Synthesis of homoallylic alcohols via lewis acid assisted enantioselective desymmetrization

Article abstract of DOI:10.1055/s-0028-1083368

A highly enantioselective allylic substitution of (Z)-but-2-ene-1,4-diol derivatives was developed using a rhodium(I) catalyst and arylboronic acids as nucleophiles. The reaction yields versatile homoallylic alcohols from readily available linear biscarbonates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083368

PAPER
853
Synthesis of Homoallylic Alcohols via Lewis Acid Assisted Enantioselective
Desymmetrization
Synthesis of
H
om
i
oallyli
n
c
A
lcohols g Yu, Frederic Menard, Naohiro Isono, Mark Lautens*
Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9468185; E-mail: mlautens@chem.utoronto.ca
Received 30 October 2008; revised 3 November 2008
dence suggests that the two reactions in fact proceed by
different mechanisms.
Abstract: A highly enantioselective allylic substitution of (Z)-but-
2-ene-1,4-diol derivatives was developed using a rhodium(I) cata-
lyst and arylboronic acids as nucleophiles. The reaction yields ver-
satile homoallylic alcohols from readily available linear
biscarbonates.
Under our previously reported conditions, the desired
branched product 2a was obtained with the best combined
yield and selectivity using Chan’s bispyridyl bisphos-
phine ligand L5 (P-Phos; Figure 1 and Table 1).15
Key words: homoallylic alcohols, rhodium, boronic acids, desym-
metrization, asymmetric allylic substitution
O
Cl
O
Chiral small molecules are of interest for their use as
building blocks in total synthesis and in medicinal chem-
istry. As part of our program aimed at developing stereo-
selective addition reactions to alkenes, we sought to
extend our rhodium-catalyzed methodology to linear al-
lylic derivatives 1.1,2 Thus, versatile chiral synthons 2
could be accessed, which bear three differentiated func-
tional groups for use as synthetic handles: a terminal alk-
ene, a protected alcohol, and a substituted arene
(Equation 1).3 We report herein a simple, useful protocol
that effects the desymmetrization of allylic carbonates
with arylboronic acids in high selectivity using a rhodi-
um(I) catalyst and P-Phos as chiral ligand.4,5
O
O
O
O
PPh2
PPh2
PPh2
PPh2
MeO
MeO
PPh2
PPh2
O
O
Cl
L3, (R)-SEGPHOS
L1, (R)-SYNPHOS
L2, (R)-Cl-MeO-BIPHEP
OMe
N
O
F
F
O
O
PPh2
PPh2
MeO
MeO
PR2
PR2
PPh2
PPh2
F
F
N
O
OMe
catalyst
ArB(OH)2
OR
Ar
Ar
L7, (R)-DIFLUORPHOS
L4, (R)-BINAP
(R)-P-PHOS
RO
OR
+
L5 R = Ph
L6 R = 3,5-(Me)2C6H3
RO
1
2
3
Figure 1 Ligands tested in this study
Equation 1
However, the regioselectivity was highly variable and de-
pended strongly on the nature of the ligand. Specifically,
P-Phos and DiFluorPhos16 (Figure 1), ligands that are
electron-donating by p-resonance but electron-deficient
by s-induction, gave optimal selectivity (entries 6 and 7).
Whereas cyclic substrates reacted best with Xyl-P-Phos
(L6) in our previous report,2 here the bulky groups on
phosphorus atoms of this ligand led to low selectivity, al-
though the yield was high (entry 4). DiFluorPhos showed
selectivities slightly higher than those obtained with P-
Phos, but we pursued our studies with P-Phos, mostly ow-
ing to its availability. It should be noted that the reaction
needs to be conducted under a strictly inert atmosphere.17
Symmetrical linear butenediol derivatives 1 are attractive
because of their ease of preparation and commercial avail-
ability. A number of palladium-catalyzed asymmetric al-
lylic substitutions (AAS) are known,6 but only a few allow
AAS with hard carbon nucleophiles7 and most are con-
ducted with more reactive cyclic substrates.8 Unsymmet-
rical allylic systems that either bear a single leaving group
or are electronically biased have led to exceptional results
with rhodium,9 iridium,10 and copper11,12 catalysts.13 Im-
portantly, Murakami and co-workers reported a simple
transformation whereby free alcohols of 1 reacted with tri-
arylboroxines to give alcohol 2b regioselectively.14 Al-
though the present reaction is very similar in appearance
to Murakami’s based on the products, experimental evi-
The effect of additives was investigated with P-Phos in or-
der to improve the conversion while maintaining the re-
gio- and enantioselectivity. When Lewis acids that might
activate the carbonate leaving groups were screened, it
was found that a substoichiometric amount of zinc triflate
SYNTHESIS 2009, No. 5, pp 0853–0859
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083368; Art ID: Z23208SS
© Georg Thieme Verlag Stuttgart · New York

