Bicyclo[3.2.0]heptane-based enamides by Ru/PNNP-catalyzed enantioselective ficini reactions: Scope and application in ligand design

Article abstract of DOI:10.1055/s-0031-1289679

Double chloride abstraction from [RuCl₂(PNNP)] [PNNP- = (S,S)-N,N-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine] gives the elusive dicationic adduct [Ru(OEt)₂(PNNP)]²⁺ which catalyzes the [2+2] cycloaddition

Full text of DOI:10.1055/s-0031-1289679

FEATURE ARTICLE
513
Bicyclo[3.2.0]heptane-Based Enamides by Ru/PNNP-Catalyzed
Enantioselective Ficini Reactions: Scope and Application in Ligand Design
R
u/PNNP-Cataly
h
zedAsymme
r
tric Fici
i
ni
R
eac
s
tions in
L
t
igandD
o
esign ph Schotes, Raphael Bigler, Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland
Fax +41(44)6321310; E-mail: mezzetti@inorg.chem.ethz.ch
Received 9 December 2011
O
O
Abstract: Double chloride abstraction from [RuCl2(PNNP)]
NEt2
[PNNP = (S,S)-N,N¢-bis[o-(diphenylphosphino)benzylidene]cyclo-
hexane-1,2-diamine] gives the elusive dicationic adduct
( )n
[Ru(OEt)2(PNNP)]2+ which catalyzes the [2+2] cycloaddition of cy-
( )n
Et2N
or
or
clic alkylidene b-keto esters with a variety of ynamides to produce
O
O
THF
O
bicyclo[3.2.0]heptane-based enamides with high yields and enan-
tioselectivity. The structural features of these products are discussed
and selected examples are converted into highly modular diene,
phosphite-alkene, and diphosphite derivatives, which were tested as
bidentate ligands with Rh(I), Ir(I), and Pd(II).
NEt2
O
Key words: asymmetric catalysis, biaryls, cycloaddition, bicyclic
n = 1, 2
compounds, ligands, phosphorus, ruthenium
Scheme 1 Original version of the Ficini reaction
Although formally a [2+2] cycloaddition, the reaction be-
tween the ynamide and the enone is likely to occur step-
wise via nucleophilic attack of the b-C-atom of the
ynamine onto the electrophilic position of the enone
(Scheme 2).4,5 The resulting dipolar intermediate is likely
to undergo rapid intramolecular ring closure by attack of
the enolate onto the iminium ion. A rationale for this as-
sumption is provided by the fact that the HOMO frontier
molecular orbital of the ynamide should have no, or very
little, electron density in the a-position to the nitrogen at-
om, and is thus not well suited for a concerted addition.4,5
Introduction
Heteroatom-substituted alkynes probably represent the
most versatile subgroup within the vast field of alkyne
chemistry. Ynamines, bearing a nitrogen-atom-substitut-
ed triple bond, have found broad application after their
discovery more than 50 years ago and have witnessed a re-
vival in the form of the less electron-rich ynamides in the
last 20 years.1 Ynamides still feature relatively strong po-
larization of the triple bond, but their electron density is
reduced by the delocalization of the nitrogen lone pair
onto the electron-withdrawing group. This renders yna-
mides more stable, usually even toward aqueous workup
and chromatography on silica gel.
LUMO
enone
O–
O
O
NR2R3
NR2R3
A second important factor for the recent popularity of
ynamides is the relatively new discovery of their simple
and inexpensive preparation by copper-catalyzed amida-
tion of alkynyl bromides.2a Recently, the range of starting
materials for ynamides has been extended to terminal
alkynes,2b geminal dibromides,2c alkynyl carboxylic
acids,2d and alkynyltrifluoroborates.2e
NR2R3
( )n
( )n
•
( )n
R1
HOMO
ynamine
R1
R1
Scheme 2 Proposed mechanism of the Ficini reaction
After 13 years of development, Hsung recently extended
the Ficini [2+2] cycloaddition to N-sulfonyl ynamides,
which were found to react with cyclohexenone in the pres-
ence of high catalyst loadings of CuCl2 (20 mol%) and
AgSbF6 (60 mol%) to the corresponding cyclobuten-
amides in 21–77% yield.6 The substitution pattern on the
ynamide is relatively general, as various combinations of
alkyl and sulfonyl substituents on the nitrogen moiety
were shown to be reactive. However, only cyclohexenone
was tested as the enone, and no diastereoselection was ob-
served when a chiral sultam group was attached to the
alkyne moiety of the ynamide (Scheme 3). This may be
due to the fact that the chiral information is relatively re-
mote from the reactive center.
The polarization of ynamides provides predictable regio-
selectivity, which was exploited by Jacqueline Ficini and
co-workers to perform their [2+2] cycloaddition on cyclic
unsaturated ketones (enones) or quinones (Scheme 1).3
The resulting highly strained bicyclic products are ther-
mally stable, as the energy required for the conrotatory
ring opening of the cyclobutene is not available under the
reaction conditions.4
SYNTHESIS 2012, 44, 513–526
x
x
.x
x
.2
0
1
2
Advanced online publication: 30.01.2012
DOI: 10.1055/s-0031-1289679; Art ID: Z114111SS
© Georg Thieme Verlag Stuttgart · New York

514
C. Schotes et al.
FEATURE ARTICLE
equiv) to form the elusive dicationic complex
[Ru(OEt2)(PNNP)](PF6)2 (2), which efficiently catalyzes
a number of asymmetric transformations of b-keto esters
such as electrophilic fluorination,8 hydroxylation,9 and
Michael addition,10 as well as Diels–Alder reactions with
their alkylidene analogues.11
O
O
O
S
CuCl2 (20 mol%)
AgSbF6 (60 mol%)
O
N
O
S
N
+
O
4Å MS, 0 °C
CH2Cl2
67%
dr = 1:1
N
(PF6)2
Et2O
Et2O
N
Scheme 3 First Ficini reaction with N-sulfonyl ynamides
Ru
P
P
2
CO2t-Bu
NBnTs
O
O
NBnTs
Enantioselective Ficini Reaction
(10 mol%)
CO2t-Bu
+
CH2Cl2
Ynamides are much less reactive than ynamines, which
makes them more attractive for enantioselective cycload-
dition reactions, as the noncatalyzed reaction can be easily
suppressed. However, to the best of our knowledge, no
enantioselective [2+2] cycloaddition of ynamides has
been reported prior to our communication that describes
the use of a chiral Ru/PNNP-derived Lewis acid as cata-
lyst for Ficini reactions.5 Complex [RuCl2(PNNP)] (1)7 in
dichloromethane was activated by double chloride ab-
straction with triethyloxonium hexafluorophosphate (2
Ph
Ph
4c
3a
5c
Scheme 4 The first enantioselective Ficini reactions
In analogy to the protocol for the latter reaction class,11
unsaturated b-keto ester 3a and ynamide 4c (1.1 equiv)
were added to catalyst 2 (10 mol%), and the mixture was
stirred at room temperature overnight (Scheme 4). As
TLC analysis revealed that substrate 3a had been only
Biographical Sketches
Christoph Schotes was his Bachelor’s degree in Antonio Mezzetti and re-
born in Mönchengladbach chemistry (with distinction) ceived his Ph.D. in Septem-
(Germany) in 1982. He in 2006. He carried out his ber 2011. His Ph.D. thesis
studied chemistry at the Master study and Ph.D. the- has been nominated for the
Technical University of sis at the ETH Zurich under medal of the ETH Zurich.
Munich, where he obtained the supervision of Prof.
Raphael Bigler was born in obtained his Bachelor’s de- of Prof. Antonio Mezzetti.
Frauenfeld (Switzerland) in gree in Chemistry in 2010. He received the Willi-Studer
1988. He studied Chemistry He carried out his Master Award for Best Academic
at the ETH Zurich, where he thesis under the supervision Record in 2011.
Antonio Mezzetti was born Associate. After sabbatical ich in 1995, where he is now
in Trieste (Italy) in 1958, stays at the ETH Zurich Titulary Professor. His re-
where he completed his with Prof. Giambattista search interests span from
studies in chemistry. In Consiglio and the late Prof. coordination chemistry to
1986, he joined the Chemis- Luigi M. Venanzi, he joined homogeneous catalysis.
try Department of the Uni- the Laboratory of Inorganic
versity of Udine as Research Chemistry of the ETH Zur-
Synthesis 2012, 44, 513–526
© Thieme Stuttgart · New York

FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
515
partially converted, the mixture was heated to 55 °C and Table 1 show that the substituent at the b-position of the
stirred overnight once again, after which full conversion ynamide is pivotal for the outcome of the reaction. By and
of 3a was observed. The corresponding cycloaddition large, n-hexyl- and cyclohexyl-substituted ynamides give
product 5c was isolated by flash column chromatography high yields (entries 1, 2, and 8–10). High enantioselectiv-
on silica gel.
ity is achieved when R1 is a phenyl or cyclohexyl group
(entries 1–7). Thus, the donor character of the alkyl sub-
stituents is crucial for high chemical yields, whereas the
steric bulk of the cyclic residues is necessary in order to
obtain high enantioselectivity. Accordingly, the cyclohex-
yl-substituted ynamides 4a and 4b give the best combina-
tion of very high yields and enantioselectivities of up to
92% ee (entries 1 and 2). The crude Ficini product 5a
(90% ee) was obtained as a single enantiomer after recrys-
tallization from hexane (entry 1).
In the optimized reaction, the reaction mixture is heated to
55 °C directly after addition of ynamide 4c. TLC analysis
after 24 hours showed full conversion of the unsaturated
b-keto ester 3a, and the corresponding cyclobutenamide
5c was isolated in 72% yield. The enantioselectivity was
determined to be 90% ee by chiral HPLC analysis
(Table 1, entry 3).
Table 1 Ficini Reaction Resultsa
When the sterically even more bulky tert-butyl analogue
of ynamide 4a was used, no reaction occurred. Consider-
ing the highly crowded situation in the bicyclic products
5, this limit to the steric bulk tolerated by the system hard-
ly surprises. On the other hand, the Ru/PNNP system is
mild enough to tolerate functionalizable moieties (entries
11 and 12), which are intrinsically less stable than their
alkyl and aryl analogues.
