Cu-catalyzed asymmetric allylic alkylation of phosphonates and phosphine oxides with grignard reagents

Article abstract of DOI:10.1002/chem.201204364

An efficient and highly enantioselective copper-catalyzed allylic alkylation of phosphonates and phosphine oxides with Grignard reagents and Taniaphos or phosphoramidites as chiral ligands is reported. Transformation of these products leads to a variety of new phosphorus-containing chiral intermediates. Copyright

Full text of DOI:10.1002/chem.201204364

DOI: 10.1002/chem.201204364
Cu-Catalyzed Asymmetric Allylic Alkylation of Phosphonates and
Phosphine Oxides with Grignard Reagents
Valentꢀn Hornillos, Manuel Pꢁrez, Martꢀn FaÇanꢂs-Mastral, and Ben L. Feringa*[a]
Abstract: An efficient and highly enantioselective copper-catalyzed allylic alkyla-
Keywords: alkylation · allylic com-
tion of phosphonates and phosphine oxides with Grignard reagents and Taniaphos
or phosphoramidites as chiral ligands is reported. Transformation of these products
leads to a variety of new phosphorus-containing chiral intermediates.
pounds
·
chirality
·
copper
·
Grignard reagents · phosphanes
Introduction
substituted a-b-unsaturated phosphonates[15] and through a
ACHTUNGTRENNUNG
Cu-catalyzed asymmetric conjugate reduction.[16]
Optically active organophosphorus compounds are frequent-
ly encountered in many areas of chemistry, in particular me-
dicinal chemistry[1] and asymmetric catalysis.[2] Within this
class of compounds, chiral phosphonic acid, phosphonate,
and phosphine oxide derivatives have attracted interest be-
cause of their interesting biological properties[3] and synthet-
ic versatility.[4] For example, phosphonates and phosphonic
acids can act as isosteres of carboxylic esters and acids,
which improves their activity or bioavailability; in addition,
they have also been used as nonhydrolyzable phosphate
mimics.[5] In addition, phosphine oxides are key components
in Wittig-type reactions,[6] ligands or organocatalysts in
asymmetric synthesis,[7] and stereogenic precursors to their
corresponding phosphines.[8]
From a synthetic perspective, a catalytic methodology
based on a general substrate class would be particularly val-
uable. To the best of our knowledge, only one method is cur-
rently available; Hayashi and co-workers described the Rh-
catalyzed asymmetric 1,4-addition of arylboroxines to 1-pro-
penylphosphonates for the b-selective introduction of aryl
groups.[17] The corresponding catalytic asymmetric conjugate
addition to introduce alkyl groups remains a major chal-
lenge. We considered the catalytic asymmetric allylic alkyla-
tion (AAA) based on Cu-ferrocenyl or phosphoramidite
chiral catalysts as a synthetically important alternative
(Scheme 1).
In view of their important role in stereoselective synthesis,
the ability to generate stereogenic centers near the phospho-
rus atom in an enantioselective fashion is particularly attrac-
tive. Although several methods have been developed to
obtain compounds with a-stereogenic centers,[9] catalytic
asymmetric methodologies to obtain chiral b-substituted an-
alogues are limited. Two complementary methods, reported
by Jørgensen[10] and Alexakis,[11] for the organocatalyzed
1,4-addition of soft carbon nucleophiles to highly activated
vinyl bis-phosphonates have been described, as well as an
intramolecular Stetter reaction that employed N-heterocy-
clic carbenes as catalysts.[12] Recently, the organocatalyzed
Michael addition of a-substituted nitrophosphonates to ni-
troolefins[13] and trimethylphosphonoacetate to a,b-unsatu-
rated aldehydes[14] has been described. Chiral b-substituted
alkylphosphonates have been prepared by using Rh-cata-
lyzed asymmetric hydrogenation of the corresponding b-di-
Scheme 1. Catalytic asymmetric methodologies based on a general sub-
strate class for the formation of b-substituted aryl- and alkylphospho-
nates and -phosphine oxides.
[a] Dr. V. Hornillos, Dr. M. Pꢀrez, Dr. M. FaÇanꢁs-Mastral,
Prof. Dr. B. L. Feringa
Copper-catalyzed AAA has proven to be a very powerful
tool for the enantioselective construction of stereogenic cen-
ters.[18] This transformation offers the possibility of using
nonstabilized organometallic nucleophiles, which thus en-
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: b.l.feringa@rug.nl
AHCTUNGTREGaNNUN bles the introduction of simple alkyl fragments. Moreover,
a major advantage of this methodology is that it gives prod-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204364.
5432
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5432 – 5441

FULL PAPER
ucts with a terminal olefin, which can be further trans-
formed into a broad range of functional groups.[19]
The reaction of MeMgBr with phosphonate 1b proved to
be even more efficient, giving the corresponding b-methyl
substituted compound 2b in 97% yield (Table 1, entry 3)
with near-perfect SN2’ selectivity (99:1) and enantioselectivi-
ty (99:1 e.r.). This transformation allows for the introduction
of a methyl unit, which is the most common and valuable
structural alkyl motif for biologically relevant systems.[21]
The reaction was extended to the related methyl phospho-
nates (Table 1, entries 4, 5) and phosphine oxides (Table 1,
entries 6, 7) by using both methyl and ethyl magnesium bro-
mide. The results summarized in Table 1 show that the cor-
responding b-alkyl-substituted phosphorus compounds were
obtained with excellent regio- and enantioselectivities in
high yields. An important feature is the scalability of the re-
action to 0.7 g (2.6 mmol) with similar results, as observed in
the reaction of phosphonate 1b and MeMgBr (see the Ex-
perimental Section, compound 2b for details).
The regioselectivity and enantiomeric ratios were more
moderate when Grignard reagents with a longer alkyl chain,
for example, hexyl- or homoallyl magnesium bromide, were
used with a (R,R)-Taniaphos-based copper catalyst (Table 1,
entries 8–14). When the substrate was added over 5 h, the
e.r. was improved (Table 1, entry 8 vs. entry 9), but slower
addition did not lead to further improvement (Table 1,
entry 9 vs. entry 10). As observed in Table 1, entry 1, the ad-
dition of the organometallic reagent to the reaction mixture
(normal addition) decreased both the regio- and enantiose-
lectivity (Table 1, entries 13, 14). To further improve the se-
lectivity with longer or functionalized alkene Grignard re-
agents (e.g., hexyl- and homoallylmagnesium bromide), we
turned our attention to other chiral ligands (Figure 1).
Herein, we report the copper-catalyzed AAA of 4-bromo-
but-2-en-1-ylphosphonates and phosphine oxides with
Grignard reagents and (R,R)-TaniaPhos or phosphorami-
dites as chiral ligands, which provides an efficient route to
chiral b-alkylsubstituted phosphonates with high yield and
high regio- and enantioselectivity.
Results and Discussion
We started our study by using TaniaPhos[20] as the chiral
ligand for copper-catalyzed AAA. Initially, a solution of
Grignard reagent in CH2Cl2 was added (normal addition)
over 2 h to a mixture of substrate and ligand–copper com-
plex at À808C. However, the expected product was obtained
but with low regio- and enantioselectivity (Table 1, entry 1).
When the substrate was added slowly to a solution of
EtMgBr and the catalyst (reverse addition), high regio-
(SN2’/SN2 99:1) and enantioselectivity (98:2 e.r.) in the for-
mation of b-ethylphosphonate 2a was obtained (Table 1,
entry 2). It should be noted that 2.2 equivalents of Grignard
reagent were necessary to reach full conversion. This obser-
vation suggests that the Grignard reagent might also interact
with the substrate either as a base that generates the corre-
sponding phosphorus ylide in situ or by forming a complex
prior to the Cu-catalyzed AAA reaction taking place (vide
infra, Scheme 4 and Figure 2).
Table 1. Cu-catalyzed AAA of phosphonates and phosphine oxides using
(+)-(R,R)-TaniaPhos.[a]
Entry
1
R
Add.
t [h]
Yield
[%][b]
2/3[c]
2 (e.r.)[d]
1[e]
2
3
4
5
6
7
8
9
10
11
12
13[e]
14[e]
1b
1b
1b
1a
1a
1c
1c
1b
1b
1b
1b
1c
1c
1b
Et
Et
Me
Et
Me
Et
Me
nHex
nHex
nHex
2
2
2
2
2
2
2
2
5
8
5
5
5
5
n.d.
96
97
95
92
89
94
89
92
n.d.
n.d.
n.d.
n.d.
n.d.
88:12
99:1
99:1
99:1
99:1
2a (76:23)
2a (98:2)
2b (99:1)
2c (95:5)
2d (99:1)
2e (98:2)
2 f (99:1)
2k (82:18)
2k (90:10)
2k (91:09)
2l (90:10)
2g (87:13)
2h (59:41)
2k (57:43)
Figure 1. Chiral ligands used for the reaction screening.
93:7
99:1
83:17
85:15
85:15
74:26
70:30
68:32
84:16
We started the screening using (S)-Tol-BINAP (L1,
6 mol%;
BINAP=2,2ꢃ-bis(diphenylphosphino)-1,1ꢃ-bi-
naphthyl) as an alternative bidentate chiral phosphine
ligand but only modest regioselectivity and only 63:37 e.r
were obtained. A dramatic improvement in selectivity was
achieved by using the easily accessible monodentate phos-
phoramidite ligands.[22] Thus, the use of L2 gave desired
product 2 with a regioselectivity of 87:13 and high enantio-
selectivity (94:6 e.r., Table 2, entry 2). Use of methoxy-sub-
stituted phosphoramidite ligand L4[23a] improved the regiose-
nHex
nHex
[a] Reactions were performed on a 0.2 mmol scale. A solution of the sub-
strate was added slowly (reverse addition) by using a syringe pump. Full
conversion was reached. [b] Isolated yield. [c] SN2’/SN2 ratio determined
by 31P and 1H NMR spectroscopy. [d] Determined by chiral HPLC.
