Asymmetric transfer hydrogenation of functionalized acetylenic ketones

Article abstract of DOI:10.1021/jo401284c

A systematic study of the asymmetric transfer hydrogenations of functionalized acetylenic ketones and diketones has been completed, together with a total synthesis of (S,S)-(-)-yashabushidiol B. In several cases, excellent enantioselectivities and yields

Full text of DOI:10.1021/jo401284c

Article
pubs.acs.org/joc
Asymmetric Transfer Hydrogenation of Functionalized Acetylenic
Ketones
Zhijia Fang and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, United Kingdom
S
* Supporting Information
ABSTRACT: A systematic study of the asymmetric transfer hydro-
genations of functionalized acetylenic ketones and diketones has been
completed, together with a total synthesis of (S,S)-(−)-yashabushidiol B.
In several cases, excellent enantioselectivities and yields were achieved.
INTRODUCTION
The reduction products may act as precursors for numerous
derivatives, including saturated chain products 5, Z- or E-
alkenes 6, and other products, for example, polyols 7. The diol
products from 4 could likewise be converted to stereochemi-
cally pure polyol products such as 8 (Scheme 1).
■
In previous reports, we have described the preparation of novel
Ru(II)-based complex 11 and its application as a catalyst in the
asymmetric transfer hydrogenation (ATH) of ketones.2 As part
of an ongoing series of investigations into the substrate scope of
complex 1,3 we undertook a systematic investigation into its
applicability to ATH of functionalized acetylenic ketones and
diketones. Substrates of this class may be reduced in high enan-
tioselectivity by a number of reagents4,5 including diisopinyl-
campheryl borane4a−d and oxazaborolidines.4e−k They are also
been reported to be highly compatible with reduction by ATH5
using the well-established catalyst 2, which were first reported
by Noyori and co-workers,6 and several applications involving
acetylenic ketones have been described.5 Specifically, we focused
on two classes of substrate: 3, containing an ester function, and
4, a diketone derivative. The effect of variations of the separa-
tion between these functional groups and of the functional
group on the alkyne were examined.
Scheme 1. Products That May Be Derived from Reduction
Products 3 and 4
RESULTS AND DISCUSSION
■
The synthesis of ester 3a1 was achieved through addition of
diethyl malonate 10 to precursor PhCCCOBt 9, followed by
monodeesterification with aqueous TsOH.7a An alternative
route, the BF3-catalyzed reaction of a terminal acetylene
with an acid chloride 11,7b was also efficient and pro-
vided access to substrates 3b1−3d1 and the α-methylated
derivatives 12−15 in good yields. Thioesters 16 and 17 were
also prepared from 9 by use of ethyl and phenyl thioacetate,
respectively.8
Received: June 14, 2013
© XXXX American Chemical Society
A
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reaction of acid chlorides with the lithium anion of the
appropriate acetylene, in the presence of either BF3·Et2O or
ZnCl2.5e 7b,12,13 A series of reductions of 3a2 were then
x,
investigated (Table 2). Both 1 and 2 were effective catalysts,
Table 2. Asymmetric Transfer Hydrogenation of Acetylenic
a
γ-Keto Ester 3a2
The subsequent ATH of β-keto esters has precedence9 and
worked well on our substrates with both 1 and 2 as catalyst,
consistently furnishing products in high yield and enantiomeric
excess (ee) (Table 1). The absolute configuration of the products
b
c
b
catalyst
solvent
S/C T, °C t, h conv,
%
ee, % yield, %
(R,R)-2 DCM
(R,R)-2 CH3CN
(R,R)-1 DCM
(R,R)-1 DCM
(R,R)-1 DCM
(R,R)-1 DCM
50
50
rt
15
15
100
100
100
73
94 (R)
90 (R)
94 (R)
95 (R)
95 (R)
94 (R)
67
rt
78
89
69
73
30
500
rt
30
Table 1. Asymmetric Transfer Hydrogenation of Acetylenic
β-Keto Esters
1000
1000
2000
rt
144
144
144
30
40
78
53
a
b
DCM, dichloromethane; rt, room temperature. Conversions and
yields were determined by separation of starting materials and
products. Enantiomeric excess values were determined by chiral
HPLC.
c
a
a
b
substrate
catalyst
(R,R)-1
S/C
yield,
%
syn/anti
ee,
92
%
3a1
3b1
3c1
3d1
12
200
200
200
200
200
100
30
95
92
92
99
98
94
99
88
92
87
92
76
97
n/a
(R,R)-1
(R,R)-1
(R,R)-1
(S,S)-1
n/a
97
97
99
n/a
although 1 was more active and could be employed at S/C up
to 500 before a drop in conversion (but not enantioselectivity)
was observed.
The γ-keto esters 3b2−3d2 and δ-keto esters 3a3−3d3 were
more reactive than β-keto esters (Table 3) and gave products in
n/a
c
13/1
13/1
24/1
11/1
14/1
27/1
14/1
31/1
12/1
27/1
99 (syn)
99 (syn)
98 (syn)
n/a
12
(R,R)-1
(R,R)-2
(TsEN)Ru
(R,R)-1
(R,R)-2
(R,R)-1
(R,R)-2
(R,R)-1
(R,R)-2
12
d
12
30
13
200
30
>99 (syn)
99 (syn)
Table 3. Asymmetric Transfer Hydrogenation of Acetylenic
γ- and δ-Keto Esters
13
14
200
30
>99 (syn)
>98 (syn)
>99 (syn)
99 (syn)
14
15
200
30
15
90
a
1
Syn/anti ratios were determined by H NMR; isolated yields are
b
given. Enantiomeric excess values were determined by chiral HPLC.
a
a
c
d
substrate
yield,
%
ee, %
(S,S)-1 used, ent-product formed. Ligand TsNHCH2CH2NH2
(TsEN) was used.
3a2
3b2
3c2
3d2
3a3
3b3
3c3
3d3
89
89
95
77
89
81
99
84
94 (R)
93 (R)
98 (R)
99 (R)
96 (R)
99 (R)
99 (R)
98 (R)
[R when (R,R)-catalyst was employed] was based upon total
synthesis of a natural product of known configuration described
below, from the product of ATH of 3a1 by use of (R,R)-1. The
observed configuration also matches that which would be
expected from the reported precedents5,9 for this class of
substrate. In addition, an efficient dynamic kinetic resolution
(DKR) was observed with the α-methylated substrates.10 In our
tests, catalyst 1 was more active than 2, and could therefore be
employed at higher substrate to catalyst (S/C) ratios. In the
DKR studies, this was also the case; however, catalyst 2
furnished products with a higher diastereomeric ratio (dr). In
all cases, the syn product was favored, and this was assigned by
a
Enantiomeric excess values were determined by chiral HPLC;
isolated yields are given.
consistently high enantiomeric excesses and yield.14 In all
cases the absolute configurations were assigned by analogy
with the reductions of 3a1−3d1 described above, and on the
basis of the known directing effect of the triple bond in ATH
reductions.5
1
comparison of the H NMR data for the reduction product of
13 with that of the analogous reported decynoate (see Supporting
Information).11 The use of a nonchiral catalyst based on TsEN1a
provided a convenient method for the preparation of racemic
products of similar dr. Thioesters 16 and 17 could not be
reduced under these conditions, however, even at a catalyst
loading as high as 10 mol %.
Next we turned to diketones.15 The acetylenic 1,3-diketone
18 was successfully prepared in the reaction between the
enolate of acetophenone and PhCCCOBt 9.16 1,3-Diketone 18
is relatively inactive to reduction, in contrast to nonacetylenic
substrates.17 This may be due to the high enol/ketone ratio it
exhibits (ca. 35/1 in CDCl3) in solution. Unfortunately all
Our studies were next extended to the γ-keto esters 3a2−3d2
and δ-keto esters 3a3−3d3, which were prepared by the
B
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attempts at ATH of 18 resulted in exclusive formation of the
cyclized product 19.18
An application of the reductive methodology directed
by a triple bond adjacent to the ketone was found in the
synthesis of (−)-yashabushidiol B 20 (Scheme 2).21 It was
possible to form the required target by sequential control of
the reduction of each acetylenic ketone in turn.5b,f The
absolute configuration of the product 20, as well as its
precursors 21 and 22, was confirmed by comparison of the
sign of the optical rotations of these compounds with those
reported (see Supporting Information).21 This also served to
confirm the absolute configuration of the reduction product of
3a1 and hence the β-keto ester reductions in Table 1.
The ee and dr of 20 were determined by comparison of the
chiral HPLC spectrum with that of a racemic/meso product
mixture.
More success was recorded with the longer-chain substrates
4a2, 4b2, 4d2, 4a3, and 4d3, which were prepared by reported
methods.19 Reduction of the 1,4- and 1,5-diketones was highly
enantioselective, with products formed in high dr and ee
(higher than 99% in all cases), with a predictable preference for
the anti isomers (Table 4). The high ees in this case arise in
With regard to control of the enantioselectivity, it has
been established that Ru(II)/TsDPEN catalysts form a
reactive hydride 23 as a single diastereoisomer, and that it is
the concerted transfer of two hydrogen atoms from this
complex to the ketone which controls the product
enantioselectivity. In the case of aryl/alkyl ketones
such as acetophenone derivatives, a strong CH/π inter-
action favors positioning of the aromatic ring of the sub-
strate in the “upper” position (as illustrated in Figure 1),5,22
thereby controlling the face to which hydride is trans-
ferred. Our results, in common with those of others, indicate
that the alkyne group has a similar dominating stereo-
controlling effect (Figure 1).5 Hence reductions of acetylenic
Table 4. Asymmetric Transfer Hydrogenation of 1,4- and
1,5-Diketones
a
a
a,b
substrate
catalyst
yield,
%
dr
ee,
%
4a2
4a2
4a3
4a3
4b2
4b2
4d2
4d2
4d3
4d3
(R,R)-1
(S,S)-1
(R,R)-1
(S,S)-1
(R,R)-1
(S,S)-1
(R,R)-1
(S,S)-1
(R,R)-1
(S,S)-1
81
78
96
81
87
82
83
70
86
97
26/1
49/1
35/1
76/1
33/1
28/1
44/1
124/1
76/1
110/1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
a
Diastereomeric ratio and enantiomeric excess values were determined
b
by chiral HPLC; isolated yields are given. The (R,R) catalyst
enantiomer gives rise to the (R,R) diol, and vice versa.
part from the double enantioselection, which results in
formation of meso product rather than a minor enantiomer.20
In all cases the absolute configurations were assigned by
analogy with the reductions of 3a1−3d1 described above and
on the basis of the known directing effect of the triple bond in
ATH reductions.5 These results indicate that 1,4- and 1,5-
acetylenic diketones are excellent substrates for ATH with
Ru(II)/N-tosyl 1,2-diphenylethylenediamine (TsDPEN) type
catalysts.
Figure 1. Contrasted stabilizing interactions in transition states of
reduction of acetophenone derivatives and acetylenic ketones with 1
[R−R′ = (CH2)3] and (R,R)-2 (R = R′ = H).
ketones are highly enantioselective in a predictable sense
and tolerant to a wide range of substituents at other
positions.
Scheme 2. Synthesis of (−)-S,S-Yashabushidiol B 20
C
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on a silica gel column (eluent hexane/EtOAc = 20/1−15/1) to afford
the pure product.
CONCLUSIONS
■
In summary, a series of functionalized acetylenic ketones have
been reduced to enantiomerically enriched alcohols via ATH
with a tethered Ru(II)/TsDPEN-derived catalyst. In the
majority of cases, the reductions proceed in excellent ee and
yield. The reductions provide a basis for the total asymmetric
synthesis of dihydroxylated natural products in high enantio-
purity.
3-Oxo-5-phenyl-4-pentynethioic Acid, S-Ethyl Ester 16. This
compound was prepared by the general procedure above with ethyl
thioacetate (52 mg, 0.5 mmol), 1-(3-phenyl-1-oxo-2-propynyl)-
benzotriazole (124 mg, 0.5 mmol), anhydrous MgBr2·OEt2 powder
(387 mg, 1.5 mmol), and i-Pr2NEt (257 mg, 2.0 mmol). The product
was isolated as a colorless oil (90 mg, 0.39 mmol, 78%, enol/β-keto =
1.9/1). Rf = 0.63 hexane/EtOAc 8/1; [found (ESI) M+ + Na,
255.0450; C13H12O2S requires M, 255.0455]; IR (neat) 2931, 2972,
2003, 1706, 1666, 1602, 1587, 1366, 1284, 1076, 865, 754, 686 cm−1;
1H NMR (400 MHz, CDCl3) 12.53 (s, 1H), 7.59−7.35 (m, 5H), 5.84
EXPERIMENTAL SECTION
■
(s, 1H), 2.97 (q, J = 7.4 Hz, 2H), 1.33−1.27 (m, 3H) for enol; 13C
NMR (100 MHz, CDCl3) 195.1, 178.2, 152.6, 133.3, 130.0, 132.3,
131.3, 130.6, 130.1, 128.7, 128.6, 120.7, 119.4, 106.3, 94.1, 83.3, 62.1,
59.4, 24.2, 23.1, 14.7, 14.1 enol and ketone mixture; m/z (EIMS)
250.0 (M + Na)+.