854
B. Yu et al.
PAPER
Table 1 Ligand Screeninga
Table 3 Influence of the Leaving Groupa
[Rh(cod)OH]2
OR
[Rh(cod)OH]2, L5
OR
ligand
4-MeC6H4B(OH)2
RO
PhB(OH)2
RO
OR
3a
+
Zn(OTf)2
Cs2CO3
dioxane, 50 °C
Cs2CO3
dioxane, 50 °C
OR
1a, 4–8
9a,c–g
9b, R = H
K2CO3
MeOH
1a, R = CO2Et
2a, R = CO2Et
2b, R = H
K2CO3
MeOH
Entry
R
Yield (%)b r.r.c
ee (%)d
93
Entry
Ligand
L1
Yield (%)b 2a/3ac
ee (%)d
50
1
2
3
4
5
6
CO2Et (1a)
CO2i-Pr (4)
CO2CH2CF3 (5)
CO2Ph (6)
59
50
76
64
35
>20:1
1
2
3
4
5
6
7
57
41
24
80
40
50
45
1:1.5
1.2:1
1.2:1
2:1
10:1
1:1
4:1
7:1
7:1
90
L2
50
53
L3
62
68
L6
70
COPh (7)
90
L4
5:1
40
COC6H4(4-OMe) (8) 36
93
L5
8:1
91
a Reagents and conditions as described in Table 2.
L7
10:1
93
b Isolated yield of combined branched 2 and linear 3 products.
c Regioisomeric ratio (branched:linear) determined by 1H NMR.
d Determined by chiral HPLC or GC analyses of deprotected 9b.
a Reagents and conditions: [Rh]2 (5 mol%), ligand (12 mol%),
PhB(OH)2 (2.0 equiv), Cs2CO3 (1.0 equiv).
b Isolated yield of combined branched 2 and linear 3 carbonates.
c Regioisomeric ratio (branched/linear) determined by 1H NMR.
d Determined by chiral HPLC or GC analyses of deprotected 2b
(K2CO3, MeOH, r.t., 3 h).
acid was used as nucleophile because its moderate reactiv-
ity would provide a reference point in seeking better con-
ditions. Ethyl biscarbonate 1 remained the best substrate
(Table 3). Substrates bearing weakly coordinating leaving
groups led to low regio- and enantioselectivity (entries 3
and 4), whereas more electron-rich leaving groups led to
higher ee (entries 2 and 6). In view of the clean reaction
profile, we settled on the use of ethyl carbonates to ex-
plore the scope of the reaction. It should be noted that un-
reacted 1a was always recovered along with the desired
products (yields were >90% when based on recovered
starting material).
Table 2 Effect of Lewis Acidsa
OR
[Rh(cod)OH]2, L5
PhB(OH)2
RO
OR
Lewis acid
Cs2CO3
dioxane, 55 °C
1a, R = CO2Et
2a, R = CO2Et
2b, R = H
Entry
Lewis acid
–
Yield (%)b 2a/3ac
ee (%)d
87
A selection of arylboronic acids tested in this reaction is
shown in Table 4. The reaction is highly enantioselective,
and we observed that electron-rich aryl groups are best
suited for this transformation in terms of regioselectivity.
Substitution at the meta- or para-position on the boronic
acid is also tolerated. However, ortho-substituents lead to
significantly diminished yields when compared to the
para-isomers. Nucleophiles that did not react under these
conditions included boronic acids bearing functional
groups such as a protected amine, aldehyde, nitro, and
bromide.
1
2
3
4
5
42
65
55
85
76
10:1
17:1
8:1
AgOTf
CuOTf
Zn(OTf)2
La(OTf)3
81
95
10:1
10:1
94
88
a Reagents and conditions: [Rh]2 (5 mol%), ligand (12 mol%),
ArB(OH)2 (2.0 equiv), Cs2CO3 (1.0 equiv), Lewis acid (20 mol%).
b Isolated yield of combined branched 2 and linear 3 carbonates.
c Regioisomeric ratio (branched/linear) determined by 1H NMR.
d Determined by chiral HPLC or GC analyses of deprotected 2b.