[e] Normal addition.
Chem. Eur. J. 2013, 19, 5432 – 5441
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5433

B. L. Feringa et al.
highly challenging task in organic synthesis.[26] The screening
of ligands for the addition of HexMgBr to E- and Z-trisub-
stituted allyl bromide phosphine oxides (Table 3) soon indi-
Table 2. Optimization of ligands and conditions for the Cu-catalyzed
AAA of hexyl and homoallyl magnesium bromide to phosphonate and
phosphine oxide allylic bromides.[a]
Table 3. Enantioselective synthesis of compounds 5 with an all-carbon
quaternary stereogenic center. For the conditions, see Table 2.[a]
Entry
1
R
Cu salt
L
2/3[b]
2 (e.r.)[c]
1
2
3
4
5
1c
1c
1c
1c
1c
1c
1c
1c
1c
1a
1a
1b
1b
nHex
nHex
nHex
nHex
nHex
nHex
nHex
nHex
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuTC
CuTC
CuTC
CuTC
CuTC
L1
L2
L3
L4
L5
L4
L2
L2
L2
L2
L2
L2
L2
66:34
87:13
80:20
92:8
84:16
92:8
87:13
92:8
93:7
95:5
97:3
91:9
78:22
2g (63:37)
2g (94:6)
2g (78:22)
2g (93:7)
2g (61:39)
2g (93:7)
2g (95:5)
2g (95:5)
2h (96:4)
2i (95:5)
2j (98:2)
2a (96:4)
2b (86:14)
6
7
Entry
4; E/Z
R
Cu salt
L
5/6[b]
5 (e.r.)[c]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
1
2
3
4
100:0
100:0
100:0
100:0
0:100
100:0
100:0
100:0
Hex
Hex
Hex
Hex
Hex
Hex
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuTC
L2
L4
L5
L6
L6
L6
L6
L6
46:54
64:36
60:40
87:13[e]
69:31[f]
87:13
89:11
92:8
5a (71:29)
5a (66:34)
5a (51:49)
5a (75:25)
5a (78:22)
5a (79:21)
5b (80:20)
5c (78:22)
nHex
CuTC
CuTC
CuTC
5
Et
Me
6[d]
7[d]
8[d]
CuTC
CuTC
[a] Reactions were performed on a 0.2 mmol scale. The substrate was
added (reverse addition) over 5 h. Full conversion was reached in all
cases. [b] SN2’/SN2 ratio determined by 31P and 1H NMR spectroscopy.
[c] Determined by chiral HPLC. [d] Normal addition; representative iso-
lated yield: 2g (85%), 2h (87%), 2i (83%), 2j (93%).
Et
[a] Full conversion was reached in all cases. [b] SN2’/SN2 ratio determined
by 31P and 1H NMR analysis. [c] Determined by chiral HPLC. [d] Com-
pounds 5a (68% yield), 5b (73% yield), 5c (85% yield). [e] Linear prod-
uct 6a was obtained as the pure E isomer. [f] Linear product 6a was ob-
tained as the pure Z isomer.
lectivity but did not enhance the e.r. (Table 2, entry 4). Con-
sideration of the data in Table 2, entries 3 and 5 shows that
L3 and L5 display a mismatch effect that gives lower e.r.
and regioselectivity. We also observed that the use of CuTC
(copper(I) thiophene-2-carboxylate)[23] as the copper salt in
combination with optimized ligand L2 provides 2g with
slightly higher e.r. than the one obtained with CuBr·SMe2
(Table 2, entries 2 and 7). Finally, we could achieve an im-
provement in the regioselectivity when the Grignard reagent
was added to the substrate (Table 2, entry 8), in contrast to
the findings observed with Taniaphos as the chiral ligand
(Table 1, entries 1, 13, and 14). Alkylation of 1c with homo-
allylmagnesium bromide also proceeded with a high level of
regio- and enantioselectivity (Table 2, entry 9). As a repre-
sentative example, this protocol was extended to phospho-
nate 1a by using hexyl- and homoallyl magnesium bromide
to give compounds 2i[24] and 2j with excellent regioselectivi-
ty and e.r. (Table 2, entries 10 and 11). Notably, compound
2j is an advanced intermediate in the synthesis of 2-(phos-
phonomethyl)pentanedioic acid (2-PMPA), the most potent
known inhibitor of the enzyme GCP II.[25] The copper/phos-
phoramidite system also proved to be a good alternative for
the addition of a shorter alkylmagnesium bromide, such as
EtMgBr, which gave rise to slightly lower selectivity that
that obtained with TaniaPhos (Table 2, entry 12). However,
as shown in Table 2, entry 13, the use of MeMgBr led to a
considerable decrease in the regio- and enantioselectivity,
which demonstrates the complementarity of both catalytic
systems.
cated L6[27] as the best ligand in terms of regio- and enantio-
selectivity (Table 3, entries 1–4). The effect of the double-
bond geometry of allyl bromide 4 was studied (Table 3, en-
tries 4 and 5). Although the nature of the double bond has
an important effect in the regioselectivity of the reaction,
both E- and Z-allyl bromides 4 gave rise to the same enan-
tiomer of product 5a with similar e.r. values. Remarkably,
no isomerization of the olefin takes places during the reac-
tion, as observed from the geometry of the resulting linear
products 6a. There was no substantial difference between
the use of CuBr·SMe2 or CuTC in terms of regio- or enan-
tioselectivity (Table 3, entries 4 and 6). The addition of
ethyl- and homoallylmagnesium bromide to E-trisubstituted
allyl bromide phosphine oxide 4 afforded products 5b and
5c, respectively, in good yields and with similar selectivity to
that obtained for 5a (Table 3, entries 7 and 8).
To further demonstrate the synthetic potential of this new
methodology, phosphine oxide 5 was used as a chiral build-
ing block in a Horner–Wittig type reaction[6] for the synthe-
sis of optically active polyunsaturated compound 7, which
has an all-carbon quaternary center (Scheme 2). Product 7,
formed by the reaction between 5 and cinnamaldehyde, fea-
tures a similar substitution pattern at the quaternary center
as the one present in bakuchiol[28] (an antimicrobial agent
isolated from the seeds of Psoralea corylifolia L.). This ole-
AHCTUNGTREGfNNNU ination proceeds in high yield and without loss of enantio-
meric purity.
The catalytic enantioselective construction of all-carbon
quaternary centers in acyclic systems continues to be a
The new terminal olefin adjacent to the stereogenic
center in AAA products 2 opens a wide array of possible
5434
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5432 – 5441

Asymmetric Allylic Alkylation
FULL PAPER
As mentioned above, at least two equivalents of RMgBr
were necessary for the copper-catalyzed AAA to reach com-
pletion. This suggests an interaction of the organometallic
reagent with the substrate prior to alkylation. To elucidate
the intermediates in this particular allylic alkylation, an
NMR spectroscopy study was performed.[31] The 31P NMR
spectrum of a mixture of substrate 1c (signal at d=29 ppm)
and a stoichiometric amount of preformed catalyst C1[32]
(signal at d=À18 ppm[33]) at À808C in CD2Cl2 (t0) is shown
in Figure 2. After the addition of excess of MeMgBr
(7.0 equiv; t1), the 31P NMR spectra were recorded at 5 min
intervals (t1–t14; for details see the Supporting Information).
Between t0 and t8 we observed the disappearance of the
phosphorus resonance of the substrate (d=29 ppm) and the
appearance of a new signal at d=37 ppm. We attributed this
downfield shift to complex C2 that formed between phos-
phine oxide 1c and the first equivalent of Grignard reagent
(Scheme 4). The expected deprotonation of phosphine oxide
Scheme 2. Horner–Wittig reaction with phosphine oxide 5b.
transformations. As an example, olefin cross metathesis[29]
with ethyl acrylate was used to functionalize the terminal
double bond in phosphonates 2a–d,i,j to give the corre-
sponding g-alkyl unsaturated esters 8 with E/Z selectivities
in excess of 10:1 to >20:1 and good yields without compro-
mising the e.r. of the allylic stereocenter (Table 4).
Table 4. Cross metathesis of phosphonates 2 with ethyl acrylate.[a]
Entry
2
R[b]
t
Yield
[%]
E/Z[b]
8 (e.r.)[c]
[h]
Scheme 4. Proposed mechanistic pathway for the Cu-catalyzed AAA of
phosphine oxide 1c with MeMgBr.
1
2
3
4
5
6
2a
2b
2c
2d
2i
Et
Me
Et
Me
Hex
8
8
8
8
8
24
75
83
80
78
62
60
15:1
11:1
14:1
>20:1
>20:1
10:1[d]
8a (98:2)
8b (99:1)
8c (95:5)
8d (99:1)
8i (95:5)
8j (98:2)
1c by the organometallic reagent, which would lead to the
corresponding ylide form, did not take place as confirmed
by quenching the reaction with D2O, CD3OD, or DCl, which
did not lead to deuterium incorporation at the a position.
This observation was confirmed by repeating the same ex-
periment with (2-methylbut-3-en-2-yl)diphenylphosphine
oxide as a model phosphine oxide with two methyl groups
in the a position. In this case, a similar downfield shift of
the phosphorus resonance was observed (see the Supporting
Information for details). Although complexes between mag-
nesium salts and phosphine oxides are known,[34] there are
no reports of the corresponding complex with Grignard re-
agents. At t9, the phosphorus resonance at d=37 ppm disap-
peared to reveal a new downfield singlet.[35] Interestingly, at
the same time, two new different doublets at d=À16 and
À19 ppm appeared. We attributed this to the formation of
diphosphine Cu–Me chiral complex C3 in accordance with
our previous NMR spectroscopy studies.[32] When the reac-
tion was allowed to go to completion,[36] the phosphine
oxide 31P resonance was split into two signals at d=39 and
40 ppm. By using 1H NMR spectroscopy at RT, we could
identify the species associated with these two absorptions as
2j
[a] Conditions: 2 (1 equiv), ethyl acrylate (3 equiv), CH2Cl2 (0.25m in 2).
