The First Enantioselective Total Synthesis of (-)-Trans-Dihydronarciclasine

Article abstract of DOI:10.1021/acs.jnatprod.7b00208

A feasible and enantioselective total synthesis of (-)-Trans-dihydronarciclasine [(-)-1], a highly biologically active alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael addition, in which an optically active nitropentanone [(-)-13] was obtained from a butenone derivative (12). Excellent enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-Amino(9-deoxy)epiquinine (16) organocatalyst. The target molecule can be prepared in 13 steps from compound (-)-13. The total synthesis has provided a facile and first access to the ent-form of naturally occurring (+)-Trans-dihydronarciclasine, a highly potent cytostatic alkaloid.

Full text of DOI:10.1021/acs.jnatprod.7b00208

Article
pubs.acs.org/jnp
The First Enantioselective Total Synthesis of (−)-trans-
Dihydronarciclasine
Gabor Varro,† Laszlo Hegedus,‡ Andras Simon,§ Attila Balogh,† Alajos Grun,† Ibolya Leveles,⊥,∥
́
́
́
́
̋
́
̈
Beata G. Vertessy,⊥,∥ and Istvan Kadas*,†
́
́
́
́
†Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki ut 8, H-1111
́
Budapest, Hungary
‡MTA−BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, Budafoki ut 8, H-1111 Budapest, Hungary
́
§Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Geller
Budapest, Hungary
́
t ter
́
4, H-1111
⊥Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudos
́
ok korutja 2, H-1117
̈
́
Budapest, Hungary
∥Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szt. Geller
́
́
t ter 4,
H-1111 Budapest, Hungary
S
* Supporting Information
ABSTRACT: A feasible and enantioselective total synthesis of (−)-trans-dihydronarciclasine [(−)-1], a highly biologically active
alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael
addition, in which an optically active nitropentanone [(−)-13] was obtained from a butenone derivative (12). Excellent
enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst. The target
molecule can be prepared in 13 steps from compound (−)-13. The total synthesis has provided a facile and first access to the ent-
form of naturally occurring (+)-trans-dihydronarciclasine, a highly potent cytostatic alkaloid.
(+)-trans-Dihydronarciclasine [(+)-1] belongs to the family of
natural phenanthridone alkaloids, a subclass of the Amaryllida-
ceae alkaloid family including pancratistatin (2), narciclasine
(3), 7-deoxy-trans-dihydronarciclasine (4), 7-deoxypancratista-
tin (5), and lycoricidine (6) (Figure 1), all possessing potent
cytostatic effects and important antiviral activity, respec-
tively.1−8 Among these phenanthridone alkaloids, (+)-trans-
dihydronarciclasine has the highest antitumor potency,
according to data from the National Cancer Institute (NCI,
USA).9 Furthermore, its antiviral activity against the flaviviruses
(e.g., Japanese encephalitis, yellow fever, or Dengue) is also
more significant than that of compounds 2−6 or commensurate
with them.10 Most recently, its remarkable anti-Zika virus
activity has also been reported.11
realized by three groups,14 including ours.14c It should be noted
that ( )-trans-dihydronarciclasine can be obtained by catalytic
hydrogenation of the naturally occurring narciclasine (3),15
which was the first isolated member of this subclass, or rather
its tetraacetyl derivative after deprotection.15c Using these
methods, however, the inactive and unwanted cis-isomer (7)
(Figure 2) with other byproducts was also be formed.15c
Moreover, the purification of (+)-1 with column chromatog-
raphy is difficult, resulting in significant loss.15c,16a,c This
obvious method was performed by some groups13 long before
the first isolation of (+)-1 from natural sources12 during the
incipient chemical and biological investigation of narciclasine
(3).13 Although the extraction of 3 from Narcissus species has
resulted in a slightly better yield16 than that of (+)-1 from
Zephyranthes candida,12 this method is, nevertheless, expensive.
Compound (+)-1 was first isolated from the bulbs of the
white rain lily (Zephyranthes candida), a tropical medicinal
plant, but in an extremely low yield.12 Since then, its
enantioselective total synthesis has been developed by four
groups,11,13 while that of the racemic alkaloid [( )-1] has been
Received: March 9, 2017
Published: June 5, 2017
© 2017 American Chemical Society and
American Society of Pharmacognosy
1909
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Figure 1. Members of the narciclasine subclass of the natural phenanthridone alkaloids (1−6).
a
Scheme 1. Synthesis of Compound (−)-13
Figure 2. Structure of cis-dihydronarciclasine (7).
Surprisingly, almost 50 total syntheses of the less active
members of this alkaloid subclass (compounds 2, 3, 5, and 6)
have been reported,1 but only a few processes (four
enantioselective11,13 and three racemic routes14) for that of
trans-dihydronarciclasine (1) have been published. In most of
these methods, expensive starting materials were used and the
intermediates were almost exclusively isolated by column
chromatography. Accordingly, the elaboration of a facile and
efficient enatioselective total synthesis for this alkaloid is
required to enable further biological studies.
Earlier we reported the stereoselective total synthesis of
racemic [( )-4]17a and the enantioselective method for (−)-7-
deoxy-trans-dihydronarciclasine [(−)-4],17b while that of
( )-trans-dihydronarciclasine [( )-1] has recently been
published as a short paper.14c In this work, based partly on
our previous experience, we describe the enantioselective total
synthesis of compound (−)-1, the enantiomer of the title
alkaloid. Furthermore, neither harsh conditions nor expensive
starting material (vanillin) and reagents are required in most of
the steps; that is, this method represents the least expensive
access to the title alkaloid.
a
Reagents and conditions: (a) I2, KI, K2CO3, H2O, rt, 3 h, 99%; (b)
20% NaOH/H2O, CuSO4, reflux, 16 h, 64%; (c) CH2Br2, K2CO3,
CuO, DMF, 110 °C, 4 h, 94%; (d) acetone, NaOH, H2O, rt, 20 h, 67%
(after distillation); (e) CH3NO2, organocatalyst 16, rt, 7 d, 57%, ee >
99%.
13. At first, we adopted the previous procedure20 in which the
Jørgensen’s organocatalyst21 [(4S,2R/S)-4-benzyl-1-methylimi-
dazolidine-2-carboxylic acid (14)] was applied in the
enantioselective synthesis of (−)-7-deoxy-trans-dihydronarci-
clasine [(−)-4].17b However, only moderate enantioselectivity
(72% ee) was achieved using this organocatalyst and the
(−)-13 enantiomer was mainly formed (Table 1, entry 1).
Moreover, it was isolated in only 37% yield even after a longer
reaction time (14 d). Therefore, other asymmetric organo-
catalysts were tested to obtain higher enantioselectivity.
Turning to the primary amine derivatives of cinchona
alkaloids, a cinchonine [(8R,9R)-9-amino(9-deoxy)-
epicinchonine (15)] and a quinine derivative [(8S,9S)-9-
amino(9-deoxy)epiquinine (16)] were assessed, since they
were shown to be highly versatile and efficient enantioselective
organocatalysts in several other cases.22 Moreover, they can
readily be synthesized from the commercially available natural
compounds cinchonine and quinine, according to the modified
procedure of Shaw and co-workers.23 In a one-pot method
compounds 15 and 16 were obtained in 85−87% yields by
application of Mitsunobu and Staudinger reactions consec-
utively. Although the use of (8R,9R)-9-amino(9-deoxy)-
epicinchonine (15) as organocatalyst resulted in higher ee
(78%) and isolated yield (70%) after 7 d, the opposite
enantiomer [(+)-13] was formed in excess (Table 1, entry 2).
When (8S,9S)-9-amino(9-deoxy)epiquinine (16) was used in
this Michael addition, excellent enantioselectivity (>99% ee) in
the formation of (−)-13 (57% isolated yield, Table 1, entry 3)
was achieved.
RESULTS AND DISCUSSION
■
As shown in Scheme 1, the first step of the total synthesis was
iodination of vanillin (8). Using a known method,18
iodovanillin (9) was obtained in 99% yield. Compound 9 was
hydrolyzed with aqueous NaOH, in the presence of CuSO4;19
however in our hands this step was accompanied by some
dehalogenation. Therefore, the crude product was recrystallized
from toluene, removing the dehalogenated byproducts
completely, to give compound 10 in 64% yield. Next, myristicin
aldehyde (11) was produced from the pure dihydroxyaldehyde
10 via a dioxolane ring closure reaction using CH2Br2 in
dimethylformamide (DMF), in the presence of K2CO3 and
CuO.19 The improved workup method, which involved
aqueous precipitation of the product instead of extraction,
afforded compound 11 in 94% yield. Claisen−Schmidt
condensation of 11 with acetone using NaOH smoothly
afforded the new butenone derivative 12 in 67% yield after
distillation.
To determine the absolute configuration of the new,
enanantiomerically pure nitropentanone derivative (−)-13,
single-crystal X-ray diffraction measurements were performed.
