Collective asymmetric synthesis of (-)-Antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine with tert- butanesulfinamide as a chiral auxiliary

Article abstract of DOI:10.1021/jo500013e

A collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular S_N2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl₃-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.

Full text of DOI:10.1021/jo500013e

Article
pubs.acs.org/joc
Collective Asymmetric Synthesis of (−)-Antofine, (−)-Cryptopleurine,
(−)-Tylophorine, and (−)-Tylocrebrine with tert-Butanesulfinamide as
a Chiral Auxiliary
Yanlong Zheng, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: A collective asymmetric synthesis of phenan-
throindolizidine and phenanthroquinolizidine alkaloids
(−)-antofine, (−)-cryptopleurine, (−)-tylophorine, and
(−)-tylocrebrine was achieved by means of a reaction
sequence involving efficient generation of chiral homoallylic
amine intermediates by asymmetric allylation of the
corresponding tert-butanesulfinyl imine. From these inter-
mediates, the pyrrolidine and piperidine rings were con-
structed by means of an intramolecular SN2 substitution
reaction and a ring-closing metathesis reaction, respectively.
The unusual C5-methoxy-substituted phenanthrene moiety of
(−)-tylocrebrine was generated by means of an InCl3-catalyzed
cycloisomerization reaction of an o-propargylbiaryl compound.
from common chiral homoallylic amine intermediates, which
were synthesized by means of a chiral auxiliary, tert-
butanesulfinamide.
INTRODUCTION
■
Approximately 100 phenanthroindolizidine and phenanthro-
quinolizidine alkaloid natural products together with their
derivatives, including (−)-antofine (1), (−)-cryptopleurine (2),
(−)-tylophorine (3), and (−)-tylocrebrine (4), have been
isolated.1,2 During the past two decades, these structurally
related alkaloids have attracted great interest because they
exhibit diverse biological activities, including antibacterial,3
antiasthmatic,4 anticancer,2 and anti-inflammatory5 activities. In
addition, we recently reported that some of these compounds
also possess antiviral activity against tobacco mosaic virus.6
(−)-Tylocrebrine was also advanced to clinical trials in the
1960s but eventually failed owing to its toxicity to the central
nervous system.7
To facilitate investigation of the biological activities of these
alkaloids, researchers have developed a number of methods for
their synthesis. Among these methods, organocatalysis,8
enantioselective transition-metal-catalyzed carboamination of
alkenes,9 enantioselective alkylation10 by means of a phase-
transfer reagent, and the use of chiral building blocks11 or a
chiral auxiliary12 are the most efficient methods reported for the
synthesis of optically active phenanthroindolizidine and
phenanthroquinolizidine alkaloids. The D and E rings have
been constructed in one step by a [2 + 2 + 2] cyclo-
isomerization reaction,13 an intramolecular Diels−Alder cyclo-
addition reaction,14 and a Schmidt/Bischler−Napieralski/imine
reduction sequence.15 As part of our continuing studies of the
synthesis and bioactivity of these compounds, we developed a
practical approach to the collective asymmetric synthesis of four
phenanthroindolizidine and phenanthroquinolizidine alkaloids
First reported by Ellman in 1997,16 enantiomerically pure
tert-butylsulfinamide is regarded as an ideal auxiliary for the
synthesis of chiral amines because of its low cost and ease of
removal from reaction products. More importantly, addition of
nucleophiles to tert-butanesulfinyl imines proceeds with
excellent diastereoselectivity to permit the synthesis of amine-
containing compounds.17 In particular, chiral homoallyl amines,
which are versatile precursors for the synthesis of complex
molecules, can be achieved by metal-mediated allylation18 of
tert-butanesulfinyl imines and subsequent removal of the chiral
auxiliary. Herein, we report that a homoallyl amine building
block could be transformed to the D and E rings of
phenanthroindolizidine and phenanthroquinolizidine alkaloids;
specifically, this powerful strategy enabled us to synthesize 1−4.
RESULTS AND DISCUSSION
■
Our retrosynthetic analysis of compounds 1−3 is shown in
Scheme 1. We envisioned that the target molecules could be
constructed by means of a late-stage Pictet−Spengler
annulation8a,9,10,11d of a 2-(arylmethyl)pyrrolidine or 2-
(arylmethyl)piperidine (5), which could in turn be obtained
from homoallyl amine derivatives 6 and 7. We expected that
these amines could be easily obtained from chiral homoallyl
Received: January 3, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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butanesulfinyl imines 10. Sulfinimines such as 10 have a
tendency to isomerize to their enamine tautomers21 14, but
fortunately, we detected no such tautomerization of either 10a
or 10b. Zinc-mediated allylation of 10 by means of Lin’s
modification18a afforded the anticipated anti-adducts 9 with
1
excellent diastereoselectivity (de > 99% deduced from the H
spectrum) and in up to 91% yield. HCl-mediated removal of
the tert-butanesulfinyl group22 cleanly provided free amines 8.
Amines 8 contained all the desired atoms for intermediates 5,
and the stereocenter had been introduced with control of
absolute chemistry. To efficiently convert 8 to 5, we had to
functionalize the double bond. Therefore, chiral amines 8 were
converted to benzyl carbamates 6 (Scheme 3), which were
subjected to hydroboration−oxidation to afford primary
alcohols 15; subsequent mesylation afforded mesylates 16 in
high yield. Initially, we envisioned that the pyrrolidine ring of 5
could be formed by removal of the Cbz protecting group from
16 by Pd/C-catalyzed hydrogenolysis, followed by intra-
molecular nucleophilic attack of the amine on the OMs
group. Unfortunately, the hydrogenolysis reaction did not
proceed in nonalcoholic solvents (e.g., CH2Cl2, EtOAc, or
THF), and when methanol or ethanol was used as the solvent,
the reaction of 16a led to the formation of N-methylpyrrolidine
17a or N-ethylpyrrolidine 17b, respectively,23 as well as the
recovery of starting material (1H NMR, 13C NMR, and HRMS
spectra are available in the Supporting Information). However,
cyclization of 16a with NaH in THF at 0 °C afforded 18a,24
and subsequent removal of the Cbz protecting group with
(TMS)I in CH2Cl2 in the same pot gave 5a. Compound 5b was
obtained more efficiently from key intermediate 6b in one pot
without purification over four steps. Finally, Pictet−Spengler
annulation of the 2-(arylmethyl)pyrrolidines under standard
conditions8a,9,10,11d (formaldehyde, HCl, EtOH, reflux) gen-
amines 8 which are obtained by allylation of tert-butanesulfinyl
imines 10. Imines 10 could be readily accessed by direct
condensation of phenanthrylacetaldehydes 11 with tert-
butylsulfinamide under mild conditions. Aldehydes 11 could
be prepared from phenanthrylmethyl bromides 13, which are
readily available by means of a procedure developed in our
group.
We began our synthesis from phenanthrylmethyl bromides
13, which were obtained as described previously.6 First,
compounds 13 were converted to phenanthrylacetonitriles 12
(Scheme 2) by means of a nucleophilic substitution reaction
with NaCN, and subsequent reduction of the cyano group19
with DIBALH gave aldehydes 11, which were directly
condensed with tert-butanesulfinamide in the presence of
copper(II) sulfate20 to give enantiomerically pure tert-
Scheme 1. Retrosynthetic Analysis of (−)-Antofine (1), (−)-Cryptopleurine (2), and (−)-Tylophorine (3)
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Scheme 2. Synthesis of Chiral Homoallyl Amines 8
Scheme 3. Syntheses of (−)-Antofine (1) and (−)-Tylophorine (3)
1
erated (−)-antofine (1) and (−)-tylophorine (3). The H and
most powerful methods for the synthesis of medium-sized
rings.25 Acylation of amine 8a with acryloyl chloride afforded
RCM precursor 7, which contains all the atoms for the E ring of
the target natural product (Scheme 4). The RCM reaction of 7
was performed with a commercially available second-generation
Grubbs catalyst (20) in CH2Cl2 at room temperature to form
6-(arylmethyl)-5,6-dihydropyridin-2(1H)-one 19 in 93% yield.
Subsequent catalytic hydrogenation of the double bond in
methanol followed by reduction of the resulting six-membered
13C NMR spectra of synthetic 1 and 3 agreed well with the
reported spectra, and the optical rotation values of 1 {[α]D20
=
−109.0 (c = 1, CHCl3)} and 3 {[α]2D0 = −87.0 (c = 1, CHCl3)}
also agreed with previously reported values for synthetic
(−)-antofine8a,11d and (−)-tylophorine.9a,11b
We next focused our attention on the preparation of
(−)-cryptopleurine (2) from intermediate 8a by means of a
ring-closing metathesis (RCM) reaction, which is one of the
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Scheme 4. Synthesis of (−)-Cryptopleurine (2)
Scheme 5. Synthesis of Biarylbenzaldehyde 26
Scheme 6. Synthesis of Phenanthrylacetaldehyde 31
lactam using LiAlH4 in refluxing THF yielded 2-(arylmethyl)-
piperidine 5c in 70% yield. Finally, reaction of 5c under Pictet−
Spengler annulation conditions yielded 2 in 94% yield; the
spectroscopic data (1H and 13C NMR) and the optical rotation
{[α]2D1 = −92.4 (c = 1, CHCl3)} of the compound were in
agreement with those previously reported for synthetic
(−)-cryptopleurine.8a,11d
Having accomplished the synthesis of 1−3, we turned our
attention to the synthesis of (−)-tylocrebrine (4),26 which has
an unusual methoxy group at C5 of the phenanthrene ring.