[b] E/Z ratio determined by 1H NMR spectroscopy. [c] Determined by
chiral HPLC. [d] (E,E) isomer/other isomers.
Finally, phosphine oxide 2 f was selectively reduced to the
corresponding chiral phosphine 9 by using tetramethyldisi-
loxane (TMDS) in the presence CuACHTNUTRGNEUNG(OTf)2, as recently de-
scribed by Beller and co-workers (Scheme 3).[8] The corre-
sponding phosphine–borane complex 10 was prepared by
treating 9 with one equivalent of BH3·THF (Scheme 3).
Competing hydroboration of the alkene was not observed,
as expected from the study of Vedejs and Shapland with
homoACHTUNGTRENNUNGallylACHTUNGTRENNUNG
diphenylphosphine.[30]
Scheme 3. Reduction of phosphine oxide 2 f to phosphine 9 and further
conversion to phosphine borane 10.
Chem. Eur. J. 2013, 19, 5432 – 5441
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5435

B. L. Feringa et al.
phoramidite L2 as
a chiral
ligand. In addition, preliminary
experiments show that this
methodology can be applied to
the enantioselective synthesis of
quaternary carbon stereogenic
centers in acyclic systems.
Transformation of these prod-
ucts leads to important new op-
tically active scaffolds with
phosphine oxide and phospho-
nates that are not easily obtain-
able by other methods. Prelimi-
nary mechanistic studies indi-
cate that the reaction takes
place with a complex formed
between the phosphorus com-
pound and the Grignard re-
agent. Detailed mechanistic
studies are ongoing and will be
reported in due course.
Experimental Section
General remarks: Chromatography
was performed on Merck silica gel
type 9385 230–400 mesh and TLC was
performed on Merck silica gel 60,
0.25 mm. Components were visualized
by UV and potassium permanganate
staining. Progress and conversion of
Figure 2. Representative 31P NMR spectra upon treatment of phosphine oxide 2 f with MeMgBr at À808C in
CD2Cl2. tnÀt(nÀ1) =5 min unless noted. PPh3 (d=À9 ppm) was used as a reference.
the reactions were determined by GC-
MS (GC, HP6890: MS HP5973) with
an HP1 or HP5 column (Agilent Tech-
the branched and linear[37] complexes C4. Quenching with
nologies, Palo Alto, CA). Mass spectra
were recorded by using an AEI-MS-
aqueous NH4Cl gave rise to a mixture of branched and
linear products 2 f and 3 f in the same ratio as observed
before quenching, with an e.r. of 99:1 for chiral SN2’ re-
gioisomer 2 f.
Based on the combined data presented here and our
recent study with organolithium reagents, we propose a
mechanistic pathway for this allylic alkylation as shown in
Scheme 4.
902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H-, 13C-,
and 31P NMR were recorded by using a Varian AMX400 or a Varian
VXR300 spectrometer with CDCl3 as the solvent. Chemical shift values
are reported in ppm with the solvent resonance as the internal standard
(CHCl3: d=7.26 for 1H, d=7.0 for 13C). Data are reported as follows:
chemical shifts, multiplicity (s=singlet, d=doublet, t=triplet, q=quar-
tet, br=broad, m=multiplet), coupling constants (Hz), and integration.
Optical rotations were measured by using a Schmidt and Haensch polar-
imeter (Polartronic MH8) with a 10 cm cell (c given in g100 mLÀ1).
Enantiomeric ratios were determined by HPLC analysis of both enan-
tiomers for every compound by using a Shimadzu LC-10ADVP HPLC
equipped with a Shimadzu SPD-M10AVP diode array detector. All reac-
Conclusion
tions were carried out under a nitrogen atmoACTHNUTRGNEsUNG phere by using oven dried
glassware and standard Schlenk techniques. Dichloromethane was dried
and distilled over calcium hydride; toluene and THF were dried and dis-
tilled over sodium. All copper salts (CuTC and CuBr·SMe2) were pur-
chased from Aldrich and used without further purification. Allyl bromide
1b was prepared by following a literature procedure.[38] MeMgBr (3.0m
in Et2O), EtMgBr[39] (3.0m in Et2O), and nHexMgBr (2.0m in Et2O) were
purchased from Aldrich and CH2CHCH2CH2MgBr was prepared as re-
ported in the literature and titrated with sBuOH and catalytic amounts
of 1,10-phenanthroline. Ligands (R,R)-TaniaPhos, (S,S)-TaniaPhos, and
(S)-Tol-BINAP were purchased from Aldrich and phosphoramidite li-
gands (L2, L3),[40] (L4, L5),[41] and L6[42] were prepared as reported in the
literature.
In summary, we have developed an efficient catalytic and
highly enantioselective methodology for the asymmetric al-
kylation of phosphonate and phosphine oxide allylic bro-
mides with Grignard reagents to form chiral b-alkylphosph-
onate and phosphine oxides in good yields. This protocol
was optimized for methyl and ethyl magnesium bromide
with CuBr·SMe2 and (R,R)-TaniaPhos as ligand and for
hexyl- and homoallyl magnesium bromide (functionalized
alkene and long-chain nucleophiles) with CuTC and phos-
5436
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5432 – 5441

Asymmetric Allylic Alkylation
FULL PAPER
(E)-Dimethyl (4-bromobut-2-en-1-yl)phosphonate (1a): The same proce-
dure as for 1b was followed (80% yield). 1H NMR (400 MHz, CDCl3):
d=5.79 (m, 2H), 3.94 (dd, J=6.8, 3.4 Hz, 1H), 3.74 (d, J=11.0 Hz, 6H),
2.62 ppm (dd, J=21.5, 7.1 Hz, 2H); 13C NMR (101 MHz, CDCl3): d=
131.5 (d, J=15.2 Hz), 124.2 (d, J=11.8 Hz), 52.8 (d, J=6.6 Hz, 2C), 31.8
(d, J=2.6 Hz), 29.3 ppm (d, J=140.0 Hz); 31P NMR (161.9 MHz, CDCl3):
d=28.7 ppm.
(+)-Diethyl (2-ethylbut-3-en-1-yl)phosphonate (2a): The title compound
was prepared from 1b by following general procedure A. Purification by
column chromatography (SiO2, eluent n-pentane/EtOAc 7:3) afforded 2a
(96% yield, 99:1 ratio (SN2’/SN2), 98:2 e.r.) as a colorless oil. The enantio-
meric ratio was determined for cross-metathesis product 8a. [a]2D0 = +2.0
(c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=5.60 (m, 1H), 5.02 (m,
2H), 4.05 (m, 4H), 2.36 (m, 1H), 1.78 (m, 2H), 1.58 (m, 1H), 1.38 (m,
1H), 1.28 (dt, J=7.0, 1.3 Hz, 6H), 0.84 ppm (t, J=7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=141.3 (d, J=10.7 Hz), 114.8, 61.2 (m, 2C), 39.7 (d,
J=4.0 Hz), 31.4 (d, J=140.0 Hz), 28.4 (d, J=14.0 Hz), 16.4 (d, J=6.3 Hz,
2C), 11.1 ppm; 31P NMR (161.9 MHz, CDCl3): d=31.1 ppm; HRMS
(ESI+): m/z calcd for C10H22O3P: 221.1307 [M+H+]; found: 221.1301.
(E)-Diphenyl (4-bromobut-2-en-1-yl) phosphine oxide (1c): HG-II cata-
lyst (0.62 mmol, 388 mg) was added to a solution of allyl diphenyl phos-
phine oxide (12.4 mmol, 3 g) and 1,4-dibromobutene (50 mmol, 10.6 g) in
dry toluene (100 mL), and the mixture was heated at 808C for 10 h. The
mixture was cooled down to RT and the solvent was removed under re-
duced pressure to give the crude product, which was purified by flash
chromatography on silica gel with n-pentane/EtOAc 1:1 as the eluent
(85% yield). 1H NMR (400 MHz, CDCl3): d=7.69 (m, 4H), 7.56 (m,
6H), 5.76 (m, 2H), 3.85 (m, 2H), 3.14 ppm (m, 2H); 13C NMR
(101 MHz, CDCl3): d=129.9–128.9 (m), 128.4 (d, J=9.2 Hz, 4C), 126.1
(d, J=12.2 Hz, 4C), 121.7 (d, J=9.2 Hz), 32.0 (d, J=67.8 Hz), 29.5 ppm
(d, J=1.9 Hz); 31P NMR (161.9 MHz, CDCl3): d=29.0 ppm. EI MS: m/z:
334 [M+] not observed, 254 (100%) [MÀHBr].
(À)-(E)-Ethyl 4-((diethoxyphosphoryl)methyl)hex-2-enoate (8a): The re-
action was performed by using the cross-metathesis protocol, with a reac-
tion time of 8 h. Purification by column chromatography (SiO2, eluent n-
pentane/EtOAc 1:1) gave 8a as a colorless oil (75% yield, E/Z 15:1, 98:2
e.r.). [a]2D0 =À62.0 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=6.74
(dd, J=15.2, 8.7 Hz, 1H), 5.83 (d, J=15.9 Hz, 1H), 4.16 (q, J=7.5 Hz,
2H), 4.05 (m, 4H), 2.54 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.43 (m,
1H), 1.27 (m, 9H), 0.85 ppm (d, J=7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=166.4, 150.8 (d, J=8.8 Hz), 121.7, 61.5 (m, 2C), 60.2, 38.4 (d,
J=3.7 Hz), 30.3(d, J=145.3 Hz), 28.2 (d, J=12.1 Hz), 16.4 (d, J=5.5 Hz,
2C), 14.2, 11.2 ppm; 31P NMR (161.9 MHz, CDCl3): d=29.5 ppm; HRMS
(ESI+): m/z calcd for C13H26O5P: 293.1518 [M+H+]; found: 293.1512;
the enantiomeric ratio was determined by chiral HPLC analysis, Chiral-
pak AD-H column, n-heptane/iPrOH 97:3, 408C, retention times: 43.9
(minor) and 47.2 min (major).
