A rhodium(I)-xylyl-BINAP catalyzed asymmetric ynamide-[2+2+2] cycloaddition in the synthesis of optically enriched N,O-biaryls

Article abstract of DOI:10.1016/j.tet.2009.03.078

A rhodium(I)-xylyl-BINAP catalyzed asymmetric [2+2+2] cycloaddition of achiral conjugated aryl ynamides with various diynes is described here. This asymmetric cycloaddition provides a series of structurally interesting chiral N,O-biaryls with excellent en

Full text of DOI:10.1016/j.tet.2009.03.078

Tetrahedron 65 (2009) 5001–5012
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A rhodium(I)-xylyl-BINAP catalyzed asymmetric ynamide-[2þ2þ2]
cycloaddition in the synthesis of optically enriched N,O-biaryls
*
Jossian Oppenheimer, Whitney L. Johnson, Ruth Figueroa, Ryuji Hayashi, Richard P. Hsung
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A rhodium(I)-xylyl-BINAP catalyzed asymmetric [2þ2þ2] cycloaddition of achiral conjugated aryl yna-
mides with various diynes is described here. This asymmetric cycloaddition provides a series of structurally
interesting chiral N,O-biaryls with excellent enantioselectivity along with a modest diastereoselectivity
with respect to both C–C and C–N axial chirality.
Received 30 January 2009
Received in revised form 23 March 2009
Accepted 26 March 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl ynamides
Asymmetric [2þ2þ2] cycloaddition
Chiral N,O-biaryls
Rhodium(I) catalyst and (S)-xylyl-BINAP
C–N axial chirality
double asymmetric induction of
non-point stereocenters
1. Introduction
bond [in blue] and C–N anilide bond [in red] in cycloadducts 5,
thereby constituting a rare example of double asymmetric in-
In the last 15 years, ynamides have captured much interest from the
synthetic community. An immense amount of efforts has led to
a numberof elegantsynthetic methodologies to be developed adopting
ynamides as a de novo functional group,1–4 and culminated in several
total syntheses employing ynamides as a versatile building block.5,6
Among these efforts [Fig. 1], both Witulski’s work on [2þ2þ2] cyclo-
additions of ynamides in the synthesis of indoles and carbazoles,7,8 and
Rainier’s formal [2þ2þ2] cycloaddition9 inspired us10,11 to develop
a new approach toward chiral N,O-biaryls through a [2þ2þ2] cyclo-
addition of conjugated aryl ynamides with diynes.12–14 This concept
was envisioned at the heel of our success in the synthesis of conjugated
aryl ynamides via Sonogashira cross-coupling.15 During our pursuit,
Tanaka16,17 beautifully demonstrated the feasibility of an asymmetric
[2þ2þ2] cycloaddition of ynamides in the synthesis of anilides with an
axially chiral C–N bond.18–20
duction of non-point stereocenters by a single catalyst.12,14d,20–22
Moreover, the coordinating ability of the achiral amido-carbonyl
group could play a role in the asymmetric induction, thereby
rendering this design an achiral-template directed asymmetric
catalysis.23 We report here our development of an asymmetric
ynamide-[2þ2þ2] cycloaddition.
2. Results and discussions
2.1. Establishing the feasibility
In our earlier work, we were intrigued by the observation that
while we could not improve the diastereoselectivity in our
RhCl(Ph3P)3-catalyzed [2þ2þ2] cycloadditions of chiral ynamide 1,
we could readily diminish the ratio from 4:1 by using an external
phosphine ligand such as BINAP [Scheme 2]. To account for the
modest diastereoselectivity, we had proposed pro-M- and pro-P-TS
models, which consist of the key bidentate coordination [in green]
of Rh(III) from both the oxazolidinone carbonyl oxygen and the
anisole oxygen atom. We concluded that neither really possesses
a distinct advantage over the other except with pro-P-TS suffering
from a remote steric interaction [red arrows] between the cyclo-
pentyl and the phenyl group on the oxazolidinone ring. Based on
these same models, the above finding suggests that an external
Because our diastereoselective ynamide-[2þ2þ2] cycloaddition
only resulted in modest selectivity through the use of chiral aryl
ynamide 1 [Scheme 1],10 we began contemplating the possibility of
pursuing an asymmetric cycloaddition employing achiral aryl
ynamides 3 and a suitable chiral rhodium(I) complex.11 If success-
ful, asymmetry could be induced at both axially chiral C–C biaryl
* Corresponding author. Tel.: þ1 608 890 1063; fax: þ1 608 262 5345.
E-mail address: rhsung@wisc.edu (R.P. Hsung).
chiral ligand [in blue] exerts
a stronger influence on this
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.078

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J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
Witulski
MeO2C
Me OH
RhCl(Ph3P)3
OH
RhCl(Ph3P)3
CO2Me
Me
H
N
N
N
Ts
Ts
NTs
Ts
Rainier
MeO
+
O
TMS
TMS
CpCo(CO)2, hυ
or Fe(CO)5, Δ
CO2Me
CO2Me
TMS
TMS
O
N
N
N
Ts
Ts
M = CpCo or Fe(CO)3
TMS
Ts
M
TMS
O
O
OMe
Our asymmetric design for constructing chiral N,O-biaryls
O
R2O
R3
N
R
R
R3
metal cat
[2 + 2 + 2]
R2O
conjugated
aryl ynamides
+
N
O
R3
O
R1
R1
R3
Sonogashira
Tanaka: Asymmetric construction of the axially chrial C-N bond
O
Bn
N
O
Ph
Me
Bn
Me
TMS
Me
10 mol% [Rh(cod)2]BF4
Ph
N
CO2Me
CO2Me
+
(S)-xylyl-BINAP
up to 97% ee
Me
TMS
MeO2C
CO2Me
Figure 1. Ynamide-[2þ2þ2] cycloadditions.
with H2, we found that the usage of 10 mol % [Rh(cod)2]BF4 and
10 mol % (S)-xylyl-BINAP at 85 ꢀC in ClCH2CH2Cl with 4 Å MS pro-
vided the best outcome when reacting 10a with diyne 11. While the
resulting diastereomeric N,O-biaryls 12-M,p and 12-P,p27 were
separable by TLC, they rapidly inter-converted to the enantiomer of
each other: 12-M,p led to 12-M,m with 12-P,p yielding 12-P,m via
C–N bond rotation [in red]. Even after a clean and facile separation
on a silica gel column, NMR analysis revealed that the two di-
astereomers of 12 have already scrambled likely during the removal
of the solvent under reduced pressure even without heating. Thus,
this complication prevented us from meaningfully determining dr
and ee.
Ultimately, cycloadditions of achiral conjugated aryl ynamides
10b and 10c allowed us to analyze possible enantioselectivity. As
shown in Scheme 5, N,O-biaryl atropisomers 14-M,p and 14-P,p
were attained in 95% yield from 10b when reacting with diyne 13a.
Although potential diastereomers of 14 due to restricted C–N bond
rotation were detectable in proton NMR, they were not separable
physically. Consequently, we were able to cleanly assess the en-
antiomeric excess using Chiral HPLC.
Furthermore, aryl ynamide 10c containing the six-membered
2-oxazinone ring also led to N,O-biaryls 15 and 16 when reacting
with diynes 13a and 13b, respectively. There was even less com-
plication in these two reactions, as only a single diastereomer was
detectable in 1H NMR presumably due to rapid free rotation at the
C–N bond. Thus, we were able to concisely calibrate ee values for
both 15 and 16, which are lower than that of 14. It is noteworthy
that since BINAP had given lower ee and yield than xylyl-BINAP, and
with Tanaka’s success using xylyl-BINAP, we did not screen beyond
these two chiral bidentate phosphines.
O
O
Ph
RhCl(PPh3)3/AgSbF6
N
Ph
Ph
Me
O
O
O
O
N
N
+
MeO
O
ClCH2CH2Cl, 4Å MS
85 °C, 24 h
MeO
M
P
94% yield
2-P
1: chiral ynamide
2-M
M : P ratio maxed out at 80 : 20
an asymmetric approach
O
R1
L*
O
R
N
RhIII
O
L*
N
R
N
R
Rh(I) metal
L*: chiral ligands
R1
MeO
MeO
R1
MeO
3: achiral ynamides
Scheme 1. An asymmetric ynamide-[2þ2þ2] cycloaddition.
4
5: ee?
cycloaddition than the stereocenter on the chiral ynamide, thereby
implying the possibility of an asymmetric cycloaddition manifold
employing achiral ynamides.
Toward this goal, we synthesized achiral conjugated aryl yna-
mides 6 and 724–26 containing a sulfonamide and an acyclic amide,
respectively, as shown in Scheme 3. However, to our disappoint-
ment, after screening several catalytic systems, we were unable to
even find the desired cycloaddition products 8 and 9 let alone an-
alyzing possible enantioselectivity. Recognizing that ynamides with
the amido group that are cyclic in nature may be better suited for
the cycloaddition, we proceeded to prepare aryl ynamide 10a
containing the 2-oxazolidinone ring [Scheme 4].
2.2. Syntheses of chiral N,O-biaryls
Having established an asymmetric protocol, a range of chiral
N,O-biaryls could be prepared as shown in Figure 1. Reactions of
aryl ynamide 10a with diyne 11 led to the respective diastereomeric
After screening again conditions such as Rh(PPh3)3Cl/AgSbF6,
[Rh(CO)2Cl]2, [Rh(cod)Cl]2/AgSbF6, and [Rh(cod)2]BF4 activated

J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
an external ligand controlled process
5003
O
L*
L*
O
Ph
N
RhIII
RhIII
RhI
RhI
L*
L*
O
O
Me
O
O
O
MeO
N
N
OMe
pro-M
1
pro-P
Ph
Ph
Me
additives 2-M
2-P
O
O
O
O
N
N
None:
R-BINAP:
S-BINAP:
( )-BINAP:
4.0
1.6
1.3
1.3
1.0
1.0
1.0
1.0
O
MeO
M
P
2-M
2-P
Scheme 2. Recognition of an external ligand controlled process.