Two proposed mechanistic scenarios are illustrated in
Scheme 1. Our results suggest that pathway (a) may be
dominant. An ionization mechanism is distinctly different
from the one proposed by Murakami.14 Pathway (a) in-
volves oxidative ionization of the catalyst to form a
Rh(III) s–enyl intermediate A, which can slowly isomer-
ize to B, as described by Nelson and Evans.18 Reductive
elimination from either A or B then yields products 2 or 3,
respectively. Therefore, the product distribution may be
dictated by the competing rates of reductive elimination
proved to be most effective (Table 2). Its presence was
crucial to get full conversion of the substrate. Other Lewis
acids were tested (TiCl4, BF3, AlCl3 and TBSOTf), but
none afforded the desired products. With an acceptable
catalytic system in hand, we looked at the influence of the
leaving groups.
A range of substrates were prepared in quantitative yield
by bis-acylation of (Z)-but-2-ene-1,4-diol. 4-Tolylboronic
Synthesis 2009, No. 5, 853–859 © Thieme Stuttgart · New York

PAPER
Synthesis of Homoallylic Alcohols
855
Table 4 Scope of Boronic Acidsa
(a) RhIII σ-enyl pathway
L.A.
RO
[Rh(cod)OH]2
P-PHOS (L5)
OR
Ar
OR
OR
ArB(OH)2
+
Zn(OTf)2
Cs2CO3
dioxane, 50 °C
RO
[RhI]
1a
2a, 9a–18a, R = CO2Et
2b, 9b–18b, R = H
1a
oxidative
addition
(P)2Rh-Ar(X)
X = OH, OR, solvent
Entry Ar
Product
Yield r.r.c
(%)b
ee
(%)d
OR
X
P
X
P
OR
RhIII
1
2
Ph
4-MeC6H4
2a
85
10:1
>20:1
>20:1
10:1
4:1
94
93
93
95
67
92
87
88
70
65
90
RhIII
Ar
P
slow
Ar
P
9a
59
60
65
66
68
45
38
66
32
61
A
B
3
4-MeOC6H4
4-ClC6H4
10a
11a
12a
13a
14a
15a
16a
17a
18a
reductive
elimination
reductive
elimination
4
OR
OR
19
5
4-FC6H4
+
Ar
Ar
2a
6
3,4-(MeO)2C6H3
3-Me-4-MeOC6H3
3-MeC6H4
7:1
3a
7
10:1
10:1
4:1
(b) Carbo-rhodation pathway
RO
P
OR
8
(P)2Rh-Ar(X)
2a
1a
RhI
Ar
9
3-ClC6H4
carbo-
β-oxy
rhodation
elimination
P
10
11
1-naphthyl
>20:1
>20:1
C
2-naphthyl
OR
OR
Ar
a Reagents and conditions as described in Table 2.
Ar
b Isolated yield of combined branched 2 and linear 3 carbonates.
c Regioisomeric ratio (branched/linear) determined by 1H NMR.
d Determined by chiral HPLC or GC analyses of deprotected 2b and
9b–18b (K2CO3, MeOH, r.t., 3 h).
19
2014
not observed
Scheme 1 Possible mechanistic pathways
versus isomerization, and may depend on the species co-
ordinated to the s–enyl complex.
electron-rich leaving groups lead to higher ee and regiose-
lectivity provides experimental support for pathway (a).
Alternatively, carbometalation of the alkene leading to C,
followed by simple elimination, cannot be ruled out (path-
way b), although it would not explain the formation of lin-
ear product 3. Notably, we did not observe by-product 20,
which was previously reported and can only occur by
pathway (b).14 The only side-product sometimes formed
was 19, which can arise from isomerization of 3. Impor-
tantly, pathway (a) may not be accessible by Murakami’s
protocol, based on stereoelectronic aspects. Indeed, these
authors have shown through control experiments that a
cyclic intermediate tying up both oxygens of C is neces-
sary for their system, and the seven-membered ring thus
formed does not allow the required alignment of allylic
oxygens with the alkene to form Rh(III) complexes A or
B. It may also explain why, in contrast to Murakami’s re-
port, carbonates are suitable substrates.
The current study shows that symmetrical, linear allylic
biscarbonates are good substrates for enantioselective de-
symmetrizations. The method complements alternative
procedures, as it provides enantioenriched, protected ho-
moallylic alcohols. Although conversion could be im-
proved, the commercial availability of starting materials
and reagents makes this system useful, yielding important
chiral building blocks in one step with high ee.
In conclusion, we report a highly enantioselective rhodi-
um-catalyzed arylative allylic substitution reaction, as-
sisted by Lewis acids. The reaction generates optically
active 2-arylbut-3-enyl carbonates in high regio- and
enantioselectivity from easily accessible substrates and
reagents.
