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Synthesis of the Alkaloid Woodinine.

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249
Alkaloid Woodinine
Synthesis of the Alkaloid Woodinine
Synthese des Alkaloids Woodinin
Siavosh M a h h b i
Institute of Pharmacy, University, P.O.Box 10 10 42, W-8400 Regensburg (Germany)
Received November 2,1991
In 1988 PUTSet al.') reported on the isolation of 5-bromo-Nfl-dimethylhyptamine from Eudisfomufragwn (Polycitoridae). Besides this compound
they found a new alkaloid, called woodinhe (9b). 5-Bromo-NJ-dimethylhyptamine and 9 b show antibacterial activities') and, therefore, are of
special interest for us2). A few weeks ago McNulty and Still3)have published a synthesis of woodinine which prompts us to publish our results
(Scheme 1).
NO-
as an oily compoundwith ee >95% (no data concerning optical rotation). In our hands 6 crystallizes in the deep freeze (20") and shows [aI2'D = -79" (crude material). Aldehyde 6
was reacted with amine 5 at room temp. (deviation from
Still3)) to afford the S c h g base which was directly cyclized
by Pictet-Spenglep)reaction at -78"under conditionssimilar
to those of Stilf, yielding diastereomers7. Whilst Stilf introduced the N-CH3-group by methyl chloroformate we used
the mixed anhydride of formic and acetic acid") (Scheme l),
yielding the diastereomers 8a and 8b. In our case the reduction with L m affording traces of 9a and 9b (main product) was smooth and was complete after 4.5 h (THF, reflux). We observed that longer reaction times lead quantitatively to diastereomer 10b of debromo-woodinine.
L-prolln
3Q
Br*N",
Scheme 2
B
As can be seen, our procedure is similar and in some steps
identical with Still's synthesis. Neither Pais') nor Still3) give
a melting point of woodinine nor quote whether it is an oily
or solid material. Our sample of woodinine melts at 111-112"
(diisopropyl ethedpetrolether) and shows [a]23D = -80.8"
(MeOH, c = 0.6), [a]23365 = -385", whilst Pui's') quotes
[(x]23D = -38' (MeOH, c = 0.6). ~ t i f Pgives [ a ] 2 3 D = -34"
(MeOH, c = 0.6). Our 'H-NMR- und MS-data (cf. Experimental Part) agree with the structure of woodinine 9b.
Especially the 'H-NMR spectrum in G j D 6 nicely shows the
substitutionpattern of the aromatic ring. The minute diastereomer of woodinine 9a is a solid but could not be obtained
in pure state. Its mass spectrum is (nearly) identical with that
of 9b.
Scheme 1
When we reduced 8 a 4 b (mixture of diastereomers of
Key intermediate in both procedures is 5-bromotryptamine unknown relation, but no doubling of signals was observed
(5)4). Whilst Still et al. have obtained amine 5 from 5-bro- at 90 MHz in CDCl3) with L i A l b in refluxing THF for 8 h,
moindole (1)via 3, 2, and 4, we obtained the nitroalkene 2 debromowoodinine (lob) was obtained by quantitative deaccording to Biichi's procedures*6).Still as well as we have bromination as crystals, m.p. 118.5-1200, [a]23D = -55.5'
reacted amine 5 with (S)-(-)-N-Boc-2-formylpymlidine
(6). (MeOH, c = 0.63). Still's values3)are: m.p. 123-125' @t@)
Still has prepared aldehyde 6 from N-Boc-L-proline methyl- and [aI2'D = -51.5". The minor diastereomer M a was not
ester which was reduced by DIBAL to afford 6, its value of detectable ('H-NMR, tlc).
optical rotation was not quoted. We have obtained aldehyde
6 by SWern oxidation following K0gen's7' Procedure Direct comparison of our material with natural woodinine by ~ r PUTS,
.
(Scheme 2). Reed and Katzenellenbogen') have described 6 indicating structural identity, is gratefully acknowledged.
2) 0diC9.COCHl / 0" / 30 mln
3)LiAlti, / THF I4.5h
A
Arch. Pham. (Weinheirn)325,249-250 (1992)
QVCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1992
.25D
0365-6233/9u0404-0249 $3.70 i
250
Experimental Part
General remarks M.p.: Btichi 510, SMP-20.- IR: Fl', Nicolet 510.- 'HNMR: Varian EM 390 (90 MHz), Bruker WM 250 (250 MHz).- 13C-NMR:
Bruker Spectrospin(62.89 MHz). MS: Varian MAT 112 S/SS 300; 70 eV.Polximeter: Perkin-Elmer 241 & 241 MC.- Temp. in "C.
