Enantioselective cycloaddition of carbonyl ylides with arylallenes using Rh2(S-TCPTTL)4

Article abstract of DOI:10.1039/c3ob41236a

The first catalytic asymmetric carbonyl ylide cycloaddition with arylallenes is described. With dirhodium(ii) tetrakis[N-tetrachlorophthaloyl-(S) -tert-leucinate], Rh₂(S-TCPTTL)₄, the cycloaddition of carbonyl ylides derived from diazoketoesters with arylallenes proceeded in a fully chemo- and regioselective manner to give highly functionalized 8-oxabicyclo[3.2.1]octanes with up to 99% ee and perfect exo diastereoselectivity.

Full text of DOI:10.1039/c3ob41236a

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Enantioselective cycloaddition of carbonyl ylides with
arylallenes using Rh2(S-TCPTTL)4†
Cite this: Org. Biomol. Chem., 2013, 11,
5374
Janagiraman Krishnamurthi,a Hisanori Nambu,a Koji Takeda,a Masahiro Anada,a
Akihito Yamanob and Shunichi Hashimoto*a
The first catalytic asymmetric carbonyl ylide cycloaddition with arylallenes is described. With dirhodium(II)
tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4, the cycloaddition of carbonyl ylides
derived from diazoketoesters with arylallenes proceeded in a fully chemo- and regioselective manner to
give highly functionalized 8-oxabicyclo[3.2.1]octanes with up to 99% ee and perfect exo diastereo-
selectivity.
Received 14th June 2013,
Accepted 27th June 2013
DOI: 10.1039/c3ob41236a
www.rsc.org/obc
Introduction
The dirhodium(II) complex-catalyzed tandem cyclic carbonyl
ylide formation 1,3-dipolar cycloaddition is one of the most
powerful methods for rapid assembly of complex oxapolycyclic
systems.1 The exceptional power of the carbonyl ylide cyclo-
addition strategy has recently been demonstrated by an
increasing number of syntheses of diverse natural products.2–4
Over the past 15 years, an enantioselective version of this
sequence catalyzed by chiral dirhodium(II) complexes has also
been realized in some selected reactions,5,6 in which a prime
Fig. 1 Dirhodium(II) complexes.
requirement for asymmetric induction is the use of chiral dir- take suitable positions for dipolar attack, which can proceed
hodium(II) catalyst-associated carbonyl ylide intermediates in with two opposite orientations.13–16 Hence, as well as enantio-
the cycloaddition step because catalyst-free carbonyl ylides are control, control of chemo-, regio-, and diastereoselectivity is a
achiral. Recently, we reported catalytic enantioselective inter- major challenge in enantioselective carbonyl ylide cycloaddi-
molecular cycloadditions of carbonyl ylides derived from tions with allene dipolarophiles. While only one example of
diazoketoesters with terminal aryl alkynes and alkenes, and asymmetric induction (up to 45% ee) in cycloaddition of car-
N-methylindoles,7 in which Rh2(S-TCPTTL)4 (1c)7,8 (Fig. 1), the bonyl ylide derived from diazodione with allene was demon-
chlorinated analogue of Rh2(S-PTTL)4 (1a), proved to be the strated by Hodgson et al. using Rh2(S-DOSP)4 (2)17 as a chiral
catalyst of choice for achieving high levels of asymmetric catalyst,11 at the outset of our studies, there were no reported
induction (up to 99% ee).9 To further advance this catalytic examples of this type of cycloaddition with substituted allenes,
process with respect to a dipolarophile, we addressed the even in a racemic reaction.18 Herein, we report the first
cycloaddition of carbonyl ylides with allenes, which has been example of enantioselective cycloaddition of carbonyl ylides
less studied.10–12
with arylallenes, in which catalysis with Rh2(S-TCPTTL)4 pro-
Allenes are interesting dipolarophiles due to the presence ceeds in a fully chemo- and regioselective manner to give
of cumulated CvC bonds. In fact, both CvC bonds of allenes highly functionalized 8-oxabicyclo[3.2.1]octane derivatives,
potentially useful chiral building blocks or intermediates in
organic synthesis,19,20 in high yields with high levels of enantio-
selectivity (up to 99% ee) and perfect exo diastereoselectivity.
aFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
E-mail: hsmt@pharm.hokduai.ac.jp; Fax: +81-11-706-4981; Tel: +81-11-706-3236
bX-ray Research Laboratory, Rigaku Corporation, 3-9-12 Matsubara, Akishima,
Tokyo 196-8666, Japan
Results and discussion
†Electronic supplementary information (ESI) available: Copies of 1H and
On the basis of our previous work,7a we initially explored the
cycloaddition of a cyclic carbonyl ylide derived from 2-diazo-
3,6-diketoester 4a with 2 equiv. of phenylallene (5a)21 in the
13C NMR spectra of all new compounds and HPLC analysis. X-ray data (CIF)
for 6d is also provided. CCDC 934102. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c3ob41236a
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significantly lower yield of 6a (entry 9). We were also surprised
to find that achiral catalysts such as Rh2(OAc)4 (3a), Rh2(oct)4
(3b), Rh2(tpa)4 (3c), and Rh2(pfb)4 (3d) gave a complex mixture
of products with no signs of cycloadduct 6a,26 although
Rh2(OAc)4 worked well in the Hodgson11 and Harned18 reac-
tion systems. Clearly, the advantage of Rh2(S-TCPTTL)4 extends
beyond stereocontrol in this system. These results indicate that
the presence of tetrachlorophthalimido groups in the bridging
ligands of 1c is crucial for the efficiency of the cycloaddition.
It seems likely that Rh2(S-TCPTTL)4 with a powerful electron-
withdrawing effect of the chlorine substituent generates an
even longer-lived catalyst-bound carbonyl ylide than does any
other dirhodium(II) catalyst to favor the cycloaddition with
phenylallene, whereas the catalyst-free ylide is too short-lived
to undergo such a cycloaddition.27
With the optimized conditions in hand, we then explored
the reaction of 4a with a range of arylallenes (Table 2). Apart
from complete chemo- and regioselectivity, perfect exo diastereo-
selectivity and high enantioselectivity were consistently observed
with arylallenes bearing methyl, methoxy, bromo, and trifluoro-
methyl groups at the para position on the benzene ring
(92–97% ee, entries 2–5). The absolute configuration of 6d was
determined to be (1R,5R,7R) by single-crystal X-ray analysis (see
the ESI†), and the stereochemistry of other cycloadducts was
assigned by analogy. High levels of asymmetric induction were
maintained with m- or o-methylphenylallenes as well as with
Table 1 Enantioselective intermolecular cycloaddition of 2-diazo-3,6-diketo-
ester 4a with phenylallene (5a) catalyzed by 1a–ca
Rh(II)
Entry catalyst
Temp.
(°C)
Yieldb
Additive (%)
eec
(%)
Solvent
1
2
3
4
5
6
7
8
9
1c
1c
1c
1c
1c
1c
1c
1a
1b
23
0
CF3C6H5
CF3C6H5
CF3C6H5
Toluene
Benzene
CH2Cl2
CF3C6H5 4 Å MS
CF3C6H5 4 Å MS
CF3C6H5 4 Å MS
—
—
—
—
—
—
63
61
24
45
99
99
96
99
90
—
99
—
96
60
23
23
23
23
23
23
34
Traced
82
Traced
20
a All reactions were carried out as follows: Rh(II) catalyst (1 mol%) was
added to a stirred solution of 4a (48 mg, 0.2 mmol) and 5a (2 equiv.)
in the indicated solvent (2 mL) at the indicated temperature. b Yields
of isolated product 6a. c Determined by HPLC analysis using a Daicel
Chiralpak IC. d Detected in a complex mixture of products.
presence of 1 mol% of Rh2(S-TCPTTL)4 (1c). The reaction in
α,α,α-trifluorotoluene proceeded smoothly at room tempera-
ture to give cycloadduct 6a as the sole product in 63% yield
(Table 1, entry 1). This result demonstrated that the reaction
proceeds in a fully regioselective fashion and undergoes cyclo-
addition across the phenyl substituted CvC bond (vide infra).
