Total synthesis of the indole alkaloids henrycinol A and B

Article abstract of DOI:10.1016/j.tet.2014.05.028

The total synthesis of new indole alkaloids henrycinol A and B were accomplished starting from l-tryptophan methyl ester. The key step is a stereochemically flexible Pictet-Spengler reaction governed by the presence or absence of an N-allyl group in the tryptophan precursor. The natural products henrycinol A and B were synthesized in good overall yield in eight and nine steps, respectively.

Full text of DOI:10.1016/j.tet.2014.05.028

Tetrahedron 70 (2014) 4611e4616
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of the indole alkaloids henrycinol A and B
*
Kavirayani R. Prasad , John Eugene Nidhiry, Makuteswaran Sridharan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2014
Received in revised form 12 May 2014
Accepted 13 May 2014
Available online 17 May 2014
The total synthesis of new indole alkaloids henrycinol A and B were accomplished starting from L-
tryptophan methyl ester. The key step is a stereochemically flexible PicteteSpengler reaction governed
by the presence or absence of an N-allyl group in the tryptophan precursor. The natural products hen-
rycinol A and B were synthesized in good overall yield in eight and nine steps, respectively.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Indole alkaloids
Henrycinols A and B
PicteteSpengler reaction
N-Allyl-tryptophan methyl ester
1. Introduction
ester 5 with hydroxy aldehyde 6 was identified as the key reaction
for the synthesis of 1,2,3,4-tetrahydro-
and 2.5 Cyclisation of the primary alcohol in 3
assemble the complete framework of henrycinols. The required
b
-carboline unit present in 1
Henrycinols A and B (Fig. 1) are two new indole alkaloids iso-
b
was envisaged to
lated from Melodinus henryi CRAIB of Apocynaceae genus by Zhang
et al.1 These alkaloids belong to the class of 1,2,3,4-tetrahydro-
b
-
aldehyde 6 can be accessed from (ꢀ)-2,3-O-isopropylidene-
D-
carbolines, a structural moiety, that is, ubiquitous in a number of
threitol.
indole alkaloids and therapeutically important molecules.2 Struc-
turally henrycinols A and B differ from simple 1,2,3,4-tetrahydro-b-
carbolines with the presence of two hydroxy groups on the D ring of
the alkaloid. We have been interested in the synthesis of indole
alkaloids3 and herein we report the first total synthesis of henry-
cinols A and B.
Fig. 1. Henrycinols A and B.
The PicteteSpengler reaction is one of the widely used reactions
Scheme 1. Retrosynthesis for henrycinol A.
for the construction of 1,2,3,4-tetrahydro-
amine derivatives with aldehydes/ketones.4 As outlined in
Scheme 1, the PicteteSpengler reaction of -tryptophan methyl
b-carbolines from trypt-
2. Results and discussion
L
Accordingly, the synthetic sequence commenced with the Pic-
teteSpengler reaction of the known aldehyde 66 derived from
* Corresponding author. Fax: þ91 80 23600529; e-mail addresses: prasad@org-
chem.iisc.ernet.in, kavirayaniprasad@yahoo.com (K.R. Prasad).
(ꢀ)-2,3-O-isopropylidene-
D
-threitol 7 with L-tryptophan methyl
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.028

4612
K.R. Prasad et al. / Tetrahedron 70 (2014) 4611e4616
ester 5 to afford a separable mixture of 1,3-cis tetrahydro-
boline 8 as the major product in 50% yield and 1,3-trans tetrahy-
dro- -carboline 8
in 18% yield.7 Since the natural product
comprise the trans tetrahydro- -carboline isomer, we were posed
with the challenge of procuring the required 1,3-trans-1,2,3,4-
b-car-
a
b
b
b
tetrahydro-b-carboline in high yield in the PicteteSpengler re-
action. Pioneering work by Cook’s group8 demonstrated the
switching of 1,3-cis to 1,3-trans products in the PicteteSpengler
reaction of tryptophan methyl ester with benzaldehyde. They ob-
served that the reaction of N-substituted tryptophan esters ren-
dered the 1,3-trans-1,2,3,4-tetrahydro-b-carbolines under non-
acidic conditions, while simple tryptophan esters without sub-
stitution afforded the 1,3-cis carbolines under acidic conditions.
Taking cue from these observations, we reasoned that the Pic-
teteSpengler reaction of N-allyl-
the aldehyde 6 should afford the 1,3-trans-1,2,3,4-tetrahydro-
carboline 4 . Indeed this was found to be the case, and the reaction
of N-allyl- -tryptophan methyl ester 9 with the aldehyde 6 (derived
L-tryptophan methyl ester 9 with
b
-
b
L
from 7), afforded the 1,3-trans-1,2,3,4-tetrahydro-b-carboline 4b as
the major product in 79% yield (Scheme 2).
Scheme 2. Synthesis of the 1,3-trans-1,2,3,4-tetrahydro-b-carboline 4b.
Reduction of the ester in 4
in 85% yield. The primary alcohol in 10
cinnamoyl ester 11 (90% yield), which on desilylation with TBAF
afforded the free alcohol 3 in 94% yield. Mesylation of the alcohol
followed by reaction with NaH furnished the cyclized product 14
in 62% yield along with the primary alcohol 13 resulting from the
cleavage of the cinnamoyl ester in 35% yield.9 Deprotection of the
acetonide in 14 furnished henrycinol (1) in 78% yield
b
with LiAlH4 furnished the alcohol
Scheme 3. Total synthesis of henrycinol A.
