Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach

Article abstract of DOI:10.1016/j.tet.2017.02.044

Lamellarin K is a complex pyrrole natural product and member of the lamellarin family – a group of natural products known for their potent biological activities, such as, antiproliferative activity and inhibition of P-gp mediated drug efflux pumps. We herein describe the synthesis of the N-benzyl-des-D ring analogue of lamellarin K using a route that centres on an acyl-Claisen reaction to eventually prepare a highly-functionalised 1-aryl-4-methyl-1,4-diketone. Paal-Knorr pyrrole formation using this diketone undergoes auto-oxidation to give a fully-substituted 5-formyl pyrrole which was converted into the natural lactone B ring. Antiproliferative testing of the N-benzyl-des-D ring analogue gave an IC₅₀ of 2.63?μM against the MDA-MB-231 breast cancer cell line.

Full text of DOI:10.1016/j.tet.2017.02.044

Tetrahedron xxx (2017) 1e14
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Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/
Paal-Knorr approach
,
*
Nora Dittrich a, Lisa I. Pilkington a, Euphemia Leung b, David Barker a
a School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand
b Auckland Cancer Society Research Centre, Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Lamellarin K is a complex pyrrole natural product and member of the lamellarin family e a group of
natural products known for their potent biological activities, such as, antiproliferative activity and in-
hibition of P-gp mediated drug efflux pumps. We herein describe the synthesis of the N-benzyl-des-D
ring analogue of lamellarin K using a route that centres on an acyl-Claisen reaction to eventually prepare
a highly-functionalised 1-aryl-4-methyl-1,4-diketone. Paal-Knorr pyrrole formation using this diketone
undergoes auto-oxidation to give a fully-substituted 5-formyl pyrrole which was converted into the
natural lactone B ring. Antiproliferative testing of the N-benzyl-des-D ring analogue gave an IC50 of
Received 21 December 2016
Received in revised form
13 February 2017
Accepted 20 February 2017
Available online xxx
Keywords:
2.63 mM against the MDA-MB-231 breast cancer cell line.
Lamellarin
Acyl-Claisen
Paal-Knorr
Antiproliferative
Synthesis
© 2017 Elsevier Ltd. All rights reserved.
1. Introduction
concentration of the drug inside cells.5 Lamellarin K (1) is perhaps
the best example of this, reported as being one of the most potent
members of its class and performing well in cytotoxicity assays in
multiple cell lines.2
We have previously reported the extensive use of the acyl-
Claisen reaction in the synthesis of a number of derivatives,
particularly lignan natural products and as precursors to
pyrroles.6e14 We wished to apply this reaction to the complex
pyrrole, lamellarin K (1), with the goal of creating a synthetic
pathway to access various analogues of 1.
Lamellarin K (1), a member of the lamellarin family of marine
alkaloids, is a complex pyrrole natural product (Fig. 1). First isolated
in 1993 by Carroll et al. from the Didemnum sp. ascidian,1 lamellarin
K (1), like all members of the lamellarin family, contains a fused
pentacyclic core (rings A-E) with a central pyrrole lactone moiety.2,3
Differences between members of this family arise primarily as a
result of the substituents around rings A, E and the un-fused ring F,
as well as the degree of saturation of the C5eC6 bond.
The majority of SAR studies have thus far focused on the most
cytotoxic member of the lamellarin family, lamellarin D (2),1,2,4
with other examples of this class remaining largely unexplored.
Of further interest, some members of the lamellarin family show
in vivo multiple drug resistance (MDR) reversal in certain cancer
cell lines at sub-cytotoxic concentrations.2 In many cancer cells,
resistance to traditional chemotherapeutic agents is achieved by
the encoding of increased numbers of P-glycoprotein (P-gp) drug
efflux pumps.2 Quesada and co-workers were able to show that
some members of the lamellarin family act as inhibitors of P-gp
We envisaged that ring B would be formed last by the depro-
tection of the benzyl group at C-18 and simultaneous cyclisation to
give the lactol which would then be subsequently oxidised to the
corresponding lactone ring in lamellarin K (1) (Fig. 2). Lactol for-
mation would be possible due to the presence of the aldehyde
functionality in 3; we have previously reported the formation of
pyrrole aldehydes as autooxidation products of Paal-Knorr cycli-
sation reactions of highly-functionalised 1,4-dicarbonyl com-
pounds.6 1,4-Dicarbonyl 4 was thought to be accessed through the
addition of the organolithiate formed from bromide 5 to amide 6,
itself the product of an acyl-Claisen rearrangement between cin-
namyl morpholine 7 and acid chloride 8.
mediated drug efflux pumps, thereby maintaining
a high
* Corresponding author.
E-mail address: d.barker@auckland.ac.nz (D. Barker).
http://dx.doi.org/10.1016/j.tet.2017.02.044
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
2.2. Synthesis of acid chloride 8 and amide 6
The second acyl-Claisen component to be synthesised was acid
chloride 8 and we envisioned commercially-available 3-methoxy-
4-hydroxybenzaldehyde 15, having an appropriate aromatic sub-
stitution pattern, would be a suitable starting material. After
reduction of the aldehyde functionality of 15, alcohol 16 was con-
verted to nitrile 17 which was then hydrolysed to 18 under basic
conditions (see Scheme 2).18 The isopropyl protection of the
phenolic acid 18 gave ester 19, which was hydrolysed with LiOH to
give carboxylic acid 20 in quantitative yield. Reaction of 20 with
SOCl2 provided acid chloride 8 which was used immediately in the
acyl-Claisen reaction.
Fig. 1. Lamellarin K (1) and lamellarin D (2).
To catalyse the acyl-Claisen reaction between 7 and 8, a number
of Lewis acids were trialed, including AlCl3, Ti(OiPr)4,
Yb(OTf)3$xH2O and Er(OTf)3, all of which failed to produce any of
the desired product.12e14 Fortunately, when using MgBr2$OEt2, 6
was produced in 93% yield as a single syn diastereoisomer. The
reactants in this acyl-Claisen rearrangement have more alkoxy
group substituents than all previous examples of this reaction. The
highly coordinating MgBr2$OEt2 appears to be favoured for re-
actions containing these groups.11 Syn-diastereoisomers are formed
preferentially in acyl-Claisen reactions due to the formation, and
rearrangement, of zwitterionic Z-enolates; generally less than 5% of
the anti product is formed when trans allylic amines are used.12
2. Results and discussion
2.1. Synthesis of cinnamyl morpholine 7
To begin, the first acyl-Claisen component to be synthesised was
cinnamyl morpholine 7 (Scheme 1). The synthesis of 7 began from
commercially-available 2,4,5-trimethoxybenzaldehyde 9, which
was selectively deprotected at the 2- and 4-positions with AlCl3 to
give diphenol 10. A number of conditions were trialled for the se-
lective isopropyl protection of the 4-hydroxy group of 10, including
bases such as KOH, K2CO3 and CsCO3, as well as the use of additives.
It was found that NaHCO3,15 using TBAI as an additive16 allowed for
the synthesis of 11 in good yield, the remaining phenol of which
was benzylated in quantitative yield to give benzyl ether 12.
Benzaldehyde 12 was then reacted with vinyl magnesium bromide
to give alcohol 13, which was then converted to an acetate leaving
group, giving 14, ready for the ensuing Tsuji-Trost-type allylic
displacement reaction. Cinnamyl morpholine 7 was successfully
produced from acetate 14 using conditions similar to those re-
ported by Thiel et al.,17 reacting 14 with morpholine using
Pd(PPh3)4 as the catalyst, gave 7 in quantitative yield.
2.3. Synthesis of arylbromide 5
The last aryl component to be synthesised was aryl bromide 5
(Scheme 3). Beginning with o-vanillin 21, selective bromination
using activated silica, CAN and Br2 in CCl419 gave bromide 22 in 81%
yield. Methylation of phenol 22, giving 23, allowed for the Dakin
oxidation of the aldehyde moiety of 23 to give phenol 24 which was
then allylated to give 25 in 67% yield over the five steps. Allyl ether
25 then underwent a Claisen rearrangement to provide allyl phenol
26 which was converted to isopropyl ether 27. Dihydroxylation of
the allyl group in 27 provided diol 28 which then underwent
Fig. 2. Retrosynthetic plan to lamellarin K (1).
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
3
2.4. Attempted synthesis of lamellarin K
With both amide 6 and bromide 5 synthesised, the next step
was the formation of the lithiate of bromide 5 and its addition to
amide 6. Similar bromoaryl Boc-protected ethyl amines have been
previously added to both aldehydes and ketones.22 Unfortunately
despite a range of parameters being altered including varying the
lithation time, lithiating agent, and equivalents of reactants and
reagents used no lithiation products were obtained. Analysis of the
products of the reaction showed debromination of 5 indicating
successful metalation had occurred. We therefore thought these
failed reactions were possibly due to steric effects of the highly-
substituted aryl bromide, 5 e to investigate this, bromide 32,
without the ortho amine tether, was synthesised from 24 through
isopropyl protection of alcohol 24 (Scheme 3). Unfortunately, the
organolithiate obtained from bromide 32 also did not undergo
addition to amide 6 to give the corresponding ketone, 33 (Scheme
4).
As aldehydes are known to be more active than the corre-
sponding morpholine amides, we decided to convert amide 6 to
aldehyde 34. Direct conversion of amide 4 to aldehyde 34 was
25
attempted using Schwartz reagent,23,24 LiAlH4 and Ti(OiPr)4/
TMDS,26,27 which all only returned unreacted starting material
(Scheme 5). Fortunately, this transformation was indirectly ach-
ieved, first by formation of iodolactone 35, then conversion to
carboxylic acid 36 which was alternatively reduced to give 37 and
then oxidised to aldehyde 34, in 66% yield over four steps.
Regrettably, the aryl lithiate formed from bromide 5 did not add to
aldehyde 34 under all conditions attempted.
Scheme 1. Synthesis of cinnamyl morpholine 7.
Following this result, a revised strategy to lamellarin K (1) was
devised (Fig. 3). This new strategy benefitted from using the
advanced precursor, aldehyde 34 however instead of adding the
organolithiate formed from bromide 5 to aldehyde 34, we envis-
aged that 34 could be converted to a dicarbonyl compound, 38,
which would then undergo Paal-Knorr reaction with amine 5 to
give pyrrole 39. Once pyrrole 39 was formed, we hoped that the D
ring could be formed through a palladium-mediated coupling and
following this, the B ring could be accessed through formation of a
lactone linkage to give 40. Finally, global deprotection would give
the desired final product, 1.
Implementing this synthetic route, we first synthesised 1,4-
dicarbonyl 38 using standard Wacker-Tsuji oxidation conditions,28
providing 38 in 65% yield. Regrettably, the ensuing Paal-Knorr re-
action of 38 with amine 31 did not give any of desired pyrrole 39,
with only a complex mixture of products obtained (Scheme 6).
Similarly, test reactions of 38 with other primary amines were also
unsuccessful.
2.5. Synthesis of N-benzyl-des-D-ring lamellarin K 47
Following this, we decided to shift our focus instead to the
synthesis of analogues of lamellarin K, specifically des-D-ring an-
alogues, as we particularly wished to investigate our recently re-
ported autooxidation during the Paal-Knorr pyrrole reaction6 and
its application to lamellarin-like pyrroles. We envisioned des-D-
ring analogues could be synthesised from the oxidations of alcohol
41, then pyrrole and lactone formation, in a manner similar to that
proposed for the synthesis of lamellarin K (Fig. 4).
Conveniently, aldehyde 34 underwent addition of 32, giving
alcohol 41, as an undetermined mixture of diasteroisomers, which
was then immediately oxidised to ketone 42 with DMP (Scheme 7).