The crystallographic data (Table S1, Supporting Information)
In the next step, a conjugate addition of nitromethane to
enone 12, there was an opportunity to accomplish this reaction
enantioselectively to give the optically active nitropentanone
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a
Table 1. Asymmetric Michael Addition Using Organocatalysts (14−16) in the Synthesis of 13
a
b
Reaction conditions: compound 12 (37 mmol), organocatalyst (20 mol %), nitromethane (30 mL), rt. Determined by chiral HPLC (Figures S83−
S85, Supporting Information).
permitted definition of its (10S) absolute configuration (Figure
3).
This strong interaction is evidenced by the significantly shifted
peak of the −OH group from 4.09 ppm to 6.02 ppm in the 1H
NMR spectrum of compound (−)-17 compared to those of
intermediates (+)-18 and (−)-19. Although compound (+)-18
also contains −NO2 and −OH groups, the lower chemical shift
value (4.09 ppm) suggests that the C-1 spiro group reduces the
strength of this hydrogen bond.
Furthermore, the crystallographic data of (−)-17 obtained by
single-crystal X-ray diffraction measurements (Table S2,
Supporting Information) also confirmed this structure and
facilitated definition of its (3R, 4S, 5S) absolute configuration
(Figure 5 and Scheme 2). Since the subsequent chemical
transformations have no influence on the configurations of the
C-4 and C-5 stereogenic centers, the final product should be
the enantiomer of naturally occurring trans-dihydronarciclasine,
i.e., (−)-1.
Protection of hydroxyketone (−)-17 was carried out using
ethylene glycol to give compound (+)-18. In this step, due to
the potential for dehydration of (−)-17 with destruction of the
C-3 and C-4 stereogenic centers, the dehydration was not done
in the usual way (p-TsOH, Dean−Stark apparatus), but it was
performed with anhydrous oxalic acid at room temperature and
in anhydrous MeCN in 90% yield. The nitro group of (+)-18
was hydrogenated quantitatively to aminoketal (−)-19 over
10% Pd/C (Selcat Q25), in MeOH. This hydrogenation
required a temperature of 80 °C most likely due to the strong
adsorption of compound (−)-19 on palladium induced by the
tetrasubstituted aromatic moiety.26 Selective conversion of
aminoketal (−)-19 to urethane (−)-20 was achieved in a
biphasic (THF/H2O) reaction with methyl chloroformate in
99% yield, while the hydroxy group remained intact. The
carbonyl group in compound (−)-20 was unmasked in acetone
containing a stoichiometric amount of p-toluenesulfonic acid,
but dehydration also took place to afford enone (−)-21 in
Figure 3. Molecular structure of compound (S)-(−)-13 determined by
the single-crystal X-ray diffraction method (ORTEP representation).
Displacement ellipsoids are drawn at the 50% probability level.
As seen in Scheme 2, conversion of enantiopure nitro-
pentanone (−)-13 into hydroxycyclohexanone (−)-17 was
achieved via a Claisen−Henry reaction in moderate yield (38%)
after recrystallization from EtOAc. This cyclization resulted in
one enantiomer, and it was likely assisted by a hydrogen bond
that formed between the nitro and hydroxy groups during the
cyclohexane ring closure (Figure 4). The stereoselectivity
strongly suggets that the nitro-aldol step occurs last after
formation of a 1,3-dicarbonyl intermediate in the Claisen
reaction. Similar observations were made by Walker24 in the
synthesis of racemic 3-hydroxy-4-nitro-5-arylcyclohexanones.
1911
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a
Scheme 2. Synthesis of Compound (−)-1
Figure 5. Molecular structure of compound (−)-17 defined by the
single-crystal X-ray diffraction method (ORTEP representation).
Displacement ellipsoids are drawn at the 50% probability level.
new, bulky hydroxy group. Since its orientation in the final
product is quasi trans-axial, it was necessary to invert the C-4
configuration. Accordingly, the conversion of (−)-22 under
Mitsunobu28 conditions (DEAD, PPh3, THF), using benzoic
acid, afforded benzoate (+)-23 in 63% yield after column
chromatography. Applying the Sharpless−Upjohn method,29
compound (+)-23 was converted stereoselectively to the cis-
diol (+)-24 in 99% yield using N-methylmorpholine N-oxide, in
the presence of OsO4 catalyst in THF/H2O. This cis-addition is
anti to the allylic bulky axial benzoate group, which resulted in
the predominant formation of the target product. Protection of
the hydroxy groups was achieved with acetyl chloride, giving
(−)-25 in quantitative yield.
Formation of the lactam moiety was performed by applying
the Banwell modification30 of the Bischler−Napieralski
reaction. The methoxyphenanthridine intermediate 26 was
obtained in 99% yield during this cyclization and was
subsequently transformed to the lactam 27 under acidic
conditions in 99% yield. The aromatic methoxy group in
compound 27 was cleaved by TMS-Cl, in the presence of KI, in
MeCN to afford phenanthridone (−)-28 in moderate yield
(54%). Finally, the acyl groups were hydrolyzed using a
methanolic solution of NaOMe, in THF, to form the title
compound (−)-1 (99%).
In conclusion, (−)-trans-dihydronarciclasine [(−)-1)] was
efficiently prepared from vanillin (8), an inexpensive and
readily available starting material, in 18 steps with 2.8% overall
yield. In addition, the synthetic potential of this newly
developed route was evidenced by the highly enantioselective
(>99% ee) organocatalytic nitromethane addition to the
butenone derivative 12, allowing the preparation of compound
(S)-(−)-13 and thereby access to the title alkaloid. Further
investigations to extend this synthesis method to the
enantioselective synthesis of other, potentially antineoplastic
phenanthridone alkaloid analogues are also in progress.
a
Reagents and conditions: (a) HCOOEt, NaOCH3, Et2O, rt, 20 h,
38%, ee 95%; (b) (CH2OH)2, (COOH)2, CH3CN, rt, 3 d, 90%, ee
99%; (c) H2, 10% Pd/C, MeOH, 80 °C, 7 h, quant.; (d) ClCOOCH3,
NaOH/H2O, THF, rt, 2 h, 99%, ee 99%; (e) p-TsOH, acetone, reflux,
1 h, 99%, ee 93%; (f) NaBH4, CaCl2, CH3OH, 0 °C, 2 h, 96%, ee 99%;
(g) PhCOOH, DEAD, PPh3, THF, rt, 4 h, 63%, ee 97%; (h) OsO4,
H2O, THF, Ar atm, rt, 24 h, 99%, ee 95%; (i) AcCl, rt, 24 h, 99%, ee
95%; (j) Tf2O, DMAP, CH2Cl2, 0 °C → rt, 22 h, 99%; (k) (i) 2 M
HCl/H2O, THF, rt, 21 h, (ii) AcCl, rt, 21 h, 99%; (l) TMS-Cl, KI,
CH3CN, 60 °C, 1.5 h, 54%; (m) NaOCH3/CH3OH, THF, rt, 2 h,
99%, ee 92%.
Figure 4. Presumed structure of the hydroxycyclohexanone derivative
(−)-17 and its stabilization by hydrogen bonding.
EXPERIMENTAL SECTION
General Experimental Procedures. Melting points were
■
quantitative yield. To convert it into allylic alcohol (−)-22,
Utimoto’s reduction method (NaBH4, CaCl2)27 was applied.
Compound (−)-22 was stereoselectively prepared in 96% yield
due to the axial attack with a small nucleophile (hydride)
derived from NaBH4, which was enhanced by coordination
with a calcium ion, resulting in an equatorial position of the
measured on a Buchi 510 apparatus using a certified mercury
̈
thermometer (ASTM 2C). Optical rotations were measured on a
PerkinElmer 241 polarimeter. The IR spectra were obtained on a
PerkinElmer 1600 FT-IR instrument. NMR spectra were recorded on
a Bruker AV-300 instrument. HPLC analyses were carried out with a
Jasco PU-1580 apparatus equipped with a Jasco UV-1575 detector.
1912
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Elemental analyses were performed on a Vario EL III instrument
56.8 (OCH3), 101.7 (4-CAr), 102.2 (OCH2O), 109.6 (6-CAr), 126.0
(CHCO), 129.4 (7a-CAr), 137.8 (5-CAr), 143.4 (Ar-CHCH),
144.0 (7-CAr), 149.6 (3a-CAr), 198.3 (CO); IR (KBr) 3024, 2848,
1668, 1511, 1327, 1231, 1141, 1101, 974, 813 cm−1; anal. calcd for
C12H12O4 (220.22) C, 65.45; H, 5.49; found C, 65.43; H, 5.50.
(S)-(−)-4-(7-Methoxybenzo[1,3]dioxol-5-yl)-5-nitropentan-2-one
[(−)-(13)]. Benzalacetone 12 (8.15 g, 0.04 mol) and (8S,9S)-9-
amino(9-deoxy)epiquinine (2.39 g, 7.40 mmol) were dissolved in
nitromethane (31 mL) and stirred for 7 d at room temperature. The
nitromethane was evaporated, and the residue was crystallized from
MeOH to give light yellow crystals. Yield was 57% (5.92 g, 0.02 mol).
