Stereoselective total synthesis of the putative structure of nitraraine

Article abstract of DOI:10.1021/jo5013543

After the structure originally proposed for nitraraine was shown to be incorrect by total synthesis, the alternative structure 5 was recently suggested for the alkaloid on biosynthetic grounds and by comparison with the ¹H NMR data of tangutorine. The unambiguous synthesis of 5 is reported from tryptophanol and ketodiester 6, via oxazoloquinolone lactam 7. However, the melting point and ¹H NMR data of 5 did not match those reported for the natural product.

Full text of DOI:10.1021/jo5013543

Note
pubs.acs.org/joc
Stereoselective Total Synthesis of the Putative Structure of
Nitraraine
Federica Arioli, Maria Perez, Fabiana Subrizi, Nuria Llor, Joan Bosch, and Mercedes Amat*
́
́
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona,
08028-Barcelona, Spain
S
* Supporting Information
ABSTRACT: After the structure originally proposed for nitraraine was shown to be incorrect by total synthesis, the alternative
1
structure 5 was recently suggested for the alkaloid on biosynthetic grounds and by comparison with the H NMR data of
tangutorine. The unambiguous synthesis of 5 is reported from tryptophanol and ketodiester 6, via oxazoloquinolone lactam 7.
1
However, the melting point and H NMR data of 5 did not match those reported for the natural product.
itraraine1 is an indole alkaloid isolated in 1985 from
Nitraria schoberi L., collected in Kyzyl-Kum (Uzbeki-
Later on, three different syntheses of pentacyclic alcohol 1,
either in enantiopure form6,7 or as a racemate,8 were reported.
N
1
stan). On the basis of its mass-spectrometric fragmentation,
The melting point and H NMR data of 1 were significantly
1
spectroscopic UV, IR, and H NMR data, chemical trans-
different from those reported for nitraraine. Similarly, the
melting point of synthetic 2 differed6 from that of the alkaloid
dihydronitraraine.2 Consequently, a reasonable doubt arose
about the correct structure of the alkaloids of the nitraraine
family.
formations and correlations, and degradation studies, the
yohimbane-type structure 1 was assigned to nitraraine (Figure
1). Catalytic hydrogenation of nitraraine afforded dihydroni-
In 2011, Poupon et al. published9 an excellent and
comprehensive article that provides a detailed analysis of the
data available for nitraraine and the above-mentioned
nitraraine-related alkaloids, suggesting pentacyclic alcohol 5, a
structural isomer of 1, as a possible structure for nitraraine. The
proposal was based on biosynthetic considerations10 and a
comparison of the physical and spectroscopic data reported for
these alkaloids with those of tangutorine11 and its O-acetyl and
dihydro derivatives (Figure 2).
Figure 1. Structures proposed for nitraraine, dihydronitraraine, O-
acetylnitraraine, and nitraraidine.
Figure 2. Structure of tangutorine and putative structure of nitraraine.
traraine (assigned as 2), which had also been isolated from the
same plant.2 Some years later, two new alkaloids, O-
acetylnitraraine3 and nitraraidine,4 were also isolated from
Nitraria species, and their structures were assigned as 3 and 4,
respectively, mainly by chemical correlations with nitraraine
and dihydronitraraine.
A pentacyclic alcohol with the structure 1 had previously
been prepared5 by LiAlH4 reduction of apo-α-yohimbine.
However, the data reported for this alcohol 1 (obtained as the
hydrochloride) did not allow the proposed structure for
nitraraine (isolated as the base) to be corroborated.
Both nitraraine and tangutorine are alkaloids isolated from
Nitraria species (Nitraria schoberi and Nitraria tangutorum,
respectively), which belong to the Nitrariaceae family, whereas
yohimbine-type alkaloids have a monoterpenoid origin and are
found in plants of the Rubiaceae, Loganiaceae, and Apocinaceae
families. Moreover, the specific rotation reported for both
Received: June 17, 2014
Published: July 14, 2014
© 2014 American Chemical Society
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alkaloids is zero, which could be attributed to similar
biosynthetic pathways that do not involve the monoterpene
secologanin. On the other hand, nitraraine, tangutorine, and
their O-acetyl derivatives each have an olefinic proton that
indoloquinolizidine derivative 11, arising from an initial α-
amidoalkylation reaction on the indole ring15 (Scheme 4).
The next stage of the synthesis was the removal of the
hydroxymethyl substituent coming from tryptophanol, which
required the selective protection of the allylic hydroxy group,
but unfortunately, the insolubility of diol 10 precluded its
manipulation. For this reason, the indole nitrogen of 7 was
protected as a p-methoxybenzyl derivative, and the resulting
lactam 12 was converted to 13 in 68% overall yield following
the above Bischler−Napieralski cyclization−LiAlH4 reduction
sequence.
Once the allylic hydroxyl group was selectively protected
with the bulky tert-butyldiphenylsilyl group, the removal of the
hydroxymethyl substituent of 14 was performed in four steps:
oxidation to aldehyde 15 using tetrapropylammonium
perruthenate in the presence of N-methylmorpholine N-oxide
as the co-oxidant (TPAP/NMO),16 subsequent dehydration of
the corresponding oxime 16 with Burgess reagent, and
reductive decyanation of the resulting α-amino nitrile.
Finally, deprotection of the indole nitrogen of pentacycle 17
using TFA in the presence of PhSH as a carbocation scavenger,
followed by desilylation of the alcohol function, gave the target
pentacyclic alcohol 5.
1
resonates at a very similar chemical shift in their H NMR
spectra. Further, the melting point of these two alkaloids differs
by only a few degrees Celsius. Another point of interest is that
treatment of dihydronitraraine with p-TsCl provides the
alkaloid nitraraidine, which is an N-quaternary hexacyclic salt,
thus pointing to a cis D/E ring junction. Taking into account all
the above, Poupon proposed the tangutorine diastereoisomer 5
as a plausible structure for nitraraine.
In this communication, we report the enantioselective total
synthesis of 5. In the context of our studies on the use of
tryptophanol-derived lactams as enantiomeric scaffolds for the
synthesis of indole alkaloids,12 we visualized a synthetic route to
this alcohol. Key steps to assemble the required pentacyclic
skeleton would be a stereoselective cyclocondensation of (S)-
tryptophanol with an appropriately substituted 6-oxocyclohex-
enepropionate derivative 6 and a Bischler−Napieralski
cyclization of the resulting oxazoloquinolone lactam 713
(Scheme 1). The synthesis would also require the subsequent
removal of the hydroxymethyl substituent coming from
tryptophanol and the reduction of the ester function.
