Synthesis of analogues of cryptopleurine

Tenakdrca.

Vol. 27. pp. 3465 to 3476.

SYNTHESIS

Pugamcm

Pm8

1971.

Printed in Chat

OF ANALOGUES

Bntma

OF CRYPTOPLEURINE

S. FOLDEAK* School of Pharmacy, Portsmouth Polytechnic (Received in the UK 13 March 1971; Accepfed for publicution 7 April 197 I )

Ah&act-New analogues of cryptopleurine with different aromatic methoxyl and chloro substituents have been synthesized. Intermediate isomeric I-hydroxyphenanthro(9.lObJquinolizidines have been isolated and characterized. Yields in the Pschorr reaction have been improved by the novel use of sulphite ion. Some of the compounds have been found to have antifungal activity.

PHENANTHROQUINOLIZIDINE alkaloids from Cryptocurpa pleurosperma (cryptopleurine.’ I, R1 = R, = R, = OCH3, R, = R5 = R, = R, = H; cryptopleuridine2 1, R,R, = OCH,O, R3 = 0CH3, R4 = R5 = R, = H, R, = OH) and the closely related phenanthroindolizidine (II) alkaloids from 7jlophora species3 are of interest not only because of problems of structure and stereochemistry but also because of a range of biological activities. Vesicam4 mitotic5 anti-leukaemic6 and selective antifungal’ effects have been reported among others. Synthesis of new anologues of cryptopieurine with different substituents in the aromatic rings was therefore undertaken. The intermediate alcohols (R6 = OH) were isolated and their stereoisomers separated and characterized. Cryptopleurine has recently been synthesized* by a route based on biogenetic considerations, but the present work followed essentially the earlier route of synthesis’. lo with some modifications by which yields were improved. In particular the synthesis of substituted phenanthrene-9-carboxylic acids by the Pschorr’ reaction * is usually effected from the appropriate 2-amino-a-phenylcinnamic acids by diazotisation followed, without isolation of the diazonium compound, by cyclization by a variety of reagents. Reaction times are long and yields variable12 between 25 and 80%. This step was therefore investigated and it was found firstly that isolation of the diazonium compounds as the quite stable hydrogen sulphates was advantageous and secondly that the cyclization was very efficiently promoted by sulphite ion giving 80% overall yields of phenanthrene acids. While the work was in progress promotion of the cyclization by potassium iodide was reported.13 Combination of these two methods was found to give optimum yields. The mechanism whereby these reagents promote cyclization is unknown, but may resemble that proposedi2* l4 for hypophosphinic acid, which functions as a reducing agent. The acids were converted to acid chlorides with oxalyl chloride. esterilied, reduced with LAH and treated with phosphorus tribromide to give the corresponding bromomethyl derivatives (III, R = Br). These reacted with ethyl pipecolinate to give the esters (IV, R = Et) which were hydrolyzed to the acids (IV, R = H). In polyphosphoric acid these gave the ketones (V) in about 8077 yield. The ketones are

l

Present address: Institute of Organic Chemistry, Josef Attila University. Szeged. Hungary. 3465

3466

S. FOLDEAK

sensitive to air and light, especially in solution. and care must be taken during their isolation. The reportedg* lo preparations employed direct reduction of the ketones by the Wolff-Kishner method, which, however, also removes OMe group~.~ Reduction to the alcohols (VI) was therefore effected by a variety of methods all of which gave mixtures of isomeric alcohols designated A and B, separable by TLC. LAH reduction gave a mixture of 60% A and 40% B generally unsuitable for preparation separation. Catalytic reduction with Adams catalyst gave a mixture with 75% A with 25% B from which pure A was obtained. In contrast the use of Pd-C in acid media gave 30”/, A and 70”/, B allowing preparation of pure B. Under these conditions aromatic halogen is removed, so that B isomers of halogenated compounds could not be obtained in this way. TABLE 1. IR ABSORPTION OF HYDROXYOROUPIN PHENANTHROQLJI~WLIZIDINES Compound

