Exploring rhodium-catalysed conjugate addition of chiral alkenylboronates using chiral olefin ligands

Article abstract of DOI:10.1055/s-0030-1258203

The rhodium-catalysed addition of chiral alkenylboron reagents to prochiral α,β-unsaturated carbonyl acceptors are demonstrated to proceed under ligand control. The highest activities were obtained with chiral olefin ligands and the configuration of the n

Full text of DOI:10.1055/s-0030-1258203

SPECIAL TOPIC
3243
Exploring Rhodium-Catalysed Conjugate Addition of Chiral
Alkenylboronates Using Chiral Olefin Ligands
Conjugate
Additi
h
on of Chira
l
r
A
lkenyl
i
boronat
s
es topher G. Frost,*a Hannah J. Edwards,a Stephen D. Penrose,a Robert Gleaveb
a
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: c.g.frost@bath.ac.uk
b
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline,
New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 4 May 2010
required the use of the commercially available
[Rh(cod)(OH)]2 catalyst with added cyclooctadiene
ligand to limit catalyst decomposition. In the challenging
coupling to acrylamide 2, the use of the trifluoro(alke-
nyl)borate salt 1 was required because significant
amounts of protodeboronation product was noted with
other boron reagents. It is important to note that no new
chiral centre is formed during the reaction, and hermit-
amide A (3) was isolated in good yield without loss of ste-
reochemical integrity (Scheme 1). In this article we
demonstrate that the rhodium-catalysed addition of a
chiral alkenylboron reagent to prochiral a,b-unsaturated
carbonyl acceptors is an efficient process and, important-
ly, proceeds under ligand-control, thus opening the door
to new applications in stereoselective synthesis.
Abstract: The rhodium-catalysed addition of chiral alkenylboron
reagents to prochiral a,b-unsaturated carbonyl acceptors are dem-
onstrated to proceed under ligand control. The highest activities
were obtained with chiral olefin ligands and the configuration of the
new stereocentre can be predicted by using established models.
Key words: alkenylboronate, conjugate addition, rhodium, cataly-
sis, chiral olefin ligands
The transition-metal-catalysed conjugate addition of or-
ganometallics is regarded as a fundamental methodology
for organic synthesis.1 In particular, the introduction of a
practical protocol for rhodium-catalysed addition of orga-
noboron reagents to activated alkenes with predictable
stereocontrol has transformed the way synthetic chemists
can employ this reaction in organic synthesis.2 In the large
majority of reported additions to prochiral acceptors, a
single stereocentre is established by an asymmetric carbo-
metalation under the control of an enantiopure rhodium
complex. The sense of asymmetric induction can be reli-
ably predicted by means of simple stereochemical models
when using chiral atropisomeric diphosphine3 and chiral
olefin ligands.4 If the rhodium-catalysed conjugate addi-
tion reaction is going to be commonly employed in the
synthesis of complex target molecules, it is crucial to gain
an understanding of the stereoselectivity issues involved
in joining together enantiopure fragments. In this context,
both substrate-control5 and ligand-control6 have been es-
tablished as useful strategies in the addition of arylboron
OMe
BF3K
5
1
O
[Rh(cod)OH]2/cod
dioxane–H2O, 80 °C
N
H
81%
2
OMe
O
N
5
H
3
donors to enantiopure acceptors. Despite the considerable Scheme 1 The catalytic synthesis of hermitamide A
advances in catalyst design and substrate (acceptor) diver-
sity, the structure of the organometallic donor remains
For the preliminary studies, we chose to employ chiral
alkenyltrifluoroborate salt 8, which is an analogue of the
donor used in the synthesis of hermitamides A and B. We
surprisingly limited to aryl (and a number of alkenyl) de-
rivatives.7 Although there are a number of useful methods
available for the preparation of complex enantiopure or-
have previously noted that alkenyltrifluoroborate salts of-
ganoboron derivatives, only isolated examples of conju-
fer practical advantages in terms of stability and product
gate addition reactions have been reported.8 In a notable
yield in rhodium-catalysed conjugate addition reactions.