NR2R3
O
O
CO2t-Bu
NR2R3
CO2t-Bu
2 (10 mol%)
+
CH2Cl2, 55 °C
sealed tube
R1
5a–k
R1
3a
4a–k
(1.1 equiv)
Entry ProductR1
R2
R3
Yield (%)ee (%)
1
2
3
5a
5b
5c
c-C6H11
c-C6H11
Ph
Bn
Me
Bn
Bn
Me
Me
Me
Bn
Me
Me
Me
Ts
Ts
Ts
Ts
Ts
Ms
97b
88
72
66
64
69
90b
92
90
92
87
83
61
78
70
78
70
76
As compared to the tert-butyl ester analogue 3a (Table 1),
the smaller ethyl ester 3b gives lower enantioselectivity
(53% ee with ynamide 4a, Scheme 5), which indicates
that a bulky ester group is pivotal, as observed in the
Diels–Alder reaction11 and in the previously reported trans-
formations with saturated b-keto esters.8–10 This general
trend is linked to the diastereoselectivity of substrate co-
ordination, which is only high for the tert-butyl substrates
and has been extensively investigated in a recent report.11c
4c 5c
Ph
5
6
5d
5e
5f
Ph
Ph
7
Ph
Mbs 75
N
(PF6)2
8
5f
n-C6H13
n-C6H13
n-C6H13
CH2OBn
Ts
99
94
Et2O
Et2O
N
Ru
9
5h
5i
Ms
P
P
O
CO2Et
O
NBnTs
10
11
12
Mbs 99
Mbs 60
2
NBnTs
(10 mol%)
CO2Et
+
5j
CH2Cl2, 55 °C
sealed tube
c-C6H11
c-C6H11
5k
(CH2)2OTBDMS Bn
Ts
86
5l
3b
4a
97%, 53% ee
a Reaction conditions: see experimental section; Mbs = 4-methoxy-
phenylsulfonyl.
(1.1 equiv)
b 75% yield, >99.5 ee after a single recrystallization (hexane).
c At r.t., 5 d.
Scheme 5 Ficini reaction with the smaller ethyl derivative 3b
Preliminary tests with a six-membered-ring substrate,
such as ethyl 6-oxocyclohex-1-enecarboxylate (3c)
(Scheme 6), suggested behavior similar to that of its cy-
clopentenone analogue 3b. Thus, we expected an analo-
gous optimization potential for the six-membered-ring
tert-butyl ester substrate 3d as for 3a. However, TLC
analysis of the reaction solution shows that 3d decom-
poses to a large extent under the reaction conditions.
To study the effect of the temperature on the yield and
enantioselectivity, the reaction of 3a with 4c was run at
room temperature for five days for comparison. The enan-
tioselectivity slightly increased to 92%, but at the cost of
a lower yield (66%) even after the prolonged reaction time
of 5 days (entry 4), whereas the reaction at 55 °C gave
72% yield after 24 hours. Thus, a reaction temperature of
55 °C was used for all further reactions.5 An advantage of
this protocol is that nearly stoichiometric amounts of the
ynamides 4 (1.1 equiv) are sufficient to obtain high yields,
which is notable for a reaction that forms an all-carbon
stereocenter at the bridgehead position of a highly strained
unsaturated [3.2.0]bicycle. The results summarized in
Due to the limited stability of the alkylidene b-keto esters,
partial degradation of the substrate competes with the cat-
alytic cycloaddition reaction, which was not observed for
any other alkylidene b-keto esters. Thus, the reaction of
tert-butyl ester 3d with 4a gives low yield and only slight-
ly improved enantioselectivity as compared to the ethyl
© Thieme Stuttgart · New York
Synthesis 2012, 44, 513–526

516
C. Schotes et al.
FEATURE ARTICLE
analogue 3c (Scheme 6). Therefore, the cyclohexenone ing angle at the C(5) bridgehead position of 5a [C(4)–
substrates were not studied further.
C(5)–C(6): 118.9(1)°].
An interesting effect is observed at the nitrogen atoms in
the two molecules. The sum of the angles around N(1) in-
dicates that the geometry at nitrogen is less flattened in
Hsung’s compound [sum of angles = 354.8(2)°] than in
5a [sum of angles = 358.3(1)°]. We attribute this fact to
the electron-donating p-methoxy group in Hsung’s com-
pound, which reduces the electron-withdrawing effect of
the sulfonyl group. This leads to less delocalization of the
lone pair at the nitrogen atom into the sulfonyl group as
compared to the corresponding tosyl-substituted com-
pound 5a.
N
(PF6)2
Et2O
Et2O
N
Ru
P
O
P
2
O
CO2R
NBnTs
NBnTs
CO2R
+
(10 mol%)
CH2Cl2, 55 °C
sealed tube
c-C6H11
c-C6H11
4a
3c R = Et
3d R = t-Bu (1.1 equiv)
5m R = Et 84%, 57% ee
5n R = t-Bu 43%, 75% ee
Scheme 6 Ficini reaction with six-membered-ring derivatives 3c
and 3d
The assignment of the absolute configuration of 5a was
independently verified by reduction of the ketone function
with sodium borohydride, which attacks diastereoselec-
tively from the exo face, and esterification of the resulting
alcohol 6a with (–)-camphanic acid chloride (Scheme 7).5
An X-ray study of a crystal of the camphanic acid ester
6b, obtained by slow evaporation of a diethyl ether solu-
tion confirmed the (1R,5S)-configuration of 5a (Figure 2).
Thus, the ynamide attacks from the unshielded re face of
the metal-bound alkylidene b-keto ester, as proposed in
our stereochemical model.5,11c
Stereoselectivity and Structural Aspects
The proposed product structure was confirmed by an X-
ray study on a single crystal of enantiomerically pure tert-
butyl 7-[N-benzyl-4-methylphenylsulfonamido]-6-cyclo-
hexyl-2-oxobicyclo[3.2.0]hept-6-ene-1-carboxylate (5a)
(obtained by recrystallization from hexane) (Figure 1).
The value of the Flack parameter indicates the 1R,5S ab-
solute configuration.
4R
O
O
1S
O
O
t-BuO2C
t-BuO2C
O
2'S
BnTsN
BnTsN
1. NaBH4, MeOH
1R
5S
1'R
5'S
2. (–)-camphanic acid
chloride, pyridine
c-C6H11
c-C6H11
H
H
5a
6b
Scheme 7 Absolute configuration of Ficini product 5a
Figure 1 Structural comparison of compound 5a5 and Hsung’s
Ficini product6
A comparison to a similar compound reported by Hsung6
shows that the bond lengths and angles of the cyclobuten-
amide motif are basically identical, although compound
5a features a relatively bulky cyclohexyl group on the vi-
nylic C-atom, whereas Hsung’s compound only bears a
methyl group in this position. This is a clear sign of the ex-
traordinary rigidity of this highly strained bicyclic system.
The presence of a quaternary stereocenter at C(1) leads to
a
significantly contracted C(2)–C(1)–C(7) angle
[113.2(1)°] as compared to the corresponding angle in
Figure 2 X-ray crystal structure of camphanic acid derivative 6b5
Hsung’s Ficini product [115.1(2)°] and to the correspond-
Synthesis 2012, 44, 513–526
© Thieme Stuttgart · New York

FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
517
CO2t-Bu
NBnTs
Cyclobutenamides as Ligand Backbone
Toward Diene Ligands
CO2t-Bu
NBnTs
TBDMSO
O
LiHMDS, TBDMSCl
THF, –78 °C to r.t.
87%
c-C6H11
c-C6H11
H
7a
H
As compound 5a was obtained in enantiomerically pure
form, we envisioned its application as stereogenic back-
bone for chelating ligands in asymmetric catalysis. In the
course of this endeavor, we investigated the behavior of
the strained and diversely functionalized bicyclo-
[3.2.0]heptene skeleton in standard organic chemistry
transformations.
5a
CO2t-Bu
NBnTs
HO
LiHMDS, PhSeCl
THF, –78 °C to .r.t
58%
MeMgI
c-C6H11
THF, 0 °C to r.t.
H
7c
99%
O
O
CO2t-Bu
CO2t-Bu
A major advantage of using the Ficini products as a start-
ing point for chiral ligands is the large number of different
ligand classes accessible in only a few reaction steps rely-
ing on basic organic chemistry. Also, each ligand class
would be highly modular as virtually any position of the
bicyclo[3.2.0]heptene skeleton is modifiable either by the
original Ficini cycloaddition or by simple organic trans-
formations (Figure 3).
NBnTs
NBnTs
H2O2
PhSe
CH2Cl2/H2O
84%
c-C6H11
c-C6H11
H
7b
H
Scheme 8 Synthesis of diene compounds 7a–c
49% yield over two steps. The yield increased to 72% by
not purifying the phenylselanyl intermediate before the fi-
nal oxidation/elimination reaction. The 1,2-addition of
methylmagnesium iodide occurred stereoselectively onto
the exo face of 7b to give a single diastereomer of the al-
lylic alcohol 7c in excellent yield. The preference for exo-
attack is probably enhanced by the bulky substituents on
the sulfonamide that shield the endo face of 7b or by a di-
recting effect of the ester group.
We started off by preparing bicyclo[3.2.0]hepta-2,6-diene
skeletons where one of the C=C double bonds is part of
the enamide moiety generated in the [2+2]-Ficini cycload-
dition. Diene ligands are a relatively recent develop-
ment,12 but highly efficient systems have already been
reported, first and foremost by Hayashi13 and Carreira
(Figure 4).14
R1
O
Unfortunately, it was not possible to protect the tertiary al-
cohol 7c when using sodium hydride as a base and methyl
iodide as an electrophile, a fact that may be accounted for
by the steric congestion between the double bonds.15
However, unprotected alcohol groups are generally not
problematic in the coordination of dienes, as Rh(I) and
Ir(I) are not particularly oxophilic. This argument is sup-
ported by the findings of Hayashi and Rawal.16
NR3R4
modifiable by standard
organic chemistry
determined by the initial
Ficini [2+2] cycloaddition
R2
H
Figure 3 Modularity of Ficini products
OMe
OMe
R
Preliminary attempts to prepare rhodium(I) complexes
of dienes 7a–c failed. The olefin proton signals in the
1H NMR spectra of deuterochloroform solutions contain-
ing 7a–c and [Rh(m-Cl)(C2H4)2]2 (0.5 equiv) or
[Rh(acac)(C2H4)2] (1 equiv) remained unchanged over
two hours (see supporting information, Table S2). Chang-
ing the solvent to coordinating solvents like tetrahydrofu-
ran or acetonitrile did not accelerate ligand exchange at
the transition metal. Likewise, the only reaction observed
upon heating the reaction solution to 45 °C or 65 °C was
the decomposition of the metal precursors. As iridium(I)–
olefin complexes are generally more stable than their
rhodium(I) analogues, we studied the reaction of
[Ir(m-Cl)(coe)2]2 (coe = cyclooctene) with 7a and 7c. No
coordination was observed, though, irrespective of wheth-
er coordinating (Et2O, THF) or non-coordinating (CDCl3)
solvents were used.
Bn
Bn
R
Hayashi
Carreira
st generation
Carreira
nd generation
1
2
Figure 4 Important diene ligands in the literature
In the course of this project, several structurally different,
potential diene ligands were prepared (Scheme 8). The
deprotonation of 5a in the a-position of the ketone with
lithium hexamethyldisilazanide, followed by enolate trap-
ping with tert-butyldimethylsilyl chloride, gave access to
the silyl enol ether 7a in good yield. The enol ether unit
should render this diene rather electron rich. The enone 7b
was prepared because it has a low-lying p*-orbital and
should thus be a good acceptor for back-donation from the
transition metal.
