Concise enantiospecific, stereoselective syntheses of (+)-Crispine A and Its (-)-antipode

Article abstract of DOI:10.1021/jo102112k

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)- propanoa

Full text of DOI:10.1021/jo102112k

ARTICLE
pubs.acs.org/joc
Concise Enantiospecific, Stereoselective Syntheses of (þ)-Crispine A
and Its (-)-Antipode
Mahender Gurram,† Balꢀazs Gyimꢀothy,‡ Ruifang Wang,† Sang Q. Lam,† Feryan Ahmed,† and R. Jason Herr*,†
†Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), P.O. Box 15098, 26 Corporate Circle, Albany, New York
12212-5098, United States
‡Chemistry & Innovation Department, AMRI, Zꢀahony utca 7, H-1031 Budapest, Hungary
S Supporting Information
b
ABSTRACT:
An enantiospecific and stereoselective total synthesis of the natural product (þ)-crispine A has been demonstrated employing a
Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)-
propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient
two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino
acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(þ)-
amino acid.
The pyrroloisoquinoline alkaloid (þ)-crispine A [(R)-(þ)-1,
Figure 1] was first isolated in 2002 from the Mongolian thistle
Carduus crispus1 and has since emerged as a natural product
target of interest, due largely to reports of its cytotoxic activity
and similarity to known congeners shown to exhibit antidepres-
sant-like activity.2 Within the decade, several concise syntheses of
racemic crispine A have been described, differing mainly in the
Figure 1. Natural product (þ)-crispine A and its unnatural (-)-
strategies utilized to construct the pyrrolidine ring.3 Interestingly,
synthetic reports of this heterocycle can also be found in the
literature prior to its identification as a natural product extract or
its naming as crispine A.4 A number of directed enantioselective
syntheses of this alkaloid have also recently appeared in the
literature,5 along with asymmetric preparations of the (S)
antipode6 as well as crispine A analogues.7 We nevertheless
sought to contribute our own novel asymmetric approach based
on a Pictet-Spengler bis-cyclization reaction between enantio-
pure methoxytyrosine derivatives and an acetal bearing a teth-
ered terminal leaving group. This was envisioned to provide
intermediate adducts that would undergo a concomitant second
cyclization to provide the tricyclic pyrrolo[2,1-a]isoquinoline
core of crispine A in one step. This communication summarizes
our results toward this goal.
antipode.
time the Pictet-Spengler condensation reaction10 has become
one of the most widely used methods for the preparation of
1-substituted tetrahydroisoquinoline and tetrahydro-β-carboline
natural products and related alkaloids with diverse biological
activities.11 When electron-rich R-substituted-β-phenethyl-
amines are condensed with aldehydes or aldehyde surrogates,
the chirality of the R-substituted center can influence the
transition state conformation such that the thermodynamically
more stable 1,3-cis stereochemistry is generally observed in the
tetrahydroisoquinoline products.12,13 Thus we envisioned the
key step of our stereocontrolled construction of the crispine A
core to provide a new chiral center through 1,3-transfer of
chirality from an enantiopure methoxytyrosine precursor to
preferentially provide a 1,3-cis adduct.
The first intermolecular condensation reaction between β-
phenethylamine and an aldehyde surrogate in the presence of
HCl to afford a tetrahydroisoquinoline was described in 1911 by
Pictet and Spengler8 and later applied to the preparation of
tetrahydro-β-carbolines from tryptamines by Tatsui.9 Since that
Received: October 25, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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Table 1. Pictet-Spengler Condensation and Cyclization Conditions for (S)-(þ)-2a
entry
precursor
conditions
ratio 7a:8a
result/yield
1
3
3
3
4
5
3
3
3
3
3
3
3
CH2Cl2/TFA (1:1), rt, 1 h
3:1
4.5:1
4.5:1
4.5:1
35%
2
CH2Cl2/TFA (4:1), rt, 4 h
38%
3
CH2Cl2/TFA (4:1), 4 Å mol. sieves, rt, 4 h
CH2Cl2/TFA (4:1), 4 Å mol. sieves, rt, 4 h
CH2Cl2/TFA (4:1), 4 Å mol. sieves, rt, 4 h
CH3CN/TFA (4:1), 4 Å mol. sieves, rt, 4 h
DME/TFA (4:1), 4 Å mol. sieves, rt, 4 h
iPrOH/TFA (3:1), 4 Å mol. sieves, 50 °C, 3 h
CH2Cl2, BF3•OEt2, rt, 15 h
98%
55%a
4
5
no reaction
95%
6
2:1
2:1
3:1
7
91%
8
95%
9
no reaction
decomposition
no reaction
no reaction
10
11
12
CH2Cl2, TiCl4, rt, 15 h
CH2Cl2, 1% TfOH, rt, 15 h
NaOAc, HOAc, rt, 15 h
a Longer reaction time (18 h) resulted in full conversion at 97% yield.
’ RESULTS AND DISCUSSION
dioxolane acetal of 4 under acidic conditions when compared to
the dimethoxy acetal of 3. Interestingly, repeated attempts to use
4-chlorobutyraldehyde (5) failed to provide any of the Pictet-
Spengler adduct or the bis-cyclized products (entry 5). Under these
conditions 5 was observed to decompose rapidly, resulting in
recovery of the unreacted precursor (S)-(þ)-2a, consistent with
our proposed acid-catalyzed mechanism (vide infra).