[Rh(cod)OH]2 was prepared from [Rh(cod)Cl]2 following a litera-
ture procedure.19 Dioxane was purified by distillation under N2 from
Na/benzophenone immediately prior to use. Pentane and EtOAc
used for chromatographic purification were purchased from Cale-
don Laboratories Ltd. and used without further purification. Micro-
wave sealed tubes (1.0–4.0 mL tubes with Teflon septa and
aluminum crimps) were purchased from Biotage. All reactions were
performed under either N2 or argon. All solvents used were freshly
distilled and degassed. Organic solvents were removed by rotary
evaporation using the house vacuum (40 torr) or a water aspirator.
The marked increase in yield when a metal-based Lewis
acid is used may be due to activation of the leaving groups
of 1a, thereby facilitating an ionization process (pathway
a). We showed that the leaving groups are clearly in-
volved, and their influence on regio- and enantioselectiv-
ity suggests that the released counterions may be bound to
rhodium complexes A and B, and influence the relative
rates of isomerization/reductive elimination. The fact that
Synthesis 2009, No. 5, 853–859 © Thieme Stuttgart · New York

856
B. Yu et al.
PAPER
Analytical TLC plates were used (glass or aluminum-backed E.M.
Merck plates; 0.25 mm, 60 Å pore size). TLC visualization: 254 nm
UV light, then immersion in acidic vanillin solution, followed by
heating with a heatgun. Purification was performed by flash chro-
matography with Silicycle™ Ultra-pure 230–400 mesh silica gel.
1H NMR and 13C NMR spectra were recorded at 25 °C either on a
Varian 400 (400/100 MHz) spectrometer with an ATB8123-400
probe, or on a Varian Mercury 400 (400/100 MHz) with a Nalorac4
N-400 probe. Chemical shifts (d) for 1H and 13C NMR spectra are
reported in ppm relative to TMS using residual solvent signal as an
internal reference. Data is represented as follows: chemical shift
(multiplicity, coupling constant and integration). Infrared spectra
were recorded using a Shimadzu FTIR-8400S spectrometer. High-
resolution EI mass spectra were obtained with a SI2 Micromass
70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar mass spec-
trometer (ESI).
IR (NaCl, neat): 2983, 1770, 1454, 1417, 1354, 1381, 1354, 1171,
1021, 968 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.86 (ddd, J = 1.2, 4.1, 5.2 Hz,
2 H), 4.82 (dd, J = 1.3, 4.1 Hz, 4 H), 4.51 (q, J = 8.2 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 153.9, 128.1, 64.2, 63.9, 63.5.
19F NMR (376 MHz, CDCl3): d = –74.67 (t, J = 8.2 Hz, 1 H).
HRMS-EI: m/z [M]+ calcd for C10H10O6F6: 340.0382; found:
340.0385.
(Z)-But-2-ene-1,4-bis(phenylcarbonate) (6)
Prepared according to the typical procedure described for 1a.
Yield: 96%; colorless oil.
IR (NaCl, neat): 3061, 2966, 1761, 1593, 1492, 1348, 1236, 1205,
1058 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.42–7.35 (m, 4 H), 7.29–7.22 (m,
2 H), 7.21–7.14 (m, 4 H), 5.94 (m, 2 H), 4.90 (t, J = 7.6 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 153.7, 151.2, 129.7, 128.2, 126.3,
121.2, 63.9.
HRMS-EI: m/z [M + Na]+ calcd for C18H16O6Na: 351.0839; found:
351.0839.
(Z)-But-2-ene-1,4-bis(ethylcarbonate) (1a); Typical Procedure
(Z)-But-2-ene-1,4-diol (5.0 g, 56.7 mmol) was suspended in CH2Cl2
(280 mL) and the flask was capped with a septum, then purged with
a stream of N2, and cooled to 5 °C using an ice bath. ClCO2Et (16.0
mL, 3.0 equiv) was added via syringe, followed by careful addition
of pyridine (16.0 mL, 4.0 equiv), ensuring a controlled exothermic
reaction. The solution turned from colorless to bright pink, together
with the formation of a white precipitate. The reaction was allowed
to warm to r.t. until completion (~4 h, reaction monitored by TLC;
longer stirring, i.e. overnight, did not affect the reaction). The reac-
tion was extracted successively with sat. aq NH4Cl (200 mL, 100
mL then 50 mL). The combined aqueous layer was extracted with
Et2O (200 mL) and the combined organic layer was dried with brine
(50 mL), then MgSO4, filtered and concentrated under reduced
pressure to yield an amber fluid (17 g). The crude oil was purified
by silica gel chromatography (EtOAc–pentane, 10%) to give 1a.
Characterization data for 1a matched those in literature reports.20
(Z)-But-2-ene-1,4-bisbenzoate (7)
Prepared according to the typical procedure described for 1a.
Yield: 94%; colorless crystals; mp 83–84 °C.
