Enantioselective approach to 13a-methylphenanthroindolizidine alkaloids

Article abstract of DOI:10.1021/jo3012122

The first enantioselective approach to 13a-methylphenanthroindolizidine alkaloids is reported, featuring an efficient stereoselective Seebach's alkylation and Pictet-Spengler cyclization. The proposed and other three most probable structures were ruled out, indicating hypoestestatin 1 needs further assignment.

Full text of DOI:10.1021/jo3012122

Article
pubs.acs.org/joc
Enantioselective Approach to 13a-Methylphenanthroindolizidine
Alkaloids
Bo Su, Chunlong Cai, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first enantioselective approach to 13a-methylphenanthroindolizidine alkaloids is reported, featuring an
efficient stereoselective Seebach’s alkylation and Pictet−Spengler cyclization. The proposed and other three most probable
structures were ruled out, indicating hypoestestatin 1 needs further assignment.
INTRODUCTION
■
Phenanthroindolizidine alkaloids, mainly isolated from Cyn-
anchum, Pergularia, Tylophora, and some genera of the
Asclepiadaceas family, have attracted great and long-lasting
attention in the past decades for their profound biological
activities, among which the excellent cytotoxic activity against
various cancer cell lines is most intriguing.1 Among the more
than 60 alkaloids of this class isolated until now, (R)-
tylophorine (1a) and (R)-antofine (1b) are well-known
representative 13a-H members (Figure 1).2 In 1984, two
novel phenanthroindolizidine alkaloids bearing a methyl group
at the 13a-position were isolated from Tylophora hirsuta and
named as 13a-methyltylohirsutine (3a) and 13a-methyltylohir-
sutinidine (3b) by Bhutani.3 In the same year, Pettit et al
reported another two 13a-methyl members, hypoestestatin 1
(2a) and hypoestestatin 2 (2b) and their very profound
cytotoxic activity (ED50 = 10−5 μg/mL against the murine P-
388 cell line).4 Some other 13a-methyl analogues (3c and 4)
and seco-analogues were subsequently reported in later years.5
Although a great many of synthetic strategies have been
developed for the 13a-H members of phenanthroindolizidine
alkaloids,6 both syntheses and bioactivities of the 13a-
Figure 1. Representative structures of phenanthroindolizidines.
methylphenanthroindolizidines were widely unexplored. The
major challenge is the installation (especially from enantiose-
lective) of the quaternary carbon center adjacent to the
nitrogen. In 2007, Ishibashi and colleagues reported the first
total synthesis of the proposed structure of hypoestestatin 1
(( )-2a) in 12 steps and 7% overall yield, featuring a radical
cascade cyclization as key step in which 39% yield was
obtained.7 Meanwhile, they gave a conclusion that the originally
reported structure of hypoestestatin 1 (2a) was wrong because
the spectroscopic data of the synthetic racemic sample could
Received: June 14, 2012
Published: September 5, 2012
© 2012 American Chemical Society
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a
not match with the literature. Further investigation on the
spectroscopic data of the proposed structure of hypoestestatin 1
was needed, since many factors, such as concentration, acid in
the solvent, the identity of the counteranion, impurity in the
sample, the degree of CDCl3 decomposition (i.e., DCl
content), and so on, could lead to variance (especially from
alkaloids) in spectroscopic data.8 As part of our ongoing
research into the synthesis and biological evaluation of
phenanthroindolizidine alkaloids,1d,6a,e,9 we herein report the
first enantioselective and general approach to the widely
unexplored 13a-methylphenanthroindolizidine alkaloids.
Scheme 2. Concise Total Synthesis of 2a
RESULTS AND DISCUSSION
■
Our synthetic program provided another opportunity to
showcase Seebach’s concept of “self-regeneration of stereo-
chemistry (SRS)”,10 a method for the asymmetric α alkylation
of amino acids that has been widely applied in the synthesis of
novel amino acids and peptidomimetics and in the total
synthesis of several natural products.11
Retrosynthetically, to guarantee the success and efficiency of
the installation of the angular methyl group in 2a, our strategy
relied on the transformation of the ester 5 (Scheme 1). The
Scheme 1. Retrosynthetic Analysis of Hypoestestatin 1 (2a)
a
Reagents and conditions: (a) PBr3, CH2Cl2; 0 °C to rt; (b)
Cl3CCH(OH)2, CHCl3, reflux for 6 h, 83%; (c) LDA, THF, −78 °C,
84% from 10; (d) Na, CH3OH, reflux for 30 min; then AcCl at 0 °C;
then reflux for 12 h; (e) HCHO, HCl, EtOH, reflux for 8 h (75% over
two steps); (f) LiAlH4, THF, rt 30 min, 98%; (g) MsCl, NEt3, CH2Cl2,
1 h; (h) LiBHEt3, THF, −5 °C to rt (73% over two steps, >99% ee).
crystalline solid and was much more convenient for operation
and storage.
With the key intermediate 7 in hand, we then subjected it to
hydrolysis. Although the alkylation precursor 8 was sensitive to
acid, 7 could not be hydrolyzed under acidic conditions. The
amine ester 6 was obtained via a one-pot transesterification
ring-opening without further purification. It was then converted
to the phenanthroindolizidine ester 5 through a Pictet−
Spengler cyclization. As we initially envisioned the angular
methyl group in the target molecule, 2 was successfully and
efficiently installed from ester 5 via a sequential LiAlH4
reduction, methanesulfonylation, and superhydride reduction.
It is also noteworthy that other deoxygenation methods, such as
Barton−McCombie radical deoxygenation, transforming 12 to
bromide then reduction, and transforming 12 to aldehyde then
reduced under Wolff−Kishner conditions did not work well.
ester can be converted to alcohol or aldehyde, both of which
can produce methyl group through deoxygenation. The D ring
of the ester 5 was envisioned to arise from intermediate 6 via a
Pictet−Spengler cyclization. We reasoned that the cyclization
precursor 6 could be derived from phenanthryl bromide 9 and
(R)-proline derivative 8 via sequential Seebach’s stereoselective
alkylation and hydrolysis.
