Stereoselective α-quaternization of 3-methoxycycloalk-2-enones via 1,4-diastereoinduction of alkoxy dienolates

Article abstract of DOI:10.1021/jo2022789

The alkylation of dienolates generated from 3-methoxycycloalk-2-enones having a 3′-hydroxyl alkenyl chain provides the corresponding quaternized cycloalkenones in a highly diastereoselective manner. The high degree of stereocontrol in the α-quaternization possibly implies intervention of a rigid chelating transition state that allows an efficient 1,4-asymmetric induction to take place.

Full text of DOI:10.1021/jo2022789

Note
pubs.acs.org/joc
Stereoselective α-Quaternization of 3-Methoxycycloalk-2-enones via
1,4-Diastereoinduction of Alkoxy Dienolates
Gamal A. I. Moustafa, Yasumasa Kamada, Tetsuaki Tanaka, and Takehiko Yoshimitsu*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The alkylation of dienolates generated from 3-methoxycycloalk-2-
enones having a 3′-hydroxyl alkenyl chain provides the corresponding quaternized
cycloalkenones in a highly diastereoselective manner. The high degree of
stereocontrol in the α-quaternization possibly implies intervention of a rigid
chelating transition state that allows an efficient 1,4-asymmetric induction to take
place.
Scheme 2. Preparation of Substrates
ecause of the ubiquity of quaternized carbon in the
chemical structures of bioactive natural products, the
B
development of methods for the synthesis of quaternary
stereocenters constitutes one of the major objectives in organic
synthesis.1,2 In the course of establishing a route to
( )-platencin, we discovered that 3-methoxycyclohex-2-enone
(1) possessing a free 3′-hydroxyalkenyl side chain underwent
highly diastereoselective alkylation to afford corresponding
quaternized product 3 with a ratio of 96:4, whereas TBS-
protected substrate 2 did not exert such a high level of
selectivity (Scheme 1).3 The observed stereochemical outcome
Scheme 1. Highly Stereoselective Quaternization of Enone 1
iodide 7 by following standard alkylation protocols to afford
enones 2 and 8 in good yields, as an essentially 1:1
diastereomeric mixture. Hydroxy enones 1 and 9 were then
successfully derived by desilylation of TBS-protected enones 2
and 8 with TBAF at 50 °C. As the first set of experiments, the
alkylative quaternization of TBS-protected enones 2 and 8 was
examined with various alkylating agents using 1.5 equiv of LDA
(Table 1). In all cases, nearly equal amounts of two
diastereomers were produced irrespective of the ring size of
the enone or the type of alkylating agent. The low
diastereoinduction was consistent with that previously observed
for the alkylation of enone 2 with 2,3-dibromopropene.3
Then, we evaluated the quaternization of hydroxy enones 1
and 9 under the same conditions except for the slightly larger
amount of LDA (3 equiv) (Table 2). In contrast to the above
cases, alkylation of the hydroxy enones was highly stereo-
selective and generally afforded the corresponding quaternized
compounds as almost single stereoisomers albeit in moderate
yields. Thus, alkoxy dienolates that were generated from enones
is attributable to the 1,4-diastereoinduction arising from a
transition state, in which an eight-membered lithium enolate
allows the alkylating agent to access from the less hindered face,
leading to essentially single stereoisomer 3.4,5
This discovery prompted us to screen various alkylating
agents and substrates and investigate the feasibility of this
simple means to access quaternized cycloalkenones, which
would serve as useful building blocks for bioactive natural
products. In the present study, we report the potential scope of
the highly stereoselective 1,4-asymmetric inductive quaterniza-
tion of 3-methoxycyclohex-2-enone (1) and 3-methoxycyclo-
pent-2-enone (9) with various alkylating agents.
The stereoselective quaternization was initially evaluated
with TBS-protected enones 2/8 and hydroxy enones 1/9,
which were prepared from 3-methoxycycloalkenones 5 and 6
(Scheme 2). Known enones 5 and 6 were each alkylated with
Received: November 17, 2011
Published: December 29, 2011
© 2011 American Chemical Society
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Note
Table 1. Alkylative Quaternization of TBS-Protected Enones
2 and 8
Table 2. Alkylative Quaternization of Hydroxy Enones 1 and
9
a
b
RX (5 equiv) and LDA (3 equiv) were used. Isolated yields. Yields
a
b
c
RX (5 equiv) and LDA (1.5 equiv) were used. Isolated yields. Yields
based on recovered starting enone are given in parentheses.
based on recovered starting enone are given in parentheses. 2-
Alkylated regioisomers were obtained (9% for entry 2, 11% for entry 6
and 14% for entry 8). See ref 6. 4-Alkylated regioisomers were
c
d
1
d
Diastereomeric ratio was determined by H NMR analysis. From
our published results (see ref 3).
obtained (14% for entry 5 and 16% for entry 7). See ref 6.
e
f
Diastereomeric ratio was determined by 1H NMR analysis. From our
1 and 9 with 3 equiv of LDA underwent methylation,
propargylation, 2-bromoallylation, and benzylation with ex-
cellent diastereoselectivities ranging from 86:14 to >99:1.
Noteworthy is the fact that methyl iodide, a sterically less
demanding alkylating agent, successfully underwent diaster-
published results (see ref 3).
in situ by the deprotonation of enones 1 and 9 with LDA are
reasonably responsible for exerting the distinct facial
selectivities.
With these intriguing results of the quaternization available,
we next examined the alkylation of 3-methoxycyclohex-2-enone
derivatives 24 and 25, both of which bear a slightly bulky
isopropyl substituent on the side chain, with a view to clarifying
the effect of the substituent on the stereoinduction. Isopropyl
derivatives 24 and 25 were readily prepared by hydrogenation
of enones 1 and 2 with PtO2 under hydrogen atmosphere in
86% and 65% yield, respectively, and subjected to alkylation.
Deprotonation of the enones with LDA, followed by alkylation
with 2,3-dibromopropene and benzyl bromide under the
established conditions, delivered corresponding quaternized
compounds 26−29 in moderate yields (Table 4).
The alkylation of hydroxy enone 24 with either 2,3-
dibromopropene or benzyl bromide took place with selectivities
of 78:22 for both cases to furnish 26 or 28 (entries 1 and 3),
whereas that of TBS-protected enone 25 showed no significant
diastereoinduction (entries 2 and 4). This result indicates that
the 1,4-asymmetric induction is also feasible with an alkyl
substituent other than isopropenyl; however, the extent of the
1,4-asymmetric induction may depend on the bulkiness of the
group. It seems that the slightly bulky isopropyl substituent
eoselective alkylation to give the quaternized products (entries
1 and 2).