IR (NaCl, neat): 3061, 3034, 2966, 1748, 1601, 1448, 1346, 1267,
1107, 1095, 1070, 1024, 966, 940 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09–7.99 (m, 4 H), 7.59–7.52 (m,
2 H), 7.43 (t, J = 7.7 Hz, 4 H), 5.98–5.89 (m, 2 H), 5.00 (d, J = 5.2
Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 166.6, 133.3, 130.2, 129.9, 128.6,
128.6, 60.8.
Yield: 13.2 g (99% yield); colorless fluid oil.
HRMS-EI: m/z [M]+ calcd for C18H16O2: 296.1049; found:
296.1042.
(Z)-But-2-ene-1,4-bis(isopropylcarbonate) (4)
Prepared according to the typical procedure described for 1a.
Yield: 100%; colorless oil.
(Z)-But-2-ene-1,4-bis(4-methoxybenzoate) (8)
Prepared according to the typical procedure described for 1a.
IR (NaCl, neat): 2965, 1747, 1471, 1400, 1381, 1377, 1371, 1244,
970 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.91–5.72 (m, 2 H), 4.83–4.66 (m,
4 H), 3.92 (m, 2 H), 0.94 (d, J = 6.7 Hz, 12 H).
Yield: 86%; yellow solid; mp 101–103 °C.
IR (NaCl, neat): 2960, 1776, 1712, 1604, 1579, 1510, 1460, 1255,
1167, 1099, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.03–7.95 (m, 4 H), 6.95–6.85 (m,
4 H), 5.96–5.89 (m, 2 H), 4.97 (d, J = 5.1 Hz, 4 H), 3.86 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 155.3, 128.2, 63.2, 28.0, 19.1.
Compound was unstable under MS conditions.
13C NMR (100 MHz, CDCl3): d = 166.3, 133.1, 131.9, 128.6, 122.6,
(Z)-But-2-ene-1,4-bis(2¢,2¢,2¢-trifluoroethylcarbonate) (5)
(Z)-But-2-ene-1,4-diol (2.0 g, 0.023 mol) along with N,N-carbonyl-
diimidazole (CDI; 11.1 g, 0.0681 mol, 3 equiv) were weighed in a
150 mL round-bottom flask. CH2Cl2 (100 mL) was then added and
the solution was stirred at r.t. for 3 h. The reaction was washed with
1 N HCl (50 mL, 30 mL and 20 mL), and the organic layer was dried
with MgSO4, filtered and the solvent removed under reduced pres-
sure. The resulting solid was dissolved in CH2Cl2 (100 mL) and
DMAP (20 mg, cat.) and CF3CH2OH (9.08 g, 4.0 equiv) were add-
ed. The resulting mixture was stirred at r.t. overnight then washed
with 1 N HCl (50 mL, 30 mL and 20 mL). The combined aqueous
layers were extracted with CH2Cl2 (25 mL) and the combined or-
ganic layers were washed with H2O (20 mL), followed by brine (20
mL), dried with MgSO4, and the solvents were removed under re-
duced pressure. The crude oil was purified by flash chromatography
(hexane–EtOAc, 90:10).
114.3, 113.8, 60.6, 55.6.
HRMS-EI: m/z [M + Na]+ calcd for C20H20O6Na: 379.1152; found:
379.1152.
2-Phenylbut-3-enyl Ethyl Carbonate (2a); Typical Procedure
In a glove box, [Rh(cod)OH]2 (3.9 mg, 0.0086 mmol, 0.05 equiv),
ligand (0.0206 mmol, 0.12 equiv), Cs2CO3 (56 mg, 0.172 mmol)
and Zn(OTf)2 (12.5 mg, 0.0344 mmol, 0.20 equiv) were weighed
into an 8 mL oven-dried microwave tube. The tube was sealed with
a septum and a crimp, and taken out of the glove box. Dioxane was
added (1.0 mL) and the resulting mixture was then stirred at r.t. for
10–15 min. Meanwhile, allylic carbonate 1a (0.172 mmol) and phe-
nyl boronic acid (0.344 mmol) were weighed into a 4 mL vial. The
vial was sealed, purged with argon, and dioxane (1.00 mL) was add-
ed. The substrate and boronic acid solution was transferred via sy-
ringe into the sealed tube containing the premixed catalyst solution.
The reaction mixture was then heated at 50 °C for 20 h, then diluted
with EtOAc (10 mL), filtered through a silica pad (~2 g), and
Yield: 100%; colorless oil.
Synthesis 2009, No. 5, 853–859 © Thieme Stuttgart · New York

PAPER
Synthesis of Homoallylic Alcohols
857
washed with EtOAc (~50 mL). The filtrate was concentrated under
reduced pressure and purified by flash chromatography (EtOAc–
pentane, 5→15%). The branched and linear products 2a and 3a
were isolated as an inseparable mixture. Regioselectivity was deter-
mined by 1H NMR analysis.