The readily prepared known phenanthryl alcohol 10 served
as the starting material in the total synthesis of 2a (Scheme
2).12 Treatment of alcohol 10 with PBr3 provided bromide 9 in
quantitative yield which was used without further purification
due to its liability to decompose. As expected, the high
stereoselectively alkylated compound 7 was obtained as the
only diastereomer (confirmed by NMR and HPLC) and in
excellent yield from bromide 9 and (R)-proline derivative 8.
Oxazolidinone 8 was prepared by a modified Seebach’s
procedure from (R)-proline.13 It is worth noting that the
modified Seebach’s oxazolidinone 8 was obtained as a white
1
Our synthetic 2a showed H NMR and 13C NMR spectra
identical with those of racemic 2a reported by Ishibashi and was
unambiguously derived, thus supporting Ishibashi’s conclusion
that hypoestestatin 1 was misassigned.7 We also found that the
synthetic 2a ([α]2D0 = +31.7 (c = 0.75, CH2Cl2) has opposite
optical rotation with the isolated sample hypoestestatin 1 ([α]D31
= −36.6 (c = 0.55, CH2Cl2),4 suggesting that the absolute
configuration of hypoestestatin 1 previously assigned by Pettit
may also be wrong. Using the same strategy, we then
synthesized its enantiomer R-2a from (S)-proline derivative
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ent-8 and the specific rotation of R-2a ([α]2D0 = −34.4 (c = 0.5,
CH2Cl2) matched well with hypoestestatin 1.
Scheme 3. Synthesis of the Three Most Probable Structures
of 2a
a
Although the NMR spectra of 2a and R-2a also could not
match with those of hypoestestatin 1, some very interesting
phenomena were noted. First, as Pettit had noted, 2a was
extremely sensitive to air and acid, especially in solution,4 so
1
great caution should be taken in its handling. Second, the H
NMR signal of 13a-methyl (varies from 1.02 to 1.6) could be
affected by trace amounts of acid in the CDCl3 and impurities
residual in the sample; third, with incremental amounts of acid
added to the sample, all of the chemical shift values of the
aromatic protons increased, but just a little, with the same trend
(Figure 2) (the titration experiment was done, see the
a
Reagents and conditions: (a) PBr3, CH2Cl2; 0 °C to rt; (b) LDA,
THF, 8, −78 °C; (c) Na, CH3OH, reflux for 30 min; then AcCl at 0
°C; then reflux for 12 h; (d) HCHO, HCl, EtOH, reflux for 8 h; (e)
LiAlH4, THF, rt 30 min; (f) MsCl, NEt3, CH2Cl2, 1 h; (g) LiBHEt3,
THF, −5 °C to rt.
methoxycarbonyl versus methyl, have little impact on the
NMR chemical shifts of the aromatic signals.
CONCLUSION
■
In conclusion, we have developed an eight-step enantioselective
strategy to both enantiomers of 13a-methylphenanthroindoli-
zidine alkaloids (37% overall yield and >99% ee) from
commercially available proline and readily prepared phenanthr-
yl alcohols. The overall procedure is simple (chromatographic
purification needed in only three steps), versatile, and
preparative and thus provides sufficient sample for biological
and SAR evaluation. In addition, besides the proposed
structure, another three possible structures of hypoestestatin
1 were ruled out. Synthesis of other 13a-methylphenanthroin-
dolizides and biological evaluation were in progress and will be
reported in due course.
1
Figure 2. Variance of H NMR of aromatic protons with incremental
amounts of acid added (red lines indicate literature values for 2a).
Supporting Information). From the interesting phenomena
mentioned above, we can only assume that acidic impurities (at
least not the only factor) in the NMR solvent or in the isolated
product were not responsible for the difference observed in
chemical shifts between the synthetic and natural materials.
In order to further demonstrate the true structure of
hypoestestatin 1, we speculated that the placement of the
three methoxyl groups on the aromatic nucleus assigned by
Pettit was probably wrong. On the basis of the methoxyl groups
distribution of the over 60 phenanthroindolizidine alkaloids
isolated, three most probable placement of methoxyl groups
were (a) 3,6,7-, (b) 2,3,7-, and (c) 2,6,7-. Although great
synthetic efforts were made (Scheme 3),14 unfortunately and
disappointingly, none of the three arrangements (a−c) proved
to be that in hypoestestatin 1, as revealed by NMR chemical
shift data for the aromatic protons. These siginals differed
significantly from those of hypoestestatin 1 (Figure 3). We also
found that the widely differing 13a-substituents, such as
EXPERIMENTAL SECTION
The melting points were determined with an X-4 binocular
microscope melting-point apparatus and were uncorrected. H NMR
■
1
spectra were obtained by using spectrometer (400 MHz). Chemical
shifts (δ) were given in parts per million (ppm) and were measured
downfield from internal tetramethylsilane. 13C NMR spectra were
recorded by using spectrometer (100 MHz) and CDCl3 or CD3OD as
solvent. Chemical shifts (δ) are reported in parts per million. The
following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, b = broad, td = triple
doublet, dt = double triplet, dq = double quartet, m = multiplet. High-
resolution mass spectra were obtained with an FT-ICR MS
spectrometer. Optical rotations were measured. The enantiomeric
excesses were determined by HPLC with a Chiralcel AD-H or AS-H
column.
