A Diels-Alder approach to biaryls (DAB): synthesis of the western portion of TMC-95

Article abstract of DOI:10.1016/j.tet.2007.10.118

The rapid synthesis of the western biaryl portion of TMC-95 is disclosed via the use of a Diels-Alder reaction with o-nitrostyrene derivative and 1-silyloxy diene with excellent regiochemical control. Subsequent sequential substitutions of a p-iodo-phenol

Full text of DOI:10.1016/j.tet.2007.10.118

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 856e865
www.elsevier.com/locate/tet
A DielseAlder approach to biaryls (DAB): synthesis of the
western portion of TMC-95
*
Bradley O. Ashburn, Lauren K. Rathbone, Elizabeth H. Camp, Rich G. Carter
Department of Chemistry, 153 Gilbert Hall, Oregon State University, Corvallis, OR, USA
Received 3 July 2007; received in revised form 24 August 2007; accepted 26 October 2007
Available online 12 November 2007
Abstract
The rapid synthesis of the western biaryl portion of TMC-95 is disclosed via the use of a DielseAlder reaction with o-nitrostyrene derivative
and 1-silyloxy diene with excellent regiochemical control. Subsequent sequential substitutions of a p-iodo-phenol derivative followed by an
o-bromo-nitrobenzene intermediate are employed to incorporate the western carbon framework of TMC-95.
Published by Elsevier Ltd.
1. Introduction
combination of an ortho-anilino and an ortho-phenolic substi-
tution patterns is present in both ligands and natural products.
One such natural product possessing this ortho-substitution
pattern is TMC-95 (1). Biaryl 1 was isolated from the fermen-
tation broth of Apiospora montagnei Sacc TC 1093 and has
displayed nanomolar (5.4 nM) chymotrypsin-like inhibitory
activity of the 20S proteasome, which helps to regulate im-
mune response, cell cycle, and cell differentiation (Scheme
1).6 In addition, 1 has been shown to reduce trypsin-like and
Biaryl compounds have captured the attention of the syn-
thetic community due to their presence in numerous pharma-
cologically active drugs1 as well as their importance as
ligands in metal-mediated transformations.2 Recent attention
in this area has been given to non-transition metal based
methods for their construction.3 One potential attractive
method for biaryl synthesis is the use of a DielseAlder cyclo-
addition. Our group4 and others5 have shown that a wide range
of structurally complex biaryl compounds can be assembled
via this approach. We have been particularly interested in
systems which possess an ortho-nitrophenyl moiety on the
dienophile for several reasons. The significant electron-with-
drawing effect of the ortho-nitro moiety helps to not only ac-
tivate the dienophile for the cycloaddition, but also control the
regiochemical outcome of the resultant biaryl moiety. Addi-
tionally, the location of a nitro moiety in the ortho position
relative to the s biaryl linkage provides an excellent handle
for subsequent functionalization to the ortho-amino moiety.
In addition, the reaction of these dienophiles with oxygenated
dienes inherently leads to placement of the remaining oxygen
functionality in the ortho and/or para positions. This
O
O
O
OH
NH
O
O
5
HO
7
7
5
8
NH
NO2
O
O
N
21
O
BnO
1
H
O
CONH2
20
13
HO
NH
O
24
13
16
NHBoc
34
15
2
N
H
O
Sequential Pd
Couplings
TMC-95A/B (1)
5
Cl
Cl
5
NO2
NO2
Diels-
Alder
HO
20
TBSO
24
19
16
3 X = H
SO2Ph
X
16
4 X = I
6
* Corresponding author. Tel.: þ1 541 737 9486; fax: þ1 541 737 9496.
E-mail address: rich.carter@oregonstate.edu (R.G. Carter).
Scheme 1. Retrosynthetic analysis for TMC-95A/B.
0040-4020/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.10.118

B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
857
peptidylglutamyl-peptide hydrolyzing activity of the 20S pro-
teasome (200 and 60 nM, respectively) while not inhibiting
m-calpain, cathepsin L, and trypsin (up to 30 mM).6a This activ-
ity data indicate that TMC-95 may be a highly selective inhibitor
for the 20S proteasome, thereby potentially leading to new
anti-tumor and autoimmune treatments.6b,7 The biological data,
coupled with the unusual biaryl moiety embedded within a cyclic
peptide backbone, have attracted considerable attention from the
synthetic community.8 To date, two total syntheses9a,b and one
formal synthesis9c have been described toward the natural
product. All of the reported approaches employ a metal-medi-
ated strategy to construct the critical C1,20 biaryl linkage.
An alternative method for the synthesis of the biaryl core of
TMC-95 could involve the use of a DielseAlder cycloaddition
(Scheme 1). We recently reported the use of mono-substituted
and di-substituted acetylenes for the synthesis of highly func-
tionalized biaryls.4 While these acetylenic dienophiles have
proven useful in numerous systems, one current limitation is
the inability to construct a 2-nitro-3-halo-20-phenolic biaryl
without additional oxygen substitution in the 40 position.4c
This substitution pattern is particularly germane with respect
to TMC-95. Consequently, we were intrigued by the possibi-
lity of using o-nitrophenyl-styrene derivatives (e.g., 5) in the
key [4þ2] reaction. To the best of our knowledge, no
DielseAlder cycloadditions have been reported on this class
of dienophiles. Herein, we report the application of this
DielseAlder approach to the western portion of TMC-95.10
Our retrosynthetic strategy is outlined in Scheme 1. Discon-
nection at C7,8 and the C13 and C34 peptide linkages leads back
to the western subunit 2. Compound 2 might be available by
sequential metal-mediated couplings of the C5 chloride and
a C16 halide (via directed halogenation of the phenolic ring)
from compound 4. Finally, the chloride-containing biaryl moi-
ety 3 would be accessible from a DielseAlder reaction
between the sulfone 5 and the known diene 6.
from the commercially available o-nitrobenzaldehyde (7), ole-
fination using the MasamuneeRoush modification11 of the
WadswortheEmmons olefination with phosphonate 812 pro-
duced the required vinyl sulfone 913 in high alkene selectivity
(>10:1 E/Z ) and yield (91%) (Scheme 2). Use of n-BuLi for
the deprotonation of the sulfone 8 leads to inferior yields
and low E/Z olefin selectivity. Heating of the sulfone 8 with
1-tert-butyldimethylsilyloxy-1,3-butadiene (6)14 produced the
DielseAlder adduct 10 as a single regio- and diastereomer
in 67% isolated yield. The stereochemical outcome of this
transformation was established through X-ray crystal analysis
(Fig. 1). The observed regiochemistry in the DielseAlder cy-
cloaddition can be explained by a larger orbital coefficient on
the b carbon of the dienophile 9 due to the electron-withdraw-
ing effect of the o-nitrotoluene function versus the sulfone
moiety (e.g., pKa of o-nitrotoluene¼20 vs methyl phenyl
sulfone¼29).15 Fluoride-containing Jones oxidation of the ad-
duct 10 followed by a basic work-up (Na2CO3) induced silyl
deprotection, oxidation, and aromatization to provide the
biaryl species 11 in 66% yield.
TBSO
LiCl, DBU
NO2
MeCN, r.t.
6
CHO
O
(EtO)2P
7
NO2
91%, d.r. >10:1
120 °C
PhMe
67%
α
β
SO2Ph
SO2Ph
8
9
NO2
SO2Ph
NO2
TBSO
CrO3, H2SO4, KF
HO
acetone; Na2CO3
66 %
10
11
Scheme 2. Proof-of-concept study in DielseAlder reaction.