IR (NaCl, neat): 3375, 3078, 2933, 1610, 1412, 1464, 1302, 1248,
1178, 1035, 918 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.21–7.08 (m, 2 H), 6.96–6.79 (m,
2 H), 5.96 (ddd, J = 7.6, 10.4, 17.2 Hz, 1 H), 5.26–5.08 (m, 2 H),
3.78 (s, 3 H), 3.77 (d, J = 7.12 Hz, 2 H), 3.47 (q, J = 7.3 Hz, 1 H),
1.24 (t, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 158.8, 138.7, 132.7, 129.1, 117.0,
114.4, 66.3, 55.5, 51.8.
HRMS-EI: m/z [M]+ calcd for C11H14O2: 178.0994; found:
178.0994.
IR (NaCl, neat): 3007, 2986, 1750, 1467, 1449, 1373, 1258, 1018,
920 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.86–5.65 (dt, J = 4.0, 1.2 Hz,
2 H), 4.82–4.62 (m, 4 H), 4.17 (d, J = 5.3 Hz, 4 H), 1.27 (t, J = 7.1
Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 155.1, 128.2, 64.3, 63.1, 14.4.
2-(4-Chlorophenyl)but-3-en-1-ol (11b)
2-Phenylbut-3-en-1-ol (2b); Typical Procedure
The carbonates were isolated in 65% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
In order to obtain the desired branched product, the carbonate mix-
ture (2a and 3a) and K2CO3 (10 equiv) were weighed into a 4 mL
vial. MeOH (2 mL) was added and the solution was stirred at r.t. for
3 h. The solvent was then concentrated under reduced pressure and
the residue was taken into EtOAc (15 mL). The organic layer was
washed with sat. aq NH4Cl (15 mL) and the aqueous layer was ex-
tracted with Et2O (15 mL and 10 mL), and the combined organic
layers were concentrated under reduced pressure. The crude oil was
purified by flash chromatography (EtOAc–pentane, 10→25%) to
give a colorless oil. Some compounds were found to be sensitive to
silica in the alcohol form.
Colorless oil; 96% ee determined by GC (Shuzimi column; 2 min at
130 °C, then 130→200 °C at 4 °C/min; tR = 11.55 min, tR¢ = 11.63
min); [a]D25 –19.6 (c 0.76, CHCl3).
IR (NaCl, neat): 3365, 3082, 2928, 2878, 1637, 1491, 1406, 1093,
1057, 922 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.27 (m, 2 H), 7.21–7.14 (m,
2 H), 5.97 (m, 1 H), 5.20 (m, 2 H), 3.81 (dd, J = 6.6 Hz, 2 H), 3.51
(q, J = 7.2 Hz, 1 H), 1.46 (t, J = 6.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 139.1, 137.7, 132.7, 129.3, 128.9,
117.5, 65.9, 51.8.
Yield: quant.; colorless oil; 94% ee determined by HPLC (Chiralcel
AD; i-PrOH–Hexanes, 0.5%; 1.0 mL/min; 208 nm; tR = 28.2 min,
tR¢ = 32.4 min); [a]D25 +118.7 (c 0.62, CHCl3).
HRMS-EI: m/z [M]+ calcd for C10H11OCl: 182.0498; found:
182.0498.
IR (NaCl, neat): 3368, 3070, 2928, 2875, 1633, 1599, 1492, 1452,
1055, 1030, 955, 918 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.29 (m, 2 H), 7.28–7.19 (m,
3 H), 6.00 (ddd, J = 7.7, 10.4, 17.2 Hz, 1 H), 5.19 (m, 2 H), 3.81
(dd, J = 1.4, 7.1 Hz, 2 H), 3.52 (q, J = 7.3 Hz, 1 H), 1.55 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 140.8, 138.4, 129.0, 128.2, 127.2,
117.3, 66.3, 52.7.
2-(4-Fluorophenyl)but-3-en-1-ol (12b)
The carbonates were isolated in 66% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
HRMS-EI: m/z [M]+ calcd for C10H12O: 148.0888; found: 148.0886.
Colorless oil; 67% ee determined by HPLC (Chiralcel AD-H; i-
PrOH–hexane, 0.9%; 0.5 mL/min; 208 nm; tR = 47.5 min, tR¢ = 50.1
min); [a]D25 +54.8 (c 0.25, CHCl3).