(3S,7aR)-3-(Trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-
1(3H)-one (8).13 To a suspension of (R)-proline 11 (11.5 g, 100
mmol) in chloroform (500 mL) was added 2,2,2-trichloroethane-1,1-
diol (chloral hydrate) (26.5 g, 120 mmol). A 25 mL Dean−Stark trap
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1
Figure 3. Aromatic H NMR of isolated product and other most probable methoxyl groups distributions.
topped with a reflux condenser was attached to the reaction vessel, and
the reaction mixture was heated at reflux until (R)-proline was no
longer visibly suspended. The reaction mixture was evaporated under
reduced pressure, and the resulting brown, crystalline solid was
recrystallized from ethanol to give 8 (18.6 g, 83%) as a colorless to
portions under an atmosphere of nitrogen. The reaction mixture was
warmed to 50 °C and kept at this temperature until the substrates
completely dissolved. The reaction mixture was then transferred to 0
°C, and AcCl (3.14 g, 40 mmol) was added through a pressure-
equalizing addition funnel over about 30 min. The reaction mixture
was stirred for an additional 1 h and then heated at reflux for 12 h. The
reaction mixture was evaporation in vacuo, and then aqueous saturated
sodium dicarbonate (30 mL) and CH2Cl2 (30 mL) were added. After
separation, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The crude amine 6, without
further purification, was dissolved in ethanol (100 mL) to which
aqueous HCHO (3 mL, 30% w/w) and HCl (12 mol/L, 3 mL) were
added. The resulting mixture was refluxed in the dark for 20 h under
an atmosphere of nitrogen. The solvents were evaporated, and the
residue was taken up in NaOH (3 mol/L, 30 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by chromatography on silica gel (50:1 CH2Cl2/
MeOH) to give 5 (0.84 g, 1.5 mmol, 75% over two steps) as a gray-
white solid: mp 187−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (s,
1H), 7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J =
8.8 Hz, 1H), 4.52 (d, J = 16.0 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.10
(s, 3H), 4.09 (s, 3H), 4.01 (s, 3H), 3.87 (d, J = 15.8 Hz, 1H), 3.56 (s,
3H), 3.39−3.31 (m, 1H), 3.29−3.21 (m, 1H), 2.98 (d, J = 15.8 Hz,
1H), 2.34−2.32 (m, 1H), 2.18−2.00 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.2, 156.6, 148.4, 147.4, 129.2, 125.8, 124.8, 123.4, 123.0,
122.9, 122.6, 113.8, 103.6, 102.9, 65.1, 55.0, 54.9, 54.5, 50.7, 50.3, 46.7,
36.5, 32.5, 20.0; HRMS (ESI) calcd for C25H28NO5 (M + H)+
422.1962, found 422.1966; [α]2D0 = +122.9 (c = 0.34, CHCl3).
(S)-(2,3,6-Trimethoxy-9,11,12,13,13a,14-hexahydrodibenzo-
[f,h]pyrrolo[1,2-b]isoquinolin-13a-yl)methanol (12). To a sol-
ution of 5 (1.26 g, 3 mmol) in THF (150 mL) was added LiAlH4 (0.12
g, 3 mmol) in portions under an atmosphere of nitrogen. Two hours
later, the reaction was quenched with aqueous saturated ammonium
chloride (20 mL). After separation, the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The combined organic phase was
concentrated in vacuo, and the residue was dissolved in CH2Cl2 (100
mL), washed with water (3 × 30 mL) and brine (30 mL), dried over
MgSO4, filtered, and concentrated in vacuo to give compound 12
(1.15 g, 2.9 mmol, 98%, >99%ee) as a light yellow solid: mp 163−165
°C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.91 (d, J = 2.2 Hz,
1H), 7.82 (d, J = 9.0 Hz, 1H), 7.31 (s, 1H), 7.21 (dd, J = 9.0, 2.2 Hz,
1H), 4.40 (d, J = 17.3 Hz, 1H), 4.29 (d, J = 17.3 Hz, 1H), 4.10 (s, 3H),
4.07 (s, 3H), 4.01 (s, 3H), 3.56 (d, J = 10.4 Hz, 1H), 3.47 (d, J = 10.4
Hz, 1H), 3.27−3.20 (m, 1H), 3.00 (d, J = 17.0 Hz, 1H), 2.87 (dd, J =
17.0, 8.5 Hz, 1H), 2.72 (d, J = 16.9 Hz, 1H), 2.30−2.20 (m, 1H),
1.96−1.84 (m, 2H), 1.83−1.74 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.7, 149.6, 148.5, 130.2, 126.7, 124.2, 124.2, 123.7, 123.3,
115.0, 104.9, 104.1, 103.6, 63.5, 61.4, 56.1, 56.0, 55.6, 52.1, 45.4, 34.3,
light brown crystals: mp 110−111 °C (lit.13 mp 107−109 °C); H
1
NMR (400 MHz, CDCl3) δ 5.17 (s, 1H) 4.12 (dd, J = 8.8, 4.6 Hz,
1H), 3.48−3.38 (m, 1H), 3.18−3.08 (m, 1H), 2.29−2.17 (m, 1H),
2.16−2.08 (m, 1H), 2.00−1.88 (m, 1H), 1.82−1.68 (m, 1H); HRMS
(ESI) calcd for C7H8Cl3NO2Na (M + Na)+ 265.9518, found
265.9512; [α]2D5 = −32.8 (c = 2, C6H6).
