Total synthesis of tubastrine and 3-dehydroxy tubastrine by microwave-assisted cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2015.09.003

The first syntheses of tubastrine and 3-dehydroxy tubastrine are described. The target compounds were prepared in four consecutive steps from commercially available starting materials. The central scaffold was formed by a microwave-assisted C-N cross-coupling reaction between 1,3-bis(tert-butoxycarbonyl)-guanidine and (E)-((4-(2-iodovinyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane) and (E)-tert-butyl(4-(2-iodovinyl)phenoxy)-dimethylsilane, respectively. The aryl vinyl iodides were obtained by a Hunsdiecker-Borodin-type reaction of aryl acrylic acids, which were easily available from trans-caffeic acid or trans-p-coumaric acid.

Full text of DOI:10.1016/j.tet.2015.09.003

Tetrahedron 71 (2015) 8278e8284
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of tubastrine and 3-dehydroxy tubastrine by
microwave-assisted cross-coupling reactions
,
a,
*
Marianne Lorentzen a, Annette Bayer b, Magne O. Sydnes a , Kare B. Jørgensen
*
ꢀ
a Department of Mathematics and Natural Science, Faculty of Science and Technology, University of Stavanger, NO-4036 Stavanger, Norway
b Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2015
Received in revised form 12 August 2015
Accepted 1 September 2015
Available online 3 September 2015
The first syntheses of tubastrine and 3-dehydroxy tubastrine are described. The target compounds were
prepared in four consecutive steps from commercially available starting materials. The central scaffold
was formed by a microwave-assisted CeN cross-coupling reaction between 1,3-bis(tert-butoxycarbonyl)-
guanidine and (E)-((4-(2-iodovinyl)-1,2-phenylene)bis(oxy))bis(tert-butyldimethylsilane) and (E)-tert-
butyl(4-(2-iodovinyl)phenoxy)edimethylsilane, respectively. The aryl vinyl iodides were obtained by
a HunsdieckereBorodin-type reaction of aryl acrylic acids, which were easily available from trans-caffeic
acid or trans-p-coumaric acid.
Keywords:
Natural product synthesis
CeN cross-coupling
HunsdieckereBorodin reaction
Tubastrine
Ó 2015 Elsevier Ltd. All rights reserved.
Microwave-assisted reaction
1. Introduction
To the best of our knowledge, tubastrines 1 and 2 have not yet been
synthesized. One attempt to prepare compound 2 has been re-
Tubastrine (1), and 3-dehydroxy tubastrine (2), shown in Fig. 1,
are two guanidine containing natural products. The former was first
isolated from the coral Tubastrea aurea by Sakai et al. in 1987.1 In
recent years tubastrine has also been found in a Dendrodoa specie,
Dendrodoa grossularia, and the ascidian Ascidiella scabra, both col-
lected from the Orkney Islands,2 as well as in a New Zealand as-
cidian, Aplidium orthium.3 Tubastrine showed antiviral,1 anticancer,
antimicrobial2 and anti-inflammatory activity,3 making it an in-
teresting starting point for further SAR studies. 3-Dehydroxy
tubastrine, in turn, has been isolated from an Australian marine
sponge, Spongosorites sp.,4 as well as in the sub-arctic ascidian,
Dendrodoa aggregate5 and displayed antimicrobial activity against
several bacteria such as Staphylococcus aureus, Serratia sp., Escher-
ichia coli4 and Corynebacterium glutamicum.5
ported in the literature, however, the synthesis failed in the final
step.6 Our endeavor into the tubastrines, motivated by their bi-
ological activity, required a convergent approach that could easily
generate analogous compounds. Two obvious disconnections could
be envisioned (Scheme 1). Disconnection A corresponds to a Heck
cross-coupling reaction7 between the respective aryl halides and
protected vinylguanidines, while disconnection B corresponds to
a CeN cross-coupling reaction8 between the respective aryl vinyl
halides and protected guanidines. In the following, we present the
first synthesis of tubastrine (1) and 3-dehydroxy tubastrine (2)
following the above outlined strategy.
Fig. 1. Tubastrine (1), and 3-dehydroxy tubastrine (2).
* Corresponding authors. Tel.: þ47 51832306; fax: þ47 51831750; e-mail
addresses: magne.o.sydnes@uis.no (M.O. Sydnes), kare.b.jorgensen@uis.no
(K.B. Jørgensen).
Scheme 1. Retrosynthetic analysis of tubastrine (1) and 3-dehydroxy tubastrine (2).
http://dx.doi.org/10.1016/j.tet.2015.09.003
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
8279
Table 1
2. Results and discussion
CeN cross-coupling of aryl vinyl halide 6 or 7a and guanidine 8
Initial studies concentrated on the approach corresponding to
disconnection A (Scheme 1). To begin with, methyl acrylate was
used as a model for vinylguanidine (route A) in a Heck cross-
coupling reaction7 with 4-bromoveratrol 3 to provide ester 4
(Scheme 2) similar to previously reported couplings.9 Later it be-
came evident that vinylguanidine was not available to us in spite of
several attempts from different starting points.y We therefore
turned our attention to the alternative approach employing the
CeN cross-coupling reaction8 of the respective aryl vinyl halides
and protected guanidines (Scheme 1, route B).
Entry
6/7a
8 (Equiv.)
Ligand (equiv.)
Time (min)
Yield (%) of 9aa
1
2
3
4
5
6
7
8
7a
6
6
6
6
7a
7a
7a
7a
7a
7a
7a
7a
7a
1.5
1
1
L1 (2.2)
L1 (2.2)
L1 (2.2)
L1 (0.2)
L1 (2.2)
L1 (2.2)
L1 (2.2)
L2 (2.2)
L3 (2.2)
L4 (2.2)
L5 (2.2)
L6 (2.2)
L7 (2.2)
d
18 (h)b
35
60
35
35
35
35
35
35
35
35
35
35
22
34
24
nr
29
49
53
nr
nr
nr
nr
30
nr
nr
1
1.5
1.5
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
Scheme 2. Reagent and conditions: (a) Methyl acrylate (1 equiv), Pd(OAc)2 (5 mol %),
P(o-tolyl)3 (10 mol %), Et3N (2 equiv), MeCN, MW (100 W), 110 ꢀC, 45 min, 81% (b)
NaOH (2 equiv), MeOH: H2O (10:1), 60 ꢀC, 18 h, 77%; (c) NBS/NIS (1 equiv), LiOAc
(0.2 equiv), MeCN: H2O (19:1), rt, 1 h, 83% (6)/80% (7a).
10
11
12
13
14
35
a
Isolated yield.
