A stereoselective synthesis of naturally occurring (+)-20R-dihydrocleavamine by photo-[2+2]-cycloreversion

Article abstract of DOI:10.1016/S0040-4039(01)01538-6

A stereoselective synthesis of (+)-20R-dihydrocleavamine, an alkaloid from Pandaca eusepala and Tabernamontana eglandulose, has been developed using an enantiopure tricyclic ketone accessible from a meso precursor by employing a photo-[2+2]-cycloreversion

Full text of DOI:10.1016/S0040-4039(01)01538-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7311–7313
A stereoselective synthesis of naturally occurring
(+)-20R-dihydrocleavamine by photo-[2+2]-cycloreversion
Regina Mikie Kanada and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 8 August 2001; revised 21 August 2001; accepted 23 August 2001
Abstract—A stereoselective synthesis of (+)-20R-dihydrocleavamine, an alkaloid from Pandaca eusepala and Tabernamontana
eglandulose, has been developed using an enantiopure tricyclic ketone accessible from a meso precursor by employing a
photo-[2+2]-cycloreversion reaction as the key step. © 2001 Elsevier Science Ltd. All rights reserved.
We have developed an efficient method for the prepara-
tion of an enantiopure tricyclic ketone 21,2 containing a
four-membered ring starting from the readily accessible
meso ene-1,2-diol bis-trimethylsilyl ether 3.3 Since it has
been previously reported4 that racemic 2 collapsed on
irradiation to give cis-4-vinylcyclopent-2-enylketene by
a photo-induced [2+2]-cycloreversion of the four-mem-
bered ring, we were attracted to the conversion of the
enantiopure ketone (−)-2 into (+)-20R-dihydro-
cleavamine 1, an Iboga indole alkaloid isolated from
Pandaca eusepala5 and Tabernaemontana eglandulose,6
by employing the photo-cleavage reaction as the key
step7 (Scheme 1).
indicating that the expected photo-[2+2]-cycloreversion
reaction did occur to give rise to vinyl-ketene 5, which
was reacted spontaneously with the solvent under the
conditions. Catalytic hydrogenation of 6 was next car-
ried out to yield 7, [h]D27 −25.2 (c 1.0, CHCl3), carrying
the 20R-ethyl functionality of the target molecule 1. On
sequential periodate cleavage and borohydride reduc-
tion in the same flask, 7 afforded g-lactone 9, [h]2D6 −0.5
(c 1.0, CHCl3), via diol 8 through a concurrent cycliza-
tion during workup. The primary hydroxy functionality
remaining in 9 was then replaced by an azide function-
ality to give the primary azide 11, [h]2D7 +0.7 (c 1.5,
CHCl3), via mesylate 10. Overall yield of 11 from (−)-2
was 43% in six steps (Scheme 2).
The synthesis was commenced with a modification of
the cyclopentene double bond of the ketone (−)-2 to
alleviate its discrimination from the side-chain double
bond generated after the irradiation. Thus, dihydroxyl-
ation of (−)-2 was first carried out to give selectively
1,2-diol 4, [h]2D9 −180.7 (c 1.0, CHCl3), as a single
isomer probably having exo-configuration in 93% yield
under catalytic osmylation conditions. On irradiation4
in methanol in a Pyrex tube, 4 furnished methyl ester 6,
[h]2D7 −39.8 (c 1.7, CHCl3), in one-step in 57% yield,
Catalytic hydrogenation of the azide 11 in methanol
containing ammonia8 brought about spontaneous lac-
tamization to give the seven-membered lactam 12, [h]D27
+1.6 (c 0.7, CHCl3), which was sequentially O-benzyl-
ated and N-tert-butoxycarbonylated (Boc)9 to give
imide 14, [h]2D6 −24.4 (c 0.6, CHCl3), via the secondary
amide 13, [h]2D6 −13.1 (c 1.0, CHCl3). Reduction of 14
with lithium triethylborohydride9 at low temperature,
followed by treating the crude product with methanolic
20
20
N
H
present study
Ref. 1, 2
14
OTMS
OTMS
14
H
N
H
O
"meso"
(–)-2
3
(+)-20R-dihydrocleavamine 1
Scheme 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01538-6