(3S,7aS)-3-(Trichloromethyl)-7a-((3,6,7-trimethoxyphe-
nanthren-9-yl)methyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-
one (7). To a solution of compound 1012 (1.79 g, 6 mmol) in CH2Cl2
(120 mL) was slowly added PBr3 (3.25 g, 12 mmol) in CH2Cl2 (10
mL) over about 10 min at 0 °C. The mixture was stirred at room
temperature for 3 h and then poured into ice−water (100 mL). The
CH2Cl2 layer was separated, washed with ice−water (2 × 50 mL) and
brine (50 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give a pale white solid. The crude phenanthrenyl
methane bromide 9 was used in the next step without further
purification due to its liability to decompose. To a solution of (i-
Pr)2NH (0.90 g, 9 mmol) in THF (10 mL) was slowly added n-BuLi
(4.3 mL, 2.2 M in hexane, 9.5 mmol) via syringe at −78 °C under an
atmosphere of nitrogen. Ten minutes later, compound 8 (2.21 g, 9
mmol) in THF (30 mL) was added to the reaction mixture via syringe
over 20 min. The reaction mixture was warmed to −35 °C and stirred
for an additional 30 min, and then the above crude phenanthrenyl
methane bromide 9 in THF (100 mL) was added via syringe over
about 30 min. The reaction mixture was warmed to room temperature,
stirred for an additional 3 h, and then quenched with a solution of
saturated aqueous ammonium chloride (100 mL). After separation, the
aqueous layer was extracted with EtOAc (2 × 100 mL). The combined
organic layer was concentrated under reduced pressure to give a yellow
oil which was purified by chromatography on silica gel (2:1 petroleum
ether (60−90 °C)/EtOAc) to give compound 7 (2.7 g, 5.2 mmol,
86%) as a white solid: mp 217−220 °C; 1H NMR (400 MHz, CDCl3)
δ 7.93 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.73
(s, 1H), 7.64 (s, 1H), 7.21 (dd, J = 8.8, 2.0 Hz, 1H), 5.05 (s, 1H), 4.13
(s, 3H), 4.09 (s, 3H), 4.03 (s, 3H), 3.73 (d, J = 14.6 Hz, 1H), 3.68 (d, J
= 14.6 Hz, 1H), 3.07−2.98 (m, 1H), 2.80−2.70 (m, 1H), 2.05 (d, 6.0
Hz, 1H), 2.03 (d, 6.0 Hz, 1H), 1.53−1.41 (m, 1H), 1.30−1.21 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 176.7, 158.3, 149.6, 148.8,
130.6, 130.1, 128.69, 127.62, 127.3, 125.8, 124.7, 115.7, 105.7, 103.7,
102.8, 100.6, 73.5, 58.2, 56.5, 56.0, 55.6, 38.84, 34.83, 25.0; HRMS
(ESI) calcd for C25H24Cl3NO5Na (M + Na)+ 546.0612, found
546.0610; [α]2D0 = +1.65 (c = 0.31, CHCl3).
(S)-Methyl 2,3,6-trimethoxy-9,11,12,13,13a,14-
hexahydrodibenzo[f,h]pyrrolo[1,2-b]isoquinoline-13a-carbox-
ylate (5). To a suspension of 7 (1.01 g, 2 mmol) in CH3OH (100
mL) at 0 °C was added sodium metal (46 mg, 2 mmol) in small
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28.1, 20.4; HRMS (ESI) calcd for C24H28NO4 (M + H)+ 394.2010,
found 394.2009; [α]2D0 = +32.6 (c = 0.74, CHCl3).
C25H28NO5 (M + H)+ 422.1962, found 422.1969; [α]2D0 = −110.1 (c =
0.37, CHCl3).
Proposed Structure of Hypoestestatin 1 (2a). To a solution of
alcohol 12 (600 mg, 1.5 mmol) and CH3SO2Cl (204 mg, 1.8 mmol) in
CH2Cl2 (50 mL) cooled with an ice−water bath was added
triethylamine (198 mg, 1.95 mmol) in CH2Cl2 (8 mL). The reaction
mixture was stirred for 2 h at room temperature and then quenched
with saturated aqueous ammonium chloride (50 mL). After separation,
the organic layer was washed with aqueous ammonium chloride (3 ×
50 mL), water (3 × 50 mL), and brine (50 mL), dried over MgSO4,
filtered, and concentrated. The methanesulfonate decomposed when
purified by chromatography. To the crude methanesulfonate without
further purification in freshly distilled THF (80 mL) at −5 °C under
N2 was added LiHBEt3 (6 mL, 6 mmol, 1 M in THF). The mixture
was transferred to room temperature, stirred for another 3 h, and
quenched with saturated aqueous ammonium chloride (50 mL). After
separation, the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic phase was concentrated under reduced
pressure and the residue was purified by chromatography on silica
gel (20:1 CH2Cl2/MeOH) to give 2a (0.42 g, 1.11 mmol, 73%, >99%
(S)-(2,3,6-Trimethoxy-9,11,12,13,13a,14-hexahydrodibenzo-
[f,h]pyrrolo[1,2-b]isoquinolin-13a-yl)methanol (ent-12). The
synthesis procedure was similar to that for compound 12 to give
1
ent-12 (99% ee) as a light yellow solid: mp 148−153 °C; H NMR
(400 MHz, CDCl3) δ 7.94 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.83 (d, J
= 9.0 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J = 9.0, 2.2 Hz, 1H), 4.41 (d, J =
17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 4.12 (s, 3H), 4.08 (s, 3H),
4.02 (s, 3H), 3.57 (d, J = 10.4 Hz, 1H), 3.48 (d, J = 10.4 Hz, 1H),
3.28−3.20 (m, 1H), 3.00 (d, J = 17.0 Hz, 1H), 2.93−2.83 (dd, J = 17.1,
8.5 Hz, 1H), 2.71 (d, J = 17.0 Hz, 1H), 2.31−2.21 (m, 1H), 1.99−1.76
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 157.7, 149.6, 148.5, 130.1,
126.7, 124.2, 124.1, 123.7, 123.3, 115.0, 104.9, 104.0, 103.5, 63.4, 56.1,
56.0, 55.6, 52.1, 45.4, 34.2, 30.3, 28.0, 20.4; HRMS (ESI) calcd for
C24H28NO4 (M + H)+ 394.2010, found 394.2012; [α]2D0 = −25.3 (c =
0.74, CHCl3).