The exo-stereochemistry of 6a was established by a 1H-NOE
between H-7 and H-3, while 1H–13C HMBC correlation between
H-9 and C-6 confirmed the position of the exocyclic methylene
group. The enantioselectivity of this reaction was determined
to be 99% ee by HPLC analysis using a Daicel Chiralpak IC
column. A series of experiments were then carried out in an
attempt to achieve a high-yielding formation of 6a. Lowering
the reaction temperature to 0 °C led to a slight decrease in the
product yield, while the same enantioselectivity was observed
(61% yield, 99% ee, entry 2). The reaction at 60 °C resulted in
a sharp drop in the product yield with a slight decrease in
enantioselectivity (24% yield, 96% ee, entry 3). Experiments
with other solvents such as toluene and benzene exhibited
high levels of enantioselectivity comparable to that found with
α,α,α-trifluorotoluene, but product yields were markedly
reduced (entries 4 and 5). CH2Cl2 was found to be the least
effective, giving only a trace amount of 6a (entry 6). To our
delight, addition of powdered 4 Å MS greatly improved the
product yield without compromising the enantioselectivity or
exo diastereoselectivity (82%, 99% ee, entry 7).22 Using
α,α,α-trifluorotoluene as a solvent and 4 Å MS as an additive,
we next evaluated the performance of Rh2(S-PTTL)4 (1a)23,24
and Rh2(S-TFPTTL)4 (1b).25 Unlike the previous work,7 catalysis
with Rh2(S-PTTL)4 led to only trace amounts of 6a (entry 8),
while the use of Rh2(S-TFPTTL)4, the fluorinated analogue
of 1a, provided a similar level of enantioselectivity but a
Table 2 Enantioselective intermolecular cycloaddition of diazoketoesters
with arylallenes 5 catalyzed by Rh2(S-TCPTTL)4 (1c)a
4
Diazoketoester
R
Dipolarophile
Ar
Product
Entry
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
Me
5a
5b
5c
5d
5e
5f
C6H5
4-MeC6H5
4-MeOC6H5 6c
4-BrC6H5
4-CF3C6H5
3-MeC6H5
2-MeC6H5
6a
6b
82
77
89
71
72
65
82
65
63
80
75
73
99
92
97
96
97
92
99
98
83
96
96
92
98
99
97
94
99
99
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
6d
6e
6f
5g
6g
5h 3-MeOC6H5 6h
5i
5a
5c
5d
5e
5g
9
2-MeOC6H5 6i
C6H5 6j
4-MeOC6H5 6k
4-BrC6H5
4-CF3C6H5
2-MeC6H5
C6H5
4-MeOC6H5 6p
4-CF3C6H5
2-MeC6H5
10
11
12
13
14
15
16
17
18
6l
6m 68
6n
6o
76
96
94
88
98
C6H5 5a
C6H5 5c
C6H5 5e
C6H5 5g
6q
6r
a All reactions were performed on a 0.2 mmol scale with 2 equiv. of 5.
b Yields of isolated product 6. c Determined by HPLC analysis.
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m-methoxyphenylallene (92–99% ee, entries 6–8), while only (cm−1). 1H NMR spectra were recorded using JEOL ECS-400
modest enantioselectivity was observed with o-methoxypheny- (400 MHz) spectrometer. Chemical shifts are reported relative
lallene (83% ee, entry 9). We finally investigated the reaction of to internal standard (tetramethylsilane; δH 0.00). Data are pre-
diazoketoesters 4b,c7,9 bearing substituents other than a sented as follows: chemical shift (δ, ppm), multiplicity (s =
methyl group at the C-5 position. The cycloaddition of formyl- singlet, d = doublet, t = triplet, m = multiplet, br = broad),
derived or phenyl-substituted carbonyl ylides with arylallenes coupling constant and integration. 13C NMR spectra were
proceeded also in a completely chemo-, and regioselective recorded using a JEOL ECS-400 (100 MHz) spectrometer.
manner to give the corresponding cycloadducts 6j–r in good to Chemical shifts are reported relative to the internal standard
high yields with high to excellent enantioselectivities (92–99% (CDCl3; δ 77.00). Optical rotations were measured using a
ee, entries 10–18).
JASCO P-1030 digital polarimeter at the sodium D line
From frontier molecular orbital (FMO) analysis for these (589 nm). ESI-MS spectra were obtained using a Thermo Scien-
reactions in the absence of a catalyst (see the ESI†), the tific Exactive spectrometer. Column chromatography was
chemo- and regiocontrol observed can be readily rationalized carried out using Kanto silica gel 60 N (63-210 mesh) or
in terms of maximum overlap of the LUMO of carbonyl ylides Wakogel® C-200 (75–200 μm). Analytical thin layer chromato-
derived from 4a–c and the HOMO of arylallene dipolarophiles graphy (TLC) was carried out using Merck Kieselgel 60 F254
5a–d and 5f–i (Table 2, entries 1–4, 6–12, 14–16 and 18).7,28 plates with visualization by ultraviolet, anisaldehyde stain
FMO analysis, however, fails to explain the same regiochem- solution or phosphomolybdic acid stain solution followed by
istry encountered with a strongly electron-deficient p-(trifluoro- heating. Analytical high performance liquid chromatography
methyl)phenylallene (5e) (Table 2, entries 5, 13 and 17). The (HPLC) was performed using a JASCO PU-1580 intelligent
calculations suggest that the favored cycloadduct should be HPLC pump with a JASCO UV-1575 intelligent UV/VIS detector.
the result of interaction between the HOMO of carbonyl ylide Detection was performed at 206 nm, 226 nm and 254 nm.
derived from 4a and the LUMO of 5e (i.e., ΔE = 7.76 eV) rather Chiralpak IC or Chiralpak AD-H columns (0.46 cm × 25 cm)
than the dipole LUMO–dipolarophile HOMO interaction (i.e., from Daicel were used. Retention times (tR) and the peak ratio
ΔE = 8.37 eV). One possible explanation for the exclusive for- were determined using a JASCO-ChromNAV analysis system.
mation of 6e, 6m and 6q is that the association of Rh2-
All non-aqueous reactions were carried out in flame-dried
(S-TCPTTL)4 with the carbonyl ylide as shown in Table 1 leads to glassware under an argon atmosphere. Reagents and solvents
significant lowering of the LUMO energy level compared with were purified by standard means. CF3C6H5 was distilled from
the catalyst-free carbonyl ylide and facilitates the interaction CaH2. 4 Å MS-powder from Fluka was used after drying
between its LUMO and the HOMO of 5e, which predicts the (100 °C, 1 mmHg, 12 h). Arylallenes 5a–i were prepared accord-
regiochemistry exactly as observed.
