Synthesis of an enantiocomplementary catalyst of β-isocupreidine (β-ICD) from quinine

Article abstract of DOI:10.1002/adsc.200505138

Compound 20, a pseudoenantiomer of β-isocupreidine (β-ICD), was synthesized from quinine employing a Barton reaction of nitrosyl ester 13 and acid-catalyzed cyclization of carbinol 18 as key steps. The Baylis-Hillman reaction of benzaldehyde, p-nitrobenza

Full text of DOI:10.1002/adsc.200505138

FULL PAPERS
DOI: 10.1002/adsc.200505138
Synthesis of an Enantiocomplementary Catalyst of
b-Isocupreidine (b-ICD) from Quinine
Ayako Nakano, Mina Ushiyama, Yoshiharu Iwabuchi, Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
Fax: þ81-95-819-2426, e-mail: susumi@net.nagasaki-u.ac.jp
Received: April 2, 2005; Accepted: June 6, 2005; Published online: September 26, 2005
Abstract: Compound 20, a pseudoenantiomer of b- purity (>91% ee) in contrast to the b-ICD-catalyzed
isocupreidine (b-ICD), was synthesized from quinine reaction which affords R-enriched adducts. This result
employinga Barton reaction of nitrosyl ester 13 and suggests that compound 20 can serve as an enantio-
acid-catalyzed cyclization of carbinol 18 as key steps. complementary catalyst of b-ICD in the asymmetric
The Baylis–Hillman reaction of benzaldehyde, p-ni- Baylis–Hillman reaction of aldehydes with HFIPA.
trobenzaldehyde, and hydrocinnamaldehyde with
1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) us-
ing 20 as a chiral amine catalyst was found to give Keywords: asymmetric catalysis; Baylis–Hillman reac-
the corresponding S-enriched adducts in high optical tion; b-isocupreidine; organic catalysis; quinine
Introduction
(Scheme 2).[4] This transformation suggests that if car-
bocation 5 is accessible from quinine, a pseudoenan-
The Baylis–Hillman reaction has attracted considerable tiomer of quinidine, then the synthesis of 6, a pseudo-
interest due to the fascinatingtandem Michael-aldol se-
quence catalyzed by a Lewis base and the promisingutil-
enantiomer of b-ICD, would also become possible.
Thus, we envisaged ketone 4 as a precursor of carboca-
ity of the multifunctional products. Recent literature tion 5 and postulated that this intermediate could be ac-
continues to record impressive progress in rate acceler- cessed via a Barton reaction[8,9] of nitrosyl ester 3, acces-
ation as well as asymmetric induction based on imagina- sible from quinine via a suitable functionalization of the
tive ideas.[1] Recently, we have developed a highly enan- C-3 vinyl group involving epimerization of the stereo-
tioselective asymmetric Baylis–Hillman reaction of al- center (Scheme 1).
dehydes[2] as well as imines[3] by use of b-isocupreidine
(b-ICD)[4,5] as a chiral Lewis base catalyst and
1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) as an
activated alkene. In addition, we have successfully dem-
onstrated the synthetic utility of this reaction via synthe-
ses of biologically intriguing natural products.[6] This b-
ICD-HFIPA method has remarkable advantages in
terms of the high enantioselectivity, the broad applica-
bility, and the availability of both b-ICD and HFIPA.
However, one serious drawback is that this method can-
not be applied to the synthesis of the products with the
opposite absolute configuration because the required
enantiomer of b-ICD is not easily available.[7] As one
solution to this problem, we investigated the synthesis
of an enantiocomplementary catalyst of b-ICD.
b-ICD can be prepared in one step from quinidine by
treatment with aqueous KBr-H3PO4 at 1008C.[2] In this
process, together with demethylation, acid-induced cy-
cloisomerization of quinidine takes place via carboca-
tions 1 and 2 as reported by Hoffmann et al. Scheme 1. The b-ICD-HFIPA method.
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Enantiocomplementary Catalyst of b-Isocupreidine (b-ICD)
FULL PAPERS
Results and Discussion
Scheme 4 illustrates the synthetic route to compound 20
which has the enantiomeric skeleton of b-ICD. RhCl3-
catalyzed isomerization[10] of quinine followed by pro-
tection of the C-9 hydroxy group as its tert-butyldime-
thylsilyl ether gave 8 as a 3:1 Z/E-isomeric mixture in
77% yield. Without separation, hydroboration of 8
with thexylborane followed by oxidation of the resulting
alkylboranes with trimethylamine N-oxide[11] afforded 9
as a 6:3:2:1 mixture of four diastereomers in 91% yield.
Swern oxidation of 9 followed by treatment with K2CO3
in methanol afforded a 1:1 mixture of methyl ketones 10
and 11. After separation, the undesired isomer 10 was
subjected to a recyclingsequence involvingthe above-
mentioned epimerization and separation. After repeat-
ingthis sequence four times, methyl ketone 11 was ob-
tained in 85% total yield from 9. Gratifyingly, it was
found that, upon treatment of 11 with NaBH4 in metha-
nol at 08C, reduction occurred with almost perfect dia-
stereoselectivity to give alcohol 12 in 85% yield. For
the subsequent Barton reaction, 12 was subjected to ni-
trosylation[12] usingnitrosyl chloride in the presence of
finely ground K2CO3 in CH2Cl2 to give nitrate 13 almost
quantitatively. Upon irradiation of 13 in benzene-tol-
uene usinga medium-pressure mercury lamp [9] and ace-
tylation of the photo-products, oxime acetate 14 was ob-
tained in 35% yield. Hydrolysis[13] of 14 with TiCl3 in
aqueous acetone followed by deacetylation with
K2CO3 in methanol furnished ketone 15 in 90% yield.
To remove the hydroxy group used for the nitrosyl trans-
Scheme 2. Cycloisomerization of quinidine leadingto b-ICD.
À
fer process, 15 was subjected to a Barton McCombie
procedure[14] via 16 to give ketone 17 in 87% yield. After
Grignard reaction of 17 with methylmagnesium bro-
mide, the resultingcarbinol 18 was directly exposed to
Scheme 3. Strategy for the synthesis of a pseudoenantiomer
of b-ICD from quinine.
Table 1. Baylis-Hillman reactions of aldehydes with HFIPA using b-ICD and 20.
Entry
R
Time [h]
Catalyst
Yield [%]:[a] config. [% ee][b]
22
23
1
2
3
4
5
6
Ph
24
1.5
15
48
1.5
15
20
20
20
b-ICD
b-ICD
b-ICD
69: S (91)
53: S (91)
54: S (98)
75: R (97)
57: R (95)
40: R (98)
0
p-NO2C6H4
Ph(CH2)2
Ph
p-NO2C6H4
Ph(CH2)2
14: S (33)
14: R (45)
0
17: R (49)
22: S (3)
[a]
Isolated yield.