2-(4-Tolyl)but-3-en-1-ol (9b)
The carbonates were isolated in 59% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
IR (NaCl, neat): 3368, 3080, 2926, 2875, 1637, 1602, 1508, 1467,
1225, 1159, 1225, 1057, 1028, 922 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.18–7.08 (m, 2 H), 7.01–6.89 (m,
2 H), 5.90 (ddd, J = 7.6, 10.4, 17.3 Hz, 1 H), 5.20–5.05 (m, 2 H),
3.74 (d, J = 7.0 Hz, 2 H), 3.45 (q, J = 5.5, 10.9 Hz, 1 H), 0.95 (t,
J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.2, 160.8, 138.2, 136.5, 136.5,
129.6, 129.6, 117.5, 115.9, 115.6, 66.2, 66.2, 51.8.
19F NMR (376 MHz, CDCl3): d = –116.4 (tt, J = 5.4, 8.7 Hz, 1 H).
HRMS-EI: m/z [M]+ calcd for C10H11OF: 166.0794; found:
Colorless oil; 93% ee determined by HPLC (Chiracel AD-H; i-
PrOH–hexane, 0.9%; 0.3mL/min; 208 nm; tR = 74.9 min, tR¢ = 80.6
min); [a]D25 +140.5 (c 0.61, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.21–7.06 (m, 4 H), 5.99 (ddd,
J = 7.7, 10.5, 17.1 Hz, 1 H), 5.24–5.12 (m, 2 H), 3.80 (t, J = 6.4 Hz,
2 H), 3.50 (q, J = 7.3 Hz, 1 H), 2.33 (s, 3 H), 1.46 (t, J = 6.3 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 138.6, 137.7, 136.8, 129.7, 128.0,
117.1, 66.3, 52.3, 21.2.
166.0791.
2-(3,4-Dimethoxyphenyl)but-3-en-1-ol (13b)
IR (NaCl, neat): 3366, 3020, 2872, 1739, 1638, 1510, 1460, 1412,
1040, 914 cm–1.
HRMS-EI: m/z [M+] calcd for C11H14O: 162.1045; found: 162.1044.
The carbonates were isolated in 68% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
2-(4-Methoxyphenyl)but-3-en-1ol (10b)
Colorless oil; 92% ee determined by HPLC (Chiracel AD-H;
i-PrOH–hexanes, 1%; 1.00 mL/min; 208 nm; tR = 73.41 min,
tR¢ = 80.90 min); [a]D25 +64.50 (c 0.11, CHCl3).
The carbonates were isolated in 60% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
IR (NaCl, neat): 3387, 2999, 2955, 1736, 1591, 1516, 1464, 1262,
1142, 1028 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.88 (d, J = 8.3 Hz, 1 H), 6.83 (d,
J = 8.2 Hz, 1 H), 6.79 (s, 1 H), 6.10–5.94 (m, 1 H), 6.03 (m, 1 H),
Colorless solid; 93% ee determined by HPLC (Chiralcel AD-H; i-
PrOH–hexane, 0.5%; 1.0 mL/min; 208 nm; tR = 81.7 min, tR¢ = 87.8
min); [a]D25 +83.7 (c 0.64, CHCl3).
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B. Yu et al.
PAPER
5.23 (m, 2 H), 3.91 (dd, J = 2.4, 7.1 Hz, 2 H), 3.85 (d, J = 7.2 Hz,
3 H), 3.85 (d, J = 7.2 Hz, 3 H), 3.52 (d, J = 7.3 Hz, 1 H).
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
13C NMR (125 MHz, CDCl3): d = 169.2, 149.2, 148.0, 138.3, 133.0,
Colorless oil; 65% ee determined by HPLC (Chiralcel AD; i-PrOH–
hexanes, 2%; 1.0 mL/min; 254 nm; tR = 42.3 min, tR¢ = 50.4 min);
[a]D25 –11.3 (c 0.54, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.8 Hz, 1 H), 7.83–
7.78 (m, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.51–7.31 (m, 4 H), 6.08
(ddd, J = 7.3, 10.7, 16.9 Hz, 1 H), 5.19 (m, 2 H), 4.34 (dd, J = 7.2,
13.5 Hz, 2 H), 3.95 (qd, J = 6.7, 10.9 Hz, 1 H).
119.8, 116.9, 111.5, 111.2, 66.1, 55.9, 52.0.
HRMS-EI: m/z [M]+ calcd for C12H16O3: 208.1099; found:
208.1099.
2-(4-Methoxy-3-methylphenyl)but-3-en-1-ol (14b)
The carbonates were isolated in 45% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
13C NMR (100 MHz, CDCl3): d = 138.5, 136.6, 134.3, 132.0, 129.2,
127.7, 126.4, 125.9, 125.7, 124.6, 123.4, 117.7, 65.7, 47.3.