HPLC conditions: TADDOL AS-H (n-hexane/isopropyl alcohol =
(Elementar Analysensysteme). Precoated silica plates (Merck 60 F254
)
were used for analytical TLC and Kieselgel 60 for column
cromatography. Single-crystal X-ray diffraction measurement was
accomplished at room temperature on a single-source microfocus
Cu X-ray sealed tube SuperNova diffractometer (Agilent Technolo-
gies) with monochromated Cu Kα radiation (λ = 1.5418 Å) and Eos
CCD detector. CCDC 1497270 [(S)-(−)-13] and CCDC 1536751
[(−)-17] contain the supplementary crystallographic data (including
structure factors) for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
8:2, flow rate 2.0 mL min−1, 256 nm, 20 °C), t(−) = 21 min and t(+)
=
Synthesis. 5-Iodovanillin (9). To a solution of NaHCO3 (22.50 g,
0.27 mol) and KI (45.00 g, 0.32 mol) in water (900 mL) was added
vanillin (33.75 g, 0.22 mol) under rigorous stirring. Then I2 (56.70 g,
0.22 mol) was added in four portions in 30 min. The reaction mixture
was stirred for 3 h at room temperature and allowed to stand
overnight. The crude product was filtered and washed with a diluted
Na2S2O3 solution and H2O to give the product as a light brown
powder. It was used without further purification. Yield: 99% (61.39 g,
0.22 mol). Mp: 166 °C (lit. 175 °C,18 179−180 °C,31a,b 179−182
29 min. Mp: 64−66 °C; [α]22 = −2.3 (c 3, CHCl3), ee > 99%; Rf =
D
0.40 (n-hexane/EtOAc = 2:1); 1H NMR (300 MHz, CDCl3) δ 6.38 (s,
2H, 4-HAr and 6-HAr), 5.94 (s, 2H, OCH2O), 4.64 (dd, J = 12.3 and
6.9 Hz, 1H, HCHNO2), 4.53 (dd, J = 12.3 and 7.5 Hz, 1H,
HCHNO2), 3.91 (quint, J = 7.2 Hz, 1H, CHCH2NO2), 3.89 (s, 3H,
OCH3), 2.86 (d, 2H, J = 6.9, Hz CHCH2CO), 2.13 (s, 3H, COCH3);
13C NMR (75 MHz, CDCl3) δ 30.6 (CH3CO), 39.4 (Ar-CH), 46.5
(CHCH2CO), 57.0 (OCH3), 79.8 (CH2NO2), 101.2 (4-CAr), 101.8
(OCH2O), 107.9 (6-CAr), 133.4 (7a-CAr), 135.0 (5-CAr), 144.0 (7-
CAr), 149.6 (3a-CAr), 205.5 (CH3COCH2); IR (KBr) 3012, 1709,
1635, 1550, 1514, 1455, 1353, 1203, 1136, 1106, 1044 cm−1; anal.
calcd for C13H15NO6 (281.26) C, 55.51; H, 5.38; N, 4.98; found C,
55.50; H, 5.40; N, 4.96.
°C31c,d); Rf = 0.37 (n-hexane/EtOAc = 2:1); H NMR (300 MHz,
1
CDCl3) δ 9.78 (s, 1H, CHO), 7.83 (s, 1H, 6-HAr), 7.45 (s, 1H, 2-HAr),
6.73 (br s, 1H, OH), 3.97 (s, 3H, OCH3); 13C NMR (CDCl3, 75
MHz) δ 56.8 (OCH3), 80.7 (5-CAr), 108.9 (2-CAr), 131.3 (1-CAr),
136.4 (6-CAr), 146.8 (3-CAr), 151.6 (4-CAr), 189.8 (CHO).
5-Hydroxyvanillin (10). A mixture of 5-iodovanillin (9) (90.48 g,
0.33 mol), CuSO4·5H2O (16.24 g, 65.10 mmol), and 20% NaOH
solution (1500 mL) was heated to reflux and stirred for 20 h. It was
cooled below 10 °C and acidified with concentrated HCl to pH = 2.
The mixture was filtered, and the aqueous phase was extracted with
EtOAc (4 × 900 mL). The combined organic phase was dried over
MgSO4 and evaporated to give the dark gray, crude product. After
recrystallization from toluene compound 10 was obtained as pale
brown crystals. Yield: 64% (35.26 g, 0.21 mol). Mp: 124−126 °C (lit.
128−131 °C,18 132−133 °C,19a 128−129 °C19b); Rf = 0.19 (n-hexane/
(3R,4S,5S)-(−)-3-Hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-
nitrocyclohexanone [(−)-(17)]. Dry NaOMe powder (1.95 g, 0.08
mol) was suspended in anhydrous Et2O (75 mL); then freshly distilled
ethyl formate (9.74 mL, 0.12 mol, 8.98 g) and nitropentanone (−)-13
(5.76 g, 0.02 mol) were added. The reaction mixture was stirred at
room temperature for 20 h, cooled at 0 °C, and quenched with H2O
(41 mL). Phases were separated, and the aqueous layer was acidified to
pH = 4 with HOAc, at 0 °C. The precipitated crystals were filtered,
washed with H2O, and dried. Recrystallization from EtOAc gave white
crystals. Yield: 38% (2.43 g, 7.86 mmol). HPLC conditions: TADDOL
AD-H (n-hexane/isopropyl alcohol = 8:2, flow rate 0.8 mL min−1, 256
1
EtOAc = 2:1); H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H, CHO),
7.16 (s, 1H, 2/6-HAr), 7.09 (s, 1H, 6/2-HAr), 6.11 (br s, 1H, OH), 5.67
(br s, 1H, OH), 3.96 (s, 3H, OCH3); 13C NMR (CDCl3, 75 MHz) δ
56.7 (OCH3), 103.1 (2-CAr), 113.3 (6-CAr), 129.2 (1-CAr), 138.7 (4-
CAr), 144.2 (5-CAr), 147.5 (3-CAr), 191.4 (CHO).
nm, 20 °C), t(+) = 33 min and t(−) = 41 min. Mp: 200−202 °C; [α]22
D
= −47.4 (c 0.5, THF), ee 95%; Rf = 0.33 (n-hexane/EtOAc = 1:1); 1H
NMR (300 MHz, DMSO-d6) δ 6.73 (s, 1H, 4′/6′-HAr), 6.72 (s, 1H,
6′/4′-HAr) 6.02 (d, J = 3.5 Hz, 1H, OH), 5.94 (d, J = 2.0 Hz, 2H,
OCH2O), 5.70 (dd, J = 12.0 and 2.0 Hz, 1H, 4-H), 4.70−4.67 (m, 1H,
3-H), 3.87 (td, J = 13.0 and 4.0 Hz, 1H, 5-H), 3.81 (s, 3H, OCH3),
3.00 (dd, J = 14.5 and 3.0 Hz, 1H, 2-Hβ), 2.68 (t, J = 14.5 Hz, 1H, 6-
Hβ), 2.41 (dt, J = 14.5 and 2.5 Hz, 1H, 2-Hα), 2.34 (ddd, J = 14.5 and
4.5 and 2.0 Hz, 1H, 6-Hα); 13C NMR (75 MHz, DMSO-d6) δ 39.5 (5-
C), 46.6 (2-C), 47.5 (6-C), 56.5 (OCH3), 69.8 (3-C), 89.5 (4-C),
101.3 (4-CAr), 101.3 (OCH2O), 107.5 (6-CAr), 133.8 (7a-CAr), 135.4
(5-CAr), 143.3 (7-CAr), 148.6 (3a-CAr), 206.3 (1-C); IR (KBr) 3505,
2902, 1636, 1546, 1455, 1328, 1132, 1081 cm−1; anal. calcd for
C14H15NO7 (309.27) C, 54.37; H, 4.89; N, 4.53; found C, 54.36; H,
4.90; N, 4.52.
Myristicin Aldehyde (11). To a solution of 5-hydroxyvanillin (10)
(20.00 g, 0.12 mol) in DMF (250 mL) were added K2CO3 (35.00 g,
0.25 mol), CuO (2.60 g, 0.03 mol), and CH2Br2 (10 mL, 24.95 g, 0.14
mol). The reaction mixture was heated to 110 °C and stirred for 4 h. It
was allowed to cool to room temperature, and the precipitated solid
was filtered. The solution was concentrated in vacuo, and the residue
was poured into H2O. The crude product was filtered and dried to give
pale gray crystals. It was used without further purification. Yield: 94%
(20.10 g, 0.11 mol). Mp: 124 °C (lit. 124−126 °C,32a 131 °C,32b,c
132−133 °C20,32d); Rf = 0.52 (n-hexane/EtOAc = 2:1); 1H NMR (300
MHz, CDCl3) δ 9.78 (s, 1H, CHO), 7.14 (s, 1H, 4/6-HAr), 7.05 (s,
1H, 6/4-HAr), 6.10 (s, 2H, OCH2O), 3.96 (s, 3H, OCH3); 13C NMR
(CDCl3, 75 MHz) δ 56.8 (OCH3), 102.8 (OCH2O), 103.8 (4-CAr),
110.6 (6-CAr), 132.0 (7a-CAr), 141.2 (5-CAr), 144.3 (7-CAr), 149.6 (3a-
CAr), 190.30 (CHO).
