The catalytic ortho-arylation of tyrosine

Article abstract of DOI:10.1039/b906119c

The rhodium-catalysed direct ortho-arylation of protected racemic 2-tert-butyl tyrosine has been developed. The subsequent removal of the tert-butyl group yields the 2-arylated tyrosine which can undergo further rhodium-based arylation at the 6-position.

Full text of DOI:10.1039/b906119c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The catalytic ortho-arylation of tyrosine†
Robin B. Bedford,*a Mairi F. Haddow,a Ruth L. Webstera and Charlotte J. Mitchellb
Received 27th March 2009, Accepted 21st May 2009
First published as an Advance Article on the web 15th June 2009
DOI: 10.1039/b906119c
The rhodium-catalysed direct ortho-arylation of protected racemic 2-tert-butyl tyrosine has been
developed. The subsequent removal of the tert-butyl group yields the 2-arylated tyrosine which can
undergo further rhodium-based arylation at the 6-position. In one instance a product formed by
further arylation of the diarylated species was isolated.
Introduction
The biaryl subunit is an important structural motif found in
many compounds including natural products, polymers, liquid
crystals and ligands for homogeneous catalysis; cross-coupling
reactions (Scheme 1), particularly the Suzuki reaction (E =
B(OH)2, B(OR)2), are routinely employed in their syntheses.1
Scheme 1 Biaryl bond-formation by catalytic cross-coupling.
One such biaryl motif is the 2-arylated tyrosine moiety which is
seen, for instance, in the proteasome inhibitor TMC-95,2 the neu-
rotensin antagonist RP-66453,3 and the antibacterial arylomycin-
A2, originally isolated from Streptomyces strain TU6075.4
A
recent synthesis of the latter compound by Roberts and co-workers
exploited a Suzuki reaction for the formation of the biaryl unit.5
A more elegant approach to biaryl bond formation involves
exploiting a catalytic aromatic C–H activation process to gen-
erate the nucleophilic coupling partner rather than relying on
organometallic aromatic nucleophiles (Scheme 2). Such aromatic
C–H activation processes are rapidly becoming powerful tools for
the construction of biaryls,6,7 not least because they circumvent
many of the steps in cross-coupling chemistry giving shorter,
cleaner syntheses with fewer purifications necessary.
One class of biaryl bond formation that proceeds through
aromatic C–H activation is the rhodium-catalysed ortho-selective
arylation of phenols (Scheme 3).8 Here the catalytic transforma-
tion is reliant on the formation of a rhodacyclic intermediate which
is produced by orthometallation of a coordinated phosphinite
or related ligand. The rhodacycle then oxidatively adds the
aryl halide; subsequent reductive elimination leads to the ortho-
arylated phenol which in turn is liberated by transesterification
with the starting phenol.9
The direct arylation of 2-substituted phenols proceeds well
using [RhCl(PPh3)3] in the presence of a co-catalytic phosphinite
ligand, PR2(OAr), the corresponding chlorophosphine, PR2Cl or
P(NMe2)3.8 Electronically activated, non-activated and deacti-
vated aryl bromides along with sterically challenging species are
all well tolerated. We wished to extend our catalytic methodology
to more challenging biologically and pharmaceutically relevant
phenols and were interested to see whether the reaction could
be adapted to the synthesis of mono- and diarylated tyrosine
substrates.10 This indeed proves to be the case and the results
from this study are presented below.
Scheme 2 C–H activation to form biaryl compounds.
aSchool of Chemistry, University of Bristol, Cantock’s Close Bristol,
UK BS8 1TS. E-mail: r.bedford@bristol.ac.uk
bGlaxoSmithKline, Stevenage, UK SG1 2NY
† Electronic supplementary information (ESI) available: General experi-
mental details; spectroscopic data for all new compounds, determination
of enantiopurity, X-ray structure data for 3a. CCDC reference number
725600. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b906119c
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Scheme 4
2,6-diarylated products (unless blocked by steric hindrance in the
meta position). Since an ortho-tert-butyl group should be relatively
easy to remove, it could in principle be exploited to speed up mono-
arylation while preventing diarylation and then be removed to
furnish the desired mono-arylated phenol which could, in turn,
be further elaborated at the 6-position. A relatively facile route to
the fully protected tyrosine substrate 1 was achieved on a multi-
gram scale following the method outlined in Scheme 5, based on
modified literature methods.11–13 Unfortunately, both polarimetry
and 1H NMR analysis with a chiral shift reagent indicated that 1
was racemic.†
Scheme 3 The rhodium-catalysed ortho-arylation of phenols.
Results and discussion
We envisaged that ortho-arylation of tyrosine could be exploited
to generate both mono- and diarylated tyrosines according to the
disconnection outlined in Scheme 4.
In the first instance it was necessary to produce a suitable
tyrosine substrate. We have found that catalytic ortho-arylation
is most effective when there is a bulky group at the 6-position
of the phenol.8a,c,d The reactions of 2,6-unsubstituted phenols
are substantially more challenging and lead exclusively to the
Scheme 5 Conditions: (i) H3PO4, tBuOH, 65 ◦C, 60 h; (ii) acetyl chloride,
MeOH, reflux, 15 h; (iii) NEt3, MeOH, 0 ◦C followed by Boc2O, 0 ◦C to
rt 18 h; (iv) PiPr2Cl, NEt3, toluene, 110 ◦C, 18 h.
Table 1 Optimisation studiesa
Entry
Rh source (mol% Rh)
Ligand (mol%)
Base
Temperature/◦C
Time/h
Conversion (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
[RhCl(PPh3)3] (5)
2 (15)
Cs2CO3
Cs2CO3
NaOtBu
K3PO4
110
110
110
110
110
120
130
130c
130
110
120
120
120
120
120
120
18
18
18
18
24
18
18
3
3
3
3
3
41
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (7.5)
[RhCl(PPh3)3] (5)
[{RhCl(PPh3)2} ] (5)
[{RhCl(NBD)}2] (5), PPh3 (4 equiv.)
[{RhCl(dppe)}22] (5)
[{RhCl(COD)} ] (5)
[{RhCl(COD)}2] (5)
[{RhCl(NBD)}22] (5)
[RhCl(COD)(PiPr2Cl)] (5)
[RhCl(PPh3)3] (7.5)
2 (22.5)
2 (15)
93.5
35.5
40
70
67
85
54
80
0
16.5
21
26
9
17.5
17
2 (15)
2 (15)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
2 (15)
2 (15)
2 (15)
2 (15)
2 (10)
2 (15)
2 (15)
PiPr2Cl (15)
PiPr2Cl (15)
—
3
3
3
3
PiPr2Cl (30)
a Conditions: 1 (0.178 mmol), 4-BrC6H4COMe (0.256 mmol), base (0.290 mmol), catalyst and co-ligands as per entry, toluene (5 mL). b Spectroscopic
yield of 3a determined by 1H NMR spectroscopy, 1,3,5-C6H3(OMe)3 internal standard, average of two runs. c Microwave heating.
