Lewis base activation of Lewis acids: Vinylogous aldol additions of silyl dienol ethers to aldehydes

Article abstract of DOI:10.1055/s-2004-834789

Highly regioselective vinylogous aldol additions of silyl dienol ethers derived from simple α,β-unsaturated ketones are described. The catalyst system of silicon tetrachloride activated by chiral bisphosphoramide (R,R)-1 effectively promotes the addition

Full text of DOI:10.1055/s-2004-834789

CLUSTER
2411
Lewis Base Activation of Lewis Acids: Vinylogous Aldol Additions of Silyl
Dienol Ethers to Aldehydes
Lewis Base
A
c
ctivation of
o
Lewis
A
cid
t
t E. Denmark,* John R. Heemstra Jr.
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Fax +1(217)3333984; E-mail: denmark@scs.uiuc.edu
Received 1 July 2004
O
OH
O
OM
Abstract: Highly regioselective vinylogous aldol additions of silyl
dienol ethers derived from simple a,b-unsaturated ketones are
described. The catalyst system of silicon tetrachloride activated by
chiral bisphosphoramide (R,R)-1 effectively promotes the addition
of both g-substituted and unsubstituted silyl dienol ethers to a
variety of aldehydes with exclusive g-regioselectivity and good to
excellent diastereo- and enantioselectivity.
R'CHO
γ
α
α
γ
and
or
R
R'
R
R
C(2) C(4)
HO
R'
Scheme 1
An alternative strategy that allows for high g-selectivity is
the use of silyl dienolates as nucleophiles in Lewis acid-
promoted vinylogous Mukaiyama-aldol additions.8 Reac-
tions of silyl dienol ethers are under frontier molecular or-
bital control whereby the higher orbital coefficient at C(4)
favors the vinylogous aldol reaction.6 Furthermore, this
Lewis acid-catalyzed reaction has provided an ideal plat-
form for development of a catalytic asymmetric variant,
and several highly selective systems have been reported.9
However, the generality of these systems is not broad as
the scope of the nucleophile is limited to lactone-, diox-
anone- and simple ester-derived silyl dienol ethers. More
importantly, the inherent g-selectivity of silyl dienol
ethers is most often modest, particularly in the case of
simple ester derived dienol ethers. A recent disclosure
from these laboratories demonstrated that the combina-
tion of catalytic amounts of the chiral bis-phosphoramide
(R,R)-110 and silicon tetrachloride is able to promote the
addition of simple ester-derived dienol ethers to alde-
hydes with almost exclusive g-regioselectivity for a vari-
ety of substitution patterns on the dienol ether while
maintaining high enantio- and diastereoselectivity
(Scheme 2).11 This conceptually novel approach to carbo-
nyl addition reactions combines the use of chiral Lewis
bases to generate catalytically active chiral Lewis acids.
In the presence of catalytic amounts of a chiral phosphora-
mide, the weak Lewis acid SiCl4 can be activated to form
a strongly Lewis acidic chiral species through coordina-
tion and subsequent ionization of a chloride ligand.12 The
extremely high selectivity of this catalyst system for the g-
position attests to the strong steric differentiation provid-
ed by the catalyst during the addition reaction.
Key words: Lewis base, asymmetric catalysis, vinylogous aldol
reactions, ketones, regioselectivity
The vinylogous aldol reaction1 has emerged as useful stra-
tegic disconnection for the stereocontrolled construction
of functionalized carbon chains. This reaction has been
featured in a number of recent total syntheses of natural
products such as callipeltoside A2 and leucascandrolide
A.3 This reaction involves the g-addition of a dienol ether
or ketene acetal to an aldehyde to generate an e-hydroxyl-
a,b-unsaturated carbonyl compound in which up to three
stereocenters can be created. Furthermore, the newly con-
structed hydroxyl stereocenter adjacent to the double
bond allows for stereoselective elaboration of the olefin
using highly predictable substrate-controlled transforma-
tions.4
Although similar to simple aldol reactions,5 the vinylo-
gous aldol reaction overlays the challenge of regioselec-
tivity onto the already present issues of diastereo- and
enantioselectivity.1 The addition of a dienolate to an alde-
hyde can generate either the a- or the g-addition products
(Scheme 1). Obtaining the g-adduct is particularly prob-
lematic when metallo-dienolates are employed, as the in-
herent kinetic selectivity of these species is for reaction at
the a-position, owing to the higher electron density at
C(2).6 An imaginative strategy to obtain the g-adduct ex-
clusively using metallo-dienolates was developed by
Yamamoto and co-workers through the use of a sterically
demanding Lewis acid.7 Pre-formation of a complex be-
tween a lithium dienolate and the bulky reagent allows for
steric blocking of the a-position and effectively forces the
reaction to occur at the remote g-position.