There are several possible explanations for the reluctance
of ligands 7a–c to coordinate to d8 transition metals, such
as the pronounced distortion of the bicyclo[3.2.0]hepta-
2,6-diene skeleton, which leads to nonparallel double
bonds and might hinder efficient back donation from the
transition metal into the p*-orbitals. Further possible ex-
Diene 7b was obtained by phenylselanylation and sele-
noxide elimination with hydrogen peroxide as oxidant in
© Thieme Stuttgart · New York
Synthesis 2012, 44, 513–526

518
C. Schotes et al.
FEATURE ARTICLE
planations are the high degree of delocalization and asym- demand on phosphorus. For comparison, we prepared the
metry of the enamide HOMO (unfavorable both for sterically more demanding (S)-BINOL-derived phosphite
donation and back donation) or too sterically demanding 8b. If this compound proved to be a promising ligand, the
substituents on the enamide moiety.
investigations of matched and mismatched situations
would be possible by alternatively using (R)-BINOL in
the derivatization.
In order to exclude some of these possible reasons, the
phenylthio derivative 7d (Scheme 9) was prepared.17
Compound 7d should be structurally and electronically The starting point for these ligands was compound 6a, the
different from 7a, as there is only one substituent on the 2-hydroxy derivative of 5a, which is an intermediate in
double bond (decreased steric demand), and the sulfur the synthesis of the camphanic acid derivative 6b de-
atom should have a considerably reduced polarizing effect scribed in Scheme 7.23 Compound 6a was isolated in 94%
as compared to nitrogen. However, no coordination of 7d yield from enantiomerically pure 5a. Derivatization with
to [Rh(acac)(C2H4)2] was observed after three days in the phosphorochloridites derived from glycol, 2,2¢-bi-
CDCl3 at room temperature. This result suggests that the phenol, or (S)-BINOL gave the phosphite-alkene ligands
main reason for the low affinity of the dienes 7a–d toward 8a–c (Scheme 10).
Rh(I) and Ir(I) is not the bulkiness of the substituents or
the electronic properties of the dienes. Rather, this points
to the possibility that the bicyclo[3.2.0]hepta-2,6-diene
skeleton is not suitable for chelation, probably due to the
twisting of the double bonds or their spatial proximity,
which leads to a too small bite angle. However, further in-
The coordination chemistry of the phosphite-alkene
hybrid ligands 8a–c was studied with Rh(I)
([Rh(acac)(C2H4)2], [Rh(m-Cl)(C2H4)2]2) and Ir(I) ([Ir(m-
Cl)(coe)2]2) as metal precursors (see supporting informa-
tion, Table S3). Ligand 8a quickly decomposed to uniden-
tified species, most probably hydrolysis products, in the
vestigations are needed in order to verify this hypothesis.
presence of [Rh(acac)(C2H4)2] in deuterochloroform at
Unfortunately, several attempts to crystallize dienes 7a–d
room temperature, whereas 8b and 8c formed several
by layering a deuterochloroform solution of the respective
complexes in solution under the same conditions.
compound with pentane or hexane were unsuccessful.
SPh
O
O
TBDMSO CO2t-Bu
O
CO2t-Bu
SPh
SPh LiHMDS
Cl
P
CO2t-Bu
CuOTf•C6H6
TBDMSCl
O
THF
–78 °C to r.t.
41%
H
H
CH2Cl2, r.t.
87%
H
7d
3a
H
CO2t-Bu
NBnTs
HO
H
O
Et3N
CH2Cl2, r.t.
5o
P
CO2t-Bu
NBnTs
O
O
H
Scheme 9 Synthesis of vinylsulfane compound 7d
c-C6H11
H
6a
c-C6H11
Toward Phosphite-Alkene Ligands
H
8c
92%
In light of the difficulties encountered in the coordination
of diene ligands 7a–d, we were eager to investigate
whether the double bond of an enamide is generally suit-
able for coordination. Therefore, we envisioned the syn-
thesis of phosphite-alkene complexes that ensure
coordination to the transition metal through the phosphite
moiety and possibly promote the coordination of the
enamide double bond due to the chelate effect.
O
O
O
P
Cl
Et3N
CH2Cl2, r.t.
P
Cl
Et3N
O
CH2Cl2, r.t.
O
P
CO2t-Bu
O
O
NBnTs
H
O
P
CO2t-Bu
NBnTs
O
O
H
Since their tumultuous development in the early 1990s,
chiral phosphite ligands have found broad application in
catalytic reactions such as asymmetric hydrogenation, al-
lylic substitution, and hydroformylation. Thus, the dis-
covery of new binding patterns and chiral backbones for
this ligand class is an area of intense research.18 In addi-
tion to simple diphosphite ligands, P(OR)3 donors have
been incorporated into bidentate ligands.19 Hybrid ligands
featuring phosphine-,20 phosphinite-,21 and phosphora-
midite-alkene22 binding patterns have been reported less
frequently. Finally, to the best of our knowledge, hybrid
ligands based on a phosphite-alkene combination like 8a–
c are unprecedented. Therefore, we chose glycol-derived
8a and 2,2¢-biphenol-derived 8c as representative exam-
ples of aliphatic and aromatic phosphites with low steric
c-C6H11
H
8a
ca. 50%
c-C6H11
H
8b
27%
Scheme 10 Synthesis of phosphite-alkene compounds 8a–c
With 8a–c, it was not possible to determine unambiguous-
ly whether the species formed contain a bidentate ligand
or rather two P-coordinated ligands with pendant C=C
double bonds. However, 13C NMR spectrum of the reac-
tion solution containing 8c and [Ir(m-Cl)(coe)2]2 (0.5
equiv) showed no significant shift of the 13C resonances of
the vinylic carbon atoms, which indicates that the alkene
Synthesis 2012, 44, 513–526
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FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
519
unit does not coordinate. A further possibility that has to The crystal structure of 8d is informative as to the lacking
be considered when investigating compounds featuring a coordinating ability of these ligands (Figure 5).26 The
flexible biphenol (tropos) unit is that atropisomers are phosphite substituent on the cyclopentane ring adopts an
formed.24 The energy barrier for the rotation around the equatorial position and points away from the enamide
biphenol bond in such complexes is highly dependent on unit. Also, there is very little space for the transition metal
the substitution pattern of the tropos unit, bulkier residues in the endo face of 8d, which is detrimental to bidentate
usually resulting in higher barriers.25
coordination. However, the crystal structure shows that
the phosphite lone pair of 8d points in the direction of the
ester group, which prompted us to investigate whether a
chelate ring may be formed by the corresponding diphos-
phite ligands obtained by reduction of the ester group.
In order to investigate whether reducing the steric bulk at
the enamide moiety would promote its coordination, we
prepared the analogous ligand 8d, which bears a methyl
and
a mesyl substituent at the nitrogen center
(Scheme 11). These groups represent the smallest alkyl-
donor/sulfonyl-acceptor combination conceivable. How-
ever, the 13C NMR spectrum of the reaction solution of
[Rh(m-Cl)(C2H4)2]2 and 8d in deuterochloroform showed
no significant shift of the vinylic carbon signals, and thus
indicated that the double bond does not coordinate.
Diphosphite Ligands
The starting material for the synthesis of the cyclobutena-
mide diphosphite ligands was diol 9, which was obtained
in 69% yield by reduction of 5a with excess lithium alu-
minum hydride in diethyl ether (Scheme 12). The trans-
diol 9 is obtained together with substantial amounts of the
corresponding cis-aldehyde, which can be separated by
flash column chromatography. The reluctance of this
compound toward further reduction may be explained by
the formation of a stable hemiacetal intermediate, which
only releases the corresponding aldehyde after aqueous
workup.
O
NMeMs
CO2t-Bu
+
O
c-C6H11
P
O
O
CO2t-Bu
NMeMs
CH2Cl2, 55 °C
sealed tube
2 (10 mol%)
2
OH
NBnTs
CO2t-Bu
NBnTs
O
H
4
O
HO
H
2
HO
c-C6H11
NBnTs
O
LiAlH4
Et2O
CO2t-Bu
H
8d
NMeMs
+
3
96% over
2 steps
O
c-C6H11
c-C6H11
c-C6H11
H
H
9
69%
H
P
c-C6H11
O
5a
Cl
H
5p
83%
74% ee
O
O
H
NBnTs
Scheme 11 Synthesis and structure of phosphite-alkene compound
8d
stable intermediate
c-C6H11
H
Scheme 12 Reduction of Ficini product 5a to diol 9
This conclusion is supported by the fact that a second re-
duction step (after aqueous workup, without chromato-
graphic separation) with sodium borohydride gives 96%
yield of the diol compounds, albeit in a 8:1 trans/cis ratio.
Diphosphite ligands 10a and 10b were obtained by de-
rivatization with the corresponding phosphorochloridites
in 61% and 47% yield, respectively (Scheme 13).
The 31P NMR spectra of both ligands show distinct signals
for the two inequivalent phosphite groups.27 The 31P NMR
spectrum of the reaction solution of ligand 10a with
[Rh(nbd)2]BF4 (1 equiv) in deuterochloroform indicates
that the only product is a chelate complex (Figure 6).28 We
attribute the signal broadening to the interconversion of
the two tropos P donors,24 which show markedly different
dynamic behaviors, in agreement with their different
chemical environment.
Both ligands were tested in asymmetric rhodium-cata-
lyzed hydrogenation and in palladium-catalyzed allylic
alkylation reactions (Scheme 14), which have both been
Figure 5 X-ray crystal structure of phosphite-alkene ligand rac-8d;
the (1R,2S,5S)-enantiomer is shown
© Thieme Stuttgart · New York
Synthesis 2012, 44, 513–526

520
C. Schotes et al.
FEATURE ARTICLE
O
O
OH
10a or 10b (1 mol%)
HO
H
R
R
NBnTs
∗
OMe
OMe
[Rh(nbd)2]BF4 (1 mol%)
H2 (4.5 bar), CH2Cl2
R = CH2CO2Me 10a 5% ee
c-C6H11
t-Bu
H
9
10b 88%, 20% ee
10b 78%, 30% ee
t-Bu
O
R = NHAc
P
Cl
O
P
RO2C
Ph
CO2R
OAc
10a or 10b (3 mol%)
CO2R
CO2R
O
Cl
+
∗
O
Ph
Ph
[Pd(μ-Cl)(C3H5)]2
(1.5 mol%), KOAc
BSA, CH2Cl2
Ph
pyridine
toluene
120 °C, 47%
Et3N, CH2Cl2
r.t., 61%
t-Bu
t-Bu
R = Me 10a 6% ee
10b 99%, 52% ee
R = Bn 10b 99%, 57% ee
t-Bu
t-Bu
Scheme 14 Catalytic hydrogenation and allylic alkylation with di-
phosphite ligands 10a and 10b
t-Bu
t-Bu
O
O
P
O
t-Bu
O
t-Bu
O
O
P
O
P
O
NBnTs
O
The best results for each reaction class were obtained in
the hydrogenation of methyl 2-acetamidoacrylate (30%
ee) and the allylic alkylation of (E)-1,3-diphenylallyl ace-
tate with dibenzyl malonate (57% ee). Though the enan-
tioselectivity remains moderate at best, it is interesting to
see the dramatic effect of increasing the steric bulk at the
biphenol moiety, which possibly favors the formation of a
single atropisomer of the complex (see above), and hence
increases the enantioselectivity.