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Previous studies showed that the ortho-arylation of 2-
substituted phenols, HOAr, is particularly effective when us-
ing the corresponding phosphinite ligands PiPr2(OAr) as co-
catalysts to direct the orthometallation.8a,c,d Therefore phosphinite
2 was synthesised by the reaction of 1 with chlorodiisopropy-
lphosphine; the 31P NMR spectrum of 2 shows a singlet at
d 138.5.
R-enantiomers; the S-enantiomer is shown in Fig. 1.†‡ The
packing in the solid state (see Fig. S2, ESI†) consists of ribbons
of pairs of enantiomers held together by hydrogen bonds. The
pairs of opposite enantiomers hydrogen bond between the NH
and the CO of the Boc-protected amino residues while one pair of
enantiomers joins to the next in the chain with pairs of hydrogen
bonds between the phenolic OHs and the acetyl oxygens.
The specific reaction chosen for the catalyst optimisation studies
is shown in Table 1. 4-Bromoacetophenone was chosen as coupling
partner since it readily undergoes oxidative addition reactions.
As can be seen, the best results were obtained when Wilkinson’s
catalyst was employed at 7.5y% with 3 equivalents of PiPr2(OAr)
using caesium carbonate as the base (entry 2), although good
conversions were seen at 5 mol% Rh loading, providing the tem-
◦
perature was increased to 130 C (entry 7). Similarly, microwave
heating could be used to good effect (compare entries 1 and
8). Under the higher temperature, conventional heating condi-
tions, the preformed dimeric complex [{RhCl(PPh3)2}2] performed
comparably to Wilkinson’s catalyst (entry 9), however the in situ
reactionof[{RhCl(NBD)}2] with triphenylphosphine did not yield
an active catalyst (entry 10) and replacing the triphenylphosphine
ligands with 1,2-bis(diphenylphosphino)ethane (dppe) proved
deleterious (entry 11). Contrary to previous findings, the use of
[{RhCl(COD)}2]–phosphinite mixtures gave poor yields (entry
12).8c Similarly, contrary to findings in the ortho-arylation of
simpler 2-tert-butylphenols,8d the formation of the phosphinite
ligand in situ from either free or coordinated PiPr2Cl and a
variety of rhodium sources gave poor results (entries 13–16).
Taken together these data indicate that in many cases the amino
acid functionality is probably retarding activity, presumably by
competitive coordination.
Having established the best catalyst system and conditions
we next applied these to a range of aryl bromide substrates
and the results from this study are summarised in Table 2. In
general electronically deactivated as well as activated substrates
are well tolerated, as are sterically hindered aryl bromides. The
isolated yields of the desired products ranged from acceptable
through to excellent, although no clear electronic trends are
immediately apparent. For instance, little variation in catalyst per-
formance was seen with 4-bromoacetophenone, 4-bromotoluene,
4-bromoanisole and 4-bromo-N,N-dimethylaniline (entries 1, 5, 6
and 7) despite the considerable difference in the electronic prop-
erties of these substrates.14 Conversely 4-bromobenzophenone,
methyl 4-bromobenzoate and bromobenzene all showed unexpect-
edly low yields (entries 2–4). 1H NMR analyses of crude product
mixtures indicated that these reactions were genuinely low yielding
and not that product was lost during work-up.
Fig. 1 X-Ray crystal structure of 3a (S-enantiomer shown), hydrogen
atoms removed for clarity.
Having established a convenient methodology for the ortho-
arylation of the substrate 1, we next attempted the removal of
the 2-tert-butyl protecting group. Various methodologies based
on reacting 1 with Lewis acids in the presence of carboxylic acids,
such as zinc acetate–acetic acid,15 proved ineffective. However, a
test reaction based on 1 with AlCl3–MeNO2 in toluene,16 followed
by reprotection of the amino acid function of the crude, unisolated
product, yielded the protected tyrosine 4a in 78% overall yield after
three steps (Scheme 6). Subjecting 3e to the same methodology
gave the desired 2-arylated tyrosine 4b in 77% overall yield.
Scheme 6 Removal of the 2-tert-butyl group. Conditions: (i) MeNO2,
AlCl3, toluene, -40 ◦C to rt, 18 h; (ii) acetyl chloride, MeOH, reflux, 15 h;
(iii) NEt3, MeOH, 0 ◦C followed by Boc2O, 0 ◦C to rt, 18 h.
Interestingly, the introduction of steric hindrance in the 2-
position of the aryl bromide gave diastereomeric products 3j and
k (entries 10 and 11) due to restricted rotation about the biaryl
axis, at least on the NMR timescale at room temperature.
With the arylated tyrosine 4b in hand, we next examined
its application to the synthesis of ortho-diarylated tyrosines,
5 (Scheme 7) employing the methodology developed above.
Reaction of 4b with 4-bromoacetophenone yielded two arylated
products: the desired species 5a and the by-product 6a, formed
by a further arylation of 5a, in a combined yield of 66%. Such
secondary arylations have been seen previously in the rhodium-
catalysed ortho-arylation of phenols.8 It appears that there is
essentially complete selectivity for the site of the secondary
arylation with none occurring on the tolyl residue. The reactions of
The single crystal X-ray structure of 3a‡ was determined
¯
and the unit cell (space group P1) contains both S- and
‡ Crystal data: 3a: C27H35NO6, M = 469.56, triclinic, a = 9.9888(10),
˚
b = 10.6897(10), c = 13.5774(13) A, a = 85.729(6), b = 68.552(5), g =
◦
3
¯
˚
71.738(5) , V = 1280.1(2) A , T = 100(2) K, space group P1, Z = 2,
m = 0.085 mm-1, Rint = 0.0373 (for 21665 measured reflections), R1
=
0.0404 [for 4427 unique reflections with >2s(I)], wR2 = 0.1054 (for all
5869 unique reflections).
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Table 2 Ortho-arylation of 1 with a range of aryl bromidesa
Entry
1
Aryl bromide
Product (yield, %)b [spec. yield]c
3a (89)
2
3
4
3b (24) [40]
3c (24) [30]
3d (41) [45]
5
6
7
8
3e (71)
3f (83)
3g (96)
3h (52)
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Table 2 (Contd.)
Entry
9
Aryl bromide
Product (yield, %)b [spec. yield]c
3i (36)
10
3j (33)d
11
12
3k (61)e
3l (67)
a Conditions: 1 (0.854 mmol), aryl bromide (1.474 mmol), Cs2CO3 (1.670 mmol), [RhCl(PPh3)3] (0.049 mmol), 2 (0.128 mmol), toluene (8 mL), 110 ◦C,
18 h. b Isolated yield. c Spectroscopic yield determined by 1H NMR spectroscopy, 1,3,5-C6H3OMe3 internal standard. d Diastereomeric ratio: 1 : 1
(determined by 1H NMR spectroscopy, CDCl3, 25 ◦C). e Diastereomeric ratio: 0.9 : 1.1 (determined by1H NMR spectroscopy, CDCl3, 25 ◦C).
4b with 4-bromostyrene and 4-bromo-N,N-dimethyl aniline gave
modest yields of the diarylated tyrosines.