The relative stereochemistry of each product was unambig-
uously determined by analyzing the coupling constants and the
NOE correlations of corresponding cyclic compounds 17a−
23a, which were readily prepared from products 17−23 by acid
treatment (Table 3). The large coupling constant between Ha
and Hb protons, i.e., Jab = ca. 12 Hz, which was observed for all
of the cyclized compounds, indicated the conformation shown
in Table 3. Furthermore, NOE analysis allowed us to confirm
the proximity of the Hb and the proton of the newly introduced
C6 or C5 substituent (numbering based on quaternized
products 3, 17−23). Thus, the stereochemical analysis
suggested that in all cases, there was exclusive production of
a stereoisomer that possesses syn-relationship between C6 or
C5 substituent and the hydroxyl group at the side chain. This
stereoselectivity strongly implies the intermediacy of a rigid
transition state, such as i shown in Scheme 3, where the
alkylating agents can effectively distinguish the two facial
environments of the dienolates. It can thus be postulated again
that the chelation structures of the alkoxy dienolates generated
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Note
Table 3. Determination of Stereochemistry of Major Isomers
entry
enone
R1/R2
product (%)
Jab (Hz)
1
2
17
18
19
20
21
22
23
3
Me/isopropenyl
17a (77%)
18a (95%)
19a (81%)
20a (78%)
21a (82%)
22a (50%)
23a (90%)
3a (83%)
12
Me/isopropenyl
11.9
12
3
propargyl/isopropenyl
propargyl/isopropenyl
2-bromoallyl/isopropenyl
Bn/isopropenyl
4
11.7
12.2
12
5
6
7
Bn/isopropenyl
12
8
2-bromoallyl/isopropenyl
2-bromoallyl/i-Pr
Bn/i-Pr
11.9 (ref 3)
12
9
26
28
26a (90%)
28a (83%)
10
12.4
Scheme 3. Plausible Mechanism for Highly Stereoselective
Quaternization of Hydroxy Enones 1 and 9
adversely affects the rigidity of the chelation intermediate,
leading to undesired erosion of the stereoselectivity.7
In conclusion, we have established an expeditious approach
to the stereoselective quaternization of cyclic dienolates via 1,4-
diastereoinduction, which is expected to find broad application
in organic synthesis. Further work to employ the present
method for the asymmetric synthesis of natural products
bearing quaternary stereocenters is underway.
EXPERIMENTAL SECTION
■
5-(3-(tert-Butyldimethylsilyloxy)-4-methylpent-4-enyl)-3-
methoxycyclopent-2-enone (8). Compounds 8 and 9 were
prepared by the protocol reported in ref 2 for compounds 1 and 2,
respectively. Pale yellow oil (dr =1:1): IR (neat) 1684 cm−1; 1H NMR
(400 MHz, CDCl3) δ 5.26 (s, 1H), 4.86 (s, 0.5H), 4.85 (s, 0.5H), 4.76
(s, 1H), 4.04−4.00 (m, 1H), 3.82 (s, 3H), 2.74 (dd, 1H, J = 17.6, 7.2
Hz), 2.49−2.43 (m, 1H), 2.26 (dd, 1H, J = 17.6, 2.4 Hz), 1.84−1.72
(m, 1H), 1.68 (s, 1.5H), 1.66 (s, 1.5H), 1.56−1.48 (m, 2H), 1.42−1.34
(m, 1H), 0.881 (s, 4.5H), 0.871 (s, 4.5H), 0.04 (s, 1.5H), 0.03 (s,
1.5H), 0.00 (s, 1.5H), −0.01 (s 1.5H); 13C NMR (100 MHz, CDCl3)
δ 207.9, 189.8, 147.3, 147.1, 111.1, 111.0, 103.7, 58.6, 45.3, 45.2, 34.9,
34.6, 33.6, 33.1, 27.2, 25.8, 21.1, 18.2, 17.2, 17.1, −4.8, −5.1; HRMS
(FAB) calcd for C18H33O3Si (M + H)+ 325.2199, found 325.2192.
5-(3-Hydroxy-4-methylpent-4-enyl)-3-methoxycyclopent-2-
enone (9). Pale yellow oil (dr =1:1): IR (neat) ν 3412, 1682 cm−1; 1H
NMR (400 MHz, CDCl3) δ 5.22 (s, 1H), 4.88 (s, 1H), 4.77 (s, 1H),
4.02−3.98 (m, 1H), 3.78 (s, 3H), 2.72 (dd, 1H, J = 18, 7.2 Hz), 2.51−
2.43 (m, 1H), 2.25 (dd, 1H, J = 18, 2.4 Hz), 1.85−1.70 (m, 1H), 1.66
(s, 1.5H), 1.65 (s, 1.5H), 1.59−1.51 (m, 2H), 1.47−1.30 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 208.2, 208.1, 190.4, 190.0, 147.2, 147.0,
111.1, 110.9, 103.6, 103.5, 58.55, 58.53, 44.9, 34.8, 34.6, 32.3, 31.7,
27.6, 27.1, 17.5, 17.4; HRMS (EI) calcd for C12H18O3 (M+) 210.1256,
found 210.1259.
Table 4. Alkylative Quaternization of Enones 24 and 25
6-(3-Hydroxy-4-methylpentyl)-3-methoxycyclohex-2-enone
(24). To a stirred solution of enone 1 (200 mg, 0.89 mmol) in
methanol (5 mL) was added PtO2 (10 mg, 0.0445 mmol). The
mixture was stirred at room temperature under hydrogen atmosphere
for 1 h and then filtered through a pad of Celite. After concentration
under reduced pressure, the residue was purified by flash silica gel
column chromatography (EtOAc/n-hexane 1:1) to give enone 24 (173
mg, 86%, colorless oil) as a mixture of two diastereomers whose ratio
was determined by analyzing the 13C NMR spectrum to be ca. 1:1: IR
(neat) 3445, 1624 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (s, 1H),
3.69 (s, 3H), 3.37−3.31 (m, 1H), 2.46−2.43 (m, 2H), 2.27−2.23 (m,
1H), 2.10−2.04 (m, 1H), 1.94−1.86 (m, 1H), 1.81−1.75 (m, 1H),
1.68−1.63 (m, 1H), 1.55−1.51 (m, 2H), 1.46−1.39 (m, 1H), 0.92 (d,
a
Isolated yields. Yields based on recovered starting enone are given in
b
c
parentheses. RX (5 equiv) and LDA (3 equiv) were used. RX (5
equiv) and LDA (1.5 equiv) were used. 2-Alkylated regioisomer
(10%) was also obtained. See ref 6. Diastereomeric ratio was
determined by H NMR analysis.
d
e
1
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Note
3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 202.0, 201.7, 177.8, 177.7, 101.7, 101.68, 55.6, 44.9, 44.88,
33.6, 33.3, 31.5, 31.1, 27.9, 27.6, 26.5, 26.4, 26.1, 25.5, 18.8, 18.7, 17.3,
17.2; HRMS (FAB) calcd for C13H23O3 (M + H)+ 227.1647, found:
227.1643.
