Synthesis of (S)- and (R)-harmicine from proline: An approach toward tetrahydro-β-carbolines

Article abstract of DOI:10.1002/ejoc.201301903

(S)- and (R)-Harmicine were synthesized from L- and D-proline, respectively. This chiral pool synthesis constitutes a new approach towards C1 substituted tetrahydro-β-carbolines. The developed route makes use of the 9-phenyl-9-fluorenyl protecting group strategy of amino acids to prevent racemization of the vulnerable α-amino carbonyl stereocenter. Enantiopure harmicine (> 99%ee) was obtained in nine steps from commercially available starting material. The synthesis was performed without the use of any silica gel flash chromatography.

Full text of DOI:10.1002/ejoc.201301903

FULL PAPER
DOI: 10.1002/ejoc.201301903
Synthesis of (S)- and (R)-Harmicine from Proline: An Approach Toward
Tetrahydro-β-carbolines
Christopher S. Lood[a] and Ari M. P. Koskinen*[a]
Keywords: Asymmetric synthesis / Natural products / Chiral pool / Alkaloids / Amino acids
(S)- and (R)-Harmicine were synthesized from L- and D-pro- zation of the vulnerable α-amino carbonyl stereocenter.
line, respectively. This chiral pool synthesis constitutes a new
approach towards C1 substituted tetrahydro-β-carbolines.
The developed route makes use of the 9-phenyl-9-fluorenyl
protecting group strategy of amino acids to prevent racemi-
Enantiopure harmicine (Ͼ 99%ee) was obtained in nine
steps from commercially available starting material. The syn-
thesis was performed without the use of any silica gel flash
chromatography.
Introduction
Tetrahydro-β-carbolines (THβC), a subgroup of the in-
dole alkaloid family, consist of a large number of natural
products with wide structural diversity, and many of these
compounds have received a lot of attention within the syn-
thetic community for decades. The large attention can
partly be attributed to the interesting structural features as-
sociated with some of these compounds and partly to the
fact that, in many cases, they possess highly interesting me-
dicinal properties.[1] For example, compounds such as vin-
camine, ajmalicine, and yohimbine (not shown) have found
some use in modern medicine, and reserpine is still being
prescribed for the treatment of hypertension. Tadalafil, a
non-natural THβC used for the treatment of erectile dys-
function, is currently one of the top grossing drugs on the
market (Figure 1).
Figure 1. Examples of members of the tetrahydro-β-carboline
family.
The synthesis of chiral C1 substituted THβCs has tradi-
tionally relied on a few classical approaches. Diastereoselec-
tive versions of the Pictet–Spengler reaction (PSR),[2,3] in-
cluding substrate controlled reactions of tryptophan deriva-
tives,[4] substrate controlled reactions of chiral aldehydes,[5]
and the use of chiral N-auxiliaries,[6] have been developed
extensively and utilized in the synthesis of a large number
of these types of natural products. Asymmetric versions of
the PSR have also been developed.[7] Furthermore, exam-
ples of asymmetric protocols using catalytic amounts of chi-
ral Brønsted acids are emerging as powerful synthetic tools
for the synthesis of THβC derivatives.[8] Another approach
that has been widely employed is the use of the Bischler–
Napieralski reaction followed by asymmetric reduction of
the 3,4-dihydro-β-carboline.[9–11] Other asymmetric strate-
gies include addition of carbon nucleophiles to 3,4-dihydro-
β-carbolines,[12] chiral formamide carbanion chemistry,[13]
and enzymatic PSR.[14]
Harmicine 1 was first isolated from the leaf extract of
the Malaysian plant Kopsia griffithii.[15] The leaf extract
possesses antileishmanial activity, and recently antinocicep-
tive properties have been assigned to 1.[16] Structure elucida-
tion revealed a new tetracyclic compound of the THβC
class to be part of this extract. Harmicine itself has pre-
viously been synthesized on a number of occasions.[17–19]
We have been involved in natural product synthesis start-
ing from compounds from the chiral pool, making use of
the stereochemical information embedded within amino ac-
ids. In this context, we envisioned a strategy in which the
side chain of amino acid 6 would end up in the C1 position
of the THβC, thereby creating a new synthetic route to the
THβC framework (Figure 2). Performing a lateral lithiation
reaction between compound 4 and Weinreb amide 5 was
[a] Department of Chemistry, Aalto University School of Chemical
Technology,
P. O. Box 16100 (Kemistintie 1), 00076 Aalto, Finland
E-mail: ari.koskinen@aalto.fi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301903.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. S. Lood, A. M. P. Koskinen
FULL PAPER
expected to generate α-amino ketone 3.[20] Further func- methylmorpholine (NMM; pKaH 7.38, a difference of ap-
tionalization of the benzylic position followed by indoliz- proximately 3.4 units to TEA, pKaH 10.75), compound 8
ation and ring closure would lead to the basic structure 2, was obtained in Ͼ 99%ee in 82% yield on a 100 mmol scale
which is a C1 substituted THβC, in enantiopure form.
(Table 1). Acid 8 was isolated after an aqueous work up.
Table 1. Phenyl fluorenylation of proline by using different bases.
Entry
Base
ee [%][a]
Yield [%][b]
1
2
3
TEA
DIPEA
NMM
89
98
Ͼ 99
91
n.d.