For the construction of methoxy-substituted phenanthrene
rings in phenanthrylmethyl bromides 13a and 13b (Scheme 1),
the predominant method is dehydrogenative coupling of biaryl
substrates, and the robust FeCl3-mediated oxidative coupling
method developed in our laboratory27 is particularly useful,
owing to its tolerance for preinstalled aryl substituents.
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Scheme 7. Synthesis of (−)-Tylocrebrine (4)
However, the inaccessibility of certain phenanthrene sub-
stitution patterns, such as the pattern in 4, is a major drawback.
strates that the phenyl ring preferred to attack the alkyne at the
less hindered position. After the oxidation state of the side
chain was changed by reduction and oxidation reactions, 30 was
readily converted to acetaldehyde 31 in one pot.
To solve this problem, we employed Furstner’s transition-
̈
metal-catalyzed cycloisomerization reaction28 of o-alkynylbiar-
yls. Sequential bromination and O-methylation of isovanillin
(21) provided tetrasubstituted bromobenzaldehyde derivative
23. As expected, a (dppf)PdCl2-catalyzed Suzuki−Miyaura
coupling reaction of 23 with boronic acid 25, which was
prepared from the corresponding aryl bromide 24 by reaction
with n-BuLi and B(i-PrO3), gave biarylbenzaldehyde 26 in 98%
yield (Scheme 5).
We next allowed aldehyde 31 to react with the tert-
butylsulfinamide auxiliary to complete our synthesis of 4
(Scheme 7). Use of the previously described condensation
conditions afforded compound 33, and subsequent asymmetric
allylation of the CN bond followed by smooth removal of
the auxiliary group afforded homoallyl amine 35, which was
protected with a Cbz group (36). Changing the oxidation state
of the double bond under hydroboration−oxidation conditions
gave the primary alcohol, which was mesylated without
purification to give compound 37 in high yield. Intermediate
4-(arylmethyl)pyrrolidine 38 was obtained through intra-
molecular SN2 substitution and the corresponding deprotection
process. Finally, 4 was synthesized via a Pictet−Spengler
With aldehyde 26 in hand, we constructed the 5-methoxy-
substituted phenanthrene moiety (Scheme 6). We initially
considered substrate 32, but we expected that, under transition-
metal-catalyzed cycloisomerization conditions, a 5-exo-dig
cyclization would be preferred over a 6-endo-dig cyclization,
owing to the electron-withdrawing bromide atom. This
potential regioselectivity problem inspired us to explore an
alternative route by considering the stereoelectronic properties
and the enthalpy of the transition state of the cyclization
reaction. According to Baldwin’s rule,29 the difference in
favorability between 5-exo-dig and 6-endo-dig ring-closure
reactions is small, and therefore, the substrate’s stereoelectronic
properties play a crucial role in the nucleophilic attack of the
alkyne by the aromatic ring. We postulated that if a methylene
group was inserted between the biaryl and alkynyl groups, we
could take advantage of the fact that a 6-exo-dig reaction is more
favored than a 7-endo-dig reaction. We also postulated that an
electron-withdrawing ester substituent on the alkyne would
stabilize the anion formed by the cyclization reaction. The
combination of these two effects might solve this regioselec-
tivity problem. The feasibility of this approach was confirmed
by Kim et al.,30 who recently used a similar method to control
the regioselectivity of cycloisomerization reactions of o-
propargylbiaryls.
annulation reaction in 74% yield; the specific rotation {[α]D22
=
1
−90.4 (c = 1, CHCl3)} and H and 13C NMR spectra were in
agreement with those reported in the literature.11c
CONCLUSION
■
In summary, we accomplished a collective asymmetric synthesis
of four phenanthroindolizidine and phenanthroquinolizidine
natural products: (−)-antofine, (−)-cryptopleurine, (−)-tylo-
phorine, and (−)-tylocrebrine. The key steps were as follows:
(1) facile asymmetric allylation of a CN bond to generate a
chiral homoallyl amine intermediate, (2) construction of the
pyrrolidine and piperidine rings via a common building block,
and (3) most notably, a quantitative InCl3-catalyzed cyclo-
isomerization of an o-propargylbiaryl compound to afford the
C5-methoxy-substituted phenanthrene ring system of (−)-ty-
locrebrine. This strategy offers a practical approach to the
synthesis of phenanthrene derivatives with other substitution
patterns.
With these considerations in mind, we reduced biaryl
aldehyde 26 to biaryl alcohol 27 with NaBH4 in methanol,
and subsequent bromination with PBr3 in CH2Cl2 cleanly gave
28 (Scheme 6). A simple copper-promoted coupling
reaction30,31 of biaryl bromide 28 with ethyl propiolate
smoothly gave o-propargylbiaryl 29. Refluxing 29 in 1,2-DCE
readily provided 6-exo-dig product 30 with nearly quantitative
yield, and none of the 7-endo-dig product was detected.
Moreover, only one regioisomer was found, which demon-
EXPERIMENTAL SECTION
■
General Information. All chemicals were of analytical grade, and
anhydrous solvents were prepared by standard methods before use. 1H
NMR and 13C NMR spectra were obtained by using a 400 MHz NMR
spectrometer with CDCl3 or DMSO-d6 as the solvent. Melting points
were uncorrected. High-resolution mass spectrometry (HRMS)
analysis was performed with an FTICR-MS spectrometer. Optical
rotations were measured with an auto digital polarimeter.
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Compound 12a. To a stirred solution of 10-(bromomethyl)-2,3,6-
trimethoxyphenanthrene (13a) (6.7 g, 18.55 mmol) in anhydrous
DMF (300 mL) was added NaCN (1.36 g, 27.82 mmol) in one
portion, and the mixture was stirred overnight. Water (600 mL) was
added, and the solution was extracted with CH2Cl2. The organic layer
was washed with water and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure to give 12a as a white solid (4.9
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J = 5.2 Hz, 1H), 7.85
(s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 4.31
(dd, J1 = 6.0 Hz, J2 = 15.2 Hz, 1H), 4.19 (dd, J1 = 5.2 Hz, J2 = 15.6 Hz,
1H), 4.13 (s, 6H), 4.04 (s, 3H), 4.03 (s, 3H), 1.17 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 167.5, 149.3, 149.1, 149.0, 148.8, 126.7, 126.2,
125.7, 125.3, 125.1, 124.2, 108.1, 104.9, 103.5, 102.8, 56.9, 56.1, 56.0,
55.9, 40.9, 22.4; HRMS (ESI) m/z calcd for C24H30NO5S [M + H]+
444.1839, found 444.1840.
1
g, 86%): mp 192−193 °C; H NMR (400 MHz, CDCl3) δ 7.94 (s,
Compound 9a. To a solution of activated zinc powder (0.42 g,
6.38 mmol), In(OTf)3 (1.80 g, 3.51 mmol), and compound 10a (1.32
g, 3.192 mmol) in freshly distilled THF (15 mL) under the protection
of argon was added allyl bromide (0.56 mL, 6.384 mmol), and the
solution was stirred overnight at room temperature. Brine (20 mL)
was added to quench the reaction, and the solution was extracted with
CH2Cl2. The organic phase was washed with brine and dried over
Na2SO4. After concentration, the residue was purified by column
chromatography (CH2Cl2:MeOH = 20:1) to afford 9a as a white foam
1H), 7.85 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.23 (d, J =
8.8 Hz, 1H), 7.16 (s, 1H), 4.13 (s, 3H), 4.10 (s, 2H), 4.08 (s, 3H),
4.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 149.7, 149.1,
131.0, 130.1, 125.4, 125.2, 124.8, 124.7, 120.7, 117.7, 115.8, 104.0,
103.9, 103.3, 56.0, 55.9, 55.5, 22.3; HRMS (ESI) m/z calcd for
C19H18NO3 [M + H]+ 308.1281, found 308.1284.
Compound 12b. Intermediate 12b was synthesized from 9-
(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene (10.4 g, 26.57
mmol) by using a procedure similar to that described for 12a as a
(1.30 g, 90%): mp 70−72 °C; [α]2D5 = 46.1 (c = 1.25, CHCl3); H
1
1
white solid (7.6 g, 85%): mp 239−241 °C; H NMR (400 MHz,
NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H),
7.73 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.43 (s, 1H), 7.19 (dd, J1 = 2.4
Hz, J2 = 8.8 Hz, 1H), 5.88−5.77 (m, 1H), 5.25−5.20 (m, 2H), 4.12 (s,
6H), 4.02 (s, 3H), 3.79−3.75 (m, 1H), 3.57 (d, J = 4.0 Hz, 1H), 3.47
(dd, J1 = 6.0 Hz, J2 = 14.0 Hz, 1H), 3.05 (dd, J1 = 8.0 Hz, J2 = 14.0 Hz,
1H), 2.54−2.48 (m, 1H), 2.39−2.31 (m, 1H), 1.15 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 158.0, 149.5, 148.7, 134.4, 130.5, 129.6, 129.1,
126.8, 126.4, 125.7, 124.8, 119.4, 115.5, 104.7, 103.9, 103.8, 56.1, 56.0,
55.8, 55.58, 53.68, 39.9, 39.7, 22.5; HRMS (ESI) m/z calcd for
C26H34NO4S [M + H]+ 456.2203, found 456.2205.
