First enantiocontrolled syntheses of (+)-uleine and (+)-dasycarpidone

Article abstract of DOI:10.1039/a700856b

Stereocontrolled syntheses of (+)-uleine and (+)-dasycarpidone are achieved for the first time in an enantiocontrolled way starting from (+)-norcamphor.

Full text of DOI:10.1039/a700856b

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First enantiocontrolled syntheses of (+)-uleine and (+)-dasycarpidone
Masanori Saito, Mitsuhiro Kawamura, Kou Hiroya and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-77, Japan
Stereocontrolled syntheses of (+)-uleine and (+)-dasycarpi-
done are achieved for the first time in an enantiocontrolled
way starting from (+)-norcamphor.
selectivity may be rationalised by intervention of the enamine
intermediate 18 which allowed epimerization of the C-20
stereogenic centre and stereoselective generation of the imi-
nium intermediate 19 followed by its stereoselective cycliza-
tion2a,b,d under the conditions. Since the amine 20 was found to
be unstable under the oxidation conditions, it was first
transformed into the carbamate 21, [a]D28 +89.4 (c 0.4, CHCl3),
in 74% overall yield by sequential catalytic debenzylation and
carbamoylation.2d The resulting carbamate 21 was then treated
with pyridinium dichromate (PDC) on Celite in the presence of
tert-butyl hydroperoxide (TBHP)11 in benzene to afford the
Although a number of racemic syntheses of the uleine type
indole alkaloids have been reported,1 no enantiocontrolled
synthesis has been disclosed to date. We report here the first
stereo- and enantio-controlled construction of the representa-
tives of this group, (+)-uleine 1 and (+)-dasycarpidone 2, using
(+)-norcamphor 3 as starting material (Scheme 1).2
(+)-Norcamphor 3† was first transformed into the d-lactone
28
43a which was then condensed with benzylamine to give the
16-ketone 22, [a]D +231.8 (c 0.2, CHCl3), in 54% yield.
33
amide alcohol 5,‡ mp 94–95 °C, [a]D 21.95 (c 0.55, CHCl3),
Concurrent N-deprotection and N-methylation of 22 under the
in 75% yield. Hydride reduction of 5 followed by N-carbamoyl-
reductive conditions2d in the presence of 37% formalin afforded
27
30
ation of the resulting amine yielded the carbamate 6, [a]D
(+)-dasycarpidone 2, [a]D +63.1 (c 0.7, CHCl3) [natural:
20.76 (c 1.0, CHCl3), which was oxidized to give the
cyclopentanone 7, [a]D30 +58.0 (c 0.9, CHCl3), in 90% overall
yield. Transformation of 7 into the a-diketone monothioketal3,4
[a]D26 +64.7 (c 1.02, CHCl3)],12 in 83% yield. By following the
established procedure,2a,b (+)-dasycarpidone 2 obtained was
27
transformed into (+)-uleine 1, [a]D +18.2 (c 0.3, CHCl3)
29
25
27
8, mp 72–74 °C, [a]D 243.5 (c 0.742, CHCl3), followed by
[natural: [a]D +16.5 (c 0.91, CHCl3);12 [a]D +20 (c 0.94,
31
alkaline cleavage3–5 yielded the acyclic methyl ester 9, [a]D
CHCl3)13], in 71% overall yield on treatment with methyl-
+43.1 (c 0.3, CHCl3), in 59% overall yield after treatment of the
resulting acid with diazomethane. Exposure of 9 to iodoethane
in the presence of sodium hexamethyldisilazide in THF
containing HMPA at 278 °C afforded the a-ethyl ester 10 in
73% yield as an inseparable epimeric mixture with recovery of
14% of the starting material. The dithiane group of 10 was
hydrolysed to give the aldehyde 11 in 92% yield which was
treated with dimethyl 1-diazo-2-oxopropylphosphonate6 in the
presence of potassium carbonate to furnish the terminal
acetylene 12 in 90% yield. Compound 12 was then converted
into the 1,3-dioxane 14 in 72% overall yield via the aldehyde 13
by sequential reduction, oxidation and acetalization7 (Scheme
2).
X
R
NBn
ref. 4
i
O
(+)-3
O
Y
H
4
5 R = H, X = H(β), OH(α), Y = O
6 R = Boc, X = H(β), OH(α), Y = H2
7 R = Boc, X = O, Y = H2
ii, iii
iv
v
O
Boc
NBn
Boc
NBn
S
MeO2C
To construct the indole framework,8,9 the acetylene 14 was
first coupled with ethyl (2-iodophenyl)carbamate in the pres-
ence of dichlorobis(triphenylphosphine)palladium(ii) [PdCl2-
(PPh3)2] and copper(i) iodide in triethylamine10 to give the
arylacetylene 15 in 86% yield. Cyclization was then carried out
by treating 15 with sodium ethoxide in ethanol8,9 at reflux to
furnish the indole 17 in 64% yield accompanied by 31% of the
de-N-acylated product 16 which, after separation, was treated
with ethyl chlorocarbonate in pyridine to recover the carbamate
15 in 81% yield. The indole 17, on reflux with TFA, afforded
S
R
H
vi
H
8
X
9 R = H, X = -S(CH2)3S-
10 R = Et, X = -S(CH2)3S-
11 R = Et, X = O
vii
viii
ix
Boc
NBn
Boc
NBn
29
stereoselectively the tetracyclic amine 20, [a]D 2155.3 (c 0.7,
X
O
O
O
CHCl3), in 54% yield accompanied by the readily separable
20-epimer (4%) by spontaneous deacetalization, decarbamoyla-
tion and stereoselective cyclization. The observed stereo-
xii
Et
Et
H
H
12 X = OMe
13 X = H
14
H
20
x, xi
O
Me
Scheme 2 Reagents and conditions: i, BnNH2, 180 °C (75%); ii, LAH, THF,
reflux; iii, Bo2O, aq. NaOH room temp. (95%); iv, pyridinium chloro-
chromate (PCC), NaOAc, CH2Cl2 (95%); v, pyrrolidine, benzene, reflux,
then TsS(CH2)3STs, Et3N, MeCN (59%); vi, KOH, ButOH, 60 °C, acid
workup, then CH2N2 (99%); vii, NaN(SiMe3)2, EtI, THF, HMPA, 278 °C
(73%, recovery of 14% of 9); viii, Hg(ClO4)2, CaCO3, 20% aq. THF (92%);
ix, AcC(NN2)P(O)(OMe)2, K2CO3, MeOH, room temp. (90%); x, LAH,
THF; xi, Swern oxidation (87%); xii, Me3SiO(CH2)3OSiMe3, Me3SiOTf
(cat.), THF, 278 °C (83%)
N
16
N
H
(+)-norcamphor 3
X
(+)-uleine 1(X = CH2)
(+)-dasycarpidone 2 (X = O)
Scheme 1
Chem. Commun., 1997
765