Compound R-2a. The synthesis procedure was similar to that of
2a to give R-2a (74% over two steps, >99%ee) as a yellow solid: mp
189−193 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.92 (d, J =
2.2 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H), 7.22 (dd, J = 9.0,
2.2 Hz, 1H), 4.46 (d, J = 16.4 Hz, 1H), 4.13 (d, J = 16.4 Hz, 1H), 4.11
(s, 3H), 4.08 (s, 3H), 4.02 (s, 3H), 3.17−3.08 (m, 1H), 3.01 (s, 2H),
2.95−2.88 (m, 1H), 2.03−1.92 (s, 4H), 1.05 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 157.5, 149.4, 148.3, 130.1, 127.4, 124.8, 124.6, 124.3,
124.2, 123.6, 114.9, 104.7, 103.9, 103.8, 57.6, 56.1, 55.9, 55.6, 50.8,
47.1, 39.4, 35.9, 20.2, 17.7. 1H NMR (400 MHz, CD3OD) δ 8.07 (s,
1H), 8.02 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H),
7.24 (dd, J = 9.0, 2.0 Hz, 1H), 4.47 (d, J = 16.3 Hz, 1H), 4.09 (s, J =
16.3 Hz, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 4.03 (s, 3H), 3.17 (d, J = 16.4
Hz, 1H), 3.17−3.10 (m, 1H), 3.06 (d, J = 16.4 Hz, 1H), 2.99−2.90
(m, 1H), 2.09−1.95 (m, 4H), 1.10 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 159.4, 151.0, 150.1, 131.7, 128.5, 125.6, 125.4, 125.2,
125.2, 125.1, 116.7, 105.7, 105.5, 105.4, 59.4, 56.6, 56.4, 56.0, 51.5,
48.0, 39.9, 37.1, 20.8, 17.5; HRMS (ESI) calcd for C24H28NO3 (M +
H)+ 378.2064, found 378.2059; [α]D20 = −34.4 (c = 0.5, CH2Cl2).
Synthesis of 15a. The synthesis procedure was similar to that of 7
from the starting material 13a.12 The crude product was purified by
chromatography on silica gel (2:1 petroleum ether (60−90 °C)/
1
ee) as a light-yellow solid: mp 195−199 °C; H NMR (400 MHz,
CD3OD) δ 8.04 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 9.0 Hz,
1H), 7.39 (s, 1H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H), 4.44 (d, J = 16.4 Hz,
1H), 4.06 (d, J = 16.4 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.99 (s,
3H), 3.14 (d, J = 16.4 Hz, 1H), 3.12−3.08 (m, 1H), 3.03 (d, J = 16.4
Hz, 1H), 2.96−2.87 (m, 1H), 2.06−1.94 (s, 4H), 1.06 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 159.3, 151.0, 150.1, 131.7, 128.2, 125.5,
125.36, 125.3, 125.2, 124.8, 124.5, 116.7, 105.4, 105.2, 60.4, 56.5, 56.3,
56.0, 51.7, 47.8, 39.7, 36.8, 20.9, 18.0; HRMS (ESI) calcd for
C24H28NO3 (M + H)+ 378.2064, found 378.2068; [α]2D0 = +31.7 (c =
0.75, CH2Cl2).
(3R,7aS)-3-(Trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-
1(3H)-one (ent-8). The synthesis procedure was similar to that of
compound 8 using (S)-proline ent-11 as starting material to give ent-8
(82%) as a colorless to light brown crystals: mp 109−110 °C (lit.13 mp
107−109 °C); 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 1H) 4.13 (dd, J
= 8.8, 4.6 Hz, 1H), 3.47−3.38 (m, 1H), 3.18−3.06 (m, 1H), 2.29−2.17
(m, 1H), 2.16−2.08 (m, 1H), 2.00−1.88 (m, 1H), 1.82−1.68 (m, 1H);
HRMS (ESI) calcd for C7H8Cl3NO2Na (M + Na)+ 265.9518, found
265.9518; [α]2D5 = +33.4 (c = 2, C6H6).
1
EtOAc) to give 15a (86%) as a white solid: mp 122−124 °C; H
NMR (400 MHz, CDCl3) δ 8.40 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.0
Hz, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 7.19 (dd, J = 9.0, 2.0 Hz, 1H),
7.15 (s, 1H), 5.03 (s, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H),
3.78 (d, J = 14.4 Hz, 1H), 3.55 (d, J = 14.4 Hz, 1H), 2.96−2.87 (m,
1H), 2.63−2.53 (m, 1H), 2.16−2.09 (m, 1H), 2.04−1.95(m, 1H),
1.50−1.35(m, 1H), 1.19−1.08 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 176.8, 157.6, 149.6, 149.2, 131.5, 129.0, 128.0, 127.4, 127.1,
126.0, 123.9, 114.8, 108.0, 104.2, 103.2, 102.8, 100.8, 73.1, 58.1, 56.1,
56.0, 55.5, 39.1, 34.5, 24.9; HRMS (ESI) calcd for C25H24Cl3NO5Na
(M + Na)+ 546.0612, found 546.0614; [α]D20 = +20.0 (c = 0.3, CHCl3).
Synthesis of 13b. The synthesis procedure of 13b was similar to
that of 10.12 Compound 13b was obtained as a white solid: mp 181−
182 °C; 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 9.1 Hz, 1H), 7.86
(s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.16 (s,
1H), 5.06 (s, 2H), 4.08 (s, 3H), 4.01 (s, 3H), 3.92 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.7, 149.3, 148.6, 134.4, 132.1, 125.8, 124.4,
124.1, 124.1, 123.7, 117.2, 108.4, 104.7, 103.2, 77.4, 77.1, 76.7, 64.6,
55.94, 55.91, 55.4; HRMS (ESI) calcd for C18H19O4 (M + H)+
299.1278, found 299.1283.