To initiate our studies, we subjected commercially available
(S)-(þ)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate
[(S)-(þ)-2a]14 to Pictet-Spengler condensation conditions,
first with 4-chloro-1,1-dimethoxybutane (3) as the coupling
partner, and using trifluoroacetic acid as the catalyst (entries
1-3, Table 1). We found that the condensation reaction was very
rapid, generating a mixture of tetrahydroisoquinoline isomers
(1RS,3S)-6ab in a short time at room temperature (as deter-
mined by 1H NMR and LC-MS analyses). Continued stirring
led directly to a mixture of the 1,3-cis isomer (5S,10bS)-7a and
1,3-trans isomer (5S,10bR)-8a in ratios that were determined by
1H NMR and LC-MS analyses. The crude reaction mixtures
were then purified by column chromatography to isolate the
stereoisomers, in every case favoring the 1,3-cis epimer as the
major product. We found that the use of 4 Å molecular sieves in a
4:1 mixture of methylene chloride and trifluoroacetic acid at
room temperature offered the best conditions to provide a 4.5:1
mixture of 1,3-cis isomer (5S,10bS)-7a and 1,3-trans isomer
(5S,10bR)-8a after four hours (entry 3). Use of other solvents
for the bis-cyclization transformation were less effective (entries
6-8), as were other acid catalysts (entries 9-12).
We also found that subjecting (S)-(þ)-2a to the optimized two-
component cyclization conditions with precursor 2-(3-chloropro-
pyl)-1,3-dioxolane (4) in place of acetal 3 had no noticeable effect
on the cis/trans product ratio, but the conversion to product was
much slower, providing a comparatively lower isolated yield of the
mixture over the same 4 h time course studied (entry 4, Table 1).
When run for a longer time, however, the mixture fully converted to
the 7a/8a mixture in a 4.5:1 ratio in comparable yield. This longer
reaction time can be attributed to the greater stability of the
Figure 2. Stereochemical assignment of the 1,3-cis and 1,3-trans
stereoisomers.
Proton and carbon NMR experiments were used to assign the
structures of (5S,10bS)-7a and (5S,10bR)-8a as shown in
Figure 2. The 1,3-cis relative stereochemistry for isomer
(5S,10bS)-7a was confirmed through NOE difference experi-
ments to measure the through-space interaction between the
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Scheme 1. Proposed Reaction Mechanism of the Pictet-Spengler bis-cyclization reaction
R-amino acid proton H-5 and the methine proton H-10b. It is
well-known that 1,3-disubstituted dihydroisoquinolines prefer to
adopt a framework resembling a half-chair conformation, where
substituents can attain pseudoequatorial dispositions.15 As a
result, irradiation of the axial H-5 proton at 3.6 ppm resulted
in an increased signal for the axial H-10b proton at 3.7 ppm, as
well as for one of the two diastereotopic protons H-6 on the
adjacent methylene at 2.5 ppm.
In contrast, 1,3-disubstitution on the 1,3-trans isomer
(5S,10bR)-8a forces the H-10b proton to assume a pseudoequa-
torial configuration to accommodate the half-chair conformation
(Figure 2). As a result, irradiation of the R-amino acid proton
H-5 at 4.2 ppm does not result in a measurable NOE enhance-
ment of the C-10b proton at 3.7 ppm and vice versa, leading to
the designation of (5S,10bR)-8a as the minor 1,3-trans stereo-
isomer. As expected, irradiation of proton H-5 resulted in signal
enhancements for one of the two diastereotopic protons H-6 on
the adjacent methylene at 2.8 ppm, as well as for the pseudoaxial
proton H-1 on the fused pyrrolidine ring at 2.4 ppm.
expulsion of methanol to provide the thermodynamically favored
(E)-iminium intermediate 10. Electrophilic aromatic substitu-
tion then takes place to ultimately form the 1-(3-chloropro-
pyl)tetrahydroisoquinoline adducts (1S,3S)-6a and (1R,3S)-6b.
This is followed by the facile intramolecular displacement of the
pendant alkyl chloride by the nitrogen to provide the tricyclic
products (5S,10bS)-7a and (5S,10bR)-8a. From our examination
of the reaction conditions, we surmise that the role of 4 Å
molecular sieves is to largely sequester the two eliminated
equivalents of methanol, driving the reaction to 10.
A rationale to describe the observed 1,3-cis stereoselectivity of
the ring closure step in the Pictet-Spengler cyclization is
proposed in Scheme 2. Intramolecular approach of the pendant
aromatic from the diastereotopic re face of the iminium species
(E)-10 forces the molecule to attain of
a half-chair
conformation15 to facilitate molecular orbital overlap and allows
both the R-ester and 3-chloropropyl substituents to adopt
pseudoequatorial dispositions in the developing transition state
configuration. Upon ring closure and rearomatization, this con-
figuration leads to a 1,3-cis relationship between the substituents
for the tetrahydroisoquinoline product (1S,3S)-6a.
We propose a plausible mechanism for the transformation as
depicted in Scheme 1. Several equivalents of trifluoroacetic acid
play a role in inducing elimination of methanol, first in elimina-
tion from dimethyl acetal 3 to provide a reactive oxonium ion
species that undergoes attack by the amino acid (S)-(þ)-2a. The
resulting hemiaminal 9 may then undergo acid-catalyzed
In order for the pendant aromatic to approach from the si face
of imine (E)-10, however, the alignment to a half-chair conformation
forces the R-ester substituent into a pseudoaxial disposition, a
less favorable energy state (Scheme 2). In addition, a developing
Scheme 2. Proposed Rationale for the Selective Generation of the cis Adduct (5S,10bS)-6a
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Scheme 3. Elaboration of L-DOPA-Derived Tricycles to (þ)- and (-)-Crispine A
A1,3 strain interaction between proton H1 and the ester moiety in
the developing transition state contributes to disfavor this
arrangement. However, ring closure and rearomatization
through this disfavored by accessible conformation leads to a
1,3-trans relationship between the substituents for the tetrahy-
droisoquinoline product (1R,3S)-6b. As one might predict on
the basis of energy considerations, the bias to pass through the
transition state conformation by attack onto the re face of
iminium intermediate 10 is reflected in the observed ratio of
products 6a:6b, favoring the 1,3-cis diastereomer 6a.