Conclusions
In summary we have developed the rhodium catalysed direct ortho-
arylation of 2-tert-butyl protected tyrosine using aryl bromide
substrates. Subsequent removal of the tert-butyl group yields the
2-arylated tyrosine, this in turn allows the introduction of a second,
different aryl group into the 6-position. Thus a small library of
mono- and diarylated tyrosines has been produced, as has an
example of a triarylated tyrosine. The protected tyrosine substrate
1 is racemic, with racemisation occurring prior to catalysis, thus
we are at present unable to determine whether the ortho-arylation
proceeds with retention of stereochemistry. We are currently
exploring ways to either produce optically pure 1 or develop new
C–H activation routes that do not require the introduction of a
tert-butyl group, in order to develop arylation reactions with a
focus on retention of chirality. These results will be published in
due course.
Scheme 7 Ortho-arylation of 4b. Conditions: (i) ArBr, [{RhCl(COD)}2],
P(NMe2)3, Cs2CO3, toluene, D, 18 h.
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1H), 5.14 (s, 1H), 4.98 (d, J = 8.6 Hz, 1H), 4.56 (app. dd, J = 8.1,
5.8 Hz, 1H), 3.73 (s, 3H), 3.07-2.97 (m, 2H), 1.45 (s, 9H), 1.40 (s,
9H); 13C NMR (100 MHz, CDCl3) d 172.9, 155.4, 153.9, 136.2,
128.1, 127.6, 127.0, 116.7, 80.3, 54.7, 52.4, 37.8, 34.6, 29.6, 28.4;
IR neat, n (cm-1) 1013 (m), 1060 (s), 1213 (m), 1360 (s), 1423 (m),
1496 (m), 1610 (w), 1701 (s), 1704 (s), 2959 (w), 3009 (w), 3439 (w);
mp 95.3–97.8 ◦C; HRMS (ESI) calcd for C19H29NNaO5 (M + Na)+
374.1938, found 374.1950; anal. calcd for C19H29NO5: C, 64.9; H,
8.3; N, 4.0%, found: C, 66.0; H, 8.2; N, 65.4%. Compound 1 was
shown to be racemic by 1H NMR experiments and polarimetry.†
Experimental section
3-tert-Butyltyrosine
L-Tyrosine (15.0 g, 82.8 mmol) was added to a solution of tert-
butanol (17.5 mL, 183.0 mmol) in conc. H3PO4 (45 mL). The
reaction mixture was stirred continuously at 65 C for 60 h then
allowed to cool to rt, and quenched by pouring into NaOH (aq.)
(1 M, 500 mL). The resulting precipitate was collected by filtration,
washed with H2O followed by Et2O and then dried under vacuum.
The product was afforded as a white powder, 15.1 g (77%). Rf
◦
1
0.3095 (MeOH–NH3 (aq., 35%), 99 : 1); H NMR (400 MHz,
Phosphinite ligand, 2
DMSO) d 7.03 (d, J = 1.9 Hz, 1H), 6.88 (dd, J = 8.0, 1.9 Hz,
1H), 6.72 (d, J = 8.0 Hz, 1H), 3.30 (app. dd, J = 8.4, 4.3 Hz, 1H),
3.03 (dd, J = 12.0, 4.0 Hz, 1H), 2.72 (dd, J = 12.0, 8.0 Hz, 1H),
1.33 (s, 9H); 13C NMR (100 MHz, DMSO) d 170.6, 155.3, 135.3,
128.1, 127.3, 116.7, 56.5, 34.8, 30.9, 29.9; IR neat, n (cm-1) 1051
(m), 1153 (m), 1229 (m), 1255 (m), 1332 (s), 1367 (m), 1423 (s),
1510 (m), 1598 (s), 1614 (s), 2956 (w), 3254 (w), 33575 (w); mp
246.5–248.3 ◦C; HRMS (EI) (M + Na)+ calcd for C13H19NNaO3
260.1257, found 260.1267; anal. calcd for C13H19NO3: C, 65.8; H,
8.1; N, 5.9%, found: C, 65.1; H, 8.2; N, 6.2%.
To 1 (0.58 g, 1.65 mmol), in a Schlenk tube under an atmosphere
of nitrogen, was added anhydrous NEt3 (0.26 mL, 1.85 mmol),
chlorodiisopropylphosphine (0.26 mL, 1.62 mmol) and anhydrous
toluene (10 mL). The mixture was then heated at reflux tempera-
ture for 18 h, allowed to cool to room temperature and then filtered
R
through a pad of Celiteꢀ under nitrogen to remove the precipitated
triethylamine hydrochloride. The solvent was removed in vacuo to
yield 2 as a white opaque gum, 0.53 g (81%). 1H NMR (300 MHz,
CDCl3) d 7.51 (dd, J = 8.1, 6.7 Hz, 1H), 6.97 (d, J = 2.2 Hz,
1H), 6.85 (dd, J = 7.3, 2.0 Hz, 1H), 4.97 (d, J = 8.2 Hz, 1H), 4.55
(app. dd, J = 8.3, 5.7 Hz, 1H), 3.70 (s, 3H), 3.11–2.99 (m, 2H),
2.09–1.92 (m, 2H), 1.42 (s, 9H), 1.37 (s, 9H), 1.18–1.06 (m, 12H);
13C NMR (75 MHz, CDCl3) d 172.6, 156.7, 155.2, 138.3, 128.1,
127.5, 116.6, 116.2, 79.8, 54.5, 52.2, 37.7, 34.8, 30.1, 28.1, 17.8,
17.6; 31P NMR (122 MHz, d8-toluene) d 138.5 (s); HRMS (ESI)
calcd for C25H42NNaO5P (M + Na)+ 490.2693, found 490.2698;
anal. calcd for C25H42NO5P: C, 64.2; H, 9.05; N, 3.0%, found: C,
64.6; H, 8.9; N, 3.1%.
Methyl 3-tert-butyltyrosinate
Acetyl chloride (6.3 mL, 88.5 mmol) was added to MeOH
(60 mL) at 0 ◦C; the solution was allowed to warm to rt
then 3-tert-butyltyrosine (3.0 g, 12.6 mmol) was added. The
solution was heated at reflux temperature for 15 h, cooled to
room temperature, poured into saturated NaHCO3 solution
(20 mL) and extracted with CH2Cl2 (3 ¥ 15 mL). The combined
organic extracts were washed with brine (3 ¥ 10 mL), dried over
MgSO4 and concentrated in vacuo. The resulting off-white solid
was sufficiently pure to use in the next step without further
purification, 1.31 g (76%). Rf 0.058 (Et2O); 1H NMR (400 MHz,
CDCl3) d 7.05 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 8.0, 2.2 Hz, 1H),
6.57 (d, J = 7.8 Hz, 1H), 3.75 (s, 1H), 3.74 (s, 3H), 3.03 (dd, J =
13.7, 5.2 Hz, 1H), 2.83 (dd, J = 13.7, 7.5 Hz, 1H), 1.40 (s, 9H);
13C NMR (100 MHz, CDCl3) d 175.5, 154.2, 136.6, 127.9, 127.7,
127.5, 116.7, 55.7, 52.2, 40.2, 34.4, 29.6; IR neat, n (cm-1) 1023
(m), 1089 (w), 1177 (s), 1199 (s), 1261 (m), 1509 (w), 1606 (w),
1733 (s), 2602 (w), 2952 (m), 3000 (w), 3135 (w), 3359 (w); mp
134.8–136.3 ◦C; HRMS (ESI) calcd for C14H21NO3Na (M + Na)+
274.1413, found 274.1421; anal. calcd for C14H21NO3: C, 66.9; H,
8.4; N, 5.6%, found: C, 66.8; H, 8.8; N, 5.7%.