With a broad scope in simple ester-derived silyl dienol
ethers demonstrated, exploration into the use of new nu-
cleophile partners has been undertaken. We report herein
a catalytic enantioselective vinylogous aldol reaction for
the addition of silyl dienol ethers derived from a,b-unsat-
urated ketones to various aldehydes.
SYNLETT 2004, No. 13, pp 2411–2416
Advanced online publication: 07.10.2004
DOI: 10.1055/s-2004-834789; Art ID: Y03604ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
4
Although the formation of cross-conjugated dienolates is
overwhelmingly favored in kinetically controlled enoliza-
tion, the extended conjugated dienolates of a,b-unsaturat-

2412
S. E. Denmark, J. R. Heemstra Jr.
CLUSTER
R5CHO
aldehyde and again the g-addition product was obtained
exclusively in high yield (94%) and enantioselectivity
(99.5:0.5 er).
TBSO
R1O
R3
O
R3
OH
SiCl4
R4
1–5 mol% (R,R)-1
R1O
R5
CH2Cl2, –78 °C
3–24 h
R2
R2
R4
To examine the scope of this process a number of alde-
hydes were surveyed in reaction with dienolate 3. Aro-
matic and olefinic aldehydes reacted with excellent
selectivities and yields (Table 1, entries 3 and 4). Also,
heteroaromatic aldehydes are competent acceptors with
only a minor decrease in selectivity (entries 5 and 6). The
propargylic aldehyde, a problematic aldehyde in many ad-
dition reactions, displayed only a slightly lower selectivity
(entry 7). Unfortunately, aliphatic aldehydes were found
to be completely unreactive with dienolate 3 (entry 8).
Even warming of the reaction temperature to 0 °C did not
allow for the formation of a vinylogous aldol product. Re-
markably, only the g-addition product could be observed
R2-R4 = Me, H
yields 76–97%
γ:α selectivity >99:1
dr >99:1
Me
N
er 91:9–99.5:0.5
O
P
(R,R)-1
N
(CH2)5
2
N
Me
Me
Scheme 2
ed ketones are difficult to obtain.13 To simplify the
analysis of the product mixture, a,b-unsaturated ketones
lacking a¢-protons were examined in this study to assure
exclusive formation of fully conjugated dienolates. Tri-
methylsilyl enol ethers 2 and 3 were prepared following
the method described by Fleming,14 by heating the corre-
sponding ketones in the presence of Et3N, TMSCl, and
NaI at 100 °C (Scheme 3). The dienol ethers were formed
as mixtures of geometrical isomers in which the major
isomer in both dienolates contains a (1Z)-double bond as
determined by analysis of their 1H NOE NMR spectra.
1
by H NMR analysis of the crude reaction mixture in all
of the aldehydes that reacted.
In view of the high selectivity observed in the addition of
g-unsubstituted enones to aldehydes, cyclic dienolate 1216
was investigated to evaluate diastereoselectivity as well as
enantio- and regioselectivity. Initial studies showed that
when 12 (1.2 equiv) was combined with benzaldehyde,
SiCl4 (1.5 equiv), i-Pr2NEt (0.1 equiv) at 0.5 M in CH2Cl2
in the presence of 5 mol% of (R,R)-1 at –78 °C for 2 hours,
the g-addition product could be obtained exclusively with
excellent anti diastereoselectivity (97.5:2.5) and enantio-
selectivity (97.5:2.5; Table 2, entry 1). Exclusive g-regio-
selectivity was also observed in the addition of dienolate
12 to 1-naphthaldehyde; however, increasing the reaction
time to 10 hours was required to obtain high yields
(Table 2, entry 2). Although the diastereoselectivity was
attenuated (89.0:11.0), both the anti and syn diastereo-
mers were formed with high enantioselectivity (95.0:5.0
and >99.5:0.5, respectively). Reactions with cinnamalde-
hyde and 2-furaldehyde provided the g-addition products
in high yield with excellent anti diastereoselectivity and
good enantioselectivity (entries 3 and 4). Despite several
attempts, dienol ether 12 did not react with aliphatic alde-
hydes (entry 5).
TMSCl, NaI,
Et3N
O
OTMS
Ph
CH3
Ph
95%
2
1.5:1.0 1Z:1E
O
TMSCl, NaI,
Et3N
OTMS
t-Bu
CH3
t-Bu
95%
3
7.9:1.0 1Z:1E
Scheme 3
Orienting experiments were conducted with dienol ether 2
and benzaldehyde under the reaction conditions devel-
oped in these laboratories for the addition of TMS enol
ethers of methyl ketones to aldehydes.15 Thus, 2 (1.2
equiv) was combined with benzaldehyde, SiCl4 (1.5
equiv), i-Pr2NEt (0.1 equiv) at 0.5 M in CH2Cl2 in the
presence of 5 mol% of (R,R)-1 at –78 °C for four hours.