O
P
H
O
NBnTs
O
H
t-Bu
c-C6H11
H
10a
t-Bu
c-C6H11
H
10b
Scheme 13 Synthesis of diphosphite compounds 10a and 10b
Conclusion and Outlook
In view of the difficulties encountered by Hsung in the
non-enantioselective Ficini reaction, the high yields and
enantioselectivity obtained with the Ru/PNNP complex 2
are remarkable. Moreover, the coordination of the unsat-
urated b-keto ester to the chiral, oxophilic Ru/PNNP frag-
ment is a more efficient strategy for enantioselection than
introducing a chiral auxiliary at the ynamide nitrogen
atom,6,30 which is remote from the triple bond. Like the
earlier reported Diels–Alder reaction,11 the Ficini reaction
has a predictable stereochemistry due to the formation of
well-defined catalyst–substrate adducts.11c,31 Besides us-
ing ynamides, the reaction is a further, but still rare exam-
ple of the use of an unsaturated b-keto ester as substrate
for an enantioselective cycloaddition reaction.5,11
Figure 6 31P NMR spectrum of the reaction solution of 10a with
1
[Rh(nbd)2]BF4 in CDCl3 (122 MHz, d = 142.0 (dd, JRh,P = 264 Hz,
1
2
2JP,P = 72 Hz, w = 36 Hz), 137.6 (dd, JRh,P = 263 Hz, JP,P = 71 Hz,
w = 9 Hz)
reported with diphosphite complexes.18 In all reactions,
the catalyst was prepared in situ.
The dienes and phosphite-alkenes prepared in the course
of the exploration of the chemistry of the bicyclic prod-
ucts turned out to be unsuitable as ligands for Rh(I) and
Ir(I), as no coordination of the enamide double bond was
observed by NMR spectroscopy with these metals. A pos-
sibility to eventually achieve coordination of the double
bond might include the use of nosyl as a protecting group
on the nitrogen to replace the very stable tosyl group.
Since the nosyl group is easily cleavable, deprotection
would give an enamine, which should be a better ligand
than an enamide. We deem that the coordination of such
ligands containing an electron-rich enamine might be pos-
sible. Also, the expansion of the five-membered ring
might enable coordination by changing the relative orien-
tation of the double bonds to each other (Figure 7, A).
Ligand 10a gave essentially racemic products both in the
hydrogenation of dimethyl itaconate and in the allylic
alkylation reaction of (E)-1,3-diphenylallyl acetate with
dimethyl malonate (Scheme 14). Therefore, the focus was
shifted to ligand 10b, which bears 3,3¢,5,5¢-tetra-tert-bu-
tylbiphenol substituents. The increase of steric bulk has
been shown to considerably improve the enantioselectivi-
ty of allylic alkylation reactions with furanoside-derived
ligands.29 Indeed, the reaction with ligand 10b increased
the enantioselectivity of the hydrogenation of dimethyl
itaconate from 5% to 20% ee, and that of the allylic alky-
lation of (E)-1,3-diphenylallyl acetate from 6% to 52% ee.
Synthesis 2012, 44, 513–526
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FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
521
was used for detection. Mass spectra were measured by the MS ser-
vice of the Laboratorium für Organische Chemie (ETH Zurich).
Enantiomeric excesses were determined by HPLC using Agilent
HPLC 1100 Series system or by chiral gas chromatography. Com-
plex [RuCl2(PNNP)] (1) [PNNP = (S,S)-N,N¢-bis[o-(diphenylphos-
phino)benzylidene]cyclohexane-1,2-diamine],7 alkylidene b-keto
esters 3,32 ynamides 4,2a Ficini products 5a–n,5 and compounds
6a,b5 that were used to determine the absolute configuration of 5a,
were prepared by published procedures.
The diphosphite ligands show some potential in asymmet-
ric catalysis, as ligand 10b achieved 57% ee in the asym-
metric allylic alkylation of (E)-1,3-diphenylallyl acetate.
Thus, further studies aimed at the optimization of the
ligand may prove fruitful. First and foremost, the rigidity
of the ligand backbone should be increased. Diol B might
be prepared by selective oxidation of the primary alcohol
group in 9 (Scheme 12) and stereoselective Grignard ad-
dition, whereas the diphenyl-substituted compound C
should easily be accessible by reacting the b-hydroxy es-
ter 6a with an excess of phenylmagnesium iodide. Both
modifications should restrict the possible conformations
as opposed to the primary alcohol group in 9.
N-(Cyclohexylethynyl)-N-methylmethanesulfonamide
Prepared according to
a
literature procedure.2a N-Methyl-
methanesulfonamide33 (390.0 mg, 3.6 mmol, 1 equiv) was added as
an emulsion in toluene (7.2 mL) to (bromoethynyl)cyclohexane
(735.3 mg, 3.9 mmol, 1.1 equiv). K2CO3 (987.7 mg, 7.1 mmol, 2
equiv), CuSO4·5 H2O (89.2 mg, 357.3 mmol, 0.1 equiv), and 1,10-
phenanthroline (128.8 mg, 714.6 mmol, 0.200 equiv) were added
and the soln was heated to 65 °C overnight. After the addition of
CHCl3, the soln was filtered and concentrated. The crude oil was
purified by flash column chromatography (silica gel, hexane–
EtOAc, 10:1); yield: 617.0 mg (2.9 mmol, 80%).
A further possible target molecule is the diphosphine
ligand D, which would probably form considerably more
rigid structures after coordination to transition metals, due
to the decreased ring size resulting from the elimination of
the oxygen spacers from the ligand. This compound may
be accessible by bistriflation of 9 with triflic acid anhy-
dride, followed by double SN2 substitution of the triflate
moieties with diphenylphosphine.
1H NMR (400 MHz, 300 K, CDCl3): d = 3.03 (s, 3 H, SO2CH3), 2.92
(s, 3 H, NCH3), 2.44–2.32 (m, 1 H, C≡CCH), 1.76–1.62 (m, 2 H),
1.62–1.52 (m, 2 H), 1.45–1.27 (m, 3 H), 1.27–1.19 (m, 3 H).
13C NMR (101 MHz, 300 K, CDCl3): d = 74.6 (NC≡C), 72.6
(NC≡C), 39.1 (SO2CH3), 35.3 (NCH3), 32.6, 28.4, 25.6, 24.5.
H
R
OH
O
CO2t-Bu
NBnTs
HO
H
NBnTs
tert-Butyl 2-Oxo-7-(phenylthio)bicyclo[3.2.0]hept-6-ene-1-car-
boxylate (5o)
Compound 5o was prepared according to a literature procedure.5
tert-Butyl 5-oxocyclopent-1-enecarboxylate (3a, 100.0 mg, 549
mmol, 1 equiv) in CH2Cl2 (5.5 mL) and CuOTf·0.5 C6H6 (1.3 mg,
5.5 mmol, 0.01 equiv) were added to ethynyl(phenyl)sulfane34
(103.1 mg, 768 mmol, 1.4 equiv). The solvent was evaporated after
stirring for 10 h at r.t. and the crude product was purified by flash
column chromatography (silica gel, hexane–EtOAc, 10:1), to obtain
5o as a colorless oil; yield: 151.5 mg (479 mmol, 87%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.51–7.46 (m, 2 H,
SCCHarom), 7.39–7.28 (m, 3 H, Harom), 5.79 (s, 1 H, Holef), 3.60 (d,
J = 6.9 Hz, 1 H), 2.96 (ddd, J = 18.2, 12.0, 9.1 Hz, 1 H), 2.33 (dd,
J = 18.2, 8.3 Hz, 1 H), 2.14–2.00 (m, 1 H), 1.94 (dd, J = 13.4, 9.1
Hz, 1 H), 1.47 [s, 9 H, OC(CH3)3].
c-C6H11
c-C6H11
H
H
A
C
B
Ph
Ph
OH
PPh2
H
HO
H
Ph2P
NBnTs
NBnTs
c-C6H11
c-C6H11
H
H
D
Figure 7 Potential developments of the ligand system
In summary, as shown by the application as a ligand back-
bone for late-transition-metal chemistry, the Ficini prod- Enantioselective Ficini Reaction; General Procedure
[RuCl2(PNNP)] (1) (10 mg, 0.012 mmol, 0.1 equiv) and (Et3O)PF6
ucts 5 may prove to be interesting synthons in view of
(6 mg, 0.024 mmol, 0.20 equiv) were stirred in CH2Cl2 (1 mL) in a
their high degree of modularity and functionalization pos-
Young Schlenk tube at r.t. overnight. A color change from red to
brown indicated the formation of the catalytically active complex.
sibilities.
The respective unsaturated b-keto ester 3a–d (0.12 mmol, 21.9 mg,
1 equiv) was added as a solution in CH2Cl2 (1 mL). After 10 min,
the ynamide 4a–k (0.13 mmol, 1.1 equiv) was added. The Young
Schlenk was closed and the mixture was heated to 55 °C. After 24
h, the solvent was evaporated under reduced pressure, and the oily
residue was subject to flash chromatography on silica gel. See the
literature5 for compound characterization data.
Unless otherwise stated, all reactions were performed under an ar-
gon atmosphere using Schlenk techniques. Et3N and pyridine were
dried with CaH2 and distilled under an argon atmosphere. PCl3 was
distilled under argon and used directly. All solvents were of puriss.
p.a. quality and were distilled under argon atmosphere with stan-
dard drying agents (CH2Cl2, MeCN, MeOH, toluene: CaH2; Et2O,
THF, toluene: Na/benzophenone; pentane: Na/benzophenone/dig-
lyme; hexane: Na/benzophenone/tetraglyme). All solvents were
freshly distilled prior to use. NMR spectra were measured on the
following instruments (frequencies in MHz): Bruker Avance DPX
250 (1H, 250.1; 13C{1H}, 62.5; 31P{1H}, 101.3), DPX 300 (1H,
300.1; 13C{1H}, 75.5; 31P{1H}, 121.5), DPX 400 (1H, 400.1;
13C{1H}, 100.6; 31P{1H}, 162.0), and DPX 700 (1H, 700.1; 13C{1H},
176.0; 31P{1H}, 283.5). The internal standard is the residual 1H peak
of the deuterated solvent used (1H NMR: CDCl3 d = 7.26; 13C NMR:
CDCl3 d = 77.16). TLC was performed on Merck Silica Gel 60 F254
TLC plates; UV-light (366 or 254 nm), KMnO4, or anisaldehyde
tert-Butyl 6-Cyclohexyl-7-(N-methylmethylsulfonamido)-2-
oxobicyclo[3.2.0]hept-6-ene-1-carboxylate (5p)
Compound 5p was prepared according to the general procedure on
a 1.14 mmol scale of 3a. Yield: 379 mg, 953.4 mmol (83%); 74% ee
[HPLC (Chiralcel AD-H hexane–i-PrOH, 80:20, flow rate 0.5 mL/
min, l = 230.4 nm): tR = 9.4 (minor), 10.7 min (major)].
