Scalable Total Syntheses of Some Natural and Unnatural Lamellarins: Application of a One-Pot Domino Process for Regioselective Access to the Central 1,2,4-Trisubstituted Pyrrole Core

Article abstract of DOI:10.1021/acs.joc.9b01521

Short and scalable total syntheses of lamellarin G trimethyl ether, lamellarin D trimethyl ether, lamellarin H, lamellarin ?, dihydrolamellarin ?, and lamellarin U have been realized in four to six linear steps with an overall yield of ≤22%. Highlights of

Full text of DOI:10.1021/acs.joc.9b01521

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Article
A Scalable Total Syntheses of some Natural and Unnatural
Lamellarins: Application of a One-Pot Domino process for
Regioselective Access to the Central 1,2,4-Trisubstituted Pyrrole Core
Virendra Kumar, Annapurna Awasthi, Abdus Salam, and Tabrez Khan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01521 • Publication Date (Web): 21 Aug 2019
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A Scalable Total Syntheses of some Natural and Unnatural Lamellarins:
Application of a One-Pot Domino process for Regioselective Access to the
Central 1,2,4-Trisubstituted Pyrrole Core
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Virendra Kumar, Annapurna Awasthi, Abdus Salam and Tabrez Khan*
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Organic Synthesis Laboratory, School of Basic Sciences, Indian Institute of Technology
Bhubaneswar, Argul, Khurdha-752050, Odisha, India.
tabrez@iitbbs.ac.in
NO2
RO
RO
RO
RO
Br
O
RO
O
N
N
RO
RO
OR
1-3 steps
O
O
N
O
Single pot
[3+2] annulation/
elimination/
RO
OR
OR
aromatization
reaction sequence
OR
1,2,4-trisubstituted pyrrole
RO
Lamellarins
RO
RO
RO
OR
(upto 22% overall yield)
(key precursor)
Abstract: A short and scalable total syntheses of lamellarin G trimethyl ether, lamellarin D
trimethyl ether, lamellarin H, lamellarin η, dihydrolamellarin η and lamellarin U has been
realized in 4-6 linear steps with an overall yield upto 22%. Highlights of the synthesis includes
a single step access to the central 1,2,4-trisubstituted pyrrole core in a highly regioselective
manner via a one-pot [3+2] cycloaddition/elimination/aromatization sequence based domino
process. Subsequent, palladium mediated double C-H oxidative coupling in a single pot
operation provides access to the pentacyclic coumarin fused pyrrolo-dihydroisoquinoline core
present in lamellarins.
Introduction
Pyrroles are among the most prevalent N-heterocycles which manifests in numerous molecules
of natural origin1 and human imagination for diverse applications ranging from pharmaceutics2
to material science.3 As far as natural products are concerned a significant number of biologically
interesting and structurally fascinating pyrrole containing alkaloids has been produced by marine
organisms.1c One such family of pyrrole alkaloids first isolated from marine prosobranch mollusk
Lamellaria sp. by Faulkner and co-workers in 1985 is the huge lamellarins family.4 With more
than 50 siblings of the family reported till date, they have been classified into Type I, II and III.1c
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Typically, the Type I and II lamellarins as depicted in Figure 1 display a pentacyclic coumarin
fused pyrrolo-dihydroisoquinoline/pyrrolo-isoquinoline ring system respectively. On the other
hand, the Type III lamellarins are relatively simple non-fused, 3,4-diarylated-pyrrole-2-
carboxylates. Differing with respect to the substitution pattern on the arylated central pyrrole
core, lamellarins are believed to biogenetically derived from L-DOPA which perhaps is also
considered responsible for the genesis of other closely related marine alkaloids such as ningalins
A-D,5a lukianols A and B,5b rigidin A-E,5c polycitrins A and B,5d polycitone A & B,5d,e
storniamides A-D5f among few others, reported over the past three decades.1c
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Type I lamellarins
OR
6
HO
7
MeO
MeO
6a
MeO
MeO
5
O
O
8
O
N
N
N
MeO
9
10b
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23
O
O
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O
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1
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OH
2
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OMe OMe
OH
MeO
14
OH
MeO
RO
OH OMe
lamellarin L
OH OMe
lamellarin U
lamellarin I (R=Me)
lamellarin K (R=H)
Type III lamellarins
Type II lamellarins
O
HO
RO
MeO
O
N
O
N
N
MeO
O
COOMe
O
MeO
MeO
OH
OH
HO
RO
MeO
OR
MeO
HO
Lamellarin O
OH
η
lamelllarin
lamellarin D (R = Me)
lamellarin H (R = H)
Figure 1. Representative members belonging to the bioactive lamellarin alkaloid family.
The marine pyrrole alkaloids (MPAs) captured in Figure 1 besides structurally
fascinating also exhibits interesting bioactivity profile including antitumor activity, multi-drug
resistant (MDR) reversal activity in cancer cells, HIV integrase inhibitor activity, antibacterial
and antioxidant activity among others.1c,6 In view of their aforementioned remarkable structural
& biological attributes these MPAs have been hot targets for total and diversity-oriented
synthesis in the eyes of synthetic and medicinal chemists over the past two decades. A vast
repertoire of synthetic endeavors towards the lamellarins family has been documented in the
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literature leading to systematic reviews by Iwao,6b Opatz7a and Alvarez7b of the notable synthetic
and SAR developments in the arena.
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Despite the existence of several total synthesis endeavors involving traditional6b,7,8 as
well as recently developed methods9 for accessing the multisubstituted central pyrrole core and
subsequently the pentacyclic lamellarins scaffold we realized that there still subsists considerable
scope for the development of new synthetic approaches. In particular, approaches which are
general, amenable for diversity creation as well as simple in terms of operational procedure
involving cheap and readily accessible bench-top stable starting materials in addition to the
exclusion of expensive reagents and transition-metal catalyst are compelling. Therefore, in view
of our on-going interest towards the development of metal/acid/base free synthetic methods for
regioselective access to pyrroles10 and other N-heterocycle based scaffolds11 as well as keeping
in mind the few lacunes in the existing synthetic strategies we were motivated to fabricate a
simple and concise route for the total synthesis of some natural and unnatural type I & type II
lamellarins. Gratifyingly, our efforts in this direction has culminated in the development of one
of the rare approaches9a-c,f which comprises of single step reaction to access the central 1,2,4-
trisubstituted pyrrole core in a highly regioselective manner unlike many others which uses
multiple steps.9d,e, 12 Also, subsequent elaboration to the pentacyclic coumarin fused pyrrolo-
dihydroisoquinoline core present in lamellarins is accomplished in a single-pot operation.