Compound 9b. Compound 9b was synthesized from 10b (0.75 g,
1.69 mmol) by using a procedure similar to that described for 9a as a
white foam (0.80 g, 91%): mp 81−82 °C; [α]2D5 = 42.6 (c = 1, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.45 (s,
1H), 7.43(s, 1H), 7.17 (s, 1H), 5.88−5.78 (m, 1H), 5.25−5.20 (m,
2H), 4.13 (s, 3H), 4.12 (s, 3H), 4.11 (s, 3H), 4.03 (s, 3H), 3.78−3.75
(m, 1H), 3.60 (d, J = 3.6 Hz, 1H), 3.49 (dd, J1 = 5.6 Hz, J2 = 14.0 Hz,
1H), 3.06 (dd, J1 = 8.0 Hz, J2 = 14.0 Hz, 1H), 2.55−2.49 (m, 1H),
2.39−2.32 (m, 1H), 1.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
149.0, 148.9, 148.8, 134.5, 129.8, 126.3, 126.0, 125.3, 124.9, 123.9,
119.3, 107.8, 104.7, 103.4, 102.7, 56.1, 56.0, 55.9, 55.8, 53.8, 39.8, 39.7,
22.6; HRMS (ESI) m/z calcd for C27H36NO5S [M + H]+ 486.2309,
found 486.2306.
CDCl3) δ 7.85 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.23 (s, 1H), 7.13
(s, 1H), 4.14 (s, 3H), 4.13 (s, 3H), 4.12 (s, 2H), 4.07 (s, 3H), 4.05 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 149.7, 149.3, 149.1, 149.05,
125.7, 125.0, 124.7, 124.4, 123.7, 121.3, 117.8, 108.2, 103.6, 103.3,
102.6, 56.1, 56.0, 56.0, 22.4; HRMS (ESI) m/z calcd for C20H20NO4
[M + H]+ 338.1387, found 338.1386.
Compound 11a. To a solution of compound 12a (3.0 g, 9.76
mmol) in CH2Cl2 (200 mL) was added DIBALH (1.0 M in hexane,
14.65 mL, 14.65 mmol) at room temperature via a syringe. After the
resulting solution was stirred for 2.5 h, 3 M HCl (50 mL) was added,
and the solution was stirred vigorously for 1 h. The mixture was
extracted with CH2Cl2, and the organic phase was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The crude aldehyde
was purified by column chromatography (CH2Cl2:EtOAc = 40:1) to
afford the aldehyde 11a as a white solid (2.5 g, 83%): mp 185−186
°C; 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.93 (s, 1H), 7.85 (s,
1H), 7.78 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.22 (d, J = 8.8 Hz,1H),
7.20 (s, 1H), 4.12 (s, 3H), 4.05 (s, 2H), 4.03 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 200.2, 158.4, 149.6, 148.9, 131.0, 129.9, 127.4, 126.6,
125.7, 124.8, 123.2, 115.7, 104.5, 103.9, 103.8, 56.0, 55.9, 55.5, 49.3;
HRMS (ESI) m/z calcd for C19H19O4 [M + H]+ 311.1278, found
311.1278.
Compound 11b. Compound 11b was synthesized from 12b (1.0
g, 2.96 mmol) by using a procedure similar to that described for 11a as
a white solid (0.95 g, 95%): mp 206−208 °C; H NMR (400 MHz,
Compound 8a. The sulfonamide 9a (0.48 g, 1.05 mmol) was
dissolved in MeOH (20 mL), and this solution was cooled to 0 °C.
Concentrated hydrochloric acid (0.19 mL, 2.2 equiv) was added, and
the reaction mixture was stirred at 0 °C for 10 h. Then the solvent was
evaporated, water was added, and acid−base workup afforded the free
amine, which was extracted with CH2Cl2. The organic phase was
washed with water and brine, dried over Na2SO4, and concentrated.
The crude product was purified by column chromatography
(CH2Cl2:EtOAc = 20:1) to give homoallyl amine 8a as a yellow oil
1
CDCl3) δ 9.77 (t, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.56 (s,
1H), 7.22 (s, 1H), 7.21 (s, 1H), 4.15 (s, 3H), 4.14 (s, 3H), 4.07 (d, J =
2.4 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.0, 148.3, 148.0, 147.84, 147.78, 125.6, 125.0, 124.3, 123.9, 123.2,
122.8, 106.8, 103.3, 102.2, 101.6, 55.0, 54.9, 54.8, 54.8, 48.2; HRMS
(ESI) m/z calcd for C20H21O5 [M + H]+ 341.1384, found 341.1385.
Compound 10a. To a solution of (R)-2-methyl-2-propane-
sulfinamide (0.39 g, 3.22 mmol) in CH2Cl2 (8 mL) was added
anhydrous CuSO4 (1.03 g, 6.44 mmol) followed by the aldehyde 11a
(1.2 g, 3.87 mmol). The mixture was stirred at room temperature for
48 h. Then the reaction mixture was filtered through a short pad of
Celite, and the filter cake was washed with CH2Cl2. After
concentration, the crude product was purified by column chromatog-
raphy (CH2Cl2:EtOAc = 10:1) to afford 10a as a yellow foam (1.33 g,
(0.35 g, 94%): [α]2D5 = −11.7 (c = 1, CHCl3); H NMR (400 MHz,
1
CDCl3) δ 7.93 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.8 Hz,
1H), 7.50 (s, 1H), 7.37 (s, 1H), 7.19 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz,
1H), 5.98−5.87 (m, 1H), 5.24−5.17 (m, 2H), 4.12 (s, 3H), 4.05 (s,
3H), 4.02 (s, 3H), 3.39−3.30 (m, 2H), 2.89 (dd, J1 = 8.0 Hz, J2 = 13.2
Hz, 1H), 2.41−2.35 (m, 1H), 2.31−2.26 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 158.0, 149.3, 148.7, 135.0, 130.5, 129.7, 126.5, 126.0,
125.8, 124.9, 118.4, 115.4, 104.8, 103.9, 103.9, 55.98, 55.96, 55.6, 50.7,
41.7, 40.9; HRMS (ESI) m/z calcd for C22H26NO3 [M + H]+
352.1907, found 352.1910.
83%): mp 58−60 °C; [α]D25 = 135.0 (c = 1, CHCl3); H NMR (400
1
MHz, CDCl3) δ 8.23 (dd, J1 = 5.2 Hz, J2 = 5.6 Hz, 1H), 7.94 (s, 1H),
7.85 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.42
(d, J = 8.8 Hz, 1H), 7.21 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 4.30 (dd, J1
= 6.0 Hz, J2 = 15.2 Hz, 1H), 4.19 (dd, J1 = 4.8 Hz, J2 = 15.6 Hz, 1H),
4.13 (s, 3H), 4.04 (s, 3H), 4.03 (s, 3H), 1.17 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 167.5, 158.3, 149.4, 148.9, 130.8, 129.9, 126.4, 126.3,
126.0, 125.8, 124.9, 115.6, 104.9, 104.0, 103.9, 56.8, 56.0, 55.9, 55.5,
40.9, 22.3; HRMS (ESI) m/z calcd for C23H28NO4S [M + H]+
414.1734, found 414.1735.
Compound 8b. Compound 8b was synthesized from 9b (0.76 g,
1.57 mmol) by using a procedure similar to that described for 8a as a
white soild (0.52 g, 87%): mp 157−159 °C; [α]2D5 = 6.8 (c = 1.0,
1
DMSO); H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.75 (s, 1H),
7.44 (s, 1H), 7.34(s, 1H), 7.17 (s, 1H), 5.95−5.89 (m, 1H), 5.23−5.16
(m, 2H), 4.12 (s, 3H), 4.11 (s, 3H), 4.03 (s, 6H), 3.35 (dd, J1 = 3.2
Hz, J2 = 13.6 Hz, 1H), 3.30−3.23 (m, 1H), 2.80 (dd, J1 = 8.8 Hz, J2 =
13.2 Hz, 1H), 2.39−2.33 (m, 1H), 2.28−2.11 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 148.9, 148.8, 148.7, 148.4, 135.5, 131.0, 126.1,
125.3, 125.0, 123.7, 117.9, 107.8, 104.8, 103.3, 102.7, 56.0, 55.9, 55.8,
Compound 10b. Compound 10b was synthesized from 11b (1.0
g, 2.94 mmol) by using a procedure similar to that described for 10a as
a yellow foam (0.90 g, 84%): mp 98−100 °C; [α]2D5 = 130.8 (c = 1,
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Article
50.6, 42.4, 41.6; HRMS (ESI) m/z calcd for C23H28NO4 [M + H]+
382.2013, found 382.2018.