Our synthetic product 5 showed mass-spectral peaks with the
same m/z as natural nitraraine.1 However, the melting point
(241−242 °C) of 5 and the chemical shift of the olefinic proton
Scheme 1. Synthetic Strategy
1
in its H NMR spectrum (δ 5.86 in CF3CO2D) were different
from those described for the alkaloid (mp 280−281 °C; δ 5.22
in CF3CO2H17) (Figure 3).
The above data made evident that the real structure of
nitraraine and related alkaloids remains an unsolved question
and that further synthetic efforts are needed to reach a
definitive conclusion.
EXPERIMENTAL SECTION
■
Ethyl 4-Oxo-3-(phenylsulfonyl)cyclohexanecarboxylate (9).
First step: LDA (4.41 mL, 8.82 mmol of a 2 M solution in THF/
heptane/ethylbenzene) was added at −78 °C to a solution of
commercial ethyl 4-oxocyclohexanecarboxylate (8; 1.5 g, 8.82 mmol)
in dry THF (90 mL), and the solution was stirred for 30 min. Then,
PhSSO2Ph (2.21 g, 8.82 mmol) in THF (10 mL) was added, and the
resulting mixture was stirred at −78 °C for 40 min. The reaction was
quenched with saturated aqueous NH4Cl (50 mL), and the resulting
mixture was extracted with EtOAc. The combined organic extracts
were dried, filtered, and concentrated to afford ethyl 4-oxo-3-
(phenylthio)cyclohexanecarboxylate, which was used in the next step
The required δ-keto ester 6 was prepared in 56% overall yield
from ethyl 4-oxocyclohexanecarboxylate 8, via keto sulfoxide 9,
as outlined in Scheme 2.
Scheme 2. Preparation of the Starting δ-Keto Ester 6
1
without purification: H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.2
Hz, 3H), 1.93−2.02 (m, 1H), 2.25−2.29 (m, 1H), 2.31−2.38 (m, 1H),
2.39−2.43 (m, 2H), 2.98−3.03 (m, 1H), 3.04−3.11 (m, 1H), 3.89 (td,
J = 4.4, 0.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 7.29 (d, J = 7.2 Hz, 2H),
7.40 (dd, J = 8.8, 2.0 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H). Second step: A
solution of m-CPBA (70%, 2.17 g, 8.82 mmol) in CH2Cl2 (20 mL)
was added at −78 °C to a solution of the above phenylthio derivative
(2.46 g, 8.82 mmol) in CH2Cl2 (180 mL). After 5 min, the reaction
was quenched with the addition of saturated aqueous Na2S2O3. The
resulting mixture was extracted with CH2Cl2, and the combined
organic extracts were washed with saturated aqueous NaHCO3 and
brine, dried, filtered, and concentrated. Flash chromatography of the
residue (4:1 hexane−EtOAc) afforded the sulfonyl derivative 9 (2.38
g, 93% yield for the two steps) as a complex mixture of
diastereoisomers. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H19O4S 295.0999; Found 295.0999.
The cyclocondensation reaction of (S)-tryptophanol with δ-
keto ester 6 stereoselectively gave tricyclic lactam 7 in 71%
yield.14 Starting from 7, the closure of the central C ring was
satisfactorily accomplished under classical Bischler−Napieralski
reaction conditions. Without purification, treatment of the
resulting hexacyclic derivative with LiAlH4 brought about both
the reductive opening of the oxazolidine ring to stereo-
selectively give the required cis-decahydroquinoline ring
junction and the reduction of the ester function, leading to
the pentacyclic diol derivative 10 in 60% overall yield (Scheme
3). In contrast, a similar sequence from 7′ led to the
Methyl 3-(Ethoxycarbonyl)-6-oxocyclohexenepropionate
(6). A solution of DBU (374 mg, 2.45 mmol) in DMF (5 mL) was
added at −40 °C, under an inert atmosphere, to a solution of the
above sulfonyl derivatives 9 (720 mg, 2.45 mmol) in DMF (15 mL),
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Scheme 3. Synthesis of 5, the Putative Structure of Nitraraine
EtOAc gave lactam 7 (109 mg, 71%). Evaporation of the solvent
afforded the (3S,7aS,11aS) diastereoisomer (7′; 19 mg, 17%). Lactam
7: [α]2D2 + 20.2 (c 1.0, CHCl3); IR (film) ν (cm−1) 1629 (NCO), 1714
Scheme 4. Cyclization of Lactam 7′
1
(COO), 3303 (NH); H NMR (400 MHz, CDCl3, COSY, g-HSQC)
δ 1.28 (t, J = 7.5 Hz, 3H, CH3), 1.56−1.68 (m, 2H, H-7, H-11), 1.95
(dm, J = 14.0 Hz, 1H, H-7), 2.05−2.10 (m, 1H, H-11), 2.25−2.30 (m,
1H, H-7a), 2.33−2.39 (m, 1H, H-10), 2.43−2.52 (m, 2H, H-6, H-10),
2.63 (dd, J = 18.4, 6.4 Hz, 1H, H-6), 2.89 (dd, J = 14.0, 10.4 Hz, 1H,
CH2-ind), 3.62 (ddd, J = 14.0, 3.4, 0.8 Hz, 1H, CH2-ind), 3.81 (dd, J =
8.8, 8.0 Hz, 1H, H-2), 4.01 (dd, J = 8.8, 8.0 Hz, 1H, H-2), 4.19 (q, J =
7.5 Hz, 2H, CH2CH3), 4.67 (dtd, J = 10.4, 8.0, 8.0, 3.4 Hz, 1H, H-3),
6.84 (dd, J = 5.0, 2.0 Hz, 1H, H-8), 7.01 (d, J = 2.4 Hz, 1H, ArH), 7.12
(td, J = 8.0, 1.2 Hz, 1H, ArH), 7.20 (td, J = 8.0, 1.2 Hz, 1H, ArH), 7.34
(d, J = 8.0 Hz, 1H, ArH), 7.89 (d, J = 8.0 Hz, 1H, ArH), 8.40 (s, 1H,
NH ind); 13C NMR (100.6 MHz, CDCl3) δ 14.2 (CH3), 22.6 (C-10),
25.5 (C-7), 26.3 (C-11), 30.2 (CH2-ind), 31.0 (C-6), 40.6 (C-7a), 56.2
(C-3), 60.6 (CH2CH3), 68.2 (C-2), 92.6 (C-11a), 111.1 (CHAr),
111.6 (CAr), 119.2 (CHAr), 119.5 (CHAr), 122.0 (CHAr), 122.1
(CHAr), 127.5 (CAr), 129.6 (C-9), 136.2 (CAr), 137.7 (C-8), 166.5
(CO2), 169.4 (CO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C23H27N2O4 395.1965; Found 395.1978. Anal. Calcd for C23H26N2O4·
1/2 H2O: C 68.47; H 6.74, N 6.94. Found: C 68.42; H 6.60; N 6.59.