1H NMR analysis of the crude reaction mixture (obtained
by quenching the reaction with a 1:1 mixture of sat. aq
KF/sat. aq NaHCO3 solutions) showed that only unreacted
starting material was present. Gratifyingly, we found
that by executing the reaction at an elevated temperature
(–50 °C) for 24 hours, the g-addition product could be ob-
tained in high yield (80%), enantioselectivity (99.0:1.0 er)
and exclusively of E configuration (Table 1, entry 1). The
a-addition product could not be found by inspection of the
1H NMR spectrum of the crude reaction mixture. Under
these conditions, dienol ether 3 also reacted with benz-
The anti-configuration of the major diastereomer was un-
ambiguously assigned by an independent synthesis of cy-
clohexenone 13. A diastereomerically enriched (anti/syn
95:5) sample of the 3-methoxy-1¢-hydroxy ketone 1817
was prepared. Reduction (LiAlH4) of 18 followed by acid-
ic hydrolysis afforded 2-cyclohexenone 13 as a 93.5:6.5
mixture of diastereomers (Scheme 4). Comparison of
1
their H NMR spectra allowed the assignment of the
major diastereomers from the reaction of 12 as anti.
O
OH
OH
1. LiAlH4
2. 1 N HCl
86%
MeO
O
18
13
dr (anti:syn) 95.0:5.0
dr (anti:syn) 93.5:6.5
Scheme 4
Synlett 2004, No. 13, 2411–2416 © Thieme Stuttgart · New York

CLUSTER
Lewis Base Activation of Lewis Acids
2413
Table 1 Vinylogous Aldol Reactions of Ketone-Derived Dienolate 2 and 3 with Aldehydesa
SiCl4
5 mol% (R,R)-1
20 mol% i-Pr2NEt
OTMS
O
OH
R2CHO
R1
+
R1
R2
CH2Cl2, 0.5 M
–50 °C, 24 h
Entry
Dienolate
R1
R2
Product
Yield (%)b
l/ac
erd
99.0:1.0
1
2
3
4
5
6e
tg
8
2
3
3
3
3
3
3
3
Ph
Ph
4
5
80
94
85
82
90
50f
40f
0
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
Ndh
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
99.5:0.5
99.0:1.0
>99.5:0.5
96.0:4.0
94.0:6.0
1-Naphthyl
6
(E)-PhCH=CH
2-Furyl
7
8
2-Thienyl
PhC≡C
9
10
11
84.0:16.0
Nd
PhCH2CH2
a Reactions employed 1.5 equiv of SiCl4, 1.2 equiv of dienolate, 0.2 equiv of i-Pr2NEt, 0.05 equiv of (R,R)-3 at 0.5 M in CH2Cl2 at –50 °C for
24 h.
b Yields of analytically pure material.
c Determined by 1H NMR analysis.
d Determined by CSP-SFC.
e Conditions as above with 0.1 equiv of (R,R)-1.
f Yield after chromatography.
g Conditions as above with 0.1 equiv of (R,R)-1 and at –68 °C.
h Nd: not determined.
To establish the absolute configuration of the adducts,
compounds 4 and 5 were subjected to ozonolysis followed
by reduction of the ozonide with a solution of lithium alu-
minum hydride which afforded the desired diols in good
yields (Scheme 5). Comparison of their optical rotations
with those reported in the literature18 showed that the ma-
jor enantiomer in both cases was the aldol adduct derived
from Re face attack on the aldehyde. In the case of aldol
adduct 13, correlation to the known 1-cyclohexyl-1-phe-
nylmethanol was made by hydrogenation of the double
bond in 13 followed by Wolff–Kishner reduction
(Scheme 5). Comparison of the optical rotation of 21 to
that in the literature shows that the C(1) center is of R-con-
figuration. Thus, the anti relationship between the two ste-
reocenters in adduct 13 allows for assignment of the
absolute configuration of the major enantiomer as
(4R,7R)-13. In all cases, the sense of asymmetric induc-
tion is consistent with that observed in all other reported
cases employing chiral bisphosphoramide (R,R)-1 and
SiCl4.
O
OH
OH
O3
HO
LiAlH4
71%
4
19
[α]D = +61.8
lit.18 [α]D = –63.0 for 3S
O
OH
OH
O3
H3C
H3C
HO
LiAlH4
76%
CH3
5
20
[α]D = +66.4
lit.18 [α]D = –63.0 for 3S
OH
OH
1. Pd/C, 1 atm H2
2. NH2NH2, KOH,
ethylene glycol
O
13
21
58%
[α]D = +26.0
lit.19 [α]D = –28.27 for 1S
To the best of our knowledge, these findings represent the
first catalytic and enantioselective vinylogous aldol reac-
tion that employ silyl dienol ethers derived from simple
a,b-unsaturated ketones. These reactions proceed with ex-
clusive g-selectivity and high enantioselectivity and
diastereoselectivity in the addition to aromatic, hetero-
aromatic, olefinic, and propargylic aldehydes. Current
Scheme 5
studies are underway to overcome the lack of reactivity
with aliphatic aldehydes and extend this methodology to
acyclic a¢-enolizable ketones.