A Wacker-Tsuji reaction gave 1,4-diketone 43 in 98% yield. A Paal-
Knorr reaction of 43 with benzylamine, using NaOAc in acetic
acid, open to air, gave both methyl pyrrole 44, and the desired auto-
oxidation product,6 formyl-pyrrole 45, in 3% and 76% yields,
Scheme 2. Synthesis of amide 6.
periodate cleavage to give aldehyde 29. Direct reductive amination
of 29 utilising a number of different conditions, including NH4OAc
and sodium cyanoborohydride20 and NH4Cl, AlMe3 followed by
sodium borohydride reduction21 were unsuccessful, which led us to
first convert aldehyde 29 to the corresponding oxime 30, which we
were then able to reduce to amine 31, in 98% yield over the two
steps. Finally, primary amine 31 was Boc-protected to give bromide
5, ready for addition to 6.
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
Scheme 3. Synthesis of amine 5.
cancer cell line. N-Benzyl des-D-ring analogue 47 was found to have
an IC50 of 2.63 M, while 44 which lacks the lactone B ring had an
IC50 > 5 M.
m
m
3. Conclusion
Despite an unsuccessful attempt at a synthesis of lamellarin K
(1), an N-benzyl des-D-ring analogue, 47 was prepared. The
analogue was obtained through the acyl-Claisen reaction of highly-
functionalised materials as well as the using auto-oxidation during
the Paal-Knorr pyrrole synthesis. Analogue 47, along with pyrrole
45 were tested for their antiproliferative activity against the MDA-
MB-231 breast cancer cell line, with 47 recording an IC50 of 2.63 mM.
The methods developed could allow for the synthesis of lamellarin
analogues with additional modification sites, especially with des-
D-ring analogues with N-substituents, which have not been pre-
pared to date.
Scheme 4. Attempted lithiate additions to amide 6.
respectively. This result is consistent with our previous report6 that
pyrrole formation using electron-rich amines results in preferential
oxidation of the 5-methyl group to an aldehyde when the reaction
is exposed to oxygen.
4. Experimental details
4.1. General details
The lactone functionality was formed first through deprotection
of the O-benzyl group of 45 using hydrogenolysis, followed by
lactonisation using conditions reported by Tamaru et al., giving 46
in 53% yield over 2 steps (Scheme 8).29 Lastly, global deprotection of
the isopropyl ethers in pyrrole lactone 46 using AlCl3 gave the N-
benzyl des-D-ring analogue of lamellarin K, 47 as a mixture of easily
rotatable atropisomers.
All reactions were carried out under a nitrogen atmosphere in
dry, freshly distilled solvents unless otherwise noted. All NMR
spectra were recorded on either Bruker Avance DRX 300 MHz or
400 MHz spectrometers at ambient temperatures. Chemical shifts
are reported relative to the solvent peak of chloroform (
and
77.0 for 13C) or CD3OD ( 3.31 for 1H and 39.5 for 13C). 1H
NMR data is reported as position ( ), relative integral, multiplicity
d
7.26 for 1H
d
d
d
d
Lamellarin analogue 47 and methyl pyrrole 44, were then tested
for their antiproliferative activity against the MDA-MB-231 breast
(s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of triplets;
dd, doublet of doublets; tt, triplet of triplets; m, multiplet; br, broad
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
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Scheme 5. Conversion of amide 6 to aldehyde 34.
Fig. 3. Revised retrosynthetic strategy to lamellarin K (1).
peak; qd, quartet of doublets), coupling constant (J, Hz), and the
assignment of the atom. 13C NMR data are reported as position (
and assignment of the atom. All NMR assignments were performed
using HSQC and HMBC experiments. High-resolution mass
spectroscopy (HRMS) was carried out by either chemical ionization
(CI) or electrospray ionization (ESI) on a MicroTOF-Q mass spec-
trometer. Unless noted, chemical reagents were used as purchased.
d)
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
Scheme 6. Attempted synthesis of 39.
Fig. 4. Retrosynthetic plan to des-D ring analogues of lamellarin K (1).
4.2. Synthesis of compounds
(50 mg, 0.30 mmol) in DMF (1 mL) under an atmosphere of nitro-
gen, was added TBAI (22 mg, 0.062 mmol), followed by 2-
iodopropane (45 L, 0.45 mmol) dropwise and the resultant sus-
4.2.1. 2,4-Dihydroxy-5-methoxybenzaldehyde 10
m
To a suspension of AlCl3 (27 g, 0.20 mol) in CH2Cl2 (60 mL) under
an atmosphere of nitrogen, was added a solution of 2,4,5-
trimethoxybenzaldehyde 9 (10 g, 0.051 mol) in CH2Cl2 (60 mL),
dropwise. After vigorous stirring for 4 h, further AlCl3 (27 g,
0.20 mol) was added and the resultant suspension was stirred for
3 d at room temperature. The mixture was poured on to ice acidi-
fied with 2 M HCl (100 mL) and was extracted with CH2Cl2
(3 ꢀ 100 mL). The combined organic extracts were filtered through
silica gel, dried (MgSO4) and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (19:1 hexanes, ethyl acetate) to give the title compound
(6.4 g, 75%) as a yellow solid. RF (2:1 hexanes, ethyl acetate) ¼ 0.74;
pension was stirred at 80 ꢁC for 3 d. Water (3 mL) and ethyl acetate
(3 mL) were added and the organic layer separated. The aqueous
mixture was extracted further with ethyl acetate (3 ꢀ 3 mL) and the
combined organic extracts were washed with water (10 mL), dried
(MgSO4) and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (2:1 hexanes,
ethyl acetate) to yield the title compound (50 mg, 80%) as a yellow
solid. RF (2:1 hexanes, ethyl acetate) ¼ 0.77; mp. 60e62 ꢁC; dH
(300 MHz; CDCl3; Me4Si) 1.43 (6H, d, J ¼ 6.1 Hz, CH(CH3)2), 3.85
(3H, s, OCH3), 4.64 (1H, sept., J ¼ 6.1 Hz, CH(CH3)2), 6.43 (1H, s, 3-H),
6.91 (1H, s, 6-H), 9.67 (1H, s, CHO), 11.36 (1H, s, OH). The 1H NMR
data for this compound is in accordance with the literature
values.30
mp. 148e149 ꢁC (lit: 150 ꢁC)30
; dH (300 MHz; CDCl3; Me4Si) 3.92
(3H, OCH3), 6.35 (1H, s, OH), 6.53 (1H, s, 3-H), 6.89 (1H, s, 6-H), 9.68
(1H, s, CHO), 11.33 (1H, s, OH). The 1H NMR data for this compound
is in accordance with the literature values.30
4.2.3. 2-(Benzyloxy)-4-isopropoxy-5-methoxybenzaldehyde 12
To a stirred solution of phenol 11 (1.2 g, 5.7 mmol) and K2CO3
(0.95 g, 6.8 mmol) in EtOH (18 mL) was added benzyl bromide
(0.81 mL, 6.7 mmol) dropwise and the resultant mixture was
heated at reflux, under an atmosphere of nitrogen, for 24 h. 2 M HCl
4.2.2. 2-Hydroxy-4-isopropoxy-5-methoxybenzaldehyde 11
To a solution of phenol 10 (50 mg, 0.30 mmol) and NaHCO3
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
7
Scheme 7. Synthesis of pyrroles 44 and 45.
(MNaþ, 100%). HRMS (ESIþ): found (MNaþ): 323.1247 C18H20NaO4
requires 323.1254.
4.2.4. 1-(2-(Benzyloxy)-4-isopropoxy-5-methoxyphenyl)prop-20-
en-10-ol 13
To a solution of aldehyde 12 (0.20 g, 0.67 mmol) in THF (3 mL),
under an atmosphere of nitrogen at 0 ꢁC, was added vinyl mag-
nesium bromide (1 M in THF, 2 mmol) dropwise. The resultant
solution was warmed to room temperature and stirred for 24 h and
then heated at 40 ꢁC for a further 5 h. A saturated aqueous solution
of NH4Cl (5 mL) and CH2Cl2 (5 mL) were added and the organic
layer was separated. The aqueous mixture was further extracted
with CH2Cl2 (3 ꢀ 5 mL). The combined organic extracts were dried
(MgSO4) and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (3:1 hexanes,
ethyl acetate) to yield the title compound (0.22 g, quant.) as a yellow
oil which was used immediately to prevent decomposition. RF (2:1
hexanes, ethyl acetate) ¼ 0.50; dH (300 MHz; CDCl3; Me4Si) 1.30
(3H, d, J ¼ 6.1 Hz, CH(CH3)2), 2.59 (1H, br s, OH), 3.80 (3H, s, OCH3),
4.43 (1H, sept., J ¼ 6.1 Hz, CH(CH3)2), 5.04 (2H, s, CH2Ar), 5.13e5.32
(2H, m, 30-H), 5.32 (1H, br s,10-H), 6.03e6.14 (1H, m, 20-H), 6.58 (1H,
s, 3-H), 6.88 (1H, s, 6-H), 7.29e7.33 (5H, m, Ar-H); dC (75 MHz;
CDCl3) 22.0 (CH(CH3)2), 56.6 (OCH3), 70.4 (C-10), 71.3 (CH2Ar), 72.0
(CH(CH3)2), 104.0 (C-3), 112.0 (C-6), 114.2 (C-30), 123.9 (C-1), 127.3,
127.9 and 128.5 (Ar-CH), 136.8 (Ar-C), 139.6 (C-20), 145.1 (C-5), 147.0
(C-4), 149.7 (C-2).
Scheme 8. Synthesis of N-benzyl des-D-ring analogue of lamellarin K, 47.
(15 mL), water (15 mL) and ethyl acetate (30 mL) were added and
the organic layer separated. The aqueous mixture was further
extracted with ethyl acetate (3 ꢀ 20 mL) and the combined organic
extracts were washed with water (5 ꢀ 20 mL), dried (MgSO4) and
the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (4:1 hexanes, ethyl
acetate) to yield the title compound (1.7 g, quantitative) as a dark
4.2.5. (E)-400-(30-(2-(Benzyloxy)-4-isopropoxy-5-methoxyphenyl)
allyl)morpholine 7
yellow solid. RF (2:1 hexanes, ethyl acetate)
¼
0.74; mp.
To a suspension of alcohol 13 (1.0 g, 3.0 mmol) and DMAP
(37 mg, 0.3 mmol) in THF (9 mL), under an atmosphere of nitrogen
at 0 ꢁC, was added pyridine (0.47 g, 6.0 mmol) and acetic anhydride
(0.41 g, 4.0 mmol) dropwise, respectively. The resultant solution
was warmed to room temperature and stirred for 24 h. A saturated
aqueous solution of NaHCO3 (15 mL) and CH2Cl2 (15 mL) were
added and the organic layer separated. The aqueous mixture was
further extracted with CH2Cl2 (4 ꢀ 15 mL). The combined organic
extracts were dried (MgSO4) and the solvent was removed under
122e123 ꢁC; dH (300 MHz; CDCl3; Me4Si) 1.36 (6H, d, J ¼ 6.1 Hz,
CH(CH3)2), 3.84 (3H, s, OCH3), 4.57 (1H, sept., J ¼ 6.1 Hz, CH(CH3)2),
5.15 (2H, s, CH2Ar), 6.52 (1H, s, 3-H), 7.33 (1H, s, 6-H), 7.34e7.43 (5H,
m, Ar-H), 10.37 (1H, s, CHO); dC (75 MHz; CDCl3) 21.7 (CH(CH3)2),
56.2 (OCH3), 71.5 (CH(CH3)2), 71.6 (CH2Ar), 100.5 (C-3), 109.4 (C-6),
117.9 (C-1), 127.2, 128.2 and 128.7 (Ar-CH), 138.2 (Ar-C), 144.8 (C-5),
154.1 (C-4), 157.4 (C-2), 187.9 (CHO); IR: nmax(film)/cmꢂ1; 2977,
2933, 2852,1657, 1599, 1500, 1265, 747, 708 and 695; m/z (ESIþ) 323
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N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
reduced pressure to yield the product acetate which was used in
the next reaction without further purification.