General Procedures. Air-sensitive reactions were carried out
under a nitrogen or argon atmosphere. NMR spectra were recorded on
a 300 or 400 MHz instrument. Chemical shifts are reported in parts
per million (ppm) downfield from TMS (Me4Si). Coupling constants
(J) are reported in hertz. Multiplicity in 1H NMR is reported as singlet
(s), doublet (d), broad singlet (br s), broad doublet (br d), triplet (t),
quartet (q), and multiplet (m). Mass spectra were recorded on an
electrospray instrument. High-resolution mass spectra were recorded
on Micro ToF. Infrared spectra were recorded on a Fourier transform
infrared (FTIR) spectrometer. Optical rotations were measured on a
polarimeter. Chiral HPLC measurements were carried out under the
conditions described on HPLC with a chiral column (250 mm ×
4.6 mm). Melting points were determined on a melting point
apparatus and are uncorrected. Purification of compounds was done by
flash column chromatography on silica gel A40−63 μm. Known
compounds were identified by comparison of their spectroscopic data
to that reported in the references cited.
3-Oxo-5-phenyl-4-pentynethioic Acid, S-Phenyl Ester 17. This
compound was prepared by the general procedure above with phenyl
thioacetate (304 mg, 2.0 mmol), 1-(3-phenyl-1-oxo-2-propynyl)-
benzotriazole (500 mg, 2.0 mmol), anhydrous MgBr2·OEt2 powder
(1.54 g, 6.0 mmol), and i-Pr2NEt (1.04 g, 8.0 mmol). The product was
isolated as a white solid (500 mg, 1.79 mmol, 88%, enol/β-keto = 2.0/
1). Rf = 0.83 hexane/EtOAc 6/1; mp 52 °C; [found (ESI) M+ + Na,
303.0449; C17H12O2S requires M, 303.0455]; IR (neat) 1632, 1580,
1546, 1368, 1079, 1022, 745, 686 cm−1; 1H NMR (400 MHz, CDCl3)
12.29 (s, 1H), 7.48−7.24 (m, 10H), 5.80 (s, 1H) for enol; 13C NMR
(100 MHz, CDCl3) 193.8, 177.9, 153.9, 135.0, 134.5, 133.4, 132.5,
131.4, 130.3, 130.0, 129.5, 129.4, 128.8, 128.7, 126.6, 120.5, 105.0,
94.9, 83.3, 58.9 enol and ketone mixture; m/z (EIMS) 303.0
(M + Na)+.
General Procedure for Synthesis of Propargylic β-Keto
Esters from Acyl Chlorides.7b To a solution of alkyne (8.6 mmol)
in anhydrous tetrahydrofuran (THF, 12 cm3) at −78 °C was added
n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0 mmol) via a syringe over 3 min.
The mixture was stirred at the same temperature for 60 min and then
BF3·Et2O (1.1 cm3, 8.5 mmol) was injected. After 10 min, malonic acid
chloride monomethyl ester (495 mg, 3.63 mmol) in THF (1 cm3) was
added. The mixture was stirred for 2 h , and then the reaction was
quenched by saturated NH4Cl (5 cm3) and water (5 cm3). The
aqueous phase was extracted with Et2O (3 × 20 cm3) and the extracts
were dried over anhydrous MgSO4. After concentration under reduced
pressure, the crude product was purified by silica gel column
chromatography (eluent hexane/EtOAc = 20/1−15/1) to afford
pure products.
3-Oxo-5-phenyl-4-pentynoic Acid, Ethyl Ester 3a1.23 Diethyl
malonate 10 (96 mg, 0.6 mmol), 1-(3-phenyl-1-oxo-2-propynyl)-
benzotriazole (123 mg, 0.50 mmol), and anhydrous MgBr2·OEt2
powder (258 mg, 1.0 mmol) were combined in a flask, and CH2Cl2
(2.5 cm3) was added. The suspension was stirred at room temperature
(rt) for 2 h, and then i-Pr2NEt (194 mg, 1.5 mmol) was added
dropwise. A clear orange solution was formed immediately, and the
solution was allowed to stir at rt for 1 h. Saturated NH4Cl (1.5 cm3)
was added, followed by aqueous HCl (10%, 1.0 cm3), and stirring was
continued for 5 min. After a clear solution was formed, the aqueous
layer was extracted with CH2Cl2 (2 × 10 cm3) and the combined
organic extract was dried over MgSO4. The solvent was evaporated
under reduced pressure and the crude product was semipurified on a
short silica gel column (eluent hexane/EtOAc = 15/1) to afford a
mixture of Claisen adduct and diethyl malonate. TsOH·H2O (20 mg)
and water (6.0 cm3) were added to the aforementioned mixture, and
the resulting solution was refluxed for 6 h. The aqueous phase was
extracted with Et2O (3 × 10 cm3) and the combined organic phase
was dried over MgSO4. The solvent was evaporated under reduced
pressure and the crude product was purified by a silica gel column
(eluent hexane/EtOAc = 15/1, Rf = 0.71 hexane/EtOAc 4/1) to afford
the product 3a1 as a colorless oil (71 mg, 0.33 mmol, 66% for two
steps, enol/β-keto = 1/2). IR (neat) 2983, 2203, 1739, 1671, 1613,
3-Oxo-4-nonynoic Acid, Methyl Ester 3b1. This compound was
prepared by the general procedure above with 1-hexyne (705 mg,
8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0 mmol), BF3·Et2O
(1.1 cm3, 8.5 mmol), and malonic acid chloride monomethyl ester
(495 mg, 3.63 mmol). The product was isolated as a colorless oil
(320 mg, 1.75 mmol, 48%). Rf = 0.66 hexane/EtOAc 4/1; [found
(ESI) M+ + Na, 205.0837; C10H14O3 requires M, 205.0840]; IR (neat)
2958, 2935, 2213, 1746, 1676, 1611, 1441, 1245, 1169, 1142,
1207, 1029, 756, 688 cm−1; H NMR (400 MHz, CDCl3) 7.58−7.32
1
1
805 cm−1; H NMR (400 MHz, CDCl3) 3.76 (s, 3H), 3.58 (s, 2H),
(m, 5H), 4.27−4.20 (m, 2H), 3.69 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H) for
ketone, 11.98 (s), 5.45 (s), 1.32 (t, J = 7.1 Hz) for enol; 13C NMR
(100 MHz, CDCl3) 178.8, 172.2, 166.1, 155.3, 133.3, 133.1, 132.2,
130.2, 130.8, 129.9, 128.7, 128.6, 128.5, 120.8, 119.5, 97.2, 93.4, 87.3,
83.4, 61.7, 60.7, 51.4, 50.6, 14.2, 14.1 enol and ketone mixture; m/z
(EIMS) 239.1 (M + Na)+.
2.41−2.35 (m, 2H), 1.61−1.54 (m, 2H), 1.48−1.39 (m, 2H), 0.93 (t,
J = 7.3 Hz, 3H) for ketone, 11.81 (s), 5.29 (s), 3.75 (s) for enol; 13C
NMR (100 MHz, CDCl3) 178.7, 172.6, 166.6, 165.9, 97.1, 96.4, 95.8,
80.3, 52.5, 51.5, 51.1, 29.9, 29.5, 21.9, 18.9, 18.7, 13.4 enol and ketone
mixture; m/z (EIMS) 205.1 (M + Na)+.
Procedure for Synthesis of Thioesters 16 and 17.16 Thioester
(2.0 mmol), 1-(3-phenyl-1-oxo-2-propynyl)benzotriazole (2.0 mmol),
and anhydrous MgBr2·OEt2 powder (1.54 g, 6.0 mmol) were
combined in a flask and CH2Cl2 (8.0 cm3) was added. The suspension
was stirred at rt for 2 h and then i-Pr2NEt (257 g, 2.0 mmol) was
added dropwise. The solution was allowed to stir at rt for 0.5 h.
Saturated NH4Cl (4 cm3) was added, followed by aqueous HCl (10%,
4 cm3), and stirring was continued for 5 min. After a clear solution was
formed, the aqueous layer was extracted with CH2Cl2 (2 × 30 cm3)
and the combined organic extract was dried over MgSO4. Solvent was
evaporated under reduced pressure and the crude product was purified
3-Oxo-7-benzyloxy-4-heptynoic Acid, Methyl Ester 3c1. This
compound was prepared by the general procedure above with alkyne
(963 mg, 6.0 mmol), n-BuLi (1.6 M in hexane, 3.5 cm3, 5.6 mmol),
BF3·Et2O (0.77 cm3, 6.0 mmol), and malonic acid chloride
monomethyl ester (300 mg, 2.2 mmol). The product was isolated as
a colorless oil (230 mg, 0.88 mmol, 45%). Rf = 0.42 hexane/EtOAc 4/
1; [found (ESI) M+ + Na, 283.0941; C15H16O4 requires M, 283.0946];
1
IR (neat) 2869, 2217, 1743, 1676, 1250, 1099, 737, 698 cm−1; H
NMR (400 MHz, CDCl3) 7.37−7.26 (m, 5H), 4.53 (s, 2H), 3.72 (s,
3H), 3.62 (t, J = 6.7 Hz, 2H), 3.57 (s, 2H), 2.67 (t, J = 6.7 Hz, 2H) for
ketone, 11.80 (s), 5.27 (s), 4.54 (s), 3.73 (s) for enol; 13C NMR (100
D
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MHz, CDCl3) 178.6, 172.6, 166.6, 155.5, 137.7, 128.5, 127.9, 127.7,
96.3, 93.5, 92.9, 80.9, 76.3, 73.1, 73.0, 67.3, 67.0, 52.5, 51.6, 51.0, 20.8,
20.6 enol and ketone mixture; m/z (EIMS) 283.1 (M + Na)+.
3-Oxo-6-benzyloxy-6 methyl-4-heptynoic Acid, Methyl Ester 3d1.
This compound was prepared by the general procedure above with
alkyne (1.36 g, 7.9 mmol), n-BuLi (1.6 M in hexane, 4.6 cm3,
7.4 mmol), BF3·Et2O (1.01 cm3, 7.8 mmol), and malonic acid chloride
monomethyl ester (390 mg, 2.8 mmol). The product was isolated as a
colorless oil (313 mg, 1.14 mmol, 40%). Rf = 0.69 hexane/EtOAc 4/1;
[found (ESI) M+ + Na, 297.1097; C16H18O4 requires M, 297.1102];
IR (neat) 2989, 2954, 2220, 1748, 1610, 1443, 1382, 1214, 1156, 805,
734, 697 cm−1; 1H NMR (400 MHz, CDCl3) 7.39−7.26 (m, 5H), 4.63
(s, 2H), 3.73 (s, 3H), 3.58 (s, 3H), 1.60 (s, 6H) for ketone, 11.79 (s),
5.35 (s), 4.62 (s), 3.76 (s) for enol; 13C NMR (100 MHz, CDCl3)
178.4, 154.9, 138.5, 138.2, 128.44, 128.39, 127.74, 127.67, 127.57,
97.0, 96.1, 82.7, 78.8, 70.8, 70.6, 67.1, 67.0, 52.6, 51.7, 51.1, 28.4, 28.1
enol and ketone mixture; m/z (EIMS) 297.1 (M + Na)+.
(400 MHz, CDCl3) 7.38−7.26 (m, 5H), 4.78−4.72 (m, 1H), 4.54
(s, 2H), 3.72 (s, 3H), 3.57 (t, J = 7.0 Hz, 2H), 2.94 (d, J = 5.9 Hz,
1H), 2.72 (d, J = 6.0 Hz, 2H), 2.52 (td, J = 7.0, 1.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) 171.7, 138.0, 128.4, 127.8, 127.7, 82.5, 80.5, 72.9,
68.2, 58.8, 51.9, 42.2, 20.1; m/z (EIMS) 285.1 (M + Na)+. HPLC
separation conditions: Chiralpak IB column (250 mm × 4.6 mm),
hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C. Retention times:
(major, R) 55.3 min, (minor, S) 53.0 min.
(3R)-Hydroxy-6-benzyloxy-6-methyl-4-heptynoic Acid, Methyl
Ester, Reduction Product of 3d1. This compound was prepared by
the general procedure above with (R,R)-Teth-TsDPEN-RuCl 1
(0.6 mg, 1.0 × 10−3 mmol), ketone 3d1 (53.2 mg, 0.20 mmol), HCOOH/
Et3N 5/2 (168 mg), and CH2Cl2 (1.0 cm3), and the product was
isolated as a colorless oil (53.1 mg, 1.92 mmol, 99%, 99% ee). Rf =
28
0.40 hexane/EtOAc 2/1; [α]D +21.4 (c 0.8 in CHCl3) 99% ee (R);
[found (ESI) M+ + Na, 299.1254; C16H20O4 requires M, 299.1259];
1
IR (neat) 3420, 2983, 1736, 1154, 1049, 735, 697 cm−1; H NMR
General Procedure for Asymmetric Transfer Hydrogenation
of Propargylic β-Keto Esters. (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg,
1.0 × 10−3 mmol) and HCO2H/Et3N 5/2 azeotropic mixture (168 mg)
was added into a flask, and freshly prepared β-keto ester (0.2 mmol) in
degassed dichloromethane (1 cm3) was injected under a nitrogen
atmosphere. The mixture was stirred at rt until the starting material
was completely consumed (1−2 days) and then concentrated and
directly purified by silica gel column chromatography (eluent hexane/
EtOAc = 10/1−5/1) to give the chiral alcohols.