General procedures for the copper-catalyzed allylic alkylation
Procedure A: In a dry Schlenk tube equipped with septum and stirring
bar, CuBr·SMe2 (0.01 mmol, 2.05 mg, 5.0 mol%) and (R,R)-Taniaphos
(0.012 mmol, 8.25 mg, 6 mol%) were dissolved in CH2Cl2 (2.0 mL) and
the mixture was stirred under a nitrogen atmosphere at RT for 20 min.
The mixture was cooled to À808C and a solution of Grignard reagent
(2.2 equiv) in Et2O diluted with CH2Cl2 (combined volume: 1 mL) was
added dropwise over 30 min through a syringe pump. Subsequently, a so-
(+)-Diethyl (2-methylbut-3-en-1-yl)phosphonate (2b): The title com-
pound was prepared from 1b (700 mg, 2.58 mmol) by following general
procedure A. Purification by column chromatography (SiO2, eluent n-
pentane/EtOAc 7:3) gave 2b as a colorless oil (97% yield, SN2’/SN2 99:1,
99:1 e.r.). The enantiomeric ratio was determined for cross-metathesis
product 8b. [a]2D0 = +2.4 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d=5.80 (m, 1H), 4.98 (m, 2H), 4.07 (m, 4H), 2.61 (m, 1H), 1.84 (m,
1H), 1.69 (m, 1H), 1.30 (t, J=7.0 Hz, 6H), 1.13 ppm (d, J=6.9 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=143.6 (d, J=12.5 Hz), 113.0, 60.6 (m,
2C), 32.6 (d, J=140.0 Hz), 32.4 (d, J=3.7 Hz), 21.2 (d, J=9.2 Hz),
16.6 ppm (d, J=5.9 Hz, 2C); 31P NMR (161.9 MHz, CDCl3): d=
30.6 ppm; HRMS (ESI+): m/z calcd for C9H20O3P: 207.1150 [M+H+];
found: 207.1145.
ACHTUNGTRENNUNGluACHTUNGTRENNUNGtion of the corresponding phosphonate or phosphine oxide allylic bro-
mide 1 (0.2 mmol) in CH2Cl2 (1.0 mL) was added dropwise over 2 h
through a syringe pump. Once the addition was complete, the resulting
mixture was stirred at À808C for 16 h. Saturated aqueous NH4Cl (2 mL)
was added and the organic phase was separated. The aqueous phase was
extracted with CH2Cl2 (3ꢄ10 mL), then the combined organic phases
were dried over Na2SO4 and concentrated under reduced pressure to give
the crude product, which was purified by flash chromatography on silica
gel with different mixtures of n-pentane/EtOAc as the eluent. Note: 31P
and 1H NMR spectroscopic analyses were carried out to determine the
branched/linear (b/l) ratio of a sample obtained after aqueous extraction
with CH2Cl2.
(À)-(E)-Ethyl 5-(diethoxyphosphoryl)-4-methylpent-2-enoate (8b): The
reaction was performed by using the cross-metathesis protocol, with a re-
action time of 8 h. Purification by column chromatography (SiO2, eluent
n-pentane/EtOAc 1:1) gave 8b as a colorless oil (83% yield, E/Z 11:1,
99:1 e.r.). [a]2D0 =À9.6 (c=1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d=
6.89 (dd, J=15.5, 7.7 Hz, 1H), 5.82 (dd, J=15.5, 1.2 Hz, 1H), 4.18 (q, J=
7.0 Hz, 2H), 4.07 (m, 4H), 2.78 (m, 1H), 1.82 (m, 1H), 1.34–1.24 (m,
9H), 1.19 ppm (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=
166.5, 152.5, 120.0, 61.6 (m, 2C), 60.3, 31.9 (d, J=140.8 Hz), 31.3 (d, J=
3.7 Hz), 20.6 (d, J=10.7 Hz), 16.3 (d, J=6.3 Hz, 2C), 14.2 ppm; 31P NMR
(161.9 MHz, CDCl3): d=29.4 ppm; HRMS (ESI+): m/z calcd for
C12H24O5P: 279.1361 [M+H+]; found: 279.1356. The enantiomeric ratio
was determined by chiral HPLC analysis, Chiralpak AD-H column,
eluent n-heptane/iPrOH 97:3, 408C, retention times: 37.4 (minor) and
41.0 min (major).
Procedure B: In a Schlenk tube equipped with septum and stirring bar,
CuTC (0.01 mmol, 1.9 mg, 5 mol%) and the appropriate phosphorami-
dite ligand (0.011 mmol, 5.5 mol%) were mixed. Dry CH2Cl2 (2 mL) was
added and the solution was stirred under nitrogen at RT for 15 min, then
the resulting solution was cooled to À808C. The corresponding phospho-
nate or phosphine oxide allylic bromide 1 (0.2 mmol) in CH2Cl2 (1 mL)
was then added. In a separate Schlenk flask, the corresponding Grignard
reagent (0.50 mmol, 2.5 equiv) was diluted with CH2Cl2 (combined
volume of 1 mL) under nitrogen and added dropwise to the reaction mix-
ture over 5 h by using a syringe pump. Once the addition was complete,
the mixture was stirred at À808C for 16 h. The reaction was quenched
with a saturated aqueous NH4Cl solution (2 mL) and the mixture was
warmed up to RT, diluted with CH2Cl2, and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3ꢄ5 mL) and the com-
bined organic layers were dried with anhydrous Na2SO4, filtered, and the
solvent was evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel with different mixtures of n-pentane/EtOAc
(+)-Dimethyl (2-methylbut-3-en-1-yl)phosphonate (2c): The title com-
pound was prepared from 1a by following general procedure A. Purifica-
tion by column chromatography (SiO2, eluent n-pentane/EtOAc 1:1) af-
forded 2c as a colorless oil (95% yield, SN2’/SN2 99:1, 95:5 e.r.). The
enantiomeric ratio was determined for cross-metathesis product 8c.
[a]2D0 = +8.0 (c=1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d=5.60 (m,
1H), 5.04 (m, 2H), 3.69 (d, J=11.0 Hz, 6H), 2.35 (m, 1H), 1.80 (dt, J=
18.3, 6.7 Hz, 2H), 1.55 (m, 1H), 1.33 (m, 1H), 0.85 ppm (t, J=7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3): d=141.1 (d, J=9.2 Hz), 115.0, 52.0
(m, 2C), 39.7 (d, J=3.7 Hz), 30.0 (d, J=139.8 Hz), 28.5 (d, J=11.1 Hz),
11.2 ppm; 31P NMR (161.9 MHz, CDCl3): d=33.6 ppm; HRMS (ESI+):
m/z calcd for C8H18O3P: 193.0994 [M+H+]; found: 193.0988.
1
as the eluent. 31P and H NMR spectroscopic analyses were carried out to
determine the b/l ratio of a sample obtained after aqueous extraction
with CH2Cl2.
General protocol for cross-metathesis reaction: HG-II catalyst
(0.01 mmol, 5 mol%) was added to a solution of the corresponding phos-
phonate
2 (0.2 mmol) and ethyl acrylate (0.6 mmol) in dry CH2Cl2
(2 mL) and the mixture was heated at reflux for the indicated time (8–
24 h). The mixture was cooled down to RT and the solvent was removed
under reduced pressure to give the crude product, which was purified by
flash chromatography on silica gel with mixtures of n-pentane/EtOAc.
Chem. Eur. J. 2013, 19, 5432 – 5441
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5437

B. L. Feringa et al.
(+)-(E)-Ethyl 5-(dimethoxyphosphoryl)-4-methylpent-2-enoate (8c): The
reaction was performed by using the cross-metathesis protocol, with a re-
action time of 8 h. Purification by column chromatography (SiO2, eluent
n-pentane/EtOAc 1:1) afforded 8c as a colorless oil (80% yield, E/Z
14:1, 95:5 e.r.). [a]2D0 =À83 (c=1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d=6.73 (dd, J=15.5, 8.9 Hz, 1H), 5.84 (d, J=15.7 Hz, 1H), 4.18 (q, J=
7.3 Hz, 2H), 3.69 (dd, J=10.8, 3.3 Hz, 6H), 2.53 (m, 1H), 1.84 (m, 2H),
1.64 (m, 1H), 1.43 (m, 1H), 1.28 (t, J=7.1 Hz, 3H), 0.86 ppm (t, J=
7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=166.4, 150.6 (d, J=8.8 Hz),
121.8, 60.3, 52.2 (m, 2C), 38.3 (d, J=3.3 Hz), 29.3 (d, J=140.8 Hz), 28.1
(d, J=11.8 Hz), 14.2, 11.3 ppm; 31P NMR (161.9 MHz, CDCl3): d=
32.3 ppm; HRMS (ESI+): m/z calcd for C11H21NaO5P: 287.1024 [M+
Na+]; found: 287.1019. The enantiomeric ratio was determined by chiral
HPLC analysis, Chiralcel OD-H column, eluent n-heptane/iPrOH 95:5,
408C, retention times: 22.04 (minor) and 24.31 min (major).
sis, Chiralcel OJ-H column, eluent n-heptane/iPrOH 98:2, 408C, reten-
tion times: 19.8 (major) and 20.5 min (minor).