6-H); Spectroscopic data were in accordance with literature
values.32
To a solution of acetate 14 (1.1 g, 3.0 mmol) in THF (12 mL),
under an atmosphere of nitrogen at room temperature, was added
morpholine (0.52 g, 6.0 mmol) dropwise, followed by tetrakis(-
triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) and the
resultant suspension was heated to 70 ꢁC for 3 d. The solvent was
removed under reduced pressure, and the residue was dissolved in
CH2Cl2 (15 mL) and washed with a saturated aqueous solution of
NaHCO3 (15 mL). The organic layer was separated and the aqueous
mixture was further extracted with CH2Cl2 (3 ꢀ 15 mL). The com-
bined organic extracts were dried (MgSO4) and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (19:1 CH2Cl2, MeOH) to yield (E)-400-(30-
(2-(benzyloxy)-4-isopropoxy-5- methoxyphenyl) allyl)morpholine
7 (1.2 g, quantitative over 2 steps) as a viscous orange oil. RF (2:1
hexanes, ethyl acetate) ¼ 0.06; dH (300 MHz; CDCl3; Me4Si) 1.30
(6H, d, J ¼ 6.1 Hz, CH(CH3)2), 2.50 (4H, t, J ¼ 4.5 Hz, N(CH2CH2)2O),
3.15 (2H, d, J ¼ 6.9 Hz, 10-H), 3.73 (4H, t, J ¼ 4.5 Hz, N(CH2CH2)2O),
3.81 (3H, s, OCH3), 4.44 (1H, sept., J ¼ 6.1 Hz, CH(CH3)2), 5.02 (2H, s,
CH2Ar), 6.13 (1H, dt, J ¼ 6.9, 16.0 Hz, 20-H), 6.53 (1H, s, 3-H), 6.85
(1H, d, J ¼ 16.0 Hz, 30-H), 7.01 (1H, s, 6-H), 7.27e7.57 and 7.63e7.71
(5H, m, Ar-H); dC (75 MHz; CDCl3) 22.0 (CH(CH3)2), 53.6
(N(CH2CH2)2O), 56.5 (OCH3), 61.8 (C-10), 66.9 (N(CH2CH2)2O), 71.8
(CH(CH3)2), 71.9 (CH2Ar), 104.3 (C-3), 110.2 (C-6), 119.1 (C-1), 124.3
(C-20), 127.6 (C-30), 127.3, 128.5 and 131.5 (Ar-CH), 137.2 (Ar-C), 145.2
(C-5), 147.5 (C-4), 150.0 (C-2); IR: nmax(film)/cmꢂ1; 2974, 2855,
2806, 1679, 1607, 1502, 1205, 1111, 1028, 972, 905, 721, 695; m/z
(ESIþ) 398 (MHþ, 100%), 311 (80), 301 (20), 269 (20). HRMS (ESIþ):
found (MHþ): 398.2320 C24H32NO4 requires 398.2326.
4.2.8. Homovanillic acid 18
To a solution of nitrile 17 (50 mg, 0.31 mmol) in EtOH (2 mL) and
H2O (1 mL), was added NaOH (49 mg, 1.21 mmol) and the resultant
solution was heated at 80 ꢁC for 2 d. The solvent was removed
under reduced pressure and the residue was diluted with ethyl
acetate (2 mL) and was poured on a slurry of conc. HCl and ice. The
organic layer was separated and the aqueous mixture was extracted
with ethyl acetate (3 ꢀ 5 mL). The combined organic extracts were
dried (MgSO4) and the solvent was removed under reduced pres-
sure to yield the title compound (50 mg, 89%) as a yellow oil which
required no further purification. RF (2:1 hexanes, ethyl
acetate) ¼ 0.24; dH (400 MHz; MeOD; Me4Si) 3.57 (2H, s, CH2Ar),
3.88 (3H, s, OCH3), 6.75e6.88 (3H, m, 2-, 5- and 6-H); Spectroscopic
data were in accordance with literature values.33,34
4.2.9. Isopropyl 20-(4-isopropoxy-3-methoxyphenyl)acetate 19
To a solution of homovanillic acid 18 (1.1 g, 6.0 mmol) in dry
DMF (30 mL), was added K2CO3 (2.7 g, 19 mmol), followed by 2-
bromopropane (2.6 mL, 28 mmol) dropwise and the resultant
suspension was heated at reflux for 24 h. Water (30 mL), conc. HCl
(30 mL) and ethyl acetate (20 mL) were added and the organic layer
was separated. The aqueous mixture was extracted further with
ethyl acetate (3 ꢀ 20 mL) and the combined organic extracts were
dried (MgSO4), and the solvent was removed under reduced pres-
sure. The crude product was purified by flash chromatography (2:1
ethyl acetate, hexanes) to yield the title compound (1.6 g, quanti-
tative) as a yellow oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.81; dH
(300 MHz; CDCl3; Me4Si) 1.22 (6H, d, J ¼ 6.3 Hz, C(O)OCH(CH3)2),
1.35 (6H, d, J ¼ 6.1 Hz, 4-OCH(CH3)2), 3.51 (2H, s, CH2Ar), 3.84 (3H, s,
OCH3), 4.49 (1H, sept., J ¼ 6.1 Hz, 4-OCH(CH3)2), 5.01 (1H, sept.,
J ¼ 6.3 Hz, C(O)OCH(CH3)2), 6.76e6.85 (3H, m, 2-, 5- and 6-H); dC
(75 MHz; CDCl3) 21.7 (C(O)OCH(CH3)2), 22.0 (4-OCH(CH3)2), 41.2
(CH2Ar), 55.8 (OCH3), 68.0 (C(O)OCH(CH3)2), 71.3 (4-OCH(CH3)2),
112.9 (C-2), 115.7 (C-5), 121.2 (C-6), 127.1 (C-1), 146.2 (C-4), 150.2 (C-
3), 171.3 (C(O)OCH(CH3)2); IR: nmax(film)/cmꢂ1; 2979, 2937, 1728,
1509, 1229, 1141, 1036, 792, 705; m/z (ESIþ) 289 (MNaþ, 100%);
HRMS (ESIþ): found (MNaþ): 289.1407 C15H22NaO4 requires
289.1410.
4.2.6. 4-(Hydroxymethyl)-2-methoxyphenol 16
To a suspension of NaBH4 (9.9 g, 0.26 mol) in MeOH (250 mL),
under an atmosphere of nitrogen at 0 ꢁC, was added a solution of
vanillin 15 (20 g, 0.13 mol) in MeOH (250 mL) dropwise over 30 min
and the resultant mixture was warmed to room temperature and
stirred for 24 h. The mixture was diluted with ethyl acetate
(100 mL) and a saturated aqueous solution of NH4Cl (50 mL) was
added. The volatile solvent was removed under reduced pressure
and the aqueous mixture was extracted with ethyl acetate
(5 ꢀ 50 mL). The combined organic extracts were washed with
brine (40 mL), dried (MgSO4) and the solvent was removed under
reduced pressure to yield the title compound (18 g, 89%) as a viscous
yellow oil which required no further purification. RF (2:1 hexanes,
ethyl acetate) ¼ 0.45; dH (400 MHz; CDCl3; Me4Si) 3.91 (3H, s,
OCH3), 4.61 (2H, d, J ¼ 5.2 Hz, CH2Ar), 5.62 (1H, s, OH), 6.83e6.93
(3H, m, 3-, 5- and 6-H), 8.80 (1H, s, OH); Spectroscopic data were in
accordance with literature values.31
4.2.10. 20-(4-Isopropoxy-3-methoxyphenyl)acetic acid 20
To a solution of ester 19 (0.12 g, 0.45 mmol) in THF (2 mL) and
water (2 mL), was added LiOH (0.15 g, 6.3 mmol) and the resultant
mixture was heated at reflux for 24 h. The solvent was removed
under reduced pressure and the residue was diluted with diethyl
ether (3 mL). The suspension was cooled to 0 ꢁC and acidified to pH
1 with 1 M HCl. The organic layer was separated and the aqueous
mixture was further extracted with diethyl ether (3 ꢀ 5 mL). The
combined organic extracts were dried (MgSO4), and the solvent
was removed under reduced pressure. The crude product was pu-
rified by flash chromatography (2:1 ethyl acetate, hexanes) to yield
the title compound (0.10 g, quantitative) as a yellow oil. RF (2:1
hexanes, ethyl acetate) ¼ 0.39; dH (300 MHz; CDCl3; Me4Si) 1.35
(6H, d, J ¼ 6.0 Hz, CH(CH3)2), 3.57 (2H, s, CH2Ar), 3.84 (3H, s, OCH3),
4.49 (1H, sept., J ¼ 6.0 Hz, CH(CH3)2), 6.77e6.85 (3H, m, 2-H, 5-H
and 6-H), 9.40 (1H, br s, OH); dC (75 MHz; CDCl3) 22.0
(CH(CH3)2), 40.6 (CH2Ar), 55.9 (3-OCH3), 71.5 (CH(CH3)2), 115.2 (C-
2), 115.7 (C-5), 121.5 (C-6), 126.1 (C-1), 146.6 (C-4), 150.3 (C-3), 177.9
(C(O)OH); IR: nmax(film)/cmꢂ1; 2979, 2937, 1708, 1509, 1453, 1260,
1233, 1109, 1036, 788, 771; m/z (ESIþ) 247 (MNaþ, 100%), 137 (80),
225 (50), 183 (50), 263 (30), 282 (20); HRMS (ESIþ): found (MNaþ):
247.0941 C12H16NaO4 requires 247.0941. Spectroscopic data were in
accordance with literature values.35
4.2.7. 20-(4-Hydroxy-3-methoxyphenyl)acetonitrile 17
To a solution of alcohol 16 (18 g, 0.12 mol) in DMF (300 mL),
under an atmosphere of nitrogen was added NaCN (6.9 g, 0.14 mol),
and the mixture was heated at 120 ꢁC and stirred for 24 h. The
solution was cooled to room temperature and water (100 mL) was
added cautiously. The reaction mixture was basified (solid NaOH) to
pH 10 and the DMF was removed by distillation. Water (250 mL)
and acetic acid (20 mL) were added until a neutral pH (~7) was
achieved. The aqueous mixture was extracted with chloroform
(5 ꢀ 100 mL) and the combined organic extracts were washed with
water (5 ꢀ 50 mL), dried (MgSO4), and the solvent was removed
under reduced pressure to give the title compound (13 g, 68%,
quantitative brsm.) as a brown oil which was used without purifi-
cation in the subsequent reaction. RF (2:1 hexanes, ethyl
acetate) ¼ 0.33; dH (400 MHz; CDCl3; Me4Si) 3.68 (2H, s, CH2Ar),
3.90 (3H, s, OCH3), 5.73 (1H, br s, OH), 6.81e6.90 (3H, m, 2-, 5- and
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
9
4.2.11. 20-(4-Isopropoxy-3-methoxyphenyl)acetyl chloride 8
4.2.14. 5-Bromo-2,3-dimethoxybenzaldehyde 23
To a solution of carboxylic acid 20 (0.15 g, 0.67 mmol) in CH2Cl2
(3 mL), was added a drop of DMF, followed by thionyl chloride
(0.14 mL, 2.0 mmol) dropwise and the resultant solution was stirred
at room temperature under an atmosphere of nitrogen for 24 h. The
volatile solvent was removed under reduced pressure to yield the
title compound (0.16 g, assumed quantitative) which was used
immediately without further purification. RF (2:1 hexanes, ethyl
acetate) ¼ 0.53; dH (300 MHz; CDCl3; Me4Si) 1.35 (6H, d, J ¼ 6.1 Hz,
CH(CH3)2), 3.58 (2H, s, CH2Ar), 3.84 (3H, s, OCH3), 4.49 (1H, sept.,
J ¼ 6.1 Hz, CH(CH3)2), 6.79e6.86 (3H, m, 2-, 5- and 6-H).