Free OH

1. R, = OH. R4 = R, = R, = H

2

1

LX

Bonded OH AY; cm-’

A(R, = Rz = R, = H)

3600

weak

-

B(R, = R2 = R, = H)

3600

65

165

-

-

-

A(R, =Rz

=OCH,R,

= H)

B(R, = R2 = 0CH3 R1 = H) A(R, = R, = H R3 = Cl,) B(R, = R2 = H R, = OCH,

3598 3602

Spectra were run in a 4 cm cell at concentrations because of the low solubility.

72 -

13.8 -

73

16.5

around 00X

;;I 3566 3568 3565 -

e.L 24

A< cm-’ 64

23

63

-

-

27

68

-

-

molar. Intensity data are approximate

The configurations of the two isomers were determined by consideration of the IR spectra (Table 1) in dilute solution in carbon tetrachloride. All the compounds show strong Bohlmann l5 bands indicating that both isomers have predominantly trans ring fusion. The configuration of the OH groups can therefore be determined from the presence or absence of intramolecular H-bonding.16T I’, la* lg The A isomers show a broad band around 3566 cm-’ indicative of intramolecularly bonded OH. Examination of Dreiding models suggests that this is due to H-bonding with the ring nitrogen, possible only with the OH in a pseudoaxial configuration trans to the bridgehead hydrogen. The closest approach of the hydroxyl H to the nitrogen in models is about 2.8 A; at least 0.3 A greater than that in l-hydroxyquinolizidines which have been foundI to show a hydroxyl-nitrogen bonded band at 3526 cm- ‘. The H-bond in the A isomers would therefore be expected to be weaker and to occur at the observed higher frequency. It also seems reasonable to attribute the small free OH band near 3600 cm-’ to a small proportion of non bonded pseudoaxial trans ring molecules rather than equilibrium with the pseudoequatorial cis ring. The B isomers show a single sharp OH band around 3600 cm-’ with much the same intensity in each case. These are clearly free OH bands, which with the absence

3467

Synthesis of analogues of cryptopleurine

of any detectable bands at lower frequencies indicate a pseudoequatorial configuration cis to the bridgehead hydrogen. The absence of detectable H-bonding also indicates the lack of an equilibrium between the two isomers. Stable conformations of dibenzoquinolizidine have been reported.20 The stereospecilic nature ofthe reductions agree with previously reported reductions of ketoquinolizidine1g*20*22 and ketoindolizidine but do not follow the postulated’ ’ “anchor effect” in quinolizidine. It seems likely that the two benzene rings alter the interaction with the catalyst surface. The two isomers are not interconverted under hydrogenation conditions. The alcohols were dehydrated with perchloric acid to give the quatemary compounds (VII). These show IR absorption at around 1700 cm-’ like the quinolizidine immonium compounds previously described23*24 and also like them showed a shift to around 1630 cm-’ in base indicative of isomerization to an eneamine. The quatemary compounds were reduced with LAH or sodium borohydride to the phenanthroquinolizidines (VIII). Reduction with LAH was slow and caused some loss of aromatic halogen. Reduction with sodium borohydride was fast and completely hydrogenolyzed aromatic halogen. The same phenanthroquinolizidine was obtained from either of the isomeric alcohols or by direct reduction” of the corresponding ketone. TABLEI2. ACIMTY OF PEIEZNAN~IR~(~. I~~~QUIXWLIZIDINES AGAINSTAchxmucor