(3R)-Hydroxy-5-phenyl-4-pentynoic Acid, Ethyl Ester, Reduction
Product of 3a1.24 This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 ×
10−3 mmol), ketone 3a1 (43.2 mg, 0.20 mmol), HCO2H/Et3N 5/2
(168 mg), and CH2Cl2 (1.0 cm3), and the product was isolated as a
colorless oil (41.4 mg, 0.19 mmol, 95%, 92% ee). Rf = 0.46 hexane/
EtOAc 4/1; [α]D26 +18.9 (c 0.6 in CHCl3) 92% ee (R); [found (ESI)
M+ + Na, 241.0835; C13H14O3 requires M, 241.0840]; IR (neat) 3429,
2982, 1717, 1159, 1025, 756, 690 cm−1; 1H NMR (400 MHz, CDCl3)
7.44−7.40 (m, 2H), 7.35−7.27 (m, 3H), 5.00 (t, J = 6.0 Hz, 1H), 4.23
(q, J = 7.1 Hz, 2H), 3.24 (br s, 1H), 2.84 (d, J = 6.0 Hz, 2H), 1.29
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 171.3, 131.8, 128.6,
128.3, 122.3, 88.3, 85.0, 61.1, 59.2, 42.2, 14.2; m/z (EIMS) 241.1 (M +
Na)+. HPLC separation conditions: Chiralpak IB column (250 mm ×
4.6 mm), hexane/i-PrOH 95/5, 0.6 cm3/min, T = 30 °C. Retention
times: (major, R) 17.0 min, (minor, S) 20.6 min. The absolute
configuration assignment of this compound is based on comparisons
to reported data for (−)-yashabushidiol B and two intermediates to
this described below.
(400 MHz, CDCl3) 7.35−7.15 (m, 5H), 4.67−4.80 (m, 1H), 4.52 (s,
2H), 3.61 (s, 3H), 3.08 (br s, 1H), 2.65 (d, J = 6.4 Hz, 2H), 1.45 (s,
6H); 13C NMR (100 MHz, CDCl3) 171.6, 139.0, 128.3, 127.7, 127.4,
87.4, 83.5, 70.5, 66.5, 58.8, 52.0, 42.0, 28.8; m/z (EIMS) 299.1 (M +
Na)+. HPLC separation conditions: Chiralpak IB column (250 mm ×
4.6 mm), hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C. Retention
times: (major, R) 18.7 min, (minor, S) 18.1 min.
General Procedure for Synthesis of Propargylic α-Methyl-β-
keto Esters.7b To a solution of alkyne (8.6 mmol) in anhydrous THF
(12 cm3) at −78 °C was added n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0
mmol) via a syringe over 3 min. The mixture was stirred at the same
temperature for 10 min and then BF3·EtO2 (1.1 cm3, 8.5 mmol) was
injected. After 10 min, 3-chloro-2-methyl-3-oxopropanoic acid ethyl
ester (510 mg, 3.10 mmol) in THF (1 cm3) was added in one portion.
The mixture was stirred for 1.5 h and then the reaction was quenched
by saturated NH4Cl (5 cm3) and water (5 cm3). The aqueous phase
was extracted with Et2O (2 × 20 cm3), and the organic phase was
dried over anhydrous MgSO4. After concentration under reduced
pressure, the crude product was purified by silica gel column
chromatography (eluent hexane/DCM = 10/1−10/3) to afford the
pure product.
2-Methyl-3-oxo-5-phenyl-4-pentynethioic Acid, Ethyl Ester 12.25
This compound was prepared by the general procedure above with
phenylacetylene (877 mg, 8.6 mmol), n-BuLi (1.6 M in hexane,
5.0 cm3, 8.0 mmol), BF3·EtO2 (1.1 cm3, 8.5 mmol), and freshly
prepared 3-chloro-2-methyl-3-oxopropanoic acid ethyl ester (510 mg,
3.10 mmol). The product was isolated as light yellow crystals (551 mg,
2.40 mmol, 77%). Rf = 0.72 hexane/EtOAc 4/1; mp 59 °C; [found
(ESI) M+ + Na, 253.0835; C14H14O3 requires M, 253.0840]; IR (neat)
2994, 2931, 2905, 2211, 1631, 1604, 1379, 1276, 1188, 1061, 789, 753,
688 cm−1; 1H NMR (400 MHz, CDCl3) 12.21 (s, 1H), 7.60−7.51 (m,
2H), 7.46−7.33 (m, 3H), 4.28−4.21 (m, 2H), 2.00 (s, 3H), 1.33 (t, J =
7.1 Hz, 3H) for enol, 3.68 (q, J 7.2), 1.50 (d, J 7.2), 1.28 (t, J = 7.1 Hz)
for ketone; 13C NMR (100 MHz, CDCl3) 128.9, 173.0, 152.0, 133.2,
132.0, 131.1, 129.7, 128.7, 128.5, 121.3, 119.6, 104.2, 97.7, 96.3, 86.4,
83.0, 61.6, 61.0, 55.0, 14.2, 14.1, 13.2, 12.9 enol and ketone mixture;
m/z (EIMS) 253.1 (M + Na)+.
2-Methyl-3-oxo-4-nonynoic Acid, Ethyl Ester 13. This compound
was prepared by the general procedure above with 1-hexyne (706 mg,
8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0 mmol), BF3·EtO2
(1.1 cm3, 8.5 mmol), and freshly prepared 3-chloro-2-methyl-3-
oxopropanoic acid ethyl ester (510 mg, 3.10 mmol). The product was
isolated as a light yellow oil (538 mg, 2.56 mmol, 82%). Rf = 0.54
hexane/EtOAc 8/1; [found (ESI) M+ + Na, 233.1148; C12H18O3
requires M, 233.1153]; IR (neat) 2961, 2935, 2211, 1741, 1678, 1644,
1600, 1334, 1243, 1121 cm−1; 1H NMR (400 MHz, CDCl3) 12.15 (s,
1H), 4.24 (q, J = 7.1 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 1.89 (s, 3H),
1.62−1.53 (m, 2H), 1.50−1.41 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H),
0.934 (t, J = 7.3 Hz, 3H) for enol; 13C NMR (100 MHz, CDCl3)
173.1, 169.7, 152.4, 103.0, 100.3, 97.1, 79.4, 74.9, 61.4, 60.8, 54.9, 30.1,
29.6, 21.94, 21.89, 19.1, 18.7, 14.2 14.0, 13.5 13.4, 12.9, 12.8 enol and
ketone mixture; m/z (EIMS) 233.1 (M + Na)+.
(3R)-Hydroxy-4-nonynoic Acid, Methyl Ester, Reduction Product
of 3b1. This compound was prepared by the general procedure above
with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 × 10−3 mmol), ketone
3b1 (41.0 mg, 0.22 mmol), HCOOH/Et3N 5/2 (168 mg), and
CH2Cl2 (1.0 cm3), and the product was isolated as a colorless oil
(38.0 mg, 20.6 mmol, 92%, 97% ee). Rf = 0.31 hexane/EtOAc 4/1;
26
[α]D +27.1 (c 0.9 in CHCl3) 97% ee (R); [found (ESI) M+ + Na,
207.0992; C10H16O3 requires M, 207.0997]; IR (neat) 3475, 2958,
1
1738, 1438, 1276, 1162, 1022 cm−1; H NMR (400 MHz, CDCl3)
4.71−4.65 (m, 1H), 3.66 (s, 3H), 3.00 (d, J = 5.7 Hz, 1H), 2.66 (d, J =
1.6 Hz, 1H), 2.65 (s, 1H), 2.13 (td, J = 7.1, 2.0 Hz, 2H), 1.45−1.26
(m, 4H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
171.8, 86.0, 79.3, 58.9, 51.9, 42.3, 30.5, 21.8, 18.3, 13.5; m/z (EIMS)
207.1 (M + Na)+. HPLC separation conditions: Chiralpak IB column
(250 mm × 4.6 mm), hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C.
Retention times: (major, R) 17.8 min, (minor, S) 17.0 min.
(3R)-Hydroxy-7-benzyloxy-4-heptynoic Acid, Methyl Ester, Re-
duction Product of 3c1. This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 ×
10−3 mmol), ketone 3c1 (52.0 mg, 0.20 mmol), HCOOH/Et3N 5/2
(168 mg), and CH2Cl2 (1.0 cm3), and the product was isolated as a
colorless oil (48.3 mg, 0.18 mmol, 92%, 97% ee). Rf = 0.26 hexane/
EtOAc 4/1; [α]D28 +17.6 (c 1.0 in CHCl3) 97% ee (R); [found (ESI)
M+ + Na, 285.1097; C15H18O4 requires M, 285.1102]; IR (neat)
1
3427, 2865, 1735, 1163, 1096, 1062, 1027, 737, 697 cm−1; H NMR
E
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-Methyl-3-oxo-7-benzyloxy-4-heptynoic Acid, Ethyl Ester 14.
This compound was prepared by the general procedure above with
acetylene (640 mg, mmol), n-BuLi (1.6 M in hexane, 2.32 cm3, 3.71
mmol), BF3·EtO2 (0.50 cm3, 3.9 mmol), and freshly prepared 3-
chloro-2-methyl-3-oxopropanoic acid ethyl ester (237 mg, 1.44 mmol).
The product was isolated as a colorless oil (298 mg, 1.03 mmol, 72%).
Rf = 0.33 hexane/EtOAc 8/1; [found (ESI) M+ + Na, 311.1254;
C17H20O4 requires M, 311.1259]; IR (neat) 2865, 2225, 1738, 1643,
>99% ee. Comparison of the 1H NMR data with that for the reported
syn-decynoate analogue11 permitted assignment of the relative con-
figuration of the product.
(2R)-Methyl-(3R)-hydroxy-7-benzyloxy-4-heptynoic Acid, Ethyl
Ester, Reduction Product of 14. This compound was prepared by
the general procedure above with (R,R)-2 (4.2 mg, 6.7 × 10−3 mmol),
ketone (61.2 mg, 0.21 mmol), HCOOH/Et3N 5/2 (168 mg), and
CH2Cl2 (1.0 cm3), and the product was isolated as a colorless oil
(46.5 mg, 0.16 mmol, 76%, >98% ee, dr 31/1). Rf = 0.23 hexane/
1
1600, 1374, 1334, 1243, 1119, 1096, 1025, 804, 734, 697 cm−1; H
28
EtOAc 4/1; [α]D +4.0 (c 0.7 in CHCl3) 98% ee, dr 31/1; [found
NMR (400 MHz, CDCl3) 12.05 (s, 1H), 7.35−7.18 (m, 5H), 4.49 (s,
2H), 4.19−4.06 (m, 2H), 3.61−3.40 (m, 3H), 2.67 (t, J = 6.9 Hz, 2H),
1.81 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) for enol; 13C NMR (100 MHz,
CDCl3) 173.1, 152.0, 137.9, 128.6, 128.5, 128.3, 128.1, 127.8, 127.7,
103.5, 96.7, 75.8, 73.1, 67.7, 67.1, 67.0, 61.5, 61.4, 60.9, 54.8, 46.2,
21.0, 20.6, 14.2, 14.0, 13.6, 13.0 enol and ketone mixture; m/z (EIMS)
311.1 (M + Na)+.
2-Methyl-3-oxo-6-benzyloxy-6 methyl-4-heptynoic Acid, Ethyl
Ester 15. This compound was prepared by the general procedure
above with acetylene (1.50 g, 8.6 mmol), n-BuLi (1.6 M in hexane,
5.0 cm3, 8.0 mmol), BF3·EtO2 (1.1 cm3, 8.5 mmol), and freshly
prepared 3-chloro-2-methyl-3-oxopropanoic acid ethyl ester (510 mg,
3.10 mmol). The product was isolated as a colorless oil (864 mg, 2.86
mmol, 92%). Rf = 0.43 hexane/EtOAc 8/1; [found (ESI) M+ + Na,
325.1410; C18H22O4 requires M, 325.1415]; IR (neat) 2986, 2218,
1735, 1643, 1600, 1374, 1333, 1207, 1155, 1086, 735, 697 cm−1;
1H NMR (400 MHz, CDCl3) 12.06 (s, 1H), 7.12−7.39 (m, 5H, m),
4.58 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.83 (s, 3H), 1.54 (s, 6H), 1.24
(t, J = 7.1 Hz, 3H) for enol; 13C NMR (100 MHz, CDCl3) 172.9,
151.5, 138.6, 128.4, 128.3, 127.8, 127.7, 127.6, 104.2, 100.3, 96.1, 86.9,
78.3, 71.0, 67.0, 61.6, 61.4, 61.0, 55.0, 46.2, 40.9, 30.5, 28.6, 28.2, 19.0,
14.2, 14.1, 13.1, 12.8 enol and ketone mixture; m/z (EIMS) 325.1
(M + Na)+.