To a solution of phenol 22 (77 mg, 0.33 mmol) in DMF (3 mL),
under an atmosphere of nitrogen was added K2CO3 (46 mg,
0.33 mmol), and the mixture was stirred for 15 min prior to the
dropwise addition of methyl iodide (19 mL, 0.33 mmol). The resul-
tant suspension was stirred at room temperature for 24 h. A 5%
aqueous solution of NaOH (10 mL) was added and the suspension
was diluted with CH2Cl2 (10 mL). The organic layer was separated
and the aqueous mixture was further extracted with CH2Cl2
(4 ꢀ 10 mL). The combined organic extracts were washed with
water (5 ꢀ 10 mL), dried (MgSO4) and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (2:1 hexanes, ethyl acetate) to yield the title
compound (82 mg, quantitative) as a pale yellow solid. RF (2:1
hexanes, ethyl acetate) ¼ 0.72; mp. 81.5e82.0 ꢁC (Lit: 82e83 ꢁC);36
dH (300 MHz; CDCl3; Me4Si) 3.91 (3H, s, 3-OCH3), 3.97 (3H, s, 2-
OCH3), 7.22 (1H, d, J ¼ 2.3 Hz, 4-H), 7.51 (1H, d, J ¼ 2.3 Hz, 6-H),
10.34 (1H, s, CHO); Spectroscopic data were in accordance with
literature values.36
4.2.12. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)-1-
morpholinopent-4-en-1-one 6
To a stirred suspension of MgBr2.OEt2 (0.29 g, 1.1 mmol) in
CH2Cl2 (5 mL), under an atmosphere of nitrogen at room temper-
ature, was added a solution of cinnamyl morpholine 7 (0.45 g,
1.1 mmol) in CH2Cl2 (5 mL) dropwise and the resultant suspension
was stirred for 5 min. DIPEA (1.65 mmol) was added dropwise and
the resultant suspension was stirred for 15 min. A solution of acid
chloride 8 (0.33 g, 1.4 mmol) in CH2Cl2 (5 mL) was added dropwise
and the resultant suspension was stirred for 24 h. A saturated
aqueous solution of NaOH (15 mL) was added and the organic layer
was separated. The aqueous mixture was further extracted with
CH2Cl2 (3 ꢀ 10 mL) and the combined organic extracts were dried
(MgSO4), and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography (2:1
hexanes, ethyl acetate) to yield the title compound (0.64 g, 93%) as a
crystalline orange solid. RF (2:1 hexanes, ethyl acetate) ¼ 0.10; mp.
39e44 ꢁC; dH (400 MHz; CDCl3; Me4Si) 1.24e1.27 (12H, m, 40-
OCH(CH3)2 and 400-OCH(CH3)2), 3.11e3.35 and 3.50e3.58 (8H, m,
N(CH2CH2)2O), 3.65 (3H, s, 300-OCH3), 3.69 (3H, s, 50-OCH3),
4.32e4.39 (4H, m, 2-H, 3-H, 40-OCH(CH3)2 and 400-OCH(CH3)2), 4.87
(2H, s, CH2Ar), 5.05e5.12 (2H, m, 5-H), 6.16e6.24 (1H, m, 4-H), 6.42
(1H, s, 30-H), 6.51e6.58 (3H, m, 200-, 500- and 600-H), 6.71 (1H, d,
J ¼ 1.8 Hz, 60-H), 7.29e7.41 (5H, m, Ar-H); dC (100 MHz; CDCl3) 22.0
(40-OCH(CH3)2 and 400-OCH(CH3)2), 42.3 and 46.0 (N(CH2CH2)2O),
49.4 (C-3 and C-2), 55.8 (300-OCH3), 56.7 (50-OCH3), 66.4 and 66.8
(N(CH2CH2)2O), 70.8 (CH2Ar), 71.1 and 71.9 (40-OCH(CH3)2 and 400-
OCH(CH3)2), 103.5 (C-30), 112.1 (C-60), 115.1 (C-5), 115.4, 115.8 and
120.8 (C-200, C-500 and C-600), 122.3 (C-10), 127.5, 127.9128.6 (Ar-CH),
130.7 (C-100), 137.2 (Ar-C), 139.1 (C-4), 144.5 (C-50), 145.8 and 146.0
(C-40 and C-400),149.8 (C-300),150.4 (C-20),171.3 (C-1); IR: nmax(neat)/
cmꢂ1; 2975, 2930, 1636, 1507, 1215, 1109, 1035, 727; m/z (ESIþ) 626
(MNaþ, 100%), 604 (80); HRMS (ESIþ): found (MHþ): 604.3277
4.2.15. 5-Bromo-2,3-dimethoxyphenol 24
To a solution of aldehyde 23 (50 mg, 0.20 mmol) in CH2Cl2
(2 mL), under an atmosphere of nitrogen at 0 ꢁC, was added mCPBA
(0.106 g, 0.61 mmol) and the resultant suspension was stirred at
0 ꢁC for 1 h prior to warming to room temperature. After 24 h a 5%
aqueous solution of Na2S2O3 (5 mL) was added and the mixture was
stirred for 10 min prior to separation of the organic layer. The
aqueous mixture was further extracted with ethyl acetate
(3 ꢀ 5 mL) and the combined organic extracts were washed with a
saturated solution of Na2CO3 (10 mL), NH4Cl (10 mL) and brine
(10 mL) and then dried (MgSO4). The solvent was removed under
reduced pressure and the resultant yellow oil was dissolved in
methanolic KOH (1 mL) and stirred at room temperature for 24 h.
2 M HCl solution (5 mL) was added and the solution was acidified to
pH 4 and extracted with ethyl acetate (5 ꢀ 5 mL). The combined
organic extracts were washed with a saturated solution of Na2CO3
(10 mL) and brine (10 mL), dried (MgSO4) and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (2:1 hexanes, ethyl acetate) to yield the
title compound (40 mg, 83% over two steps) as a white solid. RF (2:1
hexanes, ethyl acetate) ¼ 0.45; mp. 62.6e65.5 ꢁC (Lit: 68e70 ꢁC);37
dH (300 MHz; CDCl3; Me4Si) 3.84 (CH3, 3-OCH3), 3.87 (CH3, 2-
OCH3), 5.83 (1H, br s, OH), 6.60 (1H, d, J ¼ 2.2 Hz, 4-H), 6.77 (1H,
d, J ¼ 2.2 Hz, 6-H); Spectroscopic data were in accordance with
literature values.37
4.2.16. 1-(Allyloxy)-5-bromo-2,3-dimethoxybenzene 25
C
36H46NO7 requires 604.3269.
To a suspension of NaH (prewashed with pentane to remove the
mineral oil coating) (62 mg, 2.6 mmol) in THF (32 mL), under an
atmosphere of nitrogen at 0 ꢁC, was added a solution of phenol 24
(0.50 g, 2.1 mmol) dropwise in THF (10 mL). The resultant sus-
pension was warmed to room temperature and stirred for 30 min,
then cooled to 0 ꢁC and allyl bromide (0.20 mL, 2.40 mmol) was
added dropwise. The suspension was then warmed to room tem-
perature and heated at 70 ꢁC for 24 h. A saturated aqueous solution
of NH4Cl (20 mL) and ethyl acetate (10 mL) were added and the
organic layer was separated. The aqueous mixture was further
extracted with ethyl acetate (3 ꢀ 10 mL). The combined organic
extracts were dried (MgSO4) and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (3:1 hexanes, ethyl acetate) to yield the title compound
(0.59 g, quantitative) as a yellow oil. RF (2:1 hexanes, ethyl
acetate) ¼ 0.73; dH (300 MHz; CDCl3; Me4Si) 3.83 (3H, s, 2-OCH3),
3.84 (3H, s, 3-OCH3) 4.56 (2H, dt, J ¼ 1.4, 5.2 Hz, 10-H), 5.27e5.32
(1H, m, 30-HA), 5.38e5.45 (1H, m, 30-HB), 5.98e6.09 (1H, m, 20-H),
4.2.13. 5-Bromo-2-hydroxy-3-methoxybenzaldehyde 22
To a suspension of o-vanillin 21 (1.0 g, 6.6 mmol) and silica
(1.0 g) in wet CCl4 (10 mL), was added Br2 (0.34 mL, 6.6 mmol) and
CAN (9 mg, 0.013 mmol) and the resultant mixture was stirred at
room temperature for 24 h. The suspension was then diluted with
CH2Cl2 (10 mL) and filtered through Celite. The filtrate was washed
with a saturated aqueous solution of Na2S2O3 (50 mL), dried
(MgSO4) and the solvent was removed under reduced pressure. The
crude product was purified by recrystallisation from 60% ethanol/
water to afford 5-bromo-2-hydroxy-3-methoxybenzaldehyde 22
(1.2 g, 81%) as a yellow solid. RF (2:1 hexanes, ethyl acetate) ¼ 0.78;
mp. 120.5e123.6 ꢁC (Lit: 122e123 ꢁC);19 dH (300 MHz; CDCl3;
Me4Si) 3.91 (3H, s, OCH3), 7.15 (1H, s, 4-H), 7.28 (1H, s, 6-H), 9.84
(1H, s, CHO), 10.99 (1H, s, OH); Spectroscopic data were in accor-
dance with literature values.36
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

10
N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
6.71 (2H, s, 4- and 6-H); dC (75 MHz; CDCl3) 56.3 (3-OCH3), 60.8 (2-
OCH3), 70.1 (C-10), 109.2 and 110.7 (C-4 and C-6), 115.9 (C-5), 117.9
(C-30), 132.8 (C-20), 137.9 (C-2), 152.9 (C-1), 157.3 (C-3); IR: nmax(-
film)/cmꢂ1; 2924, 2854, 1587, 1495, 1449, 1232, 1121, 848, 812; m/z
(ESIþ) 297 (81BrMNaþ, 98%), 295 (79BrMNaþ, 100%), 275 (25), 194
J ¼ 4.9, 11.7 Hz, 10-HA), 3.61 (1H, dd, J ¼ 3.1, 11.7 Hz, 10-HB), 3.81 (3H,
s, 3-OCH3), 3.84 (3H, s, 4-OCH3), 3.87e3.91 (1H, m, 20-H), 4.76 (1H,
sept., J ¼ 6.2 Hz, CH(CH3)2), 6.90 (1H, s, 5-H); dC (75 MHz; CDCl3)
22.7 (CH(CH3)2), 34.4 (C-30), 56.1 (4-OCH3), 60.5 (3-OCH3), 65.5 (C-
10), 71.7 (C-20), 76.3 (CH(CH3)2), 112.0 (C-5), 118.8 (C-1), 124.7 (C-6),
141.6 (C-3), 149.9 (C-2), 152.6 (C-4); IR: nmax(film)/cmꢂ1; 3412,
2972, 2931, 1588, 1481, 1409, 1234, 1116, 1102, 1051, 824, 786; m/z
(ESIþ) 373 (81BrMNaþ, 96%), 371 (79BrMNaþ, 100%), 351 (70), 289
(95), 149 (25); HRMS (ESIþ): found
(
79BrMNaþ): 294.9936
79
C
H BrNaO3 requires 294.9940.
11 13
4.2.17. 2-Allyl-3-bromo-5,6-dimethoxyphenol 26
(40), 247 (80); HRMS (ESIþ): found 79BrMNaþ): 371.0455
(
79
A solution of allyloxybenzene 25 (0.12 g, 0.44 mmol) in toluene
(4 mL) was heated to 200 ꢁC in a sealed tube under an atmosphere
of nitrogen for 24 h, after which time the mixture was cooled to
room temperature and the solvent was removed under reduced
pressure to yield the title compound (0.12 g, quantitative) as a yel-
low oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.51; mp. 64e69 ꢁC; dH
(400 MHz; CDCl3; Me4Si) 3.49 (2H, dt, J ¼ 1.6, 6.0 Hz,10-H), 3.83 (3H,
s, 5-OCH3), 3.88 (3H, s, 6-OCH3), 5.01e5.06 (2H, m, 30-H), 5.88e5.98
(1H, m, 20-H), 6.02 (1H, br s, OH), 6.70 (1H, s, 4-H); dC (100 MHz;
CDCl3) 33.6 (C-10), 56.0 (5-OCH3), 61.0 (6-OCH3), 108.0 (C-4), 115.1
(C-30), 118.9 and 119.1 (C-2 and C-3), 135.0 (C-20), 135.9 (C-6), 148.0
(C-1), 150.8 (C-5); IR: nmax(neat)/cmꢂ1; 3492, 2939, 2838, 1638,
1606, 1579, 1492, 1455, 1117, 1033, 972, 800; m/z (ESIþ) 297
C H BrNaO5 requires 371.0465.