With a good appreciation for the selectivity in the
DielseAlder reaction, we sought to apply this strategy to
TMC-95 (Scheme 3). The necessary dienophile 5 was synthe-
sized from the commercially available acid 12 in three steps.
Aldehyde 13 had been reported previously;16 however, we
have developed a more direct and higher yielding two-step
2. Results and discussion
Prior to advancing on the chlorinated series 5, we sought
proof-of-concept for this DielseAlder approach. Starting
O2N
PhO2S
OTSB
10
Figure 1. ORTEP representation of compound 10.

858
B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
approach.4c DielseAlder reaction of dienophile 5 with the di-
ene 6 provided the adduct 14, again as approximately a 3.5:1
mixture (endo/exo isomers). The stereochemistry of 14 was
confirmed by X-ray crystal analysis of both diastereomers de-
rived from 14.17 Use of our previous fluoride-containing Jones
oxidation proved ineffective on adduct 10. Fortunately, TBAF
deprotection and Swern oxidation induced in situ elimination
and aromatization to produce the C1,20 linked biaryl 3. Mono-
iodination18 provided the poly-functionalized biaryl 4.
5
Cl
Cl
5
17, Pd2(dba)3
P(o-tol)3
NO2
O
NO2
BnO
O
PO
DMF/PhH 50 °C
78%
13
16I
16
NHBoc
15
4 P = H
BnBr, K2CO3
acetone, 93%
18
15 P = Bn
Pd cat,
Ligand
X
20, 21 or 22
O
O
O
O
M
NHBoc
15
Zn/Cu couple
PhH/DMF
50 °C
O
5
Cl
Cl
16 M = I
7
2 steps
17 M = Zn/CuI
NO2
O
NO2
See Ref 4c
NO2
BnO
O
CO2H
CHO
19 M = I
O
M
O
20 M = ZnBr
21 M = B(OH)2
22 M = SnBu3
12
13
NHBoc
O
8, LiCl, DBU
MeCN, r.t.
2
7
5
Cl
81%, d.r. >10:1
Scheme 4. Attempted synthesis of western portion of TMC-95.
Cl
NO2
20
TBSO
SO2Ph
6, PhMe
NO2
24
20
some experimentation, we found that selective palladium
coupling [Pd2(dba)3/P(o-tol)3] of iodide 15 with the organo-
metallic species 17 gave the amino acid derivative 18 in
a good yield (78%). Interestingly, use of the analogous catalyst
derived from a Pd(II) source, Pd(P(o-tol)3)2Cl2, gave an infe-
rior yield (50%). Also, the use of the organometallic species
17 derived from zinc/copper couple was critical to the success
of this reaction. Next, our initial efforts focused on a Suzuki-
based strategy for the incorporation of the final side arm. To
this end, boronic acid was constructed from the known iodide
1924 [i-PrMgCl, THF;25 B(OMe)3]; however, the boronic acid
rapidly fragmented upon reaction under a series of Suzuki
coupling conditions.26 The analogous organozinc species
was constructed [i-PrMgCl, THF; ZnBr2];27 however, the
Negishi-style coupling did not provide any of the desired
adduct 2 under a range of conditions. A similar outcome
was observed under a range of Stille conditions. We attribute
the lack of success under the palladium-mediated conditions to
the 3-substituent, which forces the nitro moiety out of the
plane of the aromatic ring, thereby making oxidative addition
difficult. In fact, treatment of 18 with 1 equiv of (t-Bu3P)2Pd at
120 ꢀC (THF, dioxane, 16 h) did not consume the aryl
chloride.
Based on this knowledge, we decided to synthesize the
analogous 3-bromo-2-nitro-1-substituted biaryl 30 (Scheme
5). 3-Bromo-2-nitrobenzaldehyde (24) is readily available
from 3-bromo-2-nitrotoluene (23) via a modified version4 of
a Pfizer protocol.28 Initial formation of the enamine via treat-
ment with DMF$DMA followed by cleavage with NaIO4 gave
the aldehyde 24 in modest yield. We reason that the orthogo-
nality of the nitro group due to the adjacent bromine atom is
the major factor for the lower yield. Conversion to the a,b-un-
saturated sulfone 25 and DielseAlder cycloaddition with di-
ene 5 followed by deprotection and oxidation gave the biaryl
27. Iodination using the NaI and NaOCl procedure followed
by benzylation gave the required coupling precursor 29. Use
of our previously optimized conditions for the Negishi-style
coupling gave the desired amino acid 30 in good yield.
125 °C, 79%
5
14
SO2Ph
TBAF, THF, 88%;
(ClCO)2, DMSO
Et3N, CH2Cl2, 92%
5
Cl
Cl
NaI, NaOCl
NaOH, MeOH
64%
NO2
NO2
HO
HO
16I
16
3
4
Scheme 3. DielseAlder approach to halogenated biaryls.
At this point, it is worth noting that each of the two palla-
dium-couplings required on a substrate such as 4 or 15 pos-
sesses inherent challenges (Scheme 4). The synthesis of aryl
amino acid derivatives via a palladium-mediated approach (in-
cluding the pioneering efforts of Jackson and co-workers19)
has met with reasonable success to date.20 Jackson has pub-
lished two nice recent reviews on the subject.21 These impres-
sive accomplishments aside, it should be noted that the yields
for these transformations are often modest unless a large ex-
cess of the organozinc species is used. For example, Jackson’s
Organic Synthesis preparation of (N-tert-butoxycarbonyl)-b-
[4-(methoxycarbonyl)phenyl]alanine methyl ester provides only
a 35e39% yield of the product.22 For the required functionali-
zation at C5 of the o-chloro-nitrobenzene derivative (e.g., 18),
successful metal-mediated couplings have been reported only
on relatively unfunctionalized systems, primarily through
SuzukieMiyaura couplings.23 No examples of palladium-
mediated couplings of 3-substituted, 2-nitrochlorobenzene de-
rivatives have been reported. In contrast, the required palladium
coupling for the TMC-95 synthesis necessitates the reaction on
the poly-functionalized biaryl-containing aryl chloride with
a coupling partner that would generate a reactive Michael accep-
tor in 2.
With these important considerations in mind, attachment of
the remaining two side arms was explored (Scheme 4). After

B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
859
Fortunately, our initial attempts at coupling the aryl bromide
have been met with greater success. While appending the
remaining side arm continued to prove challenging, we were
grateful to find that coupling of the bromide 30 with methyl
boroxine (31) using Fu’s catalyst gave the desired coupling
product 32. Use of more elaborate metallo species derived
from iodide 19 in place of boroxine 31 led to sole dehalogena-
tion of the ortho-bromide moiety present in 30.
spectrometer at 300 MHz or a Bruker 400 spectrometer at
¨
400 MHz in the indicated solvent and are reported in parts
per million relative to tetramethylsilane and referenced inter-
nally to the residually protonated solvent. 13C NMR spectra
were recorded on Bruker 300 spectrometer at 75 MHz or
¨
a Bruker 400 spectrometer at 100 MHz in the solvent indicated
¨
and are reported in parts per million relative to tetramethyl-
silane and referenced internally to the residually protonated
solvent. Optical rotations were recorded on a Perkin Elmer
243 polarimeter using a sodium lamp at 589 nm in CHCl3.
Routine monitoring of reactions was performed using EM
Science DC-Alufolien silica gel, aluminum back TLC plates.
Flash chromatography was performed with the indicated elu-
ents on EM Science Gelurian silica gel.
