Efficient enantioselective total synthesis of (-)-horsfiline

Article abstract of DOI:10.1002/chem.201301008

A new efficient and concise enantioselective synthetic method for (-)-horsfiline is reported. (-)-Horsfiline could be obtained from diphenylmethyl tert-butyl malonate in 9 steps (32 %,>99 % ee) by using the enantioselective phase-transfer catalytic allylation (91 % ee) as the key step. This approach can be applied as a practical route for the large-scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed. Practical synthesis of a spirooxindole: The total synthesis of (-)-horsfiline was accomplished from diphenylmethyl tert-butylmalonate in nine steps (32 %, >99 % ee) by using a enantioselective phase-transfer catalytic allylation (91 % ee) as the key step (see scheme). Copyright

Full text of DOI:10.1002/chem.201301008

FULL PAPER
DOI: 10.1002/chem.201301008
Efficient Enantioselective Total Synthesis of (À)-Horsfiline
Suckchang Hong,[a] Myunggi Jung,[a] Yohan Park,[b] Min Woo Ha,[a]
Cheonhyoung Park,[a] Myungmo Lee,[a] and Hyeung-geun Park*[a]
Abstract: A new efficient and concise enantioselective synthetic method for
(À)-horsfiline is reported. (À)-Horsfiline could be obtained from diphenylmethyl
tert-butyl malonate in 9 steps (32%,>99% ee) by using the enantioselective
phase-transfer catalytic allylation (91% ee) as the key step. This approach can be
applied as a practical route for the large-scale synthesis of spirooxindole natural
products, which enables a systematic investigation of their biological activity to be
performed.
Keywords: allylation · enantioselec-
tivity · synthetic methods · total
synthesis · horsfiline
Introduction
(À)-horsfiline was first isolated in 1991 from the leaves of
the Horsfieldia superba plant by Bodo et al.[3] Up until now,
many synthetic methods have been developed for the syn-
thesis of horsfiline.[4] However, only four cases of enantio-
merically enriched horsfiline were reported.[5]
The spirooxindole structure has been frequently found in bi-
ologically active alkaloids such as coerulescine, horsfiline,
elacomine, spirotryprostatin B, and strychnofoline
(Figure 1).[1] Their unique spiro structures have challenged
many synthetic chemists to develop an efficient synthetic
method for the construction of the quaternary stereogenic
center.[2] Among the various spirooxindole alkaloids,
In 1994, Borschberg et al. confirmed the absolute configu-
ration of horsfiline by the synthesis of both enantiomers
through a diastereoselective oxidative rearrangement of
chiral tetrahydro-b-carboline precursors, derived from an
(l)-5-hydroxytryptophan.[5a] In 1999, Fuji et al. employed a
chiral reagent for the a-nitroolefination of a-allyloxindole
to introduce the quaternary chiral center.[5b] In 2001, Palm-
isano et al. set the pyrrolidine moiety by using the asymmet-
ric cycloaddition of an azomethine ylide with chiral alcohol
auxiliary substituted a,b-unsaturated ester, which subse-
quently formed the oxindole by intramolecular lactamiza-
tion.[5c] In 2006, Trost et al. employed the first catalytic
method of a palladium-catalyzed asymmetric allylation of
3-carboxyoxindoles to establish the spirostereogenic center
of (À)-horsfiline (8 steps, 11%, key step 84% enantiomeric
excess (ee)).[5d] In this paper, we report a new and efficient
synthetic method for the preparation of (À)-horsfiline
through the enantioselective phase-transfer catalytic a-allyl-
AHCTUNGTRENNUNG
ation of malonate.[6]
Figure 1. Biologically active spirooxindole alkaloids.
Results and Discussion
[a] S. Hong, M. Jung, M. W. Ha, C. Park, Dr. M. Lee,
Prof. Dr. H.-g. Park
Very recently, we reported a new synthetic method for
chiral a,a-dialkylmalonates (2) by the enantioselective
phase-transfer catalytic (PTC) a-alkylation of diphenylmeth-
yl tert-butyl a-alkylmalonates (1) in the presence of (S,S)-
3,4,5-trifluorophenyl-NAS bromide (3) and successfully
proved its usefulness by conversion to versatile chiral inter-
mediates for the construction of the quaternary carbon
center including the oxindole skeleton (Scheme 1).[7] Given
this set of results, we attempted to apply our new method to
the synthesis of a representative spirooxindole alkaloid,
Institute of Pharmaceutical Sciences and
College of Pharmacy, Seoul National University
Seoul 151-742 (Korea)
Fax : (+82)2872-9129
E-mail: hgpk@snu.ac.kr
[b] Y. Park
College of Pharmacy, Inje University
607 Obang-dong, Gimhae
Gyeongnam 621-749 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301008.
Chem. Eur. J. 2013, 19, 9599 – 9605
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Scheme 1. Enantioselective PTC a-alkylation of malonates.
(À)-horsfiline, as the first application of our methodology
for the total synthesis of a natural product.
As shown in the retrosynthetic analysis (Scheme 2), the
spirooxindole skeleton can, in principle, give rise to the for-
mation of N-methylpyrrolidine through the chemical conver-
sion of a,a-disubstituents of oxindole 6, which can be ob-
tained by intramolecular lactamization of (S)-5 after reduc-
tion of the nitro group. Optically active (S)-5 can be derived
from the enantioselective phase-transfer catalytic allylation
of 4 in the presence of (R,R)-3.
Scheme 3. Enantioselective PTC a-allylation and oxindole formation.
nitro group in 5 was attempted to obtain a-allyloxindole.
However, several trials with various reduction conditions
were not successful, and both the nitro and a-allyl group of
5 were reduced to afford 9. In addition, the removal of the
tert-butyl ester group of 9, obtained through the reduction
by using Raney Ni under atmospheric H2, was accompanied
with decarboxylation under the trifluoroacetic acid (TFA)
conditions due to the b-keto functionality of oxindole 9, re-
sulting in a-propyloxindole 10. Due to the non-selective re-
duction and the decarboxylation during conversion of tert-
butyl ester group, we had to change our synthetic strategy.
The second retrosynthetic analysis is shown in Scheme 4.
We changed the synthetic route from construction of oxin-
dole moiety to introducing the N-methylpyrrolidine moiety
from (R)-5. The PTC allylation of 4 was then optimized by
variation of base and temperature conditions including allyl-
AHCTUNGTREGaNNNU ting agents in the presence of (S,S)-3 instead of (R,R)-3.