[b]
Determined by HPLC analysis usinga chiral column of the correspondingmethyl ester obtained by methanolysis.
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Scheme 4. Reagents and Conditions: (a) RhCl3 ·3 H2O (3 mol %), H2SO4, EtOH, reflux (95%); (b) TBSCl, imidazole, DMF,
1008C (81%); (c) (i) thexylborane, THF, 08C, (ii) Me3N(O), diglyme, reflux (91%); (d) (i) DMSO, (COCl)2, Et3N, CH2Cl2,
À788C to room temperature, (ii) K2CO3, MeOH, reflux, (iii) separation; (e) (i) K2CO3, MeOH, reflux, (ii) separation (85%
from 8 after 4 cycles); (f) NaBH4, MeOH, 08C (85%); (g) NOCl, K2CO3, CH2Cl2, 08C; (h) (i) hn, benzene-toluene (3:1),
48C; (ii) Ac2O, pyridine, 08C (35% from 11); (i) (1) aqueous TiCl3, acetone, (2) K2CO3, MeOH, (90%); (j) 1,1-thiocarbonyl-
diimidazole,THF, reflux; (k) Bu3SnH, cat AIBN, toluene, reflux, (87%, from 13); (l) MeMgBr, THF, 08C (86%); (m) KBr, 85%
H3PO4, 1008C, 10 days (19:20¼3:2, 54%); (n) KBr, 85% H3PO4, 1008C, 3 days (19:20¼3:2, 72%).
the conditions employed for the synthesis of b-ICD from Conclusion
quinidine. Thus, treatment of 18 with aqueous KBr-
H3PO4 at 1008C for 10 days afforded a 3:2mixture of un- We have synthesized chiral amine 20 startingfrom qui-
cyclized enamine 19 and the desired compound 20 in nine and proved that it behaves as an enantiocomple-
54% yield. After chromatographic separation, enamine mentary catalyst to b-ICD in the asymmetric Baylis–
19 was treated again with aqueous KBr-H3PO4 at 1008C Hillman reaction of aldehydes with HFIPA. Efforts to-
for 3 days to give a 3:2 mixture of 19 and 20 in 72% yield. ward improvingthe synthetic route are now underway
As a result, compound 20 was obtained in 31% yield in this laboratory.
from 17. In this particular case, the preferential produc-
tion of 19 rather than 20 can be explained by the difficul-
ty of cyclization of carbocation 21, possibly due to severe
steric hindrance between the C-3 ethyl and the C-5
Experimental Section
methyl groups. In fact, the cyclization of carbocation 2
General Remarks
havingno substituent at the C-3 position proceeded
rather smoothly to produce b-ICD in higher yield
(61%).[2]
Where appropriate, reactions were performed in flame-dried
glassware under an argon atmosphere. All extracts were dried
In order to evaluate the ability of 20 as a chiral amine over K2CO3 and concentrated by rotary evaporation below
308C at ca. 25 Torr unless otherwise noted. Analytical and
preparative thin-layer chromatography were performed with
Merck F-254 TLC plates. Column chromatography was per-
formed employingsilica gel 60 (230–400 mesh ASTM, Merck).
1,1,1,3,3,3-Hexafluoroisopropyl acrylate (HFIPA) was pur-
chased from Tokyo Chemical Industry (Tokyo Kasei) Co.
Ltd. and used without purification. b-Isocupreidine (b-ICD)
was prepared accordingto the procedure we had established
earlier.[2] Commercial reagents and solvents were used as sup-
plied with the followingexceptions. Anhydrous tetrahydrofur-
an (THF) (stabilizer free) and diethyl ether (Et2O) were pur-
catalyst complementary to b-ICD, we examined the
Baylis–Hillman reaction of benzaldehyde, p-nitroben-
zaldehyde, and hydrocinnamaldehyde with HFIPA us-
ing 20 as a catalyst (Table 1). As a result, it was found
that compound 20 catalyzed the Baylis–Hillman reac-
tion as effectively as b-ICD and resulted in opposite
enantioselectivity. This result suggests that the C-3 and
C-5 substituents on the quinuclidine ringexert little ef-
fect on the catalytic ability.
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Enantiocomplementary Catalyst of b-Isocupreidine (b-ICD)
FULL PAPERS
chased from Kanto Chemical Co., Inc. Dichloromethane
(CH2Cl2), triethylamine, dimethyl sulfoxide (DMSO), and
N,N-dimethyformamide (DMF) were distilled from CaH2.
Benzene and toluene were distilled from P2O5. Infrared spectra
were measured on a JASCO FT/IR-230 spectrometer. Optical
rotations were recorded on a JASCO DIP-370 polarimeter at
ambient temperature. 1H and 13C NMR spectra were measured
on a Varian Gemini 300 or a Varian Unity plus 500 spectrome-
ter. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS) in d units and cou-
plingconstants are igven in Hertz. TMS was defined as
0.2H), 3.96, 3.94, 3.88 (3 s,3H), 3.90–3.00 (m, 3.2H), 3.00–
2.54 (m, 2H), 2.33 (br s, 0.8H), 2.10 (br t, J¼8.4 Hz, 0.8H),
1.85–1.50 (m, 2.2H), 1.45 (d, J¼6.9 Hz, 0.7H), 1.32 (d, J¼
6.9 Hz, 2.3H), 1.35–1.18 (m, 1H), 0.96 (s, 6H), 0.89 (s, 1H),
0.87 (s, 2H), 0.16 (s, 2H), 0.02, À0.06 (2 s, 1H), À0.38 (s,
2H), À0.47 (s, 1H); 13C NMR (75 MHz, CDCl3): d¼157.9,
147.6, 147.0, 145.3, 144.2, 141.5, 121.5, 118.5, 100.4, 72.0, 61.8,
56.6, 55.7, 43.6, 33.2, 27.6, 27.0, 22.9, 12.2, À4.4, À5.3; FT-IR
(neat); n¼1619, 1257, 1240 cmÀ1; HR-MS (EI): calcd. for
C26H38O2N2Si (Mþ): 438.2703; found: 438.2696.