14 21
4.2.20. 1-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)
acetaldehyde 29
To a solution of diol 28 (0.69 g, 2.0 mmol) in MeOH/H2O (3:1,
16 mL) was added NaIO4 (0.51 g, 2.4 mmol) and the resultant sus-
pension was stirred for 4 h. Brine (10 mL) and water (10 mL) were
added and the aqueous mixture was extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic extracts were washed with
water (20 mL), dried (MgSO4) and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (3:1 hexanes, ethyl acetate) to yield the title compound
(0.59 g, 93%) as
a colourless oil. RF (2:1 hexanes, ethyl
(
(
81BrMNaþ, 98%), 295 (79BrMNaþ, 100%); HRMS (ESIþ): found
acetate) ¼ 0.77; dH (300 MHz; CDCl3; Me4Si) 1.24 (6H, d, J ¼ 6.2 Hz,
CH(CH3)2), 3.82 (3H, s, 3-OCH3), 3.83 (2H, d, J ¼ 1.5 Hz, 10-H), 3.85
(3H, s, 4-OCH3), 4.68 (1H, sept., J ¼ 6.2 Hz, CH(CH3)2), 6.92 (1H, 5-
H), 9.66 (1H, t, J ¼ 1.5 Hz, 20-H); dC (75 MHz; CDCl3) 22.4 (CH(CH3)2),
44.8 (C-10), 56.0 (4-OCH3), 60.3 (3-OCH3), 75.6 (CH(CH3)2), 111.3 (C-
5), 118.8 (C-1), 120.3 (C-6), 141.5 (C-3), 150.5 (C-2), 153.2 (C-4),
198.84 (C-20); IR: nmax(neat)/cmꢂ1; 2976, 2936, 1776, 1588, 1482,
1235, 1115, 1101, 1046, 786; m/z (ESIþ) 341 (81BrMNaþ, 98%), 339
79
79BrMNaþ): 294.9953 C11
H BrNaO3 requires 294.9940.
13
4.2.18. 2-Allyl-1-bromo-3-isopropoxy-4,5-dimethoxybenzene 27
To a solution of phenol 26 (0.28 g, 1.0 mmol) and K2CO3 (0.45 g,
3.3 mmol) in DMF (7 mL), under an atmosphere of nitrogen, was
added 2-bromopropane (0.44 mL, 4.7 mmol) and the resultant
suspension was heated at reflux for 24 h. Water (10 mL), concen-
trated HCl (0.1 mL) and ethyl acetate (10 mL) were added and the
organic layer was separated. The aqueous mixture was further
extracted with ethyl acetate (5 ꢀ 10 mL) and the combined organic
extracts were washed with water (5 ꢀ 10 mL), dried (MgSO4) and
the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (19:1 hexanes, ethyl
acetate) to yield the title compound (0.31 g, 95%) as a yellow oil. RF
(2:1 hexanes, ethyl acetate) ¼ 0.80; dH (400 MHz; CDCl3; Me4Si)
1.26 (6H, d, J ¼ 6.4 Hz, CH(CH3)2), 3.50 (2H, dt, J ¼ 1.6, 4.8 Hz, 10-H),
3.80 (3H, 4-OCH3), 3.81 (3H, 5-OCH3), 4.66 (1H, sept., J ¼ 6.4 Hz,
CH(CH3)2), 4.98e5.03 (2H, m, 30-H), 5.85e5.94 (1H, m, 20-H). 6.86
(1H, s, 6-H); dC (100 MHz; CDCl3) 22.6 CH(CH3)2, 34.2 (C-10), 55.9 (4-
OCH3), 60.2 (5-OCH3), 75.1 (CH(CH3)2), 111.3 (C-6), 115.2 (C-30),
118.5 (C-1), 126.4 (C-2), 135.4 (C-20), 141.7 (C-4), 150.1 (C-3), 152.1
(C-5); IR: nmax(film)/cmꢂ1; 2976, 2935, 1587, 1479, 1234, 1104, 987,
907, 820, 797; m/z (ESIþ) 339 (81BrMNaþ, 95%), 337 (79BrMNaþ,
(
C
79BrMNaþ, 100%); HRMS (ESIþ): found (79BrMNaþ): 339.0215
H BrNaO4 requires 339.0202.
13 17
79
4.2.21. 1-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)
ethanamine 31
To a solution of aldehyde 29 (0.11 g, 0.33 mmol) in EtOH (2 mL)
was added triethylamine (0.11 mL, 0.79 mmol) followed by hy-
droxylamine hydrochloride (44 mg, 0.63 mmol) and the resultant
mixture was heated at reflux for 2 h. The solvent was removed
under reduced pressure. The crude product was diluted with
ethyl acetate (5 mL) and washed with 2 M HCl (10 mL) and the
organic layer was separated. The aqueous mixture was further
extracted with ethyl acetate (2 ꢀ 5 mL) and the combined organic
extracts were washed with water (2 ꢀ 5 mL), a saturated aqueous
solution of NaHCO3 (10 mL) and brine (10 mL), then dried
(MgSO4). The solvent was removed under reduced pressure to
give 2-(6-bromo-2-isopropoxy-3,4-dimethoxyphenyl)acetalde-
hyde oxime 30 as a colourless oil (0.12 g, quantitative) which was
used without purification in the subsequent reaction. To a solu-
tion of oxime 30 (0.12 g, 0.35 mmol) in THF (10 mL) and 2 M HCl
(4 mL) was added zinc dust (0.45 g, 6.9 mmol) and the resultant
mixture was heated at reflux for 30 min. The suspension was
filtered through a slurry of silica gel and ethyl acetate and the
filtrate was collected. The solvent was removed under reduced
pressure and ethyl acetate (10 mL) and 2 M HCl (10 mL) were
added and the organic layer was separated. The aqueous mixture
was further extracted with ethyl acetate (3 ꢀ 10 mL) and the
combined organic extracts were dried (MgSO4). The solvent was
removed under reduced pressure to give the crude product which
was purified by flash chromatography (2:1 ethyl acetate, hexanes)
to yield the title compound (0.11 g, 98% over two steps) as an or-
ange oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.45; dH (400 MHz;
CDCl3; Me4Si) 1.32 (6H, d, J ¼ 6.2 Hz, CH(CH3)2), 3.16e3.20 (2H, m,
CH2CH2NH2), 3.25e3.28 (2H, m, CH2CH2NH2), 3.83 (3H, s, 3-
OCH3), 3.85 (3H, s, 4-OCH3), 3.93 (2H, br s, NH2), 4.79 (1H, sept.,
100%), 296 (15), 275 (20), 259 (20), 194 (15); HRMS (ESIþ): found
79
(
79BrMNaþ): 337.0424 C14
H BrNaO3 requires 337.0410.
19
4.2.19. 30-(6-Bromo-2-isopropoxy-3,4-dimethoxyphenyl)propane-
10,20-diol 28
To a solution of alkene 27 (0.62 g, 2.0 mmol) in tBuOH/H2O (1:1,
40 mL) was added NMO (0.69 g, 5.9 mmol) and OsO4 (5 mg,
0.20 mL, 0.020 mmol) dropwise respectively and the resultant so-
lution was stirred for 24 h. A saturated aqueous solution of Na2SO3
(20 mL) was added and the mixture was stirred for 1 h prior to
addition of ethyl acetate (20 mL) and separation of the organic
layer. The aqueous mixture was further extracted with ethyl acetate
(3 ꢀ 20 mL), and the combined organic extracts were dried
(MgSO4). The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography (2:1 ethyl
acetate, hexanes) to yield the title compound (0.69 g, quantitative)
as an orange oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.26; dH
(300 MHz; CDCl3; Me4Si) 1.28 (3H, d, J ¼ 6.2 Hz, CH(CH3)2),1.33 (3H,
d, J ¼ 6.2 Hz, CH(CH3)2), 3.01 (2H, d, J ¼ 6.9 Hz, 30-H), 3.44 (1H, dd,
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
11
J ¼ 6.2 Hz, CH(CH3)2), 6.90 (1H, s, 5-H). Spectroscopic data were in
mixture was further extracted with diethyl ether (3 ꢀ 30 mL) and
the combined organic extracts were dried (MgSO4). The solvent
was removed under reduced pressure to yield the crude iodo-
lactone 35, which was used without further purification in the
subsequent reaction. To a stirred solution of iodolactone 35 (1.3 g,
2.0 mmol) in acetic acid (30 mL), was added zinc (1.2 g, 1.8 mmol),
and the resultant suspension was heated at reflux for 3 d. The so-
lution was cooled to room temperature and 2 M HCl (30 mL) and
ethyl acetate (20 mL) were added and the organic layer was sepa-
rated. The aqueous mixture was further extracted with ethyl ace-
tate (3 ꢀ 20 mL) and the combined organic extracts were dried
(MgSO4). The solvent was removed under reduced pressure to give
the crude product, which was purified by flash chromatography
(1:1 hexanes, ethyl acetate) to yield the title compound (1.1 g, quant.
accordance with literature values.38
4.2.22. tert-Butyl-6-bromo-2-isopropoxy-3,4-
dimethoxyphenethylcarbamate 5
To a solution of amine 31 (44 mg, 0.14 mmol) in CH2Cl2 (3 mL),
under an atmosphere of nitrogen, was added triethylamine (28 mL,
0.21 mmol) dropwise, followed by di-tert-butyl dicarbonate
(45 mg, 0.21 mmol) and the resultant solution was stirred at room
temperature for 24 h. A saturated aqueous solution of NH4Cl (5 mL)
was added and the organic layer was separated. The aqueous
mixture was extracted further with CH2Cl2 (3 ꢀ 5 mL) and the
combined organic extracts were treated with N-methylpiperazine
to react with any di-tert-butyl dicarbonate remaining. 2 M HCl
(5 mL) was added and the organic layer was separated. The organic
extract was washed further with a saturated aqueous solution of
NaHCO3 (10 mL) and water (10 mL). The organic extract was dried
(MgSO4) and the solvent was removed under reduced pressure to
give the crude product which was purified by flash chromatog-
raphy (19:1 CH2Cl2, methanol) to yield the title compound (50 mg,
88%) as a pale yellow oil. RF (9:1 CH2Cl2, methanol) ¼ 0.16; dH
(400 MHz; CDCl3; Me4Si) 1.28 (6H, d, J ¼ 6.2 Hz, CH(CH3)2),1.42 (9H,
s, C(CH3)3), 2.93 (2H, t, J ¼ 6.7 Hz, CH2CH2NHBoc), 3.30e3.31 (2H,
m, CH2CH2NHBoc), 3.80 (3H, s, 3-OCH3), 3.83 (3H, s, 4-OCH3), 4.67
(1H, sept., J ¼ 6.2 Hz, CH(CH3)2), 4.88 (1H, br s, NH), 6.85 (1H, s, 5-
H); dC (100 MHz; CDCl3) 22.6 (CH(CH3)2), 28.4 (C(CH3)3), 30.5
(CH2CH2NHBoc), 40.1 (CH2CH2NHBoc), 56.0 (3-OCH3), 60.3 (4-
OCH3), 75.4 (CH(CH3)2), 78.6 (C(CH3)3), 106.8 (C-5), 111.4 (C-6),
125.9 (C-1), 141.6 (C-3), 150.3 (C-2), 152.4 (C-4), 155.8 (C]O); IR:
nmax(neat)/cmꢂ1; 3390, 2975, 2933, 1704, 1588, 1480, 1410, 1246,
1169, 1118, 1104, 822; m/z (ESIþ) 442 (81BrMNaþ, 100%), 440
over two steps) as
a brown oil. RF (2:1 hexanes, ethyl
acetate) ¼ 0.12; dH (400 MHz; CDCl3; Me4Si) 1.21 (6H, d, J ¼ 8.0 Hz,
40-OCH(CH3)2 or 400-OCH(CH3)2), 1.27 (6H, d, J ¼ 8.0 Hz, 40-
OCH(CH3)2 or 400-OCH(CH3)2), 3.62 (3H, s, 300-OCH3), 3.71 (3H, s, 50-
OCH3), 4.03 (1H, d, J ¼ 8.1 Hz, 2-H), 4.26e4.40 (2H, m, 40-OCH(CH3)2
and 400-OCH(CH3)2), 4.46 (1H, t, J ¼ 8.1 Hz, 3-H), 4.84 (1H, d,
J ¼ 12.1 Hz, Ar-CHA), 4.92 (1H, d, J ¼ 12.1 Hz, Ar-CHB), 5.06e5.22
(2H, m, 5-H), 6.12e6.22 (1H, m, 4-H), 6.34 (1H, s, 30-H), 6.58 (1H, s,
60-H), 6.60 (1H, d, J ¼ 8.4 Hz, 500-H), 6.69 (1H, dd, J ¼ 2.0, 8.4 Hz, 600-
H), 6.75 (1H, d, 200-H), 7.29e7.41 (5H, m, Ar-H), 9.72 (1H, br s,
COOH); dC (100 MHz; CDCl3) 21.9 and 22.0 (40-OCH(CH3)2 and 400-
OCH(CH3)2), 46.4 (C-3), 55.3 (C-2), 55.7 (300-OCH3), 56.8 (50-OCH3),
71.1 (CH2Ar), 71.2 and 71.7 (40-OCH(CH3)2 and 400-OCH(CH3)2), 103.8
(C-30), 112.3 (C-200), 114.0 (C-60), 115.1 (C-500), 116.0 (C-5), 121.0 (C-
600), 121.4 (C-10), 126.9, 127.7 and 128.5 (Ar-CH), 129.2 (C-100), 137.4
(Ar-C), 138.8 (C-4), 144.6 (C-50), 146.1 and 146.3 (C-40 and C-400),
149.8 (C-300), 150.3 (C-20), 179.3 (C-1); IR: nmax(neat)/cmꢂ1; 2977,
2935, 1707, 1607, 1507, 1465, 1454, 1215, 1107, 1036, 729, 696; m/z
(ESIþ) 557 (MNaþ, 100%), 535 (25), 311 (20), 263 (50); HRMS (ESIþ):
found (MNaþ): 557.2505 C32H38NaO7 requires 557.2510.