Lactam 7′: [α]2D2 − 40.8 (c 0.8, CHCl3); IR (film) ν (cm−1) 1628
Figure 3. Melting point and 1H NMR data of nitraraine and
compound 5.
and the resulting mixture was stirred for 20 min. A solution of methyl
acrylate (211 mg, 2.45 mmol) in DMF (5 mL) was then added to the
mixture, and the reaction was allowed to reach 10 °C over 1.5 h. The
reaction was quenched with saturated aqueous NH4Cl (20 mL), and
the resulting mixture was extracted with Et2O. The organic layer was
dried and filtered, and the filtrate was stirred at room temperature for
20 h. After this time, the solvent was evaporated under reduced
pressure. Flash chromatography of the residue (hexane to 9.5:0.5
hexane−EtOAc) afforded oxoester 6 (375 mg, 60%): IR (film) ν
(cm−1) 1678 (CO), 1736 (CO); 1H NMR (400 MHz, CDCl3, COSY,
g-HSQC) δ 1.30 (t, J = 7.1 Hz, 3H, CH3), 2.12−2.23 (m, 1H, H-4′),
2.30−2.41 (m, 2H, H-2, H-4′), 2.44−2.49 (m, 2H, H-3), 2.53−2.61
(m, 3H, H-2, H-5′), 3.36−3.42 (m, 1H, H-3′), 3.66 (s, 3H, OCH3),
1
(NCO), 1706 (COO), 3297 (NH); H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 1.28 (t, J = 7.2 Hz, 3H, CH3), 1.53−1.63 (m, 2H,
H-7, H-11), 2.02 (dd, J = 14.0, 6.0 Hz, 1H, H-7), 2.11−2.20 (m, 1H,
H-11), 2.31−2.39 (m, 2H, H-7a, H-10), 2.48−2.51 (m, 3H, H-6, H-
10), 2.76 (dd, J = 14.0, 9.6 Hz, 1H, CH2-ind), 3.79 (dd, J = 14.0, 2.0
Hz, 1H, CH2-ind), 3.97 (m, 2H, H-2), 4.18 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.42 (m, 1H, H-3), 6.90 (dd, J = 5.0, 2.4 Hz, 1H, H-8), 7.04
(d, J = 2.4 Hz, 1H, ArH), 7.13 (td, J = 7.5, 1.2 Hz, 1H, ArH), 7.20 (td,
J = 7.5, 1.2 Hz, 1H, ArH), 7.36 (d, J = 7.5 Hz, 1H, ArH), 7.80 (d, J =
7.5 Hz, 1H, ArH), 8.07 (s, 1H, NH ind); 13C NMR (100.6 MHz,
CDCl3) δ 14.2 (CH3), 22.8 (C-10), 25.7 (C-7), 26.3 (C-11), 26.6
(CH2-ind), 30.1 (C-6), 39.8 (C-7a), 56.5 (C-3), 60.6 (CH2CH3), 67.4
(C-2), 92.7 (C-11a), 111.0 (CHAr), 112.4 (CAr), 119.3 (CHAr),
119.6 (CHAr), 122.2 (CHAr), 122.3 (CHAr), 127.7 (CAr), 129.2 (C-
9), 136.1 (CAr), 138.8 (C-8), 166.6 (CO2), 168.1 (CO); HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C23H27N2O4 395.1965; Found
395.1971.
4.21 (q, J = 7.1 Hz, 2H, CH2CH3), 6.85 (d, J = 4.4 Hz, 1H, H-2′); 13
C
NMR (100.6 MHz, CDCl3) δ 14.1 (CH3), 25.4 (C-3), 25.7 (C-4′),
32.8 (C-5′), 36.6 (C-2), 42.0 (C-3′), 51.5 (OCH3), 61.3 (CH2CH3),
132.6 (C-1′), 142.3 (C-2′), 171.8 (COO), 173.3 (COO), 197.8 (CO);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H19O5 255.1227;
Found 255.1228.
( 2 a R , 6 a S , 8 S , 1 4 b S ) - 4 , 8 - B i s ( h y d r o x y m e t h y l ) -
2,2a,5,6,6a,8,9,14b-octahydro-1H-benz[f ]indolo[2,3-a]-
quinolizine (10). POCl3 (1.12 mL, 12.16 mmol) was added to a
solution of lactam 7 (600 mg, 1.52 mmol) in toluene (20 mL), and the
solution was stirred at 100 °C for 1.5 h. The solvent was evaporated,
and dry methanol (30 mL) was added to the residue. NaBH4 (173 mg,
4.57 mmol) was slowly added at 0 °C to the solution, and the mixture
was stirred, allowing it to reach room temperature (about 1.5 h). The
reaction was quenched by addition of saturated aqueous NaHCO3.
The methanol was evaporated, and the aqueous solution was extracted
Ethyl (3S,7aR,11aR)-3-(3-Indolylmethyl)-5-oxo-
2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]quinoline-9-carbox-
ylate (7). Isobutyric acid (105 μL, 1.13 mmol) was added to a
solution of tryptophanol (97 mg, 0.51 mmol) and oxoester 6 (100 mg,
0.39 mmol) in toluene (8 mL). The mixture was stirred at reflux for 24
h, with azeotropic elimination of water by a Dean−Stark system. The
resulting mixture was cooled and concentrated under reduced
pressure. The residue was dissolved in EtOAc and washed with
saturated aqueous NaHCO3. The combined organic extracts were
dried, filtered, and concentrated to give a foam. Crystallization from
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with CH2Cl2. The combined organic extracts were dried, filtered, and
concentrated. LiAlH4 (866 mg, 23 mmol) was added to a solution of
the resulting residue in anhydrous THF (25 mL), and the mixture was
stirred at reflux for 3 h. The reaction was quenched at 0 °C with water
(866 μL), and 10% aqueous NaOH (866 μL) and then water (2.5 mL)
were added. The resulting suspension was dried with MgSO4, filtered,
and concentrated. Flash chromatography of the resulting oil (9:1
CH2Cl2−MeOH) afforded pentacyclic compound 10 as a light yellow
7.06 (d, J = 8.4 Hz, 2H, ArH), 7.12 (t, J = 7.2 Hz, 1H, ArH), 7.19 (t, J
= 7.2 Hz, 1H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.78 (d, J = 8.0 Hz,
1H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 14.2 (CH3), 22.6 (C-
10), 25.6 (C-7), 26.2 (C-11), 29.9 (CH2-ind), 30.9 (C-6), 40.6 (C-7a),
49.3 (NCH2), 55.2 (CH3O), 56.3 (C-3), 60.5 (CH3CH2), 68.0
(CH2O), 92.6 (C-11a), 109.6 (CHAr), 110.8 (CAr), 114.1 (CHAr),
119.3 (CHAr), 119.5 (CHAr), 121.9 (CHAr), 126.0 (CHAr), 128.2
(CHAr), 129.4 (CAr), 129.6 (CAr), 130.0 (C-9), 136.5 (CAr), 137.7
(C-8), 159.1 (CAr), 166.5 (CO2), 169.3 (CO); HRMS (ESI-TOF) m/
z: [M + H]+ Calcd for C31H35N2O5 515.2540; Found 515.2545.