82[c]
[a] Determined by HPLC analysis. [b] Isolated yield. [c] Scale up to
100 mmol, isolated yield.
Compound 8 was then subjected to an amide coupling
reaction to obtain the corresponding Weinreb amide
(Scheme 2). Initial attempts using 1,1Ј-carbonyldiimidazole
(CDI; Table 2, entries 2–4) proved unsuccessful, and even
with the addition of 4-(dimethylamino)pyridine (DMAP),
no conversion was observed. By using N,N-dicyclohexylcar-
bodiimide (DCC), in combination with DMAP, amide 9
Figure 2. Synthetic strategy towards the THβC framework; R =
amino acid side chain, Pg = protecting group.
was obtained in
a modest yield (31%) after flash
It is known that α-amino ketones, and also to some ex-
tent α-amino amides, are prone to racemization under
strongly basic conditions. To eliminate this as a possibility,
we employed the 9-phenyl-9-fluorenyl (Pf) protecting group
strategy for amino acids. This strategy has been successfully
used in natural product synthesis and in the synthesis of
medicinally interesting compounds on a number of oc-
casions.[21,22] To demonstrate the synthetic value of such a
protocol we then embarked on the synthesis of harmicine.
chromatography (Table 2, entry 1). However, one of the
aims of the described synthesis was to keep the number of
chromatographic purification steps to a minimum and due
to the concerns associated with side-product formation
originating from this particular coupling reaction (the re-
moval of N,N-dicyclohexylurea often requires chromato-
graphic purification procedures), DCC was not further ex-
plored as a viable option. Instead, propylphosphonic anhy-
dride (T3P®), being slightly less expensive than 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDCI), and also
known to form water-soluble side products from the amide
coupling reaction, was tested. By using a reported pro-
cedure for an α-amino acid (Table 2, entry 5), a moderate
but encouraging yield of 9 of 60% was obtained.[24] Switch-
Results and Discussion
The synthesis started from proline 7, however, Pf-protec-
tion of 7 was not as trivial as first anticipated. In contrast to
the Pf-protection of alanine, by using the standard literature
procedure, partial racemization occurred at the labile
α-stereogenic center giving rise to an ee of 89%.[23] This can
most likely be attributed to the higher acidity of the cyclic
α-proton in proline compared to that in alanine (Scheme 1).
In an attempt to circumvent the problem, a more hindered
base was tested. When switching from triethylamine (TEA),
to diisopropylethylamine (DIPEA), the ee could be im-
proved to an acceptable level of 98%. However, when start-
ing from a chiral pool substrate such as proline, every small
loss in ee would constitute a disappointment. In that spirit,
and because the use of strong bases such as TEA or DIPEA
was not necessary, we opted for a weaker base. Using N-
Scheme 2. Amide coupling of 8 using different coupling reagents.
Table 2. Amide coupling reaction of 8.[a]
Entry Coupling
reagent
Base
Additive Solvent Time Yield
[h]
[%]
1
2
DCC
CDI
TEA
TEA
TEA
TEA
pyridine
TEA
TEA
DMAP[b] CH2Cl2 26
31[c]
–
–
THF
CH2Cl2 26
23
23
n.d.[d]
[d]
3
4
CDI
n.d
CDI
DMAP[b] THF
n.d.[d]
60[f]
5[e]
6[e]
7
T3P®
T3P®
T3P®
–
–
EtOAc 18
EtOAc 18
9[c]
DMAP[g] EtOAc 26
81[f],
73[h]
[a] Reactions were carried out on a 1 mmol scale with the exception
of entry 1, which was carried out on a 2 mmol scale. [b] 5 mol-%
used. [c] Isolated yield after flash chromatography. [d] No conver-
sion was detected on TLC. [e] Carried out at 0 °C. [f] Isolated yield.
[g] 20 mol-%. [h] Scale up to 56 mmol, isolated yield.
Scheme 1. Phenyl fluorenylation of proline.
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Synthesis of (S)- and (R)-Harmicine from Proline
ing the base from pyridine to non-nucleophilic TEA, not yields due to incomplete reactions, as shown by the pres-
surprisingly, diminished the yield substantially (Table 2, en- ence of unreacted starting material. The product could be
try 6). By using an even more nucleophilic additive than purified by triturating the crude material with Et2O, giving
pyridine, 20 mol-% DMAP, in combination with TEA 11 as a white solid after filtration. The reaction was scaled
(Table 2, entry 7), Weinreb amide 9 was obtained in good up to 38 mmol.
81% yield. The product was obtained in satisfactory purity
after simple aqueous work up.
Table 3. Coupling of Boc-toludine 4 and Weinreb amide 9.
An alternative route to the Weinreb amide 9 was also
developed. The commercially available proline methyl ester Entry
9 [mol-%]
4 [mol-%] sBuLi [mol-%]
Yield [%]
HCl salt 10 was Pf-protected under conditions developed
for aspartic acid, in 82% yield (Scheme 3).[23] Amide forma-
tion using iPrMgCl as the base gave the corresponding
Weinreb amide in 92% yield. The sequence was high yield-
ing but required at least one flash chromatographic step.
Furthermore, partial racemization of the α-stereocenter,
most likely in the Pf-protection step, once again proved to
be an issue. The ee of 9 obtained from this route was 97%.