(À)-(2-Vinyloctyl)diphenylphosphine oxide (2g): The title compound was
prepared from 1c by following general procedure B with (R,S,S)-L2 as
the ligand. Purification by column chromatography (SiO2, eluent n-pen-
tane/EtOAc 1:1) afforded 2g as a colorless oil (85% yield, SN2’/SN2 92:8,
1
95:5 e.r.). [a]2D0 =À60.2 (c=1.0, CHCl3). H NMR (400 MHz, CDCl3): d=
7.73 (m, 4H), 7.45 (m, 6H), 5.54 (m, 1H), 4.83 (m, 2H), 2.54 (m, 1H),
2.31 (dd, J=11.1, 6.6 Hz, 2H), 1.54 (m, 1H), 1.22 (m, 9H), 0.83 ppm (t,
J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=141.6 (d, J=7.7 Hz),
133.9 (m, 2C), 131.5 (m, 2C), 130.9 (d, J=9.2 Hz, 2C), 130.6 (d, J=
9.2 Hz, 2C), 128.5 (m, 4C), 114.7, 37.9 (d, J=3.3 Hz), 36.1 (d, J=7.7 Hz),
35.2 (d, J=70.8 Hz), 31.7, 29.0, 26.7, 22.6, 14.0 ppm; 31P NMR
(161.9 MHz, CDCl3): d=30.8 ppm; HRMS (ESI+): m/z calcd for
C22H29OP: 363.1854 [M+H+]; found: 363.1848. The enantiomeric ratio
was determined by chiral HPLC analysis, Chiralpak AS-H column,
eluent n-heptane/iPrOH 98:2, 408C, retention times: 19.0 (major) and
21.6 min (minor).
(À)-Dimethyl (2-methylbut-3-en-1-yl)phosphonate (2d): The title com-
pound was prepared from 1a by following general procedure A. Purifica-
tion by column chromatography (SiO2, eluent n-pentane/EtOAc 1:1) af-
forded 2d as a colorless oil (92% yield, SN2’/SN2 99:1, 99:1 e.r.). The
enantiomeric ratio was determined for cross-metathesis product 8d.
[a]2D0 =À2.4 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=5.77 (m,
1H), 4.99 (m, 2H), 3.69 (d, J=10.8 Hz, 6H), 2.59 (m, 1H), 1.83 (ddd, J=
18.4, 15.4, 6.3 Hz, 1H), 1.69 (ddd, J=17.9, 15.4, 7.6 Hz, 1H), 1.11 ppm (d,
J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=143.1 (d, J=12.9 Hz),
112.9, 52.0 (m, 2C), 32.3 (d, J=3.7 Hz), 31.5 (d, J=140.0 Hz), 21.1 ppm
(d, J=9.6 Hz); 31P NMR (161.9 MHz, CDCl3): d=33.4 ppm; HRMS
(ESI+): m/z calcd for C7H16O3P: 179.0837 [M+H+]; found: 179.0832.
(À)-(2-Vinylhex-5-en-1-yl)diphenylphosphine oxide (2h): The title com-
pound was prepared from 1c by following general procedure B with
(R,S,S)-L2 as the ligand. Purification by column chromatography (SiO2,
eluent n-pentane/EtOAc 1:1) afforded 2h as a colorless oil (87% yield,
SN2’/SN2 93:7, 96:4 e.r.). [a]2D0 =À27.0 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.73 (m, 4H), 7.46 (m, 6H), 5.67 (m, 1H), 5.54
(m, 1H), 4.87 (m, 4H), 2.58 (m, 1H), 2.33 (dd, J=11.1, 6.5 Hz, 2H), 2.00
(m, 1H), 1.92 (m, 1H), 1.68 (m, 1H), 1.40 ppm (m, 1H); 13C NMR
(101 MHz, CDCl3): d=141.2 (d, J=7.7 Hz), 138.2, 134.2 (d, J=73.7 Hz,
1C), 133.2 (d, J=73.7 Hz, 1C), 131.5 (m, 2C), 130.9 (d, J=8.5 Hz, 2C),
130.6 (d, J=8.5 Hz, 2C), 128.5 (m, 4C), 115.2, 114.6, 37.5 (d, J=3.3 Hz),
35.2 (d, J=70.8 Hz), 35.1 (d, J=8.1 Hz), 30.9 ppm; 31P NMR (161.9 MHz,
CDCl3): d=30.5 ppm; HRMS (ESI+): m/z calcd for C22H29OP: 333.1384
[M+H+]; found: 333.1379. The enantiomeric ratio was determined by
chiral HPLC analysis, Chiralpak AS-H column, eluent n-heptane/iPrOH
98:2, 408C, retention times: 30.9 (major) and 34.6 min (minor).
(+)-(E)-Ethyl 5-(dimethoxyphosphoryl)-4-methylpent-2-enoate (8d): The
reaction was performed by using the cross-metathesis protocol, with a re-
action time of 8 h. Purification by column chromatography (SiO2, eluent
n-pentane/EtOAc 1:1) afforded 8d as a colorless oil (78% yield, E/Z
>20:1, 99:1 e.r.). [a]2D0 = +47.0 (c=1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d=6.87 (dd, J=15.5, 7.7 Hz, 1H), 5.81 (d, J=15.5 Hz, 1H), 4.17
(q, J=7.0 Hz, 2H), 3.71 (d, J=10.8 Hz, 6H), 2.79 (m, 1H), 1.82 (m, 2H),
1.26 (t, J=7.0 Hz, 3H), 1.19 ppm (d, J=7.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=166.5, 152.1 (d, J=12.5 Hz), 120.1, 60.3, 52.2 (m,
2C), 31.2 (d, J=3.7 Hz), 30.9 (d, J=141 Hz), 20.5 (d, J=9.2 Hz),
14.2 ppm; 31P NMR (161.9 MHz, CDCl3): d=31.9 ppm; HRMS (ESI+):
m/z calcd for C10H20O5P: 251.1048 [M+H+]; found: 251.1043. The enan-
tiomeric ratio was determined by chiral HPLC analysis, Chiralpak AD-H
column, eluent n-heptane/iPrOH 97:3, 408C, retention times: 41.5
(minor) and 45.5 min (major).
(À)-Dimethyl (2-vinyloctyl)phosphonate (2i): The title compound was
prepared from 1a by following general procedure B with (R,S,S)-L2 as
the ligand. Purification by column chromatography (SiO2, eluent n-pen-
tane/EtOAc 7:3) afforded 2i as a colorless oil (83% yield, SN2’/SN2 95:5,
95:5 e.r.). The enantiomeric ratio was determined for cross-metathesis
1
product 8i. [a]2D0 =À8.0 (c=1.0, CHCl3). H NMR (400 MHz, CDCl3): d=
5.60 (m, 1H), 5.02 (m, 2H), 3.69 (d, J=10.8 Hz, 6H), 2.43 (m, 1H), 1.79
(m, 2H), 1.49 (m, 1H), 1.24 (m, 9H), 0.85 ppm (t, J=6.3 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=141.5 (d, J=8.8 Hz), 114.8, 52.1 (m,
2C), 38.2 (d, J=3.7 Hz), 35.8 (d, J=12.2 Hz), 31.7, 30.5 (d, J=139.7 Hz),
29.0, 26.7, 22.6, 14.0 ppm; 31P NMR (161.9 MHz, CDCl3): d=33.6 ppm;
HRMS (ESI+): m/z calcd for C12H26O3P: 249.1620 [M+H+]; found:
249.1614.
(+)-(2-Ethylbut-3-en-1-yl)diphenylphosphine oxide (2e): The title com-
pound was prepared from 1c by following general procedure A. Purifica-
tion by column chromatography (SiO2, eluent n-pentane/EtOAc 1:1) af-
forded 2e as a colorless oil (89% yield, SN2’/SN2 93:7, 98:2 e.r.). [a]2D0 = +
1
29.2 (c=1.0, CHCl3); H NMR (400 MHz, CDCl3): d=7.72 (m, 4H), 7.43
(m, 6H), 5.52 (m, 1H), 4.83 (m, 2H), 2.46 (m, 1H), 2.31 (dd, J=11.4,
6.6 Hz, 2H), 1.62 (m, 1H), 1.32 (m, 1H), 0.77 ppm (t, J=7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=141.2 (d, J=9.9 Hz), 133.8 (m, 2C),
131.5 (m, 2C), 130.7 (m, 4C), 128.5 (m, 4C), 114.9, 39.5 (d, J=3.3 Hz),
34.8 (d, J=73.7 Hz), 28.8 (d, J=8.1 Hz), 11.1 ppm; 31P NMR (161.9 MHz,
CDCl3): d=30.8 ppm; HRMS (ESI+): m/z calcd for C18H22OP: 285.1408
[M+H+]; found: 285.1403. The enantiomeric ratio was determined by
chiral HPLC analysis, Chiralpak AS-H column, eluent n-heptane/iPrOH
98:2, 408C, retention times: 29.7 (minor) and 31.3 min (major).
(À)-(E)-Ethyl 4-((dimethoxyphosphoryl)methyl)dec-2-enoate (8i): The
reaction was performed by using the cross-metathesis protocol, with a re-
action time of 8 h. Purification by column chromatography (SiO2, eluent
n-pentane/EtOAc 1:1) afforded 8i as a colorless oil (62% yield, E/Z
>20:1, 95:5 e.r.). [a]2D0 =À153.0 (c=1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): d=6.72 (dd, J=15.8, 9.2 Hz, 1H), 5.82 (d, J=15.8 Hz, 1H), 4.16
(q, J=7.0 Hz, 2H), 3.67 (dd, J=10.7, 2.7 Hz, 6H), 2.58 (m, 1H), 1.82 (m,
2H), 1.55 (m, 1H), 1.38 (m, 1H), 1.23 (m, 11H), 0.84 ppm (t, J=6.3 Hz,
3H); 13C NMR (101 MHz, CDCl3): d=166.4, 150.9 (d, J=8.8 Hz), 121.5,
60.3, 52.2 (m, 2C), 36.8 (d, J=4.0 Hz), 35.3 (d, J=11.8 Hz), 31.6, 29.8 (d,
J=141.2 Hz), 26.7, 22.5, 14.2, 14.0 ppm; 31P NMR (161.9 MHz, CDCl3):
d=32.2 ppm; HRMS (ESI+): m/z calcd for C15H39NaO5P: 343.1650
[M+Na+]; found: 343.1545. The enantiomeric ratio was determined by
chiral HPLC analysis, Chiralpak AD-H column, eluent n-heptane/iPrOH
97:3, 408C, retention times: 33.7 (major) and 37.8 min (minor).