(
79BrMNaþ, 100%), 362 (60); HRMS (ESIþ): found (79BrMNaþ):
79
440.1026 C
H BrNNaO5 requires 440.104.
18 28
4.2.23. 5-Bromo-1-isopropoxy-2,3-dimethoxybenzene 32
To a solution of bromophenol 26 (1.0 g, 4.3 mmol) in DMF
(20 mL), under an atmosphere of nitrogen, was added K2CO3 (1.9 g,
14 mmol) and 2-bromopropane (1.9 mL, 20 mmol) dropwise, and
the resultant supsension was stirred for 48 h. 2 M HCl solution
(30 mL) and ethyl acetate (30 mL) were added and the organic layer
was separated. The aqueous mixture was further extracted with
ethyl acetate (5 ꢀ 20 mL). The combined organic extracts were
washed with water (5 ꢀ 20 mL), dried (MgSO4) and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (9:1 hexanes, ethyl acetate) to yield the
title compound (0.84 g, 71%) as a yellow oil. RF (2:1 hexanes, ethyl
acetate) ¼ 0.72; dH (400 MHz; CDCl3; Me4Si) 1.35 (6H, d J ¼ 6.2 Hz,
CH(CH3)2), 3.80 (3H, s, 2-OCH3), 3.83 (3H, s, 3-OCH3), 4.50 (1H,
sept., J ¼ 6.2 Hz, CH(CH3)2), 6.68 (1H, d, J ¼ 2.1 Hz, 4-H), 6.71 (1H, d,
J ¼ 2.1 Hz, 6-H); dC (100 MHz; CDCl3) 22.1 (CH(CH3)2), 56.2 (3-
OCH3), 60.6 (2-OCH3), 71.8 (CH(CH3)2), 108.9 (C-4), 112.3 (C-6),
4.2.25. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)pent-4-en-1-
ol 37
To a solution of carboxylic acid 36 (46 mg, 0.086 mmol) in Et2O
(5 mL), under an atmosphere of nitrogen, was added LiAlH4 (65 mg,
0.17 mmol) and the resultant suspension was heated at reflux for
2 h. The mixture was cooled to room temperature and water (5 mL)
was added and the organic layer was separated. The aqueous
mixture was further extracted with Et2O (3 ꢀ 10 mL) and the
combined organic extracts were dried (MgSO4). The solvent was
removed under reduced pressure to yield the title compound
(40 mg, 88%) as a yellow oil which required no further purification.
RF (2:1 hexanes, ethyl acetate) ¼ 0.48; dH (400 MHz; CDCl3; Me4Si)
1.23 (6H, d, J ¼ 8.0 Hz, 40-OCH(CH3)2 or 400-OCH(CH3)2), 1.27e1.29
(6H, d, J ¼ 8.0 Hz, 40-OCH(CH3)2 or 400-OCH(CH3)2), 3.16e3.22 (1H,
m, 2-H), 3.62 (3H, s, 300-OCH3), 3.63 (3H, s, 50-OCH3), 3.72e3.78 (2H,
m, 1-HA and OH), 3.87e3.91 (1H, m, 1- HB), 4.11 (1H, t, J ¼ 9.2 Hz, 3-
H), 4.30e4.43 (2H, m, 40-OCH(CH3)2 and 400-OCH(CH3)2), 4.88 (1H,
d, J ¼ 12.0 Hz, Ar-CHA), 4.92 (1H, d, J ¼ 12.0 Hz, Ar-CHB), 5.05e5.19
(2H, m, 5-H), 6.10 (1H, dt, J ¼ 9.5, 18.0 Hz, 4-H), 6.42 and 6.43 (2H, s,
30-H and 60-H), 6.50e6.52 (2H, m, 200-H and 600-H), 6.66 (1H, d,
J ¼ 8.4 Hz, 500-H), 7.31e7.41 (5H, m, Ar-H); dC (100 MHz; CDCl3) 21.9
(40-OCH(CH3)2 and 400-OCH(CH3)2), 44.9 (C-3), 51.8 (C-2), 55.5 and
56.5 (50-OCH3 and 300-OCH3), 65.2 (C-1), 71.1 (CH2Ar), 71.5 and 71.6
(40-OCH(CH3)2 and 400-OCH(CH3)2), 103.8 (C-30), 112.7 (C-200), 114.1
(C-60), 115.3 (C-500), 115.4 (C-5), 120.8 (C-600), 123.1 (C-10), 127.1, 127.7
and 128.4 (Ar-CH), 133.0 (C-100), 137.0 (Ar-C), 140.2 (C-4), 144.5 (C-
115.8 (C-5),138.8 (C-2),152.2 (C-1),154.1 (C-3); IR: nmax(film)/cmꢂ1
;
2975, 2932, 1582, 1490, 1228, 1110, 814, 731; m/z (ESIþ) 277
(
(
81BrMHþ, 100%), 275
79BrMHþ): 275.0284 C11
(
H
79BrMHþ, 100%). HRMS (ESIþ): found
79
BrO3 requires 275.0277.
16
4.2.24. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)pent-4-enoic
acid 36
To a solution of amide 6 (1.2 g, 2.0 mmol) in THF/H2O (1:1,
80 mL), was added I2 (1.1 g, 4.4 mmol), and the resultant solution
was shielded from light and stirred vigorously at room temperature
for 2 d. Diethyl ether (50 mL) and a saturated aqueous solution of
Na2SO3 (40 mL) were added, and the resultant mixture was stirred
for 10 min prior to separation of the organic layer. The aqueous
5), 145.6 (C-40 and C-400), 149.7 (C-300 and C-50); IR: nmax(neat)/cmꢂ1
;
3482, 2974, 2933,1607,1506,1466,1454,1260,1214,1108,1028, 737,
697; m/z (ESIþ) 543 (MNaþ, 100%), 521 (25), 503 (20), 249 (45);
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

12
N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
HRMS (ESIþ): found (MNaþ): 543.2716 C32H40NaO6 requires
543.2717.
(C-600), 125.5 (C-100), 126.8, 127.9 and 128.6 (Ar-CH), 137.0 (Ar-C),
144.9 (C-50), 146.6 and 147.1 (C-40 and C-400), 150.2 (C-20), 150.6 (C-
300), 199.3 (C-1), 207.5 (C-5).
4.2.26. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)pent-4-enal
34
4.2.28. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)-1-(3000-
isopropoxy-4000,5000-dimethoxyphenyl)pent-4-en-1-one 42
To a solution of alcohol 37 (0.51 g, 0.98 mmol) in CH2Cl2
(100 mL), was added DMP (0.83 g, 1.96 mmol) and the resultant
suspension was stirred at room temperature for 24 h. A saturated
aqueous solution of Na2S2O5 (80 mL) was added followed by a
saturated aqueous solution of NaHCO3 (80 mL) and the resultant
mixture was stirred vigorously for 30 min CH2Cl2 (80 mL) was
added and the organic layer was separated. The aqueous mixture
was further extracted with CH2Cl2 (3 ꢀ 80 mL) and the combined
organic extracts were dried (MgSO4). The solvent was removed
under reduced pressure to yield the crude product which was pu-
rified by flash chromatography (2:1 hexanes, ethyl acetate) to yield
the title compound (0.38 g, 75%) as an orange oil. RF (2:1 hexanes,
ethyl acetate) ¼ 0.74; dH (400 MHz; CDCl3; Me4Si) 1.23 (6H, d,
J ¼ 6.0 Hz, 40-OCH(CH3)2 or 400-OCH(CH3)2), 1.28 (6H, d, J ¼ 6.4 Hz,
40-OCH(CH3)2 or 400-OCH(CH3)2), 3.63 (3H, s, 300-OCH3), 3.70 (3H, s,
50-OCH3), 4.01 (1H, d, J ¼ 10.8 Hz, 2-H), 4.27e4.44 (2H, m, 40-
OCH(CH3)2 and 400-OCH(CH3)2), 4.55 (1H, t, J ¼ 10.8 Hz, 3-H), 4.89
(1H, d, J ¼ 12.0 Hz, Ar-CHA), 4.95 (1H, d, J ¼ 12.0 Hz, Ar-CHB),
5.09e5.16 (2H, m, 5-H), 6.05e6.14 (1H, m, 4-H), 6.40 (1H, s, 30-H),
6.57e6.60 (3H, m, 60-H, 200-H and 600-H), 6.67 (1H, d, J ¼ 8.0 Hz, 500-
H), 7.31e7.38 (5H, m, Ar-H), 9.70 (1H, s, CHO); dC (100 MHz; CDCl3)
21.9 (40-OCH(CH3)2 and 400-OCH(CH3)2), 43.4 (C-3), 55.7 and 56.8
(50-OCH3 and 300-OCH3), 61.9 (C-2), 71.1 (CH2Ar), 71.2 and 71.7 (40-
OCH(CH3)2 and 400-OCH(CH3)2), 103.6 (C-30), 112.9 (C-60), 114.1 (C-
200), 115.5 (C-500), 116.1 (C-5), 121.5 (C-10), 121.6 (C-600), 127.0 (C-100),
127.1, 127.8 and 128.5 (Ar-CH), 137.2 (Ar-C), 138.9 (C-4), 144.7 (C-50),
146.2 and 146.4 (C-40 and C-400), 150.1 (C-300 and C-20), 199.8 (CHO);
IR: nmax(neat)/cmꢂ1; 2975, 2930, 1722, 1588, 1506, 1465, 1454, 1260,
1215, 1106, 1027, 799, 729, 696; m/z (ESIþ) 541 (MNaþ, 100%); HRMS
(ESIþ): found (MNaþ): 541.2569 C32H38NaO6 requires 541.2561.