13a
O
O
O
O
Bn
R
O
N
N
10 mol% [Rh(cod)2]BF4
10 mol% (S)-xylyl-BINAP
+
O
O
O
O
R
R
p
p
N
N
+
10 mol% (S)-xylyl-BINAP
ClCH2CH2Cl
N
Bn
N
Bn
M
P
OMe
M
P
MeO
OMe
ClCH2CH2Cl, 4Å MS
rt to 85 °C, 24-96 h
MeO
MeO
MeO
4Å MS, 85 °C
95% yield
[a]
10b
14-M,p: 99% ee
14-P,p
6: R = Ts
7: R = Bz
8-M: R = Ts
9-M: R = Bz
8-P: R = Ts
9-P: R = Bz
13a:X = O
X
X
+
X
O
13b:X = CH2
10 mol% RhCl(PPh3)3/AgSbF6:
10 mol% [Rh(cod)2]BF4:
-
-
O
N
O
O
O
N
10 mol% [Rh(cod)2]BF4
10 mol% [Rh(cod)2]BF4 with H2:
trace
O
N
M
10 mol% (S)-xylyl-BINAP
ClCH2CH2Cl
P
OMe
MeO
Scheme 3. Cycloadditions of ynamides with an acyclic amido-motif.
MeO
4Å MS, 85 °C
N,O-biaryl isomers 17 and 18 in good yields. Notably, we observed
a diastereoselectivity as high as 8:1 in favor of the isomer 17-M,p,
which also possesses an enantiomeric excess of 95%, while the
minor isomer 18-P,p has a 54% ee. The usage of (R)-xylyl-BINAP led
to chiral N,O-biaryls ent-17 and ent-18 but in slightly lower ee and
dr. Moreover, reactions of ynamide 10b containing the five-mem-
bered 2-oxazolidinone ring led to N,O-biaryls generally with higher
ee for both P,p and M,p diastereomers. For example, while di-
astereomeric isomers 23-M,p and 24-P,p were attained with a dr of
6:1, both diastereomers possess 99% ee. Finally, while the ratio
dropped for diastereomeric N,O-biaryls 27 and 28, as well as for 29
and 30, which all contain a naphthyl ring, their respective enan-
tioselectivity remained high [Fig. 2].
[a]
10c
15:X = O:
95% yield: M-enantiomer 58% ee[a]
93% yield: M-enantiomer 74% ee
16:X = CH2:
Scheme 5. An asymmetric ynamide-[2þ2þ2] cycloaddition. aThe ee was determined
using chiral HPLC [CHIRALCEL OD-H; size: 250ꢁ4.6 mm (Lꢁi.d.); eluent: i-PrOH in
hexanes].
2.3. Assignment of absolute configurations
The minor diastereomer 18-P,p is crystalline, and its absolute
configuration could be readily resolved through X-ray structure of
a single crystal [Fig. 3].28 However, assignments of the major isomer
were not as trivial. As shown in Scheme 6, absolute configurations of
major isomers 17-M,p containing the six-membered 2-oxazinone
Me
Me
E
E
11
E
E
E
E
O
10 mol% [Rh(cod)2]BF4
10 mol% (S)-xylyl-BINAP
O
Me
Me
N
p
p
+
O
O
O
O
ClCH2CH2Cl
4Å MS, 85 °C
N
N
Me
Me
MeO
M
P
OMe
MeO
E = CO2Me
95% yield
but inseparable
C-N rotamers
10a
12-M,p
12-P,p
Scheme 4. Cycloadditions of ynamides with a cyclic amido-motif.

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J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
E
E
E
E
E = CO2Me
Me
E = CO2Me
E
E
E
E
Me
O
Me
Me
O
p
p
m
m
O
O
N
N
N
N
Me
Me
Me
Me
O
O
M
P
P
M
OMe
OMe
MeO
MeO
O
O
[a]
dr: 8 : 1
dr: 5 : 1
17-M,p: 85% yield[b]
ent-17: 69% yield[d]
86% ee
18-P,p: 11% yield
54% ee
ent-18: 14% yield
47% ee
[c]
95% ee
O
O
Me
Me
Me
Me
O
O
O
O
p
p
p
p
O
O
O
O
Me
N
OMe
Me
MeO
N
N
N
OMe
Me
Me
MeO
M
P
M
P
dr: 5 : 1
dr: 5 : 1
19-M,p: 78% yield
88% ee
20-P,p: 15% yield
18% ee
21-M,p: 58% yield
98% ee
22-P,p: 12% yield
86% ee
E
E
O
O
E = CO2Me
E
E
Me
Me
Me
Me
N
O
O
O
O
p
p
N
N
Me
Me
O
O
O
O
M
P
p
p
N
OMe
Me
Me
MeO
M
P
OMe
MeO
dr: 5 : 1
dr: 6 : 1
23-M,p: 80% yield
99% ee
24-P,p: 13% yield
99% ee
25-M,p: 77% yield
99% ee
26-P,p: 15% yield
91% ee
E
E
O
O
E = CO2Me
E
E
Me
Me
Me
Me
N
O
O
O
O
p
p
N
N
Me
Me
O
O
O
O
M
P
p
p
OMe
N
Me
Me
MeO
M
P
OMe
MeO
dr: 2 : 1
dr: 3 : 1
27-M,p: 52% yield
99% ee
28-P,p: 26% yield
99% ee
29-M,p: 72% yield
98% ee
30-P,p: 24% yield
98% ee
Figure 2. Scope of Asymmetric Ynamide-[2þ2þ2] Cycloadditions. aThe dr was determined using 1H/13C NMR. bIsolated yields. cThe ee was determined using chiral HPLC
[CHIRALCEL OD-H; size: 250ꢁ4.6 mm]; eluent: i-PrOH in hexanes. d(R)-xylyl-BINAP was used.
ring, and 23-M,p containing the five-membered 2-oxazolidinone
ring, had to be assigned via X-ray structures of their respective
camphor-sulfonyl derivatives 32-M,p and 34-M,p prepared in two
steps. X-ray structures of 32-M,p and 34-M,p are shown in Figure 4.
Correlations of aromatic protons on the anisyl ring allow for the
assignment of all other isomeric N,O-biaryls.
rotational barrier being 37.7 kcal molꢂ1 [PM3 calculations], we
believe there should be very little racemization during the hy-
drogenation at rt.
2.5. Equilibration studies
We were fascinated with the unique structural feature of these
2.4. Synthesis of a chiral amino-biaryl
de novo N,O-biaryls. SpartanÔ B3LYP/6-31G
E of 1.11 kcal molꢂ1 in favor of the minor isomer 18, thereby
implying that the observed selectivity for 17 is kinetic. In addition,
B3LYP/6-31G
calculations provided Eact of 34.0 kcal molꢂ1 and
*
calculations revealed
a
D
To demonstrate that these chiral N,O-biaryls can be useful in
the venue of designing new chiral N,O-biaryl ligands, we pur-
sued the following asymmetric cycloaddition. As shown in
Scheme 7, cycloaddition of ynamide 35 containing the 2-oxa-
zolidinone ring with gem-diphenyl substitutions11,25 with diyne
36 gave cycloadducts 37-M,p and 38-P,p in 1:1 ratio with 82% ee
for each diastereomer. We took 37-M,p and removed the achiral
2-oxazolidinone ring via hydrogenations to afford aniline 39-M.
Although we were unable to clearly discern the final enantio-
meric excess of 39-M through chiral HPLC, with the C–C bond
*
94.4 kcal molꢂ1, respectively, for the axially chiral C–N and C–C
bonds. These calculations would suggest that any thermal equili-
brations would first lead to epimerization through the C–N rota-
tion. That is the equilibration between 17-M,p and ent-18-M,m, or
between 18-P,p and ent-17-P,m [see Scheme 8], should occur faster
at lower temperature than that between 17-M,p and 18-P,p, or
between ent-18-M,m and ent-17-P,m. To confirm these assertions,
we carried out the following equilibration studies.

J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
5005
continued to epimerize to ent-18-M,m with the ratio gravitating
toward 23:77, there was a noticeable loss in the ee for both 17-M,p
and ent-18-M,m. Thus, at these high temperatures, epimerization
was taking place through free rotations at both C–N and C–C
bonds, which should then lead to racemization.
Equilibrations of pure ent-17-P,m with an 86% ee led to a very
similar outcome and likewise with equilibrations of 18-P,p even
starting at a 52% ee [Table 2]. It is noteworthy that all the equili-
bration studies led to a final resting thermodynamic ratio of 22:78
for 17/18. This appears to be the thermodynamic ratio, which is
consistent with the calculation in which isomer 18 is favored by
1.11 kcal molꢂ1
.
2.6. Mechanistic considerations
Given the stereochemical outcome, we proposed a mechanistic
model that could provide a unified rationale for the observed
asymmetric inductions. As shown in Scheme 9, with the rhodio-
cyclopentadiene intermediate complexed to (S)-xylyl-BINAP, a re-
spective ynamide could approach the metal more favorably as
shown in complex A1 with the anisole ring sliding into the less
hindered space near Ar2 with a smaller amido group assuming the
relatively more crowded space next to Ar1. This binding orientation
would be the opposite in complex B1 and would lead to a less fa-
vorable fit in the two respective ‘binding pockets’.
With complex A1 in hand, a key bidentate chelation of the Rh
metal via both the anisyl OMe and the carbonyl group could occur
to assist the complexation of the ynamide unto the metal center.
The ensuing cycloaddition, in a stepwise or Diels–Alder manner,
would lead to the major diastereomer [M,p]. Because the enantio-
mer of the major isomer would come from complex B1, which is not
favored in these reactions, enantiomeric excess is high in almost all
cases for atropisomer [M,p].
