Total synthesis of artochamins F, H, I, and J through cascade reactions

Article abstract of DOI:10.1016/j.tet.2008.02.108

A concise and efficient cascade-based total synthesis of artochamins F, H, I, and J is described. The potential biogenetic connection between artochamin F, or a derivative thereof, and artochamins H, I, and J, through an unusual formal [2+2] cycloaddition

Full text of DOI:10.1016/j.tet.2008.02.108

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4736e4757
www.elsevier.com/locate/tet
Total synthesis of artochamins F, H, I, and J through cascade reactions
a
a
a
K.C. Nicolaou a,b, , Troy Lister , Ross M. Denton , Christine F. Gelin
*
a Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
b Department of Chemistry and Biochemistry, The University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Received 9 October 2007; accepted 29 February 2008
Available online 18 March 2008
Abstract
A concise and efficient cascade-based total synthesis of artochamins F, H, I, and J is described. The potential biogenetic connection between
artochamin F, or a derivative thereof, and artochamins H, I, and J, through an unusual formal [2þ2] cycloaddition process, was shown to be
feasible. An alternative mechanism for this transformation is also proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
cycloaddition process that proceeds thermally under a variety of
conditions.
The design and development of cascade reactions is a rapidly
expandingarea of research withinthe realm of chemical synthesis.1
The virtues of such synthetic sequences are brilliantly reflected by
some of the early developments in the field such as Sir Robert Rob-
inson’s total synthesis of tropinone (1917)2 and Johnson’s total
synthesis of progesterone (1971).3 During our own endeavors in to-
tal synthesis, we have demonstrated the power of cascade reactions
beginning with the total synthesis of endiandric acids (1982)4 and
followed by numerous other examples, including bisorbicillinoids
(1999),5 CP molecules (1999),6 colombiasin A (2001),7 hybocar-
pone (2001),8 diazonamide A (2003),9,10 1-O-methyl lateriflorone
(2003),11 thiostrepton (2004),12 azaspiracid-1,13 -2,14a and -314b
(2006), bisanthraquinones (2006),15 and biyouyanagin (2007).16
Cascade reactions are not only attractive due to their aesthetically
pleasing nature, but also because of their capacity to rapidly
increase molecular complexity, often efficiently and economically,
from relatively simple starting materials. Furthermore, they fre-
quently do so with savings in reagents and solvents, not to mention
energy and time. As such they constitute part of the campaign of
green chemistry to save and sustain the environment. In this article,
we describe a detailed account of the synthesis of artochamins F, H,
I, and J through cascade reactions involving a formal [2þ2]
The Artocarpus genus encompasses approximately 60
species of trees that are thriving throughout the tropical lands
of Asia. Belonging to the mulberry family Moraceae, several
members of the species are cultivated for their fruit, edible
seeds, and timber. A number of these trees are historically re-
puted to possess medicinal properties and are utilized as folk
medicines in Taiwan, Thailand, and Indonesia.17e21 Studies
directed at the elucidation of the active ingredients of Artocar-
pus chama led to the isolation of several prenylated flavonoid
compounds exhibiting cytotoxic, antiplatelet, and antibacterial
activities.20 More recent investigations with the stems of the
same plant revealed a series of weakly cytotoxic prenylated
stilbenes and derivatives thereof.22 Artochamins, F, H, I, and
J (1e4, Scheme 1) are amongst the most prominent and struc-
turally interesting members of this class of compounds.
Inspection of the structures of artochamins F (1) and HeJ (2e
4) reveals a possible biogenetic relationship between them,
whereby the stilbene-like structure 1, or a derivative thereof,
may serve as a precursor to the cyclobutane-containing structures
2e4 through a formal [2þ2] cycloaddition reaction.23 The occur-
rence of artochamins HeJ (2e4) as racemates is suggestive of
a non-enzymatic process, but does not necessarily preclude enzy-
matic intervention in the formation of the bicyclo[3.2.0]heptane
ring system, as will be discussed in greater detail below. Herein,
we describe our studies in this area that culminated in the total
syntheses of several of the artochamins and shed some light on
* Corresponding author. Tel.: þ1 858 784 2400; fax: þ1 858 784 2469.
E-mail address: kcn@scripps.edu (K.C. Nicolaou).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.108

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4737
Me
OH
OMe
OMe
H
H
H
Me
OH
Me
Me
Me
Me
Me
Me
OMe
Me
OMe
Me
O
H
H
H
HO
HO
OH
Me
Me
Me
HO
HO
HO
Me
Me
HO
HO
Me
HO
1: artochamin F
2: artochamin H
3: artochamin I
4: artochamin J
Me
Me
RO
RO
Me Me
O
PPh3Br
O
Br
O
Br
O
Me
Me
8: R=Boc
9: R=TBS
RO
RO
Me
N
O
N
olefination
Me
N
RO
RO
N
Ph
S
O O
5: R=Boc
6: R=TBS
7
10: R=Boc
11: R=TBS
Scheme 1. Structures and retrosynthetic analysis of artochamins F, H, I, and J (1e4).
the mechanistic aspects of the proposed formal [2þ2] thermal
17and phosphonium salt 9 for a Wittig-based coupling were pre-
pared as follows. As shown in Scheme 2, copper-catalyzed
etherification25 of bis-phenol 1226 with dimethylpropynyl
carbonate followed by catalytic hydrogenation under Lindlar
conditions led to bis-allyl ether 13 in 83% overall yield.
cycloaddition reaction.24
2. Results and discussion
2.1. Retrosynthetic analysis
a) CuCl2, DBU
Me Me
Me Me
The architecture of the artochamins (Scheme 1) makes
them amenable to a cascade sequence, which could potentially
deliver them sequentially and/or selectively by fine-tuning the
structure of the starting substrate. It was envisioned that a pre-
cursor such as 5 or 6 (Scheme 1), with or without protecting
groups, equipped with the necessary functionality, could enter
into a cascade sequence involving Claisen rearrangements to
install the two prenyl groups, followed by a formal intramolec-
ular [2þ2] cycloaddition to forge the cyclobutane ring. The
nature of the hydroxyl protecting groups could potentially
favor or disfavor the formal [2þ2] cycloaddition reaction,23a
thus providing access to either artochamin F (1) or the skeletal
framework of artochamins HeJ (2e4). The stilbene precursors
of 5 and 6 were traced back to phosphonium salts 8 and 9, or
sulfones 10 and 11, respectively, and aldehyde 7 with the ste-
reoselectivity of the relevant coupling reactions to be addressed
experimentally.
OH
O
OCO2Me
(83 %)
Br
Br
O
Me
Me
b) H2, Lindlar cat.
(100 %)
MeO2C
OH
MeO2C
12
13
c)
-wave
(85 %)
Me
OR
Me
Me
OMe
Br
OR
e) LiAlH4
(89 %)
Me
Me
MeO2C
Me
R
OMe
Me
Me
d) K2CO3,
MeI (95 %)
16: R=CH2OH
17: R=CHO
14: R=H
15: R=Me
f) DMP
(94 %)
Scheme 2. Construction of aldehyde 17. Reagents and conditions: (a) methyl
1,1-dimethyl-2-propynyl carbonate (3.0 equiv), CuCl2 (0.01 equiv), DBU
(3.0 equiv), CH3CN, 0 ꢀC, 14 h; (b) H2 (balloon), Lindlar catalyst (10%
w/w), quinoline (0.5 equiv), EtOAc, 23 ꢀC, 3 h; (c) m-wave, DMF, 180 ꢀC,
5 min; (d) K2CO3 (5.0 equiv), MeI (6.0 equiv), DMF, 100 ꢀC, 1 h; (e) LiAlH4
(10 equiv), THF, 50 ꢀC, 14 h; (f) DMP (1.5 equiv), CH2Cl2, 23 ꢀC, 30 min;
DMF¼N,N-dimethylformamide; TBS¼tert-butyldimethylsilyl; DMP¼Desse
Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-
one).
2.2. Synthesis of artochamin I
As a prelude to the development of a cascade-based sequence
toward the artochamins, a stepwise approach to artochamin I (3)
was designed in order to explore separately the Claisen rear-
rangements and, in particular, the feasibility of the thermal
[2þ2] cycloaddition reaction. To this end, the required aldehyde

4738
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
O
of the TBS groups from E-22 (HF$Py, 88%) afforded the
b) NaBH4
(95 %)
TBSO
TBSO
a) TBSCl, imid. (91 %)
RO
RO
OH
protected artochamin F derivative 23, setting the stage for
the projected formal [2þ2] cycloaddition reaction. We were
pleased to observe that microwave heating of 23 in DMF at
180 ꢀC resulted in the formation of artochamin I (3) as a single
diastereoisomer in 80% yield. Significantly, attempts to cy-
clize the corresponding TBS ethers (E- or Z-22) under identi-
cal conditions failed, with only trace amounts of desilylated
material visible (by TLC) after prolonged microwave heating
(>45 min). Besides constituting an efficient synthesis of arto-
chamin I (3), this study demonstrated the feasibility of both
the double Claisen rearrangement and the formal [2þ2] cyclo-
addition reaction under essentially identical reaction condi-
tions. The study also demonstrated the expected dependence
of the formal thermal cycloaddition reaction on the free
hydroxyl groups of the stilbene substrate.23c
20
c) PBr3
18: R=H
19: R=TBS
(89 %)
TBSO
TBSO
TBSO
d) PPh3
(85 %)
Br
PPh3Br
TBSO
9
21
Scheme 3. Construction of phosphonium salt 9. Reagents and conditions: (a)
TBSCl (2.0 equiv), imidazole (3.0 equiv), DMF, 23 ꢀC, 12 h; b) NaBH4
(1.0 equiv), EtOH, 0/23 ꢀC, 10 min; (c) PBr3 (0.5 equiv), CH2Cl2, 0 ꢀC,
30 min; (d) PPh3 (1.0 equiv), toluene, 110 ꢀC, 3 h.
Microwave-promoted (180 ꢀC) Claisen rearrangements27 then
afforded the bis-prenylated ester 14 in good yield (85%). Subse-
quent methylation of 14 (K2CO3, MeI) afforded bis-methyl
ether 15, which was subjected to the action of LiAlH4 to effect
reduction of both the bromine substituent and the ester function-
ality, affording benzylic alcohol 16. DesseMartin oxidation of
the latter compound then furnished the desired aldehyde 17 in
90% overall yield for the two steps.
The required phosphonium salt 9 was obtained in a straight-
forward manner from commerciallyavailable aromaticaldehyde
18 through a four-step sequence as shown in Scheme 3. Thus,
protection of aldehyde 18 as the corresponding bis-TBS ether
(TBSCl, imidazole, 91%) followed by NaBH4 reduction
afforded benzylic alcohol 20 (95%). Subsequent bromination
of 20 with PBr3 and reaction of the resulting benzylic bromide
21 with PPh3 resulted in the formation of phosphonium salt 9
in 85% yield.
´
2.3. Development of the JuliaeKocienski approach
to stilbenes and the cascade strategy for the total synthesis
of artochamins F, H, I, and J
Having established appropriate conditions for the synthesis
of the artochamins, we then proceeded to incorporate them
within a cascade sequence toward an advanced common inter-
mediate from which several of the natural products were
expected to emerge. The bromine-containing bis-Boc protected
stilbene derivative 5 (Scheme 1) was designed with the expecta-
tion that under thermal conditions it would undergo cleavage of
the Boc groups, Claisen rearrangement of the two allylic ether
moieties, and a formal [2þ2] cycloaddition reaction to afford
the tetracyclic core structure of artochamins HeJ (2e4). Our
initial route to precursor 5 involved a Wittig coupling that re-
quired aldehyde 7 (Scheme 1) and phosphonium salt 8 (Scheme
1). To this end, chemoselective reduction of methyl ester 13 with
LiAlH4 provided alcohol 24, which was oxidized to aldehyde 7
in 91% yield over the two steps as shown in Scheme 5.
The Wittig coupling between the ylide derived from phos-
phonium salt 9 and aldehyde 17 (Scheme 4) proceeded in
excellent yield (90%) and acceptable selectivity (E/Z ca. 5:1)
providing trans-stilbene E-22 as the major product. Removal
Next, the bis-Boc protected phosphonium salt 8 was prepared
from commercially available aldehyde 18 by the same sequence
as that employed to construct its bis-TBS-protected counterpart
(9, Scheme 3), as shown in Scheme 6. The two fragments, the
ylide derived from 8 and aldehyde 7, were then combined using
the Wittig reaction to afford stilbene 5 in 90% yield as a ca. 1:1
mixture of geometric isomers (Scheme 6). This stereoselectivity
setback in combination with the low-yielding bromination
(26/27, 18%) prompted us to search for an alternative route
to the targeted stilbene substrate.
Me
OMe
Me
9
TBSO
TBSO
a) nBuLi, 17
OMe
(90 %)
17
Me
Me
E-22+Z-22, (ca. 5:1)
HF py
(88 %)
b)
OMe
Me Me
O
Me Me
O
H
Me
OMe
Me
Me
Me
OMe
Br
O
Me
Me
Br
O
Me
Me
a) LiAlH4
(95 %)
H
HO
HO
c)
-wave
OMe
R
MeO2C
(80 %)
HO
Me
Me
HO
3: artochamin I
23
Me
Me
13
24: R=CH2OH
7: R=CHO
b) DMP
(97 %)
Scheme 4. Wittig reaction-based construction of stilbene 23 and synthesis of
artochamin (3). Reagents and conditions: (a) (1.2 equiv), n-BuLi
I
9
(1.2 equiv), ꢁ78 ꢀC, 30 min; then 17, ꢁ78/23 ꢀC, 30 min; (b) HF$Py (ex-
Scheme 5. Construction of aldehyde 7. Reagents and conditions: (a) LiAlH4
(1.2 equiv), THF, 0 ꢀC, 10 min; (b) DMP (1.2 equiv), CH2Cl2, 23 ꢀC, 30 min.
cess), THF, 0/23 ꢀC, 2 h; (c) m-wave, DMF, 180 ꢀC, 20 min; Py¼pyridine.

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4739
O
RO
RO
BocO
BocO
BocO
BocO
d) PPh3 (62 %)
b) NaBH4 (95 %)
a) Boc2O (100 %)
X
PPh3Br
8
18: R=H
25: R=Boc
26: X=OH
27: X=Br
c) PBr3 (18 %)
Me Me
e) tBuOK, 7
(90 %)
O
Br
O
BocO
BocO
Me
Me
E-5 + Z-5, (ca. 1:1)
Scheme 6. Wittig reaction-based construction of stilbene 5. Reagents and conditions: (a) Boc2O (2.0 equiv), 4-DMAP (0.05 equiv), i-Pr2NEt (0.1 equiv), THF,
23 ꢀC, 2 h; (b) NaBH4, (1.0 equiv), EtOH, 0/23 ꢀC, 10 min; (c) PBr3 (2.0 equiv), CH2Cl2, 0 ꢀC, 1 h; (d) PPh3 (1.5 equiv), toluene, 60 ꢀC, 14 h; (e) 8 (1.2 equiv),
t-BuOK (1.2 equiv), ꢁ78 ꢀC, 30 min; then 7, ꢁ78/23 ꢀC, 30 min; DMAP¼4-dimethylaminopyridine.
Whilst numerous examples of the Wittig reactiontoprepare stil-
benes can be found in the literature,28 precedent for the correspond-
stilbene 6 was obtained in a similar fashion from the corresponding
sulfone (11) in 95% yield, but as a ca. 2:1 mixture of E/Zisomers. In
contrast to the TBS-protected stilbenes, whose stereochemistry
could be determined by NMR spectroscopy, the geometry of the
bis-Boc protected stilbene 5 could not be comfortably assigned
from its 1H NMR spectrum. Fortunately, this compound yielded
to X-ray crystallographic analysis, which confirmed the suspected
E-geometry (see ORTEP drawing, Fig. 1).31
ing JuliaeKocienski olefination was lacking.29 Nevertheless, we
´
decided to explore this alternative in the hope that we could im-
prove upon the selectivity of the coupling reaction. Toward this
end, stilbenes 5 and 6 were targeted for synthesis according to
Scheme 7. Thus, the previously prepared benzylic alcohols 20
and 26 were subjected to thioetherification under Mitsunobu con-
ditions to afford the corresponding sulfides, which were converted
through molybdenum-catalyzed oxidation to the desired sulfone
coupling partners 10 and 11 in 79 and 82% yield, respectively,
over the two steps. In the main event of this sequence, employing
sulfone 10 as a starting material, we were pleased to observe that
With ample quantities of stilbene 5 available through the
´
JuliaeKocienski route, we were in a position to test our hy-
pothesis regarding the proposed cascade sequence to the bicy-
clo[3.2.0] ring system of artochamins HeJ (2e4). After
considerable experimentation, it was discovered that the de-
sired cascade could be realized under microwave conditions32
in o-xylene at 180 ꢀC (20 min.) in the presence of trace
amounts of Ph3PO as shown in Scheme 8. The beneficial effect
the JuliaeKocienski olefination30 with aldehyde 7 using KHMDS
´
in THF afforded the bis-Boc protected stilbene 5 in 86% yield as
a single E-stereoisomer (vide infra). The bis-TBS-protected
Me Me
N
N
O
N
Ph
Br
N
Ph
HS
N
N
N
RO
RO
RO
RO
RO
RO
c) KHMDS, 7
a) PPh3, DEAD
b) Mo(VI) cat.
N
OH
S
O O
O
Me
Me
5: R=Boc (80 %, E-only)
6: R=TBS (95 %, E:Z, 2:1)
10: R=Boc
11: R=TBS
26: R=Boc
20: R=TBS
´
Scheme 7. JuliaeKocienski reaction-based construction of stilbenes 5 and 6. Reagents and conditions: (a) 1-phenyl-1H-tetrazole-5-thiol (1.0 equiv), DEAD
(1.2 equiv), PPh3 (1.1 equiv), THF, 0 ꢀC, 30 min; (b) ammonium molybdate tetrahydrate (0.1 equiv), 30% aqueous H2O2 (20 equiv), EtOH, 0/23 ꢀC, 14 h;
(c) 10 or 11 (1.5 equiv), KHMDS (1.5 equiv), ꢁ78 ꢀC, 30 min; then 7 (1.0 equiv), THF, ꢁ78/23 ꢀC; Boc¼tert-butylcarbonate; KHMDS¼potassium bis(tri-
methylsilyl)amide; TBS¼tert-butyldimethylsilyl.
Me Me
O
Me
Me
Me
O
O
O
Br
O
Me
Me
Me
Me
O
O
5
O
Me
Figure 1. X-ray derived ORTEP drawing of stilbene 5. Thermal ellipsoids at the 30% probability level.