Optimisation of the rhodium catalysed ortho-arylation of 1 with
4-bromoacetophenone (Table 1)
To a Schlenk tube under N2 was added the appropriate rhodium
precursor, ligand(s), toluene (5 mL), 4-bromoacetophenone
(0.051 g, 0.256 mmol), 1 (0.060 g, 0.178 mmol), and Cs2CO3
(0.095 g, 0.290 mmol). The mixture was stirred at reflux tem-
perature for 18 h then allowed to cool to room temperature. HCl
(aq.) (2 M, 5 mL) was added and the organic phase extracted
into dichloromethane (3 ¥ 10 mL), dried over MgSO4, filtered and
the solvent removed under reduced pressure. A standard solution
of 1,3,5-trimethoxybenzene in CDCl3 (1.00 M, 0.178 mL) and
then CDCl3 (~1 mL) were added and the spectroscopic yield was
determined by 1H NMR spectroscopy.
Methyl N-Boc-3-tert-butyltyrosinate, 1
General methodology for the ortho-arylation of 1 using
Wilkinson’s catalyst and phosphinite 2 (Table 2)
NEt3 (1.03 mL, 7.41 mmol) was added to a solution of
methyl 3-tert-butyltyrosinate (1.24 g, 4.94 mmol) in dry methanol
(30 mL) under N2 and the mixture was cooled to 0 ◦C. Di-tert-butyl
dicarbonate (1.19 g, 5.43 mmol) was added and the reaction stirred
for 30 min, then allowed to warm to room temperature and stirred
for a further 18 h. The solution was acidified to pH 1 with HCl
(aq.) (10 mL, 2 M) and extracted with CH2Cl2 (3 ¥ 15 mL). The
combined organic extracts were washed with brine (3 ¥ 10 mL),
dried over MgSO4 and concentrated in vacuo. The resulting off-
white solid was purified by column chromatography (5% methanol
in CH2Cl2) to afford 1 as a white powder, 1.31 g (76%). Rf 0.492
(MeOH–CH2Cl2, 1 : 19); 1H NMR (400 MHz, CDCl3) d 6.97 (d,
J = 2.2 Hz, 1H), 6.81 (dd, J = 8.1, 2.0 Hz, 1H), 6.58 (d, J = 7.8 Hz,
[RhCl(PPh3)3] (0.045 g, 0.049 mmol) was added to a Schlenk
tube under an atmosphere of N2 along with toluene (8 mL),
the appropriate aryl halide (1.5 eq., 1.474 mmol), 1 (0.300 g,
0.854 mmol), phosphinite 2 (0.060 g, 0.128 mmol), and Cs2CO3
(0.544 g, 1.670 mmol). The mixture was stirred at reflux temper-
ature for 18 h then allowed to cool to room temperature. HCl
(aq.) (2 M, 5 mL) was added and the organic phase extracted
into dichloromethane (3 ¥ 20 mL), dried over MgSO4, filtered and
the solvent removed under reduced pressure. The crude mixture
was purified by column chromatography on silica gel to afford the
product.
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3a (Table 2, entry 1)
65.8, 52.2, 37.6, 34.9, 29.6, 28.3; IR neat, n (cm-1) 1016 (m), 1059
(m), 1155 (s), 1201 (m), 1364 (m), 1432 (m), 1497 (m), 1599 (w),
1710 (s), 1742 (s), 2162 (w), 2954 (w), 3407 (w), 3543 (w); mp
White solid, 0.357 g (89%); Rf 0.37 (Et2O–pentane, 7 : 3); 1H NMR
(300 MHz, CDCl3) d 8.08 (app. dt, J = 8.6, 1.9 Hz, 2H), 7.56 (app.
dt, J = 6.6, 1.8 Hz, 2H), 7.04 (d, J = 1.9 Hz, 1H), 6.83 (d, J =
1.8 Hz, 1H), 5.26 (s, 1H), 5.01 (d, J = 8.4 Hz, 1H), 4.59 (app.
dd, J = 8.6, 6.0 Hz, 1H), 3.74 (s, 3H), 3.13–3.00 (m, 2H), 2.66 (s,
3H), 1.43 (s, 18H); 13C NMR (75 MHz, CDCl3) d 197.6, 172.5,
155.1, 150.1, 142.4, 136.8, 136.5, 129.8, 129.4, 128.7, 128.5, 127.5,
80.0, 54.5, 52.3, 35.0, 29.7, 28.4, 26.8; IR neat, n (cm-1) 1027 (m),
1163 (s), 1277 (s), 1362 (s), 1432 (m), 1562 (m), 1604 (m), 1671
(s), 1701 (s),◦1748 (s), 2951 (w), 3152 (w), 3258 (w), 3344 (w); mp
153.0–153.3 C; HRMS (ESI) calcd for C27H35NNaO6 (M + Na)+
492.2357, found 492.2365; anal. calcd for C27H35NO6: C, 69.0; H,
7.5; N, 3.0%, found: C, 69.0; H, 7.7; N, 3.2%. Crystals suitable for
X-ray analysis were grown by slow evaporation of a diethyl ether
solution. See ESI for crystallographic data.†
◦
60.8–62.4 C; HRMS (ESI) calcd for C25H33NNaO5 (M + Na)+
450.2251, found 450.2265; anal. calcd for C25H33NO5: C, 70.2; H,
7.8; N, 3.3%, found: C, 70.9; H, 7.4; N, 3.6%.
3e (Table 2, entry 5)
White solid, 0.249 g (71%); Rf 0.14 (Et2O–pentane, 1 : 5); 1H NMR
(400 MHz, CDCl3) d 7.35–7.30 (m, 4H), 7.00 (d, J = 1.8 Hz, 1H),
6.82 (d, J = 1.7 Hz, 1H), 5.44 (s, 1H), 5.00 (d, J = 8.5 Hz, 1H),
4.60 (app. dd, J = 8.3, 5.6 Hz, 1H), 3.75 (s, 3H), 3.11–3.02 (m,
2H), 2.44 (s, 3H), 1.44 (s, 9H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 172.5, 155.0, 150.1, 137.8, 136.1, 134.0, 130.1, 129.3,
128.71, 128.67, 127.4, 126.7, 79.8, 54.5, 52.1, 37.6, 34.9, 29.6, 28.3,
21.2; IR neat, n (cm-1) 1015 (m), 1081 (m), 1154 (s), 1227 (s), 1286
(s), 1442 (m), 1502 (m), 1612 (w), 1712 (s), 1726 (s), 1918 (w),
2911 (w), 29◦53 (w), 2966 (w), 3426 (w), 3481 (w), 3674 (w); mp
141.5–142.2 C; HRMS (ESI) calcd for C26H35NNaO5 (M + Na)+
464.2407, found 464.2413; anal. calcd for C26H35NO5: C, 70.7; H,
8.0; N, 3.2%, found: C, 70.5; H, 8.1; N, 3.6%.
