Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives

Article abstract of DOI:10.1021/jacs.9b07885

Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis, and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereodefined 1,3-dienes, and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2 + 2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here, we disclose a broadly applicable enantioselective [2 + 2]-cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earth-abundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counterion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.

Full text of DOI:10.1021/jacs.9b07885

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Article
Catalytic Enantioselective Synthesis of
Cyclobutenes from Alkynes and Alkenyl Derivatives
Mahesh M. Parsutkar, Vinayak Vishnu Pagar, and T. V. RajanBabu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07885 • Publication Date (Web): 02 Sep 2019
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Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes
and Alkenyl Derivatives
Mahesh M. Parsutkar, Vinayak Vishnu Pagar and T. V. RajanBabu*
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Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OHIO 43210,
USA
Supporting Information
ABSTRACT: Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available pre-
cursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis and eventually manufac-
ture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural prod-
ucts and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such
as other cycloalkane derivatives, heterocyclic compounds, stereo-defined 1,3-dienes and ligands for catalytic asymmetric synthesis.
The simplest approach to make cyclobutenes is through an enantioselective [2+2]-cycloaddition between an alkyne and an alkenyl
derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of
very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here we disclose a broadly applicable
enantioselective [2+2]-cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of
organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earth-
abundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With
the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for syn-
thesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including
a key role of a cationic Co(I)-intermediate, ligand and counter ion effects on the reactions, can be expected to have broad implica-
tions in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.
INTRODUCTION
considerable room for improvement with respect to diversity
of functional groups on the ring and stereoselectivity associat-
ed with the ring formation. In this regard, a class of com-
pounds with enormous potential for diversification are the
chiral 3-substituted cyclobutenes (Figure 1, B), which allow
further modification of the small ring through a myriad of
ways involving the double bond,7 the G group,8 or through
activation of the ring C-H bonds.9 The simplest approach to
making cyclobutenes is through an enantioselective [2+2]-
cycloaddition between an alkyne and an alkenyl derivative, a
reaction with a long history, starting with mostly addition of
reactive alkynes to bicyclic10 or activated11 alkenes with the
notable exceptions of additions of activated alkynes to cyclo-
pentene (Hilt)12a and a variety of styreneyl alkenes to enynes
(Ogoshi),12b both giving racemic products. Thus, there are no
examples in the literature of a broadly applicable enantioselec-
tive version of this [2+2]-cycloaddition process. Reactions
that give acceptable enantioselectivities are limited to special-
ized substrates, most often strained alkenes or activated al-
kynes (example: Figure 1, C). 13 Here we disclose a broadly
applicable enantioselective [2+2]-cycloaddition between wide
spectrum of alkenyl derivatives and alkynes (Figure 1, D).
Recent incisive analyses of reactions1 and molecules2 of inter-
est to medicinal chemists have validated the notion that mo-
lecular complexity, measured by fraction of saturated carbons
(Fsp3) and the presence of chiral centers, correlate with suc-
cess as compounds move from discovery, through clinical
testing, to drugs. About a third of the compounds whose bio-
logical assays were analyzed had at least one chiral center.1
The improved clinical efficacy has been ascribed to solubility,
diminished promiscuity towards receptors, and occasionally,
to better transport properties across biological barriers. Practi-
cal considerations in the preparation and screening of large
and diverse array of structures, and, eventually manufacturing
of the successful candidates from readily available precursors,
provide strong justification for research into efficient and en-
antioselective synthetic methods.3 Functionalized cyclobu-
tanes and cyclobutenes are important structural motifs seen in
many bioactive natural products and pharmaceutically relevant
small molecules (Figure 1, A).4 They are also useful precur-
sors for other classes of organic compounds such as other cy-
cloalkane derivatives, heterocyclic compounds, stereo-defined
1,3-dienes and ligands for catalytic asymmetric synthesis.5
Even though direct synthesis of suitably functionalized cyclo-
butane precursors from readily available starting materials has
been the subject of a burgeoning area of research,6 there is
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A. Medicinally relevant compounds containing chiral cyclobutanes
of preparing these chiral 3-substituted cyclobutenyl derivatives
via enantioselective catalysis. However, the application of
reaction conditions described in Eq 1a led to complex mix-
tures with very little of the desired products (Eq 1b), prompt-
ing further investigations into a new strategy.
R
H
H2N
O
N
N
O
O
OMe
OMe
CO2Me
O
Me
Me
N
OMe
OMe
N
O
N
Me
CO2H
H2N
Me
O
HO
OH
ethylene (balloon)
(L)CoCl2 (0.05 equiv.)
R
Constrained
GABA analog
analgesic
Cyclomegistine
cytotoxic
(against luekemia cell)
(+)-Rumphellaone A
Lobucavir
R
*
(1a)
antiproliferative
antiviral
Et2AlCl (0.5 to 1 equiv.)
0 oC to rt, CH2Cl2
9
1
2
3
B. Chiral cyclobutenes as intermediates for other organic compounds
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• alkene functionalization
• modification of G (substitution, cross-coupling)
PPh2
PPh2
R1
R1
R2
L =
G
Fe
R
= n-C4H9, cyclohexyl
O
• reactions via π-allyl complexes
G
cycloaddition
• reactions at R1 or R2
*
+
Ph2P
R1
N
G
• conversion to stereodefined 1,3-dienes
• ring expansion reactions
• ozonolysis
dppf
R2
Ph
R1
conditions of Eq 1a
C. Cyclobutenes via enantioselective [2+2]-cycloaddition
*
G
(1b)
+
R
X
X
R
X
R2
G = CO2Me, TMS,
–CH2TMS, CH2OBn
1.6 mol% [(R)-SIPHOS]Ni(0)
R2
+
THF, 80 o
C
Ar
(X = N-Boc ee 35-93%)
4
5
6
Ar
X = O, N-Boc
A New Reaction and Optimization Studies. Following
many failed attempts to modify the reaction conditions de-
scribed in Eq 1a, we wondered if the incompatibility of the
Lewis bases in the substrates was the problem, and if so, could
it be addressed by activation of the reagents by a cationic
Co(I) species, an intermediate that was implicated in our re-
cent 1,2-hydroboration of prochiral 1,3-dienes.14 Initial scout-
ing experiments (Table 1) were conducted with a prototypical
alkyne, 4-octyne (4a) and two acrylates, methyl acrylate (5a)
and 1,1,1-trifluoroethylacrylate (5b). Concurrently, we also
studied the corresponding reaction between a more reactive
enyne and methyl acrylate (Table 2). The most pertinent re-
sults from these studies are summarized in the Tables 1 and 2.