1H NMR (400 MHz , 300 K, CDCl3): d = 3.31–3.27 (m, 1 H, CO-
CHH), 3.07 (s, 3 H, SO2CH3), 3.05–2.97 (m, 1 H, COCHH), 2.93
(s, 3 H, NCH3), 2.42–2.32 (m, 1 H), 2.28–2.20 (m, 1 H), 2.03–1.95
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Synthesis 2012, 44, 513–526

522
C. Schotes et al.
FEATURE ARTICLE
(m, 2 H), 1.94–1.82 (m, 2 H), 1.77–1.69 (m, 2 H), 1.68–1.61 (m, 1
H), 1.43 [s, 9 H, OC(CH3)3], 1.40–1.10 (m, 5 H).
13C NMR (101 MHz, 300 K, CDCl3): d = 210.8 (C=O), 167.8 (CO2t-
Bu), 155.5 (NC=C), 129.6 (NC=C), 82.1 [OC(CH3)3], 67.3 (CCO2t-
Bu), 45.4 (SO2CH3), 38.9, 37.5, 36.9, 35.1, 29.9, 28.1 [OC(CH3)3],
26.0, 25.9, 21.3.
Diene Ligands
tert-Butyl (1R,5S)-7-(N-Benzyl-4-methylphenylsulfonamido)-2-
[(tert-butyldimethylsilyl)oxy]-6-cyclohexylbicyclo[3.2.0]hepta-
2,6-diene-1-carboxylate (7a)
A 1.6 M BuLi in hexane soln (109 mL, 175 mmol, 1.6 equiv) was
added to a stirred soln of HMDS (41 mL, 197 mmol, 1.8 equiv) in
THF (3 mL) at 0 °C. After 30 min, the soln was cooled to –78 °C
and 5a (60.0 mg, 109.2 mmol, 1 equiv) was added. After 40 min,
TBDMSCl (24.7 mg, 164 mmol, 1.5 equiv) was added in THF (4
mL). After 30 min, the cooling bath was removed and the soln was
stirred for 30 min at r.t. The reaction was quenched by the addition
of Et2O and sat. NH4Cl. The soln was extracted with Et2O (3 ×). The
combined organic phases were dried (MgSO4), filtered, and concen-
trated. The crude product was purified by flash column chroma-
tography (silica gel, hexane–EtOAc, 5:1); yield: 63.0 mg (94.9
mmol, 87%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.70 (d, J = 8.4 Hz, 2 H,
SO2CCH), 7.31 (d, J = 8.4 Hz, 2 H, SO2CCHCH), 7.25–7.15 (m, 5
H, Harom), 4.65 (s, 2 H, PhCH2N), 4.53 (s, 1 H, Holef), 3.01 (d, J = 8.4
Hz, 1 H), 2.45–2.39 (m, 1 H), 2.38 (s, 3 H, ArCH3), 2.19–2.08 (m,
2 H), 1.65 (d, J = 10.2 Hz, 2 H), 1.60–1.50 (m, 2 H), 1.32 [s, 9 H,
OC(CH3)3], 1.28–0.92 (m, 6 H), 0.85 [s, 9 H, SiC(CH3)3], 0.19 (s, 3
H, SiCH3), 0.11 (s, 3 H, SiCH3).
HRMS (ESI): m/z [rac-M + NH4]+ calcd for C20H35N2O5S:
415.2261; found: 415.2244.
tert-Butyl (1R,2S,5S)-7-(N-Benzyl-4-methylphenylsulfonami-
do)-6-cyclohexyl-2-hydroxybicyclo[3.2.0]hept-6-ene-1-carbox-
ylate (6a)
Compound 5a (60.0 mg, 109 mmol, 1 equiv) in CH2Cl2 (0.4 mL)
was added to a stirred soln of NaBH4 (5.8 mg, 153 mmol, 1.4 equiv)
in MeOH (0.6 mL) at 0 °C. After 30 min, the reaction was quenched
by addition of H2O, brine, and CH2Cl2. The soln was extracted with
CH2Cl2 (3 ×). The combined organic phases were washed with sat.
NaHCO3, H2O, and brine. Each of the aqueous solns was extracted
once with CH2Cl2. The combined organic phases were dried
(MgSO4), filtered, and concentrated. The crude oil was purified by
flash column chromatography (silica gel, hexane–EtOAc, 10:1) to
give a clear oil; yield: 56.5 mg (102 mmol, 94%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.84 (d, J = 8.2 Hz, 2 H,
SO2CCH), 7.35 (d, J = 8.2 Hz, 2 H, SO2CCHCH), 7.30–7.18 (m, 5
H, Harom), 4.57 (d, J = 15.7 Hz, 1 H, PhCHHN), 4.52 (d, J = 15.7 Hz,
1 H, PhCHHN), 4.41–4.31 (m, 1 H, CHOH), 3.37 (d, J = 8.1 Hz, 1
H, bridgehead), 2.80 (d, J = 6.4 Hz, 1 H, CHOH), 2.41 (s, 3 H,
ArCH3), 2.01–1.82 [m, 2 H, CH(OH)CH2], 1.61–1.46 (m, 6 H), 1.43
[s, 9 H, OC(CH3)3], 1.24 (d, J = 11.4 Hz, 1 H), 1.14 (d, J = 11.4 Hz,
1 H), 1.07–0.77 (m, 5 H).
HRMS (ESI): m/z [M + Na]+ calcd for C38H53NNaO5SSi: 686.3311;
found: 686.3306.
tert-Butyl (1R,5S)-7-(N-Benzyl-4-methylphenylsulfonamido)-6-
cyclohexyl-2-oxobicyclo[3.2.0]hepta-3,6-diene-1-carboxylate
(7b)
A 1.6 M BuLi in hexane soln (239 mL, 382 mmol, 1.4 equiv) was
added to a stirred soln of HMDS (85 mL, 409 mmol, 1.5 equiv) in
THF (2.4 mL) at 0 °C. After 30 min, the soln was cooled to –78 °C
and 5a (150.0 mg, 272.9 mmol, 1 equiv) was added in THF (0.65
mL). After 30 min, PhSeCl (78.4 mg, 409 mmol, 1.5 equiv) was add-
ed. After 1 h, the cooling bath was removed and the soln was stirred
for 30 min at r.t. The reaction was quenched by the addition of Et2O
and sat. NH4Cl. The soln was extracted with Et2O (3 ×). The com-
bined organic phases were dried (MgSO4), filtered, and concentrat-
ed. The crude oil was purified by flash column chromatography
(silica gel, hexane–EtOAc, 10:1) to give tert-butyl (1R,5S)-7-(N-
benzyl-4-methylphenylsulfonamido)-6-cyclohexyl-2-oxo-3-(phe-
nylselanyl)bicyclo[3.2.0]hept-6-ene-1-carboxylate as an off-white
solid that decomposes at –20 °C under air within days; yield: 111.6
mg (158.3 mmol, 58%).
1H NMR (250 MHz, 300 K, CDCl3): d = 7.81 (d, J = 8.1 Hz, 2 H,
SO2CCH), 7.52–7.44 (m, 2 H, SeCCHarom), 7.38–7.14 (m, 10 H,
Harom), 4.59 (d, J = 15.0 Hz, 1 H, PhCHHN), 4.44 (d, J = 15.0 Hz, 1
H, PhCHHN), 4.31 (dd, J = 12.8, 8.3 Hz, 1 H, COCH), 3.17 (d, J =
7.1 Hz, 1 H, bridgehead), 2.43 (s, 3 H, ArCH3), 2.34–2.23 (m, 1 H),
2.05–1.88 (m, 2 H), 1.67–1.57 (m, 2 H), 1.40 [s, 9 H, OC(CH3)3],
1.30–0.77 (m, 8 H).
13C NMR (101 MHz, 300 K, CDCl3): d = 172.7 (CO2t-Bu), 153.3
(NC=C), 143.9 (NC=C), 136.9 (2 C), 129.7, 128.7, 128.3, 128.1,
127.6, 125.1, 81.0 [OC(CH3)3], 73.7 (CHOH), 64.8 (CCO2t-Bu),
52.6 (PhCH2N), 46.7 [CH(OH)CH2], 37.8, 30.6, 30.3, 28.1
[OC(CH3)3], 25.9, 25.8, 22.8, 21.6.
N-Benzyl-N-[(1S,4S,5S)-7-cyclohexyl-4-hydroxy-5-(hydroxy-
methyl)bicyclo[3.2.0]hept-6-en-6-yl]-4-methylbenzenesulfon-
amide (9)
Compound 5a (240.0 mg, 437 mmol, 1 equiv) in Et2O (20 mL) was
added to a soln of LiAlH4 (99.4 mg, 2.6 mmol, 6 equiv) in Et2O (20
mL) at 0 °C. The cooling bath was removed after 30 min and the
mixture was stirred for 2 h at r.t. The reaction was quenched by the
addition of H2O (4 mL), 10% KOH (4 mL), and H2O (8 mL) and fil-
tered through a pad of Celite with EtOAc. The solvent was evapo-
rated and the crude product was purified by flash column
chromatography (silica gel, hexane–EtOAc, 3:2) yielding a white
solid. A single diastereomer was observed by NMR. A mixture of
aldehydes was isolated as a separate fraction by flash column chro-
matography; yield: 145.0 mg (301 mmol, 69%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.81 (d, J = 7.8 Hz, 2 H,
SO2CCH), 7.37–7.22 (m, 7 H, Harom), 4.75 (d, J = 14.9 Hz, 1 H, Ph-
CHHN), 4.63 (d, J = 14.9 Hz, 1 H, PhCHHN), 3.84–3.74 (m, 1 H,
CHOH), 3.73–3.63 (m, 2 H, CH2OH), 3.16 (br s, 1 H, OH), 2.79 (br
s, 1 H, OH), 2.43 (s, 3 H, ArCH3), 2.40 (d, J = 7.2 Hz, 1 H, bridge-
head), 1.90–1.80 (m, 2 H, CHOHCH2), 1.58–1.38 (m, 5 H), 1.34–
1.22 (m, 2 H), 1.07–0.67 (m, 6 H).