1
2
3
100
100
100
120
150
200
277
300
400
60[a]
70[a]
87[b], 85[c]
[a] Isolated yield after flash chromatography. [b] Isolated yield after
trituration in Et2O. [c] Scale up to 38 mmol, isolated yield.
Ketone 11 was then enolized by using 100 mol-%
KHMDS in combination with hexamethylphosphoramide
(HMPA; needed to facilitate the formation of the enolate),
and subsequently quenched with an acetate electrophile to
give intermediate 12 (Scheme 5). Ethyl iodoacetate proved
to work very well in the reaction. However, because we were
unable to isolate 12, the crude material was treated directly
with sulfuric acid in EtOH, using CH2Cl2 as a cosolvent to
cleave the Boc group. Upon Boc cleavage the aniline nitro-
gen condensed with the ketone to give indole 13 in 69%
over two steps. Compound 13 was purified by trituration
from an EtOAc/hexane mixture, giving an amorphous solid
after filtration.
Having installed the carbon frame work, all that re-
mained was the removal of the Pf-group followed by lactam
formation and reduction to give harmicine. The Pf-depro-
tection under hydrogenolysis of 13, however, required some
optimization of the reaction conditions (Table 4). Conven-
tional hydrogenation using Pd/C under 1 atm H2 (g) gave
essentially no conversion. Using Pearlman’s catalyst under
conditions developed for a Pf-protected pyrroleproline also
proved unsuccessful (Table 4, entry 4).[26] Preparing the Pd/
C in situ from Pd(OAc)2 and activated charcoal did not
improve the reaction outcome (Table 4, entry 5).[27] By
using Pd/C, 1 atm H2 (g), and HCl in EtOH heated to re-
Scheme 3. Alternative route to Weinreb amide 9.
Boc-toluidine[25] 4, prepared from o-toluidine, was then
coupled with Weinreb amide 9, by using two equivalents of
sBuLi, giving ketone 11 in good yield (85%; Scheme 4). The
best results were obtained by using an excess (200 mol-%)
of 4 (Table 3). The use of lower amounts led to poorer
Scheme 4. Lateral lithiation of 4.
Scheme 5. Transformation of ketone 11 into harmicine 1.
Eur. J. Org. Chem. 2014, 2357–2364
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C. S. Lood, A. M. P. Koskinen
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Table 4. Pf deprotection of indole 13 to give lactam 14.
Entry
Pd source[a]
H2 source
Additive
Solvent
T [°C]
Time [h]
Yield [%][b]
1[c]
2[c]
3[c]
4[c]
5[c]
6[h]
7[i]
Pd/C
Pd/C
Pd/C
Pd(OH)2
Pd/C[f]
Pd/C
Pd/C
Pd/C
H2(g)
H2(g)
H2(g)
H2(g)
HCl
HCl
–
–
–
–
–
AcCl
–
–
EtOH
EtOH
AcOH
MeOH/THF
AcOH
EtOH
EtOH
EtOH
EtOH
EtOH
room temp.
reflux
room temp.
room temp.
room temp.
100
100
reflux
reflux
reflux
26
4
72
48
48
5
4
5
4.5
3
n.d.[d]
34[e]
n.d.[d]
n.d.[d]
n.d.[g]
n.d.[g]
0[j]
H2(g)
HCOOH
HCOOH/ammonium formate
1,4-cyclohexadiene[l]
hydrazine[m]
8[k]
9[k]
10[k]
n.d.[d]
38[e]
Pd/C
Pd/C
81[n]
[l]
NH4H2PO2
[a] Pd/C: 10 wt.-% on carbon; Pd(OH)2: 20 wt.-% on carbon. [b] Isolated yield. [c] Typical procedure: Indole 13 in the designated solvent
(with or without HCl, 300 mol-%) together with Pd (entry 1–3: 10 mol-%; entry 4: 20 mol-%) was stirred in a hydrogen atmosphere
(1 atm). [d] No conversion. [e] Isolated yield after flash chromatography. [f] Pd/C formed from Pd(OAc)2 and activated charcoal.[27] [g] Low
conversion, decomposition. [h] Reaction performed in a sealed tube with a 1:1 ratio of HCOOH/EtOH using 10 mol-% Pd. [i] Reaction
performed in a sealed tube with a 1:1 ratio of HCOOH/EtOH using Pd (10 mol-%) and ammonium formate (2000 mol-%). [j] No product
obtained. [k] Typical procedure: Indole 13 in EtOH (with or without AcCl, 200 mol-%) together with Pd (entry 8–9: 10 mol-%, entry 10:
5 mol-%) and the designated H2 source was stirred and heated to reflux. [l] 600 mol-%. [m] 2000 mol-%. [n] Isolated yield after trituration
in toluene.
flux, a yield of 34% was obtained (Table 4, entry 2). How- gel flash chromatography was required and gave the title
ever, being concerned with the safety aspects of heating a compound in a total yield of 19% over nine steps with an
Pd mixture under a hydrogen atmosphere we turned our ee of Ͼ 99%. During the course of the synthesis, some
attention to catalytic transfer hydrogenation (CTH) condi- problems concerning the use of Pf as a protecting group
tions.[28] By using HCOOH[29] with or without ammonium were encountered; however, these problems were sub-
formate[30] together with Pd/C in a sealed tube at 100 °C sequently solved. Racemization of proline in the Pf-protec-
gave low conversions and none of the desired product could tion step was circumvented by the use of a weaker base.