(+)-(2-Methylbut-3-en-1-yl)diphenylphosphine oxide (2 f): The title com-
pound was prepared from 1c by following general procedure A. Purifica-
tion by column chromatography (SiO2, eluent n-pentane/EtOAc 1:1) af-
forded 2 f as a colorless oil (94% yield, SN2’/SN2 99:1, 99:1 e.r.). [a]2D0 = +
1
12.0 (c=1.0, CHCl3); H NMR (400 MHz, CDCl3): d=7.74 (m, 4H), 7.46
(m, 6H), 5.76 (m, 1H), 4.87 (m, 2H), 2.71 (m, 1H), 2.39 (m, 1H), 2.24
(m, 1H), 1.11 ppm (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=
143.5 (d, J=10.3 Hz), 133.7 (m, 2C), 131.5 (d, J=3.0 Hz, 2C), 130.7 (m,
4H), 128.6 (m, 4H), 112.8, 36.2 (d, J=70.4 Hz), 32.1 (d, J=3.3 Hz),
21.4 ppm (d, J=6.6 Hz); 31P NMR (161.9 MHz, CDCl3): d=30.8 ppm;
HRMS (ESI+): m/z calcd for C17H20OP: 271.1252 [M+H+]; found:
271.1246. The enantiomeric ratio was determined by chiral HPLC analy-
(À)-Dimethyl (2-vinylhex-5-en-1-yl)phosphonate (2j): The title com-
pound was prepared from 1a by following general procedure B with
(R,S,S)-L2 as the ligand. Purification by column chromatography (SiO2,
eluent n-pentane/EtOAc 7:3) afforded 2j as a colorless oil (93% yield,
SN2’/SN2 97:3, 98:2 e.r.). The enantiomeric ratio was determined for cross-
metathesis product 8j. [a]D20 =À6.0 (c=1.0, CHCl3); 1H NMR (400 MHz,
5438
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5432 – 5441

Asymmetric Allylic Alkylation
FULL PAPER
CDCl3): d=5.75 (m, 1H), 5.60 (m, 1H), 4.99 (m, 4H), 3.68 (d, J=
10.7 Hz, 6H), 2.46 (m, 1H), 2.01 (m, 2H), 1.82 (m, 1H), 1.78 (m, 1H),
1.61 (m, 1H), 1.39 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=141.1
(d, J=10.7 Hz), 138.1, 115.3, 114.7, 52.1 (m, 2C), 37.7 (d, J=3.7 Hz), 34.8
(d, J=11.8 Hz), 30.9, 30.5 ppm (d, J=140.1 Hz); 31P NMR (161.9 MHz,
CDCl3): d=33.1 ppm; HRMS (ESI+): m/z calcd for C12H26O3P: 219.1150
[M+H+]; found: 219.1145.
eluent n-heptane/iPrOH 99:1, 408C, retention times: 16.7 (minor) and
17.5 min (major).
(+)-(2-Methyl-2-vinylhex-5-en-1-yl)diphenylphosphine oxide (5b): The
title compound was prepared from (E)-4 by following general procedure
B with (S,R,R)-L6 as the ligand. Purification by column chromatography
(SiO2, eluent n-pentane/EtOAc 1:1) afforded 5b as a colorless oil (73%
yield, SN2’/SN2 89:11, 80:20 e.r.). [a]2D0 = +12.2 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.76 (m, 4H), 7.44 (m, 6H), 5.71 (m, 2H), 4.85
(m, 4H), 2.41 (m, 2H), 1.90 (m, 2H), 1.61 (m, 2H), 1.19 ppm (s, 3H);
13C NMR (101 MHz, CDCl3): d=145.9 (d, J=7.7 Hz), 138.7, 135.2 (m,
2C), 131.3 (m, 2C), 130.6 (m, 4C), 128.4 (m, 4C), 114.0, 112.0, 41.1 (d, J=
7.0 Hz), 40.6 (d, J=65.9 Hz), 40.2, 28.6, 24.1 ppm (d, J=5.2 Hz);
31P NMR (161.9 MHz, CDCl3): d=27.4 ppm; HRMS (ESI+): m/z calcd
for C21H25NaOP: 347.1541 [M+Na+]; found: 347.1535. The enantiomeric
excess was determined by chiral HPLC analysis, Chiralpak AS-H
column, eluent n-heptane/iPrOH 99:1, 408C, retention times: 23.0
(minor) and 24.3 min (major).
(+)-((2E,7E)-Diethyl 4-((dimethoxyphosphoryl)methyl)nona-2,7-diene-
dioate (8j): The reaction was performed by using the cross-metathesis
protocol, with a reaction time of 24 h. Purification by column chromatog-
raphy (SiO2, eluent n-pentane/EtOAc 3:7) afforded 8j as a colorless oil
(60% yield, all E/Z 10:1, 98:2 e.r.). [a]2D0 = +83.0 (c=1.0, CHCl3);
1H NMR (400 MHz, CDCl3): d=6.88 (m, 1H), 6.71 (dd, J=15.6, 9.2 Hz,
1H), 5.83 (dd, J=23.3, 15.6 Hz, 2H), 4.18 (m, 4H), 3.72 (m, 6H), 2.65
(m, 1H), 2.15 (m, 2H), 1.87 (m, 2H), 1.80 (m, 1H), 1.56 (m, 1H),
1.27 ppm (m, 6H); 13C NMR (101 MHz, CDCl3): d=166.4, 166.1, 149.7
(d, J=9.9 Hz), 147.4, 122.4, 122.0, 60.5, 60.2, 52.3 (m, 2C), 36.4 (d, J=
3.7 Hz) 33.2 (d, J=11.4 Hz), 29.8 (d, J=141.5 Hz), 29.4, 14.2 ppm (2C);
31P NMR (161.9 MHz, CDCl3): d=33.6 ppm; HRMS (ESI+): m/z calcd
for C16H27NaO7P: 385.1392 [M+Na+]; found: 385.1387. The enantiomeric
ratio was determined by chiral HPLC analysis, Chiralpak AD-H column,
eluent n-heptane/iPrOH 92:8, 408C, retention times: 35.7 (major) and
36.9 min (minor).
(+)-Diphenyl (2-ethyl-2-methylbut-3-enyl) phosphine oxide (5c): The
title compound was prepared from (E)-4 by following general procedure
B with (S,R,R)-L6 as the ligand. Purification by column chromatography
(SiO2, eluent n-pentane/EtOAc 1:1) afforded 5c as a colorless oil (85%
yield, SN2’/SN2 92:8, 78:22 e.r.). [a]2D0 = +10.0 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.75 (m, 4H), 7.50 (m, 6H), 5.71 (dd, J=17.4,
10.8 Hz, 1H), 4.84 (m, 2H), 2.38 (d, J=10.7 Hz, 2H), 1.57 (q, J=7.4 Hz,
2H), 1.13 (s, 3H), 0.74 ppm (t, J=7.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=145.9 (d, J=7.4 Hz), 135.2 (m, 2C), 130.6 (m, 4C), 128.4 (m,
4C), 111.9, 40.5 (d, J=4.1 Hz), 40.3 (d, J=70.4 Hz), 34.5 (d, J=7.4 Hz),
23.6 (d, J=5.5 Hz), 8.6 ppm; 31P NMR (161.9 MHz, CDCl3): d=
27.7 ppm; HRMS (ESI+): m/z calcd for C19H23NaOP: 321.1384 [M+Na+
]; found: 321.1379. The enantiomeric ratio was determined by chiral
HPLC analysis, Chiralpak AS-H column, eluent n-heptane/iPrOH 99:1,
408C, retention times: 22.0 (minor) and 23.2 min (major).
Synthesis of trisubstituted allyl halides 4: Allyl bromides (4) were synthe-
sized from the corresponding (E)- and (Z)-(4-hydroxybut-2-en-1-yl)di-
phenylphosphine oxides[43] as described below.
(E)-(4-Bromo-2-methylbut-2-en-1-yl)diphenylphosphine oxide (4): PBr3
(370 mL, 3.9 mmol) was added to a suspension of (E)-(4-hydroxybut-2-en-
1-yl)diphenylphosphine oxide (930 mg, 3.25 mmol) in Et2O (17 mL) at
08C, and the mixture was stirred for 2 h at 258C. The reaction was
quenched by the addition of saturated aqueous NaHCO3 (10 mL) and
the layers were separated. The aqueous layer was extracted with Et2O
(3ꢄ5 mL) and the combined organic layers were washed with water and
dried with anhydrous Na2SO4. The solvent was evaporated in vacuo to
(5-Methyl-5-vinylnona-1,3,8-trienyl)benzene
(7):
nBuLi
(0.09 mL,
0.22 mmol, 2.5m) was added dropwise to a stirred solution of 5 (70 mg,
0.22 mmol) in dry THF (5 mL) under nitrogen at À208C. After 15 min,
the solution was cooled to À788C and cinnamyl aldehyde (31 mg,
0.23 mmol) in THF (0.5 mL) was added dropwise. The mixture was al-
lowed to warm rapidly to 08C and saturated aqueous NH4Cl (3 mL) was
added. The aqueous layer was separated and extracted with AcOEt (3ꢄ
5 mL) and the combined organic layers were dried with anhydrous
Na2SO4, filtered, and the solvent was evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel with n-pen-
tane/EtOAc 1:1 as the eluent to give the corresponding alcohol as a pale
yellow solid (yield 117 mg) This alcohol was dissolved in dry DMF
(1 mL) and added to a stirred suspension of NaH (40 mg; 60% disper-
sion in mineral oil, previously washed with dry n-pentane) in DMF
(3 mL) and the solution was stirred at 258C for 2 h. Water (3 mL) was
added, the mixture was extracted with Et2O (3ꢄ5 mL), and the combined
extracts were washed with brine (10 mL), dried with anhydrous Na2SO4,
filtered, and the solvent was evaporated in vacuo. The crude product was
purified by flash chromatography on silica gel with pentane as the eluent
to give the product as a colorless oil (86% yield, E/Z 1:1, 80:20 e.r.).[44]
1H NMR (400 MHz, CDCl3): d=7.41–7.19 (m, 10H), 6.80 (dd, J=15.7,
10.3 Hz, 1H), 6.48 (dd, J=30.5, 15.8 Hz, 2H), 6.22–6.02 (m, 3H), 5.85
(m, 4H), 5.46 (d, J=11.6 Hz, 2H), 5.08 (m, 2H), 5.18–4.93 (m, 6H), 2.07
(m, 4H), 1.59 (m, 4H), 1.31 (s, 3H), 1.19 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=146.5, 145.5, 142.3, 139.1, 138.7, 137.6, 132.9,
130.8, 129.5, 129.4, 128.6 (2C), 128.5 (2C), 128.1, 127.4, 127.2, 126.3 (2C),
126.2 (2C), 125.7, 114.2, 114.1, 122.1, 111.7, 42.8, 42.6, 42.2, 40.3, 28.9,
28.8, 26.1, 23.3 ppm; HRMS (ESI+): m/z calcd for C18H23: 239.1800
[M+H+]; found: 239.1794. The enantiomeric excess was determined by
chiral HPLC analysis, Chiralcel OB-H column, eluent n-heptane/iPrOH
100:0, 408C, retention times: 8.46 (minor) and 9.37 min (major).