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Results and discussion
The contours of the general retrosynthetic plan which we envisioned for quick access to some of
the type I & type II lamellarin alkaloids is as captured in Scheme 1. Since, a simple oxidation of
the isoquinoline core in type I lamellarin was expected to deliver the type II lamellarin core, our
initial focus was to gain access to the pentacyclic type I lamellarin core. In order to accomplish
this task, an iterative oxidative C-H coupling of pyrrole with that of peripheral phenyl rings in
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RO
RO
RO
O
N
O
N
oxidation
RO
O
O
C-H/C-H
acid-phenol
coupling
6
7
8
9
C-H/C-H
oxidative
oxidative
coupling
coupling
OR
OR
Type II lamellarin
RO
RO
RO
OR
RO
OR
RO
O
O
Type I lamellarin
N
1
RO
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RO
RO
RO
N
OR
RO
O
RO
OR
N
2
RO
O
3
OR
+
OR
NO2
Br
[3+2] cycloaddition/
RO
OR
elimination/aromatization
4
reaction sequence based
single-pot domino process
RO
OR
Scheme 1. A general retrosynthetic plan towards some natural and unnatural lamellarins.
pyrrole-2-carboxylate 1 was chosen as the preferred reaction. The key intermediate 1 was
synthetically planned to be derived from 1,4-disubstituted pyrrole-2-carboxylate (2). While the
acquisition of 2 was conceptualized from readily accessible starting materials like N-substituted
aziridine ester 3 and β-bromo-β-nitrostyrene 4, through the one-pot domino process for
regioselective access to 1,2,4-trisubstituted pyrrole developed in our laboratory.10
Therefore towards the realization of the retrosynthetic plan, we commenced our synthetic
journey as captured in Scheme 2 with the annulation of aziridine ester 510 with β-bromo- β-
nitrostyrene 610 under our optimized condition to access the 1,2,4-trisubstituted pyrrole ester 7
which was then easily elaborated to 10 via EDC. HCl mediated coupling of pyrrole-2-carboxylic
acid 8 with phenol 9.13 Having 10 in hand, the next key task was to establish two C-C bonds in
a consecutive manner between the central pyrrole core and the appended phenyl rings in the ester
functionality as well as the phenyl ring of phenethyl substitution at the pyrrole-N-atom. After
scouting several conditions for the desired task we opted for Greaney et al. reported strategy
based on catalytic Pd-mediated C-H oxidative coupling of arenes in presence of Cu(OAc)2.14
However, in view of exploration of same strategy by Itami group in context of lamellarins
synthesis,15 we straightaway exposed 10 to their optimized condition to arrive at lamellarin G
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trimethyl ether in 44% yield. Then, subjection of lamellarin G trimethyl ether to dehydrogenation
using DDQ readily introduced the C5, C6 double bond to offer lamellarin D trimethyl ether in
excellent yield. While, exposure of both lamellarin G and lamellarin D trimethyl ethers to global
methyl ether deprotection of the peripheral phenyl rings using BBr3 smoothly furnished tris-
desmethyl lamellarin G and lamellarin H respectively. While, tris-desmethyl lamellarin G has
not been reported before, the NMR spectral data of the presently synthesized trimethyl ethers of
lamellarin G & D as well as lamellarin H were in good agreement with those reported in the
literature.12e, 16
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MeO
OMe
OMe
N
MeO
MeO
HO
MeO
O
MeO
MeO
MeO
MeO
5
NaOH
N
O
O
COOEt
NO2
N
N
EtOH: H2O (3:1)
9
toluene
O
OH
OEt
3 h, reflux
72%
EDC.HCl, DMAP
150 °C, 16 h
86%
MeO
MeO
DCM, 12 h, rt
MeO
MeO
82%
MeO
MeO
MeO
MeO
Br
gram scale
gram scale
OMe
MeO
8
7
10
6
, Cu(OAc) , K
2CO3
Pd(OAc)2
2
DMAc, 95 °C, 22 h, 44%
DDQ, DCM, 12 h, rt, 91%
MeO
MeO
HO
HO
HO
HO
Tris-desmethyl lamellarin G
MeO
MeO
HO
HO
HO
O
O
N
O
O
N
N
N
O
O
O
O
, DCM
DCM, BBr3
-78 °C-rt
BBr3
-78 °C-rt
MeO
MeO
Lamellarin G Trimethyl Ether
MeO
MeO
Lamellarin D Trimethyl Ether
12 h, 83%
16 h, 71%
OMe
OH
OMe
OH
MeO
HO
MeO
HO
Lamellarin H
HO
Scheme 2. Total synthesis of several natural and unnatural lamellarins.
Similarly, the synthesis of lamellarin η and dihydrolamellarin η was realized as depicted
in Scheme 3. Pyrrole-2-carboxylic acid, 8 was coupled with 1112b using EDC. HCl to arrive at
12 which on exposure to Pd-mediated C-H oxidative coupling condition14, 15 delivered the
pentacyclic intermediate 13. Then, it was just a matter of selective stripping of the isopropyl
group from the fused coumarin domain of 13 to access dihydrolamellarin η. And for this purpose
AlCl3 proved to be a better option among other investigated conditions, offering
dihydrolamellarin η in reasonably good yield. On the other hand, first oxidation of the
pentacyclic intermediate 13 using DDQ to arrive at 14 and then followed by AlCl3 mediated
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selective isopropyl group deprotection from the fused coumarin domain of 14 readily furnished
lamellarin η. Also, the NMR spectral data of the presently synthesized dihydrolamellarin η and
7
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9
lamellarin η were found to be in good agreement with the reported data.17
OiPr
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MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
HO
MeO
MeO
, Cu(OAc)
, DMAc
OMe
Pd(OAc)2
O
2
O
O
N
N
8
N
K
CO3
952°C, 20 h, 41%
11
O
OH
O
EDC.HCl, DMAP
DCM, 12 h, rt
65%
MeO
MeO
OiPr
OiPr
MeO
13
MeO
12
, DCM
AlCl3
48 h, rt, 86%
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O
O
O
N
N
N
, DCM
AlCl3
DDQ, DCM
O
O
O
12 h, rt, 82%
37 h, rt, 84%
MeO
MeO
Lamellarin
OH
OH
OiPr
MeO
Dihydrolamellarin
MeO
MeO
MeO
14
η
η
Scheme 3. Total synthesis of dihydrolamellarin η and lamellarin η.