Formula 1. R, = H Isomer H

H

H

B

20

H

OH

A

5

H

OH

B

5

H

H

OH

A

2.5

H

H

OH

B

5

OCHl

H

H

OH

A

OCH3

OCH,

H

OH

A+B

10

H

H

OCH,

OH

B

5

H

Cl

H

H

OH

A

CG

OCH,

Cl

H

H

OH

A

0.6

OCH,

H

H

OH

-

0.16

H

-

5

-

0.05

H

H

H

H

H

OCH3

OCHS

H

H

OCH,

OCH3

H

H

H

OCH,

H

H

H

H

H

H

H OCH,

H

Min. inhib. Cont. WmI

OH

H

OCH,

R,

repens

OCH3 H

H

H

H

5

OCH,

OCHX

H

H

H

H

H

H

OCH,

H

H

H

H

H

OCH,

OCH3

H

H

-

Results awaited

H

H

H

H

OCH,

H

-

20

0CH3

OCH,

OCH,

H

H

H

0.6

O-04

3468

S. FOLDEAK

‘;$+R,

R2&

R,

R,

Synthesis of analogues of cryptopleurine

3469

EXPERIMENTAL M.ps are uncorrected. IR spectra were determined on a Perkin-Elmer 257 spectrometer as discs (KCl) or mulls (Nujol), or on a Perkin-Elmer 521 grating spectrometer for solns in Ccl,. The UV spectra were determined on a Unicam SP800. Substituted phenanthrene-9-carboxyiic acids-General procedure. The appropriate a-phenyl-2-aminocinnamic acid (OS mol) was suspended or dissolved in acetone (600 rnlb cooled (ice bath) stirred and 5N HISOd (21 ml) added followed by amyl nitrite (16 ml) in 4 portions over 20 min. The mixture was stirred at 2-5 for 2 hr and then liltered. The solid \\;Is washed with cold acetone (20 ml) and dried in wcw at 40 . yields 8&950/ In this way was prepared a+-chlorophenyl)-2-diazoniumcinnamic acid hydrogen sulphate. yellow plates from H,O~e,CO m.p. 90” v,&. 2265 cm-‘. (Found: C, 47Q H, 3.2; N. 7.4. C,,H,,CIN,S06 requires: C. 47.1; I-I, 2.9; N, 7.3%). Other diazonium compounds were used without further purilication. The diazonium compound (14 g) was suspended in acetone (150 ml). cooled (ice bath). stirred and a soln of KI (6 g) in water (10 ml) added in 3 portions over 5 min. followed by W/0 NaHSO,aq (1 to 2 ml) in water (10 ml). The mixture was stirred at room temp for 50 min and then sufficient (10 to 70 ml) water added to obtain a ppt which was collected, washed with water. dried and crystallized from solvent shown. yields 5&W/,. In this way were prepared the compounds in Table 3. Ethyl phenanthrene-9-carboxylates-General procedure. The acid (@25mol) and oxalyl chloride@75 mol) in dry CHCl, (80 ml) were kept at room temp for 30 min and then at reflux for 2 hr. The solvent was removed in uacuo and the residual solid kept with EtOH (70 ml) at reflux for4 hr, filtered hot and set aside to crystallize. The product was recrystallized from solvent shown. In this way were prepared the tsters in Table 3. 9-Hydroxymethylphenanthrene-General procedure. The ester (002 mol) was added over 5 min to LAH (I.8 g 0048 mol) in THF (100 ml) and the soln stirred for 3 hr at room temp. It was then treated with EtOH and water filtered. The ppt was washed well with THF (and also boiled with CHCI, in the preparation ofthe 2.3-dimethoxy derivative). The combined solns were concentrated in “actwand the residue crystallized from the solvents shown. In this way were prepared the compounds in Table 4.9-Hydroxymethylphenanthrene itself was prepared by Raney nickel catalyzed reduction of phenanthrene-9-aldehyde.26 9-Bromomethylphenanfhrenes--General procedure. The hydroxymethyl compound (002 mol) in dry CHCl, (70 ml) was cooled (ice bath) stirred and PBr, (OG? mol) in dry CHC& (15 ml) added over 5 to 10 min. The mixture was kept at room temp for 40 min and at 40 to 45” for 15 to 20 min. It was then poured onto ice. The CHCI, layer was separated, washed twice with water, dried (Na,S03 concentrated in cacao and the residue crystallized from the solvent shown. In this way were prepared the compounds in Table 5. 9-Q’-Ethoxycarbonylpiperidino) methylphrrlanthrenes -General procedure. The bromomethyl compound (O+l mol) ethyl pipecolate” (M)2 mol) and benzene (50 ml) were kept at reflux for 1.5 hr. The warm soln was filtered and the solid ,washed with benzene. The combined filtrate and washings were concentrated in vacua and the residue crystallized from solvent as shown. In this way were prepared the compounds in Table 6. The two compounds which did not crystallize. (but which showed only one spot on TLC) were used in the next stage without furtheT purification. l-Oxophenanthro[9.10b]quinolizidines-GeneraJ procedure. The piperidinomethylphenanthrene (DO1 mall EtOH (50 ml). KOH (4Q g) and water (6 ml) were kept at reflux for 2Omin. The clear soln was diluted with water (25 ml) and AcOH (6 ml) added. The ppt was collected and dried well at 60 to 80”. (The 2.3dimethoxy and 2.3-dimethoxy-6-chloro derivatives are more conveniently isolated as K salts), yields quantitative. This acid (01 mol) and polyphosphoric acid (20 g) were kept under N2 on an oil bath at I l&12@ for 5 to 6 hr and then cooled. The brown viscous soln was poured onto ia water (150 ml) and made alkaline (pH 8 to 9) with 50”/, NaOHaq taking esptcial care to keep the temp below 40”. The mixture was extracted with CHCI,. The extract was washed with water, dried (Na,SOJ and concentrated in uacuo at a maximum temp of 35” to give a solid which was crystallized from solvent shown. In this way were prepared the compounds in Table 7. The 6-chloro compound required heating for 20 hr with polyphosphoric acid.