If the bidentate chelation fails due to the slipping of the
weaker coordination from the anisole oxygen atom through a
C–C rotation, one would obtain complex A2, which would give
the observed minor diastereomer [P,p] after the cycloaddition. On
the other hand, if the C–N bond in A1 rotates and one loses the
stronger coordination from the carbonyl oxygen, complex A3
would be present to give the corresponding [M,m] isomer, which
is the enantiomer of the minor diastereomer. Since the carbonyl
oxygen in general possesses better coordinating ability than
a phenolic ethereal oxygen, it is reasonable to see much less
formation of [M,m], thereby rendering [P,p] as the major enan-
tiomer for the minor diastereomer.
Figure 3. X-ray structures minor atropisomer 18-P,p.
As shown in Table 1, heating pure biaryl 17-M,p with a 95% ee
at 85 ꢀC in toluene-d8 for 24 h [the original reaction temperature]
did not result in any epimerization or loss of optical integrity. At
120 ꢀC, epimerization occurred and led to a significant loss of 17-
M,p and an increase in the amount of ent-18-M,m. However, there
was no loss of enantiomeric excess [94% ee] for both 17-M,p and
ent-18-M,m, thereby suggesting that at 120 ꢀC, the epimerization
was occurring solely through rotation of the axially chiral C–N
bond [assuming enantiomers in general possess the same rate of
epimerization in first order]. At 165 ꢀC and 200 ꢀC, while 17-M,p
E
E
E
E = CO2Me
E
E = CO2Me
Finally, the importance of the carbonyl oxygen in this asym-
metric cycloaddition can also be further underscored from the fact
that 2-oxazolidinone is better chelator than 2-oxazinone. Conse-
quently, ynamides substituted with 2-oxazolidinone gave higher
ee. Overall, the current mechanistic model provides another ex-
cellent example for showcasing the versatility of enantioselective
catalysis through an asymmetric template that employs an achiral
auxiliary.23
O
ClO2S
Et3N, CH2Cl2
Me
Me
Me
1) BBr3, CH2Cl2
-78 °C
O
O
p
p
17-M,p
O
N
O
Me
N
2) NaHCO3
Me2SO4
M
M
OH
OR
acetone, rt
R =
O
S
O
O
32-M,p:85% yield
31-M,p:73% yield
E
E
E
E
E = CO2Me
3. Conclusion
same as
above
Me
same as
above
Me
We have described here a rhodium(I)-xylyl-BINAP catalyzed
asymmetric [2þ2þ2] cycloaddition of achiral conjugated aryl
ynamides with various diynes. This asymmetric cycloaddition
represents a rare example of double asymmetric induction of non-
point stereocenters by a single catalyst and provides a series of
structurally interesting chiral N,O-biaryls with excellent enantio-
selectivity in most cases along with a modest diastereomeric se-
lectivity with respect to both C–C and C–N axial chirality.
23-M,p
O
O
O
O
p
p
M
OR
N
N
Me
Me
M
OH
R =
O
S
O
O
34-M,p:56% yield
33-M,p:67% yield
Scheme 6. Syntheses of 32-M,p and 34-M,p.

5006
J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
Figure 4. X-ray structures: 18-P,p 32-M,p [left] and 34-M,p [right].
4. Experimental section
4.1. General
using UV and a suitable chemical stain. Low-resolution mass
spectra were obtained using an Agilent-1100-HPLC/MSD and can be
either APCI or ESI, or an IonSpec HiRes-MALDI FT-Mass Spectro-
meter. High-resolution mass spectral analyses were performed at
University of Wisconsin Mass Spectrometry Laboratories. All
spectral data obtained for new compounds are reported.
All reactions were performed in flame-dried glassware under
a nitrogen atmosphere. Solvents were distilled prior to use. Re-
agents were used as purchased (Aldrich, Acros), except where
noted. Chromatographic separations were performed using Bod-
man 60 Å SiO2. 1H and 13C NMR spectra were obtained on Varian
VI-300, VI-400, and VI-500 spectrometers using CDCl3 (except
where noted) with TMS or residual CHCl3 as standard. Melting
points were determined using a Laboratory Devices MEL-TEMP and
are uncorrected/calibrated. Infrared spectra were obtained using
NaCl plates on a Bruker Equinox 55/S FT-IR Spectrophotometer, and
relative intensities are expressed qualitatively as s (strong), m
(medium), and w (weak). TLC analysis was performed using Aldrich
4.2. A general procedure for the asymmetric ynamide-
[2D2D2] cycloaddition
To a solution of [Rh(cod)2]BF4 (10 mol %) and (S)-xylyl-BINAP
(10 mol %) in anhyd ClCH2CH2Cl (5.0 mM) was added 4 Å molecular
sieves in a sealed tube. The mixture was stirred at rt for 10 min
before the respective ynamide (1.00 mmol) and diyne (2.00 mmol)
were added. The solution was heated to 85 ꢀC and followed by
LCMS. After the reaction was complete, the solution was cooled to rt
and filtered through a short pad of silica gel. Elution with EtOAc/
254 nm polyester-backed plates (60 Å, 250
mm) and visualized
Me
O
O
O
O
36
Ph
Ph
Me
Me
Ph
O
Me
N
Ph
10 mol% [Rh(cod)2]BF4
O
O
O
O
p
p
N
N
Me
Me
MeO
10 mol% (S)-xylyl-BINAP
ClCH2CH2Cl
M
P
OMe
MeO
Ph
Ph
4Å MS, 85 °C
dr: 1 : 1
35
37-M,p: 34% yield
82% ee
38-P,p: 34% yield
82% ee
10% Pd-C, 1 atm H2
MeOH, rt, 72 h
O
O
Me
NH2
Me
Δ
Me
MeO
Me
NH2
P
M
C-C bond rotation
OMe
42% yield
[α]D23 = + 25.8 [c, 0.055]
E
act = 37.7 kcal mol-1
39-P
39-M
Scheme 7. Synthesis of chiral amino-biaryl 38-M.

J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
5007
Table 2
CO2Me
CO2Me
MeO2C
Heating of pure ent-17-P,m and 18-P,p diastereomers
MeO2C
faster
temp [°C] time [h]
17-M,p
ent-17-P,m [ee]
ent-18-M,m
18-P,p [ee]
Me
O
Me
Δ
p
m
starting ent-17 [86%]
93.0 [86%]
O
C-N bond rotation
Eact = 34.0 Kcal mol-1
Me
Me
N
N
M
M
Δ at 85 after 24
7.0
0.0
0.0
O
OMe
OMe
O
C-N
C-N
120
165
24
24
1.8
24.2 [86%]
5.2
68.8 [86%]
17-M,p
ent-18-M,m
C-N
C-N
C-C bond rotation
C-C bond rotation
Δ
Δ
Eact = 94.4 Kcal mol-1
Eact = 94.4 Kcal mol-1
free rotations at both C-N and C-C
1.8
21.2 [84%]
CO2Me
CO2Me
MeO2C
7.7
final dr of ent-17 : 18 = 23 : 77
69.3 [80%]
MeO2C
faster
Me
Me
Δ
O
p
m
O
C-N bond rotation
Eact = 34.0 Kcal mol-1
18 [52%]
Me
MeO
Me
MeO
N
N
free rotations at both C-N and C-C
P
P
O
Δ at 165 after 24
200
6.2
6.7
15.8 [44%]
15.3 [39%]
20.3
21.8
57.7 [48%]
56.2 [44%]
O
8
final dr of ent-17:18 = 22 : 78
ent-17-P,m
Scheme 8. Thermal equilibration and rotational barriers.
18-P,p
3.67 (m, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 4.18 (td, J¼8.7, 4.7 Hz, 1H),
6.81 (d, J¼8.4 Hz, 1H), 6.85 (d, J¼7.2 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H);
hexanes (1:1) followed by concentration in vacuo afforded a crude
mixture of diastereomers. Separation and purification of the
resulting crude residue via silica gel flash column chromatography
(gradient eluent: EtOAc in hexanes) afforded the desired N,O-biaryl
diastereomers. Diastereomeric ratios were found in crude 1H NMR,
and enantiomeric excess of each diastereomer was determined via
chiral HPLC [CHIRALCEL OD-H; size: 250ꢁ4.6 mm (Lꢁi.d.); eluent:
isopropyl alcohol in Hexanes].
13C NMR (125 MHz, CDCl3)
d 15.0, 16.4, 19.9, 30.0, 40.7, 46.3, 53.4,
55.9, 59.4, 62.3, 108.5, 122.1,126.3,126.6, 128.8, 130.06,130.08,131.1,
135.6,139.5,139.8,156.4,157.8,172.2,173.0 [missing one carbon due
to overlap]; IR (film) cmꢂ1 2896w, 2344w, 1724s, 1679s, 1443m,
1425m, 1245s, 1190m; mass spectrum (APCI): m/e (% relative in-
tensity) 468 (100) (MþH)þ; HRMS of the isomeric mixture (ESI, m/e)
calcd for C26H30NO7 468.2017, found 468.2013.