10
b
b
was transformed to the
b
b
b
b
b
A
(Scheme 3). The spectral and physical data of synthetic sample was
in fair agreement with that reported for the natural product.10
Moreover, the stereochemistry of the newly formed stereogenic
center in the PicteteSpengler reaction and the structure of the
natural product was unambiguously confirmed by X-ray crystal
structure analysis of 1.11
Scheme 4. Total synthesis of henrycinol B.
Performing the same reaction sequence with the 1,3-cis 1,2,3,4-
tetrahydro
b-carboline 4a afforded 3-epi-henrycinol A (see
Supplementary data for a chart comprising the yields in the in-
dividual steps and characterization of the compounds derived from
3. Conclusion
the 1,3-cis isomer 8a).
Reaction of henrycinol A (1) with isobutyryl chloride in presence
of Bu2SnO and CsF12 afforded henrycinol B (2) in 24% yield, the
regioisomer 15 in 10% yield and the recovered starting compound
henrycinol A in 47% yield (Scheme 4).
In conclusion, stereoselective first total synthesis of the indole
alkaloids henrycinol A (1) and B (2) were accomplished from N-
allyl-
L
-tryptophan methyl ester (9) and (ꢀ),2,3-O-isopropylidene-
D-
threitol in 34% and 8% overall yields, respectively in eight and nine

K.R. Prasad et al. / Tetrahedron 70 (2014) 4611e4616
4613
linear steps. The key transformation is the trans-selective formation
of 1,3-dialkyl-1,2,3,4-tetrahydro- -carboline in the PicteteSpengler
1457 cmꢀ1 1H NMR (400 MHz, CDCl3): dH 8.48 (br s, 1H), 7.53
;
b
(d, J¼7.6 Hz, 1H), 7.32 (dd, J¼7.6, 0.8 Hz, 1H), 7.18 (t, J¼7.6 Hz, 1H),
7.12 (t, J¼7.6 Hz, 1H), 4.79 (d, J¼4.4 Hz, 1H), 4.31 (dd, J¼7.6, 4.4 Hz,
1H), 4.08 (t, J¼5.2 Hz, 1H), 3.82 (d, J¼4.0 Hz, 2H), 3.78 (dd, J¼7.6,
4.0 Hz, 1H), 3.69 (s, 3H), 3.16 (dd, J¼15.2, 4.0 Hz, 1H), 3.08 (dd,
J¼15.2, 6.0 Hz, 1H), 2.46 (br s, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 0.93
(s, 9H), 0.10 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): dC 174.2, 135.8,
131.4, 126.7, 121.7, 119.2, 118.0, 110.8, 108.7, 108.3, 79.6, 78.6, 64.3,
53.8, 52.0, 50.0, 27.2, 26.7, 25.9 (3C), 24.2, 18.4, ꢀ5.3, ꢀ5.5 ppm;
cyclisation using Cook’s protocol.
4. Experimental section
4.1. General procedures
Column chromatography was performed on Acme’s silica gel,
100e200 mesh. TLC plates were visualized either with UV, in an
iodine chamber, or with phosphomolybdic acid spray. All reagents
were purchased from commercial sources and used without addi-
tional purification. K2CO3 was pre-dried in a hot air oven at 120 ꢁC
overnight prior to use. Benzene was distilled over phosphorus
pentoxide and stored under nitrogen. Dichloromethane was freshly
distilled over calcium hydride before use. THF was freshly distilled
over Naebenzophenone ketyl. Petroleum ether refers to the frac-
HRMS: [MþH] found 475.2625.
C25H38N2O5SiþH requires
475.2628.
4.1.2. Synthesis of 4
amine 8 (0.38 g, 0.80 mmol) in dry DMF (3 mL) was added K2CO3
b from 8b
. To a pre-cooled solution (0 ꢁC) of the
b
(0.16 g, 1.16 mmol) followed by allyl bromide (0.70 mL, 8.00 mmol)
under nitrogen. The reaction mixture was heated to 80 ꢁC and was
stirred at the same temperature for 1.5 h. After completion of the
reaction (as indicated by TLC), it was cooled to room temperature,
the contents poured into ice cold water (40 mL) and was extracted
with EtOAc (3ꢂ15 mL). The combined organic layers were washed
with brine (10 mL) and dried over anhydrous Na2SO4. Removal of
the solvent in vacuo followed by silica gel column chromatography
of the resulting residue with petroleum ether/EtOAc (9:1) as eluent
tion boiling in the 60e80 ꢁC. Melting points were uncorrected and
Ò
€
recorded on Buchi Melting Point M-560 equipment. Optical ro-
tations were recorded on Rudolph AutopolÒ IV polarimeter at 25 ꢁC
and IR spectra on Perkin ElmerÒ Spectrum BX spectrophotometer.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Bruker 400 MHz machine in CDCl3 as solvent and the chemical
shifts were reported in parts per million from the residual solvent
as an internal standard. HRMS was obtained using a Waters
Micromass-QTOF operating in the electrospray ionization (ESI)
afforded 4b (0.33 g, 80%) as a white solid. Rf 0.60 (15% EtOAc/pe-
troleum ether); mp 148e150 ꢁC; ½a D24
þ38.5 (c 1.3, CHCl3); IR (KBr):
ꢃ
nmax 3401, 2928, 1726, 1456, 1149 cmꢀ1; 1H NMR (400 MHz, CDCl3):
dH 8.47 (br s, 1H), 7.52 (d, J¼8.0 Hz, 1H), 7.32 (d, J¼8.0 Hz, 1H), 7.17
(td, J¼8.0, 0.8 Hz, 1H), 7.11 (td, J¼7.6, 0.8 Hz, 1H), 5.91 (dddd, J¼16.4,
10.0, 8.4, 5.2 Hz, 1H), 5.22 (d, J¼16.4 Hz, 1H), 5.19 (d, J¼10.0 Hz, 1H),
4.77 (br s, 1H), 4.67 (dd, J¼8.4, 3.6 Hz, 1H), 4.12 (dd, J¼5.2, 3.6 Hz,
1H), 3.87 (dd, J¼11.2, 2.0 Hz, 1H), 3.77 (dd, J¼11.2, 3.2 Hz, 1H), 3.65
(dd, J¼14.4, 4.8 Hz, 1H), 3.59 (s, 3H), 3.52e3.45 (m, 2H), 3.21
(dd, J¼15.2, 3.2 Hz, 1H), 3.00 (ddd, J¼15.2, 5.6, 1.2 Hz, 1H), 1.46
(s, 6H), 0.94 (s, 9H), 0.09 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): dC
173.2, 136.0, 135.9, 132.1, 126.4, 121.5, 119.0, 117.92, 117.85, 110.7,
108.3, 107.5, 78.5, 75.0, 63.3, 57.3, 55.9, 54.8, 51.4, 27.1, 26.9, 26.0
(3C), 24.2, 18.4, ꢀ5.2, ꢀ5.4 ppm; HRMS: [MþNa] found 537.2761.
