An enantio- and diastereocontrolled synthesis of ()-7-deoxy-Trans-dihydronarciclasine

Article abstract of DOI:10.3987/COM-05-S(K)68

An enantio- and diastereocontrolled synthesis of ()-7-deoxy-trans-dihydronarciclasine, a potent antineoplastic phenanthridone alkaloid from the bulbs of Hymenocallis carbaea and H. littoralis, has been developed starting with the chiral cyclohexanoid buil

Full text of DOI:10.3987/COM-05-S(K)68

HETEROCYCLES, Vol. 66, 2005
167
HETEROCYCLES, Vol. 66, 2005, pp. 167 – 173. © The Japan Institute of Heterocyclic Chemistry
Received, 6th October, 2005, Accepted, 16th November, 2005, Published online, 18th November, 2005. COM-05-S(K)68
AN ENANTIO- AND DIASTEREOCONTROLLED SYNTHESIS OF (+)-7-
DEOXY-TRANS-DIHYDRONARCICLASINE †
Takashi Fujimura, Masatoshi Shibuya, Kunio Ogasawara,* and Yoshiharu
Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan. E-mail:
konol@mail.tains.tohoku.ac.jp
iwabuchi@mail.pharm.tohoku.ac.jp
Abstract – An enantio- and diastereocontrolled synthesis of (+)-7-deoxy-trans-
dihydronarciclasine, a potent antineoplastic phenanthridone alkaloid from the
bulbs of Hymenocallis carbaea and H. littoralis, has been developed starting with
the chiral cyclohexanoid building block.
The polyhydroxylated phenanthridones of the Amaryllidacea group,1 represented by pancratistatin (1),2a
7-deoxypancratistatin (2),2b narciclasine (3),2c lycoricidine (4),2d trans-dihydronarciclasine (5),2e and (+)-7-
deoxy-trans-dihydronarciclasine (6),2f have attracted considerable attention due to their diverse range of
pharmacological properties, including antineoplastic,3 antiviral,4 and antiparasite activity.5 Their low
natural abundance and unique structures encompassing up to six contiguous asymmetric centers on the
cyclohexane ring have spurred synthetic researchers to develop an efficient route capable of assembling
them in a stereocontrolled manner. 6,7
OH
OH
OH
HO
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
NH
NH
NH
O
O
O
R
R
R
trans-Dihydronarciclasine: R = OH (5)
7-Deoxy-trans-dehydronarciclasine (6)
Narciclasine: R = OH (3)
Lycoricidine: R = H (4)
Pancratistatin: R = OH (1)
7-Deoxypancratistatin: R = H (2)
As part of our research interest directed toward exploiting the versatility of the chiral cyclohexanoid
building block (7),8,9 obtainable in both enantiomeric forms by the lipase-mediated asymmetric