In order to probe the effects of the phenethylamine R-
substituent on the facial selectivity of the two-step cyclization,
we made a small effort to evaluate the consequences for
selectivity utilizing the slightly larger benzyl ester (S)-(þ)-2b
(eq 1). Although it has been demonstrated that the size of the
aldehyde (or surrogate) can affect the stereochemistry at the
newly formed tetrahydroisoquinoline C-1 position,10 we were
not aware of many recent examples comparing the size of the
phenethylamine R-substituent to the resulting stereoselectivity
from 1,3-chiral transfer.16 Although examples within one report
suggested that the difference in size of phenethylamine R-esters
would not significantly change the 1,3-cis/trans product ratio,17
we were initially surprised to find that increasing the size of the R-
methyl ester (S)-(þ)-2a to the benzyl ester (S)-(þ)-2b18
diminished the preference for the 1,3-cis isomer (5S,10bS)-7
from 4.5:1 to 2:1. Although we cannot at present propose
considerations to account for this observation, these effects
may be analogous to the loss of stereoselectivity noted in similar
systems when the relative size of the aldehyde component is
increased.19
use of dimethylaluminum methaneselenolate.20 Subjection of
(5S,10bR)-11 to radical decarboxylation conditions21,22 led to
the natural product isomer of crispine A [(R)-(þ)-1]1,5 in 42%
isolated yield for the two-step process. The measured optical
rotation [R]20D þ90° (c 1.0, CHCl3) for (R)-(þ)-1was consistent
with the two literature values reported in chloroform of [R]25
D
þ97° (c 1.1)5b and [R]23 þ100° (c 1.0)5a and was a single
D
enantiomer by chiral HPLC analysis (see Supporting Information).
Similarly, the cis isomer (5S,10bS)-7a, the major adduct from
the Pictet-Spengler cyclization, was converted to the methyl-
selenyl ester (5S,10bS)-12 as shown in Scheme 3. As with the
regioisomer (5S,10bR)-11, the radical decarboxylation protocol
transformed (5S,10bS)-12 to the unnatural antipode of crispine
A [(S)-(-)-1]1,6 in 39% isolated yield for the two-step process.
The alkaloid enantiomer (S)-1 was found to rotate polarized light
in an equal but opposite manner to (R)-1 and was also shown to
be a single isomer by chiral HPLC analysis (see Supporting
Information). This confirms the identity of both intermediates
7a and 8a as a diastereomeric pair and also demonstrates that no
appreciable epimerization had occurred during the synthetic
manipulations to (S)-(-)- and (R)-(þ)-1.
The Pictet-Spengler bis-cyclization reaction was then applied to
commercially available (but quite a bit more expensive) (R)-(-)-
methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate [(R)-(-)-
2a] as shown in Scheme 4. Thus, a slight excess of 4-chloro-1,
1-dimethoxybutane (3) was added to a stirring suspension of
(R)-(-)-methyl
2-amino-3-(3,4-dimethoxyphenyl)propanoate
[(R)-(-)-2a] and 4 Å molecular sieves in a 4:1 mixture of
methylene chloride and trifluoroacetic acid at room temperature.
After 4 h, the components had converted to a mixture of tetra-
hydroisoquinoline isomers from which the 1,3-cis isomer
(5R,10bR)-7a was isolated by chromatography in 82% yield. This
preferentially formed tricyclic adduct was then subjected to the
selenyl esterification and radical decarboxylation two-step protocol
to provide the enantiopure natural product (þ)-1 with an overall
The enantiopure tricyclic tetrahydroisoquinoline isomers were
then individually elaborated to the natural product and antipode
isomers of crispine A, as shown in Scheme 3. First, 1,3-trans isomer
(5S,10bR)-8a, the minor adduct from the Pictet-Spengler cycliza-
tion, was converted to the methylselenyl ester (5S,10bR)-11 by the
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Scheme 4. Preparation of (þ)-Crispine A from D-DOPA-Derived Precursor (R)-(-)-2a
32% isolated yield from the amino acid. The optical rotation, chiral
HPLC analysis and other spectral data were found to match the
(R)-(þ)-1 isomer prepared through the route using (S)-(þ)-2a,
confirming the chiral integrity of this asymmetric approach.
as they were eluted from the chromatography column. Alterna-
tively, when the conversion from (S)-(þ)-13 to the (1RS,3S)-
14ab mixture under the Pictet-Spengler condensation
conditions was judged to be complete, the solids were removed
from the reaction mixture by filtration, the filtrate was concen-
trated, and the residue was dissolved in acetonitrile. Treatment of
the resulting mixture with triethylamine allowed the second
cyclization to take place at room temperature in 1 h, providing
(5S,10bS)-15 and (5S,10bR)-16 in a 4.5:1 ratio of stereoisomers
favoring the 1,3-cis epimer, and were separated by column
chromatography to provide the individual isomers.
In a separate experiment, we subjected the 4.5:1 mixture of
(5S,10bS)-15 and (5S,10bR)-16 diol isomers to alkylation con-
ditions with excess iodomethane and potassium carbonate in
acetonitrile at room temperature (eq 2). After separation of
the components by chromatography, the dimethoxy products
(-)-(5S,10bS)-7a and (þ)-(5S,10bR)-8a were individually iso-
lated in a ratio of yields reflecting the starting composition and
were each found to match the spectral data for (5S,10bS)-7a and
(þ)-(5S,10bR)-8a prepared by the route from amino acid ester
(S)-(þ)-2a and dimethyl acetal precursor 3.
