title the chemistry on diterpenoids in 1970 author(s) fujita, eiichi

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Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi Citation Bulletin of the Institute for Chemical Research, Kyoto University (1972), 49(6): 423-466 Issue Date 1972-02-29 URL http://hdl.handle.net/2433/76390 Right Type Departmental Bulletin Paper Textversion publisher Kyoto University

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Page 1: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Title The Chemistry on Diterpenoids in 1970

Author(s) Fujita, Eiichi

Citation Bulletin of the Institute for Chemical Research, KyotoUniversity (1972), 49(6): 423-466

Issue Date 1972-02-29

URL http://hdl.handle.net/2433/76390

Right

Type Departmental Bulletin Paper

Textversion publisher

Kyoto University

Page 2: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Bull. Inst. Chem. Res., Kyoto Univ., Vol. 49, No. 6, 1971

The Chemistry on Diterpenoids in 1970

Eiichi FUJITA*

Received October 16, 1971

I. INTRODUCTION

This is one of a series of the annual reviews'-6) on diterpenoids chemistry by the author.

In principle, in each section the full papers are first described and the short communications followed. The order of the journals follows the alphabet of their name.

II. PODOCARPANE DERIVATIVES**

12The mass spectrometric studies of podocarpa-8, 11, 13-trien- 2 9111 II 7-ones were carried out using the labelled derivatives, and it

10,1 8 was shown that these compounds underwent essentially the 5 r 4 6 same reactions on electron impact as the corresponding non-oxo

19 18compounds.7)

Low temperature ozonolysis of methyl podocarpate (1) in roclocarpane methanol -methylene chloride resulted in the formation in high

yield of hydroperoxy lactone 2. Ozonolysis followed by hydrogen peroxide work-up gave the lactone acid 3, whilst ozonolysis followed by reduction with NaBH4

gave keto-acid 4 and lactones 5 and 6 derived from peroxide 2 together with 8-lacton 7 possessing all 18 carbon atoms of methyl podocarpate. The lactone 5

()II0

CO,H COII

O

llci6ion tHII

„(0_,, vIcO:CMcO,C

(1)(2)(3) (4)

000

O O ((O ..T IIH'•. II

(5)McO.0 • 5)(6) (4)

* ii E i — : Laboratory of PhysiologicalActivity , Institute for Chemical Research, Kyoto University, Uji, Kyoto.

** See also section VI , refs. 63, 65, 67, and 70.

( 423 )

Page 3: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FuJITA

was shown to possess an 8,3-H-configuration by application of the nuclear Over-

hauser effect.'"

A linear relationship between the intramolecular nuclear Overhauser effect

(n. O. e.) and the sixth power of the internuclear distance for protons in re-asonably compact organic molecules in deuterio-chloroform solution was derived.

It was shown that application of the observed n. O. e. between two protons or

between a proton and a methyl group can be used to determine internuclear

distances in unknown structures.9' (see Table 1)

Table 1.

StructuresProton Proton n. 0. e Internuclear irradiated observed (%) distance (A)

OAc_-- -----------------------------------------------------------------------_—

SC- 5-H C- 6-H 22 2.50 C- 4-Me C- 5-H 20 2.80

,® 0C- 4-Me C- 6-H 14 3.02

x

0O

MeO

C- 7-H(eq.) C-14-H 18 2.58

x'C- 7-H(ax.) C-14-H 12 2.97 S. 11

Me0C

OAc

®C- 4-Me C- 6-H 22 2.76 11111111r oC-10-Me C- 6-H 10 3.25

i{ McO:C B,'

Temperature dependent proton magnetic resonance studies of four basic ring

C aromatic tricyclic diterpenes (8-11) were carried out, and the characterization of each stereoisomers was shown to be possible. This method was also applied

to the analyses of 7-oxo- and 20-nor derivatives.10'

. 00

ei 0. i IPOID tr~E~

CO-:Me COMeCOMeCO ,Me

(0) (9.(10)(11)

Epimeric a-cyano-a-methyl ketones (12 and 13) were prepared by stereoselect-

ive reaction of enolates. They were used in syntheses of podocarpic acid (14) and abietic acid (15). Alkylations of j3-ketonitriles were found to be stereochemi-

(424)

Page 4: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

OMeR'011

d„„0 0 R' 14,1 0.11100 111111.111 1111W •. II'', II' II

NCCN ITO,CC0.11

(12) (13a): R'--OMr. 12=—II(11) (15) (136) 1C II, R'= OMe

cally opposed to those of corresponding (3-keto esters. (Chart 1). Syntheses of

a-cyano enones by opening of epoxy ketones with cyanide and syntheses of a-cyano ketones by two reductions of a-cyano enones or by trapping of enolates,

obtained in Birch reductions of enones, with cyanogen chloride were also report-

ed.11' (Chart 2)

OMeOMeOMe

0~~--- ~2OO se LIxx

CNCN NC

Chart 1

OMe

OOMeOMe 0 Os00

O OMeLi 'NH;

/J\ 0 OH•

0 CNCN Ac_O

OAcC1OMe II, 'I'd C 0

• Ac0

CN

R'IC

~RR"

OOP01) IA NH,

0

2) CACI 0O 10 FI

R'=OMe; I2"—II

or R' II : TL= OMe

Chart 2

( 425 )

Page 5: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

ITI. LABDANE DERIVATIVES*

From the ethyl acetate extract of the roots of Solidado ,12

,7 '2 „j' 11 missouriensis, ent-13-epimanoyl oxide (16) and ent-3-oxo-13- "epimanoyl oxide (17) were isolated ,121 accompanied by 2 10 H 8 - 15

°abietane derivatives.**

f1The condensation of ambreinolal (19) , prepared by 19 18LiA1(OEt)

2H2 reduction of ambreinolide (18), with 2-carbe- Labdane

thoxyethylidenetriphenylphosphorane gave the a-methyl-

0I1 CO

off

RS0O 5,0 0,05. R~ HAH

c16) : R-111 118)(19) (20) : R CO_Et 17) : R=0(21) : R==CH_OH

(22): R=Me

cis-a,43-unsaturated ester 20, which was converted into the allyl alcohd 21 by

reduction with LiA1H4. The reaction of hemiacetal (19) with isopropylidenetri-

phenylphosphorane afforded an isopropenyl derivative 22 with the same olefinic methyl group as that of ambrein (23). By assignment of the NMR spectra of the

above compounds structurally related to ambrein (23), it was confirmed that

the configuration of ambrein is the trans form.'31

01-1%

~i7-I5i2nO~®.012 0 ,. H,. FI... }I.', H

R c23)(21,. R'— C11,011.: 26) 0?7): R=- mH„ 3-OH Ii '' II. R' -CO I1(28) : it=0

25) 1 R' =Me, R°=- OAc,129) : 12-11, IZ" = CO,Me

Copaiferolic acid (24) and methyl 11-acetoxylabda-8(17), 13-dien-15-oate (25)

were obtained from the oleoresin of Copaifera multijuga.'41

2-Oxomanoyl oxide (26) was converted into the 2-hydroxy ether 27 and the

2-oxo ether 28, both of which had ambergris-type odors similar to but much

weaker than that of odoriferous compound 29. The route affording the highest

overall yield was via the intermediates 30, 31, 32, and 33, which gave 23% of 28 and 17% of 27.151

* See also section IV, ref. 35. ** See also section VI.

( 426 )

Page 6: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

OH

r0/40 0 0 ou

(30)(21)(22) (33)

Dundathic acid which had been isolated and named by Baker and Smith16'

was shown to be a polymer consisting principally of units derived from trans

communic acid (34) by Carman et al."'

0

I o x ..on oox o

4, ODQe O OII O 1110 °. It II IIH

IIO,C,OOOO O

(31) (32) (36)(37) - (3R::: ten ally oft. an

analog

The structure of a novel C11H200; terpenoid antifungal agent, LL-Z 1271a,

which was isolated from fermentations of an unidentified Acrostalagmus species, was elucidated to be 35 by a research group of American Cyanamid Company.1 )

In addition, the chemistry of some interesting base hydrolysis products of this

mold metabolite was discussed. Biogenetically, it could arise from microbiological

degradation of a normal diterpene of the labdane type by oxidative cleavage

between C-12 and C-13. A reasonable alteranative would be the addition of a C1 unit to C-11 of a sesquiterpene precursor of the drimenin class.

A new diterpenoid isolated from Leonotis dysophylla was shown to be 8-

hydroxymarrubiin (36). The 8-hydroxy group is probably 23-oriented.19'

The structure and stereochemistry of peregrinin and tetrahydroperegrinin, which were isolated together from Marrubium peregrinum, were established to

be 37 and 38.20' Imbricatolic acid (39) was isolated from the resin of Cupressus nevadensis and shown to be present in the resins of several American and Asian

Cupressus species but absent from that of the European species C. sempervirens.21'

CH;O1-[, O0

. II'. I1. , II 110

( >9)(-10)(-11)

Analysis of the volatile leaf oil of Charnaecyparis noothatensis showed some monoterpenes as the main constituents and the presence of nine diterpene hy-

drocarbons (unknown diterpene I, isopimara-8(9), 15-diene, isohibaene, sandara-copimaradiene, isophyllocladene, isopimaradiene, phyllocladene, abieta-7, 13-diene,

and dehydroabietadiene) and the following diterpenes : 13-epimanoyl oxide, 8-

( 427 )

Page 7: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

epimanoyl oxide (40), 8, 13-diepimanoyl oxide (41), and phyllocladan-16-o1.22a,v)

Anhydrotetrahydromarrubiin (42) was reconverted into tetrahydromarrubiin

(43) . Ozonolysis of 42 to the trimethyl keto lactone 44a did not involve change of the C-8 configuration. Reduction of 44a with borohydride gave the trimethyl-

hydroxy lactones 45a and 45b ; the epimeric keto lactone 44b was reduced to 46.23)

OOH01-I 0II

s. II1,~•H

-_0 •000O.O C

00

(42)(13)(Lta) : a Me at C-S (Ca) : [-011 at C-9(16) (1-tb) : ,(-Me at C-8 (15b) : a-OH at C-9

A homo-diterpene lactone isolated from Dacrydium colensoi was shown to have

structure 47.24) The dihydro derivative of 47 was synthesized25) by two inde-

00 110 C

no•c

0>1I0 I-I H`.1I I-IQC--Me0 C

(-17)(-IS) (-19)(50)

pendent routes, thatis, the one from 48 isolated from the heartwood of D. colensoi and the other from 2-oxomanoyl oxide (26) .