1.92−1.90 (m, 1H), 1.72−1.66 (m, 1H), 1.62 (s, 3H), 1.54−1.47 (m,
1H), 1.40−1.32 (m, 2H), 0.88 (s, 4.5H), 0.87 (s, 4.5H), 0.03 (s, 1.5H),
0.01 (s, 1.5H), −0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.4,
207.3, 189.1, 189.0, 147.1, 146.4, 111.0, 110.5, 103.3, 103.2, 80.2, 80.1,
69.7, 69.6, 58.4, 49.62, 49.57, 38.4, 38.2, 32.0, 31.5, 30.4, 29.8, 26.7,
26.2, 25.51, 25.49, 17.9, 17.0, 16.9, −5.06, −5.14, −5.4; HRMS (EI)
calcd for C21H34O3Si (M+) 362.2277, found 362.2294.
6-(3-(tert-Butyldimethylsilyloxy)-4-methylpentyl)-3-methox-
ycyclohex-2-enone (25). This material was obtained as pale yellow
oil in 65% yield from enone 2 by the same protocol described for
6-(3-(tert-Butyldimethylsilyloxy)-4-methylpent-4-enyl)-3-
1
compound 24: IR (neat) 1661 cm−1; H NMR (300 MHz, CDCl3) δ
methoxy-6-(prop-2-ynyl)cyclohex-2-enone (13). Pale yellow oil:
1
5.29 (s, 1H), 3.64 (s, 3H), 3.43−3.40 (m, 1H), 2.39 (t, 2H, J = 6.0
Hz), 2.17−1.99 (m, 2H), 1.88−1.67 (m, 3H), 1.51−1.27 (m, 3H),
0.85 (s, 9H), 0.80 (d, 6H, J = 6.9 Hz), 0.01 (s, 3H), −0.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.6, 201.5, 177.5, 102.0, 101.95, 55.8,
45.6, 45.5, 32.9, 32.5, 30.9, 30.8, 27.9, 27.8, 26.5, 26.49, 26.1, 25.8,
25.5, 18.7, 18.3, 18.2, 18.0, 17.5, −4.0, −4.1, −4.3, −4.32; HRMS
(FAB) calcd for C19H37O3Si (M + H)+ 341.2512, found 341.2510.
Typical Protocol for α-Quaternization of Enones. (S*)-5-
((S*)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-5-methylcy-
clopent-2-enone (17). To a stirred solution of LDA (1.8 M in
heptane/THF/ethylbenzene; 400 μL, 0.72 mmol) in THF (3 mL) at
−78 °C was added slowly a solution of enone 9 (50 mg, 0.24 mmol) in
THF (2 mL) over a period of 5 min. Then the mixture was stirred at
the same temperature for an additional 30 min. Following dropwise
addition of methyl iodide (75 μL, 1.2 mmol), the whole mixture was
allowed to warm to 0 °C and stirring was continued for further 2 h.
Upon addition of satd NH4Cl, the mixture was transferred to a
separatory funnel where it was extracted with Et2O. The phases were
separated, and the organic phase was washed with brine, dried with
MgSO4, filtered, and concentrated. The residue was purified by flash
silica gel column chromatography (EtOAc/n-hexane 1:2) to yield
enone 17 (30.4 mg, 57%, pale yellow oil) as single diastereomer (dr
>99:1 determined by 1H NMR analysis). Further elution gave
unreacted enone 9 (8 mg, 16% recovered): IR (neat) ν 3393, 1682
cm−1; 1H NMR (500 MHz, CDCl3) δ 5.23 (s, 1H), 4.92 (s, 1H), 4.82
(s, 1H), 3.99 (dd, 1H, J = 6.5, 6.0 Hz), 3.83 (s, 3H), 2.56 (d, 1H, J =
17.5 Hz), 2.34 (d, 1H, J = 17.5 Hz), 1.69 (s, 3H), 1.55−1.51 (m, 2H),
1.46−1.38 (m, 2H), 1.15 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
210.4, 188.7, 147.1, 111.4, 102.8, 75.9, 58.5, 47.1, 41.3, 33.5, 29.7, 24.5,
17.5; HRMS (EI) calcd for C13H20O3 (M+) 224.1413, found 224.1427.
5-(3-(tert-Butyldimethylsilyloxy)-4-methylpent-4-enyl)-3-
methoxy-5-methylcyclopent -2-enone (10). Pale yellow oil: IR
IR (neat) 1653 cm−1; H NMR (300 MHz, CDCl3) δ 5.28 (s, 1H),
4.86 (s, 0.5H), 4.84 (s, 0.5H), 4.74 (brs, 1H), 3.99−3.93 (m, 1H), 3.68
(s, 3H), 2.55−2.34 (m, 4H), 2.09−2.03 (m, 2H), 1.97 (dd, 1H, J = 4.5,
4.5 Hz), 1.74−1.66 (m, 1H), 1.64 (s, 3H), 1.56−1.25 (m, 3H), 0.87 (s,
9H), 0.03 (s, 1.5H), 0.00 (s, 1.5H), −0.02 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 201.6, 176.9, 147.8, 111.11, 111.06, 101.3, 101.2, 97.5,
81.5, 71.0, 70.9, 56.0, 46.04, 46.02, 30.5, 30.4, 30.3, 30.2, 30.1, 26.10,
26.09, 25.90, 25.88, 25.1, 25.0, 18.5, 17.6, −4.4, −4.5, −4.8; HRMS
(EI) calcd for C22H36O3Si (M+) 376.2434, found 376.2434.
5-(2-Bromoallyl)-5-(3-(tert-butyldimethylsilyloxy)-4-methyl-
pent-4-enyl)-3-methoxycyclopent-2-enone (14). Pale yellow oil:
1
IR (neat) 1697 cm−1; H NMR (300 MHz, CDCl3) δ 5.64 (s, 0.5H),
5.62 (s, 0.5H), 5.54−5.52 (m, 1H), 5.29 (s, 1H), 4.85 (s, 1H), 4.78 (t,
0.5H, J = 1.5 Hz), 4.75 (t, 0.5H, J = 1.5 Hz), 3.99−3.92 (m, 1H), 3.87
(s, 3H), 3.06 (d, 0.5H, J = 18.0 Hz), 3.04 (d, 0.5H, J = 18.0 Hz), 2.73
(d, 1H, J = 14.6 Hz), 2.65 (d, 1H, J = 14.6 Hz), 2.47 (d, 0.5H, J = 18.0
Hz), 2.41 (d, 0.5H, J = 18.0 Hz), 1.64 (s, 3H), 1.57−1.47 (m, 1H),
1.43−1.26 (m, 3H), 0. 90 (s, 4.5H), 0.89 (s, 4.5H), 0.04 (s, 1.5H),
0.03 (s, 1.5H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 208.4,
208.1, 189.8, 189.6, 147.5, 146.8, 128.8, 128.7, 121.14, 121.05, 111.1,
110.7, 103.9, 103.8, 58.7, 58.6, 50.53, 50.48, 47.7, 47.1, 38.24, 38.20,
32.9, 32.7, 30.5, 29.9, 25.8, 25.78, 18.1, 17.3, 17.2, −4.8, −4.9, −5.10,
−5.12; HRMS (EI) calcd for C21H35BrO3Si (M+) 442.1539, found
442.1526.