4740
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
Me
O
Me Me
O
Me
Me
H
O
OH
Me
Me
Me
OH
Br
Me
Br
O
Me
Me
Br
O
Me
Me
[3,3]
Claisen
Me
O
[3,3]
OH
BocO
BocO
BocO
BocO
µ
a) -wave,
Ph3PO cat.
(55 %)
Claisen
O
O
O
H
Me
29
Me
5
28
OH
OH
Me
H
O
OH
Me
Me
Me
Me
Br
Br
OH
O
Br
H
Me
Me
5:1 dr
Me
[2+2]
HO
HO
O
OH
Me
OH
formal
-2 [CO2]
H
ca.
ition
cycloadd
O
HO
Me
Me
31
O
H
O
Me
30
HO
32
Scheme 8. Cascade-based synthesis of artochamin ring framework 32. Reagents and conditions: (a) m-wave, Ph3PO (5 wt %), o-xylene, 180 ꢀC, 20 min.
of Ph3PO was discovered serendipitously when a sample of
precursor 5 that had been obtained through the Wittig route
was used for the reaction (vide infra). The tetracyclic product
32 was obtained in 55% yield as a ca. 5:1 mixture of diastereo-
isomers with respect to the benzylic stereocenter adjacent to
the all-carbon quaternary center (see Scheme 8).
With common intermediate 32 available through the cas-
cade sequence, the total synthesis of artochamins HeJ (2e4)
was completed as shown in Scheme 9. Thus, treatment of 32
with PivCl (2.0 equiv) and pyridine (6.0 equiv) in CH2Cl2 fur-
nished the bis-pivalate 35 in 64% yield, with recyclable mono-
pivalates accounting for the remainder of the mass balance. As
OPiv
OH
Br
H
H
Me
Me
Me
Me
a) PivCl,
(3.0 eq.)
OH
OMe
Me
H
H
Et3N
e) LiAlH4
(88 % over
two steps)
(75 %)
PivO
HO
Me
Me
Me
PivO
33
HO
2: artochamin H
d) K2CO3, MeI
34
OH
Br
OMe
H
H
b) PivCl,
Me
Me
Me
Me
(2.0 eq.)
OH
H
OMe
Me
py
e) LiAlH4
H
32
(91 % over
two steps)
(64 %)
PivO
HO
Me
Me
Me
PivO
35
HO
3: artochamin I
d) K2CO3, MeI
36
OMe
OH
Br
b) PivCl,
(2.0 eq.)
py (64 %)
H
H
Me
HO
Me
Me
e) LiAlH4
Me
O
Me
Me
O
(88 % over
two steps)
c) PhSeCl;
H2O2
(85 %)
H
H
Me
Me
HO
PivO
PivO
37
4: artochamin J
d) K2CO3, MeI
38
Scheme 9. Total synthesis of artochamins HeJ (2e4). Reagents and conditions: (a) PivCl (3.0 equiv), Et3N (6.0 equiv), CH2Cl2, 23 ꢀC, 30 min; (b) PivCl
(2.0 equiv), Py (6.0 equiv), CH2Cl2, 23 ꢀC, 14 h; (c) PhSeCl (1.0 equiv), CH2Cl2, ꢁ78/23 ꢀC, 30 min; then H2O2 (20 equiv), CH2Cl2, 0/23 ꢀC, 3 h; (d)
K2CO3 (5.0 equiv), MeI (6.0 equiv), DMF, 100 ꢀC, 1 h; (e) LiAlH4 (6.0 equiv), THF, 0/23 ꢀC, 24 h; Piv¼trimethylacetyl; Py¼pyridine.

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4741
Me
OH
HO
HO
Me Me
Me
H
O
H
O
Me
OH
Me
H
Me
Me
Br
O
Me
Me
Br
OMe
Me
Me
H
H
TBSO
TBSO
TBSO
TBSO
a) -wave
(95 %)
OH
OH
Me
Me
HO
Me
39
6
Me
Me
HO
2
b) nBu3SnH,
AIBN cat.
c) HF Et3N
indicates ROE interaction
Figure 2. Principal ROE interactions in synthetic artochamin H (2).
(81 %, over 2 steps)
Me
anticipated, steric shielding from the adjacent bromine atom
disfavored acylation of the two remaining hydroxyl groups un-
der these conditions. Subsequent methylation of the remaining
hydroxyl groups (K2CO3, MeI) and simultaneous cleavage of
the bromine and pivalate moieties (LiAlH4) then furnished ar-
tochamin I (3) in 91% overall yield for the two steps. The total
synthesis of artochamin J (4) was completed from common in-
termediate 32 via pivalate 35 by selenoetherification33
(PhSeCl) and oxidative elimination (H2O2) to afford benzo-
pyran 37 (85% overall yield), which was converted to artocha-
min J (4) by methylation and exhaustive LiAlH4 reduction as
described above for artochamin I (3). Finally, artochamin H
(2) was secured from common intermediate 32 through tri-piv-
alate 33, obtained in 75% yield under somewhat more forcing
acylation conditions (3.0 equiv PivCl, 6.0 equiv Et3N). Meth-
ylation and deprotection as above provided artochamin H (2)
in 88% overall yield (see Scheme 9).
Me
OH
Me
OH
H
Me
Me
d) -wave
(82 %)
HO
HO
OH
OH
Me
H
HO
Me
Me
1: artochamin F
40
HO
Scheme 10. Total synthesis of artochamin F (1). Reagents and conditions: (a)
o-xylene, m-wave, 180 ꢀC, 5 min; (b) AIBN (0.1 equiv), n-Bu3SnH (2.0 equiv),
benzene, reflux, 1 h; (c) HF$Et3N (5.0 equiv), THF, 23 ꢀC, 1 h; (d) o-xylene,
m-wave, 180 ꢀC, 10 min; AIBN¼azobisisobutylonitrile.
the reaction mixture indicated that the Claisen rearrangements
proceed faster than the Boc cleavage or the formal [2þ2] cyclo-
addition reaction. Given the fact that the free hydroxyl groups
are necessary for the formal cycloaddition reaction to occur,
we surmise the sequence shown in Scheme 8 as the most reason-
able order of events in this cascade sequence. Thus, it is thought
that rapid Claisen rearrangements are followed by slower depro-
tections and ring closures (5/28/29/30/31/32,
Scheme 8).
The spectroscopic data of synthetic artochamins HeJ
(2e4) matched those reported for the natural products.34 Fur-
thermore, in the case of artochamin H (2), a ROESY NMR ex-
periment provided unequivocal support of its regiochemistry
and relative stereochemistry through the observation of the
appropriate ROE interactions, as shown in Figure 2.
The precise mechanism of the formal [2þ2] cycloaddition
reaction is quite fascinating, but not fully illuminated as yet.
At present, we can outline three potential alternatives for
this interesting transformation, the first two of which are de-
scribed in Scheme 11. The first scenario involves a concerted
[p2sþp2a] cycloaddition35 between the stilbene alkene and
one of the prenyl groups (31/32, Scheme 11). Such a process
ought to be stereospecific with respect to the geometry of the
stilbene alkene. We view this first possibility to be highly un-
likely due to the difficulty in obtaining the necessary orbital
overlap, especially when the conformational constraints im-
posed by the tether are taken into account. The second, and
more reasonable scenario, may involve a stepwise radical
mechanism in which an initial 5-exo cyclization is followed
by rapid recombination of the biradical so-obtained (31/
41/32, Scheme 11).23c The stereochemical outcome of this
process with respect to the benzylic stereocenter adjacent to
the gem-dimethyl group should be governed by the relative
rates of the indicated bond rotation and radical coupling pro-
cesses. If the radical recombination occurs faster than the
bond rotation, then the stereochemistry of the starting olefin
will be retained in the product, whereas, in the reverse sce-
nario, the formation of epi-32 will be competitive with that
of 32.
Finally, based on the results obtained during the first-gener-
ation synthesis of artochamin I (3) (see Scheme 4), the total
synthesis of artochamin F (1) was completed as shown in
´
Scheme 10. Thus, the JuliaeKocienski derived stilbene 6
(see Scheme 7) was subjected to microwave heating resulting
in the formation of bis-prenyl phenol 39 in excellent yield
(95%). As expected, no cyclobutane-containing product was
obtained from this microwave-promoted reaction. Reductive
cleavage of the bromide followed by desilylation afforded syn-
thetic artochamin F (1) in 81% yield over the two steps. Sub-
jection of artochamin F (1) to microwave heating, both in the
presence and in the absence of Ph3PO provided, in 82% yield,
derivative 40 containing the [3.2.0] ring system of artochamins
HeJ (2e4), thereby demonstrating that neither the bromine
atom nor the Ph3PO is necessary for the formal [2þ2] cyclo-
addition reaction to take place, at least in this instance.
2.4. Mechanistic studies
The cascade sequence described above could also be con-
ducted successfully by conventional heating (o-xylene,
165 ꢀC, sealed tube, PH3PO 5%, w/w), although 1 h was re-
quired for the reaction to reach completion. TLC analysis of

4742
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
OH
OH
OH
Me
Me
Br
Br
H
Br
H
H
Me
Me
recombination
2s 2a
+
HO
HO
OH
OH
OH
H
H
HO
Me
Me
31
Me
HO
OH
Me
Me
Me
HO
Me
Me
Me
Br
Me
Me
HO
41
32
HO
HO
OH
bond rotation
OH
OH
OH
31
Me
Me
Me
HO
HO
Br
H
Br
Br
H
H
Me
HO
HO
Me
2s 2a
+
recombination
OH
OH
OH
H
H
HO
Me
Me
Me
HO
Me
Me
Me
Me
Me
Z-31
42
epi-32
Scheme 11. Potential mechanistic pathways for the formal [2þ2] cycloaddition reaction.
In an initial experiment with Wittig-derived stilbenes
E- and Z-5, it was discovered that the reaction was not stereo-
specific with respect to the geometry of the alkene, although
possible E/Z isomerization of the stilbene under the reaction
conditions in the case of the Z-isomer could undermine this
conclusion. These observations corroborate the stepwise birad-
ical mechanism in which bond rotation occurs at a rate com-
petitive with radical recombination.
The third, and most attractive, alternative is the ionic mech-
anism depicted in Scheme 12. This mechanism may be partic-
ularly relevant to the formation of artochamins HeJ (2e4) in
nature due to the ease of enzymatic generation of o-quinones
from catechols.36 This alternative biosynthetic pathway ap-
pears to be more attractive than the one originally proposed
based on a [2þ2] cycloaddition mechanism since the condi-
tions typically required to bring about such transformations
are rather forcing.23 According to this newly proposed process,
initial enzymatic36 or chemical37 oxidation of the electron-rich
catechol moiety of generic stilbene 43 (Scheme 12) would fur-
nish o-quinone 44, which could readily undergo intramolecu-
lar conjugate addition as shown, affording the intermediate 45,
whose facile ring closure to tetracyclic quinone 46 would be
expected. Finally, redox reaction between quinone 46 and
dihydroquinone 43 (starting material) may be responsible for
the completion of the cascade, leading to product 47 with con-
comitant re-generation of o-quinone 44, thus necessitating
only a trace amount of the initial oxidant. This could be an en-
zyme,36 trace amounts of O2,38 or other oxidants such as DDQ
or even Ph3PO, as will be discussed further below.
The intriguing effect of Ph3PO on the cascade reaction was
´
first noticed when stilbene 5 derived from the JuliaeKocienski
olefination failed to reproducibly undergo the cascade reaction
observed previously with the Wittig-derived material. Suspect-
´
ing that a trace impurity arising from the JuliaeKocienski
olefination was causing the problem, we proceeded to further
purify our substrate by crystallization only to observe the same
OH
Me
OH
Me
OH
Me
H
Me
Me
Me
Me
oxidation
HO
HO
O
O
OH
Me
OH
OH
H
O
Me
Me
Me
Me
O
43
44
45
oxidation
44 43
OH
OH
H
H
Me
Me
Me
Me
OH
OH
Me
reduction
H
H
HO
O
Me
Me
Me
HO
O
47
46
Scheme 12. Postulated redox-based mechanistic pathway for the biogenesis of artochamins HeJ from stilbene precursors.

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4743
unsuccessful results in inducing the desired cascade reaction.
On turning our attention to possible contaminants in the Wit-
tig-derived stilbene, we begun experimentation with Ph3PO as
present in trace amounts in the reaction mixture. It should be
reiterated that only a trace amount of the o-quinone stilbene in-
termediate is necessary for the cascade sequence described in
Scheme 12 to become operative. The direct oxidation of stil-
bene 31 by molecular oxygen is another possibility38 that could
account for the generation of quinone stilbene intermediate 49.
This process is potentially more relevant in the conversion of
stilbene 23 to artochamin I (3) (Scheme 4) or the conversion
of artochamin F (1) to 40 (Scheme 10), where the stilbenes
could, in principle, already contain traces of the corresponding
o-quinones arising from aerial oxidation before entering into
the formal cycloaddition reaction. Given that deprotection of
the catechol moiety of stilbene 5 occurs during the cascade
process, the Ph3PO oxidation cycle described above may also
be relevant in the cascade sequence described in Scheme 8.
In order to gain further insight into these mechanistic pro-
posals, we considered the following experiments to be relevant.
The addition of a more conventional oxidant to the cascade reac-
tion of Scheme 8 should also have a similar effect as Ph3PO, but
obviouslywillnotprovideanyinformationwithrespecttothedif-
ferentiation of the diradical and redox/ionic mechanisms. The in-
clusion of 1 wt % DDQ in this cascade gave similar results to
those obtained with Ph3PO. Interestingly, the initial deep red
color of the reaction mixture was slowly bleached after heating
for a few minutes at 180 ꢀC in o-xylene. Presumably, this color
change signals the fact that the DDQ persists in solution until
the cleavage of both Boc groups from one or more of the cascade
intermediates has occurred, after which time it is reduced by the
free catechol moiety. In an attempt to observe this process spec-
troscopically, stilbene 31 possessing a free catechol moiety was
prepared and reacted with DDQ (1.5 equiv) in CDCl3 at ambient
´
an additive to the JuliaeKocienski derived stilbene. These exper-
iments led us to the discovery that 3e5% w/w of Ph3PO was re-
quired for the desired cascade reaction to take place smoothly.
Although we cannot at present define precisely the exact role
played by the phosphine oxide, some speculations are possible.
To recap our observations, we know that Ph3PO is neither abso-
lutely essential in every instance for the [2þ2] cycloaddition re-
action nor is it required for the Claisen rearrangements or Boc
cleavages. However that it is not essential does not preclude
a role in which it facilitates one or more of the events in the cas-
cade sequence. We suspect that this additive could potentially
facilitate the cycloaddition step based on the following consider-
ations. Proton transfer from phenols to phosphine oxides both in
solution and in solid state has been observed tovary degrees spec-
troscopically.39 In such events, it is typical to observe a downfield
shift of the 1H NMR signal of the hydroxyl group in the phenole
Ph3PO complex as the pKa of the phenol decreases. These results,
together with a recent report23a describing a base-promoted intra-
molecular [2þ2] cycloaddition reaction between a prenyl group
and a benzopyran moiety, suggest that Ph3PO may be acting as
a Lewis base providing formal HOMO activation of the stilbene
system toward cycloaddition. Additionally, it is noteworthy to
mention the distinct color differences of the reaction mixtures
of these cascade reactions in the presence and absence of
Ph3PO. The latter becomes significantly darker in color, suggest-
ing that decomposition does not occur to the same extent in the
presence of the additive.
An intriguing possibility for the role of the Ph3PO in the de-
scribed cascade reactions and in the context of the redox/ionic
mechanism proposed above (Scheme 12) for the biogenesis of
artochamins HeJ is outlined in Scheme 13.
temperature and the reaction mixturewas analyzed by1H and 13
C
NMR spectroscopy (Scheme 14). Exclusive formation of tetra-
cycle 50 was observed in minutes. Formed through initial
oxidation of 31 to o-quinone 49 followed by an intramolecular
[4þ2] cycloaddition as shown in Scheme 14, this conjugated o-
quinone proved too labile for isolation. However, upon removal
of the solvent (CDCl3), dissolution of the residue in o-xylene,
and microwave irradiation at 180 ꢀC for 30 min, cyclobutane
32 was formed (30% overall yield from 31). A most likely path-
way for the conversion of 50 to 32 involves thermally induced re-
versal of the [4þ2] cycloaddition followed by conversion of the
so-obtained o-quinone 49 to 32, via o-quinone 51, by the re-
dox/ionic mechanism described above (Scheme 12). We suspect
that under the acidic reaction conditions and high temperatures,
DielseAlder adduct 50 undergoes rapid tautomerisation to
Given that the redox-based sequence described above is de-
pendent on the initial generation of small amounts of o-qui-
none stilbene, in order to initiate we contemplated the
possible role that Ph3PO might play in this oxidation process.
The somewhat counterintuitive process, outlined in Scheme 13,
hinges upon combining the dehydration reaction known to take
place between Ph3PO and catechols40 and the chelotropic elim-
ination of Ph3P from the so-derived phospholene.38 Thus, for-
mation of phospholene 48 from stilbene 31 (Scheme 13) may
occur under the reaction conditions; its conversion to Ph3P
and o-quinone 49 (which may be reversible) could be driven
by re-oxidation of the former to Ph3PO with molecular oxygen
O2
PPh3
OH
OH
OH
Me
H2O
Ph3PO
Ph3PO
Me
Me
Me
Br
Br
Br
Me
Me
Me
HO
HO
O
O
Ph
Ph
Ph
O
O
OH
OH
OH
P
Me
31
Me
Me
48
Me
Me
49
Scheme 13. Potential role of Ph3PO in the generation of o-quinone intermediate 49.

4744
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
Me
OH
Me
OH
OH
Me
Me
Br
Br
Br
H
Me
Me
[4+2]
Me
O H
a) DDQ
Me
OH
OH
OH
retro[4+2]
100 %
H
O
O
HO
HO
O
Me
Me
49
Me
Me
50
31
b) µ-wave
30 %, 2 steps
tautomerisation
OH
Br
OH
OH
Br
Me
Br
H
H
H
Me
HO
Me
Me
Me
Me
53
OH
H
OH
OH
H
reduction
H
O
HO
O
Me
52
Me
Me
32
Me
Me
Me
HO
O
51
oxidation
OH
OH
Me
tautomerisation
Me
Br
OH
H
Me
Br
H
Me
HO
Me
O
OH
HO
O
Me
53
Me
Me
54
Scheme 14. Spectroscopic observation of DielseAlder adduct 50 from direct oxidation of stilbene 31 and its conversion to cyclobutane 32. Reagents and condi-
tions: (a) DDQ (1.5 equiv), CDCl3, 23 ꢀC, 5 min; (b) m-wave, o-xylene, 180 ꢀC, 30 min; DDQ¼2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
catechol 53, via hydroquinone 52, which may, in turn, be respon-
sible for the reduction of o-quinone 51 to cyclobutane 32, also
leadingtoo-quinone54. Thiscyclereachesequilibrium, account-
ing for the loss of reactivity over longer periods of heating. An-
other scenario in which DielseAlder adduct 50 would lead to
32 is by a formal [1,3]-alkyl shift giving o-quinone 51 directly.
We believe this pathway to be highly unlikely given the formida-
ble geometrical constraints to the required orbital overlap.35
An obvious corollary of the redox/ionic mechanism proposed
inScheme12istheavailabilityofthecatecholunit;giventhatthe
methylene acetal derivative of 58 (Scheme 15) ought to be inert
with respect to oxidation, any formal cycloaddition product ob-
tained from this substrate should be derived from the diradical
pathway shown in Scheme 11, since we have already rejected
theconcertedpathwayonthegroundsofinsufficientorbitalover-
lap. Furthermore, the absence of product in this experiment
would providecircumstantialevidencefortheredox/ionicmech-
anism proposed. We therefore prepared themethylene acetal stil-
bene 58, through intermediates 56 and 57 as depicted in Scheme
15, and subjected it to microwave heating.
Me Me
O
N
N
Ph
Br
N
N
N
N
Ph
HS
N
O
O
O
O
O
O
c) KHMDS, 7
a) Et3N,
N
Br
O
Me
Me
S
O O
(85 %)
b) m-CPBA
(97 %, 2 steps)
57
55
56
-wave
(65 %)
d)
OH
OH
Me
Br
H
Me
Me
Br
OH
e) -wave
Me
OH
Me
X
O
O
H
Me
O
Me
58
Me
O
59
Scheme 15. Construction and microwave irradiation of methylene acetal stilbene 58. Reagents and conditions: (a) 1-phenyl-1H-tetrazole-5-thiol (1.0 equiv), Et3N
(1.25 equiv), THF, 23 ꢀC; then 55 (1.25 equiv), reflux, 14 h; (b) thioether (1.0 equiv), m-CPBA (3.5 equiv), CH2Cl2, 0/23 ꢀC, 24 h; (c) 56 (1.8 equiv), KHMDS
(1.8 equiv), ꢁ78 ꢀC, 30 min; then 7 (1.0 equiv), THF, ꢁ78/23 ꢀC, 1 h, E/Z ca. 2:1; (d) o-xylene, m-wave, 180 ꢀC, 5 min; (e) o-xylene, m-wave, 180 ꢀC, >30 min;
m-CPBA¼3-chloroperbenzoic acid.