A new diterpene acid, isolated as its methyl ester from Callitris columellaris,

was shown to be an isomer of trans-communic acid (34) and to be represented

as 49. Another new isomer of communic acid was shown to result from thermal

rearrangement of trans-communic acid methyl ester on gas chromatography, and

was tentatively assigned the structure methyl labda-8(17)-trans-11(12)-cis-13(14)-trien-19-oate (50) on the basis of spectroscopic and mechanistic considerations.26)

Some reactions—reductions and rearrangements—of solidagenone, the major

diterpenoid from Solidago canadensis were investigated,27) which substantiated the structure and stereochemistry (51) previously deduced for it. The structure and

stereochemistry of oliveric acid, a principal constituent of the trunk resin of

Daniellia oliveri, were established as 52.2B) By-products formed during oxidation of sclareol to a lactone were investigat-

ed. As the unsaponifiable neutral products, 13-epimanoyl oxide and a smaller II

_C0aio

000o

g, H 0CO H

(31)(52)(53)

(428)

Page 8: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

amounts of manoyl oxide and 53 were afforded.29) Selective epoxidation in a

series of labdadienes was investigated. Epoxidation of 13-hydroxy-7, 14-labdadien-

17-al (54) with monoperphthalic acid gave 13-hydroxy-14(15)-epoxy-7-labden-17-al

(55) . However, epoxidation of 13-hydroxy-8, 14-labdadien-17-al (56) gave 13-hydroxy-8(9)-epoxy-14-labden-17-al (57). Oxidation of 56 with silver oxide fol-

lowed by methylation with diazomethane gave 17-carbomethoxy-8, 14-labdadien-13-ol (58) . Epoxidation of 58 gave a mixture of the 14(15)-epoxy- (59) and 8(9),

14(15)-diepoxy- (60) derivatives of 58. Selective epoxidation of the labdadiene

vinyl group was possible only when the double bond at position 7 was substitut-

ed (at C-8) with formyl or carbomethoxy group.3o)

0II011OHOOH CIiOso CHO0 es CHOso C140 o is

(5-I)55)(56 (57)

OHOH OI-I O

CO AleCO MeCO,AIe 0 Oe• OSP

O

1I IIIl

5',)(59)(60)

A C2o-butenolide 62 was derived from a reaction of monocyclofarnesyl bromide

(61) with di-3-methylfurylmercury followed by photo-oxidation. A successive treatment of 62 with stannic chloride yielded a- and j3- levantenolides (63 and

64).31a) A modified route involving one step cyclization of rings, A, B, and C

was also published.3lb)

0 0

o I "or. 00( \ CHzBC ----- ..0.......

OMe-

0

el IOW. 0 „ •

H

• .

.

(61) (c2) (63)(61)

The structure of nepetaefolin, a prefuranoid diterpene isolated from the leaves

and stems of Leonotis nepetaefolia, was clarified as shown in 65. The biogenetic

implication that 65 is the immediate precursor of 66 in L. nepetaefolia was upheld

by isolation studies. Details of the biosynthetic processes leading from the iso-

prenoid skeleton to the spirodihydrofuran system, however, are as yet obscure.32) About the absolute configurations of several labdane derivatives at C-13, con-

( 429 )

Page 9: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

0 g H .OH 0

'....:0 0'.O -002H.CO:H

g : 1 4,

H '11IH •

OOAc•OAc 0

(65)(66)(67)(68)

firmation was presented as follows : labdanolic acid (67) , eperuic acid (68) , im-

bricatadiol (69), 13-epimanool (70), 13-epitorulosol (71), larixol (72), and ent-13-

epimanool (73).33)

OHoHOHOH

CH_OH

tt®t® 110FI II I-IIIH

HOFhC •HOH.0OH

69) (701(71)(72) (73)

IV. CLERODANE DERIVATIVES

16 "Chettaphangkhi" is an indigenous drug applied as H z

H=Hstomachics in Thailand and is obtained from the roots of

,7713

9

210 814-43Adenochlaena siarnensis.Several furanoditerpenoids were 6 isolated from the ethylene chloride extract. The structure

,819of chettaphanin-I, the most abundant component, was

Clerodaneinvestigated and the planar structural formula 74 was

presented for it.34)

0

0/,SO OH

CO2Me (75, : R=CH.OH

(74)(76) : R- CO214

From the neutral saponified products of the petroleum ether extract of Cistus

monspeliensis, 8a, 15-labdanediol which has been isolated from C. labdaniferus

was isolated as a minor component. To the main constituent, cistodiol, structure

75 was assigned. The corresponding diacid, cistodioic acid (76), was also isolated

and characterized.35)

V. PIMARANE AND ISOPIMARANE DERIVATIVES*

The crystal structure of rimuene was determined using three-dimensional

* See also section III , ref. 22.

(430)

Page 10: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

photographic data. The molecular 17 17

12'16structurewas confirmed as 77 in 11 1s ...../~

20 9 H 14 15 H IS agreement with other studies ,30)

1

2101 8Total syntheses of racemic 4-

"\ • 6'epipimaric acid (82a) and 4-episand-

19 19aracopimaric acid (83a) were done. Pimarane Isopimarane The previously described keto ester

78 was transformed, via alcohol 79, aldo ester 80, and C-13 epimeric j3, 7-unsa-turated aldehydes 81, into a mixture of methyl rac-4-epipimarate (as 82b) and methyl rac-4-episandaracopimarate (as 83b). This was chromatographed on alumina impregnated with silver nitrate to effect separation of the C-13 epimers. The corresponding racemic acids (82a and 83a) were prepared from esters by treatment with potassium t-butoxide in DMSO.371

CHSBuCIOCHO II3 I2,~sof0•00.-

II HH

CO-.Me CO.^e CO,Me

(77)(78): R=0(80) (81)

II (79) : R=\OH

/ORH OR

11 HOI20'\r===19 RO:',S CO=RCO_I2

(82a': R = H(83a : R=H (84): R=H (85): 0-H

(828 : 0=A•1c(831,' : 12- Me (89) : R=Ac (87) : R=Ac

Dihydrodarutigenol (85) was prepared by the hydrogenation of 84 over plati-

num dioxide at the atmospheric pressure and under 90 kg H. Acetate 86 was

reduced under both conditions to give 87.38) Dihydrodarutigenol (85) with meta

periodic acid gave aldehyde 88, which was converted by methyl magnesium

is• I21I I HO I I10 IP

71I-I ` II'. H

HOH:CHOIh _C

(88) : R'=CHO,(9I) (92(: P.=OHC9 -1): R=OII

M=a-OH,.9 -H(92 : R=I1(95 : R=I-1

(89' : R'=CH—Me,

0'1 R°=n-OH, ,S-H

(90' : R' -Et,

I91 -H.

(431)

Page 11: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

iodide into 89. The compound 89 was transformed by oxidation with chromic

anhydride in acetic acid followed by Wolff-Kishner reduction into the hydrocar-

bon 90, an enantiomer of 91 prepared from dihydropimaric acid.3"' Structure of virescenols A and B, metabolites of Oospora virescens, was in-

vestigated. Virescenol A(92) was prepared by treatment of virescenoside A with

hydrochloric acid at 37° for 15 days. Similarly, virescenoside B gave virescenol B(93). Isovirescenol A(94) was obtained by the hydrochloric acid isomerization

of virescenol A. Isovirescenol B(95) was prepared similarly.4 )

Three pimarane diterpenes isolated from the heartwood of Cleistanthus sch-lechteri var. Schlechteri were identified as ent-isopimara-8(14), 15-dien-313-ol (96),

ent-3(-hydroxyisopimara-8(14), 15-dien-12-one (97), and ent-isopimara-8(14), 15-

dien-3j9, 12(3-diol (98).41) These three diterpenes are congeners of the aromatic

diterpene cleistanthol (99).

12011

HO0

110~I-IO'4110'....,

. I-I`.. I-I'. II

(00)(97) : R=0(99)

(98) : R=a 011„9-H

Novel steroidal j3-keto ester 100 was prepared by the reductive carbomethoxyl-ation of testosterone acetate. Methylation of 100 afforded selectively 101, whose

3-deoxo ester 102 was converted by a series of reactions into sandaracopimaric

acid (103a).42)

OAcOR=

A S. • . O~~HR' 110HS.S

III-I H

COzMeCO,Me C0°R R

(101) R'=0, (103a): R=1I (104): 12—Me

(100)R'=Ac

(102) : R'=H,, (103b) : 14—Me (105) : R=CO,II

R'=H

The occurrence of ent-pimara-8(14), 15-diene (104), ent-pimara-8(14), 15-dien-

19-oic acid (105), and ent-16-kaurene in Aralia racenzosa was reported.43)

Allylic photosensitized oxidation of methyl isopimarate (106) afforded methyl

7a-hydroxysandaracopimarate (107) and the same reaction of methyl pimarate

gave the hydroxy-ester 108 accompanied by methyl 7a-hydroxy pimarate (109)44). Chemical and spectral studies of the major diterpene acid component of the

bark of Croton oblongifolius and its conversion products showed that it should

be formulated as ent-isopimara-7, 15-dien-19-oic acid (110).45) The bp2 145-170° fraction of essential oil of Thuja standishii was shown to

(432 )

Page 12: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

/~ 1.100..