Scheme 2. First retrosynthetic analysis.
First, substrate (4) for PTC allylation was prepared from
diphenylmethyl tert-butyl malonate (7)[7] (Scheme 3). Nucle-
ophilic aromatic substitution of 7 with 2-fluoro-4-methoxy-1-
nitro-benzene (8)[8] under tBuOK base conditions in dime-
thylformamide (DMF) at room temperature afforded a-aryl-
malonate 4 (65%). As a preliminary study, the enantioselec-
tive allylation of 4 was performed under the previously opti-
mized phase-transfer catalysis condition.[7] The PTC allyl-
ACHTUNGTRENNUNGation of 4 in the presence of (R,R)-3, along with allyl bro-
mide (5.0 equiv) and 50% KOH (aq., 5.0 equiv) at 08C in
toluene, gave the allylated compound (S)-5 (90%, 83% ee).
Before we investigated the optimization of PTC allylation to
obtain higher enantioselectivity, we first studied the possibil-
ity of our retrosynthetic approach. Selective reduction of
Scheme 4. Second retrosynthetic analysis.
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Enantioselective Total Synthesis of (À)-Horsfiline
Table 1. Optimization of PTC a-allylation of 4.
FULL PAPER
proved the enantioselectivity in the PTC allylation
steps during the total synthesis of (À)-paroxetine
and (+)-isonitramine by switching “allyl bromide”
with “2-bromoallyl bromide” as an alternative allyl-
AHCTUNGTRENNUNG
ating reagent.[9] However, increased enantioselectiv-
ity was not observed (Table 1, entry 6), and the
other 2-substituted allylic bromides also showed
lower enantioselectivity (Table 1, entries 7 and 8).
We speculate that such no improvement of enantio-
selectivity is caused by the ortho-nitro group of 4,
which might inhibit a favorable binding conforma-
tion with PTC catalyst 3. The best enantioselectivity
was obtained in the case of allyl bromide with 50%
KOH base conditions at À408C (Table 1, entry 4,
99%, 91% ee).
Ozonolysis of 5, followed by reductive work up
in the presence of triphenylphosphine afforded the
corresponding aldehydes 13 (99%; Scheme 5). Al-
dehyde 13 was reduced by sodium borohydride in
ethanol at À208C to provide lactone 14. Without
purification, the lactone moiety of 14 could be se-
lectively reduced again to the corresponding diols
Entry
RX
Base
T
t
Yield
[%][a]
ee
A
[h]
[%][b]
1
50% KOH
50% KOH
50% KOH
50% KOH
KOH(s)
0
12
24
72
72
48
83
97
90
99
80
82
88
90
91
81
2
À20
À40
À40
À40
3
4[c]
5
6
7
8
50% KOH
50% KOH
50% KOH
À20
À20
À20
72
5
85
93
95
86
87
71
2
[a] Yields of the isolated products. [b] Enantioselectivity was determined by HPLC
analysis of a-allylated product (12) by using a chiral column (Chiralpak AD-H) with
hexanes/2-propanol as eluents. [c] 10 mol% of catalyst 3 was used.
As shown in Table 1, lower reaction temperatures gave
higher enantioselectivity with longer reaction time with
50% KOH as the base (entries 1–3). The increase of the
amount of catalyst afforded higher chemical yield with com-
parable enantioselectivity (Table 1, entries 3 and 4). Solid–
liquid PTC conditions using solid KOH base afforded both
lower enantioselectivity and lower chemical yield than those
of liquid–liquid PTC conditions using 50% KOH base
(Table 1, entries 3 and 5). With regard to the allylating
agent, allyl bromide showed the highest enantioselectivity
among the used electrophiles at À208C. We previously im-
15 in situ by additional treatment of sodium borohydride
with cerium(III) trichloride heptahydrate and tetrahydrofur-
AHCTUNGTRENNUNG
an (THF) as a co-solvent at 08C (61% from 13).[10] As a
side reaction, removal of the a-hydroxymethyl group was
partially observed by deformylation through the retroaldol
reaction of 15, caused by the a-nitrophenyl group. The
major enantiomer of diol 15 could be easily purified as a
single stereoisomer (>99% ee) with 85% yield by recrys-
tallizing out the minor/major enantiomer pair (91% ee)
using hexane and ethyl acetate (5:1). Dimesylation of 15
(99%), followed by double N-alkylation using excess meth-
Scheme 5. Completion of total synthesis of (À)-horsfiline.
Chem. Eur. J. 2013, 19, 9599 – 9605
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H.-g. Park et al.
ylamine successfully afforded N-methylpyrrolidines 11
(98%).
Conclusion
We then performed the final spiro-cyclization step. Spiro-
oxindole natural products including (À)-horsfiline, are easily
As the first application of the enantioselective phase-trans-
fer catalytic a-alkylation of malonate system,[7] a new effi-
cient synthetic approach for the synthesis of (À)-horsfiline
was developed. (À)-Horsfiline was synthesized in 9 steps
(including an in situ step) from diphenylmethyl tert-butyl
malonate (7) by using enantioselective PTC allylation as the
key step (32% overall yield,>99% ee). Both the high enan-
tioselectivity and chemical yield make this approach a prac-
tical route for the large-scale synthesis of spirooxindole nat-
ural products, which allows a systematic investigation of
their biological activity.[14] Further applications to the syn-
thesis of spirooxindole compounds are now under investiga-
tion.
G
racemized through a retro-Mannich reaction in the presence
of an acid.[11,5d] Therefore, the last spiro-cyclization step
from oxindole or pyrrolidine intermediates under acidic con-
ditions should be avoided. For the cyclization to form oxin-
dole from 11 in neutral conditions, we first needed to con-
vert the tert-butyl ester group to a smaller methyl ester
group. The removal of tert-butyl ester of 11 in the TFA
acidic conditions (17), followed by methyl ester formation
using excess TMS-diazomethane afforded the corresponding
methyl ester 18, which was readily cyclized to the final oxin-
dole product, (À)-horsfiline, under catalytic Pd/C hydroge-
nation (Scheme 6).
Experimental Section
General materials and methods: All reagents bought from commercial
sources were unpurified. Organic solvents were concentrated under re-
duced pressure by using a Bꢁchi rotary evaporator. As the commercially
available KOH was a pellet type, solid KOH should be grinded to the
powder form. 50% v/w aqueous KOH was used as a stock solution.