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4745
Ph
H
H
N
N
Me
Me
Me
O
S
N
b) -wave
N
O
Me
a) KHMDS, 61
H
X
(74 %)
Me
MeO
MeO
Me
60
E-62 + Z-62, (ca. 4:1)
63
MeO
H
61
Me
Me
Me
Me
O
b) -wave
c) nBuLi, 61
PPh3
Br
H
X
(67 %)
O2N
O2N
O2N
64
E-65 + Z-65, (ca. 1:1)
66
Ph
S
H
H
N
N
Me
Me
Me
Me
b) -wave
O
O
a) KHMDS, 61
N
N
X
(95 %)
H
67
E-68 + Z-68, (ca. 4:1)
69
Me
Me
Me
Me
c) nBuLi, 61
(92 %)
b) -wave
PPh3
Br
H
X
d) HF py
(95 %)
TBSO
HO
E-71 + Z-71, (ca. 1:1)
70
72
HO
Scheme 16. Construction and microwave irradiation of stilbenes 62, 65, 68, and 71. Reagents and conditions: (a) 60 or 67 (1.8 equiv), KHMDS (1.8 equiv), ꢁ78 ꢀC,
30 min; then 61 (1.0 equiv), THF, ꢁ78/23 ꢀC, 1 h, E/Z ca. 4:1 for 62 and 68; (b) o-xylene, m-wave, 180 ꢀC, >30 min; (c) 64 or 70 (1.2 equiv), n-BuLi (1.2 equiv),
THF, 0/23 ꢀC, 30 min; then 58 (1.0 equiv), THF, 0/23 ꢀC, 14 h, E/Z ca. 1:1 for 65 and 71; (d) HF$Py (excess), THF, 0/23 ꢀC, 2 h.
Exposure of stilbene 58 to microwave heating failed to yield
any cyclobutane-containing products; indeed, this substrate was
recovered quantitatively even after prolonged heating (>30 min
at 180 ꢀC). This provides strong circumstantial evidence for the
intervention of the o-quinone intermediate in the formation of
the bicylco[3.2.0]heptane ring system.
diversity from relatively simple starting materials in efficient
and environmentally benign ways.
4. Experimental
4.1. General experimental
In an attempt to further investigate the mechanism of the
formal cycloaddition and to probe the generality of the reac-
tion, four simplified stilbene substrates (62, 65, 68, and 71)
were prepared from known aldehyde 61 as shown in Scheme
16. After microwave heating at 180 ꢀC (>30 min), stilbenes
62, 65, 68, and 71 were recovered quantitatively, clearly dem-
onstrating their failure to undergo the formal cycloaddition
reaction (Scheme 16). These negative results provide further
evidence that the redox/ionic mechanism shown in Scheme
12 is the most likely scenario operating in these reactions.
All reactions were carried out under an argon atmosphere
with dry solvents under anhydrous conditions, unless otherwise
noted. Dry tetrahydrofuran (THF), dimethylformamide (DMF),
triethylamine (Et3N), and methylene chloride (CH2Cl2) were ob-
tained by passing commercially available pre-dried, oxygen-free
formulations through activated alumina columns. Yields refer to
chromatographically and spectroscopically (1H NMR) homoge-
neous materials, unless otherwise stated. Reagents were pur-
chased at the highest commercial quality and used without
further purification, unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
0.25 mm E. Merck silica gel plates (60F-254) using UV light
asthevisualizingagentandanethanolicsolutionofanisaldehyde
and sulfuric acid or an ethanolic solution of phosphomolybdic
acid and cerium sulfate, and heat as developing agents. Prepara-
tive thin-layer chromatographic (PTLC) separations were
carried out on 0.25 or 0.50 mm E. Merck silica gel plates
(60F-254). NMR spectra were recorded on Bruker DRX-600,
DRX-500, or AMX-400 instrument and calibrated usingresidual
undeuterated solvent as an internal reference. The following ab-
breviations were used to designate multiplicities: s¼singlet,
3. Conclusions
Described herein are a series of cascade-based strategies
whose implementation resulted in expeditious and efficient total
syntheses of artochamins HeJ (2e4) as well as artochamin F (1).
The mechanism for those cascade reactions was investigated and
a number of proposals are put forward, including a redox-based
mechanism involving o-quinone species that may be relevant to
the biosynthesis of members of this class. These cascade-based
total syntheses highlight, once again, the advantages of such syn-
thetic sequences in rapidly building molecular complexity and

4746
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, quin¼quintu-
plet, sext¼sextet, sep¼septet, br¼broad. IR spectra were
recorded on a PerkineElmer 1600 series FT-IR spectrometer.
Electrospray ionization (ESI) mass spectrometric (MS) experi-
ments were performed on an API 100 PerkineElmer SCIEX
single quadrupole mass spectrometer at 4000 Vemitter voltage.
High-resolution mass spectra (HRMS) were recorded on a VG
ZAB-ZSE mass spectrometer using MALDI (matrix-assisted
laser-desorption ionization) or ESI (electrospray ionization).
(pH 3) with HCl (1 M) and the layers were separated. The or-
ganic phase was further washed with H2O (4ꢂ2 mL) and brine
(2 mL), and then dried (MgSO4) and concentrated in vacuo.
The residue was purified by column chromatography (60%
CH2Cl2 in hexanes) to give bis-prenyl compound 14 (76.5 mg,
85%) as a clear oil. Rf¼0.22 (silica gel, 60% CH2Cl2 in hexanes);
IR nmax (film) 3464br m, 2965w, 2914w, 2856w, 1717s, 1579m,
1431s, 1363s, 1320m, 1253s, 1206m, 1144s, 1092s, 1023m,
1002w, 927w, 901w, 799w, 775w, 735w, 604w cmꢁ1; 1H NMR
(500 MHz, CDCl3) d¼5.68 (s, 2H), 5.16 (m, 2H), 3.86 (s, 3H),
3.28 (d, J¼7.0 Hz, 4H), 1.73 (s, 6H), 1.70 (s, 6H) ppm; 13C
NMR (125 MHz, CDCl3) d¼169.4, 149.4, 134.3, 133.4, 121.8,
117.2, 101.4, 52.1, 27.3, 25.7, 17.8 ppm; HRMS (ESI TOF)
m/z calcd for C18H23BrO4 [MþHþ]: 383.0852, found: 383.0850.
4.2. First-generation synthesis of artochamin I (3)
4.2.1. 4-Bromo-3,5-bis-(1,1-dimethyl-allyloxy)-benzoic acid
methyl ester (13)
To a solution of methyl 4-bromo-3,5-dihydroxybenzoate (12)
(3.0 g, 12.1 mmol) in CH3CN (120 mL) at 0 ꢀC was added
CuCl2 (30 mg, 0.12 mmol) followed by DBU (5.46 mL,
36.3 mmol). Afterstirringfor 15 min, methyl1,1-dimethyl-2-pro-
pynyl carbonate (5.19 g, 36.3 mmol) was added and the resulting
mixture was stirred at 0 ꢀC overnight. The reaction mixture was
treated with H2O (50 mL) and extracted with Et2O (3ꢂ100 mL),
and then the combined organic extracts were washed with brine
(50 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography (30%EtOAc in hexanes)
to give the bis-alkyne (3.32 g, 83%) as a clear oil. Rf¼0.50 (silica
gel, 30% EtOAc in hexanes); IR nmax (film) 2982m, 1724m,
1576m, 1415m, 1382w, 1364w, 1331m, 1240m, 1134m, 1058s,
1033s, 1014m, 840w, 771w cmꢁ1; 1H NMR (500 MHz, CDCl3)
d¼8.00 (s, 2H), 3.91 (s, 3H), 2.63 (s, 2H), 1.73 (s, 12H) ppm;
13C NMR (125 MHz, CDCl3) d¼166.4, 154.0, 129.0, 117.9,
116.1, 85.4, 74.5, 74.5, 52.4, 29.5 ppm; HRMS (ESI TOF) m/z
calcd for C18H19BrO4 [MþHþ]: 379.0539, found: 379.0544.
To a solution of bis-alkyne (2.50 g, 6.59 mmol) in EtOAc
(66 mL) under an atmosphere of argon at room temperature
was added quinoline (389 mL, 3.30 mmol) followed by 5% Pd/
CaCO3 (poisoned with Pb) (250 mg, 10% w/w). The system
was flushed with H2 and then stirred under an atmosphere of
H2 (balloon) for 3 h. The system was flushed with argon, and
the reaction mixture was filtered through Celite and the filtrate
was concentrated in vacuo. The residue was purified by column
chromatography (10% EtOAc in hexanes) to give the bis-alkene
13 (2.53 g, 100%) as a colorless oil. Rf¼0.18 (silica gel, 15%
EtOAc in hexanes); IR nmax (film) 2982m, 1725s, 1571m,
1415s, 1379w, 1364w, 1334m, 1238s, 1128m, 1072m, 1005w,
4.2.3. 4-Bromo-3,5-dimethoxy-2,6-bis-(3-methyl-but-2-
enyl)-benzoic acid methyl ester (15)
To a solution of bis-phenol 14 (200 mg, 0.52 mmol) in DMF
(10 mL) were added K2CO3 (361 mg, 2.61 mmol) and MeI
(195 mL, 3.13 mmol), and the resulting mixture was heated at
100 ꢀC for 1 h. Once cooled, the reaction mixture was diluted
with EtOAc (30 mL) and washed with H2O (5ꢂ5 mL) and brine
(5 mL), and then dried (MgSO4) and concentrated in vacuo. The
residue was purified by column chromatography (60% CH2Cl2 in
hexanes) to give the bis-methyl ether 15 (204 g, 95%) as a clear
oil. Rf¼0.38 (silica gel, 60% CH2Cl2 in hexanes); IR nmax
(film) 2934w, 2859w, 1730s, 1561w, 1450m, 1434m, 1398s,
1375w, 1319s, 1248m, 1194m, 1144m, 1093s, 1031s, 984m,
1
950w, 925w, 895w, 833w, 802w, 764w, 732w cmꢁ1; H NMR
(500 MHz, CDCl3) d¼5.09 (m, 2H), 3.81 (s, 3H), 3.78 (s, 6H),
3.35 (d, J¼6.5 Hz, 4H), 1.70 (s, 6H), 1.67 (d, J¼1.0 Hz,
6H) ppm; 13C NMR (125 MHz, CDCl3) d¼169.0, 154.6, 135.0,
132.2, 129.6, 122.4, 114.8, 60.9, 52.0, 27.0, 25.6, 17.9 ppm;
HRMS (ESI TOF) m/z calcd for C20H27BrO4 [MþHþ]:
411.1165, found: 411.1164.
4.2.4. [4-Bromo-3,5-dimethoxy-2,6-bis-(3-methyl-but-2-
enyl)-phenyl]-methanol (16)
To a solution of methyl ester 15 (180 mg, 0.44 mmol) in THF
(4.0 mL) at 0 ꢀC was added LiAlH4 (4.4 mL, 4.4 mmol, 1 M so-
lution in THF) and the resulting mixture was warmed to 50 ꢀC
and stirred for 14 h. Excess LiAlH4 was quenched by the addi-
tionof EtOAc, and then H2O (1 mL), NaOH (1 mL, 1 M aqueous
solution), and H2O (2 mL), and MgSO4 were added successively
and the mixturewas filtered. The solvent was concentrated inva-
cuo and the residue was purified by column chromatography
(CH2Cl2) to give alcohol 16 (119 mg; 89%) as a clear oil.
Rf¼0.39 (silica gel, CH2Cl2); IR nmax (film) 3418br m, 2962m,
2913m, 2855m, 1592s, 1453m, 1437m, 1375m, 1311s, 1207m,
1158m, 1114m, 1084s, 1001m, 957w, 927w, 888w, 817m,
756w cmꢁ1; 1H NMR (500 MHz, CDCl3) d¼6.50 (s, 1H), 5.13
(m, 2H), 4.65 (s, 2H), 3.84 (s, 6H), 3.46 (d, J¼7.0 Hz, 4H),
1.81 (s, 6H), 1.69 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3)
d¼156.4, 138.7, 131.0, 124.5, 121.9, 95.8, 59.1, 55.8, 25.7,
24.4, 17.8 ppm; HRMS (ESI TOF) m/z calcd for C19H28O3
[MþHþ]: 305.2111, found: 305.2102.
1
927w, 772w cmꢁ1; H NMR (500 MHz, CDCl3) d¼7.46 (s,
2H), 6.17 (dd, J¼17.6, 6.8 Hz, 2H), 5.24 (d, J¼17.6 Hz, 2H),
5.18 (d, J¼6.8 Hz, 2H), 3.86 (s, 3H), 1.53 (s, 12H) ppm; 13C
NMR (125 MHz, CDCl3) d¼166.6, 154.5, 143.6, 128.5, 118.4,
115.7, 114.1, 82.2, 52.3, 26.9 ppm; HRMS (ESI TOF) m/z calcd
for C18H23BrO4 [MþHþ]: 383.0852, found: 383.0862.
4.2.2. 4-Bromo-3,5-dihydroxy-2,6-bis-(3-methyl-but-2-
enyl)-benzoic acid methyl ester (14)
A solution of bis-alkene 13 (900 mg, 0.24 mmol) in DMF
(2.0 mL) was subjected to microwave heating for 5 min at
180 ꢀC. The reaction mixture was diluted with EtOAc (10 mL)
and H2O (2 mL) was added. The aqueous phase was acidified

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4747
4.2.5. 4-Bromo-3,5-dimethoxy-2,6-bis-(3-methyl-but-2-
enyl)-benzaldehyde (17)
4.2.9. [3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-benzyl]-
triphenylphosphonium bromide (9)
To a solution of alcohol 16 (100 mg, 0.33 mmol) in CH2Cl2
(5.0 mL) at room temperature was added DesseMartin periodi-
nane (209 mg, 0.49 mmol). After 30 min, the reaction mixture
was diluted with Et2O (30 mL) and a solution of Na2S2O3
(840 mg) in saturated aqueous NaHCO3 (10 mL) was added,
and stirring maintained until a clear biphase persisted. The aque-
ous phase was removed and the organic layer was washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL), and
then dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (30% CH2Cl2 in hexanes)
to give aldehyde 7 (93 mg, 94%) as a clear oil. Rf¼0.32 (silica
gel, 30% CH2Cl2 in hexanes); IR nmax (film) 2951m, 2925m,
2850m, 1697m, 1603m, 1588m, 1462m, 1437m, 1375w, 1311s,
1200m, 1163w, 1119w, 1097w, 1082w, 1027w, 965w,
827w cmꢁ1; 1H NMR (400 MHz, CDCl3) d¼10.44 (s, 1H), 6.64
(s, 1H), 5.10 (m, 2H), 3.85 (s, 6H), 3.54 (d, J¼6.8 Hz, 4H), 1.74
(s, 6H), 1.66 (d, J¼0.8 Hz, 6H) ppm; 13C NMR (150 MHz,
CDCl3) d¼195.3, 156.4, 134.9, 131.4, 123.8, 123.5, 99.9, 56.1,
25.8, 23.8, 17.9 ppm; HRMS (ESI TOF) m/z calcd for C19H26O3
[MþHþ]: 303.1955, found: 303.1943.
To a solution of benzyl bromide 21 (503 mg, 1.17 mmol) in
toluene (5.5 mL) was added PPh3 (300 mg, 1.17 mmol) and
the resulting mixture was heated at reflux overnight. The precip-
itate was collected by filtration and dried under vacuum to give
phosphonium bromide 9 (720 mg, 89%) as a white solid, which
displayed identical physical properties to those reported.43
4.2.10. 3-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-
phenyl]-vinyl}-1,5-dimethoxy-2,4-bis-(3-methyl-but-2-enyl)-
benzene (22)
To a solution of phosphonium bromide 9 (127 mg,
0.18 mmol) in THF (9.0 mL) at ꢁ78 ꢀC was added n-BuLi
(71 mL, 0.18 mmol, 2.5 M solution in hexanes) and the resulting
red mixture was stirred for 30 min. A solution of aldehyde 17
(45 mg, 0.15 mmol) in THF (1.0 mL) was added via cannula
and the reaction mixture was warmed to room temperature
over 30 min. Saturated aqueous NaHCO3 (5 mL) was added
and the mixture was extracted with Et2O (3ꢂ20 mL). The com-
bined organic extracts were washed with brine (5 mL), and then
dried (MgSO4) and concentrated in vacuo. The residue was pu-
rified by column chromatography (30% CH2Cl2 in hexanes) to
give Z-22 (17 mg, 18%) followed by E-22 (68 mg, 72%) as clear
oil. Physical data for E-22: Rf¼0.29 (silica gel, 30% CH2Cl2 in
hexanes); IR nmax (film) 2951s, 2928s, 2857m, 1739w, 1585m,
1507s, 1462m, 1433m, 1309m, 1297m, 1253m, 1213w,
4.2.6. 3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde
(19)
Aldehyde 19 was prepared according to the literature and
displayed identical physical properties to those reported.41
1160w, 1120w, 1081w, 991w, 908s, 839s, 806s, 782s cmꢁ1
;
4.2.7. [3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-
methanol (20)
1H NMR (500 MHz, CDCl3) d¼6.94 (d, J¼2.0 Hz, 1H), 6.89
(dd, J¼8.0, 2.0 Hz, 1H), 6.88 (d, J¼16.5 Hz, 1H), 6.80 (d,
J¼8.0 Hz, 1H), 6.46 (s, 1H), 6.38 (d, J¼16.5 Hz, 1H), 5.14
(m, 2H), 3.85 (s, 6H), 3.34 (d, J¼7.0 Hz, 4H), 1.66 (d,
J¼1.0 Hz, 6H), 1.63 (s, 6H), 1.01 (s, 18H), 0.23 (s, 6H), 0.22
(s, 6H) ppm; 13C NMR (150 MHz, CDCl3) d¼156.3, 146.8,
146.5, 139.4, 133.9, 131.6, 130.4, 124.6, 124.1, 120.9, 120.8,
119.7, 118.9, 94.8, 55.9, 26.2, 26.0, 26.0, 25.8, 18.5, 18.5,
18.0, ꢁ4.1, ꢁ4.1 ppm.
To a solution of aldehyde 19 (3.28 g, 8.96 mmol) in EtOH
(45 mL) was added NaBH4 (339 mg, 8.96 mmol) portion wise
at 0 ꢀC. After complete addition, the reaction mixture was
warmed to room temperature and stirred for 10 min. The reac-
tion was quenched with water, extracted with EtOAc
(2ꢂ50 mL), dried (MgSO4), and concentrated in vacuo to yield
benzyl alcohol 20 (3.23 g, 98%). Rf¼0.22 (silica gel, 15%
EtOAc in hexanes); IR (film) nmax 3318br w, 2954m, 2930s,
2886w, 2858s, 1605w, 1578w, 1509s, 1472m, 1422m, 1295s,
1252s, 1158m, 1123m, 904s, 777s cmꢁ1; 1H NMR (500 MHz,
CDCl3) d¼6.85 (s, 1H), 6.80 (s, 2H), 4.55 (d, J¼6.0 Hz, 2H),
1.47 (t, J¼6.0 Hz, 1H), 0.99 (s, 18H), 0.20 (s, 12H) ppm; 13C
NMR (500 MHz, CDCl3) d¼146.9, 146.5, 134.2, 121.0,
120.2, 120.1, 65.2, 25.9, 18.5 ppm; HRMS (ESI TOF) m/z calcd
for C19H36O3Si2 [MþNaþ]: 391.2095, found: 391.2111.
4.2.11. Artochamin I (3)
To a solution of bis-TBS ether E-22 (40 mg, 62.7 mmol) in
THF (500 mL) at 0 ꢀC was added HF$Py (500 mL, excess) and
the resulting mixture was warmed to room temperature and
stirred for an additional 2 h. The reaction mixture was diluted
with Et2O (10 mL) and then washed successively with saturated
aqueous CuSO4 (3ꢂ2 mL), saturated aqueous NaHCO3
(2ꢂ2 mL), and brine (2 mL). The organic layer was then dried
(MgSO4) and concentrated in vacuo. The residue was passed
through a short plug of silica gel (30% EtOAc in hexanes) to
give diol 23 (23 mg, 88%) as a clear oil, which was used directly
in the following reaction.
A solution of stilbene 23 (10 mg, 24.2 mmol) in DMF (2 mL)
was subjected to microwave heating at 180 ꢀC for 20 min. The
reaction mixture was diluted with EtOAc (10 mL) and H2O
(2 mL) was added. The aqueous phase was acidified (pH 3)
with HCl (1 M) and the layers were separated. The organic phase
was further washed with H2O (4ꢂ2 mL) and brine (2 mL), and
then dried (MgSO4) and concentrated in vacuo. The residue
4.2.8. 4-Bromomethyl-1,2-bis-(tert-butyl-dimethyl-
silanyloxy)-benzene (21)
To solution of benzyl alcohol 20 (430 mg, 1.17 mmol) in
CH2Cl2 (5 mL) at 0 ꢀC was added a solution of PBr3 (55 mL,
0.58 mmol) in CH2Cl2 (1.5 mL) and the resulting mixture was
stirred for 10 min. The reaction mixture was diluted with
CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3
(10 mL) and H2O (10 mL), and then dried (MgSO4) and concen-
trated in vacuo to give the corresponding benzyl bromide 21
(503 mg, 100%) as a yellow oil, which displayed identical phys-
ical properties to those reported.42