... OH .̀ III-i+. HH

CO,MeCO3MeCO,Me CQMe

(106) (107)(108) (109)

0 ./-'"7 0 %,.%----- H OOPelo SOile 4111 I-1 OH

IIHi H

CO,H

(110) (111)(112)(117) (114

contain the following diterpenes : 451101-rimuene (111) (1%), rimuene (77) (9%), 48191-sandaracopimaradiene (112) (0.5%), hibaene (8%), dolabradiene (113) (3%),

dehydroabietane (5%), totarol (3%), and 8(3-hydroxyisopimar-15-ene (114) (50

%),46) The calculation of NMR chemical shif values by the method previously pu-

blished by ApSimon et al.47) was extended to a derivation of the shielding effect

of the ketonic carbonyl group, and applied to a variety of substances, including a selection of diterpenes and their ketonic derivatives.48)

7-Isopimaren-18-oic acid (115) was synthesized from methyl 8(14), 15-isopi-maradien-18-oate (methyl sandaracopimarate) (103b) based on the reactivity of

a-epoxides in this series.491

HO / II0 ,®I I~0 . H

conO

(115)(110)

The structure 116 (1113-hydroxy-rosenonolactone) of rosein III, a metabolite of Trichotheciur roseum, indicated by chemical and spectroscopic evidence, was

confirmed by an x-ray analysis of the metabolite itself, using direct methods of

phase determination.")

VI. ABIETANE DERIVATIVES*

From the roots of Solidago missouriensis, 7,13-abietadien-3-one, -3(3-ol, and -2a-ol were isolated .lz)**

* See also section III , refs. 12 and 22 and section V, ref. 46. ** These abietadienes were found to be ent-abietane derivatives and artefacts from corre-

sponding 8(14)-en-13-ols. (Private communication from Dr. Anthonsen to the author.)

( 433 )

Page 13: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

1`7Controlled oxidation of methyl dehydroabietate with

i6 chromic anhydride gave methyl 7-ketodehydroabietate

(117) . Prolonged oxidation yielded increasing amounts of O:uJrIs the diketone 118. When subjected to Beckmann rearrange- :i

13ment (polyphosphoric acid) the oxime of the ketone 117 "' 'furnished the expected lactam 119. In addition, a weak

.,':cane base was formed , the spectral data of which indicated structure 120.51)

0 R'OII

0O O ISI OS R' 4011 NII 5 NH 551

CO,Me COMe 0 CQ_Me•

• (117) : R' -i-pr, (119) • (120) (121) 12= =0

(118) : R' —Ac, R"=0

In a review of the recent studies on the plant pigment, Eugster12) described

on the diterpene pigments : fuerstion (121) from Fuerstia africana, coleon A(122)

and coleon B(123) from Coleus igniarius, and coleon C(124) from Coleus aquaticus.

OH011 Me OHOHOO OH OO O1I0.,O HO O •50, 11tt\ O..III OH 0OH OH

(122,(123)(121)

A convenient route from abieta-8, 11, 13-trien-18-oic acid (125) to abieta-5, 8,

11, 13-tetraen-3-one (126) was developed involving selective epoxidation of the alkene mixture (127) obtained by oxidative decarboxylation of the acid with lead

tetraacetate. Treatment of the 3a, 4a-epoxide 128 with lithium diethylamide gave a quantitative yield of the allylic alcohol 129. Brief treatment of this alcohol

with N-lithioethylenediamine gave the a, (3-unsaturated alcohol 130, which on

oxidation afforded the enone 131. Methylation of the latter compound with methyl iodide and potassium t-butoxide in t-butanol yielded 126 in 43% overall yield

from the alkene mixture 127. Other reactions of 128 were also reported and

discussed.53 )

0 0,----) 0 5•0®t

COZH

123)(128)- (127) (128)

( 434 )

Page 14: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

A phytochemical survey of the diterpenoid resin acids of the North Queens-

land species of Agathis was presented. The methyl esters, 132 and 133, of two

new resin acids were described.5 )

01)OH

0 110' 111N11 CO MeCO -,Me

(130) : R=-•a-OH, (129)4_H (132)(133) (131) : R=0

Compounds, 134 and 135, were synthesized, in relation to cryptotanshinone

(136) and isotanshinone-II (137).55)

0

0\ 0 0 \

oO'I

t001 I t0®OCTO 0 o

(1341 (135)i (136)(137)

Hydrogenolysis under hydrogens over Pd-C in the presence of acid of hydr-

oxytanshinone (138) and tanshinone-II (139) into 140 was investigated,and its

mechanism was presented.56)

0 OAc 00 ,II•

0OAP • •

COMe CuS

(138) • R OH (110)(Llla)(141b) R=Me (139):R=H(141c):R=H. 8a , 12a-C-0

It was shown that the direct irradiation of cyclic peroxides such as ascari-

dol, and those (e.g. 141b) derived from cyclohexadiene, 1, 3, 5, 5-tetramethyl-

cyclohexadiene, and methyl levopimarate (141a) rearranged on irradiation. The

bisepoxides (e.g. 142a) were obtained as in the thermal rearrangement, together with, where the structure permited, the keto-epoxide (e.g. 143). The mechanism

of the reaction was presented.571

The reaction of levopimaric acid transannular peroxide (141c) with triphenyl

phosphine afforded a monoxide whose structure was shown to be 8a, 14a-epoxy-abiet-12-en-18-oic acid (144) . Since epoxidation of 144 afforded levopimaric acid

dioxide, the structure of the latter was shown to be 8a, 14a : 12a, 13a-bisepoxy-

abietan-18-oic acid (142b),581 which denied the previously proposed structure 145*.

* See ref . 3.

(435 )

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E. FUJITA

0 0

.1 Ole° ,~ o CO,R CO

_R 'COX

(142a) : R=Me (143) (1421)) : R=11,(144)

Ia,14a,12a,13a-C-O

Isolation of 18-norabieta-8, 11, 13-triene (146) from Thujopsis dolabrata "and from Podocarpus ferrugineus was reported.59)

HHOH

„JOH/~COzMe '. HHCO,Me CO:H

(145)(146)(147) (14S)

Syntheses of 20-nor tricyclic diterpene derivatives and their structure de-

terminations were reported. In the A/B-cis ring system, it was revealed by the analysis of NMR and IR spectra and reactions that the steroid type conforma-

tion (147) of C-10 methyl series was preferred to nonsteroid type conformation,

conversely, non steroid type conformation (148) was preferred in 20-nor deriva-

tives.60)

Syntheses of 8a-abiet-13-en-18-oic acid (149a), abiet-13-en-18-oic acid (149b),

and abiet-7-en-18-oic acid (149c) were published. The stereochemical course of

various reactions of these compounds as well as those of two abiet-8(14)-en-18-

oic acids, 150 and 151, were dicussed.61

11114r x'. x CO -HCO,HCO,HCO,HCO,II

(119a)(149b)(149c)(150)(151)

It was found that dehydroabietic acid on lead tetraacetate decarboxylation

gave three olefins, 152, 153, and 154, and 18-norabieta-8, 11, 13-trien-4-ol acetate

(155). Hydroboration-oxidation of the mixture of these olefins gave 18-norabieta-8, 11, 13-trien-19-ol (156) and 18-norabieta-8, 11, 13-trien-3a-ol (157) as major pro-

ducts and 19-nor-5,3-abieta-8, 11, 13-trien-7-one (158) as a minor product. The

reduction of dehydroabietonitrile with sodium in liquid ammonia gave 19-nor

hydrocarbon 159, instead of 18-norabieta-8, 11, 13-triene suggested first. The

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Chemistry on Diterpenoids in 1970

structure of 158 was confirmed by a two-steps synthesis from methyl 7-oxoabieta-

5, 8, 11, 13-tetraen-18-oate 160 : a vigorous basic hydrolysis accompaied by decar-

boxylation and hydrogenation over rhodium catalyst.62)

O 0••1O, tt H 23 ! H

OAc

(152) - - (153)(154) (155)

HO' .,.OW IP. O ss Il FI HH

awnCQMe

(156) (157)(15s) (159) (160)

Synthesis of (+)-4-epidehydroabietic acid (161) from podocarpic acid was

accomplished as shown in Chart 3, which constituted a formal total synthesis of 161.65)

OHOMeMeOOH

igh0 O0 O 23B'~

so H HOCMcOzC McO

,CMcO,C

N_N

NNO N• Na2I in HCONHz NzO

1-phenyl-5chloro- --~ 1-pheole SO110 MP

• H-• $

McOzCHOzC H (161)

McOzC Chart 3

The major product from the solvolysis of the methyl bromoabietate formed

by a reaction of methyl abietate (162) with NBS was methyl 12a-methoxyabietate

(163). The structure was proved by independent synthesis from 12a-hydroxy-abietic acid. Methyl 15-methoxyabietate (164) was also formed. The three

possible methyl methoxydehydroabietates were obtained as secondary reaction products from the methyl dehydroabietate (165) formed during the NBS-abietate reaction. They were also prepared by the solvolysis of NBS-methyl dehydro-abietate reaction products. The main parts of the sequences are given in Chart

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Page 17: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FU71TA

OMe Br+1 'I NBS li.McOHI~5I-i I\11I',0

elzN..1 CO,Me

H I(164)

H

BrIO CO,Me -1I'

(I62) 12 NBSIH ____,so

H

McOHOMeCO,Me

(165)

oi Chart.11110:1(163)

H COzMe

4.64)