mode. N-Allyl-L-tryptophan methyl ester was prepared according
to the procedure described.13
4.1.1. Preparation of carbolines 8a and 8b. To a stirred solution of 7
(0.58 g, 2.10 mmol) in EtOAc (7 mL) was added IBX (1.76 g,
6.30 mmol) and the resulting suspension was refluxed for 4 h. The
reaction mixture was cooled to room temperature, water (2 mL)
was added and stirred for 10 min. The clear organic layer was
passed through a short pad of CeliteÒ and the CeliteÒ pad was
washed with EtOAc (30 mL). The organic layer was washed with
satd NaHCO3 solution (2ꢂ10 mL), followed by brine (20 mL) and
dried over anhydrous Na2SO4. Removal of solvent under reduced
pressure yielded the crude aldehyde 6, which was used in the next
step without further purification.
C28H42N2O5SiþNa requires 537.2761.
4.1.3. Preparation of 4 from N-allyl-L-tryptophan methyl ester
b
To a stirred solution of the aldehyde 6 (obtained above) in dry
9. The reaction was performed using a procedure similar to that
described for the synthesis of 8 . Thus, PicteteSpengler reaction
of the crude aldehyde 6 obtained from the oxidation of 7 (0.58 g,
2.10 mmol) with N-allyl- -tryptophan methyl ester (0.65 g,
2.50 mmol) afforded 4 (0.85 g) in 79% yield. The spectral and
benzene (10 mL) was added
L-tryptophan methyl ester 5 (0.55 g,
a/b
2.52 mmol) and the resulting mixture was refluxed for 5 h under
nitrogen. After completion of the reaction (as indicated by TLC), it
was cooled to room temperature and the solvent was removed
under reduced pressure. Silica gel column chromatography of the
resulting residue using petroleum ether/EtOAc (9:1 to 4:1) as elu-
L
b
physical characteristics of the compound were identical to that
obtained above.
ent furnished 8a (0.50 g, 50%) as a white solid and 8b (0.18 g,18%) as
a pale yellow oil.
4.1.4. Preparation of 10b. A solution of the ester 4b (0.86 g,
1.67 mmol) in dry THF (6 mL) was added drop wise over 5 min to
LiAlH4 (0.13 g, 3.42 mmol) suspended in dry THF (3 mL) at 0 ꢁC. The
reaction mixture was stirred for 0.5 h at the same temperature.
After the reaction was complete (as indicated by TLC), it was cau-
tiously quenched by the addition of EtOAc (10 mL). The precipitate
formed was removed by filtering through a short pad of CeliteÒ and
the CeliteÒ pad was washed with EtOAc (40 mL). The crude residue
thus obtained after evaporation of the solvent was purified by silica
gel column chromatography using petroleum ether/EtOAc (7:3) as
4.1.1.1. Compound 8
a
. Rf 0.50 (25% EtOAc/petroleum ether);
mp 101e102 ꢁC; ½a D24
ꢃ
ꢀ20.9 (c 1.0, CHCl3); IR (KBr): nmax 3453, 3446,
2931,1733,1457 cmꢀ1; 1H NMR (400 MHz, CDCl3): dH 8.62 (br s,1H),
7.52 (d, J¼8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.21 (td, J¼7.6, 1.2 Hz,
1H), 7.13 (td, J¼7.6, 1.2 Hz, 1H), 4.36e4.23 (m, 2H), 4.18 (d, J¼7.6 Hz,
1H), 3.91 (dd, J¼11.6, 2.8 Hz, 1H), 3.84 (s, 3H), 3.85e3.77 (m, 1H),
3.66 (dd, J¼11.6, 4.0 Hz, 1H), 3.16 (ddd, J¼15.2, 4.0, 2.0 Hz, 1H), 2.85
(ddd, J¼15.2, 11.6, 2.0 Hz, 1H), 2.07 (br s, 1H), 1.58 (s, 3H), 1.53
(s, 3H), 0.95 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): dC 173.3, 135.8, 133.6, 126.7, 121.9, 119.4, 118.0,
111.0, 109.3, 108.0, 80.5, 78.6, 63.2, 56.1, 55.4, 52.1, 27.3, 27.2, 25.9
(3C), 25.7, 18.4, ꢀ5.3, ꢀ5.5 ppm; HRMS: [MþH] found 475.2625.
eluent to furnish the alcohol 10b (0.69 g, 85%) as a pale yellow oil. Rf
0.30 (30% EtOAc/petroleum ether); ½a D24
ꢃ
ꢀ19.6 (c 1.4, CHCl3); IR
(thin film): nmax 3470, 3402, 2932, 1462, 1255 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): dH 8.29 (br s, 1H), 7.52 (d, J¼8.0 Hz, 1H), 7.35
(d, J¼8.0 Hz, 1H), 7.20 (t, J¼7.6 Hz, 1H), 7.14 (t, J¼7.6 Hz, 1H),
5.92e5.83 (m, 1H), 5.19 (d, J¼16.4 Hz, 1H), 5.18 (d, J¼10.4 Hz, 1H),
4.40 (dd, J¼7.6, 3.6 Hz, 1H), 4.17 (d, J¼3.6 Hz, 1H), 4.10 (dd, J¼7.6,
3.6 Hz, 1H), 3.87e3.68 (m, 5H), 3.48 (d, J¼11.2 Hz, 1H), 2.89 (dd,
C
25H38N2O5SiþH requires 475.2628.