4748
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
was purified by column chromatography (50% EtOAc in hex-
anes) to give artochamin I (3) (8.0 mg; 80%) as a clear oil.
Rf¼0.17 (silica gel, 30% EtOAc in hexanes); IR nmax (film)
3381br m, 2926s, 2856m, 1701w, 1600s, 1518m, 1492m,
1461s, 1451s, 1436s, 1365m, 1312s, 1282m, 1260m, 1202m,
1119s, 1086s, 1033w, 867w, 806m cmꢁ1; 1H NMR (500 MHz,
(CD3)2CO) d¼7.64 (br s, 2H), 6.79 (d, J¼8.0 Hz, 1H), 6.76 (d,
J¼2.0 Hz, 1H), 6.64 (dd, J¼8.0, 2.0 Hz, 1H), 6.47 (s, 1H),
4.92 (m, 1H), 3.95 (dd, J¼8.0, 6.0 Hz, 1H), 3.84 (s, 3H), 3.79
(s, 3H), 3.03 (dd, J¼16.0, 3.0 Hz, 1H), 2.94e2.91 (m, 1H),
2.88 (dd, J¼17.0, 9.5 Hz, 1H), 2.84 (d, J¼5.5 Hz, 1H), 2.76
(m, 2H), 1.51 (d, J¼1.5 Hz, 3H), 1.42 (s, 3H), 1.01 (s, 3H),
0.75 (s, 3H) ppm; 13C NMR (150 MHz, (CD3)2CO) d¼159.6,
156.4, 150.9, 146.6, 145.2, 135.2, 131.5, 125.6, 125.6, 121.0,
119.0, 117.1, 116.7, 95.9, 59.6, 57.3, 56.5, 46.6, 46.4, 40.1,
31.7, 28.4, 27.6, 27.2, 26.8, 18.8 ppm; HRMS (ESI TOF) m/z
calcd for C26H32O4 [MþHþ]: 409.2373, found: 409.2374.
d¼9.78 (s, 1H), 7.27 (s, 2H), 6.18 (dd, J¼17.5, 11.0 Hz, 2H),
5.27 (d, J¼17.5 Hz, 2H), 5.21 (d, J¼11.0 Hz, 2H), 1.55 (s,
12H) ppm; 13C NMR (125 MHz, CDCl3) d¼191.6, 155.7,
144.0, 135.3, 121.0, 115.1, 114.8, 82.8, 27.4 ppm; HRMS
(ESI TOF) m/z calcd for C17H21BrO3 [MþHþ]: 353.0747,
found: 353.0746.
4.3.3. Carbonic acid 2-tert-butoxycarbonyloxy-4-formyl-
phenyl ester tert-butyl ester (25)
To a solution of 3,4-dihydroxybenzaldehyde 18 (2.0 g,
14.5 mmol) in THF (50 mL) at room temperature were added
di-tert-butyl dicarbonate (6.32 g, 29.0 mmol), i-Pr2NEt
(203 mL, 1.45 mmol), and DMAP (89 mg, 0.72 mmol). After
2 h, the reaction mixture was diluted with EtOAc (100 mL)
and washed with NaOH (50 mL, 1 M aqueous solution) and
brine, and then dried (MgSO4) and concentrated in vacuo to
give aldehyde 25 (4.90 g, 100%), which was used in the next re-
action without further purification. Rf¼0.38 (silica gel, 30%
EtOAc in hexanes); IR nmax (film) 2978w, 2936w, 2868w,
1767m, 1740m, 1704m, 1371m, 1243s, 1151s, 1136s, 1106s,
´
4.3. JuliaeKocienski approach to stilbenes and cascade
strategy for artochamins HeJ (2e4)
1045m, 886m, 865w, 776m, 728m, 634m cmꢁ1 1H NMR
;
4.3.1. [4-Bromo-3,5-bis-(1,1-dimethyl-allyloxy)-phenyl]-
methanol (24)
(500 MHz, CDCl3) d¼9.95 (s, 1H), 7.79 (d, J¼2.0 Hz, 1H),
7.76 (dd, J¼8.5, 2.0 Hz, 1H), 7.44 (d, J¼8.5 Hz, 1H), 1.55 (s,
18H) ppm; 13C NMR (125 MHz, CDCl3) d¼190.0, 150.3,
149.8, 147.3, 143.2, 134.5, 127.9, 124.0, 123.7, 84.5, 84.4,
27.5 ppm; HRMS (ESI TOF) m/z calcd for C17H22O7 [MþNaþ]:
361.1258, found: 361.1259.
To a solution of methyl ester 13 (1.90 g, 4.96 mmol) in THF
(50 mL) at 0 ꢀC was added a solution of LiAlH4 (5.95 mL,
5.95 mmol, 1 M solution in THF). After 10 min, the reaction
was quenched by the addition of H2O (2 mL), NaOH (2 mL,
1 M aqueous solution), and H2O (3 mL), and then MgSO4 was
added and the mixture was filtered. The solvent was concen-
trated in vacuo and the residue was purified by column chroma-
tography (40% Et2O in hexanes) to give alcohol 24 (1.67 g,
95%) as a clear oil. Rf¼0.36 (silica gel, 60% Et2O in hexanes);
IR nmax (film) 3404br w, 2981w, 1572m, 1422s, 1378m, 1363m,
4.3.4. Carbonic acid 2-tert-butoxycarbonyloxy-4-
hydroxymethyl-phenyl ester tert-butyl ester (26)
To a solution of aldehyde 25 (4.44 g, 13.1 mmol) in EtOH
(70 mL) at 0 ꢀC was added NaBH4 (548 mg, 13.1 mmol), and
the reaction mixture was warmed to room temperature and stirred
for 10 min. Saturated aqueous NH4Cl (50 mL) was added and the
mixture was extracted with Et2O (3ꢂ100 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried (MgSO4),
and concentrated in vacuo. The residue was purified by column
chromatography (30% EtOAc in hexanes) to give alcohol 26
(4.24 g, 95%)asaclearoil.Rf¼0.38 (silica gel, 30% EtOAc in hex-
anes); IR nmax (film) 3377br s, 2976w, 2934w, 2874w, 1766m,
1217w, 1127s, 1057s, 999m, 923m, 864m, 704m cmꢁ1; H
1
NMR (500 MHz, CDCl3) d¼6.82 (s, 2H), 6.18 (dd, J¼15.0,
9.0 Hz, 2H), 5.22 (d, J¼15.0 Hz, 2H), 5.14 (d, J¼9.0 Hz, 2H),
4.52 (d, J¼5.0 Hz, 2H), 1.51 (s, 12H) ppm; 13C NMR
(125 MHz, CDCl3) d¼154.6, 144.2, 139.6, 113.9, 113.6,
111.9, 81.8, 65.0, 26.9 ppm; HRMS (ESI TOF) m/z calcd for
C17H23BrO3 [MþHþ]: 355.0903, found: 355.0906.
1371m, 1252s, 1154s, 1113s, 1046m, 880m, 777m, 734m cmꢁ1
;
4.3.2. [4-Bromo-3,5-bis-(1,1-dimethyl-allyloxy)]-
benzaldehyde (7)
1H NMR (500 MHz, CDCl3) d¼7.31 (d, J¼8.5 Hz, 1H), 7.30 (d,
J¼2.0 Hz, 1H), 7.11 (dd, J¼8.5, 2.0 Hz, 1H), 4.67 (s, 2H), 1.58
(s, 18H) ppm; 13C NMR (125 MHz, CDCl3) d¼150.8, 150.8,
142.4, 141.6, 139.8, 124.5, 122.9, 121.4, 83.8, 83.7, 27.6 ppm;
HRMS (ESI TOF) m/z calcd for C24H24O7 [MþNaþ]: 363.1414,
found: 363.1414.
To a solution of alcohol 24 (1.66 g, 4.67 mmol) in CH2Cl2
(25 mL) at room temperature was added DesseMartin periodi-
nane (2.4 g, 5.61 mmol). After 30 min, the reaction mixture was
diluted with Et2O (100 mL) and a solution of Na2S2O3 (9.6 g) in
saturated aqueous NaHCO3 (20 mL) was added and stirring was
maintained until a clear biphase persisted. The aqueous phase
was removed and the organic layer was washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL), then dried
(MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (30% Et2O in hexanes) to give alde-
hyde 7 (1.60 g, 97%) as aclear oil. Rf¼0.34(silica gel, 30% Et2O
in hexanes); IR nmax (film) 2982w, 1696s, 1570s, 1421s, 1379s,
1364m, 1325m, 1217w, 1124s, 1072s, 1035s, 1001m, 924m,
4.3.5. Carbonic acid 4-bromomethyl-2-tert-butoxycar-
bonyloxy-phenyl ester tert-butyl ester (27)
To a solution of alcohol 26 (500 mg, 1.47 mmol) in CH2Cl2
(10 mL) was added PBr3 (0.28 mL, 2.94 mmol) dropwise and
the resulting solution was stirred at 0 ꢀC for 1 h. The reaction
was quenched with water (3 mL), and then extracted with Et2O
(3ꢂ5 mL), and the combined organic extracts were washed
with saturated aqueous NaHCO3 (3 mL) and brine (3 mL), then
dried (K2CO3) and concentrated in vacuo to yield the
827m, 757m, 704m cmꢁ1 1H NMR (500 MHz, CDCl3):
;

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4749
corresponding bromide (104 mg, 18%) as an orange oil. Rf¼0.69
4.3.8. Carbonic acid 2-tert-butoxycarbonyloxy-4-(1-phenyl-
1H-tetrazole-5-sulfonylmethyl)-phenyl ester tert-butyl
ester (10)
(silica gel, 50%EtOAcinhexanes); IR(film)nmax 2981w, 2935w,
1761s, 1610w, 1508m, 1457w, 1433w, 1395m, 1370m, 1248s,
1143s, 1109s, 1046w, 1014w, 888m cmꢁ1
;
1H NMR
To a solution of alcohol 26 (5.4 g, 17.5 mmol) in THF
(175 mL) at 0 ꢀC were added PPh3 (5.1 g, 19.3 mmol), 1-phe-
nyl-1H-tetrazole-5-thiol (3.12 g, 17.5 mmol), and DEAD
(3.31 mL, 21.0 mmol). After stirring for 30 min at 0 ꢀC, saturated
aqueous NaHCO3 (75 mL) was added and the reaction mixture
was extracted with Et2O (3ꢂ100 mL). The combined organic ex-
tracts were washed with brine (75 mL), dried (MgSO4), and con-
centrated in vacuo. The residue was purified by column
chromatography (30% EtOAc in hexanes) to give the sulfide
(6.74 g, 77%) as a yellow oil.
To a solution of the sulfide (5.04 g, 10.1 mmol) in EtOH
(120 mL) at room temperature was added a cooled (0 ꢀC) solution
of ammonium molybdate tetrahydrate (1.25 g, 0.10 mmol) in
H2O2 (120 mL). The resulting yellow mixture was allowed to
stir for 14 h before being diluted with H2O (100 mL) and extracted
with EtOAc (3ꢂ100 mL). The combined organic extracts were
washed with brine (100 mL), dried (MgSO4), and concentrated
in vacuo. The residue was purified by column chromatography
(40%EtOAcinhexanes)togivesulfone 10(5.31 g, 99%)asawhite
powder. Rf¼0.44 (silica gel, 40% EtOAc in hexanes); IR nmax (film)
2982w, 2935w, 1763s, 1508w, 1497w, 1371m, 1356m, 1249s,
1148s, 1112s, 1046m, 1014m, 890m, 763m, 733m, 688m,
(500 MHz, CDCl3) d¼7.34 (d, J¼1.5 Hz, 1H), 7.30e7.26 (m,
2H), 4.47 (s, 2H), 1.58 (s, 9H), 1.58 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3) d¼150.5, 150.4, 142.3, 142.2, 136.1, 126.9,
123.7, 123.2, 83.9, 31.9, 27.5 ppm; HRMS (ESI TOF) m/z calcd
for C17H23BrO6 [MþNaþ]: 425.0570, found: 425.0564.
4.3.6. [3,4-Bis-(tert-butoxycarbonyloxy)-benzyl]-triphenyl-
phosphonium bromide (8)
A mixture of bromide 27 (170 mg, 0.42 mmol) and triphenyl-
phosphine (166 mg, 0.63 mmol) in toluene (3.0 mL) was heated
to 60 ꢀC and stirred overnight. The solvent was then removed in
vacuo to give phosphonium bromide 8 (151 mg; 62%) as a white
solid. IR (film) nmax 2981w, 2870w, 2773w, 1769s, 1755s,
1589w, 1505w, 1438m, 1371m, 1284m, 1251s, 1157s, 1137m,
1113s, 886m cmꢁ1; 1H NMR (500 MHz, DMSO-d6) d¼7.93e
7.90 (m, 5H), 7.77e7.62 (m, 10H), 7.17 (d, J¼8.0 Hz, 1H),
6.96 (d, J¼8.5 Hz, 1H), 6.89 (s, 1H), 5.25 (d, J¼15.5 Hz, 2H),
1.46 (s, 9H), 1.44 (s, 9H) ppm; 13C NMR (150 MHz, DMSO-
d6) d¼149.6 (d, J¼8.6 Hz), 149.5 (d, J¼8.1 Hz), 142.0 (d,
J¼4.2 Hz), 141.7 (d, J¼3.6 Hz), 135.1 (d, J¼2.7 Hz), 134.0
(d, J¼9.9 Hz), 130.1 (d, J¼12.5 Hz), 126.7 (d, J¼8.6 Hz),
125.5 (d, J¼5.4 Hz), 123.6 (d, J¼2.9 Hz), 117.3 (d,
J¼85.1 Hz), 84.0 (s), 83.9 (s), 27.5 (d, J¼47.0 Hz), 27.0 (s),
26.9 (s) ppm; HRMS (ESI TOF) m/z calcd for C35H38O6P
535m cmꢁ1
;
1H NMR (500 MHz, CDCl3) d¼7.56e7.52 (m,
1H), 7.50e7.47 (m, 2H), 7.33e7.31 (m, 2H), 7.22 (d, J¼2.0 Hz,
1H), 7.22 (d, J¼8.5 Hz, 1H), 7.16 (dd, J¼8.5, 2.0 Hz, 1H), 4.87
(s, 2H), 1.54 (s, 9H), 1.53 (s, 9H) ppm; 13C NMR (125 MHz,
CDCl3) d¼152.6, 150.2, 143.8, 142.8, 132.6, 131.3, 129.5,
129.4, 126.3, 125.4, 123.8, 123.3, 84.2, 61.4, 27.5 ppm; HRMS
(ESI TOF) m/z calcd for C24H28N4O8S [MþNaþ]: 555.1520,
found: 555.1512.
ꢃ
[Mþ ]: 585.2406, found: 585.2392.
4.3.7. Carbonic acid 4-{2-[4-bromo-3,5-bis-(1,1-dimethyl-
allyloxy)-phenyl]-vinyl}-2-tert-butoxycarbonyloxy-phenyl
ester tert-butyl ester (5)
To a solution of phosphonium bromide 8 (200 mg,
0.30 mmol) in THF (1.2 mL) at ꢁ78 ꢀC was added t-BuOK
(34 mg, 0.30 mmol) and the resulting red mixture was stirred
for 30 min. A solution of aldehyde 7 (88 mg, 0.25 mmol) in
THF (500 mL) was added via cannula and the reaction mixture
was warmed to room temperature over 30 min. Saturated aque-
ous NaHCO3 (5 mL) was added and the mixture was extracted
with Et2O (3ꢂ15 mL). The combined organic extracts were
washed with brine (5 mL), and then dried (MgSO4) and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (30% CH2Cl2 in hexanes) to give Z-22 (16.5 mg, 44%)
followed by E-22 (17.5 mg, 46%) as clear oils. Physical data
for E-22: Rf¼0.23 (silica gel, 15% Et2O in hexanes); IR nmax
(film) 2981w, 1767s, 1582w, 1506w, 1414w, 1370w, 1253s,
4.3.9. 5-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl-
methanesulfonyl]-1-phenyl-1H-tetrazole (11)
To a solution of benzyl alcohol 20 (2.14 g, 5.80 mmol),
Ph3P (1.67 g, 6.39 mmol), and 1-phenyl-1H-tetrazole-5-thiol
(1.03 g, 5.80 mmol) at 0 ꢀC in THF (58 mL) was added
DEAD (3.17 mL, 6.97 mmol). The mixture was stirred for
30 min at 0 ꢀC and then treated with saturated aqueous
NaHCO3 (30 mL) and diluted with Et2O (55 mL). The phases
were separated and the aqueous phase was extracted with Et2O
(2ꢂ40 mL). The combined organic extracts were washed with
brine (30 mL), dried (MgSO4), and concentrated in vacuo to
yield the sulfide as a yellow oil.
A solution of the sulfide prepared above (4.47 g, 8.45 mmol)
in EtOH (84.5 mL), THF (16.9 mL), and H2O2 (31.7 mL) was
treated with ammonium molybdate tetrahydrate (2.1 g,
1.69 mmol) at room temperature. The mixture was stirred over-
night, and then partitioned with CH2Cl2 (60 mL) and saturated
aqueous NH4Cl (30 mL). The layers were separated and the
aqueous phase was extracted with CH2Cl2 (2ꢂ30 mL) and the
combinedorganicextractsweredried(MgSO4)andconcentrated
in vacuo to yield 11 (4.09 g, 86%, over two steps) as a white
foam. Rf¼0.26 (silica gel, 10% EtOAc in hexanes); IR (film)
nmax 2954w, 2930m, 2887w, 2858m, 1599w, 1577w, 1509s,
1156s, 1115m, 1072w cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d¼7.37 (d, J¼2.4 Hz, 1H), 7.32 (dd, J¼8.4, 2.4 Hz, 1H), 7.23
(d, J¼8.4 Hz, 1H), 6.95 (s, 2H), 6.83 (s, 2H), 6.22 (dd, J¼17.6,
10.8 Hz, 2H), 5.25 (dd, J¼17.6, 0.8 Hz, 2H), 5.19 (dd, J¼10.8,
0.8 Hz, 2H), 1.56 (s, 9H), 1.55 (s, 9H) 1.53 (s, 12H) ppm; 13C
NMR (125 MHz, CDCl3) d¼150.8, 150.7, 144.6, 144.4, 144.3,
144.3, 142.8, 141.9, 135.9, 135.5, 129.5, 127.4, 127.3, 124.6,
123.3, 120.9, 120.9, 120.8, 113.9, 113.8, 112.7, 83.9, 82.0,
27.8, 27.7, 27.0, 26.9 ppm; HRMS (ESI TOF) m/z calcd for
C34H43BrO8 [MþHþ]: 659.2214, found: 659.2197.