56.0, 55.5, 50.7, 40.7, 37.0, 29.7, 25.8; HRMS (ESI) m/z calcd for
C31H39N2O8S [M + NH4]+ 599.2422, found 599.2430.
Compound 6a. To a vigorously stirred solution of homoallyl
amine 8a (0.34 g, 0.968 mmol) in THF (7 mL) and H2O (3 mL) was
added K2CO3 powder (0.20 g, 1.45 mmol) under an ice bath. After 10
min, CbzCl (250 mg, 1.45 mmol) was added via a syringe. The
mixture was stirred at 0 °C for 2 h, diluted with water (20 mL), and
extracted with CH2Cl2, and the organic layer was dried over Na2SO4.
After concentration, the residue was purified by column chromatog-
raphy (CH2Cl2:EtOAc = 1:1) to afford 6a as a white solid (0.43 g,
92%): mp 177−178 °C; [α]2D5 = −14.2 (c = 1, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.93 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.86 (s, 1H),
7.72 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.39−7.29 (m, 5H), 7.19 (d, J =
8.8 Hz, 1H), 5.86−5.76 (m, 1H), 5.17−5.04 (m, 4H), 4.86−4.83 (m,
1H), 4.71 (s, 1H), 4.16 (s, 3H), 4.13 (s, 3H), 4.02 (s, 3H), 3.65−3.60
(m, 1H), 2.98−2.90 (m, 1H), 2.38−2.32 (m, 1H), 2.23−2.13 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 157.9, 155.9, 149.7, 148.7, 136.5,
134.1, 130.6, 129.6, 129.3, 128.51, 128.48, 128.1, 127.6, 126.9, 126.8,
126.2, 125.7, 124.7, 118.5, 115.4, 105.5, 103.8, 103.7, 66.6, 56.4, 56.0,
55.5, 50.3, 39.4, 37.5; HRMS (ESI) m/z calcd for C30H32NO5 [M +
H]+ 486.2275, found 486.2271.
Compound 5a. To a stirred solution of 16a (0.26 g, 1.45 mmol) in
THF (15 mL) was added NaH (0.05 g 2.08 mmol) at 0 °C. The
solution was stirred at room temperature for 2 h, quenched with water,
and extracted with CH2Cl2. The organic phase was dried over Na2SO4
and concentrated. The residue was redissolved in CH2Cl2 (10 mL). To
this solution was added (TMS)I (0.12 mL, 0.82 mmol), and the
resulting solution was stirred at room temperature for 1.5 h. After
methanol was added to quench the reaction, the solution was
concentrated. The residue was purified by column chromatography to
give 5a as a yellow solid (0.11 g, 70% over two steps): mp 143−145
°C {lit.8a mp 144−146 °C}; [α]2D0 = −16.4 (c = 0.5, DMSO); 1H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.60 (s,
1H), 7.48 (s, 1H), 7.20 (s, 1H), 7.15 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz,
1H), 4.21−4.14 (m, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.87 (s, 3H),
3.84−3.79 (m, 1H), 3.62−3.54 (m, 1H), 3.40−3.30 (m, 2H), 2.20−
2.13 (m, 1H), 2.02−1.91 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ
158.0, 149.5, 148.9, 130.5, 129.7, 128.1, 125.6, 125.2, 124.6, 116.0,
105.0, 104.8, 104.1, 59.1, 56.0, 55.9, 55.6, 44.8, 34.9, 29.8, 22.8; HRMS
(ESI) m/z calcd for C22H26NO3 [M + H]+ 352.1907, found 352.1914.
Compound 5b. Compound 5b was synthesized from 6b (0.42 g,
0.82 mmol) by using a procedure similar to the steps described
previously for 5a as a white solid (0.14 g, 65%): mp 150−152 °C;
Compound 6b. Compound 6b was synthesized from 8b (0.34 g,
0.891 mmol) by using a procedure similar to that described for 6a as a
white solid (0.38 g, 85%): mp 175−176 °C; [α]2D5 = −17.2 (c = 1,
[α]2D0 = −9.6 (c = 1, DMSO); H NMR (400 MHz, CDCl3) 7.53 (s,
1
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.83 (s, 1H),
1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.21 (s, 2H), 4.06 (s, 3H), 4.04 (s,
4H), 4.01 (s, 3H), 3.97 (s, 3H), 3.77 (dd, J1 = 4.8 Hz, J2 = 14.8 Hz,
1H), 3.58−3.51 (m, 1H), 3.39−3.32 (m, 1H), 3.21 (dd, J1 = 9.2 Hz, J2
= 14.0 Hz, 1H), 2.15−2.10 (m, 1H), 1.97−1.87 (m, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 149.0, 148.9, 148.7, 148.6, 128.7, 125.6,
124.8, 124.7, 124.4, 123.7, 108.1, 104.7, 104.5, 103.7, 59.0, 55.9, 55.9,
55.4, 54.9, 44.1, 34.8, 29.6, 22.7. HRMS (ESI) m/z calcd for
C23H28NO4 [M + H]+ 382.2013, found 382.2020.
7.78 (s, 1H), 7.39 (s, 1H), 7.37−7.29 (m, 5H), 7.16 (s, 1H), 5.87−
5.77 (m, 1H), 5.16−5.07 (m, 4H), 4.84 (d, J = 7.2 Hz, 1H), 4.18−4.11
(m, 10H), 4.03 (s, 3H), 3.63 (dd, J1 = 5.2 Hz, J2 = 14.0 Hz, 1H), 2.95
(dd, J1 = 9.6 Hz, J2 = 13.6 Hz, 1H), 2.38−2.32 (m, 1H), 2.23−2.16 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 155.9, 149.0, 148.9, 148.8,
136.5, 134.1, 130.0, 128.5, 128.1, 126.0, 125.7, 125.6, 124.9, 124.0,
118.6, 107.9, 105.5, 103.2, 102.8, 66.6, 56.4, 56.1, 56.0, 55.8, 50.4, 39.4,
37.6; HRMS (ESI) m/z calcd for C31H34NO6 [M + H]+ 516.2381,
found 516.2384.
(−)-Antofine (1). To a solution of 5a (0.10 g, 0.28 mmol) in
ethanol (10 mL) was added 37% formaldehyde (2 mL), followed by
concd HCl (0.4 mL). The resulting solution was refluxed for 6 h in the
dark, and this solution was concentrated to dryness in vacuo. The
crude was redissolved in CH2Cl2, and water was added. The aqueous
solution was extracted with CH2Cl2, and the organic phase was
successively washed with water and brine, dried over Na2SO4, and
concentrated. The residue was purified by column chromatography
(CH2Cl2:MeOH = 20:1) and afforded 1 (65 mg, 65%) as a white
solid: mp 203−204 °C {lit.8a mp 208−209 °C}; [α]2D0 = −109.0 (c = 1,
CHCl3) {lit.8a [α]D20 = −117.0 (c = 1.75, CHCl3), lit.10 [α]2D2 = −108.2
(c = 0.71, CHCl3)}; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.91
(d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.21 (dd, J1
= 2.4 Hz, J2 = 9.2 Hz, 1H), 4.75 (d, J = 14.8 Hz, 1H), 4.11 (s. 3H),
4.07 (s. 3H), 4.02 (s. 3H), 3.81 (d, J = 14.8 Hz, 1H), 3.58−3.49 (m,
1H), 3.38 (dd, J1 = 2.8 Hz, J2 = 16.0 Hz, 1H), 3.08−2.97 (m, 1H),
2.79−2.50 (m, 2H), 2.35−2.26 (m, 1H), 2.14−2.06 (m, 1H), 2.01−
1.94 (m, 1H), 1.88−1.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
157.5, 149.4, 148.4, 130.2, 126.8, 125.7, 125.2, 124.1, 123.8, 123.5,
114.9, 104.6, 103.9, 103.7, 60.3, 56.0, 55.8, 55.5, 54.8, 53.3, 33.0, 31.0,
21.4; HRMS (ESI) m/z calcd for C23H26NO3 [M + H]+ 364.1907,
found 364.1911.
Compound 15a. To a solution of Cbz-protected homoallyl amine
6a (0.24 g, 0.49 mmol) in THF (5 mL) was slowly injected BH3−THF
(1 mL, 1 mmol) at 0 °C, and the mixture was stirred at room
temperature for 1 h. Then 3 M NaOH (3.0 mL) and 30% aqueous
H2O2 (3 mL) were added successively. One hour later, saturated NaCl
solution was added, and the mixture was extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and then concentrated. The
residue was purified by column chromatography (CH2Cl2:MeOH =
40:1) to give 15a as a white solid (0.22 g, 89%): mp 156−158 °C;
[α]2D5 = −10.6 (c = 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.93 (s,
1H), 7.85 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H),
7.40 (s, 1H), 7.38−7.28 (m, 5H), 7.18 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz,
1H), 5.10 (s, 2H), 4.14 (m, 4H), 4.12 (s, 3H), 4.02 (s, 3H), 3.60−3.53
(m, 3H), 2.96−2.89 (m, 1H), 1.72−1.66 (m, 2H), 1.54−1.48 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 158.0, 156.2, 149.6, 148.7, 136.5,
130.6, 129.7, 129.2, 128.5, 128.1, 128.0, 126.8, 126.2, 125.8, 124.7,
115.4, 105.4, 103.8, 103.7, 66.6, 62.4, 56.3, 56.0, 55.6, 51.1, 40.6, 30.2,
28.9; HRMS (ESI) m/z calcd for C30H34NO6 [M + H]+ 504.2381,
found 504.2376.