Lemieux oxidation of 166 afforded 167 in 50% yield, but the Lemieux oxidation

of 141a gave varying yields of 168 and 169. Procedures for the exhaustive

ozonolysis of 166 and 141a were standardized to afford the important synthetic

intermediates, 167 and 168, in 55-60% yields. Partial ozonolysis of 166 afforded

170, 171, and 172. Oxidation of 170, 166, and 141a with Ru04 NaI04 followed by

esterification gave 167, 167, and 168 in excellent yields.65)

CQMe COzMe OH

S/ •,.®0t® 'OH H H

CO,MeO:Me CO,Me CQMe

(166) (167) (168) (169)

O

i1051:00 0 ., H H H

COzMe CO:Me COMe CQII

(170) (171) (172) (173) : R =0 (174) : R=N (CH,),OH

,175): R=NCH,CH(OH)Me

N- (Hydroxyalkyl)-maleimidopimaric acids were synthesized. Compound 173

was refluxed with (3-hydroxyethylamine in methanol to give 174, while it was

heated at 120° with 43-hydroxy-n-propylamine in dimethylformamide to afford 175. Several metallic salts of 174 were prepared. Compounds 174 and 175 are polymer

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Chemistry on Diterpenoids in 1970

intermediates.' 6 )

Podocarpic acid (14) was converted into taxodione (176) via a route shown

in Chart 5. Since the total synthesis of the former has been recorded, this con-version implies a formal total synthesis of the latter.69'

MeOPhCOOOMe OHO ;N—Q0—N=N 0 14---- 4•00 -----

x x McO,C

OMe OMe OMe Me0 OMe0 111,1 O•• OAc1;

OMeOH0 Q MeOHOHO I,I OC O 7 olo Ho~g H

OH O ClOO (170) Chart 5

From the roots of Salvia miltiorrhiza, a new red crystalline pigment, miltirone

(177), was isolated and characterized.68)

0 0

ei0 SO~,_xCO311\ ^ /CO,H O~~CO211OCO311

(177)(178)(179) (180) (181)

Microbial degradation of dehydroabietic acid was investigated. Degradation

products 178 and 179 by Flavobacterium resinovorum and 180 and 181 by Pseu-domonas resinovorans were isolated and characterized as their methyl esters.69)

Nitration of methyl 12-acetylabieta-8, 11, 13-trien-18-oate (182) gave the pro-

ducts 183 and 184, and the latter was converted into methyl 13-hydroxypodocarpa-

8, 11, 13-trien-18-oate (185) in 26% overall yield from methyl abieta-8, 11, 13-trien-18-oate (methyl dehydroabietate).40'

When methyl neoabietate (166) was photolyzed in methanol with a low pres-sure mercury lamp, the only solid methoxy compound obtained was shown to

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E. FUJITA

R' R'

OO OR' IOW R'•

•.xx

CO:MeCO_Me

(182): A' =Ac, R'=H (181): A' =Ac, Ft' —NO) (183) : R'=N0a. R'=NO (185) : R'=H, R'—OH

be 164.711

VII. TOTARANE DERIVATIVES 2 11 3

20 9 H 14,.. t /17 From the extract of the bark of Podocarpus species

0 to 1I 3 (16(cf. P. neriifolius), podolactone-A and -B, which strongly H67 inhibit expansion and mitosis of plant cells, were isolated

19 18as crystals and structures 186 and 187 were assigned to

TotaraneA and B, respectively.72>

O

I0 O~ /R"(186) :12' =H,12' =OH, CH:OH

O(187) : R'=OH,R'=OH, CH:OH R':

H 0 O

VIII. CASSANE DERIVATIVES

1;Structure 188 was suggested for cassminic acid, a 111213~16minor constituent from the bark of Erythrophleum gui-

20 9 H 14 neense.73> The assignment of the 14-methyl group in 2

510 x 67cassamic acid and its congeners (e.g. 189) to the axial 4 6

lconformation was supported by the experimental results. 19 18 M

agnetic anisotropy calculation was also in agreement

Cassanewith this assignment.74>

co,Ho N.,0

HH 0

II ANVMcO,C 0 ,1111 OH el0 HHO .̀.H H II OAc0 Me0-,C

188,(166(190i (191)

Under the conditions of the Serini reaction, the benzofuran 190 derived from

a-caesalpin rearranged to the diketone 191 with a cis-A, B ring-junction, while on mild base treatment the benzofuran mesylate 192 from 8-caesalpin underwent

( 440 )

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Chemistry on Diterpenoids in 1970

a pinacol-type rearrangement to the hemiacetal 193. On the basis of considera-tion of steric course of these reactions, in conjunction with other evidence, the

relative stereochemistry of a-, (3-, and 8-caesalpins was assigned as in 194, 195,

and 196, respectively.75)

o ^ o •o \o \

HO OO R'OAc4111griOH/',R'AcO...,OH

OH I-1 OH •off 01\16 OH R'

(192) (193) (194): R.= OAc, R'=O (197) (195) : R'=OH, R'=0

(196) : R'=OH, R'=a-OH, 9-H

From the bark of Caesalpinia pulcherrima, a new cassane derivative named

x-caesalpin was isolated. Structure 197 was proposed for this compound.7 )

IX. KAURANE DERIVATIVES*

A mixture of two grayanotoxin acetates 198 and 199,

was isolated from older extracts of leaves from Rhododen- 22 9d

roll ponticum. The corresponding alcohols, 200 and 201, l0 II N':15

I; 7were also chromatographically detectable in these extracts. HVery probably, a la, 513-configuration was assigned.77)

3 ISAnother grayanotoxin 202 was isolated from the leaves of

1,aurane th e same plant.78)

xonoto II0 d li OH©~oH~ImillOIIOH

0II0I-IOH

(19S) : R'=Ac (199) : R- Ac (202) (200) R=H(201): 12- II

Two physiologically active diterpenoids, grayanotoxin-IV and -V, were isolat-

ed from Leucothoe grayana. The structures including absolute configurations 203

and 204 were supplied respectively.7")

off iI H11,II HO ••o ,o*Akio

OH`A c 01Ib„\H

(203)(201)

* See also section III , ref. 22, section V, ref. 43, and section X, ref. 120.

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E. FUJITA

The stereochemistry of grayanotoxins, asebotoxins, and rhodojaponins, toxins of Ericaceae, however, was revised to C-1 a and C-5 ,8 configuration (A/B trans)

by several groups.80,81,83,84,85) Revised structures are as follows : grayanotoxin-I

(205), -II (206), -III (207), -IV (208), -V (209), -VI (210), -VII (211), asebotoxin-I

(212), -II (213), -III (214), rhodojaponin-I (215), -II (216), and -III (217). An x-ray analysis of grayanotoxin-I gave a confirmative evidence.")

HOHO II` HII Ti O 7I II HOHO •

OH OHOH

OR''OHOHk OH OR'OTIOR OR' OR'

'205': R'=Ac . I2'=H)20(i1: R=H .21.1): R'=H, R'=COCHIOI-I)Mc '207): R'=R"=I-I'2131: R=COIst 1213): R'==R°=Ac

[208: R'=12 =Ac(210): R'=Ac, R°=II 3212' : I2' =CORt, R==Hi 217) : R'—R=H

HOHO H `. II1I R H n H H 0 *~

~1-TOValk~~ 011TOHipP: OHOHOAc OHOH

OH 011

(209)(210) : R=a-OH , 3-Me(218)

(211) : R=CHz

The structure and stereochemistry of lyoniatoxin, a toxin of Lyonia ovalifolia,

were investigated, and formula 218 was assigned to this substance,8~1 while the A/B cis-junction with C-1 (3 H in 218 was assigned to the same compound named lyoniol A by another group.87,88)

Isolation of new constituents from Isodon trichocarpus and the structures, 219,

220, and 221, of isodonol, enmedol, and enmenol were reported.891 Isodonol is identical with oridonin elucidated already by the author et al.90)

HO 0.•HO110,HO111110,HO •OOII ••loOIIO-IH OS..OR

HH NMe II OI-I•HOR OHOH

(219)(220)(221)(222) : R=Ac (223): I3=H

The structures of enmenin, enmelol,and ememodin, isolated from Iso don

trichocarpus, were determined to be 222, 223, and 224, respectively.911 Enmenin

is the same compound as trichokaurin whose structure and absolute configura-tion has been established by the author et al.9~1

The full paper on the formal conversion of enmein (225) into ent-kaurene,

atisine, garryine, and veatchine was published.931 The preliminary communi-

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Chemistry on Diterpenoide in 1970

0 •0 II0IItioII, ,o •o° 11811HOHOOHOO .• 1I O. H ,H OHOH

(224)(225)(227)

cation had been published and the more detailed explanation had been done in

the preceding number') of this series of reviews.

The full paper on the structure and absolute configuration of oridonin (219)

isolated from Isodon japonicus and I. trichocarpus was also published.94' Oridonin (219) was transformed into isodocarpin (226) via a route shown in

Chart 6.95) Similarly, dihydroenmein (227) was also converted into enmein (225).

o offOOH 0 U 'IIolI

HO0~.0 ~~ ~•-------- I) McSO,CI

los.„)...OI-INaIO,®1)---------Jonespyridine OOO 2)I-1. Pt0 2) H, Raney Ni

O

HOHH 011HOunder high OHpressure

(219.

OHOTHP0 O ------O0II

I

~ ~0-O• 01) McOH,HCINBS

2) LAH2) CrOePhCO, II 1110 0 —2)- —250pyridine le O CHC1, Il O`HOilH OM

e

0HrO II P

01)I. HMFO

®2l.MOH, II,0 10OO H OMeH OH

(226) Chart 6

Previously, trichokaurin (222) had been converted into dihydroisodocarpin,921

and the latter has been transformed into isodocarpin (226).95) Thus, a chemical

conversion of trichokaurin into isodocarpin has been accomplished. Now, a more convenient and shorter route was developed, as shown in Chart 7.96)

All the published syntheses in the diterpene alkaloid series had involved the

total synthesis of a racemic intermediate, the correlation of this material with

an optically active degradation product of the same structure and finally the conversion of this optically active relay compound to the optically active alka-

loid. Wiesner et al.97) resolved the synthetic racemic compound (as 228) into

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E. FUJITA

0 0 II 11

HOet, 1)PCrO,JHOHO Yne DDRNaIO,

OAc 2) LAHgOO OIIOleOHpOIi HHI-1 l I 0I1

OAcOH• OH

(222)(276)

Chart 7

optically active enantiomers and converted each enantiomer into the ketone.