Phase-transfer catalyst (S,S)-3 and (R,R)-3[12] (Wako) was purchased from
the commercial source. TLC analyses were performed using Merck pre-
coated TLC plate (silica gel 60 GF254, 0.25 mm). Flash column chroma-
tography was carried out by using Merck Kieselgel 60 (230–400 mesh).
Instrument (Hitachi, l-2130) and software (Hitachi, Version LaChrom
8908800–07) were used for HPLC analysis. The enantiomeric excess (ee)
of the products were determined by HPLC using 4.6ꢂ250 mm DIACEL
Chiralpak AD-H, Chiralcel OD-H, Chiralcel OJ-H columns. Infrared
(IR) spectra were recorded on a JASCO FT/IR-300E and Perkin–Elmer
1710 FT spectrometer. Nuclear magnetic resonance (1H NMR and
13C NMR) spectra were measured on JEOL JNM-LA 300 (300 MHz
(1H)) spectrometer, JEOL JNM-GSX 400 [400 MHz (1H), 100 MHz
(13C)] spectrometer, using [D3]CHCl3 as solvent, and were reported in
ppm relative to CHCl3 (d=7.24 ppm) for 1H NMR spectroscopy and rel-
ative to the central CDCl3 (d=77.23 ppm) resonance for 13C NMR spec-
troscopy. The unit of coupling constants (J) in the 1H NMR spectra was
Hz. Low-resolution mass spectra (MS) were recorded on a VG Trio-2
GC-MS spectrometer and high-resolution mass spectra (HRMS) were
measured on a JEOL JMS 700, JEOL JMS 600-W (FAB), or Agilent
6530 Q-TOF (ESI) spectrometer. Melting points were measured on a
Bꢁchi B-540 melting point apparatus and were not corrected. Optical ro-
tations were measured on a JASCO polarimeter P-2000 series.
Scheme 6. Initial spirooxindole formation.
However, we also attempted to direct cyclization in the
presence of the tert-butyl ester group to shorten the overall
process. Reduction of the nitro group of 11 was performed
by catalytic hydrogenation using Pd/C under atmospheric
H2. Unfortunately, the corresponding amine 19 was the only
product obtained instead of further cyclized spirooxindole
(Scheme 5). However, interestingly, during purification of
the obtained amine 19 through column chromatography
(SiO2), the cyclized spirooxindole was partially obtained to-
gether with the corresponding amine 19. We speculate that
silica gel (SiO2) may directly catalyze spiro cyclization in the
presence of the tert-butyl ester group. Finally, (À)-horsfiline
([a]2D0 =À8.50 (c=5, MeOH); [a]D20 =À7.20 (c=1, MeOH)[3])
was successfully obtained by stirring amine 19 with silica gel
(SiO2) in CH2Cl2 without racemization (98%,>99% ee). As
far as we know, this is the first synthetic method to intro-
duce the N-methylpyrrolidine part prior to the construction
of the oxindole ring structure among the previously reported
enantioselective synthetic methods.
Preparation of 2-fluoro-4-methoxy-1-nitrobenzene (8): Iodomethane
(3.74 mL, 60 mmol) was added to a solution of 3-fluoro-4-nitrophenol
(4.7 g, 30 mmol) and potassium carbonate (10.37 g, 75 mmol) in acetone
(70 mL). The reaction mixture was enveloped in aluminium foil and stir-
red for 44 h at room temperature. The reaction mixture was evaporated
and diluted with ethyl acetate (600 mL). The organic layer was washed
with brine (2ꢂ150 mL), dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc=6:1) to afford 8 (5.03 g, 98% yield) as a pale-
yellow solid. M.p. 62.18C; 1H NMR (300 MHz, CDCl3): d=8.09–8.03 (m,
1H), 6.76–6.68 (m, 2H), 3.88 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=165.28 (d, J=10.8 Hz), 157.44 (d, J=263.5 Hz), 127.85(d, J=0.9 Hz),
110.33(d, J=3 Hz), 103.13(d, J=24.2 Hz), 56.30 ppm; IR (KBr): n˜ =1607,
1511, 1341, 849 cmÀ1
;
HRMS (FAB): m/z calcd for [C7H7FNO3]+:
172.0410; found: 172.0420; The spectral data was identical with the re-
ported data.[8]
1-Benzhydryl 3-tert-butyl 2-(5-methoxy-2-nitrophenyl) malonate (4): Po-
tassium tert-butoxide (617 mg, 5.5 mmol) was added to a stirred solution
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Enantioselective Total Synthesis of (À)-Horsfiline
FULL PAPER
of benzhydryl tert-butyl malonate (7, 1.63 g, 5 mmol) in DMF (12 mL) at
08C. After stirring for 10 min, a solution of 2-fluoro-4-methoxy-1-nitro-
benzene (8, 856 mg, 5 mmol) in DMF (3 mL) was slowly added to the re-
action mixture and stirred for 48 h.[13] The reaction mixture was evaporat-
ed and diluted with ethyl acetate (150 mL), quenched with saturated
aqueous solution of ammonium chloride (40 mL), washed with brine
(40 mL), dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (silica gel,
hexane/EtOAc=20:1–7:1) to afford 4 (1.55 g, 65% yield) as a yellow
solid. M.p. 68.28C; 1H NMR (300 MHz, CDCl3): d=8.11 (d, J=9.2 Hz,
1H), 7.37–7.22 (m, 10H), 6.98 (s, 1H), 6.89 (dd, J1 =9.2 Hz, J2 =2.8 Hz,
1H), 6.77 (d, J=2.7 Hz, 1H), 5.47 (s, 1H), 3.65 (s, 3H), 1.40 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=166.84, 165.94, 141.59, 139.21,
131.33, 128.50, 128.46, 128.13, 128.11, 127.88, 127.30, 127.26, 115.51,
114.18, 83.25, 78.50, 55.91, 55.71, 27.72 ppm; IR (KBr): n˜ =2979, 1732,
1583, 1518, 1339, 1252, 1143, 752, 700 cmÀ1; HRMS (FAB): m/z calcd for
[C27H28NO7]+: 478.1866; found: 478.1862.