Next attention was turned towards the synthesis of lamellarin U and as highlighted in
Scheme 4, a similar reaction sequence as employed for the other lamellarins described above
was adopted. Applying our reported condition10 for the annulation of azirdine-2-carboxylate 5
with β-bromo-β-nitrostyrene 15 smoothly furnished the 1,4-disubstituted pyrrole-2-carboxylate
16 in good yield. Saponification on 16 followed by coupling of the resultant acid 17 with phenol
1112b delivered the key intermediate 18 for executing the Pd-mediated C-H/C-H oxidative
coupling14, 15 of arenes to access the pentacyclic isoquinoline-coumarin fused pyrrole 19 in
decent yield. Towards the end game the isopropyl phenyl ethers were deprotected using AlCl3 to
expose the phenolic –OH groups and access the natural product lamellarin U. To our delight, the
NMR spectral data of the synthetic lamellarin U was found to be in close agreement with the one
reported in the literature.18
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MeO
MeO
MeO
NaOH
EtOH: H
O
iPrO
MeO
NO2
O
N
2O (3:1)
5, toluene
reflux, 9 h
76%
N
MeO
iPrO
MeO
3 h, reflux
OH
63%
Br
OEt
15
iPrO
MeO
17
16
9
11, EDC.HCl, DMAP
DCM, 12 h, rt
10
11
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13
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83%
MeO
MeO
MeO
MeO
iPrO
MeO
MeO
,
O
O
O
Pd(OAc)2
N
N
N
AlCl
Cu(OAc)2
3
K
MeO
O
DCM, rt, 48 h
O
O
DMAc,
2CO3,
100 °
70%
C, 36 h,
42%
iPrO
MeO
HO
MeO
Lamellarin U
OH
iPr
iPr
O
O
MeO
MeO
MeO
18
19
Scheme 4. Total synthesis of lamellarin U.
Conclusion
In summary, we have demonstrated a concise and general route for the total syntheses of
several natural and unnatural lamellarins in 4-6 steps starting from very cheap and readily
accessible starting materials. The synthetic route comprises of two key single-pot
transformations which provides rapid acquisition of the pentacyclic coumarin fused pyrrolo-
dihydroisoquinoline core present in the lamellarin alkaloids. Lamellarin G trimethyl ether,
lamellarin D trimethyl ether and lamellarin H have been accessed with an overall yield of 22%
(4 steps), 20% (5 steps) and 14% (6 steps) respectively. While, dihydrolamellarin η, lamellarin
η and lamellarin U has been synthesized with an overall yield of 14% (5 steps), 11% (6 steps)
and ~12% (5 steps). In view of the relatively simple operational procedure of the steps involved
it is a very much scalable synthetic approach. A further exploration of the present synthetic
strategy towards the synthesis of other pyrrole alkaloids is under investigation and shall be
communicated in due course of time.
Experimental Section
General Method: All the reagents were purchased from commercial suppliers and used without
further purification. While most of the desired solvents supplied by commercial suppliers were
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dried using the standard drying procedures.19 All the moisture and air sensitive reactions were
performed under a flow of nitrogen or argon atmosphere using flame-dried or oven-dried
glassware with magnetic stirring. All purifications were done using column chromatography
with 100-200 mesh size SiO2-gel as the stationary phase. Distilled EtOAc and petroleum ether
were typically used for column chromatography. The 1H & 13C{1H} NMR spectra were recorded
on 400 MHz Bruker spectrometer using CDCl3 (H: δ = 7.26 and C: δ = 77.0 ppm) or TMS (δ =
0.0) residual solvent peaks as internal standard and DMSO-d6 ((H: δ = 2.50 and C: δ =
39.52±0.06 ppm). The following abbreviations are used for spin multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, p = quintet/pentet, sept. = septet, dd = doublet of doublet, ddd=
doublet of doublet of doublet, td = triplet of doublet, dq = doublet of quartet and m = multiplet.
The chemical shifts are reported as δ values (ppm) and the coupling constants (J) values are
reported in Hz. High Resolution Mass Spectra (HRMS) were obtained using electron spray
ionization (ESI) technique and TOF mass analyser. IR spectra were recorded on a Bruker FT/IR-
460 Plus spectrometer. Melting points were determined on a Buchi M-560 apparatus and are
uncorrected. Progress of the reactions were monitored using precoated SiO2-gel GF254 TLC
plates while spot visualizations were done under UV light and using spot developing stains like
p-anisaldehyde, ceric ammonium molybdate, ninhydrin or KMnO4.
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Gram Scale Synthesis of Ethyl 1-(3,4-dimethoxyphenethyl)-4-(3,4-dimethoxyphenyl)-1H-
pyrrole-2-carboxylate (7):- As per our optimized procedure,10 using 5 [ethyl 1-(3,4-
dimethoxyphenethyl)aziridine-2-carboxylate] (1.6 g, 5.7 mmol, 1 equiv.) and 6 [(Z)-4-(2-bromo-
2-nitrovinyl)-1,2-dimethoxybenzene]10 (1.3 g, 5.7 mmol, 1 equiv.) with a reaction time of 16 h,
7 was was obtained after flash column chromatography as pale yellow oil (2.16 g, 86% yield);
Rf = 0.7 (20% EtOAc + pet. ether). IR (neat): νmax 2935, 2835, 1697, 1589, 1564, 1515, 1465,
1419, 1250, 1195, 1092, 1027, 801, 762 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 2 Hz,
1H), 6.97 (dd, J1 = 2 Hz, J2 = 8.6 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H),
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6.81 (d, J = 2 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.71 (dd, J1 = 1.6 Hz, J2 = 8 Hz, 1H), 6.55 (d,
J = 3.2 Hz, 1H), 4.52 (t, J = 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H),
3.85 (s, 3H), 3.78 (s, 3H), 3.02 (t, J = 7.2 Hz, 2H), 1.40 (t, J =7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 161.1, 149.1, 148.8, 147.7, 147.6, 131.0, 127.7, 125.4, 123.8, 122.2, 120.9,
117.4, 115.1, 112.1, 111.6, 111.2, 108.7, 59.99, 55.97, 55.87, 55.86, 55.75, 51.2, 37.8, 14.5.