5-Benzyl-5-(3-(tert-butyldimethylsilyloxy)-4-methylpent-4-
enyl)-3-methoxycyclopent−2-enone (15). Pale yellow oil: IR
(neat) 1693 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25−7.10 (m, 5H),
5.15 (s, 0.5H), 5.13 (s, 0.5H), 4.85 (s, 0.5H), 4.84 (s, 0.5H), 4.77 (s,
0.5H), 4.74 (s, 0.5H), 3.99−3.93 (m, 1H), 3.70 (s, 1.5H), 3.68 (s,
1.5H), 3.01 (d, 0.5H, J = 13.2 Hz), 2.97 (d, 0.5H, J = 13.2 Hz), 2.65
(d, 0.5H, J = 13.2 Hz), 2.61 (d, 0.5H, J = 13.2 Hz), 2.58 (d, 0.5H, J =
18.0 Hz), 2.55 (d, 0.5H, J = 18.0 Hz), 2.31 (d, 0.5H, J = 18.0 Hz), 2.27
(d, 0.5H, J = 18.0 Hz), 1.65 (s, 1.5H), 1.64 (s, 1.5H), 1.61−1.50 (m,
1H), 1.49−1.29 (m, 3H), 0.88 (s, 4.5H), 0.86 (s, 4.5H), 0.02 (s, 1.5H),
0.01 (s, 1.5H), 0.00 (s, 1.5H), −0.02 (s, 1.5H); 13C NMR (100 MHz,
CDCl3) δ 209.4, 209.3, 189.3, 189.2, 147.5, 146.9, 137.4, 137.3,
130.18, 130.17, 128.4, 127.99, 127.96, 126.32, 126.28, 111.1, 110.7,
104.22, 104.17, 58.40, 58.36, 51.9, 43.1, 42.4, 37.2, 37.1, 33.5, 33.3,
30.8, 30.3, 25.8, 18.1, 17.2, 17.1, −4.77, −4.84, −5.08, −5.11; HRMS
(EI) calcd for C25H38O3Si (M+) 414.2590, found 414.2611.
6-Benzyl-6-(3-(tert-butyldimethylsilyloxy)-4-methylpent-4-
enyl)-3-methoxycyclohex-2-enone (16). Pale yellow oil: IR (neat)
1627 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.24−7.11 (m, 5H),
5.30(s, 0.5H), 5.28 (s, 0.5H), 4.84 (brs, 1H), 4.74 (brs, 1H), 3.99−
3.95 (m, 1H), 3.65 (s, 1.5H), 3.64 (s, 1.5H), 3.18 (d, 0.5H, J = 13.5
Hz), 3.13 (d, 0.5H, J = 13.5 Hz), 2.60 (d, 0.5H, J = 13.5 Hz), 2.59 (d,
0.5H, J = 13.5 Hz), 2.44−2.30 (m, 2H), 1.78−1.71 (m, 2H), 1.66 (s,
1.5H), 1.64 (s, 1.5H), 1.48−1.25 (m, 3H), 0.87 (s, 4.5H), 0.85 (s,
4.5H), 0.00 (s, 3H), −0.01 (s, 1.5H), −0.02 (s, 1.5H); 13C NMR (100
MHz, CDCl3) 202.5, 202.47, 176.4, 176.3, 147.6, 147.3, 138.2, 137.9,
130.7, 130.6, 127.9, 127.87, 126.2, 126.1, 110.8, 110.6, 101.8, 101.6,
55.6, 55.5, 47.5, 47.4, 40.9, 40.4, 31.5, 31.0, 30.7, 30.3, 28.9, 28.6, 26.3,
25.8, 25.7, 25.6, 18.1, 17.34, 17.28, −4.7, −4.8, −5.1; HRMS (EI) calcd
for C26H40O3Si (M+) 428.2747, found 428.2731.
1
(neat) 1697 cm−1; H NMR (500 MHz, CDCl3) δ 5.14 (s, 1H), 4.76
(brs, 1 H), 4.66 (s, 0.5H), 4.76 (s, 0.5H), 3.91−3.87 (m, 1H), 3.76 (s,
3H), 2.44 (dd, 1H, J = 17.5, 9 Hz), 2.24 (d, 1H, J = 17.5 Hz), 1.56 (s,
1.5H), 1.55 (s, 1.5H), 1.44−1.23 (m, 4H), 1.06 (s, 1.5H), 1.05 (s,
1.5H), 0.81 (s, 4.5H), 0.79 (s, 4.5H), −0.04 (s, 1.5H), −0.06 (s, 1.5H),
−0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210, 188.23, 188.16,
146.9, 146.5, 110.8, 110.5, 102.4, 102.2, 58.1, 46.73, 46.72, 41.2, 41.0,
33.2, 32.8, 30.6, 30.3, 25.5, 25.4, 24.0, 23.5, 17.84, 17.82, 16.8, 16.7,
−5.1, −5.2, −5.42, −5.44; HRMS (EI) calcd for C19H34O3Si (M+)
338.2277, found 338.2263.
6-(3-(tert-Butyldimethylsilyloxy)-4-methylpent-4-enyl)-3-
methoxy-6-methylcyclohex-2-enone (11). Pale yellow oil: IR
(neat) ν 1658 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.22 (s, 1H), 4.82
(s, 0.5H), 4.80 (s, 0.5H), 4.72 (brs, 1H), 3.96−3.93 (m, 1H), 3.63 (s,
3H), 2.45−2.31 (m, 2H), 1.90−1.83 (m, 1H), 1.73−1.67 (m, 1H),
1.62 (s, 1.5H), 1.61 (s, 1.5H), 1.55−1.28 (m, 4H), 1.04 (s, 1.5H), 1.03
(s, 1.5H), 0.0842 (s, 4.5H), 0.0837 (s, 4.5H), 0.00 (s, 1.5H), −0.02 (s,
1.5H), −0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0, 203.9,
176.3, 176.2, 147.3, 147.2, 110.79, 110.76, 100.9, 100.7, 55.5, 42.9,
42.8, 32.5, 32.3, 32.1, 32.0, 30.4, 30.2, 25.7, 22.3, 22.0, 18.12, 18.11,
17.2, 17.1, −4.82, −4.84, −5.13, −5.15; HRMS (EI) calcd for
C20H36O3Si (M+) 352.2434, found 352.2449.