One of them was proved to be identical with degradation product 229 from

natural alkaloid. This enantiomer was converted into N-acetate 230, which had

been converted into garryine and veatchine by themselves. Thus, the total

synthesis of the natural optically active form of these alkaloids was complete.

OOMc

400p,:OIIO ...oCCCII),CO.OO•

\Is....R.........rj~II iIHI-iO lI

CO,H

(22S)(229) : R=SQMe(231)(232) (230): R-Ac

A diterpene acid wasisolated from Enhydra fluctuans ; its propert ies and

spectral data, and its dehydration with phosphoryl chloride and pyridine, or

refluxing with acetic anhydride and pyridine to ent-kaur-16-en-19-oic acid led to

its identification as ent-16j3-hydroxykauran-19-oic acid (231). The latter was

prepared by hydration of the former.901 The synthesis of 232, a cafestol intermediate was reported.991

The ent-norkauranol tosylates 233 and 234 each furnished six acetates and

three olefins on buffered acetolysis. The equivalent norphyllocladanol tosylates

235 and 236 gave the enantiomers of these six acetates, one additional acetate

237, and only one olefin 238. These transformations provided a route for the conversion of ent-16-kaurene (239) into ent-phyllocladene (240) , atisirene (241) ,

and neoatisirene (242) and could in principle be utilized for the formation of

kaurene, anti-atisirene, and anti-neoatisirene from phyllocladene. Mechanistic

aspects of the solvolysis were discussed : in particular, a pathway, which includ-

ed a 1, 2-hydride shift from C-15 to C-16, was tentatively suggested as a ration-

alization of the high yield of 238 from 236.'°°)

Aconitine, songorine, and songoramine were isolated from Aconitum karakoli-cum. UV, IR, NMR, and mass spectral analyses suggested structure 243 for son-

goramine.101' The mass spectra of ent-kauran-16-ols were reported.102' These compounds

differ either by stereochemistry at C-16 or in the substituent at C-4. In all cases, the most characteristic ions corresponded to a loss of ring D as a C311e0 frag-

ment. The substituent R at C-4 was deduced from such typical ions as (M-R)+

( 444 )

Page 24: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

0.41, elj, QTi,~ OTS, H/® .®OAc 400

' I-I. I1 '. H'., H

(233) : 16n1-1 (-OTs 235) : 16a H, 3 OTs 237)238)

231 : 16n-OTs, 3-11 r 235l : 1((n-OTs, 3-H

4•40.

., g. H. H'. H

239) 220)(241)(242)

O

H•

ti...It ._.......N 1110OH, OH CHO

CO311HO:C

(243) (24-1) (245)

or (M-R-H2O)+. Kauranols epimeric at C-16 showed little difference in their mass spectra ; the assignment of configuration at this center requires the spectra

of both epimers.

ent-Kauran-16-ol and ent-16-kauren-19-oic acid were isolated from Enhydra

fluctuans.'°31 Diterpenes from the leaves of Cryptomeria japonica were investigat-ed. Consequently, C. japonica trees were sub-divided into four chemically dis-

tinct varieties on the basis of the diterpene hydrocarbon content of their leaves.

Seven other species from the Taxodiaceae were analyzed for diterpenes.lo41

(17-14^,_ent-6a, 7a-Dihydroxy-16-kauren-19-oic acid (244) was prepared and fed to Gibberella fujikuroi. It was not useful as the precursor of gibberellic acid, but

was incorporated into fujenal. However, dilution analysis showed the dihydroxy acid 244 to be a metabolite of G. fujikuroi, and the acid was shown to be more

active than kaurenoic acid and dehydro acid 245 in four bioassays to gibberellins.

Thus, a possibility that a derivative of dihydroxy acid 244, e.g. a 6-pyrophos-

phate, could be a precursor of gibberellins can not be excluded, according to Cross and Stewart.lo5)

The complete configuration 246 of atractyligenin was obtained by a three-

dimensional single-crystal x-ray diffraction study of epoxybromoatractyligenin.'°61 The complete structure 247 of abbeokutone was presented.107) It was identi-

cal with the previously assigned structure. A new trachylobane derivative 248 together with the biogenetically related ent-16-kauren-19-oic acid was isolated

from the flowers of Helianthus annuus.t001

Culture filtrates of Fusarium moniliforme was shown to contain ent-16(3-

( 445 )

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E. FUJITA

Op Iltp, OH

CII;OH I{OOH60 OH 0,•II'00 00 HHHH

CO:•HCO2HR

(246)(247) (248)(249) : R=CHO

(250) : R=CO,H

(251) : R=Me

hydroxykauran-19-a1 (249) and ent-16Q-hydroxykauran-19-oic acid (250)—two di-

terpenoids related to the intermediates in the biosynthesis of gibberellins.1091 ent-Kauran-16,l-ol (251) was isolated from Anthelia julacea and A. juratz-

kana."01

It was observed that a common stereoelectronic requirement is satisfied in

the epimerization by weak alkali of the cis-alcohols, 252, 254, 256, and 258, into

the trans-epimers, 253, 255, 257, and 259, respectively and also in the epimeriza-

tion of the 9-axial alcohol 260 of the gibberellin series into its a-equatorial epimer 261.'11)

OH OHOHOH 15

McO,C. McO;C McO,C' - McO.0

OH 4111 - . • (., RHORII. O,"O tL0SS, - CO:Me

(252) : R=a-OH (253) : 12=a-0I1 (256: : 15a-OH (256) : 15,3 OH (260) : 3,3 OH (251) : R—,3 OH (255) : R=,9-OH (257) : 15,3 OH(259) : 15a OH (21)1) : 3a OH

Structures 262 and 263 were assigned to sodoponin and epinodosinol, respec-

tively, new minor diterpenoids of Isodon japonicus.121

off

O -------LIOMe OacO :-••HO ..011011004 OH-°oxO11

I-I ox Ii OH H II OH

(262) (263)(261)(265)

Several approaches to further development of intermediate 264 to songorine

265 were tested. In a communication,131 a simple and stereoselective new method

of conversion of phenol 266 into two tetracyclic diketones 267 and 268. The outline is shown in Chart 8.

The metabolites from the succinate ester (269) of ent-16-kauren-19-ol in Gib-

berella fujikuroi were investigated and, diol 270 and triol 271 were isolated in 12

and 20% yields, respectively, after hydrolysis of acidic fraction."

( 446 )

Page 26: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

OHOH. OMe ^ / ~ `CHO

O1) CH,-CH:C1 K2C0~, KI•1) Mez50,, NaOHO

op2)---------------1in 15'2) 0,04 180-165`3) NataiOa•~/J

(266)

OMe

OH0 I)LOH, p-TsOHO(CO:H),, aq. McOH 2) Li N143, t-BuOH

II O00

0CHO

401) 0.1% KOH -MeOHI 1) 1% KOH- O~refluxMcOH1) H,1-C, 0 2) 70% AcOH2) Ac,O2) 5% KOH-MeOH pyridine'OAc

00 I 75%a

h 90-, 5hr.. H~JonesOp •OH® O

(267)

OO

0

0 . 0 OH

(268)

Chart 8

0010-ox/~ox off

CH,000(CH2)2CO,H CH.OHCH;OH

(269)(270)(271)

Syntheses of steviol (272), the aglucon of stevioside, the remarkably sweet

glucoside abundant in Stevia rebaudiana, were carried out by two groups. A Japanese groups151 synthesized rac-steviol following the route shown in Chart 9.

Australian group116) synthesized optically active steviol following the route shown in Chart 10.

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Page 27: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FuJITA

OH

Siio; /O~ 2) Jones 1) B:H~-H2O,O H.Jones

H CH,CH~>H

p Ol

CQble0 CQMe

0 . OHOHOH cp jp O el ClemmensenH±H 1) Wittig H 2) f-BuOK

\HHHin DMSO ... H CQMeCO,MeCO_It 19%41%

(272)

Chart 9

O1111,O1) hydrolysis Baeyer-p 2)methylatio^

~~Villiger~~3) oxidation HgFI(CrO,-pyridine;

COHO=MeCO:.Me

p,OHOHOH

0OH...pLIOHCQMer gILI (171-11,, r-Bnox-------,010+ ,.

CO,.M>CQHCO,HCO,H 27%J%10%

a dinner ofO 1)Wittig uncertain structure .OH --- >Silyl ether ----------------->272 54%002) hydrolysis

CO,H Chart 10

X. BEYERANE DERIVATIVES* 17 12 it 13

20 a1"Unusual oxidations had been reported on erythroxylol

2 `0 hI 8A(273) .11~1 Now, other related compounds were investi- 3 5

"..

• iegated. Derivatives 274 a, b, c were oxidzed by chromic

19 18anhydride in aqueous acetic acid to yield 275 a, b, c and

Beyerane276 a, b, c as major products and 277 to 279 as minor

products. Oxidations of compounds 280, 281, and 282, were checked, and

* See section V, ref. 46.

