Hydroxyl-directed intermolecular ketone-olefin couplings promoted by SmI2

Article abstract of DOI:10.1002/(SICI)1521-3765(19991105)5:11<3252::AID-CHEM3252>3.0.CO;2-D

SmI₂-promoted intermolecular ketone-olefin couplings are facilitated and stereocontrolled by hydroxyl groups incorporated within the starting materials. For example, the SmI₂-induced ketone-olefin coupling reactions of α-hydroxy ketone 5 with ethyl acrylate, acrylonitrile, ethyl crotonate, and 2(5H)-furanone proceeded with high stereocontrol to afford the syn-1,2-diol products 6-9 in good yields. Excellent diastereoselectivity was achieved in the reductive couplings of β-hydroxy aldehyde 21 and erythro-β-hydroxy ketone 24 with acrylonitrile using SmI₂, to produce the anti-1,3-diols 22 and 25 in good yields. The sense of the stereoselectivity was in full accord with a chelation-control model. In the proposed model, the stereochemistry of the reaction product is explained by assuming that a cyclic ketyl radical is generated during the initial single-electron reduction by SmI₂. This radical species results from the chelation of the Sm(III) cation, attached to the ketyl radical, with the hydroxyl group.

Full text of DOI:10.1002/(SICI)1521-3765(19991105)5:11<3252::AID-CHEM3252>3.0.CO;2-D

FULL PAPER
Hydroxyl-Directed Intermolecular Ketone ± Olefin Couplings
Promoted by SmI2
Fuyuhiko Matsuda,* Motoi Kawatsura, Ken-ichi Hosaka, and Haruhisa Shirahama[a]
Abstract: SmI2-promoted intermolecu-
lar ketone ± olefin couplings are facili-
tated and stereocontrolled by hydroxyl
groups incorporated within the starting
materials. For example, the SmI2-in-
duced ketone ± olefin coupling reactions
of a-hydroxy ketone 5 with ethyl acryl-
ate, acrylonitrile, ethyl crotonate, and
2(5H)-furanone proceeded with high
stereocontrol to afford the syn-1,2-diol
products 6 ± 9 in good yields. Excellent
diastereoselectivity was achieved in the
reductive couplings of b-hydroxy alde-
hyde 21 and erythro-b-hydroxy ketone
24 with acrylonitrile using SmI2, to
produce the anti-1,3-diols 22 and 25 in
good yields. The sense of the stereo-
selectivity was in full accord with a
chelation-control model. In the pro-
posed model, the stereochemistry of
the reaction product is explained by
assuming that a cyclic ketyl radical is
generated during the initial single-elec-
tron reduction by SmI2. This radical
species results from the chelation of the
SmIII cation, attached to the ketyl radi-
cal, with the hydroxyl group.
Keywords: C ± C couplings
´ ke-
tones ´ radical reactions ´ reagents
´ samarium
Previous research from this laboratory demonstrated the
powerful influence of appropriately positioned hydroxyl
groups in facilitating the SmI2-promoted reductive couplings
and controlling the stereochemical outcome.[4±7] For these
hydroxyl-directed transformations, the diastereoselectivity
was always excellent, and the sense of the stereoselectivity
agreed fully with a chelation-control model. The proposed
model explains the observed stereochemistry of the reaction
product by assuming that a cyclic ketyl radical forms. This
radical species arises when the SmIII cation, generated during
the initial single-electron transfer from SmI2 to the carbonyl
group of the starting material, chelates with the hydroxyl
group. Representative examples include the SmI2-promoted
cyclizations of g-hydroxy ketone 1 and b-hydroxy ketone 3
(Scheme 1).[4b,c] Their hydroxyl-directed couplings occurred
Introduction
There has been a significant growth in the number of
applications of samarium(II) iodide (SmI2) in synthetic
organic chemistry in recent years.[1] The pioneering studies
of Kagan on SmI2 provided a framework for the use of this
reagent in organic synthesis. Kaganꢀs investigations were
followed by reports from the laboratories of Curran, Mo-
lander, Enholm, Inanaga, and others, showing that SmI2 is an
extremely useful reagent for promoting reductive coupling
reactions that are difficult to accomplish by any other existing
methodologies. For example, SmI2 has been used as a reagent
substitute in Barbier reactions, Reformatsky reactions, ke-
tone ± olefin reductive couplings, and pinacol couplings. Much
research has been directed towards developing stereocon-
trolled carbon ± carbon bond formation reactions promoted
by SmI2. Especially the intramolecular variants of this process
proceeded stereoselectively, to provide, in many cases,
functionalized carbocycles. In contrast, only a limited number
of stereocontrolled SmI2-induced intermolecular couplings
have been reported.[2, 3]
H
O
H
SmI2
O
O
OH
O
O
OH
OH
1
2
[a] Prof. Dr. F. Matsuda,[‡] Dr. M. Kawatsura, K. Hosaka,
Prof. Dr. H. Shirahama
HO
HO
Department of Chemistry, Faculty of Science,
Hokkaido University, Sapporo 060-0810 (Japan)
H
O
H
SmI2
[‡] Present address: Division of Material Science,
Graduate School of Environmental Earth Science,
Hokkaido University, Sapporo 060-0810 (Japan)
Fax: (‡81)11757-5995
HO
CO2Me
CO2Me
3
4
E-mail: fmatsuda@ees.hokudai.ac.jp
Scheme 1. SmI2-promoted cyclizations of 1 and 3.
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3252±3259
with complete stereochemical control to provide diols 2 and 4,
respectively, as the sole products. It is obvious that the
stereochemistry of the 1,3-diol parts results from chelation of
the SmIII cations with the hydroxyl groups. The impact of this
new methodology on synthetic organic chemistry is clearly
evident from its applicability to total synthesis, with ( )-
grayanotoxin III, a unique tetracyclic diterpene, as a notable
example.[4a,b, 8]
Particularly impressive is that intermolecular hydroxyl-
directed SmI2-mediated ketone ± olefin couplings occur with
nearly complete diastereoselectivity.[5, 7] As previously men-
tioned, intermolecular stereoselective couplings induced by
SmI2 are much less common than intramolecular ones. This
paper describes a new type of SmI2-promoted intermolecular
carbon ± carbon bond formation reaction chelation-controlled
by a hydroxyl group.
products 6 ± 9 in good yields. The a-hydroxy ketone 5 was
prepared from 3-phenylpropionaldehyde as follows: 1) addi-
ꢀ
tion of LiC CSiMe3, 2) desilylation, 3) acetylation of the
hydroxyl group of 5-phenyl-1-pentyn-3-ol, 4) hydration of the
acetylene group with NaAuCl4,[9] and 5) hydrolysis.
First, to examine the stereochemical control, 5 was inter-
molecularly coupled with ethyl acrylate. The reductive
coupling was performed at 08C in the presence of MeOH as
proton donor to produce syn-g-lactone 6 along with a small
amount of its anti counterpart in a ratio of syn:anti of 90:10.
The diastereomeric ratios were determined from the 1H NMR
spectra (400 MHz) of the syn- and anti-1,2-diol product
mixtures. Lowering the reaction temperature from 0 to
788C led, interestingly, to a drop in diastereoselectivity
(syn:anti ˆ 82:18).[10, 11] Enhanced diastereoselectivities were
found for the reductive coupling of 5 with acrylonitrile. A high
diastereomeric ratio was also obtained at a reaction temper-
ature of 08C, with 99:1 for the syn-diol 7 to its anti
diastereoisomer, whereas a lower ratio of 92:8 resulted when
the coupling reaction was carried out at 788C.
Results and Discussion
In the SmI2-promoted coupling of 5 with ethyl crotonate
and 2(5H)-furanone, excellent diastereoselectivities were
achieved at three contiguous stereocenters to afford the syn-
1,2-diol products, syn-g-lactone 8 and syn-diol 9, respectively.
In both cases a small amount of another diastereomeric
product was obtained along with 8 or 9. None of the other
a-Hydroxyl-directed ketone ± olefin couplings promoted by
SmI2: SmI2-induced reductive coupling of a-hydroxy ketone 5
was carried out with various radical acceptors (Scheme 2).
The intermolecular coupling reactions generally proceeded
with high diastereoselectivity to provide the syn-1,2-diol
1
stereoisomers could be detected from the H NMR spectra
HO
HO
HO
HO
(400 MHz) or chromatographic analyses. Although these
minor diastereoisomers were anti-1,2-diol stereoisomers, the
relative configurations of their two new stereocenters were
the same as that of their respective syn counterparts 8 and 9.[12]
Obviously, the geometry of the carbon ± carbon double bond
of ethyl crotonate and 2(5H)-furanone determines the
relative stereochemistry of the two new stereogenic centers
of 8 and 9. It can therefore be deduced that ethyl crotonate
and 2(5H)-furanone have the same facial preference in the
SmI2-mediated coupling of 5.
The diastereoselectivity of the coupling of 5 with ethyl
crotonate had the same temperature dependence as that of
the reactions with ethyl acrylate and acrylonitrile. In contrast,
a decrease in reaction temperature resulted in increased
stereoselectivity in the reductive coupling of 5 with 2(5H)-
furanone. Thus, 8 and 9 were obtained in 99:1 and 96:4
product ratios, respectively, from the reactions with ethyl
crotonate and 2(5H)-furanone at 0 and 788C, respectively.