Synlett 2004, No. 13, 2411–2416 © Thieme Stuttgart · New York

2414
S. E. Denmark, J. R. Heemstra Jr.
CLUSTER
Table 2 Vinylogous Aldol Reactions of Ketone-Derived Dienolate 12 with Aldehydesa
SiCl4
OH
5 mol% (R,R)-1
10 mol% i-Pr2NEt
+
RCHO
R
CH2Cl2, 0.5 M
–72 °C, 2 h
TMSO
O
12
Entry
R1
Product
13
Yield (%)b
g/ac
dr (anti/syn)d
97.5:2.5
89.0:11.0
98.0:2.0
95.5:4.5
Nd
er antid
97.5:2.5
95.0:5.0
84.5:15.5
81.5:18.5
Nd
er synd
Nd
1
2f
3
4
5
Ph
90e
80e
74
94
0
>99:1
>99:1
>99:1
>99:1
Ndg
1-Naphthyl
14
>99.5:0.5
Nd
(E)-PhCH=CH 15
2-Furyl
16
17
Nd
PhCH2CH2
Nd
a Reactions employed 1.5 equiv of SiCl4, 1.2 equiv of dienolate, 0.1 equiv of i-Pr2NEt, 0.05 equiv of (R,R)-1 at 0.5 M in CH2Cl2 at –72 °C for 2 h.
b Yields of analytically pure material.
c Determined by 1H NMR analysis.
d Determined by CSP-SFC.
e Yield after chromatography.
f Conditions as above for 10 h.
g Nd: not determined.
24
General Procedure for the Aldol Reaction of 2.
(+)-(R)-5-Hydroxy-1,5-diphenyl-2-penten-1-one (4).
125.76, 73.14, 42.80, 42.18, 26.03. [a]D +6.12 (c 0.95, EtOH).
SFC: (R)-5 tR 5.63 min (99.5%); (S)-5 tR 6.41 min (0.5%) (AD col-
umn, 150 bar, 3.0 mL/min, 3.5% MeOH). Anal. Calcd for C15H20O2
(232.32): C, 77.55%; H, 8.68%. Found: C, 77.58%; H, 8.72%.
Diisopropylethylamine (35 mL, 0.2 mmol, 0.2 equiv) was added via
syringe to a flame-dried, 5 mL, Schlenk flask under Ar containing a
solution of 42 mg (0.05 mmol, 0.05 equiv) of bis-phosphoramide
(R,R)-1 in CH2Cl2 (2 mL). To this solution was added 102 mL (1.0
mmol) of benzaldehyde in one portion. To the resulting solution
was added 172 mL (1.5 mmol, 1.5 equiv) of SiCl4 in one portion. To
the resulting solution was added 172 mL (1.5 mmol, 1.5 equiv) of
SiCl4 in one portion and the reaction mixture was cooled to –50 °C
over 15 min. Then, 284 mL (1.2 mmol, 1.2 equiv) of 2 was added
dropwise over 1 min. The resulting mixture was stirred at –50 °C for
24 h whereupon 3 mL of chilled CH2Cl2 was added before the cold
reaction mixture was poured into a rapidly stirring solution of 1:1
sat. aq NaHCO3/sat. aq KF (25 mL) at 0 °C. This biphasic mixture
was stirred vigorously for 1 h before being filtered through Celite.
The phases were then separated and the aqueous layer was washed
with CH2Cl2 (3 × 40 mL). The combined organic extracts were
dried over Na2SO4, filtered and the filtrate was concentrated in vac-
uo. The residue was purified by column chromatography (silica gel,
hexanes–EtOAc, 4:1) to give 201 mg (80%) of (+)-4 as thick oil,
(+)-(R)-7-Hydroxy-2,2-dimethyl-7-(1-naphthalenyl)-4-hepten-
3-one (6).
1H NMR (500 MHz, CDCl3): d = 8.07 (d, J = 8.3 Hz, 1 H), 7.89 (d,
J = 8.8 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.67 (d, J = 7.1 Hz, 1 H),
7.56–7.47 (m, 3 H), 7.08–7.02 (m, 1 H), 6.57 (dd, J = 15.3, 1.4 Hz,
1 H), 5.64 (dd, J = 8.0, 4.4 Hz, 1 H), 2.92–2.75 (m, 2 H), 2.11 (br s,
1 H), 1.11 (s, 9 H). 13C NMR (125 MHz, CDCl3): d = 204.33,
143.11, 139.10, 133.73, 130.04, 128.96, 128.29, 128.12, 126.77,
126.11, 125.54, 125.40, 122.93, 122.79, 69.74, 42.76, 41.22, 26.00.