HRMS (ES) m/z calcd for C25H30NO6 (M+H)+ : 440.2068; found: 440.2088.
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1-(3,4-dimethoxyphenethyl)-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid (8):-
To a solution of 7 (1.5 g, 3.42 mmol, 1 equiv.) in ethanol : water (3:1, 40 mL), crushed NaOH
pellets (0.68 g, 17 mmol, 5 equiv.) was added at rt and the reaction was then allowed to reflux
for 3 h, until completion of the saponification process was indicated by TLC analysis. The
reaction was worked up by removing the volatiles under reduced pressure and then neutralization
of the resultant residue by 1N HCl. The aqueous phase was subjected to extraction with EtOAc
(4 × 30 mL). Drying of the organic phase over Na2SO4 and then removal of solvent under reduced
pressure gave a crude residue which was subjected to SiO2-gel column chromatography to access
pure acid 8 as a yellow solid (1.01 g, 72% yield); Rf = 0.4 (50% EtOAc + pet. ether); m.p. 164-
166 °C. IR (neat): νmax 2935, 1666, 1565, 1515, 1463, 1254, 1140, 1094, 1026, 802, 763 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 2 Hz, 1H), 6.97 (dd, J1 = 2 Hz, J2 = 8.4 Hz, 1H),
6.92 (d, J = 2 Hz, 1H), 6.87 (d, J = 2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H 2H), 6.80 (d, J = 8.4
Hz, 1H), 6.70 (dd, J1 = 2 Hz, J2 = 7.8 Hz, 1H), 6.58 (d, J = 2 Hz, 1H), 4.52 (t, J = 7.2 Hz, 2H),
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3.92 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H); C{1H} NMR
(100 MHz, CDCl3) δ 165.7, 149.2, 148.9, 147.8, 147.7, 130.8, 127.3, 126.9, 124.4, 120.9, 120.8,
117.5, 117.3, 112.1, 111.6, 111.3, 108.8, 56.0, 55.91, 55.88, 55.7, 51.6, 37.8. HRMS (ES) m/z
calcd for C23H26NO6 (M+H)+ : 412.1755; found: 412.1773.
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3,4-dimethoxyphenyl 1-(3,4-dimethoxyphenethyl) 4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-
carboxylate (10):- In an dry 25 mL round bottom flask under nitrogen atmosphere, 8 (0.617 g,
1.5 mmol, 1 equiv.) and 9 [3,4-dimethoxyphenol] (0.23 g, 1.5 mmol, 1 equiv.) were taken and
dichloromethane (10 mL) was added. Then, EDC.HCl (0.306 g, 1.7 mmol, 1.1 equiv.) and
DMAP (0.21 g, 1.7 mmol, 1.1 equiv.) were added sequentially at rt and the reaction was allowed
to stir at rt for 12 h until complete consumption of starting materials was indicated by TLC
analysis. The reaction was worked up by removing the solvent under reduced pressure and
subjection of the resultant residue to SiO2-gel flash column chromatography to access 10 as a
pale yellow oil (0.673 g, 82% yield); Rf = 0.3 (30% EtOAc + pet. ether). IR (neat): νmax 3059,
2999, 2936, 2835, 1715, 1604, 1589, 1563, 1514, 1465, 1419, 1231, 1189, 1154, 1050, 1027,
764, 734 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 2 Hz, 1H), 7.02 (dd, J1 = 2 Hz, J2 =
8 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 2 Hz, 1H), 6.93-6.87 (m, 2H), 6.80-6.77 (m,
3H), 6.71 (dd, J1 = 2.0 Hz, J2 = 8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 4.56 (t, J = 7.2 Hz, 2H),
3.94 (s, 3H), 3.91 (s, 6H), 3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.06 (t, J = 7.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 149.5, 149.3, 148.8, 147.84, 147.77, 146.9, 144.2,
130.8, 127.4, 126.5, 124.4, 121.2, 121.0, 117.5, 116.4, 113.3, 112.2, 111.7, 111.3 (2C), 108.8,
106.1, 56.2, 56.0, 55.99, 55.90 (2C), 55.8, 51.3, 37.8. HRMS (ES) m/z calcd for C31H34NO8
(M+H)+ : 548.2279; found: 548.2309.
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Lamellarin G trimethyl ether: Using the earlier reported procedure,17 an oven dried schlenk
tube was charged with 18 (0.54 g, 1 mmol, 1 equiv.), Pd(OAc)2 (0.45 g, 2 mmol, 2 equiv.) and
Cu(OAc)2 (1.09 g, 6 mmol, 6 equiv.) under N2 atmosphere. Then, dimethylacetamide (3 mL)
followed by K2CO3 (0.28 g, 2 mmol, 2 equiv.) was added maintaining the inert atmosphere and
the reaction was allowed to stir at 95 °C for 22 h. Upon reaction completion indication by TLC
analysis, the reaction was filtered through celite and the celite bed was washed with EtOAc (4 ×
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15 mL). The filtrate were combined and subjected to solvent removal under reduced pressure to
arrive at a crude residue which was purified by SiO2-gel flash column chromatography to access
lamellarin G trimethyl ether as a white solid (0.24 g, 44% yield); Rf = 0.5 (50% EtOAc + pet.
ether); m.p. 234-236 °C. Also, the spectroscopic data of our synthesized lamellarin G trimethyl
ether compares favourably with the previously reported data.16a IR (neat): νmax 1702, 1513, 1485,
1462, 1414, 1338, 1269, 1240, 1214, 1165, 1040 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.11 (dd,
J1 = 2.0 Hz, J2 = 8 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 7.04 (d, J = 2 Hz, 1H), 6.90 (s,1H), 6.76
(s, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 4.86-4.73 (m, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H),
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3.86 (s, 3H), 3.45 (s, 3H), 3.36 (s, 3H), 3.12 (t, J = 7.2 Hz, 2H); C{1H} NMR (100 MHz,
CDCl3) δ 155.6, 149.7, 149.0, 148.84, 148.81, 147.5, 146.1, 145.5, 136.0, 128.2, 128.0, 126.6,
123.6, 120.0, 114.8, 114.0, 113.8, 111.8, 111.0, 110.3, 108.6, 104.5, 100.5, 56.24, 56.16, 56.1,
55.94, 55.5, 55.2, 42.4, 28.7. HRMS (ES) m/z calcd for C31H30NO8 (M+H)+ : 544.1966; found:
544.1994.