During the time we were determining suitable conditions for
the bis-condensation reaction with the bis-methoxy precursor
(S)-(þ)-2a, we also explored the feasibility for synthesis with the
much less expensive (S)-(þ)-methyl 2-amino-3-(3,4-dihydroxy-
phenyl)propanoate [(S)-(þ)-13],23 which is derived from
L-DOPA (Scheme 5). Thus, (S)-(þ)-13 was subjected to the
Pictet-Spengler condensation conditions with 2-(3-chloro-
propyl)-1,3-dioxolane (4) at room temperature, cleanly provid-
ing a 4:1 mixture of tetrahydroisoquinoline isomers (1RS,3S)-
14ab in a 4.5:1 ratio (as determined by 1H NMR and LC-MS
analyses). However, even upon prolonged stirring at room
temperature, the mixture of diastereomers did not cyclize to
the tricyclic adducts, as was seen with the bis-methoxy precursors
(S)-(þ)-2a, although upon workup and purification of the crude
reaction mixture, we found that the individual adducts sponta-
neously cyclized on exposure to silica gel, providing both the
1,3-cis isomer (5S,10bS)-15 and 1,3-trans isomer (5S,10bR)-16
Scheme 5. Pictet-Spengler Cyclization of (S)-(þ)-13 with 2-(3-Chloropropyl)-1,3-dioxolane (4)
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(3.70 ppm) as well as 3% for H3R (2.90 ppm) and 2% for H6R (2.49 ppm).
Further elution afforded the more polar isomer (5S,10bR)-8a (0.25 g, 18%)
as an amorphous colorless solid: [R]20D þ0.09° (c 1.0, CHCl3); mp 91-
95 °C; 1H NMR (500 MHz, CDCl3) δ 6.59 (s, 1H), 6.57 (s, 1H), 4.25 (t, J
=7.5Hz, 1H), 3.84(s, 6H), 3.76(t, J= 5.5 Hz, 1H), 3.70 (s, 3H), 3.19-3.14
(m, 1H), 3.07 (dd, J= 5.5, 15.8 Hz, 1H), 2.97 (dd, J= 5.5, 15.8 Hz, 1H), 2.82
(q,J= 7.4 Hz, 1H), 2.43-2.36 (m, 1H), 1.96-1.84(m, 2H), 1.73-1.66(m,
1H); 13C NMR (125 MHz, CDCl3) δ 173.3, 147.7, 147.3, 130.7, 124.2,
110.0, 109.0, 58.9, 57.9, 55.9, 55.9, 52.1, 51.9, 32.8, 29.5, 23.3; ESI MS m/z
292.1 [M þ H]þ; HRMS (ESI) m/z 292.1555 [M þ H]þ (292.1549
calculated for C16H21NO4 þ H). The relative 1,3-stereochemistry was
In summary, we have demonstrated an asymmetric total synth-
esis of both the natural product (þ)-crispine A and its unnatural
(-) antipode employing a Pictet-Spengler bis-cyclization reac-
tion between commercially available L- and D-DOPA-derived
precursors and an aldehyde surrogate bearing a terminal leaving
group. This procedure preferentially provides 1,3-cis tetrahydro-
isoquinoline adducts that undergo a concomitant second cycliza-
tion to generate the tricyclic pyrrolo[2,1-a]isoquinoline core of
crispine A in one step. Decarboxylation by a convenient two-step
protocol provides the enantiopure natural product in three steps
from the amino acid. The opposite antipode may also be similarly
prepared from the minor 1,3-trans adduct formed during the bis-
cyclization. We have since this time applied our strategy to the
asymmetric preparation of other natural product alkaloids, which
willbe reportedindue course. Wehave also initiated investigations
into computational analyses of transition state models, which we
also hope to advance as warranted.
1
determined as trans based on a H NOE NMR experiments (500 MHz,
CDCl3): irradiation of the H5 proton (4.25 ppm) resulted in no enhance-
ment of the H10b proton signal (3.76 ppm) but did result in 3%
enhancement for H6R (2.97 ppm) and 2% for H7 (6.57 ppm); irradiation
of the H10b proton (3.76 ppm) resulted in no enhancement of the H5
proton signal (4.25 ppm), but did result in 3% enhancement for H1β(1.73-
1.66 ppm) and 1% for H2β (1.96-1.84 ppm).
Preparation of (5S,10bS)-Methyl 8,9-Dimethoxy-1,2,3,5,
6,10b-hexahydropyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,
10bS)-7a] and (5S,10bR)-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bR)
-8a] by Pictet-Spengler Bis-cyclization Reaction with 2-(3-
Chloropropyl)-1,3-dioxolane (4). Using the procedure described for
the preparation of (5S,10bS)-7a and (5S,10bR)-8a from (S)-(þ)-2a, but
instead utilizing 2-(3-chloropropyl)-1,3-dioxolane (4, 1.8 mL, 12.0 mmol),
flash column chromatography on silica gel afforded the mixture of isomers
(5S,10bS)-7a and (5S,10bR)-8a (2.10 g, 75%) as an off-white solid. The
mixture was determined to be a 4.5:1 mixture of isomers by 1H NMR and
HPLC analyses, but was not further purified to isolate the diastereomers.