be isolated (Table 4, entries 6 and 7). 1,4-Cyclohexadiene[31] We also report, to the best of our knowledge, the first Pf-
proved completely inactive in EtOH at reflux (Table 4, en- deprotection under transfer hydrogenation conditions. As a
try 8). Hydrazine[32,33] gave full conversion but only pro- final conclusion, this study constitutes a new approach to
vided 14 in a modest yield of 38% (Table 4, entry 9). Suc- the synthesis of chiral tetrahydro-β-carbolines and further
cess was achieved by using ammonium hypophosphite[34] in work involving the synthesis of other natural products from
ethanol at reflux. Full conversion was achieved in only three the tetrahydro-β-carboline class by using different amino
hours, and, after treatment of the crude mixture with acids will be reported in due time.
Na2CO3, lactam 14 was obtained in good yield (81%). The
product was isolated by triturating the crude mixture with
toluene, once again avoiding the use of silica gel chromatog-
raphy. To the best of our knowledge, this approach consti-
tutes the first reported Pf-hydrogenolysis reaction under
transfer hydrogenation conditions.
Experimental Section
General Information: Dry solvents (THF, MeCN, CH2Cl2 and tolu-
ene) were obtained from a solvent drying system (MB SPS-800,
using neutral alumina as desiccant). Other solvents used where of
P.A. quality, with the exception of HPLC grade hexane for the in-
The synthesis of harmicine was then completed by reduc-
ing the lactam with lithium aluminum hydride (LAH) in
tetrahydrofuran (THF) at room temp. Harmicine was iso-
lated after aqueous work up in 78% yield. Both (S)-harmic-
ine (from l-proline) and (R)-harmicine (from d-proline)
were synthesized and chiral HPLC analysis confirmed the
ee to be Ͼ 99%. The nine-step sequence from commercially
available starting material was performed without the use
of any flash chromatographic purification and the synthesis
was scaled up to give 1.16 g of (S)-harmicine in one batch.
tended use of HPLC analysis, and used as such directly from the
bottles. HMPA and NMM were distilled from CaH2 and stored
over 4 Å molecular sieves. TMSCl was distilled from CaH2.
Pb(NO3)2 and K3PO4 were dried in an oven prior to use. Reagents
were obtained from Sigma–Aldrich, TCI Europe, or Johnson Mat-
they Chemicals Limited. Celite used for filtration was Celite 535,
purchased from Sigma–Aldrich. TLC monitoring was performed
on silica gel 60 F254 on aluminum support obtained from Merck.
Visualization of TLC plates was done using UV light (λ = 254 nm)
and/or staining the plates with ninhydrin solution (1 g of ninhydrin
dissolved in 100 mL of EtOH and 0.2 mLglacial AcOH) or vanillin
solution (2.4 g of vanillin dissolved in 100 mL of EtOH, 2 mL of
conc. H2SO4 and 1.2 mLglacial AcOH). NMR spectra were re-
corded with a Bruker Avance 400 spectrometer at ambient tempera-
ture and the peaks were calibrated to TMS (1H: δ = 0.00 ppm), or
residual solvent 13C in CDCl3 (13C: δ = 77.0 ppm) or [D6]DMSO
(13C: δ = 39.5 ppm). Optical rotations were measured with a Per-
Conclusions
The synthesis of (S)-harmicine and (R)-harmicine was
completed from l-proline and d-proline, respectively, by
using the Pf-group as an amine protecting group strategy.
The synthesis was optimized to the point where no silica kin–Elmer 343 Polarimeter equipped with a sodium lamp and a
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Synthesis of (S)- and (R)-Harmicine from Proline
10 cm quartz cuvette. HRMS spectra were recorded with a Waters
(230 mL) were added Et3N (35.1 mL, 252 mmol, 450 mol-%) and
Micromass LCT Premier (ESI/TOF) mass spectrometer. Elemental DMAP (1.37 g, 11.2 mmol, 20 mol-%). T3P (50 mL, 84 mmol, 150
analysis was recorded with a Perkin–Elmer 2400 Series II CHNS/ mol-%, 50 wt.-% solution in EtOAc) was then added by using an
O Analyzer . IR was recorded either with a Perkin–Elmer Spectrum addition funnel at room temp. The suspension was stirred for 23 h,
One FTIR spectrometer (KBr disc) or a Bruker ALPHA ECO-
ATR FTIR spectrometer (film).
then the reaction was quenched with 0.5 m aqueous HCl (400 mL).