1
0 ppm for H NMR spectra and the center of the triplet of
CDCl3 was defined as 77.10 ppm for 13C NMR spectra. HR-
MS (EI) spectra were measured on a JEOL JMS-DX303 or a
(8S,9R)-9-(tert-Butyldimethylsilyloxy)-10,11-dihydro-
10-hydroxy-6’-methoxycinchonane (9) (6:3:2:1
Diastereoisomeric Mixture)
1
JEOL JMS-700N. Note that H NMR and 13C NMR spectra
of all compounds except for 7 and 20 were complex because ro-
tational isomers at the C-9 center were present.
To a stirred solution of 8 (13.91 g, 31.7 mmol) in THF (40 mL)
at À408C was added dropwise thexylborane-THF, freshly pre-
pared from BH3 (1 M in THF, 220 mL, 220 mmol) and 2,3-di-
methyl-2-butene (26.4 mL, 269 mmol). After beingstirred at
08C for 16 h, the mixture was concentrated. The residue was
dissolved in diglyme (168 mL) and trimethylamine N-oxide
(70.9 g, 945 mmol) was added. After being refluxed for 14 h,
the reaction mixture was concentrated, extracted with
CHCl3, washed with 10% K2CO3 and brine, dried, and concen-
trated. Purification of the residue by column chromatography
on silica gel (CHCl3/MeOH¼10/1) gave 9, a white amorphous
solid, as a 6:3:2:1 mixture of four diastereomers; yield: 13.20 g
(91%).
(8S,9R)-3-Ethylidene-6’-methoxyrubane (7) (3:1 Z/E-
Mixture)
To a solution of quinine (5.56 g, 17.1 mmol) in EtOH (110 mL)
was added concentrated H2SO4 (1.83 mL) and the mixture was
stirred for 10 min at room temperature. RhCl3 ·3 H2O (136 mg,
0.517 mmol) was added and the mixture was refluxed for 2 h.
After evaporation of the EtOH, the reaction mixture was dilut-
ed with CHCl3, basified with 10% K2CO3, washed with brine,
dried, and concentrated. Purification of the residue by column
chromatography on silica gel (CHCl3/MeOH¼20/1) gave 7, a
white amorphous solid, as a 3:1 Z/E-mixture; yield: 5.30 g
1
(95%). H NMR (300 MHz, CDCl3): d¼8.53 (d, J¼4.3 Hz,
(3S,8S,9R)-9-(tert-Butyldimethylsilyloxy)-10,11-
dihydro-6’-methoxycinchonan-10-one (11)
1H), 7.88 (d¼9.3 Hz,1H), 7.49 (d, J¼4.3 Hz, 1H), 7.24 (dd,
J¼2.7, 9.6 Hz, 1H), 7.18 (d, J¼2.4 Hz, 0.7H), 7.15 (d, J¼
2.4 Hz, 0.3H), 5.71 (br s, 1H), 5.52–5.04 (m, 2H), 3.83 (s, 3H),
3.78–3.61 (m, 1H), 3.54–3.32 (m, 2H), 3.10 (br t, J¼7.5 Hz,
1H), 2.84–2.66 (m, 1H), 2.33 (br s, 1H), 1.97 (br dd, J¼9.0,
12.0 Hz, 1H), 1.85–1.77 (m, 1H), 1.65–1.24 (m, 2H), 1.53 (d,
J¼6.9 Hz, 0.8H), 1.41 (d, J¼6.9 Hz, 2.2H); 13C NMR
(75 MHz, CDCl3): d¼157.4, 148.1, 147.2, 143.8, 139.7, 131.1,
126.4, 121.4, 118.5, 118.4, 115.1, 101.4, 70.9, 60.8, 58.8, 56.5,
55.7, 44.0, 33.2, 27.5, 12.4; FT-IR (neat): n¼3162, 1621, 1509,
1241, 1228, 1029 cmÀ1; HR-MS (EI): calcd. for C20H24O2N2
(Mþ): 324.1838; found: 324.1833.
Toa solution of oxalylchloride(8.26 mL, 86.9 mmol) in CH2Cl2
(160 mL) was added DMSO (12.3 mL, 180 mmol) at À788C.
After stirringfor 30 min at À788C, a solution of 9 (13.18 g,
28.86 mmol) in CH2Cl2 (40 mL) was added, and stirringwas
continued at À788C for 1 h. The reaction mixture was treated
with triethylamine (36.4 mL, 261 mmol) and allowed to warm
to room temperature, and stirred for 1 h. The reaction mixture
was diluted with CHCl3, washed with saturated NaHCO3 and
brine, dried, and concentrated to give a 1:1 mixture of 3a-iso-
mer 10 and 3b-isomer 11 as a yellow oil; yield: 15.2 g. To a sol-
ution of this mixture (15.2 g) in MeOH (200 mL) was added
K2CO3 (4.0 g, 28.9 mmol) and the mixture was refluxed for
1 h. After evaporation of the MeOH, the residue was extracted
with CHCl3, washed with 10% K2CO3, dried, and concentrated.
Purification of the residue by column chromatography on silica
gel (t-BuOMe/MeOH¼50/1) gave 10 (yield: 4.54 g) and 11
(yield: 3.76 g). This epimerization-separation sequence was re-
peated four times to afford additional 11 (yield: 7.34 g).
(8S,9R)-9-(tert-Butyldimethylsilyloxy)-3-ethylidene-6’-
methoxyrubane (8) (3:1 Z/E-Mixture)
To a solution of 7 (1.07 g, 3.30 mmol) in DMF (5 mL) was add-
ed imidazole (450 mg, 6.62 mmol) and tert-butyldimethylsilyl
chloride (745 mg, 4.98 mmol) and the mixture was the heated
at 1008C for 3 h. The reaction mixture was diluted with Et2O,
washed with water and brine, dried, and concentrated. Purifi-
cation of the residue by column chromatography on silica gel
(CHCl3/MeOH¼20/1) gave 8, a yellow oil, as a 3:1 Z/E-mix-
ture; yield: 1.17 g(81%). 1H NMR (300 MHz, CDCl3): d¼
8.71 (d, J¼4.8 Hz, 0.8H), 8.64 (d, J¼3.9 Hz, 0.2H), 7.99 (d,
J¼9.0 Hz, 0.8H), 7.97 (d, J¼7.8 Hz, 0.2H), 7.84 (d, J¼
2.4 Hz, 0.2H), 7.49 (d, J¼4.8 Hz, 0.8H), 7.35 (dd, J¼2.4,
9.0 Hz, 0.8H), 7.30–7.22 (m, 1H). 7.12 (d, J¼4.8 Hz, 0.2H),
5.76 (br s, 0.8H), 5.21–5.00 (m , 1H), 4.84 (d, J¼9.3 Hz,
Compound 11 (11.10 g, 85% total yield) was obtained as a
1
white amorphous solid: [a]2D6: À151.58 (c 0.13, CHCl3); H
NMR (300 MHz, CDCl3): d¼8.75 (d, J¼4.8 Hz, 0.8H), 8.65
(d, J¼3.9 Hz, 0.2H), 8.04 (d, J¼9.3 Hz, 1H), 7.86 (d, J¼
3.0 Hz, 0.2H), 7.54 (d, J¼4.5 Hz, 0.8H), 7.38 (dd, J¼2.7,
9.3 Hz, 1H), 7.17 (d, J¼2.1 Hz, 0.8H), 7.10 (d, J¼4.5 Hz,
0.2H), 5.63 (br s, 0.8H), 4.82 (d, J¼9.6 Hz , 0.2H), 3.95 (s,
2.4H), 3.92 (s, 0.6H), 3.41 (m, 1H), 3.22 (dd, J¼7.5, 13.5 Hz,
0.8H), 3.06–2.81 (m, 2H), 2.80–2.68 (m, 0.8H), 2.61 (br s,
0.8H), 2.49 (br t, J¼8.7 Hz, 0.8H), 2.30–2.18 (m, 0.1H), 2.08
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Ayako Nakano et al.