(2aR,6aS,8S,14bS)-4,8-Bis(hydroxymethyl)-14-(4-methoxy-
benzyl)-2,2a,5,6,6a,8,9,14b-octahydro-1H-benz[f ]indolo[2,3-
a]quinolizine (13). Operating as in the preparation of compound 10,
from lactam 12 (2.04 g, 4.66 mmol) in toluene (58 mL) and POCl3
(3.4 mL, 37.3 mmol), then NaBH4 (540 mg, 14 mmol) in anhydrous
methanol (92 mL), and finally LiAlH4 (1.77 g, 46.6 mmol) in THF
(90 mL), pentacyclic diol 13 (1.45 g, 68%) was obtained after
purification by column chromatography (99:1 CH2Cl2−MeOH): mp:
119−122 °C; [α]2D2 − 34.0 (c 0.4, CHCl3); IR (film) ν (cm−1) 3428
1
foam (308 mg, 60%): IR (film) ν (cm−1) 3402 (OH, NH); H NMR
(400 MHz, CDCl3, COSY, g-HSQC) δ 1.14 (qd, J = 12.8, 4.8 Hz, 1H,
H-6), 1.40 (qd, J = 13.2, 4.8 Hz, 1H, H-2), 1.67 (m, 2H, H-2, H-6),
1.78 (dd, J = 17.2, 4.0 Hz, 1H, H-5), 1.91 (m, 1H, H-5), 2.12 (m, 1H,
H-1), 2.35 (m, 2H, H-1, H-2a), 2.80 (dd, J = 8.8, 1.6 Hz, 2H, H-9),
3.27 (dq, J = 12.8, 2.4 Hz, 1H, H-6a), 3.51 (m, 1H, H-8), 3.82 (s, 2H,
CH2OH), 3.86 (dd, J = 11.6, 6.4 Hz, 1H, CH2OH), 4.04 (dd, J = 11.6,
7.6 Hz, 1H, CH2OH), 4.27 (brs, 1H, H-14b), 5.55 (d, J = 4.0 Hz, 1H,
H-3), 6.99 (td, J = 7.6, 0.8 Hz, 1H, ArH), 7.06 (td, J = 8.0, 1.2 Hz, 1H,
ArH), 7.33 (d, J = 8.0 Hz, 1H, ArH), 7.37 (d, J = 7.6 Hz, 1H, ArH);
13C NMR (100.6 MHz, CDCl3) δ 24.2 (C-6), 25.1 (C-2), 26.5 (C-9),
27.1 (C-1), 27.3 (C-5), 37.6 (C-2a), 53.8 (C-14b), 55.9 (C-6a), 62.9
(C-8), 64.3 (CH2OH), 66.7 (CH2OH), 108.5 (CAr), 112.0 (CHAr),
118.3 (CHAr), 119.7 (CHAr), 121.7 (CHAr), 127.1 (C-3), 128.9
(CAr), 137.5 and 137.8 (2CAr, C-4); HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C21H27N2O2 339.2067; Found 339.2064.
1
(OH); H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 1.26−1.41
(m, 2H, H-2, H-6), 1.60−1.70 (m, 2H, H-2, H-6), 1.81 (dd, J = 14.4,
3.2 Hz, 1H, H-5), 1.87−2.02 (m, 2H, H-1, H-5), 2.19−2.25 (m, 1H,
H-1), 2.39 (m, 1H, H-2a), 2.78−2.82 (m, 2H, H-9), 3.31 (ddd, J =
12.0, 5.2, 3.2 Hz, 1H, H-6a), 3.53 (tt, J = 8.8, 6.4 Hz, 1H, H-8), 3.75 (s,
3H, CH3O), 3.75−3.81 (dd, J = 11.2, 5.2 Hz, 1H, CH2OH), 3.90 (s,
2H, CH2OH), 3.87−3.95 (dd, J = 12.0, 5.2 Hz, 1H, CH2OH), 4.22 (t,
J = 5.2 Hz, 1H, H-14b), 5.25 (d, J = 17.2 Hz, 1H, NCH2), 5.43 (d, J =
17.2 Hz, 1H, NCH2), 5.48 (d, J = 3.2 Hz, 1H, H-3), 6.78 (d, J = 8.4
Hz, 2H, ArH), 6.83 (d, J = 8.4 Hz, 2H, ArH), 7.11 (td, J = 7.2, 1.2 Hz,
1H, ArH), 7.15 (td, J = 6.8, 1.2 Hz, 1H, ArH), 7.23 (d, J = 8.0 Hz, 1H,
ArH), 7.47 (d, J = 6.8 Hz, 1H, ArH); 13C NMR (100.6 MHz, CDCl3)
δ 24.8 (C-6), 25.0 (C-2), 25.2 (C-9), 26.2 (C-5), 27.1 (C-1), 36.2 (C-
2a), 47.5 (NCH2), 53.0 (C-6a), 54.5 (C-14b), 55.2 (CH3O), 61.0 (C-
8), 62.5 (CH2OH), 66.6 (CH2OH), 109.3 (CHAr), 110.0 (CAr),
114.2 (CHAr), 117.8 (CHAr), 119.4 (CHAr), 121.5 (CHAr), 126.4
(C-3), 126.6 (CHAr), 126.9, 130.1, and 136.9 (C-4, 2CAr), 137.9
(CAr), 158.7 (CAr); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C29H35N2O3 459.2642; Found 459.2628.