ing to literature procedures.29 Chiral dirhodium(II) carboxy-
lates 1a–c were prepared according to our previous reports.30
Typical procedure for Rh(II)-catalyzed enantioselective 1,3-
dipolar cycloaddition: (1R*,5R*,7R*)-1-tert-butoxycarbonyl-5-
methyl-6-methylene-7-phenyl-8-oxabicyclo[3.2.1]octan-2-one
(6a) (Table 1, entry 7). Rh2(S-TCPTTL)4 (1c) (3.95 mg,
0.0020 mmol, 1 mol%) was added to a stirred solution of 4 Å
MS-powder (50 mg), α-diazo-β-ketoester 4a5d (48.0 mg,
0.20 mmol) and phenylallene (5a)29a (46.4 mg, 0.40 mmol) in
CF3C6H5 (2.0 mL) at 23 °C. After stirring for 30 minutes, the
reaction mixture was filtered through Celite. The filtrate was
concentrated in vacuo and the residue was purified using
column chromatography (silica gel, 15 g, 8 : 2 hexane–EtOAc)
to provide cycloadduct 6a (54 mg, 82%) as a white solid;
Conclusions
In summary, we have developed a catalytic enantioselective
cycloaddition of carbonyl ylides derived from diazoketoesters
with a broad range of arylallenes, in which the unique ability
of Rh2(S-TCPTTL)4 has been demonstrated. The LUMO-con-
trolled carbonyl ylide cycloaddition reaction (even with the
electron-deficient p-(trifluoromethyl)phenylallene) in the pres-
ence of 4 Å MS proceeded in a fully chemo- and regioselective
fashion to give 7-aryl-6-methylene-8-oxabicyclo[3.2.1]octane
derivatives otherwise difficult to construct in high yields with
exceptionally high levels of enantioselectivity (up to 99% ee)
and perfect exo diastereoselectivity. Notably, this is the first
example of the use of arylallenes as dipolarophiles in enantio-
selective cycloaddition reactions with any type of 1,3-dipoles.16
Applications of this method to catalytic asymmetric synthesis
of biologically active natural products as well as mechanistic
and stereochemical studies are currently in progress.
Rf (7 : 3 hexane–EtOAc) = 0.50; M.p. 140–142 °C (99% ee); [α]D24
+95.9 (c 1.0, CHCl3); IR (KBr): ν = 2978, 2933, 1738, 1367, 1314,
1164, 1078 cm−1 1H NMR (400 MHz, CDCl3): δ 1.06 (s, 9H,
=
;
C(CH3)3), 1.67 (s, 3H, CH3), 2.01–2.06 (m, 1H, CH2), 2.33–2.41
(m, 1H, CH2), 2.50–2.56 (m, 1H, CH2), 2.64–2.70 (m, 1H, CH2),
4.00 (d, J = 1.6 Hz, 1H, CH), 4.98 (d, J = 1.6 Hz, 1H, C10–H),
5.15 (d, J = 1.6 Hz, 1H, C10–H), 7.21–7.29 (m, 5H, Ar); 13C
NMR (100 MHz, CDCl3): δ 23.5 (CH3), 27.2 (C(CH3)3), 34.4
(CH2), 39.8 (CH2), 56.3 (CH), 82.1 (C), 83.6 (C), 92.0 (C), 109.2
(CH2), 127.0 (CH), 128.2 (CH), 128.5 (C), 142.4 (C), 157.0 (C),
164.8 (C), 200.7 (C); HRMS (ESI) m/z calcd for C20H24O4Na
Experimental
General methods
IR spectra were recorded using a JASCO FT/IR-5300 spectro- [M + Na]+ 351.1566, found 351.1567. Anal. Calcd for C20H24O4:
meter and absorbance bands are reported in wavenumber C, 73.15; H, 7.37. Found: C, 72.97; H, 7.32.
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The enantiomeric excess of 6a was determined to be 99%
(1R,5R,7R)-7-(4-Bromophenyl)-1-tert-butoxycarbonyl-5-methyl-
by HPLC analysis using a Daicel Chiralpak IC column 6-methylene-8-oxabicyclo[3.2.1]octan-2-one (6d). According to
(9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): tR the typical procedure for Rh(II)-catalyzed enantioselective 1,3-
(minor) = 18.9 min; tR (major) = 20.4 min.
dipolar cycloaddition, 6d was prepared from α-diazo-β-keto-
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-5-methyl-6-methylene-7- ester 4a (48.0 mg, 0.20 mmol) and 4-bromophenylallene (5d)29b
(4-methylphenyl)-8-oxabicyclo[3.2.1]octan-2-one (6b). Accord- (78.0 mg, 0.40 mmol). The crude product was purified using
ing to the typical procedure for Rh(II)-catalyzed enantio- column chromatography (silica gel, 8 : 2 hexane–EtOAc) to
selective 1,3-dipolar cycloaddition, 6b was prepared from provide 6d (57.8 mg, 71%) as
a pale yellow solid; Rf
α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 4-methyl- (7 : 3 hexane–EtOAc) = 0.50; M.p. 158–159 °C (96% ee); [α]D22
=
phenylallene (5b)29a (52.0 mg, 0.40 mmol). The crude product +88.7 (c 1.2, CHCl3); IR (KBr): ν = 2982, 2921, 1735, 1486, 1368,
was purified using column chromatography (silica gel, 1314, 1160, 1076, 897, 838 cm−1; 1H NMR (400 MHz, CDCl3): δ
8 : 2 hexane–EtOAc) to afford 6b (53.0 mg, 77%) as a white 1.10 (s, 9H, C(CH3)3), 1.66 (s, 3H, CH3), 2.00–2.05 (m, 1H,
solid; Rf (7 : 3 hexane–EtOAc) = 0.65; M.p. 159–161 °C (92% ee); CH2), 2.33–2.40 (m, 2H, CH2), 2.50–2.56 (m, 1H, CH2),
[α]2D4 = +108.2 (c 1.3, CHCl3); IR (KBr): ν = 2981, 2925, 1730, 2.62–2.71 (m, 1H, CH2), 3.98 (s, 1H, CH), 4.97 (d, J = 2.0 Hz,
1513, 1366, 1313, 1163, 1079 cm−1; 1H NMR (400 MHz, CDCl3): 1H, C10–H), 5.16 (d, J = 2.0 Hz, 1H, C10–H), 7.13 (d, J = 7.9 Hz,
δ 1.01 (s, 9H, C(CH3)3), 1.66 (s, 3H, CH3), 1.99–2.05 (m, 1H, 2H, Ar), 7.40 (d, J = 7.9 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
CH2), 2.30 (s, 3H, CH3), 2.32–2.39 (m, 1H, CH2), 2.48–2.55 (m, δ 23.6 (CH3), 27.3 (C(CH3)3), 34.3 (CH2), 39.6 (CH2), 55.6 (CH),
1H, CH2), 2.63–2.72 (m, 1H, CH2), 3.97 (t, J = 2.0 Hz, 1H, CH), 82.4 (C), 83.6 (C), 91.8 (C), 109.6 (CH2), 120.9 (C), 129.8 (CH),
4.97 (d, J = 2.0 Hz, 1H, C10–H), 5.13 (d, J = 2.0 Hz, 1H, C10–H), 131.5 (CH), 141.5 (C), 156.5 (C), 164.6 (C), 200.3 (C); HRMS
7.07 (d, J = 8.3 Hz, 2H, Ar), 7.13 (d, J = 8.3 Hz, 2H, Ar); 13C (ESI) m/z calcd for C20H23BrO4Na [M + Na]+ 429.0671, found
NMR (100 MHz, CDCl3): δ 21.0 (CH3), 23.5 (CH3), 27.2 429.0672. Anal. Calcd for C20H23BrO4: C, 58.98; H, 5.69; Br,
(C(CH3)3), 34.4 (CH2), 39.8 (CH2), 56.0 (CH), 82.0 (C), 83.5 (C), 19.62. Found: C, 58.70; H, 5.66; Br, 19.23.