Compound 16a. To a mixture of 15a (0.14 g, 0.28 mmol), Et3N
(42.2 mg, 0.42 mmol), and 4-DMAP (5.0 mg, 0.042 mmol) in CH2Cl2
(10 mL) was added methanesulfonyl chloride (47.8 mg, 0.42 mmol) at
0 °C. After 1 h, the solution was diluted with water and extracted with
CH2Cl2. The organic phase was washed with brine, dried over Na2SO4,
and concentrated. The residue was purified by column chromatog-
raphy (petroleum ether:EtOAc = 2:1) to give 16a as a white solid
(−)-Tylophorine (3). The same procedure as that for (−)-antofine
was followed. A solution of 2-(arylmethyl)pyrrolidine 5b (0.20 g, 0.52
mmol) in EtOH (10 mL), 37% formaldehyde (3 mL), and concd HCl
(0.5 mL) was refluxed for 9 h in the dark. After workup, 3 was
obtained as a white solid (0.17 g, 81%): mp 268−270 °C {lit.9a mp
272−274 °C}; [α]D20 = −87.0 (c = 1, CHCl3); {lit.11c [α]2D2 = −99 (c =
(0.16 g, 99%): mp 131−132 °C; [α]2D5 = −6.7 (c = 1, CHCl3); H
1
1, CHCl3), lit.28c [α]D20 = −77.6 (c = 0.65, CHCl3)}; H NMR (400
1
NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H),
7.76 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.39−7.29 (m,
5H), 7.19 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 5.11 (t, J = 13.2 Hz, 2H),
4.75 (d, J = 9.2 Hz, 1H), 4.20−4.05 (m, 9H), 4.02 (s, 3H), 3.58 (dd, J1
= 4.0 Hz, J2 = 13.6 Hz, 1H), 2.90 (dd, J1 = 9.2 Hz, J2 = 13.2 Hz, 1H),
2.78 (s, 3H), 1.94−1.82 (m, 1H), 1.79−1.71 (m, 1H), 1.68−1.61 (m,
1H), 1.52−1.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.1,
156.1, 149.7, 148.8, 136.4, 130.6, 129.7, 128.8, 128.5, 128.1, 128.0,
126.6, 126.3, 125.7, 124.7, 115.5, 105.2, 103.8, 103.8, 69.4, 66.7, 56.3,
MHz, CDCl3) δ 7.84 (s, 2H), 7.32 (s, 1H), 7.17 (s, 1H), 4.64 (d, J =
14.4 Hz, 1H), 4.12 (s, 6H), 4.06 (s, 6H), 3.68 (d, J = 14.8 Hz, 1H),
3.51−3.47 (m, 1H), 3.41−3.37 (m, 1H), 2.96−2.89 (m, 1H), 2.54−
2.44 (m, 2H), 2.30−2.22 (m, 1H), 2.09−2.02 (m, 1H), 1.96−1.91 (m,
1H), 1.82−1.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 148.7,
148.5, 148.4, 126.2, 125.8, 124.3, 123.6, 123.4, 103.9, 103.4, 103.3,
103.0, 60.2, 56.0, 55.9, 55.8, 55.1, 54.0, 33.7, 31.2, 21.6; HRMS (ESI)
m/z calcd for C24H28NO4 [M + H]+ 394.2013, found 394.2017.
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Compound 7. To a solution of 8a (0.45 g, 1.28 mmol) in CH2Cl2
(25 mL) was added Et3N (0.36 mL, 2.56 mmol) at 0 °C, followed by
acryloyl chloride (0.17 g, 1.92 mmol) via a syringe. The solution was
stirred at 0 °C for 1 h, and water was added. The aqueous solution was
extracted with CH2Cl2, and the organic phase was washed with water
and brine, dried over Na2SO4, and concentrated. The residue was
purified by column chromatography (CH2Cl2:MeOH = 40:1) to give 7
(500 mg, 96%) as a white solid: mp 170−171 °C; [α]2D5 = −34.0 (c =
J = 2.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.20 (dd, J1 =
2.4 Hz, J2 = 9.2 Hz, 1H), 4.47 (d, J = 15.2 Hz, 1H), 4.11 (s. 3H), 4.07
(s. 3H), 4.01 (s. 3H), 3.67 (d, J = 15.2 Hz, 1H), 3.30 (d, J = 11.2 Hz,
1H), 3.12 (dd, J1 = 3.6 Hz, J2 = 16.4 Hz, 1H), 2.96−2.87 (m, 1H),
2.48−2.40 (m, 1H), 2.36−2.29 (m, 1H), 2.09−2.02 (m, 1H), 1.92−
1.88 (m, 1H), 1.84−1.80 (m, 2H), 1.60−1.47 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 156.4, 148.3, 147.3, 129.1, 125.4, 124.3, 123.3,
123.1, 122.6, 122.4, 113.8, 103.7, 102.8, 56.5, 55.1, 55.0, 54.9, 54.5,
33.5, 32.5, 24.8, 23.2; HRMS (ESI) m/z calcd for C24H28NO3 [M +
H]+ 378.2064, found 378.2064.
1
0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.93 (s,
1H), 7.86 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H),
7.19 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.27 (dd, J1 = 1.2 Hz, J2 = 16.8
Hz, 1H), 6.09 (dd, J1 = 10.4 Hz, J2 = 17.2 Hz, 1H), 5.87−5.78 m (m,
1H), 5.65 (dd, J1 = 1.2 Hz, J2 = 10.4 Hz, 1H), 5.60 (d, J = 7.6 Hz, 1H),
5.15 (s, 1H), 5.14−5.10 (m, 1H), 4.53−4.46 (m, 1H), 4.21 (s, 3H),
4.13 (s, 3H), 4.02 (s, 3H), 3.70 (dd, J1 = 4.0 Hz, J2 = 13.6 Hz, 1H),
2.93 (dd, J1 = 9.6 Hz, J2 = 13.6 Hz, 1H), 2.39−2.33 (m, 1H), 2.25−
2.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 165.4, 158.0, 149.8,
148.8, 134.2, 131.1, 130.7, 129.6, 129.2, 126.9, 126.28, 126.25, 125.7,
124.6, 118.5, 115.4, 105.8, 103.8, 103.6, 56.6, 56.0, 55.6, 48.7, 38.8,
37.1; HRMS (ESI) m/z calcd for C25H28NO4 [M + H]+ 406.2013,
found 406.2010.
Compound 23. 2-Bromo-3-hydroxy-4-methoxybenzylaldehyde
(22) (7.0 g, 30.30 mmol) was dissolved in a solution of KOH (3.1
g, 55.45 mmol) in water (35 mL). To the vigorously stirred bright
yellow solution was added dimethyl sulfate (6.1 g, 48.48 mmol)
dropwise within a period of 10 min at 50 °C. After being stirred for
another 10 min, the pale yellow solution containing the solid product
was cooled and filtered. The precipitate was washed twice with 1 M
NaOH and water and then dissolved in CH2Cl2. The resulting solution
was washed with brine and dried over Na2SO4. After removal of
solvent under reduced pressure, white solid 23 was obtained (6.8 g,
1
92%): mp 82−83 °C; H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H),
Compound 19. To a solution of 7 (0.46 g, 1.13 mmol) in CH2Cl2
(25 mL) was added Grubbs’s second-generation catalyst 20 (48 mg,
0.057 mmol). The solution was stirred at room temperature for 10 h
under argon. The solvent was evaporated, and the crude mixture was
purified by column chromatography (CH2Cl2:MeOH = 40:1) to give
target compound 19 as a white solid (0.40 g, 93%): mp 207−208 °C;
7.75 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 3.89.
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.1, 158.8, 146.5, 127.5,
126.6, 123.3, 111.1, 60.8, 56.4.
Compound 25. 4-Bromoveratrole (24) (5.0 g, 23.00 mol) was
added to dry THF (250 mL) under argon, and the reaction mixture
was cooled to −78 °C for 30 min. To this solution was added n-BuLi
(2.4 M, 19.2 mL, 46.10 mmol) dropwise via a constant-pressure drop
funnel. After addition of the n-BuLi, the solution was stirred for
another hour. B(i-PrO)3 (8.0 mL, 34.50 mmol) was added dropwise at
−78 °C, and the reaction mixture was allowed to warm room
temperature over 3−4 h. The solution was quenched with 3 M HCl to
pH 2−3, and the mixture was extracted with EtOAc. The combined
organic phase was washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy (petroleum ether:EtOAc = 1:1) to give 25 as a white solid (3.1
g, 74%): mp 224−225 °C; 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J1
= 2.0 Hz, J2 = 8.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.0
Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 150.6, 147.9, 127.7, 117.2, 110.9, 55.33, 55.26.