(3R,4S,5S)-(+)-3-Hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-
nitrocyclohexanone Ethylene Acetal [(+)-(18)]. To a solution of
anhydrous oxalic acid (6.47 g, 0.07 mol) in anhydrous MeCN (109
mL) were added ethylene glycol (18.5 mL, 20.48 g, 0.33 mol) and
nitrocyclohexanolone (−)-17 (2.38 g, 7.70 mmol). The reaction
mixture was stirred at room temperature for 3 d and poured into a
saturated NaHCO3 solution (305 mL) at 0 °C. The precipitated
crystals were filtered, washed with H2O, and dried. Yield: 90% (2.45 g,
6.93 mmol). HPLC conditions: TADDOL AD-H (n-hexane/isopropyl
alcohol = 8:2, flow rate 2.0 mL min−1, 256 nm, 20 °C), t(+) = 21 min
4-(7-Methoxybenzo[1,3]dioxol-5-yl)but-3-en-2-one (12). A solu-
tion of myristicin aldehyde (11) (20.35 g, 0.11 mol) in acetone (102
mL) was added into H2O (47 mL), when the starting material was
precipitated in a fine crystalline form. Aqueous NaOH solution (from
1.69 g, 0.04 mol of NaOH, and 7.6 mL of water) and finally water (424
mL) were also added, and the yellow mixture was stirred for 20 h at
room temperature and left standing for 2 h. The yellow crude product
was filtered, washed with H2O, and dried. Purification via distillation in
vacuo gave pale yellow crystals. Yield: 67% (16.74 g, 76.01 mmol). Mp:
74−75 °C, bp: 149−152 °C (0.4 mmHg); Rf = 0.49 (n-hexane/EtOAc
and t(−) = 40 min. Mp: 141−143 °C; [α]22 = +13.8 (c 1, THF), ee
D
99%; Rf = 0.81 (CHCl3/acetone = 3:1); 1H NMR (300 MHz, CDCl3)
δ 6.43 (s, 2H, 4′-HAr and 6′-HAr), 5.93 (s, 2H, OCH2O), 4.70 (dd, J =
12.0 and 2.7 Hz, 1H, 4-H), 4.63 (dq, J = 10.2 and 2.7 Hz, 1H, 3-H),
4.09−3.99 (m, 5H, OCH2CH2O and OH), 3.89 (s, 3H, OCH3), 3.79
(td, J = 12.9 and 3.9 Hz, 1H, 5-H), 2.19 (dt, J = 14.4 and 2.7 Hz, 1H,
2-Hα), 2.07−1.98 (m, 2H, 2-Hβ and 6-Hα), 1.80 (t, J = 13.5 Hz, 1H, 6-
Hβ); 13C NMR (75 MHz, CDCl3) δ 38.7 (2-C), 38.7 (5-C), 41.8 (6-
1
= 2:1); H NMR (300 MHz, CDCl3) δ 7.39 (d, 1H, J = 16.2 Hz,
CHCH), 6.77 (s, 1H, 4/6-HAr), 6.73 (s, 1H, 6/4-HAr), 6.57 (d, 1H,
J = 16.2 Hz, CHCH), 6.03 (s, 2H, OCH2O), 3.93 (s, 3H, OCH3),
2.36 (s, 3H, CH3CO); 13C NMR (75 MHz, CDCl3) δ 27.7 (COCH3),
1913
DOI: 10.1021/acs.jnatprod.7b00208
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Journal of Natural Products
Article
C), 56.9 (OCH3), 64.7 (OCH2CH2O), 65.4 (OCH2CH2O), 69.8 (3-
C), 91.3 (4-C), 101.3 (4-CAr), 101.7 (OCH2O), 107.8 (6-CAr), 107.8
(1-C), 132.9 (7a-CAr), 134.3 (5-CAr), 143.9 (7-CAr), 149.4 (3a-CAr);
IR (KBr) 3506, 2902, 1636, 1455, 1329, 1131, 1081 cm−1; anal. calcd
for C16H19NO8 (353.32) C, 54.39; H, 5.42; N, 3.96; found C, 54.38;
H, 5.44; N, 3.94.
6.43 (s, 1H, 4′/6′-HAr), 6.40 (s, 1H, 6′/4′-HAr), 6.08 (dd, J = 10.2 and
1.8 Hz, 1H, 3-H), 5.97 (s, 2H, OCH2O), 4.82 (br s, 1H, NH), 4.65−
4.59 (m, 1H, 1-H), 3.90 (s, 3H, OCH3), 3.62 (s, 3H, NHCOOCH3),
3.23−3.14 (m, 1H, 6-H), 2.68−2.65 (m, 2H, 5-Hα and 5-Hβ); 13C
NMR (75 MHz, CDCl3) δ 45.3 (5-C), 48.1 (6-C), 52.6
(NHCOOCH3), 53.5 (1-C), 56.7 (OCH3), 101.4 (4-CAr), 101.8
(OCH2O), 107.4 (6-CAr), 129.5 (3-C), 134.5 (7a-CAr), 135.0 (5-CAr),
143.9 (7-CAr), 149.5 (3a-CAr), 151.8 (2-C), 156.4 (NHCOOCH3),
197.5 (4-C); IR (KBr) 3323, 2916, 1696, 1637, 1539, 1449, 1384,
1323, 1263, 1188, 1134, 1100, 1058, 930, 863, 836, 777 cm−1; anal.
calcd for C16H17NO6 (319.31) C, 60.18; H, 5.37; N, 4.39; found C,
60.19; H, 5.36; N, 4.37.
(3R,4S,5S)-(−)-4-Amino-5-(7-methoxybenzo[1,3]dioxol-5-yl)-
cyclohexan-3-ol Ethylene Acetal [(−)-(19)]. Over 10% Pd/C catalyst
(Selcat Q, 0.67 g) nitroketal (+)-18 (2.24 g, 6.34 mmol) was
hydrogenated in MeOH (60 mL), in a 250 mL stainless steel autoclave
equipped with a magnetic stirrer (stirring speed: 1100 rpm). The
reduction was carried out at 12 bar and 80 °C. After finishing the
hydrogen uptake (7 h), the catalyst was filtered off and the filtrate was
evaporated in vacuo to give a dark green solid in quantitative yield
(2.04 g, 6.32 mmol). Mp: 48 °C; [α]22D = −10.0 (c 1, CH3OH); Rf =
(1R,4S,6S)-(−)-[4-Hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)-
cyclohex-2-enyl]carbamic Acid Methyl Ester [(−)-(22)]. A mixture of
enone (−)-21 (0.93 g, 2.89 mmol), anhydrous MeOH (110 mL), and
anhydrous CaCl2 (0.65 g, 5.82 mmol) was stirred at room temperature
for 30 min. It was cooled to 0 °C, and NaBH4 (0.16 g, 4.26 mmol) was
added. It was further stirred for 2 h at 0 °C, poured into H2O (124
mL), and extracted with EtOAc (3 × 80 mL). The combined organic
layer was dried over Na2SO4, and the solvent was evaporated in vacuo.
Recrystallization of the crude product from 1:3 MeOH/H2O gave a
white solid. Yield: 96% (0.89 g, 2.77 mmol). HPLC conditions:
TADDOL AD-H (n-hexane/isopropyl alcohol = 8:2, flow rate 0.8 mL
min−1, 256 nm, 10 °C), t(−) = 15 min and t(+) = 33 min. Mp: 172−174
1
0.26 (CHCl3/MeOH = 9:1); H NMR (300 MHz, CDCl3) δ 6.42 (s,
1H, 4′/6′-HAr), 6.40 (s, 1H, 6′/4′-HAr), 5.94 (s, 2H, OCH2O), 4.09 (s,
1H, OH), 4.06−3.92 (m, 5H, OCH2CH2O and 3-H), 3.89 (s, 3H,
OCH3), 2.80−2.78 (m, 2H, 4-H, 5-H), 2.20 (br s, 2H, NH2), 2.13 (dt,
J = 14.4 and 3.0 Hz, 1H, 2-Hα), 1.94 (dd, J = 14.4 and 3.0 Hz, 1H, 2-
Hβ), 1.88 (dt, J = 17.1 and 3.0 Hz, 1H, 6-Hα), 1.78 (t, J = 12.3 Hz, 1H,
6-Hβ); 13C NMR (75 MHz, CDCl3) δ 39.1 (2-C), 41.7 (6-C), 43.3 (5-
C), 56.9 (OCH3), 57.6 (4-C), 64.3 (OCH2CH2O), 65.1
(OCH2CH2O), 69.5 (3-C), 101.6 (4-CAr), 101.7 (OCH2O), 108.1
(6-CAr), 108.7 (1-C), 134.5 (7a-CAr), 136.0 (5-CAr), 143.9 (7-CAr),
149.5 (3a-CAr); IR (KBr) 3494, 2891, 1635, 1513, 1452, 1316, 1196,
1134, 1091, 921 cm−1; anal. calcd for C16H21NO6 (323.34): C, 59.43;
H, 6.55; N, 4.33; found C, 59.45; H, 6.56; N, 4.30.