(2aR,6aS,8S,14bS)-4-[(tert-Butyldiphenylsilyloxy)methyl]-8-
(hydroxymethyl)-14-(4-methoxybenzyl)-2,2a,5,6,6a,8,9,14b-
octahydro-1H-benz[f ]indolo[2,3-a]quinolizine (14). Imidazole
(32 mg, 0.48 mmol) and tert-butyldiphenylsilyl chloride (191 μL,
0.72 mmol) were added at 0 °C to a solution of diol 13 (220 mg, 0.48
mmol) in CH2Cl2 (25 mL). The solution was stirred for 15 min at this
temperature. Then, saturated aqueous NH4Cl was added, and the
mixture was extracted with CH2Cl2. The combined organic extracts
were dried, filtered, and concentrated. Flash chromatography (99:1
CH2Cl2−MeOH) of the residue afforded alcohol 14 as a yellow foam
(254 mg, 76%): IR (film) ν (cm−1) 3428 (OH), 1109 (OSi); 1H NMR
(400 MHz, CDCl3, COSY, g-HSQC) δ 1.02 [s, 9H, C(CH3)3], 1.26−
1.37 (m, 2H, H-2, H-6), 1.60−1.66 (m, 2H, H-2, H-6), 1.80−1.83 (m,
2H, H-5), 1.93−2.04 (m, 1H, H-1), 2.25−2.29 (m, 1H, H-1), 2.39 (m,
1H, H-2a), 2.79−2.82 (m, 2H, H-9), 3.31 (dm, J = 12.0 Hz, 1H, H-
6a), 3.53−3.57 (m, 1H, H-8), 3.73 (s, 3H, CH3O), 3.81 (dd, J = 10.8,
4.8 Hz, 1H, CH2OH), 3.94 (s, 2H, CH2OSi), 3.91−3.96 (m, 1H,
CH2OH), 4.26 (m, 1H, H-14b), 5.27 (d, J = 17.6 Hz, 1H, NCH2),
5.45 (d, J = 17.6 Hz, 1H, NCH2), 5.48 (m, 1H, H-3), 6.79 (d, J = 8.4
Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 2H, ArH), 7.11 (td, J = 7.6, 1.2 Hz,
1H, ArH), 7.16 (td, J = 8.0, 1.2 Hz, 1H, ArH), 7.24 (d, J = 7.2 Hz, 1H,
ArH), 7.31−7.41 (m, 6H, ArH), 7.47 (d, J = 6.8 Hz, 1H, ArH), 7.60−
7.64 (m, 4H, ArH); 13C NMR (100.6 MHz, CDCl3) δ 19.2
[C(CH3)3], 24.7 and 24.8 (C-6, C-2), 25.2 (C-9), 26.1 (C-5), 26.8
[C(CH3)3], 27.1 (C-1), 36.3 (C-2a), 47.5 (NCH2), 53.0 (C-6a), 54.6
(C-14b), 55.2 (CH3O), 61.3 (C-8), 62.4 (CH2OH), 67.1 (CH2OSi),
109.3 (CHAr), 110.0 (CAr), 114.2 (CHAr), 117.8 (CHAr), 119.4
(CHAr), 121.5 (CHAr), 125.1 (C-3), 126.6 (CHAr), 126.9 (CAr),
130.1 (CAr), 133.7 (CAr), 133.7 (CAr), 136.2 (C-4, CAr), 137.9
(CAr), 158.7 (CAr); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C45H53N2O3Si 697.3820; Found 697.3807.
(9S,4aS,15bR)-3,9-Bis(hydroxymethyl)-1,2,4a,5,6,7,9,10-
octahydrobenz[i]indolo[2,3-a]quinolizine (11). Operating as in
the above cyclization of lactam 7, from the minor isomer 7′ (180 mg,
0.35 mmol) in toluene (5.0 mL) and POCl3 (257 μL, 2.79 mmol),
then NaBH4 (40 mg, 1.05 mmol) in anhydrous methanol (7.0 mL),
and finally LiAlH4 (200 mg, 5.25 mmol) in THF (6 mL), compound
11 (77 mg, 65%) was obtained after column chromatography (9:1
1
CH2Cl2−MeOH): IR (film) ν (cm−1) 3405 (OH, NH); H NMR
(400 MHz, CDCl3, COSY, g-HSQC) δ 1.40 (dm, J = 12.4 Hz, 1H, H-
6), 1.51 (dt, J = 14.4, 4.4 Hz, 1H, H-5), 1.58 (dm, J = 12.4 Hz, 1H, H-
5), 1.60 (m, 1H, H-6), 1.79 (m, 1H, H-1), 2.01 (dm, J = 16.0 Hz, 1H,
H-2), 2.25 (dm, J = 16.0 Hz, 1H, H-2), 2.30 (ddd, J = 13.2, 4.4, 2.8 Hz,
1H, H-1), 2.38 (td, J = 12.0, 2.4 Hz, 1H, H-7), 2.51 (dd, J = 15.6, 4.0
Hz, 1H, H-10), 2.63 (dd, J = 15.6, 10.4 Hz, 1H, H-10), 2.73 (m, 1H,
H-7), 2.84 (brs, 1H, H-4a), 3.64 (d, J = 5.2 Hz, 1H, CH2OH), 3.75−
3.79 (m, 2H, H-9, CH2OH), 4.12 (s, 2H, CH2OH), 7.10 (td, J = 7.2,
0.8 Hz, 1H, ArH), 7.16 (td, J = 7.2, 0.8 Hz, 1H, ArH), 7.33 (d, J = 7.6
Hz, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH); 13C NMR (100.6 MHz,
CDCl3) δ 19.3 (C-10), 21.1 (C-6), 22.6 (C-2), 27.4 (C-5), 34.6 (C-1),
38.7 (C-4a, C-7), 54.0 (C-9), 56.5 (C-15b), 61.2 (CH2OH), 66.5
(CH2OH), 107.1 (CAr), 110.9 (CHAr), 118.0 (CHAr), 119.5
(CHAr), 121.5 (CHAr), 125.0 (C-4), 127.4 (CAr), 135.4 (CAr),
137.9 (CAr), 138.5 (C-3); HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C21H27N2O2 339.2067; Found 339.2066.