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‡ Satisfactory analytical (combustion and/or high resolution mass) and
spectral (IR, 1H NMR, and MS) data were obtained for all new isolable
compounds.
O
O
i
Et
14
References
NH
R
H
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2 Racemic syntheses: (a) A.Jackson, N. D. V. Wilson, A. J. Gaskell and
J. A. Joule, J. Chem. Soc. C, 1969, 2738; (b) L. J. Dolby and H. Biere,
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3 Utilization of (+)-norcamphor as a starting material for enantio-
controlled syntheses of natural products: (a) M. Kawamura and
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1995, 2403; (d) M. Kawamura and K. Ogasawara, Heterocycles, 1997,
44, 129.
NBn
Boc
ii
O
15 R = CO2Et
16 R = H
iii
Et
O
N
H
NBn
Boc
H
17
iv
H+
+
N
H
Bn
H
NBn
N
H
H
N
H
H
18
19
4 Cf. S. Takano and K. Ogasawara, J. Synth. Org. Chem. Jpn., 1977, 35,
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R
N
H
R
N
H
H
H
vi
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N
H
H
N
H
H
X
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31.
20 R = Bn
21 R = Z
22 R = Z, X = O
(+)-dasycarpidone 2 R = Me, X = O
(+)-uleine 1 R = Me, X = CH2
vii
v
viii
Scheme 3 Reagents and conditions: i, PdCl2(PPh3)2 (10 mol%), CuI (10
mol%), 2-IC6H4NHCO2Et, Et3N, reflux (86%); ii, NaOEt, EtOH, reflux
(16: 31% and 17: 64%); iii, ClCO2Et, pyridine (81%); iv, TFA, reflux (54%;
20-epimer 4%); v, 10% Pd–C, HCO2NH4, MeOH, reflux, then ClCO2Bn,
K2CO3, CH2Cl2 (74%); vi, PDC–Celite, TBHP, benzene, room
temp. (54%); vii, H2, 10% Pd–C, 37% formalin, MeOH (83%); viii, MeLi,
THF, then neutral Al2O3 (activity I), 120 °C (71% overall)
9 Utilization of this procedure for the natural product synthesis:
S. Takano, T. Sato, K. Inomata and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1991, 402; K. Shin and K. Ogasawara, Chem. Lett., 1995,
289; K. Shin and K. Ogasawara, Synlett, 1995, 859; K. Shin and
K. Ogasawara, Synlett, 1996, 922.
10 K. Sonogashira, Y. Tohda and N. Hagiwara, Tetrahedron Lett., 1975,
4467.
11 N. Chidambaram and S. Chandrasekaran, J. Org. Chem., 1987, 52,
5048.
12 J. A. Joule, M. Ohashi, B. Gilbert and C. Djerassi, Tetrahedron, 1965,
21, 1717.
lithium followed by dehydration of the resulting tertiary alcohol
with neutral alumina.
Footnotes
13 R. F. Garcia and K. S. Brown, Jr., Phytochemistry, 1976, 15, 1093.
* E-mail: konol@mail.cc.tohoku.ac.jp
† Prepared from (+)-endo-norborneol (ca. 95% ee) kindly provided by
Chisso Corporation, Japan.
Received in Cambridge, UK, 6th February 1997; Com.
7/00856B
766
Chem. Commun., 1997