[a]D24 +57.11 (c 1.10, EtOH). SFC: (S)-6 tR 3.59 min (1.0%); tR (R)-
6 4.81 min (99.0%) (OD column, 125 bar, 3.0 mL/min, 17.5%
MeOH). Anal. Calcd for C19H22O2 (282.38): C, 80.82%; H, 7.85%.
Found: C, 80.70%; H, 7.83%.
(–)-(R)-7-Hydroxy-2,2-dimethyl-9-phenyl-4,8-nonadien-3-one
(7).
1
which solidified upon standing. Data for 4: H NMR (500 MHz,
1H NMR (500 MHz, CDCl3): d = 7.37 (d, J = 7.1 Hz, 2 H), 7.32 (t,
J = 7.5 Hz, 2 H), 7.27–7.24 (m, 1 H), 6.96 (dt, J = 15.1, 7.6 Hz, 1
H), 6.64–6.60 (m, 2 H), 6.23 (dd, J = 15.9, 6.6 Hz, 1 H), 4.84 (dd,
J = 7.6, 5.4 Hz, 1 H), 2.56 (t, J = 7.1 Hz, 2 H), 1.82 (br s, 1 H), 1.15
(s, 9 H). 13C NMR (125 MHz, CDCl3): d = 204.14, 142.37, 136.34,
131.02, 130.93, 128.60, 127.85, 127.08, 126.52, 71.53, 42.84,
40.47, 26.07. [a]D24 –27.42 (c 0.90, EtOH). SFC: (R)-7 tR 2.93 min
(>99.5%); (S)-7 tR 3.62 min (<0.5%) (OD column, 125 bar, 3.0 mL/
min, 15.0% MeOH). Anal. Calcd for C17H22O2 (258.36): C,
79.03%; H, 8.58%. Found: C, 79.00%; H, 8.71%.
CDCl3): d = 7.88 (d, J = 7.1 Hz, 2 H), 7.55 (dt, J = 7.5, 1.5 Hz, 1 H),
7.43 (t, J = 7.6 Hz, 2 H), 7.39–7.35 (m, 4 H), 7.32–7.28 (m, 1 H),
7.06–7.00 (m, 1 H), 6.91 (dt, J = 15.4, 1.3 Hz, 1 H), 4.90 (dd,
J = 7.7, 5.1 Hz, 1 H), 2.83–2.71 (m, 2 H), 2.31 (br s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 190.71, 144.99, 143.47, 137.62, 132.77,
128.63, 128.60, 128.55, 128.51, 127.92, 125.75, 73.15, 42.45.
[a]D24 +14.40 (c 1.00, EtOH). SFC: (R)-4 tR 3.04 min (99.0%); (S)-
4 tR 4.06 min (1.0%) (AD column, 175 bar, 3.0 mL/min, 20.0%
MeOH). Anal. Calcd for C17H16O2 (252.31): C, 80.93%; H, 6.39%.
Found: C, 80.63%; H, 6.33%.
(+)-(R)-7-Hydroxy-2,2-dimethyl-7-(2-furanyl)-4-hepten-3-one
(8).
(+)-(R)-7-Hydroxy-2,2-dimethyl-7-phenyl-4-hepten-3-one (5).
1H NMR (500 MHz, CDCl3): d = 7.38–7.27 (m, 5 H), 6.94–6.88 (m,
1 H), 6.53 (dt, J = 15.3, 1.4 Hz, 1 H), 4.84 (dd, J = 7.6, 5.4 Hz, 1 H),
2.72–2.61 (m, 2 H), 2.02 (br s, 1 H), 1.11 (s, 9 H). 13C NMR (125
MHz, CDCl3): d = 204.17, 143.47, 142.56, 128.55, 127.83, 127.03,
1H NMR (500 MHz, CDCl3): d = 7.38 (dd, J = 1.7, 0.9 Hz, 1 H),
6.89 (dt, J = 15.4, 7.5 Hz, 1 H), 6.58 (dt, J = 15.3,1.3 Hz, 1 H), 6.33
(dd, J = 3.2, 1.7 Hz, 1 H), 6.26 (d, J = 3.2 Hz, 1 H), 4.85 (t, J = 6.6
Hz, 1 H), 2.80–2.76 (m, 2 H), 2.02 (br s, 1 H), 1.13 (s, 9 H). 13C
Synlett 2004, No. 13, 2411–2416 © Thieme Stuttgart · New York

CLUSTER
Lewis Base Activation of Lewis Acids
2415
NMR (125 MHz, CDCl3): d = 204.09, 155.41, 142.20, 141.71,
127.12, 110.24, 106.48, 66.54, 42.84, 38.54, 26.03. [a]D24 +3.80° (c
1.0, EtOH). SFC: (R)-7 tR 5.73 min (96.0%); (S)-7 tR 6.63 min
(4.0%) (AD column, 150 bar, 3.0 mL/min, 2.5% MeOH). Anal.
Calcd for C13H18O3 (222.28): C, 79.24%; H, 8.16%. Found: C,
69.89%; H, 8.20%.