(ESI) M+ + Na, 313.1410; C17H22O4 requires M, 313.1415]; IR (neat)
1
3446, 2981, 2939, 1729, 1187, 1094, 1027, 736, 698 cm−1; H NMR
(400 MHz, CDCl3) 7.37−7.26 (m, 5H), 4.62−4.58 (m, 1H), 4.53 (s,
2H), 4.17 (q, J = 7.1 Hz, 2H), 3.57 (t, J = 7.1 Hz, 2H), 3.02 (d, J = 6.9
Hz, 1H), 2.70 (qd, J = 7.2, 4.2 Hz, 1H), 2.52 (td, J = 7.2, 2.0 Hz, 2H),
1.28 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 174.3, 138.0, 128.4, 127.71, 127.70, 83.1, 79.6,
73.0, 68.3, 63.9, 60.9, 45.4, 20.1, 14.2, 11.8; m/z (EIMS) 313.1 (M +
Na)+. HPLC separation conditions: Chiralpak IC column (250 mm ×
4.6 mm), hexane/i-PrOH 96/4, 0.8 cm3/min, T = 30 °C. Retention
times: (major, 2R,3R) 39.9 min, (minor, 2S,3S) 57.0 min. (R,R)-Teth-
TsDPEN-RuCl 1 (S/C = 200/1) 92% yield, 14/1 dr, >99% ee.
(2R)-Methyl-(3R)-hydroxy-6-benzyloxy-6-methyl-4-heptynoic
Acid, Ethyl Ester, Reduction Product of 15. This compound was
prepared by the general procedure above with (R,R)-2 (4.2 mg, 6.7 ×
10−3 mmol), ketone (60.4 mg, 0.20 mmol), HCOOH/Et3N 5/2 (168 mg),
and CH2Cl2 (1.0 cm3), and the product was isolated as a colorless oil
(54.9 mg, 0.18 mmol, 90%, 99% ee, dr 27/1). Rf = 0.30 hexane/EtOAc
28
4/1; [α]D +5.4 (c 0.6 in CHCl3) 99% ee, dr 27/1; [found (ESI)
M+ + Na, 327.1567; C18H24O4 requires M, 327.1572]; IR (neat) 3441,
1
2983, 1732, 1244, 1186, 1156, 1041, 1028, 735, 696 cm−1; H NMR
(400 MHz, CDCl3) 7.37−7.22 (m, 5H), 4.62 (dd, J = 7.1, 4.3 Hz, 1H),
4.60 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.12 (d, J = 7.1 Hz, 1H), 2.78−
2.71 (m, 1H), 1.53 (s, 6H), 1.30−1.24 (m, 6H); 13C NMR (100 MHz,
CDCl3) 174.0, 139.0, 128.3, 127.7, 127.4, 87.9, 82.8, 70.6, 66.6, 63.8,
61.0, 45.5, 28.9, 14.2, 12.1; m/z (EIMS) 327.1 (M + Na)+. HPLC
separation conditions: Chiralpak IC column (250 mm × 4.6 mm),
hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C. Retention times:
(major, 2R,3R) 16.6 min, (minor, 2S,3S) 18.5 min. (R,R)-Teth-
TsDPEN-RuCl 1 (S/C = 200/1) 97% yield, 12/1 dr, >99% ee.
General Procedure for Synthesis of Propargylic γ-Keto
Esters.7b To a solution of acetylene (7.5 mmol) in anhydrous THF
(6 cm3) at −78 °C was added n-BuLi (1.6 M in hexane, 4.7 cm3, 7.5
mmol) over 3 min. The mixture was stirred at 0 °C for 1 h and then
recooled to −78 °C, at which point BF3·Et2O (1.46 g in 8 cm3 of THF,
10.0 mmol) was added dropwise after 10 min. The mixture was cooled
to −90 °C, and 4-chloro-4-oxobutanoic acid methyl ester (1.46 g in
2 cm3 of THF, 10.0 mmol) was added in one portion. The reaction
was quenched by saturated NH4Cl (8 cm3) and water (8 cm3) after 2
h, extracted with Et2O (2 × 30 cm3), and dried over anhydrous
MgSO4. After concentration under reduced pressure, the crude
product was purified by silica gel column chromatography (eluent
hexane/EtOAc = 15/1−8/1).
General Procedure for Asymmetric Transfer Hydrogena-
tion/Dynamic Kinetic Resolution of α-Methyl-β-keto Esters.
(2R)-Methyl-(3R)-hydroxy-5-phenyl-4-pentynoic Acid, Ethyl Ester,
Reduction Product of 12. This compound was prepared by the
general procedure above with (R,R)-2 (1.7 mg, 2.7 × 10−3 mmol),
ketone (20.0 mg, 0.087 mmol), HCOOH/Et3N 5/2 (84 mg), and
CH2Cl2 (0.5 cm3), and the product was isolated as a colorless oil
(20.0 mg, 0.086 mmol, 99%, 98% ee, dr 24/1). Rf = 0.46 hexane/
EtOAc 4/1; [α]D23 +2.1 (c 0.3 in CHCl3) 98% ee (R), dr 24/1; [found
(ESI) M+ + Na, 255.0992; C14H16O3 requires M, 255.0997]; IR (neat)
1
3450, 2982, 1717, 1188, 1027, 755, 690 cm−1; H NMR (400 MHz,
CDCl3) 7.45−7.40 (m, 2H), 7.34−7.27 (m, 5H), 4.83 (dd, J = 6.9,
4.1 Hz, 1H), 4.22 (q, J = 6.7 Hz, 2H), 3.15 (d, J = 6.9 Hz, 1H), 2.88−
2.81 (m, 1H), 1.37 (d, J = 7.2 Hz, 3H), 1.29 (t, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 174.2, 131.8, 128.6, 128.3, 122.4, 87.3, 85.7,
64.3 61.0, 45.5, 14.2, 12.0; m/z (EIMS) 255.1 (M + Na)+. HPLC
separation conditions: Chiralpak IB column (250 mm × 4.6 mm),
hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C. Retention times:
(major, 2R,3R) 17.7 min, (minor, 2S,3S) 25.2 min. (R,R)-Teth-TsDPEN-
RuCl 1 (S/C = 200/1) 94% yield, 13/1 dr, >99% ee.
(2R)-Methyl-(3R)-hydroxy-4-nonynoic Acid, Ethyl Ester, Reduc-
tion Product of 13. This compound was prepared by the general
procedure above with (R,R)-2 (4.2 mg, 6.7 × 10−3 mmol), ketone
(41.0 mg, 0.20 mmol), HCOOH/Et3N 5/2 (168 mg), and CH2Cl2
(1.0 cm3), and the product was isolated as a colorless oil (35.9 mg,
0.17 mmol, 87%, 99% ee, dr 27/1). Rf = 0.43 hexane/EtOAc 4/1;
[α]D28 +4.7 (c 1.0 in CHCl3) 99% ee (2R,3R), dr 27/1; [found (ESI)
M+ + Na, 235.1305; C12H20O3 requires M, 235.1310]; IR (neat) 3442,
2958, 2934, 2874, 1732, 1251, 1184, 1025 cm−1; 1H NMR (400 MHz,
CDCl3) 4.61−4.57 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.04 (d, J = 7.1
Hz, 1H), 2.71 (td, J = 7.2, 4.2 Hz, 1H), 2.20 (td, J = 6.9, 2.0 Hz, 2H),
1.52−1.35 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 1.28 (d, J = 7.2 Hz, 3H),
0.90 (t, J = 7. Hz, 3H); 13C NMR (100 MHz, CDCl3) 174.3, 86.4,
78.5, 62.9, 60.8, 45.7, 30.6, 21.8, 18.3, 14.2, 13.5, 11.9; m/z (EIMS)
235.1 (M + Na)+. HPLC separation conditions: Chiralpak IC column
(250 mm × 4.6 mm), hexane/i-PrOH 96/4, 0.5 cm3/min, T = 30 °C.
Retention times: (major, 2R,3R) 23.8 min, (minor, 2S,3S) 21.4 min.
(R,R)-Teth-TsDPEN-RuCl 1 (S/C = 200/1) 92% yield, 14/1 dr,
4-Oxo-6-phenyl-5-hexynoic Acid, Methyl Ester 3a2.26 This
compound was prepared by the general procedure above with phenyl-
actylene (1.63 g, 16 mmol), n-BuLi (1.6 M in hexane, 9.5 cm3,
15.0 mmol), BF3·EtO2 (2.0 cm3, 16.0 mmol), and 4-chloro-4-
oxobutanoic acid methyl ester (2.62 g, 17.4 mmol). The product
was isolated as a colorless oil (1.61 g, 7.4 mmol, 49%). Rf = 0.33
hexane/EtOAc 8/1; [found (ESI) M+ + Na, 239.0682;C13H12O3
requires M, 239.0684]; IR (neat) 2953, 2200, 1734, 1667, 1205,
1
1168, 1093, 758, 688 cm−1; H NMR (400 MHz, CDCl3) 7.60−7.56
(m, 2H), 7.49−7.44 (m, 1H), 7.41−7.36 (m, 2H), 3.71 (s, 3H), 3.03
(t, J = 6.7 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) 185.4, 172.5, 133.0, 130.8, 128.7, 119.8, 91.4, 87.4, 51.9, 40.0,
27.8; m/z (EIMS) 239.1 (M + Na)+.
4-Oxo-5-decynoic Acid, Methyl Ester 3b2.27 This compound was
prepared by the general procedure above with 1-hexyne (705 mg,
8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0 mmol), BF3·EtO2
(1.1 cm3, 8.5 mmol), and 4-chloro-4-oxobutanoic acid methyl ester
F
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1.57 g, 10.4 mmol). The product was isolated as a colorless oil
(417 mg, 2.1 mmol, 27%). Rf = 0.58 hexane/EtOAc 4/1; [found (ESI)
M+ + Na, 219.0992; C11H16O3 requires M, 219.0997]; IR (neat) 2958,
anhydrous ZnCl2 (3.77 g, 28 mmol), and 4-chloro-4-oxobutanoic acid
methyl ester (1.97 g, 12.0 mmol). The product was isolated as a
colorless oil (1.33 g, 6.3 mmol, 53%). Rf = 0.20 hexane/EtOAc 8/1;
[found (ESI) M+ + Na, 233.1148; C12H18O3 requires M, 233.1153];
IR (neat) 2958, 2210, 1736, 1671, 1196, 1161 cm−1; 1H NMR
(400 MHz, CDCl3) 3.60 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.30 (t, J =
7.0 Hz, 2H), 2.29 (t, J = 7.2 Hz, 2H), 1.94−1.86 (m, 2H), 1.56−1.50
(m, 2H), 1.48−1.43 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) 187.0, 173.3, 94.6, 80.7, 51.5, 44.3, 32.8, 29.6, 21.9,
19.1, 18.5, 13.4. m/z (EIMS) 233.1 (M + Na)+.
5-Oxo-9-benzyloxy-6-nonynoic Acid, Methyl Ester 3c3. This
compound was prepared by the general procedure above with acetylene
(1.50 g, 8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0 mmol),
anhydrous ZnCl2 (1.90 g, 14.0 mmol), and 4-chloro-4-oxobutanoic
acid methyl ester (987 mg, 6.0 mmol). The product was isolated as a
colorless oil (1.274 g, 4.4 mmol, 73%). Rf = 0.35 hexane/EtOAc 4/1;
[found (ESI) M+ + Na, 311.1254; C17H20O4 requires M, 311.1259];
IR (neat) 2952, 2866, 2214, 1733, 1671, 1199, 1162, 1099, 737, 698
cm−1; 1H NMR (400 MHz, CDCl3) 7.38−7.26 (m, 5H), 4.62 (s, 2H),
3.66 (s, 3H), 3.63 (t, J = 6.7 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 2.61 (t,
J = 7.2 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.00−1.92 (m, 2H); 13C
NMR (100 MHz, CDCl3) 186.9, 173.3, 137.8, 128.5, 127.8, 127.7,
91.1, 81.3, 73.1, 67.2, 51.6, 44.3, 32.8, 20.5, 19.0. m/z (EIMS) 311.1
(M + Na)+.
1
2210, 1737, 1675, 1208, 1154 cm−1; H NMR (400 MHz, CDCl3)
3.69 (s, 3H), 2.88 (t, J = 6.7 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.38
(t, J = 7.1 Hz, 2H), 1.63−1.51 (m, 2H), 1.51−1.35 (m, 2H), 0.93
(t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) 185.5, 172.6, 95.1,
80.4, 51.8, 40.0, 29.6, 27.8, 21.9, 18.6, 13.4; m/z (EIMS) 219.1
(M + Na)+.