example, the synthesis of hermitamides A and B (natural
This is proposed to be due to the slow release of alkenyl-
products isolated from the marine cyanobacterium Lyng-
boronic acid and a concomitant reduction in competing
protodeboronation pathways.9 The chiral alkenyltrifluo-
roborate salt 8 was prepared by the route shown in
Scheme 2. Initial addition of the alkynyllithium salt to the
commercially available chiral epoxide 4 furnished the al-
cohol product, which was subsequently methylated to af-
ford 5 in excellent yield over the two steps. The syn-
addition of pinacolborane was achieved using the zirconi-
bya majuscula) have been completed using rhodium-ca-
talysed addition of an enantiopure alkenylboron reagent to
an acrylamide.9 The optimised conditions for the addition
SYNTHESIS 2010, No. 19, pp 3243–3247
x
x.
x
x
.
2
0
1
0
Advanced online publication: 13.08.2010
DOI: 10.1055/s-0030-1258203; Art ID: C04010SS
© Georg Thieme Verlag Stuttgart · New York

3244
C. G. Frost et al.
SPECIAL TOPIC
um-mediated procedure reported by Pereira and comparable activity. Other atropisomeric bidentate phos-
Srebnik.10 Following this protocol, alkyne 5 was treated phine ligands such as tol-BINAP, SYNPHOS, and
with 0.1 equivalents of Schwartz reagent 6 and anhydrous DIFLUORPHOS afforded similar selectivities to BINAP
triethylamine in neat pinacolborane. The reaction pro- and the same sense of asymmetric induction, albeit with
ceeded with complete conversion into the chiral alke- slightly lower conversions. Other privileged ligand struc-
nylpinacol boronic ester 7. After purification, an 81% tures such as Me-DUPHOS and H8-MONOPHOS were
yield of 7 with high E/Z selectivity (98:2) was obtained. less effective in this particular reaction. The highest con-
This product could be directly converted into the trifluo- version into product was observed with the commercially
ro(alkenyl)borate salt 8 by treatment with potassium dif- available chiral bicyclo[2.2.2]octadiene (DOLEFIN)
luorohydride.
ligands described by Carreira and co-workers.11 Thus, the
(R,R,R)-ligand provided the (4R,8R,E)-diastereomer with
good diastereoselectivity. For both the chiral diphosphine
and chiral olefin ligands, the configuration of the new ste-
reocentre was consistent with the simple predictive mod-
els presented in the literature.4
OMe
O
(i) lithium acetylide–EDA
(ii) NaH, THF, 0 °C
then MeI
4
5
86% over two steps
O
Cp2Zr(H)Cl 6
CH3
9a
pinacolborane
Et3N, 60 °C
δ
H 2.36 (s)
O
81%
OMe
O
B
O
O
OMe
[Rh(ethylene)2Cl]2
ligand
dioxane–H2O
80 °C
7
BF3K
O
KHF2
Et2O–H2O, 0 °C
Ph
8
O
92%
O
O
OMe
BF3K
+
OMe
O
OMe
O
8
Ph
CH3
H 1.95 (s)
Ph
CH3
δH 1.97 (s)
(4R,8R,E)-10a
δ
(4S,8R,E)-10a
Scheme 2 The synthesis of chiral alkenylboron reagent
Scheme 3 Stereoselective addition of chiral alkenylboron reagent
With the desired alkenylboron species in hand, rhodium-
catalysed conjugate additions could now be investigated.
The acyclic enone 9a was selected as a substrate to bench-
mark the selectivity of the conjugate addition (Scheme 3).