92.0 (C), 108.9 (CH2), 128.0 (CH), 129.0 (CH), 136.6 (C), 139.4
The enantiomeric excess of 6d was determined to be 96%
(C), 157.1 (C), 164.8 (C), 200.7 (C); HRMS (ESI) m/z calcd for by HPLC analysis using a Daicel Chiralpak IC column
C21H26O4Na [M + Na]+ 365.1723, found: 365.1724. Anal. Calcd (9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
for C21H26O4: C, 73.66; H, 7.65. Found: C, 73.80; H, 7.61.
tR (minor) = 14.7 min for (1S,5S,7S)-enantiomer; tR (major) =
The enantiomeric excess of 6b was determined to be 92% 17.5 min for (1R,5R,7R)-enantiomer.
by HPLC analysis using a Daicel Chiralpak IC column
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-(trifluoromethyl)-
(3 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): phenyl)-5-methyl-6-methylene-8-oxabicyclo[3.2.1]octan-2-one
tR (minor) = 10.2 min; tR (major) = 11.7 min.
(6e). According to the typical procedure for Rh(II)-catalyzed
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-methoxyphenyl)-5- enantioselective 1,3-dipolar cycloaddition, 6e was prepared
methyl-6-methylene-8-oxabicyclo[3.2.1]octan-2-one (6c). Accord- from α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 4-(tri-
ing to the typical procedure for Rh(II)-catalyzed enantio- fluoromethyl)phenylallene (5e)29c (73.7 mg, 0.40 mmol). The
selective 1,3-dipolar cycloaddition, 6c was prepared from crude product was purified using column chromatography
α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 4-methoxy- (silica gel, 8 : 2 hexane–EtOAc) to afford 6e (57.0 mg, 72%) as a
phenylallene (5c)29a (58.4 mg, 0.40 mmol). The crude product pale yellow solid; Rf (7 : 3 hexane–EtOAc)
= 0.45; M.p.
was purified using column chromatography (silica gel, 161–161.5 °C (97% ee); [α]2D2 = +55.0 (c 1.2, CHCl3); IR (KBr):
8 : 2 hexane–EtOAc) to give 6c (63.7 mg, 89%) as a colorless ν = 3001, 2984, 2936, 1730, 1618, 1421, 1370, 1332, 1163, 1120,
1
solid; Rf (7 : 3 hexane–EtOAc) = 0.50; M.p. 161–161.5 °C (97% 1081, 1021, 902, 825 cm−1; H NMR (400 MHz, CDCl3): δ 1.06
ee); [α]2D4 = +184.0 (c 1.3 CHCl3); IR (KBr): ν = 2979, 1743, 1728, (s, 9H, C(CH3)3), 1.68 (s, 3H, CH3), 2.02–2.08 (m, 1H, CH2),
1
1510, 1241, 1077 cm−1; H NMR (400 MHz, CDCl3): δ 1.10 (s, 2.35–2.43 (m, 1H, CH2), 2.53–2.59 (m, 1H, CH2), 2.63–2.69 (m,
9H, C(CH3)3), 1.66 (s, 3H, CH3), 1.99–2.05 (m, 1H, CH2), 1H, CH2), 4.08 (s, 1H, CH), 4.98 (s, 1H, C10–H), 5.20 (s, 1H,
2.33–2.40 (m, 1H, CH2), 2.49–2.55 (m, 1H, CH2), 2.62–2.69 (m, C10–H), 7.38 (d, J = 7.5 Hz, 2H, Ar), 7.54 (d, J = 7.5 Hz, 2H, Ar);
1H, CH2), 3.77 (s, 3H, CH3), 3.98 (s, 1H, CH), 4.96 (d, J = 1.6 13C NMR (100 MHz, CDCl3): δ 23.6 (CH3), 27.2 (C(CH3)3), 34.3
Hz, 1H, C10–H), 5.12 (d, J = 1.6 Hz, 1H, C10–H), 6.80 (d, J = 8.3 (CH2), 39.6 (CH2), 55.9 (CH), 82.6 (C), 83.7 (C), 91.8 (C), 109.9
Hz, 2H, Ar), 7.15 (d, J = 8.3 Hz, 2H, Ar); 13C NMR (100 MHz, (CH2), 125.4 (CH), 127.8 (C), 128.4 (CH), 129.2 (C), 146.4 (C),
CDCl3): δ 23.6 (CH3), 27.4 (C(CH3)3), 34.4 (CH2), 39.8 (CH2), 156.3 (C), 164.5 (C), 200.1 (C); HRMS (ESI) m/z calcd for
55.3 (OCH3), 55.7 (CH), 82.1 (C), 83.5 (C), 92.1 (C), 108.9 (CH2), C21H23F3O4Na [M + Na]+ 419.1549, found 419.1548. Anal.
113.8 (CH), 129.3 (CH), 134.7 (C), 157.3 (C), 158.7 (C), 164.8 Calcd for C21H23F3O4: C, 63.63; H, 5.85; F, 14.38. Found: C,
(C), 200.7 (C); HRMS (ESI) m/z calcd for C21H26O5Na [M + Na]+ 63.52; H, 5.81; F, 14.5.
381.1672, found 381.1673. Anal. Calcd for C21H26O5: C, 70.37;
H, 7.31. Found: C, 70.11; H, 7.35.
The exo-stereochemistry of 6e was established by using a
1H-NOE between H-7 and H-3, while 1H–13C HMBC correlation
The enantiomeric excess of 6c was determined to be 97% between H-9 and C-6 confirmed the position of the exocyclic
by HPLC analysis using a Daicel Chiralpak IC column methylene group (see the ESI†).
(3 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
tR (minor) = 11.4 min; tR (major) = 14.4 min.