4-Oxo-8-benzyloxy-5-octynoic Acid, Methyl Ester 3c2. This
compound was prepared by the general procedure above with alkyne
(674 mg, 4.3 mmol), n-BuLi (1.6 M in hexane, 2.5 cm3, 4.0 mmol),
anhydrous ZnCl2 (950 mg, 7.0 mmol), and 4-chloro-4-oxobutanoic
acid methyl ester (451 mg, 3.0 mmol). The product was isolated as a
colorless oil (204.9 mg, 0.75 mmol, 25%). Rf = 0.26 hexane/EtOAc
4/1; [found (ESI) M+ + Na, 297.1097; C16H18O4 requires M, 297.1102];
IR (neat) 2952, 2864, 2213, 1734, 1674, 1208, 1155, 1100, 738,
1
698 cm−1; H NMR (400 MHz, CDCl3) 7.39−7.27 (m, 5H), 4.56 (s,
2H), 3.68 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H),
2.69 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) 185.4, 172.6, 137.7, 128.5, 127.9, 127.7, 91.5, 81.0, 73.1,
67.1, 51.9, 40.0, 27.8, 20.5; m/z (EIMS) 275.1 (M + H)+.
4-Oxo-7-benzyloxy-7-methyl-5-octynoic Acid, Methyl Ester 3d2.
This compound was prepared by the general procedure above with
alkyne (1.50 g, 8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0
mmol), BF3·EtO2 (1.1 cm3, 8.5 mmol), and 4-chloro-4-oxobutanoic
acid methyl ester (1.57 g, 10.4 mmol). The product was isolated as a
colorless oil (541 mg, 1.9 mmol, 22%). Rf = 0.67 hexane/EtOAc 4/1;
[found (ESI) M+ + Na, 311.1254; C17H20O4 requires M, 311.1259];
5-Oxo-8-benzyloxy-8-methyl-6-nonynoic Acid, Methyl Ester 3d3.
This compound was prepared by the general procedure above with
acetylene (1.50 g, 8.6 mmol), n-BuLi (1.6 M in hexane, 5.0 cm3, 8.0
mmol), anhydrous ZnCl2 (1.90 g, 14.0 mmol), and 4-chloro-4-
oxobutanoic acid methyl ester (987 mg, 6.0 mmol). The product was
isolated as a colorless oil (884 mg, 2.90 mmol, 48%). Rf = 0.53 hexane/
EtOAc 4/1; [found (ESI) M+ + Na, 325.1410; C18H22O4 requires M,
325.1415]; IR (neat) 2987, 2952, 2213, 1734, 1676, 1156, 1049, 737,
1
IR (neat) 3032, 2210, 1737, 1679, 1122, 736, 697 cm−1; H NMR
(400 MHz, CDCl3) 7.38−7.24 (m, 5H), 4.62 (s, 2H), 3.68 (s, 3H),
2.89 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.59 (s, 6H); 13C
NMR (100 MHz, CDCl3) 185.1, 172.4, 138.4, 128.4, 127.7, 127.6,
94.2, 82.9, 70.6, 67.0, 51.9, 40.1, 28.2, 27.6; m/z (EIMS) 311.1 (M +
Na)+.
1
697 cm−1; H NMR (400 MHz, CDCl3) 7.38−7.24 (m, 5H), 4.62 (s,
2H), 3.66 (s, 3H), 2.63 (t, J = 7.2 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H),
2.00−1.93 (m, 2H), 1.60 (s, 6H); 13C NMR (100 MHz, CDCl3)
186.5, 173.2, 138.4, 128.4, 127.63, 127.60, 93.8, 83.2, 70.6, 67.0, 51.7,
44.4, 32.7, 28.3, 19.0. m/z (EIMS) 325.1 (M + Na)+.
Synthesis of 5-oxo-7-phenyl-6-heptynoic Acid, Methyl Ester
3a3.26,28 To a solution of phenylacetylene (326 mg, 3.2 mmol) in
anhydrous THF (6 cm3) at −78 °C was added n-BuLi (1.6 M in
hexane, 1.9 cm3, 3.0 mmol) in 3 min. The mixture was stirred at
−78 °C for 1 h and then BF3·Et2O (454 mg, 0.4 cm3, 3.2 mmol) was
added dropwise. After 10 min, the mixture was cooled to −90 °C and
glutaric acid monomethyl ester chloride (526 mg in 1 cm3 of THF,
3.2 mmol) was added in one portion. After 2 h at −78 °C, the reaction
was quenched by saturated NH4Cl (6 cm3) and water (6 cm3),
extracted with Et2O (2 × 15 cm3), and dried over anhydrous MgSO4.
After concentration under reduced pressure, the crude product was
purified by silica gel column chromatography (eluent hexane/EtOAc =
15/1−8/1) to afford the product as a colorless oil (300 mg, 1.3 mmol,
43%). Rf = 0.54 hexane/EtOAc 4/1; [found (ESI) M+ + Na, 253.0833;
C14H14O3 requires M, 253.0840]; IR (neat) 2952, 2199, 1733, 1667,
Asymmetric Transfer Hydrogenation of γ- and δ-Keto Esters.
(R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 × 10−3 mmol) was dissolved
in HCOOH/Et3N 5/2 azeotropic mixture, and γ-keto ester in degassed
dichloromethane was injected under a nitrogen atmosphere. The
mixture was stirred at rt until starting material was completely
consumed (2−3 days). After the reaction was complete, the reaction
mixture was concentrated and directly purified by silica gel column
chromatography (eluent hexane/EtOAc = 10/1−5/1) to give the
products.
(4R)-Hydroxy-6-phenyl-5-hexynoic Acid, Methyl Ester, Reduction
Product of 3a2.30 This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 ×
10−3mmol), 4-oxo-6-phenyl-5-hexynoic acid methyl ester (118.0 mg,
5.5 mmol), HCOOH/Et3N 5/2 (105 mg), and CH2Cl2 (2.5 cm3), and
the product was isolated as a colorless oil (106.5 mg, 4.9 mmol, 89%,
94% ee). Rf = 0.22 hexane/EtOAc 4/1; [α]D24 +13.3 (c 0.7 in CHCl3)
94% ee (R); [found (ESI) M+ + Na, 241.0835; C13H14O3 requires M,
241.0841]; IR (neat) 3414, 2952, 1733, 1490, 1440, 1254, 1200, 1166,
1
1197, 1168, 758, 689 cm−1; H NMR (400 MHz, CDCl3) 7.60−7.55
(m, 2H), 7.49−7.43 (m, 1H), 7.41−7.35 (m, 2H), 3.69−3.66 (m, 3H),
2.82−2.73 (m, 2H), 2.44−2.35 (m, 2H), 2.10−2.01 (m, 2H); 13C
NMR (100 MHz, CDCl3) 186.8, 173.3, 133.0, 130.8, 128.6, 119.8,
90.9, 87.7, 51.6, 43.3, 32.8, 19.1. m/z (EIMS) 253.1 (M + Na)+.
General Procedure for Synthesis of Other Propargylic
δ-Keto Esters.13 To a solution of acetylene (8.6 mmol) in anhydrous
THF (20 cm3) at −78 °C was added n-BuLi (1.6 M in hexane, 5.0 cm3,
8.0 mmol) in 3 min. The mixture was stirred at −78 °C for 1 h,
anhydrous ZnCl2 (1.90 g in 8 cm3 of THF, 14.0 mmol) was added,
and the mixture was warmed to 0 °C for 30 min, then glutaric acid
monomethyl ester chloride (987 mg, 6.0 mmol) was added in one
portion. The reaction was stirred overnight and quenched by saturated
NH4Cl (10 cm3) and water (10 cm3), extracted with Et2O (2 ×
30 cm3), and dried over anhydrous MgSO4. After concentration under
reduced pressure, the crude product was purified by silica gel column
chromatography (eluent hexane/EtOAc = 15/1−8/1).
1
1067, 756, 691 cm−1; H NMR (400 MHz, CDCl3) 7.50−7.27 (m,
5H), 4.71 (t, J = 6.0 Hz, 1H), 3.69 (m, 3H), 2.70−2.54 (m, 3H),
2.19−2.10 (m, 2H); 13C NMR (100 MHz, CDCl3) 174.1, 131.7,
128.5, 128.3, 122.4, 89.1, 85.4, 62.0, 51.8, 32.5, 29.8; m/z (EIMS)
241.1 (M + Na)+. HPLC separation conditions: Chiralpak IB column
(250 mm × 4.6 mm), hexane/i-PrOH 95/5, 0.8 cm3/min, T = 30 °C.
Retention times: (major, R) 18.6 min, (minor, S) 49.1 min.
(4R)-Hydroxy-5-decynoic Acid, Methyl Ester, Reduction Product
of 3b2. This compound was prepared by the general procedure above
with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 × 10−3 mmol), ketone
(101 mg, 0.52 mmol), HCOOH/Et3N 5/2 (210 mg), and CH2Cl2
(2.5 cm3), and the product was isolated as a colorless oil (90.8 mg,
0.46 mmol, 89%, 93% ee). Rf = 0.22 hexane/EtOAc 4/1; [found (ESI)
M+ + Na, 221.1148; C11H18O3Na requires M, 221.1153]; IR (neat)
3435, 2957, 2934, 1737, 1437, 1167, 1061 cm−1; 1H NMR (400 MHz,
5-Oxo-6-undecynoic Acid, Methyl Ester 3b3.29 This compound
was prepared by the general procedure above with 1-hexyne (1.42 g,
17.2 mmol), n-BuLi (1.6 M in hexane, 10.0 cm3, 16.0 mmol),
G
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) 7.50−7.27 (m, 5H), 4.38 (br s, 1H), 3.61 (s, 3H), 2.64 (br s,
1H), 2.53−2.39 (m, 2H), 2.13 (t, J = 6.9 Hz, 2H), 1.98−1.90 (m, 2H),
1.44−1.28 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 174.2, 85.9, 80.3, 61.5, 51.7, 32.8, 30.6, 29.8, 21.9, 18.3, 13.5;
m/z (EIMS) 221.1 (M + Na)+. HPLC separation conditions:
Chiralpak IC column (250 mm × 4.6 mm), hexane/i-PrOH 94/6,
0.8 cm3/min, T = 30 °C. Retention times: (major, R) 28.5 min,
(minor, S) 50.8 min.
0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 174.0, 85.7,
80.8, 62.1, 52.5, 37.4, 33.6, 30.7, 21.9, 20.6, 18.3, 13.6. m/z (EIMS)
235.1 (M + Na)+. HPLC separation conditions: Chiralpak IA column
(250 mm × 4.6 mm), hexane/i-PrOH 100/0, 0.8 cm3/min, T = 30 °C.
Retention times: (major, R) 13.35 min, (minor, S) 13.02 min. Chiral
and racemic standards were analyzed by HPLC after being converted
to tert-butyldiphenylsilyl (TBDPS) ethers.
(5R)-Hydroxy-9-benzyloxy-6-nonynoic Acid, Methyl Ester, Reduc-
tion Product of 3c3. This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.4 mg, 6.7 ×
10−4 mmol), ketone (101.2 mg, 3.51 mmol), HCOOH/Et3N 5/2 (277 mg),
and CH2Cl2 (1.6 cm3), and the product was isolated as a colorless oil
(101.1 mg, 3.48 mmol, 99%, 99% ee). Rf = 0.33 hexane/EtOAc 2/1;
(4R)-Hydroxy-8-benzyloxy-5-octynoic Acid, Methyl Ester, Reduc-
tion Product of 3c2. This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.4 mg, 6.7 ×
10−4 mmol), ketone (92.2 mg, 0.335 mmol), HCOOH/Et3N 5/2
(278 mg), and CH2Cl2 (1.5 cm3), and the product was isolated as a
colorless oil (87.9 mg, 0.318 mmol, 95%, 98% ee). Rf = 0.15 hexane/
30
[α]D +5.5 (c 1.4 in CHCl3) 99% ee (R); [found (ESI) M+ + Na,
34
313.1410; C17H22O4 requires M, 313.1415]; IR (neat) 3431, 2950,
EtOAc 4/1; [α]D +8.3 (c 0.7 in CHCl3) 98% ee (R); [found (ESI)
1
2866, 1733, 1096, 1078, 1027, 737, 698 cm−1; H NMR (400 MHz,
M+ + Na, 299.1254; C16H20O4 requires M, 299.1259]; IR (neat) 3415,
1
2951, 2864, 1733, 1096, 1063, 737, 697 cm−1; H NMR (400 MHz,
CDCl3) 7.37−7.25 (m, 5H), 4.54 (s, 2H), 4.37−4.31 (m, 1H), 3.66
(m, 3H), 3.57 (t, J = 7.0 Hz, 2H), 2.55 (br s, 1H), 2.51 (td, J = 7.0, 2.0
Hz, 2H), 2.35 (t, J = 7.1 Hz, 2H), 1.83−1.73 (m, 2H), 1.73−1.64 (m,
2H); 13C NMR (100 MHz, CDCl3) 174.0, 138.0, 128.4, 127.8, 127.7,
82.2, 82.1, 72.9, 68.3, 62.0, 51.6, 37.2, 33.6, 20.6, 20.1. m/z (EIMS)
313.1 (M + Na)+. HPLC separation conditions: Chiralpak IC column
(250 mm × 4.6 mm), hexane/i-PrOH 94/6, 1.0 cm3/min, T = 30 °C.