5-(3-(tert-Butyldimethylsilyloxy)-4-methylpent-4-enyl)-3-
(S*)-6-((S*)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-6-
methoxy-5-(prop-2-ynyl)cyclopent-2-enone (12). Pale yellow
methylcyclohex-2-enone (18). Pale yellow oil: IR (neat) 3416,
1
1
oil: IR (neat) 1697 cm−1; H NMR (500 MHz, CDCl3) δ 5.28 (s,
1645 cm−1; H NMR (300 MHz, CD3OD) δ 5.28 (s, 1H), 4.89 (s,
0.5H), 5.27 (s, 0.5H), 4.84 (s, 1H), 4.77 (s, 0.5H), 4.74 (s, 0.5H),
3.98−3.93 (m, 1H), 3.85 (s, 3H), 2.72 (d, 0.5H, J = 17.5 Hz), 2.71 (d,
0.5H, J = 17.5 Hz), 2.47 (d, 0.5H, J = 17.5 Hz), 2.42 (d, 0.5H, J = 17.5
Hz), 2.39 (dd, 1H, J = 16.5, 2.5 Hz), 2.34 (dd, 1H, J = 16.5, 2.5 Hz),
1H), 4.80 (s, 1H), 3.93 (dd, 1H, J = 6.0, 5.7 Hz), 3.72 (s, 3H), 2.47 (t,
2H, J = 6.3 Hz), 2.00−1.91 (m, 1H), 1.77−1.70 (m, 1H), 1.68 (s, 3H),
1.54−1.41 (m, 4H), 1.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
204.9, 177.5, 148.1, 112.1, 102.0, 101.9, 56.5, 43.9, 33.6, 33.5, 33.0,
1205
dx.doi.org/10.1021/jo2022789 | J. Org. Chem. 2012, 77, 1202−1207

The Journal of Organic Chemistry
Note
32.96, 30.4, 30.3, 26.7, 23.6, 18.5; HRMS (EI) calcd for C14H22O3
(M+) 238.1569, found 238.1573.
55.6, 47.6, 41.2, 33.5, 31.5, 28.7, 28.6, 25.7, 18.9, 17.2; HRMS (EI)
calcd for C20H28O3 (M+) 316.2039, found 316.2039.
6-(2-Bromoallyl)-6-(3-(tert-butyldimethylsilyloxy)-4-methyl-
(R*)-5-((S*)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-5-
(prop-2-ynyl)cyclopent-2-enone (19). Pale yellow oil: IR (neat)
3420, 1688 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.29 (s, 1H), 4.93 (s,
1H), 4.84 (s, 1H), 4.00 (t, 1H, J = 6.5 Hz), 3.86 (s, 3H), 2.74 (d, 1H, J
= 18.0 Hz), 2.50 (d, 1H, J = 18.0 Hz), 2.41 (dd, 1H, J = 16.5, 2.5 Hz),
2.37 (dd, 1H, J = 16.5, 2.5 Hz), 1.94 (t, 1H, J = 2.5 Hz), 1.74−1.70 (m,
1H), 1.69 (s, 3H), 1.58−1.55 (m, 1H), 1.45−1.39 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 207.7, 189.6, 147.1, 111.4, 103.6, 80.3, 75.7, 70.1,
58.7, 49.8, 38.5, 32.1, 29.2, 26.9, 17.4; HRMS (EI) calcd for C15H20O3
(M+) 248.1413, found 248.1420.
pentyl)-3-methoxycyclohex-2-enone (27). Pale yellow oil: IR
1
(neat) ν 1653 cm−1; H NMR (300 MHz, CDCl3) δ 5.61 (s, 0.5H),
5.60 (s, 0.5H), 5.54 (brs, 1H), 5.30 (s, 0.5H), 5.29 (s, 0.5H), 3.68 (s,
3H), 3.39−3.32 (m, 1H), 3.13 (d, 0.5H, J = 14.7 Hz), 3.05 (d, 0.5H, J
= 14.7 Hz), 2.59−2.43 (m, 2H), 2.23−2.08 (m, 1H), 2.00−1.89 (m,
1H), 1.71−1.63 (m, 2H), 1.51−1.36 (m, 2H), 1.31−1.19 (m, 2H),
0.87 (s, 9H), 0.82 (d, 6H, J = 6.9 Hz), 0.02 (s, 1.5H), 0.01 (s, 1.5H),
0.007 (s, 1.5H), −0.01 (s, 1.5H); 13C NMR (75 MHz, CDCl3) δ
201.4, 201.3, 176.33, 176.30, 129.4, 129.3, 121.3, 121.2, 101.3, 101.2,
55.64, 55.61, 47.1, 47.0, 45.1, 44.9, 33.1, 32.6, 31.5, 30.6, 29.7, 28.9,
28.8, 26.9, 26.7, 25.91, 25.87, 25.7, 25.6, 18.09, 18.06, 18.04, 17.9, 17.6,
−4.27, −4.30, −4.5; HRMS (FAB) calcd for C22H4079BrO3Si (M +
H)+ 459.1930, found 459.1917.
(S*)-6-((S*)-3-Hydroxy-4-methylpent-4-enyl)-3-methoxy-6-
(prop-2-ynyl)cyclohex-2-enone (20). Pale yellow oil: IR (neat)
1
3302, 1645 cm−1; H NMR (300 MHz, CDCl3) δ 5.29 (s, 1H), 4.93
(brs, 1H), 4.83 (s, 1H), 3.99 (dd, 1H, J = 6.0, 5.7 Hz), 3.69 (s, 3H),
2.55−2.35 (m, 4H), 2.08−2.04 (m, 2H), 2.00 (dd, 1H, J = 2.7, 2.1
Hz), 1.71 (s, 3H), 1.67−1.62 (m, 2H), 1.52−1.37 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 201.3, 176.9, 147.1, 111.3, 101.0, 80.9, 75.8, 70.9,
55.7, 45.7, 29.9, 29.8, 29.1, 25.6, 25.1, 17.5; HRMS (EI) calcd for
C16H22O3 (M+) 262.1569, found 262.1574.
6-Benzyl-6-(3-(tert-butyldimethylsilyloxy)-4-methylpentyl)-
3-methoxycyclohex-2-enone (29). Pale yellow oil: IR (neat) ν
1
1653 cm−1; H NMR (300 MHz, CDCl3) δ 7.28−7.11 (m, 5H), 5.31
(s, 0.5H), 5.28 (s, 0.5H), 3.65 (s, 1.5H), 3.64 (s, 1.5H), 3.40−3.35 (m,
1H), 3.20 (d, 0.5H, J = 13.4 Hz), 3.14 (d, 0.5H, J = 13.4 Hz), 2.60 (d,
0.5H, J = 13.4 Hz), 2.57 (d, 0.5H, J = 13.4 Hz), 2.47−2.24 (m, 2H),
1.83−1.65 (m, 4H), 1.59−1.39 (m, 2H), 1.33−1.19 (m, 1H), 0.86 (s,
4.5H), 0.84 (s, 4.5H), 0.82 (d, 6H, J = 6.9 Hz), 0.01 (s, 1.5H), 0.00 (s,
1.5H), −0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.6, 202.5,
176.3, 138.2, 137.9, 130.7, 130.6, 127.92, 127.90, 126.2, 126.1, 101.8,
101.6, 55.6, 55.5, 47.7, 47.6, 40.8, 40.5, 33.1, 32.6, 31.8, 30.9, 29.7,
28.9, 28.7, 27.1, 26.9, 25.91, 25.87, 25.7, 25.6, 18.1, 18.0, 17.8, 17.6,
−4.28, −4.32, −4.5; HRMS (FAB) calcd for C26H43O3Si (M + H)+
431.2981, found 431.2973.