• High ee’s limited to reactions of bicyclic [2.2.1]-alkenes and activated alkynes (ref 13a)
• [2+2]-Cycloadditions between enynes and activated alkenes give modest ee’s (ref 11e)
D. A general enantioselective synthesis of cyclobutenes (This work)
O
Si(OEt)3
R2
R1
94% ee
NHTs
R2
R1
SO2Ph
R2
R1
87% ee
SO2Me
96% ee
O
R2
R1
N
BPin
CO2Me
Me
G
+
R1
Cy
92% ee
97% ee
OMe
Details of initial optimization of the reaction conditions, from
which the results in Tables 1 and 2 are abbreviated, can be
found in the Supporting Information (See Tables S1-S7, pp.
S12-S20). These experiments include effects of the following
parameters on the efficiency and selectivity of the reactions:
(i) cobalt(II) halide (Br or Cl) complexes of 1,n-bis-
diphenylphosphinoalkanes of varying bite angles [Ph2P–
(CH2)n–PPh2, n = 1-5)], including chiral variants such as chi-
raphos, BDPP, BDPH, DIOP, and other chelates with different
backbone motifs such as dppf, biaryl, Josiphos ligands and
phosphino-oxazoline ligands [see Figure 2 for structures of the
ligands and Figure S1 (p. S12) in the Supporting Information,
which contains a complete list of all ligands]; (ii) zinc, man-
ganese, and, various 1,4-bis-trimethylsilyldihydropyrazines
R2
R1
TMS
Me
R2
R1
O
OH
95% ee
86% ee
Cy
95% ee
Figure 1. A. Cyclobutane and cyclobutene motifs occur in many
medicinally important small molecules and natural products. B.
Cyclobutenes are excellent precursors for cyclobutanes and other
useful intermediates. C. Current methods for their direct prepara-
tion via [2+2]-cycloaddition are applicable only to activated al-
kenes and/or activated alkynes. D. This work documents a practi-
cal, catalytic enantioselective (enantiomeric excess: 86-97%, ~50
examples) approach to the most diverse set of cyclobutenes re-
ported to-date.
14,15
as reducing agents; (iii) activators such as ZnX2, AgOTf,
AgSbF6,
InBr3,
sodium
tetrakis-[3,5-(bis-
trifluoromethyl)phenyl]borate (NaBARF); (iv) solvents, di-
chloromethane (DCM), 1,2-dichloroethane (DCE), toluene,
hexanes, THF, ether, ethyl acetate or acetonitrile; (v) reaction
temperature. In general, it was found that the reactions pro-
ceed best at or near room temperature in non-coordinating
solvents such as DCM, DCE or toluene, with NaBARF as the
most suitable activator. As expected, none of the solvents
containing heteroatoms were suitable for this reaction. For
enantioselective reactions, toluene was found to be a better
solvent (giving 5-10% higher enantioselectivities vis-à-vis
DCM) in several instances.
RESULTS AND DISCUSSION
For the enantiopure, substituted cyclobutenes (Figure 1, B) as
the targets, we recognized that none of the existing
methods11c.11e-g.13a including our own recently disclosed7a enan-
tioselective cobalt-catalyzed cycloaddition between an enyne
(1) and ethylene (Eq 1a) are suitable. The use of ethylene as
the 2p-component necessarily leaves two prochiral carbons of
the cyclobutene unfunctionalized. An attractive way to cir-
cumvent this problem would be to access precursor cyclo-
butenes (6) with the use of alkenyl derivatives (5) in place of
ethylene (Eq 1b). This further raises the intriguing possibility
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nPr
nPr
1
(L)CoBr2 (5 mol%)
NaBARF (10 mol%)
nPr
CO2Me
+
nPr
nPr
(L)CoBr2 (10 mol%)
NaBARF (20 mol%)
CO2R
2
CO2Me
Cy
CO2R
3
(2)
+
+
+
(3)
+
Zn (0.5 eq), CH2Cl2
23 oC, 12-24 h
4
Zn (1 eq), CH2Cl2
23 oC, 24-30 h
Cy
CO2Me
Cy
9a
nPr
Cy
8a
CO2R
7a,b
CO2Me
5a R = Me
4a
6a,b
5a
10a
11a
5b R = CH2CF3
Table 2. Optimization of Co-catalyzed enantioselective
[2+2]-cycloadditions between acrylate 5a and an enyne 8aa
Table 1. Optimization of Co-catalyzed enantioselective
[2+2]-cycloadditions between acrylates and an alkyne (4a) a
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entry ligandb
conv.