Ethyl (3S,7aR,11aR)-3-[1-(4-Methoxybenzyl)-3-indolyl-
methyl]-5-oxo-2,3,5,6,7,7a,10,11-octahydrooxazolo[2,3-j]-
quinoline-9-carboxylate (12). Lactam 7 (195 mg, 0.49 mmol) was
added at 0 °C under a nitrogen atmosphere to a suspension of NaH
(60% dispersion in mineral oil, 18 mg, 0.74 mmol) in dry DMF (5
mL), and the resulting mixture was stirred for 30 min. 4-
Methoxybenzyl chloride (80 μL, 0.59 mmol) was added, and the
stirring was continued at 0 °C for 1 h. After neutralization with
saturated aqueous NH4Cl, the mixture was extracted three times with
Et2O. The combined organic extracts were washed with brine, dried,
filtered, and concentrated. Flash chromatography of the residue (4:1
hexane−EtOAc) provided lactam 12 (170 mg, 67%): IR (film) ν
1
(cm−1) 1643 (NCO), 1707 (COO); H NMR (400 MHz, CDCl3,
COSY, g-HSQC) δ 1.28 (t, J = 6.8 Hz, 3H, CH3), 1.53−1.57 (m, 2H,
H-7, H-11), 1.84 (dd, J = 14.0, 5.6 Hz, 1H, H-11), 2.04−2.10 (m, 1H,
H-7), 2.25−2.29 (m, 1H, H-7a), 2.29−2.34 (m, 1H, H-10), 2.39 (m,
1H, H-10), 2.46 (ddd, J = 18.8, 11.6, 7.2 Hz, 1H, H-6), 2.62 (dd, J =
18.8, 5.2 Hz, 1H, H-6), 2.93 (dd, J = 14.4, 4.0 Hz, 1H, CH2-ind), 3.56
(dd, J = 14.4, 3.2 Hz, 1H, CH2-ind), 3.77 (s, 3H, CH3O), 3.79 (t, J =
8.8 Hz, 1H, CH2O), 4.00 (t, J = 8.8 Hz, 1H, CH2O), 4.18 (q, J = 6.8
Hz, 2H, CH2CH3), 4.64 (ddd, J = 11.2, 8.0, 3.2 Hz, 1H, H-3), 5.20 (s,
2H, NCH2), 6.83 (d, J = 8.4 Hz, 3H, H-8, ArH), 6.93 (s, 1H, H-2 ind),
7743
dx.doi.org/10.1021/jo5013543 | J. Org. Chem. 2014, 79, 7740−7745

The Journal of Organic Chemistry
Note
(2aR,6aS,8S,14bS)-4-[(tert-Butyldiphenylsilyloxy)methyl]-8-
formyl-14-(4-methoxybenzyl)-2,2a,5,6,6a,8,9,14b-octahydro-
1H-benz[f ]indolo[2,3-a]quinolizine (15). 4 Å powdered sieves
(376 mg) and NMO (115 mg, 0.96 mmol) were added at room
temperature under an inert atmosphere to a solution of alcohol 14
(190 mg, 0.27 mmol) in CH3CN (6 mL). Tetrapropylammonium
perruthenate (19 mg, 0.054 mmol) was then added in one portion,
and the resulting mixture was stirred at room temperature for 30 min.
The solvent was evaporated, and the dark residue was dissolved in
CH2Cl2. The solution was filtered through a short pad of silica using
CH2Cl2 as the eluent. The filtrate was concentrated to give aldehyde
15 (95 mg, 50%), which was used in the next step without purification:
ArH), 7.09 (s, 1H, ArH), 7.28−7.36 (m, 7H, ArH), 7.48 (m, 1H,
ArH), 7.64−7.68 (m, 4H, ArH).
(2aR,6aS,14bS)-4-[(tert-Butyldiphenylsilyloxy)methyl]-14-(4-
methoxybenzyl)-2,2a,5,6,6a,8,9,14b-octahydro-1H-benz[f ]-
indolo[2,3-a]quinolizine (17). First step: Burgess reagent was added
in three portions (3 × 30 mg) to a solution of oximes 16 (88 mg, 0.12
mmol) in CH2Cl2 (1.25 mL) over a period of 2 h. The resulting
solution was stirred at room temperature for 2 h. Water was then
added, and the mixture was extracted with CH2Cl2. The combined
organic extracts were dried, filtered, and concentrated to afford the
corresponding cyano derivative, which was used in the next step
without purification. Second step: AcOH (17 μL) was added to a
solution of NaBH3CN (28 mg, 0.45 mmol) in CH3CN (120 μL), and
the solution was stirred at room temperature for 30 min. Then, a
solution of the above cyano compound (88 mg, 0.075 mmol) in
CH3CN (115 μL) was added, and the resulting mixture was stirred at
room temperature for 9 h. CH2Cl2 and 4 N aqueous NaOH were then
added, and the mixture was extracted with CH2Cl2. The organic
extracts were washed with brine, dried, filtered, and concentrated.
Flash chromatography of the residue (9:1 hexane−EtOAc) afforded
compound 17 (35 mg, 70%, two steps): IR (film) ν (cm−1) 1111
1
IR (film) ν (cm−1) 1656 (CHO), 1110 (OSi); H NMR (400 MHz,
CDCl3, COSY, g-HSQC) δ 1.03 [s, 9H, C(CH3)3], 1.49 (qd, J = 12.8,
4.0 Hz, 1H, H-1), 1.65−1.79 (m, 3H, H-2, H-6), 1.83 (dm, J = 12.8
Hz, 1H, H-1), 1.93−1.96 (m, 2H, H-5), 2.14 (m, 1H, H-6), 2.47 (s,
1H, H-2a), 3.04 (ddd, J = 15.2, 5.6, 2.0 Hz, 1H, H-9), 3.23 (d, J = 15.2
Hz, 1H, H-9), 3.73 (m, 1H, H-6a), 3.74 (s, 3H, CH3O), 3.97 (m, 1H,
H-8), 4.08 (s, 2H, CH2OSi), 4.18 (d, J = 10.8 Hz, 1H, H-14b), 5.14 (d,
J = 16.8 Hz, 1H, NCH2), 5.23 (d, J = 16.8 Hz, 1H, NCH2), 5.27 (s,
1H, H-3), 6.78 (d, J = 8.8 Hz, 2H, ArH), 6.87 (d, J = 8.8 Hz, 2H,
ArH), 7.03 (m, 1H, ArH), 7.06−7.09 (m, 2H, ArH), 7.24−7.34 (m,
6H, ArH), 7.51 (m, 1H, ArH), 7.64−7.68 (m, 4H, ArH), 9.66 (s, 1H,
CHO); 13C NMR (100.6 MHz, CDCl3) δ 19.2 [C(CH3)3], 21.3 (C-
5), 23.3 (C-9), 26.8 [C(CH3)3, C-6], 29.4 (C-1), 30.6 (C-2), 35.9 (C-
2a), 47.2 (NCH2), 55.2 (CH3O), 55.3 (C-6a), 55.6 (C-14b), 59.8 (C-
8), 67.6 (CH2OSi), 107.1 (CAr), 110.0 (CHAr), 114.1 (CHAr), 117.9
(CHAr), 119.4 (CHAr), 121.4 (CHAr), 124.3 (C-3), 126.7 (CAr),
127.0 (CHAr), 127.5 (CHAr), 129.5 (CHAr), 135.4 (CAr), 135.5
(CAr), 137.1 (CAr), 137.8 (C-4), 137.9 (CAr), 158.7 (CAr), 205.6
(CHO); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C45H51N2O3Si
695.3663; Found 695.3636.