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Page 28: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

0.••J!•,•~HH H

aH:OH R",HR~O OR~

(273( (274a) : R=Me(275a) : R=Me(370a) : R=Me

(274b) : R=Et(2750) : R=Et(270b) : R=Et

(274c) : R=Ph 275c) : R=Ph(270c) : R— Ph

40. ' I I r''L''I I/ 0 ;!;'" 0 HII

OHC19 ,OHC112OH/ OH

(277) : Ice OH (279) (280)(281) J~ ;27Si:dr-UH

mechanism for formation of 18- or 19-nor-products was suggested.118

ent-15-Beyeren-2)3, 3,8, and 3a-alcohols were prepared, and their stereochemis-

try assigned. ent-2)3-Hydroxybeyer-15, 16-epoxide (283) underwent reaction with

lead tetraacetate to form a 2-20 ether 284 which could be rearranged to a kaurenoid skeleton. Reduction of ent-313-hydroxy-15-beyeren-2-one (285) afforded

2a, 3a-diol 286. Treatment of the 3-monotosylate of the diol with alumina af-

forded the 2-ketone.15-Beyeren-3-one underwent acetoxylation to furnish the

corresponding 2,9-acetate 287 which was reduced to a 2,3, 3a-diol 288. The solvent shifts in the NMR spectra of these compounds were studied.u9)

0 HO.. I•~O• 0411..A•R10,ac0HO'' •0, II ILHHH

(283)(2S-1)(285) : R—O(287)

(280) : R=a-OH, ,4-II

(288) : It= cr-if, ,9 OH

Steviol (272) was converted into erythroxydiol A(289) via an acid-catalyzed rearrangement from 290 to 291.120)

CH,041 :onCH:OH

///~O

OO.•~t H%H CH:OHCO:MeCO2Me

(289)(290)(291)

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Page 29: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

XI. GIBBERELLANE DERIVATIVES*

20 HHexahydrofluorene derivatives, 293 and 294, were Ir

2 10 4 2

Hsynthesized via an intermediate 292 from abietic acid. 'a 0Compounds 293 and 294 were converted into methyl esters, 19 18 7 5 and the latter compounds were transformed into all the

Gbberellaneremaining C-5 , C-6 epimers of free acid and ester.12'1

xIIx

II 5,0 0.0 0. 0~thit • O~O Ono.0 CO2HCO,HOCH.OI-I NHCH.OH OH

(292)(293): 5rc-Lr, 6a-H(295)(296)(297) (29-1) : 5,0-I-I, 0,4-H (298) : 16-epimer

Epoxidation and hydration of an unsaturated keton of the gibberellin series

were investigated.1221

Gibberic acid (295) was converted into amine 296, which was deaminated to

give 297 accompanied by 16-epimer 298. Oxidation of 297 gave the expected acid in addition to unexpected 6-ketone 299.125'

HHHH

O•Ore —OH 0./.....OHS OHCO212CO,R CH.OHCO.Me

(299) (300): R (302): R=H(30 -0 (301) : R.-Me (303) : R=Me

Attempts to photo-oxygenate the 2, 3-and 16, 17-double bonds in some deriva-tives of ent-gibberellane were unsuccessful except in the case of allogibberic acid

(300) and its methyl ester (301) , which reacted at the 16, 17-double bond to give the expected 15-en-17-ols, 302 and 303, respectively. Acid-catalyzed rearrangement

of 303 gave the hydroxymethyl derivative 304 of methyl gibberate, which was identical with the methyl ester of the rearranged product obtained from gibberel-

lin-A1 16, 17-epoxide (305) at 100° in 2N-HC1. The major product from the rear-

rangement (treatment with 2N HC1) of the product (303) of photo-oxygenation

of methyl allogibberate (301) was the 7, 15-olide 306 of 15-hydroxyallogibberic

acid.1~41

C10011 OH

OOOlI ®IHO....OHO ./....OHIrOOFIIIOCO.,.... o x CO.H 0 o 6CO,H

(305) (300)(307)

* See section IX, refs. 105, 109, and 111.

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Page 30: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

The stereoselective labelling of the gibberellins and the kaurenolides with 2-

(R)-, 2-(S)-, and 5-(R)-(3H) mevalonate was studied. The results led to the conclusion that the dehydrogenation of ring A in gibberellic acid biosynthesis is

a cis-process and that the hydroxylation of ring B in the formation of the kaureno-

lides takes place with retention of configuration. One tritium atom from (1-'H2,

2-14C) geranyl pyrophosphate was retained at position 6 in gibberellic acid. How-

ever, 5-(R)-mevalonoid hydrogen was lost from ring B during the formation of

the gibberellins. Consequently, ring contraction took place with the displacement of an equatorial hydrogen atom from kauranoid C-6 position.'25)

From fresh immature fruits of Phaseolus coccineus a polar gibberellin (previ-

ously named "Phaseolus s") was isolated in an overall yield of 3.8 x 10-' %. Its structure was shown by chemical and physical methods to be gibberellin As-O(2)-

18-glucopyranoside (307) .126)

0 0.-..,,,,,,0 O ------Ac,OOBF; AcOH

CH:CO,Me -----CO:H

CO:MeCO:H OOO

H 1;yridine

®.,O--'Ole°a O.'OHr---------p ge2)Huan,..A•lon RaneyNi3) me[h}~'.ation

kidlill0 pO

CO:HCO,MeO~ CO_Me O~

H11II

010110 CFiCO,H01110-----2) Jones-OAc'° OCH,CPQH •

CO.MeO McO,CCO_H 0

liHI-1 1) CII,N•

000O PhCH2OH,_O.•O2)IIPd -C ;01111110O------= CH,CO,CH,PhCH,CO,H

pO0COeHCO,Me

H IIH

Zn, AcOH1) Wittig

011011)O----- ••0H2) aq. NaOHwe .e OH COzMeCO311CO,A4e

)308)

Chart 11

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Page 31: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

The presence of gibberellic acid (G A3) in the petals and stamens of Cassia

fistula was reported on the basis of chromatography, bioassays, spectrofluorometry, superimposed IR spectrum and mass fragmentation pattern.'")

A total synthesis of rac-epiallogibberic acid (as 308) was reported. The routs

is shown in Chart 11.120,129)

A list of references for physiologically active substances of plants including

gibberellins was published in Japanese.l3°) A photochemical behavior of the a, ,8-unsaturated ketone 309 derived from

gibberellin A3 in absolute dioxane was investigated. The products were shown to be an adduct 310 and a dimer 311.131)

011

r7-() II O

O 011OHO'II11 n

~~.... O Albt. 71~~f1CO.A1 CO

OOH...OH McQ:C

H0 7I 1I

U CO,MeCO Me

. H HO

309)(110: ;311)

From immature seeds of Calonyction aculeaturn, twelve gibberellins (or methyl

esters) were isolated and five of them were identified as known gibberellins,

namely GA8, GA,7, GA,9, GA27, and GA29, by melting points, gas chromatography, IR, and mass spectra. The other gibberellins were shown to be new ones. Struc-

tures of two of them, named GA39 and GA31, were determined, that is, structure

312 was assigned to GA30, while 313 to GA31.132)

0 n O HI I 1

~; .. OII.. OH • ::'~~..... off

CO _I COGOOH Ilo"IIO x''

GO,HCOOOH

CO I

)312'(313.f1111

A new water-soluble gibberellin(GA32) , which is not gibberellin glucoside,

was isolated from immature seeds of Prunus persica, and its structure was deter-

mined as 314.'33' Partial synthesis of gibberellin A15 norketone (316) from 7-hydroxykaurenolide

(315) was reported,134) as shown in Chart 12. Gibbereliin-A15 (317) was derived from enmein (225) via a route shown in

Chart 13.13J'

The stereocontrolled total synthesis of racemic gibberellin An (317) was ac-

complished.136' The route is shown in Chart 14.

As an approach to the total synthesis of gibberellic acid, a simple route to

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Page 32: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

! II,, 14.n *IVOII2:. U,U,- NaIO, -WO

II UII 113 acetylationIii O 110.0C110 CH2OAc0

315i

IPIIf ila b>Jones LbiOAc ,--Is ' Oler ISIIIP. FlHH

11.NOCC11,OAcOOCIC_UI-I OC041 (310 Ch

art 12

0 U II

°®oacHON=CH~~ 13:-N ,

HOU--------> •''oTHI--------------->....Oil —a Ii

OH

?25)

0110wI) HNO, ,,IJones'''.•`O ~IUrOH---- •®®"OkIII2tII9.

gIIIIII 1) NaBII,

2) mesylationdicthyleneglycoKHl OO o+ ~I3).‘1 in collidinc,•/.sopo --III `':

0CO311

CO (317)Chart 1

O~.CO,II

tetracarbocyclic network was developed,1371 as shown in Chart 15.

Tetrahydro-derivative of gibberellic acid was isolated from leaves of Sonneratia apetala.1381 Gibberellin A25 was used for this compound, but gibberellin A25 had

been allocated to the metabolite 318 from G. fujihuroi. To remove all ambiguity

it was hoped that this name for the compound from S. apetala will be with-drawn.I39)

Structure 319 was assigned to a new gibberellin glucoside, which was tetatively

termed F-VuI in immature seeds of Pharbitis nil.14o1 The cis-1, 2, 3, 4, 4a, 9a-hexahydro-1-methyl-6-methoxy-9-oxofluorene-1-carboxy-

lic acids 321 and 322, potential intermediates in the synthesis of gibberellins were

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Page 33: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

~N~1) dienol-. acetylatioa~21).redOuction 2)NoBH,Ms....I....NIA. '' OH'

(IHI1-Iacetyiation (1

• II1) WittigHIT1; i-BuxAIII •

Ms- 2) OH- --------------,--Ms+ 1) Rt,A1CN3)NaOACACOH C(7.1.''' 3) CrOr IISO,O 2) AI(0i-P 2in aq. TIII r _ ¶/II

OROAc 4) SOC]_ (-73')C.OH 3)Dl1P

O 1I

IEli'II 1) tosylation

1) wittig2) Ac.,O,znCl. XI. L2) hydrolysis3)®~OTs (mu,''OH 4) Zn-ACOlI/OAc C

HOCH =CH-CHOCH-CHCH CHO OAc

1) 2------eq.