Lamellarin D trimethyl ether: To a solution of lamellarin G trimethyl ether (120 mg, 0.22
mmol, 1 equiv.) in DCM (5 mL), DDQ (125 mg, 0.55 mmol, 2.5 equiv.) was added at rt. The
reaction was then allowed to stir at room temperature for 12 h until complete consumption of
starting material was indicated by TLC analysis. Subjection of the crude reaction mixture to
SiO2-gel flash column chromatography afforded lamellarin D trimethyl ether as white solid (108
mg, 91% yield); Rf = 0.5 (50% EtOAc + pet. ether); m.p. 278-280 °C. Also, the spectroscopic
data of our synthesized lamellarin D trimethyl ether compares favourably with the previously
reported data.16b IR (neat): νmax 2924, 2853, 1699, 1512, 1491, 1463, 1429, 1416, 1225, 1167,
1088, 1045, 1010, 970, 941 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 7.6 Hz, 1H), 7.25
(dd, J1 = 1.6 Hz, J2 = 8 Hz, 1H), 7.19-717 (m, 3H), 7.12 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.97
(s,1H), 6.76 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.49 (s, 3H), 3.48 (s,
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3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.5, 150.2, 149.9, 149.6, 149.2, 149.1, 146.8, 145.6,
134.5, 129.5, 128.2, 124.9, 124.1, 123.4, 119.1, 114.4, 112.4, 112.0, 111.0, 109.9, 107.9, 107.4,
105.3, 105.1, 100.6, 56.3, 56.2, 56.1, 56.0, 55.5, 55.2. HRMS (ES) m/z calcd for C31H28NO8
(M+H)+ : 542.1809; found: 542.1833.
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Lamellarin H: To a cold solution of lamellarin D trimethyl ether (54 mg, 0.1 mmol, 1 equiv.)
in DCM (5 ml) at -78 °C, BBr3 (1M solution in DCM, 2 mL, 2 mmol, 20 equiv.) was added
dropwise over 10 min. and after stirring at the same temperature for almost 20 min., the reaction
was allowed to warm to rt and stirred for another 12 h until formation of a prominent new spot
was indicated by TLC analysis. The reaction was worked up by quenching it with MeOH (5 mL)
followed by removal of the volatiles under reduced pressure. To the resultant residue H2O (3mL)
was added and extracted with EtOAc (3 × 15 mL). Drying of the organic phase over Na2SO4 and
then removal of solvent under reduced pressure gave a crude residue which was subjected to
SiO2-gel flash column to access lamellarin H as a white solid (32.5 mg, 71% yield); Rf = 0.3
(80% EtOAc + pet. ether); m.p. >300 °C. Also, the spectroscopic data of our synthetic lamellarin
H compares favourably with the previously reported data.12e IR (neat): νmax 1676, 1558, 1472,
1417, 1260, 1191, 1155, 1080, 1033, 955, 849, 752 cm-1; 1H NMR (400 MHz, DMSO-d6) δ
10.00 (s,1H), 9.77 (s, 1H), 9.43 (s, 1H), 9.22 (s, 1H), 9.21 (s, 1H), 8.99 (d, J = 7.6 Hz, 1H), 8.92
(s, 1H), 7.15 (d, J = 8 Hz, 1H), 7.14 (s, 1H), 6.99 (d, J = 8 Hz, 1H), 6.96 (s, 1H), 6.83 (s, 1H),
6.79 (d, J = 2 Hz, 1H), 6.71 (dd, J1 = 2.0 Hz, J2 = 8 Hz, 1H), 6.57 (s, 1H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 155.0, 148.1, 147.3, 147.0, 146.7, 146.0, 145.7, 142.6, 134.4, 129.3, 125.9,
124.2, 121.9, 121.6, 118.6, 118.0, 117.5, 113.0, 111.9 (2C), 110.1, 110.0, 109.2, 106.8, 103.8.
HRMS (ES) m/z calcd for C25H16NO8 (M+H)+ : 458.0870; found: 458.0889.
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Tris-desmethyl Lamellarin G:- :- Applying the above described procedure for global phenyl
methyl ether deprotection on lamellarin G trimethyl ether (30 mg, 0.055 mmol), tris-desmethyl
lamellarin G was obtained as white solid (22 mg, 83% yield); Rf = 0.8 (EtOAc); m.p. >300 °C.
IR (neat): νmax 1643, 1477, 1427, 1391, 1345, 1281, 1233, 1156, 1031, 865, 473, 449, 438 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.37 (s, 1H), 9.10 (s, 2H), 8.82 (s, 1H), 8.63 (s,
1H), 6.87 (d, J = 8 Hz, 2H), 6.72 (s, 1H), 6.67 (d, J = 2 Hz, 1H), 6.66 (s, 1H), 6.59 (dd, J1 =
1.6 Hz, J2 = 8 Hz, 1H), 6.50 (s, 1H), 6.44 (s, 1H), 4.63-4.47 (m, 2H), 2.92 (t, J = 6.4 Hz, 2H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 154.9, 146.5, 146.4, 146.3, 145.6, 145.1, 144.0, 142.4,
136.4, 127.9, 126.2, 125.8, 121.7, 118.9, 117.9, 117.2, 115.5, 115.1, 113.8, 112.6, 109.7, 109.3,
103.6, 42.4, 28.3. HRMS (ES) m/z calcd for C25H18NO8 (M+H)+ : 460.1027; found: 460.1044.