It is noteworthy that, in each case, the product consisted
mainly of only one of the four possible stereoisomers.
Optimum reaction conditions for these ketone ± olefin
couplings consist of the addition of SmI2 in THF (2.5 equiv
of a 0.1m solution) to a solution made up of 5, MeOH (5
equiv), and either ethyl acrylate, acrylonitrile, ethyl crotonate,
or 2(5H)-furanone (10 equiv), in THF cooled at 08C or
788C. Whereas the SmI2-induced couplings of the a-
hydroxy ketone 5 with ethyl acrylate, acrylonitrile, and ethyl
crotonate were complete within 5 min at 08C, 5 was consumed
only after 3 h under identical conditions with 2(5H)-furanone
as the ketyl radical acceptor. The anomalous temperature
dependence of the reaction with 2(5H)-furanone, as describ-
ed previously, may be ascribed to the low reactivity of 2(5H)-
CO2Et
SmI2, MeOH
O
O
O
O
O
5
5
5
6
THF, 0 °C
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
91% 90:10
84% 82:18
95% 79:21
92% 74:26
HO
CN
CN
SmI2, MeOH
OH
7
THF, 0 °C
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
77% 99:1
92:8
94:6
85:15
86%
96%
94%
HO
CO2Et
SmI2, MeOH
O
O
8
THF, 0 °C
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
74% 99:1
62% 98:2
83% 92:8
74% 88:12
O
O
HO
HO
O
O
SmI2, MeOH
O
OH
5
9
THF, 0 °C
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
71% 91:9
62% 96:4
83% 88:12
74% 83:17
Scheme 2. SmI2-induced reductive coupling of 5 with various radical
receptors.
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3253

F. Matsuda et al.
FULL PAPER
furanone. The reaction mixtures were subsequently quenched
with saturated aqueous NaHCO3. A simple extractive work-
up, followed by chromatographic purification provided the
desired 1,2-diol products. Reactions run in the presence of
HMPA resulted in some depression of the diastereoselection
in all cases.[13]
A critical component of these studies was the assignment of
relative stereochemistry. The syn-1,2-diol stereochemistry of
the syn-g-lactone 6 and the syn-diol 7 was assigned as follows
(Figure 1): In the 2D-NOESY spectra of the 1,2-diol borate
15
R
R
X
H
H
SmI2
OH
OH
SmI2
•
O
O
5
14
R=CH2Ph
X
X
R
R
•
H
H
SmI2
MeOH
Ph
Ph
Ph
OH
OH
SmI2
2
2
2
B
B
3 O
3 O
3 O
B
OH
O
4
4
4
1
1
1
O
R
O
R
O
R
5
5
5
17
16
1”
1”
1”
1’
Scheme 3. Chelation-control model.
1’
3’
CN
10
11
12
OH
O
O
from the less hindered face of 14 to form the carbon ± carbon
bond with high stereoselectivity. The chelate appears to act as
a template for the stereocontrol about the new asymmetric
centers. A second equivalent of SmI2 reduces the resulting
radical 16 to the SmIII-enolate, which, after protonation with
MeOH, results in addition product 17.
Control experiments were carried out, in which protected
derivatives of 5 were subjected to the same reductive
reactions induced by SmI2. For both a-acetoxy ketone 18
and a-tert-butyldimethylsilyloxy ketone 19, prepared from 5,
OH
HO
1’
HO
1’
4
4
5
5
R
R
3
2
3
2
R=CH2Ph
O
O
O
O
8
1
13
1
Figure 1. NOE correlations for the compounds 8, 10 ± 13, used in the
determination of the stereochemistry of 6 and 7.
(1,3,2-dioxaborolane) 10, prepared from 7, NOE correlations
were observed between C4-H and C5-CH2 (C1'-H2) and
between C4-CH2 (C1''-H2) and C5-Me (dioxaborolane number-
ing). Hydrolysis of the nitrile group of 7 gave 6, implying that
the stereochemistry of 6 is the same as that of 7.
X
5
X=OH
18 X=OAc
19 X=OSitBuMe2
20 X=H
O
The 1,2-diol borates (1,3,2-dioxaborolanes) 11 and 12,
derived from syn-g-lactone 8 and syn-diol 9, respectively,
were also studied by 2D-NOESY spectroscopy. NOEs were
observed between C4-H and C5-CH (C1'-H or C3'-H) and
between C4-CH2 (C1''-H2) and C5-Me (dioxaborolane number-
ing) for both 11 and 12. These NMR data confirm the syn-1,2-
diol stereochemistry of coupling products 8 and 9. In a 2D-
NOESY experiment on the syn-g-lactone (tetrahydro-2-
furanone) 8, C4-H gave an NOE correlation peak with C5-
CH (C1'-H), while C4-Me also gave an NOE with C5-Me
(furanone numbering), establishing that the two vicinal
methyl groups of 8 were situated cis on the g-lactone ring.
On the other hand, 2D-NOESY spectra established a trans
relative configuration between the methyl and hydroxymethyl
groups of syn-g-lactone (tetrahydro-2-furanone) 13, prepared
from the syn-diol 9: NOE correlations were found between
C4-H and C5-Me and between C4-CH2 and C5-CH (C1'-H)
(furanone numbering).
The diastereofacial preference of the starting a-hydroxy
ketone 5 is apparently independent of the ketyl radical
acceptor. The observed syn-1,2-diol stereochemistry of reac-
tion products 6 ± 9 can be explained by the chelation-control
model illustrated in Scheme 3. Thus, single-electron transfer
occurs from SmI2 to the ketone functionality of 5, and the
SmIII cation generated during this initial reduction process
forms a chelate with the a-hydroxy group, to produce the five-
membered ring ketyl radical 14. The olefin 15 approaches
reaction with SmI2 in the presence of ethyl acrylate, acryloni-
trile, ethyl crotonate, or 2(5H)-furanone always resulted in
reductive removal of the acetoxyl or tert-butyldimethylsily-
loxyl groups and the only product isolated was 5-phenyl-2-
pentanone (20). As previously mentioned, the hydroxyl-
directed coupling reactions took place smoothly at 788C
even in the absence of HMPA, although a promoter such as
HMPA was usually required to promote efficient intermole-
cular ketyl ± olefin couplings at low temperature.[14] Therefore,
the a-hydroxyl group of 5 plays a definite role in enhancing
the reactivity of the substrate and in controlling the stereo-
chemical course through chelation.
b-Hydroxyl-directed ketone ± olefin couplings promoted by
SmI2: The SmI2-induced intermolecular ketone ± olefin cou-
plings were also chelation-controlled by the b-hydroxyl
groups. Scheme 4 shows that excellent diastereoselectivities
were achieved in the reductive couplings of b-hydroxy
aldehyde 21 and erythro-b-hydroxy ketone 24 with SmI2.
The b-hydroxy aldehyde 21 was prepared by a three-step
process involving an initial cross-aldol reaction between
3-phenylpropionaldehyde and the lithium enolate of methyl
isobutyrate, followed by reduction with LiAlH4, and finally
Dess ± Martin oxidation. The erythro-b-hydroxy ketone 24
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SmI2-Promoted Couplings
3252±3259
HO
O
HO
OH
Ph
B 2
CN
H
CN
1
1
1
3
O
O
SmI2, MeOH
X
X
X
5
Y
Y
26 X=Y=CH2CH=CH2
6
4
21
22
28 X=CH2Ph, Y=CH2CN
THF, 0 °C
73% 99:1
68% 93:7
81% 94:6
75% 85:15
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
Ph
B 2
3
O
O
HO
O
HO HO
5
27 X=Y=CH2CH=CH2
29 X=CH2Ph, Y=CH2CN
6
4
CN
CN
SmI2, MeOH
24
25
Ph
B 2
THF, 0 °C
85% 100:0
78% 100:0
89% 100:0
82% 100:0
O
O3
THF, –78 °C
THF-HMPA, 0 °C
THF-HMPA, –78 °C
1”Y
1’
5
30 X=CH2Ph, Y=CH2CN
6
4
Scheme 4. Diastereoselectivities achieved in the reductive couplings of 21
and 24 with SmI2.
Figure 2. Relative stereochemistry of 26 ± 30, used in the assignment of the
stereochemistry of 22 and 23.
was synthesized by an erythro-selective aldol reaction[15] of
3-phenylpropionaldehyde with the 9-BBN-enolate generated
from 3-pentanone and 9-BBN triflate.
whereas gem-dimethyl signals of the syn isomer 29 were
detected at d ˆ 0.80 and 0.91. The stereostructure of the anti-
1,3-diol 25 was established by the 2D-NOESY spectral data of
the 1,3-diol borate (1,3,2-dioxaborane) 30 prepared from 25.
In the 2D-NOESY experiment of 30, NOE correlations were
observed between C4-Et (C1''-H2) and C5-Me and between C4-
CH2CH2CN (C1'-H2) and C6-H (dioxaborane numbering).