4.2.1. Establishing the feasibility
4.2.1.2. Chiral biaryl 14-M. Rotamers observed on the NMR time-
scale; Rf¼0.34 [60% EtOAc in hexanes]; pale solid; mp 185–188 ꢀC;
4.2.1.1. Chiral biaryl 12-major. Rf¼0.52 [20% EtOAc in chloroform];
20
[a
]
ꢂ16.7 (c 2.14, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 0.53 (s, 3H),
thick oil; 1H NMR (500 MHz, CDCl3)
d 1.81 (s, 3H), 1.96 (s, 3H), 2.16
D
0.73 (s, 3H),1.25 (s, 3H),1.26 (s, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 3.66 (d,
J¼8.4 Hz, 1H), 3.68 (s, 6H), 3.75 (d, J¼8.4 Hz, 1H), 3.97 (d, J¼8.0 Hz,
1H), 3.99 (d, J¼8.0 Hz, 1H), 5.09–5.20 (m, 8H), 6.73 (d, J¼8.4 Hz, 1H),
6.77 (d, J¼8.4 Hz, 1H), 6.85 (d, J¼6.8 Hz, 1H), 6.87 (d, J¼7.6 Hz, 1H),
7.13 (s, 2H), 7.15 (s, 1H), 7.19 (s, 1H), 7.22 (t, J¼8.0 Hz, 1H), 7.23 (t,
(s, 3H), 3.35 (td, J¼8.9, 4.6 Hz, 1H), 3.54–3.59 (m, 2H), 3.61–3.74 (m,
4H), 3.68 (s, 3H), 3.792 (s, 3H), 3.797 (s, 3H), 4.22 (td, J¼8.6, 4.6 Hz,
1H), 6.77 (d, J¼8.5 Hz, 1H), 6.90 (d, J¼8.0 Hz, 1H), 7.23 (t, J¼8.0 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 15.0, 16.4, 20.0, 40.66, 40.68, 46.9,
53.36, 53.43, 55.6, 59.4, 62.9, 107.7, 123.4, 126.8, 128.6, 129.9, 131.1,
133.2, 136.2, 139.3, 139.4, 139.7, 156.6, 156.8, 172.4, 172.8; IR (film)
cmꢂ1 2946w, 2354w, 1730s, 1688s, 1461m, 1439m, 1235s, 1183m;
mass spectrum (APCI): m/e (% relative intensity) 468 (100) (MþH)þ.
Compound 12-Minor: Rf¼0.52 [20% EtOAc in chloroform]; thick oil;
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 20.2, 21.1, 23.5, 23.8,
24.9, 55.3, 55.6, 62.2, 62.5, 73.5, 73.6, 75.0, 75.3, 107.7, 107.8, 122.69,
122.72, 124.5, 125.0, 125.2, 125.5, 127.9, 128.2, 128.7, 128.9, 133.8,
134.1, 137.4, 137.5, 138.0, 139.76, 139.83, 139.91, 139.95, 157.3, 157.6,
158.4 [missing four carbons due to overlap]; IR (film) cmꢂ1 2935w,
1746s, 1466m, 1389s, 1259s, 1068s, 1029s, 734s; mass spectrum
(APCI): m/e (% relative intensity) 354 (100) (MþH)þ; HRMS (ESI,
m/e) calcd for C21H23NO4 353.1622, found 353.1626.; HPLC (80:20
hexane/2-propanol): tR¼major 15.6 min, and minor 12.0 min.
1H NMR (500 MHz, CDCl3)
d 1.88 (s, 3H), 1.93 (s, 3H), 2.17 (s, 3H),
3.01 (td, J¼8.6, 4.7 Hz,1H), 3.48 (q, J¼8.8 Hz,1H), 3.54–3.75 (m, 5H),
Table 1
Heating of pure 17-M,p diastereomer
temp [°C] time [h] 17-M,p [ee] ent-17-P,m
starting 17 [95%]
ent-18-M,m [ee]
18-P,p
4.2.1.3. Chiral biaryl 15-M. Rf¼0.10 [50% EtOAc in hexanes]; pale
20
solid; mp 96–100 ꢀC; [
a]
ꢂ27.5 (c 2.0, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) d 0.58 (br s, 3H), 0.92–0.96 (br m, 3H), 2.09 (s, 3H), 3.02–3.09
Δ at 85 after 24 97.5 [95%]
2.5
0.0
0.0
(br m, 2H), 3.62–3.70 (br m, 1H), 3.70 (s, 3H), 3.84–3.87 (br m, 1H),
5.12 (s, 2H), 5.16 (s, 2H), 6.78 (d, J¼8.5 Hz,1H), 6.89 (d, J¼7.5 Hz,1H),
7.04 (s, 1H), 7.23 (t, J¼8.0 Hz, 1H), 7.27 (s, 1H); 13C NMR (125 MHz,
isomerizing via C-N
via C-N
120
24
58.2 [94%]
1.8
38.8 [94%]
1.2
CDCl3)
d 20.8, 22.0, 22.8, 29.2, 31.1, 55.9, 59.9, 73.9, 76.3, 108.0,
isomerizing via C-N
via C-N
122.0, 123.2, 124.7, 127.4, 129.5, 135.6, 139.4, 140.7, 140.9, 141.5,
152.3, 156.8; IR (film) cmꢂ1 2959w, 2927w, 2361w, 2249w, 1735s,
1698s, 1476m, 1356m; mass spectrum (APCI): m/e (% relative in-
tensity) 368 (100) (MþH)þ.
C-N &
C-C
C-N &
C-C
via C-C
165
200
24
24
24.0 [92%]
22.1 [92%]
1.0
0.9
71.3 [90%]
72.8 [89%]
3.7
4.2
via C-C
via C-C
4.2.1.4. Chiral biaryl 16-M. Rf¼0.38 [60% EtOAc in hexanes]; pale
20
solid; mp 74–80 ꢀC; [
a
]
ꢂ25.3 (c 2.16, CH2Cl2); 1H NMR (400 MHz,
D
final dr of 17 : ent-18 = 23 : 77
CDCl3)
d 0.56 (br s, 3H), 0.98 (br m, 3H), 2.09 (s, 3H), 2.12 (quintet,

5008
J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
(S)-xylyl-BINAP
Me
n = 0 or 1
Ar2
Ar2
R
R
O
Rh(III)
O
Me
Rh(III)
O
Me
OMe
= 3,5-xylyl
P
P
C-C rotating out or
P
P
loss of chelation from OMe
N
N
Ar1
Ar1
n
R
R
n
R1
R1
R1
R1
O
O
A1
[M, p] major
A2
[P, p] minor diastereomer
diastereo- and enantiomer
C-N rotation
loss of chelation from C O
=
BINAP omitted
R1
O
R1
Me
Ar2
R
R
O
Ar2
R
n
Me
N
O
P
Rh(III)
P
P
Rh(III)
P
N
O
Me
O
Ar1
n
Ar1
R1
R
Me
O
R1
A3
[M, m] minor enantiomer
of the minor diastereomer
B1
[P, m] minor enantiomer
of the major diastereomer
Scheme 9. A proposed asymmetric model.
J¼7.6 Hz, 2H), 2.89–3.08 (br m, 6H), 3.65 (br m, 1H), 3.69 (s, 3H),
3.86–3.87 (br m, 1H), 6.76 (d, J¼8.4 Hz, 1H), 6.87 (d, J¼7.6 Hz, 1H),
7.01 (s, 1H), 7.20 (t, J¼8.0 Hz, 1H), 7.22 (s, 1H); 13C NMR (100 MHz,
21.9, 23.2, 29.1, 40.7, 40.8, 53.3, 53.4, 55.3, 58.8, 59.4, 76.0, 107.7,
123.5, 126.8, 128.5, 129.2, 131.4, 135.1, 138.0, 138.7, 139.2, 140.5,
152.1, 156.7, 172.4, 172.9; IR (Neat) cmꢂ1 2957w, 2360w, 1734s,
1697s, 1467m, 1427m, 1251s, 1172s, 1061s; mass spectrum (APCI):
m/e (% relative intensity) 510 (100) (MþH)þ; HRMS (ESI, m/e) calcd
for C29H35NO7 510.2487, found 510.2494.; HPLC (95:5 hexane/
2-propanol): tR¼major 40.9 min and minor 40.0 min.
CDCl3) d 20.4, 21.8, 22.9, 25.8, 29.0, 32.8, 33.0, 55.6, 59.9, 76.4, 107.9,
123.1, 124.6, 127.4, 128.0, 128.5, 133.6, 139.3, 140.5, 144.2, 145.0,
152.7, 156.9; IR (film) cmꢂ1 2959w, 2839w, 1791s, 1473s, 1371m,
1260s, 1200s, 1148m, 1057m; mass spectrum (APCI): m/e (% relative
intensity) 366 (100) (MþH)þ.
4.2.2.3. Chiral biaryl 19-M,p. Rf¼0.34 [60% EtOAc in hexanes]; pale
20
4.2.2. Synthesis of chiral N,O-biaryls
solid; mp 80–83 ꢀC; [
(400 MHz, CDCl3)
a
]
D
ꢂ65.1 (c 0.723, CH2Cl2); 1H NMR
d 0.54 (s, 3H), 1.02 (s, 3H), 1.86 (s, 3H), 1.89–1.92
4.2.2.1. Chiral biaryl 17-M,p. Rf¼0.28 [60% EtOAc in hexanes]; pale
(m, 1H), 1.94 (s, 3H), 2.00–2.15 (m, 2H), 2.16 (s, 3H), 2.60 (d,
J¼10.4 Hz, 1H) 2.83–2.94 (m, 4H), 3.35 (d, J¼10.0 Hz, 1H), 3.69 (s,
3H), 3.71 (dd, J¼6.8, 1.2 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H), 6.84 (d,
J¼7.6 Hz, 1H), 7.22 (t, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
20
solid; mp 111–113 ꢀC; [
a
]
ꢂ46.7 (c 1.0, CH2Cl2). Compound ent-17-
D
20
P,m: [
a
]
D
þ39.5 (c 0.72, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d 0.53
(s, 3H), 1.01 (s, 3H), 1.85 (s, 3H), 1.91 (s, 3H), 2.15 (s, 3H), 2.57 (d,
J¼11.0 Hz, 1H), 2.82 (dd, J¼11.2, 1.2 Hz, 1H), 3.34 (d, J¼10.5 Hz, 1H),
3.59 (ABq, Dn¼19.7 Hz, J¼17.0 Hz, 2H), 3.65 (ABq, Dn¼18.2 Hz,
J¼17.0 Hz, 2H), 3.67 (s, 3H), 3.70 (dd, J¼10.5,1.0 Hz,1H), 3.78 (s, 3H),
3.80 (s, 3H), 6.79 (d, J¼8.5 Hz, 1H), 6.83 (d, J¼7.5 Hz, 1H), 7.23 (t,
d
15.0, 16.6, 20.0, 22.3, 23.2, 24.4, 29.2, 32.67, 32.70, 55.9, 58.7, 75.4,
108.3,121.9,127.2,128.4,129.3,131.0,133.5,136.6,137.9,143.0,143.3,
151.7, 158.3; IR (film) cmꢂ1 2949s, 2923s, 2852s, 2362m, 2344m,
1685s, 1469s, 1373m, 1256m; mass spectrum (APCI): m/e (% relative
intensity) 394 (100) (MþH)þ; HRMS of mixture of 19-M,p and 20-
P,p (ESI, m/e) calcd for C25H31NO3 393.2299, found 393.2303; HPLC
(95:5 hexane/2-propanol): tR¼major 26.7 min and minor 25.5 min.