Retention times: (major, R) 67.7 min, (minor, S) 66.2 min.
CDCl3) 7.35−7.26 (m, 5H), 4.54 (s, 2H), 4.43 (tt, J = 6.1, 2.0 Hz,
1H), 3.67 (m, 3H), 3.57 (t, J = 7.0 Hz, 2H), 2.59−2.45 (m, 5H), 1.99
(td, J = 7.2, 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) 174.1, 138.0,
128.4, 127.8, 127.7, 82.7, 81.5, 73.0, 68.3, 61.6, 51.8, 32.7, 29.8, 20.1;
m/z (EIMS) 299.1 (M + Na)+. HPLC separation conditions:
Chiralpak IB column (250 mm × 4.6 mm), hexane/i-PrOH 95/5,
0.7 cm3/min, T = 30 °C. Retention times: (major, R) 26.4 min,
(minor, S) 27.9 min.
(5R)-Hydroxy-8-benzyloxy-8-methyl-6-nonynoic Acid, Methyl
Ester, Reduction Product of 3d3. This compound was prepared by
the general procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.4
mg, 6.7 × 10−4 mmol), ketone (101.0 mg, 0.334 mmol), HCOOH/
Et3N 5/2 (280 mg), and CH2Cl2 (1.6 cm3), and the product was
isolated as a colorless oil (85.7 mg, 0.28 mmol, 84%, 98% ee). Rf =
(4R)-Hydroxy-7-benzyloxy-7-methyl-5-octynoic Acid, Methyl
Ester, Reduction Product of 3d2. This compound was prepared
by the general procedure above with (R,R)-Teth-TsDPEN-RuCl 1
(0.4 mg, 6.7 × 10−4 mmol), ketone (104 mg, 0.36 mmol), HCOOH/Et3N
5/2 (277 mg), and CH2Cl2 (1.6 cm3), and the product was isolated as
a colorless oil (80.2 mg, 0.28 mmol, 77%, 99% ee). Rf = 0.38 hexane/
28
0.28 hexane/EtOAc 4/1; [α]D +10.1 (c 1.2 in CHCl3) 98% ee (R);
[found (ESI) M+ + Na, 327.1567; C18H24O4 requires M, 327.1572];
28
EtOAc 4/1; [α]D +5.4 (c 1.2 in CHCl3) 99% ee (R); [found (ESI)
1
IR (neat) 3432, 2984, 1736, 1153, 1051, 1028, 736, 697 cm−1; H
M+ + Na, 313.1410; C17H22O4 requires M, 313.1415]; IR (neat) 3424,
1
2987, 2935, 1736, 1244, 1154, 1052, 1027, 736, 697 cm−1; H NMR
NMR (400 MHz, CDCl3) 7.38−7.22 (m, 5H), 4.61 (s, 2H), 4.39
(t, J = 6.2 Hz, 1H), 3.65 (m, 3H), 2.35 (t, J = 7.2 Hz, 2H), 2.24 (br s,
1H), 1.83−1.74 (m, 2H), 1.74−1.65 (m, 2H), 1.53 (s, 6H); 13C NMR
(100 MHz, CDCl3) 173.9, 139.1, 128.3, 127.6, 127.4, 87.2, 85.1, 70.6,
66.5, 61.9, 51.6, 37.1, 33.5, 29.0, 20.6. m/z (EIMS) 327.1 (M + Na)+.
HPLC separation conditions: Chiralpak IC column (250 mm × 4.6
mm), hexane/i-PrOH 94/6, 1.0 cm3/min, T = 30 °C. Retention times:
(major, R) 15.8 min, (minor, S) 19.1 min.
(400 MHz, CDCl3) 4.37−4.23 (m, 5H), 4.60 (s, 2H), 4.51 (t, J = 6.1
Hz, 1H), 3.68 (m, 3H), 2.66−2.46 (m, 2H), 2.14 (br s, 1H), 2.05−
1.98 (m, 2H), 1.53 (s, 6H); 13C NMR (100 MHz, CDCl3) 174.0,
139.0, 128.3, 127.6, 127.4, 87.6, 84.3, 70.6, 66.5, 61.4, 51.8, 32.5, 29.8,
29.0; m/z (EIMS) 313.1 (M + Na)+. HPLC separation conditions:
Chiralpak IC column (250 mm × 4.6 mm), hexane/i-PrOH 94/6,
0.8 cm3/min, T = 30 °C. Retention times: (major, R) 20.4 min,
(minor, S) 19.2 min.
Synthesis of 1,5-Diphenyl-4-pentyne-1,3-dione 18.16 Aceto-
phenone (873 mg, 7.4 mmol), 1-(3-phenyl-1-oxo-2-propynyl)benzo-
triazole (1.84 g, 7.6 mmol), and anhydrous MgBr2·OEt2 powder (3.92 g,
15.2 mmol) were added to a flask, and laboratory-grade CH2Cl2
(1.5 cm3) was added via syringe. The suspension was stirred at rt for
3 h and then i-Pr2NEt (2.51 g, 20.0 mmol) was added dropwise. A
clean yellow solution was formed immediately, and the solution was
allowed to stir at rt for 5 h. Saturated NH4Cl (3 cm3) was added,
followed by aqueous HCl (10%, 1 cm3), and stirring was continued for
5 min. After a clear solution had formed, the aqueous layer was
extracted with CH2Cl2 (2 × 5 cm3) and the combined organic extract
was dried over MgSO4. The solvent was evaporated under reduced
pressure and the yellow solid product was dissolved in the minimum
amount of CH2Cl2 and purified by silica gel column chromatography
[eluent hexane/CH2Cl2/EtOAc = 10/1/0−10/1/(0.2−0.4)]. The
product was isolated as light yellow crystals (1.49 g, 6.0 mmol,
(5R)-Hydroxy-7-phenyl-6-heptynoic Acid, Methyl Ester, Reduc-
tion Product of 3a3. This compound was prepared by the general
procedure above with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 ×
10−3 mmol), 5-oxo-7-phenyl-6-heptynoic acid methyl ester (115 mg,
5.0 mmol), HCOOH/Et3N 5/2 (105 mg), and CH2Cl2 (2.5 cm3), and
the product was isolated as a colorless oil (104 mg, 0.45 mmol, 89%,
24
96% ee). Rf = 0.24 hexane/EtOAc 4/1; [α]D +0.5 (c 0.7 in CHCl3)
96% ee (R); [found (ESI) M+ + Na, 255.0992; C14H16O3 requires M,
255.0997]; IR (neat) 3407, 2952, 1733, 1097, 1053, 756, 691 cm−1; 1H
NMR (400 MHz, CDCl3) 7.36−7.34 (m, 2H), 7.26−7.19 (m, 3H),
4.54 (t, J = 6.0 Hz, 1H), 3.60 (m, 3H), 2.35−2.32 (m, 2H), 2.26 (br s,
1H), 1.85−1.73 (m, 4H); 13C NMR (100 MHz, CDCl3) 174.0, 131.7,
128.4, 128.3, 122.5, 89.8, 85.1, 62.4, 51.6, 37.1, 33.6, 20.6. m/z (EIMS)
255.1 (M + Na)+. HPLC separation conditions: Chiralpak IB column
(250 mm × 4.6 mm), hexane/i-PrOH 95/5, 0.8 cm3/min, T = 30 °C.
Retention times: (major, R) 16.4 min, (minor, S) 68.5 min.
1
81%). H NMR (400 MHz, CDCl3) 7.71−7.68 (m, 2H), 7.38−7.31
(m, 3H), 7.27−7.13 (m, 5H), 6.29 (s, 1H); 13C NMR (100 MHz,
CDCl3) 184.7, 169.7, 133.9, 132.3, 132.1, 129.8, 128.3, 128.2, 128.0,
126.7, 119.8, 100.7, 93.3, 85.5.
(5R)-Hydroxy-6-undecynoic Acid, Methyl Ester, Reduction Prod-
uct of 3b3. This compound was prepared by the general procedure
above with (R,R)-Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 × 10−3 mmol),
ketone (105 mg, 1.0 × 10−3 mmol), HCOOH/Et3N 5/2 (415 mg),
and CH2Cl2 (2.0 cm3), and the product was isolated as a colorless oil
(85.6 mg, 4.0 mmol, 81%, 99% ee). Rf = 0.26 hexane/EtOAc 4/1;
Synthesis of 19 via Attempted Asymmetric Transfer
Hydrogenation of 18.18c,d Complex (R,R)-2 (1.2 mg, 2 × 10−3
mmol) was dissolved in HCO2H/Et3N 5/2 azeotropic mixture (42 mg)
under a nitrogen atmosphere, and ketone 18 (24 mg, 0.96 mmol) in
degassed dichloromethane (0.5 cm3) was injected. The mixture was
stirred at rt until starting material was completely consumed (12 h),
and then the reaction was quenched by saturated NaHCO3 (0.5 cm3).
The resulting mixture was extracted with EtOAc (3 × 5 cm3) and
the combined organic phase was dried over anhydrous MgSO4.
34
[α]D +4.1 (c 1.1 in CHCl3) 99% ee (R); [found (ESI) M+ + Na,
235.1305; C12H20O3 requires M, 235.1310]; IR (neat) 3441, 2955,
2933, 1732, 1236, 1196, 1161, 1028 cm−1; 1H NMR (400 MHz,
CDCl3) 4.37 (tt, J = 6.4, 1.9 Hz, 1H), 3.68 (s, 3H), 2.37 (t, J = 7.5 Hz,
2H), 2.20 (td, J = 6.9, 1.9 Hz, 2H), 2.16 (br s, 1H), 1.84−1.75 (m,
2H), 1.75−1.67 (m, 2H), 1.53−1.44 (m, 2H), 1.44−1.35 (m, 2H),
H
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
After concentration, the crude product was purified by silica gel
column chromatography (eluent hexane/EtOAc = 6/1−3/1) to give
19 as an oil (20 mg, 0.081 mmol, 84%). Rf = 0.18 hexane/EtOAc 8/1.
1H NMR (400 MHz, CDCl3) 7.89−7.86 (m, 4H), 7.55−7.53 (m, 6H),
with Weinreb diamide (327 mg, 1.5 mmol), n-BuLi (3.0 cm3,
4.8 mmol), and alkyne (870 mg, 5.0 mmol), and the product was
isolated as described above as a yellow oil (527 mg, 1.19 mmol, 79%).
Rf = 0.33 hexane/EtOAc 8/1; [found (ESI) M+ + Na, 467.2193;
C29H32O4 requires M, 467.2198); IR (neat) 2982, 2937, 2211, 1674,
1236, 1156, 1047, 735, 696 cm−1; 1H NMR (400 MHz, CDCl3) 7.32−
7.18 (m, 10H), 4.54 (s, 4H), 2.54 (t, J = 7.1 Hz, 4H), 1.90 (q, J = 7.1
Hz, 2H), 1.52 (s, 12H); 13C NMR (100 MHz, CDCl3) 186.4, 138.4,
128.4, 127.6, 93.9, 83.2, 70.6, 67.0, 44.1, 28.3, 17.7; m/z (EIMS) 467.1
(M + Na)+.
General Procedure for Asymmetric Transfer Hydrogenation
of 1,4- and 1,5-Diketones. (R,R)-Teth-TsDPEN-RuCl or (S,S)-
Teth-TsDPEN-RuCl 1 (0.6 mg, 1.0 × 10−3 mmol) was dissolved in
HCO2H/Et3N 5/2 azeotropic mixture (372 mg), and 1,4-diketone
(0.2 mmol) in degassed dichloromethane (1.0 cm3) was injected under
nitrogen atmosphere. The mixture was stirred at rt until starting
material was completely consumed. After the reaction was complete,
saturated NaHCO3 (4 cm3) and water (4 cm3) were added and the
reaction mixture was extracted with CH2Cl2 (3 × 15 cm3),
concentrated, dried over anhydrous MgSO4, and purified by silica
gel column chromatography (eluent hexane/EtOAc = 6/1−3/1) to
give the title products. The position of the meso compound in the
chiral HPLC was established in each case by reducing a sample of
ketone with a racemic sample of catalyst 2 under the general
conditions above.
6.83 (s, 2H). Data for the cyclization product 19, which was formed in
all attempts at ATH, matched those reported.18c,d
Synthesis of 1,4- and 1,5-Diketones. To a solution of acetylene
(7.5 mmol) in anhydrous THF (6 cm3) at −78 °C was added n-BuLi
(1.6 M in hexane, 4.7 cm3, 7.5 mmol) in 3 min. The mixture was
stirred at −78 °C for 1 h and was added dropwise to a diester
(2.5 mmol in 8 cm3 of THF) and BF3·OEt2 (6.5 mmol) mixture at
−78 °C. After 1 h, saturated NH4Cl (10 cm3) was added and the
mixture was extracted with diethyl ether (3 × 30 cm3). The combined
organic phase was washed with brine and dried over anhydrous
MgSO4. The crude product was purified by silica gel column
chromatography (eluent hexane/EtOAc = 15/1).