Traditional heating (oil bath).
b
The aryl vinyl halides were obtained by a HunsdieckereBorodin-
type decarboxylation/halogenation reaction10 of aryl acrylic acids
(Scheme 2). Treatment of acid 5a with N-bromosuccinimide (NBS)
or N-iodosuccinimide (NIS) gave the corresponding aryl vinyl bro-
mide 6 and -iodide 7a in 83% and 80% yields, respectively. Acid 5a
was either obtained by hydrolysis of ester 4 with NaOH in metha-
nol/water in 77% isolated yield (Scheme 2) or from commercial
sources.
Table 2
CeN cross-coupling of arylvinyliodide 7a and guanidine 8
Next, a CeN cross-coupling reaction11 between 1,3-bis(tert-
butoxycarbonyl)guanidine (8) and either aryl vinyl bromide 6 or
aryl vinyl iodide 7a forming the protected tubastrine precursor 9a
was investigated. Using different conditions (ligands, catalyst,
heating source, solvents, base and reaction time), product 9a was
formed in yields as shown in Tables 1 and 2. Microwave-assisted
reactions gave improved yields of 9a (49%; Entry 6, Table 1) com-
pared to traditional heating using an oil bath at 65 ꢀC (22%; Entry 1,
Table 1). The aryl vinyl iodide 7a performed better in the cross-
coupling reaction (Entries 6 and 7, Table 1) than the aryl vinyl
bromide 6 (Entries 2, 3 and 5, Table 1). A stoichiometric amount of
CuI was necessary for the reaction to occur (Entries 1e3 and 5e7,
Table 1). Catalytic amounts of CuI gave no trace of product as ob-
served by TLC analysis. A number of ligands were tested (see Table
1). N,N0-Dimethylethylenediamine (DMEDA, L1) (Entries 1,3 and
5e7, Table 1) and (1R,2R)-(ꢁ)-1,2-diaminocyclohexane (L6) (Entry
Entry
Copper source
Base (equiv.)
Solvent
Yield (%) of 9aa
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuOAc
K3PO4 (2)
K3PO4 (1)
K3PO4 (2)
K3PO4 (4)
K2CO3 (2)
Cs2CO3 (2)
Et3N (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Toluene
CH2Cl2
MeCN
MeCN
MeCN
34b
26b
49
29
39
45
29
19
Trace
Trace
Trace
nr
9
10
11
12
13
c
Cu(OAc)2
CuCl
Trace
a
Isolated yield.
From bromostyrene (6).
Ascorbinic acid (1.1 equiv) as reducing agent was added.
b
c
12, Table 1) promoted the cross-coupling reaction, while
L
-proline
(L2), trans-4-hydroxy- -proline (L3), N,N-diethylsalicylamide (L4),
L
N-(2-hydroxybenzoyl)pyrrolidine (L5) and 1,10-phenanthroline
(L7) gave no trace of product (Entries 8e11, Table 1). No product
was observed when CuI was used as catalyst without ligands (Entry
14, Table 1). The ideal reaction time was found to be 35 min (Entries
2, 5e7 and 12, Table 1), since longer reaction time decreased the
yield of product 9a (Entry 3, Table 1).
The cross-coupling reaction was also tested with different sol-
vents (THF, toluene, CH2Cl2 or MeCN), copper sources (CuI, CuOAc,
Cu(OAc)2 or CuCl) and bases (K3PO4, Cs2CO3, K2CO3 or Et3N). The
y
In the early stages of this project, vinylguanidine was listed as commercially
available in ScifinderÒ, but the source turned out to be a custom synthesis company
that did not have the compound in stock. No straightforward synthesis of this
compound was found.

8280
M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
amount of base was important for the yield. Two equivalents of
K3PO4 gave higher yield of product 9a (Entries 1 and 3, Table 2) than
one equivalent (Entry 2, Table 2), while four equivalents gave
a significant decrease in the yield of product 9a (Entry 4, Table 2).
With K2CO3 or Et3N as base lower yield of compound 9a was ob-
tained (Entries 5 and 7, Table 2), while Cs2CO3 gave approximately
the same yield as with K3PO4 (Entry 6, Table 2). Changing solvent
from MeCN to THF, toluene or CH2Cl2 was not beneficial for the
cross-coupling reaction. Only trace amounts of product were ob-
served using toluene or CH2Cl2 as solvent (Entries 9 and 10, Table
2), while a 19% yield of product 9a was obtained with THF (Entry
8, Table 2). With CuOAc or CuCl only trace amounts of product were
observed by TLC analysis (Entries 11 and 13, Table 2), while
Cu(OAc)2 did not promote the reaction in any way (Entry 12,
Table 2).
butyldimethylsilyl (TBDMS) protected analogues were envisioned
to be better precursors for target compounds 1 and 2.
The TBDMS protected analogues 9c and 9d were prepared by the
established strategy (Scheme 4). Commercially available trans-caf-
feic acid (10) and p-coumaric acid (11) were silylated with
TBDMSCl/Et3N in CH2Cl2, followed by hydrolysis of the silyl ester
with K2CO3 in methanol/water to afford the protected aryl acrylic
acids 5c and 5d in 76% and 44% yields.10b,13 The Hunsdieck-
ereBorodin-type reaction10 of 5c and 5d with NIS gave aryl vinyl
iodides 7c and 7d in 71% and 74% yield, respectively. In the
microwave-assisted CeN cross-coupling reaction with guanidine 8
products 9c and 9d were formed in 45% or 37% yield, respectively.
The synthesis was completed by desilylation with tetrabuty-
lammonium fluoride (TBAF), followed by a Boc deprotection using
TFA, providing target compounds 1 and 2 in 64% and 61% yield,
respectively.
Typical side products observed in the cross-couplings
were
1,2-dimethoxy-4-vinylbenzene
and
(E)-tert-butyl
3,4-dimethoxystyrylcarbamate, which accounted for approxi-
mately 20e25% of the starting material 7a. Under most of the
reaction conditions tested, the reaction did not go to completion.
However, longer reaction time only resulted in a decreased yield
of product 9a and an increased yield of (E)-tert-butyl
3,4-dimethoxystyrylcarbamate.
Less
(E)-tert-butyl
3,4-dimethoxystyrylcarbamate was isolated when using K3PO4 as
base compared to Cs2CO3. In addition, trace amounts of several
other side products were observed by TLC and 1H NMR analysis of
the crude reaction mixture, but these products were difficult to
isolate.