7.57–7.50 (m, 3 H), 7.23 (dt, J = 10.3, 1.8 Hz, 1 H), 6.08 (dd,
J = 10.3, 2.2 Hz, 1 H), 5.38 (d, J = 6.6 Hz, 1 H), 3.06–3.01 (m, 1 H),
2.48 (dt, J = 16.8, 4.2 Hz, 1 H), 2.23 (ddd, J = 16.8, 13.4, 5.1 Hz, 1
H), 2.21 (br s, 1 H), 1.99–1.91 (m, 1 H), 1.84–1.80 (m, 1 H). 13C
NMR (125 MHz, CDCl3): d = 200.04, 151.43, 137.77, 133.83,
130.36, 129.83, 129.08, 128.50, 126.23, 125.70, 125.33, 125.25,
24
124.01, 122.86, 73.35, 42.77, 36.87, 26.51. [a]D +89.08 (c 0.90,
(–)-(R)-7-Hydroxy-2,2-dimethyl-7-(2-thienyl)-4-hepten-3-one
(9).
EtOH). SFC: (4S,7S)-15 tR 2.50 min (5.0%); (4R,7R)-15 tR 5.08 min
(95.0%) (OJ column, 150 bar, 4.0 mL/min, 20.0% MeOH). HRMS
(ES+) m/z calcd for C17H17O2: 253.1229; found: 253.1244.
1H NMR (500 MHz, CDCl3): d = 7.27–7.25 (m, 1 H), 6.99–6.93 (m,
2 H), 6.89 (dt, J = 15.4, 7.4 Hz, 1 H), 6.58 (dt, J = 15.1, 1.5 Hz, 1
H), 5.09 (dd, J = 7.0, 6.1 Hz, 1 H), 2.82–2.71 (m, 2 H), 2.12 (br s, 1
H), 1.13 (s, 9 H). 13C NMR (125 MHz, CDCl3): d = 204.25, 147.35,
141.92, 127.21, 126.68, 124.79, 123.97, 66.98, 42.83, 42.21, 26.00.
[a]D24 –5.26 (c 1.00, EtOH). SFC: (R)-7 tR 5.63 min (94.0%); (S)-7
tR 6.63 min (4.0%) (AD column, 125 bar, 2.75 mL/min, 5.0%
MeOH). Anal. Calcd for C13H18O2S1 (238.35): C, 65.51%; H,
7.61%. Found: C, 65.30%; H, 7.66%.
(+)-(4R,7R)-4-[Hydroxy-(3-phenylpropenyl)]-2-cyclohexen-1-
one (anti-16).
1H NMR (500 MHz, CDCl3): d = 7.41 (d, J = 7.8 Hz, 2 H), 7.34 (t,
J = 7.3 Hz, 2 H), 7.30–7.27 (m, J = 7.3, 1.2 Hz, 1 H), 7.16 (ddd,
J = 10.3, 2.3, 1.6 Hz, 1 H), 6.67 (d, J = 15.9 Hz, 1 H), 6.26 (dd,
J = 15.9, 6.8 Hz, 1 H), 6.10 (ddd, J = 10.3, 2.4, 0.7 Hz, 1 H), 4.23
(t, J = 6.8 Hz, 1 H), 2.69–2.63 (m, 1 H), 2.55 (dt, J = 16.8, 4.2 Hz,
1 H), 2.39 (ddd, J = 16.8, 13.2, 5.0 Hz, 1 H), 2.14–2.08 (m, 1 H),
1.90–1.82 (m, 1 H), 1.71 (br s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 199.84, 151.13, 136.00, 132.27, 130.19, 129.56, 128.66, 128.08,
(–)-(R)-7-Hydroxy-2,2-dimethyl-9-phenyl-4-nonen-8-yn-3-one
(10).
1H NMR (500 MHz, CDCl3): d = 7.43–7.41 (m, 2 H), 7.35–7.29 (m,
3 H), 7.02 (dt, J = 15.4, 7.5 Hz, 1 H), 6.69 (dt, J = 15.4, 1.2 Hz, 1
H), 4.75 (t, J = 6.1 Hz, 1 H), 2.73 (dt, J = 6.1, 1.2 Hz, 2 H), 1.65 (br
s, 1 H), 1.16 (s, 9 H). 13C NMR (125 MHz, CDCl3): d = 204.08,
141.11, 131.70, 128.61, 128.30, 127.52, 122.20, 88.76, 85.84,
61.63, 42.89, 40.72, 26.07. [a]D24 –15.96 (c 0.99, EtOH). SFC: (R)-
7 tR 1.90 min (84.0%); (S)-7 tR 3.60 min (16.0%) (OD column, 125
bar, 3.00 mL/min, 17.5% MeOH). Anal. Calcd for C17H20O2
(256.34): C, 79.65%; H, 7.86%. Found: C, 79.68%; H, 7.72%.