(%)
9a
10a
11a
ee
entry ligandb
conv. 6a
7a
ee
(%) c (%) c (%) c (9a)
(%)
55
(%)
(%)
(6)
Achiral Ligands
1
2
3
4
5
6
7
8
dppp
36
35
73
74
5
15
0
0
1
2
3
4
dppp
dppf
100
36
78
23
45
92
3
-
19
-
0
0
0
0
dppf c
(S)-BINAP
(S,S)-BDPP
L1
40
0
100
100
5
23
22
-
84
16
0
dPEPhos
L1
45
-
-
5a
100
4
-
Chiral Ligands
L2
L8 d
L9 e
55
25
87
92
6b
47
>95
>95
28
0
-
5
(S,S)-BDPP
97
80
80
40
0
3
13
10
2
52
56
64
0
95
90
91
6
(S,S)-BDPH 100
5
100
0
7
Josiphos 1
Josiphos 2
(S)-BINAP
L2
50
40
0
7b
42
0
8
0
0
9
(R)-BINAP
L8 d
L9 d
100
100
100
90
84
88
9
100
100
100
100
100
100
100
100
100
80
97
93
94
82
95
92
98
90
b
-
16
0
18
62
54
80
10
82
94
90
90
5b
10
11
10
11
12
13
14
15 d
2
0
L3
2
0
a See Eq 2 for a typical procedure. b For structures of ligands, see
Figure 2. c at 50 oC. d in toluene. e in toluene at 40 oC.
L4
4
0
ent-L7
L8
17
3
0
0
L8
4
0
16 d,e L8
<1
10
0
17 d
L9
0
a
See Eq 3 for typical procedure. See Figure 2 for structures of
ligands. c. Yield determined by internal standard method. d Tolu-
e
ene used as a solvent.
methyl acrylate.
Trifluoroethylacrylate used instead of
O
PPh2
PPh2
n
Fe
O
O
O
PPh2
PPh2
Ph2P
PPh2
PPh2
PPh2
Ph2P
PPh2
(S,S )-BDPP
O
PPh2
Ph2P
PPh2
PPh2
PPh2
Ph2P
n = 0 dppm
n = 1 dppe
n = 2 dppp
n = 3 dppb
n = 4 dpppent
dppf
DPEPhos
O
(S,S )-BDPH
(S)-BINAP
(S,S )-CHIRAPHOS
(S)-SEGPHOS
R
(S)
P
O
O
O
O
Ph
R
P
R
O
O
PPh2
PPh2
Fe
Ar2P
N
Cy2P
N
Ph2P
N
Ph2P
N
Cy2P
N
(R)
R
Me
R
Ph
Ph
L1
L2 Ar = Ph
L5 R = i-Pr
L8
Cy = cyclohexyl
L9
L3 3,5-(CH3)2-phenyl
L4 3,5-(CF3)2-phenyl
L6 R = CH2Ph
ent-L7 R = t-Bu
R = H Josiphos-1
R = CF3 Josiphos-2
(S,S)-DIOP
Figure 2. Partial list of ligands examined for cobalt-catalyzed [2+2]-cycloaddition between alkynes and alkenyl derivatives
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[2+2]-Cycloadditions between an alkyne (4a) and alkyl
selectivity. However, the phosphino-oxazoline (PHOX)
acrylates (5a and 5b) (Eq 2, Table 1). The results for the
[2+2]-cycloaddition reactions of a prototypical alkyne, 4-
octyne show that for the reaction with methyl acrylate,
among the 1,n-bis-diphenylphosphino-alkane [Ph2P-(CH2)n-
PPh2] ligands, only dppp (n = 3) gave moderate yield of the
expected cyclobutene 6a, the others producing significant
amounts of a diene byproduct 7a [Table 1, entry 1, see also:
Supporting Information Table S1 (p. S13) in for a more de-
tails]. The byproduct contamination was also a major prob-
lem with other commonly used chiral bis-phosphines includ-
ing (S)-BINAP (entry 3) and (S,S)-BDPP (entry 4).
ligands, including the achiral ligand L1, are excellent ligands
for this transformation giving almost exclusively the ex-
pected cyclobutene product 9a. Recall that L1 was surpris-
ingly ineffective in the cycloadditions of simple alkynes
(e.g., Table 1, entry 5). Changing the 4-aryl substituent on
the oxazoline moiety in the PHOX ligands to alkyl groups (e.
g., from Ph in L2 to t-Bu in L7, entries 10-13) led to poorer
ligands. In sharp contrast, tuning of the P-aryl substituents
led to significant improvements in enantioselectivites (the
ee’s improving from 62% to 80%, entries 10-12). The best
results were obtained when the P-aryl groups were replaced
by cyclohexyl groups as in L8, which resulted in the highest
yield (98%), regioselectivity (regioisomeric ratio, rr =
>95:5), and enantioselectivity (ee = 94%) for this substrate,
especially when the reaction was carried out in toluene as the
solvent (entries 15 and 16). For an ORTEP representing the
solid-state structure of the pre-catalyst, [(R)-L8]CoBr2, see
Figure 4 (A). The norephedrine-derived ligand L9, also
gave high enantioselectivity (ee = 90%), albeit with only
modest regioselectivity (9a:10a = 90:10, entry 17). With the
identification of a viable protocol for the reaction and the
availability of several useful ligands, the stage is now set for
a broader investigation of the scope of vinyl derivatives and
the alkynes.
9
10
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Phosphino-oxazoline Ligands. While these studies were in
progress, we were also examining the related [2+2]-
cycloaddition of the acrylate 5a with the enyne 8a (see: Eq 3,
Table 2), where it was found that the phosphino-oxazoline
ligands, including the easily synthesized achiral ligand L1
and chiral ligand L2 (Figure 2), were much superior in giv-
ing the cyclobutene product (9a) with very high chemo- and
regioselectivity. These observations, along with the highly
tunable nature of the phosphino-oxazoline ligands prompted
us to examine this ligand system for further detailed investi-
gations. Accordingly, several of phosphino-oxazoline lig-
ands (L1-L9) were prepared (Figure 2), and their cobalt (II)
complexes studied as catalysts for the cycloaddition reaction
at room temperature under conditions described in Eq 2. As
can been seen in entries 7 and 8 (Table 1), with the new Co-
complexes of these ligands, the [2+2]-cycloaddition between
4-octyne and methyl acrylate proceeded to give synthetically
useful yield in unprecedented levels of enantioselectivity for
the cyclobutene products. Most notably, replacing the P-
diarylphosphino group in L2 with a dicyclohexylphosphino
group (L8) produced a very active Co-catalyst that gave
exclusively the cyclobutene adduct 6a in an enantiomeric
excess (ee) of 90% in toluene, with none of the undesired
heterodimerization product 7a. With yet another modifica-
tion, viz., introduction of 4,5-disubstitution on the oxazoline
as in the ligand L9 [readily prepared from (1S,2R)-
norephedrine], further improvements in both the reactivity
and selectivity of the reaction were observed (entry 8). With
these new ligands and use of an activated trifluoroethyl acry-
late 5b, a quantitative reaction ensued with minimal loss in
selectivity (Table 1, entries 10 and 11). For the effects of a
more complete set of ligands, see Supporting Information,
Table S6 (p. S19).