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3-isopropoxy-4-methoxyphenyl-1-(3,4-dimethoxy phenethyl)-4-(3,4-dimethoxyphenyl)-
1H-pyrrole-2-carboxylate (12): Following similar procedure as described for synthesis of 10,
using 8 (411 mg, 1 mmol, 1 equiv.) and 3-isopropoxy-4-methoxyphenol, 11 (182 mg, 1 mmol, 1
equiv.), 12 was obtained as pale yellow oil (373 mg, 65% yield); Rf = 0.5 (30% EtOAc + pet.
ether). IR (neat): νmax 2974, 2934, 2853, 1714, 1605, 1515, 1466, 1260, 1186, 1156, 1069, 1049,
1028, 801, 763, 734 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2 Hz, 1H), 7.00 (dd, J1 =
2 Hz, J2 = 8.2 Hz, 1H), 6.96 (d, J = 2 Hz, 1H), 6.93 (d, J = 2 Hz, 1H), 6.89 (d, J = 8.4 Hz,
1H), 6.85 (d, J = 8 Hz, 1H), 6.78-6.74 (m, 3H), 6.89 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.55
(d, J = 1.6 Hz, 1H), 4.57-4.51 (m, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H),
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3.76 (s, 3H), 3.03 (t, J = 7.2 Hz, 2H), 1.39 (d, J = 6.4 Hz, 6H); C{1H} NMR (100 MHz,
CDCl3) δ 159.6, 149.2, 148.8, 148.1, 147.8 (2C), 147.7, 144.1, 130.8, 127.4, 126.5, 124.3, 121.2,
121.0, 117.4, 116.4, 113.6, 112.2, 112.0, 111.6, 111.2, 109.7, 108.8, 71.5, 56.4, 56.0, 55.9 (2C),
55.8, 51.3, 37.8, 22.0 (2C). HRMS (ES) m/z calcd for C33H38NO8 (M+H)+ : 576.2592; found:
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14-(3,4-dimethoxyphenyl)-3-isopropoxy-2,11,12-trimethoxy-8,9-dihydro-6H-
chromeno[4',3':4,5] pyrrolo[2,1-a]isoquinolin-6-one (13): Applying similar procedure for the
oxidative coupling as described for lamellarin G trimethyl ether, on 12 (287.5 mg, 0.5 mmol),
13 was obtained as white solid (118 mg, 41% yield); Rf = 0.4 (50% EtOAc + pet. ether); m.p.
207-210 °C. IR (neat): νmax 2924, 1645, 1515, 1414, 1261, 1239, 1214, 1164, 1112, 1037, 492,
472, 461 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H),
7.05 (s,1H), 7.04 (dd, J1 = 2 Hz, J2 = 8 Hz, 1H), 6.98 (s, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 4.71-
4.57 (m, 3H), 3.81 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.30 (s, 3H), 3.22 (s, 3H), 3.12 (t, J = 7.2
Hz, 2H), 1.24 (d, J = 6 Hz, 3H), 1.23 (d, J = 6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
155.6, 149.6, 148.9, 148.7, 147.4, 147.0, 146.5, 145.9, 135.8, 128.2, 128.0, 126.6, 123.5, 120.0,
114.7, 113.9, 113.7, 111.8, 110.9, 110.3, 108.6, 104.8, 103.4, 71.4, 56.2, 56.1, 55.9, 55.5, 55.1,
42.3, 28.6, 21.8 (2C). HRMS (ES) m/z calcd for C33H34NO8 (M+H)+ : 572.2279; found:
572.2292.
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14-(3,4-dimethoxyphenyl)-3-isopropoxy-2,11,12-trimethoxy-6H-
chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (14): To a solution of 13 (57.5 mg, 0.1
mmol, 1 equiv.) in DCM (2.5 mL), DDQ (57 mg, 0.25 mmol, 2.5 equiv.) was added at rt. The
reaction was then allowed to stir at room temperature for 12 h until complete consumption of
starting material was indicated by TLC analysis. Subjection of the crude reaction mixture to
SiO2-gel flash column chromatography afforded 14 as white solid (47 mg, 82% yield); Rf = 0.4
(50% EtOAc + pet. ether); m.p. 229-230 °C. IR (neat): νmax 1639, 1510, 1463, 1430, 1416, 1267,
1224, 1179, 1104, 1042, 751, 451, 438 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.2
Hz, 1H), 7.41 (s, 1H), 7.30 (d J = 7.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 1.2 Hz,
1H), 7.14 (dd, J1 = 1.6 Hz, J2 = 8 Hz, 1H), 7.11 (s, 1H), 7.08 (s, 1H), 6.67 (s, 1H), 4.69-4.63
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Hz, 6H); C{1H} NMR (100 MHz, DMSO-d6) δ 154.8, 150.5, 150.4, 149.53, 149.49, 148.1,
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109.6, 108.7, 107.3, 105.9, 105.2, 103.7, 71.0, 56.5, 56.3, 56.1, 55.3, 55.0, 22.2, 22.1. HRMS
(ES) m/z calcd for C33H32NO8 (M+H)+ : 570.2122; found: 570.2127.
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Lamellarin η: In an oven round bottom flask, under N2 atmosphere 14 (57 mg, 0.1 mmol, 1
equiv.) was dissolved in DCM (2.5 mL) before adding anhydrous AlCl3 (133 mg, 1 mmol, 10
equiv.) in small portions over 10 min. The reaction was stirred at rt for 48 h until complete
consumption of starting material was indicated by TLC analysis. The reaction was worked up by
quenching it with water (5 mL) followed by extraction with EtOAc (3 × 10 mL). Drying of the
organic phase over Na2SO4 and then removal of solvent under reduced pressure gave a crude
residue which was subjected to SiO2-gel flash column to access lamellarin η as a white solid
(43.5 mg, 84% yield); Rf = 0.2 (50% EtOAc + pet. ether); m.p. 261-263 °C. Also, the
spectroscopic data of our synthesized lamellarin η compares favourably with the previously
reported data.17IR (neat): νmax 3054, 2986,1714, 1606, 1422, 1326, 1264, 1165, 1123, 895 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.06 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.31 (d,
J = 7.2 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2 Hz, 1H), 7.15 (dd, J1 = 1.6 Hz, J2 =
8.4 Hz, 1H), 7.08 (s, 1H), 6.86 (s, 1H), 6.66 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H), 3.33
(s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 154.4, 150.0, 149.9, 149.0, 149.0, 147.9, 146.3,
144.6, 133.7, 128.9, 127.2, 124.4, 123.7, 122.2, 118.3, 114.6, 113.0, 112.7, 110.8, 108.2 (2C),
106.6, 105.6, 104.8, 103.8, 56.0, 55.9, 55.6, 55.1, 54.5. HRMS (ES) m/z calcd for C30H26NO8
(M+H)+ : 528.1653; found: 528.1660.