Br
Br
DMF•DMA
DMF, pyrrolidine
NO2
NO2
then NaIO4,
DMF, H2O
35%
CHO
24
23
8, LiCl, DBU
MeCN, r.t.
95%, d.r. >10:1
Air and/or moisture sensitive reactions were performed
under usual inert atmospheric conditions. Reactions requiring
anhydrous conditions were performed under a blanket of ar-
gon, in glassware dried in an oven at 120 ꢀC or by a Bunsen
flame, and then cooled under argon. Solvents and commercial
reagents were purified in accord with Perrin and Armarego29
or used without further purification.
5
Br
Br
NO2
SO2Ph
20
TBSO
6, PhMe
125 °C, 77%
NO2
24
20
25
26
SO2Ph
TBAF, THF, 83%;
(ClCO)2, DMSO
3.2. Diene 6
Et3N, CH2Cl2, 88%
5
Br
Br
To a stirring solution of freshly distilled 2-butenal (3.15 g,
44.9 mmol, 3.72 mL) in pentane (108 mL) were added sequen-
tially TBSCl (8.50 g, 56.4 mmol), triethylamine (7.81 mL,
5.67 g, 55.9 mmol), CH3CN (55.8 mL), and NaI (8.39 g,
55.9 mmol) at rt. After 18 h, the solution was warmed to
40 ꢀC. After 6 h, the reaction was quenched with ice (110 g)
and extracted with pentane (3ꢁ150 mL). The dried extract
(MgSO4) was purified by vacuum distillation (41e43 ꢀC,
1 mm Hg) to give the known 630 (5.20 g, 28.2 mmol, 63%)
NaI, NaOCl
NaOH,MeOH
98%
NO2
NO2
16I
HO
PO
16
27
28 P = H
BnBr, K2CO3
acetone, 97%
29 P = Bn
Me
O
O
O
B
17, Pd2(dba)3
Me B
P(o-tol)3
B
DMF / PhH 50 °C
70% borsm
Me
1
31
as a colorless oil. H NMR (300 MHz, CDCl3) d 6.59 (d,
Br
5
J¼10.5 Hz, 1H), 6.24 (dt, J¼10.8, 16.8 Hz, 1H), 5.75 (t, J¼
10.9 Hz, 1H), 5.00 (dd, J¼1.9, 16.8 Hz, 1H), 4.83 (dd,
J¼1.8, 10.5 Hz, 1H), 0.93 (s, 9H), 0.18 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 145.7, 133.7, 114.5, 112.2, 26.0, 18.7,
ꢂ4.85.
Me
5
31 (5 equiv.)
6
(t-Bu3P)2Pd
NO2
O
KF, NMP
80 °C, 13 h
54%
NO2
O
BnO
O
BnO
O
13
13
16
NH
15
16
NH
Boc
15
30
Boc
32
3.3. Phosphonate 8
Scheme 5. Revised approach to western portion of TMC-95.
To a stirring solution of methyl phenyl sulfone (8.48 g,
54.2 mmol) and THF (54.2 mmol) was added n-BuLi
(47.7 mL, 119 mmol, 2.5 M in hexanes) at 0 ꢀC. After
30 min, freshly distilled diethyl chlorophosphate (9.41 mL,
11.2 g, 65.1 mmol) was added dropwise. After 1 h, the reac-
tion was quenched with satd aq NH4Cl (10 mL). The organic
volatiles were removed in vacuo and the residue was extracted
with CH2Cl2 (2ꢁ100 mL). The dried extract (Na2SO4) was
concentrated in vacuo and purified by chromatography over
silica gel, eluting with 60e100% EtOAc/hexanes, to give the
known 831 (13.5 g, 46.2 mmol, 85%) as a white solid. 1H
NMR (400 MHz, CDCl3) d 8.00e8.03 (m, 2H), 7.68e7.72
(m, 1H), 7.57e7.62 (m, 2H), 4.14e4.19 (m, 4H), 4.14 (d,
J¼16.9 Hz, 2H), 1.31 (td, J¼7.0, 0.6 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 140.4 (d, JCeP<10 Hz, 1C), 134.5,
In conclusion, the utility of a DielseAlder approach to the
synthesis of the biaryl core 32 of TMC-95 has been demon-
strated (11 steps from the commercially available toluene
23). The future application of this DielseAlder approach to
biaryl compounds (DAB) will be reported in due course.
3. Experimental section
3.1. General
Melting points were taken on a Mel-Temp apparatus and
are uncorrected. Infrared spectra were recorded on a Nicolet
Nexus 470 FT-IR spectrophotometer, neat unless otherwise
1
indicated. H NMR spectra were recorded on a Bruker 300
¨

860
B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
129.5, 128.8, 63.8 (d, JCeP<10 Hz, 1C), 54.25 (d, JCeP
140 Hz, 1C), 16.6 (d, JCeP<10 Hz, 1C).
¼
(44 mg, 0.754 mmol) and Jones reagent32 (0.187 mL,
0.22 mmol) in a sequential fashion. The orange solution was
then allowed to warm to rt and stirred for 26 h. An additional
portion of Jones reagent (90 mL, 0.0026 mmol) was added
over during this period. Isopropanol (1.0 mL), H2O
(0.7 mL), and Na2CO3 (0.634 g, 5.98 mmol) were then added
sequentially. After 8 h, the reaction mixture was filtered
through Celite, concentrated in vacuo, and purified by chroma-
tography over silica gel, eluting with 8e18% EtOAc/hexanes,
to give the known 1133 as a yellow oil in 49% yield (34.8 mg,
3.4. E-2-(2-Nitro-phenyl)-1-phenylsulfonyl-ethene (9)
To a suspension of LiCl (0.600 g, 14.2 mmol) in anhydrous
CH3CN (75 mL) was added a solution of 8 (2.73 g,
9.33 mmol) in CH3CN (3 mL). An additional portion of
CH3CN was used to wash the phosphonate flask (3ꢁ2 mL).
Promptly, DBU (1.16 mL, 1.16 mL) was added to form a yel-
low mixture. A solution of 2-nitrobenzaldehyde (1.17 g,
7.75 mmol) in CH3CN (5 mL) was then added dropwise and
an additional portion of CH3CN was then added to wash the
aldehyde flask (3ꢁ1.3 mL). The resulting light brown mixture
was stirred for 110 min, quenched with satd aq NH4Cl
(20 mL), and the volatiles were removed in vacuo. The or-
ganics were then extracted with CH2Cl2 (4ꢁ60 mL). The dried
(MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 10e28%
EtOAc/hexanes, to yield 9 as a pale yellow solid (2.02 g,
7.00 mmol, 90%). Mp¼145e46 ꢀC; IR (neat) 3033, 2854,
1
0.162 mmol). H NMR (400 MHz, CDCl3) d 8.01 (dd, J¼8.1,
1.3 Hz, 1H), 7.70 (td, J¼7.6, 1.3 Hz, 1H), 7.53e7.57 (m, 1H),
7.48 (dd, J¼7.6, 1.2 Hz, 1H), 7.29e7.34 (m, 1H), 7.28 (dd,
J¼7.6, 1.7 Hz, 1H), 7.08 (td, J¼7.5, 1.1 Hz, 1H), 6.87
(dd, J¼8.1, 1.1 Hz, 1H), 5.10 (s, 1H); 13C NMR (400 MHz,
CDCl3) d 152.7, 150.1, 133.3, 133.1, 132.9, 130.3, 128.9,
125.5, 124.6, 121.8, 116.1, 30.1.