The organic phase was separated and washed with 0.5 m aqueous
HCl (2ϫ 300 mL), then the combined aqueous phases were back-
extracted once with EtOAc (300 mL). The combined organic
phases were washed with 10 wt.-% K2CO3 (300 mL), brine
(300 mL), dried with Na2SO4, filtered and finally evaporated to
dryness to give a thick red oil. Upon addition of Et2O (50 mL)
followed by evaporation, the oil solidified into a red-orange solid
(16.3 g, 73%), which was subjected to chiral HPLC analysis (Chi-
ralpak IA; Hex/EtOH, 98:2; 1 mL/min): Rt = 9.8 (S), 10.6 (R) min;
Ͼ 99%ee for both (S) and (R) enantiomers; Rf = 0.45 (Hex/EtOAc,
1:1); [α]2D0 +49.8 (S) (c = 0.8, CH2Cl2); [α]2D0 –49.1 (R) (c = 0.78,
tert-Butyl o-Tolylcarbamate (4): To THF (100 mL) was added o-
toluidine (19.8 mL, 187 mmol, 100 mol-%) and Boc2O (44.8 g,
205 mmol, 110 mol-%), and the solution was heated to reflux for
3 h, after which it was cooled to room temp. Evaporation gave an
orange oil, which was crystallized from hexane (20 mL) to form
white translucent needles, yield 33 g (85%); Rf = 0.36 (Hex/EtOAc,
9:1). IR (film): ν = 3271, 2983, 2967, 1701, 1678, 1585, 1521, 1456,
˜
1390, 1363, 1292, 1263, 1245, 1198, 1153, 1050, 1024, 988, 948,
1
910, 860, 843, 777, 744, 733, 710, 635 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.79 (br. d, J = 7.8 Hz, 1 H), 7.19 (t, 7.8 Hz, 1 H),
7.14 (d, J = 7.4 Hz, 1 H), 6.99 (t, J = 7.4 Hz, 1 H), 2.25 (s, 3 H),
1.52 (s, 9 H) ppm. 13C NMR (CDCl3): δ = 153.0, 136.3, 130.2,
127.2, 126.7, 123.6, 120.9, 80.3, 28.3, 17.6 ppm. C12H17NO2
(207.27): calcd. C 69.54, H 8.27, N 6.76; found C 69.51, H 8.39, N
6.74.
CH Cl ). IR (film): ν = 3059, 2964, 2868, 1667, 1599, 1487, 1449,
˜
2
2
1386, 1352, 1314, 1281, 1175, 1114, 1087, 1031, 1000, 909, 763,
734, 704, 641, 618 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.70 (d,
J = 7.3 Hz, 1 H), 7.63–7.59 (m, 4 H), 7.45 (d, J = 7.7 Hz, 1 H),
7.39 (m, 1 H), 7.30 (m, 1 H), 7.27–7.14 (m, 5 H), 3.71 (br., 1 H),
3.29 (m, 1 H), 2.91 (br. m, 7 H), 1.93 (m, 1 H), 1.74 (m, 1 H), 1.61
(m, 2 H) ppm. 13C NMR (CDCl3): δ = 177.1, 148.7, 147.9, 144.1,
140.9, 139.7, 128.1, 128.0, 127.8, 127.5, 127.4, 127.3, 126.9, 126.8,
126.4, 119.4, 119.2, 77.0, 60.2, 57.6, 50.1, 32.0, 32.0, 24.8 ppm.
HRMS: calcd. for C26H27N2O2 [M + H]+ 399.2073; found
399.2062.
(S)-1-(9-Phenyl-9H-fluoren-9-yl)pyrrolidine-2-carboxylic Acid (8):
To a suspension of l-proline (11.5 g, 100 mmol, 100 mol-%) in an-
hydrous CH2Cl2 (400 mL) and anhydrous MeCN (50 mL) in a
flame-dried Morton flask under argon was added TMSCl
(12.7 mL, 100 mmol, 100 mol-%). The resulting solution was
heated to reflux for 1 h, after which it was cooled to room temp.
NMM (24.2 mL, 220 mmol, 220 mol-%) was added followed by
PfBr (38.5 g, 120 mmol, 120 mol-%) and Pb(NO3)2 (22.1 g,
67 mmol, 67 mol-%) as solids, giving a yellow/brown suspension,
which was stirred at room temp. for 65 h. MeOH (10.1 mL,
250 mmol, 250 mol-%) was added, the reaction mixture was filtered
through Celite, and the resulting filter cake was washed with
CH2Cl2 (ca. 200 mL, or until no UV activity could be observed in
the filtrate). The filtrate was evaporated to give a thick red oil,
which was then partitioned between Et2O (600 mL) and 5 wt.-%
aqueous citric acid (600 mL). The organic phase was removed and
the aqueous phase was extracted with Et2O (4ϫ 150 mL). The
combined organic phases were extracted with 1 m NaOH (300 mL)
and discarded. The aqueous phase was washed with Et2O (200 mL)
and AcOH was added until ca. pH 7, giving a suspension. The
suspension was extracted with 20% iPrOH in CHCl3 (3ϫ 300 mL)
and the combined organic phases were washed with brine
(500 mL), dried with Na2SO4, filtered, and the solvents evaporated.
