Enantioselective total synthesis and X-ray structures of the tetrahydroprotoberberine alkaloids (-)-(S)-tetrahydropalmatrubine and (-)-(S)-corytenchine

Article abstract of DOI:10.1021/np1001169

Enantioselective total syntheses and X-ray structures of both (S)-tetrahydropalmatrubine (2) and (S)-corytenchine (3) are reported for the first time. They were both derived from (S)-N-norlaudanidine, a benzyltetrahydroisoquinoline that was synthesized with high (>95% ee) enantioselectivity using a chiral auxiliary-assisted Bischler-Napieralski cyclization/reduction approach.

Full text of DOI:10.1021/np1001169

J. Nat. Prod. 2010, 73, 1427–1430
1427
Enantioselective Total Synthesis and X-ray Structures of the Tetrahydroprotoberberine
Alkaloids (-)-(S)-Tetrahydropalmatrubine and (-)-(S)-Corytenchine
Ahmed L. Zein, Louise N. Dawe, and Paris E. Georghiou*
Department of Chemistry, Memorial UniVersity of Newfoundland, St. John’s, Newfoundland and Labrador, A1B3X7, Canada
ReceiVed February 19, 2010
Enantioselective total syntheses and X-ray structures of both (S)-tetrahydropalmatrubine (2) and (S)-corytenchine (3)
are reported for the first time. They were both derived from (S)-N-norlaudanidine, a benzyltetrahydroisoquinoline that
was synthesized with high (>95% ee) enantioselectivity using a chiral auxiliary-assisted Bischler-Napieralski cyclization/
reduction approach.
1-Benzyltetrahydroisoquinolines (BTHIQs) such as tetrahydro-
papaverine (1), in which the B ring is reduced at the C-1, C-2 and
C-3, C-4 positions, are key biosynthetic precursors to many naturally
occurring alkaloids. These include morphine and codeine, which
are found in, or are derived from, the opium poppy, PapaVer
somniferum L.1 BTHIQs are also biosynthetic precursors to the
tetrahydroprotoberberines (THPBs),2 a class of naturally occurring
tetracyclic alkaloids that also contain an isoquinoline core,3 and
are a subclass of the protoberberine alkaloids.4 These compounds
are found in at least eight plant families and possess a variety of
biological activities including, for example, anti-inflammatory,
antimicrobial, antifungal, and antitumor properties.5 The most
common of these THPB derivatives, such as (S)-tetrahydropal-
matrubine (2), have oxygen functionalities at the C-2, C-3 and C-9,
C-10 positions on the A and D aromatic rings, respectively.2 Less
common is the class of “pseudo-THPBs” such as (S)-corytenchine
(3) and (S)-xylopinine (4), for which oxygen functionalities are on
the C-2, C-3 and C-10, C-11 positions (Figure 1).
We reported recently the enantioselective syntheses and X-ray
structures of (S)-N-norlaudanidine (5) and its R enantiomer using
a chiral auxiliary-assisted Bischler-Napieralski cyclization/reduc-
tion approach.6 These BTHIQs are known to be trace opium
constituents and, as a racemic mixture (also referred to in the
literature as “(()-norlaudanine”), have been shown also by Isawa
et al.2 to be bioconverted into stereoisomeric mixtures of both 2
and 3. Interestingly, these authors concluded that the R isomer of
2 and the S isomer of 3 are the major enantiomers formed in their
metabolic studies using cell cultures of Macleaya and Corydalis
species, suggesting “stereospecific bioconversion”.2 In this study,
however, a racemic mixture of (S)- and (R)-N-norlaudanidine, which
was isolated from a mixture produced by an acid-mediated reaction
of racemic tetrahydropapaverine (1), was employed. Herein, we
report the enantioselective syntheses and X-ray structures of both
(S)-tetrahydropalmatrubine (2) and (S)-corytenchine (3), which were
derived directly from (S)-N-norlaudanidine.
>99% ee enantioselective synthesis of (S)-stepholidine (7), a
compound that has attracted a great deal of attention since it was
reported to display a unique pharmacological profile toward
dopamine receptors.11 This alkaloid has a 2,11-dihydroxy-3,10-
dimethoxy substitution pattern on the A and D rings and was
synthesized via an asymmetric Bischler-Napieralski cyclization/
reduction approach.12
On the basis of our recent synthetic studies,6,13 we targeted the
synthesis of a 2,3,10-trimethoxy-11-hydroxy-functionalized THPB,
i.e., (S)-corytenchine (3), using the chiral auxiliary (S)-R-methyl-
benzylamine, in an asymmetric Bischler-Napieralski cyclization/
reduction sequence, as shown in Scheme 1.