4.1.1.2. Compound 8 . Rf 0.30 (25% EtOAc/petroleum ether);
b
½ ꢃ
a 2D4
þ28.9 (c 1.5, CHCl3); IR (thin film): nmax 3469, 3352, 2931, 1737,

4614
K.R. Prasad et al. / Tetrahedron 70 (2014) 4611e4616
J¼14.0, 8.0 Hz, 1H), 2.65e2.53 (m, 2H), 1.49 (s, 3H), 1.40 (s, 3H), 0.94
(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): dC
136.3, 136.2, 131.1, 126.8, 121.8, 119.4, 118.1, 118.0, 110.9, 109.8, 108.8,
79.3, 78.4, 63.6, 61.6, 56.6, 56.0, 48.7, 27.1, 26.8, 25.9 (3C), 19.6, 18.4,
ꢀ5.3, ꢀ5.4 ppm; HRMS: [MþH] found 487.2991. C27H42N2O4SiþH
requires 487.2992.
pyridine (0.24 mL, 1.90 mmol) followed by methanesulphonyl
chloride (0.10 mL, 1.29 mmol) and the resulting mixture was stirred
at the same temperature for 1.5 h. The reaction was poured into ice
cold water (10 mL) and extracted with EtOAc (2ꢂ20 mL). The
combined organic layers were washed with brine (10 mL) and dried
over anhydrous Na2SO4. Evaporation of the solvent under reduced
pressure gave the crude residue, which on silica gel column chro-
matography using petroleum ether/EtOAc (3:2) as eluent yielded
4.1.5. Preparation of 11
b
. To a pre-cooled (0 ꢁC), well stirred solu-
tion of the alcohol 10
b
(0.25 g, 0.51 mmol) in dry CH2Cl2 (3 mL)
the mesylate 12b (0.37 g, 86%) as a pale yellow oil. Rf 0.50 (40%
were sequentially added Et3N (0.22 mL, 1.59 mmol), cinnamoyl
chloride (0.13 g, 0.78 mmol) and DMAP (0.01 g, 0.08 mmol). The
reaction mixture was warmed to room temperature and stirred at
the same temperature for 1.5 h. After completion of the reaction
(as indicated by TLC), the contents were poured into ice cold water
(20 mL) and extracted with EtOAc (2ꢂ15 mL). The combined
organic layers were washed with brine (5 mL) and dried over
anhydrous Na2SO4. The crude residue obtained after removal of
solvent under reduced pressure was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1) as eluent to
EtOAc/petroleum ether); ½a D24
ꢃ
ꢀ17.1 (c 1.1, CHCl3); IR (thin film):
nmax 3405, 3401, 2934, 1710, 1637, 1356, 1174 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): dH 8.32 (br s, 1H), 7.71 (d, J¼16.0 Hz, 1H),
7.58e7.53 (m, 3H), 7.45e7.38 (m, 3H), 7.36 (d, J¼8.0 Hz, 1H), 7.20
(td, J¼7.6, 1.2 Hz, 1H), 7.14 (td, J¼7.6, 1.2 Hz, 1H), 6.49 (d, J¼16.0 Hz,
1H), 5.86 (dddd, J¼16.8, 9.6, 7.2, 5.2 Hz, 1H), 5.20 (d, J¼16.8 Hz, 1H),
5.19 (d, J¼9.6 Hz, 1H), 4.66 (dd, J¼11.2, 6.4 Hz, 1H), 4.54 (dd, J¼11.2,
2.4 Hz, 1H), 4.42e4.33 (m, 2H), 4.20 (dd, J¼11.2, 6.4 Hz, 1H),
4.19e4.13 (m, 2H), 3.87 (dt, J¼12.4, 6.4 Hz, 1H), 3.53 (dd, J¼14.0,
5.2 Hz, 1H), 3.12 (dd, J¼14.0, 7.6 Hz, 1H), 3.06 (s, 3H), 2.81
(d, J¼6.0 Hz, 2H), 1.48 (s, 3H), 1.42 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): dC 166.8, 145.1, 136.2, 136.1, 134.2, 130.3, 130.2, 128.9 (2C),
128.1 (2C), 126.7, 121.9, 119.4, 118.4, 118.2, 117.7, 110.9, 109.7, 109.5,
78.0, 74.9, 68.8, 63.7, 54.7, 54.3, 51.6, 37.7, 26.9, 26.5, 21.3 ppm;
HRMS: [MþH] found 581.2333. C31H36N2O7SþH requires 581.2321.