3b (Table 2, entry 2)
1
White solid, 0.109 g (24%); Rf 0.67 (MeCN–CH2Cl2, 1 : 10); H
NMR (300 MHz, CDCl3) d 7.92 (d, J = 7.9 Hz, 2H), 7.84 (dd,
J = 8.2, 1.2 Hz, 2H), 7.62-7.46 (m, 5H), 7.04 (s, 1H), 6.86 (s, 1H),
5.32 (s, 1H), 5.00 (d, J = 8.2 Hz, 1H), 4.58 (app. dd, 8.4, 5.7 Hz,
1H), 3.73 (s, 3H), 3.13–2.99 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H);
13C NMR (75 MHz, CDCl3) d 196.1, 172.4, 155.0, 150.0, 141.6,
137.4, 137.0, 136.7, 132.6, 131.1, 130.0, 129.4, 128.6, 128.4, 128.3,
127.4, 79.9, 54.4, 52.2, 37.6, 34.9, 29.7, 28.3; IR neat, n (cm-1) 1025
(m), 1063 (m), 1159 (s), 1222 (m), 1276 (m), 1360 (m), 1446 (m),
1601 (w), 1650 (s), 1681 (s), 1713 (s), 1753 (m), 2870 (w), 2957
(w), 3329 (w), 3557 (w); mp 99.5–101.0 ◦C; HRMS (ESI) calcd for
C32H37NNaO6 (M + Na)+ 554.2513, found 554.2532; anal. calcd
for C32H37NO6: C, 72.3; H, 7.0; N, 2.6%, found: C, 72.75; H, 7.2;
N, 3.05%.
3f (Table 2, entry 6)
1
White solid, 0.324 mg (83%); Rf 0.33 (Et2O–pentane, 2 : 5); H
NMR (400 MHz, CDCl3) d 7.34 (app. dt, J = 8.8, 2.5 Hz, 2H),
7.01 (app. dt, J = 8.8, 2.5 Hz, 2H), 6.97 (d, J = 1.7 Hz, 1H), 6.79
(s, 1H), 5.38 (s, 1H), 5.00 (d, J = 8.3 Hz, 1H), 4.56 (app. dd, J =
8.1, 5.6 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.08–2.99 (m, 2H),
1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) d 172.6, 159.5, 155.2,
150.3, 136.2, 130.8, 128.9, 127.4, 126.8, 114.9, 113.6, 79.9, 55.5,
54.6, 52.3, 37.7, 35.0, 29.7, 28.4; IR neat, n (cm-1) 1023 (m), 1160
(s), 1246 (s), 1364 (m), 1432 (m), 1513 (m), 1609 (w), 1700 (s),
1741 (s), 2957 (w), 3362 (w), 3536 (w), 3675 (w); mp 62.9–64.9 ◦C;
HRMS (ESI) calcd for C26H35NNaO6 (M + Na)+ 480.2357, found
480.2351; anal. calcd for C26H35NO6: C, 68.25; H, 7.7; N, 3.1%,
found: C, 68.20 H, 7.6; N, 3.5%.
3c (Table 2, entry 3)
1
White solid, 0.099 g (24%); Rf 0.47 (MeCN–CH2Cl2, 1 : 40); H
NMR (400 MHz, CDCl3) d 8.14 (app. dt, J = 8.0, 2.0 Hz, 2H),
7.51 (app. dt, J = 8.5, 2.0 Hz, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.81
(d, J = 1.7 Hz, 1H), 5.29 (s, 1H), 5.00 (d, J = 8.3 Hz, 1H), 4.56
(app. dd, J = 8.4, 5.6 Hz, 1H), 3.94 (s, 3H), 3.71 (s, 3H), 3.10-2.98
(m, 2H), 1.41 (s, 9H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) d
172.5, 166.8, 155.1, 150.0, 142.2, 136.8, 130.7, 129.7, 129.6, 128.7,
128.4, 127.9, 127.4, 116.5, 80.0, 54.5, 52.3, 37.7, 35.0, 29.7, 28.4; IR
neat, n (cm-1) 1102 (m), 1115 (m), 1161 (s), 1280 (s), 1436 (m), 1505
(m), 1610 (m), 1703 (s), 1720 (s), 1734 (s), 2246 (w), 2957 (w), 2991
(w), 3419 (w), 3458 (w); mp 90.0–91.5 ◦C; HRMS (ESI) calcd for
C27H35NNaO7 (M + Na)+ 508.2306, found 508.2314; anal. calcd
for C27H35NO7: C, 66.8; H, 7.3; N, 2.9%, found: C, 67.1; H, 6.8;
N, 2.9%.
3g (Table 2, entry 7)
White solid, 0.386 g (96%); Rf 0.30 (Et2O–pentane, 2 : 5); 1H NMR
(400 MHz, CDCl3) d 7.28 (app. dt, J = 8.8, 2.5 Hz, 2H), 6.95 (d,
J = 1.7 Hz, 1H), 6.83–6.80 (m, 3H), 5.53 (s, 1H), 5.01 (d, J =
9.0 Hz, 1H), 4.56 (app. dd, J = 8.8, 5.5 Hz, 1H), 3.72 (s, 3H),
3.03 (d, J = 5.2 Hz, 2H), 2.99 (s, 6H), 1.42 (s, 9H), 1.41 (s, 9H);
13C NMR (100 MHz, CDCl3) d 172.7, 150.5, 150.3, 135.9, 130.3,
129.1, 128.9, 126.9, 126.6, 124.3, 113.2, 79.9, 54.6, 52.3, 40.6, 37.8,
35.0, 29.8, 28.5; IR neat, n (cm-1) 1018 (m), 1059 (w), 1161 (s),
1357 (s), 1433 (m), 1522 (s), 1611 (m), 1712 (s), 1743 (m), 2953
(w), 3442 (w), 3521 (w); mp 67.1–68.6 ◦C; HRMS (ESI) calcd for
C27H38N2NaO5 (M + Na)+ 493.2673, found 493.2672; anal. calcd
for C27H38N2O5: C, 68.9; H, 8.1; N, 5.95%, found: C, 68.8; H, 8.0;
N, 6.3%.