J¼8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 14.9, 16.5, 20.0, 22.4,
23.2, 29.2, 40.7, 40.8, 53.3, 53.4, 55.9, 58.7, 59.4, 75.4, 108.3, 122.0,
126.7, 128.7, 129.6, 131.2, 134.7, 137.7, 137.9, 138.9, 139.2, 151.6, 158.3,
172.2, 173.1; IR (Neat) cmꢂ1 2958w, 2360m, 2342m, 1734m, 1696m,
1433w, 1265s, 1109m, 734s; mass spectrum (APCI): m/e (% relative
intensity) 510 (100) (MþH)þ; HRMS (ESI, m/e) calcd for C29H35NO7
510.2487, found 510.2482; HPLC (95:5 hexane/2-propanol):
tR¼major 11.4 min, and minor 14.7 min.
4.2.2.4. Chiral biaryl 20-P,p. Rf¼0.48 [60% EtOAc in hexanes]; thick
20
oil; [
a
]
D
þ7.5 (c 0.185, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 0.44 (s,
3H), 0.88 (s, 3H), 1.70–1.76 (m, 1H), 1.72 (s, 3H), 1.97 (s, 3H), 2.05
(quintet, J¼7.4 Hz, 2H), 2.10 (s, 3H), 2.80–2.95 (m, 4H), 3.50 (dd, J¼
11.6, 1.8 Hz, 1H), 3.41 (dd, J¼10.6, 1.8 Hz, 1H), 3.62 (s, 3H), 3.74 (d,
J¼10.8 Hz, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.83 (d, J¼7.6 Hz, 1H), 7.13 (t,
4.2.2.2. Chiral biaryl 18-P,p. Rf¼0.35 [60% EtOAc in hexanes]; pale
20
solid; mp 187–190 ꢀC; [
a
]
þ5.9 (c 2.40, CH2Cl2). Compound ent-
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 15.0, 16.5, 20.2, 21.9,
D
20
18-M,m: [
a
]
D
ꢂ3.2 (c 0.12, CH2Cl2); 1H NMR (400 MHz, CDCl3)
23.2, 24.3, 29.0, 29.9, 32.67, 32.75, 55.4, 58.9, 76.0, 107.7, 123.4,
127.3, 128.3, 131.2, 133.8, 137.0, 140.6, 142.9, 143.5, 152.2, 156.7; IR
(film) cmꢂ1 2969s, 2918s, 2850s, 2360m, 2340m, 1686s, 1467s,
1378m, 1256m; mass spectrum (APCI): m/e (% relative intensity)
394 (100) (MþH)þ; HRMS of mixture of 19-M,p and 20-P,p (ESI,
m/e) calcd for C25H31NO3 393.2299, found 393.2303; HPLC (95:5
hexane/2-propanol): tR¼major 26.7 min and minor 25.5 min.
d
0.51 (s, 3H), 0.95 (s, 3H), 1.78 (s, 3H), 2.01 (s, 3H), 2.15 (s, 3H), 2.92
(d, J¼11.6 Hz, 1H), 2.99 (dd, J¼11.8, 1.6 Hz, 1H), 3.47 (dd, J¼10.4,
1.6 Hz, 1H), 3.65 (ABq, Dn¼71.6 Hz, J¼16.8 Hz, 2H), 3.66 (ABq,
Dn¼24.1 Hz, J¼17.2 Hz, 2H), 3.67 (s, 3H), 3.789 (s, 3H), 3.795 (s, 3H),
3.80 (d, J¼10.5 Hz, 1H), 6.75 (d, J¼8.0 Hz, 1H), 6.89 (d, J¼7.6 Hz, 1H),
7.21 (t, J¼8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 14.9, 16.4, 20.2,

J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
5009
4.2.2.5. Chiral biaryl 21-M,p. Rf¼0.17 [60% EtOAc in hexanes]; pale
24.6, 25.8, 55.8, 61.9, 74.5, 74.6, 108.3, 122.2, 127.0, 129.0, 129.5,
129.6, 133.6, 137.5, 139.0, 139.06, 139.1, 157.1, 157.9 [missing one
carbon due to overlap]; IR (film) cmꢂ1 2968w, 2858w, 2369w,
2335w, 1745s, 1582w, 1397m, 1210m; mass spectrum (APCI): m/e (%
relative intensity) 382 (100) (MþH)þ; HRMS (ESI, m/e) calcd for
C23H27NO4 381.1935, found 381.1938; HPLC (95:5 hexane/2-prop-
anol): tR¼major 27.0 min and minor 26.0 min.
20
solid; mp 174–176 ꢀC; [
(400 MHz, CDCl3)
a
]
ꢂ71.3 (c 1.42, CH2Cl2); 1H NMR
D
d
0.55 (s, 3H), 1.03 (s, 3H), 1.83 (s, 3H), 1.95 (s,
3H), 2.14 (s, 3H), 2.62 (d, J¼10.4 Hz, 1H), 2.85 (dd, J¼11.2, 1.6 Hz,
1H), 3.37 (d, J¼10.4 Hz, 1H), 3.69 (s, 3H), 3.72 (dd, J¼10.6, 1.4 Hz,
1H), 5.07–5.16 (m, 4H), 6.82 (d, J¼8.0 Hz, 1H), 6.86 (d, J¼7.6 Hz,
1H), 7.25 (t, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.9, 16.3,
19.8, 22.3, 23.0, 29.1, 55.8, 58.6, 74.3, 75.4, 108.3, 122.0, 126.0,
127.3, 128.8, 128.9, 135.2, 137.7, 137.99, 138.02, 138.5, 151.5, 158.1
[missing one carbon due to overlap]; IR (film) cmꢂ1 3418w,
2967w, 2360w, 1692s, 1578w, 1468s, 1373m, 1259m, 1175m; mass
spectrum (APCI): m/e (% relative intensity) 396 (100) (MþH)þ;
HRMS (ESI, m/e) calcd for C24H29NO4 395.2092, found 395.2093;
HPLC (95:5 hexane/2-propanol): tR¼major 27.0 min and minor
26.5 min.
4.2.2.10. Chiral biaryl 26-P,p. Rf¼0.41 [60% EtOAc in hexanes];
20
thick oil; [
a
]
þ65.0 (c 0.85, CH2Cl2); 1H NMR (400 MHz, CDCl3)
D
d
0.63 (s, 3H), 1.13 (s, 3H), 1.76 (s, 3H), 2.05 (s, 3H), 2.11 (s, 3H),
3.72 (s, 3H), 3.92 (d, J¼8.4 Hz, 1H), 4.07 (d, J¼8.0 Hz, 1H), 5.12–
5.21 (m, 4H), 6.72 (d, J¼8.4 Hz, 1H), 6.90 (d, J¼7.6 Hz, 1H), 7.23 (t,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 16.6, 16.9, 20.1, 23.1,
26.1, 55.2, 62.0, 74.5, 74.6, 77.7, 107.4, 123.3, 127.3, 128.8, 128.9,
129.6, 133.7, 137.6, 138.5, 139.0, 139.7, 157.80, 157.85; IR (film)
cmꢂ1 2956w, 2360w, 1735s, 1698s, 1468m, 1433m, 1252s, 1173m;
mass spectrum (APCI): m/e (% relative intensity) 496 (100)
(MþH)þ; HRMS (ESI, m/e) calcd for C23H27NO4 382.2013, found
382.2013; HPLC (95:5 hexane/2-propanol): tR¼major 24.3 min
and minor 25.8 min.
4.2.2.6. Chiral biaryl 22-P,p. Rf¼0.26 [60% EtOAc in hexanes]; thick
20
oil; [a
]
þ21.4 (c 0.075, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 0.52
D
(s, 3H), 0.96 (s, 3H), 1.76 (s, 3H), 2.04 (s, 3H), 2.14 (s, 3H), 2.95 (d,
J¼11.6 Hz, 1H), 3.01 (dd, J¼11.6, 1.6 Hz, 1H), 3.50 (dd, J¼10.8, 2.0 Hz,
1H), 3.70 (s, 3H), 3.83 (d, J¼10.4 Hz, 1H) 5.14–5.19 (m, 4H), 6.77 (d,
J¼8.4 Hz, 1H), 6.95 (d, J¼7.6 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
14.9, 16.3, 20.1, 21.8, 23.2, 29.0, 55.3, 58.7, 74.3,
4.2.2.11. Chiral biaryl 27-M,p. Rf¼0.17 [10% EtOAc in CH2Cl2]; yel-
20
76.0, 77.4, 107.8, 123.5, 126.2, 127.0, 128.7, 129.1, 135.6, 137.9, 138.4,
138.6, 140.4, 152.0, 156.6; IR (film) cmꢂ1 2969w, 2884w, 2839w,
2360m, 2342m, 1754s, 1699s, 1468s, 1258s; mass spectrum (APCI):
m/e (% relative intensity) 396 (100) (MþH)þ; HRMS (ESI, m/e) calcd
for C24H29NO4 395.2092, found 395.2081; HPLC (95:5 hexane/
2-propanol): tR¼major 24.3 min and minor 25.8 min.