3.7. 3-Chloro-2-nitro-benzoic acid methyl ester (33)
Cl
1522, 1446, 1351, 1140, 1080 cmꢂ1 1H NMR (300 MHz,
;
NO2
CO2Me
CDCl3) d 7.75 (dd, J¼8.1, 1.4 Hz, 1H), 7.52e7.58 (m, 4H),
7.40e7.45 (m, 2H), 7.30e7.35 (m, 1H), 7.23 (td, J¼7.6,
1.3 Hz, 1H), 5.91e5.96 (m, 2H), 5.84e5.88 (m, 1H), 4.47
(t, J¼3.9 Hz, 1H), 4.14 (td, J¼10.0, 3.8 Hz, 1H), 2.50e2.69
(m, 2H), 0.80 (s, 9H), ꢂ0.14 (s, 3H), ꢂ0.15 (s, 3H); 13C
NMR (400 MHz, CDCl3) d 148.3, 140.2, 139.5, 134.5,
134.2, 132.6, 131.6, 130.0, 129.9, 129.4, 128.4, 125.6;
HRMS (CIþ) calcd for C14H12NO4S (MþH) 290.04870, found
290.04806.
33
To a stirred solution of 12 (0.740 g, 3.67 mmol) in DMF
(3.67 mL) were added K2CO3 (1.52 g, 11.0 mmol) and MeI
(1.04 g, 0.457 mL, 7.34 mmol) sequentially at rt. The solution
was warmed to 40 ꢀC for 1 h, and then diluted with EtOAc
(50 mL), washed with H2O (2ꢁ25 mL), and satd aq NaCl
(25 mL). The dried extract (Na2SO4) was concentrated in va-
cuo to give the known 334c (0.745 g, 3.46 mmol, 94%) as
3.5. TBS DielseAlder adduct 10
1
a light yellow solid. H NMR (400 MHz, CDCl3) d 8.01e
8.03 (dd, J¼1.3, 7.9 Hz, 1H), 7.74e7.76 (dd, J¼1.3, 7.9 Hz,
1H), 7.54e7.57 (t, J¼7.9 Hz, 1H), 3.95 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 163.0, 149.8, 135.2, 131.1, 130.1,
126.7, 124.8, 53.8.
To a suspension of 9 (543 mg, 1.88 mmol) in PhMe
(2.13 mL) was added diene 6 (1.63 mL, 7.51 mmol). The reac-
tion tube was then sealed and heated to 120 ꢀC. After 3.5 days,
the rust orange solution was allowed to cool, and volatiles were
then removed in vacuo and purified by chromatography over
silica gel, eluting with 8e35% EtOAc/hexanes (with 1%
Et3N), to give 10 as a white solid in 67% yield (615 mg,
1.30 mmol). Mp¼115e17 ꢀC; IR (neat) 3033, 2854, 1522,
3.8. 3-Chloro-2-nitro-benzaldehyde (13)
To a stirred solution of 33 (723 mg, 3.35 mmol) in CH2Cl2
(16.8 mL) at e78 ꢀC was slowly added DIBAL-H (5.03 mL,
5.03 mmol, 1.0 M in CH2Cl2) over 10 min. After 1 h, the
reaction was quenched with MeOH (0.55 mL) and warmed
to rt. Following dilution with CH2Cl2 (5 mL), satd aq sodium
tartrate (10 mL) was added and the solution was stirred
vigorously for 15 min. The product was extracted with
CH2Cl2 (2ꢁ8 mL), and washed with H2O (30 mL) and satd
aq NaCl (30 mL). The dried extract (MgSO4) was concen-
trated in vacuo and recrystallized with EtOAc/hexanes to
give the known 134c,16 (0.575 g, 3.10 mmol, 92%) as a white
1
1446, 1351, 1140, 1080 cmꢂ1; H NMR (300 MHz, CDCl3)
d 7.75 (dd, J¼8.1, 1.4 Hz, 1H), 7.52e7.58 (m, 4H), 7.40e
7.45 (m, 2H), 7.30e7.35 (m, 1H), 7.23 (td, J¼7.6, 1.3 Hz,
1H), 5.91e5.96 (m, 2H), 5.84e5.88 (m, 1H), 4.47 (t,
J¼3.9 Hz, 1H), 4.14 (td, J¼10.0, 3.9 Hz, 1H), 2.50e2.69
(m, 2H), 0.80 (s, 9H), ꢂ0.14 (s, 3H), ꢂ0.15 (s, 3H); 13C NMR
(400 MHz, CDCl3) d 151.1, 138.9, 134.8, 133.8, 131.4, 130.6,
129.7, 129.5, 128.7, 128.2, 125.9, 123.9, 67.3, 59.7, 41.6,
26.6, 26.2, ꢂ18.4, ꢂ4.58, ꢂ5.06; HRMS (CIþ) calcd for
C24H32NO5SSi (MþH) 474.17839, found 474.17844.
1
crystalline solid. H NMR (400 MHz, CDCl3) d 9.93 (s, 1H),
3.6. 20-Nitro-biphenyl-2-ol (11)
7.88e7.90 (dd, J¼1.4, 7.7 Hz, 1H), 7.78e7.80 (dd, J¼1.4,
8.1 Hz, 1H), 7.64e7.68 (dd, 7.8. 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 186.0, 152.5, 136.4, 131.9, 129.8,
129.0, 127.1.
To a stirred solution of DielseAlder adduct 10 (155 mg,
0.328 mmol) in acetone (1.64 mL) at 0 ꢀC were added KF

B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
861
3.9. E-2-(3-Chloro-2-nitro-phenyl)-1-phenylsulfonyl-
ethene (5)
stirring for 1 h was added TBAF (1 mL) followed by two
additional 1 mL portions of TBAF at 30 min. intervals. After a
total of 2.5 h, the solution was quenched with H2O (10 mL),
diluted with Et2O (10 mL), and washed with brine (10 mL).
The dried extract (MgSO4) was concentrated in vacuo and pu-
rified by chromatography over silica gel, eluting with 60%
EtOAc/hexanes, to give 34 (229 mg, 0.583 mmol, 88%) as a
white solid. Mp¼155e157 ꢀC; IR (neat) 3484, 1535, 1305,
To a stirred solution of LiCl (0.311 g, 7.34 mmol) and
CH3CN (36 mL) were added sequentially
8 (1.71 g,
8.86 mmol) in CH3CN (6 mL), DBU (0.892 g, 0.876 mL,
5.86 mmol), and 13 (0.892 g, 4.89 mmol) in CH3CN (6 mL)
at rt. After 1.5 h, the reaction was quenched with satd aq
NH4Cl (20 mL) and volatiles were removed in vacuo. The res-
idue was extracted with CH2Cl2 (60 mL) and washed with satd
aq NH4Cl (60 mL). The aqueous phase was extracted once
with CH2Cl2 (20 mL). The dried extract (MgSO4) was concen-
trated in vacuo and purified by recrystallization from EtOAc to
yield 5 as a white solid. The mother liquor was purified by
chromatography over silica gel, eluting with 20e50%
EtOAc/hexanes, to yield 5 (total of 1.27 g, 3.92 mmol, 80%)
as a white solid. Mp¼166e167 ꢀC; IR (neat) 3067, 1528,
1143 cmꢂ1 1H NMR (400 MHz, CDCl3) d 7.62e7.65 (m,
;
2H), 7.54e7.59 (m, 1H), 7.43 (t, J¼7.4 Hz, 2H), 7.34 (d,
J¼8.0 Hz, 2H), 7.08 (t, J¼8.0 Hz, 1H), 3.87e3.98 (m, 2H),
4.27e4.35 (m, 1H), 3.95e4.08 (m, 1H), 3.20 (dd, J¼3.6,
9.8 Hz, 1H), 2.54e2.59 (m, 2H), 1.63 (d, J¼5.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 150.1, 138.8, 134.1, 130.9,
130.7, 129.7, 129.6, 129.4, 128.9, 128.0, 127.7, 125.2, 66.4,
58.7, 41.9, 26.1; HRMS (CIþ) calcd for C18H17NO5SCl
(MþH) 394.0579, found 394.05159.