Evidently, the starting b-hydroxy ketones 21 and 24 have
the same, diastereofacial preference. The sense of the
diastereoselectivity may also be predicted from a chelation-
control model, depicted in Scheme 5. Thus, the six-membered
ring ketyl radicals 31 and 32, produced by chelation of the
SmIII cations to the b-hydroxyl groups after single-electron
transfer to the carbonyl groups of 21 and 24, take on chairlike
conformations. In each case, the acrylonitrile approaches from
The SmI2-induced reductive couplings of the b-hydroxy
aldehyde 21 and erythro-b-hydroxy ketone 24 were carried
out with acrylonitrile as the ketyl radical acceptor to afford
the anti-1,3-diols 22 and 25 with nearly complete stereocontrol
and in good yields. The starting materials 21 and 24 were
treated with a solution of SmI2 (0.1m, 2.5 equiv) in THF in the
presence of MeOH (5.0 equiv) and acrylonitrile (10.0 equiv)
in THF at 08C or 788C. The desired 1,3-diol products were
isolated by chromatography. Once again, a higher reaction
temperature was accompanied by better diastereoselectivity
in the reductive coupling of the b-hydroxy aldehyde 21. Thus
the diastereomeric ratio of the anti-1,3-diol 22 to its syn-
counterpart 23 was 99:1 when the coupling reaction was
performed at 08C, and a ratio of 93:7 was obtained at a
reaction temperature of 788C. The diastereomeric ratios
were determined from the 1H NMR spectra (400 MHz) of the
epimeric mixture of the 1,3-diols. Reactions run in the
presence of HMPA resulted in some depression of the
diastereoselection.[13]
R
OH
R
OH
H
H
21
24
O
O
In contrast, the anti-diol 25 was exclusively obtained by
reductive coupling of the erythro-b-hydroxy ketone 24 with
acrylonitrile. A syn epimer was not detected in the H NMR
SmI2
SmI2
R=CH2Ph
1
spectra (400 MHz) and by chromatographic analysis. In this
case, stereochemical control was unaffected by changing the
reaction temperature or by adding HMPA to the reaction
medium.[13]
R
OH
R
OH
H
H
O
O
SmI2
SmI2
•
•
The relative stereochemistries of the anti-1,3-diol 22 and its
syn epimer 23 were assigned on the basis of the similarities
between their 1H NMR chemical shifts and those of the gem-
dimethyl groups of the 1,3-diol borates (1,3,2-dioxaboranes)
26 ± 29 (Figure 2). The relative stereochemistries of 26 and 27
were determined during the total synthesis of (‡)-pederine.[16]
31
32
NC
NC
MeOH SmI2
MeOH SmI2
R
OH
R
OH
1
The anti isomer 26 has H NMR resonances for the gem-
H
dimethyl groups at d ˆ 0.99, and the gem-dimethyl resonances
of the syn isomer 27 appear at d ˆ 0.83 and 0.95. In the
1H NMR spectra of 28 and 29, derived from 22 and its syn
epimer 23, respectively, both signals due to the gem-dimethyl
groups of the anti isomer 28 were observed at d ˆ 0.96,
H
OH
OH
NC
NC
22
25
Scheme 5. Chelation-control model used to predict the sense of the
diastereoselectivity of 21 and 24.
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3255

F. Matsuda et al.
FULL PAPER
the direction opposite to the sterically congested axial methyl
group, to result in highly diastereoselective carbon ± carbon
bond formation.[17] Subsequent reduction of the resulting
radicals adjacent to the cyano groups by the second equivalent
of SmI2 and protonation of the SmIII-enolates with MeOH
produce the observed anti-1,3-diol products 22 and 25.
This model shows the strong influence of an a-substituent in
an axial orientation in the resulting high diastereoselectivity.
Indeed, the SmI2-promoted ketone ± olefin coupling of the b-
hydroxy ketone 33 or threo-b-hydroxy ketone 34 with
acrylonitrile under the same conditions always led to the
Experimental Section
General methods: Melting points were determined in an open capillary
tube and are uncorrected. IR spectra were recorded on a JASCO IR-S
spectrometer in a NaCl cell. 1H NMR spectra were recorded on Hitachi
Model R-250H (250 MHz) and JEOL Model JMN-FX-400 (400 MHz)
spectrometers. Chemical shifts are reported in ppm downfield from the
peak of Me4Si, the internal standard. Splitting patterns are designated as
ªsº, ªdº, ªtº, ªqº, and ªbrº; these symbols indicate ªsingletº, ªdoubletº,
ªtripletº, ªquartetº, and ªbroadº, respectively. Mass spectra were recorded
on
a JEOL Model JMS-DX 300, a JMS-DX 303, and a 01SG-2
spectrometer.
Unless indicated otherwise, nonaqueous reactions were carried out under
an Ar atmosphere. Dichloromethane (CH2Cl2) was distilled from CaH2.
Methanol (MeOH) was distilled from Mg(OMe)2. Tetrahydrofuran (THF)
was distilled immediately prior to use from Na/benzophenone ketyl under
an Ar atmosphere. All other commercially obtained reagents were used as
received. Analytical and preparative thin layer chromatography was run on
pre-coated silica gel plates (Macherey-Nagel DC-Fertigplatten SIL G-25
UV254). The silica gel used for column chromatography was Merck
Kieselgel 60 Art 7734.
HO
XO
XO
O
O
O
33 X=H
34 X=Me
X
21 X=H
H
35 X=Ac
ꢀ
(Æ)-5-Phenyl-1-trimethylsilyl-1-pentyn-3-ol: To a solution of HC CSiMe3
36 X=SitBuMe2
(3.80 mL, 26.9 mmol) in THF (10 mL) cooled at 788C was added a
solution of nBuLi (1.61m, 15.4 mL, 24.8 mmol) in hexane. The reaction was
allowed to warm to 08C for 30 min and then, after it was recooled to
788C, a solution of 3-phenylpropionaldehyde (4.30 g, 32.0 mmol) in THF
(5.0 mL) was introduced. The mixture was stirred at 788C for 1 h,
quenched with saturated aqueous NaHCO3, and extracted with diethyl
ether. The combined ethereal layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residual oil was purified
by silica gel column chromatography (AcOEt/hexane 10:90) to afford the
24 X=H
37 X=Ac
38 X=SitBuMe2
formation of nearly equal mixtures of the two diastereomers.
Apparently, the absence of the axial substituent at the a-
position in the 6-membered ring ketyl radicals generated from
33 and 34 resulted in a complete loss of diastereofacial
selectivity.
title compound (5.65 g, 90%) as a colorless oil: IR (neat): nÄ ˆ 3300, 2960,
1
2200, 1490, 1450, 1250, 1040, 1010, 960, 840 cm
;
1H NMR (250 MHz,
CDCl3): d ˆ 0.19 (s, 9H), 2.02 (m, 2H), 2.79 (t, J ˆ 7.8 Hz, 2H), 4.36 (t, J ˆ
‡
‡
6.6 Hz, 1H), 7.17 ± 7.31 (m, 5H); EI-MS: m/z: 232 [M ], 217 [M
C14H20O3Si (264.40): calcd C 72.36, H 8.67; found C 72.41, H 8.61.
Me];
In contrast, the same reactions of b-acetoxy aldehyde 35, b-
tert-butyldimethylsilyloxy aldehyde 36, b-acetoxy ketone 37,
and b-tert-butyldimethylsilyloxy ketone 38, synthesized from
21 and 24, led to virtually complete and consistent recoveries
of the starting materials. Moreover, the hydroxyl-directed
coupling reactions of 21 and 24 proceeded quite sufficiently
even at 788C and without needing a promoter such as
HMPA, as already described. Therefore, not only do the b-
hydroxyl groups control the stereochemistry of reductive
coupling reactions, they also have the added function of
accelerating the reaction.
(Æ)-5-Phenyl-1-pentyn-3-ol: To a solution of 5-phenyl-1-trimethylsilyl-1-
pentyn-3-ol (4.45 g, 19.2 mmol) in THF (10 mL) was added a solution of
nBu4NF (1.00m, 30.0 mL, 30.0 mmol) in THF. After the reaction mixture
was stirred at room temperature for 10 min, brine was added and the
mixture was extracted with diethyl ether. The ethereal phases were
combined, washed with brine, dried over Na2SO4, and filtered. The extract
was concentrated in vacuo and purified by silica gel column chromatog-
raphy (AcOEt/hexane 10:90) to give the title compound (2.79 g, 91%) as a
colorless oil: IR (neat): nÄ ˆ 3300, 2950, 2850, 2130, 1490, 1450, 1300, 1150,
1
1040, 1010 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 2.04 (m, 2H), 2.51 (d,
J ˆ 2.0 Hz, 1H), 2.83 (t, J ˆ 7.8 Hz, 2H), 4.37 (dt, J ˆ 2.0, 6.8 Hz, 1H), 7.18 ±
‡
‡
7.31 (m, 5H); EI-MS: m/z: 160 [M ], 142 [M
H2O]; C11H12O (160.21):
calcd C 82.46, H 7.55; found C 82.55, H 7.38.