(2aR,6aS,8S,14bS)-4-[(tert-Butyldiphenylsilyloxy)methyl]-8-
[ (hydr ox yim in o)m e thyl ]- 14- (4- me th ox y be nzy l ) -
2,2a,5,6,6a,8,9,14b-octahydro-1H-benz[f ]indolo[2,3-a]-
quinolizine (16). NH2OH·HCl (42 mg, 0.59 mmol) was added to a
solution of aldehyde 15 (75 mg, 0.11 mmol) in pyridine (250 μL) and
ethanol (250 μL). The mixture was heated at reflux for 2 h, and then
the solvent was removed under reduced pressure. Aqueous H2SO4 (0.2
N, 2 mL) was added, and the mixture was stirred for 10 min and
extracted with EtOAc. The organic extracts were washed with 2 N
aqueous NaOH, dried, filtered, and concentrated to afford oximes 16
(44 mg, 56%): Major isomer: IR (film) ν (cm−1) 1110 (OSi); 1H NMR
(400 MHz, CDCl3, COSY, g-HSQC) δ 1.02 [s, 9H, C(CH3)3], 1.48−
1.52 (m, 2H, H-2, H-5), 1.64−1.67 (m, 3H, H-1, H-2, H-6), 1.91 (m,
1H, H-5), 2.00 (m, 1H, H-1), 2.32 (d, J = 14.0 Hz, 1H, H-6), 2.46 (m,
1H, H-2a), 2.79 (d, J = 15.2 Hz, 1H, H-9), 3.06 (brs, 1H, H-6a), 3.16
(ddd, J = 15.2, 5.2, 2.0 Hz, 1H, H-9), 3.68 (d, J = 10.4 Hz, 1H, H-14b),
3.75 (s, 3H, CH3O), 4.08 (s, 2H, CH2OSi), 4.15 (m, 1H, H-8), 5.17
(d, J = 17.2 Hz, 1H, NCH2), 5.29 (m, 1H, H-3), 5.30 (d, J = 17.2 Hz,
1H, NCH2), 6.80 (d, J = 8.4 Hz, 2H, ArH), 6.88 (d, J = 8.4 Hz, 2H,
ArH), 7.09 (d, J = 4.8 Hz, 2H, ArH), 7.28−7.36 (m, 7H, ArH), 7.33
(m, 1H, CHNOH), 7.48 (m, 1H, ArH), 7.64−7.68 (m, 4H, ArH); 13C
NMR (100.6 MHz, CDCl3) δ 19.3 [C(CH3)3], 21.2 (C-2), 26.6 (C-9),
26.8 [C(CH3)3, C-6], 29.7 (C-1), 29.7 (C-5), 36.0 (C-2a), 47.4
(NCH2), 50.0 (C-8), 55.2 (CH3O), 55.4 (C-6a), 55.6 (C-14b), 67.5
(CH2OSi), 107.0 (CAr), 109.8 (CHAr), 114.1 (CHAr), 118.0
(CHAr), 119.3 (CHAr), 121.4 (CHAr), 124.2 (C-3), 127.0 (CHAr),
127.2 (CHAr), 127.5 (CHAr), 127.6 (CHAr), 129.5 (CHAr), 129.7
(CAr), 133.9 (CAr), 134.0 (CAr), 135.4 (CHAr), 135.5 (CHAr),
136.7 (CAr), 137.5 (C-4), 138.3 (CAr), 151.2 (CHNOH), 158.8
(CAr); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C45H52N3O3Si
710.3772; Found 710.3762. Minor isomer: 1H NMR (400 MHz,
CDCl3, COSY, g-HSQC, selected resonances) δ 1.02 [s, 9H,
C(CH3)3], 2.35 (dm, J = 14.0 Hz, 1H, H-6), 2.43 (m, 1H, H-2a),
2.89 (d, J = 15.2 Hz, 1H, H-9), 2.96 (brs, 1H, H-6a), 3.10 (m, 1H, H-
9), 3.65 (d, J = 10.4 Hz, 1H, H-14b), 3.75 (s, 3H, CH3O), 4.08 (s, 2H,
CH2OSi), 4.82 (m, 1H, H-8), 5.18 (d, J = 17.2 Hz, 1H, NCH2), 5.27
(m, 1H, H-3), 5.33 (d, J = 17.2 Hz, 1H, NCH2), 6.76 (m, 1H,
CHNOH), 6.78 (d, J = 8.4 Hz, 2H, ArH), 6.87 (d, J = 8.4 Hz, 2H,
1
(OSi); H NMR (400 MHz, CDCl3, COSY, g-HSQC) δ 1.06 [s, 9H,
C(CH3)3], 1.56 (td, J = 11.6, 4.8 Hz, 1H, H-1), 1.62−1.72 (m, 3H, H-
2, H-6), 1.88−1.92 (m, 2H, H-1, H-5), 2.11 (t, J = 14.8 Hz, 1H, H-5),
2.22−2.28 (m, 2H, H-6, H-8), 2.48 (brs, 1H, H-2a), 2.70−2.76 (m,
2H, H-6a, H-9), 2.88 (m, 1H, H-9), 3.40−3.47 (m, 2H, H-8, H-14b),
3.77 (s, 3H, CH3O), 4.11 (s, 2H, CH2OSi), 5.18 (d, J = 17.2 Hz, 1H,
NCH2), 5.30 (d, J = 17.2 Hz, 1H, NCH2), 5.33 (m, 1H, H-3), 6.80 (d,
J = 8.8 Hz, 2H, ArH), 6.88 (d, J = 8.8 Hz, 2H, ArH), 7.06−7.10 (m,
3H, ArH), 7.29−7.37 (m, 7H, ArH), 7.51−7.53 (m, 1H, ArH), 7.48
(m, 1H, ArH), 7.67−7.70 (m, 2H, ArH); 13C NMR (100.6 MHz,
CDCl3) δ 19.3 [C(CH3)3], 21.3 (C-5), 23.1 (C-9), 26.8 [C(CH3)3],
27.1 (C-6), 28.5 (C-1), 30.2 (C-2), 36.0 (C-2a), 46.3 (C-8), 47.6
(NCH2), 55.2 (CH3O), 58.6 (C-6a), 59.9 (C-14b), 67.5 (CH2OSi),
109.7 (CHAr), 114.0 (CHAr), 118.0 (CHAr), 119.2 (CHAr), 121.1
(CHAr), 124.6 (C-3), 127.0 (CHAr), 127.1 (CHAr), 127.5 (CHAr),
129.0 (CAr), 129.5 (CHAr), 129.5 (CHAr), 129.9 (CAr), 133.9
(CAr), 134.0 (CAr), 135.4 (CHAr), 135.5 (CHAr), 137.7 (CAr),
137.9 (C-4), 138.1 (CAr), 158.6 (CAr); HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C44H51N2O2Si 667.3714; Found 667.3711.