1
give the bromide as a pale yellow solid (90% yield). H NMR (400 MHz,
CDCl3): d=7.74 (m, 4H), 7.49 (m, 6H), 5.42 (q, J=5.5 Hz, 1H), 3.87
(dd, J=8.5, 2.3 Hz, 2H), 3.14 (d, J=14.1 Hz, 2H), 1.79 ppm (brs, 3H);
13C NMR (101 MHz, CDCl3): d=133.9 (d, J=10.7 Hz), 132.2 (d, J=
99.1 Hz, 2C), 131.9 (d, J=2.6 Hz, 2C), 131.0 (d, J=9.2 Hz, 4C), 128.6 (d,
J=11.4 Hz, 4C), 126.0 (d, J=10.3 Hz), 41.2 (d, J=67.1 Hz), 28.2,
18.1 ppm; 31P NMR (161.9 MHz, CDCl3): d=29.8 ppm; HRMS (ESI+):
m/z calcd for C17H19BrOP: 349.0357 [M+H+]; found: 349.0351.
(Z)-Diphenyl (4-bromo-2-methylbut-2-enyl) phosphine oxide ((Z)-4):
The title compound was prepared from (Z)-(4-hydroxybut-2-en-1-yl)di-
phenylphosphine oxide (540 mg, 1.89 mmol), and PBr3 (215 mL,
2.26 mmol) in Et2O (10 mL) by following the procedure described for
(E)-4 (93% yield). 1H NMR (400 MHz, CDCl3): d=7.7 (m, 4H), 7.5 (m,
6H), 5.7 (q, J=4.9 Hz, 1H), 3.7 (d, J=8.5 Hz, 2H), 3.2 (d, J=14.6 Hz,
2H), 1.7 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=132.8 (d, J=
9.5 Hz), 132.5 (d, J=98.4 Hz, 2C), 132.0 (d, J=2.9 Hz, 2C), 130.9 (d, J=
9.2 Hz, 4C), 128.7 (d, J=11.8 Hz, 4C), 125.9 (d, J=9.6 Hz), 34.9 (d, J=
68.0 Hz), 29.2, 25.7 ppm; 31P NMR (161.9 MHz, CDCl3): d=27.5 ppm;
HRMS (ESI+): m/z calcd for C17H19BrOP: 349.0357 [M+H+]; found:
349.0351.
(+)-Diphenyl (2-methyl-2-vinyloctyl) phosphine oxide (5a): The title
compound was prepared from (E)-4 by following general procedure B
with (S,R,R)-L6 as the ligand. Purification by column chromatography
(SiO2, eluent n-pentane/EtOAc 1:1) afforded 5a as a colorless oil (68%
yield, SN2’/SN2 87:13, 79:21 e.r.). [a]2D0 = +19.2 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.76 (m, 4H), 7.45 (m, 6H), 5.74 (dd, J=17.6,
10.7 Hz, 1H), 4.85 (m, 2H), 2.39 (m, 2H), 1.48 (m, 2H), 1.30–1.00 (m,
8H), 1.12 (s, 3H), 0.83 ppm (t, J=7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=146.5 (d, J=7.7 Hz), 135.3 (m, 2C), 131.2 (m, 2C), 130.6 (m,
4C), 128.4 (m, 4C), 111.5, 42.2 (d, J=7.0 Hz), 40.5 (d, J=70.4 Hz), 40.3
(d, J=4.3 Hz), 31.7, 29.7, 24.3 (d, J=5.9 Hz), 24.2, 22.6, 14.0 ppm;
31P NMR (161.9 MHz, CDCl3): d=27.5 ppm; HRMS (ESI+): m/z calcd
for C23H31NaOP: 377.2010 [M+Na+]; found: 377.2004. The enantiomeric
ratio was determined by chiral HPLC analysis, Chiralpak AS-H column,
(2-Methylbut-3-en-1-yl)diphenylphosphine (9): Compound 2 f (64.0 mg,
0.24 mmol) and CuACTHNUTRGNEUNG(OTf)2 (13.0 mg, 0.025 mmol) were added to a 10 mL
Schlenk tube at RT. Silane (90 mL, 0.5 mmol) and toluene (2 mL) were
then added under an argon flow. The reaction mixture was stirred for 3 h
at 1008C and the solvent was then removed under vacuum. The residue
Chem. Eur. J. 2013, 19, 5432 – 5441
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5439

B. L. Feringa et al.
was dissolved in degassed CDCl3 and the conversion was determined by
31P NMR spectroscopy, as described by Beller and co-workers[8] (89%
conversion, 68% yield). 1H NMR (400 MHz, CDCl3): d=7.43 (m, 4H),
7.31 (m, 6H), 5.82 (m, 1H), 4.95 (m, 2H), 2.24 (m, 1H), 2.15 (m, 1H),
2.05 (m, 1H), 1.14 ppm (d, J=6.6 Hz, 3H); 31P NMR (161.9 MHz,
CDCl3): d=À20.6 ppm; EI MS: m/z (%): 253 [M+], 239 (100) [MÀCH3].
This transformation proceeded without loss of enantiomeric purity, as
confirmed by reoxidation to phosphine oxide 2 f under air followed by
chiral HPLC analysis.
[5] Biomedical Chemistry, Applying Chemical Principles to the Under-
standing and Treatment of Disease, (Ed: P. F. Torrence), Wiley, New
York, 2000, pp. 195–199.
[6] Modern Carbonyl Olefination, (Ed: T. Takeda), Wiley-VCH, Wein-
heim, 2004.
[7] S. Aoki, S. Kotani, M. Sugiura, M. Nakajima, Chem. Commun. 2012,
48, 5524–5526.
[8] Y. Li, S. Das, S. Zhou, K. Junge, M. Beller, J. Am. Chem. Soc. 2012,
134, 9727–9732.
[9] a) S. E. Denmark, C.-T. Chen, J. Am. Chem. Soc. 1995, 117, 11879;
b) W. Bhanthumnavin, W. G. Bentrude, J. Org. Chem. 2001, 66, 980
and references cited therein; c) M. O. Shulyupin, G. Francioꢆ, I. P.
Beletskaya, W. Leitner, Adv. Synth. Catal. 2005, 347, 667; d) P. Cher-
uku, A. Paptchikhine, T. L. Church, P. G. J. Andersson, J. Am.
Chem. Soc. 2009, 131, 8285–8289 and references cited there; e) K.
Dong, Z. Wang, K. Ding, J. Am. Chem. Soc. 2012, 134, 12474–
12477; f) N. S. Goulioukina, T. M. Dolgina, G. N. Bondarenko, I. P.
Beletskaya, M. M. Ilyin, V. A. Davankov, A. Pfaltz, Tetrahedron:
Asymmetry 2003, 14, 1397–1401.
(+)-[(2-Methylbut-3-en-1-yl)diphenylphosphonio]trihydroborate (10): In
an oven-dried Schlenk tube equipped with septum and stirring bar under
a N2 atmosphere, phosphine 9 (0.16 mmol, 45 mg) was dissolved in anhy-
drous THF (1.0 mL) and BH3THF (1m) in THF (0.16 mmol, 160 mL) was
then added dropwise. The reaction mixture was stirred for 30 min, then
the solvent was concentrated in vacuo. Flash column chromatography
(SiO2, eluent EtOAc/pentane 1:9) afforded 10 as a waxy solid (74%
yield). [a]2D0 =+14 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.68
(m, 4H), 7.44 (m, 6H), 5.66 (m, 1H), 4.85 (m, 2H), 2.70 (m, 1H), 2.36
(m, 1H), 2.20 (m, 1H), 1.58 (brs, 3H), 1.10 ppm (d, J=6.7 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=143.3 (d, J=9.3 Hz), 132.1 (m, 2C),
131.0 (m, 6C), 128.7 (m, 4C), 113.1, 32.9 (d, J=45.4 Hz), 29.7, 21.7 ppm
(d, J=6.6 Hz); 31P NMR (161.9 MHz, CDCl3): d=14.4 ppm; HRMS
(ESI+): m/z calcd for C17H22BP: 269.1625 [M+H+]; found: 269.1625.
[10] M. Capuzzi, D. Perdicchia, K. A. Jørgensen, Chem. Eur. J. 2008, 14,
128–135.
[11] S. Sulzer-Mossꢀ, M. Tissot, A. Alexakis, Org. Lett. 2007, 9, 3749–
3752.
Mechanistic studies: 31P NMR spectroscopy experiments were carried out
[12] S. C. Cullen, T. Rovis, Org. Lett. 2008, 10, 3141–3144.