The enantiomeric excess of 6e was determined to be
97% by HPLC analysis using a Daicel Chiralpak IC column
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(19 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): to the typical procedure for Rh(II)-catalyzed enantioselective
tR (minor) = 15.7 min; tR (major) = 19.5 min. 1,3-dipolar cycloaddition, 6h was prepared from α-diazo-
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-5-methyl-6-methylene-7- β-ketoester 4a (48.0 mg, 0.20 mmol) and 3-methoxyphenyl-
(3-methylphenyl)-8-oxabicyclo[3.2.1]octan-2-one (6f). Accord- allene (5h)29b (58.4 mg, 0.40 mmol). The crude product was puri-
ing to the typical procedure for Rh(II)-catalyzed enantio- fied using column chromatography (silica gel, 8 : 2 hexane–
selective 1,3-dipolar cycloaddition, 6f was prepared from EtOAc) to afford 6h (46.5 mg, 65%) as a white solid; Rf
α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 3-methyl- (7 : 3 hexane–EtOAc) = 0.50; M.p. 144–145 °C (98% ee); [α]D20
=
phenylallene (5f)29b (52.0 mg, 0.40 mmol). The crude pro- +88.6 (c 1.2, CHCl3); IR (KBr): ν = 3001, 2978, 2936, 1746, 1725,
duct was purified using column chromatography (silica gel, 1598, 1489, 1311, 1247, 1077 cm−1; 1H NMR (400 MHz, CDCl3):
8 : 2 hexane–EtOAc) to give 6f (44.5 mg, 65%) as a white solid; δ 1.08 (s, 9H, C(CH3)3), 1.74 (s, 3H, CH3), 2.00–2.04 (m, 1H,
Rf (7 : 3 hexane–EtOAc) = 0.5; M.p. 138–139 °C (92% ee); [α]D20
=
CH2), 2.32–2.39 (m, 1H, CH2), 2.49–2.55 (m, 1H, CH2),
+121.8 (c 1.2, CHCl3); IR (KBr): ν = 2981, 2933, 1742, 1728, 2.62–2.69 (m, 1H, CH2), 3.76 (s, 3H, CH3), 3.96 (t, J = 2.0 Hz,
1
1313, 1166, 1081 cm−1; H NMR (400 MHz, CDCl3): δ 1.06 (s, 1H, CH), 5.00 (d, J = 1.6 Hz, 1H, C10–H), 5.13 (d, J = 1.6 Hz,
9H, C(CH3)3), 1.67 (s, 3H, CH3), 2.00–2.08 (m, 1H, CH2), 2.31 1H, C10–H), 6.75–6.85 (m, 3H, Ar), 7.17 (t, J = 7.52 Hz, 1H, Ar);
(s, 3H, CH3), 2.34–2.40 (m, 1H, CH2), 2.49–2.55 (m, 1H, CH2), 13C NMR (100 MHz, CDCl3): δ 23.6 (CH3), 27.3 (C(CH3)3), 34.4
2.63–2.72 (m, 1H, CH2), 3.96 (t, J = 2.0 Hz, 1H, CH), 4.98 (d, J = (CH2), 39.8 (CH2), 55.2 (OCH3), 56.3 (CH), 82.1 (C), 83.5 (C),
2.0 Hz, 1H, C10–H), 5.14 (d, J = 2.0 Hz, 1H, C10–H), 7.02–7.04 92.0 (C), 109.1 (CH2), 112.6 (CH), 113.6 (CH), 120.4 (CH), 129.4
(m, 3H, Ar), 7.13–7.17 (m, 1H, Ar); 13C NMR (100 MHz, CDCl3): (CH), 143.8 (C), 156.7 (C), 159.5 (C), 164.7 (C), 200.6 (C); HRMS
δ 21.3 (CH3), 23.5 (CH3), 27.2 (C(CH3)3), 34.4 (CH2), 39.8 (CH2), (ESI) m/z calcd for C21H26O5Na [M + Na]+ 381.1673, found
56.3 (CH), 82.0 (C), 83.5 (C), 92.0 (C), 109.0 (CH2), 125.1 (CH), 381.1673. Anal. Calcd for C21H26O5: C, 70.37; H, 7.31. Found:
127.7 (CH), 128.4 (CH), 128.9 (CH), 137.9 (C), 142.3 (C), 156.9 C, 70.12; H, 7.27.
(C), 164.7 (C), 200.7 (C); HRMS (ESI) m/z calcd for C21H26O4Na
[M + Na]+ 365.1723, found 365.1724. Anal. Calcd for C21H26O4: by HPLC analysis using a Daicel Chiralpak IC column
C, 73.66; H, 7.65. Found: C, 73.42; H, 7.63.
(19 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
The enantiomeric excess of 6f was determined to be 92% by tR (minor) = 43.1 min; tR (major) = 53.1 min.
HPLC analysis using Daicel Chiralpak IC column (1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(2-methoxyphenyl)-5-
(9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): tR methyl-6-methylene-8-oxabicyclo[3.2.1]octan-2-one (6i). Accord-
(minor) = 20.9 min; tR (major) = 24.1 min. ing to the typical procedure for Rh(II)-catalyzed enantio-
The enantiomeric excess of 6h was determined to be 98%
a
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-5-methyl-6-methylene-7- selective 1,3-dipolar cycloaddition, 6i was prepared from
(2-methylphenyl)-8-oxabicyclo[3.2.1]octan-2-one (6g). Accord- α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 2-methoxy-
ing to the typical procedure for Rh(II)-catalyzed enantio- phenylallene (5i)29b (58.4 mg, 0.40 mmol). The crude product
selective 1,3-dipolar cycloaddition, 6g was prepared from was purified using column chromatography (silica gel,
α-diazo-β-ketoester 4a (48.0 mg, 0.20 mmol) and 2-methylphe- 8 : 2 hexane–EtOAc) to give 6i (45.0 mg, 63%) as a white solid;
nylallene (5g)29a (52.0 mg, 0.40 mmol). The crude product was Rf (7 : 3 hexane–EtOAc) = 0.45; M.p. 134–135 °C (83% ee); [α]D24
purified using column chromatography (silica gel, = +114.7 (c 1.0, CHCl3); IR (KBr): ν = 3001, 2977, 2932, 1746,
8 : 2 hexane–EtOAc) to provide 6g (56.0 mg, 82%) as a white 1726, 1492, 1311, 1247, 1077 cm−1; 1H NMR (400 MHz, CDCl3):
solid; Rf (7 : 3 hexane–EtOAc) = 0.55; M.p. 158–159 °C (99% ee); δ 1.01 (s, 9H, C(CH3)3), 1.64 (s, 3H, CH3), 2.00–2.05 (m, 1H,
[α]2D4 = +137.2 (c 1.2, CHCl3); IR (KBr): ν = 2985, 2976, 2922, CH2), 2.31–2.39 (m, 1H, CH2), 2.47–2.53 (m, 1H, CH2),
1744, 1725, 1315, 1159, 1075 cm−1; 1H NMR (400 MHz, CDCl3): 2.70–2.76 (m, 1H, CH2), 3.84 (s, 3H, CH3), 4.83 (s, 1H, CH),
δ 1.04 (s, 9H, C(CH3)3), 1.66 (s, 3H, CH3), 2.00–2.05 (m, 1H, 4.96 (s, 1H, C10–H), 5.06 (s, 1H, C10–H), 6.84–6.88 (m, 2H, Ar),
CH2), 2.32–2.40 (m, 1H, CH2), 2.42 (s, 3H, CH3) 2.50–2.56 (m, 7.15–7.17 (m, 1H, Ar), 7.25 (d, J = 7.1 Hz, 1H, Ar); 13C NMR
1H, CH2), 2.67–2.76 (m, 1H, CH2), 4.35 (s, 1H, CH), 4.91 (s, 1H, (100 MHz, CDCl3): δ 23.5 (CH3), 27.2 (C(CH3)3), 34.4 (CH2),
C10–H), 5.10 (s, 1H, C10–H), 7.08–7.11 (m, 3H, Ar), 7.23 (m, 40.0 (CH2), 46.3 (OCH3), 55.4 (CH), 81.7 (C), 83.6 (C), 92.0 (C),
1H, Ar); 13C NMR (100 MHz, CDCl3): δ 20.6 (CH3), 23.5 (CH3), 108.1 (CH2), 110.0 (CH), 121.2 (CH), 127.7 (CH), 128.1 (CH),
27.2 (C(CH3)3), 34.3 (CH2), 39.8 (CH2), 50.5 (CH), 82.2 (C), 83.6 131.6 (C), 156.1 (C), 157.4 (C), 165.1 (C), 200.8 (C); HRMS (ESI)
(C), 92.1 (C), 108.5 (CH2), 126.8 (CH), 127.0 (CH), 127.2 (CH), m/z calcd for C21H26O5Na [M + Na]+ 381.1673, found 381.1672.