afford the ester 11b (0.30 g, 94%) as a pale yellow oil. Rf 0.40 (10%
EtOAc/petroleum ether); ½a D24
ꢀ15.9 (c 1.75, CHCl3); IR (thin film):
ꢃ
nmax 3395, 2932, 1707, 1254, 1168 cmꢀ1; 1H NMR (400 MHz, CDCl3):
dH 8.33 (br s, 1H), 7.71 (d, J¼16.0 Hz, 1H), 7.63e7.52 (m, 3H),
7.45e7.38 (m, 3H), 7.36 (d, J¼8.0 Hz, 1H), 7.20 (t, J¼7.6 Hz, 1H), 7.14
(t, J¼7.6 Hz, 1H), 6.47 (d, J¼16.0 Hz, 1H), 5.92 (ddt, J¼16.8, 10.0,
6.8 Hz, 1H), 5.24 (d, J¼17.6 Hz, 1H), 5.19 (d, J¼10.0 Hz, 1H), 4.62 (dd,
J¼10.8, 5.2 Hz, 1H), 4.55 (dd, J¼8.0, 3.2 Hz, 1H), 4.22 (br s, 2H),
3.95e3.83 (m, 3H), 3.79 (dd, J¼10.8, 3.2 Hz, 1H), 3.53 (dd, J¼14.0,
6.4 Hz, 1H), 3.32 (dd, J¼14.0, 6.4 Hz, 1H), 2.85 (d, J¼5.2 Hz, 2H), 1.51
(s, 3H), 1.45 (s, 3H), 0.95 (s, 9H), 0.12 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) dC 166.8, 144.9, 136.4, 136.1, 134.3, 131.2, 130.3,
128.8 (2C), 128.1 (2C), 126.9, 121.7, 119.2, 118.1, 117.8, 117.7, 110.8,
109.3, 108.5, 78.1, 77.3, 63.5, 63.2, 55.5, 53.9, 52.1, 27.0, 26.8, 26.0
(3C), 21.9, 18.4, ꢀ5.2, ꢀ5.3 ppm; HRMS: [MþH] found 617.3414.
4.1.8. Preparation of 13
dispersion in mineral oil, 0.72 mmol) was added in two portions to
a well stirred, pre-cooled (0 ꢁC) solution of the mesylate 12
(0.21 g,
b and 14b. Sodium hydride (0.029 g of 60%
b
0.36 mmol) in dry THF (4 mL) under nitrogen atmosphere. The
reaction mixture was slowly warmed to room temperature and
stirred at the same temperature for 2.5 h. After the reaction was
complete (as indicated by TLC), it was cautiously quenched by ad-
dition of cold satd NH4Cl solution (5 mL), water (10 mL) and
extracted with EtOAc (2ꢂ20 mL). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous Na2SO4. The
crude residue resulting from the removal of the solvent in vacuo
was purified by silica gel column chromatography using petroleum
C
36H48N2O5SiþH requires 617.3411.
4.1.6. Preparation of 3
b
. To a pre-cooled (0 ꢁC) solution of the TBS
ether 11 (0.29 g, 0.47 mmol) in dry THF (5 mL) was added TBAF
b
ether/EtOAc (9:1 to 3:2) to afford 13b (0.042 g, 35%) and 14b
(0.70 mL of 1.0 M solution in THF, 0.70 mmol) drop wise under
nitrogen atmosphere. The reaction mixture was warmed to room
temperature and stirred at the same temperature for 1 h. After
completion of the reaction (as indicated by TLC), the reaction
mixture was diluted with ice cold water (10 mL) and extracted with
EtOAc (2ꢂ15 mL). The combined organic layers were washed with
brine (15 mL) and dried over anhydrous Na2SO4. Most of the solvent
was removed in vacuo and the resulting crude residue was purified
by silica gel column chromatography using petroleum ether/EtOAc
(0.108 g, 62%) as a pale yellow solids.
4.1.8.1. Compound 13
b
. Rf 0.40 (40% EtOAc/petroleum ether);
ꢀ23.4 (c 1.2, CHCl3); IR (KBr): nmax 3462, 2926,
1H NMR (400 MHz, CDCl3): dH 7.50
mp 156e157 ꢁC; ½a D24
ꢃ
1458, 1225, 1104 cmꢀ1
;
(d, J¼8.0 Hz, 1H), 7.29 (d, J¼8.0 Hz, 1H), 7.25 (td, J¼7.6, 1.2 Hz, 1H),
7.15 (td, J¼7.6, 1.2 Hz, 1H), 5.98 (dddd, J¼17.2, 10.0, 8.0, 5.2 Hz, 1H),
5.20 (dd, J¼17.2, 1.2 Hz, 1H), 5.16 (dd, J¼10.0, 1.2 Hz, 1H), 4.68 (dd,
J¼10.0, 5.6 Hz, 1H), 4.32 (d, J¼10.4 Hz, 1H), 4.19 (ddd, J¼14.4, 8.8,
5.6 Hz, 1H), 3.92 (dd, J¼10.4, 8.8 Hz, 1H), 3.81 (d, J¼4.8 Hz, 1H), 3.76
(d, J¼10.0 Hz, 1H), 3.68e3.62 (m, 2H), 3.58 (dd, J¼13.2, 4.8 Hz, 1H),
3.21 (dd, J¼13.2, 8.0 Hz, 1H), 2.96 (ddd, J¼16.4, 6.4, 2.4 Hz, 1H), 2.40
(dd, J¼16.4, 1.6 Hz, 1H), 1.59 (s, 3H), 1.52 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): dC 136.5, 136.3, 130.0, 128.2, 121.9, 119.7, 118.5,
117.4, 112.9, 109.3, 106.0, 77.6, 75.6, 61.0, 55.4, 53.5, 51.9, 46.0, 27.1,
26.8, 18.6 ppm; HRMS: [MþH] found 355.2025. C21H26N2O3þH
requires 355.2022.