Mahboobi
(Np~S04)and evaporated in vacuo to give 1.75 g (91%) of a yellowish
powder.- IR (KBr): 1663 cm-' (broad, 2 x CO).- 'H-NMR (90 MHz)
(-13):
6 (ppm) = 1.37 (s; 9H, C(CH3)3), 7.12 (m; 2H arom.), 7.45 (br s;
1H arom.), 8.1 (s; 0.69 H, N-(CO)H), 8.3 (s; 0.31 H, N-(CO)H), 8.9 (br s;
IH. NH).- MS (70 eV): m / ~
= 447/449 (0.8%. M+), 346/348 (1; M CO-O-C&)+, 170 (35; N-Boc-pplidinyl)+, 114 (86; 170 - C4H8)+, 70
(100, pyrrol-1-inium-ion). 57 (62: C&$.
245' -Bromo-3'-indobl)-l
-nitroethene (2)
To 16.3 g (140.3 mmol) Nfl-dimethyl-2-nitthenamine (Scheme 1) in
130 ml of absol. CHZC12 were added drop by drop 25.5 ml (330 mmole)
CF3COOH at 0" under N,. This solution was stirred for 15 min at 0". Then
25 g (127.5 mmole) 5-bromoindole (1) in 260 ml of absol. CHzC12 were
added dropwise at 0" followed by stirring for 10 h a t 0-5". For precipitation
the mixture was stirred at -30 - -20" for 60 h: Red-omge crystals of 2
separated which were collected and washed two times each with benzene
and CH2CI2of -2V, yield 19.8 g (58%) (the crude material was reduced to
the nitro alkane 4 directly).- 2 m.p. 195-197.5" (MeOH); liL4): 196.5198.5O.- 'H-NMR: lL4!
2-(5'-Bromo-3'-indolyl)-I-nitroethane(4)
4.45 g (17 mmole) 2 and 34 g S i Q (for flash chromatography, J.T.
Baker, no. 7024-1) were suspended in 290 ml of absol. CHC13 and 34 ml of
absol. propan-2-01.Under Nz 2.65 g NaB& were added in portions under
stirring. Stirring was continued for 2.5 h. After cooling to 0" excess of
NaB& was destroyed by 2N HCI. SiOz was separated by filtration in
vacuo and washed with CH2CIz. The org. phase was washed with a saturated solution of NaHCO3, then with brine, dried (Na2S04)and evaporated
in vacuo: yellowish powder, purified by cc (SiOz; CHzClz/hexane21).
ColourIess crystals, 4 g, m-p. 92-93' (lit.? 91-92.5").- 'H-NMR:!til
Woodinine (9b)
897 mg (2 mmol) 8 a 4 b in 8 ml of absol. THF were added drop by drop
to 132 mg (3.5 mmole) L w in 6 ml of absol. THF at 0" under Nz. After
2 h of reflux 57 mg (1.5 mmole) L i W were added, followed by reflux for
2.5 h. Hydrolysis at 0" with ice water. Ether extraction led to 680 mg (>
95%) yellowish oil. which was purified by cc (SiOz; EtOH/CH~CIz/EtOAc
1:3:1): 1. Fraction: Wocdinine (9b), 130 mg (18.7%), yellowish crystals,
which were quickly washed with diisopropyl ether of 00:white plates, m.p.
111-112".- [aIz3~
= -80.8" (MeOH,c = 0.6).- C17HzBrN3 (348.1) calc. C
58.6 H 6.37 N 12.1 found C 58.9 H 6.40 N 12.0.- IR (KBr): t= 3338,2952,
2793, 1456. 1383, 793 cm".- 'H-NMR (250 M H z ) (CDCl3): 6 (ppm) =
1.26-3.24 (m; 11 H), 2.53 (s; 3H, N-CH3), 2.54 (s; 3H. N-CH3), 3.58 (br s;
lH, H-1). 7.181 (s; 1H arom.), 7.186 (s; 1H arom.), 7.59 (s; 1H arom.),
10.01 (br s; IH, NH; exch.).- 'H-NMR (250 MHz) (C6D6): 6 (ppm) =
1.13-2.77 (m; 11 H), 2.10 (s; 3H, N-CH3). 2.24 (s; 3H, N-CH3), 3.34 (br s;
lH, H-I), 6.82 (d; J = 8.5 HZ, lH, H-8), 7.30 (dd; Jo = 8.5, J, = 2 Hz,lH,
H-7), 7.78 (d;Jm = 2Hs lH, H-5). 9.82 (br s; IH, NH).- MS (70 eV): m/z
= 347M9 (0.3%, M"),2631265 (6; M - GHifl)', 84 (100; CsHlfl)+.I3C-NMR: see Still3'.
Debromo-woodinine (lob)
250 mg (0.56 mmole) of 8aGb in 4 ml of absol. THF were added drop
by drop to 150 mg LiAlfh in 3 ml of absol. THF at 0" under Nz. After 8 h
reflux and cooling to 00 the mixture was hydrolized by ether (saturated with
From compound 4 according to Stilt'.
water) and cooled to 00. After extraction with ether, drying (NaZSOd,
( S ) - ( - ) - N - ( t e r t - B ~ o ~ c a r b o n y l ) - p y r r o l i d i n e - 2 - c ~(6)
b o ~ ~ e h y ~ evaporation in vacuo, and flash chromatography (SiOz; CHzC12/E1oAc/
EtOH 3:l:l) 40 mg of 10b were obtained as yellowish crystals, m.p. 118.5Aldehyde 6 was prepared analogously to Kogen et al?'. For data see
= -55.5" (MeOH, c = 0.63) (lit?': [ a l Z=3 ~
1200 (lit.3): 123-125'1.- [aIz3~
Katzeneflenbogen6);[ a J Z=3
-79'
~ (c = 1, MeOH) (crude product).