low solid; mp 110–114 ꢀC; [
a
]
ꢂ24.4 (c 1.53, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
ꢂ0.096 (s, 3H), 0.99 (s, 3H), 1.73 (s, 3H), 2.18 (s,
3H), 3.65 (d, J¼7.8 Hz, 1H), 3.66 (s, 2H), 3.71 (ABq, Dn¼19.9 Hz,
J¼17.0 Hz, 2H), 3.81 (s, 3H), 3.82 (s, 6H), 3.94 (d, J¼8.0 Hz, 1H), 7.23
(dd, J¼8.4, 0.8 Hz, 1H), 7.27–7.35 (m, 2H), 7.35 (d, J¼9.2 Hz, 1H), 7.79
(dd, J¼7.9, 1.4 Hz, 1H), 7.87 (d, J¼9.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 16.9, 18.0, 24.1, 26.4, 40.9, 41.3, 53.4, 56.4, 59.1, 61.9, 77.0,
4.2.2.7. Chiral biaryl 23-M,p. Rf¼0.32 [60% EtOAc in hexanes]; pale
77.5, 113.3, 121.3, 123.3, 125.1, 127.0, 128.6, 128.7, 129.8, 131.9, 132.6,
133.9, 134.9, 135.8, 139.8, 140.1, 154.9, 157.3, 172.2, 173.1; IR (film)
cmꢂ1: 2930w, 1735s, 1623w, 1595w, 1436m, 1397w, 1371m, 1351m,
1337m, 1272s, 1249s, 1167s, 1060s; mass spectrum (APCI): m/e (%
relative intensity) 532 (100) (MþH)þ, 474 (7); HRMS (ESI, m/e) calcd
for C31H33NO7 532.2330, found 532.2320; HPLC (95:5 hexane/
2-propanol): tR¼major 26.4 min and minor 25.2 min.
20
solid; mp 96–100 ꢀC; [
a
]
ꢂ6.8 (c 1.18, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3)
d 0.45 (s, 3H), 1.14 (s, 3H), 1.88 (s, 3H), 2.00 (s, 3H), 2.14 (s,
3H), 3.61 (s, 2H), 3.65 (ABq, Dn¼17.1 Hz, J¼16.8 Hz, 2H), 3.66 (s, 3H),
3.75 (d, J¼8.0 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 4.00 (d, J¼8.0 Hz,
1H), 6.77 (d, J¼8.0 Hz, 1H), 6.81 (d, J¼7.5 Hz, 1H), 7.21 (d, J¼8.0 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 16.9, 17.5, 20.2, 24.7, 25.8, 40.9,
41.2, 53.38, 53.40, 55.8, 59.2, 62.0, 77.0, 108.2, 122.1, 127.7, 128.8,
131.79, 131.85, 133.1, 137.0, 139.3, 139.7, 139.8, 157.2, 158.0, 172.2,
173.1; IR (film) cmꢂ1 2972w, 2360w, 1735s, 1434m, 1374m, 1264s,
1061m, 733s; mass spectrum (APCI): m/e (% relative intensity) 496
(100) (MþH)þ; HRMS (ESI, m/e) calcd for C28H33NO7 496.2330,
found 496.2339; HPLC (80:20 hexane/2-propanol): tR¼major
28.2 min and minor 25.8 min.
4.2.2.12. Chiral biaryl 28-P,p. Rf¼0.39 [10% EtOAc in CH2Cl2]; yel-
20
low solid; mp 245–250 ꢀC; [
a
]
ꢂ19.6 (c 1.13, CHCl3); 1H NMR
D
(400 MHz, CDCl3) d 0.38 (s, 3H), 1.12 (s, 3H), 1.80 (s, 3H), 2.17 (s, 3H),
3.50 (d, J¼8.2 Hz, 1H), 3.60–3.80 (m [two ABq], 4H), 3.81 (s, 3H),
3.82 (s, 3H), 3.87 (s, 3H), 3.89 (d, J¼8.0 Hz, 1H), 7.26 (d, J¼9.2 Hz,
1H), 7.28–7.35 (m, 2H), 7.50–7.52 (m, 1H), 7.73–7.75 (m, 1H), 7.88 (d,
J¼9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 16.9, 17.2, 23.9, 25.7,
4.2.2.8. Chiral biaryl 24-P,p. Rf¼0.44 [60% EtOAc in hexanes]; thick
41.0, 41.2, 53.3, 53.4, 55.7, 59.1, 62.0, 77.7, 111.8, 122.2, 124.3, 126.6,
126.9, 127.2, 129.0, 129.9, 131.6, 132.7, 133.3, 133.6, 135.8, 139.5,
139.9, 154.5, 157.2, 172.4, 172.9; IR (film) cmꢂ1 3003w, 1730s, 1592w,
1512w, 1462w, 1433w, 1397w, 1368w, 1268s, 1246s, 1199m, 1168m,
1062s; mass spectrum (APCI): m/e (% relative intensity) 532 (100)
(MþH)þ; HRMS (ESI, m/e) calcd for C31H33NO7 532.2330, found
532.2327; HPLC (95:5 hexane/2-propanol): tR¼major 20.7 min and
minor 15.7 min.
20
oil; [a
]
þ29.8 (c 0.33, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 0.61 (s,
D
3H), 1.10 (s, 3H), 1.77 (s, 3H), 2.01 (s, 3H), 2.12 (s, 3H), 3.65 (ABq,
Dn¼61.3, J¼16.8 Hz, 2H), 3.67 (ABq, Dn¼31.7 Hz, J¼17.2 Hz, 2H), 3.69
(s, 3H), 3.796 (s, 3H), 3.804 (s, 3H), 3.89 (d, J¼8.0 Hz, 1H), 4.05 (d,
J¼8.0 Hz, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.87 (d, J¼7.6 Hz, 1H), 7.20 (d,
J¼8.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 16.8,17.0, 20.1, 23.1, 26.1,
40.9, 41.1, 53.3, 53.4, 55.1, 59.1, 61.9, 107.3, 123.2, 127.9, 128.6, 131.1,
131.7, 133.2, 137.0, 139.2, 139.5, 139.8, 157.8, 157.9, 172.4, 172.9,
[missing one carbon due to overlap]; IR (film) cmꢂ1 2956w, 2360w,
1735s, 1698s, 1468m, 1433m, 1252s, 1173m; mass spectrum (APCI):
m/e (% relative intensity) 496 (100) (MþH)þ; HRMS (ESI, m/e) calcd
for C28H33NO7 496.2330, found 496.2320; HPLC (95:5 hexane/
2-propanol): tR¼major 25.5 min and minor 19.3 min.
4.2.2.13. Chiral biaryl 29-M,p. Rf¼0.25 [60% EtOAc in hexanes];
20
yellow solid; mp 105–110 ꢀC; [
a]
ꢂ40.8 (c 2.055, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
ꢂ0.052 (s, 3H), 1.02 (s, 3H), 1.71 (s, 3H), 2.17 (s,
3H), 3.70 (d, J¼8.0 Hz, 1H), 3.85 (s, 3H), 3.97 (d, J¼8.0 Hz, 1H), 5.12–
5.25 (m, 4H), 7.26–7.38 (m, 3H), 7.37 (d, J¼9.2 Hz, 1H), 7.82 (dd,
J¼7.8, 1.2 Hz, 1H), 7.90 (d, J¼9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.2.2.9. Chiral biaryl 25-M,p. Rf¼0.35 [60% EtOAc in hexanes]; pale
d 16.7, 17.9, 24.1, 26.4, 56.5, 61.9, 74.5, 74.6, 77.1, 113.3, 120.7, 123.4,
20
solid; mp 110–113 ꢀC;
[a
]
ꢂ4.3 (c 3.15, CH2Cl2); 1H NMR
124.9, 127.2, 128.69, 128.73, 129.6, 130.1, 130.5, 134.4, 134.8, 136.4,
139.1, 139.5, 155.0, 157.3; IR (film) cmꢂ1 2933w, 2839w, 1747s,
1620w, 1593w, 1507w, 1457w, 1416w, 1367m, 1345m, 1296w,
1274m, 1261m; mass spectrum (APCI): m/e (% relative intensity)
418 (100) (MþH)þ; HRMS of mixture of 29-M,p and 30-P,p (ESI,
D
(400 MHz, CDCl3) d 0.48 (s, 3H), 1.17 (s, 3H), 1.86 (s, 3H), 2.04 (s, 3H),
2.13 (s, 3H), 3.68 (s, 3H), 3.79 (d, J¼8.4 Hz, 1H), 4.03 (d, J¼8.0 Hz,
1H), 5.07–5.19 (m, 4H), 6.79 (d, J¼8.4 Hz, 1H), 6.83 (d, J¼7.6 Hz, 1H),
7.24 (t, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 16.7, 17.2, 20.1,

5010
J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
m/e) calcd for C26H27NO4 417.1935, found 417.1928; HPLC (80:20
hexane/2-propanol): tR¼major 17.1 min and minor 13.2 min.