(3:2) as eluent to afford the alcohol 3b (0.21 g, 90%) as a pale yellow
oil. Rf 0.40 (40% EtOAc/petroleum ether); ½a D24
ꢀ38.5 (c 1.8, CHCl3);
ꢃ
IR (thin film): nmax 3461, 3401, 2932,1709,1637, 1170 cmꢀ1; 1H NMR
(400 MHz, CDCl3): dH 8.46 (br s, 1H), 7.63 (d, J¼16.0 Hz, 1H), 7.55
(d, J¼7.6 Hz, 1H), 7.52e7.48 (m, 2H), 7.45e7.36 (m, 3H), 7.33
(d, J¼7.6 Hz, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.13 (t, J¼7.2 Hz, 1H), 6.41
(d, J¼16.0 Hz, 1H), 5.96 (ddt, J¼17.2, 10.4, 6.8 Hz, 1H), 5.33
(d, J¼17.2 Hz, 1H), 5.28 (d, J¼10.4 Hz, 1H), 4.59 (dd, J¼11.2, 4.8 Hz,
1H), 4.36 (dd, J¼8.0, 3.6 Hz, 1H), 4.26 (br s, 2H), 4.09 (dd, J¼11.2,
7.2 Hz, 1H), 3.79 (ddd, J¼9.2, 4.8, 4.4 Hz, 1H), 3.76e3.68 (m, 1H),
3.69e3.55 (m, 3H), 3.51 (dd, J¼14.0, 6.0 Hz, 1H), 2.95 (d, J¼4.0 Hz,
2H), 1.48 (s, 3H), 1.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): dC
166.7, 145.2, 136.0, 134.7, 134.2, 130.4, 130.2, 128.8 (2C), 128.1 (2C),
126.7, 121.9, 119.4 (2C), 118.3, 117.5, 110.8, 108.6, 108.4, 80.2, 77.1,
62.1, 61.9, 55.2, 53.7, 53.6, 26.9, 26.8, 22.9 ppm; HRMS: [MþH]
found 503.2549. C30H34N2O5þH requires 503.2546.
4.1.8.2. Compound 14
b
. Rf 0.60 (20% EtOAc/petroleum ether);
ꢀ56.1 (c 1.2, CHCl3); IR (KBr): nmax 2930, 1713,
1H NMR (400 MHz, CDCl3): dH 7.58
mp 140e141 ꢁC; ½a D24
ꢃ
1637, 1458, 1166 cmꢀ1
;
(d, J¼16.0 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.48e7.42 (m, 2H),
7.41e7.35 (m, 3H), 7.29 (d, J¼8.0 Hz, 1H), 7.25 (t, J¼7.6 Hz, 1H), 7.16
(td, J¼7.6, 1.2 Hz, 1H), 6.46 (d, J¼16.0 Hz, 1H), 6.05e5.95 (m, 1H),
5.33 (d, J¼17.2 Hz, 1H), 5.21 (d, J¼10.4 Hz, 1H), 4.69 (dd, J¼10.0,
5.6 Hz, 1H), 4.63 (dd, J¼10.8, 4.8 Hz, 1H), 4.37 (dd, J¼10.8, 7.6 Hz,
1H), 4.23 (ddd, J¼10.8, 9.2, 5.6 Hz, 1H), 4.16 (d, J¼10.0 Hz, 1H),
3.85e3.68 (m, 4H), 3.54 (dd, J¼14.0, 7.6 Hz, 1H), 3.01 (dd, J¼16.0,
4.1.7. Preparation of mesylate 12
the alcohol 3 (0.37 g, 0.74 mmol) in dry CH2Cl2 (4 mL) was added
b
. To a pre-cooled (0 ꢁC) solution of
b

K.R. Prasad et al. / Tetrahedron 70 (2014) 4611e4616
4615
6.0 Hz,1H), 2.87 (d, J¼16.0 Hz,1H), 1.58 (s, 3H), 1.50 (s, 3H) ppm; 13
C
1H), 4.54 (dd, J¼11.2, 6.8 Hz, 1H), 4.32 (dd, J¼11.2, 6.8 Hz, 1H), 4.24
(d, J¼9.6 Hz, 1H), 4.05 (t, J¼9.6 Hz, 1H), 3.72 (td, J¼6.4, 6.0 Hz, 1H),
3.66 (dd, J¼11.2, 9.6 Hz, 2H), 3.54 (dd, J¼14.0, 4.8 Hz, 1H), 3.22 (dd,
J¼14.0, 8.0 Hz, 1H), 2.97 (dd, J¼16.0, 4.8 Hz, 1H), 2.69e2.60 (m, 2H),
1.22 (d, J¼6.8 Hz, 3H), 1.21 (d, J¼7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): dC 176.7, 166.9, 145.2, 136.9, 136.3, 134.3, 130.3,
128.8 (2C), 128.2, 128.1 (3C), 121.7, 119.9, 118.5, 117.8, 117.6, 109.5,
105.4, 72.3, 70.3, 64.7, 55.9, 54.5, 51.4, 44.7, 34.0, 19.0, 18.88,
18.85 ppm; HRMS: [MþNa] found 537.2367. C31H34N2O5þNa re-
quires 537.2365.
NMR (100 MHz, CDCl3): dC 166.9, 145.0, 137.3, 136.2, 134.2, 131.3,
130.3, 128.8 (2C), 128.6, 128.0 (2C), 121.9, 119.8, 118.6, 117.8, 117.5,
112.6, 109.4, 107.1, 80.3, 75.3, 62.2, 56.3, 53.6, 52.5, 46.1, 27.1, 26.8,
22.2 ppm; HRMS: [MþH] found 485.2440. C30H32N2O4þH requires
485.2440.