(S*)-5-(2-Bromoallyl)-5-((S*)-3-hydroxy-4-methylpent-4-
enyl)-3-methoxycyclopent-2-enone (21). Pale yellow oil: IR
1
(neat) 3419, 1683 cm−1; H NMR (500 MHz, CDCl3) δ 5.61 (s,
1H), 5.52 (s, 1H), 5.28 (s, 1H), 4.92 (s, 1H), 4.83 (s, 1H), 3.97 (t, 1H,
J = 6.5 Hz), 3.85 (s, 3H), 3.05 (d, 1H, J = 17.5 Hz), 2.76 (d, 1H, J =
14.5 Hz), 2.69 (d, 1H, J = 14.5 Hz), 2.47 (d, 1H, J = 17.5 Hz), 1.68 (s,
3H), 1.65−1.58 (m, 1H), 1.57−1.50 (m, 1H), 1.43−1.35 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 208.1, 189.8, 171.1, 147.1, 121.3, 111.5,
104.0, 60.4, 47.6, 38.2, 32.9, 29.1, 21.0, 17.5, 14.2; HRMS (EI) calcd
for C15H2179BrO3 (M+) 328.0674, found 328.0669.
(R*)-5-Benzyl-5-((S*)-3-hydroxy-4-methylpent-4-enyl)-3-me-
thoxycyclopent-2-enone (22). Colorless needles: mp 113−114 °C
(EtOAc/n-hexane); IR (neat) ν 3412, 1681 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.17−7.00 (m, 5H), 5.05 (s, 1H), 4.83 (s, 1H), 4.74
(s, 1H), 3.90 (t, 1H, J = 6.5 Hz), 3.58 (s, 3H), 2.92 (d, 1H, J = 13.5
Hz), 2.52 (d, 1H, J = 13.5 Hz), 2.48 (d, 1H, J = 18.0 Hz), 2.24 (d, 1H,
J = 18.0 Hz), 1.60 (s, 3H), 1.57−1.54 (m, 1H), 1.52−1.46 (m, 1H),
1.39−1.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 209.4, 189.5,
147.2, 137.2, 130.2, 128.0, 126.4, 111.4, 104.4, 75.8, 58.4, 51.9, 43.0,
37.0, 33.5, 29.3, 17.4; HRMS (EI) calcd for C19H24O3 (M+) 300.1726,
found 300.1711.
Determination of Stereochemistry of Quaternized Com-
pounds via Acidic Cyclization. Typical Protocol: (2S*,4aS*)-
4a-Methyl-2-(prop-1-en-2-yl)-4,4a,5,6-tetrahydro-2H-chro-
men-7(3H)-one (18a). To a stirred solution of enone 18 (12 mg,
0.05 mmol) in toluene (3 mL) at room temperature was added PPTS
(25 mg, 0.10 mmol). The mixture was heated at 60 °C for 35 h.
Following addition of satd NaHCO3, the mixture was transferred to a
separatory funnel where it was extracted with Et2O. The phases were
separated, and the organic phase was washed with brine, dried with
MgSO4, filtered, and concentrated. The residue was purified by flash
silica gel column chromatography (EtOAc/n-hexane 1:3) to yield
enone 18a (9.9 mg, 95%) as a colorless oil: IR (neat) ν 1655 cm−1; 1H
NMR (400 MHz CDCl3) δ 5.48 (s, 1H), 5.05 (s, 1H), 4.95 (brs, 1H),
4.24 (dd, 1H, J = 11.9, 2.8 Hz), 5.59−5.49 (m, 1H), 2.42−2.36 (m,
1H), 2.13−2.02 (m, 1H), 1.91−1.83 (m, 1H), 1.81 (s, 3H), 1.79−1.70
(m, 4H), 1.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 199.7, 181.7,
143.7, 112.5, 109.5, 83.7, 36.2, 35.7, 33.8, 33.4, 25.3, 22.9, 17.8; HRMS
(EI) calcd for C13H18O2 (M+) 206.1307, found 206.1333.
(S*)-6-Benzyl-6-((S*)-3-hydroxy-4-methylpent-4-enyl)-3-me-
thoxycyclohex-2-enone (23). Pale yellow oil: IR (neat) ν 3420,
1
1645 cm−1; H NMR (300 MHz, CDCl3) δ 7.28−7.11 (m, 5H), 5.32
(s, 1H), 4.93 (s,1H), 4.83 (brs, 1H), 3.99 (dd, 1H, J = 5.1, 4.8 Hz),
3.66 (s, 3H), 3.13 (d, 1H, J = 13.2 Hz), 2.62 (d, 1H, J = 13.2 Hz),
2.46−2.36 (m, 2H), 1.84−1.76 (m, 2H), 1.71 (s, 3H), 1.64−1.45 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 202.5, 176.6, 147.2, 137.6,
130.5, 127.9, 126.2, 111.0, 101.8, 55.5, 47.5, 41.1, 31.1, 29.3, 28.6,
25.62, 25.59, 17.6; HRMS (EI) calcd for C20H26O3 (M+) 314.1882,
found 314.1892.
(2S*,4aS*)-4a-Methyl-2-(prop-1-en-2-yl)-3,4,4a,5-
tetrahydrocyclopenta[b]pyran-6(2H)-one (17a). Colorless amor-
1
phous solid: IR (neat) ν 1637 cm−1; H NMR (300 MHz CDCl3) δ
5.36 (s, 1H), 5.10 (s, 1H), 5.00 (brs, 1H), 4.37 (dd, 1H, J = 12.0, 2.7
Hz), 2.40 (d, 1H, J = 17.4 Hz), 2.34 (d, 1H, J = 17.4 Hz), 2.17−2.06
(m, 1H), 2.03−1.95 (m, 1H), 1.85 (s, 3H), 1.83−1.76 (m, 2H), 1.37
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 204.5, 195.3, 143.2, 113.0,
109.6, 85.8, 51.3, 38.6, 33.3, 26.5, 25.7, 17.7; HRMS (EI) calcd for
C12H16O2 (M+) 192.1150, found 192.1167.
(S*)-6-(2-Bromoallyl)-6-((S*)-3-hydroxy-4-methylpentyl)-3-
methoxycyclohex-2-enone (26). Pale yellow oil: IR (neat) ν 3416,
1
1628 cm−1; H NMR (500 MHz, CDCl3) δ 5.61 (s, 1H), 5.56 (brs,
1H), 5.31 (s, 1H), 3.69 (s, 3H), 3.29−3.25 (m, 1H), 2.99 (d, 1H, J =
14.5 Hz), 2.61 (d, 1H, J = 14.5 Hz), 2.53−2.46 (m, 2H), 2.19−2.10
(m, 1H), 2.00−1.93 (m, 1H), 1.82−1.76 (m, 1H), 1.69−1.61 (m, 2H),
1.54−1.40 (m, 1H), 1.35−1.27 (m, 1H), 0.90 (d, 3H, J = 7.0 Hz), 0.89
(d, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 201.5, 176.7,
128.9, 121.5, 101.4, 55.7, 46.9, 45.4, 33.5, 31.2, 28.8, 28.4, 25.7, 18.9,
17.2; HRMS (FAB) calcd for C16H2679BrO3 (M + H)+ 345.1065,
found 345.1045.