7312
R. M. Kanada, K. Ogasawara / Tetrahedron Letters 42 (2001) 7311–7313
HO
HO
HO
HO
HO
HO
i
ii
(–)-2
CO2Me
O
O
6
5
4
HO
HO
HO
HO
O
O
X
iii
iv
CO2Me
CO2Me
H
H
9 : X = OH
10 : X = OMs
11 : X = N3
7
8
v
iv
Scheme 2. Reagents and conditions: (i) OsO4 (cat.), 4-methylmorphorine N-oxide (NMO) (93%). (ii) hw, MeOH (57%). (iii) H2,
PtO2, AcOEt (99%). (iv) NaIO4, then NaBH4 (83%). (v) Ms–Cl, Et3N. (vi) NaN3, DMF, 80°C (92%, two steps).
hydrogen chloride, yielded the N-Boc-amino acetal 15
as an epimeric mixture. Treatment of 15 with the
acetylide generated in situ from trimethylsilylacetylene
with butyllithium in dichloromethane in the presence of
dimethylaluminum chloride10 allowed the replacement
of the methoxy functionality by trimethylsilylacetylene
to furnish the seven-membered amine carbamate 16
after desilylation of the resulting silylacetylene mixture
with tetrabutylammonium fluoride (TBAF). The Sono-
gashira reaction11 of 16 with N-ethoxycarbonyl-2-
iodoaniline proceeded without difficulty to afford the
arylacetylene 17 as an epimeric mixture in excellent
yield. Overall yield of 17 from 11 was 47% in six steps
(Scheme 3).
alkynylaniline precursors originally developed by
Yamanaka and co-workers.13 Employing the same con-
ditions, 17 was refluxed with sodium ethoxide in etha-
nol to generate a two-substituted indole. The expected
cyclization reaction took place to give the indole 18 in
65% yield as an epimeric mixture with spontaneous
N-decarboethoxylation under the conditions. Employ-
ing standard procedure, the 3-acetaldehyde moiety was
next installed on the indole ring of 18 obtained. Thus,
on exposure to dimethylmethyleneammonium chlo-
ride,14 18 gave the gramine 19 which, after transforma-
tion into trimethylammonium iodide, was reacted with
potassium cyanide to give 3-acetonitrile 20. Reaction of
20 with diisobutylaluminum hydride15 (DIBAL) at
−78°C, followed by acid hydrolytic workup led to the
generation of 3-acetaldehyde 21 in 75% overall yield
through an imine intermediate.
We have so far synthesized some indolic natural prod-
ucts by employing the indole synthesis12 through 2-
R1
N
Boc
N
O
MeO
iv
i
11
H
H
H
OR2
H
OBn
12 : R1 = R2 = H
13 : R1 = H, R2 = Bn
14 : R1 = Boc, R2 = Bn
15
ii
iii
Boc
N
Boc
N
vi
v
H
H
NH
CO2Et
H
OBn
H
OBn
16
17
Scheme 3. Reagents and conditions: (i) H2, Pd–C, MeOH–NH3 (95%). (ii) BnBr, NaH, THF (84%). (iii) (Boc)2O, ButLi, −78°C
(100%). (iv) LiEt3BH, −78°C, then HCl–MeOH (78%). (v) BuLi, TMS–acetylene, Me2AlCl, CH2Cl2, −78 to 0°C, then TBAF
(75%). (vi) Ar–I, (Ph3P)2PdCl2 (cat.), CuI (cat.), Et3N, reflux (89%).

R. M. Kanada, K. Ogasawara / Tetrahedron Letters 42 (2001) 7311–7313
7313
X
Boc
N
Boc
N
N
ii
v
N
H
i
N
H
N
H
17
H
H
H
H
H
H
H
OBn
H
OBn
H
OX
18
22 : X = Bn
23 : X = H
24 : X = Ms
19 : X = NMe2
20 : X = CN
21 : X = CHO
vi
iii
iv
vii
20
MsO–
+
N
H
viii
14
N
N
H
H
H
N
H
H
H
(+)-20R-dihydrocleavamine 1
25
Scheme 4. Reagents and conditions: (i) NaOEt, EtOH, reflux (65%). (ii) CH2NMe2Cl. (iii) MeI, then KCN, DMF, 100°C (83%,
three steps). (iv) DIBAL, −78°C then 1.6N H2SO4 (92%). (v) BF3, AcOH, CH2Cl2, 0°C then NaBH3CN (60%). (vi) Na, liq. NH3,
ButOH, THF (85%). (vii) Ms–Cl, Et3N. (viii) Na, liq. NH3, ButOH, THF (64%, two steps).
Upon treatment with boron trifluoride–acetic acid com-
plex in dichloromethane, followed by sodium
cyanoborohydride in the same flask, 21 furnished tetra-
cyclic amine 22 in 60% yield through a sequential
N-deprotection and reductive cyclization.16 In order to
construct the ring system of the target molecule 1, 22
was debenzylated to give the primary alcohol 23 which
was then mesylated to form ammonium salt 25,
directly, without isolation of the mesylate 24. As has
been established,7a,17 both of the two epimers consisted
of the mesylate 24 formed ammonium salt 25 as a
mixture of epimers, which, on Birch reduction with
sodium in liquid ammonia, allowed regioselective CꢀN
bond cleavage to afford the targeted (+)-20R-dihydro-
cleavamine 1, [h]2D6 +65.1 (c 0.2, CHCl3) {natural: [h]D
+68 (CHCl3);5 [h]D20 +133 (c 0.078, CHCl3)6}, in 64%
yield as a single product (Scheme 4).
2. Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 1997, 38,
6429.
3. Miller, R. D.; Dolce, D. L.; Merritt, V. Y. J. Org. Chem.
1976, 41, 1204.
4. Miller, R. D.; Abraitys, V. Y. J. Am. Chem. Soc. 1972, 94,
663.
5. Quirin, F.; Debray, M.-M.; Sigaut, C.; Thepenier, P.; Le
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6. van Beek, T. A.; Verpoorte, R.; Svendsen, A. B. Tetra-
hedron 1984, 737.
7. For previous chiral synthesis of 1, see: (a) Takano, S.;
Uchida, W.; Hatakeyama, S.; Ogasawara, K. Chem. Lett.
1982, 733; (b) Danieli, B.; Lesma, G.; Passarella, D.;
Silvani, A. Tetrahedron Lett. 2000, 41, 3489.
8. Sajiki, H. Tetrahedron Lett. 1995, 36, 3465.
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12. (a) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K. J.
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1986, 24, 31.
In conclusion, we have developed an alternative route
to (+)-20R-dihydrocleavamine from a readily accessible
enantiopure precursor containing a cyclobutane moiety
by employing a photo-[2+2]-cycloreversion reaction as
the key step.
Acknowledgements
We are grateful to the Japan Society for the Promotion
of Science for a scholarship (to R.M.K).
14. Gaudry, M.; Jasor, Y.; Khac, B. K. Org. Synth. Col. Vol.
1988, 6, 474.
15. Hayashi, M.; Yoshiga, T.; Oguni, N. Synlett 1991, 479.
16. So¨dergren, M. J.; Andersson, P. G. J. Am. Chem. Soc.
1998, 120, 10760.
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