4.1.9. Synthesis of henrycinol A (1). Pyridinium p-toluenesulpho-
nate (1.13 g, 4.50 mmol) was added to a solution of 14b (0.216 g,
0.45 mmol) in ethanol (8 mL) and the resulting solution was
refluxed for 16 h. After completion of the reaction (as indicated by
TLC), excess ethanol was removed under reduced pressure and the
resulting residue was dissolved in CH2Cl2 (10 mL). The solution was
made basic by addition of solid NaHCO3 (5.0 g) in portions. The
solids were removed by filtration through a short pad of CeliteÒ and
the CeliteÒ pad was washed with CH2Cl2 (40 mL). Removal of the
solvent in vacuo gave a crude residue, which was purified by silica
gel column chromatography using petroleum ether/EtOAc (2:3) as
eluent to furnish henrycinol A (1) (0.155 g, 78%) as a pale yellow
solid. Recrystallisation of 1 from petroleum ether:EtOH solvent
system (4:1) gave crystals suitable for X-ray diffracꢁtion analysis. Rf
4.1.10.2. Compound 15. Rf 0.40 (30% EtOAc/petroleum ether);
½
a 2D4
ꢃ
ꢀ23.4 (c 0.35, CHCl3); IR (thin film): nmax 3460, 1733, 1714,
1638, 1458 cmꢀ1; 1H NMR (400 MHz, CDCl3): dH 7.61 (d, J¼16.0 Hz,
1H), 7.52 (d, J¼8.0 Hz, 1H), 7.51e7.45 (m, 2H), 7.44e7.38 (m, 3H),
7.30 (d, J¼8.0 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 7.15 (t, J¼7.6 Hz, 1H),
6.45 (d, J¼16.0 Hz, 1H), 5.85e5.75 (m, 1H), 5.21 (d, J¼17.2 Hz, 1H),
5.19 (d, J¼9.6 Hz, 1H), 5.12 (d, J¼10.4 Hz, 1H), 4.53 (dd, J¼11.2,
5.6 Hz, 1H), 4.51e4.47 (m, 1H), 4.36 (d, J¼9.6 Hz, 2H), 4.26 (dd,
J¼11.2, 7.2 Hz, 1H), 3.80e3.70 (m, 2H), 3.42 (t, J¼14.0 Hz, 1H), 2.99
(dd, J¼13.2, 7.2 Hz, 2H), 2.68 (sept, J¼7.2 Hz, 1H), 2.58 (d, J¼16.4 Hz,
1H), 1.22 (d, J¼7.2 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) dC 178.1,
166.8, 145.0, 136.6, 136.2, 134.3, 130.3, 130.0, 128.9 (2C), 128.2, 128.0
(2C),121.7,119.8,118.5,117.9,117.2, 109.5,105.6, 73.6, 70.4, 65.1, 53.7,
53.3, 50.8, 47.5, 34.2, 19.1, 18.9, 18.3 ppm; HRMS: [MþH] found
515.2541. C31H34N2O5þH requires 515.2546.
a 24
0.20 (60% EtOAc/petroleum ether); mp 176e177 C; ½ ꢃD ꢀ35.5
(c 0.4, CHCl3), lit.1
½
a 2D4
ꢃ
ꢀ43.7 (c 0.4, CHCl3); IR (KBr): nmax 3410,
2853, 1718, 1458, 1165 cmꢀ1 1H NMR (400 MHz, CDCl3): dH 7.61
;
(d, J¼16.0 Hz, 1H), 7.55 (d, J¼7.6 Hz, 1H), 7.47e7.41 (m, 2H),
7.39e7.32 (m, 3H), 7.29 (d, J¼7.6 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 7.17
(t, J¼7.6 Hz, 1H), 6.44 (d, J¼16.0 Hz, 1H), 6.30e6.19 (m, 1H), 5.27
(d, J¼16.0 Hz, 1H), 5.24 (d, J¼8.8 Hz, 1H), 4.79 (dd, J¼10.8, 4.8 Hz,
1H), 4.59 (dd, J¼10.8, 6.0 Hz, 1H), 4.38e4.23 (m, 3H), 4.05
(t, J¼9.2 Hz, 1H), 3.78e3.70 (m, 1H), 3.65 (t, J¼10.4 Hz, 1H), 3.60
(d, J¼14.8 Hz, 1H), 3.09 (dd, J¼12.8, 9.2 Hz, 1H), 2.96 (dd, J¼16.4,
4.8 Hz,1H), 2.74 (d, J¼16.4 Hz,1H) ppm; 13C NMR (100 MHz, CDCl3):
dC 166.7, 145.3, 136.6, 135.2, 134.2, 130.3, 129.6, 128.8 (2C), 128.04
(2C), 127.99, 121.6, 119.7, 118.9, 118.4, 117.6, 109.7, 104.1, 71.8, 71.0,
65.9, 55.1, 53.8, 50.8, 46.9, 17.9 ppm; HRMS: [MþH] found 467.1947.
Acknowledgements
J.E.N. and M.S. thank the Council of Scientific and Industrial
Research (CSIR) for fellowships. The authors are grateful to Mr. K.
Durga Prasad and Prof. T.N. Guru Row of Solid State and Structural
Chemistry Unit, Indian Institute of Science for their kind help in the
single crystal X-ray diffraction analysis of henrycinol A.
C
27H28N2O4þNa requires 467.1947.
Supplementary data
4.1.10. Synthesis of henrycinol B (2). Di-n-butyltin oxide (0.050 g,
0.20) was added to a solution of henrycinol A (1) (0.058 g,
0.13 mmol) in toluene (2 mL) and the resulting mixture was
refluxed for 4 h under nitrogen. Most of the solvent was removed
under reduced pressure and the resulting residue was dried under
vacuum for 0.5 h. Cesium fluoride (0.041 g, 0.26 mmol) was added
to the residue and the combined contents dried under vacuum for
another 2 h. These contents were suspended in dry CHCl3 (5 mL),
cooled to 0 ꢁC and stirred well under an atmosphere of nitrogen.