General procedure for the asymmetric PTC allylation of 4: Substituted
allyl bromide (2 mmol) was added to a solution of 1-benzhydryl 3-tert-
butyl 2-(5-methoxy-2-nitrophenyl) malonate (4, 191 mg, 0.4 mmol) and
(S,S)-3,4,5-trifluorophenyl-NAS bromide ((S,S)-3, 18.3 mg, 0.02 mmol) in
toluene (1.4 mL). At the designated temperature, the base (2 mmol) was
added to the reaction mixture and stirred for designated time. EYELA
PSL-1400 was used for low temperature stirring and the stirring rate was
7. The reaction mixtures was diluted with ethyl acetate (50 mL), washed
with brine (2ꢂ15 mL), dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc=15:1) to afford 5 or 12a–c.
(R)-1-Benzhydryl 3-tert-butyl 2-allyl-2-(5-methoxy-2-nitrophenyl)malo-
nate (5): Following the general procedure, the reaction was started with
allyl bromide (169 mL, 2 mmol), (S,S)-3,4,5-trifluorophenyl-NAS bromide
(3, 36.6 mg, 0.04 mmol). At À408C, aq 50% KOH (225 mL, 2 mmol) was
added to the reaction mixture. After stirring for 72 h, (R)-5 was obtained
as a yellow oil (204.9 mg, 99% yield). The enantioselectivity was deter-
mined by chiral HPLC analysis (DIACEL Chiralpak AD-H, hexane/2-
propanol=95:5), flow rate=1.0 mLminÀ1, 208C, l=254 nm, retention
(S)-1-Benzhydryl 3-tert-butyl 2-allyl-2-(5-methoxy-2-nitrophenyl)malo-
nate (5): Allyl bromide (85 mL, 1 mmol) was added to a solution of 4
(95.5 mg, 0.2 mmol) and (R,R)-3,4,5-trifluorophenyl-NAS bromide
((R,R)-3, 9.1 mg, 0.01 mmol) in toluene (0.7 mL). At 08C, aqueous 50%
KOH (112 mL, 1 mmol) was added to the reaction mixture and stirred for
20 h.[7] EYELA PSL-1400 was used for low temperature stirring and the
stirring rate was 7. The reaction mixture was diluted with ethyl acetate
(30 mL), washed with brine (2ꢂ10 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc=15:1) to afford (S)-5
(93.2 mg, 90% yield) as a yellow oil. The enantioselectivity was deter-
mined by chiral HPLC analysis [chiral HPLC analysis (DIACEL Chiral-
pak AD-H, hexane/2-propanol=95:5), flow rate=1.0 mLminÀ1, 238C,
time,
R (major) 15.9 min, S
(minor) 21.6 min, 91% ee. [a]2D0 =6.62
(91% ee, c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.07 (d, J=
9.1 Hz, 1H), 7.30–7.17 (m, 10H), 6.91 (s, 1H), 6.82 (dd, J1 =9.1 Hz, J2 =
2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.73–5.59 (m, 1H), 4.95 (dd, J1 =
17.1 Hz, J2 =1.8 Hz, 1H), 4.88 (dd, J1 =10.2 Hz, J2 =1.8 Hz, 1H), 3.66 (s,
3H), 3.22 (d, J=7.0 Hz, 2H), 1.25 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=168.43, 167.02, 162.48, 142.22, 139.44, 139.39, 135.45, 133.30,
128.36, 128.32, 127.95, 127.93, 127.36, 127.29, 118.82, 117.17, 111.89, 83.36,
78.37, 63.88, 55.63, 39.48, 27.52 ppm; IR (KBr): n˜ =2979, 1732, 1580,
1520, 1346, 1252, 1152, 1018, 843, 756, 700 cmÀ1; HRMS (FAB): m/z calcd
for [C30H32O7N]+: 518.2179; found: 518.2201.
(R)-1-Benzhydryl 3-tert-butyl 2-(2-bromoallyl)-2-(5-methoxy-2-nitro-
phenyl) malonate (12a): Following the general procedure, the reaction
was started with 2,3-dibromopropene (196 mL, 2 mmol). At À208C, aq
50% KOH (225 mL, 2 mmol) was added to the reaction mixture. After
stirring for 72 h, (R)-12a was obtained as a yellow oil (202.6 mg, 85%
yield). The enantioselectivity was determined by chiral HPLC analysis
(DIACEL Chiralpak AD-H, hexane/2-propanol=95:5), flow rate=
1.0 mLminÀ1, 208C, l=254 nm, retention time, R (major) 10.1 min, S
(minor) 23.5 min, 86% ee. [a]2D0 =52.92 (86% ee, c=1, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.05 (d, J=9.0 Hz, 1H), 7.31–7.22 (m, 10H), 7.0
(s, 1H), 6.82 (dd, J1 =9.0 Hz, J2 =2.7 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H),
5.70 (s, 1H), 5.38 (d, J=1.7 Hz, 1H), 3.82 (dd, J1 =22.0 Hz, J2 =15.4 Hz,
2H), 3.59 (s, 3H), 1.22 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
167.83, 166.15, 162.06, 142.97, 139.11, 138.94, 133.20, 128.43, 128.38,
128.10, 128.06, 128.01, 127.83, 127.47, 127.36, 122.75, 118.41, 112.88, 84.02,
78.88, 64.84, 55.53, 44.83, 27.33 ppm; IR (KBr): n˜ =2979, 1737, 1580,
1521, 1348, 1252, 1207, 1184, 1147, 757, 700 cmÀ1; HRMS (FAB): m/z
calcd for [C30H31BrNO7]+: 596.1284; found: 596.1299.
l=254 nm, retention time,
R (minor) 16.2 min, S (major) 21.5 min,
83% ee]. [a]2D0 =À11.19 (83% ee, c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.07 (d, J=9.1 Hz, 1H), 7.30–7.17 (m, 10H), 6.91 (s, 1H),
6.82 (dd, J1 =9.1 Hz, J2 =2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.73–5.59
(m, 1H), 4.95 (dd, J1 =17.1 Hz, J2 =1.8 Hz, 1H), 4.88 (dd, J1 =10.2 Hz,
J2 =1.8 Hz, 1H), 3.66 (s, 3H), 3.22 (d, J=7.0 Hz, 2H), 1.25 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=168.43, 167.02, 162.48, 142.22, 139.44,
139.39, 135.45, 133.30, 128.36, 128.32, 127.95, 127.93, 127.36, 127.29,
118.82, 117.17, 111.89, 83.36, 78.37, 63.88, 55.63, 39.48, 27.52 ppm; IR
(KBr): n˜ =2979, 1732, 1580, 1520, 1346, 1252, 1152, 1018, 843, 756,
700 cmÀ1; HRMS (FAB): m/z calcd for [C30H32NO7]+: 518.2179; found:
518.2201.