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HETEROCYCLES, Vol. 66, 2005
desymmetrization of a meso precursor 8, we examined a diastereo- and enantiocontrolled construction of
(+)-7-deoxy-trans-dihydronarciclasine (6), 2f,10 isolated in 1993 by Pettit and coworkers as the principal
substance responsible for the antitumor activity of the bulbs of Hymenocallis carbaea and H. littoralis.
We report here an enantio- and diastereocontrolled synthesis of (+)-7-deoxy-trans-dihydronarciclasine (6)
accomplished in a sequence of 21 steps from (+)-7.
OH
OH
Present
study
OAc
OH
ref. 8
O
O
OH
NH
HO
HO
O
(+)-7
(+)-7-Deoxy-trans-dehydronarciclasine (6)
Scheme 1.
meso-8
With our intent on employing the Banwell-Bischler-Napieralski reaction11 for the B-ring construction and
our interest in verifying the stereoelectronic bias of the tricyclic system as the diastereocontrolling
element, we selected
a
route that involves Pd-catalyzed coupling for installing the
3,4-methylenedioxyphenyl moiety onto the cyclohexane frame. Thus, we first transformed (+)-7 into
the α-iodo enone (11). On treatment with NBS in dichloromethane at -20 °C, the cyclopentene olefin
and the hydroxy group of 7 was simultaneously protected by the formation of a bromo ether to give 9 in
62% yield. 9 was converted into the enone (10), through sequential deacetylation and oxidation. The
12
exposure of (+)-10 to iodine in pyridine and CCl4 gave the desired α-iodo enone (11), which was
immediately subjected to the Pd-catalyzed cross-coupling reaction employing suitable aryl donors.
After considerable experimentation, we found that the addition of CuCl13 and Ph3As14 markedly enhances
the
catalytic
efficiency
of
PdCl2(PPh3)2
for
Stille
coupling
using
3,4-methylenedioxyphenyltributylstannane15 at an ambient temperature to furnish 12, mp 194-195 °C,
32
[α]D –715° (c 0.58, CHCl3), in 65% yield in two steps. In our hands, the attempted Suzuki coupling
required harsh conditions, leading to a considerable decomposition of 11.
To introduce a carbamate functionality which is destined to constitute the B-ring, 12 was reacted with a
mixture of DIBAH and 2,6-di-tert-butyl-4-methylphenol, 16 prepared in situ in CH2Cl2 at -78 °C, to give
24
endo-13, mp 232-233 °C, [α]D +102° (c 0.68, CHCl3), exclusively via a chemo- and diastereoselective
delivery of a hydride from a convex face. On Mitsunobu reaction using (PhO)2PON3, DIPT and PPh3,17
31
the allylic alcohol (13) furnished the azide (14a), [α]D –10.9° (c 0.73, CHCl3), as a single isomer,
presumably via the SN2’ pathway.18, 19 No trace amount of the normal SN2 product (14b) was detected in
this particular case. 14a was then reduced, carbamoylated, and hydrogenated to furnish 15, mp

HETEROCYCLES, Vol. 66, 2005
169
29
131-132 °C, [α]D +66.7° (c 0.78, CHCl3), as a sole product in 98% yield, confirming again the
excellent diastereocontrolling potency of the tricyclic system. Having secured the three requisite
contiguous stereogenic centers, the bromo ether moiety of 15 was reductively disarmed to give rise to 16,
mp 152-153 °C, [α]D27 +43.1° (c 0.52, CHCl3), on Zn-mediated reduction in the presence of acetic acid,20
with the regeneration of a cyclopentene olefin and the hydroxy functionalities. After the protection of
the hydroxy group by the TBS group, the resulting 17 was heated at reflux in Ph2O in the presence of
28
NaHCO321 to give cyclohexene (18), [α]D –36.0° (c 0.45, CHCl3), by retro Diels-Alder reaction.
Without the TBS protection or in the absence of NaHCO3, the yield of 18 was reduced considerably.
Br
Br
Br
OAc
OAc
O
O
v
i
iv
ii, iii
HO
(+)-7
O
O
O
I
11
(+)-10
9
Br
Br
Br
Br
OH
O
N3
vi
vii
N3
O
O
O
O
O
O
O
O
O
O
O
O
14b
12
13
14a
Br
NHCO2Me
xi
xiii
NHCO2Me
vii, ix, x
O
O
O
HO
OTBS
NHCO2Me
O
O
O
O
18
15
16: R =!H
xii
17: R = TBS
Scheme 2. Reagents and conditions: (i) NBS (4 equiv.), CH2Cl2, -30 °C, 2.5 h, 62%; (ii) K2CO3, MeOH, rt,
1 h, 99%; (iii) PDC (2.2 equiv.), CH2Cl2, rt, 2 h, 96%; (iv) I2 (2 equiv.), pyridine-CCl4 (1 : 5), rt, 2 h; (v)
3,4-methylenedioxy- phenyltributylstannane (1.5 equiv.), PdCl2(PPh3)2 (0.1 equiv.), Ph3As (0.2 equiv.),
CuCl (2 equiv.), THF, rt, 18 h, 63% (2 steps); (vi) DIBAH (5 equiv.), 2,6-di-tert-butyl-4-methylphenol (7.5
equiv.), CH2Cl2, -78 oC, 1.5 h, 86%; (vii) DPPA (2.5 equiv.), PPh3 (2.5 equiv.), DIAD (2.5 equiv.), rt, 2 h,
76%; (viii) H2, 10% Pd/C, AcOEt, rt, 10 h, 95%; (ix) ClCO2Me, 1N NaOH, THF, rt, 1.5 h, 95% (2 steps);
(x) H2, 50% Pd(OH)2/C, MeOH, rt, 92%; (xi) Zn (20 equiv.), MeOH-AcOH-THF (60 : 6 : 10), reflux, 2.5
h, 94%; (xii) TBSOTf, Et3N, CH2Cl2, -78 oC, 2 h, 95%; (xiii) NaHCO3 (5.6 equiv.), Ph2O, reflux, 12 min,
87%.
To install the remaining two hydroxy groups at a suitable diastereoselectivity, the TBS group in 18 was
27
replaced with the 2-naphthoyl group to give 20, mp 161-162 °C, [α]D –255° (c 1.32, CHCl3), via 19.