4750
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
1472m, 1424m, 1346s, 1304s, 1253s, 1154s, 1137s, 985s, 905s,
1
4.3.12. 5-Bromo-2-(3,4-dihydroxy-phenyl)-1,1-dimethyl-3-
(3-methyl-but-2-enyl)-2,2a,7,7a-tetrahydro-1H-cyclobuta-
[a]indene-4,6-diol (32)
780s, 761s cmꢁ1; H NMR (500 MHz, CDCl3) d¼7.59e7.55
(m, 1H), 7.52e7.49 (m, 2H), 7.38 (m, 2H), 6.82 (d, J¼2.5 Hz,
1H), 6.78 (d, J¼8.5 Hz, 1H), 6.74 (dd, J¼8.0, 2.0 Hz, 1H),
4.81 (s, 2H), 0.97 (s, 9H), 0.96 (s, 9H), 0.19 (s, 6H), 0.15 (s,
6H) ppm; 13C NMR (150 MHz, CDCl3) d¼153.0, 148.6,
147.3, 132.9, 131.3, 129.4, 125.3, 124.7, 124.1, 121.2, 117.0,
62.0, 25.8, 25.8, 18.4, 18.3, ꢁ4.1, ꢁ4.2 ppm; HRMS (ESI
TOF) m/z calcd for C26H40N4O4SSi2 [MþHþ]: 561.2381, found:
561.2379.
Stilbene 31 (12.2 mg, 18.5 mmol) and Ph3PO (0.6 mg, 5%
w/w) were dissolved in o-xylene (1.5 mL), and the resulting so-
lution was subjected to microwave heating at 180 ꢀC for 20 min.
Alternatively, heating could be conducted conventionally with
an oil bath at 165 ꢀC for 1 h. The cooled reaction mixturewas di-
rectly loaded onto a silica gel column packed with hexanes as the
eluant and the o-xylene was run off. The eluant was switched to
10% Et2O in CH2Cl2 and the cycloaddition product 32 (4.7 mg,
55%) was obtained as an inseparable 5:1 mixture of diastereo-
mers. Major diastereomer: Rf¼0.13 (silica gel, 5% MeOH in
CH2Cl2); IR nmax (film) 3475br s, 2956m, 2928m, 2855m,
1719w, 1600m, 1517m, 1441s, 1367m, 1285s, 1249s, 1188m,
1158m, 1105m, 1093m, 966w, 804w, 786w, 766w,
4.3.10. Carbonic acid 4-{2-[4-bromo-3,5-bis-(1,1-dimethyl-
allyloxy)-phenyl]-vinyl}-2-tert-butoxycarbonyloxy-phenyl
ester tert-butyl ester (5)
To a solution of sulfone 10 (1.13 g, 2.12 mmol) in THF
(20 mL) at ꢁ78 ꢀC was added KHMDS (4.24 mL, 2.12 mmol,
0.5 Msolutionintoluene)andthe resultingbrightyellow solution
was stirred for 30 min. A solution of aldehyde 7 (500 mg,
1.42 mmol) in THF (5 mL) was then added via cannula and the
reaction mixture was slowly warmed to room temperature. The
reaction was quenched by the addition of saturated aqueous
NaHCO3 (20 mL) and then extracted with Et2O (3ꢂ30 mL).
The combined organic extracts were washed with brine
(20 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography (15% Et2O in hexanes)
to give stilbene 5 (747 mg, 80%, 100% E) as a white powder. For
physical data see Section 4.3.7.
741w cmꢁ1
;
1H NMR (500 MHz, CDCl3) d¼6.82 (d,
J¼8.0 Hz, 1H), 6.76 (d, J¼2.0 Hz, 1H), 6.67 (dd, J¼8.0,
2.0 Hz, 1H), 5.48 (s, 1H), 5.25 (s, 1H), 5.11 (s, 1H), 5.00 (m,
1H), 4.97 (s, 1H), 3.95 (ddd, J¼8.0, 6.0, 1.0 Hz, 1H), 3.13
(ddd, J¼16.0, 3.0, 1.0 Hz, 1H), 3.08 (d, J¼7.0 Hz, 1H), 3.01
(dd, J¼16.5, 9.5 Hz, 1H), 3.00 (m, 1H), 2.89 (d, J¼6.0 Hz,
1H), 2.80 (m, 1H), 1.61 (d, J¼1.0 Hz, 3H), 1.54 (s, 3H), 1.05
(s, 3H), 0.76 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d¼149.8, 149.3, 146.6, 143.2, 141.6, 134.6, 133.5, 122.8,
121.9, 120.4, 115.6, 115.1, 115.0, 97.6, 57.4, 44.7, 44.6, 38.7,
30.5, 27.3, 27.0, 25.8, 25.7, 17.5 ppm; HRMS (ESI TOF) m/z
calcd for C24H27BrO4 [MþHþ]: 459.1165, found: 459.1145.
4.3.11. 5-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-
phenyl]-vinyl}-2-bromo-1,3-bis-(1,1-dimethyl-allyloxy)-
benzene (6)
4.3.13. 2,2-Dimethyl-propionic acid 5-[5-bromo-6-(2,2-
dimethyl-propionyloxy)-4-hydroxy-1,1-dimethyl-2,2a,7,7a-
tetrahydro-1H-cyclobuta[a]inden-2-yl]-2-(2,2-dimethyl-
propionyloxy)-phenyl ester (33)
To a solution of sulfone 11 (163 mg, 0.29 mmol) in DME
(26 mL) at ꢁ78 ꢀC was added KHMDS (0.6 mL, 0.30 mmol,
0.5 M solution in toluene) and the resulting bright yellow solu-
tion was stirred for 30 min. A solution of aldehyde 7 (57.0 mg,
0.16 mmol) in DME (1.4 mL) was then added via cannula and
the reaction mixture was slowly warmed to room temperature.
The reaction was quenched by the addition of saturated aqueous
NaHCO3 (3 mL) and the mixture was extracted with Et2O
(3ꢂ6 mL). The combined organic extracts were washed with
brine (3 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography (25% benzene
in hexanes) to give stilbene 6 (107 mg, 95%, E/Z ca. 2:1) as a yel-
low oil. Rf¼0.57 (silica, 10% EtOAc in hexanes); IR (film) nmax
2951m, 2930s, 2858m, 1566m, 1508s, 1472w, 1421m, 1291m,
To a solution of tetraol 32 (16.0 mg, 34.8 mmol) in CH2Cl2
(300 mL) at room temperature was added Et3N (29 mL,
209 mmol) followed by trimethylacetyl chloride (105 mL,
104.5 mmol, 1 M solution in CH2Cl2). After 30 min, the reaction
mixture was diluted with EtOAc (2 mL) and the aqueous layer
was acidified to pH 3 with aqueous HCl (1 M). The layers
were separated and the aqueous phase was further extracted
with EtOAc (3ꢂ2 mL). The combined extracts were washed
with brine (1 mL), dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography (10e
20% Et2O in hexanes) to afford the tris-protected compound
33 (18.6 mg, 75%) as a white foam. Rf¼0.23 (silica gel, 20%
Et2O in hexanes); IR nmax (film) 3473br s, 2962m, 2929m,
2855m, 1760s, 1505m, 1480m, 1460m, 1397s, 1368s, 1271m,
1253m, 1128m, 1069m, 994w, 906m, 839s, 804w, 782s cmꢁ1
;
1H NMR (500 MHz, CDCl3) d¼6.98e6.91 (m, 4H), 6.81e
6.79 (m, 1H), 6.76 (d, J¼16.2 Hz, 1H), 6.68 (d, J¼16.2 Hz,
1H), 6.23 (dd, J¼17.4, 10.8 Hz, 2H), 5.24 (d, J¼17.4 Hz, 2H),
5.17 (d, J¼17.4 Hz, 2H), 1.54 (s, 6H), 1.53 (s, 6H), 1.01 (s,
9H), 0.98 (s, 9H), 0.22 (s, 6H), 0.21 (s, 6H) ppm; 13C NMR
(150 MHz, CDCl3) d¼154.5, 147.1, 147.0, 144.4, 136.3,
130.7, 129.0, 126.4, 121.2, 120.1, 119.2, 113.8, 113.5, 112.1,
81.9, 26.8, 26.0, 25.9, 18.4, ꢁ4.1, ꢁ4.1 ppm; HRMS (ESI
TOF) m/z calcd for C36H55BrO4Si2 [MþHþ]: 687.2895, found:
687.2879.
1259m, 1115s, 1029s, 890w cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d¼7.10e7.07 (m, 2H), 6.96 (d, J¼2.0 Hz, 1H), 5.56
(s, 1H), 4.99 (m, 1H), 4.00 (dd, J¼7.0, 5.0 Hz, 1H), 3.03 (dd,
J¼16.0, 4.5 Hz, 1H), 2.99 (d, J¼5.0 Hz, 1H), 2.96e2.86 (m,
3H), 2.82 (m, 1H), 1.60 (d, J¼1.0 Hz, 3H), 1.47 (s, 3H), 1.42
(s, 9H), 1.36 (s, 9H), 1.35 (s, 9H), 1.05 (s, 3H), 0.75 (s,
3H) ppm; 13C NMR (150 MHz, CDCl3) d¼176.0, 175.7,
175.2, 150.3, 147.9, 142.4, 142.2, 140.8, 139.7, 133.4, 130.0,
125.5, 125.4, 122.8, 122.5, 121.2, 103.2, 57.0, 44.7, 44.6,
39.4, 39.1, 38.9, 30.3, 29.7, 27.3, 25.6, 17.8 ppm; HRMS (ESI

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4751
TOF) m/z calcd for C39H51BrO7 [MþNaþ]: 733.2710, found:
4.3.16. 2,2-Dimethyl-propionic acid 5-(5-bromo-4,6-
733.2724.
dihydroxy-1,1-dimethyl-2,2a,7,7a-tetrahydro-1H-cyclobuta-
[a]inden-2-yl)-2-(2,2-dimethyl-propionyloxy)-phenyl
ester (35)
4.3.14. 2,2-Dimethyl-propionic acid 5-[5-bromo-6-(2,2-
dimethyl-propionyloxy)-4-methoxy-1,1-dimethyl-2,2a,7,7a-
tetrahydro-1H-cyclobuta[a]inden-2-yl]-2-(2,2-dimethyl-
propionyloxy)-phenyl ester (34)
To a solution of tetraol 32 (15.0 mg, 32.7 mmol) in CH2Cl2
(300 mL) at room temperature was added pyridine (16.0 mL,
196 mmol) followed by trimethylacetyl chloride (66 mL,
66.0 mmol, 1 M solution in CH2Cl2). After stirring at room tem-
perature overnight, the reaction mixture was diluted with EtOAc
(2 mL) and the aqueous layer was acidified to pH 3 with aqueous
HCl (1 M). The layers were separated and the aqueous phase was
further extracted with EtOAc (3ꢂ2 mL). The combined extracts
werewashed with brine (1 mL), dried (MgSO4), and then concen-
trated invacuo. The residuewas purified by column chromatogra-
phy (30e40% Et2O in hexanes) to afford the bis-protected
compound 35 (13.1 mg, 64%) as a white foam. Rf¼0.24 (silica
gel, 30% Et2O in hexanes); IR nmax (film) 3450brm, 2970m,
2931m, 2865w, 1758m, 1737m, 1595w, 1505w, 1480w, 1458w,
1367w, 1276w, 1259m, 1228m, 1117s, 1032w, 891w,
To a solution of phenol 33 (5.5 mg, 7.73 mmol) in DMF
(250 mL) was added K2CO3 (5.3 mg, 38.5 mmol) followed by
MeI (3.0 mL, 46.2 mmol) and the resulting mixture was stirred
at 100 ꢀC for 1 h. Upon cooling the reaction mixture was diluted
with EtOAc (2 mL), washed with H2O (5ꢂ1 mL) and brine
(1 mL), and finally dried (MgSO4) before removal of the solvent
in vacuo. The residue was purified by column chromatography
(20% Et2O in hexanes) to afford the methylated compound 34
(5.3 mg, 95%) as a white foam. Rf¼0.36 (silica gel, 20% Et2O
in hexanes); IR nmax (film) 2956m, 2925m, 2860m, 1760s,
1501w, 1476w, 1458w, 1395w, 1365w, 1319w, 1260m, 1111s,
1
1026m, 800w cmꢁ1; H NMR (500 MHz, CDCl3): d¼7.08 (d,
1
790w cmꢁ1; H NMR (600 MHz, CDCl3) d¼7.10e7.07 (m,
J¼8.0 Hz, 1H), 7.02 (dd, J¼8.0, 2.0 Hz, 1H), 6.94 (d,
J¼2.0 Hz, 1H), 4.91 (m, 1H), 4.02 (dd, J¼8.0, 6.0 Hz, 1H),
3.76 (s, 3H), 3.04e2.87 (m, 5H), 2.81 (m, 1H), 1.56 (s, 3H),
1.43 (s, 9H), 1.42 (s, 3H), 1.35 (s, 9H), 1.35 (s, 9H), 1.06 (s,
3H), 0.75 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) d¼176.0,
175.7, 175.3, 155.1, 148.1, 143.2, 142.2, 140.8, 139.6, 134.5,
132.5, 129.8, 125.3, 122.8, 122.4, 121.9, 110.1, 61.1, 56.9,
44.6, 44.4, 39.4, 39.1, 39.1, 38.9, 31.0, 30.3, 27.3, 27.3, 27.3,
25.8, 25.5, 17.8 ppm; HRMS (ESI TOF) m/z calcd for
C40H53BrO7 [MþHþ]: 725.3047, found: 725.3042.
2H), 6.96 (d, J¼1.2 Hz, 1H), 5.51 (s, 1H), 5.26 (s, 1H), 5.02 (m,
1H), 3.95 (dd, J¼7.8, 5.4 Hz, 1H), 3.14e3.09 (m, 2H), 3.04e
2.98 (m, 3H), 2.85 (m, 1H), 1.62 (d, J¼1.2 Hz, 3H), 1.54 (s,
3H), 1.35 (s, 9H), 1.35 (s, 9H), 1.07 (s, 3H), 0.77 (s, 3H) ppm;
13C NMR (150 MHz, CDCl3) d¼176.0, 175.7, 149.9, 147.9,
146.6, 142.2, 140.7, 139.8, 133.9, 125.4, 122.8, 122.8, 122.5,
121.7, 115.7, 97.8, 57.1, 44.7, 44.6, 39.1, 39.1, 39.0, 30.5, 27.3,
27.3, 27.3, 27.1, 25.9, 25.7, 17.8 ppm; HRMS (ESI TOF) m/z
calcd for C34H43BrO6 [MþNaþ]: 649.2135, found: 649.2123.
4.3.15. Artochamin H (2)
4.3.17. Artochamin I (3)
To a solution of compound 34 (4.0 mg, 5.51 mmol) in THF
(100 mL) at 0 ꢀC was added LiAlH4 (33 mL, 33.1 mmol, 1 M so-
lution in THF). The resulting mixture was warmed to room tem-
perature and allowed to stir for 24 h. Excess LiAlH4 was
destroyed bytheadditionof EtOAcand themixturewasacidified
to pH 3 with aqueous HCl (1 M). The layers were separated and
the aqueous phase was extracted with EtOAc (3ꢂ2 mL). The
combined organic extracts werewashed with brine (1 mL), dried
(MgSO4), andconcentratedinvacuo. Theresiduewaspurifiedby
column chromatography (50% EtOAc in hexanes) to afford arto-
chamin H (2) (2.0 mg, 93%) as a clear oil. Rf¼0.43 (silica gel,
50% EtOAc in hexanes); IR nmax (film) 3366s, 2955m, 2925m,
2856m, 1691m, 1599s, 1518m, 1445s, 1365m, 1347m, 1309m,
1280s, 1256s, 1191s, 1160m, 1109s, 1059m, 960w, 868m,
To a solution of bis-phenol 35 (6.0 mg, 9.56 mmol) in DMF
(300 mL) was added K2CO3 (6.6 mg, 47.8 mmol) followed by
MeI (3.6 mL, 57.4 mmol) and the resulting mixture was stirred
at 100 ꢀC for 1 h. Upon cooling the reaction mixture was
diluted with EtOAc (2 mL), washed with H2O (5ꢂ1 mL)
and brine (1 mL), and finally dried (MgSO4) before removal
of the solvent in vacuo. The residue was purified by column
chromatography (20% Et2O in hexanes) to afford the methyl-
ated compound 36 (6.0 mg, 96%) as a foam, which was used
directly in the following reaction.
To a solution of compound 36 (3.7 mg, 5.64 mmol) in THF
(100 mL) at 0 ꢀC was added LiAlH4 (33.6 mL, 33.6 mmol, 1 M so-
lution in THF). The resulting mixturewas warmed to room temper-
ature and allowed to stir for 24 h. Excess LiAlH4 was destroyed by
the addition of EtOAc and the mixture was acidified to pH 3 with
aqueous HCl (1 M). The layers were separated and the aqueous
phasewasextracted with EtOAc (3ꢂ2 mL). The combined organic
extracts were washed with brine (1 mL), dried (MgSO4), and con-
centrated invacuo. The residuewas purified by column chromatog-
raphy (30% EtOAc in hexanes) to afford artochamin I (3) (2.2 mg,
95%) as a clear oil. Rf¼0.17 (silica gel, 30% EtOAc in hexanes); IR
nmax (film) 3381br m, 2926s, 2856m, 1701w, 1600s, 1518m,
1492m, 1461s, 1451s, 1436s, 1365m, 1312s, 1282m, 1260m,
1
806m, 784m cmꢁ1; H NMR (600 MHz, (CD3)2CO) d¼7.79
(br s, 1H), 7.66 (br s, 2H), 6.79 (d, J¼7.8 Hz, 1H), 6.78 (d,
J¼1.8 Hz, 1H), 6.64 (dd, J¼7.8, 1.8 Hz, 1H), 6.31 (s, 1H),
4.91 (m, 1H), 3.96 (dd, J¼7.8, 6.0 Hz, 1H), 3.70 (s, 3H), 3.07
(ddd, J¼16.8, 3.0, 1.2 Hz, 1H), 3.01 (dd, J¼14.4, 6.0 Hz, 1H),
2.90 (dd, J¼16.8, 9.6 Hz, 1H), 2.80 (m, 2H), 2.75 (m, 1H),
1.50 (d, J¼1.2 Hz, 3H), 1.41 (s, 3H), 1.03 (s, 3H), 0.75 (s,
3H) ppm; 13C NMR (150 MHz, (CD3)2CO) d¼159.5, 153.6,
151.1, 146.5, 145.1, 135.3, 131.3, 125.8, 124.0, 121.2, 118.2,
117.1, 116.6, 99.4, 59.6, 57.0, 46.7, 46.5, 40.1, 31.4, 28.5,
27.6, 27.2, 26.8, 18.7 ppm; HRMS (ESI TOF) m/z calcd for
C25H30O4 [MꢁHꢁ]: 393.2071, found: 393.2079.
1202m, 1119s, 1086s, 1033w, 867w, 806m cmꢁ1 1H NMR
;
(500 MHz, (CD3)2CO) d¼7.64 (br s, 2H), 6.79 (d, J¼8.0 Hz,
1H), 6.76 (d, J¼2.0 Hz, 1H), 6.64 (dd, J¼8.0, 2.0 Hz, 1H), 6.47