The two diastereomers of product (4R,8R,E)-10a and
OMe
PAr2
PAr2
1
(4S,8R,E)-10a could be distinguished by H NMR spec-
troscopy and, interestingly, in the absence of added
ligand, a 50:50 mixture was observed with a range of
rhodium pre-catalysts. A brief study revealed that
[Rh(ethylene)2Cl]2 in dioxane/water at 80 °C afforded sat-
isfactory conversion into the product (up to 55%) along-
side a competing protodeboronation process. Notably, the
remote stereocentre on the alkenylboron donor did not in-
duce any stereoselectivity in the formation of the new car-
bon–carbon bond. This presented the opportunity to
introduce the chiral alkene fragment using ligand control
and switching the diastereoselectivity of the process by
changing the enantiomer of ligand employed in the addi-
tion. A range of enantiopure ligands (Figure 1) were test-
(R,R,R)-DOLEFIN
Ar = C6H5 = (R)-BINAP
Ar = C6H5Me = (R)-tol-BINAP
Ar = C6H3(Me)2 = (R)-Xylyl-BINAP
O
O
O
PPh2
PPh2
P
P
O
(R,R)-Me-DUPHOS
(R)-SYNPHOS
O
F
F
O
O
PPh2
PPh2
Me
Me
O
P
N
1
O
F
ed and H NMR spectroscopic analysis was used to
facilitate the identification of the optimum system
(Table 1). The application of (R)-BINAP as ligand dem-
onstrated a preference for the (4R,8R,E)-diastereomer of
10a. As expected, with (S)-BINAP the stereoselectivity
switched to afford the (4S,8R,E)-diastereomer of 10a with
F
O
(R)-H8-MONOPHOS
(R)-DIFLUORPHOS
Figure 1 Chiral ligands used in stereoselective additions
Synthesis 2010, No. 19, 3243–3247 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of Chiral Alkenylboronates
3245
Table 1 Ligand Control of Stereoselectivity
OMe
BF3K
Conv. (%)a
dr (4R/4S)-10aa
50:50
Ph
O
OMe
R
O
Ligand
8
[Rh(ethylene)2Cl]2
R
Ph
none
55
(R,R,R)-DOLEFIN
KOH, 80 °C
dioxane–H2O
9a–e
10a–e
(R)-BINAP
62
87:13
(S)-BINAP
62
13:87
O
O
(R)-tol-BINAP
(R)-xylyl-BINAP
(R)-SYNPHOS
(R)-DIFLUORPHOS
(R,R,R)-DOLEFIN
(R,R)-Me-DUPHOS
(R)-H8-MONOPHOS
(R,R,R)-DOLEFINc
(R,R,R)-DOLEFINd
(R,R,R)-DOLEFINe
53
85:15
58
82:18
OMe
O
OMe
O
O
O
43
89:11
Ph
Ph
(4R,8R,E)-10a
91%, 88:12 dr
(4R,8R,E)-10d
82%, 90:10 dr
41
87:13
NO2
82
87:13
24
52:48
OMe
Ph
O
OMe
Ph
69
66:34
98 (91b)
89
88:12
(4R,8R,E)-10b
Cl
(4S,8R,E)-10e
91%, 95:5 dr
82%, 94:6 dr
89:11
OMe
Ph
O
OMe
Ph
82
88:12
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield after flash chromatography.
c Aqueous KOH (1.5 M, 0.1 mL) added.
(4R,8R,E)-10c
(4R,8R,E)-10e using
(S,S,S)-DOLEFIN
74%, 93:7 dr
88%, 95:5 dr
d Aqueous K2CO3 (1.5 M, 0.1 mL) added.
e Aqueous K3PO4 (1.5 M, 0.1 mL) added.
Scheme 4 Exploring the scope of the addition
prochiral a,b-unsaturated carbonyl acceptors can be an ef-
ficient process that enables the construction of highly
functionalised alkenes under ligand control. Central to the
success of this approach was the use of chiral olefin
ligands to provide high stereoselectivity and superior ac-
tivity in the carbometalation step.
The introduction of a base resulted in further improve-
ments to the efficiency of the process. In particular, the
use of potassium hydroxide afforded excellent conversion
into product (4R,8R,E)-10a with good diastereoselectivity
and, importantly, a high isolated yield. Given that the
chiral alkenylboron donor is the most valuable component
of the reaction mixture, the results suggest that chiral ole-
fin ligands are superior to phosphine-based systems for
this particular application.