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(s, 3H), 2.05–1.98 (m, 1H), 1.80–1.18 (m, 3.7H), 0.98 (s, 7.2H),
0.85 (s, 1.8H), 0.14 (s, 2.4H), 0.10 (s, 0.6H), À0.34 (s, 2.4H),
À0.44 (s, 0.6H); 13C NMR (75 MHz, CDCl3): d¼158.1, 147.5,
144.4, 132.0, 126.2, 121.7, 121.3, 118.7, 108.2, 100.6, 72.7, 77.3,
61.2, 55.9, 51.8, 49.0, 43.6, 29.3, 25.8, 22.3, 18.2, À4.2, À5.1;
FT-IR (neat): n¼1705, 1622, 1508, 1466, 1362, 1250, 1119,
1038, cmÀ1; HRMS (EI): calcd. for C26H38O3N2Si (Mþ):
454.2652; found: 454.2652.
a yellow oil; yield: 385 mg(35%); [ a]2D1: À101.58 (c 0.83,
1
CHCl3); H NMR (300 MHz, CDCl3): d¼8.74 (d, J¼4.5 Hz,
0.8H), 8.67 (d, J¼4.5 Hz, 0.2H), 8.06 (d, J¼9.3 Hz, 0.8H),
8.02 (d, J¼9.3 Hz, 0.2H), 7.82 (d, J¼2.8 Hz, 0.2H), 7.44 (d,
J¼4.5 Hz, 1H), 7.40 (dd, J¼2.8, 9.3 Hz, 1H), 7.15 (br s,
0.8H), 7.10 (d, J¼4.5 Hz, 0.2H), 5.73 (br s, 0.8H), 4.72 (d, J¼
9.2 Hz, 0.2H), 4.60–4.45 (m, 1H), 4.34 (d, J¼19.2 Hz, 0.8H),
4.08 (m, 0.2H), 3.99 (s, 2.4H), 3.91 (s, 0.6H), 3.76 (d, J¼
19.2 Hz, 0.2H), 3.51 (d, J¼19.2 Hz, 0.8H), 3.33 (d, J¼
19.2 Hz, 0.2H), 3.20–2.91 (m, 2.6H), 2.30 (br dt, J¼2.3,
12.9 Hz, 2H), 2.12, 2.08, 1.98 (3 s, 6H), 1.95–1.85 (m, 1H),
1.49–1.37 (m, 1H), 1.12 (d, J¼6.3 Hz, 3H), 0.93 (s, 9H),
À0.02 (s, 2.4H), À0.06 (s, 0.6H), À0.37 (s, 2.4H), À0.46 (s,
0.6H); 13C NMR (75 MHz, CDCl3): d¼169.9, 169.7, 168.1,
157.9, 147.1, 146.3, 144.0, 131.8, 125.5, 121.4, 118.3, 100.2,
71.8, 59.2, 55.5, 54.1, 49.1, 40.7, 31.6, 25.6, 24.3, 20.8, 17.9,
(3S,8S,9R,10S)-9-(tert-Butyldimethylsilyloxy)-10,11-
dihydro-6’-methoxycinchonan-10-ol (12)
To a solution of 11 (11.1 g, 24.4 mmol) in MeOH (200 mL) was
added NaBH4 (4.61 g, 121.9 mmol) at À788C and the mixture
was stirred at À788C for 16 h. After evaporation of the
MeOH, the residue was extracted with CHCl3, washed with
10% K2CO3 and brine, dried, and concentrated. Purification
of the residue by column chromatography on silica gel
(CHCl3/MeOH¼10/1) gave 12 as a yellow oil; yield: 9.49 g
17.7, À4.38, À5.40; FT-IR (neat): n¼1619, 1508, 1241 cmÀ1
;
HRMS (EI): calcd. for C29H40O6N3Si [(MÀCH3)þ]: 554.2686;
found: 554.2677.
1
(85%); [a]2D1: À148.38 (c 1.00, CHCl3); H NMR (300 MHz,
CDCl3): d¼8.71 (d, J¼4.8 Hz, 0.8H), 8.61 (d, J¼4.5 Hz,
0.2H), 8.00 (d, J¼9.3 Hz, 0.8H), 7.97 (d, J¼9.3 Hz, 0.2H),
7.86 (d, J¼2.4 Hz, 0.2H), 7.52 (d, J¼4.8 Hz, 0.8H), 7.35 (dd,
J¼2.7, 9.9 Hz, 0.8H), 7.08 (d, J¼4.5 Hz, 0.2H), 5.64 (br s,
0.8H), 4.80 (d, J¼9.3 Hz, 0.2H), 3.95 (br s, 2.4H), 3.84 (br s,
0.6H), 3.75–3.23 (m, 2H), 2.90 (br s, 1.6H), 2.60–1.90 (m,
5.4H), 1.65 (br t, J¼9.8 Hz, 1H), 1.35–1.45 (m, 1.6H), 1.23–
0.60 (m, 2.4H), 1.06 (t, J¼6.9 Hz, 2.4H), 1.03 (t, J¼6.9 Hz,
0.6H), 0.96 (s, 7.2H), 0.82 (s, 1.8H), 0.14 (s, 2.4H), 0.09 (s,
0.6H), À0.37 (s, 2.4H), À0.45 (s, 0.6H); 13C NMR (75 MHz,
CDCl3): d¼158.0, 147.4, 146.9, 144.0, 131.5, 126.2, 121.7,
118.7, 100.7, 72.3, 67.6, 60.7, 60.5, 55.9, 54.8, 53.9, 43.9, 43.4,
32.9, 25.9, 22.8, 21.8, 21.3, À4.3, À5.2; FT-IR (neat): n¼
3160, 1621, 1509, 1257, 1242 cmÀ1; HR-MS (EI): calcd. for
C26H40O3N2Si (Mþ): 456.2808; found: 456.2814.