(5S,10bS)-Benzyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bS)-7b] and
(5S,10bR)-Benzyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bR)-8b] from
(S)-Benzyl 2-Amino-3-(3,4-dimethoxyphenyl)propanoate [(S)-
2b]. Using the procedure described for the preparation of (5S,10bS)-7a
and (5S,10bR)-8a from (S)-(þ)-2a, but instead utilizing the free base
derived from (S)-benzyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate
’ EXPERIMENTAL SECTION
General Experimental. Allnonaqueousreactionswereperformed
under an atmosphere of dry nitrogen unless otherwise specified. Com-
mercial grade reagents and anhydrous solvents were used as received
from vendors, and no attempts were made to purify or dry these
components further. Removal of solvents under reduced pressure was
accomplished with a rotary evaporator using a Teflon-lined KNF vacuum
pump. Flash columnchromatographywasperformed using an automated
medium-pressure chromatography system using normal-phase disposa-
ble prepacked silica gel columns. Melting points are uncorrected. Data for
proton NMR spectra were obtained 300 or 500 MHz and are reported in
ppm δ values, using tetramethylsilane as an internal reference. Low-
resolution mass spectroscopic analyses were performed on a single
quadrupole mass spectrometer utilizing electrospray ionization (ESI).
High-resolution mass spectroscopic analyses were performed on a time-
of-flight mass spectrometer utilizing electrospray ionization (ESI).
(5S,10bS)-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexahydr-
opyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bS)-7a] and
(5S,10bR)-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyr-
rolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bR)-8a] from
(S)-(þ)-Methyl 2-Amino-3-(3,4-dimethoxyphenyl)propanoate
[(S)-(þ)-2a]. 4-Chloro-1,1-dimethoxybutane (3, 0.90 mL, 6.0 mmol)
was added to a stirring suspension of commercially available (S)-(þ)-methyl
2-amino-3-(3,4-dimethoxyphenyl)propanoate [(S)-(þ)-2a, 1.3 g, 5 mmol]
and 4 Å molecular sieves (1 g) in a mixture of anhydrous methylene chloride
(20 mL) and trifluoroacetic acid (5 mL) at room temperature under
nitrogen. The mixture was stirred for 4 h, at which time the conversion to
the intermediate (1RS,3S)-methyl 1-(3-chloropropyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate [(1RS,3S)-6ab] was judged to
be complete (>99% conversion of the intermediate by LC-MS analysis).
The solids were removed by filtration, and the solvents were removed from
the organic filtrate under reduced pressure. The residue was purified by flash
column chromatography on silica gel, eluting with THF/methylene chloride
(1:4), to first afford the less polar isomer (5S,10bS)-7a (1.1 g, 80%) as a light
orange solid: [R]20D -0.12° (c 1.0, CHCl3); mp 91-94 °C; 1H NMR (500
MHz, CDCl3) δ 6.58 (s, 1H), 6.57 (s, 1H), 3.85 (s, 6H), 3.80 (s, 3H), 3.70
(t, J = 7.3 Hz, 1H), 3.59 (dd, J = 5.2, 6.8 Hz, 1H), 3.17 (dd, J = 11.5, 3.5 Hz,
1H), 3.08 (dd, J = 8.5, 6.0 Hz, 1H), 2.90 (dd, J = 4.5, 11.5 Hz, 1H), 2.49 (dd,
J = 8.0, 4.0 Hz, 1H), 2.41-2.32 (m, 1H), 1.92-1.80 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 172.9, 147.6, 147.6, 130.2, 124.7, 111.0, 108.5, 63.1,
61.6, 56.0, 55.9, 52.1, 48.8, 30.0, 29.3, 22.0; ESI MS m/z 292.1 [M þ H]þ;
HRMS (ESI) m/z 292.1555 [M þ H]þ (292.1549 calculated for C16H21
NO4 þ H). The relative 1,3-stereochemistry was determined as cis based on
an 1H NOE NMR experiment (500 MHz, CDCl3): irradiation of the H5
proton (3.59 ppm) resulted in a 4% enhancement of the H10b proton signal
p-toluenesulfonate [(S)-2b pTsOH,18 0.40 g, 1.2 mmol), flash column
3
chromatography on silica gel first afforded the less polar isomer
1
(5S,10bS)-7b (0.27 g, 60%) as a brown gum: H NMR (CDCl3, 500
MHz) δ 7.40-7.32 (m, 5H), 6.57 (s, 1H), 6.56 (s, 1H), 5.23 (s, 2H),
3.84 (s, 3H), 3.82 (s, 3H), 3.69-3.59 (m, 2H), 3.21-3.07 (m, 2H), 2.91
(dd, J = 4.6, 16.3 Hz, 1H), 2.50-2.44 (m, 1H), 2.37-2.35 (m, 1H),
1.89-1.81 (m, 3H); ESI MS m/z 368.1 [M þ H]þ. Further elution
afforded the more polar isomer (5S,10bR)-8b (0.13 g, 31%) as an orange
gum: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.27 (m, 3H), 7.22-7.18
(m, 2H), 6.56 (s, 1H), 6.54 (s, 1H), 5.13 (s, 2H), 4.28 (t, J = 7.9 Hz, 1H),
3.84 (s, 3H), 3.83 (s, 4H) 3.20-3.16 (m, 1H), 3.16-2.93 (m, 2H), 2.83
(q, J = 7.1 Hz, 1H), 2.40-2.35 (m, 1H), 1.91-1.86 (m, 2H), 1.97-1.60
(m, 1H); ESI MS m/z 368.1 [M þ H]þ.
(5S,10bR)-Se-Methyl
8,9-Dimethoxy-1,2,3,5,6,10b-hexa-
hydropyrrolo[2,1-a]isoquinoline-5-carboselenoate [(5S,10bR)
-11]. A solution of dimethylaluminum methaneselenolate (0.60 mL,
1.2 mmol, ca. 2 M in toluene) was added dropwise to a degassed stirring
solution of (5S,10bR)-methyl 8,9-dimethoxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bR)-8a, 290 mg, 1.0
mmol] in anhydrous methylene chloride (5 mL) at 0 °C under nitrogen.