(3R,7aR)-3-(Trichloromethyl)-7a-((3,6,7-trimethoxyphe-
nanthren-9-yl)methyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-
one (ent-7). The synthesis procedure was similar to that of
compound 7 to give compound ent-7 (85% over two steps) as a
white solid: mp 218−221 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s,
1H), 7.84 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H),
7.64 (s, 1H), 7.21 (dd, J = 8.8, 2.4 Hz, 1H), 5.04 (s, 1H), 4.12 (s, 3H),
4.09 (s, 3H), 4.02 (s, 3H), 3.72 (d, J = 14.6 Hz, 1H), 3.68 (d, J = 14.6
Hz, 1H), 3.06−2.98 (m, 1H), 2.81−2.71 (m, 1H), 2.05 (d, 6.0 Hz,
1H), 2.03 (d, 6.0 Hz, 1H), 1.53−1.40 (m, 1H), 1.30−1.20 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 176.7, 158.3, 149.6, 148.8, 130.6,
130.1, 128.7, 127.6, 127.2, 125.8, 124.7, 115.7, 105.7, 103.8, 103.8,
102.8, 100.6, 73.5, 58.2, 56.5, 56.0, 55.6, 38.8, 34.8, 25.0; HRMS (ESI)
calcd for C25H24Cl3NO5Na(M + Na)+ 546.0612, found 546.0615;
[α]2D0 = +0.91 (c = 0.66, CHCl3).
(R)-2,3,6-Trimethoxy-13a-((methylperoxy)methyl)-
9,11,12,13,13a,14-hexahydrodibenzo[f,h]pyrrolo[1,2-b]-
isoquinoline (ent-5). The synthesis procedure was similar to that of
compound 5 to give compound ent-5 (80% over 2 steps, >99%ee) as a
1
gray-white solid: mp 158−164 °C; H NMR (400 MHz, CDCl3) δ
Synthesis of 15b. Using the synthesis procedure similar to that of
7, compound 15b (66% from 13b) was obtained as white crystalline
7.92 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.35
(s, 1H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H), 4.53 (d, J = 16.0 Hz, 1H), 4.46
(d, J = 16.0 Hz, 1H), 4.11 (s, 3H), 4.09 (s, 3H), 4.01 (s, 3H), 3.88 (d, J
= 15.9 Hz, 1H), 3.56 (s, 3H), 3.35 (dd, J = 14.8, 7.6 Hz, 1H), 3.25 (dd,
J = 14.8, 7.6 Hz, 1H), 2.99 (d, J = 15.9 Hz, 1H), 2.42−2.34 (m, 1H),
2.19−2.11 (m, 1H), 2.10−2.03(m, 2H); 13C NMR (100 MHz,
CDCl3) δ 175.2, 157.6, 149.4, 148.4, 130.2, 126.8, 125.8, 124.4, 124.1,
123.9, 123.6, 114.9, 104.7, 103.9, 100.0, 77.4, 77.1, 76.75, 66.2, 56.1,
56.0, 55.6, 51.8, 51.3, 47.8, 37.6, 33.6, 21.0; HRMS (ESI) calcd for
1
solid: mp 203−204 °C; H NMR (400 MHz, CDCl3) δ 8.41 (d, J =
9.0 Hz, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.24 (dd, J = 9.0,
2.6 Hz, 1H), 7.19 (d, J = 2.6 Hz, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.11 (s,
3H), 4.08 (s, 3H), 3.97 (s, 3H), 3.75 (d, J = 14.5 Hz, 1H), 3.70 (d, J =
14.5 Hz, 1H), 3.07−2.99 (m, 1H), 2.82−2.75(m, 1H), 2.08−2.02 (m,
2H), 1.54−1.42 (m, 1H), 1.32−1.23 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 176.7, 157.8, 149.3, 148.8, 132.2, 130.5, 128.5, 126.0, 125.7,
123.7, 117.2, 108.1, 105.8, 103.2, 102.8, 100.6, 73.5, 58.2, 56.49, 55.9,
7985
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Article
55.5, 39.1, 34.9, 25.0; HRMS (ESI) calcd for C25H24Cl3NO5Na (M +
Na)+ 546.0612, found 546.0621; [α]D20 = +120.7 (c = 0.43, CHCl3).
Synthesis of 13c. The synthesis procedure of 13c was similar to
that of 10.12 Compound 13c was obtained as a white solid: mp 172−
173 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 9.1 Hz, 1H), 7.77
(s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.24 (d, J = 10.0 Hz, 1H), 7.05 (s,
1H), 5.04 (s, 2H), 4.05 (s, 3H), 3.94 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 157.6, 149.4, 148.6, 132.1, 130.7, 125.9, 125.2, 125.1, 124.6,
124.2, 116.5, 108.3, 105.0, 102.6, 64.3, 55.9, 55.8, 55.4; HRMS (ESI)
calcd for C18H19O4 (M + H)+ 299.1278, found 299.1274.
1.76−1.67 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.9, 149.7,
148.6, 130.7, 125.5, 125.2, 124.9, 124.7, 123.3, 122.1, 115.1, 104.8,
104.0, 102.9, 63.7, 56.1, 56.0, 55.6, 52.6, 45.8, 34.1, 28.2, 20.8; HRMS
(ESI) calcd for C24H28NO4 (M + H)+ 394.2013, found 394.2009;
[α]2D0 = +117.5 (c = 0.57, CHCl3).