Next, the 3-dehydroxy tubastrine precursor 9b was prepared
employing the optimized conditions for the formation of 9a
(Scheme 3). (E)-1-(2-Iodovinyl)-4-methoxybenzene (7b) was ob-
tained from commercially available (E)-3-(4-methoxyphenyl)
acrylic acid (5b) after treatment with NIS at room temperature for
1 h to yield product 7b in 74% yield. The cross-coupling of substrate
7b with guanidine 8 using either K3PO4, or Cs2CO3 as base, resulted
in the formation of product 9b. For the reaction using K3PO4 as base
substrate 9b was formed in 45% yield. In addition, the corre-
sponding product with a Boc group on the internal N atom instead
of one of the terminal N atoms was isolated in 13% yield, thus giving
in total 58% yield of isomers relevant for the synthesis of target
compound 2. Utilizing Cs2CO3 as base resulted only in the forma-
tion of product 9b in 50% yield.
Scheme 4. Reagent and conditions: (a) (i) Et3N, TBDMSCl, CH2Cl2, rt, 18 h (ii) K2CO3
(1 equiv), MeOH: H2O (1:1), rt, 1 h, 76% (5c)/44% (5d); (b) NIS (1 equiv), LiOAc
(0.2 equiv), MeCN: H2O (19:1), rt, 1 h, 71% (6c)/74% (6d); (c)
8 (1.5 equiv), CuI
(1.1 equiv), DMEDA (2.2 equiv), K3PO4 (2 equiv), MeCN, MW (50 W), 65 ꢀC, 35 min, 45%
(9c)/37% (9d); (d) (i) TBAF, THF, rt, 18 h (ii) TFA (4.4 equiv), MeCN, MW, 100 ꢀC, 15 min,
64%. (1)/61% (2).
3. Conclusion
The first total synthesis of tubastrine (1) and 3-dehydroxy
tubastrine (2) were completed utilizing a microwave-assisted
CeN cross-coupling reaction between 1,3-bis(tert-butox-
ycarbonyl)guanidine (8) and (E)-((4-(2-iodovinyl)-1,2-phenylene)
bis(oxy))bis(tert-butyldimethylsilane) (7c) or (E)-tert-butyl(4-(2-
iodovinyl)phenoxy)dimethylsilane (7d), respectively. Target com-
pounds 1 and 2 were prepared in four steps from commercially
available starting materials with overall yields of 15.5% and 7.3%,
respectively. The total synthesis opens up for further biological
evaluation of the two natural products and analogues thereof.
Scheme 3. Reagent and conditions: (a) NIS (1 equiv), LiOAc (0.2 equiv), MeCN: H2O
(19:1), rt, 1 h, 74%; (b) 8 (1.5 equiv), CuI (1.1 equiv), DMEDA (2.2 equiv), base (2 equiv),
MeCN, MW (50 W), 65 ꢀC, 35 min, with K3PO4, 45%, or with Cs2CO3, 50%.
4. Experimental
4.1. General
The Boc groups in compound 9a and 9b were easily removed
using TFA at 100 ꢀC (microwave) for 20 min. The removal of the
methoxy groups in substrate 9a and 9b was more difficult than first
anticipated. Treatment with BBr3 gave an intractable mixture of
products, while a premixture of NaI and TMSCl12 was inefficient in
the removal of the methoxy groups. Due to the difficulties with the
final deprotection of substrate 9a and 9b, the corresponding tert-
Acetonitrile (MeCN) was dried over molecular sieves (oven
dried) three times, and stored over molecular sieves under nitrogen
atmosphere. Anhydrous Toluene, THF and CH2Cl2 were purchased
from VWR and used as received. N,N0-Dimethylethylenediamine

M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
8281
(DMEDA) was distilled and stored over KOH, the same was Et3N.
Copper(I)iodide was recrystallized from potassium iodide solution
(concentrated) and water, and dried in an oven prior to use. All
reactions were carried out under argon atmosphere if not other-
wise specified. The microwave reactions were performed in 10 mL
pressure vials with caps using Discover SP from CEM. TLC was
performed on Merck silica gel 60 F254 plates, using UV light at
254 nm and 5% alcoholic molybdophosphoric acid for detection.
1299 (m), 1265 (s), 1211 (m), 1169 (w), 1142 (s), 1025 (m), 976 (w),
841 (m), 770 (w); Mass spectrum m/z (relative intensity %) 207.2
[M]- (100); HRMS (ESI) calcd for C11H11O4: 207.0663, found
207.0663.
4.4. (E)-3-(3,4-Bis((tert-butyldimethylsilyl)oxy)phenyl)acrylic
acid (5c)
Normalsil 60, 40e63
m
m silica gel was used for flash chromatog-
tert-Butyldimethylsilyl chloride (3.396 g, 22.53 mmol) in anhy-
drous CH2Cl2 (15 mL) was added slowly to a precooled solution of
trans-caffeic acid (1.196 g, 6.66 mmol) in anhydrous CH2Cl2 (15 mL)
and Et3N (6.1 mL, 43.74 mmol) at 0 ꢀC. The mixture was warmed to
room temperature and stirred overnight (18 h), washed with 1 M
HCl (2ꢂ30 mL) and water (30 mL), dried over MgSO4, filtered and
concentrated in vacuo. The brown oil was dissolved in MeOH
(30 mL) and water (30 mL) before K2CO3 (949 mg, 6.87 mmol) was
added. The mixture was stirred for 4 h and concentrated in vacuo to
half of the volume. EtOAc (50 mL) and concentrated HCl (4 mL, pH
0) were added, the phases were separated and the water layer was
extracted with EtOAc (2ꢂ50 mL). The combined organic layer was
washed with brine (100 mL), dried over MgSO4, filtered and con-
centrated in vacuo. The crude product was purified by flash column
chromatography (petroleum ether: EtOAc 3:1) to afford 1.979 g
(73%) of product 5c as a white solid. Mp 157.8e158.8 ꢀC (hexane),
lit.13 152e155 ꢀC. Published data13 were in accordance with ours:
raphy. Reverse phase purification of compound 1 and 2 were per-
formed on C18 prepacked IsoluteÒ SPE columns. 1H NMR and 13C
NMR spectra were recorded on a Bruker Avance 400 MHz, all at
room temperature. Chemical shifts were reported in ppm com-
pared to TMS (
to CDCl3 77.0, triplet). The splitting pattern was recorded as
d
0, singlet, for 1H NMR), or for 13C resonance signal
(d
a singlet, s; doublet, d; triplet, t; double doublet, dd; double triplet,
dt; quartet, q; multiplet, m; broad, br. IR was recorded on a Perkin
Elmer FT-IR spectrometer, version 3.02.01. Melting points were
determined on a Stuart Scientific melting point apparatus SMP3.
