Asymmetric synthesis of crispine A: Constructing tetrahydroisoquinoline scaffolds using pummerer cyclizations

Article abstract of DOI:10.1002/ejoc.201300748

For the first time, a concise, linear and stereoselective synthesis of both enantiomers of the natural product crispine A has been achieved in six steps with an overall yield of ≥ 20 %, starting from commercially available veratraldehyde. Asymmetric Keck allylation and trifluoroacetic anhydride-mediated Pummerer cyclization were the key transformations used to construct the tetrahydroisoquinoline core structure. Copyright

Full text of DOI:10.1002/ejoc.201300748

Job/Unit: O30748
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DOI: 10.1002/ejoc.201300748
Asymmetric Synthesis of Crispine A: Constructing Tetrahydroisoquinoline
Scaffolds Using Pummerer Cyclizations
Sateesh Chandra Kumar Rotte,[a] Amar G. Chittiboyina,*[a] and Ikhlas A. Khan[a,b]
Keywords: Asymmetric synthesis / Natural products / Alkaloids / Allylation / Cyclization
For the first time, a concise, linear and stereoselective syn-
thesis of both enantiomers of the natural product crispine A
has been achieved in six steps with an overall yield of Ն
20%, starting from commercially available veratraldehyde.
Asymmetric Keck allylation and trifluoroacetic anhydride-
mediated Pummerer cyclization were the key transforma-
tions used to construct the tetrahydroisoquinoline core struc-
ture.
some C. crispus extracts have been reported to show signifi-
Introduction
cant cytotoxic properties against SKOV3, HeLa and KB
Tetrahydroisoquinoline alkaloids with chirality at the C-1 human cancer cell lines.[2]
position are widely distributed in nature and significant be-
Bischler–Napieralski, Pictet–Spengler reactions and in-
cause of their unique biogenetic origin. Tetrahydroisoquin- troduction of nucleophilic or electrophilic carbon units into
oline alkaloids, including their unnatural isomers are the C-1 position of an isoquinoline scaffold are the most
known to possess diverse biological activities as well as often explored strategies by which to construct tetrahydro-
interesting chemical and pharmacological properties.[1] Cri- isoquinoline systems.[1c] Pummerer type cyclization reac-
spine A (1) is a naturally occurring tetrahydroisoquinoline tions are also established ways to generate tetrahydroisoqui-
alkaloid isolated from Carduus crispus along with four new noline cores in Erythrina alkaloids, starting from their cor-
alkaloids (Figure 1) crispines B–E 2–5. Traditionally, C. responding deactivated amide[3] in which additional protec-
crispus has been used in Chinese folk medicine for the treat- tion and deprotection transformations are sometimes neces-
ment of colds, stomach-ache and rheumatism.[2] Moreover; sary. The use of basic amines in Pummerer type cyclizations
Figure 1. Isoquinoline alkaloids crispine A–E (1–5).
is rare. Development of new synthetic strategies to con-
[a] National Center for Natural Products Research, School of
struct tetrahydroisoquinoline systems by employing a short
synthetic sequence and a protecting group-free asymmetric
approach to establish stereochemistry C-1 would be of great
interest. In addition to the challenge of making these com-
pounds, their remarkable biological properties and struc-
tural diversity have attracted the attention of many syn-
thetic and medicinal chemists. As a consequence, numerous
Pharmacy, University of Mississippi,
University, MS-38677, USA
E-mail: amar@olemiss.edu
Homepage: http://www.pharmacy.olemiss.edu/ncnpr/
[b] Department of Pharmacognosy, School of Pharmacy,
University of Mississippi,
University, MS-38677, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300748.