129.8 (CH), 134.9 (C), 141.6 (C), 157.4 (C), 164.9 (C), 200.7 (C); Anal. Calcd for C21H26O5: C, 70.37; H, 7.31. Found: C, 70.17;
HRMS (ESI) m/z calcd for C21H26O4Na [M + Na]+ 365.1723, H, 7.28.
found 365.1724. Anal. Calcd for C21H26O4: C, 73.66; H, 7.65.
Found: C, 73.38; H, 7.62.
The enantiomeric excess of 6i was determined to be 83% by
HPLC analysis using Daicel Chiralpak AD-H column
a
The enantiomeric excess of 6g was determined to be 99% (9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
by HPLC analysis using a Daicel Chiralpak IC column tR (major) = 7.4 min; tR (minor) = 10.7 min.
(9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 205 nm):
tR (major) = 16.8 min; tR (minor) = 22.0 min.
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-6-methylene-7-phenyl-8-
oxabicyclo[3.2.1]octan-2-one (6j). According to the typical pro-
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(3-methoxyphenyl)-5- cedure for Rh(II)-catalyzed enantioselective 1,3-dipolar cyclo-
methyl-6-methylene-8-oxabicyclo[3.2.1]octan-2-one (6h). According addition, 6j was prepared from α-diazo-β-ketoester 4b9a (45.2 mg,
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0.20 mmol) and phenylallene (5a) (46.4 mg, 0.40 mmol). The 1.2 Hz, 1H, CH), 4.99 (t, J = 1.6 Hz, 1H, C10–H), 5.11 (br s, 1H,
crude product was purified using column chromatography CH), 5.26 (t, J = 1.6 Hz, 1H, C10–H), 7.12–7.15 (m, 2H, Ar),
(silica gel, 8 : 2 hexane–EtOAc) to provide 6j (50.0 mg, 80%) as 7.39–7.43 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3): δ 27.5
a white solid; Rf (7 : 3 hexane–EtOAc) = 0.50; M.p. 139–142 °C (C(CH3)3), 33.4 (CH2), 33.7 (CH2), 54.7 (CH), 78.8 (CH), 82.8 (C),
(96% ee); [α]2D4 = +110.4 (c 1.1, CHCl3); IR (KBr): ν = 2980, 2929, 94.1 (C), 110.4 (CH2), 121.2 (C), 130.2 (CH), 131.6 (CH), 141.1
1
1744, 1717, 1367, 1312, 1181, 1152, 1094, 1058, 700 cm−1; H (C), 153.0 (C), 164.4 (C), 200.3 (C); HRMS (ESI) m/z calcd for
NMR (400 MHz, CDCl3): δ 1.07 (s, 9H, C(CH3)3), 2.04–2.08 (m, C19H21BrO4Na [M + Na]+ 415.0514, found 415.0526. Anal.
1H, CH2), 2.48–2.58 (m, 2H, CH2), 2.63–2.70 (m, 1H, CH2), Calcd for C19H21BrO4: C, 58.03; H, 5.38; Br, 20.32. Found: C,
3.94 (d, J = 1.2 Hz, 1H, CH), 4.99 (s, 1H, C10–H), 5.11 (br s, 1H, 57.76; H, 5.32; Br, 20.04.
CH), 5.23 (s, 1H, C10–H), 7.21–7.28 (m, 5H, Ar); 13C NMR
The enantiomeric excess of 6l was determined to be 92% by
(100 MHz, CDCl3): δ 27.3 (C(CH3)3), 33.4 (CH2), 33.6 (CH2), HPLC analysis using a Daicel Chiralpak IC column (9 : 1 hexane–
55.3 (CH), 78.7 (CH), 82.3 (C), 94.1 (C), 109.8 (CH2), 127.1 2-propanol, flow rate = 1.0 mL min−1, 226 nm): tR (minor) =
(CH), 128.3 (CH), 128.4 (CH), 141.9 (C), 153.4 (C), 164.5 (C), 16.0 min; tR (major) = 45.1 min.
200.4 (C); HRMS (ESI) m/z calcd for C19H22O4Na [M + Na]+
337.1411, found 337.1410.
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-(trifluoromethyl)-
phenyl)-6-methylene-8-oxabicyclo[3.2.1]octan-2-one (6m). Accord-
The enantiomeric excess of 6j was determined to be 96% by ing to the typical procedure for Rh(II)-catalyzed enantio-
HPLC analysis using Daicel Chiralpak IC column selective 1,3-dipolar cycloaddition, 6m was prepared from
(9 : 1 hexane–2-propanol, flow rate = 1.5 mL min−1, 205 nm): α-diazo-β-ketoester 4b (45.2 mg, 0.20 mmol) and 4-(trifluoro-
tR (minor) = 13.5 min; tR (major) = 35.2 min. methyl)phenylallene (5e) (73.7 mg, 0.40 mmol). The crude
a
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-methoxyphenyl)-6- product was purified using column chromatography (silica gel,
methylene-8-oxabicyclo[3.2.1]octan-2-one (6k). According to 8 : 2 hexane–EtOAc) to provide 6m (52.0 mg, 68%) as a pale
the typical procedure for Rh(II)-catalyzed enantioselective 1,3- yellow solid; Rf (7 : 3 hexane–EtOAc) = 0.45; M.p. 164–165 °C
dipolar cycloaddition, 6k was prepared from α-diazo-β-keto- (98% ee); [α]2D2 = +150.6 (c 0.9, CHCl3); IR (KBr): ν = 2995, 2987,
ester 4b (45.2 mg, 0.20 mmol) and 4-methoxyphenylallene (5c) 2952, 1747, 1724, 1617, 1423, 1326, 1162, 1129, 1110, 1096,
(58.4 mg, 0.40 mmol). The crude product was purified using 1069 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.01 (s, 9H, C(CH3)3),
column chromatography (silica gel, 8 : 2 hexane–EtOAc) to 1.99–2.04 (m, 1H, CH2), 2.44–2.63 (m, 3H, CH2), 3.95 (d, J =
afford 6k (51.4 mg, 75%) as a white solid; Rf (7 : 3 hexane– 1.6 Hz, 1H, CH), 4.94 (s, 1H, C10–H), 5.07 (br s, 1H, CH),
EtOAc) = 0.45; M.p. 130–132 °C (96% ee); [α]2D4 = +93.3 (c 1.0, 5.22 (s, 1H, C10–H), 7.31 (d, J = 7.9 Hz, 2H, Ar), 7.47 (d, J =
CHCl3); IR (KBr): ν = 3001, 2981, 2961, 1745, 1719, 1607, 1509, 7.9 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3) δ 27.3 (C(CH3)3),
1242, 1065 cm−1 1H NMR (400 MHz, CDCl3): δ 1.11 (s, 9H, 33.2 (CH2), 33.5 (CH2), 54.8 (CH), 78.7 (CH), 82.7 (C), 93.9 (C),
;
C(CH3)3), 2.02–2.07 (m, 1H, CH2), 2.45–2.57 (m, 2H, CH2), 110.5 (CH2), 125.3 (CH), 128.1 (C), 128.7 (CH), 129.2 (C),
2.62–2.71 (m, 1H, CH2), 3.26 (s, 3H, CH3), 3.91 (s, 1H, CH), 145.8 (C), 152.6 (C), 164.2 (C), 199.9 (C); HRMS (ESI) m/z
4.98 (t, J = 1.6 Hz, 1H, C10–H), 5.10 (br s, 1H, CH), 5.23 (t, J = calcd for C20H21F3O4Na [M + Na]+ 405.1393, found 405.1392.