[2+2]-Cycloaddition between a 1,3-enyne (8a) and methyl
acrylate (Eq 3, Table 2). The cycloadditions of 1,3-enynes
presented further challenges, the increased reactivity of the
enynes notwithstanding. In the initial investigations, we
found that 1- or 2-substituted alkenyl alkynes were the best
substrates for this reaction (vide infra). For example, one
such substrate, 8a, with a C1-methyl substituent (Eq 3, Table
2), gave varying amounts of codimerization product (11a)
along with regioisomeric mixtures, 9a and 10a, of the [2+2]-
cycloadducts. Most gratifyingly, these selectivity problems
could be readily solved by examination of ligand effects on
this reaction. See Supporting Information Tables S2-S5 (p.
S14-S18) for complete optimization of reaction conditions.
Initially, we found that cobalt-complexes of achiral (entries
1-3) and chiral (entries 5-9) bisphosphine ligands were gen-
erally unsatisfactory either because of low reactivity or low
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R1
[L*]CoBr2 (10 mol%)
Zn (1 equiv), NaBARF (20 mol%)
R1
R2
G
G
O
O
+
L* =
Ph
(4)
or
toluene (0.3M), rt, 15 - 30 h
Cy2P
N
Cy2P
N
R2
Ph
Me
7
4
5
6
L9
(rac) or (R)-L8
8
9
Alkene + Symmetric Alkynes
6a
6b
6c
6d
6e
6f
6g
6h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Si(OEt)3
nPr
SiMe3
nPr
Z =
R =
BPin
nPr
BPin
Ph
Me
CH2CF3
Et
t-Bu
R =
nPr
nPr
CO2R
R
R
Z
% yield (L9)
92
91
97
88
98
89
91
90
90
94
93
% yield (L9)
95
97
89
95
91
86
97
89
95
97
98
% ee
% ee
(6a-d)
(6e-h)
% yield (rac-L8) 95
% yield (rac-L8) 93
Unsymmetric Alkynes
Symmetric Alkynes
6i
6j a
6ka 6la
6m
6n
6o
6p a
R1
E
R1
R2
=
=
Ph
Ph
Et
Me
Me
Me
Ph
CO2Me
E
Ph
Ph
E
TMSO
TMSO
R2
E= CO2CH2CF3
Me
Bu
i-Pr
t-Bu
(6k-o)
Me
% yield (L9)
% ee
91
95
75
95
% yield (L9)
92
89
90
92
88
89 (rr = 62:38) 96 (rr = 87:13) 91 (rr = 100:0)
92 91
90 (rr = 51:49) 95 (rr = 75:26) 88 (rr = 98:2)
87
91
89
90
85
% ee
-
% yield (rac-L8)
% yield (rac-L8) 90
Alkenes + Functionalized Alkynes
6q
6r
6s
6t
6u
6v
OMe
O
Ph
N
BPin
O
O
Me
Si(OEt)3
Si(OEt)3
Me
Si(OEt)3
CH2TMS
Z =
MeO
Ms
BPin
Z
O
Me
C3H7
TBSO
% yield (L9)
92
86
88
94
89
81
97
84
86
95
86
t-Bu
% ee
Cy
% yield (rac-L8) 81%
86%
% yield (rac-L8) 87
Diverse Fuctional Groups in Alkynes
Me
F
OMe
F
F
MeO
Ph
E
2-Nap
E
E
E
E
Ph
E
Me
E
E = CO2CH2CF3
% yield (rac-L8)
Me
Me
Me
Me
i-Pr
3
Cl
(PHT)N
OMe
OH
3
6w
89 (rr = 92:8)
6x
6y
6z
92
6aa
6ab
6ac
84
40
93
88 (rr = 85:15)
81
Alkynyl thioether
Biaryl Alkyne
Heteroaryl Alkynes
Ynamide
nBu
BPin
Me(O)C
O
S
E
nBuS
nPr
Si(OEt)3
E
Ph
Si(OEt)3
BPin
E = CO2CH2CF3
% yield (rac-L8)
Ms
N
Cy
i-Pr
6ad
85 (rr = 87:13)
Me
Me
6ae
80 (rr = 82:18)
6af
89 (rr = 88:12)
6ag
74 (rr 77:23)
6ai
6ah
MeO
82 (rr = 1:1)
87
a Ligand L8 at 40 oC was used. For 6a, 6c, 6d, 6v to 6ae reaction performed at 40 oC. For 6e, 6f, 6g, 6m, and 6n reaction performed with 5 mol% catalyst loading.
Figure 3. Scope of [2+2]-Cycloaddition between Alkenyl Derivatives and Alkynes. The versatility of the reaction is illustrated by the
diverse functional group present in the two coupling partners. In unsymmetrical alkynes regioselectivities of the products (6) are >95:5
unless otherwise indicated. The structures shown are for the major regioisomers and the corresponding ee’s were determined by using
CSP-GC or CSP-HPLC. See the Supporting Information for further details. Yields shown are for isolated products.