(3S,8S,9R,10S)-9-(tert-Butyldimethylsilyloxy)-10,11-
dihydro-10-hydroxy-6’-methoxycinchonan-5-one (15)
To a solution of 14 (933 mg, 1.64 mmol) in acetone (30 mL) was
added aqueous TiCl3 (1.3 M, 2.91 mL, 3.78 mmol) at room tem-
perature and the mixture was stirred for 3 h. After the reaction
was quenched with 10% K2CO3, the reaction mixture was stir-
red until it became a white suspension and filtered through a
pad of Celite. The filtrate was extracted with CH2Cl2, washed
with brine, dried, and concentrated. The residue was dissolved
in MeOH (20 mL) and K2CO3 (500 mg, 3.62 mmol) was added.
After beingstirred at room temperature for 6 h, most of the
MeOH was removed under vacuum and the residue was ex-
tracted with CHCl3. The extract was washed with water and
brine, dried, and concentrated. Purification of the residue by
column chromatography on silica gel (CHCl3/MeOH¼50/1)
gave 15; yield: 697 mg(90%); [ a]2D1: À103.58 (c 1.11, CHCl3);
1H NMR (300 MHz, CDCl3): d¼8.74 (d, J¼4.5 Hz, 0.8H),
8.67 (d, J¼4.5 Hz, 0.2H), 8.06 (d, J¼9.2 Hz, 0.8H), 8.00 (d,
J¼9.2 Hz, 0.2H), 7.55 (d, J¼9.2 Hz, 0.2H), 7.48 (d, J¼
4.5 Hz, 0.8H), 7.40 (dd, J¼2.7, 9.2 Hz, 1H), 7.16 (br s, 0.8H),
7.08 (br s, 0.2H), 5.70 (br s, 0.8H), 4.72 (d, J¼9.5 Hz, 0.2H),
4.20–3.88 (m, 1H), 3.96 (s, 2.4H), 3.93 (s, 0.6H), 3.52–3.36
(m, 1H), 3.21–1.86 (m, 8H), 1.58 (ddd, J¼4.2, 8.4, 12.0 Hz,
0.8H), 1.52–1.41 (m, 0.2H), 1.19 (br d, J¼3.3 Hz, 0.6H), 1.11
(d, J¼6.3 Hz, 2.4H), 0.99 (s, 1.8H), 0.93 (s, 7.2H), 0.13 (s,
2.4H), 0.05 (s, 0.6H), À0.34 (s, 2.4H), À0.47 (s, 0.6H); 13C
NMR (75 MHz, CDCl3): d¼219.9, 158.1, 147.4, 144.2, 132.0,
125.9, 121.5, 118.5, 100.5, 79.1, 72.3, 68.9, 59.5, 55.5, 55.0, 45.8,
42.0, 25.9, 24.3, 21.2, 18.0, À4.32, À5.11; FT-IR (neat): n¼
3343, 2931, 2857, 1729, 1621, 1508, 1257 cmÀ1; HR-MS (EI):
calcd. for C26H38O4N2Si (Mþ): 470.2601; found: 470.2611.
(3S,8S,9R,10S)-10-Acetoxy-9-(tert-
butyldimethylsilyloxy)-10,11-dihydro-6’-
methoxycinchonan-5-one Oxime Acetate (14)
Nitrosyl chloride was freshly generated by adding dropwise
33% aqueous NaNO2 (24 mL) to concentrated HCl (32 mL)
at 08C and introduced to a mixture of 12 (3.29 g, 7.20 mmol)
and K2CO3 (50.0 g, 362 mmol) in CH2Cl2 (350 mL) at 08C
over 3 h. The organic layer was separated, washed with water
and brine, dried, and concentrated to afford crude 13 (3.16 g)
as a yellow oil which was used for the next reaction without pu-
rification.
Crude nitrate 13 (3.16 g) was dissolved in benzene (240 mL)
and toluene (80 mL) and argon was introduced into the solu-
tion for 10 min. This mixture was then irradiated usinga
high-pressure mercury lamp at 28C for 3 h. The reaction mix-
ture was diluted with AcOEt, washed with 10% K2CO3 and
brine, dried, and concentrated to give crude oxime (1.74 g).
To a solution of the oxime in pyridine (20 mL) was added acetic
anhydride (6 mL, 63.5 mmol) at 08C and the mixture was stir-
red for 12 h. After removal of the pyridine, the residue was ex-
tracted with CH2Cl2, washed with 10% Na2CO3 and brine,
dried, and concentrated. Purification of the residue by column
chromatography on silica gel (CHCl3/MeOH¼50/1) gave 14 as
(3S,8S,9R)-9-tert-Butyldimetylsilyloxy-10,11-dihydro-
6’-methoxycinconan-5-one (17)
To a solution of 15 (697 mg, 1.48 mmol) in THF (60 mL) was
added N,N-thiocarbonyldiimidazole (1.63 g, 8.89 mmol) at
room temperature and the mixture was refluxed for 42 h. The
reaction mixture was diluted with CH2Cl2, washed with 10%
1794
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Adv. Synth. Catal. 2005, 347, 1790 – 1796

Enantiocomplementary Catalyst of b-Isocupreidine (b-ICD)
FULL PAPERS
Na2CO3 and brine, dried, and concentrated to give crude thio-
carbamate 16 (1.50 g).