Compound 26. To a solution of 3,4-dimethoxyphenylboronic acid
(25) (2.41 g, 13.24 mmol) and 2-bromo-3,4-dimethoxybenzylaldehyde
(23) (3.25 g, 13.24 mmol) in toluene/ethanol/water (4:2:1, 140 mL)
was added K2CO3 (3.66 g, 26.48 mmol). The solution was stirred and
degassed with argon three times, and catalyst (dppf)PdCl2 (0.48 g, 5%
mol.) was added. The dark solution was warmed to reflux for 6 h with
the total consumption of starting material. Then the solution was
cooled to room temperature, water (100 mL) was added, and the
solution was extracted with EtOAc. The combined organic phase was
washed with water and brine, dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy (petroleum ether:EtOAc = 4:1) to afford 26 as a white solid
(3.90 g, 98%): mp 125−126 °C; 1H NMR (400 MHz, CDCl3) δ 9.66
(s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.96 (d, J =
8.0 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.95
(s, 3H), 3.88 (s, 3H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.3, 157.5, 148.8, 148.4, 146.2, 140.0, 128.4, 125.3, 124.5, 123.3,
113.7, 111.1, 110.5, 60.7, 56.0, 55.9, 55.8; HRMS (ESI) m/z calcd for
C17H19O5 [M + H]+ 303.1227, found 303.1228.
[α]2D5 = 8.6 (c = 1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.95 (s,
1
1H), 7.85 (d, J = 2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H),
7.27 (s, 1H), 7.22 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.68−6.63 (m,
1H), 5.95 (d, J = 10.0 Hz, 1H), 5.46 (s, 1H), 4.13 (s, 3H), 4.12−4.08
(m, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.40 (dd, J1 = 5.6 Hz, J2 = 14.0
Hz, 1H), 3.18 (dd, J1 = 8.8 Hz, J2 = 14.0 Hz, 1H), 2.55−2.48 (m, 1H),
2.44−2.36 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 166.2, 158.3,
149.5, 149.0, 140.4, 130.7, 129.9, 127.1, 126.3, 126.0, 125.6, 125.2,
124.8, 115.7, 104.2, 104.2, 103.9, 56.03, 56.0, 55.6, 50.6, 39.5, 30.5;
HRMS (ESI) m/z calcd for C23H24NO4 [M + H]+ 378.1700, found
378.1699.
Compound 5c. A solution of 19 (0.22 g, 0.583 mmol) in MeOH
(20 mL) was stirred with activated Pd/C (25 mg, 10%) under H2 (1
atm) at room temperature for 10 h, at which time TLC indicated
complete consumption of starting material. The solution was filtered,
and the filtrate was concentrated in vacuo. The residue was redissolved
in THF (20 mL), and LiAlH4 powder (50 mg, 1.32 mmol) was added
slowly to this solution at 0 °C. Then the solution was refluxed for 1.5
h. After cooling, ice−water was added slowly, and the mixture was
extracted with CH2Cl2. The organic phase was washed with water and
brine, dried over Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (CH2Cl2:MeOH = 20:1) to give
5c as a white solid (0.15 g, 70%): mp 147−149 °C {lit.11d mp 147−
148 °C}; [α]2D0 = −19.2 (c = 1, CHCl3) {lit.8a [α]2D0 = −20.6 (c = 1,
CHCl3), lit.11d [α]D20 = −18.8 (c = 1, CHCl3)}; H NMR (400 MHz,
1
CDCl3) δ 7.92 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz,
1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.19 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz,
1H), 4.12 (s. 3H), 4.08 (s. 3H), 4.01 (s. 3H), 3.25 (dd, J1 = 5.6 Hz, J2
= 13.6 Hz, 1H), 3.16−3.06 (m, 2H), 3.03−2.95 (m, 1H), 2.55 (dd, J1
= 3.2 Hz, J2 = 11.6 Hz, 1H), 1.86−1.76 (m, 2H), 1.66−1.54 (m, 2H),
1.46−1.38 (m, 1H), 1.37−1.30 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.9, 149.3, 148.7, 130.4, 129.7, 129.2, 126.6, 126.0, 125.8,
124.9, 115.4, 105.0, 103.9, 103.8, 56.4, 56.1, 56.0, 55.5, 46.7, 40.9, 32.6,
29.7, 25.5, 24.5; HRMS (ESI) m/z calcd for C23H28NO3 [M + H]+
366.2064, found 366.2058.
Compound 27. To a stirred solution of aldehyde 26 (4.0 g, 13.24
mmol) from the previous step in methanol (300 mL) was added
NaBH4 (1.0 g, 26.46 mmol) at 0 °C, and the solution was stirred at
room temperature. After TLC analysis showed the complete
consumption of starting material (1 h), 3 M HCl (20 mL) was
added to quench the reaction. This solution was preconcentrated and
extracted with EtOAc. The organic phase was washed with brine, dried
over Na2SO4, and concentrated to afford 27 as a colorless oil (3.7 g,
(−)-Cryptopleurine (2). The same procedure as that for
(−)-antofine was followed. To a solution of 5c (100 mg, 0.27
mmol) in ethanol (6 mL) were successively added 37% formaldehyde
(2 mL) and concd HCl (0.4 mL). The solution was refluxed for 11 h
in the dark. After workup, 2 was obtained as a white solid (97 mg,
94%): mp 191−192 °C {lit.11d mp 195−197 °C}; [α]2D1 = −92.4 (c =
1, CHCl3) {lit.11d [α]2D1 = −108.7 (c = 1, CHCl3), lit.8a [α]2D0 = −87.2
(c = 1, CHCl3)}; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.90 (d,
1
93%): H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.4 Hz, 1H), 6.95
(s, 1H), 6.93 (s, 1H), 6.87 (m, 2H), 4.41 (s, 2H), 3.94 (s, 3H), 3.91 (s,
3H), 3.86 (s, 3H), 3.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
3355
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152.4, 148.4, 148.2, 135.7, 132.2, 128.3, 124.0, 121.8, 113.1, 111.3,
110.7, 63.1, 60.7, 55.8, 55.8; HRMS (ESI) m/z calcd for C17H20NaO5
[M + Na]+ 327.1203, found 327.1201.
Compound 33. Following the procedure of compound 10,
compound 33 was synthesized from 31 (1.0 g, 2.94 mmol) as a
yellow oil (0.99 g, 91%): [α]2D5 = 131.2 (c = 1, CHCl3); 1H NMR (400
MHz, CDCl3) δ 9.34 (s, 1H), 8.23 (t, J = 5.6 Hz, 1H), 7.60 (d, J = 8.4
Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.28 (dd,
J1 = 5.6 Hz, J2 = 15.2 Hz, 1H), 4.16 (dd, J1 = 4.8 Hz, J2 = 15.6 Hz, 1H),
4.08 (s, 3H), 4.04 (s, 6H), 3.95 (s, 3H), 1.18 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 167.5, 151.1, 148.6, 148.1, 145.7, 127.2, 127.1, 126.7,
126.6, 124.7, 123.9, 112.5, 109.1, 104.4, 59.9, 56.7, 56.4, 55.61, 55.59,
40.8, 22.2; HRMS (ESI) m/z calcd for C24H30NO5S [M + H]+
444.1839, found 444.1846.
Compound 34. Following the procedure of compound 9,
compound 34 was synthesized from 33 (0.90 g, 2.03 mmol) as a
white solid (0.89 g, 91%): mp 154−155 °C; [α]2D5 = 38.8 (c = 1.2,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 7.58 (d, J = 8.8
Hz, 1H), 7.44 (s, 2H), 7.28 (d, J = 8.8 Hz, 1H), 5.88−5.77 (m, 1H),
5.26−5.18 (m, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 4.04 (s, 3H), 3.95 (s,
3H), 3.83−3.75 (m, 1H), 3.56 (d, J = 3.6 Hz, 1H), 3.47 (dd, J1 = 6.0
Hz, J2 = 14.0 Hz, 1H), 3.04 (dd, J1 = 8.0 Hz, J2 = 14.0 Hz, 1H), 2.55−
2.48 (m, 1H), 2.39−2.31 (m, 1H), 1.15 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 150.8, 148.7, 148.0, 145.7, 134.4, 129.7, 127.3, 127.2, 127.2,
124.6, 124.5, 123.7, 119.3, 112.5, 109.1, 104.2, 60.0, 56.5, 55.9, 55.73,
55.66, 53.5, 39.8, 39.7, 22.5; HRMS (ESI) m/z calcd for C27H36NO5S
[M + H]+ 486.2309, found 486.2310.
Compound 28. To a stirred solution of 2-(3,4-dimethoxyphenyl)-
3,4-dimethoxybenzyl alcohol (27) (3.6 g, 11.83 mmol) in dry CH2Cl2
(300 mL) at 0 °C was added dropwise a solution of PBr3 (3.84 g,
14.20 mmol) in CH2Cl2 (15 mL). The solution was stirred at room
temperature for 3 h, and ice−water was added. This mixture was
extracted with CH2Cl2. The organic phase was dried over Na2SO4,
filtered, and concentrated to give 28 as a colorless oil (4.05 g, 93%):
1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 1H), 6.97−6.92
(m, 4H), 4.31 (d, J = 3.2 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.90 (s,
3H), 3.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.0, 148.3,
148.2, 146.7, 136.7, 129.1, 127.8, 126.4, 121.8, 113.0, 111.59, 110.60,
60.7, 55.8, 55.8, 55.8, 33.1; HRMS (ESI) m/z calcd for [C17H19BrO4 −
Br]+ 287.1278, found 287.1283.