1
1363, 1303, 1149, 1083 cmꢂ1; H NMR (400 MHz, CDCl3)
d 7.95e7.98 (m, 2H), 7.62 (d, J¼16.3 Hz, 1H), 7.29e7.72
(m, 6H), 6.96 (d, J¼16.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 139.7, 134.5, 134.4, 134.3, 133.0, 131.8, 130.0,
128.4, 127.4, 126.8, 126.7; HRMS (CIþ) calcd for
C14H10NO4SCl (Mþ) 324.00973, found 324.00849.
3.12. 30-Chloro-20-nitro-biphenyl-2-ol (3)
To a stirred solution of oxalyl chloride (130 mL, 202 mg,
1.59 mmol) in CH2Cl2 (2.5 mL) was added DMSO (230 mL,
249 mg, 3.18 mmol) at ꢂ78 ꢀC. After 15 min, 34 (209 mg,
0.531 mmol) in CH2Cl2 (2.0 mL) and DMSO (0.2 mL) was
added. After stirring for an additional 15 min, Et3N (1.08 g,
10.6 mmol, 1.49 mL) was added. The solution was allowed
to warm to rt over 1 h. Next, the solution was quenched
with satd aq NH4Cl (10 mL), diluted with CH2Cl2 (10 mL),
and washed with H2O (10 mL) and satd aq NaCl (10 mL).
The dried extract (MgSO4) was concentrated in vacuo and pu-
rified by chromatography over silica gel, eluting with 20%
EtOAc/hexanes, to give 3 (122 mg, 0.489 mmol, 92%) as
a white solid. Mp¼94e96 ꢀC; IR (neat) 3484, 1536, 1450,
3.10. TBS DielseAlder adduct 14
To a stirred solution of 5 (576 mg, 1.78 mmol) in PhMe
(3.6 mL) in a sealed tube was added 6 (1.31 g, 1.53 mL,
7.11 mmol). After 72 h, the volatiles were removed in vacuo.
The crude material was purified by chromatography over silica
gel, eluting with 50% CH2Cl2/hexanes/1% Et3N, to give 14 as
two exo/endo adducts (714 mg, 1.41 mmol, 79%) in a 3.5:1 ra-
tio. endo Isomer: Mp¼174e175 ꢀC; IR (neat) 2929, 1537,
1
1307, 1145 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.77 (dt,
1
1367 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.56 (dd, J¼1.6,
J¼1.1, 6.3 Hz, 2H), 7.58 (dd, J¼1.2, 8.0 Hz, 1H), 7.49 (t, J¼
6.5 Hz, 2H), 7.42 (dd, J¼1.1, 8.1 Hz, 1H), 7.36 (dd, J¼1.1,
8.1 Hz, 1H), 7.11 (t, J¼11.2 Hz, 1H), 5.81e5.90 (m, 2H),
4.34 (t, J¼4.2 Hz, 1H), 4.03 (dt, J¼8.2, 10.0 Hz, 1H), 3.20
(dd, J¼4.0, 10.0 Hz, 1H), 2.53e2.55 (m, 2H), 0.79 (s, 9H),
ꢂ0.09 (s, 3H), ꢂ0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.7, 134.1, 132.1, 131.1, 129.6, 129.5, 129.3, 129.0,
128.9, 126.0, 124.5, 66.98, 59.43, 42.07, 26.19, 25.79,
18.33, ꢂ4.50, ꢂ5.08; HRMS (EIþ) calcd for C24H31NO5SiSCl
(Mþ) 508.1365, found 508.1381.
8.1 Hz, 1H), 7.49 (t, J¼8.1 Hz, 1H), 7.34 (dd, J¼1.6, 9.9 Hz,
1H), 7.29 (ddd, J¼1.7, 7.7 Hz, 1H), 7.15 (dd, J¼1.2,
7.6 Hz, 1H), 6.98 (td, J¼1.0, 7.6 Hz, 1H), 6.91 (dd, J¼0.8,
8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 153.0, 150.1,
132.7, 131.32, 131.3, 130.9, 130.7, 130.5, 126.1, 122.6,
121.6, 116.8; HRMS (CIþ) calcd for C12H9NO3Cl (MþH)
250.0273, found 250.0271.
3.13. 30-Chloro-5-iodo-20-nitro-biphenyl-2-ol (4)
To a stirred solution of 3 (81.0 mg, 0.324 mmol) in MeOH
(2.2 mL) were added NaI (48.6 mg, 0.324 mmol) and NaOH
(13.0 mg, 0.324 mmol) at rt. Solution was cooled to 0 ꢀC be-
fore the slow addition of NaOCl (392 mg, 0.324 mmol, w/v
in H2O) over 45 min. After 1 h, the reaction was quenched
with 10% aq sodium thiosulfate (10 mL) and satd aq NH4Cl
(10 mL), diluted with Et2O (10 mL), and washed with H2O
(10 mL) and satd aq NaCl (10 mL). The dried extract
(MgSO4) was concentrated in vacuo and purified by chroma-
tography over silica gel, eluting with 50% CH2Cl2/hexanes,
to give 4 (93.0 mg, 0.248 mmol, 76%) as a white solid.
3.11. 5-Benzenesulfonyl-6-(3-chloro-2-nitro-phenyl)-
cyclohex-2-enol (34)
Cl
NO2
HO
SO2Ph
34
To a stirred solution of 14 (334 mg, 0.657 mmol) in THF
(1 mL) was added a solution of TBAF in AcOH [100 mL
AcOH in 900 mL of 10% TBAF (1.0 M in THF)] at rt. After
Mp¼154e155 ꢀC; IR (neat) 3456, 1534, 1364 cmꢂ1
;
1H
NMR (400 MHz, CDCl3) d 7.59 (dd, J¼1.4, 8.1 Hz, 1H),

862
B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
7.56 (d, J¼2.2 Hz, 1H), 7.53 (t, J¼7.6 Hz, 1H), 7.48 (d,
J¼2.2 Hz, 1H), 7.35 (dd, J¼1.4, 7.6 Hz, 1H), 6.68 (d,
J¼8.6 Hz, 1H), 5.41 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 153.1, 149.9, 139.9, 139.0, 131.6, 131.5, 131.0, 130.8,
126.3, 125.2, 118.9, 83.1; HRMS (FABþ) calcd for
C12H7NO3ClI (Mþ) 374.9169, found 374.9159.
ZnBr2 (48.1 mg, 0.214 mmol) was added. The mixture was
stirred at ꢂ40 ꢀC for 10 min and then let warm to rt and the
organozinc species 20 was used in situ.
3.17. Boronic acid 21
To a stirred solution of 19 (164 mg, 0.558 mmol) in
THF (1.6 mL) at ꢂ40 ꢀC was added i-PrMgCl (0.39 mL,
0.614 mmol, 1.57 M in THF). After 10 min, freshly distilled
B(OMe)3 (86.9 mg, 0.0932 mL, 0.836 mmol) was added.