8.0 mg, 27%). As a result, the total yield of 20 from 17 is calcu-
lated to be 31%. Compound 20 is a colorless powder; [a]1D7:
À21.48 (c 0.140, CHCl3); H NMR (300 MHz, CDCl3): d¼
1
To a solution of crude 16 (1.50 g) in toluene (120 mL) were
added 2,2-azobisisobutyronitrile (36.5 mg, 0.222 mmol) and
tributyltin hydride (1.23 mL, 4.44 mmol). After beingrefluxed
for 30 min, the reaction mixture was diluted with AcOEt,
washed with saturated KF, 10% K2CO3, and brine, dried, and
concentrated. Purification of the residue by column chroma-
tography on silica gel (CHCl3/MeOH¼100/1) gave 17 as a
white amorphous solid; yield: 590 mg(87%); [ a]2D1: À147.28
(c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3): d¼8.74 (d, J¼
4.4 Hz, 0.8H), 8.67 (d, J¼3.9 Hz, 0.2H), 8.05 (d, J¼9.1 Hz,
0.8H), 7.86 (brs, 0.2H), 7.47 (d, J¼4.4 Hz, 1H), 7.40 (dd, J¼
2.4, 9.1, 1H), 7.25 (brs, 0.8H), 7.08 (d, J¼4.5 Hz, 0.2H), 6.20–
5.56 (m, 0.8H), 4.73 (d, J¼9.3 Hz, 0.2H), 4.07–4.18 (m,
0.8H), 3.99 (s, 2.4H), 3.92 (s, 0.6H), 3.56–2.81 (m, 3.2 H),
2.50–1.79 (m, 3H), 1.58 (ddd, J¼4.1, 9.3, 13.5, 1H), 1.35–
1.13 (m, 3H), 0.94 (s, 9H), 0.84 (t, J¼7.5 Hz, 3H), 0.18 (s,
8.72 (d, J¼4.4 Hz, 1H), 8.00 (br s, 1H), 7.99 (d, J¼9.0 Hz,
1H), 7.66 (d, J¼4.4 Hz, 1H), 7.25 (dd, J¼2.4, 9.0 Hz, 1H),
6.01 (s, 1H), 3.74 (d, J¼12.6 Hz, 1H), 3.42 (br d, J¼6.3 Hz,
1H), 3.30–3.19 (m, 1H), 2.93 (d, J¼12.0 Hz, 1H), 2.89 (d, J¼
12.0 Hz, 1H), 2.27–2.19 (m, 1H), 2.04 (dd, J¼6.6, 12.6 Hz,
1H), 1.79–1.49 (m, 3H), 1.38 (s, 3H), 1.09 (dd, J¼6.0,
12.6 Hz, 1H), 1.02 (t, J¼6.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d¼156.3, 146.9, 143.3, 141.3, 131.4, 128.3, 127.0,
122.0, 118.9, 76.4, 74.3, 72.3, 55.5, 52.5, 40.1, 38.2, 37.2, 28.9,
26.5, 23.7, 12.6; FT-IR (neat): n¼1469, 1238, 1062 cmÀ1; HR-
MS (EI): calcd. for C20H24O2N2 (Mþ): 324.1838; found:
324.1848.
2.4H), 0.06 (s, 0.6H), À0.33 (s, 2.4H), À0.47 (s, 0.6H); 13C Baylis–Hillman Reaction of Aldehydes with HFIPA
NMR (75 MHz, CDCl3): d¼158.4, 147.4, 144.4, 132.1, 125.9,
using 20 as a Catalyst
121.9, 118.6, 104.6, 100.4, 80.4, 71.8, 59.4, 58.4, 56.2, 45.8, 45.6,
To a solution of the aldehyde (1.0 mmol) and 20 (31 mg, 0.
1 mmol) in DMF (2 mL) at À558C was added HFIPA
(220 mL, 1.3 mmol). After stirringat À558C for the time indi-
cated in Table 1, the reaction was quenched by the addition of
0.1 M HCl (3 mL). The reaction mixture was extracted with
EtOAc, washed with saturated NaHCO3 and brine, dried
over MgSO4, concentrated, and chromatographed (SiO2, sol-
vent system: EtOAc/hexane).
The optical purity and absolute configuration of 22 and 23
were determined by HPLC analysis usinga chiral column of
the correspondingmethyl ester obtained as follows. A mixture
of 22 or 23 (1.0 mmol) and triethylamine (0.7 mL) in MeOH
(7 mL) was stirred at room temperature for 30 min and the re-
action was quenched by the addition of Dowex 50 (Hþ form).
The reaction mixture was filtered, concentrated, and chroma-
tographed (SiO2, solvent system: EtOAc/hexane).
¼
40.1, 28.3, 25.9, 18.1, 11.5, À4.3, À5.0; FT-IR (neat): n 1731,
1619, 1255 cmÀ1; HR-MS (EI): calcd. for C26H38O3N2Si (Mþ):
454.2652; found: 454.2626.
(3S,5S,8S,9R)-10,11-Dihydro-5,9-epoxy-6’-methoxy-5-
methylcinconane (20)
To a stirred solution of 17 (312 mg, 0.686 mmol) in THF (8 mL)
at 08C was added methylmagnesium bromide (3.0 M, 2.29 mL,
6.86 mmol). After beingstirred at 0 8C for 1 h, the reaction mix-
ture was diluted with water, extracted with CH2Cl2, washed
with 10% Na2CO3 and brine, dried, and concentrated to give
18 (330 mg) which was used for the next reaction without puri-
fication. Pure 18, a white amorphous solid, was obtained as an
epimeric mixture by preparative TLC (CHCl3/MeOH¼10/1).
1H NMR (300 MHz, CDCl3): d¼8.74 (d, J¼4.5 Hz, 0.8H), 8.65
(d, J¼4.4 Hz, 0.2H), 8.00 (d, J¼10.0 Hz, 0.8H), 7.87 (d, J¼
2.4 Hz, 0.2H), 7.52 (d, J¼4.4 Hz, 1H), 7.38 (dd, J¼10.0,
2.4 Hz, 1H), 7.18 (br s, 0.8H), 7.08 (d, J¼4.2 Hz, 0.2H), 5.67
(br s, 0.8H), 4.73 (d, J¼9.3 Hz, 0.2H), 3.96 (s, 2.4H), 3.93 (s,
0.6H), 3.57–3.38 (m, 1H), 3.17–2.30 (m, 4H), 1.99–1.28 (m,
8H), 1.19–1.04 (m, 2H), 0.95 (s, 7.2H), 0.83 (s, 1.8H), 0.79 (t,
J¼7.5 Hz, 3H), 0.13–0.01 (m, 3H), À0.31 (s, 2.4H), À0.44
(s, 0.6H); 13C NMR (75 MHz, CDCl3): d¼147.4, 144.4, 132.0,
126.1, 121.7, 121.3, 118.8, 104.9, 100.5, 77.3, 73.2, 60.1, 59.1,
55.9, 39.5, 38.8, 28.6, 26.1, 25.8, 18.1, 12.9, À4.5, À4.7; FT-IR
(neat): n¼3354, 1620, 1508, 1468, 1255, 1111 cmÀ1; HRMS
(EI): calcd. for C27H42O3N2Si (Mþ): 470.2965; found: 470.2947.