(Æ)-1-(2-Phenylethyl)-3-propynyl acetate: A solution of 5-phenyl-1-pen-
tyn-3-ol (2.70 g, 16.9 mmol) in pyridine (10 mL) was treated with DMAP
(10.0 mg, 0.082 mmol) and Ac2O (1.70 mL, 18.0 mmol). After the mixture
was stirred at room temperature for 30 min, it was diluted with diethyl
ether. The ethereal solution was washed with saturated aqueous CuSO4,
H2O, saturated aqueous NaHCO3, and brine and was then dried over
Na2SO4, filtered, and concentrated in vacuo. Silica gel column chromatog-
raphy (AcOEt/PhMe 20:80) afforded the title compound (2.92 g, 85%) as a
Conclusion
SmI2-promoted intermolecular ketone ± olefin couplings were
shown to be facilitated and stereocontrolled by hydroxyl
groups incorporated within the starting materials. The reac-
tions generally proceeded in good yields with high and
reproducible stereochemical control. For all the hydroxyl-
directed reductive coupling reactions, the observed stereo-
chemistry in the reaction products could be rationalized by
assuming that a cyclic ketyl radical intermediate forms by
chelation between the SmIII cation, generated during the
initial single-electron reduction of the carbonyl group, and the
hydroxyl group. We could develop an efficient, powerful, and
general method to exercise stereocontrol over various types of
intermolecular ketone ± olefin coupling reactions induced by
SmI2.
colorless oil: IR (neat): nÄ ˆ 3310, 2950, 2140, 1740, 1500, 1450, 1370, 1230,
1
1180, 1120, 970 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 2.08 (s, 3H), 2.10,
2.15 (each ddt, J ˆ 6.8, 11.0, 7.8 Hz, 1H), 2.50 (d, J ˆ 2.0 Hz, 1H), 2.78 (t,
J ˆ 7.8 Hz, 2H), 5.35 (dt, J ˆ 2.0, 6.8 Hz, 1H), 7.18 ± 7.31 (m, 5H); EI-MS:
‡
m/z: 143 [M
OAc]; C13H14O2 (202.25): calcd C 77.20, H 6.98; found C
77.35, H 7.03.
(Æ)-3-Hydroxy-5-phenyl-2-pentanone (5): A solution of 1-(2-phenylethyl)-
3-propynyl acetate (2.60 g, 12.9 mmol) and NaAuCl4 ´ 2H2O (50.0 mg,
0.126 mmol) in a mixture of MeOH (15 mL) and H2O (1.0 mL) was heated
at reflux for 2 h. After the reaction mixture was cooled to room
temperature, saturated aqueous K2CO3 (2.0 mL) was added. The resulting
mixture was stirred at the same temperature for 30 min, quenched with
brine, and extracted with diethyl ether. The combined extracts were washed
3256
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0947-6539/99/0511-3256 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 11

SmI2-Promoted Couplings
3252±3259
with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residual oil was purified by silica gel column chromatography (AcOEt/
NaHCO3 and extracted with diethyl ether. The combined ethereal layers
were washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Silica gel column chromatography (AcOEt/hexane
30:70) gave a 91:9 mixture (400 MHz 1H NMR) of 9 and its (4S*,1'S*,2'R*)-
anti isomer (63.0 mg, 71%). Further purification of the mixture by
preparative silica gel TLC (AcOEt/hexane 50:50) afforded a pure sample
of 9 as a colorless oil: IR (neat): nÄ ˆ 3450, 2950, 1770, 1500, 1190, 1020,
950 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 1.11 (s, 3H), 1.72 (dddd, J ˆ 5.6,
7.8, 9.3, 13.8 Hz, 1H), 1.75 (dddd, J ˆ 2.9, 7.8, 11.2, 13.8 Hz, 1H), 2.43 (dd,
J ˆ 8.3, 16.8 Hz, 1H), 2.62 (dd, J ˆ 9.8, 16.8 Hz, 1H), 2.62 ± 2.74 (m, 2H),
2.91 (ddd, J ˆ 5.6, 7.8, 13.5 Hz, 1H), 3.30 (dd, J ˆ 2.9, 9.3 Hz, 1H), 4.01 (dd,
J ˆ 7.8, 9.0 Hz, 1H), 4.19 (t, J ˆ 9.0 Hz, 1H), 7.19 ± 7.33 (m, 5H); FAB-MS:
hexane 30:70) to give 5 (2.21 g, 96%) as a colorless oil: IR (neat): nÄ ˆ 3500,
1
2950, 1710, 1490, 1450, 1350, 1260, 1160, 1090, 810, 750 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 1.83 (dddd, J ˆ 4.8, 8.3, 9.1, 13.7 Hz, 1H), 2.15
(dddd, J ˆ 3.4, 7.3, 9.5, 13.7 Hz, 1H), 2.16 (s, 3H), 2.74 (ddd, J ˆ 4.8, 9.5,
14.0 Hz, 1H), 2.80 (ddd, J ˆ 7.3, 9.1, 14.0 Hz, 1H), 4.16 (dd, J ˆ 3.4, 8.3 Hz,
‡
‡
1H), 7.19 ± 7.32 (m, 5H); EI-MS: m/z: 178 [M ], 160 [M
H2O]; C11H14O2
(178.22): calcd C 74.13, H 7.92; found C 74.02, H 8.03.
Preparation of THF solution of SmI2: To a slurry of Sm metal powder
(2.00 g, 13.3 mmol) in THF (100 mL) was added CH2I2 (0.900 mL,
11.2 mmol). The mixture was stirred at room temperature for 3 h. The
resulting blue solution was used directly to effect the following reductive
couplings.
‡
‡
m/z: 264 [M ‡ H], 246 [M
H2O]; C15H20O4 (264.32): calcd C 68.16, H
7.63; found: C 68.07, H 7.72.
(4R,*5R*)-5-(2-Cyanoethyl)-5-methyl-2-phenyl-4-(2-phenylethyl)-1,3,2-
dioxaborolane (10): A solution of the syn-diol 7 (20.0 mg, 0.086 mmol) and
PhB(OH)2 (105 mg, 0.861 mmol) in PhMe (1.0 mL) was stirred at room
temperature for 24 h. The solvent was evaporated in vacuo, and the residue
was purified by silica gel column chromatography (AcOEt/hexane 5:95) to
(5R*,1'R*)-Tetrahydro-5-(1-hydroxy-3-phenylpropyl)-5-methyl-2-fura-
none (syn-g-lactone 6): To a solution of 5 (60.0 mg, 0.337 mmol), ethyl
acrylate (0.365 mL, 3.37 mmol), and MeOH (0.069 mL, 1.70 mmol) in THF
(1.0 mL), cooled to 08C, was added a solution of SmI2 (0.10m, 8.40 mL,
0.840 mmol) in THF. After the reaction mixture was stirred at 08C for
5 min, it was analyzed by TLC which showed that the starting a-hydroxy
ketone was completed consumed. The reaction mixture was quenched with
saturated aqueous NaHCO3 and extracted with diethyl ether. The
combined ethereal extracts were washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (AcOEt/hexane 30:70) to provide a
90:10 mixture (determined by 400 MHz 1H NMR) of 6 and its (5S*,1'R*)-
anti isomer (71.8 mg, 91%). Further purification of the mixture by
preparative silica gel TLC (AcOEt/hexane 50:50) afforded a pure sample
of 6 as a colorless oil: IR (neat): nÄ ˆ 3450, 2950, 1750, 1490, 1450, 1380, 1230,
1150, 1080, 940 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 1.22 (s, 3H), 1.74 (m,
2H), 1.89 (ddd, J ˆ 5.4, 9.8, 12.7 Hz, 1H), 2.10 (dt, J ˆ 12.7, 9.8 Hz, 1H),
2.58 (ddd, J ˆ 5.4, 9.8, 18.0 Hz, 1H), 2.62 (dt, J ˆ 18.0, 9.8 Hz, 1H), 2.68 (dt,
J ˆ 13.7, 8.3 Hz, 1H), 2.96 (dt, J ˆ 13.7, 6.8 Hz, 1H), 3.53 (dd, J ˆ 5.8, 6.7 Hz,
afford 10 (27.0 mg, 98%) as a colorless oil: IR (neat): nÄ ˆ 3000, 2950, 2280,
1
1500, 1440, 1410, 1350, 1250, 1090, 1030, 920 cm
;
1H NMR (400 MHz,
CDCl3): d ˆ 1.30 (s, 3H), 1.77 (dddd, J ˆ 2.9, 6.8, 9.5, 13.5 Hz, 1H), 1.95
(dddd, J ˆ 4.9, 9.8, 10.5, 13.5 Hz, 1H), 1.99, 2.51 (each m, 2H), 2.77 (ddd,
J ˆ 6.8, 9.8, 13.8 Hz, 1H), 3.03 (ddd, J ˆ 4.9, 9.5, 13.8 Hz, 1H), 4.12 (dd, J ˆ
2.9, 10.5 Hz, 1H), 7.20 ± 7.36 (m, 5H), 7.37 (t, J ˆ 7.6 Hz, 2H), 7.43 (tt, J ˆ 1.7,
‡
7.6 Hz, 1H), 7.84 (dd, J ˆ 1.7, 7.6 Hz, 2H); EI-MS: m/z: 319 [M ];
C20H22BNO2 (319.21): calcd C 75.25, H 6.95, N 4.39; found: C 75.38, H
6.88, N 4.28.