[isocratic eluent: 40% EtOAc in hexanes] afforded the product 32-
M,p in 85% yield. Compound 32-M,p: Rf¼0.46 [50% EtOAc in hex-
20
anes]; clear crystals; mp 230–233 ꢀC; [
a
]
ꢂ39.2 (c 1.66, CH2Cl2);
D
4.2.2.14. Chiral biaryl 30-P,p. Rf¼0.42 [60% EtOAc in hexanes];
1H NMR (400 MHz, CDCl3)
d 0.49 (s, 3H), 0.73 (s, 3H), 0.79 (s, 3H),
20
yellow solid; mp 115–120 ꢀC; [
a
]
ꢂ57.8 (c 0.79, CHCl3); 1H NMR
0.97 (s, 3H), 1.20–1.28 (m, 1H), 1.36–1.43 (m, 1H), 1.52–1.59 (m, 1H),
1.71–1.80 (m, 1H), 1.80 (d, J¼18.4 Hz, 1H), 1.89 (s, 3H), 1.97 (t,
J¼4.4 Hz, 1H), 2.01 (s, 3H), 2.15 (s, 3H), 2.27 (ddd, J¼17.2, 4.4,
3.2 Hz, 1H), 2.47 (d, J¼10.8 Hz, 1H), 2.84 (d, J¼10.8 Hz, 1H), 3.40
(ABq, Dn¼85.5 Hz, J¼15.2 Hz, 2H), 3.49 (d, J¼10.0 Hz, 1H), 3.58
(ABq, Dn¼33.3 Hz, J¼17.0 Hz, 2H), 3.66 (ABq, Dn¼54.1 Hz,
J¼16.6 Hz, 2H), 3.78 (d, J¼9.2 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 7.17
(d, J¼7.6 Hz, 1H), 7.29 (t, J¼8.0 Hz, 1H), 7.44 (d, J¼8.4 Hz, 1H); 13C
D
(400 MHz, CDCl3) d 0.38 (s, 3H), 1.15 (s, 3H), 1.78 (s, 3H), 2.16 (s, 3H),
3.53 (d, J¼8.2 Hz, 1H), 3.89 (s, 3H), 3.91 (d, J¼8.2 Hz, 1H), 5.15–5.25
(m, 4H), 7.28 (d, J¼9.2 Hz, 1H), 7.30–7.38 (m, 2H), 7.52–7.55 (m, 1H),
7.75–7.78 (m, 1H), 7.91 (d, J¼9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
16.8,17.1, 23.9, 25.7, 55.8, 62.0, 74.57, 74.64, 77.0, 111.8,121.5,124.4,
126.3,127.1,127.4,129.0,129.4,130.2,130.6,133.2,134.1,136.4,138.7,
139.4, 154.5, 157.2; IR (film) cmꢂ1 2840w, 1743m, 1592w, 1510w,
1462w 1362w, 1345w, 1300w, 1258m, 1244m; mass spectrum
(APCI): m/e (% relative intensity) 418 (100) (MþH)þ; HRMS of
mixture of 29-M,p and 30-P,p (ESI, m/e) calcd for C26H27NO4
417.1935, found 417.1928; HPLC (80:20 hexane/2-propanol):
tR¼major 18.7 min and minor 15.2 min.
NMR (400 MHz, CDCl3)
d 15.1, 16.7, 19.4, 19.6, 20.0, 22.1, 23.1, 24.0,
27.1, 29.1, 40.7, 42.6, 43.1, 48.3, 49.7, 53.3, 53.4, 58.3, 58.8, 59.0,
75.6, 120.1, 127.9, 129.0, 130.1, 130.8, 132.0, 132.8, 138.3, 138.6, 139.1,
139.8, 147.4, 151.4, 172.2, 172.7, 214.1; IR (film) cmꢂ1 2959w, 2889w,
2360w, 2254w, 1734s, 1697s, 1467m, 1402m; mass spectrum
(APCI): m/e (% relative intensity) 709 (100) (MþH)þ; HRMS (ESI,
m/e) calcd for C38H47NO10S 710.2994, found 710.3004.
4.2.3. Assignment of absolute configurations
4.2.3.1. Demethylation procedure. A solution of 17-M,p (30.0 mg,
0.059 mmol) in anhyd CH2Cl2 was cooled to ꢂ78 ꢀC under an argon
atmosphere. To this reaction mixture was added BBr3 (1.0 M soln in
CH2Cl2, 5.0 equiv) carefully dropwise. The reaction mixture was
warmed to ꢂ25 ꢀC and stirred for 24 h. After the reaction was
complete, the solution was quenched with H2O and the reaction
mixture was warmed to rt. The layers were separated and the or-
ganic layer extracted with CH2Cl2 (2ꢁequal volume). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure.
The crude product was re-dissolved in anhyd acetone and
2.5 equiv of Me2SO4, and anhyd solid NaHCO3 (2.5 equiv) was
added under an argon atmosphere. The reaction mixture was stir-
red at rt for 48 h. After the reaction was complete, the mixture
filtered through a short pad of CeliteÔ. Acetone was removed under
reduced pressure and the crude mixture was re-dissolved in EtOAc.
The reaction mixture was washed with water followed by satd aq
NaCl (equal volume). The organic layer was dried over MgSO4, fil-
tered, and concentrated under reduced pressure. Purification of the
crude residue by silica gel flash column chromatography [isocratic
eluent: 50% EtOAc in hexanes] yielded the desired phenol 31-M,p in
4.2.3.3. Free phenol 33-M,p. 1H NMR (400 MHz, CDCl3)
d 0.66 (s,
3H), 1.17 (s, 3H), 1.87 (s, 3H), 1.99 (s, 3H), 2.14 (s, 3H), 3.59–3.72 (m,
3H), 3.81 (s, 3H), 3.81 (s, 3H), 6.05 (s,1H), 6.79 (d,1H, J¼7.6 Hz), 6.89
(d, J¼8.0 Hz), 7.14 (t, J¼8.0 Hz, 1H); mass spectrum (APCI): m/e (%
relative intensity) 496 (10) (MþH)þ, 483 (30), 482 (100). Compound
34-M,p: 1H NMR (500 MHz, CDCl3)
d 0.47 (s, 3H), 0.75 (s, 3H), 0.84
(s, 3H), 1.11 (s, 3H), 1.40 (ddd, J¼4.4, 9.2, 13.6 Hz, 1H), 1.65–1.83 (m,
4H), 1.92 (s, 3H), 1.97 (t, J¼4.4 Hz, 1H), 2.11 (s, 3H), 2.15 (s, 3H), 2.30
(ddd, J¼2.8, 4.4, 18.4 Hz, 1H), 2.93 (d, J¼15.2 Hz, 1H), 3.61 (t,
J¼6.4 Hz, 2H), 3.66 (d, J¼6.8 Hz, 2H), 3.80 (s, 6H), 4.03 (d, J¼8.0 Hz,
1H), 7.15 (d, J¼7.2 Hz, 1H), 7.28 (t, J¼9.2 Hz, 1H), 7.36 (d, J¼7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 17.0,17.5, 19.5, 19.6, 20.3, 24.4,
25.9, 27.1, 40.9, 41.1, 42.6, 43.3, 48.0, 49.6, 53.3, 53.4, 58.4, 58.8, 62.1,
120.8, 128.1, 129.0, 132.2, 132.3, 132.5, 133.5, 135.3, 137.2, 139.5,
140.3, 140.6, 147.3, 153.9, 157.2, 169.4, 172.2, 172.8; IR (neat) cmꢂ1
3474w, 2967m, 2893m, 23841w, 2340w, 1737s, 1686m, 1578w,
1481m, 1433s, 1398m, 1374m, 1355m; mass spectrum (APCI): m/e
(% relative intensity) 695 (40) (MþH)þ, 694 (100), 481 (20), 480
(90), 422 (20), 231(20); HRMS (ESI, m/e) calcd for C37H45NNaO10
S
718.2657, found 718.2643.
73% yield. Compound 31-M,p: Rf¼0.52 [50% EtOAc in hexanes];
4.2.4. Synthesis of a chiral amino-biaryl ligand
20
white solid; mp 165–168 ꢀC; [
a
]
þ7.8 (c 2.05, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3)
d
0.50 (s, 3H), 0.96 (s, 3H),1.84 (s, 3H),1.94 (s, 3H),
4.2.4.1. Ynamide 35. Rf¼0.58 [50% EtOAc in hexanes]; 1H NMR
2.16 (s, 3H), 2.69 (dd, J¼11.2, 2.0 Hz, 1H), 3.08 (d, J¼11.2 Hz, 1H),
3.57–3.71 (m, 5H), 3.79 (s, 3H), 3.80 (s, 3H), 3.94 (d, J¼10.8 Hz, 1H),
6.28 (s, 1H), 6.82 (d, J¼7.2 Hz, 1H), 6.89 (d, J¼7.6 Hz, 1H), 7.14 (t,
(400 MHz, CDCl3) d 2.12 (s, 3H), 3.72 (s, 3H), 4.88 (s, 2H), 6.62 (d,
J¼8.0 Hz, 1H), 6.70 (d, J¼7.6 Hz, 1H), 7.07 (t, J¼8.0 Hz, 1H), 7.36–7.41
(m, 6H), 7.41–7.46 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
20.9, 53.7,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
14.5, 16.4, 20.2, 21.3,
56.0, 70.4, 71.8, 76.6, 86.0, 108.0, 111.9, 121.8, 127.7, 128.7, 128.9,
139.7, 142.1, 155.3, 160.5 [missing eight carbons due to symmetry
and overlap]; IR (film) cmꢂ1 2969w, 2900w, 2839w, 2360w, 2248m,
1777w, 1716s, 1472s; mass spectrum (APCI): m/e (% relative in-
23.0, 29.1, 40.6, 53.3, 53.4, 58.4, 59.3, 60.6, 76.1, 116.2, 122.5, 125.8,
129.0, 129.2, 132.5, 133.5, 136.7, 137.8, 139.9, 140.3, 154.1, 155.0,
172.0, 172.7 [missing one carbon due to overlap]; IR (film) cmꢂ1
3332s, 2959w, 2889w, 2360w, 2254w, 1734s, 1697s, 1467m, 1402m;
mass spectrum (APCI): m/e (% relative intensity) 496 (100) (MþH)þ;
HRMS (ESI, m/e) calcd for C28H33NO7 496.2330, found 496.2318.
tensity) 384 (100) (MþH)þ; HRMS (ESI, m/e) calcd for C38H47NO10
S
383.1516, found 383.1505.