4752
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
(s, 1H), 4.92 (m, 1H), 3.95 (dd, J¼8.0, 6.0 Hz, 1H), 3.84 (s, 3H),
3.79 (s, 3H), 3.03 (dd, J¼16.0, 3.0 Hz, 1H), 2.94e2.91 (m, 1H),
2.88 (dd, J¼17.0, 9.5 Hz, 1H), 2.84 (d, J¼5.5 Hz, 1H), 2.76 (m,
2H), 1.51 (d, J¼1.5 Hz, 3H), 1.42 (s, 3H), 1.01 (s, 3H), 0.75 (s,
3H) ppm; 13C NMR (150 MHz, (CD3)2CO) d¼159.6, 156.4,
150.9, 146.6, 145.2, 135.2, 131.5, 125.6, 125.6, 121.0, 119.0,
117.1, 116.7, 95.9, 59.6, 56.5, 46.6, 46.4, 40.1, 31.7, 28.4, 27.6,
27.2, 26.8, 18.8 ppm; HRMS (ESI TOF) m/z calcd for C26H32O4
[MþHþ]: 409.2373, found: 409.2374.
d¼7.12e708 (m, 2H), 6.99 (d, J¼1.8 Hz, 1H), 5.93 (d,
J¼10.2 Hz, 1H), 5.45 (d, J¼10.2 Hz, 1H), 3.96 (dd, J¼8.4,
5.4 Hz, 1H), 3.87 (s, 3H), 3.17 (dd, J¼16.8, 1.8 Hz, 1H), 3.07
(dd, J¼16.8, 9.6 Hz, 1H), 3.00 (d, J¼5.4 Hz, 1H), 2.85 (m,
1H), 1.45 (s, 3H), 1.39 (s, 3H), 1.36 (s, 9H), 1.35 (s, 9H), 1.07
(s, 3H), 0.76 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d¼176.1, 175.9, 153.1, 149.9, 144.1, 142.2, 140.7, 139.7,
135.8, 130.1, 129.8, 125.5, 125.4, 122.9, 122.5, 119.4, 114.2,
103.9, 59.9, 56.7, 44.9, 43.3, 39.2, 39.1, 34.7, 34.2, 30.9, 30.3,
28.1, 27.6, 27.3, 27.3, 27.1, 25.8, 14.1 ppm; HRMS (ESI TOF)
m/z calcd for C35H43BrO6 [MþHþ]: 639.2316, found: 639.2319.
4.3.18. Benzopyran 37
To a solution of the bis-protected compound 35 (8.6 mg,
13.7 mmol) in CH2Cl2 (350 mL) at ꢁ78 ꢀC was added a solution
of PhSeCl (3.0 mg, 13.7 mmol)in CH2Cl2 (50 mL). After 30 min,
the reaction mixture was briefly warmed to room temperature
before being diluted with CH2Cl2 (2 mL) and washed with
H2O (1 mL). The organic phase was dried (MgSO4) and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (20% Et2O in hexanes) to afford the corresponding
selenide (10.2 mg, 95%) as a yellow oil, which was subjected
to oxidation without further analysis.
To a solution of the above selenide (10.2 mg, 13.0 mmol) in
CH2Cl2 (200 mL) at 0 ꢀC was added H2O2 (16.0 mL, 30% aq).
The resulting biphase was warmed to room temperature and
stirred rapidly for 3 h before being diluted with CH2Cl2 (2 mL),
washedwithH2O(1 mL),dried(MgSO4),andconcentratedinva-
cuo. The residue was purified by column chromatography (20%
Et2O in hexanes) to afford benzopyran 37 (7.3 mg, 89%) as
a white foam. Rf¼0.46 (silica gel, 20% Et2O in hexanes); IR
nmax (film) 3483br w, 2956m, 2929m, 2860m, 1716m, 1596w,
1505w, 1479w, 1462w, 1393w, 1367w, 1259w, 1226w, 1201w,
1120s, 1029w, 943w, 895w cmꢁ1; 1H NMR (500 MHz, CDCl3)
d¼7.10 (m, 2H), 6.98 (m, 1H), 5.92 (d, J¼10.2 Hz, 1H), 5.61
(s, 1H), 5.36 (d, J¼10.2 Hz, 1H), 3.98 (t, J¼6.0 Hz, 1H), 3.12
(dd, J¼16.5, 2.0 Hz, 1H), 3.02 (d, J¼6.0 Hz, 1H), 3.00 (dd,
J¼16.5, 9.6 Hz, 1H), 2.85 (m, 1H), 1.38 (s, 3H), 1.36 (s, 9H),
1.35 (s, 9H), 1.35 (s, 3H), 1.09 (s, 3H), 0.77 (s, 3H) ppm; 13C
NMR (150 MHz, CDCl3) d¼176.1, 175.9, 149.3, 148.3, 144.2,
142.2, 140.7, 139.7, 135.7, 128.3, 125.5, 125.3, 123.0, 122.7,
122.4, 119.5, 110.1, 97.7, 56.7, 45.0, 43.4, 39.2, 39.2, 34.2,
30.4, 30.3, 29.7, 28.1, 27.5, 27.3, 27.3, 27.1, 25.8, 16.2 ppm;
HRMS (ESI TOF) m/z calcd for C34H41BrO6 [MþHþ]:
625.2159, found: 625.2141.
4.3.20. Artochamin J (4)
To a solution of methylbenzopyran 38 (4.3 mg, 6.72 mmol) in
THF (100 mL) at 0 ꢀC was added LiAlH4 (40 mL, 40.2 mmol,
1 M solution in THF). The resulting mixture was warmed to
room temperature and allowed to stir for 24 h. Excess LiAlH4
was destroyed by the addition of EtOAc and the mixture was
acidified to pH 3 with aqueous HCl (1 M). The layers were sep-
arated and the aqueous phase was extracted with EtOAc
(3ꢂ2 mL). The combined organic extracts were washed with
brine (1 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography (40% EtOAc
in hexanes) to afford artochamin J (4) (2.5 mg, 94%) as a clear
oil. Rf¼0.32 (silica gel, 40% EtOAc in hexanes); IR nmax
(film) 3387s, 2951s, 2926s, 2855m, 1706w, 1605s, 1519m,
1483m, 1461m, 1440m, 1364m, 1317m, 1259m, 1199m,
1124s, 1065w, 1019w, 910w, 857w, 802m cmꢁ1 1H NMR
;
(600 MHz, (CD3)2CO) d¼7.72 (br s, 2H), 6.81 (d, J¼7.8 Hz,
1H), 6.79 (d, J¼1.8 Hz, 1H), 6.66 (dd, J¼7.8, 1.8 Hz, 1H),
6.20 (s, 1H), 6.00 (d, J¼10.2 Hz, 1H), 5.37 (d, J¼10.2 Hz,
1H), 3.96 (dd, J¼7.8, 6.6 Hz, 1H), 3.80 (s, 3H), 3.01 (dd,
J¼16.8, 1.8 Hz, 1H), 2.89e2.76 (m, 2H), 2.75 (m, 1H), 1.33
(s, 3H), 1.31 (s, 3H), 1.05 (s, 3H), 0.76 (s, 3H) ppm; 13C NMR
(150 MHz, (CD3)2CO) d¼157.4, 154.7, 146.6, 145.8, 144.4,
133.8, 128.1, 125.3, 120.7, 120.0, 115.9, 115.9, 110.5, 98.6,
76.5, 58.3, 55.6, 45.8, 44.5, 39.4, 30.8, 28.4, 27.8, 27.4,
26.1 ppm; HRMS (ESI TOF) m/z calcd for C25H28O4
[MþHþ]: 393.2060, found: 393.2062.
4.3.21. 5-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-
phenyl]-vinyl}-2-bromo-4,6-bis-(3-methyl-but-2-enyl)-
benzene-1,3-diol (39)
Stilbene 6 (10.0 mg, 14.5 mmol) was dissolved in o-xylene
(1.0 mL) and the resulting solution was subjected to microwave
heating at 180 ꢀC for 5 min. The reaction mixture was then di-
rectly loaded onto a silica gel column packed with hexanes as
the eluant and o-xylene was run off. The eluant was switched
to 2% EtOAc in hexanes and the Claisen product 39 (9.5 mg,
95%) was obtained as a yellow oil. Rf¼0.11 (silica gel, 4%
EtOAc in hexanes); IR (film) nmax 3423br m, 2956m, 2929m,
2858m, 1569m, 1507s, 1472w, 1440w, 1299s, 1252s, 1151m,
1123m, 1091m, 981m, 905s, 837s, 805s, 732s cmꢁ1; 1H NMR
(600 MHz, CDCl3) d¼6.93e6.90 (m, 2H), 6.82 (d, J¼16.2 Hz,
1H), 6.80 (d, J¼7.8 Hz, 1H), 6.36 (d, J¼16.8 Hz, 1H), 5.54 (s,
2H), 5.18 (m, 2H), 3.42 (d, J¼6.6 Hz, 4H), 1.70 (s, 6H), 1.68
(s, 6H), 1.00 (s, 9H), 0.99 (s, 9H), 0.22 (s, 6H), 0.21 (s,
4.3.19. Methylbenzopyran 38
To a solution of pyran 37 (5.0 mg, 7.99 mmol) in DMF
(150 mL) was added K2CO3 (5.5 mg, 40.0 mmol) followed by
MeI (3.0 mL, 48.0 mmol), and the resulting mixture was stirred
at 100 ꢀC for 1 h. Upon cooling the reaction mixture was diluted
with EtOAc (2 mL), washed with H2O (5ꢂ1 mL) and brine
(1 mL), and finally dried (MgSO4) before removal of the solvent
in vacuo. The residue was purified by column chromatography
(10% Et2O in hexanes) to afford the methylated compound 38
(4.8 mg, 94%) as a foam. Rf¼0.36 (silica gel, 20% Et2O in hex-
anes); IR nmax (film) 2962m, 2933m, 2870w, 1760s, 1590w,
1505w, 1480w, 1460w, 1417w, 1397w, 1367w, 1258m, 1119s,
1097s, 1029w, 993w, 891w cmꢁ1; 1H NMR (600 MHz, CDCl3)

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4753
6H) ppm; 13C NMR (150 MHz, CDCl3) d¼149.1, 146.9, 146.8,
1138.4, 134.7, 132.8, 130.9, 125.5, 123.7, 122.7, 121.0, 119.8,
118.9, 118.8, 98.7, 30.3, 27.4, 25.9, 25.8, 18.5, 18.4, 18.0 ppm;
HRMS (ESI TOF) m/z calcd for C36H55BrO4Si2 [MþHþ]:
687.2895, found: 687.2896.
1193m, 1160m, 1109m, 1088s, 971w cmꢁ1
,
1H NMR
(600 MHz, (CD3)2CO) d¼7.67 (s, 1H), 7.66 (s, 1H), 7.41 (br s,
1H), 6.77 (s, 1H), 6.76 (d, J¼8.4 Hz, 1H), 6.59 (dd, J¼8.4,
1.5 Hz, 1H), 6.25 (s, 1H), 4.97 (br t, 1H), 3.89 (t, J¼6.6 Hz,
1H), 3.01e2.98 (m, 2H), 2.87e2.79 (m, 3H), 2.70 (br t,
J¼6.6 Hz, 1H), 1.49 (br s, 3H), 1.38 (br s, 3H), 0.99 (br s, 3H),
0.71 (br s, 3H) ppm; 13C NMR (150 MHz, (CD3)2CO) d¼156.6,
153.5, 151.2, 146.5, 145.1, 135.4, 131.2, 126.0, 123.3, 121.2,
117.1, 116.6, 103.0, 59.6, 46.7, 46.6, 40.0, 29.7, 28.5, 27.6, 27.2,
26.8, 18.8 ppm; HRMS (ESI TOF) m/z calcd for C24H28O4
[MþHþ]: 381.2060, found: 381.2051.
4.3.22. Artochamin F (1)
A solution of Claisen product 39 (10.0 mg, 14.5 mmol) and
Bu3SnH (8.0 mL, 30.0 mmol) in benzene (200 mL) at room tem-
peraturewas stirredfor30 min. Thena catalytic amount ofAIBN
was added and the mixture was heated at reflux for 1 h. The re-
actionmixturewasconcentratedinvacuoandtheresiduewaspu-
rified by column chromatography (silica gel, 30% EtOAc in
hexanes) to give the de-brominated material (8.0 mg, 88%) as
a brown oil. Rf¼0.22 (silica gel, 30% EtOAc in hexanes); IR
(film) nmax 3427br s, 2929s, 2858s, 1594s, 1508s, 1472m,
1301s, 1253s, 1160m, 1124m, 1085m, 981m, 907s, 839s,
4.3.24. 5-Bromo-2-(3,4-dihydroxy-phenyl)-1,1-dimethyl-3-
(3-methyl-but-2-enyl)-2,2a,7,7a-tetrahydro-1H-cyclobuta-
[a]indene-4,6-diol (32)
To a solution of bis-silyl ether 39 (82.2 mg, 0.12 mmol) in
THF (500 mL) at 0 ꢀC was added HF$Py (200 mL, excess) and
the reaction mixture was warmed to ambient temperature and
stirred for 2 h. The reaction mixture was diluted with Et2O
(20 mL) and then washed successively with saturated aqueous
CuSO4 (3ꢂ5 mL), saturated aqueous NaHCO3 (2ꢂ5 mL), and
brine (5 mL). The organic layer was then dried (MgSO4) and
concentrated in vacuo. The residue was passed through a short
plug of silica gel (30% EtOAc in hexanes) to give diol 31
(52 mg, 95%) as a clear oil, which was used directly in the fol-
lowing reaction. Rf¼0.20 (silica gel, 30% EtOAc in hexanes);
IR nmax (film) 3440br s, 2974m, 2913m, 1595m, 1574m,
1515m, 1436s, 1404w, 1375w, 1348w, 1315w, 1283s, 1254s,
1191m, 1151m, 1090s, 1029w, 957w, 908w, 874w, 814w,
781s cmꢁ1
;
1H NMR (600 MHz, CDCl3) d¼6.93e6.91 (m,
2H), 6.86 (d, J¼16.2 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H), 6.33 (d,
J¼16.8 Hz, 2H), 5.21e5.19 (m, 2H), 5.07 (s, 2H), 3.37 (d,
J¼6.6 Hz, 4H), 1.73 (s, 12H), 1.54 (s, 18H), 1.00 (s, 6H), 0.99
(s, 6H) ppm; 13C NMR (150 MHz, CDCl3) d¼154.7, 146.8,
139.0, 134.5, 133.8, 131.0, 125.5, 124.6, 122.8, 121.0, 119.7,
118.9, 117.7, 102.7, 30.3, 26.9, 25.9, 25.8, 18.5, 18.4,
18.0 ppm; HRMS (ESI TOF) m/z calcd for C36H56O4Si2
[MþHþ]: 609.3790, found: 609.3780.
To a solution of bis-silyl ether 39 (8.0 mg, 13.1 mmol) in THF
(1.0 mL) at room temperature was added HF$NEt3 (13 mL, ex-
cess) and the reaction mixture was stirred for 2 h. The reaction
mixture was quenched with saturated aqueous NaHCO3
(3 mL), extracted with EtOAc (3ꢂ4 mL), and the combined or-
ganic extracts were washed with brine (3 mL), dried (MgSO4),
and concentrated in vacuo to yield artochamin F (1) (4.6 mg,
92%) as a white foam. Rf¼0.14 (silica gel, 35% EtOAc in hex-
anes); IR nmax (film) 3358br s, 2951m, 2925s, 2855m, 1718m,
1
786m, 661w cmꢁ1; H NMR (500 MHz, CDCl3) d¼6.68 (d,
J¼8.5 Hz, 1H), 6.56e6.52 (m, 3H), 6.33 (d, J¼12.5 Hz, 1H),
5.66 (s, 2H), 5.56 (br s, 1H), 5.47 (br s, 1H), 5.00e4.96 (m,
2H), 3.30 (d, J¼7.0 Hz, 4H), 1.68 (s, 6H), 1.60 (d, J¼1.0 Hz,
6H) ppm; 13C NMR (125 MHz, CDCl3) d¼149.5, 143.4,
142.8, 137.8, 133.2, 131.2, 130.1, 125.5, 122.5, 122.1, 118.1,
115.2, 115.0, 98.6, 27.4, 25.7, 17.8 ppm; HRMS (ESI TOF)
m/z calcd for C24H27BrO4 [MþHþ]: 459.1165, found: 459.1166.
To a solution of stilbene 31 (5.9 mg, 12.8 mmol) in CDCl3
(400 mL) was added a solution of DDQ (4.4 mg, 19.2 mmol) in
CDCl3 (200 mL) at ambient temperature. After 5 min, the mix-
ture was filtered through cotton wool and the 1H and 13C NMR
1
1602m, 1512w, 1444s, 1260s, 1088s, 802m cmꢁ1; H NMR
(500 MHz, (CD3)2CO) d¼7.90 (br s, 1H), 7.88 (br s, 1H), 7.78
(s, 1H), 7.04 (d, J¼1.5 Hz, 1H), 6.91 (d, J¼16.5 Hz, 1H), 6.84
(dd, J¼6.5, 2.0 Hz, 1H), 6.82 (d, J¼8.0 Hz, 1H), 6.42 (s, 1H),
6.36 (d, J¼16.5 Hz, 1H), 5.18 (br t, J¼6.5 Hz, 2H), 3.32 (d,
J¼7.0 Hz, 4H), 1.64 (br s, 6H), 1.62 (br s, 6H) ppm; 13C NMR
(150 MHz, (CD3)2CO) d¼154.7, 146.5, 146.2, 140.8, 134.9,
131.6, 130.2, 126.2, 125.5, 120.0, 118.8, 116.6, 114.0, 102.6,
27.2, 26.3, 18.6 ppm; HRMS (ESI TOF) m/z calcd for
C24H28O4 [MþHþ]: 381.2060, found: 381.2043.
1
spectra were recorded. H NMR (500 MHz, CDCl3) d¼6.27
(dd, J¼12.0, 1.0 Hz, 1H), 6.50 (d, J¼12.0 Hz, 1H), 6.42 (dd,
J¼7.0, 1.5 Hz, 1H), 5.46 (s, 1H), 5.34 (s, 1H), 5.10e5.07 (m,
1H), 3.50e3.46 (m, 1H), 3.44 (dd, J¼3.5, 2.0 Hz, 1H), 3.39
(dd, J¼16.0, 7.0 Hz, 1H), 3.16 (d, J¼6.5 Hz, 1H), 3.12 (dd,
J¼13.0, 5.0 Hz, 1H), 2.35 (ddd, J¼13.0, 5.0, 3.5 Hz, 1H), 2.13
(t, J¼13.0 Hz, 1H), 1.79 (s, 3H), 1.71 (d, J¼1.0 Hz, 3H), 1.15
(s, 3H), 1.09 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3)
d¼193.6, 190.0, 149.4, 148.9, 148.1, 144.5, 136.3, 133.6,
128.3, 128.1, 127.2, 121.3, 119.8, 117.3, 100.4, 62.3, 46.7,
44.5, 30.0, 28.4, 27.0, 25.7, 25.4, 18.0 ppm.
4.3.23. 2-(3,4-Dihydroxy-phenyl)-1,1-dimethyl-3-(3-methyl-
but-2-enyl)-2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene-
4,6-diol (40)
Artochamin F (1) (5.0 mg, 13.1 mmol) was dissolved in o-xy-
lene (0.5 mL) and the resulting solution was subjected to micro-
wave heating at 180 ꢀC for 10 min. The reaction mixture was
then purified by preparatory thin-layer chromatography (50%
EtOAc in hexanes, few drops AcOH) to yield cycloadduct 40
(4.0 mg, 82%) as a clear oil. Rf¼0.11 (silica gel, 55% EtOAc in
hexanesþ0.5% AcOH); IR nmax (film) 3364br s, 2956m, 2925s,
2856w, 2504br w, 1697s, 1602s, 1516s, 1440s, 1365s, 1255s,
The crude reaction mixture from above was concentrated in
vacuo, and then re-dissolved in o-xylene (2 mL) and heated at
180 ꢀC for 30 min by microwave irradiation. The reaction
mixture was concentrated in vacuo and purified by column
chromatography (10% Et2O in CH2Cl2) to give cyclobutane