l-Hydroxyphenunthro[9.1Ob]quinolizidines. Three general methods were used. The ratio of A to B isomers produced was established by TLC on KieselgelG nach Stahl (Merck) developing with benzene (20): EtOH(l):MeOH(l) mixture and reading density on a Vitatron. (A) Reduction with Adams catalyst. The ketone (380 mg) in THF (50 ml) and EtOH (20 ml) with Adams catalyst (380 mg) was hydrogenated at room temp and 3 atm pressure for 8 hr. The soln was filtered and concentrated in ~ocuo. The residue was suspended in acetonz in which oily products rapidly solidilied_ and

filtered to give a white solid. A/B ratio about 75:25.

RI

OCH,

H

H

H

H

OCH,

OCH,

OCH,

H

H

H

H

OCHJ

OCH,

OCH,

OCH3

H

H

H

H

OCH,

OCH3

H

H

H

H

O-3

OCH3

OCH3

Cl

Cl

H

H

OCH,

OCH3

R3

R,

H

H

H

OCH3

H

H

H

H

._

H

H

H

H

H

OCH,

H

H

H

R.

H

R2

OCHS

Cl

Cl

H

OCH,

OCH,

H

H

R,

H

RI

H

R,

H

--.

1

H

OCH,

H

H

H

H

H

H

CmH,sO~

CI,H,~CJO~

CISHII~O

GJ31402

C17H1603

C,c.H1403

H

H

OCH3

C,,H1,03

H

H

Formula III. R = OH

GSHIZO

H

sil

5.7

5.8

135136

148

95

62-63

113

53

131

m.p. “C

__

13&137”

-

67.4

73.8

8@3

75.8

-

-

-

C

Formula

9495”

-

4345

-

4.7

4.5

6.3

6.2

-

-

H

%

-

67.4

74.2

4.9

46

5.9

186187

198-199

155

120-121

158-159

6.0

76.1 806

147-148

-

152-153

-

-

_

m.P. “C

80

80

80

70

85

86

90

Yield %

204

H

?!, C

Required

EtOH

CHCl,/EtOH

EtOH

EtOH/H,O

CHClJEtOH

EtOH

Rccryet.