4.2.4.2. Chiral biaryl 37-M,p. Rf¼0.39 [60% EtOAc in hexanes]; pale
ꢂ21.6 (c 0.98, CH2Cl2); 1H NMR
20
4.2.3.2. Preparation of camphor-sulfonyl derivative. A solution of
31-M,p (55.0 mg, 0.11 mmol) in anhyd CH2Cl2 was cooled to 0 ꢀC
under an argon atmosphere. To the reaction mixture was added
(1S)-(þ)-10-camphor sulfonyl chloride (31.0 mg, 0.122 mmol) fol-
lowed by catalytic DMAP and Et3N (0.122 mmol). The reaction
mixture was warmed to rt and stirred for 12 h. After the reaction
was complete, the solution was quenched with pH 7.0 aqueous
buffer and the layers were separated. The organic layer was
extracted with CH2Cl2 (2ꢁequal volume), dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification of
the crude residue by silica gel flash column chromatography
solid; mp 103–106 ꢀC; [
(400 MHz, CDCl3)
a]
D
d
1.41 (s, 3H), 1.42 (s, 3H), 1.64 (s, 3H), 3.78 (s, 3H),
4.40 (d, J¼8.4 Hz, 1H), 4.95 (ABqd, Dn¼29.9 Hz, J¼12.4, 2.2 Hz, 2H),
5.10 (ABqd, Dn¼37.2 Hz, J¼12.8, 1.6 Hz, 2H), 5.20 (d, J¼8.4 Hz, 1H),
6.19 (d, J¼7.6 Hz, 1H), 6.51 (d, J¼7.6 Hz, 2H), 6.78 (d, J¼8.0 Hz, 1H),
6.84 (t, J¼8.0 Hz, 2H), 7.01 (d, J¼8.0 Hz, 3H), 7.05 (t, J¼8.0 Hz, 1H),
7.23–7.27 (m, 2H), 7.35 (t, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
15.8, 17.03, 20.0, 55.9, 71.2, 74.4, 74.6, 77.0, 107.8, 123.1, 126.5,
126.7, 127.1, 128.07, 128.15, 128.4, 128.6, 128.7, 129.8, 130.9, 135.9,
137.4, 137.9, 138.6, 138.7, 139.2, 144.0, 157.7, 158.0 [missing four
carbons due to symmetry]; IR (film) cmꢂ1 3058w, 2840w, 2360w,

J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
5011
4. For our own efforts, see: (a) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.;
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P.; Wei, Y.; Yao, P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780; (c) Yao, P.-Y.;
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1760s, 1579w, 1469m,1262m, 1069m, 908w; mass spectrum (APCI):
m/e (% relative intensity) 506 (100) (MþH)þ; HRMS (ESI, m/e) calcd
for C33H31NO4 505.2253, found 505.2250; HPLC (95:5 hexane/
2-propanol): tR¼major 27.5 min and minor 26.4 min.
4.2.4.3. Chiral biaryl 38-P,p. Rf¼0.62 [60% EtOAc in hexanes]; thick
20
oil; [
a]
þ74.5 (c 0.98, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 1.43 (s,
D
3H), 1.62 (s, 3H), 2.19 (s, 3H), 2.92 (s, 3H), 4.31 (d, J¼8.0 Hz, 1H), 4.92
(ABq, Dn¼49.9 Hz, J¼12.2 Hz, 2H), 5.12 (ABq, Dn¼28.7 Hz,
J¼12.5 Hz, 2H), 5.29 (d, J¼3.2 Hz, 1H), 5.31 (d, J¼4.0 Hz, 1H), 5.89 (d,
J¼8.4 Hz, 1H), 6.43 (br d, J¼7.2 Hz, 2H), 6.86 (t, J¼7.6 Hz, 1H), 6.88
(d, J¼6.8 Hz, 1H), 7.01 (dt, J¼6.8, 0.8 Hz, 1H), 7.04 (d, J¼8.0 Hz, 1H),
5. Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron 2006, 62, 3882.
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2005, 7, 1047.
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`
`
Stengel, T.; Fernandez-Hernandez, J.M.Chem.Commun. 2000,1965;(c)Witulski, B.;
Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281.
7.34–7.35 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 15.5, 16.8, 20.2,
8. For a review, see: Zhang, Y.; Hsung, R. P. ChemTracts 2004, 17, 442.
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P.; Figueroa, R.; Johnson, W. L. Org. Lett. 2007, 9, 3969.
53.9, 71.0, 74.2, 74.5, 77.1, 107.7, 122.7, 125.4, 126.8, 127.0, 127.9,
128.2, 128.5, 128.7, 129.5, 129.9, 135.3, 136.4, 138.2, 138.9, 139.0,
139.2, 145.2, 156.7, 158.9 [missing four carbons due to symmetry
and one carbon due to overlap]; IR (film) cmꢂ1 3058w, 2839w,
2360w, 2341w, 1753s, 1598w, 1492m, 1468m, 1301m; mass spec-
trum (APCI): m/e (% relative intensity) 506 (100) (MþH)þ; HRMS
(ESI, m/z) calcd for C33H31NO4 505.2253, found 505.2257; HPLC
(95:5 hexane/2-propanol): tR¼major 11.5 min and minor 16.3 min.
12. For recent reviews, see: (a) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197; (b)
Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Graner, J.; Breuning,
´
M. Angew. Chem., Int. Ed. 2005, 44, 5384; (c) Varela, J. A.; Saa, C. Chem. Rev. 2003,
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4.2.4.4. Preparation of chiral amino-biaryl 39-M. To a solution of
chiral biaryl 37-M,p (13.0 mg, 82% ee) in MeOH (3 mL) flushed with
argon was added 10 mol % Pd/C (3.0 mg). The reaction mixture was
flushed with H2 gas and then stirred under a balloon of H2 for 3 days.
The resulting mixture was filtered though a short pad of CeliteÔ and
solvent was removed under reduced pressure. The crude product was
purified by preparative TLC (1:1 Hex/EtOAc) and 3.0 mg of the desired
13. (a) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem., Int. Ed. 2007,
46, 3951; (b) Yamamoto, Y.; Ishii, J.-I.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc.
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Sung, M. J.; Pang, J.-H.; Park, S. B.; Cha, J. K. Org. Lett. 2003, 5, 2137.
amino-biaryl 39-M was isolated (42% yield). Compound 39-M:
23
Rf¼0.55 [10% CH2Cl2/EtOAc]; [
a
]
þ25.8 (c 0.0039, CH2Cl2); 1H NMR
D
14. Also see: (a) Bon˜aga, L. V. R.; Zhang, H. C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.;
Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473 and references therein;
(b) Tanaka, K.; Nishida, G.; Ogino, M.; Hirano, M.; Noguchi, K. Org. Lett. 2005, 7,
(500 MHz, CDCl3)
d
1.75 (s, 3H),1.98 (s, 3H), 2.05 (s, 3H), 3.21–3.56 (br
s,1H), 3.66 (d, 1H, J¼3.0 Hz), 3.73 (s, 3H), 5.15 (d, 4H, J¼21.5 Hz), 6.87
3119; (c) Stara
´, I. G.; Alexandrova´a´, Z.; Teply, F.; Sehnal, P.; Stary, I.; Saman, D.;
(d, 1H, J¼10.5 Hz), 6.96 (d, J¼9.5 Hz), 7.25–7.29 (m, 3H); 13C NMR
Budesinsky, M.; Cvacka, J. Org. Lett. 2005, 7, 2547; (d) Shibata, T.; Fujimoto, T.;
Yokota, K.; Takagi, K. J. Am. Chem. Soc. 2004, 126, 8382; (e) Gutnov, A.; Heller, B.;
Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C. An-
gew. Chem., Int. Ed. 2004, 43, 3795; (f) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K.
Angew. Chem., Int. Ed. 2004, 43, 6510; (g) Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe,
Y. J. Am. Chem. Soc. 2004, 126, 5358.
(100 MHz, CDCl3)
d 14.2, 16.5, 19.7, 29.9, 56.1, 74.4, 74.4, 108.8, 112.7,
114.1, 122.5, 123.1, 125.9, 127.5, 127.8, 128.8, 137.6, 139.3, 141.5, 141.7,
157.7; IR (neat) cmꢂ1 2918s, 2849s, 2361m, 2340w, 1732w, 1618w,
1578w, 1467s, 1367m; mass spectrum (APCI): m/e (% relative in-
tensity) 352 (100) (MþH)þ, 285 (20), 284 (100).
15. Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.; Hsung, R. P. Org. Lett.
2004, 6, 2209.
16. Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586.
17. Tanaka, K.; Takeishi, K. Synthesis 2007, 2920.
Acknowledgements
18. For some elegant examples of axially chiral amido–aryl bonds: (a) Kitagawa, O.;
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21. For an excellent book on concepts of asymmetric catalysis, see: Walsh, P. J.;
Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science
Books: Sausalito, CA, 2008.
22. For leading examples, see: (a) Xie, X.; Phuan, P. W.; Kozlowski, M. C. Angew.
Chem., Int. Ed. 2003, 42, 2168; (b) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K.
J. Am. Chem. Soc. 2004, 126, 8382; (c) For a diastereoselective example, see:
Fogel, L.; Hsung, R. P.; Wulff, W. D.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem.
Soc. 2001, 123, 5580.
23. For elegant examples of achiral template based asymmetric catalysis, see: (a)
Sibi, M. P.; Soeta, T. J. Am. Chem. Soc. 2007, 129, 4522; (b) Sibi, M. P.; Stanley, L.
M.; Nie, X.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129,
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(d) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 8277; (e)
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24. For a review on synthesis of ynamides, see: Tracey, M. R.; Hsung, R. P.; Antoline,
J. A.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In Science of Synthesis,
Authors thank NIH-NIGMS [GM066055]. Authors also thank Dr.
Victor Young and Mr. Ben Kucera [University of Minnesota] for
providing X-ray structural analysis. Finally, we thank Professor
Marisa Kozlowski for invaluable discussions.
References and notes
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J. Oppenheimer et al. / Tetrahedron 65 (2009) 5001–5012
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27. Throughout the paper, the capital M and P denote C–C axial chirality while
small m and p denote C–N axial chirality and are listed second.
28. CCDC for compounds 32-M,p,18-P,p, and 34-M,p are 665008, 665009, and 722530,
respectively. CCDC 665008, 665009, and 722530 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request.cif.