(S)-tert-Butyl
5-methoxy-2-oxo-3-propylindoline-3-carboxylate
(9):
Raney nickel (13 mg) was added to a stirred solution of (S)-5 (52 mg,
0.1 mmol) in methanol (2 mL) under H2 gas and stirred for 2 h.[7] The re-
action mixture was filtered through the Celite 545 and concentrated in
vacuo. The residue was purified by column chromatography (silica gel,
hexane/EtOAc=3:1) to afford 9 (20.2 mg, 66% yield) as a white solid.
M.p. 160.68C; [a]2D0 =44.31 (83% ee, c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=9.10 (s, 1H), 6.83–6.72 (m, 3H), 3.75 (s, 3H), 2.22–2.02 (m,
2H), 1.34 (s, 9H), 1.23–1.06 (m, 1H), 1.02–0.88 (m, 1H), 0.81 ppm (t, J=
7.1, 3H); 13C NMR (100 MHz, CDCl3): d=177.24, 168.23, 155.74, 134.96,
130.58, 113.09, 110.33, 82.26, 61.49, 55.72, 36.16, 27.70, 17.06, 14.02 ppm;
IR (KBr): n˜ =3251, 2962, 1738, 1492, 1251, 1203, 1158, 1033 cmÀ1; HRMS
(FAB) : m/z calcd for [C17H23NO4]+: 305.1627; found: 305.1635.
AHCTUNGTERG(NNUN R,E)-1-Benzhydryl 3-tert-butyl 2-(but-2-en-1-yl)-2-(5-methoxy-2-nitro-
phenyl) malonate (12b): Following the general procedure, the reaction
was started with crotyl bromide (206 mL, 2 mmol). At À208C, aq 50%
KOH (225 mL, 2 mmol) was added to the reaction mixture. After stirring
for 5 h, (R)-12b was obtained as a yellow oil (197.5 mg, 93% yield). The
enantioselectivity was determined by chiral HPLC analysis (DIACEL
Chiralpak AD-H, hexane/2-propanol=95:5), flow rate=1.0 mLminÀ1
,
208C, l=254 nm, retention time, R (major) 18.9 min, S (minor) 21.5 min,
87% ee. [a]2D0 =À12.45 (87% ee, c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.11 (d, J=9.0 Hz, 1H), 7.27–7.24 (m, 10H), 6.92 (s, 1H),
6.86 (dd, J1 =9.0 Hz, J2 =2.5 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 5.47–5.26
(m, 2H), 3.73 (s, 3H), 3.16 (d, J=6.2 Hz, 2H), 1.47 (d, J=5.9 Hz, 3H),
1.29 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=168.38, 166.99,
162.54, 142.25, 139.56, 135.90, 129.81, 128.28, 128.14, 127.86, 127.78,
127.29, 127.22, 125.29, 117.00, 111.72, 83.01, 78.18, 63.83, 55.61, 38.55,
27.52, 17.78 ppm; IR (KBr): n˜ =2979, 1732, 1580, 1520, 1346, 1258, 1202,
1184, 1152, 757, 701 cmÀ1; HRMS (FAB): m/z calcd for [C31H34NO7]+:
532.2335; found: 532.2317.
5-Methoxy-3-propylindolin-2-one (10): Trifluoroacetic acid (0.5 mL) was
added to a solution of 9 (31 mg, 0.1 mmol) in dichloromethane (1.5 mL).
At room temperature, the reaction mixture was stirred for 4 h. The reac-
tion mixture was evaporated and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/EtOAc=1:1) to
afford 10 (17.5 mg, 85% yield) as a white solid. M.p. 101.18C; 1H NMR
(300 MHz, CDCl3): d=9.18 (s, 1H), 6.82–6.69 (m, 3H), 3.76 (s, 3H), 3.44
(t, J=6.1 Hz, 1H), 2.02–1.82 (m, 2H), 1.51–1.21 (m, 2H), 0.90 ppm (t,
J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=180.84, 155.62, 135.22,
131.36, 112.00, 111.55, 109.92, 55.76, 46.51, 32.63, 19.01, 13.99 ppm; IR
(KBr): n˜ =3222, 2958, 1705, 1490, 1208, 1034 cmÀ1; HRMS (FAB): m/z
calcd for [C12H15NO2]+: 205.1103; found: 205.1100.
(R)-1-Benzhydryl 3-tert-butyl 2-(5-methoxy-2-nitrophenyl)-2-(3-methyl-
but-2-en-1-yl) malonate (12c): Following the general procedure, the reac-
Chem. Eur. J. 2013, 19, 9599 – 9605
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9603

H.-g. Park et al.
tion was started with 3,3-dimethylallyl bromide (231 mL, 2 mmol). At the
À208C, aq 50% KOH (225 mL, 2 mmol) was added to the reaction mix-
(300 MHz, CDCl3): d=8.00 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H),
6.84 (dd, J1 =9.0 Hz, J2 =2.6 Hz, 1H), 4.13 (dd, J1 =126.0 Hz, J2 =11.6 Hz,
2H), 3.88 (s, 3H), 3.88–3.79 (m, 1H), 3.67–3.59 (m, 1H), 3.33 (s, 1H),
2.57–2.34 (m, 2H), 2.28 (s, 1H), 1.39 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=172.08, 162.88, 142.74, 137.57, 128.40, 116.57, 111.31, 83.23,
67.79, 59.09, 55.85, 55.14, 37.79, 27.74 ppm; IR (KBr): n˜ =3403, 2925,
1721, 1578, 1519, 1348, 1256, 1158, 1036, 842, 756 cmÀ1; HRMS (FAB):
m/z calcd for [C16H24NO7]+: 342.1553; found: 342.1544.
ture. After stirring for 2 h, (R)-12c was obtained as
a yellow oil
(207.4 mg, 95% yield). The enantioselectivity was determined by chiral
HPLC analysis (DIACEL Chiralpak AD-H, hexane/2-propanol=95:5),
flow rate=1.0 mLminÀ1, 208C, l=254 nm, retention time, R (major)
18.2 min,
S
(minor) 20.3 min, 71% ee. [a]2D0 =À11.42 (71% ee, c=1,
CHCl3); 1H NMR (300 MHz, CDCl3): d=8.09 (d, J=9.1 Hz, 1H), 7.30–
7.17 (m, 10H), 6.89 (s, 1H), 6.83 (dd, J1 =9.1 Hz, J2 =2.7 Hz, 1H), 6.73
(d, J=2.7 Hz, 1H), 5.01 (t, J=6.4 Hz, 1H), 3.70 (s, 3H), 3.22–3.06 (m,
2H), 1.51 (s, 3H), 1.44 (s, 3H), 1.27 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=168.53, 167.09, 162.54, 142.33, 139.62, 136.00, 135.27, 128.28,
128.03, 127.86, 127.77, 127.30, 127.21, 118.62, 117.07, 111.78, 82.96, 78.20,
63.74, 55.59, 34.23, 27.50, 25.68, 17.79 ppm; IR (KBr): n˜ =2978, 2931,
1732, 1580, 1520, 1345, 1316, 1250, 1183, 1150, 845, 757, 700 cmÀ1; HRMS
(FAB): m/z calcd for [C32H36NO7]+: 546.2492; found: 546.2476.