A 30% aq H2O2 soln (146 mL, 1.4 mmol, 10 equiv) was added to a
soln of the selenide compound (100.0 mg, 141.9 mmol, 1 equiv) in
CH2Cl2 (1 mL) and stirred for 3 h. The soln was extracted with
CH2Cl2 (3 ×) The combined organic phases were dried (MgSO4),
filtered, and concentrated. The crude product was purified by flash
column chromatography (silica gel, hexane–EtOAc, 10:1) to give a
white solid; yield: 65.0 mg (119 mmol, 84%). A total yield of 72%
was obtained when tert-butyl (1R,5S)-7-(N-benzyl-4-methyl-
phenylsulfonamido)-6-cyclohexyl-2-oxo-3-(phenylselanyl)bicyclo-
[3.2.0]hepta-6-ene-1carboxylate was used directly and not purified
by flash column chromatography.
13C NMR (101 MHz, 300 K, CDCl3): d = 156.5 (NC=C), 144.0
(NC=C), 137.2, 136.9, 129.8, 129.0, 128.5, 128.0, 128.0, 127.8,
75.1 (CHOH), 66.2 (CH2OH), 62.5 (CCH2OH), 53.4 (PhCH2N),
42.0 [CH(OH)CH2], 38.0, 30.8, 30.4, 26.1, 23.9, 22.3, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C28H36NO4S: 417.2418;
found: 417.2415.
1H NMR (400 MHz, 300 K, CDCl3): d = 7.81 (d, J = 8.3 Hz, 2 H,
SO2CCH), 7.49 (dd, J = 5.8, 2.6 Hz, 1 H, COCHCH), 7.31–7.17 (m,
7 H, Harom), 5.89 (d, J = 5.8 Hz, 1 H, COCH), 4.70 (d, J = 15.7 Hz,
Synthesis 2012, 44, 513–526
© Thieme Stuttgart · New York

FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
523
1 H, PhCHHN), 4.62 (d, J = 15.7 Hz, 1 H, PhCHHN), 3.73 (d, J =
tert-Butyl (1R,2S,5S)-7-(N-Benzyl-4-methylphenylsulfonami-
2.6 Hz, 1 H, bridgehead), 2.43 (s, 3 H, ArCH3), 2.30–2.20 (m, 1 H,
do)-6-cyclohexyl-2-[(dinaphtho[2,1-d:1¢,2¢-f][1,3,2]dioxaphos-
phepin-4-yl)oxy]bicyclo[3.2.0]hept-6-ene-1-carboxylate (8b)
Et3N (23 mL, 163 mmol, 3 equiv) and 4-chlorodinaphtho[2,1-d:1¢,2¢-
f][1,3,2]dioxaphosphepine35 (35.8 mg, 80%, 82 mmol, 1.5 equiv) in
CH2Cl2 (0.6 mL) were added to a stirred soln of 6a (30.0 mg, 54
mmol, 1 equiv) in CH2Cl2 (0.8 mL). The solvent was evaporated af-
ter 84 h and the crude product was purified by flash column chro-
matography (silica gel, hexane–EtOAc, 10:1) to give a white solid;
yield: 12.6 mg (14.6 mmol, 27%).
Hallyl), 1.71–1.60 (m, 3 H), 1.54–1.45 (m, 1 H), 1.39 (s, 9 H,
OC(CH3)3], 1.34–0.98 (m, 5 H), 0.92–0.78 (m, 1 H).
tert-Butyl (1R,2S,5S)-7-(N-Benzyl-4-methylphenylsulfonami-
do)-6-cyclohexyl-2-hydroxy-2-methylbicyclo[3.2.0]hepta-3,6-
diene-1-carboxylate (7c)
A 3 M MeMgI in Et2O soln (33 mL, 98 mmol, 1.05 equiv) was added
to a stirred soln of 7b (51.1 mg, 93 mmol, 1 equiv) in THF (2 mL) at
0 °C. After 15 min, the cooling bath was removed and the mixture
was stirred for 1 h at r.t. The reaction was quenched by the addition
of H2O and brine. The soln was extracted with Et2O (4 ×). The com-
bined organic phases were dried (MgSO4), filtered, and concentrat-
ed. The crude oil was purified by flash column chromatography
(silica gel, hexane–EtOAc, 15:1) to give a white solid; yield: 52.5
mg (93.1 mmol, >99%).
1H NMR (400 MHz, 300 K, CDCl3): d = 8.11 (d, J = 8.0 Hz, 2 H,
SO2CCH), 7.39–7.23 (m, 7 H, Harom), 5.79 [dd, J = 5.7, 2.4 Hz, 1 H,
CMe(OH)CHCH], 5.46 [d, J = 5.7 Hz, 1 H, CMe(OH)CHCH], 4.35
(d, J = 14.9 Hz, 1 H, PhCHHN), 4.27 (d, J = 14.9 Hz, 1 H, Ph-
CHHN), 3.53 (d, J = 2.4 Hz, 1 H, bridgehead), 2.43 (s, 3 H, ArCH3),
1.72–1.60 (m, 1 H), 1.58 [s, 9 H, OC(CH3)3], 1.56–1.50 (m, 2 H),
1.26 [s, 3 H, C(CH3)OH], 1.15–0.70 (m, 7 H), 0.61–0.51 (m, 1 H).
1H NMR (400 MHz, 300 K, CDCl3): d = 8.02 (d, J = 8.9 Hz, 1 H,
Harom), 7.95 (d, J = 8.4 Hz, 1 H, Harom), 7.89 (d, J = 8.7 Hz, 1 H,
Harom), 7.81 (d, J = 8.1 Hz, 1 H, Harom), 7.62–7.54 (m, 3 H, Harom),
7.50–7.16 (m, 7 H, Harom), 7.05–6.98 (m, 1 H, Harom), 6.96–6.89 (m,
4 H, Harom), 6.84 (d, J = 7.4 Hz, 2 H, Harom), 4.95–4.86 [m, 1 H,
CHOP(OR)2], 4.29 (d, J = 15.8 Hz, 1 H, PhCHHN), 4.21 (d, J = 15.8
Hz, 1 H, PhCHHN), 2.93 (d, J = 6.3 Hz, 1 H, bridgehead), 2.19 (s,
3 H, ArCH3), 2.11–1.99 [m, 2 H, Hallyl + CHOP(OR)2CHH], 1.98–
1.85 [m, 1 H, CHOP(OR)2CHH], 1.70–1.46 (m, 6 H), 1.42 [s, 9 H,
OC(CH3)3], 1.35–0.72 (m, 6 H).
31P NMR (162 MHz, 300 K, CDCl3): d = 155.2.
tert-Butyl (1R,2S,5S)-7-(N-Benzyl-4-methylphenylsulfonami-
do)-6-cyclohexyl-2-[(dibenzo[d,f][1,3,2]dioxaphosphepin-6-
yl)oxy]bicyclo[3.2.0]hept-6-ene-1-carboxylate (8c)
Et3N (92 mL, 680 mmol, 7.5 equiv) and 6-chlorodiben-
zo[d,f][1,3,2]dioxaphosphepine36 (102.2 mg, 408 mmol, 4.5 equiv)
were added to a stirred soln of 6a (50.0 mg, 91 mmol, 1 equiv) in
CH2Cl2 (2.4 mL). The solvent was evaporated after 2 h and the
crude product was purified by flash column chromatography (silica
gel, hexane–EtOAc–Et3N, 18:1:1) to give a white solid; yield: 63.8
mg (83.3 mmol, 92%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.75, (d, J = 8.0 Hz, 2 H,
SO2CCH), 7.59–7.44 (m, 2 H, Harom), 7.41–7.34 (m, 2 H, Harom),
7.32–7.20 (m, 4 H, Harom), 7.16–7.07 (m, 7 H, Harom), 4.94–4.85 [m,
1 H, CHOP(OR)2], 4.41 (d, J = 16.2 Hz, 1 H, PhCHHN), 4.37 (d,
J = 16.2 Hz, 1 H, PhCHHN), 2.89 (d, J = 6.2 Hz, 1 H, bridgehead),
2.33 (s, 3 H, ArCH3), 2.18–2.04 (m, 1 H, Hallyl), 1.94–1.85 (m, 1 H),
1.84–1.72 (m, 1 H), 1.70–1.63 (m, 1 H), 1.62–1.43 (m, 4 H), 1.41
[s, 9 H, OC(CH3)3], 1.35–0.75 (m, 7 H).
tert-Butyl 2-[(tert-Butyldimethylsilyl)oxy]-7-(phenylthio)bi-
cyclo[3.2.0]hepta-2,6-diene-1-carboxylate (7d)
A 1.6 M BuLi in hexane soln (168 mL, 269 mmol, 1.7 equiv) was
added to a stirred soln of HMDS (63 mL, 300 mmol, 1.9 equiv) in
THF (3 mL) at 0 °C. After 30 min, the soln was cooled to –78 °C
and 5o (50.0 mg, 158.0 mmol, 1 equiv) was added. After 45 min,
TBDMSCl (35.7 mg, 237 mmol, 1.5 equiv) was added. After 45
min, the cooling bath was removed and the soln was stirred for 1.5
h at r.t. The reaction was quenched by the addition of Et2O and sat.
NH4Cl. The soln was extracted with Et2O (3 ×). The combined or-
ganic phases were dried (MgSO4), filtered, and concentrated. The
crude oil was purified by flash column chromatography (silica gel,
hexane–EtOAc, 15:1); yield: 28.2 mg (65.5 mmol, 41%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.54 (d, J = 7.5 Hz, 2 H,
SCCHarom), 7.40–7.23 (m, 3 H, Harom), 5.71 (s, 1 H, Holef), 4.58 (s, 1
H, Holef), 3.31 (d, J = 9.2 Hz, 1 H, bridgehead), 2.52 (dd, J = 15.9,
9.2 Hz, 1 H, Hallyl), 2.07 (d, J = 15.9 Hz, 1 H, Hallyl), 1.50 [s, 9 H,
OC(CH3)3], 0.96 [s, 9 H, SiC(CH3)3], 0.25 (s, 3 H, SiCH3), 0.22 (s,
3 H, SiCH3).
13C NMR (101 MHz, 300 K, CDCl3): d = 171.4 (CO2t-Bu), 154.0
(NC=C), 149.7 (CO, arom), 149.6 (CO, arom), 142.9 (NC=C),
138.0–122.2 (22 C, arom), 81.6 [OC(CH3)3], 74.5 (d, J = 20 Hz,
CHOH),
64.6
(CCO2t-Bu),
51.6
(PhCH2N),
45.1
{CH[OP(OR)2]CH2}, 37.9, 30.3, 30.2, 28.1 [OC(CH3)3], 26.1, 26.0,
22.3, 21.6.