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Scheme 1. Retrosynthesis of (+)-crispine A.
reports of the isoquinoline alkaloids in racemic as well as prior reports in the literature.[15b] To test the synthetic feasi-
optically active forms can be found in the literature.[4–13] bility of obvious synthetic approaches, racemic homoallyl
The majority of these citations detail extensive protection/ alcohols 10 and 11 were synthesized by treating aldehydes
deprotection schemes. Although there are many reports 7 and 8 with allylmagnesium bromide. A complex generated
available; there remains the need for a concise and flexible from diphenylphosphoryl azide and DBU was treated with
synthetic approach that enables facile study of structure ac- homoallyl alcohols [(–)-9, (Ϯ)-10 and (Ϯ)-11] to afford
tivity relationships of isoquinoline scaffolds. In this regard, homoallyl azides [(+)-12, (Ϯ)-13 and (Ϯ)-14] with complete
we have developed concise, asymmetric syntheses of both inversion of stereochemistry as anticipated.[16] Successful
antipodes of crispine A with improved overall yield.
participation of (+)-12 and (Ϯ)-13 in hydroboration–cyclo-
alkylation[17] led to corresponding pyrrolidines (+)-15 and
(Ϯ)-16, whereas reaction of compound (Ϯ)-14 resulted in a
complex mixture of products. Pyrrolidines (+)-15 and (Ϯ)-
Results and Discussion
Our approach to synthesis of crispine A is based on the 16 were protected with (Boc)2O to yield the corresponding
retrosynthesis shown in Scheme 1. We envisioned that con- Boc-protected pyrrolidines (+)-17 and (Ϯ)-18 in almost
struction of the piperidine ring in crispine A would result quantitative yields thus facilitating structure isolation and
from a Pummerer-type cyclization of a chiral 2-arylpyrroli- characterization.
dine scaffold which could be synthesized using a one-pot
hydroboration followed by cyclization.
Next, we turned our attention to functionalization of Ar-
Br in (Ϯ)-16 and (Ϯ)-18 by employing Pd-catalysis for effec-
The asymmetric center was thought to be formed by a tive C–C bond formation. Stille coupling,[14b] using tetra-
Keck asymmetric allylation reaction. As shown in vinyl tin in the presence of Pd0 and a catalytic amount of
Scheme 2, commercially available veratraldehyde (6) was BHT in toluene, did not yield the required product. Chang-
converted to bromo derivative 7 and corresponding vinyl- ing the solvent, temperature, ligand and Pd-metal oxidation
ated aldehydes 8 using a known procedure.[14] Keck asym- state did not solve the problem.[18] However, some success
metric allylation of veratraldehyde (6) furnished the corre- was achieved in C–C bond formation by switching our fo-
sponding homoallyl alcohol (–)-9 in good yield.[15a] The op- cus to the use of Suzuki coupling conditions. The classical
tical rotation of compound (–)-9 was in agreement with Suzuki coupling partners (boronic acids) for vinylation and
Scheme 2. Synthesis of 2-aryl pyrrolidines 17 and 18; reagents and conditions: a) i) S-BINOL, Ti(OiPr)4, 4-Å molecular sieves powder,
allyltributyl tin, –20 °C, DCM, 72 h; ii) allylmagnesium bromide, THF, 0 °C-r.t., 1 h; b) DPPA, DBU, toluene, 0 °C-r.t., 3 h; c) dicyclohex-
ylborane, THF, 0 °C-r.t., 12 h, MeOH; d) (Boc)2O, Et3N, THF, 0 °C-r.t., 2 h.
2
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Exploiting Pummerer Chemistry
allylation were not satisfactory. Again, altering solvent, li- which is trapped by a nucleophile present in the reaction
gand and Pd source failed to yield any beneficial effects. medium. Michael addition of compound (+)-15 with phenyl
Alternatively, advanced Suzuki reaction with vinyl MIDA vinyl sulfoxide in the presence of triethylamine was success-
boronates[19] gave the required product albeit in poor (20– ful and furnished N-alkylated product (+)-19 in good yield.
23%) yields (Scheme 3).
Pummerer cyclization of compound (+)-19 was tested using
various Lewis acidic conditions[20d] and most of the condi-
tions yielded the expected cyclization product (+)-20 with
low to moderate yields (18–45%).[20] After screening vari-
ous Lewis acids for use in Pummerer cyclization, the combi-
nation of TFA and TFAA in DCM was found to afford a
better yield (55%). Moreover, excess TFAA in DCM at
room temperature was found to be ideal providing the tetra-
hydroisoquinoline core in very good yield (79%, de Ͼ
90%).[20c,20d]
Scheme 3. Pd-mediated coupling reactions; reagents and conditions:
a) vinyl MIDA, Pd(OAc)2, XPHOS, K3PO4, dioxane/H2O (5:1),
100 °C, 2 h. For the attempted failed reactions, refer to Table S1 in
the Supporting Information.
