with the N-methylated enamide directly. We were
delighted to note that the reaction was successful and resulted in
the synthesis of target compound palmyrolide A 1 in 51% yield
(69%, based on recovery of starting material) (Scheme 5). This
reaction also becomes the first procedure16 for an intramolecular
coupling of trans-vinyl iodide with the secondary amide to
generate N-methyl trans enamide. The spectroscopic data17 of
our synthetic compound was found to be identical with those of
the reported natural product3 and synthetic product.5
Table 1. Examples for intramolecular N-methyl-trans enamide
formation.
Entry
Substrate
Producta
Yield
CH3
O
O
N
H3C
I
1
50%
( )10
N
H
( )5
1a
2a
1b
2b
CH3
N
O
O
H3C
I
2
3
48%
68%
N
H
( )11
( )6
I
CH3
N
CH3
O
HN
O
O
O
3a
3b
I
O
O
4
51%
CH3
N
N
H
O
CH3
O
O
O
Scheme 5. Reagents and conditions: (i) 4, 2, 4, 6-trichloro
benzoyl chloride, DIPEA, THF, DMAP, toluene, 18 h, 81%, (ii)
CuI (0.5 eq), CsF, trans-1, 2-diamino cyclohexane, toluene, 90
oC, 36 h, 51%.
4b
4a
CH3
HN
O
O
CH3
To further check the scope of the optimized procedure for
generating secondary enamide large ring macrocycles, we further
investigated substrates with α, ω-vinyl iodide and secondary
amide functionality having variable chain length (Entry 1,2,4,5 &
6, Table 1) and aromatic moiety (Entry 3, and 7, Table 1) within
the chain to provide the corresponding coupled enamide
macrolides. The methodology was also successfully utilized for
the synthesis of an analogue compound desmethyl palmyrolide A
(4b, Table 1).
I
N
5
55%
( )2
5b
6b
5a
6a
CH3
NH
I
CH3
N
O
O
6
7
54%
60%
O
O
( )7
( )8
In conclusion, we report a procedure for an intramolecular
coupling of trans-vinyl iodide with secondary amide to provide
the corresponding N-methyl trans enamide. This procedure was
successfully utilized for the synthesis of a secondary enamide
motif that ended up in the accomplishment of the total synthesis
of palmyrolide A along with several other variable ring size
macrocycles and an analogue compound desmethyl palmyrolide
A. Application of this methodology for the synthesis of other
natural products with N-methyl enamide motif is being currently
pursued in the laboratory.
O
O
O
O
CH3
NH
N
I
CH3
7a
7b
aThe reaction was performed in toluene at 90 oC with CsF(2 eq),
CuI (0.7 eq) and (+/-)-1, 2-diamino cyclohexane (0.7 eq).
Acknowledgements
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:.
The authors thank CSIR, New Delhi for funding from the XII
Five Year Plan project ORIGIN (under budget head CSC-0108).
JSY thanks CSIR, New Delhi for Bhatnagar Fellowship. BS and
ASK thank CSIR, New Delhi for financial support in the form of
fellowship
References and notes
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20
(17) Spectroscopic data for 3. [α]D = + 32.6 (c 0.85, CHCl3);
IR (neat) 3306, 2953, 2869, 1652, 1560, 769 cm−1; 1H NMR (300
MHz, CDCl3): δ 5.60 (bs, 1H), 3.28 (dd, J = 10.2 Hz, J = 1.9 Hz,
1H), 2.81 (d, J = 4.9 Hz, 3H), 2.17 (t, J = 8.3 Hz, 2H), 1.79-1.46
(m, 4H), 1.40-1.32 (m, 1H), 1.27-1.17 (m, 1H), 1.12-1.02 (m,
1H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H); 13C NMR (75 MHz,
CDCl3): δ 174.0, 77.2, 39.0, 36.5, 34.9, 34.5, 29.3, 26.3, 25.7
(3C), 23.1, 20.9; HRMS (ESI) m/z calculated for C13H27O2NNa
[M + Na]+: 252.19340, found 252.19245. 4. [α]D20 = - 16.8 (c 1.0,
CHCl3); IR (neat) 3063, 3031, 2933, 2861, 1707, 1455, 1100,
772, 736, 698 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.52-6.46 (m,
1H), 6.06 (td, J = 14.3 Hz, J = 1.4 Hz, 1H), 2.49 (sextet, J = 6.9
Hz, 1H), 2.12 (dq, J = 7.6 Hz, J = 1.2 Hz, 2H), 1.78-1.77 (m,
1H), 1.61–1.50 (m, 1H), 1.19 (d, J = 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 182.7, 145.2, 75.6, 38.5, 33.5, 31.8, 16.8;
HRMS (ESI): m/z calculated for C7H11IO2 [M]+ 253.98037, found
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20
253.98119. 2. [α]D = + 14.78 (c 1.05, CHCl3); IR (neat) 3301,
3090, 2959, 1727, 1648, 1555, 1461, 1369, 1163, 1064, 959
1
cm−1; H NMR (300 MHz, CDCl3): δ 6.51 (dt, J = 14.3 Hz, J =
6.8 Hz, 1H), 6.04 (d, J =14.3 Hz, 1H), 5.96 (bs, 1H), 4.82-4.73
(m, 1H), 2.82 (d, J = 5.3 Hz, 3H), 2.53-2.40 (m, 1H), 2.24-2.01
(m, 4H), 1.90-1.70 (m, 3H), 1.57-1.34 (m, 5H), 1.17 (d, J = 6.8
Hz, 3H), 1.08-0.96 (m, 1H), 0.94-0.83 (m, 12H); 13C NMR (75
MHz, CDCl3): δ 176.4, 173.9, 145.4, 79.0, 75.3, 39.3, 37.6, 36.2,
34.6 (2C), 33.7, 32.1, 29.0, 26.2, 26.0 (3C), 22.9, 20.9, 17.4;
HRMS (ESI) m/z calculated for C20H36O3NINa [M + Na]+:
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20
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1
cm−1; H NMR (500 MHz, CDCl3): δ 6.47 (d, J = 13.9 Hz, 1H),
5.28 (dt, J = 14.0 Hz, J = 7.0 Hz, 1H), 4.89 (dd, J = 11.0 Hz, J =
1.4 Hz, 1H), 3.05 (s, 3H), 2.50-2.44 (m, 1H), 2.43-2.34 (m, 2H),
2.33-2.26 (m, 2H), 1.84-1.73 (m, 3H), 1.70-1.51 (m, 2H), 1.51-
1.44 (m, 1H), 1.39 (ddd, J = 14.3 Hz, J = 8.7 Hz, J =1.9 Hz, 1H),
1.37-1.31 (m, 1H), 1.21 (d, J = 7.2 Hz, 3H), 1.09-1.03 (m, 1H),
0.90 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H); 13C NMR (125 MHz,
CDCl3): δ 175.3, 172.9, 130.6, 117.3, 77.0, 38.9, 35.7, 35.3, 34.6,
34.5, 32.8, 31.7, 29.3, 27.0, 26.1 (3C), 24.3, 20.6, 16.8; HRMS
(ESI): m/z calculated for C20H35O3NNa [M + Na]+ 360.25092,
found 360.24971.
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5
Highlights
ꢀ Intramolecular coupling of vinyl iodide with
secondary amide is achieved for the first time.
ꢀ Large ring size macrolides with trans enamide
functionality are synthesized.
ꢀ This method is very much useful for generating
trans enamides exclusively.