Isovanillin (8) was converted into benzylic substance 9 in five
steps in an overall 78% yield using Kim’s methodology.14 For the
isoquinoline fragment, vanillin (10) was converted into 5 via the
(S)-R-methylbenzylamine chiral auxiliary-protected amide, 13, in
70% overall yield from 10. As ascertained from its 1H NMR
spectrum, 12 was formed in ca. 95% de. Conversion of 5 into (S)-
corytenchine (3) was then effected by reaction at 0 °C with
formaldehyde (37% formalin) in acetonitrile, followed by addition
of NaBH3CN and then by acetic acid.13a The reaction afforded
almost quantitative formation of 3, for which the NMR spectro-
scopic properties are generally in agreement with those reported
by da Silva15 and Martinez-Vazquez,16 who, respectively, isolated
3 from Xylopia langsdorffiana A. St.-Hil. & Tul. (Annonaceae) and
from the roots of Annona cherimolia Mill. (Annonaceae). Earlier,
Kametani reported the isolation of 3 from Corydalis ochotensis
Turcz17 but had previously synthesized a “dibenzo[a,g]quinolizine”,
which they called “O-demethyltetrahydroxylopine”, having the same
substitution pattern as 3, presumably as a racemate, by a similar
procedure from racemic 5 using formalin in ethanol “without
acid”.18 In this paper, the authors reported that they were unable
to obtain a compound having the same substitution pattern as
tetrahydropalmatrubine (2).
Since the product obtained in the present study had physical
properties similar to those reported above but with slight differences
in several of the NMR assignments, unequivocal evidence from
X-ray crystallography was sought. The X-ray structure shown in
Figure 2 confirmed the structure as (S)-corytenchine (3), based upon
the absolute structure of the precursor 5, for which the X-ray
structure was previously established.6
Among the different strategies that have been used for the
construction of a THPB core, the classical Pictet-Spengler7 or the
Bischler-Napieralski cyclization/reduction8 procedures have been
the most widely used. Although several racemic syntheses of
THPBs have been reported, there are only a small number of
asymmetric syntheses having the desired ring substitution patterns.
Several of these asymmetric syntheses have been of (S)-(-)-
xylopinine (4), using different approaches,9 and also of (S)-
tetrahydropalmatine (6).10 These two compounds, however, are both
tetramethoxylated, i.e., a 2,3,10,11- and a 2,3,9,10-tetramethox-
yTHPB, respectively. Very recently, Cheng and Yang reported a
When Kametani’s methodology was employed as described,18
1
a mixture was obtained that by its H NMR spectroscopic data
showed approximately 70% of 3 and 30% of the regioisomeric
product, for which the spectroscopic properties and X-ray structure
(Figure 3, as the hydrochloride salt) showed it to be (S)-
tetrahydropalmatrubine (2).
Compound 3 has also been named “schefferine” in several
publications in the literature, and in some cases this is confusing.
* To whom correspondence should be addressed. Phone: +1-709-
7378517. Fax: +1-709-737-3702. E-mail: parisg@mun.ca.
10.1021/np1001169  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/09/2010

1428 Journal of Natural Products, 2010, Vol. 73, No. 8
Notes
Figure 1. (()-Tetrahydropapaverine (1) and THPB alkaloids 2-7.
Scheme 1. Synthesis of (S)-Tetrahydropalmatrubine (2) and
(S)-Corytenchine (3)a
Figure 2. X-ray structure of 3 with 50% probability ellipsoids.
a Reagents and conditions: a: 1. BnBr, DMSO, 98%; 2. CBr4, PPh3, CH2Cl2,
93%; 3. pyrrolidine, H2O, rt, 91%; 4. 1.0 M HClaq/dioxane; 5. (COCl)2, benzene,
94%. b: 1. (CH3)2SO4, K2CO3, acetone, 95%; 2. CBr4, PPh3, CH2Cl2, 92%; 3.
pyrrolidine, H2O, rt, 91%; 4. 1.0 M HClaq/dioxane; 5. (COCl)2, benzene, 96%;
6. CA* ) (S)-R-methylbenzylamine, 5% NaOHaq, CH2Cl2, 92%; c: B2H6, THF,
BF3 ·Et2O, 86%. d: 9, 5% NaOHaq, CH2Cl2, 72%; e: 1. POCl3, benzene; 2. NaBH4,
MeOH, 89%, (95% ee); f: H2, 10% Pd/C, EtOH, 10% HClaq: 5 ∼72%; g: 1.
HCHO, CH3CN; 2. NaBH3CN; CH3CO2H, 95%; h: 1. HCHO, MeOH; 2. NaBH4,
∼70% 3 and ∼30% 2.