Finally, reductive radical elimination of the thiophenyl
group using Bu3SnH and cat. AIBN in toluene at refluxing
conditions yielded target compound R(+)-crispine A in ex-
cellent yield (Scheme 4).[21] The analytical and spectro-
scopic data of the obtained product was identical to those
of the natural product[2] with optical rotation [α]2D5 = +93 (c
= 1, CHCl3) [Reported[2] [α]2D5 = +91 (MeOH)].
To overcome the unforeseen difficulty in C–C bond for-
mation for the construction of the six-membered ring, a
Pummerer type cyclization was attempted. Pummerer type
Similarly, using the same set of reactions, the unnatural
transformations have widespread applications in heter- isomer (–)-crispine A was also synthesized (In Keck asym-
ocyclic syntheses, especially in the production of various metric allylation R-BINOL was employed) with very good
alkaloid skeletons.[20e,20f] The Pummerer cyclization reac- overall (19.7%) yield (Scheme 5). Both (+)-crispine A and
tion proceeds through an initially generated thionium ion its precursor (+)-20 were tested against NCI’s 60-cell line
Scheme 4. Synthesis of (+)-crispine A; reagents and conditions: e) phenyl vinyl sulfoxide, Et3N, THF, 0 °C-r.t., 4 h, 81%; f) TFAA (excess),
DCM, room temp., 3 h, 79%;g) Bu3SnH, cat. AIBN, toluene, reflux, 1 h, 80%.
Scheme 5. Synthesis of S-(–)-crispine A; reagents and conditions: h) R-BINOL, Ti(OiPr)4, 4-Å molecular sieves powder, allyltributyl tin,
–20 °C, DCM, 72 h, 71%; i) DPPA, DBU, toluene, 0 °C-r.t., 3 h, 77%; j) dicyclohexyl borane, THF, 0 °C-r.t., 12 h, MeOH, 78%; k) phen-
ylvinyl sulfoxide, Et3N, THF, 0 °C-r.t., 4 h, 77%; l) TFAA (excess), DCM, room temp., 3 h, 76%; m) Bu3SnH, cat. AIBN, toluene, reflux,
1 h, 79%.
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S. C. K. Rotte, A. G. Chittiboyina, I. A. Khan
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134.6, 118.1, 110.9, 109.0, 73.2, 55.97, 43.8 ppm. HRMS (ESI+)
Calcd. for C12H16NaO3 231.0997, found 231.0997.
panel. Neither compound showed any promising cytotoxi-
city in any cell line in the preliminary screening at single
dose.[22]
(+)-(R)-1-(3,4-Dimethoxyphenyl)but-3-en-1-ol (9): Using the same
procedure, (R)-BINOL as chiral catalyst, compound (+)-9 was syn-
thesized. Yield obtained was 71%. Spectroscopic data and optical
rotation are in full agreement with reported literature.[23] [α]2D5
+33 (c = 1, CHCl3).
=
Conclusions
In summary, we have demonstrated a concise (6 steps),
asymmetric total synthesis of both enantiomers of crispine
A by employing Keck asymmetric allylation and Pummerer
cyclization as crucial steps. TFAA-mediated Pummerer cy-
clization led to the tetrahydroisoquinoline core in high yield
and paves way for the synthesis of various structurally sim-
ilar pyrroloisoquinoline alkaloids in an efficient manner, to
investigate their intriguing biological properties.