-

124-126”

Lit. m.p.

Ester X = C,H,

CARBOXYLATaS

HYDROXYMETHYLPHENAN~

662

77.1

73.5

Rwid% C H

H

R,

4.

4.8

5.3

42

TABLE

66.4

17.4

72.9

Found % C H

H

R,

C,pH,,aO.

C,,H,,aO,

C,.H,,O,

C,,H,,O.

Ester X = C,H, Formula VIII

TAIILEZ3. hENANTHRi?NE

267”

Lit. m.p.

215”

217

217-218’O

268-2693’

184-187’

-

_.

-

14314528

19‘+196=

14933

Lit. m.p. “C

276211

291-298 291-292”

216

248-249 25219

241.-242 2393’

212

m.p. “C

Acid X = H

EtOH

EtOH

EtOH

EtOH

EtOH

EtOH

EtOH

PhH

Recryst.

HOAc

-

EtOH

-

HOAc

HOAc

HOAc

Rccryst

85

90

85

81

86

88

92

80

Yield “/ 0

65

Quant.

90

88

48

88

70

Yield %

:

5

3

r

ti

6

. ..

H

H

H

H

OCH,

OCH,

H

H

H

H

OCH3

OCH3

H H H

H H H

Cl

Cl

OCH,

H

OCH,

OCH3

H

OCH3

OCH3

R,

OCH,

H

H

H

H

H

OCH,

mH3

H

H

H

OCH,

H

H

H

H

OCH,

OCH,

H

H

H

H H

R4

H

H

H

H

OCH,

H

H

H

R,

H

R3

0CH5

Cl

Cl

H

OCH,

OCHs

H

H

R,

H

RZ

OCH,

OCH3

RI

H

R,

H

RI

C,sH,,BrO,

C,,H,,BrClO,

C,sH,oBr~

C,cH,,BrO

G,H,,BrO,

C,&bBrO

C,,H,,BrO,

C,sH,,Br

.-

Formula I1I.R = Br

600

55.7

58.3

635

62.2

63.3

61.3

66.2

C

Found

4.8

3.7

3.2

4.4

47

4.2

4.6

4Q

H

%

Formula IV. R = C,Hs

7.1 64 74

71.9 67.2 71.1

7.1

7.1

73.3

73.2

6.7

H

79.5

-.

C

Found

%

598

55.8

589

63.8

61.6

638

61.6

3.5

2.9

3.4

71.4

67.9

72.3

-

7.1

6.4

%

157

210

173

N

3.2

3.2

3.7

3.4

3.4

41)

124-126

174-175

125-126

159-160

6.3

69

-

73.7

3.3

69 -

m.p. “C

122-123

7.2

H

73.7

79.5

C

Required

47

3.9

3.2

4.3

46

4.3

4.6

4.1

H

%

3.5

4.1

N

C

Required _~

66.4

TABLE 6. (ETHOXYCARB~~LPIPD~~)~HYLPHENANI

H

H

H

OCH,

H

H

H

H

RS

TABLE 5. BROMOMETWLPHENAN~W~N~~

145

191-192

83-84

Oil

98-99

Oil

117-117.5

90

m.p. “C

-

-

121-1222s

162-16328

1 14-11533

Lit. mp. “C

96 91 95

PhH EtOH

90

90

90

95

90

Yield “/n

85

83

95

80

85

80

80

80

%

Yield

EtOH

EtOH

EtOH

EtOH

Re=ryst.

PhH

PhH

CHCI,

PhH

PhH

WH

PhH

PhH

Recryst.

=!

g

G. -. g

$I 2 b

s

1

:’ 2 z 0’

fj

r”

Cl

OCH,

WH3

mH3

H

CI

H

OCH,

H

H

H

OCHs

OCH,

OCH,

H

H

H

H

0CH3

H

GH,,ClNOs GHzsNO.