The solution was stirred for an additional 30 min before warm-
ing to rt. The mixture was quenched with satd aq NH4Cl
(10 mL), diluted with EtOAc (15 mL), and washed with H2O
(10 mL) and satd aq NaCl. The dried extract (MgSO4) was pu-
rified by chromatography over silica gel, eluting with 3e6%
MeOH/CH2Cl2, to give 21 (88.3 mg, 0.368 mmol, 80%) as a
3.14. 20-Benzyloxy-3-chloro-50-iodo-2-nitro-biphenyl
(15)
To a stirred solution of 4 (108 mg, 0.288 mmol) in acetone
(2.88 mL) were added K2CO3 (47.7 mg, 0.0345 mmol) and
BnBr (37 mL, 54.2 mg, 0.317 mmol). After heating at 70 ꢀC
for 1 h, the clear solution was diluted with Et2O (10 mL),
and washed with H2O (10 mL) and satd aq NaCl (10 mL).
The dried extract (MgSO4) was concentrated in vacuo and pu-
rified by chromatography over silica gel, eluting with 50%
CH2Cl2/hexanes, to give 15 (124 mg, 0.266 mmol, 93%) as a
1
white solid. H NMR (300 MHz, CDCl3) d 7.67 (s, 1H), 5.82
(br s, 2H), 1.93e2.07 (m, 4H), 1.51e1.77 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 167.5, 166.1, 109.1, 53.9, 34.2, 24.8, 22.4.
white solid. Mp¼127e128 ꢀC; IR (neat) 1536 cmꢂ1
;
1H
NMR (400 MHz, CDCl3) d 7.58 (dd, J¼2.3, 8.7 Hz, 1H),
7.54 (d, J¼1.5 Hz, 1H), 7.50 (dd, J¼1.5, 4.7 Hz, 1H), 7.45
(t, J¼7.6 Hz, 1H), 7.21e7.34 (m, 6H), 6.69 (d, J¼8.7 Hz,
1H), 5.02 (s, 2H); 13C NMR (100 MHz, CDCl3) d 155.9,
149.4, 139.6, 139.1, 136.6, 132.6, 131.1, 130.8, 130.5, 129.0,
128.4, 127.3, 127.2, 125.9, 115.6, 63.4, 71.0; HRMS (CIþ)
calcd for C19H13NO3ClI (Mþ) 464.9632, found 464.9629.
3.18. Stannane 22
To a stirred solution of 19 (57.7 mg, 0.232 mmol) in
THF (0.66 mL) at ꢂ40 ꢀC was added i-PrMgCl (0.162 mL,
0.225 mmol, 1.57 M in THF). After 10 min, Bu3SnCl (113 mg,
0.0940 mL, 0.348 mmol) was added. The yellow solution
was stirred for an additional 30 min before warming to rt.
The mixture was quenched with satd aq NH4Cl (10 mL), di-
luted with EtOAc (15 mL), and washed with H2O (10 mL)
and satd aq NaCl. The dried extract (MgSO4) was used crude.
3.15. Chloro amino acid derivative 18
To
a
stirred solution of Zn/Cu couple34 (330 mg,
2.56 mmol) in PhH (8.4 mL) and DMF (9.3 mL) was added
16 (611 mg, 1.86 mmol). After heating at 50 ꢀC for 30 min,
Pd2dba3 (17.0 mg, 0.0188 mmol), P(o-tol)3 (22.6 mg,
0.0742 mmol), and 15 (173 mg, 0.371 mmol) in PhH (4 mL)
were added. After 2 h at 50 ꢀC, the solution was quenched
with 10% aq citric acid (15 mL), diluted with Et2O (20 mL),
and washed with H2O (15 mL) and satd aq NaCl (15 mL).
The dried extract (MgSO4) was concentrated in vacuo and pu-
rified by chromatography over silica gel, eluting with 10e50%
EtOAc/hexanes, to give 18 (156 mg, 0.288 mmol, 78%) as an
off-white solid. Mp¼62e64 ꢀC; [a]D þ37.2 (c 1.52, CHCl3);
3.19. 3-Bromo-2-nitro-benzaldehyde (24)
To a stirred solution of 23 (10.02 g, 46.38 mmol) in DMF
(37 mL) were added DMF$DMA (19.0 mL, 16.91 g,
141.91 mmol) and pyrrolidine (3.80 mL, 3.29 g, 46.29 mmol)
at rt. The solution was then heated to 115 ꢀC. After 22 h, the so-
lution was cooled to rt and added dropwise to a stirring solution
of NaIO4 (29.80 g, 139.2 mmol), DMF (75 mL), and H2O
(100 mL) at 0 ꢀC. The reaction mixture was then allowed to
warm to rt. After 3 h at rt, the reaction mixture was filtered
through sand, eluting with EtOAc (400 mL). The organic layer
was then washed with H2O (3ꢁ200 mL). The dried extract
(MgSO4) was purified by chromatography over silica gel,
eluting with 5e40% EtOAc/hexanes, to give 24 (3.70 g,
16.09 mmol, 35%) as a dark red solid. Mp¼75e77 ꢀC; IR
IR (neat) 3364, 2977, 1744, 1712, 1538, 1501 cmꢂ1 1H
;
NMR (400 MHz, CDCl3) d 7.53 (dd, J¼1.1, 7.8 Hz, 1H),
7.47 (t, J¼7.8 Hz, 1H), 7.27e7.36 (m, 6H), 7.12 (dd, J¼2.2,
8.5 Hz, 1H), 7.00 (d, J¼2.1 Hz, 1H), 6.90 (d, J¼8.5 Hz,
1H), 5.06 (s, 2H), 4.52e4.62 (m, 1H), 3.73 (s, 3H), 3.05e
3.08 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 172.6, 155.5, 155.1, 149.6, 137.1, 133.9, 131.8, 131.7,
131.0, 130.6, 130.0, 129.1, 128.9, 128.2, 172.2, 125.7, 125.3,
113.5, 80.4, 70.9, 54.82, 52.75, 37.83, 28.70; HRMS (CIþ)
calcd for C28H30N2O7Cl (MþH) 541.1723, found 541.1742.
(neat) 1702, 1539, 1368, 1191, 1118, 912, 847, 785, 700 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 9.93 (s, 1H), 7.96e7.99 (m,
2H), 7.62 (t, J¼8.0 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 185.7, 150.5, 139.1, 131.7, 130.2, 128.7, 114.7; HRMS (CIþ)
calcd for C7H4BrNO3 (Mþ) 228.9377, found 228.9375.
3.16. Organozinc 20
3.20. E-2-(3-Bromo-2-nitro-phenyl)-1-phenylsulfonyl-
ethene (25)
To a stirred solution of 19 (41.9 mg, 0.142 mmol) in THF
(0.7 mL) at ꢂ40 ꢀC was added a solution of i-PrMgCl
(0.100 mL, 0.156 mmol, 1.57 M in THF). After 10 min,
To a stirring solution of LiCl (0.481 g, 11.35 mmol) and
CH3CN (55 mL) at rt was added sequentially a solution of 8

B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
863
(3.99 g, 13.68 mmol) in CH3CN (9.8 mL), DBU (1.36 g,
8.97 mmol), and a solution of 24 (1.72 g, 7.48 mmol) in
CH3CN (12.5 mL). After 12 h, the reaction was quenched
with sat. aq. NH4Cl (75 mL) and the organic solvents were re-
moved in vacuo. The residue was then extracted with CH2Cl2
(50 mL), washed with satd aq. NH4Cl (30 mL), and the aque-
ous layer was extracted with CH2Cl2 (2ꢁ50 mL). The dried
extract (MgSO4) was concentrated in vacuo and purified by
recrystallization from EtOAc to yield 25 (2.62 g, 7.12 mmol,
95%) as an orange solid. Mp¼175e78 ꢀC; IR (neat) 1534,
1445, 1364, 1308, 1149, 1085, 963, 830, 728, 748,
to give 35 (814 mg, 1.86 mmol, 83%) as a white solid.