(R)-tert-Butyl 3-(5-methoxy-2-nitrophenyl)-2-oxotetrahydrofuran-3-car-
boxylate (14): Lactone 14 could be obtained by the selective reduction of
13. Sodium borohydride (45.4 mg, 1.2 mmol) was added to a solution of
13 (519.5 mg, 1 mmol) in ethanol (6 mL) at À208C. The reaction mixture
was stirred for 1 h until entire substrate was converted into lactone 14 by
TLC analysis. 1 N NaOH (3–4 drops) was added dropwise to the reaction
mixture for quenching the extra sodium borohydride. After all solvent
was removed on a rotary evaporator, the mixture was diluted with ethyl
acetate (20 mL) and brine (20 mL). The layers were separated and the
aqueous layer was extracted with ethyl acetate (2ꢂ20 mL). The com-
bined organic layers were dried with MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, hexane/
EtOAc=5:1–3:1) to afford 14 (313.5 mg, 93% yield) as a white solid.
M.p. 109.58C; [a]2D0 =8.00 (91% ee, c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.20 (d, J=9.1 Hz, 1H), 6.91 (dd, J1 =9.1 Hz, J2 =2.7 Hz,
1H), 6.83 (d, J=2.7 Hz, 1H), 4.55 (td, J1 =8.5 Hz, J2 =4.2 Hz, 1H), 4.21
(q, J=8.5 Hz, 1H), 3.87 (s, 3H), 3.62 (dt, J1 =13.7 Hz, J2 =8.2 Hz, 1H),
2.50 (dq, J1 =13.8 Hz, J2 =4.2 Hz, 1H), 1.38 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=173.82, 165.94, 163.59, 140.86, 135.33, 129.02,
115.99, 112.57, 84.09, 66.42, 61.72, 56.02, 36.02, 27.46 ppm; IR (KBr): n˜ =
(R)-1-Benzhydryl 3-tert-butyl 2-(5-methoxy-2-nitrophenyl)-2-(2-oxoethyl)
malonate (13):
A solution of (R)-5 (440 mg, 0.85 mmol) in EtOAc
(10 mL) was purged with O3 at À788C until no more starting material
was observed by TLC analysis (20 min). The excess O3 in the solution
was removed by purging of argon at À788C for 20 min. To the mixture,
four equivalents of triphenyl phosphine (892 mg, 3.4 mmol) were added
at À788C, and then stirred at À788C to room temperature for 20 min.
After all solvent was removed on a rotary evaporator, the residue was
purified by column chromatography (silica gel, hexane/EtOAc=5:1) to
afford 13 (437 mg, 99% yield) as a pale-yellow viscous oil. [a]2D0 =65.18
(91% ee, c=1, CHCl3); 1H NMR (400 MHz, CDCl3): d=9.68 (s, 1H),
8.13 (d, J=9.1 Hz, 1H), 7.31–7.24 (m, 10H), 7.02 (s, 1H), 6.88 (dd, J1 =
9.1 Hz, J2 =2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 3.60 (s, 3H), 3.45 (ddd,
J1 =59.0 Hz, J2 =17.2 Hz, J3 =1.79 Hz, 2H), 1.25 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=198.61, 167.98, 166.29, 162.84, 141.61, 138.71,
138.56, 134.25, 128.93, 128.49, 128.43, 128.38, 128.26, 128.18, 127.45,
127.21, 116.39, 112.91, 84.74, 79.37, 62.43, 55.61, 48.21, 27.29 ppm; IR
(KBr): n˜ =2979, 1726, 1580, 1521, 1346, 1261, 1150, 756, 700 cmÀ1; HRMS
(ESI): m/z calcd for [C29H29NO8Na]+: 542.1785; found: 542.1810.
2979, 1773, 1731, 1581, 1519, 1344, 1260, 1155, 1032, 841, 756 cmÀ1
;
HRMS (FAB): m/z calcd for [C16H20NO7]+: 338.1240; found: 338.1252.
(R)-tert-Butyl 2-(5-methoxy-2-nitrophenyl)-2-(methanesulfonyloxymeth-
yl)-4-methanesulfonyloxybutanoate (16): Methanesulfonyl chloride
(116 mL, 1.5 mmol) was added to a solution of 15 (170.7 mg, 0.5 mmol)
and triethylamine (209 mL, 1.5 mmol) in dichloromethane (8 mL) at 08C.