4754
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
32 (2.4 mg, 40%, two steps), which displayed identical phys-
ical properties to those reported above.
101.2, 81.8, 26.8 ppm; HRMS (ESI TOF) m/z calcd for
C25H27BrO4 [MþHþ]: 471.1165, found: 471.1144.
4.3.25. 5-(Benzo[1,3]dioxol-5-ylmethanesulfonyl)-1-phenyl-
1H-tetrazole (56)
4.3.27. 5-(2-Benzo[1,3]dioxol-5-yl-vinyl)-2-bromo-4,6-bis-
(3-methyl-but-2-enyl)-benzene-1,3-diol (58)
To a solution of 1-phenyl-1H-tetrazole-5-thiol (432 mg,
2.42 mmol) in dry THF (9.0 mL) was added Et3N (0.42 mL,
3.03 mmol) and the mixture was stirred at room temperature. Af-
ter 40 min, 5-bromomethyl-benzo[1.3]dioxole 55 (651 mg,
3.03 mmol) was added and the reaction mixture was heated at re-
flux overnight, and then diluted with water (20 mL) and extracted
with Et2O (3ꢂ20 mL). Thecombined organic extracts were dried
(MgSO4) and concentrated in vacuo to give the crude thioether.
m-CPBA (251 mg, 1.12 mmol, 77% w/w) was added in
small portions to a solution of the crude thioether (100 mg,
0.32 mmol) in CH2Cl2 (2.0 mL) at 0 ꢀC and the mixture was
then stirred at room temperature for 24 h. The reaction mixture
was washed with saturated aqueous Na2S2O3 (2ꢂ5 mL) and
saturated aqueous NaHCO3 (3ꢂ2 mL). The organic layer
was then dried (MgSO4) and the solvent removed in vacuo to
yield 56 (107 mg, 97%) as a white foam. Rf¼0.30 (silica gel,
30% EtOAc in hexanes); IR (film) nmax 3072w, 2997w,
2912w, 1765w, 1595w, 1489s, 1445s, 1339s, 1245s, 1216w,
1154s, 1134m, 1101m, 1015m, 1035s, 925s, 812s,
Stilbene 57 (15 mg, 25.3 mmol) was dissolved in o-xylene
(2 mL) and the resulting solution was subjected to microwave
heating at 180 ꢀC for 5 min. The reaction mixture was then di-
rectly loaded onto a silica gel column packed with hexanes as
the eluant and the o-xylene was run off. The eluant was switched
to 10e30% Et2O in hexanes and the Claisen product 58 (10 mg,
65%) was obtained as a white powder. Rf¼0.21 (silica, 20% Et2O
in hexanes); IR (film) nmax 3452br m, 2956w, 2920w, 2855w,
1723w, 1568w, 1502m, 1487s, 1444s, 1365w, 1314w, 1253s,
1194m, 1155m, 1086m, 1040m, 975m, 933m, 869w,
801m cmꢁ1
;
1H NMR (500 MHz, CDCl3) d¼7.02 (d,
J¼1.5 Hz, 1H), 6.86 (d, J¼16.5 Hz, 1H), 6.85 (dd, J¼8.0,
1.5 Hz 1H), 6.80 (d, J¼8.0 Hz, 1H), 6.41 (d, J¼16.5 Hz, 1H),
5.98 (s, 2H), 5.54 (s, 2H), 5.17 (m, 2H), 3.41 (d, J¼7.0 Hz,
4H), 1.71 (d, J¼1.0 Hz, 6H), 1.69 (s, 6H) ppm; 13C NMR
(125 MHz, CDCl3) d¼149.1, 148.1, 147.4, 138.2, 134.6,
132.8, 131.7, 124.0, 122.7, 121.3, 118.9, 108.5, 105.4, 101.1,
98.8, 27.4, 25.8, 18.0 ppm; HRMS (ESI TOF) m/z calcd for
C25H27BrO4 [MꢁHꢁ]: 469.1009, found: 469.1014.
1
761s cmꢁ1; H NMR (500 MHz, CDCl3) d¼7.56 (tt, J¼7.5,
1.5 Hz, 1H), 7.50 (m, 2H), 7.42 (m, 2H), 6.80 (d, J¼1.5 Hz,
1H), 6.77 (dd, J¼8.0, 2.0 Hz, 1H), 6.74 (d, J¼8.0 Hz, 1H),
5.94 (s, 2H), 4.83 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3)
d¼152.9, 148.9, 148.1, 132.7, 131.2, 129.3, 125.7, 125.1,
117.6, 111.4, 108.6, 101.5, 62.0 ppm; HRMS (ESI TOF) m/z
for C15H12N4O4S [MþHþ]: 345.0652, found: 345.0656.
4.3.28. 5-(4-Methoxy-phenylmethanesulfonyl)-1-phenyl-1H-
tetrazole (60)
To a solution of p-methoxybenzyl alcohol (500 mg,
3.62 mmol), Ph3P (1.04 g, 3.98 mmol), and 1-phenyl-1H-tetra-
zole-5-thiol (645 mg, 3.62 mmol) at 0 ꢀC in THF (36 mL) was
added DEAD (2.0 mL, 4.34 mmol). The mixture was stirred for
30 min at 0 ꢀC, treated with saturated aqueous NaHCO3
(15 mL), and diluted with Et2O (20 mL). The layers were sepa-
rated and the aqueous phase was extracted with Et2O
(2ꢂ20 mL). The combined organic extracts were washed with
brine (15 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography (15% EtOAc
in hexanes) to yield the corresponding sulfide (975 mg, 90%)
as a yellow oil.
A solution of the sulfide from above (975 mg, 3.27 mmol) in
EtOH (33 mL), THF (6.5 mL), and H2O2 (12.6 mL) was treated
with ammonium molybdate (808 mg, 0.65 mmol) at room tem-
perature. The mixture was stirred overnight and then partitioned
between CH2Cl2 (15 mL) and saturated aqueous NH4Cl
(15 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2ꢂ15 mL). The combined organic ex-
tracts were dried (MgSO4) and then concentrated in vacuo to
yield sulfone 60 (1.09 g, 100%) as a white solid. Rf¼0.26 (silica
gel, 20% EtOAc in hexanes); IR (film) nmax 2970w, 2913w,
1611m, 1512m, 1493m, 1463w, 1446w, 1352s, 1307m, 1251s,
1180m, 1154s, 1137s, 1025s, 878m, 849m, 838m, 754s,
684s cmꢁ1; 1H NMR (500 MHz, CDCl3) d¼7.56 (m, 1H), 7.49
(m, 2H), 7.36 (d, J¼8.0 Hz, 2H), 7.24 (d, J¼8.5 Hz, 2H), 6.86
(d, J¼8.5 Hz, 2H), 4.87 (s, 2H), 3.80 (s, 3H) ppm; 13C NMR
(125 MHz, CDCl3) d¼160.8, 152.9, 132.9, 131.3, 129.3,
125.2, 116.3, 114.6, 61.8, 55.4 ppm;HRMS(ESITOF) m/z calcd
for C15H14N4O3S [MþHþ]: 331.0859, found: 331.0859.
4.3.26. 5-{2-[4-Bromo-3,5-bis-(1,1-dimethyl-alloxy)-
phenyl]-vinyl}-benzo[1,3]dioxole (57)
To a solution of sulfone 56 (87.7 mg, 0.26 mmol) in THF
(2.6 mL) at ꢁ78 ꢀC was added KHMDS (540 mL, 0.27 mmol,
0.5 M solution in toluene) and the resulting bright yellow solu-
tion was stirred for 30 min. A solution of aldehyde 7 (50 mg,
0.14 mmol) in THF (1.4 mL) was then added via cannula and
the reaction mixture was slowly warmed to room temperature.
The reaction was quenched by the addition of saturated aqueous
NaHCO3 (10 mL) and then extracted with Et2O (3ꢂ15 mL). The
combined organic extracts were washed with brine (10 mL),
dried (MgSO4), and concentrated in vacuo. The residue was pu-
rified by column chromatography (5e10% Et2O in hexanes) to
give stilbene 57 (57 mg, 85%, E/Z 2:1) as a white powder.
Rf¼0.15 (silica, 10% Et2O in hexanes); IR (film) nmax 2981m,
2931w, 1578m, 1560s, 1503s, 1489s, 1445s, 1413s, 1378m,
1363m, 1331w, 1252s, 1235m, 1196w, 1161w, 1128s, 1069m,
1039s, 1003w, 956m, 930m, 858w, 823w, 798w cmꢁ1 1H
;
NMR (500 MHz, CDCl3) d¼7.03 (d, J¼1.5 Hz, 1H), 6.94 (s,
2H), 6.91 (dd, J¼8.0, 1.5 Hz, 1H), 6.81 (d, J¼16.0 Hz, 1H),
6.79 (d, J¼8.0 Hz, 1H), 6.73 (d, J¼16.0 Hz, 1H), 6.23 (dd,
J¼17.5, 11.0 Hz, 2H), 5.97 (s, 2H), 5.52 (dd, J¼17.5, 1.0 Hz,
2H), 5.18 (dd, J¼17.5, 1.0 Hz, 2H), 1.53 (s, 12H) ppm; 13C
NMR (125 MHz, CDCl3) d¼154.6, 148.2, 147.4, 144.4, 136.0,
131.5, 128.7, 126.6, 121.6, 113.7, 113.6, 112.1, 108.4, 105.5,

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4755
4.3.29. 2-(3-Methyl-but-2-enyl)-benzaldehyde (61)
Aldehyde 61 was prepared according to the literature and
displayed identical physical properties to those reported.44
126.9, 126.5, 125.9, 124.2, 123.4, 122.8, 32.4, 25.7, 18.0 ppm;
HRMS (ESI TOF) m/z calcd for C19H19NO2 [MþHþ]:
294.1488, found: 294.1480.
4.3.30. 1-(3-Methyl-but-2-enyl)-2-(4-methoxystyryl)-
benzene (62)
4.3.33. 1-Phenyl-5-phenylmethanesulfonyl-1H-tetrazole (67)
Sulfone 67 was prepared according to the literature and
displayed identical physical properties to those reported.45
To a solution of sulfone 60 (228 mg, 0.69 mmol) in THF
(70 mL) at ꢁ78 ꢀC was added KHMDS (1.4 mL, 0.69 mmol,
0.5 M solution in toluene) and the resulting solution was stirred
for 30 min. A solution of aldehyde 61 (100 mg, 0.57 mmol) in
THF (6.0 mL) was then added via cannula and the reaction mix-
ture was slowly warmed to room temperature. The reaction was
quenched by the addition of saturated aqueous NaHCO3
(30 mL) and then extracted with Et2O (3ꢂ40 mL). The com-
bined organic extracts were washed with brine (30 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by column chromatography (2% Et2O in hexanes) to give stil-
bene 62 (118 mg, 74%, E/Z 4:1) as a yellow oil. Rf¼0.08 (silica
gel, 10% CH2Cl2 in hexanes); IR (film) nmax 2911w, 2854w,
2835w, 1605s, 1509s, 1450m, 1440m, 1294m, 1247s, 1173s,
4.3.34. 1-(3-Methyl-but-2-enyl)-2-styryl-benzene (68)
To a solution of sulfone 67 (310 mg, 1.03 mmol) in THF
(103 mL) at ꢁ78 ꢀC was added KHMDS (2.2 mL, 1.1 mmol,
0.5 M solution in toluene) and the resulting solution was stirred
for 30 min. A solution of aldehyde 61 (100 mg, 0.57 mmol) in
THF (6.0 mL) was then added via cannula and the reaction mix-
ture was slowly warmed to room temperature. The reaction was
quenchedby the addition of saturatedaqueous NaHCO3 (30 mL)
and then extracted with Et2O (3ꢂ40 mL). The combined organic
extracts were washed with brine (30 mL), dried (MgSO4), and
concentrated invacuo. The residuewas purified by column chro-
matography (2% Et2O in hexanes) to give stilbene 68 (136 mg,
95%, E/Z 4:1) as a yellow oil. Rf¼0.28 (silica gel, 2% Et2O in
hexanes); IR (film) nmax 3025w, 2967w, 2912w, 2854w,
1599m, 1577w, 1494m, 1480w, 1449m, 1375m, 959s, 757s,
1
1033s, 960s, 816s, 746s cmꢁ1; H NMR (600 MHz, CDCl3)
d¼7.58 (d, J¼6.6 Hz, 1H), 7.44 (d, J¼8.4 Hz, 2H), 7.23 (d,
J¼15.6 Hz, 1H), 7.21e7.18 (m, 3H), 6.94 (d, J¼16.2 Hz, 1H),
6.91 (d, J¼9.0 Hz, 2H), 5.29e5.26 (t, J¼7.2 Hz, 1H), 3.84 (s,
3H), 3.46 (d, J¼7.2 Hz, 2H), 1.77 (s, 3H), 1.74 (s, 3H) ppm;
13C NMR (150 MHz, CDCl3) d¼159.2, 139.1, 132.2, 130.6,
129.6, 129.3, 127.7, 127.3, 126.2, 125.5, 124.4, 123.0, 114.1,
55.3, 32.4, 25.7, 18.0 ppm; HRMS (ESI TOF) m/z calcd for
C20H22O [MþHþ]: 278.1706, found: 279.1706.
689s cmꢁ1
;
1H NMR (600 MHz, CDCl3) d¼7.62e7.61 (m,
1H), 7.51 (d, J¼7.8 Hz, 2H), 7.40e7.37 (m, 2H), 7.37 (d,
J¼15.6 Hz, 1H), 7.28e7.27 (m, 1H), 7.23e7.21 (m, 3H), 6.99
(d, J¼16.2 Hz, 1H), 5.28 (t, J¼7.2 Hz, 1H), 3.48 (d, J¼7.2 Hz,
2H), 1.77 (s, 3H), 1.74 (s, 3H) ppm; 13C NMR (150 MHz,
CDCl3) d¼139.4, 137.7, 136.1, 132.3, 130.0, 129.3, 128.7,
127.7, 127.6, 127.5, 126.6, 126.5, 126.4, 126.3, 125.7, 123.0,
32.4, 25.7, 18.0 ppm; HRMS (ESI TOF) m/z calcd for C19H20
[MþHþ]: 248.1638, found: 249.1632.
4.3.31. (4-Nitro-benzyl)-triphenylphosphonium bromide (64)
Phosphonium bromide 64 was purchased from Aldrich
Chemical Co.
4.3.35. [4-[(tert-Butyldimethysilyl)oxy]benzyl]triphenyl-
phosphonium bromide (70)
Phosphonium bromide 70 was prepared according to the lit-
erature and displayed identical physical properties to those
reported.46
4.3.32. 1-(3-Methyl-but-2-enyl)-2-(4-nitrostyryl)-benzene (65)
To a solution of (4-nitrobenzyl)triphenylphosphonium bro-
mide (64) (329 mg, 0.69 mmol) in THF (7.0 mL) at 0 ꢀC was
added n-BuLi (274 mL, 0.69 mmol, 2.5 M solution in hexanes)
dropwise, and the resulting mixture was warmed to room tem-
perature and stirred for 30 min. The bright red solution was
re-cooled to 0 ꢀC and a solution of aldehyde 61 (100 mg,
0.57 mmol) in THF (6 mL) was added via cannula, and the reac-
tion mixture was warmed to room temperature and stirred
overnight. The reaction was quenched with addition of water
(3 mL) and then extracted with Et2O (3ꢂ10 mL). The organic
phase was washed with brine (3 mL), dried (MgSO4), and
concentrated in vacuo. The residue was purified by column
chromatography (25% benzene in hexanes) to yield stilbene
65 (113 mg, 67%, E/Z 1:1). Rf¼0.24 (silica gel, 30% benzene
in hexanes); IR (film) nmax 2968w, 2926w, 2852w, 1593s,
1513s, 1449w, 1338s, 1182w, 1109m, 965w, 856m,
4.3.36. 1-(3-Methyl-but-2-enyl)-2-styryl-benzene (71)
To a solution of phosphonium bromide 70 (388 mg,
0.69 mmol) in THF (10.0 mL) at ꢁ78 ꢀC was added n-BuLi
(275 mL, 0.69 mmol, 2.5 M solution in hexanes) dropwise, and
the resulting mixture was stirred for 30 min. To the bright red so-
lution was added a solution of aldehyde 61 (100 mg, 0.57 mmol)
in THF (2 mL) via cannula, and the reaction mixture was warmed
to room temperature over 30 min. The reaction was quenched with
addition of saturated aqueous NaHCO3 (10 mL) and then extracted
with Et2O (3ꢂ20 mL). The organic phase was washed with brine
(10 mL), dried (MgSO4) and concentrated in vacuo. The residue
was purified by column chromatography (5% CH2Cl2 in hexanes)
to yield first the cis-stilbene and then the trans-stilbene (206 mg;
92%; E/Z 1:1). Rf¼0.20 (silica gel, 5% CH2Cl2 in hexanes); IR
(film) nmax 2956w, 2929w, 2857w, 1602m, 1507s, 1471w,
1463w, 1449w, 1390w, 1376w, 1362w, 1254s, 1168m, 1101w,
1048w, 1007w, 961w, 909s, 837s, 821s, 803m, 779s,
756m cmꢁ1
;
1H NMR (600 MHz, CDCl3) d¼8.23 (d,
J¼10.2 Hz, 2H), 7.63e7.60 (m, 3H), 7.55 (d, J¼19.2 Hz, 1H),
7.30e7.28 (m, 1H), 7.26e7.22 (m, 2H), 7.03 (d, J¼19.2 Hz,
1H), 5.27e5.24 (t, J¼9.0 Hz, 1H), 3.49 (d, J¼8.4 Hz, 2H),
1.78 (s, 3H), 1.74 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d¼144.2, 140.1, 135.0, 132.6, 131.2, 129.7, 128.8, 127.6,
749m cmꢁ1
;
1H NMR (500 MHz, CDCl3) d¼7.61e7.59 (m,