3d (Table 2, entry 4)
White solid, 0.150 g (41%); Rf 0.37 (Et2O–pentane, 2 : 5); 1H NMR
(300 MHz, CDCl3) d 7.51–7.40 (m, 5H), 7.01 (d, J = 2.0 Hz, 1H),
6.82 (d, J = 1.8 Hz, 1H), 5.41 (s, 1H), 5.01 (d, J = 8.3 Hz, 1H),
4.58 (app. dd, J = 8.4, 5.6 Hz, 1H), 3.72 (s, 3H), 3.11–2.99 (m,
2H), 1.42 (s, 18H); 13C NMR (75 MHz, CDCl3) d 172.5, 155.0,
150.0, 137.1, 136.2, 129.5, 128.7, 128.0, 127.9, 127.6, 126.8, 79.8,
3h (Table 2, entry 8)
1
White solid, 0.216 g (52%); Rf 0.60 (MeCN–CH2Cl2, 1 : 10); H
NMR (400 MHz, CDCl3) d 7.01 (d, J = 2.2 Hz, 1H), 6.85 (d,
J = 1.5 Hz, 1H), 6.56 (d, J = 2.2 Hz, 2H), 6.51 (t, J = 2.2 Hz,
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1H), 5.63 (s, 1H), 5.01 (d, J = 9.2 Hz, 1H), 4.59 (app. dd, J = 9.2,
5.9 Hz, 1H), 3.85 (s, 6H), 3.75 (s, 3H), 3.11–3.02 (m, 2H), 1.44 (s,
9H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) d 172.6, 161.8,
155.2, 150.2, 139.2, 136.3, 128.7, 128.4, 127.8, 126.8, 107.3, 100.2,
79.9, 55.6, 54.6, 52.3, 37.7, 35.0, 29.7, 28.4; IR neat, n (cm-1) 1018
(m), 1062 (m), 1260 (s), 1204 (m), 1362 (m), 1417 (m), 1591 (m),
1712 (s), 1743 (m), 2015 (w), 2953 (w), 3387 (w), 3517 (w); mp
C29H35NNaO5 (M + Na)+ 500.2407, found 500.2412; anal. calcd
for C29H35NO5: C, 72.9; H, 7.4; N, 2.9%, found: C, 72.4; H, 7.4; N,
3.1%.
3l (Table 2, entry 12)
White solid, 0.259 g (67%); Rf 0.17 (Et2O–pentane, 1 : 4); 1H NMR
(300 MHz, CDCl3) d 7.53 (app. dt, J = 8.3, 1.8 Hz, 2H), 7.39 (app.
dt, J = 8.3, 1.9 Hz, 2H), 7.00 (d, J = 1.8 Hz, 1H), 6.81 (s, 1H), 6.77
(dd, J = 17.5, 10.9 Hz, 1H), 5.82 (dd, J = 17.6, 0.8 Hz, 1H), 5.37 (s,
1H), 5.32 (dd, J = 10.8, 0.7 Hz, 1H), 5.00 (d, J = 8.3 Hz, 1H), 4.57
(app. dd, J = 8.3, 6.0 Hz, 1H), 3.72 (s, 3H), 3.11–2.98 (m, 2H), 1.41
(s, 18H); 13C NMR (75 MHz, CDCl3) d 172.3, 155.2, 150.2, 137.4,
136.6, 136.4, 136.2, 129.7, 128.7, 128.5, 127.8, 127.3, 127.0, 114.8,
79.9, 54.6, 52.3, 37.8, 35.0, 34.2, 29.7, 28.4, 22.5, 14.2; IR neat,
n (cm-1) 1019 (m), 1065 (m), 1142 (s), 1193 (m), 1366 (m), 1434
(m), 1515 (m), 1594 (w), 1697 (s), 1738 (s), 2184 (w), 2929 (w),
2969 (w), 3368 (w); mp 112.1–113.4 ◦C; HRMS (ESI) calcd for
C27H35NNaO5 (M + Na)+ 476.2407, found 476.2396; anal. calcd
for C27H35NO5: C, 71.5; H, 7.8; N, 3.1%, found: C, 71.8; H, 7.8; N,
3.2%.
◦
58.4–60.4 C; HRMS (ESI) calcd for C27H37NNaO7 (M + Na)+
510.2462, found 510.2468; anal. calcd for C27H37NO7: C, 66.5; H,
7.65; N, 2.9%, found: C, 66.8; H, 7.75; N, 2.9%.
3i (Table 2, entry 9)
1
White solid, 0.145 g (36%); Rf 0.56 (MeCN–CH2Cl2, 1 : 20); H
NMR (400 MHz, CDCl3) d 6.90 (s, 1H), 6.85–6.79 (m, 3H), 6.71
(s, 1H), 5.94 (s, 2H), 5.36 (s, 1H), 4.91 (d, J = 7.6 Hz, 1H), 4.49
(app. dd, J = 7.3, 5.4 Hz, 1H), 3.65 (s, 3H), 3.01–2.90 (m, 2H), 1.35
(s, 9H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) d 171.4, 154.0,
149.1, 147.6, 146.5, 135.1, 129.6, 127.7, 127.3, 126.4, 125.7, 121.6,
109.0, 108.0, 100.3, 78.8, 53.4, 51.2, 36.6, 33.8, 28.6, 27.3; IR neat,
n (cm-1) 1037 (m), 1161 (s), 1201 (m), 1228 (s), 1364 (m), 1437 (m),
1490 (m), 1503 (m), 1607 (w), 1710 (s), 1743 (s), 2187 (w), 2959
(w), 3405 (w), 3528 (w); mp 128.2–129.9 ◦C; HRMS (ESI) calcd for
C26H33NNaO7 (M + Na)+ 494.2149, found 494.2153; anal. calcd
for C26H33NO7: C, 66.2; H, 7.05; N, 3.0%, found: C, 65.7; H, 6.9;
N, 3.1%.
Removal of tert-butyl groups of 1 and 3e
To a Schlenk tube under an atmosphere of N2, 1 or 3e was added
(0.23 or 0.45 mmol respectively) in 15 mL toluene. The reaction
vessel was cooled to -40 ◦C at which point MeNO2 (33 equiv.) and
AlCl3 (7.75 equiv.) were added. The reaction was allowed to warm
to rt over the course of 18 h. The reaction mixture was quenched
with H2O (~1 mL) and the solvent was removed in vacuo. The crude
mixture was then subjected to esterification and Boc protection
following earlier protocol to provide 4a or 4b.
3j (Table 2, entry 10)
White gum, 0.128 g (33%), inseparable mixture of diastereomers
1
(1 : 1); Rf 0.48 (MeCN–CH2Cl2, 1 : 30); H NMR (400 MHz,
CDCl3) d 7.24 (s, 1H), 7.22 (s, 1H), 7.16 (d, J = 1.7 Hz, 1H), 7.14
(d, J = 1.5 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 1.2 Hz,
1H), 7.00 (d, J = 2.1 Hz, 2H), 6.73 (d, J = 1.2 Hz, 2H), 5.03 (d,
J = 8.3 Hz, 1H), 4.98 (d, J = 8.3 Hz, 1H), 4.94 (s, 1H), 4.93 (s, 1H),
4.61–4.55 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.10-3.01 (m, 4H),
2.37 (2 s, 6H), 2.11 (s, 3H), 2.09 (s, 3H), 1.44 (2 s, 18H), 1.43 (2 s,
18H); 13C NMR (100.5 MHz, CDCl3) d 172.5, 155.1, 150.1, 136.8,
136.5, 129.8, 129.4, 128.7, 128.5, 127.5, 80.0, 54.5, 52.3, 35.0, 29.7,
28.4; IR neat, n (cm-1) 1017 (m), 1060 (m), 1164 (s), 1230 (m),
1364 (m), 1436 (m), 1498 (m), 1612 (w), 1709 (s), 1743 (s), 2248
(w), 2872 (w), 2954 (w), 3442 (w), 3533 (w); HRMS (ESI) calcd for
C27H37NNaO5 (M + Na)+ 478.2564, found 478.2571; anal. calcd
for C27H37NO5: C, 71.2; H, 8.2; N, 3.1%, found: C, 71.7; H, 7.6; N,
3.1%.