1,8-Diphenyl-1,7-octadiyne-3,6-dione 4a2.19b,c This compound
was prepared by the general procedure above with phenylacetylene
(1.76 g, 17.2 mmol), n-BuLi (10.0 cm3, 16.0 mmol), dimethyl succinate
(778 mg, 5.3 mmol), and BF3·OEt2 (1.73 cm3, 13.8 mmol). The
product was isolated as a white solid (394 mg, 1.38 mmol, 26%). Rf =
0.77 hexane/EtOAc 4/1; mp 102−103 °C; 1H NMR (400 MHz,
CDCl3) 7.60−7.57 (m, 4H), 7.49−7.44 (m, 2H), 7.41−7.37 (m, 4H),
3.12 (s, 4H); 13C NMR (100 MHz, CDCl3) 185.1, 133.1, 130.9, 128.7,
119.8, 91.7, 87.5, 34.0.
1,9-Diphenyl-1,8-nonadiyne-3,7-dione 4a3.19a This compound
was prepared by the general procedure above with phenylacetylene
(0.88 g, 8.6 mmol), n-BuLi (5.0 cm3, 8.0 mmol), dimethyl glutarate
(457 mg, 2.86 mmol), and BF3·OEt2 (1.1 cm3, 8.5 mmol). The pro-
duct was isolated as a white solid (148 mg, 0.49 mmol, 17%). Rf =
0.62 hexane/EtOAc 4/1; mp 51−52 °C; 1H NMR (400 MHz, CDCl3)
7.60−7.23 (m, 10H), 2.71 (t, J = 7.2 Hz, 4H), 2.12−2.05 (m, 2H); 13C
NMR (100 MHz, CDCl3) 186.9, 133.1, 130.8, 128.7, 119.8, 91.2, 87.7,
44.2, 18.3.
1,8-Diphenyl-1,7-octadiyne-(3R, 6R)-diol, Reduction Product of
4a2.19b,c This compound was prepared by the general procedure
above with (R,R)-Teth-TsDPEN-RuCl or (S,S)-Teth-TsDPEN-RuCl
1 (0.6 mg, 1.0 × 10−3 mmol), HCO2H/Et3N 5/2 azeotropic mixture
(84 mg), diketone (57.2 mg, 0.2 mmol), and degassed dichloro-
methane (1 cm3). The product was isolated as described above as
white crystals [47.1 mg, 0.16 mmol, 81%, >99% ee, dr 26/1 for (R,R)
diol; 45.0 mg, 0.15 mmol, 78%, >99% ee, dr 49/1 for (S,S) diol]. Rf =
0.11 hexane/EtOAc 4/1; [α]D28 +9.2 [c 0.9 in CHCl3 for (R,R) diol];
28
[α]D −8.5 [c 0.7 in CHCl3 for (S,S) diol]; mp 79−80 °C; [found
General Procedure for Synthesis of 1,4- and 1,5-Diketones
from Weinreb Amides.19a To a solution of acetylene (2.4 mmol) in
anhydrous THF (10 cm3) at −78 °C was added n-BuLi (1.6 M in
hexane, 1.5 cm3, 2.4 mmol) in 3 min. The mixture was stirred at
−78 °C for 1 h, and a Weinreb diamide (204 mg in 3 cm3 THF,
1.0 mmol) solution was added dropwise. After 1 h at −78 °C, the
temperature was raised to −10 °C during 2 h, and saturated NH4Cl
(20 cm3) and 2 M HCl solution (5 cm3) were added at −10 °C. The
mixture was extracted with diethyl ether (3 × 20 cm3), and the
combined organic phase was dried over anhydrous MgSO4. The crude
product was purified by silica gel column chromatography (eluent
hexane/EtOAc = 12/1−8/1).
(ESI) M+ + Na, 313.1199; C20H18O2 requires M, 313.1204]; IR (neat)
3191, 1488, 1004, 750, 687 cm−1; 1H NMR (400 MHz, CDCl3) 7.44−
7.42 (m, 4H), 7.37−7.26 (m, 6H), 4.74 (t, J = 5.7 Hz, 2H), 2.81
(s, 2H), 2.16−2.01 (m, 4H); 13C NMR (100 MHz, CDCl3) 131.8,
128.5, 128.3, 122.5, 89.6, 85.3, 62.5, 33.4; m/z (EIMS) 313.1 (M + Na)+.
HPLC separation conditions: Chiralpak IB column (250 mm × 4.6 mm),
hexane/i-PrOH 80/20, 0.8 cm3/min, T = 30 °C. Retention times: (R)
9.3 min, (meso) 24.8 min, (S) 51.2 min.
1,8-Dibutyl-1,7-octadiyne-(3R, 6R)-diol, Reduction Product of
4b2. This compound was prepared by the general procedure above
with (R,R)-Teth-TsDPEN-RuCl or (S,S)-Teth-TsDPEN-RuCl 1 (0.6 mg,
1.0 × 10−3 mmol), HCO2H/Et3N 5/2 azeotropic mixture (372 mg),
diketone (54.5 mg, 0.2 mmol), and degassed dichloromethane (2.0
cm3). The product was isolated as described above as a colorless oil
[48.1 mg, 0.19 mmol, 87%, >99% ee, dr 33/1 for (R,R) diol; 45 mg,
0.18 mmol, 82%, >99% ee, dr 28/1 for (S,S) diol]. Rf = 0.26 hexane/
1,8-Dibutyl-1,7-octadiyne-3,6-dione 4b2.31 This compound was
prepared by the general procedure above with Weinreb diamide
(326 mg, 1.6 mmol), n-BuLi (3.0 cm3, 4.8 mmol), and 1-hexyne
(417 mg, 2.4 mmol), and the product was isolated as described above
as a colorless oil (361 mg, 1.47 mmol, 92%). Rf = 0.48 hexane/EtOAc
8/1; [found (ESI) M+ + Na, 269.1512; C16H22O2 requires M,
269.1517]; IR (neat) 2959, 2934, 2872, 2219, 1670, 1192, 1150 cm−1;
1H NMR (400 MHz, CDCl3) 2.89 (s, 4H), 2.37 (t, J = 7.3 Hz, 4H),
30
30
EtOAc 2/1; [α]D +14.9 [c 0.8 in CHCl3 for (R,R) diol], [α]D
−14.6 [c 0.7 in CHCl3 for (S,S) diol]; [found (ESI) M+ + Na,
273.1825; C16H26O2 requires M, 273.1830); IR (neat) 3329, 2957,
2931, 2862, 1456, 1328, 1022 cm−1; H NMR (400 MHz, CDCl3)
1
1.61−1.53 (m, 4H), 1.48−1.39 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H); 13C
NMR (100 MHz, CDCl3) 185.4, 95.2, 80.5, 38.9, 29.6, 21.9, 18.6, 13.5;
m/z (EIMS) 268.9 (M + Na)+.
4.45 (br s, 2H), 2.38−2.32 (br s, 2H), 2.20 (td, J = 6.8, 1.8 Hz, 4H),
1.94−1.82 (m, 4H), 1.52−1.45 (m, 4H), 1.45−1.36 (m, 4H), 0.91
(t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) 85.9, 80.8, 62.3,
33.7, 30.7, 21.9, 18.4, 13.6; m/z (EIMS) 272.9 (M + Na)+. HPLC
separation conditions: Chiralpak IB column (250 mm × 4.6 mm),
hexane/i-PrOH 90/10,0.6 cm3/min, T = 30 °C. Retention times: (R)
10.7 min, (meso) 12.5 min, (S) 11.1 min.
1,10-Dibenzyloxy-1,10-tetramethyl-2,8-octadiyne-(4R,7R)-diol,
Reduction Product of 4d2. This compound was prepared by the
general procedure above with (R,R)-Teth-TsDPEN-RuCl or (S,S)-
Teth-TsDPEN-RuCl 1 (0.3 mg, 5.0 × 10−4 mmol), HCO2H/Et3N 5/2
azeotropic mixture (186 mg), diketone (41 mg, 0.1 mmol), and
degassed dichloromethane (1.0 cm3). The product was isolated as
described above as a colorless oil [34.5 mg, 0.079 mmol, 83%, >99%
ee, dr 44/1 for (R,R) diol; 29.1 mg, 0.067 mmol, 70%, >99% ee, dr
1,10-Dibenzyloxy-1,10-tetramethyl-2,8-octadiyne-4,7-dione 4d2.
This compound was prepared by the general procedure above with
Weinreb diamide (204 mg, 1.0 mmol), n-BuLi (1.5 cm3, 2.4 mmol),
and alkyne (417 mg, 2.4 mmol), and the product was isolated as
described above as a yellow oil (186 mg, 0.43 mmol, 43%). Rf = 0.25
hexane/EtOAc 8/1; [found (ESI) M+ + Na, 453.2036; C28H30O4
requires M, 453.2041]; IR (neat) 2987, 2210, 1675, 1235, 1157, 1113,
1
1047, 735, 696 cm−1; H NMR (400 MHz, CDCl3) 7.38−7.24 (m,
10H), 4.62 (s, 4H), 2.91 (m, 4H), 1.59 (s, 12H); 13C NMR
(100 MHz, CDCl3) 184.6, 183.3, 128.4, 127.67, 127.64, 94.4, 82.9,
70.6, 67.1, 38.8, 28.2; m/z (EIMS) 453.1 (M + Na)+.
1,11-Dibenzyloxy-1,11-tetramethyl-2,9-nonadiyne-4,8-dione
4d3. This compound was prepared by the general procedure above
I
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
26
124/1 for (S,S) diol]. Rf = 0.31 hexane/EtOAc 2/1; [α]D +13.5 [c
for 4 h, then quenched with saturated NH4Cl (6 cm3) and extracted
with EtOAc (3 × 20 cm3); the combined organic layers were dried
over MgSO4 and concentrated. The crude product was purified by
silica gel column chromatography (eluent hexane/EtOAc = 4/1−1/1)
to afford the Weinreb amide (288.1 mg, 1.28 mmol, 90% for two steps
30
1.3 in CHCl3 for (R,R) diol]; [α]D −13.0 [c 1.5 in CHCl3 for (S,S)
diol]; [found (ESI) M+ + Na, 457.2349; C28H34O4 requires M,
457.2354]; IR (neat) 3395, 2983, 1244, 1152, 1048, 1027, 734, 695
cm−1; H NMR (400 MHz, CDCl3) 7.39−7.22 (m, 10H), 4.60 (s,
1
22
from alkyne, Rf = 0.09 hexane/EtOAc 2/1;). [α]D +34.5 (c 0.5 in
4H), 4.45 (br s, 2H), 2.62 (s, 2H), 1.96−1.77 (m, 4H), 1.52 (s, 12H);
CHCl3); 1H NMR (400 MHz, CDCl3) 7.30−7.16 (m, 5H), 4.08−4.01
(m, 1H), 3.88 (d, J = 2.9 Hz, 1H), 3.67 (s, 3H), 3.19 (s, 3H), 2.86
(ddd, J = 13.8, 10.0, 5.4 Hz, 1H), 2.76−2.64 (m, 2H), 2.48 (dd, J =
16.8, 9.5 Hz, 1H), 1.94−1.84 (m, 1H), 1.78−1.70 (m, 1H); 13C NMR
(100 MHz, CDCl3) 173.8, 142.0, 128.5, 128.4, 125.8, 67.2, 61.3, 38.2
(2C), 31.9 (2C); m/z (ESI-MS) 238.1 (M + H)+. Lit.34 (S)-Weinreb
13C NMR (100 MHz, CDCl3) 139.0, 128.4, 127.7, 127.4, 87.4, 84.9,
70.7, 66.5, 61.8, 33.3, 29.0; m/z (EIMS) 457.1 (M + Na)+. HPLC
separation conditions: Chiralpak IB column (250 mm × 4.6 mm),
hexane/i-PrOH 95/5, 0.6 cm3/min, T = 30 °C. Retention times: (R)
17.7 min, (meso) 21.0 min, (S) 19.6 min.
1,8-Nonadiyne-1,9-diphenyl-(3R,7R)-diol, Reduction Product of
4a3.19a,32 This compound was prepared by the general procedure
above with (R,R)-Teth-TsDPEN-RuCl or (S,S)-Teth-TsDPEN-RuCl
1 (0.2 mg, 3.3 × 10−4 mmol), HCOOH/Et3N 5/2 azeotropic mixture
(56 mg), diketone (19.9 mg, 0.067 mmol), and degassed dichloro-
methane (0.5 cm3). The product was isolated as described above as
white crystals [19.4 mg, 0.064 mmol, 96%, >99% ee, dr 35/1 for (R,R)
diol; 16.3 mg, 0.054 mmol, 81%, >99% ee, dr 78/1 for (S,S) diol]. Rf =
25
amide [α]D +28.6 (c 1.08, CHCl3, >99% ee).