53
54
55
56
57
58
59
60
Scope of [2+2]-Cycloadditions between Alkynes and
Alkenyl Derivatives. The optimized reaction conditions
with minor modifications (Figure 3, Eq 4) were employed in
the [2+2]-cycloaddition reactions of a wide variety of al-
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8
kynes and alkenyl derivatives. The enantioselective reac-
relatively low selectivity (62:38 and 87:13 for 6m and 6n),
tions were carried out using the ligand L9 unless otherwise
noted, and authentic racemic products were synthesized us-
ing the ligand rac-L8. In general, excellent yields and enan-
tioselectivities were observed for both sets of ligands for a
broad range of cyclobutenes carrying many common organic
functional groups, originating either from the alkyne or the
alkene. Details of the synthesis of each of the specific ad-
ducts can be found in the Supporting Information. For the
sake of brevity and clarity, the products are classified ac-
cording to the types of alkyne precursors (4), and, within
each type, by the alkenyl partners. The simplest alkynes are
the symmetric ones (R = n-Pr, Ph, CH2OTMS) leading to
products 6a-6j. The alkenyl derivatives include alkyl and
trifluoroethyl acrylates (6a-6d), vinyltriethoxysilane (6e),
vinyltrimethylsilane (6f), vinylboronic acid pinacolate (6g
and 6h), each giving excellent yields (86-97%) and ee’s (88-
97%). The trifluoroethyl acrylates were generally more re-
active and the reactions proceeded at a faster rate compared
to the alkyl acrylates. This permits lower temperatures for
the reactions, leading to improved yields but with little
change in selectivities. Among the acrylates t-butyl acrylate
gave the product 6d with the highest enantioselectivity
(94%) with 4-octyne. The hydroxymethyl-bearing product
6i,was formed in very good yield and excellent ee (95%).
Products derived from unsymmetrical alkynes bearing an
aryl group and an alkyl group are represented by 6k–6t. 1-
Phenylpropyne and 1-phenylbutyne gave high yields of the
[2+2]-adducts 6k, 6l and 6p upon reaction with the respec-
tive acrylates in excellent regioselectivity (rr >95:5) and
enantioselectivity (ee >89%), with the ester moiety placed
adjacent to the aromatic substituent. Ligand L8 was found
to be the most optimal for these aromatic substrates. The
regioselectivity in the products from unsymmetrical dialkyl
alkynes depends on the difference in the size of the two alkyl
groups. Methyl/butyl and methyl/i-propyl combination gave
even though the enantioselectivity reached >91% ee for the
major product in both cases. Significantly, the norephedrine-
derived ligand L9 gave better regioselectivity compared to
L8. t-Butylmethyl acetylene with a significant size differ-
ence between the groups underwent a highly regioselective
[2+2]-cycloaddition to give the product 6o.
Products 6q-6ai derived from functionalized, unsymmetrical
alkynes, including some carrying hetero-atoms (N, S) on the
alkynyl carbon (6s, 6ag, 6ah), demonstrate the vast func-
tional group compatibility of the reaction. The following
additional substituents on the alkynes are tolerated: carbonyl
group as in a ketone or ester (6q, 6r, 6t, 6u, 6v and 6ai),
electron-rich or electron-poor aryl and heteroaryl groups (6t,
6w, 6x, 6y, 6z, 6aa, 6ab, 6ac, 6ad, 6ae, 6af, 6ai), alkyl
sidechains with -OH (6y), -Cl (6z), or phthalimido- (6aa)
groups, cyclopropyl groups (6ab). In general, very good to
excellent yields of the isolated products were obtained for a
wide variety of alkenyl derivatives previously shown to work
with simpler symmetric alkyne substrates. The regioselec-
tivity observed was also high (>95:5) except for a few in-
stances (6m, 6ag, 6ai). Where ever we have carried out the
enantioselective reactions (6a-6t), the ee’s are very high (86-
97%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
B
Figure 4. A. Solid-state structure (ORTEP) of the pre-catalyst [(R)-L8]CoBr2 (Cambridge Crystallographic Data Centre CCDC #
1860755). B. Absolute configuration (S) established by X-ray crystallography of a 1,6-dibromo-2-naphthoate corresponding to cyclobu-
tene 9a (Cambridge Crystallographic Data Centre CCDC # 1921037). See Supporting Information for details.
Scope of [2+2]-Cycloadditions between 1,3-Enynes and
Alkenyl Derivatives. 1,3-Enynes as the alkyne components
in the [2+2]-cycloadditions increase the versatility and ap-
plicability of this chemistry by placing yet another function-
alizable carbon in the form of an alkenyl substituent on the
product cyclobutene (9, Eq 5, Figure 5). The (E)-1-propenyl
moiety was chosen as the optimal substituent on many of the
enynes in this study for three reasons: (a) the substrates bear-
ing this group can be easily synthesized in high yield by
cross-coupling chemistry; (b) the propenyl derivative can be
readily converted into a more versatile cyclobutenyl alde-
hyde by chemoselective ozonolysis (Figure 6, A); (c) 1,3-
enynes with no alkenyl substituents require three equivalents
of the alkenyl partner to promote efficient [2+2]-
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Journal of the American Chemical Society
cycloaddition (for example, to prepare 9ac or 9ad) and to
>90:10) and enantioselectivities (> 89% ee) were observed
for the corresponding substrates.
2
prevent a competitive co-dimerization of such enynes (ex-
ample, to give 13ad, Figure 6, B) to 1,6-dialkylvinylaromatic
compounds. See Supporting Information Table S7 for fur-
ther details.