(؎)-1-(4,5-Dimethoxy-2-vinylphenyl)but-3-en-1-ol (11): In a 100 mL
two neck round-bottomed flask, the vinyl aldehyde 8 (5.8 g,
30 mmol) was dissolved in THF (30 mL) and cooled to 0 °C under
N2 atmosphere. To this cold solution, allylmagnesium bromide
solution (36 mL, 1.0 m in Et2O) was added dropwise and stirring
continued. After 1 h, saturated NH4Cl solution was added and the
mixture was extracted with diethyl ether (3ϫ35 mL). The com-
bined organic layers were dried with anhydrous MgSO4, concen-
trated and purified by column chromatography using 10% EtOAc
1
in hexanes to yield 11 (5.83 g, 83%) as a viscous liquid. H NMR
(400 MHz, CDCl3): δ = 7.06 (s, 1 H), 7.04–6.91 (m, 2 H), 5.96–
5.79 (m, 1 H), 5.56 (dd, J = 17.2, 1.3 Hz, 1 H), 5.31–5.13 (m, 3 H),
5.06 (dtd, J = 10.8, 6.3, 5.4, 3.0 Hz, 1 H), 3.92 (s, 6 H), 2.57–2.29
(m, 2 H), 2.07 (d, J = 2.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.0, 148.1, 134.6, 133.7, 133.3, 127.7, 118.3, 114.6,
108.7, 108.3, 69.2, 55.9, 55.9, 43.2 ppm. HRMS (ESI+) Calcd. for
C14H17O2 [M + H – H2O] 217.1229, found 217.1226.
Experimental Section
General Methods: 1H and 13C NMR spectra were measured in
CDCl3 with a 400 MHz (100 MHz) instrument. Chemical shifts
were reported in ppm downfield from tetramethylsilane (δ) as the
internal standard and coupling constants are reported in Hertz
(Hz). Assignment of proton resonances was confirmed by corre-
lation spectroscopy. IR spectra were recorded using a universal at-
tenuated total reflection sampling accessory with a diamond ATR
(attenuated total reflectance) on bench top Cary 630 FT-IR spec-
trometer. The high-resolution mass spectra (HRMS) were recorded
on a Q-Tof Micro mass spectrometer with lock spray source. Op-
tical rotations were measured using an Autopol V automatic polari-
meter in a 1 dm or a 5 dm cell. The reaction progress was moni-
tored on precoated silica gel TLC plates. Spots were visualized un-
der 254 nm UV light and/or by dipping the TLC plate into a solu-
tion of 2 mL anisaldehyde, 10 mL of glacial acetic acid and 5 mL
of H2SO4 in 340 mL MeOH followed by heating with a heat gun.
Column chromatography was performed with silica gel (230–
400 mesh). All solvents (hexanes, EtOAc, CH2Cl2, Et2O) were dis-
tilled prior to use. All reactions were performed under an atmo-
sphere of argon using oven-dried glassware and standard syringe/
septa techniques. The solvent THF was distilled from sodium-
benzophenone, and CH2Cl2 was dried with P2O5. Triethylamine
was distilled from CaH2.
(+)-(R)-4-(1-Azidobut-3-en-1-yl)-1,2-dimethoxybenzene (12): In a
50 mL round-bottomed flask, a mixture of alcohol (–)-9 (0.75 g,
3.6 mmol) and diphenylphosphoryl azide (3 g, 10.81 mmol) was
dissolved in dry toluene (10 mL). The mixture was cooled to 0 °C
under N2, and neat DBU (1.65 g, 10.81 mmol) was added. The re-
action was stirred for 2 h at 0 °C and then at 20 °C for 1 h. The
resulting two-phase mixture was diluted with diethyl ether and
washed with H2O (2 X 10 mL) followed by 5% HCl (5 mL). The
organic layer was concentrated in vacuo and purified by silica gel
chromatography using 95:5 hexane/EtOAc to afford (+)-12 (0.62 g,
74%) as a colorless oil. [α]2D5 = +91 (c = 1, CHCl ); IR: ν = 2934,
˜
3
2835, 2091, 1592, 1513, 1463, 1259 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 6.87–6.81 (m, 3 H), 5.73 (ddt, J = 17.1, 10.2, 6.9 Hz,
1 H), 5.11 (m, 2 H), 4.43 (t, J = 7.2 Hz, 1 H), 3.90 (s, 3 H), 3.88
(s, 3 H), 2.68–2.41 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 149.3, 149.1, 134.0, 119.5, 118.2, 111.1, 109. 9, 65.8, 56.0,
40.7 ppm. HRMS (ESI+) Calcd. for C12H15O2 [M + H – HN3]
191.1072, found 191.1075.