IR spectra were recorded on a Perkin-Elmer 1600 FT IR spectro-
photometer, using NaCl discs. 1H NMR spectra were obtained on a
Bruker Avance 300 spectrometer operating at 300 MHz, unless oth-
erwise noted, with tetramethylsilane as an internal standard. J val-
ues are given in Hz. 13C NMR spectra were obtained on a Bruker
Avance 300 spectrometer operating at 75 MHz, unless otherwise
noted. Mass spectra were obtained on a Bruker Time-of-Flight mass
spectrometer (ESI-TOF). Enantiomeric excesses were determined
using HPLC (see individual compounds for details) with a UV de-
tector at 254 nm. All dry solvents were freshly distilled under nitro-
gen prior to use. Tetrahydrofuran was distilled over an alumina
column. Petroleum ether refers to that fraction obtained between
40–60 °C. All other reagents were obtained from commercial sup-
pliers and used as received. All glassware used under anhydrous
conditions was dried in an oven and allowed to cool under nitrogen
prior to use. All reactions were carried out under argon unless oth-
erwise stated. Flash chromatography was conducted under medium
pressure, using matrix 60 silica.
With the optimised set of reaction conditions, we next ex-
plored the scope of the process with respect to the acyclic
enones 10a–e; in all cases the chiral alkenylboron reagent
8 was employed as donor (Scheme 4).
The diastereoselectivity was consistently high for acyclic
substrates featuring aryl and an alkyl substituent on the
alkene. In all cases, isolated yields were excellent. It is
useful to note that both electron-donating and electron-
withdrawing substituents were tolerated on the aryl group
(10a–d). The highest selectivity was observed with the
isopropyl-substituted substrate 10e, again, this is consis-
tent with literature precedent for the enantioselective ad-
dition of arylboron reagents to this class of compound.
Thus, the (R,R,R)-ligand gave the (4S,8R,E)-diastereomer
of 10e in high yield and with 95:5 dr. The (S,S,S)-ligand
provided the complementary (4R,8R,E)-diastereomer of
10e with identical selectivity.
2-[(E)-(R)-4-Methoxy-4-phenylbut-1-enyl]-4,4,5,5-tetrameth-
yl[1,3,2]dioxaborolane (7)
[(R)-1-Methoxybut-3-ynyl]benzene12 (5; 4.00 g, 25.0 mmol) and pi-
nacolborane (3.36 g, 26.3 mmol) were charged to a 25-mL Schlenk
tube under a positive pressure of dry argon. To the resulting solution
was added sequentially bis(cyclopentadienyl)zirconium(IV) chlo-
ride hydride (6; 0.65 g, 2.5 mmol) followed by Et3N (0.25 g, 2.5
In conclusion, we have demonstrated that the rhodium-
catalysed addition of a chiral alkenylboron reagent to
Synthesis 2010, No. 19, 3243–3247 © Thieme Stuttgart · New York

3246
C. G. Frost et al.
SPECIAL TOPIC
mmol), the mixture was capped then heated at 60 °C for 16 h with
protection from light. Upon completion, hexane (5 mL) was added
and the mixture was stirred for 10 min in air. The material was iso-
lated through a short silica pad (elution with hexanes) to give the ti-
tle product.
The crude residue was purified by flash column chromatography on
silica gel (PE–EtOAc, 9:1) to give the product.
(4R,8R,E)-4-(Benzo[d][1,3]dioxol-5-yl)-7-methoxy-7-phenyl-
hept-5-en-2-one (10a)
The crude residue was purified by flash column chromatography on
silica gel (petrol–EtOAc, 4:1) to give the title product.
Yield: 5.83 g (81%); colourless oil; Rf = 0.15 (PE–EtOAc, 9:1);
[a]D20 +12.9 (c 0.95, CH3OH).
IR (neat): 2980, 2931 (C=C), 1640 (C–O), 1358, 1323 (B–O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.62–6.48 (m, 5 H, PhH), 6.55 (dt,
J = 19.6, 6.41 Hz, 1 H, CH alkene), 5.43 (dt, J = 19.6, 1.51 Hz, 1 H,
CH alkene), 4.15 (dd, J = 8.29, 5.28 Hz, 1 H, CHOCH3), 3.13 (s,
Yield: 0.058 g (91%); 88:12 ratio of diastereomers; colourless oil;
Rf = 0.20 (petrol–EtOAc, 4:1); [a]D20 –28.2 (c 0.80, CHCl3).