3
4
5
6
7
8
9
The most general reaction conditions, applicable to the
broadest spectrum of substrates, is shown in Eq 5 (Figure 5),
and, the corresponding substrate scope is illustrated by the
accompanying structures. The electron-rich phosphino-
oxazoline ligand L8 appears to be the best ligand to obtain
the highest regio- and enantioselectivity under the previously
optimized conditions for this transformation. See also Table
2, and, a more elaborate Table S2 in the Supporting Infor-
mation (p. S14) for the effect of other ligands, and Table S3
(p. S16) for the effect of solvents. Solid state structure of the
most useful CoBr2-complex is shown in Figure 4 (A). The
authentic racemic products were synthesized using ligand
L1. The diverse structures of products in Figure 5 validate
the broad scope of this [2+2]-cycloaddition reaction with
respect to the enynes and the alkenyl derivatives. The abso-
lute configuration of the products is based on the X-ray crys-
tallographic structure of a 1,6-dibromo-2-naphthoate corre-
sponding to the methyl ester 9a (Figure 4, B). Configuration
of the other products are assumed by analogy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For convenience, the products from enynes are classified
into six somewhat arbitrary groups, five of them showing the
variations in the starting alkenyl components – alkyl acry-
lates (9a-9e), hetero-functionalized alkenes (9f-9i: starting
from trialkoxyvinylsilane, trialkylvinylsilane, vinylboronate
and vinylsulfone), allyl derivatives (9j-9n: from allyl ethers,
allyl amides, allyl pinacolboronates, allyl sulfones and allyl
trialkylsilanes), vinylarenes (9o-9s), and disubstituted al-
kenes such as dihydrofuran (9t), norbornene (9u) and trans-
anethole (9v). Another group of adducts (9w – 9ag) show
the variations possible in the enynes.
In most of the adducts derived from alkyl acrylates, the het-
ero-functionalized alkenes, and the allyl derivatives (9a-9n),
the major product carries the alkenyl substituent adjacent to
the 2-propenyl group of the enyne (>95:5 rr). The enantiose-
lectivities in these instances are also excellent (generally
>90% ee), except for the adducts from allyl N-tosylamide
(9k, 87%) and allyl phenyl sulfone (9m, 55%). Cycloaddi-
tions with allyl derivatives also revealed a remarkable ligand
effect. While the cycloaddition reactions carried out using
the PHOX ligands (L1 or L8) gave excellent yields of the
[2+2]-cycloaddition (9j-9n) with outstanding regioselectivi-
ty, the (dppp)CoBr2 complex gave adducts corresponding to
a formal ene reaction (Figure 6, C).12a See Supporting In-
formation for other substrates showing similar behavior
(Supporting Information Table S8, p. S21). Simple internal
alkynes give only ene-products with 1-alkenes irrespective
of the ligands.12c The vinylarenes (corresponding to the
products 9o-9s) are excellent alkenes for the cycloaddition,
even though the enantioselectivities seen are unacceptably
low, except for the benzofuranyl compound 9s (ee 86%).
Compatibility of functional groups in the cyclization of
enynes is similar to what was previously observed for simple
alkynes (Figure 3). Thus, cyclopropyl (9w), alkyl (9x – 9z),
chloroalkyl (9aa), phthalimido-alkyl (9ab) or trimethylsilyl-
vinyl (9af) groups presented no complications in the reac-
tion. In general, very good to excellent regioselectivities (rr
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2
3
4
5
6
7
8
R3
R3
R2
B.
A.
R2
(L)CoBr2 (5 mol%)
Zn (0.5 equiv)
G
O
G
O
L =
+
(5)
NaBARF (10 mol%)
Toluene (0.2 M), rt, 12-36 h
Cy2P
N
or
Ph2P
N
Ph
R1
R1
8
5
9
L1
(R)-L8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Functionalized Alkenes
9f 9g
Si(OEt)3 Si(Me)3
Alkyl Acrylates
9h b
9i
9a
9b
9c
9d
9e
CH2CF3
CH(CF3)2
SO2Ph
Me
Et t-Bu
Z =
BPin
R =
73 a
93
72
94
46 c
96
% yield (L8)
% ee
86
97
89
CO2R % yield (L8)
% ee
Z
94
94
96
98
90
99
96
94
97
97
97
98
97
92
99
% yield (L1)
88 (rr 91:9) 80 (rr 92:8) 69 c,d
% yield (L1)
Cy
Cy
Allyl Derivatives
Vinylarenes
9p
Me OMe
9k
9l b
9m
SO2Ph SiMe3
9n
9o
9r
9j
9q
Z
Z
OBn
NHTs
Br
2-Naphthyl
Z =
BPin
Z =
% yield (L8)
% ee
66 c
87
41
55
48
91 a
90
% yield (L8) 91
93
39
97
74
45
97
96
41
95
87
92
92
74
—
70
nd
nd
% ee
—
Cy
Cy
% yield (L1)
51
91
% yield (L1) 96
Cy
Enynes
di-Substituted Alkenes
Vinyl Benzofuran
OMe
OMe
E
E
E
E
O
E = CO2Me
O
tBu
n-Bu
Cy
Cy
Cy
Cy
Me
9s
9t
9u
95
9v
9w
9x
9y
91
9z
93 f
65 d
48
<10
—
% yield (L8)
% ee
92
95
94
96
90
% yield (L8)
% ee
% yield (L1)
nd
nd
—
93
93
95
72
96
86
75 e
98
82 (rr 90:10)
% yield (L1)
86 (rr 89:11)
88
Enynes
E
TMS
E
E
E
E
CO2CH2CF3
E
E = CO2Me
Cl
Ph
Cy
n-Bu
Et
3
3
(Pth)N
9ag
9ac
9aa
9ab
9ad
9ae
9af
90
94
88
88
94
67
92
47
94
90
89
94
92
94
91
85
93
% yield (L8)
% ee
% yield (L1)
90 (rr 90:10)
65 (rr 91:9) g 52 (rr 92:8) g
74 (rr 65:35)
a Ligand L9 was used. b identified as the alcohol (yields over two steps). c 10 mol% of catalyst was used.d DPPP was used as ligand. e (S,S)-BDPP was used.
f Ligand L2 was used. g 3 eq methyl acrylate was used, major byproduct: 1-vinyl-2,6-dicyclohexylbenzene (from homodimerization of enyne). nd not determined.