Compound 29. To a solution of compound 28 (200 mg, 0.54
mmol) in dry acetonitrile (3 mL) were successively added CuI (104
mg, 0.54 mmol), K2CO3 (75.3 mg, 0.54 mmol), (n-Bu)4NI (201 mg,
0.54 mmol), and ethyl propiolate (165 μL, 1.63 mmol), and the
mixture was stirred at 75 °C for 5 h. The reaction was quenched with
saturated NH4Cl solution and extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography
(petroleum ether:EtOAc = 5:1) to give 29 as a yellow oil (160 mg,
Compound 35. Following the procedure of compound 8,
1
compound 35 was synthesized from 34 (0.85 g, 1.75 mmol) as a
77%): H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.8 Hz, 1H), 6.94
colorless oil (0.63 g, 94%): [α]2D5 = −7.3 (c = 1.5, CHCl3); H NMR
1
(d, J = 3.6 Hz, 1H), 6.92 (d, J = 4.0 Hz, 1H), 6.83−6.79 (m, 2H), 4.21
(q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.54 (s,
3H), 3.40 (d, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 153.7, 152.1, 148.5, 148.2, 146.9, 136.1, 128.4, 125.6,
124.3, 121.7, 112.9, 111.5, 110.8, 87.4, 74.4, 61.8, 60.7, 55.9, 55.8, 55.8,
22.8, 14.0; HRMS (ESI) m/z calcd for C22H25O6 [M + H]+ 385.1646,
found 385.1646.
(400 MHz, CDCl3) δ 9.35 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.45 (s,
1H), 7.37 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 5.98−5.88 (m, 1H), 5.26−
5.15 (m, 2H), 4.09 (s, 3H), 4.05 (s, 3H), 4.03 (s, 3H), 3.95 (s, 3H),
3.40−3.30 (m, 2H), 2.84 (dd, J1 = 8.4 Hz, J2 = 13.2 Hz, 1H), 2.42−
2.33 (m, 1H), 2.31−2.26 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
150.8, 148.5, 148.0, 145.8, 135.3, 130.7, 127.4, 127.3, 126.4, 124.8,
124.6, 123.7, 118.1, 112.6, 109.2, 104.4, 60.0, 56.5, 55.72, 55.68, 50.4,
42.3, 41.5; HRMS (ESI) m/z calcd for C23H28NO4 [M + H]+
382.2013, found 382.2020.
Compound 30. To a solution of coupling product 29 (250 mg,
0.65 mmol) from the previous step in 1,2-DCE (10 mL) was added
InCl3 (14.4 mg, 0.065 mmol). Under the protection of argon, the
mixture was warmed to reflux for 1 h, and TLC showed complete
consumption of the starting material. The solution was cooled to room
temperature and filtered through a pad of Celite, and then the filtrate
was concentrated. The crude product was purified by column
chromatography (petroleum ether:EtOAc = 5:1) to give 30 as a
Compound 36. Following the procedure of compound 6,
compound 36 was synthesized from 35 (0.57 g, 1.49 mmol) as a
colorless oil (0.73 g, 95%): [α]2D5 = −16.3 (c = 2, CHCl3); H NMR
1
(400 MHz, CDCl3) δ 9.33 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz,
1H), 7.41−7.32 (m, 6H), 7.29 (s, 1H), 5.88−5.76 (m, 1H), 5.18−5.06
(m, 4H), 4.85 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 1H), 4.17 (s,
3H), 4.09 (s, 3H), 4.04 (s, 3H), 3.95 (s, 3H), 3.63 (dd, J1 = 4.8 Hz, J2
= 13.6 Hz, 1H), 2.91 (dd, J1 = 9.6 Hz, J2 = 13.6 Hz, 1H), 2.38−2.30
(m, 1H), 2.20−2.13 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.9,
150.8, 148.9, 148.1, 145.8, 136.5, 134.1, 129.9, 128.53, 128.48, 128.1,
127.6, 127.5, 127.4, 126.9, 126.7, 124.5, 123.9, 118.6, 112.4, 108.9,
105.1, 66.6, 60.0, 56.6, 56.3, 55.7, 50.2, 39.4, 37.6; HRMS (ESI) m/z
calcd for C31H34NO6 [M + H]+ 516.2381, found 516.2381.
1
yellow oil (130 mg, quantative): H NMR (400 MHz, CDCl3) δ 9.33
(s, 1H), 7.61 (d, J = 11.6 Hz, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.29 (d, J
= 12.0 Hz, 1H), 4.16 (q, J = 9.2 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H),
4.04 (s, 3H), 4.01 (s, 2H), 3.95 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 171.8, 151.1, 148.7, 148.1, 145.7, 127.4,
127.3, 126.6, 124.9, 124.6, 124.1, 112.4, 109.1, 104.5, 61.0, 60.0, 56.5,
55.7, 55.7, 40.4, 14.2; HRMS (ESI) m/z calcd for C22H25O6 [M + H]+
385.1646, found 385.1645.
Compound 37. Following the procedure of compounds 15 and
16, compound 37 was synthesized from 36 (0.72 g, 1.40 mmol) as a
white solid (0.55 g, 65% over two steps): mp 56−58 °C; [α]2D5 = −8.0
(c = 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.74 (s,
1H), 7.57 (d, J = 8.8 Hz, 1H), 7.39−7.32 (m, 6H), 7.28 (d, J = 9.2 Hz,
1H), 5.11 (t, J = 12.8 Hz, 2H), 4.76 (d, J = 8.4 Hz, 1H), 4.17−4.07 (m,
9H), 4.04 (s, 3H), 3.95 (s, 3H), 3.57 (dd, J1 = 3.2 Hz, J2 = 13.6 Hz,
1H), 2.88 (dd, J1 = 9.6 Hz, J2 = 13.2 Hz, 1H), 2.80 (s, 3H), 1.92−1.84
(m, 1H), 1.79−1.72 (m, 1H), 1.69−1.62 (m, 1H), 1.51−1.45 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 156.1, 150.9, 148.9, 148.1, 145.7,
136.4, 129.4, 128.5, 128.1, 128.0, 127.4, 127.2, 126.8, 124.6, 124.5,
123.8, 112.5, 109.0, 104.7, 69.4, 66.7, 60.0, 56.5, 56.2, 55.7, 50.5, 40.8,
37.0, 29.7, 25.8; HRMS (ESI) m/z calcd for C32H41N2O9S [M +
NH4]+ 629.2527, found 629.2524.
Compound 31. To a stirred solution of the corresponding acetic
ester 30 (2.39 g, 6.21 mmol) in THF (100 mL) was added LiAlH4
(472 mg, 12.42 mmol), and the mixture was stirred at room
temperature for 30 min. The reaction was quenched with diluted HCl
and extracted with CH2Cl2. The combined organic phase was dried
over Na2SO4, filtered, and concentrated to yield the expected ethyl
alcohol as an oil which was used in the next step without any
purification. To a solution of the crude alcohol in DMSO (20 mL) was
added IBX (5.22 g, 18.63 mmol), and the crimson solution was stirred
at room temperature for 2 h. The solution was diluted with H2O (100
mL), and the white precipitate was filtered out and extracted with
CH2Cl2. The organic phase was dried over Na2SO4, filtered, and
purified by column chromatography (petroleum ether:EtOAc = 5:1)
to give the corresponding aldehyde 31 as a yellow solid (1.5 g, 71% for
two steps): mp 106−108 °C; 1H NMR (400 MHz, CDCl3) δ 9.76 (t, J
= 2.8 Hz, 1H), 7.35 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H),
7.32 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 4.09 (s, 3H), 4.05 (s, 5H), 4.03
(s, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 151.1,
148.7, 148.1, 145.6, 127.7, 127.2, 127.0, 124.6, 124.5, 123.9, 123.8,
112.4, 109.0, 104.0, 59.8, 56.3, 55.5, 49.1; HRMS (ESI) m/z calcd for
C20H21O5 [M + H]+ 341.1384, found 341.1388.
Compound 38. Following the procedure of compound 5,
compound 38 was synthesized from 37 (0.45 g, 0.74 mmol) as a
yellow solid (0.25 g, 89% over two steps): mp 230 °C; [α]2D0 = −16.8
1
(c = 0.5, DMSO); H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 7.62
(d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.4 Hz,
1H), 4.26−4.19 (m, 1H), 4.14 (s, 3H), 4.05 (s, 3H), 4.03−4.00 (m,
1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.64−3.56 (m, 1H), 3.50 (dd, J1 =
3356
dx.doi.org/10.1021/jo500013e | J. Org. Chem. 2014, 79, 3348−3357

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Article
10.0 Hz, J2 = 13.6 Hz, 1H), 3.40−3.33 (m, 1H), 2.21−2.12 (m, 1H),
2.06−1.92 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ 156.0, 148.7,
148.1, 145.2, 128.6, 126.7, 126.5, 125.9, 124.7, 124.0, 123.1, 113.4,
108.9, 104.7, 59.5, 59.0, 56.5, 55.7, 55.3, 44.8, 35.0, 29.8, 22.8; HRMS
(ESI) m/z calcd for C23H28NO4 [M + H]+ 382.2013, found 382.2020.