IR (KBr): 2897, 2824, 1715 (C=O), 1504, 1488 cm–1.
1H NMR (500 MHz, C6D6): d = 7.33–7.10 (m, 5 H, PhH), 6.62 (d,
J = 7.91 Hz, 1 H, ArH), 6.52 (d, J = 1.51 Hz, 1 H, ArH), 6.47 (dd,
J = 7.91, 1.51 Hz, 1 H, ArH), 5.83 (s, 2 H, OCH2O), 5.40 (dd, J =
15.5, 6.78 Hz, 1 H, CH alkene), 5.21 (dt, J = 15.5, 6.78 Hz, 1 H, CH
alkene), 4.02 (t, J = 6.78 Hz, 1 H, CHOCH3), 3.66 (q, J = 7.16 Hz,
1 H, CH), 3.12 (s, 3 H, OCH3), 2.68–2.53 (m, 2 H, CH2), 2.51–2.35
(m, 1 H, CH), 2.34–2.15 (m, 1 H, CH), 1.97 (s, 1 H, COCH3, minor
diastereomer), 1.95 (s, 3 H, COCH3, major diastereomer).
13C NMR (125.8 MHz, CDCl3): d = 207.5, 148.0, 146.4, 141.8,
137.6, 135.3, 128.7, 128.7, 127.9, 127.2, 126.4, 120.8, 108.5, 108.3,
101.2, 84.2, 56.9, 49.9, 43.6, 41.3, 31.0, 15.6.
HRMS (ESI+): m/z [M + Na+] calcd for C22H24NaO4: 375.1572;
found: 375.1558.
3 H, OCH3), 2.59 (ddt,
J
=
15.1, 6.41, 1.51 Hz, 1 H,
CHCH2CHCH), 2.40 (ddt,
J = 15.1, 8.29, 1.51 Hz, 1 H,
CHCH2CHCH), 1.18 (s, 12 H, 4 × CH3).
13C NMR (75.5 MHz, CDCl3): d = 150.1, 141.7, 128.3, 127.5,
126.6, 83.0, 82.9, 56.6, 44.5, 24.7; C–B peak not observed.
11B NMR (96.3 MHz, CDCl3): d = 31.2.
HRMS (ESI+): m/z [M + Na+] calcd for C17H25B1Na1O3: 311.1794;
found: 311.1791.
Potassium (R,E)-4-Methoxy-4-phenylbut-1-enyl Trifluorobo-
rate (8)
2-[(E)-(R)-4-Methoxy-4-phenylbut-1-enyl)-4,4,5,5-tetrameth-
yl[1,3,2]dioxaborolane (7; 2.31 g, 8.0 mmol) in Et2O (25 mL), was
charged to a 100-mL round-bottom flask. The flask was cooled to
0 °C (ice/salt) and to the resulting solution was added sequentially
potassium hydrogen difluoride (2.34 g, 30 mmol) followed by H2O
(5 mL). The mixture was warmed to r.t. and stirred for 3 h until a
thick white precipitate formed. Upon completion, the reaction mix-
ture was concentrated in vacuo and thoroughly dried under high
vacuum (0.01 mmHg). The solids were then washed with acetone
(250 mL) and filtered to remove inorganic salts. The solvent was
concentrated to approximately 20 mL, Et2O (100 mL) was added
and the suspension was triturated to precipitate the product. Storage
overnight at –20 °C in a freezer gave the product.
(4R,8R,E)-7-Methoxy-4-(4-nitrophenyl)-7-phenylhept-5-en-2-
one (10b)
The crude residue was purified by flash column chromatography on
silica gel (petrol–EtOAc 4:1) to give the title product.
Yield: 0.052 g (82%); 94:6 ratio of diastereomers; colourless oil;
Rf = 0.20 (petrol–EtOAc, 9:1); [a]D20 –38.2 (c 0.95, CHCl3).
IR (KBr): 2937, 1717 (C=O), 1643 (NO2), 1520, 1348 cm–1.