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HETEROCYCLES, Vol. 66, 2005
The projected ring B formation was carried out at this point by treating 20 with Tf2O and DMAP in cold
CH2Cl212 to predominantly afford the desired product (21) in 84 % yield.
Although all the attempted diastereoselective epoxidations were unsuccessful, the catalytic osmylation of
21 gave the diol (22) in 92% yield as an inseparable 11 : 1 mixture,22 in which the stereochemistry of the
major diastereomer was tentatively assigned as α-diol, on the basis of steric considerations. On
treatment with thionyl chloride followed by oxidation with RuCl3/NaIO4,23 the diol (22) provided two
diasteromeric cyclic sulfates, from which 23, mp 222-223 °C, [α]D27 +134° (c 0.22, CHCl3), was obtained
in 52% yield. The cyclic sulfate 23 was cleaved through the participation of the naphthoate functionality
to give a mixture of 24a and 24b, by heating in pyridine at reflux and the following hydrolysis with 2 N
aq. H2SO4 in acetonitrile. Finally, the mixture was subjected to methanolysis to furnish (+)-7-deoxy-
25
trans-dihydronarciclasine (6), mp 299-303 °C, [α]D27 +124° (c 0.1, DMSO), [lit.,2f mp 303-304 °C, [α]D
+138° (c 0.96, DMSO)], in 84% yield. The overall yield of (+)-7-deoxy-trans-dihydronarciclasine (6)
from the chiral building block (+)-7 was 3.2 % in 21 steps.
OH
OH
v, vi
iv
O
O
O
O
OR
iii
OR
O
O
OR
NH
NH
NHCO2Me
O
O
18: R = TBS
19: R = H
i
22: R = 2-Naphthoyl
21: R = 2-Naphthoyl
ii
20: R = 2-Naphthoyl
O
O
O
O
S
O
OH
NH
S
O
O
OR2
OR1
O
O
vii
Ar
O
O
O
O
O
O
OR
NH
NH
O
O
O
O
24a: R1 = 2-Naphthoyl, R2 = H
24b: R1= H, R2 = 2-Naphthoyl!!!!!
23: R = 2-Naphthoyl
viii
(+)-7-Deoxy-trans-dihydronarciclasine (6) R1 = R2= H
Scheme 3. Reagents and conditions: (i) TBAF, THF, rt, 5.5 h, 97%; (ii) 2-naphthoyl chloride (1.5 equiv.),
pyridine (15 equiv.), DMAP (0.2 equiv.), rt, 1.5 h, 97%; (iii) Tf2O (6 equiv.), DMAP (6 equiv.), CH2Cl2, 0
°C, 4 h, 84%; (iv) OsO4 (0.5 equiv.), NMO (1.5 equiv.), THF-H2O (10 : 1), 10 h, 92%; (v) SOCl2 (1.4 equiv.),
pyridine, –30 °C to –20 °C, 1.5 h; (vi) RuCl3·3H2O (0.2 equiv.), NaIO4 (4 equiv.), CCl4-MeCN (1 : 1), rt, 1.5
h, 52% (2 steps); (vii) pyridine, reflux, 1.5 h then 2N H2SO4-CHCl3 (1 : 4), 70 °C, 12 h, 64%; (viii) NaOMe
(10 equiv.), MeOH, rt, 2 h, 84%.
In conclusion, we have demonstrated an alternative utilization of the cyclohexanoid chiral building block
[(+)-7] in the total synthesis of (+)-7-deoxy-trans-dihydronarciclasine.

HETEROCYCLES, Vol. 66, 2005
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