A solution of bromide 32 (0.12 g, 0.43 mmol) in THF (5 mL)
under an atmosphere of nitrogen, was precooled to ꢂ78 ꢁC for
5 min. 1.6 M tBuLi (0.63 mL, 1.0 mmol) was added dropwise, and the
resultant solution was stirred at ꢂ78 ꢁC for 5 min to allow for
lithium-halogen exchange, prior to the addition of a solution of
aldehyde 34 (0.16 g, 0.31 mmol) in THF (5 mL) dropwise. The
mixture was stirred for 24 h and allowed to warm to room tem-
perature over this time. NH4Cl (20 mL) was added and the organic
layer was separated. The aqueous mixture was extracted with
CH2Cl2 and the combined organic extracts were dried (MgSO4) and
the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (4:1 hexanes, ethyl
acetate) to yield alcohol 41 (0.13 g, 58%) as a yellow oil. To a solution
of alcohol 41 (0.13 g, 0.18 mmol) in CH2Cl2 (20 mL), was added DMP
(153 mg, 0.36 mmol) and the resultant suspension was stirred at
room temperature for 24 h. A saturated aqueous solution of
Na2S2O5 (15 mL) was added followed by a saturated aqueous so-
lution of NaHCO3 (15 mL) and the resultant mixture was stirred
vigorously for 30 min CH2Cl2 (15 mL) was added and the organic
layer was separated. The aqueous mixture was further extracted
with CH2Cl2 (3 ꢀ 15 mL) and the combined organic extracts were
dried (MgSO4). The solvent was removed under reduced pressure to
yield the crude product which was purified by flash (4:1 hexanes,
ethyl acetate) to yield the title compound (0.12 g, 90%) as a yellow
oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.58; dH (400 MHz; CDCl3;
Me4Si) 1.22e1.25 (18H, m, 40-OCH(CH3)2, 400-OCH(CH3)2 and 5000-
OCH(CH3)2), 3.59 (3H, s, 50-OCH3), 3.73 (3H, s, 300-OCH3), 3.78 (6H, s,
5000-OCH3), 3.86 (3H, s, 4000-OCH3), 4.29e4.37 (2H, m, 40-OCH(CH3)2
and 400-OCH(CH3)2), 4.42 (1H, sept., J ¼ 6.0 Hz, 3000-OCH(CH3)2), 4.64
(1H, dd, J ¼ 7.2, 10.6 Hz, 3-H), 4.86 (2H, d, J ¼ 12.0 Hz, Ar-HA), 4.93
(2H, d, J ¼ 12.0 Hz, Ar-HB), 5.02e5.10 (3H, m, 2-H and 5-H), 6.19 (1H,
ddd, J ¼ 3.2, 10.0, 17.2 Hz, 4-H), 6.40 (1H, s, 30-H), 6.53e6.60 (2H, m,
60- and 500-H), 6.65 (2H, d, J ¼ 2.0 Hz, 200- and 600-H), 7.20e7.47 (7H,
m, 2000-, 6000-H and Ar-H); dC (100 MHz; CDCl3) 21.9, 22.0 and 22.1 (40-
OCH(CH3)2, 400-OCH(CH3)2 and 3000-OCH(CH3)2), 48.2 (C-3), 55.6 (50-
OCH3), 55.9 (C-2), 56.0 (300-OCH3) 56.9 (5000-OCH3), 60.0 (4000-OCH3),
70.8 (CH2Ar), 71.1, 71.6 and 71.8 (40-OCH(CH3)2, 400-OCH(CH3)2 and
3000-OCH(CH3)2),103.8 (C-30),105.8 (C-2000), 110.1 (C-6000),112.2 (C-600),
115.4 (C-5), 115.5 and 115.7 (C-60 and C-200), 121.1 (C-500), 122.6 (C-
10), 126.8, 127.7 and 128.5 (Ar-CH), 130.4 (C-100), 133.1 (C-1000), 137.4
(Ar-C), 139.4 (C-4), 143.7 (C-4000), 144.6 (C-300), 145.9 and 146.1 (C-40
and C-400), 150.0 (C-50), 150.5 (C-20), 150.9 (C-5000), 153.1 (C-3000), 198.1
(C-1); IR: nmax(film)/cmꢂ1; 2976, 2934, 1589, 1506, 1671, 1260, 1214,
1107, 910, 728; m/z (ESIþ) 735 (100%); HRMS (ESIþ): found (MNaþ):
735.3500 C43H52NaO9 requires 735.3504.
4.2.27. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)-4-
oxopentanal 38
To a solution of aldehyde 34 (0.15 g, 0.29 mmol) in DMF/H2O
(3:1, 33 mL) was added PdCl2 (30 mg, 0.17 mmol) and CuCl (40 mg,
0.4 mmol) and the resultant suspension was stirred vigorously for
48 h open to air. The mixture was filtered through a slurry of silica
and ethyl acetate and was washed with ethyl acetate (3 ꢀ 30 mL).
The solvent was removed under reduced pressure, the residue was
diluted with ethyl acetate and water and the organic layer was
separated. The aqueous mixture was further extracted with ethyl
acetate and the combined organic extracts were washed with wa-
ter, dried (MgSO4) and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(9:1 hexanes, ethyl acetate) yield the title compound (92 mg, 65%) as
a viscous yellow oil which was used immediately in the next re-
action. RF (2:1 hexanes, ethyl acetate) ¼ 0.62; dH (400 MHz; CDCl3;
Me4Si) 1.21 (6H, d, J ¼ 6.0 Hz, 40-OCH(CH3)2 and 400-OCH(CH3)2),
2.10 (3H, s, 5-H), 3.48 (3H, s, 300-OCH3), 3.65 (3H, s, 50-OCH3),
4.21e4.36 (4H, m, 40-OCH(CH3)2, 400-OCH(CH3)2, 2-H and 3-H), 4.64
(1H, d, J ¼ 12.1 Hz, Ar-CHA), 4.78 (1H, d, J ¼ 12.1 Hz, Ar-HB), 6.28 (1H,
s, 30-H), 6.31 (1H, d, J ¼ 2.0 Hz, 200-H), 6.38 (1H, dd, J ¼ 2.0, 8.2 Hz,
600-H), 6.50 (1H, s, 60-H), 6.56 (1H, d, J ¼ 8.2 Hz, 500-H), 7.19e7.34 (5H,
m, Ar-H), 9.70 (1H, s, CHO); dC (100 MHz; CDCl3) 21.9 and 22.0 (40-
OCH(CH3)2 and 400-OCH(CH3)2), 29.0 (C-5), 51.7 (C-3), 55.7 (300-
OCH3), 56.7 (50-OCH3), 59.9 (C-2), 70.9 (40-OCH(CH3)2 or 400-
OCH(CH3)2), 71.0 (CH2Ar), 71.6 (40-OCH(CH3)2 or 400-OCH(CH3)2),
103.1 (C-30), 113.1 (C-200), 113.4 (C-60), 115.5 (C-500), 116.1 (C-10), 122.2
4.2.29. (2S*,3S*)-3-(20-(Benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-2-(400-isopropoxy-300-methoxyphenyl)-1-(3000-
isopropoxy-4000,5000-dimethoxyphenyl)pentane-1,4-dione 43
To a solution of ketone 42 (29 mg, 0.041 mmol) in DMF/H2O (3:1,
4 mL) was added PdCl2 (3.5 mg, 0.02 mmol) and CuCl (5 mg,
0.05 mmol) and the resultant suspension was stirred vigorously for
48 h open to air. The mixture was filtered through a slurry of silica
and ethyl acetate and was washed with ethyl acetate (3 ꢀ 100 mL).
The solvent was removed under reduced pressure, the residue was
diluted with ethyl acetate and water and the organic layer was
separated. The aqueous mixture was further extracted with ethyl
acetate and the combined organic extracts were washed with
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
13
water, dried (MgSO4) and the solvent was removed under reduced
20), 151.3 (C-5000), 153.2 (C-3000), 180.9 (CHO); IR: nmax(film)/cmꢂ1
;
2974, 2933,1652,1528, 1497, 1464,1455,1233,1212,1032, 1112, 805,
733; m/z (ESIþ) 836 (100%), 852 (20); HRMS (ESIþ): found (MNaþ):
836.3768 C50H55NNaO9 requires 836.3769. 1-Benzyl-3-(20-(benzy-
loxy)-40-isopropoxy-50-methoxyphenyl)-4-(400-isopropoxy-300-
pressure. The crude product was purified by flash chromatography
(3:1 hexanes, ethyl acetate) to yield the title compound (29 mg, 98%)
as a colourless oil. RF (2:1 hexanes, ethyl acetate) ¼ 0.18; dH
(300 MHz; CDCl3; Me4Si) 1.23e1.26 (18H, m, 40-OCH(CH3)2, 400-
OCH(CH3)2 and 3000-OCH(CH3)2), 2.17 (3H, s, 5-H), 3.49 (3H, s, 50-
OCH3), 3.76 (3H, s, 300-OCH3), 3.79 (3H, s, 5000-OCH3), 3.84 (3H, s, 4000-
OCH3), 4.28e4.45 (3H, m, 40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-
OCH(CH3)2), 4.62 (1H, d, J ¼ 12.2 Hz, Ar-CHA), 4.82 (1H, d,
J ¼ 12.2 Hz, Ar-CHB), 5.03e5.12 (2H, m, 2-H and 3-H), 6.37 (1H, s, 30-
H), 6.43e6.47 (2H, m, 60- and 600-H), 6.56 (1H, d, J ¼ 8.0 Hz, 500-H),
6.68 (1H, s, 200-H), 7.19 (2H, s, 2000-H and 6000-H), 7.28e7.40 (5H, m, Ar-
H); dC (75 MHz; CDCl3) 21.9 (40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-
OCH(CH3)2), 29.0 (C-5), 55.6 (50-OCH3, C-2 and C-3), 56.0 (300-
OCH3), 57.0 (5000-OCH3), 60.6 (4000-OCH3), 70.9 (CH2Ar), 71.2, 71.5 and
71.7(40-OCH(CH3)2 and 400-OCH(CH3)2 and 3000-OCH(CH3)2), 103.4
(C-30), 106.0 (C-2000 and C-6000), 110.4 (C-600), 111.9 (C-60), 114.1 (C-200),
115.7 (C-500), 116.8 (C-10), 126.6, 127.7 and 128.5 (Ar-CH), 123.0 (C-
100), 131.6 (C-1000), 137.1 (Ar-C), 143.6 (C-4000), 144.9 (C-300), 146.0 (C-
3000), 147.1 (C-400), 150.2 (C-50), 150.8 and 151.0 (C-20 and C-40), 153.1
(C-5000), 198.5 (C-1), 208.1 (C-4); IR: nmax (film)/cmꢂ1; 2933, 2878,
2839,1711, 1661, 1595, 1584, 1512, 1461, 1259,1243, 1160, 1138,1023,
819, 766, 755; m/z (ESIþ) 751 (100%); HRMS (ESIþ): found (MNaþ):
751.3429 C43H52NaO10 requires 751.3453.
methoxyphenyl)-5-(3000-isopropoxy-4000,5000-dimethoxyphenyl)-2-
methyl-1H-pyrrole 44 (1.5 mg, 3%) was also isolated as a yellow oil.