The mixture was stirred at 0 °C for 30 min and then warmed to room
temperature, stirring for a total of 1 h. The mixture was treated with wet
sodium sulfate and extracted with diethyl ether (2 ꢀ 25 mL). The
combined organic extracts were dried with anhydrous magnesium
sulfate and filtered, and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography on
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The Journal of Organic Chemistry
ARTICLE
silica gel, eluting with hexanes/ethyl acetate (9:1), to provide (5S,10bR)-
enantiomeric purity was determined by HPLC (Chiralcel, OJ, hep-
tane/ethanol = 95:5, 1.0 mL/min, 240 nm, tR (major) = 9.6 min, tR
(minor) = 10.8 min): 96.6% ee.
Se-methyl
8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinoline-5-carboselenoate [(5S,10bR)-11, 270 mg, 76%] as a light
orange solid (this material was stored in the dark and used immediately
(5R,10bR)-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5R,10bR)-7a] from
(R)-(-)-Methyl 2-Amino-3-(3,4-dimethoxyphenyl)propanoate
[(R)-(-)-2a]. Using the procedure described for the preparation of
(5S,10bS)-7a from (S)-(þ)-2a, but instead utilizing commercially available
(R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate [(R)-(-)-
2a, 0.24 g, 1.0 mmol], flash column chromatography on silica gel afforded
the less polar isomer (5R,10bR)-7a (0.23 g, 82%) as a viscous orange oil.
The spectral data were matched with the data from the corresponding
antipode (5S,10bS)-7a.
1
in the next step): [R]20 þ0.06° (c 1.0, CHCl3); mp 95-97 °C; H
D
NMR (500 MHz, CDCl3) δ 6.63 (s, 1H), 6.58 (s, 1H), 4.40 (t, J = 7.5
Hz, 1H), 3.84 (s, 6H), 3.34 (t, J = 6.5 Hz, 1H), 3.32 (t, J = 2.5 Hz, 1H),
2.92 (d, J = 5.5 Hz, 2H), 2.78-2.75 (m, 1H), 2.40-2.38 (m, 1H), 2.06
(s, 3H), 1.98-1.84 (m, 2H), 1.79-1.76 (m, 1H); 13C NMR (125, MHz
CDCl3) δ 209.9. 147.8, 147.7, 131.2, 124.6, 111.1, 109.0, 69.6, 57.5,
56.0, 55.9, 54.2, 33.9, 29.7, 25.3, 3.8; ESI MS m/z 356.0 [M þ H]þ;
HRMS (ESI) m/z 356.0765 [M þ H]þ (356.0765 calculated for
C16H21NO3Se þ H).
(R)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline [(þ)-Crispine A, (R)-1]1,5 from Selenyl Ester
(5S,10bR)-11. Tri-n-butyltin hydride (300 mg 1.0 mmol) was added
to a stirring mixture of (5S,10bR)-Se-methyl 8,9-dimethoxy-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-5-carboselenoate [(5S,10bR)-11,
180 mg, 0.50 mmol) and AIBN (14 mg, 0.080 mmol) in anhydrous
benzene (85 mL) at room temperature under nitrogen, after which the
mixture was heated to reflux and stirred for 3 h. The cooled mixture was
treated with saturated aqueous sodium fluoride (15 mL), and the biphasic
mixture was stirred at room temperature for 15 min. The mixture was
extracted with methylene chloride(3ꢀ 20 mL), andthe combined organic
extracts were dried with magnesium sulfate and filtered, and the solvents
were removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel, eluting with methylene chloride/
methanol (49:1), to provide (þ)-crispine A [(R)-1, 64 mg, 55%] as a
colorless solid: [R]20D þ90° (c 1.0, CHCl3) {lit. [R]23D þ100.4° (c 1.0,
CHCl3),5a [R]25D þ96.9° (c 1.1, CHCl3)5b}; mp 86-88 °C(lit. mp1 87-
89 °C); 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 1H), 6.57 (s, 1H), 3.84
(s, 6H), 3.41 (t, J = 9.7 Hz, 1H), 3.18 (dd, J = 2.8, 4.6 Hz, 1H), 3.09-2.86
(m, 2H), 2.73 (dt, J = 16.8, 3.8 Hz, 1H), 2.66-2.60 (m, 1H), 2.55 (dd,
J = 11.0, 9.5 Hz, 1H), 2.36-2.28 (m, 1H), 1.98-1.88 (m, 1H), 1.88-1.82
(m, 1H), 1.77-1.67 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 147.4,
147.3, 130.8, 126.2, 111.4, 108.9, 62.9, 56.0, 55.9, 53.1, 48.3, 30.5, 28.0,
23.3; ESI MS m/z 234.1 [M þ H]þ; HRMS (ESI) m/z 234.1495 [M þ
H]þ (234.1494 calculatedfor C14H19NO2 þ H). The enantiomeric purity
wasdeterminedbyHPLC(Chiralcel, OJ, heptane/ethanol=95:5, 1.0 mL/
min, 240 nm, tR (minor) = 9.6 min, tR (major) = 10.6 min): 97.8% ee.
(5S,10bS)-Se-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexa-
hydropyrrolo[2,1-a]isoquinoline-5-carboselenoate
(5R,10bR)-Se-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-hexa-
hydropyrrolo[2,1-a]isoquinoline-5-carboselenoate
[(5R,10bR)-12]. Using the procedure described for compound
(5S,10bR)-12, but instead utilizing (5R,10bR)-7a (0.20 g, 0.60 mmol),
(5R,10bR)-12 (0.17 g, 71%) was isolated as a light orange solid, which
was stored in the dark and used immediately in the next step: [R]20
D
þ0.36° (c 1.0, CHCl3); mp 95-97 °C. The spectral data were matched
with the data from the corresponding antipode (5S,10bS)-12.