Synthesis of 17b. The synthesis procedure was similar to that of
compound 12 to give compound 17b (94%) as a light yellow solid: mp
168−172 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 9.0 Hz, 1H),
7.95 (s, 1H), 7.31 (s, 1H), 7.23 (dd, J = 9.0, 2.4 Hz, 2H), 7.23 (d, J =
2.4 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 4.11
(s, 3H), 4.07 (s, 3H), 3.97 (s, 3H), 3.56 (d, J = 10.4 Hz, 1H), 3.48 (d, J
= 10.4 Hz, 1H), 3.30−3.21 (m, 1H), 3.03 (d, J = 17.2 Hz, 1H), 2.95−
2.80 (m, 1H), 2.75 (d, J = 17.2 Hz, 1H), 2.32−2.21 (m, 1H), 2.00−
1.76 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 157.8, 148.8, 148.7,
130.6, 126.5, 124.9, 124.4, 124.2, 123.6, 123.0, 115.5, 103.6, 103.3,
63.4, 61.4, 56.0, 55.4, 52.1, 45.5, 34.2, 28.3, 20.4; HRMS (ESI) calcd
for C24H28NO4 (M + H)+ 394.2013, found 394.2018; [α]2D0 = +29.6 (c
= 0.67, CHCl3).
Synthesis of 15c. Using the similar synthesis procedure with that
of 7, conpound 15c (60% from 13c) was obtained as white crystalline
1
solid: mp 186−188 °C; H NMR (300 MHz, CDCl3) δ 8.48 (d, J =
9.0 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.28
(dd, J = 9.0, 2.4 Hz, 1H), 7.17 (s, 1H), 5.05 (s, 1H), 4.11 (s, 3H), 4.04
(s, 3H), 4.00 (s, 3H), 3.71 (s, 2H), 3.09−2.98 (m, 1H), 2.82−2.72 (m,
1H), 2.10−2.04 (m, 2H), 1.55−1.41 (m, 1H), 1.35−1.24 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 176.7, 157.9, 149.7, 148.9, 132.8, 130.3,
128.2, 125.4, 124.8, 124.2, 116.3, 108.1, 106.2, 102.8, 102.6, 100.6,
73.5, 58.2, 56.02, 55.99, 55.8, 38.6, 34.9, 25.0; HRMS (ESI) calcd for
Synthesis of 18a. The synthesis procedure was similar to that of
compound 2a. The crude product was purified by chromatography on
silica gel (20:1 CH2Cl2/MeOH) to give compound 18a (75%, over
C25H24Cl3NO5Na (M + Na)+ 546.0612, found 546.0618; [α]2D0
=
1
two steps) as a yellow solid: mp 189−192 °C; H NMR (400 MHz,
+47.9 (c = 0.52, CHCl3).
CDCl3) δ 7.94 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.92 (d, J = 2.4 Hz,
1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 7.15 (s, 1H), 4.49 (d, J = 16.2 Hz,
1H), 4.32−4.20 (m, 1H), 4.12 (s, 3H), 4.07 (s, 3H), 4.03 (s, 3H),
Synthesis of 16a. The synthesis procedure was similar to that of
compound 5. The crude product was purified by chromatography on
silicon gel (50:1 CH2Cl2/MeOH) to give compound 16a (62%, over
1
1
3.30−3.05 (s, 4H), 2.18−1.95 (m, 4H), 1.22 (s, 3H); H NMR (400
two steps) as a pale white solid: mp 203−204 °C; H NMR (400
MHz, CD3OD) δ 7.97 (s, 1H), 7.93 (s, H), 7.18 (s, 2H), 4.68 (d, J =
16.0 Hz, 1H), 4.42 (d, J = 16.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H),
3.92 (s, 3H), 3.34 (d, J = 16.4 Hz, 1H), 3.40−3.22 (m, 2H), 3.19 (d, J
= 16.4 Hz,1H), 2.15−1.98 (m, 1H), 1.24 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 157.9, 149.7, 148.6, 130.8, 125.3, 125.2, 125.1, 125.1,
124.9, 123.4, 115.01, 104.8, 104.0, 103.0, 56.1, 56.08, 56.03, 55.6, 51.0,
46.6, 38.7, 35.1, 20.0, 18.4; HRMS (ESI) calcd for C24H28NO3 (M +
H)+ 378.2064, found 378.2063; [α]D20 = +90.9 (c = 0.46, CHCl3).
Synthesis of 18b. The synthesis procedure was similar to that of
compound 2a. The crude product was purified by chromatography on
silicon gel (20:1 CH2Cl2/MeOH) to give compound 18b (60%, over 2
steps) as a yellow solid: 132 °C dec. This compound was extremely
MHz, CDCl3) δ 7.99 (d, J = 9.0 Hz, 1H), 7.90 (s, 2H), 7.23 (dd, J =
9.0, 2 Hz, 1H), 7.17 (s, 1H), 4.49 (d, J = 15.8 Hz, 1H), 4.38 (d, J =
15.8 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 4.02 (s, 3H), 3.99 (d, J = 16.0
Hz, 1H), 3.53 (s, 3H), 3.42−3.33 (m, 1H), 3.32−3.26 (m, 1H), 3.01
(d, J = 16.0 Hz, 1H), 2.39−2.34 (m, 1H), 2.16−2.02 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.2, 157.6, 149.4, 148.4, 130.5, 125.53,
125.4, 125.3, 125.1, 124.6, 123.3, 114.7, 104.7, 103.8, 103.2, 66.1, 56.0,
55.9, 55.6, 51.7, 51.4, 48.0, 37.5, 33.9, 21.0; HRMS (ESI) calcd for
C25H28NO5 (M + H)+ 422.1962, found 422.1968; [α]2D0 = +117.5 (c =
0.57, CHCl3).