°C; [α]22 = −143.0 (c 1, acetone), ee 99%; Rf = 0.44 (CHCl3/
D
1
acetone = 3:1); H NMR (300 MHz, CDCl3) δ 6.42 (s, 1H, 4′-HAr),
6.38 (s, 1H, 6′-HAr), 5.94 (s, 2H, OCH2O), 5.82 (dd, J = 10.2 and 1.2
Hz, 1H, 3-H), 5.74 (d, J = 9.9 Hz, 1H, 2-H), 4.59 (br s, 1H, NH),
4.47−4.43 (m, 1H, 4-H), 4.32 (t, J = 10.4 Hz, 1H, 1-H), 3.89 (s, 3H,
OCH3), 3.56 (s, 3H, NHCOOCH3), 2.63 (t, J = 11.4 Hz, 1H, 6-H),
2.26 (dd, J = 12.2 and 5.4 Hz, 1H, 5-Hα), 1.81 (td, J = 12.7 and 9.8 Hz,
1H, 5-Hβ); 13C NMR (75 MHz, CDCl3) δ 40.7 (5-C), 46.5 (6-C),
52.1 (NHCOOCH3), 53.5 (1-C), 56.7 (OCH3), 67.7 (4-C), 101.3 (4-
CAr), 101.4 (OCH2O), 106.9 (6-CAr), 131.0 (2-C), 132.6 (3-C), 134.1
(7a-CAr), 136.5 (5-CAr), 143.5 (7-CAr), 149.1 (3a-CAr), 156.5 (NH-
COOCH3); IR (KBr) 3327, 2926, 1688, 1633, 1537, 1513, 1452, 1323,
1245, 1194, 1138, 1099, 1051, 819 cm−1; anal. calcd for C16H19NO6
(321.33) C, 59.81; H, 5.96; N, 4.36; found C, 59.82; H, 5.97; N, 4.34.
(1R,4R,5S)-(+)-Benzoic Acid 5-(7-Methoxybenzo[1,3]dioxol-5-yl)-
4-methoxycarbonylaminocyclohex-2-enyl Ester [(+)-(23)]. Enol
(−)-22 (0.97 g, 3.02 mmol) and Ph3P (0.95 g, 3.63 mmol) were
dissolved in anhydrous THF (47 mL) and cooled to 0 °C. Diisopropyl
azodicarboxylate (0.73 mL, 0.75 g, 3.71 mmol) in anhydrous THF (2.2
mL) was added dropwise at 0 °C and stirred for 10 min. Benzoic acid
(0.44 g, 3.60 mmol) was added, and the mixture was stirred at 0 °C for
45 min, then allowed to warm to room temperature and further stirred
for 4 h. The solvent was removed in vacuo, and the product was
isolated by column chromatography, as a white solid, on silica
(CHCl3/acetone = 20:1). Yield: 63% (0.81 g, 1.90 mmol). HPLC
conditions: TADDOL AD-H (n-hexane/isopropyl alcohol = 8:2, flow
rate 0.8 mL min−1, 256 nm, 10 °C), t(−) = 20 min and t(+) = 26 min.
(3R,4S,5S)-(−)-3-Hydroxy-4-methoxycarbonylamino-5-(7-
methoxybenzo[1,3]dioxol-5-yl)cyclohexanone Ethylene Acetal
[(−)-(20)]. To a solution of aminoketal (−)-19 (1.94 g, 6.00 mmol)
in THF (37 mL) were added half of the required methyl
chloroformate (0.47 mL, 0.59 g, 6.18 mmol) and aqueous 3%
NaOH solution (15 mL) followed by the second half of methyl
chloroformate (0.47 mL, 0.59 g, 6.18 mmol). The biphasic mixture
was stirred vigorously at room temperature for 2 h, poured into H2O
(82 mL), and extracted with CHCl3 (3 × 72 mL). The combined
organic layer was dried over Na2SO4, and the solvent was evaporated
in vacuo to give a pale yellow solid. Yield: 99% (2.28 g, 5.98 mmol).
HPLC conditions: TADDOL AS-H (n-hexane/isopropyl alcohol =
8:2, flow rate 2.0 mL min−1, 256 nm, 20 °C), t(+) = 14 min and t(−)
=
20 min. Mp: 185−188 °C; [α]22 = −4.3 (c 1, CHCl3), ee 99%; Rf =
D
1
0.73 (CHCl3/MeOH = 9:1); H NMR (300 MHz, CDCl3) δ 6.42 (s,
2H, 4′-HAr and 6′-HAr), 5.93 (s, 2H, OCH2O), 4.99 (d, J = 9.3 Hz, 1H,
NH), 4.13−4.10 (m, 1H, 3-H), 4.03−3.97 (m, 4H, OCH2CH2O), 3.89
(s, 3H, OCH3), 3.83−3.80 (m, 1H, 4-H), 3.58 (d, J = 8.7 Hz, 1H,
OH), 3.52 (s, 3H, NHCOOCH3), 2.92 (td, J = 12.3 and 2.7 Hz 1H, 5-
H), 2.09 (dt, J = 14.1 and 2.7 Hz, 1H, 2-Hα), 2.01 (dd, J = 14.1 and 2.1
Hz, 1H, 2-Hβ), 1.93 (dt, J = 12.9 and 3.0 Hz, 1H, 6-Hα), 1,84 (t, J =
13.2 Hz, 1H, 6-Hβ); 13C NMR (75 MHz, CDCl3) δ 38.9 (2-C), 41.9
(5-C), 43.0 (6-C), 52.2 (NHCOOCH3), 56.4 (4-C), 56.8 (OCH3),
64.4 (OCH2CH2O), 65.1 (OCH2CH2O), 69.9 (3-C), 101.5
(OCH2O), 102.0 (4-CAr), 107.2 (6-CAr), 108.7 (1-C), 134.2 (7a-
CAr), 136.2 (5-CAr), 143.9 (7-CAr), 149.1 (3a-CAr), 156.5
(NHCOOCH3); IR (KBr) 3477, 3355, 2927, 1723, 1638, 1541,
1516, 1450, 1319, 1129, 1073, 914 cm−1; anal. calcd for C18H23NO8
(381.38) C, 56.69; H, 6.08; N, 3.67; found C, 56.68; H, 6.06; N, 3.69.
(1R,6S)-(−)-[6-(7-Methoxybenzo[1,3]dioxol-5-yl)-4-oxocyclohex-
2-enyl]carbamic Acid Methyl Ester [(−)-(21)]. Carbamate (−)-20
(2.25 g, 5.90 mmol) and p-toluenesulfonic acid monohydrate (2.01 g,
0.01 mol) were dissolved in acetone (140 mL). The reaction mixture
was heated to reflux and stirred for 1 h. It was cooled to room
temperature, poured into saturated NaHCO3 solution (275 mL), and
extracted with CHCl3 (3 × 150 mL). The combined organic layer was
dried over Na2SO4, and the solvent was evaporated in vacuo to give a
white solid. Yield: 99% (1.86 g, 5.83 mmol). HPLC conditions:
TADDOL AD-H (n-hexane/isopropyl alcohol = 8:2, flow rate 0.8 mL
min−1, 256 nm, 10 °C), t(−) = 18 min and t(+) = 21 min. Mp: 153−157
°C; [α]22D = −142.6 (c 1, CHCl3), ee 93%; Rf = 0.51 (CHCl3/acetone
= 3:1); 1H NMR (300 MHz, CDCl3) δ 6.93 (d, J = 9.9 Hz, 1H, 2-H),
Mp: 147−151 °C; [α]22 = +121.2 (c 1, CHCl3), ee 97%; Rf = 0.59
D
(CHCl3/acetone = 20:1); 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J =
7.5 Hz, 2H, 2″-HBz and 6″-HBz), 7.58 (t, J = 7.2 Hz, 1H, 4″-HBz), 7.46
(t, J = 7.5 Hz, 2H, 3″-HBz and 5″-HBz), 6.44 (s, 1H, 4′-HAr), 6.42 (s,
1H, 6′-HAr), 6.05−6.02 (m, 2H, 2-H and 3-H), 5.95 (s, 2H, OCH2O),
5.53−5.52 (m, 1H, 1-H), 4.65 (br s, 1H, NH), 4.37 (t, J = 9.4 Hz, 1H,
4-H), 3.90 (s, 3H, OCH3), 3.59 (s, 3H, NHCOOCH3), 2.91 (td, J =
10.6 and 4.0 Hz, 1H, 5-H), 2.19−2.16 (m, 2H, 6-Hα and 6-Hβ); 13C
NMR (75 MHz, CDCl3) δ 36.0 (6-C), 42.5 (5-C), 52.2
(NHCOOCH3), 53.1 (4-C), 56.8 (OCH3), 66.8 (1-C), 101.4
(OCH2O), 101.6 (4-CAr), 107.2 (6-CAr), 125.7 (2-C), 128.4 (3-CBz
and 5-CBz), 129.7 (2-CBz and 6-CBz), 130.4 (1-CBz), 133.1 (4-CBz),
134.2 (7a-CAr), 135.8 (3-C), 136.5 (5-CAr), 143.6 (7-CAr), 149.1 (3a-
CAr), 156.5 (NHCOOCH3), 165.9 (Ph−CO); IR (KBr) 3296, 2937,
1718, 1686, 1633, 1548, 1512, 1452, 1434, 1270, 1135, 1093, 959, 930,
713 cm−1; anal. calcd for C23H23NO7 (425.43) C, 64.93; H, 5.45; N,
3.29; found C, 64.91; H, 5.47; N, 3.28.