(–)-(S)-4-(1-Azidobut-3-en-1-yl)-1,2-dimethoxybenzene (12): Using
the same procedure, compound (–)-12 was synthesized in 77% yield
starting from (+)-9. [α]2D5 = –86 (c = 1, CHCl3).
(–)-(S)-1-(3,4-Dimethoxyphenyl)but-3-en-1-ol (9): In
a 2 neck
100 mL round-bottomed flask, a mixture of (S)-BINOL (0.5 mmol,
0.143 g), 1.0 m Ti(OiPr)4 in DCM (0.5 mmol, 0.1 equiv.) and freshly
activated 4-Å molecular sieves powder (2 g) in DCM (10 mL) was
refluxed for 1 h. The red brown mixture was cooled to room tem-
perature and veratraldehyde 6 (5 mmol, 0.83 g) was added. After
being stirred for 10 min, the contents were cooled to –78 °C and
allyltributyl tin (5.5 mmol, 1.76 mL) was added. The reaction mix-
ture was stirred for 10 min and then placed in a –20 °C freezer.
After 70 h, saturated NaHCO3 1.5 mL was then added and con-
tents were stirred for 1 h, dried with anhydrous Na2SO4 and con-
centrated. The residue was purified by flash column chromatog-
raphy on silica gel using hexane/EtOAc (8.5:1.5) as eluent to give
(–)-9 (0.78 g, 75%) as a white crystalline solid. [α]2D5 = –36 (c = 1,
(+)-(R)-2-(3,4-Dimethoxyphenyl)pyrrolidine (15): To a stirred solu-
tion of freshly distilled cyclohexene (1.56 mL, 15.45 mmol) in
10 mL of THF at 0 °C was added dropwise 2.0 m BH3–Me2S com-
plex in THF (3.85 mL, 7.72 mmol). The resulting white suspension
of dicyclohexylborane was stirred for 1 h at 0 °C and then cooled
to –15 °C prior to the addition of azide (+)-12 (0.6 g, 2.57 mmol)
in 5 mL of THF. The resulting mixture was warmed to room tem-
perature. After 12 h, the reaction was quenched with MeOH and
diluted with diethyl ether, and the organic layer was extracted with
1 n aqueous HCl. The combined aqueous layers were basified with
30% aqueous NaOH solution until pH 13–14 and then extracted
with EtOAc. The combined extracts were dried with anhydrous
CHCl ); m.p. 95–97 °C; IR: ν = 3393, 2955, 2917, 2855, 1640,
˜
3
1455 cm–1. H NMR (400 MHz, CDCl3): δ = 6.90 (d, J = 1.9 Hz, Na2SO4, filtration and concentration furnished a pale yellow vis-
1
1 H), 6.85 (dd, J = 8.2, 1.9 Hz, 1 H), 6.81 (d, J = 8.2 Hz, 1 H),
5.78 (ddt, J = 17.2, 10.2, 7.1 Hz, 1 H), 5.18–5.07 (m, 2 H), 4.65 (t,
J = 6.5 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 2.48 (t, J = 6.4 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149, 148.4, 136.6,
cous liquid (+)-15 in (79%, 0.453 g), which was pure enough to
carry out next reaction. [α]2D5 = +49 (c = 1, CHCl ). IR: ν = 2935,
˜
3
2834, 1591, 1512, 1450, 1388, 1253, 1136, 1022, 806, 760 cm–1. H
1
NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 1.9 Hz, 1 H), 6.86–6.82
4
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Exploiting Pummerer Chemistry
(dd, J = 8.2, 1.9 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H), 4.01 (d, J = 8.1 Hz, 1 H), 3.89 (s, 3 H), 3.82 (s, 3 H), 3.25 (ddd, J = 19.6, 8.8,
8.1 Hz, 1 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 3.22 (br. s, 1 H), 3.19–
3.11 (m, 2 H), 3.00–2.89 (m, 1 H), 2.17–2.05 (m, 1 H), 1.95–1.74
6.4 Hz, 2 H), 3.10 (dt, J = 12.7, 8.2 Hz, 1 H), 2.85–2.77 (m, 2 H),
2.35 (ddd, J = 12.6, 6.3, 4.6 Hz, 1 H), 2.19 (q, J = 8.7 Hz, 1 H),
(m, 4 H), 1.70–1.58 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): 2.16–2.06 (m, 1 H), 1.96–1.84 (m, 1 H), 1.79 (dddd, J = 12.5, 9.5,
δ = 148.9, 147.9, 136.2, 118.6, 110.9, 109.9, 62.5, 55.8, 46.6, 34.0,
25.3 ppm. HRMS (ESI+) Calcd. for C12H18NO2 208.1338, found
208.1341.