Two portions of hexane were added (to remove remaining iPrOH
and CHCl3) and the product was evaporated to dryness giving an
orange foam, yield 29.1 g (82%); Rf = 0.15 (Hex/EtOAc, 1:1);
[α]2D0 +258.7 (S) (c = 1.10, CH2Cl2); [α]2D0 –259.8 (R) (c = 1.09,
(S)-tert-Butyl (2-{2-Oxo-2-[1-(9-phenyl-9H-fluoren-9-yl)pyrrolidin-
2-yl]ethyl}phenyl)carbamate (11): Compound 4 (15.1 g, 76 mmol,
200 mol-%) was dissolved in anhydrous THF (160 mL) in a flame-
dried flask under argon, and the solution was cooled to –30 °C.
sBuLi (1.4 m in cyclohexane, 109 mL, 76 mmol, 400 mol-%) was
added dropwise by using an addition funnel. After approximately
half the volume of sBuLi had been added, the solution took on a
bright-yellow color. The solution was stirred for 1 h, then 9 (15.8 g,
38 mmol, 100 mol-%), dissolved in anhydrous THF (55 mL) was
added to the yellow solution by using a Teflon cannula. After
30 min, the reaction was quenched with saturated NH4Cl (150 mL)
and H2O (20 mL) and allowed to warm to room temp. The organic
phase was separated and the aqueous phase was extracted with
CH2Cl2 (2ϫ 50 mL). The combined organic phases were dried with
Na2SO4, filtered, and evaporated to give a thick oil (occasionally a
solid), which was then dissolved (or suspended in case of a solid)
in Et2O (60 mL). After a few minutes a precipitate started to form,
and the suspension was stored in a refrigerator overnight. Filtration
with subsequent washing of the filter cake with ice-cold Et2O (3ϫ
15mL) and hexane (2ϫ 15 mL) gave a white amorphous solid
(17.6 g, 85%). The solid was subjected to chiral HPLC analysis
(Chiralpak IB; Hex/EtOH, 95:5; 1 mL/min): Rt = 5.7 (R), 6.2
(S) min; Ͼ 99%ee for both (S) and (R) enantiomers. Rf = 0.55
(Hex/EtOAc, 75:25). [α]2D0 +80.8 (S) (c = 0.81, CH2Cl2); [α]2D0 –81.7
CH Cl ). IR (film): ν = 3059, 2966, 2874, 1716, 1647, 1636, 1488,
˜
2
2
1449, 1362, 1316, 1203, 1156, 907, 732, 702, 666, 644 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 1 H), 7.64 (d,
J = 7.5 Hz, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.50–7.44 (m, 3 H),
7.40–7.20 (m, 7 H), 3.43 (m, 1 H), 3.21 (dd, J = 9.1, 2.2 Hz, 1 H),
3.10 (app. dt, J = 10.6, 8.3 Hz, 1 H), 1.96 (m, 1 H), 1.76 (m, 2 H),
1.63 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 175.0, 145.9, 144.6,
141.4, 140.6, 139.3, 129.2, 129.0, 128.6, 128.0, 127.8, 127.7, 126.8,
126.0, 125.8, 120.3, 120.0, 76.9, 62.5, 50.7, 30.9, 24.7 ppm. HRMS:
calcd. for C24H22NO2 [M + H]+ 356.1651; found 356.1647.
(R) (c = 0.81, CH Cl ). IR (film): ν = 3338, 3059, 2976, 2869, 1719,
˜
2
2
1589, 1512, 1477, 1449, 1391, 1366, 1343, 1302, 1235, 1156, 1051,
1
1024, 909, 733, 703, 640, 619 cm–1. H NMR (400 MHz, CDCl3):
δ = 7.77 (d, J = 7.5 Hz, 1 H), 7.70 (br. d, J = 8.1 Hz, 1 H), 7.64–
7.42 (m, 6 H), 7.34 (m, 1 H), 7.30–7.17 (m, 6 H), 7.10 (m, 1 H),
6.95 (m, 1 H), 6.88 (m, 1 H), 3.40 (m, 1 H), 3.35 (s, 2 H), 3.13 (m,
2 H), 1.83 (m, 1 H), 1.61 (m, 3 H), 1.54 (s, 9 H) ppm. 13C NMR
(CDCl3): δ = 212.8, 153.6, 149.1, 146.0, 143.0, 141.9, 139.3, 137.4,
130.2, 128.7, 128.6, 128.4, 127.8, 127.7, 127.5, 127.4, 126.8, 126.5,
123.9, 120.0, 119.8, 80.0, 76.8, 67.2, 51.1, 42.9, 30.7, 28.4,
25.2 ppm. HRMS: calcd. for C36H37N2O3 [M + H]+ 545.2804;
found 545.2801.
(S)-N-Methoxy-N-methyl-1-(9-phenyl-9H-fluoren-9-yl)pyrrolidine-
2-carboxamide (9): To a suspension of 8 (19.9 g, 56 mmol, 100 mol-
%) and HCl·HN(OMe)Me (8.19 g, 84mmol, 150 mol-%) in EtOAc
Eur. J. Org. Chem. 2014, 2357–2364
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2361

C. S. Lood, A. M. P. Koskinen
FULL PAPER
(S)-Ethyl
2-{2-[1-(9-Phenyl-9H-fluoren-9-yl)pyrrolidin-2-yl]-1H-
EtOH (100 mL). The EtOH was evaporated and the resulting solid
was partitioned between CH2Cl2 (300 mL) and 10 wt.-% K2CO3
(200 mL). The aqueous phase was extracted with CH2Cl2 (200 mL)
and the combined organic phase was washed with brine (200 mL),
dried with Na2SO4, filtered, and evaporated to give a yellow solid.