High-resolution mass spectra (HRMS) were recorded from MeOH
solutions on an LTQ Orbitrap XL (Thermo Scientific) in positive or
negative electrospray ionization (ESI) mode.
4.2. (E)-Methyl 3-(3,4-dimethoxyphenyl)acrylate (4)
4-Bromoveratrol (3) (90
mL, 0.713 mmol), methyl acrylate
1H NMR (CDCl3, 400 MHz):
2H), 6.84 (d, J¼8.8 Hz, 1H), 6.25 (d, J¼15.9 Hz, 1H), 1.00 (s, 9H), 0.99
(s, 1H), 0.23 (s, 6H), 0.22 (s, 6H); 13C NMR (CDCl3, 100 MHz):
172.3
d
7.67 (d, J¼15.9 Hz, 1H), 7.05e7.04 (m,
(130 L, 1.43 mmol) and Et3N (0.2 mL, 1.43 mmol) were added to
m
a pre-stirred solution of Pd(OAc)2 (8 mg, 0.035 mmol) and P(o-
tolyl)3 (22 mg, 0.070 mmol) in MeCN (2 mL). The mixture was
microwave heated (150 W, 110 ꢀC) for 45 min, cooled to room
temperature and concentrated in vacuo on silica gel. The crude
product was purified by flash column chromatography (petroleum
ether: EtOAc 5:1) to afford 133 mg (84%) of product 4 as a white
solid. Mp 67.9e69.4 ꢀC (hexane), lit.14a 68e69 ꢀC. Published data14
d
(CO), 149.9 (C), 147.2 (C), 147.0 (CH), 127.6 (C), 122.7 (CH), 121.2 (CH),
120.6 (CH), 114.7 (CH), 125.9 (3ꢂCH3), 25.8 (3ꢂCH3), 18.5 (C), 18.4
(C), O4.1(0) (2ꢂCH3), O4.1(1) (2ꢂCH3); IR (KBr) 2929 (m), 2857
(m),1679 (m),1629 (m),1596 (m),1507 (s), 1472 (w),1426 (m),1292
(s), 1253 (m), 1202 (m), 1165 (w), 1126 (w), 993 (w), 916 (m), 860
(m), 836 (m), 812 (w), 781 (m), 679 (w); Mass spectrum m/z (rel-
ative intensity %) 431.2 [MþNa]þ (100); HRMS (ESI) calcd for
were in accordance with ours: 1H NMR (CDCl3, 400 MHz):
d 7.64 (d,
J¼16.0 Hz, 1H), 7.11 (dd, J¼8.3, 2.0 Hz, 1H), 7.05 (d, J¼2.0 Hz, 1H),
C21H36O4NaSi2: 431.2044, found 431.2046.
6.87 (d, J¼8.3 Hz, 1H), 6.32 (d, J¼16.0 Hz, 1H), 3.92 (s, 6H), 3.80 (s,
3H); 13C NMR (CDCl3, 100 MHz):
d
167.6 (CO), 151.1 (C), 149.1 (C),
4.5. (E)-3-(4-((tert-Butyldimethylsilyl)oxy)phenyl)acrylic acid
144.8 (CH), 127.3 (C), 122.6 (CH), 115.4 (CH), 110.9 (CH), 109.5 (CH),
55.9 (CH3), 55.8 (CH3), 51.6 (CH3); IR (KBr) 2945 (w), 2840 (w), 1697
(s), 1626 (m),1596 (m),1511 (m),1465 (m),1440 (m),1422 (m),1348
(w), 1254 (s), 1232 (m), 1162 (m), 1145 (m), 1040 (m), 1022 (m), 984
(m), 870 (w), 857 (w), 815 (w)757 (w); Mass spectrum m/z (relative
intensity %) 245.2 [MþNa]þ (100); HRMS (ESI) calcd for
C12H14O4Na: 245.0784, found 245.0787.
(5d)
tert-Butyldimethylsilyl chloride (2.452 g, 16.27 mmol) in anhy-
drous CH2Cl2 (15 mL) was added slowly to a precooled solution of
trans-p-coumaric acid (1.205 g, 7.31 mmol) in anhydrous CH2Cl2
(15 mL) and Et3N (4.5 mL, 32.27 mmol) at 0 ꢀC. The mixture was
warmed to room temperature and stirred overnight (18 h), washed
with 1 M HCl (2ꢂ30 mL) and water (30 mL), dried over MgSO4,
filtered and concentrated in vacuo. The brown oil was solved in
MeOH (30 mL) and water (30 mL) before K3CO3 (1.050 g,
7.60 mmol) was added. The mixture was stirred for 4 h and con-
centrated in vacuo to half of the volume. EtOAc (50 mL) and con-
centrated HCl (4 mL, pH 0) was added. The two phases were
separated and the water layer was extracted with EtOAc (2ꢂ50 mL).
The combined organic layer was washed with brine (100 mL), dried
over MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography (petroleum ether:
EtOAc 3:1) to afford 887 mg (44%) of product 5d as a white solid. Mp
129.4e130.4 ꢀC (hexane), lit.13c 128.5e130 ꢀC. Published data10b,13c
4.3. (E)-3-(3,4-Dimethoxyphenyl)acrylic acid (5a)
To a solution of acrylate 4 (1.997 g, 8.98 mmol) in MeOH (50 mL)
and water (5 mL) was added KOH (715 mg, 17.88 mmol). The re-
action mixture was heated to 60 ꢀC for 18 h, before concentrated in
vacuo. The residue was dissolved in water (50 mL), added 2 M
aqueous NaOH solution (1 mL) and extracted with Et2O (2ꢂ60 mL).