31P NMR (162 MHz, 300 K, CDCl3): d = 153.4.
Monophosphite Ligands
tert-Butyl (1R,2S,5S)-7-(N-Benzyl-4-methylphenylsulfon-
amido)-6-cyclohexyl-2-[(1,3,2-dioxaphospholan-2-yl)oxy]bi-
cyclo[3.2.0]hept-6-ene-1-carboxylate (8a)
Et3N (23 mL, 163 mmol, 3 equiv) and 79.1 mM 2-chloro-1,3,2-dioxa-
phospholane in CH2Cl2 (1.0 mL, 82 mmol, 1.5 equiv) were added to
a stirred soln of 6a (30.0 mg, 54.4 mmol, 1 equiv) in CH2Cl2 (0.8
mL). The solvent was evaporated after 2.5 h and the solid residue
was washed with Et2O (4 × 3 mL). The combined organic phases
were dried in vacuo yielding a white, air-sensitive solid. The purity
was determined by NMR to be about 85%. It was not possible to fur-
ther purify the product by recrystallization or flash column chroma-
tography; yield: 20.5 mg (ca. 27 mmol, ca. 50%).
tert-Butyl (1R,2S,5S)-6-Cyclohexyl-2-[(dibenzo[d,f][1,3,2]di-
oxaphosphepin-6-yl)oxy]-7-(N-methylmethylsulfonamido)bi-
cyclo[3.2.0]hept-6-ene-1-carboxylate (8d)
Compound 5p (210.0 mg, 528 mmol, 1 equiv) in CH2Cl2 (1.5 mL)
was added to a stirred soln of NaBH4 (28.0 mg, 740 mmol, 1.4 equiv)
in MeOH (4 mL) at 0 °C. After 1 h, the reaction was quenched by
addition of H2O, brine, and CH2Cl2. The soln was extracted with
CH2Cl2 (3 ×). The combined organic phases were dried (MgSO4),
filtered, and concentrated. The crude oil was purified by flash col-
umn chromatography (silica gel, hexane–EtOAc, 4:1) to give a clear
oil; yield: 211.0 mg (528 mmol, >99%).
1H NMR (400 MHz, 300 K, CDCl3): d = 4.40–4.32 (m, 1 H,
CHOH), 3.45 (s, 1 H, OH), 3.13 (s, 3 H, SO2CH3), 3.08 [m, 1 H,
CH(OH)CHH], 3.02 (s, 3 H, NCH3), 2.82 (d, J = 6.8 Hz, 1 H,
bridgehead), 2.49–2.38 (m, 1 H, Hallyl), 2.09–1.53 (m, 7 H), 1.46 [s,
9 H, OC(CH3)3], 1.44–1.11 (m, 6 H).
1H NMR (250 MHz, 300 K, CDCl3): d = 7.70 (d, J = 8.3 Hz, 2 H,
SO2CCH), 7.32–7.13 (m, 7 H, Harom), 4.68–4.52 [m, 2 H,
CHOP(OR)2 + PhCHHN], 4.43 (d, J = 16.3 Hz, 1 H, PhCHHN),
4.26–4.13 [m,
2 H, P(OCH2CH2O)], 4.07–3.85 [m, 2 H,
P(OCH2CH2O)], 2.77 (d, J = 6.1 Hz, 1 H, bridgehead), 2.37 (s, 3 H,
ArCH3), 2.17–2.01 (m, 1 H, Hallyl), 1.67–1.40 (m, 4 H), 1.29 [s, 9 H,
OC(CH3)3], 1.24–0.70 (m, 10 H).
31P NMR (162 MHz, 300 K, CDCl3): d = 136.9.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 513–526

524
C. Schotes et al.
FEATURE ARTICLE
13C NMR (101 MHz, 300 K, CDCl3): d = 172.8 (CO2t-Bu), 146.1
(NC=C), 127.1 (NC=C), 81.1 [OC(CH3)3], 72.6 (CHOH), 63.9
(CCO2t-Bu), 47.1 (SO2CH3), 38.1, 37.5, 36.5, 31.0, 30.4, 28.1
[OC(CH3)3], 26.2, 25.9, 22.6.
yielding a white solid; yield: 156.0 mg (171 mmol, 61%). When a
mixture of diastereomers of N-benzyl-N-[(1S,5S)-7-cyclohexyl-4-
hydroxy-5-(hydroxymethyl)bicyclo[3.2.0]hept-6-en-6-yl]4-meth-
ylbenzenesulfonamide (4R/S)-9 was used as reagent, the product
was obtained as an inseparable mixture of diastereomeric diphos-
phites in similar yield.
1H NMR (400 MHz, 300 K, CDCl3): d = 7.54 (t, J = 6.7 Hz, 2 H,
Harom), 7.48 (t, J = 6.1 Hz, 2 H, Harom), 7.44–7.16 (m, 17 H, Harom),
7.13 (d, J = 7.9 Hz, 2 H, Harom), 6.89 (d, J = 7.9 Hz, 2 H, Harom),
4.72–4.63 [m, 1 H, CHOP(OR)2], 4.47 (d, J = 15.1 Hz, 1 H, Ph-
CHHN), 4.27 (d, J = 15.1 Hz, 1 H, PhCHHN), 3.80–3.68 [m, 2 H,
CH2OP(OR)2], 2.56 (d, J = 6.9 Hz, 1 H, bridgehead), 2.14 (s, 3 H,
ArCH3), 2.01–1.81 (m, 2 H), 1.72–1.62 (m, 1 H), 1.61–1.48 (m, 2
H), 1.48–1.37 (m, 1 H), 1.37–1.24 (m, 2 H), 1.22–1.09 (m, 2 H),
1.08–0.94 (m, 2 H), 0.93–0.75 (m, 2 H), 0.55–0.42 (m, 1 H).
Et3N (154 mL, 1.1 mmol,
9 equiv) and 6-chlorodiben-
zo[d,f][1,3,2]dioxaphosphepine35 (184.4 mg, 736 mmol, 6 equiv)
were added to a stirred soln of tert-butyl (1R,2S,5S)-6-cyclohexyl-
2-hydroxy-7-(N-methylmethylsulfonamido)bicyclo[3.2.0]hept-6-
ene-1-carboxylate (49.0 mg, 123 mmol, 1 equiv) in CH2Cl2 (3 mL).
The solvent was evaporated after 1.5 h and the crude product was
purified by flash column chromatography (silica gel, hexane–
EtOAc–Et3N, 28:5:2) to give a clear oil; yield: 72.4 mg (118 mmol,
96%).
1H NMR (400 MHz, 300 K, CDCl3): d = 7.48–7.39 (m, 2 H, Harom),
7.37–7.31 (m, 2 H, Harom), 7.30–7.21 (m, 2 H, Harom), 7.18 (d, J = 7.7
Hz, 1 H, Harom), 7.09 (d, J = 7.9 Hz, 1 H, Harom), 5.07–4.98 [m, 1 H,
CHOP(OR)2], 2.84 (d, J = 2.85, 1 H, bridgehead), 2.80 (s, 3 H,
SO2CH3), 2.64–2.54 (m, 1 H, Hallyl), 2.24 (s, 3 H, NCH3), 2.21–2.06
{m, 2 H, CH[OP(OR)2]CH2}, 1.85–1.75 (m, 2 H), 1.71–1.58 (m, 4
H), 1.53 [s, 9 H, OC(CH3)3], 1.42–1.14 (m, 6 H).
13C NMR (101 MHz, 300 K, CDCl3): d = 157.5 (NC=C), 151.2–
149.2 [4 C, CO (arom)], 142.8 (NC=C), 138.4–121.9 (32 C, arom),
72.3 [d, J = 16 Hz, 1 C, CHOP(OR)2], 65.2 [CH2OP(OR)2], 61.5
[CCH2OP(OR)2], 51.9 (PhCH2N), 43.1 [CH(OP(OR)2CH2], 37.5,
30.2, 30.1, 26.1, 25.9, 22.3, 21.4.
13C NMR (101 MHz, 300 K, CDCl3): d = 172.0 (CO2t-Bu), 149.6
(CO, arom), 149.1 (CO, arom), 148.6 (NC=C), 131.5, 131.1, 129.9,
129.3, 126.2 (NC=C), 125.8, 125.5, 125.2, 122.3, 122.2, 122.0, 81.5
[OC(CH3)3], 74.3 (d, J = 24 Hz, CHOH), 62.6 (CCO2t-Bu), 45.7
(SO2CH3), 37.7, 37.0, 34.1, 30.1, 30.0, 28.2 [OC(CH3)3], 26.3, 25.8,
22.4.
31P NMR (162 MHz, 300 K, CDCl3): d = 157.4.
HRMS (ESI): m/z [M – C12H8O3P + NH4]+ calcd for C20H37N2O5S:
31P NMR (162 MHz, 300 K, CDCl3): d = 150.1, 139.0.
HRMS (ESI): m/z [M + H]+ calcd for C52H50NO8P2S: 910.2727;
found: 910.2722.
N-Benzyl-N-[(1S,4S,5S)-7-cyclohexyl-4-[(2,4,8,10-tetra-tert-bu-
tyldibenzo[d,f][1,3,2]-dioxaphosphepin-6-yl)oxy]-5-{[(2,4,8,10-
tetra-tert-butyldibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)oxy]-
methyl}bicyclo[3.2.0]hept-6-en-6-yl]-4-methylbenzenesulfon-
amide (10b)
417.2418; found: 417.2415.
Pyridine (292 mL, 3.6 mmol, 13 equiv) and 2,4,8,10-tetra-tert-butyl-
6-chlorodibenzo[d,f][1,3,2]dioxaphosphepine37 (528.3 mg, 1.1
mmol, 4 equiv) were added to a stirred soln of a mixture of diaste-
reomers (4R/S)-9 (130.0 mg, 8:1 mixture of diastereomers, 278.0
mmol, 1 equiv) in toluene (8 mL) in a Schlenk tube fitted with a
Young valve and heated to 120 °C overnight. The solvent was evap-
orated and the crude product was purified by flash column chroma-
tography (silica gel, hexane–Et3N, 99:1) yielding a white solid.
Even though a mixture of diastereomers (4R/S)-9 was used as re-
agent, the product was obtained as a single diastereomer as deter-
mined by NMR; yield: 178.0 mg (131 mmol, 47%, 53% based on 9
used).