1.6 Hz, 1H, C10–H), 6.78–6.82 (m, 2H, Ar), 7.13–7.16 (m, 2H,
The enantiomeric excess of 6m was determined to be 98%
Ar); 13C NMR (100 MHz, CDCl3): δ 27.4 (C(CH3)3), 33.4 (CH2), by HPLC analysis using a Daicel Chiralpak IC column
33.6 (CH2), 54.6 (OCH3), 55.3 (CH), 78.6 (CH), 82.2 (C), 94.2 (3 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
(C), 109.5 (CH2), 113.7 (CH), 129.5 (CH), 134.1 (C), 153.6 (C), tR (minor) = 6.8 min; tR (major) = 13.7 min.
158.7 (C), 164.5 (C), 200.6 (C); HRMS (ESI) m/z calcd for
C20H24O5Na [M + Na]+ 367.1516, found 367.1516. Anal. Calcd phenyl)-8-oxabicyclo[3.2.1]octan-2-one (6n). According to the
for C20H24O5: C, 69.75; H, 7.02. Found: C, 69.58; H, 6.99. typical procedure for Rh(II)-catalyzed enantioselective 1,3-
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-6-methylene-7-(2-methyl-
The enantiomeric excess of 6k was determined to be 96% dipolar cycloaddition, 6n was prepared from α-diazo-β-ketoe-
by HPLC analysis using a Daicel Chiralpak AD-H column ster 4b (45.2 mg, 0.20 mmol) and 2-methylphenylallene (5g)
(9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): (52.0 mg, 0.40 mmol). The crude product was purified using
tR (minor) = 10.6 min; tR (major) = 17.0 min.
column chromatography (silica gel, 8 : 2 hexane–EtOAc) to
(1R*,5R*,7R*)-7-(4-Bromophenyl)-1-tert-butoxycarbonyl-6- afford 6n (49.6 mg, 76%) as a white solid; Rf (7 : 3 hexane–
methylene-8-oxabicyclo[3.2.1]octan-2-one (6l). According to EtOAc) = 0.50; M.p. 111–113 °C (99% ee); [α]2D4 = +128.9 (c 1.2,
the typical procedure for Rh(II)-catalyzed enantioselective 1,3- CHCl3); IR (KBr): ν = 2981, 2953, 2936, 1722, 1367, 1301, 1161,
dipolar cycloaddition, 6l was prepared from α-diazo-β-ketoester 1090, 1076, 761 cm−1 1H NMR (400 MHz, CDCl3): δ 1.06 (s,
;
4b (45.2 mg, 0.20 mmol) and 4-bromophenylallene (5d) 9H, C(CH3)3), 2.05–2.10 (m, 1H, CH2), 2.44 (s, 3H, CH3),
(78.0 mg, 0.40 mmol). The crude product was purified using 2.50–2.60 (m, 2H, CH2), 2.68–2.74 (m, 1H, CH2), 4.28 (d, J = 1.6
column chromatography (silica gel, 8 : 2 hexane–EtOAc) to give Hz, 1H, CH), 4.93–4.94 (m, 1H, C10–H), 5.11 (br s, 1H, CH),
6l (57.4 mg, 73%) as a pale yellow solid; Rf (7 : 3 hexane–EtOAc) 5.21 (s, 1H, C10–H), 7.09–7.13 (m, 3H, Ar), 7.24–7.26 (m,
= 0.40; M.p. 157–159 °C (92% ee); [α]2D2 = +74.6 (c 1.0, CHCl3); 1H, Ar); 13C NMR (100 MHz, CDCl3): δ 20.5 (CH3), 27.2
IR (KBr): ν = 2981, 1745, 1723, 1482, 1369, 1311, 1159, 1094, (C(CH3)3), 33.4 (CH2), 33.5 (CH2), 49.5 (CH), 78.8 (CH), 82.3 (C),
1064 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.12 (s, 9H, C(CH3)3), 94.3 (C), 109.2 (CH2), 126.9 (CH), 127.4 (CH), 128.7 (CH), 129.7
2.04–2.09 (m, 1H, CH2), 2.50–2.69 (m, 3H, CH2), 3.92 (t, J = (CH), 135.2 (C), 141.0 (C), 153.9 (C), 164.6 (C), 200.4 (C);
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HRMS (ESI) m/z calcd for C20H24O4Na [M + Na]+ 351.1566,
The enantiomeric excess of 6p was determined to be
found 351.1567. Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. 94% by HPLC analysis using
a Daicel Chiralpak AD-H
Found: C, 72.93; H, 7.41.
column (AD-H + AD-H, 9 : 1 hexane–2-propanol, flow rate =
The enantiomeric excess of 6n was determined to be 99% 1.0 mL min−1, 226 nm): tR (major) = 18.9 min; tR (minor) =
by HPLC analysis using a Daicel Chiralpak IC column 20.5 min.
(3 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
tR (minor) = 9.9 min; tR (major) = 18.2 min.
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-(trifluoromethyl)-
phenyl)-6-methylene-5-phenyl-8-oxabicyclo[3.2.1]octan-2-one
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-6-methylene-5,7-diphenyl- (6q). According to the typical procedure for Rh(II)-catalyzed
8-oxabicyclo[3.2.1]octan-2-one (6o). According to the typical enantioselective 1,3-dipolar cycloaddition, 6q was prepared
procedure for Rh(II)-catalyzed enantioselective 1,3-dipolar from α-diazo-β-ketoester 4c (60.4 mg, 0.20 mmol) and 4-(tri-
cycloaddition, 6o was prepared from α-diazo-β-ketoester 4c5d fluoromethyl)phenylallene (5e) (73.7 mg, 0.40 mmol). The
(60.4 mg, 0.20 mmol) and phenylallene (5a) (46.4 mg, crude product was purified using column chromatography
0.40 mmol). The crude product was purified using column (Wakogel® C-200, 8 : 2 hexane–EtOAc) to afford 6q (81.0 mg,
chromatography (Wakogel® C-200, 8 : 2 hexane–EtOAc) to give 88%) as a white solid; Rf (8 : 2 hexane–EtOAc)
= 0.45;
6o (74.9 mg, 96%) as a white solid; Rf (8 : 2 hexane–EtOAc) = M.p. 166–167 °C (99% ee); [α]2D2 = +69.9 (c 0.8, CHCl3); IR (KBr):
0.60; M.p. 148–150 °C (97% ee); [α]2D3 = +62.0 (c 1.2, CHCl3); ν = 2983, 2931, 1747, 1723, 1616, 1480, 1322, 1123, 1059 cm−1
;
IR (KBr): ν = 2975, 1752, 1731, 1368, 1311, 1158, 1078, 1H NMR (400 MHz, CDCl3): δ 1.11 (s, 9H, C(CH3)3), 2.66–2.73
1
700 cm−1; H NMR (400 MHz, CDCl3): δ 1.10 (s, 9H, C(CH3)3), (m, 3H, CH2), 2.84–2.91 (m, 1H, CH2), 4.24 (s, 1H, CH), 5.04 (s,
2.64–2.70 (m, 3H, CH2), 2.88–2.95 (m, 1H, CH2), 4.16 (m, 1H, 1H, C10–H), 5.18 (s, 1H, C10–H), 7.34–7.46 (m, 5H, Ar), 7.54
CH), 5.02 (d, J = 1.6 Hz, 1H, C10–H), 5.12 (d, J = 1.6 Hz, 1H, (d, J = 7.5 Hz, 2H, Ar), 7.68 (d, J = 7.5 Hz, 2H, Ar); 13C NMR
C10–H), 7.19–7.27 (m, 5H, Ar), 7.32–7.36 (m, 1H, Ar), 7.40–7.44 (100 MHz, CDCl3): δ 27.3 (C(CH3)3), 34.2 (CH2), 38.9 (CH2),
(m, 2H, Ar), 7.69–7.71 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3): 55.9 (CH), 82.8 (C), 86.1 (C), 91.7 (C), 112.6 (CH2), 125.3 (CH),
δ 27.3 (C(CH3)3), 34.2 (CH2), 38.9 (CH2), 56.3 (CH), 82.3 (C), 125.4 (CH), 128.0 (CH), 128.5 (C), 128.6 (CH), 128.8 (CH), 129.3
86.0 (C), 91.9 (C), 112.0 (CH2), 125.4 (CH), 127.1 (CH), (C), 140.4 (C), 145.8 (C), 155.1 (C), 164.3 (C), 199.8 (C); HRMS
127.8 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 140.7 (C), (ESI) m/z calcd for C26H25F3O4Na [M + Na]+ 481.1597, found
141.9 (C), 155.8 (C), 164.6 (C), 200.2 (C); HRMS (ESI) m/z 481.1590. Anal. Calcd for C26H25F3O4: C, 68.11; H, 5.50; F,
calcd for C25H26O4Na [M + Na]+ 413.1724, found 413.1723. 12.43. Found: C, 67.99; H, 5.60; F, 12.4.