The water layer was adjusted to pH 0 by the addition of 6 M HCl
(4 mL) and extracted a second time with CH2Cl2 (5ꢂ50 mL). The
latter organic layer was dried over MgSO4, filtered and concen-
trated in vacuo. The crude product was purified by flash column
chromatography (petroleum ether: EtOAc 1:2) to afford 1.443 g
(77%) of product 5a as a white solid. Mp 180.7e181.8 ꢀC (hexane),
lit.15 181e182 ꢀC. Published data15 were in accordance with ours: 1H
were in accordance with ours: 1H NMR (CDCl3, 400 MHz):
d 7.74 (d,
J¼15.9 Hz, 1H), 7.45 (d, J¼8.6 Hz, 2H), 6.85 (d, J¼8.6 Hz, 2H), 6.32 (d,
J¼15.9 Hz, 1H), 0.99 (s, 9H), O0.23 (s, 6H); 13C NMR (CDCl3,
NMR (CDCl3, 400 MHz):
d
7.74 (d, J¼15.9 Hz, 1H), 7.14 (dd, J¼8.4,
100 MHz):
d
172.8 (CO), 158.3 (C), 146.8 (CH), 130.1 (2ꢂCH), 127.4
1.96 Hz, 1H), 7.08 (d, J¼1.92 Hz, 1H), 6.89 (d, J¼8.4 Hz, 1H), 6.33 (d,
(C), 120.6 (2ꢂCH), 114.9 (CH), 25.6 (3ꢂCH3), 18.3 (C), O4.4 (2ꢂCH3);
IR (KBr) 2928 (m), 2857 (m), 2606 (w), 1682 (s), 1623 (m), 1599 (s),
1573 (m), 1508 (s), 1471 (m), 1426 (m), 1361 (w), 1334 (m), 1311 (m),
1286 (m), 1258 (s), 1223 (m), 1168 (m), 1101 (w), 1005 (w), 985 (m),
912 (m), 837 (m), 802 (w), 778 (m), 685 (w), 633 (w); Mass
J¼15.9 Hz, 1H), 3.93 (s, 6H); 13C NMR (CDCl3, 100 MHz):
d 172.4
(CO), 151.5 (C), 149.2 (C), 147.0 (CH), 127.0 (C), 123.2 (CH), 114.8 (CH),
111.0 (CH), 109.7 (CH), 56.0 (CH3), 55.9 (CH3); IR (KBr) 2840 (w),
1683 (s), 1625 (m), 1597 (m), 1517 (s), 1459 (m), 1427 (m), 1341 (m),

8282
M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
spectrum m/z (relative intensity %) 301.1 [MþNa]þ (100); HRMS
(concentrated, 2e3 drops) and silica gel and concentrated in vacuo.
The crude product was purified by flash column chromatography
(2% EtOAc in petroleum ether) to afford 396 mg (74%) of product 7d
(ESI) calcd for C15H22O3NaSi: 301.1230, found 301.1228.
4.6. (E)-4-(2-Iodovinyl)-1,2-dimethoxybenzene (7a)
as a yellow oil. 1H NMR (CDCl3, 400 MHz):
d
7.35 (d, J¼14.8 Hz, 1H),
7.17 (d, J¼8.7 Hz, 2H), 6.78 (d, J¼8.6 Hz, 2H), 6.62 (d, J¼14.8 Hz, 1H),
0.98 (s, 9H), O0.20 (s, 6H); 13C NMR (CDCl3, 100 MHz):
156.0 (C),
To a solution of acrylic acid 5a (1.088 g, 5.23 mmol) in MeCN:
H2O (19:1, 60 mL) were added LiOAc (69 mg, 1.05 mmol) and NIS
(1.178 g, 5.23 mmol) at room temperature. The orange mixture was
stirred at room temperature for 1 h before being concentrated in
vacuo on silica gel. The crude product was purified by flash column
chromatography (petroleum ether: EtOAc 5:1) to afford 1.206 g
(80%) of product 7a as a white solid. Mp 76.6e77.7 ꢀC (hexane). 1H
d
144.4 (CH), 131.3 (C), 127.2 (2ꢂCH), 120.3 (2ꢂCH), 73.8 (CH), 25.7
(3ꢂCH3), 18.2 (C), O4.4 (2ꢂCH3); IR (KBr) 2956 (m), 2929 (m), 2858
(m), 1601 (m), 1508 (s), 1472 (m), 1362 (w), 1266 (br s), 1175 (m),
949 (w), 914 (s), 839 (m), 800 (w), 781 (m), 682 (w); Mass spectrum
m/z (relative intensity %) 264.9 [M]þ (100); HRMS (ESI) calcd for
C10H11O2BrNa: 264.9835, found 264.9839.
NMR (CDCl3, 400 MHz):
d
7.35 (d, J¼14.9 Hz,1H), 6.86e6.80 (m, 3H),
6.65 (d, J¼14.9 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3,
4.10. (E)-4-(2-Bromovinyl)-1,2-dimethoxybenzene (6)
100 MHz):
d 149.4 (C), 149.0 (C), 144.5 (CH), 130.9 (C), 119.3 (CH),
110.9 (CH), 108.2 (CH), 73.9 (CH), 55.9 (CH3), 55.8 (CH3); IR (KBr)
2925 (w), 2833 (w), 1601 (m), 1573 (w), 1514 (s), 1460 (m),1336 (w),
1305 (m), 1264 (s), 1180 (m), 1154 (m), 1136 (s), 1024 (m), 949 (s),
855 (w), 811 (w), 764 (m); Mass spectrum m/z (relative intensity %)
312.9 [MþNa]þ (100); HRMS (ESI) calcd for C10H11O2INa: 312.9696,
found 312.9699.
To a solution of acrylic acid 5a (400 mg, 1.92 mmol) in MeCN:
H2O (19:1, mL) was added LiOAc (25 mg, 0.38 mmol) and NIS
(343 mg, 1.92 mmol) at room temperature. The yellow mixture was
stirred at room temperature for 1 h before concentrated in vacuo on
silica gel. The crude product was purified by flash column chro-
matography (petroleum ether: EtOAc 5:1) to afford 387 mg (83%) of
product 6 as a white solid. Mp 61.8e63.2 ꢀC (hexane), lit.17 66 ꢀC.
Published data17 were in accordance with ours: 1H NMR (CDCl3,
4.7. (E)-1-(2-Iodovinyl)-4-methoxybenzene (7b)
400 MHz):
d
7.03 (d, J¼14.0 Hz, 1H), 6.86e6.80 (m, 3H), 6.62 (d,
To a solution of 4-methoxycinnamic acid (1.028 g, 5.77 mmol) in
MeCN: H2O (19:1, 60 mL) was added LiOAc (77 mg, 1.17 mmol) and
NIS (1.291 g, 5.74 mmol) at room temperature. The orange mixture
was stirred at room temperature for 1 h before concentrated in
vacuo on silica gel. The crude product was purified by flash column
chromatography (petroleum ether: EtOAc 19:1) to afford 1.111 g
(74%) of product 7b as a beige solid (turned black after 2 days in
fridge). Published data16 were in accordance with ours: 1H NMR
J¼13.9 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
149.2 (C), 149.0 (C), 136.7 (CH), 128.9 (C), 119.3 (CH), 111.1 (CH),
108.4 (CH), 104.2 (CH), 55.9 (CH3), 55.8 (CH3); IR (KBr) 3081 (w),
2953 (w), 2835 (m),1602 (m),1577 (w),1512 (s),1461 (m),1438 (m),
1418 (m), 1328 (w), 1304 (w), 1263 (s), 1249 (m), 1208 (m), 1193 (m),
1155 (m), 1139 (s), 1037 (m), 1024 (m), 943 (m), 854 (w), 813 (w),
773 (m), 712 (w); Mass spectrum m/z (relative intensity %) 312.9
[MþNa]þ (100); HRMS (ESI) calcd for C10H11O2INa: 312.9696, found
312.9699.