The crude product was suspended together with Na2CO3 (10.6 g,
100 mmol, 1000 mol-%) in EtOH (200 mL) and stirred at room
temp. for 20 h. The reaction solvent was evaporated and the solid
was partitioned between CH2Cl2 (300 mL) and H2O (200 mL). The
aqueous phase was extracted with CH2Cl2 (2ϫ 200 mL) and the
combined organic phases where washed with brine (400 mL), dried
with Na2SO4, filtered, and evaporated to give a yellow solid. The
solid was suspended in toluene (5 mL) and filtered. The filter cake
was washed with toluene (3ϫ 3 mL) and hexane (5 mL) to give 14
(1.83 g, 81%) as a pale-yellow powder. Rf = 0.28 (CH2Cl2/MeOH,
95:5); [α]2D0 –107.1 (S) (c = 0.4, DMSO); [α]2D0 +108.2 (R) (c = 0.4,
indol-3-yl}acetate (13): To a flame-dried 500 mL flask was added
anhydrous toluene (230 mL) and KHMDS (0.5 m in toluene,
48.3 mL, 24.1 mmol, 100 mol-%), the solution was cooled to
–78 °C and HMPA (24 mL, 137.9 mmol, 600 mol-%) was added.
Compound 11 (12.5 g, 23 mmol, 100 mol-%) was added as a solid
in four portions, giving a pale-yellow suspension. The suspension
was taken to room temp. and stirred for 1 h until an orange solu-
tion had formed. The reaction mixture was cooled to –78 °C and
ethyl iodoacetate (5.44 mL, 46.0 mmol, 200 mol-%) was added. The
reaction was quenched after 15 min by pouring the reaction mix-
ture into saturated NH4Cl (200 mL). Water (50 mL) was added and
the phases were separated. The organic phase was washed with
0.5 m HCl (3ϫ 100 mL) and the combined aqueous phases were
extracted once with Et2O (200 mL). The organic phases where
pooled and subsequently washed with brine (400 mL), dried with
Na2SO4, filtered, and finally evaporated to dryness to give a yellow
oil. The yellow oil was dissolved in CH2Cl2 (230 mL) and cooled
to 0 °C. A 6M stock solution of H2SO4 in EtOH (38.3 mL,
230 mmol, 1000 mol-% of H2SO4) was added by using a dropping
funnel, initially giving a forest green solution, which grew darker
with time. The reaction mixture was carefully poured into a separa-
tory funnel containing ice-cold sat NaHCO3 (500 mL); CAUTION:
vigorous gas evolution. The biphasic mixture was gently shaken
and the phases where separated. The organic phase was washed
with additional sat NaHCO3 (2ϫ 500 mL) until the pH of the com-
bined aqueous phases was Ն 7. The combined aqueous phases were
extracted with CH2Cl2 (300 mL) and the combined organic phases
were washed with brine (300 mL), dried with Na2SO4, filtered, and
evaporated to give a wet brown solid. The solid residue was sus-
pended in Hex/EtOAc (4:1, 30 mL) and filtered. The filtrate was
washed with ice-cold Hex/EtOAc (3ϫ 5 mL, 4:1) to give a pale-
brown powder (7.65 g). The mother liquid was evaporated and re-
dissolved in Hex/EtOAc (4:1, 10 mL) and placed in a freezer over-
night. Filtration and washing of the filtrate with ice-cold Hex/
EtOAc (4:1, 3ϫ 2 mL) gave an additional 0.51 g of pale-brown
solid, giving a combined weight of 8.16 g (69% yield) over two
steps. The solid was subjected to chiral HPLC analysis (Chiralpak
IB; Hex/EtOH, 95:5; 1 mL/min): Rt = 8.0 (R), 9.5 (S) min;
Ͼ 99%ee for both (S) and (R) enantiomers. Rf = 0.27 (toluene/
isopropanol, 98:2), 0.55 (Hex/EtOAc, 75:25); [α]2D0 –20.1 (S) (c =
DMSO). IR (KBr disk): ν = 3165, 3114, 3070, 2984, 2949, 2912,
˜
2879, 2828, 2752, 1602, 1502, 1463, 1386, 1337, 1318, 1278, 1268,
1256, 1222, 1203, 1150, 1117, 1009, 962, 874, 760, 732, 666, 633,
608, 563, 500 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.18 (s,
1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.09
(ddd, J = 8.0, 7.1, 1.1 Hz, 1 H), 7.00 (ddd, J = 7.8, 7.1, 0.9 Hz, 1
H), 4.72 (m, 1 H), 3.65 (app. dt, J = 11.8, 8.8 Hz, 1 H), 3.55 (dd,
J = 20.0, 4.5 Hz, 1 H), 3.48 (dd, J = 19.9, 2.9 Hz, 1 H), 3.34 (m, 1
H), 2.53 (m, 1 H), 1.99 (m, 2 H), 1.59 (m, 1 H) ppm. 13C NMR
([D6]DMSO): δ = 166.5, 136.8, 131.9, 125.4, 121.2, 118.8, 118.0,
111.3, 104.1, 60.0, 44.2, 31.3, 29.9, 22.1 ppm. HRMS: calcd. for
C14H15N2O [M + H]+ 227.1184; found 227.1193.
(S)-Harmicine (1): In a flame-dried flask under argon, 14 (1.58 g,
7 mmol, 100 mol-%) was suspended in anhydrous THF (70 mL).