(2S*,4aR*)-2-(Prop-1-en-2-yl)-4a-(prop-2-ynyl)-3,4,4a,5-
tetrahydrocyclopenta[b]pyran-6(2H)-one (19a). Colorless oil: IR
(neat) ν 1697 cm−1; 1H NMR (500 MHz CDCl3) δ 5.45 (s, 1H), 5.10
(s, 1H), 5.00 (s, 1H), 4.38 (dd, 1H, J = 12.0, 2.5 Hz), 2.72 (dd, 1H, J =
17.0, 2.0 Hz), 2.66 (d, 1H, J = 18.0 Hz), 2.39−2.34 (m, 2H), 2.25 (d,
1H, J = 18.0 Hz), 2.08 (t, 1H, J = 2.0 Hz), 2.03−1.94 (m, 1H), 1.84 (s,
3H), 1.82−1.75 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 203.8, 191.9,
142.9, 113.1, 111.2, 85.9, 79.3, 72.0, 48.6, 41.5, 30.5, 27.8, 25.4, 17.8;
HRMS (EI) calcd for C14H16O2 (M+) 216.1150, found 216.1175.
(2S*,4aS*)-2-(Prop-1-en-2-yl)-4a-(prop-2-ynyl)-4,4a,5,6-tet-
rahydro-2H-chromen-7(3H)-one (20a). Colorless amorphous
(S*)-6-Benzyl-6-((S*)-3-hydroxy-4-methylpentyl)-3-methox-
ycyclohex-2-enone (28). Pale yellow oil: IR (neat) ν 3408, 1639
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.26−7.12 (m, 5H), 5.33 (s,
1H), 3.67 (s, 3H), 3.28−3.25 (m, 1H), 3.09 (d, 1H, J = 13.5 Hz), 2.66
(d, 1H, J = 13.5 Hz), 2.48−2.36 (m, 2H), 1.86−1.74 (m, 2H), 1.66−
1.61 (m, 2H), 1.53−1.30 (m, 3H), 0.90 (d, 6H, J = 7.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 202.8, 176.7, 137.7, 130.6, 128.0, 126.3, 101.9,
1
solid: IR (neat) ν 1649 cm−1; H NMR (300 MHz CDCl3) δ 5.53
(s, 1H), 5.05 (s, 1H), 4.96 (s, 1H), 4.27 (dd, 1H, J = 11.7, 3.0 Hz),
2.73 (dt, 1H, J = 17.7, 2.1 Hz), 2.57−2.41 (m, 3H), 2.33 (dt, 1H, J =
1206
dx.doi.org/10.1021/jo2022789 | J. Org. Chem. 2012, 77, 1202−1207

The Journal of Organic Chemistry
Note
13.8, 3.0 Hz), 2.25 (ddd, 1H, J = 13.5, 5.1, 1.8 Hz), 1.80 (s, 3H),
1.78−1.67 (m, 2H), 1.54 (ddt, 1H, J = 13.8, 4.2, 1.5 Hz); 13C NMR
(75 MHz, CDCl3) δ 199.6, 179.8, 143.8, 113.1, 111.0, 84.3, 79.5, 72.4,
36.4, 33.9, 32.5, 31.7, 25.3, 24.0, 18.3; HRMS (EI) calcd for C15H18O2
(M+) 230.1307, found 230.1301.
Sciences of the National Institute of Biomedical Innovation
(NIBIO), and a Grant-in-Aid for Scientific Research on
Innovative Areas [No. 22136006] from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT).
(2S*,4aS*)-4a-(2-Bromoallyl)-2-(prop-1-en-2-yl)-3,4,4a,5-
tetrahydrocyclopenta[b]pyran-6(2H)-one (21a). Colorless amor-
1
phous solid: IR (neat) ν 1686 cm−1; H NMR (500 MHz CDCl3) δ
REFERENCES
■
5.67 (s, 1H), 5.64 (s, 1H), 5.48 (s, 1H), 5.12(s, 1H), 5.01(s, 1H), 4.39
(dd, 1H, J = 12.2, 3.5 Hz), 2.98 (d, 1H, J = 15.5 Hz), 2.94 (d, 1H, J =
17.5 Hz), 2.64 (d, 1H, J = 15.5 Hz), 2.31 (dt, 1H, J = 13.0, 3.0 Hz),
2.25 (d, 1H, J = 17.5 Hz), 2.09−2.00 (m, 1H), 1.86 (s, 3H), 1.83−1.72
(m, 2H)); 13C NMR (125 MHz, CDCl3) δ 203.9, 192.8, 143.0, 127.8,
122.2, 113.1, 112.2, 85.8, 48.4, 46.9, 42.1, 31.0, 25.7, 17.9; HRMS (EI)
calcd for C14H1779BrO2 (M+) 296.0412, found 296.0418.
(1) Selected reviews for the stereoselective construction of the
quaternary carbon center: (a) Das, J. P.; Marek, I. Chem. Commun.
2011, 47, 4593−4623. (b) Shimizu, M. Angew. Chem., Int. Ed. 2011,
50, 5998−6000. (c) Wang, B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44,
1207−1222. (d) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46,
7295−7306. (e) Bella, M.; Gasperi, T. Synthesis 2009, 1583−1614.
(f) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488−
5508. (g) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5,
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Chem. 2007, 36, 5969−5994. (i) Mohr, J. T.; Stoltz, B. M. Chem.
Asian J. 2007, 2, 1476−1491. (j) Quaternary Stereocenters: Challenges
and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Ley,
S. V., Foreword; John Wiley & Sons: New York, 2006. (k) Trost, B.
M.; Jiang, C. Synthesis 2006, 369−396. (l) Christoffers, J.; Baro, A.
Adv. Synth. Catal. 2005, 347, 1473−1482. (m) Peterson, E. A.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943−11948.
(n) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105−10146.
(o) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591−
4597. (p) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388−401.