(CDCl3, 400 MHz):
d
7.36 (d, J¼14.8 Hz, 1H), 7.23 (d, J¼6.8 Hz, 2H),
6.88 (d, J¼6.8 Hz, 2H), 6.63 (d, J¼14.8 Hz, 1H), 3.81 (s, 3H); 13C NMR
(CDCl3, 100 MHz):
d
159.7 (C), 144.3 (CH), 130.7 (C), 127.3 (2ꢂCH),
4.11. (Z)-1-((E)-3,4-Dimethoxystyryl)-2,3-bis(tert-butox-
ycarbonyl)guanidine (9a)
114.1 (2ꢂCH), 73.6 (CH), 55.3 (CH3).
4.8. (E)-((4-(2-Iodovinyl)-1,2-phenylene)bis(oxy))bis(tert-bu-
tyldimethylsilane) (7c)
A vial loaded with compound 8 (80 mg, 0.309 mmol), 6 (51 mg,
0.209 mmol) or 7a (58 mg, 0.200 mmol), K3PO4 (87 mg, mmol) and
CuI (43 mg, mmol) were evacuated and backfilled with argon three
To a solution of acrylic acid 5c (693 mg, 1.70 mmol) in MeCN:
H2O (19:1, 20 mL) was added LiOAc (26 mg, 0.36 mmol) and NIS
(385 mg, 1.71 mmol) at room temperature. The orange mixture was
stirred at room temperature for 3 h, added sodium thiosulphate
(concentrated, 2e3 drops) and silica gel and concentrated in vacuo.
The crude product was purified by flash column chromatography
(2% EtOAc in petroleum ether) to afford 594 mg (71%) of product 7c
times. DMEDA (50 mL, 0.46 mmol) and MeCN (1.5 mL) was added
and the turkish-blue mixture was microwave heated (50 W, 65 ꢀC)
for 35 min, cooled and concentrated in vacuo on silica gel. Purifi-
cation by flash column chromatography (petroleum ether: EtOAc
5:1) afforded 41 mg (49%) from 7a, or 26 mg (29%) from 6, of
product 9a as a fluffy white foamy oil. 1H NMR (CDCl3, 400 MHz):
d
11.61 (br s, 1H), 10.26 (d, J¼10.3 Hz, 1H), 7.52 (dd, J¼14.6, 10.4 Hz,
as a pale pink oil. 1H NMR (CDCl3, 400 MHz):
1H), 6.77e6.76 (m, 3H), 6.56 (d, J¼14.8 Hz, 1H), 0.99 (s, 9H), 0.98 (s,
9H), 0.20 (s, 12H); 13C NMR (CDCl3, 100 MHz):
147.6 (C), 147.0 (C),
d
7.28 (d, J¼14.6 Hz,
1H), 6.92 (d, J¼1.9 Hz, 1H), 6.83 (dd, J¼8.3, 1.9 Hz, 1H), 6.78 (d,
J¼8.3 Hz), 6.12 (d, J¼14.6 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.54 (s,
d
9H),1.53 (s, 9H); 13C NMR (CDCl3, 100 MHz):
d 163.0 (CO), 153.1 (C]
144.5 (CH), 131.5 (C), 121.1 (CH), 119.6 (CH), 118.6 (CH), 73.7 (CH),
25.9 (6ꢂCH3), 18.5 (C), 18.4 (C), O4.0(8) (2ꢂCH3), O4.0(7) (2ꢂCH3);
IR (KBr) 2956 (m), 2930 (m), 2895 (w), 2858 (m), 1596 (w), 1561
(m), 1508 (s), 1472 (m), 1419 (w), 1405 (w), 1362 (w), 1295 (s), 1254
(m), 1234 (m), 1175 (m), 1124 (w), 983 (w), 906 (m), 839 (s), 781
(m), 685 (w); Mass spectrum m/z (relative intensity %) 513.1
[MþNa]þ (100); HRMS (ESI) calcd for C20H35O2INaSi2: 513.1112,
found 513.1116.
N), 152.8 (C), 149.0 (C), 148.3 (C), 128.7 (C), 120.6 (CH), 119.4 (CH),
115.1 (CH), 111.1 (CH), 108.0 (CH), 83.9 (C), 80.0 (C), 56.0 (OCH3),
55.9 (OCH3), 28.2 (3ꢂCH3), 28.0 (3ꢂCH3); IR (KBr) 3263 (w), 2977
(m), 2932 (m), 1720 (m), 1638 (br s), 1614 (br s), 1513 (m), 1454 (m),
1407 (br. m), 1368 (m), 1310 (s), 1265 (m), 1233 (m), 1206 (m), 1153
(br s),1104 (s),1057 (m),1027 (m), 943 (br. w), 854 (w), 803 (w), 771
(w); Mass spectrum m/z (relative intensity %) 444.2 [MþNa]þ (100);
HRMS (ESI) calcd for C21H31O6N3Na: 444.2105, found 444.2101.
4.9. (E)-tert-Butyl(4-(2-iodovinyl)phenoxy)dimethylsilane
4.12. (Z)-1-((E)-4-Methoxystyryl)-2,3-bis(tert-butoxycarbonyl)
(7d)
guanidine (9b)
To a solution of acrylic acid 5d (415 mg, 1.49 mmol) in MeCN:
H2O (19:1, 20 mL) was added LiOAc (20 mg, 0.30 mmol) and NIS
(335 mg, 1.49 mmol) at room temperature. The orange mixture was
stirred at room temperature for 18 h, added sodium thiosulphate
A vial loaded with compound 8 (80 mg, 0.309 mmol), 7b (53 mg,
0.204 mmol), K3PO4 (87 mg, 0.410 mmol) and CuI (43 mg,
0.226 mmol) were evacuated and backfilled with argon three times.