H

C2,H,,CIN0

G,H,,NOz

CZ~H,,NOJ

CXHI,NO,

H

H

WH,

H

H

G~Hz~NOJ

H

H

H

OCH,

G,H,,NO

Formula V

H

Rs

H

-. _.

R,

OCH3

H

Rs

H

R2

H

RI

~.

--

69.2

75.2

79.0

5.4

55

6.4

66

6.4

79.9 762)

6.8

76.1

698 -

-

75.1

79.7

76,4

797

3.2

3.8

3.8

3.8

3.9

3.6

764

---

-.

-

C

-

5.6

5-4

6.4

6.4

6-4

6.4

H

N

.-

3.5

4.2

4.2

39

4.2

3.6

Required %

IO~JQUINOLIWDINFS

Found % C H N

TABLE7.Oxo~m1~am~~o[9.

142

175-176

173-174

“’

158-159

225-226

112-113

150-152

212-213

-.

aP.

Recryst.

1w

-

-

-

-

-

-

PhH

CH,ClzMe,CO

CH&Me,CO

Me&O

Me,CO

CH,CI,Me&O Me,CO

16&-1696 CH,CI,-EtOH

Lit. ntp. “C

1672

1666

1675

1660

1662

1670

1670

1676

v, cm-’

76

69 -

71

50

70

60

80

6

--

Yield %

?’ ;: s 9 x

H

H

H

mH3

=H3

mH3

H

H

H

NH3

WHJ

mH3

H

H

H

@=3

WH:,

H

QCH3

(XX

H

H

H

H

H

R2

H

--. -._

R,

H

H

H

wH3

H H H H

H H H

cl

WH,

mH3

H

H

R,

H

H

H

H

H

H

H

H

H

OCH,

OCH3

&

cl

mH3

OCHS

WH3

H

H

mH3

H

H

H

H

H

R3

78.9 76.2 76.1 79.2

G2H2sNOz G#,sNO3 CnH2,NO, G,H,,NO,

72.7

72.8

%HnNO+ G&,NO4

69-7

C2,H2,ClN03

74.2

18.8

G2HuNOz

CttH2&IN0

76.1

CnH21N03

83.4 159

G,%NO W&NO,

83.3

C

G,H,,NO

VI

Fomula

69

6.8

6.3

6.2

6.9

6.9

6.8

6.8

7.0

6.8

7.1

7.1

70

H

Found %

37

3.2

3.2

4.3

4.2

36

3.7

4.4

4.2

3.8

3.7

4.6

4.4

N -

732

73.2

69.4

74-6

79.2

76Q

760

792

79.2

76.0

76.0

83.1

831

- .-

C

69

6.9

6-1

6Q

69

6.9

69

69

69

6.9

69

7.0

70

.--

H

Required %

3.5

3.5

3-5

4.1

42

3.8

3.8

4.2

4.2

3.8

3-8

+6

4-6

N

TABLE 8. HY~R~~YPHEN,~~H~~[~).~O~)~~~NOLI~IDINE~

B

A

A+B

A+B

B

B

A

B

A

B

A

B

A

Isomer

208-209

236-237

233-235

238-242

253-255

221-228

201-203

215-216

208-209

266-267

2!So-251

208-209

231-233

(decomp.)

“C

mP.

50

40

60

65

60

50

50

80

65

60

45

68

63

%

Yield

Me,CO

Me&O

PhH-petrol

PhH

CHCI-PhH

PhH

PhH-EtOH

PhH-EtOH

PhH

PhH-EtOH

PhH

PhH-EtOH

PhH

Remyst.

Cat(B)

Cat(A)

LAH(C)

LAH(C)

Cat(B)

cat@)

Cat(A)

Cat(B)

at(A)

Cat(B)

LAH(C)

Cat(B)

Cat(A)

Method

w

%! 51. 4,

2

f!j

j

C

5 Ix ;

r”

H

H

H

OCH,

H

H

OCHj

ocH3

WH3

H

H

R2

H

R,

OCHB

H

OCHS

0CH3

R

H

R3

H

H

H

H

H

Rs

H

WH,

CXTHs H

R

H

H

%

1700

1712

1708

1704

1710

1705

C&&Q

C23W25NO2

CZZHZSNO

C23H2802

-

83.5

79G

83.3

79.2

.