Conversion of the syn-diol 7 into the syn-g-lactone 6: To a solution of 7
(20.0 mg, 0.086 mmol) in MeOH (1.0 mL) was added NaOMe (10.0 mg,
0.185 mmol). The resulting mixture was stirred at ambient temperature for
24 h and acidified with aqueous HCl (1m). After the MeOH was
evaporated in vacuo, the residue was extracted with AcOEt. The combined
organic layers were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Purification by silica gel column chromatography (AcOEt/
hexane 10:90) provided 6 (17.0 mg, 84%).
‡
‡
1H), 7.14 ± 7.36 (m, 5H); EI-MS: m/z: 234 [M ], 216 [M
H2O]; C14H18O3
(234.28): calcd C 71.77, H 7.74; found: C 71.85, H 7.68.
(4R*,5R*)-4,5-Dihydroxy-4-methyl-7-phenylheptanenitrile (syn-diol 7):
The previously outlined procedure was followed to react 5 with acryloni-
(4R,*5R,*1'R*)-5-(3-Hydroxy-1-methylpropyl)-5-methyl-2-phenyl-4-(2-
phenylethyl)-1,3,2-dioxaborolane (11): To a solution of the syn-g-lactone 8
(20.0 mg, 0.081 mmol) in diethyl ether (2.0 mL) cooled at 08C was added
LiAlH4 (10.0 mg, 0.264 mmol). The reaction mixture was stirred at 08C for
12 h and then quenched with AcOEt. The mixture was treated with
successive additions of H2O (0.01 mL), aqueous NaOH (15%, 0.01 mL),
and H2O (0.03 mL). The resultant white precipitate was filtered off and the
filtrate was concentrated in vacuo. The residual oil was dissolved in PhMe
(2.0 mL) and PhB(OH)2 (99.0 mg, 0.811 mmol) was added. Stirring was
continued at room temperature for 24 h and the PhMe was evaporated in
vacuo. The crude material was purified by silica gel column chromatog-
raphy (AcOEt/hexane 10:90) to give 11 (23.0 mg, 84%) as a colorless oil:
IR (neat): nÄ ˆ 3400, 2950, 1500, 1440, 1410, 1380, 1350, 1260, 1090, 1020,
920 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 0.84 (d, J ˆ 6.8 Hz, 3H), 1.21 (s,
3H), 1.41 (ddt, J ˆ 7.9, 13.8, 5.8 Hz, 1H), 1.75 (dddd, J ˆ 2.4, 7.3, 9.5,
13.7 Hz, 1H), 1.84 (m, 1H), 1.96 (dddd, J ˆ 4.4, 9.5, 11.0, 13.7 Hz, 1H), 1.99
(dddd, J ˆ 4.9, 6.2, 9.5, 13.8 Hz, 1H), 2.78 (ddd, J ˆ 7.3, 9.5, 13.8 Hz, 1H),
3.07 (ddd, J ˆ 4.4, 9.5, 13.8 Hz, 1H), 3.68 (ddd, J ˆ 5.8, 7.9, 11.0 Hz, 1H),
3.78 (ddd, J ˆ 4.9, 9.5, 11.0 Hz, 1H), 4.18 (dd, J ˆ 2.4, 11.0 Hz, 1H), 7.19 ±
7.35 (m, 5H), 7.38 (t, J ˆ 7.8 Hz, 2H), 7.46 (tt, J ˆ 1.5, 7.8 Hz, 1H), 7.85 (dd,
1
trile to afford a 99:1 mixture (400 MHz H NMR) of 7 and its (4S*,5R*)-
anti isomer in 77% yield, which was isolated by silica gel column
chromatography (AcOEt/hexane 40:60). Further purification of the
mixture by preparative silica gel TLC (AcOEt/hexane 50:50) yielded a
pure sample of 7 as a colorless oil: IR (neat): nÄ ˆ 3450, 2950, 2260, 1495,
1
1450, 1375, 1070, 930, 750 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 1.33 (s,
3H), 1.68 (dddd, J ˆ 5.5, 8.8, 10.5, 14.1 Hz, 1H), 1.73 ± 1.90 (m, 3H), 2.39 (t,
J ˆ 7.3 Hz, 2H), 2.68 (ddd, J ˆ 7.3, 8.8, 13.7 Hz, 1H), 2.91 (ddd, J ˆ 5.5, 8.8,
13.7 Hz, 1H), 3.40 (dd, J ˆ 2.2, 10.5 Hz, 1H), 7.20 ± 7.33 (m, 5H); EI-MS:
‡
m/z: 233 [M ]; C14H19NO2 (233.31): calcd C 72.07, H 8.21, N 6.00; found C
72.03, H 8.18, N 6.09.
(4R*,5R*,1'R*)-Tetrahydro-5-(1-hydroxy-3-phenylpropyl)-4,5-dimethyl-2-
furanone (syn-g-lactone 8): The same procedure was used again to react 5
with ethyl crotonate to afford a 99:1 mixture (400 MHz 1H NMR) of 8 and
its (4S*,5S*,1'R*)-anti isomer in 74% yield. It was isolated by silica gel
column chromatography (AcOEt/hexane 30:70). Further purification of
the mixture by preparative silica gel TLC (AcOEt/hexane 50:50) afforded a
pure sample of 8 as a colorless oil: IR (neat): nÄ ˆ 3500, 2950, 1760, 1490,
1
1450, 1420, 1380, 1240, 1050, 930, 850 cm 1; H NMR (400 MHz, CDCl3):
‡
‡
J ˆ 1.5, 7.8 Hz, 2H); EI-MS: m/z: 338 [M ], 320 [M
H2O]; C21H27BO3
d ˆ 1.05 (d, J ˆ 6.7 Hz, 3H), 1.22 (s, 3H), 1.76 (dddd, J ˆ 5.2, 8.8, 10.2,
14.0 Hz, 1H), 1.89 (dddd, J ˆ 2.6, 7.5, 8.8, 14.0 Hz, 1H), 2.27 (dd, J ˆ 10.0,
16.7 Hz, 1H), 2.58 (tq, J ˆ 10.0, 6.7 Hz, 1H), 2.66 (dd, J ˆ 10.0, 16.7 Hz,
1H), 2.67 (ddd, J ˆ 7.5, 8.8, 13.8 Hz, 1H), 2.96 (ddd, J ˆ 5.2, 8.8, 13.8 Hz,
1H), 3.50 (dd, J ˆ 2.6, 10.2 Hz, 1H), 7.19 ± 7.36 (m, 5H); EI-MS: m/z: 248
(338.25): calcd C 74.57, H 8.05; found: C 74.48, H 8.17.
(4R,*5R,*3'R*)-5-Methyl-2-phenyl-4-(2-phenylethyl)-5-(tetrahydro-5-oxo-
3-furanyl)-1,3,2-dioxaborolane (12): The procedure described for the
preparation of the 1,3,2-dioxaborolane 10 was followed to prepare the
title compound from the syn-diol 9 in 91% yield as a colorless oil: IR
(neat): nÄ ˆ 2900, 1780, 1500, 1440, 1400, 1360, 1250, 1230, 1180, 1090, 1020,
930 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 1.37 (s, 3H), 1.76 (dddd, J ˆ 4.8,
9.4, 11.0, 13.8 Hz, 1H), 1.98 (dddd, J ˆ 2.4, 7.3, 8.8, 13.8 Hz, 1H), 2.56 (dd,
J ˆ 2.0, 16.5 Hz, 1H), 2.58 (d, J ˆ 16.5 Hz, 1H), 2.74 (dt, J ˆ 2.0, 8.3 Hz,
1H), 2.77 (ddd, J ˆ 7.3, 9.4, 14.5 Hz, 1H), 3.03 (ddd, J ˆ 4.8, 8.8, 14.5 Hz,
1H), 4.29 (m, 2H), 7.21 ± 7.34 (m, 5H), 7.40 (t, J ˆ 7.7 Hz, 2H), 7.45 (tt, J ˆ
‡
‡
[M ], 230 [M
72.48, H 8.21.
H2O]; C15H20O3 (248.32): calcd C 72.55, H 8.12; found: C
(4R*,1'R*,2'R*)-4-(1,2-Dihydroxy-1-methyl-4-phenylbutyl)tetrahydro-2-
furanone (syn-diol 9): To a solution of 5 (60.0 mg, 0.337 mmol), 2(5H)-
furanone (0.240 mL, 3.38 mmol), and MeOH (0.069 mL, 1.70 mmol) in
THF (1.0 mL) cooled at 08C was added a solution of SmI2 (0.10m, 8.40 mL,
0.840 mmol) in THF. After the reaction mixture was stirred at 08C for 3 h,
TLC analysis showed complete consumption of the starting a-hydroxy
ketone. The reaction mixture was quenched with saturated aqueous
‡
1.7, 7.7 Hz, 1H), 7.84 (dd, J ˆ 1.7, 7.7 Hz, 2H); FAB-MS: m/z: 351 [M ‡ H];
C21H23BO4 (350.22): calcd C 72.02, H 6.62; found: C 72.18, H 6.51.