(1R,2R,3R,4S,5S)-(+)-Benzoic Acid 2,3-Dihydroxy-5-(7-
methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonyl-
1914
DOI: 10.1021/acs.jnatprod.7b00208
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Journal of Natural Products
Article
aminocyclohexyl Ester [(+)-(24)]. Benzoate (+)-23 (0.50 g, 1.18
mmol) was dissolved in a mixture of THF (7.2 mL) and H2O (1.2
mL). Subsequently N-methylmorpholine N-oxide (0.30 g, 2.54 mmol)
and 4% aqueous OsO4 solution (0.52 mL, 0.02 g, 0.08 mmol) were
added under an Ar atmosphere and stirred at room temperature, under
Ar, for 24 h. The reaction mixture was poured into a saturated
Na2S2O3 solution (47 mL) and extracted with EtOAc (4 × 40 mL).
The combined organic layer was dried over MgSO4, and the solvent
was removed in vacuo to give a white solid. Yield: 99% (0.54 g, 1.18
mmol). HPLC conditions: TADDOL AD-H (n-hexane/isopropyl
alcohol = 8:2, flow rate 2.0 mL min−1, 256 nm, 10 °C), t(+) = 17 min
MgSO4 and evaporated in vacuo to give the crude product containing
two regioisomers. Yield: 99% (0.55 g, 1.05 mmol). H NMR (300
1
MHz, CDCl3) δ 8.07 (d, J = 7.8 Hz, 2H, 2′-HBz and 6′-HBz), 7.58 (t, J
= 7.5 Hz, 1H, 4′-HBz), 7.46 (t, J = 7.4 Hz, 2H, 3′-HBz and 5′-HBz), 6.53
(s, 1H, 11-H), 6.00−5.97 (m, 2H, OCH2O), 5.55 (s, 1H, 3-H), 5.50
(dd, J = 10.6 and 2.8 Hz, 1H, 4-H), 5.49−5.42 (m, 1H, 2-H), 3.93 (s,
3H, OCH3), 3.83 (s, 3H, Ar−CNOCH3), 3.39 (dd, J = 13.4 and 10.7
Hz, 1H, 4a-H), 2.75 (td, J = 13.1 and 3.8 Hz, 1H, 11b-H), 2.58 (dt, J =
14.3 and 3.6 Hz, 1H, 1-Hα), 1.98−1.94 (m, 1H, 1-Hβ); 13C NMR (75
MHz, CDCl3) δ 21.1 (CH3CO), 21.2 (CH3CO), 27.8 (1-C), 34.2
(11b-C), 52.7 (Ar−CNOCH3), 57.0 (4a-C), 60.9 (OCH3), 69.2 (3-
C), 69.6 (2-C), 72.5 (4-C), 99.8 (11-C), 101.6 (9-C), 113.0 (6a-C),
128.6 (3-CBz and 5-CBz), 129.4 (1-CBz), 129.9 (2-CBz and 6-CBz), 133.5
(4-CBz), 137.5 (7a-C), 138.4 (11a-C), 142.2 (7-C), 151.1 (10a-C),
160.7 (6-C), 165.2 (Ph−CO), 169.4 (CH3CO), 170.5 (CH3CO); anal.
calcd for C27H27NO10 (525.51) C, 61.71; H, 5.18; N, 2.67; found C,
61.73; H, 5.19; N, 2.65.
and t(−) = 23 min. Mp: 82−86 °C; [α]22 = +60.0 (c 1, CHCl3), ee
D
95%; Rf = 0.39 (CHCl3/acetone = 3:1); 1H NMR (300 MHz, CDCl3)
δ 8.04 (d, J = 7.5 Hz, 2H, 2″-HBz and 6″-HBz), 7.60 (t, J = 7.5 Hz, 1H,
4″-HBz), 7.49 (t, J = 7.5 Hz, 2H, 3″-HBz and 5″-HBz), 6.44 (s, 1H, 4′-
HAr), 6.38 (s, 1H, 6′-HAr), 5.93−5.92 (m, 2H, OCH2O), 5.42−5.41
(m, 1H, 1-H), 4.75 (d, J = 7.1 Hz, 1H, NH), 4.22 (s, 1H, 2-H), 4.04
(ddd, J = 10.9 and 10.1 and 7.1 Hz, 1H, 4-H), 3.99−3.95 (m, 1H, 3-
H), 3.88 (s, 3H, OCH3), 3.59 (s, 3H, NHCOOCH3), 2.85 (td, J = 13.0
and 3.5 Hz 1H, 5-H), 2.31 (ddd, J = 14.0 and 13.0 and 2.3 Hz, 1H, 6-
Hβ), 2.04 (dt, J = 14.4 and 3.2 Hz, 1H, 6-Hα); 13C NMR (75 MHz,
CDCl3) δ 33.1 (6-C), 42.9 (5-C), 52.6 (NHCOOCH3), 55.7 (4-C),
56.8 (OCH3), 70.2 (2-C), 71.4 (1-C), 74.0 (3-C), 101.5 (OCH2O),
101.6 (4-CAr), 107.3 (6-CAr), 128.6 (3-CBz and 5-CBz), 129.7 (2-CBz
and 6-CBz), 130.0 (1-CBz), 133.4 (4-CBz), 134.3 (7a-CAr), 135.4 (5-
CAr), 143.7 (7-CAr), 149.3 (3a-CAr), 158.8 (NHCOOCH3), 165.2
(Ph−CO); IR (KBr) 3396, 2950, 1712, 1635, 1513, 1452, 1434, 1316,
1274, 1096, 1044, 930, 825, 714 cm−1; anal. calcd for C23H25NO9
(459.45) C, 60.13; H, 5.48; N, 3.05; found C, 60.14; H, 5.46; N, 3.03.
(1R,2S,3R,4S,5S)-(−)-Benzoic Acid 2,3-Diacetoxy-5-(7-
Methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonyl-
aminocyclohexyl Ester [(−)-(25)]. cis-Diol (+)-24 (0.53 g, 1.16 mmol)
was dissolved in acetyl chloride (4.30 mL, 4.79 g, 0.06 mol) and stirred
at room temperature for 24 h. The reaction mixture was added
dropwise to a saturated NaHCO3 solution (378 mL) at 0 °C. The
product was extracted with CHCl3 (3 × 80 mL), and the combined
organic layer was dried over MgSO4. The solvent was removed in
vacuo to give a white solid. Yield: 99% (0.62 g, 1.14 mmol). HPLC
conditions: TADDOL AD-H (n-hexane/isopropyl alcohol = 8:2, flow
rate 2.0 mL min−1, 256 nm, 10 °C), t(+) = 8 min and t(−) = 14 min.
(2R,3S,4R,4aS,11bS)-Benzoic Acid 3,4-Diacetoxy-7-methoxy-6-
oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-
2-yl Ester (27). Methoxyphenantridine 26 (0.53 g, 1.00 mmol) was
dissolved in THF (12 mL), a 2 M aqueous HCl solution (12 mL) was
added, and the mixture was stirred at room temperature for 24 h. The
reaction mixture was poured into a saturated NaHCO3 solution (200
mL) and extracted with CHCl3 (3 × 50 mL). The combined organic
layer was dried over MgSO4 and evaporated in vacuo. The residue was
dissolved in acetyl chloride (9.9 mL, 10.93 g, 139.23 mmol) and stirred
at room temperature for 21 h, poured into a saturated NaHCO3
solution (500 mL) at 0 °C, and extracted with CHCl3 (4 × 60 mL).
The combined organic layer was dried over MgSO4 and evaporated in
vacuo to give a pale brown solid. Yield: 99% (0.51 g, 0.99 mmol). Rf =
0.58 (CHCl3/acetone = 3:1); 1H NMR (300 MHz, CDCl3) δ 8.05 (d,
J = 7.5 Hz, 2H, 2-HBz and 6-HBz), 7.62 (t, J = 7.5 Hz, 1H, 4-HBz), 7.49
(t, J = 7.5 Hz, 2H, 3-HBz and 5-HBz), 6.51 (s, 1H, 11-HAr), 6.09 (s, 1H,
NH), 6.02−5.99 (m, 2H, OCH2O), 5.59−5.57 (m, 1H, 2-H/3-H),
5.45−5.44 (m, 1H, 2-H/3-H), 5.32 (dd, J = 10.8 and 2.7 Hz, 1H, 4-H),
4.08 (s, 3H, Ar-OCH3), 3.77 (t, J = 11.7 Hz, 1H, 4a-H), 3.23−3.13 (m,
1H, 11b-H), 2.61−2.55 (m, 1H, 1-Hα), 2.13 (s, 3H, OCOCH3), 2.12
(s, 3H, OCOCH3), 2.06−2.02 (m, 1H, 1-Hβ); 13C NMR (75 MHz,
CDCl3) δ 20.8 (CH3CO), 20.8 (CH3CO), 27.1 (1-C), 36.2 (11b-C),
52.2 (4a-C), 60.9 (OCH3), 67.5 (3-C), 69.1 (2-C), 71.8 (4-C), 99.1
(11-C), 101.7 (9-C), 108.2 (6a-C), 128.7 (3-CBz and 5-CBz), 129.1 (1-
CBz), 129.8 (2-CBz and 6-CBz), 132.8 (7a-C), 133.7 (4-CBz), 137.3
(11a-C), 142.0 (7-C), 152.1 (10a-C), 163.8 (Ph−CO), 164.9 (6-C),
169.2 (CH3CO), 170.4 (CH3CO); anal. calcd for C26H25NO10
(511.48) C, 61.06; H, 4.93; N, 2.74; found C, 61.08; H, 4.95; N, 2.73.