6.6, 3.0 Hz, 1 H), 1.72–1.61 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.3, 148.1, 144.7, 130.8, 129.2, 123.8, 119.6, 110.9,
109.8, 69.9, 57.4, 55.9, 53.2, 47.2, 35.3, 22.2 ppm. HRMS (ESI+)
Calcd. for C20H26NO3S 360.1633, found 360.1630.
(–)-(S)-2-(3,4-Dimethoxyphenyl)pyrrolidines (15): Using the same
procedure, compound (–)-15 was synthesized in 78% starting from
(–)-12. [α]2D5 = –54 (c = 1, CHCl3).
(–)-(2S)-2-(3,4-Dimethoxyphenyl)-1-[2-(phenylsulfinyl)ethyl]pyrroli-
dine (19): Using the same procedure as above (for (+)-19), com-
pound (–)-19 was synthesized in 77% with [α]2D5 = –118 (c = 1,
CHCl3).
(؎)-2-(2-Bromo-4,5-dimethoxyphenyl)pyrrolidines (16): By follow-
ing the above procedure, (؎)-16 (0.88 g, 80%) was prepared from
1
(؎)-13 (1.2 g, 3.84 mmol). H NMR (400 MHz, CDCl3): δ = 7.17
(+)-(10bR)-8,9-Dimethoxy-6-(phenylthio)-1,2,3,5,6,10b-hexahydro-
(s, 1 H), 6.94 (s, 1 H), 4.40 (t, J = 7.8 Hz, 1 H), 4.03 (br. s, 1 H), pyrrolo[2,1-a]isoquinoline (20): To a stirred solution of compound
3.85 (s, 3 H), 3.82 (s, 3 H), 3.19 (ddd, J = 10.0, 7.5, 5.3 Hz, 1 H),
3.03 (ddd, J = 10.0, 8.2, 6.7 Hz, 1 H), 2.34–2.21 (m, 1 H), 1.96–1.72
(+)-19 (0.54 g, 1.5 mmol) in 5 mL of dry DCM at room tempera-
ture, excess TFAA (3 mL) was added in a dropwise manner and
(m, 2 H), 1.59–1.42 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ allowed to stir for 3 h at same temperature. Solvent was evaporated
= 148.4, 148.1, 135.0, 115.2, 112.7, 110.1, 60.9, 56.1, 56.0, 46.5,
in vacuo; the remaining residue was basified with sat. NaHCO3
32.9, 24.9 ppm. HRMS (ESI+) Calcd. for C12H17BrNO2 286.0443, solution and extracted with EtOAc (3ϫ25 mL). Combined organic
found 286.0444.