(5S)-Hydroxy-1,7-diphenylhept-1-yn-3-one 22.35,36 To a solution
of phenylacetylene (146 mg, 1.45 mmol) in anhydrous THF (6 cm3)
at −78 °C was added n-BuLi (1.6 M in hexane, 0.79 cm3, 1.26 mmol)
in 3 min. The mixture was stirred at −78 °C for 1 h and a Weinreb
amide (81.1 mg in 0.5 cm3 of THF, 0.36 mmol) solution was added
dropwise. After 30 min at −78 °C, the temperature was raised to
−10 °C for 2 h and saturated NH4Cl (5 cm3) was added at −10 °C.
The mixture was extracted with EtOAc (3 × 20 cm3) and the
combined organic phase was dried over anhydrous MgSO4. The crude
product was purified by silica gel column chromatography (eluent
hexane/EtOAc = 8/1−5/1, Rf = 0.31 hexane/EtOAc 4/1) to afford the
ketone as a light yellow solid (86.0 mg, 0.30 mmol, 85%); mp 43−44 °C;
23
0.16 hexane/EtOAc 2/1; [α]D −26.2 (c 0.4 in CHCl3) >99% ee
(S,S), 97% de; [α]D23 +30.9 (c 0.2 in CHCl3) >99% ee (R,R), 97% de;
mp 102 °C; [found (ESI) M+ + Na, 327.1356; C21H20O2 requires M,
327.1361]; IR (neat) 3348, 2949, 2915, 1489, 1416, 1107, 1068, 914,
758, 689 cm−1; H NMR (400 MHz, CDCl3) 7.43−7.37 (m, 4H),
1
7.32−7.23 (m, 6H), 4.64 (t, J = 6.4 Hz, 2H), 2.24 (s, 2H), 1.93−1.84
(m, 4H), 1.83−1.74 (m, 2H); 13C NMR (100 MHz, CDCl3) 131.7,
128.4, 128.3, 122.6, 89.9, 85.1, 62.8, 37.4, 21.1; m/z (EIMS) 327.1
(M + Na)+. HPLC separation conditions: Chiralpak IB column (250
mm × 4.6 mm), hexane/i-PrOH 80/20, 0.8 cm3/min, T = 30 °C.
Retention times: (R) 9.0 min, (meso) 24.5 min, (S) 51.2 min.
1,11-Dibenzyloxy-1,11-tetramethyl-2,9-octadiyne-(4R,8R)-diol,
Reduction Product of 4d3. This compound was prepared by the
general procedure above with (R,R)-Teth-TsDPEN-RuCl or (S,S)-
Teth-TsDPEN-RuCl 1 (0.3 mg, 5.0 × 10−4 mmol), HCO2H/Et3N 5/2
azeotropic mixture (186 mg), diketone (45.0 mg, 0.1 mmol), and
degassed dichloromethane (1.0 cm3). The product was isolated as
described above as a colorless oil [38.9 mg, 0.8 mmol, 86%, >99% ee,
dr 76/1 for (R,R) diol; 43.6 mg, 0.1 mmol, 97%, >99% ee, dr 110/1 for
(S,S) diol]. Rf = 0.29 hexane/EtOAc 2/1; [α]D28 +0.29 [c 0.9 in CHCl3
26
1
[α]D +27.6 (c 0.5 in CHCl3); H NMR (400 MHz, CDCl3) 7.60−
1.54 (m, 2H), 7.50−7.45 (m, 1H), 7.42−7.37 (m, 2H), 7.32−7.27 (m,
2H), 7.24−7.17 (m, 3H), 4.24−4.17 (m, 1H), 2.91−2.80 (m, 3H),
2.77−2.69 (m, 2H), 1.93−1.73 (m, 2H); 13C NMR (100 MHz,
CDCl3) 186.3, 140.6, 132.1, 130.0, 127.6, 127.4(2C), 124.9, 118.6,
90.9, 86.8, 65.9, 51.3, 37.0, 30.7; m/z (ESI-MS) 279.1 (M + H)+. Lit.35
mp 45−50 °C; S enantiomer [α]D +17.7 (c 1.0 in CHCl3, 96% ee).
(−)-Yashabushidiol B 20.21 (R,R)-Teth-TsDPEN-RuCl 1 (0.3 mg,
5 × 10−4 mmol) was dissolved in HCO2H/Et3N 5/2 azeotropic
mixture (60 mg), and ketone 22 (13.2 mg, 0.047 mmol) in degassed
dichloromethane (0.5 cm3) was injected under a nitrogen atmosphere.
The mixture was stirred at rt until starting material was completely
consumed, and then the reaction was quenched by aqueous NaHCO3
(0.5 cm3), extracted with EtOAc (3 × 5 cm3), and the combined
organic phase was dried over anhydrous MgSO4. After concentration,
Pd(OH)2/C [5 mg, 20% Pd(OH)2] and MeOH (2.0 cm3) were
added. The solution was degassed once and stirred vigorously at 1 atm
H2 atmosphere for 1 h. The catalyst was removed by filtration, washed
by MeOH, concentrated, and purified by silica gel column chromato-
graphy (eluent hexane/EtOAc = 6/1−2/1) to afford (−)-yashabush-
idiol B as white needles (13.2 mg, 0.047 mmol, 98%, >99 ee, dr >20/1
28
for (R,R) diol]; [α]D −0.23 [c 0.6 in CHCl3 for (S,S) diol]; [found
(ESI) M+ + Na, 471.2506; C29H36O4 requires M, 471.2511]; IR (neat)
1
3380, 2984, 2934, 1243, 1152, 1049, 1027, 734, 695 cm−1; H NMR
(400 MHz, CDCl3) 7.38−7.22 (m, 10H), 4.60 (s, 4H), 4.37 (t, J = 6.1
Hz, 2H), 1.86 (s, 2H), 1.78−1.66 (m, 4H), 1.66−1.58 (m, 2H), 1.53
(s, 12H); 13C NMR (100 MHz, CDCl3) 139.1, 128.3, 127.6, 127.4,
87.2, 85.3, 70.6, 66.5, 62.2, 37.4, 29.0, 21.0; m/z (EIMS) 471.1
(M + Na)+. HPLC separation conditions: Chiralpak IB column
(250 mm × 4.6 mm), hexane/i-PrOH 95/5, 0.5 cm3/min, T = 30 °C.
Retention times: (R) 28.6 min, (meso) 31.8 min, (S) 33.2 min.
Synthesis of (−)-Yashabushidiol B. Ethyl (3S)-Hydroxy-5-
phenylpentanoate.33,34 Alcohol (R configuration reduction product
of 3a1, 92% ee) (306 mg, 1.40 mmol) was stirred vigorously with
Pd(OH)2/C (129 mg, 20% Pd(OH)2) at 1 atm H2 atmosphere at rt in
degassed MeOH (10 cm3). After 1 h the catalyst was removed by
filtration and washed with MeOH. The eluent was concentrated and
used in the next step without purification. 1H NMR (400 MHz,
CDCl3) 7.31−7.24 (m, 2H), 7.22−7.15 (m, 3H), 4.16 (s, J = 7.2 Hz,
2H), 4.06−3.98 (m, 1H), 2.86−2.78 (d, J = 2.8 Hz, 1H), 2.74−2.66 (s,
1H), 2.51 (dd, J = 12.4, 3.4 Hz, 1H), 2.44 (dd, J = 12.4, 8.6 Hz, 1H),
1.90−1.69 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 173.0, 141.7, 128.5, 128.4, 125.9, 76.2, 60.8, 41.3, 38.1, 31.8,
14.2. The configurational assignment is based on conversion to amide
in the next step and to yashabushidiol B.
1
(determined by H NMR), dr = 75/1 (determined by HPLC), Rf =
22
0.43 hexane/EtOAc 2/1); mp 87 °C; [α]D −5.0 (c 0.5 in CHCl3);
1H NMR (400 MHz, CDCl3) 7.31−7.24 (m, 4H), 7.22−7.16 (m, 6H),
4.03−3.94 (m, 2H), 2.78 (ddd, J = 13.7, 8.9, 5.8 Hz, 2H), 2.66 (ddd,
J = 13.7, 8.4, 6.5 Hz, 2H), 2.34 (br s, 2H), 1.91−1.82 (m, 2H), 1.82−
1.71 (m, 2H), 1.67 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
141.9, 128.5, 128.4, 125.9, 68.9, 42.6, 39.1, 32.2. m/z (ESI-MS)
285.1 (M + H)+. HPLC separation conditions: Chiralpak IC column
(250 mm × 4.6 mm), hexane/i-PrOH 92/8, 0.8 cm3/min, T = 30 °C.
Retention times: (R,R) 16.0 min, (S,S) 17.9 min, (meso) 21.6 min.
Lit.21a mp 91−92 °C; (S,S)-(−) [α]D −7.3 (c 1, CHCl3). The synthetic
approach to a racemic/meso mixture of yashabushidiol B for HPLC
comparison is given in a following section.
Racemic Ethyl-3-hydroxy-5-phenylpentanoate. To a solution of
diisopropylamine (3.23 g, 32 mmol) in THF (40 cm3) at −78 °C was
added n-BuLi (1.6 M in hexane, 20.0 cm3, 32 mmol) dropwise over
20 min. A solution of ethyl acetate (2.45 g, 27.8 mmol) in THF
(10 cm3) was then added dropwise over 20 min. After the mixture was
stirred for 1.5 h, 3-phenylpropionaldehyde [3.16 g, 23.5 mmol in THF
(10 cm3)] was added in one portion. The resulting mixture was stirred
at −78 °C for 2 h, after which time saturated NH4Cl (50 cm3) was
added. The mixture was extracted with ethyl acetate (3 × 50 cm3) and
the combined organic phase was washed with brine (15 cm3) and
dried over anhydrous MgSO4. The crude product was purified by silica
(3S)-Hydroxy-N-methoxy-N-methylbenzene Pentanamide
21.34,35 To a solution of N,O-dimethylhydroxylamine hydrochloride
(549 mg, 5.6 mmol) in THF (8 cm3) was added n-BuLi (1.6 M in
hexane, 6.9 cm3, 11.0 mmol) dropwise at −78 °C. After being stirred at
room temperature for 10 min, the mixture was cooled to −78 °C and a
solution of the crude ester from the previous step (1.40 mmol) in
THF (2.0 cm3) was added. The reaction mixture was stirred at −78 °C
J
dx.doi.org/10.1021/jo401284c | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
gel column chromatography (eluent hexane/EtOAc = 8/1) to afford
the racemic compound as a colorless oil (4.5 g, 20.2 mmol, 86%). The
data matched those for the enantiomerically enriched product
described above.
1308. (e) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem.
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Racemic/meso Mixture of Yashabushidiol B 20. The substrate for
this reaction was prepared from racemic ethyl-3-hydroxy-5-phenyl-
pentanoate by the procedure for the enantiomerically enriched
compound. Racemic reduction catalyst 2 was prepared by combining
equal masses of each enantiomerically pure catalyst. Due to weighing
errors on the small scale required, the product exhibits a small residual
enantiomeric excess (see HPLC in Supporting Information). Racemic
catalyst 2 (6 mg, 0.01 mmol) was dissolved in HCO2H/Et3N
5/2 azeotropic mixture (84 mg), and racemic ketone 22 (60 mg,
0.21 mmol) in degassed CH2Cl2 (1.5 cm3) was injected under a
nitrogen atmosphere. The mixture was stirred at rt until starting
material 22 was completely consumed, and the reaction was quenched
by saturated NaHCO3 (1 cm3). The aqueous phase was extracted with
CH2Cl2 (3 × 5 cm3), and the combined organic phase was dried over
anhydrous MgSO4. After concentration, Pd(OH)2/C [30 mg, 20%
Pd(OH)2] and MeOH (10 cm3) were added. The solution was
degassed once and stirred vigorously under a H2 atmosphere (1 atm)
for 1.5 h. The catalyst was removed by filtration and washed by MeOH
(20 cm3), concentrated, and purified by silica gel column
chromatography (eluent hexane/EtOAc = 4/1−2/1) to afford the
diol as white solid (racemic/meso 5/1). The 1H NMR features of the
major diastereoisomer (yashabushidiol) match those previously
reported. The only distinct peaks for the meso diastereoisomer can
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1
be observed at H NMR (400 MHz, CDCl3) 3.90−3.70 (m, 2H),
1
which permits a d.e. to be assigned. All other H NMR peaks overlap
with the racemic compound. HPLC separation conditions: Chiralpak
IC column (250 mm × 4.6 mm), hexane/i-PrOH 92/8, 0.8 cm3/min,
T = 30 °C. Retention times: (R,R) 16.0 min, (S,S) 17.9 min, (meso)
21.6 min.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all intermediates and products and
chiral HPLC spectra of reduction products (ee determination
data). This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail m.wills@warwick.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Warwick University for partial support of Z.F. and
Johnson Matthey (Cambridge) for a generous gift of catalyst 1
that is now commercially available.
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