X-ray Structure of 8d
CCDC Deposition number: CCDC-856610.26 Although the starting
Ficini product 5p was enantiomerically enriched, recrystallization
of 8d (74% ee) from hot hexane gave colorless X-ray quality crys-
tals of the P21/c space group that contained racemic 8d. Crystal data
for C32H40NO7PS: prism (0.30 × 0.21 × 0.14 mm), monoclinic, P21/c,
cell dimensions (100 K) a = 10.5931(15), b = 20.825(3), c =
15.4905(15) Å, b =113.258(7)°, and V = 3 139(7) Å3 with Z = 4,
Dc = 1.298 Mg/m3, m = 0.202 mm–1 (MoKa, graphite monochromat-
ed), l = 0.71073 Å, F(000) = 1 304. The data were collected at 100
K on a Bruker AXS SMART APEX platform in the range 1.73–
28.53°. The structure was solved with SHELXTL using direct meth-
ods. Of the 31,460 measured reflections with index ranges –14 £ h
1H NMR (400 MHz, 300 K, CDCl3): d = 7.65 (d, J = 8.1 Hz, 2 H,
SO2CCH), 7.46–7.43 (m, 3 H, Harom), 7.38 (d, J = 2.4 Hz, 1 H,
Harom), 7.23–7.19 (m, 2 H, Harom), 7.15 (d, J = 8.1 Hz, 2 H,
£ 14, –27 £ k £ 27, –20 £ l £ 20, 7,940 independent reflections (Rint
=
0.0891) were used in the refinement (full-matrix least squares on
F2) with anisotropic displacement parameters for all non-H atoms.
Hydrogen atoms at calculated positions and refined with the riding
model and individual isotropic thermal parameters for each group.
Final residuals were R1 = 0.0389 [for 5,014 reflections with I >
2s(I)] and wR2 = 0.0811 (all data), GOF = 0.849. Max and min dif-
ference peaks were +0.37 and –0.43 eÅ–3, the largest and mean
D/s = –0.002 and 0.000. Selected bond lengths and angles are given
in Table S1 (see Supporting Information); the numbering scheme is
given in Figure 5 (ellipsoids at 30% probability).
SO2CCHCH), 7.08–7.04 (m, 3 H, Harom), 7.02–6.95 (m, 4 H, Harom),
4.78–4.70 [m, 1 H, CHOP(OR)2], 4.24–4.07 [m, 3 H, CH2OP(OR)2
+ PhCHHN], 3.69 (d, J = 15.5 Hz, 1 H, PhCHHN), 2.48 (d, J = 6.4
Hz, 1 H, bridgehead), 2.38 (s, 3 H, ArCH3), 1.91–1.73 (m, 2 H),
1.70–1.61 (m, 1 H), 1.58–1.11 [m, 75 H, 8 C(CH3)3 + 3 H], 1.10–
1.06 (m, 1 H), 0.98–0.71 (m, 6 H), 0.62–0.48 (m, 2 H).
13C NMR (101 MHz, 300 K, CDCl3): d = 157.8 (NC=C), 146.6–
145.7 [4 C, CO (arom)], 143.1 (NC=C), 140.4–123.8 (32 C, arom),
73.4 [d, J = 29 Hz, 1 C, CHOP(OR)2], 65.3 {d, J = 15 Hz, 1 C,
[CH2OP(OR)2]}, 61.7 [CCH2OP(OR)2], 50.4 (PhCH2N), 43.5
[CH(OP(OR)2CH2], 37.7, 35.7–34.6 [8 C, C(CH3)3], 32.2–31.1 [24
C, C(CH3)3], 30.3, 29.8, 26.3, 25.9, 22.3, 21.6.
Diphosphite Ligands
N-Benzyl-N-[(1S,4S,5S)-7-cyclohexyl-4-[(dibenzo[d,f][1,3,2]di-
oxaphosphepin-6-yl)oxy]-5-{[(dibenzo[d,f][1,3,2]dioxaphos-
phepin-6-yl)oxy]methyl}bicyclo[3.2.0]hept-6-en-6-yl]-4-
methylbenzenesulfonamide (10a)
31P NMR (162 MHz, 300 K, CDCl3): d = 159.2, 144.7.
HRMS (ESI): m/z [M + H]+ calcd for C84H114NO8P2S: 1358.7735;
found: 1358.7732.
Et3N (468 mL, 3.4 mmol, 12 equiv) and 6-chlorodiben-
zo[d,f][1,3,2]dioxaphosphepine36 (421.5 mg, 1.7 mmol, 6 equiv)
were added to a stirred soln of 9 in CH2Cl2 (6.5 mL). The solvent
was evaporated after 9 h and the crude product was purified by flash
column chromatography (silica gel, hexane–EtOAc–Et3N, 35:3:2)
Dimethyl 2-Methylsuccinate; Typical Procedure by Asymmet-
ric Hydrogenation of Dimethyl 2-Methylenesuccinate
Using ligand 10a: Bis(norbornadiene)rhodium(I) tetrafluoroborate
(1.2 mg, 3.2 mmol, 0.01 equiv) and 10a (2.9 mg, 3.2 mmol, 0.01
Synthesis 2012, 44, 513–526
© Thieme Stuttgart · New York

FEATURE ARTICLE
Ru/PNNP-Catalyzed Asymmetric Ficini Reactions in Ligand Design
525
equiv) were stirred in CH2Cl2 (0.8 mL) for 5 min. Dimethyl 2-meth-
ylenesuccinate (50.0 mg, 316 mmol, 1 equiv) was added and the soln
was transferred into an autoclave with CH2Cl2 (0.5 mL). After stir-
ring for 5.5 h at with H2 (4.5 bar), the pressure was released and the
crude mixture was filtered through a pad of Celite with Et2O.; yield:
not determined; 5% ee [HPLC (Chiralcel OD-H, hexane–i-PrOH,
98:2, flow rate 0.8 mL/min, l = 210.8 nm): tR = 9.9 (minor), 17.3
min (major)].
1H NMR (400 MHz, 300 K, CDCl3): d = 3.69 (s, 3 H, CO2CH3),
3.68 (s, 3 H, CO2CH3), 2.92 (dqd, J = 8.1, 7.2, 6.0 Hz, 1 H,
CHMeCO2Me), 2.74 (dd, J = 16.6, 8.1 Hz, 1 H, CHHCO2CH3), 2.41
(dd, J = 16.6, 6.0 Hz, 1 H, CHHCO2CH3), 1.22 (d, J = 7.2 Hz, 3 H,
CH3).
J = 12.4 Hz, 1 H, CO2CHHPh), 4.90 (d, J = 12.4 Hz, 1 H,
CO2CHHPh), 4.32 (dd, J = 10.9, 8.2 Hz, 1 H), 4.06 [d, J = 10.9 Hz,
1 H, CH(CO2Bn)2].
Coordination Studies
Coordination of Dienes; General Procedure
Diene ligand 7a–d (20.0 mg, 1 equiv) and metal precursor [Rh(m-
Cl)(C2H4)2]2, [Ir(m-Cl)(coe)2]2, or [Rh(acac)(C2H4)2] (1 equiv) were
dissolved in CDCl3, MeCN, THF, or Et2O (0.5 mL) and transferred
into a Young NMR tube under argon. For MeCN, THF and Et2O,
the 1H NMR spectra were measured after evaporating the solvent in
vacuo and dissolving the residue in CDCl3. The results are summa-
rized in Table S2 (see Supporting Information).
Using ligand 10b: yield: 44.8 mg (280 mmol, 88%); 20% ee (HPLC:
Coordination of Phosphite–Alkenes; General Procedure
conditions as above).
Phosphite-alkene ligands 8a–d (20.0 mg, 1 equiv) and metal precur-
sor [Rh(m-Cl)(C2H4)2]2, [Ir(m-Cl)(coe)2]2, or [Rh(acac)(C2H4)2] (1
equiv) were dissolved in CDCl3, MeCN, THF, or Et2O (0.5 mL) and
transferred into a Young NMR tube under argon. For experiments
under H2 atmosphere, 1 mL of solvent was used and H2 was bubbled
Methyl 2-(Acetylamino)propanoate by Asymmetric Hydro-
genation of Methyl Acetamidoacrylate
Following the typical procedure using methyl acetamidoacrylate
ligand 10b for 10 h with H2 4.7 (bar). The crude product was filtered
through a pad of silica gel with EtOAc; yield: 39.5 mg (272 mmol,
78%); 30% ee [GC (Supelco a-dex column, 30 m × 0.25 mm, 0.25
m film, isotherm at 110 °C): tR = 12.08 (major), 12.20 min (minor)].
through the soln until the solvent was reduced to ca. 0.5 mL. The 31
P
chemical shifts (162 MHz, 300 K) and coupling constants of the ob-
served complexes are summarized in Table S3 (see Supporting In-
formation).
1H NMR (400 MHz, 300 K, CDCl3): d = 6.22 (br s, 1 H, NH), 4.62–
4.52 [m, 1 H, CH(NHAc)(CO2CH3)], 3.72 (s, 3 H, CO2CH3), 1.99
[s, 3 H, NHC(=O)CH3], 1.37 (d, J = 7.2 Hz, 3 H, CH3).
Coordination of Diphosphites; General Procedure
Diphosphite ligand 10a or 10b (20.0 mg, 1 equiv) and metal precur-
sor [Rh(nbd)2]2 BF4 or [Rh(acac)(C2H4)2] (1 equiv) were dissolved
in CDCl3 (0.5 mL) and transferred into a Young NMR tube under
argon.
Dimethyl (E)-2-(1,3-Diphenylallyl)malonate; Typical Proce-
dure by Asymmetric Allylic Alkylation of Dimethyl Malonate
Using ligand 10a: [Pd(m-Cl)(allyl)]2 (1.1 mg, 3.0 mmol, 0.015
equiv) and 10a (5.5 mg, 6.0 mmol, 0.03 equiv) were stirred in
CH2Cl2 (0.4 mL) for 20 min. (E)-1,3-Diphenylallyl acetate38 (50.4
mg, 200 mmol, 1 equiv) in CH2Cl2 (0.6 mL), dimethyl malonate (68
mL, 600 mmol, 3 equiv), BSA (147 mL, 600 mmol, 3 equiv), and
KOAc (1.0 mg, 10 mmol, 0.05 equiv) were added and the soln was
stirred for 12 h at r.t. The reaction was quenched by the addition
H2O and CH2Cl2. The soln was extracted with CH2Cl2 (4 ×). The
combined organic phases were dried (MgSO4), filtered, and concen-
trated. The crude oil was purified by flash column chromatography
(silica gel, hexane–EtOAc, 9:1) to give an off-white solid; yield: not
determined; 6% ee [HPLC (Chiralcel OD-H, hexane–i-PrOH, 99:1,
flow rate 0.4 mL/min, l = 280.2 nm): tR = 30.2 (minor), 32.5 min
(major)].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We thank Mr. Raphael Aardoom for the X-ray crystal structure de-
terminations.
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1H NMR (400 MHz, 300 K, CDCl3): d = 7.38–7.18 (m, 10 H, Harom),
6.50 (d, J = 15.7 Hz, 1 H, PhCH=CH), 6.35 (dd, J = 15.7, 8.5 Hz, 1
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Dibenzyl (E)-2-(1,3-Diphenylallyl)malonate by Asymmetric Al-
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Synthesis 2012, 44, 513–526
© Thieme Stuttgart · New York