Chem. Eur. J. 1999, 5, No. 11
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0511-3257 $ 17.50+.50/0
3257

F. Matsuda et al.
FULL PAPER
(4R*,5R*,1'R*)-Tetrahydro-4-hydroxymethyl-5-(1-hydroxy-3-phenylpro-
pyl)-5-methyl-2-furanone (syn-g-lactone 13): A solution of the syn-diol 9
(30.0 mg, 0.113 mmol) in THF (2.0 mL) was treated with saturated aqueous
NaHCO3 (1.0 mL). The mixture was stirred at room temperature for 20 min
and extracted with diethyl ether. The combined ethereal extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by silica gel column chromato graphy (AcOEt/PhMe 20:80)
for 2 h, and then quenched with MeOH (5.0 mL) and aqueous H2O2 (30%,
5.0 mL). The resulting mixture was stirred at room temperature for 1 h,
cooled to 08C, treated with saturated aqueous Na2S2O3, and extracted with
diethyl ether. The combined ethereal layers were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel
column chromatography (AcOEt/hexane 20:80) gave 24 (5.40 g, 98%) as a
colorless oil: IR (neat): nÄ ˆ 3550, 2950, 1720, 1490, 1450, 1410, 1380, 1110,
1
afforded 13 (27.0 mg, 90%) as a colorless oil: IR (neat): nÄ ˆ 3400, 2950,
1080, 1030, 970, 930 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 1.04 (t, J ˆ
1
1760, 1500, 1450, 1420, 1380, 1270, 1230, 1140, 1090, 1030, 950 cm
;
7.3 Hz, 3H), 1.15 (d, J ˆ 7.3 Hz, 3H), 1.59 (dddd, J ˆ 3.1, 7.0, 9.6, 14.0 Hz,
1H), 1.84 (ddt, J ˆ 5.2, 14.0, 9.1 Hz, 1H), 2.46, 2.54 (each dq, J ˆ 18.0,
7.3 Hz, 1H), 2.57 (dq, J ˆ 3.1, 7.3 Hz, 1H), 2.65 (ddd, J ˆ 7.0, 9.1, 13.5 Hz,
1H), 2.84 (ddd, J ˆ 5.2, 9.6, 13.5 Hz, 1H), 3.94 (dt, J ˆ 9.1, 3.1 Hz, 1H),
1H NMR (400 MHz, CDCl3): d ˆ 1.37 (s, 3H), 1.92 (m, 2H), 2.49 (m, 1H),
2.58 (dd, J ˆ 6.8, 16.2 Hz, 1H), 2.67 (dt, J ˆ 13.7, 8.3 Hz, 1H), 2.82 (dd, J ˆ
9.7, 16.2 Hz, 1H), 2.91 (ddd, J ˆ 5.4, 9.0, 13.7 Hz, 1H), 3.77 (dd, J ˆ 2.9,
10.3 Hz, 1H), 3.83 (d, J ˆ 4.4 Hz, 2H), 7.12 ± 7.32 (m, 5H); EI-MS: m/z: 246
‡
‡
7.16 ± 7.35 (m, 5H); EI-MS: m/z: 220 [M ], 202 [M
H2O]; C14H20O2
‡
‡
[M
H2O]; FAB-MS: m/z: 265 [M ‡ H]; C15H20O4 (264.32): calcd C
(220.31): calcd C 76.33, H 9.15; found: C 76.45, H 9.28.
68.16, H 7.63; found: C 68.25, H 7.57.
(4R*,6R*)-4,6-Dihydroxy-5,5-dimethyl-8-phenyloctanenitrile
(anti-diol
(Æ)-Methyl 3-hydroxy-2,2-dimethyl-5-phenylvalerate: To a solution of
iPr2NH (10.1 mL, 72.1 mmol) in THF (150 mL) cooled at 08C was added
a solution of nBuLi (1.61m, 37.3 mL, 60.1 mmol) in hexane. The resultant
solution was stirred at 08C for 10 min and cooled to 788C, and then a
solution of methyl isobutyrate (5.73 mL, 50.0 mmol) in THF (50 mL) was
added. After the reaction mixture was stirred at 788C for 1 h, a solution
of 3-phenylpropionaldehyde (6.71 g, 50.0 mmol) in THF (50 mL) was
introduced. The reaction was stirred at 788C for 1 h, quenched with
saturated aqueous NH4Cl, and extracted with diethyl ether. The combined
ethereal layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Silica gel column chromatography (AcOEt/hexane
5:95) furnished the title compound (9.40 g, 80%) as a colorless oil: IR
(neat): nÄ ˆ 3500, 2950, 1720, 1490, 1470, 1450, 1430, 1390, 1360, 1270, 1190,
1130, 1080, 1040, 990, 920 cm 1; 1H NMR (250 MHz, CDCl3): d ˆ 1.16, 1.18
(each s, 3H), 1.60 (dddd, J ˆ 5.2, 9.5, 10.2, 13.5 Hz, 1H), 1.77 (dddd, J ˆ 2.0,
7.2, 10.2, 13.5 Hz, 1H), 2.65 (ddd, J ˆ 7.2, 9.5, 13.5 Hz, 1H), 2.96 (ddd, J ˆ
5.2, 10.2, 13.5 Hz, 1H), 3.62 (dd, J ˆ 2.0, 10.2 Hz, 1H), 3.69 (s, 3H), 7.14 ±
22) and its (4S*,6R*) isomer (syn-diol 23): To a solution of 21 (60.0 mg,
0.291 mmol), acrylonitrile (0.192 mL, 2.92 mmol), and MeOH (0.059 mL,
1.46 mmol) in THF (1.00 mL), cooled at 08C, was added a solution of SmI2
(0.10m, 7.27 mL, 0.727 mmol) in THF. After the reaction mixture was
stirred at 08C for 1 h, TLC analysis showed completed consumption of the
starting b-hydroxy aldehyde. The reaction mixture was quenched with
saturated aqueous NaHCO3 and extracted with diethyl ether. The
combined ethereal extracts were washed with H2O and brine, dried over
Na2SO4, and filtered. Concentration in vacuo and purification by silica gel
column chromatography (AcOEt/hexane 30:70) afforded a 99:1 mixture
(400 MHz, 1H NMR) of 22 and 23 (55.5 mg, 73%). Further purification of
the mixture by preparative silica gel TLC (AcOEt/hexane 50:50) afforded
pure samples of 22 and 23.
anti-Diol 22: white solid, M.p. 88 ± 898C; IR (CHCl3): nÄ ˆ 3350, 2910, 2250,
1
1490, 1460, 1380, 1320, 1260, 1150, 1090, 1040, 930 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 0.90 (s, 6H), 1.62 ± 1.93 (m, 4H), 2.47 (dt, J ˆ 17.0,
8.0 Hz, 1H), 2.59 (ddd, J ˆ 5.8, 7.8, 17.0 Hz, 1H), 2.65 (ddd, J ˆ 7.5, 8.5,
13.5 Hz, 1H), 2.89 (ddd, J ˆ 6.0, 9.1, 13.5 Hz, 1H), 3.56 (dd, J ˆ 2.2, 10.0 Hz,
‡
‡
7.38 (m, 5H); EI-MS: m/z: 236 [M ], 218 [M
calcd C 71.16, H 8.53; found: C 70.99, H 8.54.
H2O]; C14H20O3 (236.31):
‡
‡
1H), 7.18 ± 7.40 (m, 5H); EI-MS: m/z: 261 [M ], 243 [M
H2O];
(Æ)-2,2-Dimethyl-5-phenyl-1,3-pentanediol: To a solution of methyl 3-
hydroxy-2,2-dimethyl-5-phenylvalerate (1.89 g, 8.00 mmol) in diethyl ether
(20.0 mL) cooled at 08C was added LiAlH4 (500 mg, 13.2 mmol). The
reaction was stirred at 08C for 1 h and quenched with AcOEt. The mixture
was treated with successive additions of H2O (0.50 mL), aqueous NaOH
(15%, 0.50 mL), and H2O (1.5 mL). The resultant white precipitate was
filtered off and the filtrate was concentrated in vacuo. The residual solid
was recrystallized from hexane to provide the title compound (1.21 g, 73%)
C16H23NO2 (261.31): calcd C 73.53, H 8.87, N 5.36; found: C 73.41, H 9.01,
N 5.25.
syn-Diol 23: colorless oil; IR (neat): nÄ ˆ 3400, 2980, 2250, 1490, 1450, 1380,
1
1310, 1180, 1090, 1070, 930 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 0.76,
0.90 (each s, 3H), 1.57 ± 2.02 (m, 4H), 2.47 (dt, J ˆ 16.0, 8.1 Hz, 1H), 2.55
(ddd, J ˆ 5.5, 7.8, 16.0 Hz, 1H), 2.64 (ddd, J ˆ 7.0, 8.8, 13.3 Hz, 1H), 2.86
(ddd, J ˆ 5.8, 9.5, 13.3 Hz, 1H), 3.55 (dd, J ˆ 2.0, 10.5 Hz, 1H), 3.62 (dd, J ˆ
as colorless crystals, M.p. 79 ± 808C: IR (CHCl3): nÄ ˆ 3390, 3300, 2940, 1580,
‡
‡
2.6, 11.0 Hz, 1H), 7.19 ± 7.41 (m, 5H); EI-MS: m/z: 261 [M ], 243 [M
1
1450, 1380, 1360, 1310, 1290, 1230, 1200, 1070, 1040, 1020, 930, 880 cm
;
H2O]; C16H23NO2 (261.36): calcd C 73.53, H 8.87, N 5.36; found: C 73.62, H
8.70, N 5.18.