1H NMR (500 MHz, C6D6): d = 8.10–8.0 (m, 2 H, PhH), 7.33–7.10
(m, 7 H, PhH), 5.39 (dd, J = 15.5, 6.78 Hz, 1 H, CH alkene), 5.19
(dt, J = 15.5, 6.78 Hz, 1 H, CH alkene), 4.04 (t, J = 6.78 Hz, 1 H,
CHOCH3), 3.72 (q, J = 7.16 Hz, 1 H, CH), 3.12 (s, 3 H, OCH3),
2.80–2.62 (m, 2 H, CH2), 2.53–2.34 (m, 1 H, CH), 2.28–2.17 (m,
1 H, CH), 2.01 (s, 3 H, COCH3, minor diastereomer), 1.99 (s, 1 H,
COCH3, major diastereomer).
20
Yield: 1.97 g (92%); white solid; mp 185 °C (acetone) (dec.); [a]D
+13.4 (c 0.65, MeOH).
IR (KBr): 2992, 2931 (C=C), 1652 (C–O), 1107, 946 (B–F) cm–1.
1H NMR (300 MHz, CD3OD): d = 8.32–8.15 (m, 5 H, PhH), 6.69
(dt, J = 17.7, 6.78 Hz, 1 H, CH alkene), 6.39 (dt, J = 17.7, 3.77 Hz,
1 H, CH alkene), 5.10–4.24 (dd, J = 7.54, 6.03 Hz, 1 H, CHOCH3),
4.12 (s, 3 H, OCH3), 3.44 (ddt, J = 15.5, 6.41, 1.51 Hz, 1 H,
13C NMR (125.8 MHz, CDCl3): d = 206.2, 151.5, 141.6, 133.7,
128.8, 128.8, 128.7, 128.1, 128.0, 128.0, 127.1, 127.1, 124.1, 83.9,
57.0, 49.1, 43.4, 41.3, 31.0, 30.9.
HRMS (ESI+): m/z [M + Na+] calcd for C21H23NNaO4: 376.1524;
found: 376.1514.
CHCH2CHCH), 3.44 (ddt,
CHCH2CHCH).
J = 15.5, 7.54, 1.51 Hz, 1 H,
13C NMR (75.5 MHz, CD3OD): d = 143.5, 133.7, 133.7, 129.3,
128.5, 127.9, 86.0, 56.7, 45.7; C–B peak not observed.
(4R,8R,E)-4-(4-Chlorophenyl)-7-methoxy-7-phenylhept-5-en-
2-one (10c)
The crude residue was purified by flash column chromatography on
silica gel (petrol–EtOAc 9:1) to give the title product.
11B NMR (96.3 MHz, CD3OD): d = 4.12
HRMS (ESI–): m/z [M + H+] calcd for C11H14BF3O: 229.1011;
Yield: 0.048 g (74%); 93:7 ratio of diastereomers; colourless oil;
found: 229.1009.
Rf = 0.20 (petrol–EtOAc, 9:1); [a]D20 –48.6 (c 0.90, CHCl3).
Rhodium-Catalysed Addition of Chiral Alkenylboron Reagent
8; General Procedure
IR (KBr): 3029, 2934, 2824, 1717 (C=O), 1492, 1360, 1093 cm–1.
1H NMR (500 MHz, C6D6): d = 7.36–7.16 (m, 7 H, PhH), 7.15–6.98
(m, 2 H, PhH), 5.40 (dd, J = 15.5, 6.78 Hz, 1 H, CH alkene), 5.22
(dt, J = 15.5, 6.78 Hz, 1 H, CH alkene), 4.02 (t, J = 6.78 Hz, 1 H,
CHOCH3), 3.72 (q, J = 7.16 Hz, 1 H, CH), 3.12 (s, 3 H, OCH3),
2.71–2.61 (m, 2 H, CH2), 2.52–2.34 (m, 1 H, CH), 2.31–2.20 (m,
1 H, CH), 1.97 (s, 3 H, COCH3, major diastereomer), 1.94 (s, 1 H,
COCH3, minor diastereomer).