Synthesis of 16b. The synthesis procedure was similar to that of
compound 5 to give compound 16b (71% over two steps) as a light
1
1
unstable, so great caution should be taken when using it. H NMR
yellow solid: mp 207−209 °C; H NMR (400 MHz, CDCl3) δ 8.45
(300 MHz, MeOD) δ 8.48 (d, J = 9.0 Hz, 1H), 7.96 (s, 1H), 7.36 (s,
1H), 7.21 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.38 (d, J = 16.0 Hz, 1H),
4.01 (d, J = 16.0 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H),
3.17−2.99 (m, 2H), 2.96−2.88 (s, 1H), 2.83 (brs, 1H), 1.97 (brs, 4H),
1.04 (s, 3H); 13C NMR (75 MHz, MeOD) δ 159.4, 150.4, 150.1,
131.7, 128.8, 126.6, 126.1, 125.5, 124.7, 124.6, 116.7, 105.4, 104.9,
104.5, 59.4, 56.4, 56.4, 55.8, 51.6, 39.9, 37.2, 20.9, 17.6; HRMS (ESI)
(d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.35 (s, 1H), 7.23 (d, J = 9.0 Hz,
1H), 7.20 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.42 (d, J = 16.0 Hz, 1H),
4.10 (s, 3H), 4.08 (s, 3H), 3.97 (s, 3H), 3.92 (d, J = 15.6 Hz, 1H), 3.56
(s, 3H), 3.44−3.34 (m, 1H), 3.34−3.24 (m, 1H), 3.03 (d, J = 15.6 Hz,
1H), 2.44−2.34 (m, 1H), 2.21−2.11 (m, 1H), 2.11−1.98 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 157.7, 148.8, 148.7, 130.6, 126.5, 124.9,
124.4, 124.2, 123.6, 123.0, 115.5, 103.6, 103.3, 63.4, 61.4, 55.95, 55.9,
55.4, 52.1, 45.5, 34.2, 28.3, 20.4; HRMS (ESI) calcd for C25H28NO5
(M + H)+ 422.1962, found 422.1973; [α]2D0 = +121.9 (c = 0.72,
CHCl3).
calcd for C24H28NO3 (M + H)+ 378.2064, found 378.2067; [α]2D0
+47.2 (c = 0.46, CHCl3).
=
ASSOCIATED CONTENT
Synthesis of 16c. The synthesis procedure was similar to that of
■
compound 5 to give compound 16c (67% over two steps) as a light
S
* Supporting Information
1
yellow solid: mp 297−199 °C; H NMR (400 MHz, CDCl3) δ 8.43
1H and 13NMR spectra for all of the new compounds, variation
(d, J = 9.0 Hz, 1H), 7.87 (s, 1H), 7.34 (s, 1H), 7.30 (d, J = 9.0 Hz,
1H), 7.13 (s, 1H), 4.94 (d, J = 17.2 Hz, 1H), 4.71 (d, J = 17.2 Hz, 1H),
4.12 (d, J = 14.6 Hz, 1H), 4.10 (s, 3H), 4.03 (s, 3H), 3.94 (s, 3H), 3.78
(s, 3H), 3.10 (d, J = 14.6 Hz, 1H), 2.96−2.81 (m, 1H), 2.45−2.25 (m,
2H), 2.08−1.98 (m, 1H), 1.86−1.74 (m, 1H), 1.56−1.41 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 177.0, 156.3, 149.4, 149.0, 132.0, 131.6,
129.7, 125.5, 125.5, 124.8, 124.7, 122.6, 112.3, 107.6, 103.1, 70.4, 56.9,
56.0, 55.9, 52.4, 51.4, 43.8, 43.5, 33.3, 23.7; HRMS (ESI) calcd for
C25H28NO5 (M + H)+ 422.1962, found 422.1957; [α]2D0 = +147.9 (c =
0.68, CHCl3).
1
of H NMR resonances of (R)-2a with added trifluoroacetic
acid, and HPLC for 2a, 5, 7, and their enantiomers. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wang98h@263.net; wangqm@nankai.edu.cn.
■
Synthesis of 17a. The synthesis procedure was similar to that of
compound 12 to give compound 17a (95%) as a light yellow solid: mp
178−182 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 9.2 Hz, 1H),
7.94 (s, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.24 (dd, J = 9.2, 1.8 Hz, 1H),
7.18 (s, 1H), 4.45 (d, J = 16.4 Hz, 1H), 4.32 (d, J = 16.4 Hz, 1H), 4.12
(s, 3H), 4.06 (s, 3H), 4.03 (s, 3H), 3.70−3.58 (s, 2H), 3.45−3.36 (m,
1H), 3.16 (d, J = 17.0 Hz, 1H), 2.91 (d, J = 17.0 Hz, 1H), 2.85−2.74
(m, 1H), 2.26−2.15 (m, 1H), 2.01−1.91 (m, 1H), 1.88−1.77 (m, 1H),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Key Project for Basic Research
(2010CB126100), the National Natural Science Foundation of
China (21132003, 21121002), the Tianjin Natural Science
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Article
Brandi, A. Eur. J. Org. Chem. 2008, 2817−2824. (f) Vartak, A.; Yong,
V. G.; Johnson, R. L. Org. Lett. 2005, 7, 35−38. (g) Williams, R. M.;
Glinka, T.; Kwast, E. J. Am. Chem. Soc. 1988, 110, 5927−5929.
(h) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115−119.
(12) Su, C. R.; Damu, A. G.; Chiang, P. C.; Bastow, K. F.; Morris
Natschke, S. L.; Lee, K. H.; Wu, T. S. Bioorg. Med. Chem. 2008, 16,
6233−6241.
Foundation (11JCZDJC20500), and the National Key
Technology Research and Development Program
(2011BAE06B02-17) for generous financial support for our
programs. We also thank Professor Guangxin Liang for helpful
discussions about NMR experiments.
REFERENCES
(13) Harris, P. W. R.; Brimble, M. A.; Muir, V. J.; Lai, M. Y. H.;
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■
(1) For recent selected examples, see: (a) Gao, W.; Chen, A. P. C.;
Leung, C. H.; Gullen, E. A.; Furstner, A.; Shi, Q.; Wei, L.; Lee, K. H.;
̀
procedure was much easier to operate, and unlike Seebachs
̈
oxazolidinone, oxazolidinone 8 was air- and moisture-stable and
could be stored upon the bench top for more than 30 days without
decomposition.
(14) Although great effort was made to convert the ester group of
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