The reaction mixture was allowed to warm to room temperature and stir-
red for 2 h. Saturated aqueous solution of NaHCO3 (15 mL) was added
dropwise to the reaction mixture for quenching and the mixture was di-
luted with dichloromethane (20 mL). The layers were separated and the
aqueous layer was extracted with dichloromethane (2ꢂ20 mL). The com-
bined organic layers were washed with brine (20 mL), dried with MgSO4,
and concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexane/EtOAc=1:1) to afford 16 (246 mg, 99%
(R)-tert-Butyl 4-hydroxy-2-(hydroxymethyl)-2-(5-methoxy-2-nitrophenyl)
butanoate (15): Sodium borohydride (45.4 mg, 1.2 mmol) was added to a
solution of 13 (519.5 mg, 1 mmol) in ethanol (6 mL) at À208C. The reac-
tion mixture was stirred for 1 h and allowed to warm to 08C until the
entire substrate was converted into intermediate 14 by TLC analysis. Tet-
rahydrofuran (1.5 mL) and ceriumACTHNUTRGNEUGN(III) trichloride heptahydrate
(745.2 mg, 2 mmol) were then added at 08C. After stirring the reaction
mixture for 10 min at 08C, sodium borohydride (189 mg, 5 mmol) was
added and stirred for 10 min then a second charge of sodium borohydride
(189 mg, 5 mmol) was added.[10] The reaction mixture was stirred for 2 h
until no more intermediate 14 was observed by TLC analysis, then
AcOH (0.5 mL) was added dropwise for quenching the extra sodium bor-
ohydride. After all of solvent was removed in vacuo, the reaction mixture
was diluted with of ethyl acetate (20 mL) and of water (20 mL). The or-
ganic layers were separated and the aqueous layer was extracted with
ethyl acetate (2ꢂ20 mL). The combined organic layers were washed with
a saturated aqueous solution of NaHCO3 (20 mL) and brine (20 mL),
dried with MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, hexane/EtOAc=1:1 to only
EtOAc) to afford 15 (208.1 mg, 61% yield) as a white solid. The enantio-
selectivity was determined by chiral HPLC analysis [chiral HPLC analy-
sis (DIACEL Chiralpak AD-H, hexane/2-propanol=90:10), flow rate=
1.0 mLminÀ1, 208C, l=254 nm, retention time, S (minor) 18.5 min, R
(major) 21.0 min, 91% ee]. The obtained 15 was recrystallized three
times with hexane-ethyl acetate (5:1) to afford the R-enantiomer 15
(131.2 mg, 63%) as a single stereoisomer. The residual liquid was evapo-
rated in vacuo to give an enantiomeric mixture of 15 as a solid. The re-
sidual solid was recrystallized six times again as the same procedure
above to afford the R enantiomer 15 (45.6 mg, 22%). The enantioselec-
tivity of the combined R enantiomer 15 (total 176.8 mg, 85%) was deter-
mined by chiral HPLC analysis [chiral HPLC analysis (DIACEL Chiral-
pak AD-H, hexane/2-propanol=90:10), flow rate=1.0 mLminÀ1, 208C,
l=254 nm, retention time, R (only major peak) 21.8 min,>99% ee].
m.p. 122.88C; [a]2D0 =À87.79 (>99% ee, c=1, CHCl3); 1H NMR
yield) as
a
colorless oil. [a]2D0 =À116.20 (>99% ee, c=1, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.05 (d, J=9.0 Hz, 1H), 6.96 (d, J=
2.6 Hz, 1H), 6.91 (dd, J1 =9.0 Hz, J2 =2.6 Hz, 1H), 4.85 (dd, J1 =45.6 Hz,
J2 =10.2 Hz, 2H), 4.18 (t, J=7.3 Hz, 2H), 3.90 (s, 3H), 2.96 (s, 3H), 2.88
(s, 3H), 2.78–2.59 (m, 2H), 1.41 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=168.32, 162.90, 142.45, 13380, 128.72, 116.67, 112.41, 84.46,
71.88, 65.55, 56.01, 52.99, 37.39, 37.26, 33.54, 27.62 ppm; IR (KBr): n˜ =
1726, 1580, 1522, 1355, 1261, 1175, 960, 840, 755 cmÀ1; HRMS (FAB) :
m/z calcd for [C18H27NO11S2]+: 497.1026; found: 497.1034.
(R)-tert-Butyl 3-(5-methoxy-2-nitrophenyl)-1-methylpyrrolidine-3-carbox-
ylate (11): Compound 16 (199 mg, 0.4 mmol) was dissolved in methyla-
mine solution (33 wt% in absolute ethanol (10 mL).[4k] At room tempera-
ture, the reaction mixture was stirred for 48 h. After all of solvent was re-
moved in vacuo, the residue was purified by column chromatography
(silica gel, hexane/EtOAc/acetone/methanol=10:16:4:1) to afford 11
(313.5 mg, 93% yield) as a yellow solid. The enantioselectivity was deter-
mined by chiral HPLC analysis [chiral HPLC analysis (DIACEL Chiral-
cel OD-H, hexane/2-propanol=99:1), flow rate=1.0 mLminÀ1, 208C, l=
254 nm, retention time, R (only major peak) 11.9 min,>99% ee]. M.p.
89.78C; [a]2D0 =86.23 (>99% ee, c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.97 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H), 6.76 (dd,
J1 =9.0 Hz, J2 =2.8 Hz, 1H), 3.85 (s, 3H), 3.26 (d, J=10.3 Hz, 1H), 3.01–
2.84 (m, 2H), 2.75 (d, J=10.3 Hz, 1H), 2.46 (q, J=8.6 Hz, 1H), 2.35 (s,
3H), 2.15–2.05 (m, 1H), 1.33 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d=172.59, 163.10, 142.75, 141.27, 127.66, 115.53, 110.44, 81.55, 66.92,
57.55, 56.28, 55.66, 41.80, 38.24, 27.57 ppm; IR (KBr): n˜ =2975, 2940,
9604
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 9599 – 9605

Enantioselective Total Synthesis of (À)-Horsfiline
FULL PAPER
2788, 1731, 1612, 1577, 1518, 1347, 1273, 1258, 1155, 1074, 1035, 842,
756 cmÀ1; HRMS (FAB): m/z calcd for [C17H25N2O5]+: 337.1763; found:
337.1762.
Acknowledgements
This work was supported by the National Research Foundation of Korea
(NRF) grants funded by the Korea government (MEST) (2012–002956
and NRF-C1ABA001–2010–0020428).
(R)-Methyl 3-(5-methoxy-2-nitrophenyl)-1-methylpyrrolidine-3-carboxy-
late (18): Trifluoroacetic acid (1.2 mL) was added to a stirred solution of
11 (80 mg, 0.24 mmol) in dichloromethane (2 mL). After stirring for 1 h,
both dichloromethane and trifluoroacetic acid were removed in vacuo.