Mp¼168e9 ꢀC; IR (neat) 3484, 1656, 1534, 1449, 1360,
1303, 1143, 1080, 1027, 726 cmꢂ1 1H NMR (300 MHz,
;
CDCl3) d 7.66 (d, J¼7.2 Hz, 2H), 7.59 (t, J¼7.5 Hz, 2H),
7.33e7.52 (m, 2H), 7.43 (t, J¼7.5 Hz, 2H), 7.02 (t, J¼
8.1 Hz, 1H), 5.84e6.00 (m, 2H), 4.32 (s, 1H), 4.03 (dd,
J¼8.7, 17.8 Hz, 1H), 3.22 (dd, J¼3.5, 10.8 Hz, 1H), 2.58 (d,
J¼7.5 Hz, 2H); 13C NMR (300 MHz, CDCl3) d 151.5,
138.5, 133.7, 132.5, 131.0, 130.5, 129.2, 129.1, 128.1,
127.7, 127.6, 127.3, 112.6, 66.0, 58.3, 41.6, 25.7; HRMS
(CIþ) calcd for C18H17NO5SBr (MþH) 438.00107, found
437.99984.
1
686 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.96 (d, J¼8.0 Hz,
2H), 7.76 (d, J¼8.0 Hz, 1H), 7.642e7.725 (m, 1H), 7.561e
7.642 (m, 4H), 7.43 (t, J¼8.0 Hz, 1H), 6.94 (d, J¼15.2 Hz,
1H); 13C NMR (400 MHz, CDCl3) d 139.3, 135.7, 13.0,
134.0, 131.5, 129.6, 128.1, 127.1, 127.0, 114.2; HRMS
(CIþ) calcd for C14H11NO4SBr (MþH) 367.9592, found
367.9610.
3.23. 30-Bromo-20-nitro-biphenyl-2-ol (27)
To a solution of DMSO (69.8 mg, 0.894 mmol, 63.4 mL) in
CH2Cl2 (750 mL) at ꢂ78 ꢀC was added oxalyl chloride
(56.7 mg, 0.447 mmol, 39.0 mL). After 15 min, a solution of
35 (65.3 mg, 0.149 mmol) in CH2Cl2 (550 mL) and DMSO
(100 mL) was added. After 15 min, Et3N (304 mg,
2.98 mmol, 418 mL) was added. The solution was allowed to
warm to rt over 1 h. After an additional 1 h, the solution
was quenched with satd aq NH4Cl (5 mL), diluted with
CH2Cl2 (5 mL), and washed sequentially with H2O (5 mL)
and satd aq NaCl (2 mL). The dried extract (MgSO4) was con-
centrated in vacuo and purified by chromatography over silica
gel, eluting with 60% EtOAc/hexanes, to give 27 (38.5 mg,
0.131 mmol, 88%) as a white solid. Mp¼111e114 ꢀC; IR
3.21. Bromo DielseAlder adduct 26
To diene 6 (4.38 g, 23.8 mmol) in a sealed tube were added
25 (2.18 g, 5.93 mmol) and PhMe (12.1 mL). The neat solu-
tion was then heated to 135 ꢀC. After 5 days, the volatiles
were removed in vacuo and were purified by chromatography
over silica gel, eluting with 5e40% EtOAc/hexanes, to give 26
(2.53 g, 4.57 mmol, 77%) as a yellow solid. IR (neat) 2954,
2929, 2890, 2856, 1538, 1363, 1307, 1256, 1145, 1082,
(neat) 3442, 2090, 1646, 1110 cmꢂ1 1H NMR (400 MHz,
;
1062, 837, 777, 727 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
CDCl3) d 7.73 (dd, J¼4.0, 5.2 Hz, 1H), 7.45e7.44 (m, 2H),
7.04 (ddd, J¼1.6, 8.0, 15.2 Hz, 1H), 7.17 (dd, J¼1.6,
7.6 Hz, 1H), 6.99 (t, J¼7.2 Hz, 1H), 6.99 (d, J¼8.0 Hz, 1H),
5.51 (s, 1H); 13C NMR (400 MHz, CDCl3) d 152.8, 133.2,
132.6, 131.2, 131.1, 130.8, 130.2, 122.3, 121.0, 116.4,
113.4, 29.7; HRMS (CIþ) calcd for C12H8NO3IBr (Mþ)
292.9688, found 294.9667.
d 7.70 (d, J¼7.6 Hz, 2H), 7.60e7.64 (m, 1H), 7.44e7.52
(m, 4H), 7.04 (t, J¼8.0 Hz, 1H), 5.82e5.87 (m, 2H), 4.02
(dd, J¼8.0, 17.6 Hz, 1H), 3.20 (dd, J¼4.0, 10.0 Hz, 1H),
2.55 (d, J¼7.6 Hz, 2H), 0.79 (s, 9H), ꢂ0.09 (s, 3H), ꢂ0.37
(s, 3H); 13C NMR (400 MHz, CDCl3) d 151.5, 138.3, 133.7,
132.3, 132.1, 130.8, 129.2, 129.1, 128.8, 128.7, 125.6,
111.9, 66.6, 59.1, 41.8, 25.3, 25.2, 17.9, ꢂ4.9, ꢂ5.5; HRMS
(CIþ) calcd for C24H31NO5SBr (MþH) 552.08755, found
552.08841.
3.24. 30-Bromo-5-iodo-20-nitro-biphenyl-2-ol (28)
To a solution of 27 (331 mg, 1.13 mmol) in MeOH
(7.5 mL) were added NaOH (45.0 mg, 1.13) and NaI
(169 mg, 1.13 mmol) at rt. The solution was then cooled to
0 ꢀC. Next, NaOCl (1.36 mL, 83.8 mg, 1.13 mmol, 6.15%
w/v in H2O) was added to the reaction over a period of
45 min. After an additional 1 h, the reaction was quenched
with aq sodium thiosulfate (30 mL, 10%), diluted with EtOAc
(30 mL), and washed sequentially with satd aq NH4Cl
(30 mL), H2O (30 mL), and satd aq NaCl (30 mL). The dried
extract (MgSO4) was concentrated in vacuo and purified via
chromatography over silica gel, eluting with 75% CH2Cl2/hex-
anes, to give 28 (474 mg, 1.13 mmol, 98%) as a white solid.