IR (NaCl, neat): 3363, 3047, 2926, 2874, 1637, 1597, 1510, 1396,
1259, 1167, 1035, 798 cm–1.
HRMS-EI: m/z [M]+ calcd for C14H14O: 198.1045; found: 198.1045.
Colorless oil; 88% ee determined by HPLC (Chiralcel AD; i-PrOH–
hexanes, 2%; 1.00 mL/min; 208 nm; tR = 24.4 min, tR¢ = 26.7 min);
[a]D25 +116.40 (c 0.92, CHCl3).
IR (NaCl, neat): 3384, 3080, 2924, 1635, 1608, 1504, 1464, 1254,
1136, 1034, 916 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.06–6.97 (m, 2 H), 6.79 (d,
J = 8.2 Hz, 1 H), 5.98 (ddd, J = 7.7, 10.5, 17.1 Hz, 1 H), 5.21–5.11
(m, 2 H), 3.81 (s, 3 H), 3.78 (d, J = 7.1 Hz, 2 H), 3.45 (q, J = 7.3 Hz,
1 H), 2.21 (s, 3 H).
2-(Naphthalen-2-yl)but-3-en-1-ol (18b)
The carbonates were isolated in 61% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
Colorless oil; 90% ee determined by HPLC (Chiralcel AD; i-PrOH–
hexane, 1.25%; 1.00 mL/min; 215 nm; tR = 32.0 min, tR¢ = 37.5
min); [a]D25 +25.6 (c 0.46, CHCl3).
13C NMR (100 MHz, CDCl3): d = 157.0, 138.8, 132.3, 130.4, 127.2,
126.3, 116.8, 110.4, 66.4, 55.6, 51.9, 16.5.
HRMS-EI: m/z [M]+ calcd for C12H16O2: 192.1150; found:
192.1155.
IR (NaCl, neat): 3364, 2055, 2924, 2870, 1634, 1599, 1506, 1464,
1376, 1055, 1028, 914 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79–7.68 (m, 3 H), 7.62 (s, 1 H),
7.45–7.34 (m, 2 H), 7.30 (dd, J = 1.7, 8.5 Hz, 1 H), 6.03 (ddd,
J = 7.5, 10.4, 17.2 Hz, 1 H), 5.26–5.05 (m, 2 H), 4.01–3.75 (m,
2 H), 3.64 (q, J = 7.2 Hz, 1 H), 1.20 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 138.1, 138.0, 133.5, 132.5, 128.4,
127.6, 127.6, 126.6, 126.1, 125.7, 117.3, 66.0, 52.6, 31.0.
2-(2-Tolyl)but-3-en-1-yl Ethyl Carbonate (15a)
Yield: 38%; colorless oil; 88% ee determined by HPLC (Chiralcel
AD; i-PrOH–hexanes, 0.4%; 1.00 mL/min; 208 nm; tR = 34.8 min,
tR¢ = 42.1 min); [a]D25 +24.8 (c 0.83, CHCl3).
IR (NaCl, neat): 3080, 2982, 2920, 2872, 1745, 1607, 1466, 1396,
1259, 1115, 1009, 922, 877 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.21 (m, 1 H), 7.13–6.95 (m, 3 H),
6.12–5.91 (m, 1 H), 5.22–5.10 (m, 2 H), 4.35 (dd, J = 3.6, 7.3 Hz,
1 H), 4.17 (m, 2 H), 3.68 (q, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.28 (t,
J = 7.1 Hz, 3 H).
HRMS-EI: m/z [M]+ calcd for C14H14O: 198.1045; found: 198.1045.
Acknowledgment
We gratefully acknowledge NSERC (Canada), Merck-Frosst Cana-
da, and the University of Toronto for financial support, as well as
Solvias AG, Digital Specialty Chemicals and Takasago for ge-
nerous gifts of ligands. F.M. thanks the Ontario government for a
postgraduate scholarship (OGS). N.I. thanks Otsuka Pharmaceuti-
cals Co. for financial support.
13C NMR (100 MHz, CDCl3): d = 155.1, 139.8, 138.3, 137.5, 128.7,
128.5, 127.8, 124.9, 116.8, 70.1, 64.0, 48.7, 21.4, 14.2.
HRMS-EI: m/z [M]+ calcd for C14H18O3Na: 257.1148; found:
257.1143.
2-(2-Chlorophenyl)but-3-en-1-ol (16b)
The carbonates were isolated in 66% yield as a colorless oil. The
mixture was treated with K2CO3 in MeOH according to the typical
procedure for 2b and the desired branched product was character-
ized as the free alcohol.
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Synthesis 2009, No. 5, 853–859 © Thieme Stuttgart · New York

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