The crude product (17) was concentrated in vacuo for 3 h and dissolved
[1] C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902;
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in
a mixture of toluene/MeOH=5:2 (3 mL). TMS-diazomethane
(0.48 mL, 0.95 mmol) was added to a stirred solution. After stirring for
2 h, the reaction mixture was evaporated in vacuo and diluted with
EtOAc (50 mL), washed with brine (2ꢂ20 mL), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, dichloromethane/methanol=20:1) to
afford 18 (64.4 mg, 92% yield) as a yellow oil. 1H NMR (300 MHz,
CDCl3): d=8.01 (d, J=9.0 Hz, 1H), 7.25 (s, 1H), 6.80 (dd, J1 =9.0 Hz,
J2 =2.8 Hz, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 3.04 (dd, J1 =115.9 Hz, J2 =
10.1 Hz, 2H), 2.97–2.90 (m, 2H), 2.54 (q, J=7.3 Hz, 1H), 2.36 (s, 3H),
2.16–2.06 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=174.24, 163.27,
142.11, 141.14, 127.95, 115.64, 110.77, 66.69, 56.81, 56.05, 55.74, 52.30,
41.76, 38.02 ppm; IR (KBr): n˜ =2950, 2841, 2789, 1739, 1577, 1516, 1346,
1257, 1034 cmÀ1; HRMS (FAB) : m/z calcd for [C14H19N2O5]+: 295.1294;
found: 295.1306.
[2] For review on the synthesis of spirooxindole alkaloids, see: C. Marti,
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[3] A. Jossang, P. Jossang, H. Hadi, T. Sevenet, B. Bodo, J. Org. Chem.
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[4] a) K. Jones, J. Wilkinson, J. Chem. Soc. Chem. Commun. 1992, 1767;
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1175; d) U. K. Syam Kumar, H. Illa, H. Junjappa, Org. Lett. 2001, 3,
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Biomol. Chem. 2003, 1, 117; g) J. A. Murphy, R. Tripoli, T. A. Khan,
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Smith, A. M. Z. Slawin, A. D. Smith, Tetrahedron 2010, 66, 3801;
l) M. G. Kulkarni, A. P. Dhondge, S. W. Chavhan, A. S. Borhade,
Y. B. Shaikh, D. R. Birhade, M. P. Desai, N. R. Dhatrak, Beilstein J.
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[5] a) C. Pellegrini, C. Strꢃssler, M. Weber, H. Borschberg, Tetrahedron:
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(R)-tert-Butyl 3-(2-amino-5-methoxyphenyl)-1-methylpyrrolidine-3-car-
boxylate (19): Amine 19 could be isolated by the reduction (Pd/C, H2) of
11 without further intramolecular lactonization using silica gel in the fol-
lowing procedure. [a]D20 =À25.53 (>99% ee, c=1, CHCl3); 1H NMR
(300 MHz, CDCl3): d=6.65–6.53 (m, 3H), 3.97 (s, 2H), 3.71 (s, 3H), 3.09
(dd, J1 =70.7 Hz, J2 =9.7 Hz, 2H), 2.94–2.85 (m, 1H), 2.68–2.50 (m, 2H),
2.34 (s, 3H), 2.15–2.06 (m, 1H), 1.36 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3): d=174.30, 152.05, 138.93, 128.20, 117.77, 113.86, 112.74, 81.07,
64.41, 57.91, 55.76, 55.69, 42.09, 33.81, 27.77 ppm; IR (KBr): n˜ =3438,
3370, 3188, 2974, 2937, 2833, 2783, 1718, 1503, 1455, 1368, 1275, 1252,
1224, 1156, 1045, 847, 812 cmÀ1
; HRMS (FAB): m/z calcd for
[C17H26N2O3]+: 306.1943; found: 306.1947.
(À)-Horsfiline: Pd/C (17 mg) was added to a stirred solution of 11
(67.3 mg, 0.2 mmol) in methanol (4 mL) under H2 gas and stirred for 1 h.
The reaction mixture was filtered through the Celite 545 and concentrat-
ed in vacuo to afford quantitative 19 as a yellow oil. Silica gel (673 mg)
was added to a stirred solution of 19 (67.3 mg, 0.2 mmol) in dichlorome-
thane (2 mL) and stirred for 3 h. The absorbed residue was purified by
column chromatography (silica gel, dichloromethane/methanol=20:1–
8:1) to afford (À)-horsfiline (45.5 mg, 98% yield) as a white solid. The
enantioselectivity was determined by chiral HPLC analysis [chiral HPLC
analysis (DIACEL Chiralcel OJ-H, hexanes/2-propanol=98:2), flow
[8] E. Deiters, B. Song, A.-S. Chauvin, C. D. B. Vandevyver, F. Gumy,
J.-C. G. Bunzli, Chem. Eur. J. 2009, 15, 885.
[9] a) M.-h. Kim, Y. Park, B.-S. Jeong, H.-g. Park, S.-s. Jew, Org. Lett.
2010, 12, 2826; b) Y. Park, Y. J. Lee, S. Hong, M. Lee, H.-g. Park,
Org. Lett. 2012, 14, 852.
rate=1.0 mLminÀ1
, 208C, l=254 nm, retention time, R (only major
peak) 31.1 min,>99% ee]. M.p. 163.88C; [a]2D0 =À8.5 (>99% ee, c=5,
MeOH) (Reported value for natural (À)-horsfiline[3] : [a]D20 =À7.2 (c=1,
MeOH)); 1H NMR (400 MHz, CDCl3): d=9.49 (s, 1H), 6.97 (d, J=
2.1 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.67 (dd, J1 =8.4 Hz, J2 =2.1 Hz,
1H), 3.74 (s, 3H), 2.96 (q, J=8.1 Hz, 1H), 2.83 (q, J=9.4 Hz, 2H), 2.76
(q, J=7.9 Hz, 1H), 2.42 (s, 3H), 2.42–2.35 (m, 1H), 2.09–2.01 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3): d=183.37, 156.00, 137.53, 133.73,
112.30, 110.11, 110.02, 66.22, 56.65, 55.75, 54.18, 41.72, 37.93 ppm; IR
(KBr): n˜ =3222, 2925, 2851, 1709, 1490, 1305, 1205, 1033, 811, 755, 683,
624 cmÀ1; HRMS (FAB): m/z calcd for [C13H17N2O2]+: 233.1290; found:
233.1292.
[10] C. L. Martin, L. E. Overman, J. M. Rohde, J. Am. Chem. Soc. 2010,
132, 4894.
[11] R. T. Brown, In Heterocyclic Compounds (Ed.: J. E. Saxon), Wiley
Interscience, New York, 1983, Vol. 25, part 4, pp. 85–97.
[12] T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 2003, 125,
5139.
[13] I. T. Forbes, Tetrahedron Lett. 2001, 42, 6943.
[14] The same chemical yield and enantioselectivity in PTC a-allylation
were confirmed with 1 g scale synthesis.
Received: March 16, 2013
Published online: June 7, 2013
Chem. Eur. J. 2013, 19, 9599 – 9605
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9605