126.51, 75.04, 42.25, 36.86, 25.47. [a]D +52.73 (c 1.43, EtOH).
24
SFC: (4R,7R)-16 tR 4.91 min (84.5%); (4S,7S)-16 tR 6.47 min
(15.5%) (OD column, 125 bar, 3.0 mL/min, 20.0% MeOH). Anal.
Calcd for C15H16O2 (228.29): C, 78.92%; H, 7.06%. Found: C,
79.03%; H, 7.06%.
(+)-(4R,7R)-4-[Hydroxy-(2-furanyl)methyl]-2-cyclohexen-1-
one (anti-17).
1H NMR (500 MHz, CDCl3): d = 7.41 (t, J = 1.5 Hz, 2 H), 7.35 (t,
J = 2.0 Hz, 1 H), 6.38 (dd, J = 3.2, 2.0 Hz, 1 H), 6.33 (d, J = 3.2 Hz,
1 H), 6.10 (dd, J = 10.3, 2.4 Hz, 1 H), 4.64 (dd, J = 7.5, 5.0 Hz, 1
H), 2.98–2.94 (m, 1 H), 2.51 (dt, J = 16.8, 4.4 Hz, 1 H), 2.38 (ddd,
J = 16.8, 12.9, 5.1 Hz, 1 H), 2.03 (d, J = 5.1 Hz, 1 H), 1.90–1.74 (m,
2 H). 13C NMR (125 MHz, CDCl3): d = 199.84, 154.36, 151.05,
General Procedure for the Aldol Reaction of 12.
(+)-(4R,7R)-4-(Hydroxyphenylmethyl)-2-cyclohexen-1-one
(anti-13).
Diisopropylethylamine (18 mL, 0.1 mmol, 0.1 equiv) was added via
syringe to a flame-dried, 5 mL, Schlenk flask under N2 containing a
solution of 42 mg (0.05 mmol, 0.05 equiv) of bis-phosphoramide
(R,R)-1 in CH2Cl2 (2 mL). To this solution was added 102 mL (1.0
mmol) of benzaldehyde in one portion. To the resulting solution
was added 172 mL (1.5 mmol, 1.5 equiv) of SiCl4 in one portion and
the reaction mixture was cooled to –72 °C over 15 min. Then, 224
mL (1.2 mmol, 1.2 equiv) of 12 was added dropwise over 1 min. The
resulting mixture was stirred at –72 °C for 2 h whereupon 3 mL of
chilled CH2Cl2 was added before the cold reaction mixture was
poured into a rapidly stirring solution of 1:1 sat. aq NaHCO3/sat. aq
KF (25 mL) at 0 °C. This biphasic mixture was stirred vigorously
for 1 h before being filtered through Celite. The phases were then
separated and the aqueous layer was washed with CH2Cl2 (3 × 40
mL). The combined organic extracts were dried over Na2SO4, fil-
tered and the filtrate was concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel, pentane–Et2O, 1:1) to
give 182 mg (90%) of (+)-137a as thick oil, which solidified upon
standing. Data for (anti-13): 1H NMR (500 MHz, CDCl3): d = 7.43–
7.32 (m, 5 H), 7.25 (dt, J = 10.3, 1.7 Hz, 1 H), 6.09 (dd, J = 10.3,
2.4 Hz, 1 H), 4.59 (dd, J = 7.8, 3.2 Hz, 1 H), 2.78–2.73 (m, 1 H),
2.49–2.21 (m, 1 H), 2.35–2.28 (m, 1 H), 2.03 (br s, 1 H), 1.75–1.68
(m, 2 H). 13C NMR (125 MHz, CDCl3): d = 199.95, 151.63, 142.17,
24
142.43, 130.17, 110.29, 107.47, 70.13, 41.49, 36.73, 25.40. [a]D
+58.18 (c = 1.05, EtOH). SFC: (4S,7S)-17 tR 5.77 min (18.5%);
(4R,7R)-17 tR 7.14 min (81.5%) (OJ column, 125 bar, 2.5 mL/min,
5.0% MeOH). Anal. Calcd for C11H12O3 (192.21): C, 68.74%; H,
6.29%. Found: C, 68.59%; H, 6.34%.
Acknowledgment
We are grateful for the National Science Foundation generous
financial support (NSF CHE0105205 and CHE0414440).
References
(1) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929.
(2) (a) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am.
Chem. Soc. 2002, 124, 5654. (b) Paterson, I.; Davies, R. D.
M.; Heimann, A. C.; Marquez, R.; Meyer, A. Org. Lett.
2003, 5, 4477.
(3) Fettes, A.; Carreira, E. M. Angew. Chem. Int. Ed. 2002, 41,
4098.
(4) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307.
(5) (a) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24.
(b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(c) Carreira, E. M. In Comprehensive Asymmetric Catalysis,
Vol. 3; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer-Verlag: Heidelberg, 1999. (d) Machjewski, T. D.;
Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39, 1352.