13C NMR (125.8 MHz, CDCl3): d = 207.1, 142.2, 141.8, 134.8,
132.4, 129.5, 129.2, 128.9, 128.7, 128.4, 127.9, 127.2, 127.2, 127.1,
127.0, 127.0, 84.0, 57.0, 57.0, 50.5, 49.6, 43.3, 41.4, 31.0, 31.0.
A 24-mL screw-capped vial equipped with a rubber septum was
charged with rhodium(bisethylene)chloride dimer (3 mol%) and
ligand (7 mol%), potassium (R,E)-4-methoxy-4-phenylbut-1-enyl
trifluoroborate (8; 0.40 mmol) and aq KOH (1.5 M, 0.1 mL) were
added by syringe and the vessel was purged with argon. After 10
min stirring at r.t., enone 10 (0.20 mmol) in dioxane (0.5 mL) was
added in a single portion via syringe. The mixture was transferred
with stirring to a preheated hotplate at 80 °C for 20 h. The crude re-
action mixture was taken up in Et2O (5 mL) and filtered through a
short plug of silica (Et2O) and the solvent was removed in vacuo.
Synthesis 2010, No. 19, 3243–3247 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of Chiral Alkenylboronates
3247
HRMS (ESI+): m/z [M + Na+] calcd for C21H23ClNaO2: 365.1284;
found: 365.1280.
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Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108,
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Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039.
(2) For reviews, see: (a) Hayashi, T. Synlett 2001, 879.
(b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(c) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
(d) Darses, S.; Genêt, J.-P. Eur. J. Org. Chem. 2003, 4313.
(e) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C.
G. Chem. Soc. Rev. 2010, 39, 2093.
(4R,8R,E)-7-Methoxy-4,7-diphenylhept-5-en-2-one (10d)
The crude residue was purified by flash column chromatography on
silica gel (petrol–EtOAc, 9:1) to give the title product.
Yield: 0.049 g (82%); 90:10 ratio of diastereomers; colourless oil;
Rf = 0.25 (petrol–EtOAc, 9:1); [a]D20 +46.1 (c 1.0, CHCl3).
IR (neat): 2979, 2935, 2824, 1722 (C=O), 1367, 1145, 1102 cm–1.
1H NMR (500 MHz, C6D6): d = 7.36–7.16 (m, 8 H, PhH), 7.15–6.98
(m, 2 H, PhH), 5.44 (dd, J = 15.4, 7.16 Hz, 1 H, CH alkene), 5.22
(dt, J = 15.4, 6.78 Hz, 1 H, CH alkene), 4.03 (t, J = 6.78 Hz, 1 H,
CHOCH3), 3.74 (q, J = 7.16 Hz, 1 H, CH), 3.12 (s, 3 H, OCH3),
2.71–2.61 (m, 2 H, CH2), 2.52–2.34 (m, 1 H, CH), 2.31–2.20 (m,
1 H, CH), 1.97 (s, 1 H, COCH3, major diastereomer), 1.94 (s, 3 H,
COCH3, minor diastereomer).
13C NMR (125.8 MHz, CDCl3): d = 208.8, 208.7, 141.6, 133.2,
133.2, 128.3, 127.6, 127.5, 126.8, 126.8, 84.1, 84.0, 56.6, 46.9,
46.8, 41.2, 31.7, 30.5, 30.5, 20.4, 20.3, 18.8, 16.7.
(3) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M.
J. Am. Chem. Soc. 2002, 124, 5052.
(4) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K.
J. Am. Chem. Soc. 2003, 125, 11508. (b) Defieber, C.;
Grützmacher, H.; Carreira, E. M. Angew. Chem. Int. Ed.
2008, 47, 4482. (c) Shintani, R.; Hayashi, T. Aldrichimica
Acta 2009, 42, 31.
HRMS (ESI+): m/z [M + Na+] calcd for C21H24NaO2: 331.1764;
(5) (a) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.;
Maddaford, S. P. Org. Lett. 2001, 3, 2571. (b) Chen, Q.;
Kuriyama, M.; Soeta, T.; Hao, X.; Yamada, K.; Tomioka, K.