RF (2:1 hexanes, ethyl acetate) 0.51; dH (300 MHz; CDCl3; Me4Si)
1.25e1.27 (18H, m, 40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-
OCH(CH3)2), 2.13 (2-CH3), 3.30 (50-OCH3), 3.44 (5000-OCH3), 3.65 (300-
OCH3), 3.79 (4000-OCH3), 4.05e4.09 (1H, m, 3000-OCH(CH3)2),
4.31e4.48 (2H, m, 40-OCH(CH3)2 and 400-OCH(CH3)2), 4.65 (2H, d,
J ¼ 5.8 Hz, OCH2Ar), 6.33 (2H, s, NCH2Ar), 6.33 (1H, d, J ¼ 1.8 Hz, 2000-
H or 6000-H), 6.37 (1H, d, J ¼ 1.8 Hz, 2000-H or 6000-H), 6.41 (1H, dd,
J ¼ 1.9, 8.2 Hz, 600-H), 6.46 (1H, d, J ¼ 1.9 Hz, 200-H), 6.54e6.59 (2H,
m, 30- and 500-H), 6.70 (1H, s, 60-H), 7.01e7.36 (10H, m, Ar-H); dC
(75 MHz; CDCl3) 11.2 (2-CH3), 22.1, 22.2 and 22.3 (40-OCH(CH3)2, 400-
OCH(CH3)2 and 3000-OCH(CH3)2), 47.9 (NCH2Ar), 55.2 (50-OCH3), 55.7
(5000-OCH3), 56.5 (300-OCH3), 60.6 (4000-OCH3), 71.0, 71.2, 71.3, 71.4
(OCH2Ar, 40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-OCH(CH3)2), 105.7
(C-30), 108.1 and 111.9 (C-2000 and C-6000), 114.1 (C-200), 115.6 (C-500),
117.3 (C-60), 119.3 (C-4), 121.8 (C-3), 121.9 (C-600), 125.7 (Ar-CH),
126.1 (C-10), 126.9, 127.9, 128.2, 128.6 and 128.8 (Ar-CH, C-2, C-100
and C-1000), 130.0 (C-100), 133.5 (C-1000), 138.2 (OCH2Ar), 138.4 (C-5),
139.2 (C-5), 139.3 (NCH2Ar), 144.3 (C-300), 144.9 (C-400), 146.2 (C-40),
149.3 (C-50), 150.9 (C-20), 150.0 (C-5000), 152.9 (C-3000); IR: nmax(film)/
cmꢂ1; 2976, 2931, 1663, 1595, 1459, 1418, 1235, 1184, 1113, 920, 855.
4.2.30. 1-Benzyl-3-(20-(benzyloxy)-40-isopropoxy-50-
methoxyphenyl)-4-(400-isopropoxy-300-methoxyphenyl)-5-(3000-
isopropoxy-4000,5000-dimethoxyphenyl)-2-methyl-1H-pyrrole 44 and
1-benzyl-3-(20-(benzyloxy)-40-isopropoxy-50-methoxyphenyl)-4-
(400-isopropoxy-300-methoxyphenyl)-5-(3000-isopropoxy-4000,5000-
dimethoxyphenyl)-1H-pyrrole-2-carbaldehyde 45
4.2.31. 4-Benzyl-20-isopropoxy-1-(14-isopropoxy-13-
methoxyphenyl)-10b-(7-isopropoxy-8,9-dimethoxyphenyl)-21-
methoxychromeno[3,4-b]pyrrol-4(3H)-one 46
To a suspension of diketone 43 (45 mg, 0.060 mmol) and NaOAc
(5.4 mg, 0.066 mmol) in acetic acid (2 mL) was added benzylamine
To a solution of pyrrole aldehyde 45 (31 mg, 0.038 mmol) in
ethyl acetate (4 mL), was added Pd/C (10 mg, 7.6 mmol) and the
(6.7
m
L, 0.060 mmol) dropwise and the resultant mixture was
reaction was stirred under an atmosphere of hydrogen for 2 d. The
crude reaction mixture was filtered through a slurry of silica gel and
ethyl acetate. The filtrate was collected and the solvent was
removed under reduced pressure to yield the crude deprotection
product which was reacted in the subsequent reaction without
further purification. To a solution of the crude mixture (17 mg,
stirred vigorously and heated at reflux at 80 ꢁC for 3 d. The mixture
was cooled to room temperature and neutralised to pH 7 using 1 M
NaOH solution. Ethyl acetate (15 mL) was added and the organic
layer was separated. The aqueous mixture was extracted further
with ethyl acetate (3 ꢀ 15 mL). The combined organic extracts were
dried (MgSO4) and the solvent was removed under reduced pres-
sure to give the crude product which was purified by flash chro-
matography (9:1 hexanes, ethyl acetate) to yield 1-benzyl-3-(20-
(benzyloxy)-40-isopropoxy-50-methoxyphenyl)-4-(400-isopropoxy-
300-methoxyphenyl)-5-(3000-isopropoxy-4000,5000-dimethoxyphenyl)-
1H-pyrrole-2-carbaldehyde 45 (38 mg, 76%) as a yellow oil. RF (2:1
hexanes, ethyl acetate) ¼ 0.39; dH (300 MHz; CDCl3; Me4Si) 1.27
2.3
added Pd(PPh3)4 (<1.0 mg, 0.31
PPh3 (<1.0 mg, 0.92 mol) followed by bromobenzene (5.0
4.9
mol) dropwise. The resultant mixture was stirred at 120 ꢁC
m
mol) in DMF (0.50 mL), under an atmosphere of nitrogen, was
mol), K2CO3 (7.0 mg, 4.9 mol) and
L,
m
m
m
m
m
under an atmosphere of nitrogen for 24 h. Water (2 mL) and diethyl
ether (2 mL) were added and the organic layer was separated. The
aqueous mixture was further extracted with diethyl ether
(3 ꢀ 2 mL) and the combined organic fractions were washed with
water (3 ꢀ 2 mL) and then dried (MgSO4). The solvent was removed
under reduced pressure to give the crude product, which was pu-
rified by flash chromatography (3:1 hexanes, ethyl acetate) to give
the title compound as an orange oil (15 mg, 53% over two steps). RF
(2:1 hexanes, ethyl acetate) ¼ 0.47; dH (400 MHz; CDCl3; Me4Si) 1.11
(6H, d, J ¼ 6.1 Hz, 7-OCH(CH3)2 or 14-OCH(CH3)2 or 20-OCH(CH3)2),
1.34 (6H, d, J ¼ 6.1 Hz, 7-OCH(CH3)2 or 14-OCH(CH3)2 or 20-
(18H, d,
J
¼
6.1 Hz, 40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-
OCH(CH3)2), 3.30 (3H, s, 50-OCH3), 3.48 (3H, s, 5000-OCH3), 3.68 (3H,
s, 300-OCH3), 3.82 (3H, s, 4000-OCH3), 4.09 (1H, sept., J ¼ 6.1 Hz, 3000-
OCH(CH3)2), 4.36 (1H, sept., J ¼ 6.1 Hz, 40-OCH(CH3)2 or 400-
OCH(CH3)2), 4.43 (1H, sept., J ¼ 6.1 Hz, 40-OCH(CH3)2 or 400-
OCH(CH3)2), 4.66 (1H, d, J ¼ 12.4 Hz, OCHAAr), 4.87 (1H, d,
J ¼ 12.4 Hz, OCHBAr), 5.57 (1H, d, J ¼ 15.7 Hz, NCHAAr), 5.75 (1H, d,
J ¼ 15.7 Hz, NCHBAr), 6.30e6.37 (4H, m, 200-, 600-, 2000- and 6000-H),
6.54e6.56 (2H, m, 30- and 500-H), 6.77 (1H, s, 60-H), 7.01e7.27 (10H,
m, OCH2Ar-H and NCH2Ar-H), 9.53 (1H, s, CHO); dC (75 MHz; CDCl3)
22.0 (40-OCH(CH3)2, 400-OCH(CH3)2 and 3000-OCH(CH3)2), 49.3
(NCH2Ar), 55.2 (50-OCH3), 55.8 (300-OCH3), 56.6 (5000-OCH3), 60.7
(4000-OCH3), 71.1, 71.3 and 71.7 (OCH2Ar, 40-OCH(CH3)2, 400-
OCH(CH3)2 and 3000-OCH(CH3)2), 104.4 (C-30), 107.8 and 111.7 (C-2000
and C-6000), 113.8 (C-200), 114.8 (C-4), 115.2 (C-500), 117.1 (C-60), 122.0
(C-600), 124.6 (C-10), 125.4, 126.1, 126.7, 126.9, 127.1, 127.4, 127.9,
128.2 and 128.4 (C-2, C-100, C-1000, OCH2Ar-CH and NCH2Ar-CH),134.1
(C-3), 137.5 (OCH2Ar-C), 139.1 (NCH2Ar-C), 139.6 (C-5), 140.2 (C-4000),
144.7 and 145.1 (C-40 and C-400), 147.6 (C-300), 149.3 (C-50), 150.8 (C-
OCH(CH3)2), 1.40 (6H, d,
J
¼
6.0 Hz, 7-OCH(CH3)2 or 14-
OCH(CH3)2 or 20-OCH(CH3)2), 3.46 (3H, s, 9-OCH3), 3.48 (3H, s,
21-OCH3), 3.68 (3H, s, 13-OCH3), 3.81 (3H, s, 8-OCH3), 4.06 (1H,
sept., J ¼ 6.0 Hz, 7-OCH(CH3)2 or 14-OCH(CH3)2 or 20-OCH(CH3)2),
4.47e4.59 (2H, m, 7-OCH(CH3)2 and/or 14-OCH(CH3)2 and/or 20-
OCH(CH3)2), 5.75 (2H, br s, 5-H), 6.25 (1H, d, J ¼ 1.8 Hz, 22-H),
6.31 (1H, d, J ¼ 1.8 Hz, 10-H), 6.79 (1H, s, 19-H), 6.88 (1H, s, 6-H),
6.94 (1H, d, J ¼ 5.2 Hz, 15-H), 7.03 (1H, d, J ¼ 7.1 Hz, 12-H), 7.21 (1H,
d, J ¼ 7.0 Hz, 16-H), 7.25e7.29 (5H, m, Ar-H); dC (100 MHz; CDCl3)
21.8, 21.9 and 22.0 (7-OCH(CH3)2, 14-OCH(CH3)2 and 20-
OCH(CH3)2), 49.5 (C-5), 55.7 and 55.9 (9-OCH3, 13-OCH3 and 21-
Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044

14
N. Dittrich et al. / Tetrahedron xxx (2017) 1e14
OCH3), 60.7 (8-OCH3), 71.4, 71.5 and 71.6 (7-OCH(CH3)2, 14-
OCH(CH3)2 and 20-OCH(CH3)2), 103.5 (C-12), 105.3 (C-15), 107.7
(C-6), 110.2 (C-17), 111.7 (C-10), 114.9 (C-19), 115.9 (C-22), 118.8 (C-
3), 123.5 (C-16), 124.7 (C-10a), 126.3, 127.2 and 128.6 (Ar-CH), 127.6
(C-1 and C-2), 128.4 (C-11), 138.8 (Ar-C), 139.8 (C-8), 143.2 (C-10b),
146.3 (C-21), 146.6 and 147.3 (C-20, C-14 and C-18), 150.3 (C-13),
151.2 (C-7), 153.1 (C-9), 155.4 (C-23); IR: nmax(film)/cmꢂ1; 2923,
2853, 1713, 1509, 1462, 1249, 1115, 740, 700; m/z (ESIþ) 744 (100%),
413 (20); HRMS (ESIþ): found (MHþ): 744.3164 C43H47NNaO9 re-
quires 744.3143.
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7.20e7.54 (6H, 16-H and Ar-H); dC (100 MHz; CDCl3) 49.3 (C-5),
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103.4 (C-12), 104.3 (C-15), 107.3 (C-6), 110.7 (C-17), 111.9 (C-10),
113.6 (C-19), 114.2 (C-22), 119.6 (C-3), 124.3 (C-16), 125.6 (C-10a),
126.4, 127.2 and 128.6 (Ar-CH), 127.5 (C-1, C-2), 128.5 (C-11), 138.6
(Ar-C), 139.8 (C-8), 143.3 (C-10b), 143.9 (C-21), 144.9, 145.0 and
146.3 (C-20, C-14 and C-18), 149.0 (C-13), 151.8 (C-7), 152.4 (C-9),
155.4 (C-23); IR: nmax(film)/cmꢂ1; 3387, 2922, 2852, 1715, 1592,
1467, 1280, 1207, 1118, 859, 744; m/z (ESIþ) 618 (MNaþ, 95%), 449
(100); HRMS (ESIþ): found (MNaþ): 618.1751 C34H29NNaO9 requires
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Acknowledgements
ꢁ
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Funding for this work was obtained from the Faculty Research
Development Fund from the University of Auckland (grant number
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Please cite this article in press as: Dittrich N, et al., Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.044