1H NMR (250 MHz, CDCl3): d ˆ 0.88 (s, 6H), 1.68 (dddd, J ˆ 4.3, 9.5, 10.5,
13.7 Hz, 1H), 1.82 (dddd, J ˆ 2.2, 6.6, 10.0, 13.7 Hz, 1H), 2.64 (ddd, J ˆ 6.6,
9.5, 14.0 Hz, 1H), 2.94 (ddd, J ˆ 4.3, 10.0, 14.0 Hz, 1H), 3.45 (d, J ˆ 11.2 Hz,
1H), 3.51 (dd, J ˆ 2.2, 10.5 Hz, 1H), 3.57 (d, J ˆ 11.2 Hz, 1H), 7.16 ± 7.38 (m,
(4R*,5S*,6R*)-4-Ethyl-4,6-dihydroxy-5-methyl-8-phenyloctanenitrile
(anti-diol 25): The previously outlined procedure was followed to react 24
with acrylonitrile to afford 25 in 85% yield. The product was isolated by
‡
‡
5H); EI-MS: m/z: 208 [M ], 190 [M
74.96, H 9.68; found: C 74.90, H 9.51.
H2O]; C13H20O2 (208.30): calcd C
preparative silica gel TLC (AcOEt/hexane 50:50) as a colorless oil: IR
1
(neat): nÄ ˆ 3300, 2830, 2330, 1460, 1380, 1330, 1110, 1060, 970, 920 cm
;
(Æ)-3-Hydroxy-2,2-dimethyl-5-phenylvaleraldehyde (21): To a solution of
2,2-dimethyl-5-phenyl-1,3-pentanediol (0.500 g, 2.40 mmol) in CH2Cl2
(15 mL) was added Dess ± Martin periodinane (2.04 g, 4.81 mmol). After
stirring at room temperature for 1 h, the mixture was quenched with
saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 and extracted
with diethyl ether. The combined extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel
column chromatography (AcOEt/hexane 10:90) afforded 21 (0.307 g,
1H NMR (400 MHz, CDCl3): d ˆ 0.79 (d, J ˆ 7.2 Hz, 3H), 0.98 (d, J ˆ
6.8 Hz, 3H), 1.43 (dq, J ˆ 15.6, 7.2 Hz, 1H), 1.49 (dq, J ˆ 2.0, 6.8 Hz, 1H),
1.57 (dq, J ˆ 15.6, 7.2 Hz, 1H), 1.74 (dddd, J ˆ 4.9, 6.3, 9.8, 13.7 Hz, 1H),
1.81 (ddd, J ˆ 5.8, 10.5, 13.5 Hz, 1H), 1.93 (ddt, J ˆ 8.3, 13.7, 6.8 Hz, 1H),
2.08 (ddd, J ˆ 5.0, 11.0, 13.5 Hz, 1H), 2.28 (ddd, J ˆ 5.8, 11.0, 16.8 Hz, 1H),
2.50 (ddd, J ˆ 5.0, 10.5, 16.8 Hz, 1H), 2.68 (ddd, J ˆ 6.3, 6.8, 13.7 Hz, 1H),
2.73 (ddd, J ˆ 6.8, 9.8, 13.7 Hz, 1H), 4.15 (ddd, J ˆ 2.0, 4.9, 8.3 Hz, 1H),
‡
7.20 ± 7.33 (m, 5H); EI-MS: m/z: 275 [M ]; C17H25NO2 (275.39): calcd C
62%) as a colorless oil: IR (neat): nÄ ˆ 3300, 2950, 1720, 1490, 1460, 1450,
74.14, H 9.15, N 5.09; found: C 74.08, H 8.99, N 4.96.
1
1380, 1360, 1270, 1130, 1070, 1040, 980, 930 cm
;
1H NMR (400 MHz,
CDCl3): d ˆ 1.01, 1.08 (each s, 3H), 1.72 (m, 2H), 2.67 (dt, J ˆ 13.3, 7.5 Hz,
(4R,*6R*)-4-(2-Cyanoethyl)-5,5-dimethyl-2-phenyl-6-(2-phenylethyl)-
1,3,2-dioxaborane (28): The procedure described for the preparation of the
1,3,2-dioxaborolane 10 was followed to prepare the title compound from
syn-diol 22 in 83% yield as a colorless oil: IR (neat): nÄ ˆ 2980, 2250, 1490,
1450, 1400, 1380, 1360, 1330, 1300, 1260, 1160, 1130, 1090, 1070, 1010, 950,
930 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 0.96 (s, 6H), 1.68 ± 2.00 (m, 2H),
2.55 ± 2.66 (m, 2H), 2.78 (dt, J ˆ 13.5, 8.1 Hz, 1H), 3.07 (ddd, J ˆ 5.1, 9.3,
13.5 Hz, 1H), 3.75 (dd, J ˆ 2.6, 10.2 Hz, 1H), 3.89 (dd, J ˆ 2.1, 11.0 Hz, 1H),
7.17 ± 7.34 (m, 5H), 7.40 (t, J ˆ 7.5 Hz, 2H), 7.45 (tt, J ˆ 1.6, 7.5 Hz, 1H), 7.86
1H), 2.94 (ddd, J ˆ 5.5, 8.8, 13.3 Hz, 1H), 3.76 (dd, J ˆ 3.0, 9.1 Hz, 1H),
‡
‡
7.14 ± 7.35 (m, 5H), 9.50 (s, 1H); EI-MS: m/z: 206 [M ], 189 [M
H2O];
C13H18O2 (206.28): calcd C 75.69, H 8.79; found: C 75.53, H 8.83.
(4S*,5R*)-5-Hydroxy-4-methyl-7-phenyl-3-heptanone (24): To a solution
of iPr2NEt (4.79 mL, 27.5 mmol) in diethyl ether (80 mL) cooled at 788C
was added a solution of 9-BBNOTf (0.50m, 50.0 mL, 25.0 mmol) in hexane
and a solution of 3-pentanone (2.50 mL, 24.8 mmol) in diethyl ether
(5.0 mL). After stirring at 788C for 10 min, a solution of 3-phenyl-
propionaldehyde (3.35 g, 25.0 mmol) in diethyl ether (5.0 mL) was
introduced. The reaction was stirred at 788C for 1 h, warmed to 08C
‡
(dd, J ˆ 1.6, 7.5 Hz, 2H); EI-MS: m/z: 347 [M ]; C22H26BNO2 (347.26):
calcd C 76.09, H 7.55, N 4.03; found: C 76.25, H 7.37, N 3.92.
3258
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Chem. Eur. J. 1999, 5, No. 11

SmI2-Promoted Couplings
3252±3259
(4S,*6R*)-4-(2-Cyanoethyl)-5,5-dimethyl-2-phenyl-6-(2-phenylethyl)-
1,3,2-dioxaborane (29): The procedure described for the preparation of the
1,3,2-dioxaborolane 10 was followed to prepare the title compound from
anti-diol 23 in 88% yield as a colorless oil: IR (neat): nÄ ˆ 2960, 2300, 1480,
[5] For a preliminary account of part of this work, see: a) M. Kawatsura,
F. Matsuda, H. Shirahama, J. Org. Chem. 1994, 59, 6900; b) M.
Kawatsura, K. Hosaka, F. Matsuda, H. Shirahama, Synlett 1995, 729.
[6] The SmI2-mediated 5- and 6-exo-trig cyclizations stereocontrolled by
hydroxyl groups were recently reported by Molander and Losada. The
observed diastereoselectivities of these hydroxyl-directed transforma-
tions can be rationalized by our chelation-control model. See: G. A.
Molander, C. P. Losada, J. Org. Chem. 1997, 62, 2934.
[7] We also found that the intermolecular ketone ± olefin couplings of a-
(alkoxycarbonyl)amino ketones with a,b-unsaturated esters, induced
by SmI2, are chelation-controlled by the a-(alkoxycarbonyl)amino
groups. See: M. Kawatsura, F. Dekura, H. Shirahama, F. Matsuda,
Synlett 1996, 373.
[8] a) T. Kan, S. Nara S. Ito, F. Matsuda, H. Shirahama, J. Org. Chem.
1994, 59, 5111; b) T. Kan, M. Oikawa, S. Hosokawa, M. Yanagiya, F.