(R)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]
isoquinoline [(þ)-Crispine A, (R)-1]1,5 from Selenyl Ester
(5R,10bR)-12. Using the procedure described for compound (R)-1
from selenyl ester (5S,10bR)-11, but instead utilizing (5R,10bR)-12
(0.10 g, 0.30 mmol), (þ)-crispine A [(R)-1, 0.030 g, 55%] was isolated as
a colorless solid: [R]20D þ95° (c 1.0, CHCl3) {lit. [R]23D þ100.4° (c 1.0,
CHCl3),5a [R]25 þ96.9° (c 1.1, CHCl3)5b}; mp 86-88 °C (lit. mp
D
87-89 °C). The spectral data were matched with the data from the
corresponding compound (R)-1 prepared from the selenyl ester
(5S,10bR)-11. The enantiomeric purity was determined by HPLC
(Chiralcel, OJ, heptane/ethanol = 95:5, 1.0 mL/min, 240 nm, tR
(minor) = 9.6 min, tR (major) = 10.6 min): 97.8% ee.
(5S,10bS)-Methyl 8,9-Dihydroxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bS)-15] and
(5S,10bR)-Methyl 8,9-Dihydroxy-1,2,3,5,6,10b-hexahydropyr-
rolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bR)-16] from
(S)-(þ)-Methyl 2-Amino-3-(3,4-dihydroxyphenyl)propanoate
[(S)-(þ)-13]. 2-(3-Chloropropyl)-1,3-dioxolane (4, 0.90 mL, 6.0 mmol)
was added to a stirring suspension of commercially available (S)-(þ)-methyl
2-amino-3-(3,4-dihydroxyphenyl)propanoate [(S)-(þ)-13, 1.2 g, 5.0
mmol] and 4 Å molecular sieves (1 g) in a mixture of anhydrous methylene
chloride (20 mL) and trifluoroacetic acid (5 mL) at room temperature under
nitrogen. The mixture was stirred at room temperature for 4 h, at which time
the conversion to the intermediate (1RS,3S)-methyl1-(3-chloropropyl)-6,7-
dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate [(1RS,3S)-14ab]
was judged to be complete (>99% by LC-MS analysis). The solids were
removed by filtration, and the solvents were removed from the organic
filtrate under reduced pressure. The residue was dissolved in anhydrous
acetonitrile (50 mL), triethylamine (0.45 mL, 16 mmol) was added, and the
mixture was stirred at room temperature under nitrogen for 1 h. The solvent
was removed under reduced pressure to provide a crude residue that was
judged to be a mixture of tricyclic compounds (5S,10bS)-15 and (5S,10bR)-
16 in a 4.5:1 ratio (HPLC and 1H NMR analyses). The residue was purified
by flash column chromatography on silica gel, eluting with THF/methylene
chloride (1:4), to first afford the less polar isomer (5S,10bS)-methyl 8,9-
dihydroxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-5-carboxylate
[(5S,10bS)-15, 0.91 g, 76%] as a light yellow solid: [R]20D -0.36° (c 1.3,
CH3OH); mp 95-99 °C; 1H NMR (CD3OD, 500 MHz) δ 6.51 (s, 1H),
6.50 (s, 1H), 3.75 (s, 3H), 3.43-3.37 (m, 2H), 3.19-3.15 (m, 1H), 3.00
(dd, J = 4.9, 13.1 Hz, 1H), 2.88 (dd, J = 5.0, 13.0 Hz, 1H), 2.37-2.27 (m,
2H), 1.89-1.82 (m, 2H), 1.76-1.74 (m, 1H); 13C NMR (125 MHz,
CD3OD) δ 174.1, 145.3, 145.0, 129.8, 124.7, 115.6, 113.1 65.0, 63.8,
52.5, 50.8, 31.6, 30.1, 22.5; ESI MS m/z 264.1 [M þ H]þ; HRMS (ESI)
[(5S,10bS)-12]. Using the procedure described for compound
(5S,10bR)-8a, but instead utilizing (5S,10bS)-7a, (5S,10bS)-12 (250
mg, 71%) was isolated as a light orange solid (this material was stored in
the dark and used immediately in the next step): [R]20D -0.36° (c 1.0,
CHCl3); mp 95-98 °C; 1H NMR (500 MHz, CDCl3) δ 6.63 (s, 1H),
6.61 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79-3.78 (m, 1H), 3.66 (t, J = 7
Hz, 1H), 3.13-3.11 (m, 1H), 3.04-2.92 (m, 2H), 2.68-2.63 (m, 1H),
2.36-2.32 (m, 1H), 2.07 (s, 3H), 1.99-1.86 (m, 3H); 13C NMR (125,
MHz CDCl3) δ 210.6, 147.8, 147.4, 131.3, 125.0, 111.1, 109.0, 69.6, 59.5,
57.4, 56.5, 55.3, 33.9, 28.2, 22.4, 3.8; ESI MS m/z 356.0 [M þ H]þ;
HRMS (ESI) m/z 356.0765 [M þ H]þ (356.0765 calculated for
C16H21NO3Se þ H).
(S)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline [(-)-Crispine A, (S)-1]1,5,6 from Selenyl Ester
(5S,10bS)-12. Using the procedure described for compound (R)-1,
but instead utilizing (5S,10bS)-12, (-)-crispine A [(S)-1, 65 mg, 56%)
was isolated as a colorless solid: [R]20 -95° (c 1.3, CHCl3) {lit. for
D
antipode [R]23 þ100.4° (c 1.0, CHCl3),5a [R]25 þ96.9° (c 1.1,
D
D
CHCl3)5b}; mp 86-88 °C (lit. mp for antipode1 87-89 °C). The
spectral data were matched with the data from the corresponding
antipode (R)-1. The compound was shown to be a single enantiomer
by chiral HPLC analysis (see Supporting Information). The
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The Journal of Organic Chemistry
ARTICLE
m/z 264.1233 [M þ H]þ (264.1236 calculated for C14H17NO4 þ H).