[13] C. B. Tripathi, S. Kayal, S. Mukherjee, Org. Lett. 2012, 14, 3296–
3299.
[14] A. Albrecht, F. Morana, A. Fraile, K. A. Jørgensen, Chem. Eur. J.
2012, 18, 10348–10354.
[15] a) Z.-C. Duan, X.-P. Hu, D.-Y. Wang, J.-D. Huang, S.-B. Yu, J. Deng,
Z. Zheng, Adv. Synth. Catal. 2008, 350, 1979–1983; b) Z.-C. Duan,
X.-P. Hu, C. Zhang, D.-Y. Wang, S.-B. Yu, Z. Zheng, J. Org. Chem.
2009, 74, 9191–9194; c) T. Konno, K. Shimizu, K. Ogata, S.-i. Fuku-
zawa, J. Org. Chem. 2012, 77, 3318–3324.
in NMR tubes under
a
nitrogen atmosphere at À808C by adding
MeMgBr (7.0 equiv, 3m) in Et2O to a mixture of phosphine oxide and
preformed catalyst (1.0 equiv of copper bromide-(R,R)-Taniaphos) at
À808C in CD2Cl2. The conversion was monitored by recording a spec-
trum every 5 min unless noted (Scheme 1). The sample was rapidly re-
moved and inserted into an NMR spectrometer (keeping the temperature
at À808C) before recording each spectrum to facilitate the stirring of the
reaction mixture. PPh3 in a sealed capillary tube was used as a reference.
Allyl diphenyl phosphine oxide (11) or 2-methylbut-3-en-2-yl-diphenyl-
phosphine oxide[45] (12; 15 mg) in CD2Cl2 (800 mL) were also treated with
MeMgBr (100 mL) at RT in an NMR tube. As observed before for com-
pound 2 f, in both cases the phosphorus resonance evolved rapidly to a
new signal at low field (d=38.1 (11) and 36.2 ppm (12)). After quenching
the reaction of 11 with D2O, CD3OD, or DCl, deuterium incorporation in
the a position was not observed (for details see the Supporting Informa-
tion).
[16] Z.-C. Duan, X.-P. Hu, D.-Y. Wang, S.-B. Yu, Z. Zheng, Tetrahedron
Lett. 2009, 50, 6720–6722.
[17] T. Hayashi, T. Senda, Y. Takaya, M. Ogasawara, J. Am. Chem. Soc.
1999, 121, 11591–11592.
[18] For reviews, see: a) J.-B. Langlois, A. Alexakis, in Transition Metal
Catalyzed Enantioselective Allylic Substitution in Organic Synthesis
(Ed: U. Kazmaier), Springer-Verlag: Berlin Heidelberg 2012;
b) S.R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard,
B. L. Feringa, Chem. Rev. 2008, 108, 2824–2852; c) A. Alexakis,
J. E. Bꢇckvall, N. Krause, O. Pꢈmies, M. Diꢀguez, Chem. Rev. 2008,
108, 2796–2823; d) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem.
2008, 3765–3780; e) A. S. E. Karlstrçm, J. E. Bꢇckvall, in Modern
Organocopper Chemistry (Ed: N. Krause), Wiley-VCH, Weinheim,
2002.
[19] a) T. den Hartog, B. Maciꢁ, A. J. Minnaard, B. L. Feringa, Adv.
Synth. Catal. 2010, 352, 999–1013; b) A. W. van Zijl, F. Lꢉpez, A. J.
Minnaard, B. L. Feringa, J. Org. Chem. 2007, 72, 2558.
[20] F. Lꢉpez, A. W. van Zijl, A. J. Minnaard, B. L. Feringa, Chem.
Commun. 2006, 409–411.
Acknowledgements
We thank the Netherlands Organization for Scientific Research (NWO-
CW) and the National Research School Catalysis (NRSC-C) for financial
support. V.H. thanks the Spanish Ministry of Science and Innovation
(MICINN) for a postdoctoral fellowship. M.P. thanks the Xunta de Gali-
cia for an ꢅngeles AlvariÇo contract.
[21] L. Raffier, O. Piva, Beilstein J. Org. Chem. 2011, 7, 151.
[22] J. F. Teichert, B. L. Feringa, Angew. Chem. 2010, 122, 2538–2582;
Angew. Chem. Int. Ed. 2010, 49, 2486–2528.
[23] a) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. 2004, 116,
2480–2482; Angew. Chem. Int. Ed. 2004, 43, 2426–2428; Angew.
Chem. 2004, 116, 2480–2482; b) M. FaÇanꢁs-Mastral, B. L. Feringa,
J. Am. Chem. Soc. 2010, 132, 13152–13153; c) J.-B. Langlois, A.
Alexakis, Adv. Synth. Catal. 2010, 352, 447–457.
[24] When the reaction was performed with a Cu/L2 ratio of 1:2, product
2i was obtained with a branched/linear ratio of 90:10 and 88:12 e.r.
[25] J. Zhou, J. H. Neale, M. G. Pomper, A. P. Kozikowski, Nat. Rev.
Drug Discovery 2005, 4, 1015–1026.
[1] J. T. Hwang, J. R. Choi, Drugs Future 2004, 29, 163–177.
[2] a) W. J. Tang, X. M. Zhang, Chem. Rev. 2003, 103, 3029–3069;
b) Y. G. Zhou, Acc. Chem. Res. 2007, 40, 1357–1366.
[3] a) R. L. Hilderbrand, in the Role of Phosphonates in Living Systems,
CRC Press, Boca Raton, 1983; b) C.-H. L. Lo, P. Wentworth, K. W.
Jung, J. Yoon, J. A. Ashley, K. D. Janda, J. Am. Chem. Soc. 1997,
119, 10251–10252; c) A. Datta, P. Wentworth, J. P. Shaw, A. Simeo-
nov, K. D. Janda, J. Am. Chem. Soc. 1999, 121, 10461–10467; d) P.
Kafarski, B. Lejczak, Curr. Med. Chem.-Anti-Cancer Agents 2001, 1,
301–312; e) O. I. Kolodiazhnyi, Tetrahedron: Asymmetry 2005, 16,
3295–3340; f) C. S. Demmer, N. Krogsgaard-Larsen, L. Bunch,
Chem. Rev. 2011, 111, 7981–8006.
[4] a) S. E. Kelly, in Comprehensive Organic Synthesis Vol. 1, (Eds:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 761–773; b) P.
Savignac, B. Iorga, in Modern Phosphonate Chemistry, CRC Press,
BocaRaton, 2003.
5440
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5432 – 5441

Asymmetric Allylic Alkylation
FULL PAPER
[26] For a recent review, see: J. Prakash, I. Marek, Chem. Commun.
2011, 47, 4593–4623.
[27] M. FaÇanꢁs-Mastral, M. Pꢀrez, P. H. Bos, A. Rudolph, S. R. Haru-
tyunyan, B. L. Feringa, Angew. Chem. 2012, 124, 1958–1961; Angew.
Chem. Int. Ed. 2012, 51, 1922–1925.
[28] R. Majeed, M. V. Reddy, P. K. Chinthakindi, P. L. Sangwan, A.
Hamid, I. A. Khan, S. S. Chimni, S. Koul, Eur. J. Med. Chem. 2012,
49, 55–67 and references cited therein.
[36] The solution in the NMR tube was allowed to warm to RT because
of the slow reaction rate in the absence of stirring.
[37] The fact that the linear product was also observed in these experi-
ments is attributed to an increase in the temperature of the solution.
[38] Y. Kabbaj, H. B. Lazrek, J. L. Barascut, J. L. Imbach, Nucleosides
Nucleotides Nucleic Acids 2005, 24, 161–172.
[39] M. J. Williams, H. L. Deak, M. L. Snapper, J. Am. Chem. Soc. 2007,
129, 486–487.
[29] R. H. Grubbs, Angew. Chem. 2006, 118, 3845–3850; Angew. Chem.
Int. Ed. 2006, 45, 3760–3765.
[40] B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. De V-
ries, Angew. Chem. 1997, 109, 2733–2736; Angew. Chem. Int. Ed.
Engl. 1997, 36, 2620–2623.
[41] K. Tissot-Croset, D. Polet, S. Gille, C. Hawner, A. Alexakis, Synthe-
sis 2004, 2586–2590.
[30] P. Shapland, E. Vedejs, J. Org. Chem. 2004, 69, 4094–4100.
[31] For more details about the mechanism of the Cu-catalyzed AAA,
see: a) N. Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339–
2372; b) C. C. Tseng, S. D. Paisley, H. L. Goering, J. Org. Chem.
1986, 51, 2884.
[42] Y. H. Choi, J. Y. Choi, H. Y. Yang, Y. H. Kim, Tetrahedron: Asym-
metry 2002, 13, 801–804.
[32] M. Pꢀrez, M. FaÇanꢁs-Mastral, P. H. Bos, A. Rudolph, S. R. Haru-
tyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 377–381.
[33] At this temperature a broad singlet was observed instead of the two
distinct expected doublets (À18 and À20 ppm) for the phosphorus–
phosphorus coupling. For the characterization of complex C1, see
reference [32].
[43] P. S. Brown, N. Greeves, A. B. McElroy, S. Warren, J. Chem. Soc.
Perkin Trans. 1 1991, 1485–1492.
[44] R. K. Haynes, S. C. Vonwiller, T. W. Hambley, J. Org. Chem. 1989,
54, 5162.
[45] J. I. Grayson, S. Warren, A. T. Zaslona, J. Chem. Soc. Perkin Trans.
1 1987, 967–976.
[34] M. F. Davis, W. Levason, R. Ratnani, G. Reid, M. Webstera, New J.
Chem. 2006, 30, 782–790 and references cited there.
[35] The appearance of these new peaks (t9–t14) are attributed to the for-
mation of different reaction intermediates, however, their structure
have not been identified yet.
Received: December 7, 2012
Published online: February 27, 2013
Chem. Eur. J. 2013, 19, 5432 – 5441
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5441