Org. Lett. 2005, 7, 4439. (c) de la Herran, G.; Mba, M.;
Murcia, M. C.; Plumet, J.; Csaky, A. G. Org. Lett. 2005, 7,
1669. (d) Hargrave, J. D.; Bish, G.; Frost, C. G. Chem.
Commun. 2006, 4389. (e) Segura, A.; Csaky, A. G. Org.
Lett. 2007, 9, 3667. (f) Chapman, C. J.; Matsuno, A.; Frost,
C. G.; Willis, M. C. Chem. Commun. 2007, 3903.
(g) Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Deng, J. Z.;
Nguyen, D. N.; Potteiger, C. M.; Graham, S. L.; Vacca, J. P.;
Williams, T. M. Org. Lett. 2008, 10, 3235. (h) Chapman, C.
J.; Hargrave, J. D.; Bish, G.; Frost, C. G. Tetrahedron 2008,
64, 9528.
(6) Zoute, L.; Kociok-Köhn, G.; Frost, C. G. Org. Lett. 2009, 11,
491.
(7) Hargrave, J. D.; Allen, J. C.; Frost, C. G. Chem. Asian J.
2010, 5, 386.
(8) Wu, Y.; Gao, J. Org. Lett. 2008, 10, 1533.
(9) Frost, C. G.; Penrose, S. D.; Gleave, R. Org. Biomol. Chem.
2008, 6, 4340.
(10) (a) Pereira, S.; Srebnik, M. J. Org. Chem. 1995, 60, 4316.
(b) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
(11) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628.
found: 331.1760.
(4R,8R,E)-4-Isopropyl-7-methoxy-7-phenylhept-5-en-2-one
(10e)
The crude residue was purified by flash column chromatography on
silica gel (petrol–EtOAc, 20:1) to give the title product.
Yield: 0.051 g (91%); 95:5 ratio of diastereomers; colourless oil;
Rf = 0.3 (petrol–EtOAc, 20:1); [a]D20 –53.2 (c 0.81, CHCl3).
IR (neat): 2959, 2931, 2822, 1711 (C=O), 1357, 1101.
1H NMR (500 MHz, C6D6): d = 7.36–7.31 (m, 2 H, PhH), 7.29–7.23
(m, 3 H, PhH), 5.30 (dt, J = 15.4, 6.62 Hz, 1 H, CH alkene), 5.22
(dd, J = 15.5, 7.88 Hz, 1 H, CH alkene), 4.08 (t, J = 6.62 Hz, 1 H,
CHOCH3), 3.21 (s, 3 H, OCH3), 2.52 (dt, J = 13.6, 6.94 Hz, 1 H,
CH), 2.44–2.28 (m, 4 H), 2.06 (s, 1 H, COCH3, minor diastere-
omer), 2.04 (s, 3 H, COCH3, major diastereomer), 1.51 [sept, J =
6.62 Hz, 1 H, CH(CH3)2], 0.83 [dd, J = 19.9, 6.62 Hz, 6 H,
CH(CH3)2, major diastereomer], 0.76 [dd, J = 19.9, 6.62 Hz, 0.6 H,
CH(CH3)2, minor diastereomer].
13C NMR (125.8 MHz, CDCl3): d = 208.8, 208.7, 141.6, 133.2,
133.2, 128.3, 127.6, 127.5, 126.8, 126.8, 84.1, 84.0, 56.6, 46.9,
46.8, 41.2, 31.7, 30.5, 30.5, 20.4, 20.3, 18.8, 16.7
HRMS (ESI+): m/z [M + Na+] calcd for C18H26NaO2: 297.1831;
found: 297.1826.
(12) Niimi, L.; Hiraoka, S.; Yokozawa, T. Tetrahedron 2002, 58,
245.
Acknowledgment
We are grateful to the EPSRC (H.J.E.) and GlaxoSmithKline Li-
mited (CASE award to S.D.P.) for funding. Dr Anneke Lubben
(Mass Spectrometry Service at the University of Bath) is thanked
for valuable advice and assistance.
Synthesis 2010, No. 19, 3243–3247 © Thieme Stuttgart · New York