layers were dried with Na2SO4, concentrated in vacuo and purified
by silica gel column chromatography using 98:2 chloroform/meth-
anol to afford (+)-20 in (79%, 0. 4 g) yield. [α]2D5 = +52 (c = 1,
(+)-tert-Butyl (R)-2-(3,4-Dimethoxyphenyl)pyrrolidine-1-carboxyl-
ate (17): The crude product (+)-15 (0.06 g, 0.24 mmol) was dis-
solved in THF (2 mL) and cooled to 0 °C prior to the addition
of Boc2O (+)-12 (0.15 g, 0.48 mmol) in THF (3 mL). To this cold
solution, triethylamine (0.134 mL, 0.96 mmol) was added and stir-
ring continued. After completion of the reaction (monitored by
TLC), the whole mixture was concentrated and purified by column
chromatography using 30% EtOAc in hexanes to yield (+)-17
(0.07 g, 97%) as a viscous liquid. [α]2D5 = +79 (c = 1, CHCl3) (Mix-
CHCl ); IR: ν = 2923, 2851, 1511, 1462, 1252, 1213, 1137, 1023,
˜
3
744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.49–7.37 (m, 2 H),
7.34–7.20 (m, 3 H), 7.02 (s, 1 H), 6.53 (s, 1 H), 4.64–4.51 (m, 1 H),
4.10–4.03 (m, 1 H), 3.84 (s, 3 H), 3.79 (s, 4 H), 3.71–3.57 (m, 2 H),
3.38 (dd, J = 11.9, 5.6 Hz, 1 H), 3.06–2.93 (m, 1 H), 2.80 (tt, J =
17.7, 8.4 Hz, 2 H), 2.39–2.20 (m, 1 H), 1.95–1.80 (m, 3 H), 1.80–
1.67 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3, major isomer): δ
= 148.1, 147.4, 132.2, 131.4, 129, 128.9, 127.3, 125.4, 111.1, 108.3,
77.2, 62.3, 55.80, 55.7, 53.2, 45.3, 30.6, 22.0 ppm. 13C NMR
(100 MHz, CDCl3, minor isomer): δ = 148.4, 147.5, 134.4, 130.5,
128.9, 128.6, 127.1, 124.5, 111.6, 108.2, 76.6, 62.8, 55.8, 55.7, 53.1,
46, 30.3, 21.8 ppm. HRMS (ESI+) Calcd. for C20H24NO2S
342.1528, found 342.1526.
1
ture of rotamers). H NMR (400 MHz, CDCl3): δ = 6.78 (d, J =
8.1 Hz, 1 H), 6.72–6.65 (m, 2 H), 4.70–4.88 (m, 1 H), 3.84 (s, 6 H),
3.59 (t, J = 6.9 Hz, 2 H), 2.27 (dt, J = 13.5, 7.6 Hz, 1 H), 1.95–
1.75 (m, 3 H), 1.45 (s, 3 H), 1.19 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.6, 148.6, 147.4, 137.8, 117.5, 110.7,
108.6, 79.1, 61.0, 55.8, 47.0, 36.0, 28.4, 28.2, 23.1 ppm. HRMS
(ESI+) Calcd. for C17H25NNaO4 330.1681, found 330.1681.
(–)-(10bS)-8,9-Dimethoxy-6-(phenylthio)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinoline (20): Using the same procedure as above
(for (+)-20), compound (–)-20 was synthesized in 76% yield start-
ing from (–)-19. [α]2D5 = –60 (c = 1, CHCl3).
(؎)-tert-Butyl 2-(2-Bromo-4,5-dimethoxyphenyl)pyrrolidine-1-carb-
oxylate (18): By following the procedure for the preparation of (+)-
17, compound (؎)-18 (0.37 g, 0.94 mmol) was also prepared start-
ing from (؎)-16 (0.29 g, 1 mmol) and Boc2O (0.44 g, 2 mmol) in
95% yield. Viscous liquid, mixture of rotamers and major isomer
1H NMR (500 MHz, CDCl3): δ = 6.99 (s, 1 H), 6.63 (s, 1 H), 5.02
(dd, J = 8.3, 4.8 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.65 (t, J =
(+)-(R)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinoline [(+)-crispine] (1): To a solution of thioether (+)-20 (34 mg,
0.1 mmol) in toluene (2 mL) was added tri-n-butyltin hydride
(58 mg, 0.2 mmol) and a few crystals of 2, 2Ј-azobis(isobutyronitr-
8.6 Hz, 2 H), 2.42–2.32 (m, 1 H), 1.92–1.83 (m, 2 H), 1.81–1.71 (m, ile). The solution was degassed by means of two freeze-pump-thaw
1 H), 1.21 (s, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 154.4,
cycles, and then stirred at 100 °C for 30 min. After cooling, the
mixture was concentrated under reduced pressure and the residue
148.3, 148.0, 135.9, 115.2, 111.5, 108.8, 79.3, 60.8, 56.1, 56.0, 47.3,
34.2, 28.1, 23.1 ppm. HRMS (ESI+) Calcd. for C17H25BrNO4 was directly purified by chromatography on silica gel (chloroform/
386.0967, found 386.0970.
methanol/triethylamine, 98:1.5:0.5) to give 18 mg of crispine-A (+)-
1 (80%) as a colorless semi-solid which solidified on long standing.