-51.5").- 'H-NMR (250 MHz) (CDC13): 6 (ppm) = 1.28-3.22 (m; IlH),
2.51 (s; 3H, N-CH3). 2.54 (s; 3H, N-CH3). 3.59 (br s; IH, H-1). 7.08 (m;
I-[(S)-(N-tert-Buto~car~nyl)pyrrolidin-2-yl]-6-bromo-~
,2,3,4-tetrahydro- 2H arom.), 7.32 (m; 1H arom.), 7.48 (m; 1H arom.), 9.87 (br s; IH, NH,
~-carboline,
minrure of diastereomeres (7a+7b)
exch.).- MS (70 eV): m h = 269 (4%. M+), 185 (53; M - C 5 H , ~ ) +84
,
1.32 g (5.52 mmole) 5 and 1.1 g (5.52 mmole) 6 were dissolved under Nz
( l a 0 9 C5Hlfl)+.
in 30 ml of absol. CHzClz and stirred for 1 h at room temp. The solution,
which became turbid by formation of water, was cooled to -78' and 1.38 g
References
(0.94 ml, 12.14 mmol) trifluoroacetic acid in 3 ml of absol. CH$Zlz were
added dropwise within 10 min. After stirring for 1 h at -78" the cooling
1 C. Debitus, D. Lament, and M.Pds, J. Nat.Prod. 51.799 (1988).
bath was removed and the mixture was allowed to warm to m m temp.
2 S. Mahboobi, Pharm.Unserer &it 20,129 (1991); regretably, Dr.Pats
After cooling to -10" the mixture was neutralized by a sat. solution of
did not reply to the request for comparing OUT material with natural
NaHC03. the CHzC12 phase was washed with brine, sat. NaHC03solution,
woodine.
3 J. McNulty and I.W.J. Still, Tetrahedron Lett. 32,4875 (1991).
water, and dried (NazSO4). Evaporation in vacuo: yellowish powder, puri4 I.W.J. Still and J.R. Strautmanis, Can. J. Chem. 68,1408 (1990).
fied by cc (SiO2, ethyl acetate): 2.28 g (98%) yellowish powder.- 'H-NMR
5 G. Btichi and C.P. Mak, J. Org. Chem. 42,1784 (1977).
(90 MHz) (CDCl3): 6 (ppm) = 1.5 (s; 9H, C(CH&, 7.2 (m; 2H, arom.),
7.6 (s; 1H arom.), 8.1 (br s; IH, NH).- MS (70 eV): m/z = 419/421 (5%. 6 S.Mahbwbi and K.Bemauer, Helv. Chim. Acta 71,2034 (1988).
Mt), 346/348 (2; M - C4H90)+,249f251 (100; M-(N-Boc-pyrrolidinyl))+, 7 H. Kogen, H. Kadokawa, and M. Kurabayashi. J. Chem. Soc. Chem.
comm. 1990,1240.
170 (17; N-Boc-pyrrolidinyl)+, 70 (81), 57 (61; C4Hg)+.
8 P.E. Reed and J.A. Katzenellenbogen,J. Org. Chem.56,2624 (1991).
9 a) Isoquinolines, part 2. F.G. Kathawala, G.M. Coppola, and H.F.
I -[(S)-(N-tert-Buto~carbonyl)pyrrolidin-2-yl]-6-bromo-2-fo~yl~
Schuster, ed.. J. Willey & Sons Inc., New York 1990. b) J. Kobayashi,
I,23,4-tetrahydro$-carboline,
mixture of diastereomers (8a+8b)
J. Cheng, T. Ohta, S. Nozoe, Y.Ohizumi, and T. Sasaki,J. Org. Chem.
To 1.8 g (4.28 mmol) 7a+7b in 10 mi of absol. CH2Clzwas added 1 ml
55,3666 (1990).
of acetic-fonnic anhydride drop by drop at 0" under Nz and stirring. After
10 a) LF. Fieser and M. Fieser, Reagents for Organic Synthesis, Vol. 1, p.
30 min stimng at 0" the mixture was alkalized by 2N N&03 (pH 8-9) and
4, J. Willey & Sons Inc., New York 1967. b) S. Mahboobi and W.
Wiegrebe, Arch. Pharm. (Weinheim)324,275 (1991).
[KPh572]
extracted with CH2C12. The org. phase was washed with brine, dried
5-Bromotryptarnine (5)
Arch. Pharm. (Weinheirn) 325.249-250 (1992)
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