(−)-Tylocrebrine (4). Following the procedure of (−)-antofine (1)
and (−)-tylophorine (3), (−)-tylocrebrine was prepared from
intermediate 38 (0.15 g, 0.39 mmol) as a yellow solid (0.12 g,
74%): mp 207−209 °C {lit.26 mp 218−220 °C}; [α]2D2 = −90.4 (c = 1,
CHCl3) {lit.11c [α]2D2 = −105 (c = 1, CHCl3), lit.26 [α]D24 = −45 2 (c
(8) (a) Cui, M. B.; Song, H. J.; Feng, A. Z.; Wang, Z. W.; Wang, Q.
M. J. Org. Chem. 2010, 75, 7018−7021. (b) Pansare, S. V.;
Lingampally, R.; Dyapa, R. Eur. J. Org. Chem. 2011, 12, 2235−2238.
(9) (a) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157−
12159. (b) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045−
6047.
(10) Kim, S.; Lee, J. K.; Lee, T. H.; Park, H. G.; Kim, D. Org. Lett.
2003, 5, 2703−2706.
(11) (a) Yang, X.; Shi, Q.; Bastow, K. F.; Lee, K. H. Org. Lett. 2010,
12, 1416−1419. (b) Stoye, A.; Opatz, T. Org. Lett. 2010, 12, 2140−
2141. (c) Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 196−199.
(d) Kim, S.; Lee, T.; Lee, E.; Lee, J.; Fan, G. J.; Lee, S. K.; Kim, D. J.
Org. Chem. 2004, 69, 3144−3149.
1
= 0.74, CHCl3)}; H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.61
(d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.70 (d, J =
14.8 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 4.03 (s, 3H), 3.92 (s, 3H),
3.72 (d, J = 14.8 Hz, 1H), 3.49 (t, J = 7.6 Hz, 1H), 3.32 (s, J = 15.6 Hz,
1H), 2.96 (dd, J1 = 10.8 Hz, J2 = 15.2 Hz, 1H), 2.65−2.46 (m, 2H),
2.31−2.20 (m, 1H), 2.11−2.01 (m, 1H), 1.99−1.89 (m, 1H), 1.87−
1.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 150.6, 148.6, 147.8,
146.2, 127.7, 126.2, 125.5, 123.5, 123.3, 118.7, 112.0, 109.0, 103.4,
60.2, 60.0, 56.4, 55.7, 54.9, 53.7, 33.3, 31.0, 21.5; HRMS (ESI) m/z
calcd for C24H28NO4 [M + H]+ 394.2013, found 394.2021.
(12) Dumoulin, D.; Lebrun, S.; Couture, A.; Deniau, E.;
Grandclaudon, P. Eur. J. Org. Chem. 2010, 10, 1943−1950.
(13) McIver, A.; Young, D. D.; Deiters, A. Chem. Commun. 2008, 39,
4750−4752.
(14) Bremmer, M. L.; Khatri, N. A.; Weinreb, S. M. J. Org. Chem.
1983, 48, 3661−3666.
(15) Su, B.; Chen, F. Z.; Wang, Q. M. J. Org. Chem. 2013, 78, 2775−
2779.
ASSOCIATED CONTENT
(16) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913−9914.
■
S
* Supporting Information
(17) For reviews, see: (a) Cogan, D. A.; Liu, G.; Ellman, J.
Tetrahedron 1999, 55, 8883−8904. (b) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984−995. (c) Ferreira, F.;
1H and 13C NMR spectra of compounds 1−12, 15−17, 19, 22,
23, 25−31, and 33−38. This material is available free of charge
via the Internet at http://pubs.acs.org.
́
Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38,
1162−1186. (d) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem.
Rev. 2010, 110, 3600−3740. (e) Lin, G. Q.; Xu, M. H.; Zhong, Y. W.;
Sun, X. W. Acc. Chem. Res. 2008, 41, 831−840.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wang98h@263.net, wangqm@nankai.edu.cn.
Notes
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(18) (a) Sun, X. W.; Xu, M. H.; Lin, G. Q. Org. Lett. 2006, 8, 4979−
4982. (b) Sun, X. W.; Liu, M.; Xu, M. H.; Lin, G. Q. Org. Lett. 2008,
10, 1259−1262. (c) Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.;
Marek, I. Angew. Chem., Int. Ed. 2007, 46, 9291−9294.
(19) Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.; Burke,
S. D. J. Org. Chem. 2008, 73, 8452−8457.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(20) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278−1284.
This work was supported by the National Key Project for Basic
Research (Grant 2010CB126106), the National Natural
Science Foundation of China (Grants 21132003, 21121002,
and 21372131), the Tianjin Natural Science Foundation (Grant
11JCZDJC20500), and the Specialized Research Fund for the
Doctoral Program of Higher Education (Grant
20130031110017).
(21) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Carroll, P. J. J. Org. Chem. 1997, 62,
2555−2563.
(22) Cui, L.; Li, C.; Zhang, L. Angew. Chem., Int. Ed. 2010, 49, 9178−
9181.
(23) Bailey, P. D.; Beard, M. A.; Dang, H.; Phillips, T. R.; Price, R. A.;
Whittaker, J. H. Tetrahedron Lett. 2008, 49, 2150−2153.
(24) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52,
1956−1962.
REFERENCES
■
(1) (a) Gellert, E. J. Nat. Prod. 1982, 45, 50−73. (b) Li, Z. G.; Jin, Z.;
Huang, R. Q. Synthesis 2001, 2365−2378.
(25) (a) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 19, 3693−
3712. (b) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073−2077.
(26) Gellert, E.; Govindachari, T. R.; Lakshmikantham, M. V.;
Ragade, I. S.; Rudzats, R.; Viswanathan, N. J. Chem. Soc. 1962, 189,
1008−1014.
(2) Chemler, S. R. Curr. Bioact. Compd. 2009, 5, 2−19 and references
therein.
(3) Krishna, R. B.; Balaji, M.; Uma, R. P.; Sailaja, G.; Vaidyanath, K.;
Narasimha, G. Afr. J. Biochem. Res. 2009, 3, 393−397.
(4) (a) Ganguly, T.; Sainis, K. B. Phytomedicine 2001, 8, 348−355.
(b) Yadav, M.; Dwivedi, P.; Singh, P.; Singh, V. K. Indian J. Plant
Physiol. 2010, 15, 297−301.
(5) (a) You, X.; Pan, M.; Gao, W.; Shiah, H. S.; Tao, J.; Zhang, D.;
Koumpouras, F.; Wang, S.; Zhao, H.; Madri, J. A.; Baker, D.; Cheng, Y.
C.; Yin, Z. Arthritis Rheum. 2006, 54, 877−886. (b) Yang, C. W.;
Chen, W. L.; Wu, P. L.; Tseng, H. Y.; Lee, S. J. Mol. Pharmacol. 2006,
69, 749−758. (c) Min, H. Y.; Song, S. H.; Lee, B.; Kim, S. H.; Lee, S.
K. Chem. Biodiversity 2010, 7, 409−413. (d) Lee, Y. Z.; Huang, C. W.;
Yang, C. W.; Hsu, H. Y.; Kang, I. J.; Chao, Y. S.; Chen, I. S.; Chang, H.
Y.; Lee, S. J. Planta Med. 2011, 77, 1932−1938.
(27) Wang, K. L.; Lu, M. Y.; Yu, A.; Zhu, X. Q.; Wang, Q. M. J. Org.
̈
Chem. 2009, 74, 935−938.
(28) (a) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264−
̈
6267. (b) Mamane, V.; Hannen, P.; Furstner, A. Chem.Eur. J. 2004,
̈
10, 4556−4575. (c) Furstner, A.; Kennedy, J. W. J. Chem.Eur. J.
̈
2006, 12, 7398−7410.
(29) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 18, 734−736.
(30) Kwon, Y.; Cho, H.; Kim, S. Org. Lett. 2013, 15, 920−923.
(31) Davies, K. A.; Abel, R. C.; Wulff, J. E. J. Org. Chem. 2009, 74,
3997−4000.
(6) Wang, K. L.; Su, B.; Wang, Z. W.; Wu, M.; Li, Z.; Hu, Y. N.;
Wang, Q. M. J. Agric. Food. Chem. 2010, 58, 2703−2709.
(7) Suffness, M.; Douros, J. In Anticancer Agents Based on Natural
Product Models; Cassady, J. M., Douros, J. D., Eds.; Medicinal
Chemistry Series, Vol. 16; Academic Press: London, 1980; pp 465−
487.
3357
dx.doi.org/10.1021/jo500013e | J. Org. Chem. 2014, 79, 3348−3357