4a
Isolated as a white solid 0.052 g (77%). Spectroscopically identical
to the known compound.12
4b
1
White solid, 133 mg (78%); Rf 0.53 (MeOH–CH2Cl2, 1 : 20); H
NMR (300 MHz, CDCl3) d 7.34 (d, J = 7.9 Hz, 2H), 7.27 (d, J =
7.5 Hz, 2H), 7.00–6.93 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 5.62
(br. s, 1H), 5.03 (d, J = 6.1 Hz, 1H), 4.56 (app. dd, J = 7.8, 5.8 Hz,
1H), 3.71 (s, 3H), 3.11–2.97 (m, 2H), 2.40 (s, 3H), 1.41 (s, 9H); 13
C
NMR (75 MHz, CDCl3) d 172.6, 155.3, 151.9, 137.7, 134.2, 131.2,
129.9, 129.7, 129.0, 128.2, 128.0, 116.0, 80.1, 54.6, 52.3, 37.5, 28.4,
21.3; IR neat, n (cm-1) 1148 (m), 1163 (s), 1221 (s), 1363 (s), 1439
(m), 1505 (s)◦, 1609 (w), 1692 (s), 1740 (s), 2924 (w), 3319 (w); mp
104.1–105.7 C; HRMS (ESI) calcd for C22H27NNaO5 (M + Na)+
408.1781, found 408.1786; anal. calcd for C22H27NO5: C, 68.55; H,
7.1; N, 3.6%, found: C, 68.2; H, 7.2; N, 3.8%.
3k (Table 2, entry 11)
White solid, 0.249 g (61%); inseparable mixture of diastereomers
1
(0.9 : 1.1); Rf 0.36 (Et2O–pentane, 2 : 5); H NMR (300 MHz,
CDCl3) d 7.94 (s, 2H), 7.91 (s, 2H), 7.60–7.48 (m, 10H), 7.09 (d,
J = 2.2 Hz, 2H), 6.85 (s, 2H), 5.06 (d, J = 8.4 Hz, 1H), 5.02 (d,
J = 9.4 Hz, 1H), 4.96 (s, 1H), 4.92 (s, 1H), 4.63–4.56 (m, 2H),
3.71 (s, 3H), 3.66 (s, 3H), 3.13–3.00 (m, 4H), 1.43 (s, 18H), 1.42
(s, 9H), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3) d 172.5, 155.1,
151.0, 136.3, 134.2, 132.3, 129.7, 129.0, 128.5, 128.0, 126.9, 126.5,
125.9, 125.8, 79.9, 54.7, 52.3, 37.9, 35.0, 29.7, 28.4; IR neat, n
(cm-1) 1018 (m), 1058 (m), 1160 (s), 1259 (m), 1364 (m), 1434 (m),
1505 (m), 1591 (w), 1710 (s), 1742 (m), 2869 (w), 2963 (w), 3049
(w), 3442 (w), 3534 (w); mp 65.9–67.9 ◦C; HRMS (ESI) calcd for
General method for the ortho-arylation of 4b
[{RhCl(COD)}2] (0.003 g, 0.011 mmol) was added to a Schlenk
tube under an atmosphere of N2 along with toluene (5 mL),
the appropriate aryl halide (1.5 eq., 0.163 mmol), 4b (0.042 g,
0.109 mmol), P(NMe2)3 (0.012 mL, 0.065 mmol), and Cs2CO3
(0.060 g, 0.185 mmol). The mixture was stirred at reflux temper-
ature for 18 h then allowed to cool to room temperature. HCl
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(aq.) (2 M, 5 mL) was added and the organic phase extracted
into dichloromethane (3 ¥ 10 mL), dried over MgSO4, filtered and
the solvent removed under reduced pressure. The crude mixture
was purified by column chromatography on silica gel to afford the
product.
6.89 (s, 1H), 6.87 (s, 1H), 4.94–4.89 (m, 2H), 4.52 (app. dd, J =
6.3 Hz, 1H), 3.68 (s, 3H), 3.07–2.95 (m, 2H), 2.68 (s, 3H), 2.59 (s,
3H), 2.36 (s, 3H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3) d
197.8, 197.5, 172.1, 154.9, 148.1, 145.7, 141.1, 138.0, 136.8, 135.5,
131.5, 131.1, 130.5, 130.0, 129.7, 129.3, 128.7, 128.0, 127.9, 80.0,
54.5, 52.2, 37.5, 28.3, 26.7, 21.2; IR neat, n (cm-1) 1015 (m), 1162
(s), 1231 (s), 1357 (m), 1459 (m), 1514 (m), 1605 (m), 1682 (s),
1712 (s), 1742 (s), 1750 (s), 2925 (w), 3350 (w); mp 87.0–88.3 ◦C;
HRMS (ESI) calcd for C38H39NNaO7 (M + Na)+ 644.2619, found
644.2651; anal. calcd for C38H39NO7: C, 73.4; H, 6.3; N, 2.25%,
found: C, 73.1; H, 7.0; N, 2.6%.
5a
1
White solid, 17 mg (31%); Rf 0.31 (MeOH–CH2Cl2, 1 : 20); H
NMR (500 MHz, CDCl3) d 8.04 (app. dt, J = 8.5, 2.0 Hz, 2H),
7.69 (app. dt, J = 8.6, 2.0 Hz, 2H), 7.39 (app. dt, J = 6.1, 1.7 Hz,
2H), 7.33 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 7.02 (s, 1H), 5.41 (s,
1H), 5.06 (d, J = 8.3 Hz, 1H), 4.62 (app. dd, J = 13.2, 5.6 Hz,
1H), 3.74 (s, 3H), 3.17 (dd, J = 13.8, 5.7 Hz, 1H), 3.06 (dd, J =
14.3, 5.7 Hz, 1H), 2.65 (s, 3H), 2.43 (s, 3H), 1.41 (s, 9H); 13C NMR
(126 MHz, CDCl3) d 196.7, 171.3, 154.0, 147.5, 141.9, 137.1, 134.8,
132.6, 130.2, 129.7, 129.0, 128.5, 128.0, 127.4, 127.2, 126.5, 79.0,
53.4, 51.3, 36.4, 27.3, 25.6, 20.2; IR neat, n (cm-1)1015 (s), 1112
(m), 1163 (s), 1222 (s), 1267 (s), 1363 (m), 1462 (m), 1512 (m),
1604 (m), ◦1680 (m), 1710 (s), 1740 (s), 2974 (w), 3361 (w); mp
81.8–82.5 C; HRMS (ESI) calcd for C30H33NNaO6 (M + Na)+
526.2200, found 526.2202; anal. calcd for C30H33NO6: C, 71.55; H,
6.6; N, 2.8%, found: C, 71.45; H, 6.9; N, 3.05%.