Figure 3. X-ray structure of 2 with 50% probability ellipses. Solvent
water molecules and chloride ion omitted for clarity.
reported the synthesis of schefferine via a photochemical route25a
and stated it to be “identical with an authentic sample”, although
the compound they were referencing it to was ambiguous with
respect to the ring-D substitution pattern.25b In 2000, Bianchi and
Kaufman26 published two papers in which they reported the
synthesis via a tosyliminium ion-based route, of “(()-schefferine”,
to which was assigned the substitution pattern of 2. However, their
NMR spectroscopic data were not consistent with the proposed
structure and are at odds with those determined herein for
(S)-tetrahydropalmatrubine (2). 13C NMR spectra were also reported
by Kametani et al. for a series of dibenzo[a,g]quinolizidines, which
included a structure (identified only as compound “16”) identical
to 2.27
In 1972, Gellert and Rudzats19 isolated two THPBs from Scheff-
eromitra subaequalis Diels, of which one was named “schefferine”
and with the same structure represented as 2. However, Brochmann-
Hanssen20 later reassigned this structure as being the regioisomeric
compound having the substitution pattern on the D ring transposed,
with the hydroxy group at C-10 and the methoxy group at C-9,
and indicated that it was the same as “kikemanine”. Kikemanine
was so named by Kametani,21 who isolated it from Corydalis
pallida Pers. in 1970, and was also equivalent to “corydalmine”,
previously isolated by Imaseki and Taguchi22 from another Cory-
dalis species (named as “engosan”). This was obtained also by
Cava23 in 1968 from Stephania glabra Miers. Corydalmine was
synthesized by Bradsher24 in 1965. In 1977, Kametani’s group also
Experimental Section
General Experimental Procedures. Optical rotations were recorded
1
on a JASCO DIP-370 polarimeter. H and 13C NMR spectra, HSQC,
and COSY spectra were recorded on a Bruker 500 MHz NMR

Notes
Journal of Natural Products, 2010, Vol. 73, No. 8 1429
spectrometer and were referenced to the solvent (CDCl3) and TMS.
LC-MS and HRMS were conducted using a GCT Premier Micromass
spectrometer. X-ray structures were measured with a Rigaku Saturn
CCD area detector equipped with a SHINE optic using Mo KR
radiation. Silicycle Ultrapure silica gel (0-20 µm) G and F-254 was
used for the preparative-layer TLC, and Silicycle Silia-P Ultrapure Flash
silica gel (40-63 µm) was used for flash column chromatography. TLC
was conducted on Polygram SIL G/UV254 precoated plastic sheets.
Solvents were purified using standard conditions before use.
Method a. Formalin (37% HCHO(aq), 2.0 mL) was added to a
solution of 146 (250 mg, 0.75 mmol) in MeOH (6.0 mL). After the
mixture had been stirred at 25 °C for 3 h, NaBH4 (319 mg, 8.44 mmol)
was slowly added. Subsequently, the reaction mixture was stirred at
25 °C for an additional 16 h. Then, aqueous saturated NH4Cl (25 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were dried over MgSO4, and after filtering,
the solvent was evaporated under a vacuum to afford a mixture of 2
and 3, which was purified by preparative TLC (silica gel, 20% EtOH
in hexane) to give 2 (78 mg) as a colorless solid, mp 178-179 °C (as
the hydrochloride), and 3 (181 mg) as a colorless solid, mp 257-258
°C.
3418 independent reflections (Rint ) 0.0245). The final R1 values were
0.0325 (I > 2σ(I)), and the final wR(F2) values were 0.0844 (all data).
The goodness of fit on F2 was 1.057. Flack parameter ) 0.0(8). Non-
hydrogen atoms were refined anisotropically, while all hydrogen atoms
were located in difference map positions and refined on a geometry-
constrained (riding) model. CCDC #766064.
Acknowledgment. This work was supported by Memorial University
of Newfoundland, the Natural Sciences and Engineering Research
Council of Canada (NSERC), and the Ministry of Higher Education
of Egypt (for a scholarship to A.L.Z.).
Supporting Information Available: Copies of the spectra and the
crystallographic information files (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org. Crystallographic data
for 2 (CCDC 766063) and 3 (CCDC 766064) have been deposited with
the Cambridge Data Centre.