INin McOH H KOH<<+ `)HIIII

s ----------------------------------1yMs._Collins Me ..OTs 2) 5% AcOIIHWI

Me° 0100CHO0 0 CHO

CHOII

r'H1)Wolff-Kishner4HPCILN,

aq. IC_CO,2) LiNH,)K2(... ~,a Mn._.~ .---------------—F,000... 3) (CFxCO),OMcOH

~ Pd(OAc),

C0 H CHOCOLL

HO

,,,~/Collins N—------ •,IIOj --->

/' HHpI-I

CO,MeHO/

(1 • H

preparativeLiI,reflux,collidine O tic-----~.~triphenylphosphine-------------------- 317 OHOiH CO:Me

Chart 14

prepared in high yield by a novel photocyclization. The photolysis of 320, pre-

pared from the Friedel-Crafts reaction between 1-methyl-2-cyclohexene-1, 2-di-carboxylic anhydride and anisole, gave a mixture of 321 and 322 in nearly

quantitative yield.141)

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Page 34: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

0 \/o/~o 0 00~NO^9(„)OTHF, 0'O----- O >-----O

N..„-~~NOH

O \ p0 0O HBrCH— CBr=CH,HO H~t ----------- ->.Br > 3

/\~I HCH; C~CH,--C OO'''CH,O ------~CHe 0 0'\~CHOMc

o11

ui -rr-butylcopper-H 1010ip .- oil lithium ether

CHOMe

/N~0.OHGO:OII HYHII•II~O illpBr --------Br------- 0CH.~~~0~i~VGH., OTI I(' O'CHI'

Chart 15

CO,HHCH_OHO

---- 0\ ^0II /)H

II'HO -----/ hi HO,CCOMOHCOrH

(3IS)(319)

II® OMe 11OMeH ~~O O1IH•

IIO,C°O110,CO CO:H

(320)(321)(322)

XII. ATISANE DERIVATIVES

......... .. •

The x-ray analysis showed that 323 is the correct

t1121316stereochemical structure of kobusine, with both hydroxy 23 9 Ihavintheconfiuration, and therefore,seudo- ?groupshavingagl~

- 10 it rikobusine is represented as 324.142' Another x-ray crys-

H6tallographic determination of the structure 325 of denuda- 19 13tine was reported ,1431 which revised the previously assi-

Aresane gned formula.

Atisine (326) in solution was shown to contain a 2 : 1 mixture of two isomeric species whose rate of interconversion is fast on the NMR time scale in polar

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Page 35: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

ill IIO 20

or 011,'OFI N HIIH

R15

(323) : R=--H(325)(326) (324) : R-011

hydrogen-bonding solvents, but relatively slow in solvents which would not

stabilize an ionic species, leading to the suggestion that it is a mixture of con-

figurational isomers at C-20 interconvertible via a zwitterion as shown in Chart

16.144)

C-3C-)C-3 C-18..... 4 19 C-18 V/\C-is

e C-1 120C-IC-1 20 C 6.......0C-6......H0_<---------C.6......O

H 10 HHH H

C-9C-9C-9

Chart 16

Miyaconitine and miyaconitinone, the major alkaloids from Aconiturn miyabei

were studied. On the basis of the chemical and spectral data found in continuing

investigations as well as the biogenetical consideration, formulas 327 and 328

were shown to be most valid for these alkaloids.145) The x-ray determination of

the structure 329 of miyaconitine hydrobromide dihydrate was also reported.146'

00

AcO .,,AcO..IIO. .OH \Ie°°~.RMe....~~'"OIIHO 11II 0011 Bt .211O

i327) : R=a-0I7, (7-H(329)(330, (32S) : R-0

The structure of anhydroignavinol, the alkaline hydrolysis product of ignavine,

was investigated. Anhydroignavinol methiodide was prepared and subjected to

a single-crystal x-ray analysis. The correct structure of anhydroignavinol was

established as 330. The absolute configuration indicated was based on analogy

with the other diterpene alkaloids.'47)

XIII. ACONANE DERIVATIVES 17 1' 13'

II The full paper of the crystal and molecular structure 3 5of lappaconine hydrobromide was published.148) The struc-

ture of lappaconine was shown to be 331. 10 18A stereoselective synthesis of an advanced relay

compound for the total synthesis of delphinine (333) was.

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Page 36: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

OMe IIO

Me0~OMeOAc Me0 OMeO

OHnc .........N.. ..Me...,H

HI 013I IO..... II : OAc OHMe0.OHOMe M eO

(331)(332)(333)

published.1491 This compound 332, which has five rings and five substituents, is obtained easily from delphinine.

NMR and mass spectral investigation of talatisamine, its diacetyl, benzoyl,

benzoylacetyl, and oxo-derivatives, and its pyrolytic products suggested the struc-

ture 334 for talatisamine.'")

................ OMe .Me0OMe \ic0.. /OMcMeQ .......

..

. .• 0• '• IL ITII0 o I-I OHII OH ,OH

OMe Me0

(33-1)(333)(336)

Delphatine, isolated from the seeds of Delphinium biternatum, was shown to

have structure 335.15') Lappaconitine, isolated from Aconiturn leucostomum, was

shown to have structure 336.'52) Structure of lapaconidine extracted from A.

leucostomum roots was shown to be 337.103)

OMe IIO ..Me0

OOMe1all •0I-II~, OHN OH' OI-ICH2OMe

(337)(338)

Pyrolysis of diacetyltalatisamine (diacetate of 334) in glycerol at 210-220°

afforded 338 and a second unidentified product.1531

XIV. TAXANE DERIVATIVES

18 H ° 9 19. The structure of baccatin-III isolated from Taxus 1~1G 33illbaccata was shown to be 339.154) The signs of Cotton

3

1effects involving each of mono-olefinic centers of taxane II II 20 derivatives were shown to be applicable to assignment

Taxane of the absolute configuration of molecule."5)

Paccatin-I isolated from the heartwood of Taxus baccata was shown to be

340. 5-Deacetylbaccatin-I (341) and 1j3-hydroxybaccatin-I (342) were also isolated

and characterized.1561

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E. FUJITA

OAc OOAc OAcAc0 0 OAcOAcOH

_/

110-..t1c0....IIO._. OIIO 11 0HR'eip 1OOII .II CII,000Ph~iOAc OAcOAcPhCOO

(339)1:00, : R'- II, R Ac(313) t.111): I2' =II, R- II (112.:: I2' - OH, I2' -=Ac

Baccatin-V, a new diterpenoid from Taxus baccata was shownby x-ray

analysis to contain an oxetane ring and to be 343•1J7) Its biogenesis was presented

as shown in Chart 17.

AcO 011' OXOX~OX

•xoi—~343 'OII,2 OHf.) OH OHII 0HH

OBz HO CH2OHAcO CH_-O

H

Chart 17

XV. THE OTHERS

Wiesner and Ho attempted to prepare the lactam 344 and intended to use it

as an intermediate for a synthesis of hexacyclic diterpene alkaloids.Although

the material which they obtained gave the correct elemental analysis, its UV and

NMR spectra did not agree with the proposed structure. This crystal structure

determination, which was undertaken in order to establish unambiguously the

structure of the synthetic intermediate, revealed the structure to be 345. The

synthesis of this compound and the results of this x-ray analysis had been

published in a preliminary communication.1581 Now, the full paper of this x-ray analysis was published.1591

O0 R OO"AcO;OAc N 40., H OAc , :HHH

N~~ 0p

(314)(345)(346) : R=CH, (317) : R-ce-Br, p-CH:13r

The structure 346 of eunicellin, a compound extracted from Eunicella stricta

had been determined1661 from the chemical evidence and an x-ray analysis of the

dibromide derivative (347). Now, the full paper of this x-ray analysis was

published.1611 By-products in culture fitrates of Fusicoccum amygdali were characterized.

( 458 )

Page 38: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

Compound F III was shown to be an isomer of fusicoccin and named isofusicoccin.

Quite possibly, the formation of isofusicoccin from fusicoccin (348) only involves a reversible rearrangement concerning the acetyl group present in the glucose

moiety. Compound F IV was shown to be monodeacetylfusicoccin (349), while compound F VII was proved to be dideacetylfusicoccin (350).162'

RTO ~/~/ CH:OC (Me) :CH= CI-12

"O ~ CH2OR' n

/g~OO COII

Izo ~ OII ~ A A JO H O

CH OMe HOOOOIIO O O

(3>9): R'=R'=Ac (351)(352) (353) (354) (349) : R'=Ac, R°=H (350): R'==I2"=H

The base-catalyzed rearrangement of the unsaturated hydroxy ketone 351

was shown to generate the diosphenol 352 in virtually quantitative yield. Oxida-

tion of 352 and then polyphosphoric acid catalyzed cyclization of the resulting

anhydride 353 produced 354, but no 355. The driving force of the rearrangement

reaction was discussed in terms of the steric crowding in the hydroxy ketone

351.165)

/\o 0

O

II''• . H`. H CO.H (355)(356)(357)

The main diterpenoid constituents of the oleoresin of Pinus horaensis were

investigated.164> Diterpenoids from oleoresin of Picea obovata were examined.165'

Mass spectra of some diterpene lactones, that is, 12-norambrienolide (356)

and its 213-hydroxy-, 8-epi-, 2Q-hydroxy-8-epi-, 2-oxo-8-epi-, and 2-oxo-derivatives, and ambrienolide (357) and its 8-epimer, were investigated. Consequently, the

following facts were clarified. The molecular ions of some diterpenoid trans-r-and 6-lactones lose the elements of carbon dioxide. The corresponding cis-lactones

do not undergo fission in this manner. A mechanism for this stereoselective

fragmentation was proposed.166'

Several reports on the chemistry of phorbols were published. Oxidation of

phorbol pentaacetate (358) with one mole of osmium tetroxide yielded small amounts of triol 359. As the main product, diol 360 was obtained in addition to

361. Oxidation of phorbol triacetate 362 mainly yielded triacetate 363, besides

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Page 39: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FuJITA

OAcOAcOAcOAc

OAc: OAc,oAc:OAc .1101AcO..,AcO:......: HO....HO....,...