LAH (1.59 g, 42 mmol, 600 mol-%) was added to the reaction in
two equally sized portions. The reaction mixture was stirred at
room temp. for 5 h, then cooled to 0 °C and water (1.6 mL) was
carefully added dropwise (CAUTION: vigorous gas evolution).
NaOH (1.6 mL, 4 m aqueous solution) was added dropwise and the
reaction was taken to room temp., then water (6.3 mL) was added
and the reaction was stirred for 30 min. The resulting yellow sus-
pension was filtered through Celite and eluted with THF (20 mL)
followed by CH2Cl2 (20 mL). The filtrate was evaporated and then
portioned between CH2Cl2 (70 mL) and sat aqueous NH4Cl solu-
tion (100 mL). The aqueous phase was extracted with CH2Cl2
(35 mL), then the combined organic phases were washed with sat
aq. NaHCO3 (100 mL). The phases were separated and the aque-
ous phase was extracted with CH2Cl2 (2ϫ 50 mL). The combined
organic phases were washed with brine (100 mL), dried with
Na2SO4, filtered, and evaporated to give harmicine as a yellow so-
lid (1.16 g, 78%). The solid was subjected to chiral HPLC analysis
(Chiralpak IB; Hex/EtOH, 93:7 with 0.1% ethylene diamine; 1 mL/
min) Rt = 9.0 (S), 11.2 (R) min; Ͼ 99%ee for both (S) and (R)
enantiomers. Rf = 0.14 (CH2Cl2/MeOH, 9:1). [α]2D0 –112.0 (S) (c =
0.79, CH2Cl2); [α]2D0 +21.1 (R) (c = 0.83, CH Cl ). IR (film): ν =
˜
2
2
3398, 3058, 2974, 2868, 1718, 1600, 1487, 1461, 1448, 1368, 1343,
1299, 1266, 1239, 1154, 1131, 1105, 1065, 1031, 905, 725, 700, 638,
618 cm–1. H NMR (400 MHz, CDCl3): δ = 8.29 (s, 1 H), 7.76 (d,
1
J = 7.5 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.49–7.45 (m, 4 H),
7.37–7.31 (m, 3 H), 7.24–7.16 (m, 3 H), 7.10 (m, 1 H), 7.01 (m, 1
H), 6.84 (dt, J = 7.5, 1.0 Hz, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 6.20
(dt, J = 7.5, 1.0 Hz, 1 H), 3.93 (q, J = 7.1 Hz, 2 H), 3.73 (m, 1 H),
3.47 (m, 1 H), 3.20 (m, 1 H), 3.11 (d, J = 15.2 Hz, 1 H), 2.77 (d, J
= 15.0 Hz, 1 H), 1.93 (m, 2 H), 1.68 (m, 2 H), 1.09 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (CDCl3): δ = 171.9, 148.3, 146.3, 143.5, 142.4,
141.4, 138.0, 134.5, 128.9, 128.7, 128.2, 127.5, 127.4, 127.1, 126.7,
126.6, 125.0, 120.8, 119.7, 118.9, 118.9, 118.0, 110.4, 102.9, 77.0,
60.3, 54.2, 51.1, 35.2, 30.0, 25.2, 14.1 ppm. HRMS: calcd. for
C35H33N2O2 [M + H]+ 513.2542; found 513.2551.
0.77, CH Cl ), (R) +113.4 (c = 0.69, CH Cl ). IR (film): ν = 3400,
˜
2
2
2
2
3149, 3055, 2919, 2848, 2746, 2244, 1450, 1349, 1326, 1313, 1281,
1200, 1165, 1142, 1122, 1009, 906, 727, 646 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.01 (br. s, 1 H), 7.48 (m, 1 H), 7.27 (m, 1
H), 7.10 (m, 2 H), 4.21 (m, 1 H), 3.32 (ddd, J = 12.8, 5.3, 2.3 Hz,
1 H), 3.07 (m, 1 H), 2.98–2.83 (m, 3 H), 2.64 (m, 1 H), 2.25 (m, 1
H), 1.87 (m, 3 H) ppm. 13C NMR (CDCl3): δ = 136.0, 135.4, 127.3,
121.3, 119.3, 118.0, 110.7, 107.7, 56.9, 49.3, 45.9, 29.4, 23.4,
17.8 ppm. HRMS: calcd. for C14H17N2 [M + H]+ 213.1392; found
213.1389.
(S)-2,3,11,11b-Tetrahydro-1H-indolizino[8,7-b]indol-5(6H)-one (14):
A one-necked flask equipped with a condenser was charged with
13 (5.13 g, 10 mmol, 100 mol-%), NH4H2PO2 (4.98 g, 60 mmol, 600
mol-%) and EtOH (100 mL). The suspension was degassed and 10
wt.-% Pd/C (0.53 g, 0.5 mmol, 5 mol-%) was added. The reaction
mixture was heated to reflux for 3 h, then cooled to room temp.
The thick suspension was filtered through Celite and eluted with
Supporting Information (see footnote on the first page of this arti-
cle): Alternative synthesis of 9 via 15, HPLC chromatograms for
2362
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2357–2364

Synthesis of (S)- and (R)-Harmicine from Proline
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Acknowledgments
The National Graduate School of Organic Chemistry and Chemi-
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Received: December 22, 2013
Published Online: February 12, 2014
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