References and Notes
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Method b. To a stirred solution of 14 (180 mg, 0.54 mmol) and
formalin (37% HCHO(aq), 2.0 mL) in MeCN (1 mL) was added
NaBH3CN (0.294 mg, 0.892 mmol). The reaction mixture was stirred
for 1 h, and HOAc was then added. After being stirred for 1 h, the
reaction mixture was quenched with water and neutralized to pH 8
with aqueous saturated NaHCO3, and the mixture was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried over
MgSO4, and after filtering, the solvent was evaporated under a vacuum
to afford 3 (175 mg) as a colorless solid, mp 257-258 °C (245-246
°C).16
(S)-(-)-Tetrahydropalmatrubine (2): colorless solid that slowly
developed color on standing, mp 178-179 °C (as the hydrochloride);
1
[R]25 -115 (c 0.09, MeOH) (as the hydrochloride); H NMR δ 6.74
D
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(1H, d, J ) 8.5 Hz, H-11), 6.74 (1H, s, H-1), 6.68 (1H, d, J ) 8.5 Hz,
H-12), 6.62 (1H, s, H-4), 4.25 (1H, d, J ) 15.0 Hz, H-8ax), 3.89 (3H,
s, OCH3; C-2), 3.87 (6H, s, OCH3; C-3, C-10), 3.58 (1H, dd, J ) 12.0
and 3.5 Hz, H-13a), 3.53 (1H, d, J ) 15.0 Hz, H-8eq), 3.26 (1H, dd,
J ) 15.5 and 3.5 Hz, H-13eq), 3.23-3.12 (2H, m, H-6eq and H-5eq),
2.84 (1H, dd, J ) 15.5 and 12.0 Hz, H-13ax), 2.69-2.64 (2H, m, H-6ax
and H-5ax); 13C NMR δ 147.5 (C-11), 147.4 (C-10), 144.0 (C-2), 141.5
(C-3), 129.8 (C-13b), 128.1 (C-4a), 126.9 (C-8a), 121.3 (C-12a), 119.3
(C-4), 111.4 (C-12), 108.9 (C-9), 108.7 (C-1), 59.3 (C-13a), 56.2
(OCH3; C-2), 56.1 (OCH3; C-3), 55.9 (OCH3; C-10), 53.5 (C-8), 51.4
(C-6), 36.4 (C-13), 29.1 (C-5); APCIMS m/z 342.1 (M+ + 1, 100);
HREIMS m/z 341.1620 (calcd for C20H23NO4, 341.1614).
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Crystal data for 2: (C20H24NO4)·Cl·2(H2O), prism crystals (of the
hydrochloride) from methanol/HCl, M ) 413.90, monoclinic, a )
11.197(6) Å, b ) 7.218(4) Å, c ) 12.421(7) Å, ꢀ ) 99.841(11)°, V )
989.2(9) Å3, T ) 153(1) K, space group P21 (#4), Z ) 2, µ(Mo KR)
) 0.230 mm-1, 8699 reflections measured, 4013 independent reflections
(Rint ) 0.0451). The final R1 values were 0.0962 (I > 2σ(I)), and the
final wR(F2) values were 0.2646 (all data). The goodness of fit on F2
was 1.051. Flack parameter ) 0.07(18). Non-hydrogen atoms were
refined anisotropically, while all hydrogen atoms were located in
difference map positions and refined on a geometry-constrained (riding)
model. CCDC #766063.
(S)-(-)-Corytenchine (3): colorless, cubic crystals; mp 257-258
1
°C; [R]25 -271 (c 0.09, MeOH); H NMR δ 6.74 (1H, s, H-1), 6.72
D
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(1H, s, H-4), 6.62 (1H, s, H-12), 6.56 (1H, s, H-9), 3.93 (1H, d, J )
14.5 Hz, H-8ax), 3.90 (3H, s, OCH3; C-2), 3.87 (3H, s, OCH3; C-10),
3.86 (3H, s, OCH3; C-3), 3.68 (1H, d, J ) 14.5 Hz, H-8eq), 3.57 (1H,
dd, J ) 11.5 and 3.5 Hz, H-13a), 3.21 (1H, dd, J ) 15.5 and 3.5 Hz,
H-13eq), 3.17-3.13 (2H, m, H-6eq and H-5eq), 2.81 (1H, dd, J )
15.5 and 11.5 Hz, H-13ax), 2.69-2.60 (2H, m, H-6ax and H-5ax); 13
C
NMR δ 147.5 (C-11), 147.5 (C-10), 145.1 (C-2), 144.1 (C-3), 129.8
(C-13b), 127.1 (C-4a), 126.7 (C-8a), 125.8 (C-12a), 114.3 (C-4), 111.4
(C-12), 108.6 (C-9), 108.3 (C-1), 59.6 (C-13a), 58.4 (C-8), 56.1 (OCH3;
C-2), 56.0 (OCH3; C-3), 55.9 (OCH3; C-10), 51.4 (C-6), 36.2 (C-13),
29.1 (C-5); APCIMS m/z 342.1 (M+ + 1, 100); HREIMS m/z 341.1627
(calcd for C20H23NO4, 341.1627).
Crystal data for 3: C20H23NO4, colorless prisms from methanol, M
) 341.41, orthorhombic, a ) 7.2621(12) Å, b ) 8.0445(13) Å, c )
28.318(5) Å, V ) 1654.3(5) Å3, T ) 153(1) K, space group P212121
(#19), Z ) 4, µ(Mo KR) ) 0.095 mm-1, 22 912 reflections measured,
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1430 Journal of Natural Products, 2010, Vol. 73, No. 8
Notes
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