(2aR,6aS,14bS)-4-(Hydroxymethyl)-2,2a,5,6,6a,8,9,14b-octa-
hydro-1H-benz[f ]indolo[2,3-a]quinolizine (5). First step: Thio-
phenol (125 μL, 2.25 mmol) and cold TFA (1.40 mL) were added at 0
°C to compound 17 (30 mg, 0.045 mmol), and the mixture was stirred
for 2 h. The solution was poured into a cold saturated solution of
NaHCO3, and the resulting mixture was extracted with CH2Cl2. The
combined organic extracts were dried, filtered, and concentrated. Flash
chromatography (4:1 hexane−EtOAc) afforded the deprotected indole
derivative (22 mg, 90%): 1H NMR (400 MHz, CDCl3, COSY, g-
HSQC) δ 1.01 [s, 9H, C(CH3)3], 1.57−1.69 (m, 2H, H-1), 1.82 (m,
3H, H-2, H-5, H-6), 2.05 (m, 1H, H-5), 2.28 (m, 2H, H-6, H-8), 2.55
(brs, 1H, H-2a), 2.65 (brs, 1H, H-6a), 2.70 (d, J = 15.2 Hz, 1H, H-9),
2.82 (m, 1H, H-9), 3.35 (brd, J = 10.4 Hz, 1H, H-14b), 3.47 (dd, J =
11.2, 4.0 Hz, 1H, H-8), 4.02 (d, J = 13.2 Hz, 1H, CH2OSi), 4.09 (d, J =
13.2 Hz, 1H, CH2OSi), 5.38 (m, 1H, H-3), 7.07−7.20 (m, 6H, ArH),
7.27−7.32 (m, 4H, ArH), 7.62−7.67 (m, 4H, ArH), 7.69 (brs, 1H,
NH); 13C NMR (100.6 MHz, CDCl3) δ 19.3 [C(CH3)3], 20.8 (C-5),
22.6 (C-9), 26.8 [C(CH3)3], 26.9 and 27.1 (C-6, C-1), 30.1 (C-2),
36.3 (C-2a), 47.4 (C-8), 58.0 (C-6a), 59.8 (C-14b), 67.3 (CH2OSi),
108.7 (CAr), 110.7 (CHAr), 118.0 (CHAr), 119.3 (CHAr), 121.1
(CHAr), 123.9 (C-3), 127.4 (CHAr), 127.5 (CHAr), 129.4 (CHAr),
129.5 (CHAr), 133.8 (CAr), 134.0 (CAr), 135.4 (CHAr), 135.5
(CHAr), 136.0 (CAr), 137.9 (C-4). Second step: TBAF (55 μL, 0.055
mmol) was added at 0 °C to a solution of the above deprotected
indole derivative (15 mg, 0.028 mmol) in THF (2.8 mL). The mixture
was stirred for 4 h, and then concentrated under reduced pressure.
Flash chromatography of the residue afforded pentacyclic alcohol 5 (7
mg, 85%): mp: 241−242 °C; 1H NMR (500 MHz, CD3OD, g-HSQC)
δ 1.33 (m, 1H, H-1), 1.56−1.64 (m, 1H, H-2), 1.72 (td, J = 14.0, 6.0
Hz, 1H, H-6), 1.86−1.96 (m, 2H, H-1, H-5), 2.16−2.22 (m, 2H, H-2,
7744
dx.doi.org/10.1021/jo5013543 | J. Org. Chem. 2014, 79, 7740−7745

The Journal of Organic Chemistry
Note
H-5), 2.40 (dm, J = 14.0 Hz, 1H, H-6), 2.46 (m, 1H, H-8), 2.62 (brs,
1H, H-2a), 2.77 (dd, J = 16.0, 4.0 Hz, 1H, H-9), 2.82 (brs, 1H, H-6a),
2.93 (dm, J = 16.0 Hz, 1H, H-9), 3.56 (brs, 1H, H-14b), 3.68 (m, 1H,
H-8), 3.92 (s, 2H, CH2OH), 5.39 (brs, 1H, H-3), 6.95 (td, J = 8.0, 1.5
Hz, 1H, ArH), 7.03 (td, J = 8.0, 1.5 Hz, 1H, ArH), 7.27 (d, J = 7.5 Hz,
1H, ArH), 7.37 (d, J = 7.5 Hz, 1H, ArH); when the spectrum was
recorded in CF3CO2D (400 MHz), the olefinic proton appeared at δ
5.86 as a broad singlet; 13C NMR (125.0 MHz, CD3OD) δ 22.1 (C-5),
22.5 (C-9), 26.9 and 27.3 (C-2, C-6), 30.7 (C-1), 37.3 (C-2a), 48.8
(C-8), 60.8 (C-6a), 62.4 (C-14b), 67.7 (CH2OH), 108.2 (CAr), 111.9
(CHAr), 118.6 (CHAr), 119.8 (CHAr), 122.0 (CHAr), 127.2 (C-3),
128.3 (CAr), 136.0 (CAr), 138.1 (CAr), 139.9 (C-4); m/z (%) 308
(91, M+), 307 (100, [M − 1]+), 291 (44), 277 (17), 223 (15), 197
(24), 184 (36), 171 (29), 170 (58), 169 (68), 156 (21), 144 (31);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H25N2O 309.1961;
Found 309.1954.
(14) Minor amounts (17%) of a second cis-diastereoisomer, 7′, were
also isolated.
(15) For similar α-amidoalkylation reactions from (S)-tryptophanol-
derived lactams lacking the substituent at the aminal carbon under
Bischler−Napieralski conditions, see ref 12b.
(16) This oxidation proved to be difficult, and other methods
(Swern, Dess−Martin, IBX) were unsatisfactory. For a review on
TPAP as a catalytic oxidant, see: Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639−666.
(17) Unfortunately, this is the only NMR data reported1 for the
natural product.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of compounds 5, 7, 7′, and
10−17, and a table with mass-spectral fragmentations of natural
nitraraine and compound 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: amat@ub.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the MINECO, Spain (Project
CTQ2012-35250) is gratefully acknowledged. Thanks are also
due to the MECD (Spain) for a fellowship to F.A.
REFERENCES
■
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