7.1

6.9

7.2

7.3

4.3

4.2

4.5

4Q

83.2

795

83.2

19.5

I.3

7.3

7.3

7.3

4.4

40

4.4

4-o

-.~.-

197-198

170

165-166

16f

18&-189

174-175

199-201’

-

-

-

i68- 1706

Lit. m.p.

56

69

76

82

88

74

Yield %I

Me2CQ

Me$O

PhH-pctrol

PhH-EtOH

PhH-EtOH

Me&O

..-

Recrystl. -

7p

fj

B

m

Synthesis of analogues of cryptoplcurine

3415

(B) Reduction with palladium catalyst. The ketone (380 mg) in THF (50 ml), EtOH (50 ml), water (5 ml) and DSN HCI (4 ml) with loO/, PdC (380 mg) was hydrogenated at room temp and 1 atm for 16 hr. The soln was liltered concentrated in tmcrw to one third of its volume and water (50 ml) and 2N NaOH (2 ml) added. The mixture was extracted with CHsCl,. The extract was washed with water. dried (NasSOA and concentrated to give a residue which was treated with acetone as above. A/B ratio about 22:78. (c) Reduction with complex hydride. The ketone (380 mg) was added to LAH (200 mg) suspended in THF (30 ml) aud the mixture was stirred at room temp for 40 to 50 min. It was then cooled (ice bath). treated cautiously with EtOH and then water. filtered and washed with THF. The combined filtrate and washings were concentrated in vacrw and the residue treated with acetone as above. A/B ratio about 60:40. In these ways were prepared the compounds shown in Table 8. Pure isomers were separated by repeated recrystallization from solvents shown. AU compounds decomposed at the temps given for m.p. Phenonthro[9.lOb]quinolizidine. Phenanthro[9.lOb]quinolixidin-l-o1 A isomer (100 mgk AcOH (20 ml) and 60,,, perchloric acid (03 ml) were kept at 135’ (bath) for 3 hr. The ppt was then collected and washed with EtOH. White solid mp. 325” (deck This compound (105 mg) and LAH (100 mg) in THF (5 ml) were kept at room temp for 8 hr. The mixture was treated as in method C above and the resultant solid crystallized from acetone to give the phenunrhroquinolizidiae m.p. 174-175’ (60 mg). The m.p. was not depressed by product similarly obtained from the B isomer. or by product obtained by reduction of the immonium salt wnh borohydride ethanol at room temp for 50 min. The m.p. was also not depressed by material prepared as previously described.’ In this way were obtained also the compounds shown in Table 9. Reduction of halogenated compounds with borohydride gave the corresponding dehalogenated derivatives. identified by mixed m.p. and elemental analysis Reduction of halogenated compounds with LAH gave mixtures. Acknowledgements-I thank the President and Governors of Portsmouth Polytechnic for a Research Fellowship during which this work was carried out. and Professor K. Kovacs for the opportunity to work with alkaloids. I am indebted to Mr. A. Wood of the Tropical Products Institute for determination of the high resolution IR spectra. and to Dr. L. Ferencxy of the Josef Atila University of Sxeged for determination of the antifungal activity. I am grateful to Dr. E. Crundwell for help and advice and for his assistance in preparing the manuscript.