(2R,3S,4R,4aS,11bS)-(−)-Benzoic Acid 3,4-Diacetoxy-7-hydroxy-
6-oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]-
phenanthridin-2-yl Ester [(−)-(28)]. Lactam 27 (0.51 mg, 0.99 mmol)
was dissolved in anhydrous MeCN (45.4 mL), and subsequently KI
(0.17 mg, 1.02 mmol) and a 0.5 M solution of TMS-Cl (0.14 g, 0.16
mL, 1.30 mmol) in anhydrous MeCN were added. The reaction
mixture was heated to 60 °C and stirred for 1.5 h. After quenching the
reaction with H2O (64 mL) added dropwise at 0 °C and extraction
with EtOAc (3 × 50 mL), the combined organic layer was dried over
MgSO4 and evaporated in vacuo to give the crude product. The major
isomer was isolated by column chromatography on silica (n-hexane/
Mp: 92−96 °C; [α]22 = −22.4 (c 1, CHCl3), ee 95%; Rf = 0.78
D
1
(CHCl3/acetone = 3:1); H NMR (300 MHz, CDCl3) δ 8.09 (d, J =
7.5 Hz, 2H, 2″-HBz and 6″-HBz), 7.63 (t, J = 7.5 Hz, 1H, 4″-HBz), 7.51
(t, J = 7.5 Hz, 2H, 3″-HBz and 5″-HBz), 6.44 (s, 1H, 4′-HAr), 6.39 (s,
1H, 6′-HAr), 5.94 (s, 2H, OCH2O), 5.50 (t, J = 3.4 Hz, 1H, 1-H/2-H),
5.37 (dd, J = 10.5 and 3.0 Hz, 1H, 3-H), 5.30 (q, J = 3.2 Hz, 1H, 1-H/
2-H), 4.45 (d, J = 9.3 Hz, 1H, NH), 4.20−4.15 (m, 1H, 4-H), 3.89 (s,
3H, OCH3), 3.53 (s, 3H, NHCOOCH3), 3.00 (td, J = 10.4 and 7.0 Hz,
1H, 5-H), 2.24 (s, 3H, OCOCH3), 2.06−2.18 (m, 2H, 6-Hα and 6-
Hβ), 2.03 (s, 3H, OCOCH3); 13C NMR (75 MHz, CDCl3) δ 20.8
(CH3CO), 21.1 (CH3CO), 33.9 (6-C), 43.6 (5-C), 52.2
(NHCOOCH3), 53.4 (4-C), 56.8 (OCH3), 69.3 (2-C), 69.5 (1-C),
71.4 (3-C), 101.5 (OCH2O), 101.6 (4-CAr), 107.5 (6-CAr), 128.7 (3-
CBz and 5-CBz), 129.4 (1-CBz), 129.9 (2-CBz and 6-CBz), 133.6 (4-CBz),
134.3 (7a-CAr), 134.9 (5-CAr), 143.5 (7-CAr), 149.1 (3a-CAr), 156.5
(NHCOOCH3), 164.9 (Ph−CO), 169.5 (CH3CO), 170,9 (CH3CO);
IR (KBr) 2958, 2850, 1726, 1701, 1515, 1453, 1367, 1248, 1137, 1097,
1047, 820, 716 cm−1; anal. calcd for C27H29NO11 (543.52) C, 59.66;
H, 5.38; N, 2.58; found C, 59.65; H, 5.39; N, 2.56.
(2R,3S,4R,4aS,11bS)-Benzoic Acid 3,4-Diacetoxy-6,7-dimethoxy-
1,2,3,4,4a,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl
Ester (26). Carbamate (−)-25 (0.50 g, 1.06 mmol) and 4-
dimethylaminopyridine (0.33 g, 3.22 mmol) were dissolved in
anhydrous CH2Cl2 (27.7 mL) and cooled to 0 °C. A solution of
triflic anhydride (0.94 mL, 1.58 g, 5.60 mmol) in anhydrous CH2Cl2
(4.7 mL) was added dropwise in 15 min. The reaction mixture was
stirred for 22 h while it was allowed to warm to room temperature.
After quenching the reaction, the mixture was extracted with saturated
NaHCO3 solution (267 mL), aqueous 20% HOAc (267 mL), and
again saturated NaHCO3 (267 mL). The organic phase was dried over
EtOAc = 1:1). Yield: 54% (0.27 g, 0.53 mmol). Mp: 256−266 °C;
1
[α]22 = −82.6 (c 1, CHCl3); Rf = 0.63 (n-hexane/EtOAc = 1:1); H
D
NMR (300 MHz, CDCl3) δ 12.28 (s, 1H, OH), 8.05 (d, J = 7.5 Hz,
2H, 2-HBz and 6-HBz), 7.60 (t, J = 7.5 Hz, 1H, 4-HBz), 7.47 (t, J = 7.5
Hz, 2H, 3-HBz and 5-HBz), 6.35 (s, 1H, 11-H), 6.04 (s, 3H, NH,
OCH2O), 5.61 (t, J = 3.9 Hz, 1H, 3-H), 5.44 (q, J = 3.3 Hz, 1H, 2-H),
5.35 (dd, J = 10.8 and 2.7 Hz, 1H, 4-H), 3.87 (t, J = 12.8 Hz, 1H, 4a-
H), 3.24 (td, J = 12.6 and 3.3 Hz, 1H, 11b-H), 2.62 (dt, J = 14.2 and
3.6 Hz, 1H, 1-Hα), 2.13 (s, 3H, OCOCH3), 2.11 (s, 3H, OCOCH3),
2.01−1.96 (m, 1H, 1-Hβ); 13C NMR (75 MHz, CDCl3) δ 20.8
(CH3CO), 20.8 (CH3CO), 26.9 (1-C), 34.8 (11b-C), 52.9 (4a-C),
67.5 (3-C), 69.1 (2-C), 71.8 (4-C), 96.8 (11-C), 102.4 (9-C), 107.0
(6a-C), 128.7 (3-CBz and 5-CBz), 129.1 (1-CBz), 129.8 (2-CBz and 6-
CBz), 133.2 (7a-C), 133.8 (4-CBz), 135.8 (11a-C), 146.5 (7-C), 153.0
1915
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J. Nat. Prod. 2017, 80, 1909−1917

Journal of Natural Products
Article
(10a-C), 164.9 (Ph−CO), 169.2 (COCH3), 170.2 (COCH3), 170.3
(6-C); IR (KBr) 3345, 2926, 1754, 1727, 1673, 1465, 1370, 1340,
1269, 1235, 1060, 1029, 929, 803, 712 cm−1; anal. calcd for
C25H23NO10 (497.45) C, 60.36; H, 4.66; N, 2.82; found C, 60.35;
H, 4.67; N, 2.82.
(8S,9S)-9-Amino(9-deoxy)epiquinine (16). Yield: 87%; [α]22
=
D
+103 (c 0.524, CHCl3) {lit. [α]25D = +80 (c 1.1, CHCl3)22a}; 1H NMR
(300 MHz, CDCl3) δ 8.76 (d, J = 4.5 Hz, 1H, 2-Hquin), 8.04 (d, J = 9.3
Hz, 1H, 8-Hquin), 7.65 (br s, 1H, 5-Hquin), 7.47 (d, J = 4.2 Hz, 1H, 3-
Hquin), 7.39 (dd, J = 9.3 and 2.7 Hz, 1H, 7-Hquin), 5.81 (ddd, J = 17.1
and 10.0 and 7.5 Hz, 1H, CH2CH), 5.02 (dt, J = 17.1 and 1.5 Hz,
1H, HCHCH), 4.99 (d, J = 10.1 Hz, 1H, HCHCH) 4.60 (d, J =
9.9 Hz, 1H, H2N-CH), 3.98 (s, 3H, Ar-OCH3), 3.29 (dd, J = 13.8 and
10.2 Hz, 1H, 2-Hα quinuc), 3.21 (q, J = 6.9 Hz, 1H, 6-Hquinuc), 3.09 (q, J
= 8.1 Hz, 1H, 8-Hquinuc), 2.86−2.76 (m, 2H, 2-Hquinuc and 6-Hquinuc),
2.30−2.22 (m, 1H, 3-Hquinuc), 2.01 (s, 2H, NH2), 1.64−1.54 (m, 3H,
4-Hquinuc, 5-Hα quinuc and 5-Hβ quinuc), 1.44 (t, J = 10.8 Hz, 1H, 7-
Hquinuc), 0.77 (dd, J = 12.8 and 6.8 Hz, 1H, 7-Hquinuc); 13C NMR (75
MHz, CDCl3) δ 26.0 (7-Cquinuc), 27.6 (4-Cquinuc), 28.1 (5-Cquinuc), 39.8
(3-Cquinuc), 41.0 (6-Cquinuc), 55.6 (OCH3 and H2N−CH2), 56.3 (2-
Cquinuc), 61.9 (8-Cquinuc), 102.0 (5-Cquin), 114.4 (CH2−CH), 121.3 (3-
Cquin and 7-Cquin), 128.8 (4a-Cquin), 131.9 (8-Cquin), 141.7 (CH2-CH),
144.8 (8a-Cquin), 146.9 (4-Cquin), 147.9 (2-Cquin), 157.7 (6-Cquin).