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Dihydrolamellarin η: Applying the above described procedure for selective isopropyl group
deprotection, on 13 (57 mg, 0.1 mmol, 1 equiv.), dihydrolamellarin η was obtained as white solid
(46 mg, 86% yield); Rf = 0.3 (50% EtOAc + pet. ether); m.p. 237-239 °C. Also, the spectroscopic
data of our synthesized dihydrolamellarin η compares favourably with the previously reported
data.17 IR (neat): νmax 2931, 1666, 1547, 1516, 1486, 1462, 1415, 1338, 1245, 1216, 1163, 1042,
956, 861, 734 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J1 = 1.6 Hz, J2 = 8 Hz, 1H), 7.07
(d, J = 8 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.96 (s, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 6.63 (s, 1H),
5.72 (s, 1H), 4.86-4.72 (m, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.48 (s, 2H), 3.36 (s,
3H), 3.12 (t, J = 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.6, 149.8, 149.0, 148.9,
147.5, 146.5, 145.5, 143.3, 135.9, 128.2, 128.2, 126.7, 123.6, 120.1, 114.6, 114.0, 113.7, 111.9,
111.0, 110.3, 108.7, 104.0, 103.5, 56.3, 56.2, 55.9, 55.8, 55.2, 42.4, 28.7.
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Ethyl
1-(3,4-dimethoxyphenethyl)-4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-2-
carboxylate (16):- As per our optimized procedure,10 using 5 (388 mg, 1.22 mmol, 1 equiv.) and
15 [(Z)-4-(2-bromo-2-nitrovinyl)-2-isopropoxy-1-methoxybenzene] (342.5 mg, 1.22 mmol, 1
equiv.) with a reaction time of 9.5 h, 16 was obtained after flash column chromatography as pale
yellow oil (436 mg, 76% yield); Rf = 0.7 (30% EtOAc + pet. ether). IR (neat): νmax 2365, 2356,
1698, 1563, 1513, 1465, 1418, 1385, 1248, 1194, 1139, 1091, 1028 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.16 (d, J = 2 Hz, 1H), 6.97-6.95 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 1.6
Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.69 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.53 (d, J = 2 Hz,
1H), 4.57 (sept, J = 6.0 Hz, 1H), 4.50 (t, J = 7.2 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.85 (s,
3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.00 (t, J = 7.2 Hz, 2H), 1.39 (t, J =7.2 Hz, 3H), 1.38 (d, J = 6.0
13
Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 161.1, 149.1, 148.8, 147.6, 147.4, 131.0, 127.6,
125.4, 123.8, 122.1, 120.9, 118.0, 115.1, 113.6, 112.3, 112.1, 111.1, 71.5, 60.0, 56.1, 55.9, 55.8,
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1-(3,4-dimethoxyphenethyl)-4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-2-carboxylic
acid (17):- To a solution of 16 (404 mg, 0.86 mmol, 1 equiv.) in ethanol : water (3:1, 12 mL),
crushed NaOH pellets (173 mg, 4.3 mmol, 5 equiv.) was added at rt and the reaction was then
allowed to reflux for 3 h, until completion of the saponification process was indicated by TLC
analysis. The reaction was worked up by removing the volatiles under reduced pressure and then
neutralization of the resultant residue by 1N HCl. The aqueous phase was subjected to extraction
with EtOAc (4 × 15 mL). Drying of the organic phase over Na2SO4 and then removal of solvent
under reduced pressure gave a crude residue which was subjected to SiO2-gel column
chromatographyto access pure acid 17 as a yellow solid (240 mg, 63% yield); Rf = 0.5 (50%
EtOAc + pet. ether); m.p. 161-163 °C. IR (neat): νmax 2374, 2364, 1667, 1564, 1514, 1456, 1419,
1383, 1357, 1297, 1253, 1190, 1139, 1097, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J
= 2.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.69
(dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H), 4.56 (sept, J = 6.0 Hz, 1H), 4.51
(t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.03 (t, J = 7.2 Hz, 2H), 1.38 (d, J
13
= 6.0 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 165.6, 149.3, 148.8, 147.7, 147.4, 130.8,
127.2, 126.8, 124.3, 121.1, 120.8, 118.0, 117.1, 113.6, 112.4, 112.0, 111.2, 71.6, 56.1, 55.9, 55.7,
51.6, 37.8, 22.2 (2C). HRMS (ES) m/z calcd for C25H30NO6 (M+H)+ : 440.2068; found:
440.2095.