Matsuda, H. Shirahama, Synlett 1994, 801; c) T. Kan, M. Oikawa, S.
Hosokawa, M. Yanagiya, F. Matsuda, H. Shirahama, Synlett 1994, 805.
[9] Y. Fukuda, K. Utimoto, J. Org. Chem. 1991, 56, 3729.
[10] The SmI2-promoted ketone ± olefin couplings between the a-(alkoxy-
carbonyl)amino ketones and a,b-unsaturated esters were more
stereoselective at higher temperatures.[7]
[11] Fallis and Sturino also observed similar temperature trends for the
diastereoselectivity of the 5-exo-trig cyclization of 5-(diphenylhydra-
zono)pentanal induced by SmI2. See: C. F. Sturino, A. G. Fallis, J. Am.
Chem. Soc. 1994, 116, 7447.
1450, 1410, 1380, 1360, 1320, 1290, 1260, 1170, 1130, 1080, 1010, 960,
1
920 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 0.80, 0.91 (each s, 3H), 1.70 ±
2.02 (m, 2H), 2.58 ± 2.69 (m, 2H), 2.81 (dt, J ˆ 14.1, 7.9 Hz, 1H), 3.12 (ddd,
J ˆ 5.3, 9.1, 14.1 Hz, 1H), 3.77 (dd, J ˆ 2.7, 10.8 Hz, 1H), 3.83 (dd, J ˆ 2.1,
11.3 Hz, 1H), 7.16 ± 7.35 (m, 5H), 7.38 (t, J ˆ 7.7 Hz, 2H), 7.43 (tt, J ˆ 1.8,
‡
7.7 Hz, 1H), 7.82 (dd, J ˆ 1.8, 7.7 Hz, 2H); EI-MS: m/z: 347 [M ];
C22H26BNO2 (347.26): calcd C 76.09, H 7.55, N 4.03; found: C 75.91, H
7.27, N 3.88.
(4R,*5S,*6R*)-4-(2-Cyanoethyl)-4-ethyl-5-methyl-2-phenyl-6-(2-phenyl-
ethyl)-1,3,2-dioxaborane (30): The procedure described for the preparation
of the 1,3,2-dioxaborolane 10 was followed to prepare the title compound
from syn-diol 25 in 85% yield as a colorless oil: IR (neat): nÄ ˆ 2920, 2320,
1
1460, 1380, 1360, 1310, 1290, 1260, 1140, 1020, 960 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 0.89 (t, J ˆ 7.3 Hz, 3H), 0.91 (d, J ˆ 7.0 Hz, 3H),
1.62 ± 1.82 (m, 4H), 1.96 (ddd, J ˆ 6.2, 10.0, 14.2 Hz, 1H), 2.06 (ddt, J ˆ 5.5,
18.6, 9.3 Hz, 1H), 2.12 (ddd, J ˆ 4.6, 10.0, 14.2 Hz, 1H), 2.42 (ddd, J ˆ 6.2,
10.0, 16.5 Hz, 1H), 2.51 (ddd, J ˆ 5.5, 10.0, 16.5 Hz, 1H), 2.78 (ddd, J ˆ 6.6,
9.3, 13.6 Hz, 1H), 2.98 (ddd, J ˆ 5.5, 10.0, 13.6 Hz, 1H), 4.33 (dt, J ˆ 9.3,
3.5 Hz, 1H), 7.19 ± 7.33 (m, 5H), 7.36 (t, J ˆ 7.9 Hz, 2H), 7.44 (tt, J ˆ 1.5,
‡
7.9 Hz, 1H), 7.80 (dd, J ˆ 1.5, 7.9 Hz, 2H); EI-MS: m/z: 361 [M ];
C23H28BNO2 (361.29): calcd C 76.46, H 7.81, N 3.88; found: C 76.55, H
7.72, N 4.01.
[12] The relative stereochemistry of the anti-g-lactones was verified by 2D-
NOESY experiments similar to those performed for the stereo-
chemical assignment of the syn-g-lactones 8 and 9.
[13] Interestingly, in the other cases of stereoselective SmI2-promoted
intermolecular couplings, there was always an almost complete loss of
diastereoselectivity if HMPA was added to the reaction system. A
reasonable explanation for this is that the high stereoselectivity results
from the chelation of the ester or amide carbonyl groups with SmIII
cations attached to the ketyl intermediates.[2] For a related example,
see: G. A. Molander, J. C. McWilliams, B. C. Noll, J. Am. Chem. Soc.
1997, 119, 1265.
Acknowledgments
The present work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas No. 8245203 from the Ministry of Education, Science,
Sports and Culture of the Japanese Government. The authors are greatly
indebted to Professor Dennis P. Curran (University of Pittsburgh) for
helpful discussions.
[14] Many SmI2-induced reactions benefit from the presence of HMPA.
See: a) K.Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986,
27, 5763; b) J. Inanaga, M. Ishikawa, M. Yamaguchi, Chem. Lett. 1987,
1485; c) K. Otsubo, K. Kawamura, J. Inanaga, M. Yamaguchi, Chem.
Lett. 1987, 1487; d) K. Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron
Lett. 1987, 28, 4437; e) K. Kusuda, J. Inanaga, M. Yamaguchi,
Tetrahedron Lett. 1989, 30, 2945; f) J. Inanaga, Rev. Heteroat. Chem.
1990, 3, 75; g) G. A. Molander, J. A. McKie, J. Org. Chem. 1992, 57,
3132.
[15] a) D. A. Evans, E. Vogel, J. V. Nelson, J. Am. Chem. Soc. 1979, 101,
6120; b) D. A. Evans, J. V. Nelson, E. Vogel, T. R. Taber, J. Am. Chem.
Soc. 1981, 103, 3099; c) T. Inoue, T. Mukaiyama, Bull. Chem. Soc. Jpn.
1980, 53, 174; d) D. E. Van Horn, S. Masamune, Tetrahedron Lett.
1979, 2229.
[1] For reviews, see: a) H. B. Kagan, M. Sasaki, J. Collin, Pure Appl.
Chem. 1988, 60, 1725; b) H. B. Kagan, New J. Chem. 1990, 14, 453;
c) G. A. Molander, Chem. Rev. 1992, 92, 2; d) G. A. Molander, Org.
React. 1994, 46, 211; e) G. A. Molander, R. H. Harris, Chem. Rev.
1996, 96, 307.
[2] a) K. Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986, 27,
576; b) J. Inanaga, O. Ujikawa, Y. Handa, K. Otsubo, M. Yamaguchi, J.
Alloys Compd. 1993, 192, 197; c) N. Taniguchi, N. Kaneta, M. Uemura,
J. Org. Chem. 1996, 61, 6088; d) N. Taniguchi, M. Uemura,
Tetrahedron Lett. 1997, 38, 7199; e) S. Fukuzawa, K. Seki, M.
Tatsuzawa, K. Mutoh, J. Am. Chem. Soc. 1997, 119, 1482.
[3] Pedersen and Kondradi described the [V2Cl3(thf)6]2[Zn2Cl6]-promot-
ed intermolecular pinacol coupling reactions chelation-controlled by
the a-(alkoxycarbonyl)amino group. See: a) A. W. Kondradi, S. F.
Pedersen, J. Org. Chem. 1990, 55, 4506; b) A. W. Kondradi, S. F.
Pedersen, J. Org. Chem. 1992, 57, 28.
[16] a) K. Tsuzuki, Y. Nakajima, T. Watanabe, M. Yanagiya, T. Matsu-
moto, Tetrahedron Lett. 1978, 989; b) M. Yanagiya, F. Matsuda, K.
Hasegawa, T. Matsumoto, Tetrahedron Lett. 1982, 23, 4039; c) F.
Matsuda, M. Yanagiya, T. Matsumoto, Tetrahedron Lett. 1982, 23,
4043.
[4] a) T. Kan, F. Matsuda, M. Yanagiya, H. Shirahama, Synlett 1991, 391;
b) M. Kito, T. Sakai, K. Yamada, F. Matsuda, H. Shirahama, Synlett
1993, 158; c) T. Kan, S. Hosokawa, S. Nara, M. Oikawa, S. Ito, F.
Matsuda, H. Shirahama, J. Org. Chem. 1994, 59, 5532; d) F. Matsuda, J.
Synth. Org. Chem. Jpn. 1995, 53, 987; e) M. Kito, T. Sakai, N. Haruta,
H. Shirahama, F. Matsuda, Synlett 1996, 1057; f) M. Kawatsura, E.
Kishi, M. Kito, T. Sakai, H. Shirahama, F. Matsuda, Synlett 1997, 479.
[17] Substituent effects on the stereoselectivities of reactions of cyclic
radicals are well known. See: a) W. Damm, B. Giese, J. Hartung, T.
Hasskerl, K. N. Houk, O. Hüter, H. Zipse, J. Am. Chem. Soc. 1992,
114, 4067; b) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of
Radical Reactions, VCH, Weinheim, 1996.
Received: March 8, 1999 [F 1658]
Chem. Eur. J. 1999, 5, No. 11
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0947-6539/99/0511-3259 $ 17.50+.50/0
3259