3.22. Bromo alcohol 35
Br
NO2
SO2Ph
HO
35
To biaryl 26 (1.23 g, 2.23 mmol) was added a premixed so-
lution of AcOH (0.5 mL) and TBAF (9.5 mL, 9.5 mmol, 1.0 M
in THF) at rt. The solution was stirred for 45 min and addi-
tional TBAF (15 mL, 15 mmol, 1 M in THF) was added por-
tionwise over a period of 2 h. After an additional 1 h, the
solution was quenched with H2O (50 mL), diluted with Et2O
(50 mL), and washed with satd aq NaCl (50 mL). The dried
extract (MgSO4) was concentrated in vacuo and purified by
chromatography over silica, eluting with 60% EtOAc/hexanes,
Mp¼164e167 ꢀC; IR (neat) 3441, 2090, 1646, 1110 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.79 (dd, J¼1.2, 8 Hz, 1H),
7.62 (dd, J¼2.2, 8.6 Hz, 1H), 7.78 (dd, J¼1.8, 8.0 Hz, 2H),
7.40 (dd, J¼1.2, 7.9 Hz, 1H), 6.73 (d, J¼8.6 Hz, 1H), 4.90
(s, 1H); 13C NMR (400 MHz, CDCl3) d 152.7, 139.6, 138.6,
133.9, 131.3, 131.0, 130.8, 124.9, 118.7, 113.7, 82.8; HRMS

864
B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
(CIþ) calcd for C12H7NO3IBr (Mþ) 418.8654, found
418.8654.
satd aq NH4Cl (15 mL), diluted with EtOAc (20 mL), and
washed with H2O (15 mL) and satd aq NaCl (15 mL). The
dried extract (MgSO4) was purified via chromatography over
silica gel, eluting with 10e30% EtOAc/hexanes, to give 32
(19.9 mg, 0.0384 mmol, 54%) as a clear oil. [a]D þ34.9 (c
3.25. 20-Benzyloxy-3-bromo-50-iodo-2-nitro-
biphenyl (29)
1
1.05, CHCl3); IR (neat) 2980, 1745, 1715, 1528 cmꢁ1; H
To a solution of 28 (474 mg, 1.13 mmol) in acetone
(11 mL) were added K2CO3 (469 mg, 3.39 mmol) and BnBr
(0.389 mL, 0.580 mg, 3.39 mmol) at rt. The solution was
heated to 70 ꢀC. After 1 h, the solution was cooled to rt, di-
luted with EtOAc (30 mL), and washed sequentially with
satd aq NH4Cl (30 mL), H2O (30 mL), and satd aq NaCl
(30 mL). The dried extract (MgSO4) was concentrated in va-
cuo and purified via chromatography over silica gel, eluting
with 10e33% CH2Cl2/hexanes, to give 29 (538 mg,
1.05 mmol, 97%) as a white solid. Mp¼126e127 ꢀC; IR
NMR (400 MHz, CDCl3) d 7.43 (t, J¼7.6 Hz, 1H), 7.24e
7.34 (m, 7H), 7.07 (dd, J¼8.5, 2.2 Hz, 1H), 6.99 (d,
J¼2.2 Hz, 1H), 6.87 (d, J¼8.4 Hz, 1H), 5.03 (s, 2H), 5.02e
5.05 (br s, 1H), 4.55e4.61 (m, 1H), 3.72 (s, 3H), 3.05 (d, J¼
5.0 Hz, 2H), 2.43 (s, 3H), 1.44 (s, 9H); 13C NMR (400 MHz,
CDCl3) d 172.3, 155.1, 154.7, 151.0, 136.9, 131.8, 131.5,
130.6, 130.5, 130.1, 130.0, 129.7, 128.6, 128.4, 127.6,
126.7, 126.6, 113.0, 70.5, 54.5, 52.3, 37.5, 28.3, 18.3;
HRMS (CIþ) calcd for C29H33N2O7 (MþH) 521.22878, found
521.22638.
1
(neat) 1536, 1489, 1453, 1366, 1276, 1227, 1028, 697; H
NMR (400 MHz, CDCl3) d 7.73 (dd, J¼0.8, 7.7 Hz, 1H),
7.62 (dd J¼2.2, 7.7 Hz, 1H), 7.53 (d, J¼2.2 Hz, 1H), 7.30e
7.42 (m, 6H), 7.26 (d, J¼7.0 Hz, 2H), 6.73 (d, J¼8.7 Hz,
2H); 13C NMR (400 MHz, CDCl3) d 155.6, 139.2, 138.7,
136.2, 133.2, 131.0, 130.8, 128.6, 127.9, 127.4, 126.8,
115.2, 113.3, 82.9, 70.6, 29.7; HRMS (CIþ) calcd for
C19H13NO3IBr (Mþ) 508.9124, found 508.9124.
4. Supplementary material
Supplementary material (experimental procedure for the
preparation of compound 19, copies of 1H and 13C NMR spec-
tra, and crystallographic data for compounds 10, 14, and 34) is
available via the internet at www.sciencedirect.com.
Acknowledgements
3.26. Bromo amino acid derivative 30
Financial support was provided by Oregon State University
(OSUdTartar Fellowships for B.O.A. and L.K.R., Pipeline
Fellowship for B.O.A., URISC Fellowship for E.H.C.) and
the National Science Foundation (CHE-0549884). The authors
would also like to thank Professor Max Deinzer and Dr. Jeff
To
a
stirred solution of Zn/Cu couple34 (182 mg,
2.79 mmol) in PhH (5.5 mL) and DMA (0.4 mL) was added
16 (517 mg, 1.57 mmol). After heating at 50 ꢀC for 30 min,
Pd2dba3 (3.6 mg, 0.00390 mmol), P(o-tol)3 (5.80 mg,
0.0191 mmol), and 29 (40.5 mg, 0.0794 mmol) were added.
After 8 h at 50 ꢀC, the solution was quenched with 10% aq cit-
ric acid (10 mL), diluted with Et2O (10 mL), and washed with
H2O (10 mL) and satd aq NaCl (10 mL). The dried extract
(MgSO4) was concentrated in vacuo and purified by chroma-
tography over silica gel, eluting with 5e10% EtOAc/hexanes,
to give 30 (21.0 mg, 0.0359 mmol, 46%, 70% borsm) as an
off-white solid. Mp¼45e48 ꢀC; [a]D þ39.2 (c 1.03, CHCl3);
´
Morre (OSU) for mass spectral data, Rodger Kohnert (OSU)
for NMR assistance, Professor Alex Yokochi (OSU), Dr.
Alan Richardson (OSU), Professor Michael Drew (University
of Reading), and Dr. Lev Zakharov (OSU) for X-ray crystallo-
graphic analysis, and Dr. Roger Hanselmann (Rib-X Pharma-
ceuticals) for his helpful discussions.
References and notes
IR (neat) 3318, 2978, 1717, 1540, 1160 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 7.70 (t, J¼5.1 Hz, 1H), 7.31e7.42 (m,
5H), 7.28 (d, J¼7.2 Hz, 2H), 7.12 (d, J¼8.4 Hz, 1H), 6.99
(s, 1H), 6.90 (d, J¼8.4 Hz, 1H), 5.06 (s, 3H), 4.59 (d,
J¼6.9 Hz, 1H), 3.72 (s, 3H), 3.01e3.11 (m, 2H), 1.45 (s,
9H); 13C NMR (400 MHz, CDCl3) d 172.2, 155.1, 154.7,
151.0, 136.7, 133.5, 132.8, 131.4, 131.3, 130.6, 128.7,
128.5, 127.8, 126.8, 125.0, 124.9, 113.1, 80.0, 70.5, 54.4,
52.4, 37.43, 28.3; HRMS (CIþ) calcd for C28H29N2O7Br
(Mþ) 584.1158, found 585.1236.
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3.27. Western fragment 32
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To a pressure vessel were added bromide 30 (41.0 mg,
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80 ꢀC for 13 h, the dark brown solution was quenched with

B.O. Ashburn et al. / Tetrahedron 64 (2008) 856e865
865
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AcOH (12.5 mL) at rt. The mixture was heated to reflux for 5 min and
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´
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17. See supporting information for details.