3-isopropoxy-4-methoxyphenyl
1-(3,4-dimethoxyphenethyl)-4-(3-isopropoxy-4-
methoxyphenyl)-1H-pyrrole-2-carboxylate (18):- In an dry 25 mL round bottom flask under
nitrogen atmosphere, 17 (0.210 g, 0.478 mmol, 1 equiv.) and 11 [3-isopropoxy-4-
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methoxyphenol] (0.087 g, 0.478 mmol, 1 equiv.) were taken and dichloromethane (5 mL) was
added. Then, EDC.HCl (0.182 g, 0.956 mmol, 2 equiv.) and, DMAP (0.116 g, 0.956 mmol, 2
equiv.) were added sequentially at rt and the reaction was allowed to stir at rt for 12 h until
complete consumption of starting materials was indicated by TLC analysis. The reaction was
worked up by removing the solvent under reduced pressure and subjection of the resultant residue
to SiO2-gel flash column chromatography to access 26 as a pale yellow oil (0.237 g, 83% yield);
Rf = 0.6 (40% EtOAc + pet. ether). IR (neat): νmax 2976, 2934, 1715, 1604, 1563, 1513, 1467,
1419, 1385, 1335, 1261, 1185, 1156, 1068, 1049, 989 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39
(d, J = 2.0 Hz, 1H), 7.02-7.00 (m, 2H), 6.92 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.87
(d, J = 8.8 Hz, 1H), 6.78-6.74 (m, 3H), 6.70 (dd, J1 = 2.0 Hz, J2 = 8 Hz, 1H), 6.56 (d, J = 1.6
Hz, 1H), 4.63-4.48 (m, 4H), 3.87 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.03 (t, J = 7.2
Hz, 2H), 1.40 (d, J = 6.0 Hz, 6H), 1.39 (d, J = 6.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.7, 149.3, 148.8, 148.1, 147.8, 147.7, 147.5, 144.0, 130.8, 127.3, 126.4, 124.3, 121.2, 121.0,
118.0, 116.3, 113.61, 113.57, 112.4, 112.1, 112.0, 111.2, 109.7, 71.6, 71.5, 56.4, 56.1, 55.9, 55.8,
51.3, 37.8, 22.2 (2C), 22.0 (2C). HRMS (ES) m/z calcd for C35H42NO8 (M+H)+ : 604.2905;
found: 604.2921.
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3-isopropoxy-14-(3-isopropoxy-4-methoxyphenyl)-2,11,12-trimethoxy-8,9-dihydro-6H-
chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (19): Applying similar procedure for the
oxidative coupling as described for lamellarin G trimethyl ether, on 18 (0.212 g, 0.351 mmol),
19 was obtained as a white solid (0.088 g, 42% yield); Rf = 0.5 (50% EtOAc + pet. ether); m.p.
229-230 °C. IR (neat): νmax 1704, 1620, 1484, 1439, 1415, 1269, 1240, 1211, 1165, 1136, 1041,
851 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 1.6 Hz, 1H), 7.07 (s,1H), 7.04 (s, 1H),
6.91 (s, 1H), 6.75 (s, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 4.86-4.72 (m, 2H), 4.57-4.48 (m, 2H), 3.92
(s, 3H), 3.88 (s, 3H), 3.43 (s, 3H), 3.36 (s, 3H), 3.11 (t, J = 6.8 Hz, 2H), 1.38 (d, J = 6 Hz, 6H),
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1.34 (d, J = 6.0 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)δ 155.7,
150.0, 148.9, 148.0, 147.4, 147.0, 146.5, 146.0, 135.9, 128.3, 127.9, 126.6, 123.7, 120.1, 117.8,
114.9, 113.7, 112.6, 111.0, 110.4, 108.6, 104.9, 103.4, 71.4, 71.3, 56.3, 55.9, 55.5, 55.1, 42.4,
28.7, 22.0, 21.9, 21.8 (2C). HRMS (ES) m/z calcd for C35H38NO8 (M+H)+ : 600.2592; found:
600.2618.
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Lamellarin U: In an oven dried round bottom flask, under N2 atmosphere 19 (60 mg, 0.1 mmol,
1 equiv.) was dissolved in DCM (2.5 mL) before adding anhydrous AlCl3 (133 mg, 1 mmol, 10
equiv.) in small portions over 10 min. The reaction was stirred at rt for 48 h until complete
consumption of starting material was indicated by TLC analysis. The reaction was worked up by
quenching it with water (5 mL) followed by extraction with EtOAc (3 × 10 mL). Drying of the
organic phase over Na2SO4 and then removal of solvent under reduced pressure gave a crude
residue which was subjected to SiO2-gel flash column to access lamellarin U as a white solid
(36.5 mg, 70% yield); Rf = 0.3 (80% EtOAc + pet. ether); m.p. 201-203 °C. Also, the
spectroscopic data of our synthesized lamellarin U compares favourably with the previously
reported data.18 IR (neat): νmax 2365, 2355, 1679, 1549, 1513, 1486, 1461, 1414, 1273, 1247,
1212, 1164, 1044, 766, 723 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 2.0 Hz, 1H), 7.03
(d, J = 8.0 Hz, 1H), 6.99 (dd, J1 = 1.6 Hz, J2 = 8.2 Hz, 1H), 6.92 (s, 1H), 6.75 (s, 1H), 6.72 (s,
1H), 6.69 (s, 1H), 5.84 (s, 1H), 5.76 (s, 1H), 4.81 (dt, J1 = 6.6 Hz, J2 = 13.2 Hz, 1H), 4.72 (dt,
J1 = 6.8 Hz, J2 = 13.2 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.51 (s, 3H), 3.39 (s, 3H), 3.09 (t, J
= 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 148.9, 147.4, 146.43, 146.40, 146.37,
145.4, 143.2, 135.9, 128.7, 128.2, 126.7, 123.1, 120.1, 117.5, 114.5, 113.6, 111.3, 110.9, 110.3,
108.8, 104.2, 103.3, 56.3, 55.9, 55.6, 55.1, 42.4, 28.7.
Associated Content:
Supporting Information:
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Copies of 1H/13C NMR spectra for all the compounds reported herein.
Author Information:
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Corresponding Author
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*Email: tabrez@iitbbs.ac.in
ORCID
Virendra Kumar: 0000-0002-7044-9327
Abdus Salam: 0000-0002-3115-8287
Tabrez Khan: 0000-0002-9875-3101
Notes
The authors declare no competing financial interest.
DEDICATION
This work is dedicated to Prof. Goverdhan Mehta (Univ. of Hyderabad, India) on the occassion
of his 76th birthday.
ACKNOWLEDGMENT
T. K. gratefully acknowledges the financial support from Council of Scientific and Industrial
Research (CSIR), India (Sanction No. 02(0320)/17/EMR-II) as well as Science and Engineering
Research Board (SERB), DST, India (Sanction No. EMR/2014/000826). V.K is thankful to
MHRD for the SRF, A.A. and A. S. to CSIR, India for the financial support. All authors wish
to thank IIT Bhubaneswar for the financial and infrastructural support.
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