4756
K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
B. E.; Parry, R. J.; Ratcliffe, B. E. J. Am. Chem. Soc. 1978, 100,
4274e4282.
1H), 7.41 (d, J¼8.5 Hz, 2H), 7.26 (d, J¼16.0 Hz, 1H), 7.24e7.20
(m, 3H), 6.95(d, J¼16.0 Hz, 1H), 6.86 (d, J¼8.5 Hz, 2H), 5.31 (m,
1H), 3.48 (d, J¼7.0 Hz, 2H), 1.79 (s, 3H), 1.77 (d, J¼1.0 Hz, 3H),
1.03 (s, 9H), 0.25 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3)
d¼155.4, 139.2, 136.4, 132.2, 131.1, 130.1, 129.7, 129.3, 127.7,
127.3, 126.3, 125.5, 124.5, 123.1, 120.3, 32.4, 25.7, 25.7, 18.2,
18.0, ꢁ4.4 ppm; HRMS (ESI TOF) m/z calcd for C25H34OSi
[MþHþ]: 379.2452, found: 379.2458.
4. (a) Bandaranayake, W. M.; Banfield, J. E.; Black, D. St. C. J. Chem. Soc.,
Chem. Commun. 1980, 902e903 (isolation); (b) Nicolaou, K. C.; Petasis,
N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555e5557;
(c) Nicolaou, K. C.; Petasis, N. A.; Uenishi, J.; Zipkin, R. E. J. Am. Chem.
Soc. 1982, 104, 5557e5558; (d) Nicolaou, K. C.; Zipkin, R. E.; Petasis,
N. A. J. Am. Chem. Soc. 1982, 104, 5558e5560; (e) Nicolaou, K. C.; Petasis,
N. A.;Zipkin, R.E.J.Am. Chem. Soc. 1982, 104, 5560e5562 (total synthesis).
5. For total syntheses, see: (a) Nicolaou, K. C.; Simonsen, K. B.; Vassiliko-
giannakis, G.; Baran, P. S.; Viladi, V. P.; Pitsinos, E. N.; Couladouros,
E. A. Angew. Chem., Int. Ed. 1999, 38, 3555e3559; (b) Nicolaou,
K. C.; Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.; Zhong, Y.-
L.; Viladi, V. P. J. Am. Chem. Soc. 2000, 122, 3071e3079; (c) Barnes-See-
man, D.; Corey, E. J. Org. Lett. 1999, 1, 1503e1504. For biosynthetic pro-
posals for the oxidative dimerization route to the bisorbicillinoids, see: (d)
Abe, N.; Murata, T.; Hirota, A. Biosci. Biotechnol. Biochem. 1998, 62,
2120e2126; (e) Nicolaou, K. C.; Jautelat, R.; Vassilikogiannakis, G.;
Baran, P. S.; Simonsen, K. B. Chem.dEur. J. 1999, 5, 3651e3665.
6. (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon,
W. H.; Choi, H.-S. Angew. Chem., Int. Ed. 1999, 38, 1669e1675; (b)
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon,
W. H.; Choi, H.-S. Angew. Chem., Int. Ed. 1999, 38, 1676e1678; (c)
Nicolaou, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y. Angew. Chem., Int.
Ed. 2000, 39, 1829e1832; (d) Nicolaou, K. C.; Jung, J.-K.; Yoon,
W. H.; Fong, K. C.; Choi, H.-S.; Zhong, Y.-L.; Baran, P. S. J. Am.
Chem. Soc. 2002, 124, 2183e2189; (e) Nicolaou, K. C.; Baran, P. S.;
Zhong, Y.-L.; Fong, K. C.; Choi, H.-S. J. Am. Chem. Soc. 2002, 124,
2190e2201; (f) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Jung, J.-K.;
Choi, H.-S.; Yoon, W. H. J. Am. Chem. Soc. 2002, 124, 2202e2211.
The Shair group has also completed a total synthesis featuring a cascade
reaction, see: (g) Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D.
J. Am. Chem. Soc. 2000, 122, 7424e7425.
To a solutionoftrans-stilbene fromabove (59 mg, 0.16 mmol)
in THF (500 mL) at 0 ꢀC was added HF$Py (300 mL, excess), and
theresultingmixturewaswarmedtoroomtemperatureandstirred
for an additional 2 h. The reaction mixture was diluted with Et2O
(20 mL) and then washed successively with saturated aqueous
CuSO4 (3ꢂ3 mL), saturated aqueous NaHCO3 (2ꢂ3 mL), and
brine (3 mL). The organic layer was then dried (MgSO4) and con-
centrated in vacuo. The residue was purified by column chroma-
tography (30% Et2O in hexanes) to give stilbene 71 (43 mg, 95%)
as a white powder. Rf¼0.24 (silica gel, 30% Et2O in hexanes); IR
(film) nmax 3362br m, 3025w, 2968w, 2912w, 1607m, 1591m,
1510s, 1481w, 1449m, 1375m, 1238s, 1171s, 1103m, 1047m,
1
963m, 923w, 856w, 838w, 815m, 777w, 750m cmꢁ1; H NMR
(500 MHz, CDCl3) d¼7.61e7.59 (m, 1H), 7.42 (d, J¼8.5 Hz,
2H), 7.25 (d, J¼16.0 Hz, 1H), 7.24e7.20 (m, 3H), 6.95 (d,
J¼16.0 Hz, 1H), 6.85 (d, J¼8.5 Hz, 2H), 5.30 (m, 1H), 5.04 (br
s, 1H), 3.50 (d, J¼7.0 Hz, 2H), 1.79 (s, 3H), 1.76 (s, 3H) ppm;
13C NMR (125 MHz, CDCl3) d¼155.1, 139.2, 136.3, 132.2,
130.8, 129.5, 129.3, 127.9, 127.4, 126.3, 125.5, 124.5, 123.0,
115.6, 32.3, 25.7, 17.7 ppm; HRMS (ESI TOF) m/z calcd for
C19H20O [MþHþ]: 265.1587, found: 265.1587.
7. (a) Nicolaou, K. C.; Vassilikogiannakis, G.; Magerlein, W.; Kranich, R.
¨
Angew. Chem., Int. Ed. 2001, 40, 2482e2486; (b) Nicolaou, K. C.;
Vassilikogiannakis, G.; Magerlein, W.; Kranich, R. Chem.dEur. J.
¨
2001, 7, 5359e5371; (c) Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.;
Jacobsen, E. R. Angew. Chem., Int. Ed. 2005, 44, 6046e6050; (d)
Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew.
Chem., Int. Ed. 2005, 44, 1221e1222; (e) Davies, H. M. L.; Dai, X.;
Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485e2490; (f) Kim, A. I.;
Rychnovsky, S. D. Angew. Chem., Int. Ed. 2003, 42, 1267e1270.
8. (a) Nicolaou, K. C.; Gray, D. L. F. Angew. Chem., Int. Ed. 2001, 40,
761e763; (b) Nicolaou, K. C.; Gray, D. L. F. J. Am. Chem. Soc. 2004,
126, 607e612.
9. For the first total synthesis of diazonamide, see: (a) Nicolaou, K. C.; Bella,
M.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Snyder, S. A. Angew. Chem., Int.
Ed. 2002, 41, 3495e3499; (b) Nicolaou, K. C.; Chen, D. Y.-K.; Huang,
X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126,
12888e12896. For the second total synthesis of diazonamide, see: (c)
Nicolaou, K. C.; Bheema Roa, P.; Hao, J.; Reddy, M. V.; Rassias, G.;
Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003,
42, 1753e1758; (d) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Bheema
Roa, P.; Rassias, G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzo-
vich, W. E.; Giuseppone, N.; Giannakakou, P.; O’Brate, A. J. Am.
Chem. Soc. 2004, 126, 12897e12906.
Acknowledgements
We wish to thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr.
R. J. Chadha for assistance with NMR spectroscopy, mass
spectrometry, and X-ray crystallography, respectively. We
also wish to thank Dr. W. Robert Tao for helpful discussions.
Financial support for this work was provided by grants from
the National Institutes of Health (USA) and the National Sci-
ence Foundation (No. 06032187), the Skaggs Institute for
Chemical Biology, and a National Science Foundation predoc-
toral fellowship (to C.F.G.).
References and notes
1. For recent reviews on cascade reactions in total synthesis, see: (a)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134e7186; (b) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551e564; (c) Nicolaou, K. C.; Snyder,
S. A. Actual. Chim. 2003, 4 and 5, 83e88; (d) Tietze, L. F. Chem. Rev.
1996, 96, 115e136; (e) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131e163; (f) Pellissier, H. Tetrahedron 2006, 62,
1619e1665; (g) Pellissier, H. Tetrahedron 2006, 62, 2142e2173; (h)
Bunce, R. A. Tetrahedron 1995, 51, 13103e13159; (i) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006; pp 631; (j) Hao, T.-L. Tandem Organic
Reactions; Wiley: New York, NY, 1992; pp 502.
10. For the total synthesis of the proposed structure of diazonamide A, see: (a)
Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40,
4765e4770; (b) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran,
P. G. Angew. Chem., Int. Ed. 2001, 40, 4770e4773. For total synthesis of
the corrected structure, see: (c) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran,
P. G. Angew. Chem., Int. Ed. 2003, 42, 4961e4966.
´
11. Nicolaou, K. C.; Sasmal, P. K.; Xu, H.; Namoto, K.; Ritzen, A. Angew.
Chem., Int. Ed. 2003, 42, 4255e4299; Nicolaou, K. C.; Sasmal, P. K.;
Xu, H. J. Am. Chem. Soc. 2004, 126, 5493e5501.
12. (a) Nicolaou, K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S.
Angew. Chem., Int. Ed. 2002, 41, 1941e1945; (b) Nicolaou, K. C.; Safina,
B. S.; Zak, M.; Estrada, A. A.; Lee, S. H. Angew. Chem., Int. Ed. 2004, 43,
2. Robinson, R. J. Chem. Soc. Trans. 1917, 762e768.
3. (a) Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am. Chem. Soc.
1971, 93, 4332e4334; (b) Gravestock, M. B.; Johnson, W. S.; McCarry,

K.C. Nicolaou et al. / Tetrahedron 64 (2008) 4736e4757
4757
5087e5092; (c) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.;
Estrada, A. A. Angew. Chem., Int. Ed. 2004, 43, 5092e5097; (d) Nico-
laou, K. C.; Safina, B. S.; Zak, M.; Estrada, A. A.; Lee, S. H.; Nevalainen,
24. For a preliminary communication of this work, see: Nicolaou, K. C.;
Lister, T.; Denton, R. M.; Gelin, C. F. Angew. Chem., Int. Ed. 2007, 46,
7501e7505.
´
M.; Bella, M.; Estrada, A. A.; Funke, C.; Zecri, F. J.; Bulat, S. J. Am.
25. Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.;
Colandrea, V. Tetrahedron Lett. 1994, 35, 6405e6408. This copper-
catalyzed protocol was found to be superior to procedures involving in
situ generation of dimethylpropynyltrilfate.
Chem. Soc. 2005, 127, 11159e11175; (e) Nicolaou, K. C.; Zak, M.;
Safina, B. S.; Estrada, A. A.; Lee, S. H.; Nevalainen, M. J. Am. Chem.
Soc. 2005, 127, 11176e11183.
13. For the total synthesis and structural revision of azaspiracid-1, see: (a)
Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou, N.; Bernal, F. Angew.
Chem., Int. Ed. 2001, 40, 1262e1265; (b) Nicolaou, K. C.; Qian, W.;
Bernal, F.; Uesaka, N.; Pihko, P. M.; Hinrichs, J. Angew. Chem., Int.
Ed. 2001, 40, 4068e4071; (c) Nicolaou, K. C.; Li, Y.; Uesaka, N.; Koftis,
T. V.; Vyskocil, S.; Ling, T.; Govindasamy, M.; Qian, W.; Bernal, F.;
Chen, D. Y.-K. Angew. Chem., Int. Ed. 2003, 42, 3643e3648; (d)
Nicolaou, K. C.; Chen, D. Y.-K.; Li, Y.; Ling, T.; Vyskocil, S.; Koftis,
T. V.; Govindasamy, M.; Uesaka, N. Angew. Chem., Int. Ed. 2003, 42,
3649e3653; (e) Nicolaou, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada,
Y. M. A.; Ling, T.; Chen, D. Y.-K.; Tang, W.; Petrovic, G.; Frederick,
M. O.; Li, Y.; Satake, M. Angew. Chem., Int. Ed. 2004, 43, 4312e4318;
(f) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.;
Yamada, Y. M. A.; Tang, W.; Frederick, M. O. Angew. Chem., Int. Ed.
2004, 43, 4318e4324; (g) Nicolaou, K. C.; Pihko, P. M.; Bernal, F.; Fred-
erick, M. O.; Qian, W.; Uesaka, N.; Diedrichs, N.; Hinrichs, J.; Koftis,
T. V.; Loizidou, E.; Petrovic, G.; Rodriquez, M.; Sarlah, D.; Zou, N.
J. Am. Chem. Soc. 2006, 128, 2244e2257; (h) Nicolaou, K. C.; Chen,
D. Y.-K.; Li, Y.; Uesaka, N.; Petrovic, G.; Koftis, T. V.; Bernal, F.;
Frederick, M. O.; Govindasamy, M.; Ling, T.; Pihko, P. M.; Tang, W.;
Vyskocil, S. J. Am. Chem. Soc. 2006, 128, 2258e2267; (i) Nicolaou,
K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Tang, W.; Frederick,
M. O.; Chen, D. Y.-K.; Li, Y.; Ling, T.; Yamada, Y. M. A. J. Am.
Chem. Soc. 2006, 128, 2259e2272.
26. Prepared from the commercially available acid, see: Wang, Q.; Huang, Q.;
Chen, B.; Lu, J.; Wang, H.; She, X.; Pan, X. Angew. Chem., Int. Ed. 2006,
45, 3651e3653.
27. For other synthetic applications of the microwave-promoted Claisen
rearrangement, see: (a) Davis, C. J.; Moody, C. J. Synlett 2002,
1874e1876; (b) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J.
J. Org. Chem. 2005, 70, 4414e4422; (c) Durand-Reville, T.; Gobbi,
L. B.; Gray, B. L.; Ley, S. V.; Scott, J. S. Org. Lett. 2002, 4, 3847e3850.
28. For Wittig approaches to oxygenated stilbenes, see: (a) Harrowven, D. C.;
Pascoe, D. D.; Guy, I. L. Angew. Chem., Int. Ed. 2007, 46, 425e428; (b)
Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem., Int. Ed. 2006, 45,
7609e7611; (c) Gao, M.; Wang, M.; Miller, K. D.; Sledge, G. W.; Hutch-
ins, G. D.; Zheng, Q.-H. Bioorg. Med. Chem. Lett. 2006, 16, 5767e5772.
For an interesting alternative to the Wittig reaction, see: (d) An interesting
alternative approach to stilbenes was recently described, see: Robinson,
J. E.; Taylor, R. J. K. Chem. Commun. 2007, 1617e1619.
29. The use of 3,5-bis(trifluoromethylphenylsulfones) in the JuliaeKocienski
olefination with aromatic aldehydes has been reported, see: Alonso, D. A.;
Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404e6416.
30. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26e28.
31. CCDC-648446 contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge via www.ccdc.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: þ44 1223 336
033 or e-mail: deposit@ccdc.cam.co.uk).
14. For the total synthesis and structural confirmation of azaspiracids-2 and -3,
see: (a) Nicolaou, K. C.; Frederick, M. O.; Petrovic, G.; Cole, P. M.; Loi-
zidou, E. Z. Angew. Chem., Int. Ed. 2006, 45, 2609e2615; (b) Nicolaou,
K. C.; Frederick, M. O.; Louzidou, E.; Petrovic, G.; Cole, K. P.; Koftis,
T. V.; Yamada, Y.; Yoichi, M. A. Chem.dAsian J. 2006, 1, 245e263.
15. For the total synthesis of rugolosin, and related natural products, see: (a)
Nicolaou, K. C.; Papageorgiou, C. D.; Piper, J. L.; Chadha, R. K. Angew.
Chem., Int. Ed. 2005, 44, 5846e5851; (b) Nicolaou, K. C.; Lim, Y. H.;
Papageorgiou, C. D.; Piper, J. L. Angew. Chem., Int. Ed. 2005, 44,
7917e7921; (c) Nicolaou, K. C.; Lim, Y. H.; Piper, J. L.; Papageorgiou,
C. D. J. Am. Chem. Soc. 2007, 129, 4001e4013; (d) Snider, B. B.; Gao,
X. J. Org. Chem. 2005, 70, 6863e6869.
32. A Discovery System model number 908005 was used for all microwave
reactions.
33. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem., Int. Ed.
2000, 39, 734e739; (b) Nicolaou, K. C.; Cao, G.-Q.; Pfefferkorn, J. A.
Angew. Chem., Int. Ed. 2000, 39, 739e743; (c) Nicolaou, K. C.; Pfeffer-
korn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J.
J. Am. Chem. Soc. 2000, 122, 9939e9953.
34. We are grateful to Dr. Ai-Jun Hou for kindly providing the 1H and 13C
NMR spectra of natural artochamins F, H, I, and J for comparison purposes.
35. (a) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8,
781e853; (b) Woodward, R. B.; Hoffman, R. The Conservation of Orbital
Symmetry; Academic: New York, NY, 1970; (c) Fleming, I. Frontier
Orbitals and Organic Chemical Reactions; Wiley: Chichester, UK,
1976; (d) Houk, K. N.; Yi, L.; Evanseck, J. D. Angew. Chem., Int. Ed.
16. Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem., Int. Ed. 2007, 46,
4708e4711.
17. Chen, C.-C.; Huang, Y.-L.; Ou, J.-C. J. Nat. Prod. 1993, 56, 1594e1597.
18. Hakim, E. H.; Asnizar; Yurnawilis; Aimi, N.; Kitajima, M.; Takayama, H.
Fitoterapia 2002, 73, 668e673.
`
Engl. 1992, 31, 682e702; (e) Houk, K. N.; Gonzalez, J.; Li, Y. Acc.
19. Fernando, M. R.; Nalinie Wickramasinghe, S. M. D.; Thabrew, M. I.; Ariya-
nanda, P. L.; Karunanayake, E. H. J. Ethnopharmacol. 1991, 31, 277e282.
20. Wang, Y. H.; Hou, A. J.; Chen, L.; Chen, D. F.; Sun, H. D.; Zhao, Q. S.;
Bastow, K. F.; Nakanish, Y.; Wang, X. H.; Lee, K. H. J. Nat. Prod. 2004,
67, 757e761.
Chem. Res. 1995, 28, 81e90.
36. Eicken, C.; Krebs, B.; Sacchettini, J. C. Curr. Opin. Struct. Biol. 1999, 9,
677e683.
37. Saeed, M.; Rogan, E.; Cavalieri, E. Tetrahedron Lett. 2005, 46,
4449e4451.
21. Boonlaksiri, C.; Oonanant, W.; Kongsaeree, P.; Kittakoop, P.; Tantichar-
oen, M.; Thebtaranonth, Y. Phytochemistry 2000, 54, 415e417.
22. Wang, Y. H.; Hou, A. J.; Chen, D. F.; Weiller, M.; Wendel, A.; Staples,
R. J. Eur. J. Org. Chem. 2006, 15, 3457e3463.
38. Kelly, J. W.; Robinson, P. L.; Evans, S. A. J. Org. Chem. 1986, 51,
4473e4475.
39. Lagier, C. M.; Scheler, U.; Mc George, G.; Gonzalez, M.; Alejandro,
C. O.; Harris, R. K. J. Chem. Soc., Perkin Trans. 2 1996, 1325e1329.
40. Bidan, T. A. Russ. J. Gen. Chem. 2001, 71, 1545e1546.
41. Cardona, M. L.; Fernandez, M. I.; Garcia, M. B.; Pedro, J. R. Tetrahedron
1986, 42, 2725e2730.
42. Berkowitz, D. B.; Smith, M. K. J. Org. Chem. 1995, 60, 1233e1238.
43. Singh, S. B.; Pettit, G. R. J. Org. Chem. 1989, 54, 4105e4114.
44. Padwa, A.; Lipka, H.; Watterson, S. H.; Murphree, S. S. J. Org. Chem.
2003, 68, 6238e6250.
23. For related formal cycloaddition reactions involving a benzopyran and
a prenyl group, see: (a) Mondal, M.; Puranik, V. G.; Argade, N. P.
J. Org. Chem. 2007, 72, 2068e2076. For a related formal [2þ2] cycload-
dition reaction involving an allylic cation and a benzopyran, see: (b) Kur-
dyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006, 128, 6272e6273.
The [2þ2] cycloaddition chemistry of allenes and ketenes has been stud-
ied in great detail, see: (c) Ohno, H.; Mizutani, T.; Kadoh, Y.; Aso, A.;
Miyamura, K.; Fujii, N.; Tanaka, T. J. Org. Chem. 2007, 72, 4378e
4389; (d) Murakami, M.; Matsuda, T. Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 727e
815; (e) Wang, X.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 1754.
ˆ
´
ˆ
45. de Fatima, A.; Kohn, L. K.; Antonio, M. A.; de Carvalho, J. E.; Pilli, R. A.
Bioorg. Med. Chem. 2005, 13, 2927e2933.
46. Olszewski, J. D.; Marshalla, M.; Sabat, M.; Sundberg, R. J. J. Org. Chem.
1994, 59, 4285e4296.