DMEDA (50 mL, 0.46 mmol) and MeCN (1.5 mL) was added and the

M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
8283
turkish-blue mixture was microwave heated (50 W, 65 ꢀC) for
4.15. Tubastrine (1)
35 min, cooled and concentrated in vacuo on silica gel. Purification
by flash column chromatography (petroleum ether: EtOAc 5:1)
afforded 36 mg (45%) of product 9b as a fluffy white foamy oil. 1H
To a solution of compound 9c (53 mg, 0.085 mmol) in THF (3 mL)
was added TBAF (1 M in THF 0.18 mL, 0.18 mmol) dropwise at
O10 ꢀC (brine/ice). The green solution was stirred for 5 min,
quenched with NH4Cl (satd, 10 mL) and extracted with Et2O
(3ꢂ15 mL). The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether: EtOAc 2:1) to afford
32 mg (97%) of product as a fluffy white foamy oil. 1H NMR (CDCl3,
NMR (CDCl3, 400 MHz):
d
11.57 (s, 1H), 10.20 (d, J¼10.4 Hz, 1H), 7.52
(dd, J¼14.6, 10.4 Hz, 1H), 7.27 (dd, J¼8.8 Hz, 2H), 6.82 (dd, J¼8.8 Hz,
2H), 6.12 (d, J¼14.6 Hz, 1H), 3.79 (s, 3H), 1.53 (s, 9H), 1.52 (s, 9H); 13
C
NMR (CDCl3,100 MHz): d 163.0 (C),158.6 (C]N),153.1 (C),153.1 (C),
152.7 (C), 128.4 (C), 127.0 (2ꢂCH), 120.6 (CH), 114.6 (CH), 114.0
(2ꢂCH), 83.8 (C), 79.8 (C), 55.2 (OCH3), 28.2 (3ꢂCH3), 28.0 (3ꢂCH3);
IR (KBr) 3267 (w), 3093 (w), 2978 (m), 2932 (w), 1722 (m), 1639 (br
s), 1615 (br s), 1509 (w), 1408 (br. m), 1368 (m), 1319 (s), 1293 (m),
1247 (s), 1155 (s), 1112 (s), 1057 (m), 1030 (m), 945 (w), 843 (w), 805
(w); Mass spectrum m/z (relative intensity %) 392.2 [M]þ (100);
HRMS (ESI) calcd for C20H30O5N3: 392.2176, found 392.2176.
400 MHz):
d
11.56 (s, 1H), 10.19 (d, J¼10.4 Hz, 1H), 7.35 (dd, J¼14.4,
10.4 Hz, 1H), 6.84 (d, J¼2.0 Hz, 1H), 6.77 (d, J¼8.2 Hz, 1H), 6.60 (dd,
J¼8.2, 2.0 Hz, 1H), 5.99 (d, J¼14.5 Hz, 1H), 1.52 (s, 9H), 1.51 (s, 9H);
13C NMR (CDCl3,100 MHz):
d 162.6 (C),153.0 (C),152.9 (C),143.7 (C),
143.5 (C), 128.6 (C), 120.2 (CH), 119.7 (CH), 115.6 (CH), 115.3 (CH),
111.5 (CH), 84.1 (C), 80.5 (C), 28.2 (3ꢂCH3), 28.0 (3ꢂCH3). A solution
of the tubastrine precursor (26 mg, 0.066 mmol) and TFA (0.02 mL,
0.27 mmol) in MeCN (2 mL) was microwave heated (100 W, 100 ꢀC)
for 20 min, cooled to room temperature and concentrated in vacuo.
The crude product was purified by a C18-column using water:
MeCN gradient to obtain 14 mg (67% (64% from 9c)) as a fluffy pale
yellow foamy oil. Published data1e3 were in accordance with ours:
4.13. (Z)-1-((E)-3,4-Bis((tert-butyldimethylsilyl)oxy)styryl)-
2,3-bis(tert-butoxycarbonyl)guanidine (9c)
A vial loaded with compound 8 (102 mg, 0.393 mmol), 7c
(129 mg, 0.263 mmol), K3PO4 (112 mg, 0.528 mmol) and CuI (55 mg,
0.289 mmol) were evacuated and backfilled with argon three times.
1H NMR (CD3OD, 400 MHz):
d
6.93 (d, J¼13.9 Hz, 1H), 6.82 (s, 1H),
DMEDA (60
m
L, 0.55 mmol) and MeCN (1.5 mL) was added and the
6.70 (s, 2H), 6.16 (d, J¼13.9 Hz, 1H); 13C NMR (CD3OD, 100 MHz):
turkish-blue mixture was microwave heated (50 W, 65 ꢀC) for
35 min, cooled and concentrated in vacuo on silica gel. Purification
by flash column chromatography (petroleum ether: EtOAc 5:1)
afforded 74 mg (45%) of product 9c as a fluffy white foamy oil. 1H
d 156.1 (C), 146.6 (C), 146.2 (C), 128.7 (C), 120.0 (C), 119.0 (CH), 118.3
(CH), 116.5 (CH), 113.8 (CH); Mass spectrum m/z (relative intensity
%) 194.2 [M]þ (100); HRMS (ESI) calcd for C9H11O2N3: 194.0924,
found 194.0924.
NMR (CDCl3, 400 MHz):
d
11.6 (s, 1H), 10.18 (d, J¼10.3 Hz, 1H), 7.45
(dd, J¼14.6, 10.4 Hz, 1H), 6.87 (dd, J¼8.3, 2.1 Hz, 1H), 6.73 (dd, J¼5.4,
3.2 Hz, 2H), 6.05 (d, J¼14.6 Hz, 1H), 1.53 (s, 9H), 1.52 (s, 9H), 0.98 (s,
9H), 0.97 (s, 9H), 0.19 (s, 6H), 0.18 (s, 9H); 13C NMR (CDCl3,
4.16. 3-Dehydroxy-tubastrine (2)
100 MHz):
d
163.0 (C), 153.1 (CO), 152.7 (CO), 146.7 (C), 146.1 (C),
To a solution of compound 9d (47 mg, 0.096 mmol) in THF
(3 mL) was added TBAF (1 M in THF, 0.12 mL, 0.12 mmol) dropwise
at room temperature. The yellow solution was stirred for 30 min,
quenched with water (10 mL) and extracted with Et2O (3ꢂ15 mL).