Figure 5. Scope of [2+2]-Cycloaddition between Enynes and Alkenyl Derivatives. A. Typical reaction conditions. Broad scope of the
reaction is illustrated by diverse functional groups tolerated in the two coupling partners. Regioisomeric ratio of product 9 was >95:5 un-
less otherwise indicated. The structures shown are for the major regioisomers and the corresponding ee’s were determined by using CSP-
GC or CSP-HPLC. See the Supporting Information for further details. B. Most useful ligands for the [2+2]-additions of 1,3-enynes and
alkenyl derivatives.
As alluded to earlier, 1,3-enynes lacking substituents on the
Csp2-carbons (R2 or R3) gave only modest yields (e.g., 67%
for 9ac; 47% for 9ad), even though the observed enantiose-
lectivity was very high (92% ee and 94% ee respectively). A
competing homodimerization of these enynes to give 1-
vinyl-2,6-dialkylbenzenes (Figure 6, B) can be avoided by
using excess of the alkenyl derivative (up to 3 equivalents in
the case of 9ac and 9ad). As illustrated by the high yields
and selectivities observed for examples 9ae, 9af, and 9ag
(under near stoichiometric ratios of the starting materials),
substitution at the internal Csp2 carbon of the enynes also
promotes facile [2+2]-cycloaddition without any complica-
tion from the homodimerization of the enyne.
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1
B. Effect of MA concentration on homodimerization of enyne
A. Chemoselective ozonolyis
2
3
4
5
6
7
8
9
O
(L)CoBr2 (5 mol%)
NaBARF (10 mol%)
CO2Me
+
CO2Me
CO2Me
O3, DCM, -78 o
(~ 30 sec.)
C
CO2Me
H9C4
C4H9
+
Zn (0.5 eq), CH2Cl2, rt
C4H9
C4H9
Cy
9a (94% ee)
Cy
12a (74%, 92% ee)
(MA)
9ad
13ad
L
MA (equiv.) 9ad (%) 13ad (%)
L1
L1
2
3
60
40
38
56
10
11
12
13
14
15
16
C. Remarkable ligand effect. Ene reaction vs cycloaddition
D. Gram-scale reaction; Diastereoselective Hydrogenation
Y
Ph
Ph
Ph
Ph
(L)CoBr2 (5 mol%)
NaBARF (10 mol%)
Y
Cy
5 mol% Pd/C,
2 (balloon)
H
or
+
O
O
Zn (0.5 eq), CH2Cl2, rt
B
B
EtOH, 12h
Cy
O
O
Cy
Y
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14, from dppp)
9 (from L1)
Ligand (L, yield %)
6h
15h
Y
dppp
L1
1.7 g, 92% yield,
97% ee, (from 1g scale)
96% yield, dr > 98:2
ee >95%
OBn
SO2Ph
86 (14j)
92 (9j)
66 (14m)
48 (9m)
Figure 6. A. A propenyl substituent in an enyne (thus in the cycloadduct 9a) is useful as an aldehyde surrogate. B. This group also pre-
vents homodimerization of the enyne to a vinyl aromatic (13ad). C. Allyl derivatives give [2+2]-cycloadducts with ligand L1, but an ene-
products with dppp. D. A gram-scale reaction and a diastereoselective transformation of a cyclobutene.
Role of Cationic Cobalt (I) in the [2+2]-Cycloaddition
Reaction and a Possible Mechanism of the Reaction. In
the initial studies we have recognized a prominent role for a
cationic cobalt (I) species in these reactions. Control exper-
iments (Eq 6 and the accompanying Table 3) confirm that no
reaction ensues in the presence of isolated Co(I) complex
(dppp)3Co2Cl214 or a Co(I) complex formed by in situ reduc-
tion of LCoBr2 (L = dppp or L1) using Zn as a reducing
agent (See Supporting Information Table S5 for further de-
tails) in the absence of NaBARF (entry 4 and 9 versus 1 and
2). A possible unified mechanism that accounts for all prod-
ucts formed and the various experimental observations is
shown in Figure 7. The presence of NaBARF, which pre-
sumably generates a cationic Co(I) species (15), under these
reaction conditions is essential for the success of the reac-
tion. Oxidative dimerization of the alkyne and the alkenyl
reactant gives the metallacycle 17, which could undergo
reductive elimination to give the cyclic product 6 or 9. Al-
ternately, b-hydride elimination followed by reductive elim-
ination could give either 7 or 14 depending upon the sub-
strate. Allylic derivatives with an exo-cyclic CH2 group (17,
G = CH2Y) gives the formal ene-product via 19. That coor-
dinating solvents such as THF, acetonitrile and even ethyl
acetate are not suitable for the reaction also supports the
intermediacy of the cationic Co(I) species 15 as a viable
catalyst. Thus, this cycloaddition reaction joins a growing
list of other alkene functionalization reactions such as diene-
acrylate dimerization16 and HBPin-mediated hydroboration14
and hydrogenation17 of prochiral alkenes where cationic
Co(I) have been invoked as intermediates.
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6
catalyst (5 mol%),
activator (10 mol%),
reducing agent (0.5 eq),
CO2Me
CO2Me
(6)
+
solvent (0.2M), rt, time (h)
Cy
8a
Cy
9a
Table 3. Role of cationic Co(I) in [2+2]-cycloaddition a
7
8
9
entry catalyst
(L1)CoBr2
activator reductant solvent. time (h)
9a (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PPh2 PPh2
dppp
1
NaBARF Zn
NaBARF Zn
NaBARF none
CH2Cl2 15
CH2Cl2
96
>80
0
2
(dppp)CoBr2
(L1)CoBr2
(L1)CoBr2
(L1)CoBr2
(L1)CoBr2
(dppp)CoBr2
6
3
CH2Cl2 24
CH2Cl2 24
O
4
none
Zn
0
Ph2P
L1
Cl
N
5
NaBARF Zn
NaBARF Zn
NaBARF Zn
THF
24
0
Cl
6
CH3CN 24
0
P
P
P
7 b
8 c
9
CH2Cl2
CH2Cl2
6
6
16
9
Co
Co
P
P
P
(dppp)3Co2Cl2 NaBARF none
(dppp)3Co2Cl2 none none
P = PPh2
[(dppp)3Co2Cl2]
CH2Cl2 24
0
a See Eq 6 for a typical procedure and SI for further details. Solvent and additive effects support a key role for cationic Co(I)-species in
b
[2+2]-cycloadditions. Additionally, 2.5 mol% dppp was used. Note that addition of extra ligand inhibits the reaction (Table entry 2 vs
c
7). 2.5 mol% catalyst loading (5 mol% in Co).