24
129.83, 128.62, 128.142, 126.24, 76.54, 43.58, 36.74, 25.82. [a]D
+114.38 (c 1.00, EtOH). SFC: (4S,7S)-13 tR 6.52 min (2.5%);
(4R,7R)-13 tR 9.65 min (97.5%) (OJ column, 150 bar, 2.75 mL/min,
6.0% MeOH).
(+)-(4R,7R)-4-[Hydroxy-(1-naphthalenyl)methyl]-2-cyclo-
hexen-1-one (anti-15).
1H NMR (500 MHz, CDCl3): d = 8.12 (d, J = 8.3 Hz, 1 H), 7.91 (d,
J = 9.3 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.68 (d, J = 7.1 Hz, 1 H),
Synlett 2004, No. 13, 2411–2416 © Thieme Stuttgart · New York

2416
S. E. Denmark, J. R. Heemstra Jr.
CLUSTER
(6) (a) Fleming, I. Frontier Orbitals and Organic Chemical
Reactions; Wiley-Interscience: New York, 1996, 45.
(b) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R.
H. Tetrahedron Lett. 1973, 26, 2433.
(7) (a) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am.
Chem. Soc. 1998, 120, 813. (b) Saito, S.; Nagahara, T.;
Shiozawa, M.; Nakadai, M.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 6200.
(8) (a) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 319.
(b) Ishida, A.; Mukaiyama, T. Chem. Lett. 1975, 1167.
(c) Ishida, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1977,
50, 1161.
(9) (a) Boron: Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C.
Chem. Pharm. Bull. 1994, 42, 839. (b) Titanium: Sato, M.;
Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995, 41,
1435. (c) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc.
1995, 117, 12360. (d) DeRosa, M.; Soriente, A.; Scettri, A.
Tetrahedron: Asymmetry 2000, 11, 3187. (e) Soriente, A.;
De Rosa, M.; Stanzione, M.; Villano, R.; Scettri, A.
Tetrahedron: Asymmetry 2001, 12, 959. (f) Szlosek, M.;
Franck, X.; Figadère, R.; Cavè, A. J. Org. Chem. 1998, 63,
5169. (g) Szlosek, M.; Figadère, R. Angew. Chem. Int. Ed.
2000, 39, 1799. (h) Soriente, A.; De Rosa, M.; Apicella, A.;
Scettri, A.; Sodano, G. Tetrahedron: Asymmetry 1999, 10,
4481. (i) De Rosa, M.; Acocella, M. R.; Soriente, A.; Scettri,
A. Tetrahedron: Asymmetry 2001, 12, 1529. (j) De Rosa,
M.; Acocella, M. R.; Villano, R.; Soriente, A.; Scettri, A.
Tetrahedron: Asymmetry 2003, 14, 2499. (k) Bluet, G.;
Bazán-Tejeda, B.; Campagne, J.-M. Org. Lett. 2001, 3,
3807. (l) Copper: Kruger, J.; Carreira, E. M. J. Am. Chem.
Soc. 1998, 120, 837. (m) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.;
Staples, R. J. J. Am. Chem. Soc. 1999, 121, 666. (n) Bluet,
G.; Campagne, J.-M. Tetrahedron Lett. 1999, 40, 5507.
(o) Bluet, G.; Campagne, J.-M. J. Org. Chem. 2001, 66,
4293. (p) Chromium: Shimada, Y.; Matsuoka, Y.; Katsuki,
T. Synlett 2004, 57. (q) Matsuoka, Y.; Irie, R.; Katsuki, T.
Chem. Lett. 2003, 32, 584. (r) Onitsuka, S.; Matsuoka, Y.;
Irie, R.; Katsuki, T. Chem. Lett. 2003, 32, 974.
(10) Catalyst (R,R)-1 is commercially available from Obiter
Research, LLC, contact waboulanger@obiterresearch.com.
(11) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
7800.
(12) (a) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199. (b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am.
Chem. Soc. 2002, 124, 13405.
(13) (a) Carruthers, W. Some Modern Methods of Organic
Synthesis; Cambridge University Press: Cambridge, 1986,
20–24. (b) Caine, D. In Comprehensive Organic Synthesis,
Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991, 1–63.
(14) Fleming, I.; Iqbal, J. Tetrahedron Lett. 1983, 24, 2913.
(15) Denmark, S. E.; Heemstra, J. R. Jr. Org. Lett. 2003, 5, 2303.
(16) Fleming, I.; Goldhill, J.; Paterson, I. Tetrahedron Lett. 1979,
20, 3205.
(17) Torii, S.; Inokuchi, T.; Ogawa, H. Bull. Chem. Soc. Jpn.
1979, 52, 1233.
(18) Masamune, S.; Sato, T.; Kim, B.; Wollman, T. A. J. Am.
Chem. Soc. 1986, 108, 8279.
Synlett 2004, No. 13, 2411–2416 © Thieme Stuttgart · New York