Acknowledgements
We thank the EPSRC (Advanced Research Fellowship for RBB,
Organic Synthetic Studentship Initiative support for RLW) and
GlaxoSmithKline for funding and Johnson Matthey for the loan
of rhodium trichloride.
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Ohnuki and S. Komatsubara, J. Antibiot., 2000, 53, 105.
3 (a) O. Skaff, K. A. Jolliffe and C. A. Hutton, J. Org. Chem., 2005, 70,
7353; (b) M. Bois-Choussy, P. Cristau and J. Zhu, Angew. Chem., Int.
Ed., 2003, 42, 4238; (c) P. J. Krenitsky and D. L. Boger, Tetrahedron
Lett., 2003, 44, 4019; (d) G. Helynck, C. Dubertret, D. Frechet and J.
Leboul, J. Antibiot., 1998, 51, 512.
5b
1
White solid, 15 mg (28%); Rf 0.40 (MeOH–CH2Cl2, 1 : 20); H
NMR (500 MHz, CD3CN) d 7.45 (app. dt, J = 8.3, 1.8 Hz, 2H),
7.40 (app. dt, J = 8.9, 2.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.04 (s,
1H), 7.03 (s, 1H), 6.88 (app. dt, J = 8.8, 1.8 Hz, 1H), 5.97 (s, 1H),
5.56 (s, 1H), 4.62 (app. dd, J = 12.3, 5.8 Hz, 1H), 3.71 (s, 3H), 3.13
(dd, J = 14.1, 5.8 Hz, 1H), 3.00 (s, 6H), 2.99 (dd, J = 14.3, 5.5 Hz,
1H), 2.42 (s, 3H), 1.37 (s, 9H); 13C NMR (126 MHz, CD3CN) d
172.8, 149.0, 137.2, 135.6, 130.5, 130.2, 130.1, 129.6, 129.2, 112.9,
79.1, 55.1, 54.5, 51.2, 49.1, 40.0, 36.6, 27.7, 20.4; HRMS (ESI)
calcd for C30H37N2O5 (M + H)+ 505.2697, found 505.2721.
4 (a) A. Holtzel, D. G. Schmid, G. J. Nicholson, S. Stevanovic, J.
Schimana, K. Gebhardt, H. P. Fiedler and G. Jung, J. Antibiot., 2002,
55, 571; (b) J. Schimana, K. Gebhardt, A. Holtzel, D. G. Schmid, R.
Sussmuth, J. Muller, R. Pukall and H. P. Fiedler, J. Antibiot., 2002, 55,
565.
5 T. C. Roberts, P. A. Smith, R. T. Cirz and F. E. Romesberg, J. Am.
5c
Chem. Soc., 2007, 129, 15830.
1
6 For a recent review see: D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174.
White solid, 21 mg (40%); Rf 0.64 (MeOH–CH2Cl2, 1 : 20); H
NMR (400 MHz, CDCl3) d 7.54 (s, 4H), 7.44 (d, J = 8.1 Hz, 2H),
7.32 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 7.02 (s, 1H), 6.80 (dd, J =
17.5, 10.9 Hz, 1H), 5.84 (d, J = 17.5 Hz, 1H), 5.41 (s, 1H), 5.33
(dd, J = 10.8, 4.7 Hz, 1H), 5.08 (d, J = 8.3 Hz, 1H), 4.64 (app.
dd, J = 7.9, 5.7 Hz, 1H), 3.76 (s, 3H), 3.19–3.06 (m, 2H), 2.44 (s,
3H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) d 172.6, 155.2,
148.6, 137.8, 137.0, 136.5, 130.8, 130.7, 129.8, 129.6, 129.4, 129.2,
128.1, 126.7, 114.4, 80.1, 54.6, 52.4, 37.5, 28.4, 21.3; IR neat, n
(cm-1)1015 (s), 1162 (s), 1221 (m), 1248 (m), 1365 (m), 1457 (m),
1495 (m), ◦1607 (w), 1711 (s), 1742 (s), 2971 (w), 3421 (w); mp
81.8–82.5 C; HRMS (ESI) calcd for C30H33NNaO5 (M + Na)+
510.2251, found 510.2274; anal. calcd for C30H33NO5: C, 73.9; H,
6.8; N, 2.9%, found: C, 74.3; H, 7.2; N, 3.1%.
7 For recent overviews, see: (a) Catalytic Aromatic C–H Activation
(Symposium in Print), Tetrahedron, 2008, 64, 5693–6138; (b) Handbook
of C–H Transformations, ed. G. Dyker, Wiley-VCH, Weinheim, 2005.
8 (a) R. B. Bedford, S. J. Coles, M. B. Hursthouse and M. E. Limmert,
Angew. Chem., Int. Ed., 2003, 42, 112; (b) S. Oi, S. Watanabe, S. Fukita
and Y. Inoue, Tetrahedron Lett., 2003, 44, 8665; (c) R. B. Bedford and
M. E. Limmert, J. Org. Chem., 2003, 68, 8669; (d) R. B. Bedford, M.
Betham, A. J. M. Caffyn, J. P. H. Charmant, L. C. Lewis-Alleyne, P. D.
Long, D. Polo-Ceron and S. Prashar, Chem. Commun., 2008, 990.
9 For preliminary mechanistic details see ref. 8d; further mechanistic
details will be published shortly.
10 For the recent Suzuki arylation of simple 2-bromotyrosine substrates
see: M. Prieto, S. Mayor, K. Rodriguez, P. Lloyd-Williams and E. Giralt,
J. Org. Chem., 2007, 72, 1047.
11 R. B. Bedford, M. Betham, M. E. Blake, S. J. Coles, S. M. Draper, M. B.
Hursthouse and P. N. Scully, Inorg. Chim. Acta, 2006, 359, 1870.
12 J. M. Richter, B. W. Whitefield, T. J. Maimone, D. W. Lin, M. P.
Castroviejo and P. S. Baran, J. Am. Chem. Soc., 2007, 129, 12857.
13 M. E. Jung and T. I. Lazarova, J. Org. Chem., 1997, 62, 1553.
14 Previous studies indicate that the oxidative addition of the aryl bromide
is not the rate determining step, see ref. 8c.
6a
1
White solid, 19 mg (35%); Rf 0.22 (MeOH–CH2Cl2, 1 : 20); H
NMR (500 MHz, CDCl3) d 8.05–8.03 (m, 2H), 7.85 (dd, J = 8.5,
1.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.30 (app. dt, J = 8.4,
1.8 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H),
15 F. Liu and L. S. Liebeskind, J. Org. Chem., 1998, 63, 2835.
16 For methods for removing tert-butyl groups from phenols see: M.
Tashiro, Synthesis, 1979, 921.
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