Isobutyryl chloride (0.04 mL, 0.38 mmol) was added slowly and the
resulting mixture stirred at 0 ꢁC for 1 h. The contents of the reaction
were passed through a short pad of CeliteÒ and the CeliteÒ pad
washed with CH2Cl2 (20 mL). The organic layer was washed with
satd NaHCO3 solution (10 mL) followed by brine (15 mL), and dried
over anhydrous Na2SO4. Removal of the solvent under reduced
pressure at 30 ꢁC gave a crude residue, which was subjected to silica
gel column chromatography using petroleum ether/EtOAc (17:3 to
3:2) as eluent to afford 15 (7 mg, 10%) as a pale yellow oil and
henrycinol B (2) (0.016 g, 24%) as a pale yellow solid along with
henrycinol A (1) (0.027 g).
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.05.028.
References and notes
1. Zhang, Y. W.; Yang, R.; Cheng, Q.; Ofuji, K. Helv. Chim. Acta 2003, 86, 415e419.
2. Rahman, A. U.; Basha, A. Indole Alkaloids; Hardwood Academic: Reading, UK,
1999.
3. (a) Prasad, K. R.; Nidhiry, J. E. Synlett 2012, 1477e1480; (b) Nidhiry, J. E.; Prasad,
K. R. Tetrahedron 2013, 69, 5525e5536.
4. (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797e1842; (b) Larghi, E. L.;
Amongero, M.; Bracca, A. B. J.; Kaufman, T. S. ARKIVOC 2005, xii, 98e153; (c)
€
Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011,
50, 8538e8564.
5. For recent applications of the PicteteSpengler reaction of tryptophan methyl
ester with protected hydroxy aldehydes, see: (a) Zhang, Q.; Dong, J.; Shi, X.-X.;
Lu, X. Eur. J. Org. Chem. 2012, 3317e3325; (b) Zhang, Q.; Fan, Z.; Dong, J.; Shi, X.-
X.; Lu, X. Tetrahedron: Asymmetry 2013, 24, 633e637; (c) Senthilkumar, S.;
Prasad, S. S.; Kumar, P. S.; Baskaran, S. Chem. Commun. 2014, 1549e1551.
6. (a) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337e3342; (b)
Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron 2002, 58,
1983e1995.
7. At this stage we were not able to ascertain the stereochemistry at the newly
formed stereogenic center in 8a and 8b. However, the stereochemistry of the
newly formed stereogenic center was assigned and confirmed at a later stage by
its conversion to the natural product and by the X-ray crystal structure of the
natural product synthesized.
4.1.10.1. Henrycinol B (2). Rf 0.30 (30% EtOAc/petroleum ether);
mp 73e75 ꢁC; ½a 2D4
ꢃ
ꢀ55.7 (c 0.6, CHCl3), lit.1
½
a 2D4
ꢃ
ꢀ60.7 (c 0.7,
CHCl3); IR (KBr): nmax 3442, 1715, 1634, 1459, 1165 cmꢀ1
;
1H NMR
8. (a) Jawdosiuk, M.; Cook, J. M. J. Org. Chem. 1984, 49, 2699e2701; (b) Sandrin, J.;
Hollinshead, S. P.; Cook, J. M. J. Org. Chem. 1989, 54, 5636e5640; (c) Cox, E. D.;
Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J.
M. J. Org. Chem. 1997, 62, 44e61; (d) Kumpaty, H. J.; Van Linn, M. L.; Kabir, M. S.;
(400 MHz, CDCl3): dH 7.63 (d, J¼16.0 Hz, 1H), 7.50 (d, J¼7.6 Hz, 1H),
7.49e7.45 (m, 2H), 7.43e7.35 (m, 3H), 7.26 (d, J¼7.6 Hz, 1H), 7.22
(t, J¼7.6 Hz, 1H), 7.15 (t, J¼7.6 Hz, 1H), 6.46 (d, J¼16.0 Hz, 1H), 5.99
(dddd, J¼17.6, 10.0, 7.6, 4.8 Hz, 1H), 5.41 (td, J¼9.2, 5.6 Hz, 1H), 5.29
(d, J¼16.4 Hz, 1H), 5.20 (d, J¼10.0 Hz, 1H), 4.58 (dd, J¼11.2, 6.0 Hz,
€
Forsterling, F. H.; Deschamps, J. R.; Cook, J. M. J. Org. Chem. 2009, 74,
2771e2779; (e) Van Linn, M. L.; Cook, J. M. J. Org. Chem. 2010, 75, 3587e3599.
9. Compound 13
b was converted to its corresponding cinnamate ester 14b in 79%
yield, following the procedure described for the preparation of 11
b.

4616
K.R. Prasad et al. / Tetrahedron 70 (2014) 4611e4616
10. A table comprising the 1H and 13C NMR data of the isolated and synthesized
samples of henrycinol A 1 is enclosed in the Supplementary data.
11. Crystal structure was deposited with Cambridge crystallographic data center
(CCDC No. 992874). The data can be collected free of charge from CCDC www.
ccdc.cam.ac.uk/data_request/cif. For ORTEP diagram of 1 see Supplementary
data.
12. (a) Nagashima, N.; Ohno, M. Chem. Lett. 1987, 16, 141e144; (b) Nagashima, N.;
Ohno, M. Chem. Pharm. Bull. 1991, 39, 1972e1982.
13. (a) Leonard, J.; Jones, M. F.; Hague, A. B.; Harms, G. Tetrahedron Lett. 1999, 40,
8141e8145; (b) Ascic, E.; Jensen, J. F.; Nielsen, T. E. Angew. Chem., Int. Ed. 2011,
50, 5188e5191.