The organic layer was dried over MgSO4, filtered and concentrated
in vacuo. The crude product was purified by flash column chro-
matography (petroleum ether: EtOAc 2:1) to afford 33 mg (92%) of
product as a fluffy white foamy oil. 1H NMR (CDCl3, 400 MHz):
129.4 (C), 121.2 (CH), 120.8 (CH), 119.5 (CH), 118.7 (CH), 115.0 (CH),
83.8 (C), 79.8 (C), 28.2 (3ꢂCH3), 28.0 (3ꢂCH2), 25.9 (6ꢂCH3), 18.5
(C), 18.4 (C), O4.1(0) (2ꢂCH3), O4.1(1) (2ꢂCH3); IR (KBr) 3264 (w),
2958 (m), 2931 (m), 2859 (m), 1721 (m), 1642 (s), 1617 (s), 1563 (m),
1509 (s), 1473 (m), 1412 (s), 1369 (m), 1316 (s), 1275 (s), 1253 (s),
1232 (m), 1154 (s), 1124 (m), 1105 (m), 1058 (m), 1029 (w), 983 (w),
940 (w), 908 (m), 840 (m), 806 (m), 781 (m), 733 (w), 695 (w); Mass
spectrum m/z (relative intensity %) 644.4 [MþNa]þ (100); HRMS
(ESI) calcd for C31H55O6N3NaSi2: 644.3522, found 644.3522.
d
11.55 (s, 1H), 10.22 (d, J¼10.3 Hz, 1H), 7.40 (dd, J¼14.4, 10.3 Hz,
1H), 7.03 (d, J¼8.1 Hz, 2H), 6.82 (br s, 1H), 6.75 (d, J¼7.9 Hz, 2H),
6.08 (d, J¼14.5 Hz, 1H), 1.52 (s, 9H), 1.51 (s, 9H); 13C NMR (CDCl3,
100 MHz): d 162.8 (C), 155.4 (C), 153.1 (C), 152.8 (C), 127.8 (C), 127.2
4.14. (Z)-1-((E)-4-((tert-Butyldimethylsilyl)oxy)styryl)-2,3-
bis(tert-butoxycarbonyl)guanidine (9d)
(2ꢂCH), 120.2 (CH), 115.7 (2ꢂCH), 115.4 (CH), 84.0 (C), 80.2 (C), 28.2
(3ꢂCH3), 28.1 (3ꢂCH3). A solution of the 3-dehydroxy tubastrine
precursor (27 mg, 0.072 mmol) and TFA (0.02 mL, 0.27 mmol) in
MeCN (2 mL) was microwave heated (100 W, 100 ꢀC) for 20 min,
cooled to room temperature and concentrated in vacuo. The crude
product was purified by a C18-column using water: MeCN gradient
to obtain 15 mg (68% (61% from 9d)) as a fluffy pale yellow foamy
oil. Published data4,5 were in accordance with ours: 1H NMR
A vial loaded with compound 8 (135 mg, 0.521 mmol), 6d
(125 mg, 0.347 mmol), Cs2CO3 (226 mg, 0.693 mmol) and CuI
(73 mg, 0.383 mmol) were evacuated and backfilled with argon
three times. DMEDA (80 mL, 0.73 mmol) and MeCN (1.5 mL) was
added and the turkish-blue mixture was microwave heated (50 W,
65 ꢀC) for 35 min, cooled and concentrated in vacuo on silica gel.
Purification by flash column chromatography (petroleum ether:
EtOAc 5:1) afforded 63 mg (37%) of product 9d as a fluffy white
(CD3OD, 400 MHz):
d
7.20 (d, J¼8.5 Hz, 2H), 6.98 (d, J¼14 Hz, 1H),
6.72 (d, J¼8.7 Hz, 2H), 6.22 (d, J¼14.0 Hz, 1H); 13C NMR (CD3OD,
100 MHz):
d 158.1 (C), 156.0 (C), 128.1(1) (CH), 128.1(0) (C), 120.0
foamy oil. 1H NMR (CDCl3, 400 MHz):
d
11.56 (s, 1H), 10.19 (d,
(2ꢂCH), 118.0 (CH), 116.6 (CH); Mass spectrum m/z (relative in-
tensity %) 178.2 [M]þ (100); HRMS (ESI) calcd for C9H11ON3:
178.0975, found 178.0972, which is in accordance with
literature.4,5
J¼10.4 Hz, 1H), 7.51 (dd, J¼14.6, 10.4 Hz, 1H), 7.21 (d, J¼8.6 Hz, 2H),
6.75 (d, J¼8.6 Hz, 2H), 6.11 (d, J¼14.6 Hz, 1H), 1.52 (s, 9H), 1.52 (s,
9H), 0.97 (s, 9H), O0.19 (s, 6H); 13C NMR (CDCl3, 100 MHz):
d 163.1
(C), 154.8 (C), 153.1 (CO), 152.8 (CO), 129.0 (C), 127.0 (2ꢂCH), 120.8
(CH), 120.2 (2ꢂCH), 114.8 (CH), 83.9 (C), 80.1 (C), 28.2 (3ꢂCH3), 28.1
(3ꢂCH3), 25.7 (3ꢂCH3), 18.2 (C), O4.4 (2ꢂCH3); IR (KBr) 2929 (m),
1720 (m), 1639 (s), 1615 (s), 1407 (m), 1368 (m), 1316 (s), 1252 (s),
1154 (s), 1108 (s),1057 (m), 912 (w), 839 (w), 805 (w), 780 (w); Mass
spectrum m/z (relative intensity %) 492.7 [MþNa]þ (100); HRMS
(ESI) calcd for C25H42O5N3Si: 492.2888, found 492.2897.
Acknowledgements
This work has received support from the University of Stavanger
and the Research Council of Norway through a project grant
(224790/O30).

8284
M. Lorentzen et al. / Tetrahedron 71 (2015) 8278e8284
10. (a) Borodin, A. Ann. 1861, 119, 121e123; (b) Hunsdiecker, H.; Hunsdiecker,
Supplementary data
C. Ber. 1942, 75, 291e297; (c) Chowdhury, S.; Roy, S. J. Org. Chem. 1997, 62,
199e200; (d) Georgiades, S. N.; Clardy, J. Bioorg. Med. Chem. Lett. 2008, 18,
3117e3121; (e) Zhang, W.; Su, C.; Kuang, C.; Yang, Q. Russ. Chem. Bull., Int.
Ed. 2010, 59, 452e456; (f) Xu, R. S.; Yue, L.; Pan, Y. J. Tetrahedron 2012, 68,
5046e5052; (g) Kuang, C.; Senboku, H.; Tokuda, M. Synlett 2000,
1439e1442.
1H NMR and 13C NMR spectra of all new and known compounds
are provided. Supplementary data associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2015.09.003. These data include MOL files and InChiKeys of the
most important compounds described in this article.
11. (a) Gao, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 6864e6866;
(b) Cortes-Salva, M.; Nguyen, B. L.; Cuevas, J.; Pennypacker, K. R. Org. Lett. 2010,
12, 1316e1319; (c) Xing, H.; Zhang, Y.; Lai, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2012,
77, 5449e5453; (d) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc. Rev. 2012, 41,
2463e2497; (e) Hammound, H.; Schmitt, M.; Bihel, F.; Antheaume, C.; Bour-
guignon, J. J. J. Org. Chem. 2012, 77, 417e423.
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