NaBARF
+
[(P~Z)Co(L)X]
[(P~Z)CoX2] + Zn
Co
Co =
P
Z
(I)
[(P~N)Co(L)]+
Z = P or N
15
R1
R2
R1
H
R1
G
R1
R2
H
G
+
Y
R2
G
R2
14
7
(III)
CoH
6 or 9
R1
R2
5
Reductive elimination
G
18
(III)
R1
R2
(III)
CoH
R1
R1
R2
G = CH2Y
(I)
Co
β-Hydride
Co
Y
elimination
G
Z = P
G
R2
19
17
16
β-Hydride elimination
Oxidative cyclization
Figure 7. A possible mechanism that accounts for the observed ligand, counter ion and solvent effects.
CONCLUSIONS
from readily available amino-alcohols and an earth-abundant
metal, cobalt. These enantioselective cycloaddition reactions
are easily scaled up to gram scale. With the diverse func-
tional groups present in the cyclobutenes, further diastere-
oselective transformations are easily envisaged for synthesis
of other useful intermediates including highly functionalized
cyclobutanes, cyclopentanes and stereo-defined 1,3-dienes. .
Experimental observations implicate a cationic cobalt(I)-
Cyclobutanes are important structural motifs in many biolog-
ically relevant compounds. We report a practical approach
to diverse array of nearly enantiopure cyclobutenes from
which these compounds can be easily accessed. Two of the
most abundant organic precursors, alkynes and alkenyl de-
rivatives are used in the key enantioselective [2+2]-
cycloaddition reaction, which employs catalysts derived
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Journal of the American Chemical Society
species in the mechanism of this reaction. Such species may
ACKNOWLEDGMENTS
2
3
4
have broader applications for other carbon-carbon and car-
bon-heteroatom bond-forming reactions.
We thank Dr. J. C. Gallucci and Dr. D. Ho for the determination
of the solid-state structures. Financial assistance for this re-
search provided by the US National Institutes of Health (R01
GM108762) and the US National Science Foundation (CHE-
1900141) is gratefully acknowledged.
5
6
EXPERIMENTAL SUMMARY
In an N2-filled glovebox, an 8-mL vial equipped with a sep-
tum screw cap was charged with a magnetic stirrer bar,
[LCoBr2] (0.01 mmol, 0.05 equiv), activated zinc-dust (0.1
mmol, 0.5 equiv), NaBARF (0.02 mmol, 0.1 equiv), and
toluene (0.20 - 0.25 M). The vial was capped and after stir-
ring the mixture for 5-10 minutes, the alkyne (0.20 mmol, 1
equiv) was added neat using microliter syringe via the sep-
tum, followed by the alkenyl derivative (0.22 – 0.30 mmol,
1.1-1.5 equiv). The resulting mixture was stirred at rt. The
progress of the reaction was monitored by taking an aliquot
using a glass pipette, diluting with ether and filtering through
a pad of silica before analyzing via GC-FID or TLC. Upon
completion of the reaction (4 h-24 h), the vial was taken out
of the box and quenched with ether (5 mL). The resulting
mixture was filtered over a short pad of silica eluting with
ether. Concentration on a rotary evaporator, and subsequent
purification by column chromatography eluting with hex-
ane/ethyl acetate (0 to 20%) afforded the products. Full ex-
perimental details, spectroscopic and analytical data includ-
ing chiral stationary phase chromatograms can be found in
the Supporting Information under each new compound.
7
8
9
REFERENCES
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11
12
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44
45
46
47
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50
51
52
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ASSOCIATED CONTENT
Supporting information
This Information is available free of charge via the Internet at
http://pubs.acs.org. Experimental procedures, syntheses and
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optimization studies. Spectroscopic and chromatographic data
showing compositions of products under various reaction condi-
tions (PDF).
Crystallographic Information for complex [(R)-L8]CoBr2 (CIF)
receptor
(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide
03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-
antagonists:
trans-N-ethyl-3-fluoro-3-[3-fluoro-4-
Crystallographic
Information
for
(S)-9-1,6-dibromo-2-
(PF-
naphthoate ester (CIF). Data have been deposited at the Cam-
bridge Crystallographic Data Centre under accession numbers
CCDC 1860755 and 1921037 respectively.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: rajanbabu.1@osu.edu
ORCID
T. V. RajanBabu: 0000-0001-8515-3740
M. M. Parsutkar: 0000-0001-6320-2345
V. Pagar: 0000-0002-6729-693X
Notes
The authors declare no competing financial interest.
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1
2
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TOC Abstract
4
5
6
7
Z
[L*]CoBr2 (5-10 mol%),
Z
G
G
O
NaBARF (10-20 mol%)
Ph
+
*
Cy2P
N
8
9
Zn (1 equiv), toluene, rt
R
R
or
Me
O
L* =
R = alkyl, aryl, N(Me)Ms
>50 examples
yield up to 99%
ee up to 97%
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Z = alkyl, alkenyl, aryl, C(O)R, SR
G = -CO2R, -SO2Ph or functional groups
linked to -B, -N, -O, -Si
Cy2P
N
Ph
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