(+)-(2R)-2-(3,4-Dimethoxyphenyl)-1-(2-phenylsulfinyl)ethylpyrroli-
dine (19): A mixture of compound (+)-15 (0.414 g, 2 mmol) and
triethylamine (0.404 g, 4 mmol) in THF at 0 °C was added drop-
wise phenyl vinyl sulfoxide (0.365 g, 2.4 mmol) in 2 mL of THF
and was warmed to room temperature. After 4 h reaction mixture
diluted with EtOAc (10 mL) and washed with H2O (2 X 5 mL)
followed by brine (2 X 5 mL), combined extracts were dried with
anhydrous Na2SO4. Removal of the solvent in vacuo left a pale
yellow liquid, which was purified by silica gel chromatography
using 98:2 chloroform/methanol to afford (+)-19 in (81%, 0. 58 g)
[α]2D5 = +93 (c = 1, CHCl ); IR: ν = 2933, 2794, 1610, 1510, 1463,
˜
3
1374, 1252, 1212, 1128, 1161, 1012, 856, 747 cm–1
.
1H NMR
(400 MHz, CDCl3): δ = 6.59 (s, 1 H), 6.55 (s, 1 H), 3.83 (d, J =
1.7 Hz, 6 H), 3.43 (t, J = 8.3 Hz, 1 H), 3.16 (ddd, J = 11.3, 6.2,
3.0 Hz, 1 H), 2.72 (dt, J = 16.2, 3.8 Hz, 1 H), 2.67–2.60 (m, 1 H),
2.56 (q, J = 8.6 Hz, 1 H), 2.37–2.24 (m, 1 H), 1.97–1.78 (m, 3 H),
1.77–1.64 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.3,
147.2, 130.8, 126.1, 111.2, 108.7, 62.9, 56.0, 55.9, 53.1, 48.3, 30.5,
28.0, 22.2 ppm. HRMS (ESI+) Calcd. for C14H20NO2 234.1494,
found 234.1493.
yield. [α]2D5 = +125 (c = 1, CHCl ); IR: ν = 3051, 2939, 2793, 1591,
˜
3
1513, 1462, 1442, 1418, 1260, 1229, 1135, 1024, 729 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.59–7.54 (m, 2 H), 7.45 (m, 3 H), 6.98 (d,
J = 1.9 Hz, 1 H), 6.83 (dd, J = 8.2, 1.9 Hz, 1 H), 6.77 (d, J =
(–)-(S)-8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinoline [(–)-crispine] (1): Using the same procedure as above (for
(+)-1) compound (–)-1 was synthesized in 79% yield. Spectroscopic
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30748
/KAP1
Date: 12-08-13 11:24:20
Pages: 7
S. C. K. Rotte, A. G. Chittiboyina, I. A. Khan
FULL PAPER
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Supporting Information (see footnote on the first page of this arti-
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NCI screening data are also available.
Acknowledgments
This study was supported in part by United States Department
of Agriculture, Agricultural Research Service, Specific Cooperative
Agreement, grant number 58-6408-2-0009. The authors thank the
Developmental Therapeutics Program (NCI) for 60-cell testing.
The authors are thankful to Prof. Jon Parcher for his valuable in-
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Received: May 21, 2013
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30748
/KAP1
Date: 12-08-13 11:24:20
Pages: 7
Exploiting Pummerer Chemistry
Alkaloid Synthesis
For the first time, a concise, linear and
stereoselective synthesis of both enantio-
mers of crispine A has been achieved in six
steps with an overall yield of Ն 20%, start-
ing from commercially available veratral-
dehyde.
S. C. K. Rotte, A. G. Chittiboyina,*
I. A. Khan ......................................... 1–7
Asymmetric Synthesis of Crispine A: Con-
structing Tetrahydroisoquinoline Scaffolds
Using Pummerer Cyclizations
Keywords: Asymmetric synthesis / Natural
products / Alkaloids / Allylation / Cycli-
zation
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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