Further elution afforded the more polar isomer (5S,10bR)-methyl 8,9-
dihydroxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-5-carbox-
ylate [(5S,10bR)-16, 0.22 g, 12%] as an amorphous colorless solid:
[R]20D þ0.14° (c 1.0, CH3OH); 1H NMR (CD3OD, 500 MHz) δ 6.52
(s, 1H), 6.51 (s, 1H), 4.10 (t, J = 8.5 Hz, 1H), 3.67 (s, 3H), 3.36 (dd, J =
7.0, 2.0 Hz, 1H), 3.10-3.06 (m, 1H), 2.94-2.89 (m, 1H), 2.85-2.76
(m, 2H), 2.34-2.27 (m, 1H), 1.88-1.82 (m, 2H), 1.67-1.59 (m, 1H);
13C NMR (125 MHz, CD3OD) δ 174.6, 145.3, 145.0, 130.2, 124.1,
115.5, 113.9, 60.2, 60.1, 53.5, 52.4, 35.9, 30.8, 24.0; ESI MS m/z 264.1
[M þ H]þ.
Ojima, I. Org. Lett. 2009, 11, 2659. (i) Adams, H.; Elsunaki, T. M.; Ojea-
Jimꢀenez, I.; Jones, S.; Meijer, A. J. H. M. J. Org. Chem. 2010, 75, 6252. (j)
Yioti, E. G.; Mati, I. K.; Arvanitidis, A. G.; Massen, Z. S.; Alexandraki,
E. S.; Gallos, J. K. Synthesis 2011, 142.
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(5S,10bS)-Methyl
8,9-Dimethoxy-1,2,3,5,6,10b-hexa-
hydropyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bS)-
7a] and (5S,10bR)-Methyl 8,9-Dimethoxy-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline-5-carboxylate
[(5S,10bR)-8a]. Iodomethane (0.12 mL, 11 mmol) and potassium
carbonate (0.41 g, 3.0 mmol) were added to a solution of crude isomers
(5S,10bS)-15 and (5S,10bR)-16 (0.26 g, 1.0 mmol, 4.5:1 ratio) in anhydrous
acetonitrile (10 mL) at room temperature under nitrogen. The mixture was
stirred for 14 h, after which the solvents were removed under reduced
pressure, and the residue was purified by flash column chromatography on
silica gel, eluting with THF/methylene chloride (1:4), to first afford the less
polar isomer (5S,10bS)-methyl 8,9-dimethoxy-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline-5-carboxylate [(5S,10bS)-7a, 0.22 g, 75%] as
a light orange solid. Further elution afforded the more polar isomer
(5S,10bR)-methyl 8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinoline-5-carboxylate [(5S,10bR)-8a, 0.050 g, 16%] as a colorless solid.
The spectral data for both compounds matched with the data from the
corresponding compounds as prepared from the dimethoxyphenyl pre-
cursor (S)-(þ)-2a.
(10) For the most recent reviews, see: (a) Cox, E. D.; Cook, J. M.
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A.; Szawkato, J. Curr. Org. Chem. 2005, 2, 301. (d) Youn, S. W. Org. Prep.
Proced. Intl. 2006, 38, 505.
(11) For the most recent reviews, see: (a) Scott, J. D.; Williams,
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M. D. Chem. Rev. 2004, 104, 3341. (c) Edwankar, C. R.; Edwankar, R. V.;
Namjoshi, O. A.; Rallapalli, S. K.; Yang, J.; Cook, J. M. Curr. Opin. Drug
Disc. Devel. 2009, 12, 752. (d) Nielsen, T. E.; Meldal, M. Curr. Opin. Drug
Discovert Dev. 2009, 12, 798.
’ ASSOCIATED CONTENT
S
Supporting Information. Proton and carbon NMR spec-
b
tra for all compounds prepared. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rjason.herr@amriglobal.com.
(12) This is the general case in which the intermediate iminium salt
is linear (i.e., not cyclic), allowing the adoption of the (E)-configuration
in the chairlike transition state. For examples, see: (a) Yamada, S.;
Konda, M.; Shioiri, T. Tetrahedron Lett. 1972, 22, 2215. (b) Massiot, G.;
Mulamba, T. J. Chem. Soc., Chem. Commun. 1983, 1147. (c) Domínguez,
E.; Lete, E.; Badía, D.; Villa, M. J.; Castedo, L.; Domínguez, D.
Tetrahedron 1987, 43, 1943. (d) Van der Eycken, J.; Bosmans, J.-P.;
Van Haver, D.; Vandewalle, M.; Hulkenberg, A.; Veerman, W.; Nieu-
wenhuizen, R. Tetrahedron Lett. 1989, 30, 3873. (e) Bailey, P. D.;
Hollinshead, S. P.; McLay, N. R.; Morgan, K.; Palmer, S. J.; Prince,
S. N.; Reynolds, C. D.; Wood, S. D. J. Chem. Soc., Perkin Trans. 1
1993, 431. (f) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.;
Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877. (g) Carrillo,
L.; Badía, D.; Domínguez, E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vicario,
J. L. J. Org. Chem. 1999, 64, 1115. (h) Katritzky, A. R.; Mehta, S.; He, H.-
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’ ACKNOWLEDGMENT
The authors wish to thank AMRI colleagues Larry Yet for
many helpful chemistry discussions, Hꢀelꢁene Y. Decornez and
Douglas B. Kitchen for computational consultation, and Kent
Kaltenborn for high resolution mass spectrometry data.
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