REFERENCES

’ E. Gellert and N. V. Riggs Austral. J. Chem. 1, 113 (1954) :

’ 3 * ’ 6 ’ s 9 ” i’ i2 ” i* ” I6 ”

E. Gellert. Ibid. 9.489 (1956); H. Hoffman, Auctral. J. Expt. Biol. Med. Sci. 30, 541 (1952); N. K. Hart. S. R. Johns and J. A. Lamberton, Austral. J. Ckem. 21.2579 (1968) S. R. Johns, J. A. Lamberton. A. A. Sioumis and R. I. Willing Ibid. 23. 353 (1970) T. R. Govindachari The Alkaloids (Ed. R. H. Manske) Vol. 9. p. 517. Academic Press. New York (1967) I. S. de la Lauda Austral. J. Expt. Biol. Med. Sci. 26, 181 (1948) C. Barnard, At&ml. J. Sci. 12.30 (1949) K. W. Cleland, Ibid. 12 144 (1950) E. Gellert and R. Rudzat’s J. Medic. Chem. 7, 361 (1964) L. Ferencxy et al.. Lecture abstract ofthe First International Congress qfPlant Pathology. London. 14-16. July (1968) T. M. Paton. P. L. Pauson and T. S. Stevens. J. Chem. Sot. 1309 (1969) P. Marchini and B. Belleau. Canad. J. Chem. 36. 581 (1958) C. K. Bradsher and H. Berger. J. Am. Chem. Sot. 79.3287 (1957) I. Leake. Chem. Rev. 56.27 (1956) DeLos F. Detar, The Pschorr Synthesis in Organic Reactions IX p. 409. Wiley. New York (1957) B. Chauncy and E Gellert. Ausrral. J. Chum 22 993 (1969) N. Komblum G. D. Cooper and J. E. Taylor, J. Am. Chem. Sot. 72 3013 (1950) F. Bohlmann. Chem. Ber. 91.2157 (1958) H. S. Aaron, Ch. P. Rader and G. E. Wicks. J. Org. Chem. 31. 3502 (1966) H. S. Aaron. C&m. & Ind. 1338 (1965)

3416

S. FOLDFAK

I* Ch. P. Rader. R. L. Young and H. S. Aaron, J. Org. Chem. 30. 1536 (1965) H. S. Aaron, C. Parker Ferguson and Ch. P. Rader. J. Am. Chem. Sot. 89. 1431 (1967) ” A. S. Aaron. G. E. Wicks. Ch. P. Rader. J. Org. Chem. 29. 2248 (1964) A. S. Aaron and C. P. Ferguson. Tetrahedron Letters. 6191 (1968) *’ T. Takemoto. Y. Kondo. Pharm. Sot. Japan 83,162 (1963) ‘I Ch. P. Rader. G. E. Wicks R. L. Young. H. S. Aaron, J. Org. Chem. 29.2252 (1964) ” H. Mohrle. Chr. Karl and U. Scheidegger. Tetrahedron24.6813 (1968) 23 N. J. Leonard and V. W. Gash. J. Am. Chem. Sot. 76.2781 (1954) ‘* N. J. Leonard. A. S. Hay. R. W. Fulmer and V. W. Gash. Ibid. 77.439 (1955) *’ T. R. Govindachari. M. V. Laksmikanthan. K. Nagarajan and B. R. Pai. Tetrahedron 4.311 (1958) T. R. Govindachari. I. S. Ragada. N. Viswanathan, J. Chem. Sot. 1357 (1%2) *s A. Rieche. H. Gross and E. Hall. Chem. Ber. 93.88 (1960) *’ W. A. Reckov and D. S. Tarbel. 1. Am. Chem. Sot. 74.4960 (1952) ** C. K. Bradsher and R. B. Desai. Rec. 7kw. Chim. g3(6). 593 (1954) ” J. W. Cook, J. D. London and R. K. Razdan. J. Chem. Sot. 4234 (1954) 3o P. Nylen. Chem. Ber. 53B. 158 (1920) 31 R. Pschorr. 0. Wolfes and W. Buchow. Dtsch. Chem. Ges. 33. 176 (1900) 32 E. L. May, J. Am. Chem. Sot. 69. 717 (1947) 33 E. Mosettig and J. Van de Camp. Ibid. 55. 2995 (1933)