A solution of crude 18 (322 mg) and KBr (816.3 mg,
6.86 mmol) in 85% aqueous H3PO4 (12.3 mL) was heated at
1008C for 10days. The reaction mixture was basified to pH 9
with 2 M KOH, extracted with CHCl3, washed with 10%
K2CO3 and brine, dried, and concentrated. Purification of the
residue by column chromatography on silica gel (CHCl3/
MeOH¼100/1) gave 19 (yield: 66.6 mg, 31%) and 20 (yield:
49.7 mg, 23%). Compound 19 (29.8 mg, 0.092 mmol) was again
subjected to cyclization by heatingwith KBr (164 m,g
1.38 mmol) and 85% aqueous H3PO4 (2.5 mL) at 1008C for 3
days. The reaction mixture was worked up and purified as men-
tioned above to give 19 (yield: 13.4 mg, 45%) and 20 (yield:
1,1,1,3,3,3-Hexafluoroisopropyl (S)-3-hydroxy-3-phenyl-
2-methylenepropanoate: colorless oil; [a]2D8: þ50.58 (c 1.02,
CHCl3); 1H NMR (300 MHz, CDCl3): d¼7.37–7.30 (m, 5H),
6.60 (s, 1H), 6,24 (s, 1H), 5.75 (hept, J¼6.0 Hz, 1H), 5.63 (br
s, 1H), 2.45 (br s, 1H); 13C NMR (75 MHz, CDCl3): d¼162.6,
1
140.5, 140.0, 129.6, 128.8, 128.5, 126.8, 120.4 (q, JC,F
¼
2
305.6 Hz), 72.6, 66.8 (hept, JC,F ¼35.3 Hz); FT-IR (neat): n¼
3375, 2970, 1755, 1387, 1298, 1132 cmÀ1; HR-MS: calcd. for
C13H10NO5F6 (Mþ): 328.0534; found: 328.0538.
Methyl (S)-3-hydroxy-3-phenyl-2-methylenepropanoate:
colorless oil (91% ee); [a]2D8: þ93.28 (c 0.21, MeOH); 1H
NMR (300 MHz, CDCl3): d¼7.40–7.26 (m, 5H), 6.34 (s,
1H), 5.84 (s, 1H), 5.57 (d, J¼5.4 Hz, 1H), 3.73 (s, 3H), 3.02
(d, J¼5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d¼166.8,
142.1, 141.3, 128.5, 127.9, 126.6, 126.1, 73.3, 52.0; FT-IR
(neat): n¼3363, 3032, 2952, 1704, 1496, 1450 cmÀ1; HR-MS:
calcd. for C11H12O5 (Mþ): 192.0786; found: 192.0788. HPLC
conditions: Daicel Chiralcel OJ, 2-propanol:hexane¼1:5
(0.5 mL/min), tR ¼26.4 min (R) and 32.4 min (S).
1,1,1,3,3,3-Hexafluoroisopropyl (S)-3-hydroxy-3-(p-ni-
trophenyl)-2-methylenepropanoate: colorless oil (91% ee);
1
[a]2D0: þ45.98 (c 2.32, CHCl3); H NMR (300 MHz, CDCl3):
d¼8.23 (d, J¼8.7 Hz, 2H), 7.58 (d, J¼8.7 Hz, 2H), 6.66 (s,
1H), 6.27 (s, 1H), 5.80–5.74 (m, 2H), 2.47 (d, J¼4.5 Hz, 1H);
13C NMR (75 MHz, CDCl3): d¼162.5, 147.9, 147.5, 139.2,
1
130.9, 127.6, 123.9, 120.3 (q, JC,F ¼281 Hz), 71.8, 66.9 (hept,
Adv. Synth. Catal. 2005, 347, 1790 – 1796
ꢀ 2005 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
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Ayako Nakano et al.
FULL PAPERS
2J C,F ¼34.2 Hz); FT-IR (neat): n¼3533, 1751, 1525, 1352, 1286,
1232, 1120, 1115 cmÀ1; HR-MS: calcd. for C13H9NO5F6 (Mþ):
373.0385; found: 373.0389.
Acknowledgements
This work was partly supported by a Grant-in-Aid for Scientific
Research from Ministry of Education, Culture, Sports, Science
and Technology, Japan.
(2S,6S)-2,6-Di(p-nitrophenyl)-5-methylene-1,3-dioxan-
4-one: colorless oil (33% ee); [a]2D2: þ1.08 (c 0.220, CHCl3); 1H
NMR (300 MHz, CDCl3): d¼8.32 (d, J¼8.7 Hz, 2H), 8.31 (d,
J¼8.7 Hz, 2H), 7.79 (d, J¼8.7 Hz, 2H), 7.64 (d, J¼8.7 Hz,
2H), 6.74 (d, J¼2.7 Hz, 1H), 6.62 (s, 1H), 5.92 (br s, 1H), 5.42
(d, J¼2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d¼161.3,
149.0, 148.6, 144.2, 141.1, 135.2, 130.6, 128.8, 127.5, 124.3,
123.9, 99.5, 80.4; FT-IR (neat): n¼3082, 2862, 1741, 1523,
1348, 1173 cmÀ1; HR-MS: calcd. for C17H12N2O7 (Mþ):
356.0644; found: 356.0663.
References and Notes
[1] a) D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev.
2003, 103, 811–892; b) Y. Iwabuchi, S, Hatakeyama, J.
Synth. Org. Chem. Jpn. 2002, 60, 4–16; c) P. Langer, An-
gew. Chem. Int. Ed. 2000, 39, 3049–3052; d) E. Ciganek
in: Organic Reactions, Vol. 51 (Ed.: L. A. Paquette), Wi-
ley, New York, 1997, pp. 201–350; e) D. Basavaiah, P.
Darma Rao, R. Suguna Hyma, Tetrahedron 1996, 52,
8001–8062; S. E. Drewes, G. H. P. Roos, Tetrahedron
1988, 44, 4653–4670.
[2] Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeya-
ma, J. Am. Chem. Soc. 1999, 121, 10219–10220.
[3] S. Kawahara, A. Nakano, T. Esumi, Y. Iwabuchi, S. Ha-
takeyama, Org. Lett. 2003, 5, 3103–3105.
[4] a) C. von Riesen, H. M. R. Hoffmann, Chem. Eur. J.
1996, 2, 680–684; b) W. Braje, J. Frackenpohl, P. Langer,
H. M. R. Hoffmann, Tetrahedron 1998, 54, 3495–3512.
[5] For other works using b-ICD, see: a) M. Shi, Y.-M. Xu,
Y.-L. Shi, Chem. Eur. J. 2005, 11, 1794–1802; b) S. Saaby,
M. Bella, K. A. Jorgensen J. Am. Chem. Soc. 2004, 126,
8120–8121; c) D. Balan, H. Adolfsson, Tetrahedron
Lett. 2003, 44, 2521–2524; d) M. Shi, Y.-M. Xu, Angew.