Preparation of Single Crystals of Compounds (S)-(−)-13 and
(−)-17. For determining the absolute configurations of compounds
(−)-13 and (−)-17, single crystals were grown as follows. For (−)-13,
a small portion of the pure product (0.2 g) was dissolved in methanol
(10 mL), and it was allowed to crystallize at room temperature for 10
d, while for compound (−)-17 (0.1 g) an isopropyl alcohol solution
(10 mL) was made and it was also crystallized at room temperature for
10 d. Well-developed single crystals were formed that proved to be
suitable for the single-crystal X-ray diffraction measurements. The
crystallographic data were obtained in the Biostruct Laboratory at the
Budapest University of Technology and Economics and are
summarized in Tables S1 and S2 (Supporting Information).
(2R,3S,4R,4aS,11bS)-(−)-2,3,4,7-Tetrahydroxy-1,3,4,4a,5,11b-
hexahydro[4,5-j]phenanthridin-6-one [(−)-trans-Dihydronarcicla-
sine (−)-1]. To a solution of phenanthridone (−)-28 (0.26 g, 0.52
mmol) in anhydrous THF (38 mL) was added dropwise a 0.5 M
methanolic solution of NaOMe (21 mL) at room temperature and
stirred for 1 h, while gradual salt precipitation was observed. After
quenching the reaction mixture with a saturated NH4Cl solution (106
mL) at room temperature it was extracted with EtOAc (3 × 100 mL),
and the combined organic layer was dried over MgSO4 and evaporated
in vacuo to give a white solid. Yield: 99% (0.16 g, 0.51 mmol). HPLC
conditions: TADDOL AS-H (n-hexane/isopropyl alcohol = 8:2, flow
rate 2.0 mL min−1, 256 nm, 20 °C), t(−) = 12 min, t(+) = 18 min. Mp:
272−273 °C; [α]22 = −8.0 (c 0.25, THF), de 100%, ee 92%; Rf =
D
1
0.46 (EtOAc/MeOH = 10:1); H NMR (300 MHz, DMSO-d6) δ
12.97 (s, 1H, Ar−OH), 7.51 (s, 1H, NH), 6.47 (s, 1H, 11-H), 6.03−
6.01 (m, 2H, OCH2O), 5.13 (s, 1H, OH), 5.00 (s, 1H, OH), 4.95 (s,
1H, OH), 3.88 (s, 1H, 2-H), 3.75−3.70 (m, 2H, 3-H and 4-H), 3.32
(dd, J = 12.8 and 10.4 Hz, 1H, 4a-H), 2.85 (td, J = 12.5 and 3.2 Hz,
1H, 11b-H), 2.09 (dt, J = 13.4 and 3.4 Hz, 1H, 1-Hα), 1.63 (td, J =
13.0 and 2.1 Hz, 1H, 1-Hβ); 13C NMR (75 MHz, DMSO-d6) δ 28.4
(1-C), 34.0 (11b-C), 55.4 (4a-C), 68.7 (4-C), 69.8 (2-C/3-C), 71.9
(2-C/3-C), 96.9 (11-C), 102.1 (9-C), 107.1 (6a-C), 132.2 (7a-C),
138.7 (11a-C), 145.6 (7-C), 152.5 (10a-C), 170.0 (6-C); IR (KBr)
3421, 2921, 2852, 1671, 1466, 1339, 1262, 1229, 1079, 1031, 918, 803,
582 cm−1; anal. calcd for C14H15NO7 (309.27) C, 54.37; H, 4.89; N,
4.53; found C, 54.35; H, 4.88; N, 4.52.
ASSOCIATED CONTENT
* Supporting Information
General Procedure for the Preparation of Chinchona-Based
Organocatalysts. To a solution of cinchonine or quinine (18.5
mmol) in anhydrous THF (60 mL) was added Ph3P (22 mmol), and
the reaction mixture was cooled to 0 °C. Diisopropyl azodicarboxylate
(22 mmol) was added dropwise, and the reaction mixture was stirred
for 10 min. Next, diphenylphosphoryl azide (22 mmol) was added
dropwise, and the reaction mixture was allowed to warm to room
temperature. After stirring for 4 h at room temperature, it was heated
to 45 °C and stirred for 3 h. Ph3P (22 mmol) was added carefully (N2
released) and stirred for a further 2 h. After that, the reaction was
quenched with H2O (6 mL) and stirred overnight. The solvent was
evaporated in vacuo, and the residue was dissolved in CH2Cl2 (60 mL).
It was extracted with a 2 M HCl solution (2 × 50 mL). The aqueous
layer was purified with CH2Cl2 (2 × 35 mL). The aqueous phase was
evaporated in vacuo to obtain a yellow solid. The crude product was
recrystallized from a 1:1 EtOAc/MeOH mixture (50 mL) to give a
pale yellow hydrochloride salt. It was dissolved in water (100 mL), a
25% NH4OH solution (25 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 60 mL). The organic layer was dried over
MgSO4 and evaporated in vacuo to give an orange oil.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00208.
1
Copies of H and 13C NMR spectra for compounds
(−)-1, 9−(S)-(−)-13, 15, 16, and (−)-16−(−)-27, as
well as chiral HPLC chromatograms of compounds
(−)-1, (S)-(−)-13, (−)-17, (+)-18, and (−)-20−(−)-25
(PDF)
Crystallographic data of compound (S)-(−)-13 (CIF)
Crystallographic data of compound (−)-17 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*Tel (I. Kad
́
as): +36-1-463-3695. Fax: +36-1-463-3648. E-mail:
ikadas@mail.bme.hu.
(8R,9R)-9-Amino(9-deoxy)epicinchonine (15). Yield: 85%; [α]22
ORCID
D
= +104 (c 0.5, CHCl3) {lit. [α]25 = +105 (c 1.0, CHCl3)22a}; H
1
D
Laszlo Hegedus: 0000-0002-7980-0443
́
́
̋
NMR (300 MHz, CDCl3) δ 8.88 (d, J = 4.5 Hz, 1H, 2-Hquin), 8.35 (d,
Istvan Kadas: 0000-0001-8928-3841
́
́
J = 5.4 Hz, 1H, 5-Hquin), 8.13 (dd, J = 8.4 and 0.6 Hz, 1H, 8-Hquin),
7.71 (td, J = 7.2 and 1.2 Hz, 1H, 7-Hquin), 7.59 (dd, J = 7.2 and 1.2 Hz,
1H, 3/6-Hquin), 7.56 (dd, J = 6.9 and 1.2 Hz, 1H, 3/6-Hquin), 5.85
(ddd, J = 16.8 and 10.8 and 6.9 Hz, 1H, CH2CH), 5.08 (d, J = 1.8
Hz, 1H, HCHCH), 5.04 (dt, J = 7.8 and 1.2 Hz, 1H, HCHCH),
4.75 (d, J = 9.6 Hz, 1H, H2N-CH), 3.08−2.89 (m, 5H, 2-Hα quinuc, 6-
Hquinuc, 8-Hquinuc, 2-Hquinuc, and 6-Hquinuc), 2.26 (q, J = 8.1 Hz, 1H, 3-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was partially supported by the National Research,
Development and Innovation Office (K109486 and K119493).
■
Hquinuc), 2.08 (s, 2H, NH2), 1.58−1.50 (m, 3H, 4-Hquinuc, 5-Hα quinuc
,
and 5-Hβ quinuc), 1.10 (dd, J = 13.2 and 9.0 Hz, 1H, 7-Hquinuc), 0.97−
0.90 (m, 1H, 7-Hquinuc); 13C NMR (75 MHz, CDCl3) δ 25.0 (7-
Cquinuc), 26.6 (5-Cquinuc), 27.6 (4-Cquinuc), 37.5 (H2N−CH), 39.6 (3-
Cquinuc), 47.4 (6-Cquinuc), 49.5 (2-Cquinuc), 62.2 (8-Cquinuc), 114.5 (CH2-
CH), 119.6 (3-Cquin), 123.3 (5-Cquin), 126.3 (6-Cquin), 127.8 (4a-
Cquin), 128.9 (7/8-Cquin), 130.4 (7/8-Cquin), 140.5 (CH2−CH), 148.5
(4-Cquin), 148.9 (8a-Cquin), 150.3 (2-Cquin).
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