(2S*,4aR*)-4a-Benzyl-2-(prop-1-en-2-yl)-3,4,4a,5-
tetrahydrocyclopenta[b]pyran-6(2H)-one (22a). Colorless amor-
1
phous solid: IR (neat) ν 1703 cm−1; H NMR (300 MHz, CDCl3) δ
7.30−7.09 (m, 5H), 5.36 (s, 1H), 5.17 (s, 1H), 5.05 (brs, 1H), 4.44
(dd, 1H, J = 12.0, 2.7 Hz), 2.98 (d, 1H, J = 13.5 Hz), 2.91 (d, 1H, J =
13.5 Hz), 2.62 (d, 1H, J = 17.4 Hz), 2.35−2.20 (m, 1H), 2.15−2.09
(m, 1H), 2.11 (d, 1H, J = 17.4 Hz), 1.99 (s, 3H), 1.88−1.75 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 203.8, 192.9, 143.2, 136.2, 130.3, 128.3,
127.0, 113.1, 112.1, 85.9, 47.8, 43.1, 42.4, 32.0, 25.8, 17.9; HRMS (EI)
calcd for C18H20O2 (M+) 268.1463, found 268.1471.
(2S*,4aS*)-4a-Benzyl-2-(prop-1-en-2-yl)-4,4a,5,6-tetrahydro-
2H-chromen-7(3H)-one (23a). Pale yellow amorphous solid: IR
1
(neat) ν 1626 cm−1; H NMR (300 MHz, CDCl3) δ 7.35−7.15 (m,
5H), 5.62 (s, 1H), 5.12 (s, 1H), 5.00 (s, 1H), 4.30 (dd, 1H, J = 12.0,
2.4 Hz), 3.07 (d, 1H, J = 14.1 Hz), 2.96 (d, 1H, J = 14.1 Hz), 2.62−
2.51 (m, 1H), 2.43−2.31 (m, 1H), 2.29−2.17 (m, 1H), 1.94−1.88 (m,
1H), 1.86 (s, 3H), 1.82−1.74 (m, 1H), 1.67- 1.56 (m, 2H), 1.47−1.36
(m, 1H) ; 13C NMR (75 MHz, CDCl3) δ 199.6, 181.4, 143.6, 136.3,
130.2, 128.4, 127.0, 112.5, 111.0, 83.9, 38.8, 37.6, 33.9, 31.9, 31.4, 25.3,
18.0; HRMS (EI) calcd for C19H22O2 (M+) 282.1620, found 282.1619.
(2S*,4aS*)-4a-(2-Bromoallyl)-2-isopropyl-4,4a,5,6-tetrahy-
dro-2H-chromen-7(3H)-one (26a). Colorless amorphous solid: IR
(2) Selected instances of alkylative stereoselective quaternization of
enolates having a chiral auxiliary: (a) Kummer, D. A.; Chain, W. J.;
Morales, M. R.; Quiroga, O.; Myers, A. G. J. Am. Chem. Soc. 2008, 130,
13231−13233. (b) Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem.
Soc. 1984, 106, 1146−1148. (c) Romo, D.; Meyers, A. I. Tetrahedron
1991, 47, 9503−9569. (d) Schultz, A. G.; Sundararaman, P.
Tetrahedron Lett. 1984, 25, 4591−4594. (e) Schultz, A. G.;
Sundararaman, P.; Macielag, M.; Lavieri, F. P.; Welch, M. Tetrahedron
Lett. 1985, 26, 4575−4578. (f) Schultz, A. G.; Macielag, M.;
Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc.
1988, 110, 7828−7841. (g) Abe, T.; Suzuki, T.; Sekiguchi, K.;
Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2003, 44, 9303−9305.
(h) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123,
2091−2092. (i) Manthorpe, J. M.; Gleason, J. L. Angew. Chem., Int. Ed.
2002, 41, 2338−2341. (j) Boeckman, R. K. Jr.; Boehmler, D. J.;
Musselman, R. A. Org. Lett. 2001, 3, 3777−3780.
(3) Yoshimistu, T.; Nojima, S.; Hashimoto, M.; Tanaka, T. Org. Lett.
2011, 13, 3698−3701.
(4) For the pioneering work on the 1,4-chiral induction of δ-hydroxyl
acyclic esters in which a tertiary stereocenter α to the ester carbonyl
group is successfully created by δ-hydroxyl directed alkylation or
aldolization, see: Narasaka, K.; Ukaji, Y.; Watanabe, K. Bull. Chem.
Soc., Jpn. 1987, 60, 1457−1464.
1
(neat) ν 1655 cm−1; H NMR (300 MHz, CDCl3) δ 5.72 (d, 1H, J =
1.8 Hz), 5.66 (d, 1H, J = 1.8 Hz), 5.50 (s, 1H), 3.61 (ddd, 1H, J =
12.0, 6.0, 3.3 Hz), 2.94 (d, 1H, J = 15.3 Hz), 2.77 (d, 1H, J = 15.3 Hz),
2.63−2.51 (m, 1H), 2.43−2.24 (m, 3H), 2.00−1.84 (m, 2H), 1.74−
1.62 (m, 2H), 1.51−1.41 (m, 1H), 1.01 (d, 3H, J = 6.9 Hz), 0.97 (d,
3H, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) δ 199.5, 180.8, 127.2,
122.3, 110.3, 85.8, 42.7, 37.5, 33.8, 32.8, 31.7, 31.0, 22.6, 17.8, 17.7;
HRMS (EI) calcd for C15H2179BrO2 (M+) 312.0752, found 312.0754.
(2S*,4aS*)-4a-Benzyl-2-isopropyl-4,4a,5,6-tetrahydro-2H-
chromen-7(3H)-one (28a). Colorless amorphous solid: IR (neat) ν
1
1657 cm−1; H NMR (400 MHz, CDCl3) δ 7.34−7.15 (m, 5H), 5.56
(s, 1H), 3.60 (ddd, 1H, J = 12.4, 6.0, 3.2 Hz), 3.02 (d, 1H, J = 14.0
Hz), 2.93 (d, 1H, J = 14.0 Hz), 2.59−2.50 (m, 1H), 2.40−2.35 (m,
1H), 2.14−2.03 (m, 1H), 1.99−1.77 (m, 3H), 1.70−1.61 (m, 2H),
1.37−1.29 (m, 1H), 1.05 (d, 3H, J = 6.8 Hz), 1.02 (d, 3H, J = 6.8 Hz) ;
13C NMR (75 MHz, CDCl3) δ 199.7, 182.1, 136.4, 130.2, 128.4, 126.9,
110.3, 85.9, 38.8, 37.8, 33.9, 32.9, 31.9, 31.3, 22.6, 17.9, 17.8; HRMS
(EI) calcd for C19H24O2 (M+) 284.1776, found 284.1778.
(5) For a recent report on the remote 1,4-stereoinduction via tandem
Reformatsky/Claisen condensation, see: Greszler, S. N.; Malinowski,
J. T.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 17393−17395.
1
(6) Copies of H and 13C NMR spectra of the regioisomers are
provided in the Supporting Information.
(7) For determination of stereochemistry of compounds 26 and 28,
see Table 3.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H/13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yoshimit@phs.osaka-u.ac.jp.
ACKNOWLEDGMENTS
■
This work was supported in part by Hoansha Foundation, the
Program for Promotion of Fundamental Sciences in Health
1207
dx.doi.org/10.1021/jo2022789 | J. Org. Chem. 2012, 77, 1202−1207