Chem. Int. Ed. 2002, 41, 4507–4510.
[6] a) Y. Iwabuchi, M. Furukawa, T. Esumi, S. Hatakeyama,
Chem. Commun. 2001, 2030–2031; b) Y. Iwabuchi, T. Su-
gihara, T. Esumi, S. Hatakeyama, Tetrahedron Lett. 2001,
42, 7867–7871.
[7] Recently, an asymmetric synthesis of (þ)-quinidine was
reported by Jacobsen et al. This method can be applied
to the synthesis of (–)-quinidine, which is required for
the preparation of the enantiomer of b-ICD: I. T. Ra-
heem, S. N. Goodman, E. N. Jacobsen, J. Am. Chem.
Soc. 2004, 126, 706–707.
[8] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pe-
chet, J. Am. Chem. Soc. 1961, #83#86, 4076–4083.
[9] L. P. Stotter, K. A. Hill, M. D. Friedman, Heterocycles
1987, 25, 259–262.
[10] F. Asinger, B. Fell, P. Krings, Tetrahedron Lett. 1966,
633–641.
[11] G. W. Kabalka, H. C. Jr. Hedgecock, J. Org. Chem. 1975,
40, 1976–1979.
[12] N. A. Poter, S. E. Caldwell, J. R. Lowe, J. Org. Chem.
1998, 63, 5547–5554.
[13] E. Wildsmith, G. H. Timms, Tetrahedron Lett. 1971, 195–
198.
Methyl (S)-3-hydroxy-3-(p-nitrophenyl)-2-methylenepro-
panoate: colorless oil (91%ee); [a]2D3: þ85.68 (c 0.54,
1
MeOH); H NMR (300 MHz, CDCl3): d¼8.21 (dd, J¼6.9,
1.8 Hz, 2H), 7.58 (d, J¼6.9 Hz, 2H), 6.40 (s, 1H), 5.87 (s, 1H),
5.64 (d, J¼6.3 Hz, 1H), 3.75 (s, 3H), 3.30 (d, J¼6.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): d¼169.5, 147.8, 146.0, 127.9,
123.5, 71.5, 58.4, 53.0, 50.0; FT-IR (neat): n¼3427, 2962,
1751, 1387, 1232, 1120 cmÀ1
; HR-MS (EI): calcd. for
C11H11NO6 (Mþ): 253.0586; found: 253.0578. HPLC condi-
tions: Daicel Chiralcel OJ, 2-propanol:hexane¼1:10
(0.5 mL/min), tR ¼29.0 min (R) and 32.4 min (S).
1,1,1,3,3,3-Hexafluoroisopropyl (S)-3-hydroxy-2-methyl-
ene-5-phenylpentanoate: colorless oil; [a]2D2: À10.48 (c 1.264,
CHCl3); 1H NMR (300 MHz, CDCl3): d¼7.32–7.24 (m, 2H),
7.22–7.17 (m, 3H), 6.49 (s, 1H), 6.15 (s, 1H), 5.85 (hept, J¼
6.0 Hz, 1H), 4.52 (dd, J¼3.6, 4.2 Hz, 1H), 2.85–2.66 (m, 2H),
2.24 (br s, 1H), 2.08–1.89 (m, 2H); 13C NMR (75 MHz,
CDCl3): d¼162.7, 142.2, 140.6, 129.2, 128.6, 128.5, 126.2,
1
2
120.5 (q, JC,F ¼282.3 Hz), 70.1, 66.7 (hept, JC,F ¼34.7 Hz),
37.8, 32.0; FT-IR (neat): n¼3427, 2962, 1751, 1387, 1232,
;
1120 cmÀ1 HR-MS (EI): calcd. for C15H14F6O3 (Mþ):
356.0847; found: 356.0863.
(6R)-2,6-Diphenethyl-5-methylene-1,3-dioxan-4-one
(7:3 diastereoisomeric mixture): colorless oil; 1H NMR
(300 MHz, CDCl3): d¼7.33–7.28 (m, 4H), 7.23–7.17 (m,
10H), 6.49–6.47 (m, 1H), 5.58 (d, J¼2.1 Hz, 0.7H), 5.54 (d,
J¼2.1 Hz, 0.3H), 5.45 (t, J¼5.1 Hz, 0.3H), 5.27 (d, J¼
5.1 Hz, 0.7H), 4.71–4.67 (m, 0.3H), 4.51–4.46 (m, 0.7H),
2.93–2.65 (m, 4H), 2.22–1.90 (m, 4H); 13C NMR (75 MHz,
CDCl3): d¼163.7, 140.9, 140.6, 140.5, 136.8, 136.0, 128.7,
128.6, 128.5, 128.4, 126.8, 126.4, 126.2, 125.7, 101.1, 96.4, 77.5,
77.1, 76.7, 76.5, 74.2, 36.6, 35.8, 35.6, 35.3, 31.4, 30.8, 29.4,
29.3; FT-IR (neat): n¼3028, 2931, 1730, 1446, 1379, 1234,
1161, 1030 cmÀ1; HRMS (EI): calcd. for C21H22O3 (Mþ):
322.1569; found: 322.1567.
Methyl (S)-3-hydroxy-2-methylene-5-phenylpentanoate:
1
colorless oil (98% ee): [a]2D2: À11.38 (c 0.654, MeOH); H
NMR (300 MHz, CDCl3): d¼7.31–7.15 (m, 5H), 6.24–6.23
(m, 1H), 5.81 (t, J¼0.9 Hz, 1H), 4.45–4.39 (m, 1H), 3.76 (s,
3H), 2.87–2.64 (m, 3H), 2.01–1.93 (m, 2H); 13C NMR
(75 MHz, CDCl3): d¼167.1, 142.2, 141.7, 128.5, 128.5, 126.0,
125.4, 71.2, 52.0, 37.7, 32.1; FT-IR (neat): n¼3487, 3024,
2947, 1720, 1631, 1444, 1149, 1074 cmÀ1; HR-MS (EI): calcd.
for C15H16O3 (Mþ): 220.1099; found: 220.1123. HPLC condi-
tions: Daicel Chiralcel OJ, 2-propanol:hexane¼5:1 (0.5 mL/
min), tR ¼26.0 min (R), tR ¼27.7 min (S).
[14] D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin
Trans. 1 1975, 1574–1585.
1796
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Adv. Synth. Catal. 2005, 347, 1790 – 1796