Anal. Calcd for C25H26O4: C, 76.90; H, 6.71. Found: C, 76.81;
H, 6.74.
The enantiomeric excess of 6q was determined to be 99%
by HPLC analysis using a Daicel Chiralpak IC column
The enantiomeric excess of 6o was determined to be 97% (50 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
by HPLC analysis using a Daicel Chiralpak IC column tR (major) = 28.6 min; tR (minor) = 34.2 min.
(9 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm):
tR (major) = 17.3 min; tR (minor) = 24.3 min.
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-6-methylene-7-(3-methyl-
phenyl)-5-phenyl-8-oxabicyclo[3.2.1]octan-2-one (6r). Accord-
(1R*,5R*,7R*)-1-tert-Butoxycarbonyl-7-(4-methoxyphenyl)-6- ing to the typical procedure for Rh(II)-catalyzed enantio-
methylene-5-phenyl-8-oxabicyclo[3.2.1]octan-2-one (6p). Accord- selective 1,3-dipolar cycloaddition, 6r was prepared from
ing to the typical procedure for Rh(II)-catalyzed enantio- α-diazo-β-ketoester 4c (60.4 mg, 0.20 mmol) and 2-methylphe-
selective 1,3-dipolar cycloaddition, 6p was prepared from nylallene (5g) (52.0 mg, 0.40 mmol). The crude product was
α-diazo-β-ketoester 4c (60.4 mg, 0.20 mmol) and 4-methoxy- purified using column chromatography (Wakogel® C-200,
phenylallene (5c) (58.4 mg, 0.40 mmol). The crude product 8 : 2 hexane–EtOAc) to give 6r (79.2 mg, 98%) as a white solid;
was purified by column chromatography (Wakogel® C-200, Rf (8 : 2 hexane–EtOAc) = 0.50; M.p. 154–155 °C (99% ee); [α]D19
8 : 2 hexane–EtOAc) to provide 6p (79.0 mg, 94%) as a white = +82.7 (c 1.0, CHCl3); IR (KBr): ν = 2980, 2922, 1747, 1727,
1
solid; Rf (8 : 2 hexane–EtOAc) = 0.50; M.p. 154–155 °C (94% ee); 1368, 1310, 1159, 1084, 755 cm−1; H NMR (400 MHz, CDCl3):
[α]2D0 = +83.2 (c 1.0, CHCl3); IR (KBr): ν = 2979, 2930, 1733, δ 1.09 (s, 9H, C(CH3)3), 2.45 (s, 3H, CH3), 2.64–2.70 (m, 3H,
1
1610, 1511, 1311, 1244, 1158, 1081 cm−1; H NMR (400 MHz, CH2), 2.90–2.99 (m, 1H, CH2), 4.51 (s, 1H, CH), 4.95 (d, J = 1.6
CDCl3): δ 1.15 (s, 9H, C(CH3)3), 2.62–2.69 (m, 3H, CH2), Hz, 1H, C10–H), 5.07 (d, J = 1.6 Hz, 1H, C10–H), 7.06–7.14 (m,
2.84–2.90 (m, 1H, CH2), 3.76 (s, 3H, CH3), 4.14 (s, 1H, CH), 3H, Ar), 7.26–7.29 (m, 1H, Ar), 7.32–7.36 (m, 1H, Ar), 7.41–7.44
5.02 (d, J = 1.2 Hz, 1H, C10–H), 5.12 (d, J = 1.2 Hz, 1H, C10–H), (m, 2H, Ar), 7.70–7.72 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3):
6.79–6.81 (m, 2H, Ar), 7.17–7.19 (m, 2H, Ar), 7.32–7.36 (m, 1H, δ 20.6 (CH3), 27.3 (C(CH3)3), 34.1 (CH2), 38.9 (CH2), 50.5 (CH),
Ar), 7.41–7.44 (m, 2H, Ar), 7.69–7.71 (m, 2H, Ar); 13C NMR 82.4 (C), 86.0 (C), 91.9 (C), 111.3 (CH2), 125.4 (CH), 126.8 (CH),
(100 MHz, CDCl3): δ 27.4 (C(CH3)3), 34.3 (CH2), 39.0 (CH2), 127.0 (CH), 127.6 (CH), 127.8 (CH), 128.5 (CH), 129.8 (CH),
55.3 (OCH3), 55.7 (CH), 82.3 (C), 85.9 (C), 91.9 (C), 111.7 (CH2), 135.2 (C), 140.7 (C), 141.0 (C), 156.2 (C), 164.7 (C), 200.3 (C);
113.8 (CH), 125.4 (CH), 127.8 (CH), 128.5 (CH), 129.6 (CH), HRMS (ESI) m/z calcd for C26H28O4Na [M + Na]+ 427.1880,
134.1 (C), 140.8 (C), 156.0 (C), 158.7 (C), 164.7 (C), 200.4 (C); found: 427.1891. Anal. Calcd for C26H28O4: C, 77.20; H, 6.98.
HRMS (ESI) m/z calcd for C26H28O5Na [M + Na]+ 443.1827, Found: C, 76.81; H, 6.97.
found: 443.1840. Anal. Calcd for C26H28O5: C, 74.26; H, 6.71.
Found: C, 73.81; H, 6.86.
The enantiomeric excess of 6r was determined to be
99% by HPLC analysis using a Daicel Chiralpak IC column
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(3 : 1 hexane–2-propanol, flow rate = 1.0 mL min−1, 226 nm): tR
(major) = 7.2 min; tR (minor) = 12.8 min.
4 For asymmetric total synthesis of vindoline and vindoro-
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Acknowledgements
This research was supported, in part, by a Grant-in Aid for
Scientific Research on Innovative Areas “Organic Synthesis
Based on Reaction Integration” (no. 2105) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. We
thank Ms S. Oka and M. Kiuchi of the Center for Instrumental
Analysis at Hokkaido University for technical assistance with
the MS and elemental analysis.
6 (a) S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno,
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