.40 II '11.410 'IIill ,1 7 '.4-1 0 OHO OAc!OHi-OH O'

CH2OAcH.OR'CH:OAcCH2OR

(358) (359) : 121 —II, R°=Ac(362)(363) : R=Ac (360) : R'=R'=Ac(361) : R=H (361): R'=Ac, IV —H

some diacetate 364. By cleavage of 363 with sodium periodate or lead tetraacetate

the expected 6, 7-seco compound was obtained as its hemiacetal 365. The

corresponding cleavage of 364 yielded 366. By reduction with sodium borohydride

and subsequent acetylation, 366 was converted into 367. This compound showed

some interesting long range coupling in its NMR spectrum.1643

OAcOAcOAc OAc .. OAcOAc

I30..HO..HO. ..

...~g/'~H"~..~II

OAc

I3H H*gip O OH•OHOAc

O0 OHAcO off • CH,000H:OAc0OAc

(365){:366)(367)

From the mother liquor of preparations of phorbol (368), an isomer 369 (iso-

phorbol) was isolated. This compound was obtained from phorbol by base-catalyzed epimerization. In contrast to phorbol, base-catalyzed acetylation of 369

yielded both 370 and 371. By methylation of 370 with methyl iodide-silver oxide in dimethylformamide three products were obtained : 372, 373 and 374. On reduc-tion with zinc and acetic acid, 370 yielded 375.168)

H OR:1 , Me. C

IIO L11z33.1517 11".. '16 H MeMe

19 /"1-III-:0-CO-CH

ii~/H/•OH.H iiAle •: O/ R'OOH

CH:OI2'CH2OR

(369) : R'—R'=12'=FL 12'=,4-OH (376) : R=H .369) : R'=R'—R'=II, R' --a-011 (377) : R=Ac (370): R'=12==R'=Ac, R'—a-OH (371) : R' =R'—R'=Ac, R' =a-OAc (:372): R'=R°=R'—Ac,R'=a-OMe (373) : R' •=R°=Ac, R'=H, R'=a-OMe (371) : R'=R°=Ac, R'—Me, R'=a-OMe (:373): R'=R'=R'=Ac,R'=a-II

From latex of Euphorbia cooperi, two new irritant and tumor promoting com-

pounds, di- (376) and tri- (377) esters of 16-hydroxy-12-desoxyphorbol were isolated

(460 )

Page 40: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

Chemistry on Diterpenoids in 1970

and characterized.169'

Dilution of the seed oil of Euphorbia lathyris with acetone resulted in the

separation of a crystalline compound, previously named "euphorbiasteroid." This

substane was the diacetate-phenylacetate 378 of a diterpene alcohol 379, for which

Hecker et al.101 proposed the name 6, 20-epoxylathyrol. The geometry of the

double bond at C-11 had not been known, but recently, an x-ray analysis171' con-

firmed the structure 378 and elucidated the trans-configuration of the double bond.

O C.

H 18 O .

R O12 H t7.`I;O \p ••• 9 11/

18 4011013H• 611,15'76/H 58H.'. OR'R'OOAc0 OHOO014b 20OAcCH2OAcOH OH coo

(37S): R'=COCH,Ph,(380)(331) C3S2) IC—Ac

(379; R'=R"=H

A new irritant and cocarcinogenic hexadecanoic acid monoester, C36H5806, was isolated from the latex of Euphorbia ingens and from the seed oil of E. lathyris. This substance was subjected to a mild base-catalyzed transesterification to afford biologically inactive resinous parent diterpene alcohol (ingenol), which was converted into a crystalline triacetate. The x-ray analysis of the latter compound confirmed its structure 380.'72'

A new diterpene, the structure (381) of which was closely related to 379, was isolated from a Bertya sp. nov., named bertyadionol, and characterized.173'

Daphnetoxin, the poisonous principle of Daphne mezereum and other species of the thymelaeaceous genus Daphne, was isolated from methylene chloride ex-tracts of D. mezereum bark or commercial "mezeron" bark (D. mezereum, D. laureola, and D. gnidium), and its bisbromoacetate was subjected to an x-ray analysis. Consequently, the structure of daphnetoxin was determined as shown in formula 382.174>

A novel macrocyclic diterpenoid tumor inhibitor, named jatrophone, was iso-lated from Jatropha gossypiifolia, and characterized. Dry hydrogen bromide was allowed to react with this substance in glacial acetic acid to yield a dibromo derivative, which was subjected to an x-ray analysis. The structure 383 was confirmed for dibromide and therefore, structure 384 for jatrophone was elucidated. A suspension of 383 with neutral alumina in chloroform was stirred to regenerate 384 in high yield.175'

A brief introduction on some diterpenoids possessing the growth-inhibitory activity for plants was published in Japanese.176'

A review on the alkaloids of Daphniphyllum macropodum was published in Japanese.i77' The biogenesis suggested that they come from four isoprene units, one acetic acid, and one nitrogen, as shown in formula 385.

A review "biogenetic-type syntheses and reactions of natural products, mainly

( 461 )

Page 41: Title The Chemistry on Diterpenoids in 1970 Author(s) Fujita, Eiichi

E. FUJITA

00

0

Vo' 1), xo~.

Er O Br

(387)(384)

(385) : • isoprene un/t acetic acid unit

on terpenoids and simple phenolic compounds" was published in Japanese, in

which several syntheses of diterpenoids were described.148)

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(3) E. Fujita, ibid., 45, 229 (1967). (4) E. Fujita and T. Fujita, ibid., 47, 522 (1969).

(5) E. Fujita, ibid., 48, 111 (1970). (6) E. Fujita, ibid., 48, 294 (1970). (7) C. R. Enzell and I. Wahlberg, Acta Chem. Scand., 24, 2498 (1970).

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(17) R. M. Carman, D. E. Cowley and R. A. Marty, Australian J. Chem., 23, 1655 (1970). (18) G. A. Ellestad, R. H. Evans, Jr., M. P. Kunstmann, J. E. Lancaster and G. O. Morton, J. Am. Chem. Soc., 92, 5483 (1970).

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(Chem. Abstr., 73, 87700 g (1970D.) (21) L. J. Gough and J. M. Mills, Phytochenistry, 9, 1093 (1970).

(22 a) Y. S. Cheng and E. von Rudloff, Tetrahedron Letters, 1131 (1970). (22 b) Y. S. Cheng and E. von Rudloff, Phytochemistry, 9, 2517 (1970).

(23) L. J. Stephens and D. M. S. Wheeler, Tetrahedron, 26, 1561 (1970). (24) P. K. Grant and M. J. A. McGrath, ibid., 26, 1619 (1970).

(25) P. K. Grant, L. N. Nixon and J. M. Robertson, ibid., 26, 1631 (1970). (26) P. W. Atkinson and W. D. Crow, ibid., 26, 1935 (1970).

(27) T. Anthonsen, P. H. McCabe, R. McCrindle, R. D. H. Murray and G. A. R. Young, ibid., 26, 3091 (1970).

(28) J. Haeuser, S. F. Hall, A. C. Oehlschlager and G. Ourisson, ibid., 26, 3461 (1970). (29) V. E. Sibirtseva and S. D. Kustova, Zh. Obshch. Khim., 40, 2514 (1970). (Chem. Abstr.,

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(30) V. V. Titov and D. P. Popa, Zh. Org. Khim., 6, 2468 (1970). (Chem. Abstr., 74, 64316 t [19713.)

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(Chem. Abstr., 73, 56261 k (1970).) (39) F. Derguini and A. Diara, ibid., 3057 (1970). (Chem. Abstr., 74, 23032 d (1971).) (40) J. Polonsky, Z. Baskevitch, N. C. Bellavita and P. Ceccherelli, ibid., 1912 (1970).

(Chem. Abstr., 73, 66744 j (1970).) (41) H. A. Candy, J. M. Pakshong and K. H. Pegel, J. Chem. Soc. (C), 2536 (1970). (42) A. Afonso, J. Org. Chem., 35, 1949 (1970). (43) J. R. Hanson and A. F. White, Phytochemistry, 9, 1359 (1970). (44) J. L. Fourrey, J. Rondest and J. Polonsky, Tetrahedron, 26, 3839 (1970). (45) V. N. Aiyar and T. R. Seshadri, ibid., 26, 5275 (1970). (46) M. Kitadani, Nippon Kagaku Zasshi, 91, 664 (1970). (47) J. W. ApSimon, W. G. Craig, P. V. Demarco, D. W. Mathieson, L. Saunders and W. B.

Whalley, Tetrahedron, 23, 2339 (1967). (48) J. W. ApSimon, P. V. Demarco, D. W. Mathieson, W. G. Craig, A. Karim, L. Saunders

and W. B. Whalley, ibid., 26, 119 (1970).

(49) J. W. ApSimon, Chem. Comm., 83 (1970). (50) R. Guttormson, P. Main, A. J. Allison and K. H. Overton, ibid., 719 (1970). (51) H. Erdtman and L. Malmborg, Acta Chem. Scand., 24, 2252 (1970). (52) C. H. Eugster, Angew. Chem., 82, 259 (1970). (53) R. C. Cambie and R. A. Franich, Australian J. Chem., 23, 93 (1970). (54) R. M. Carman and R. A. Marty, ibid., 23, 1457 (1970). (55) H. Kakisawa and M. Tateishi, Bull. Chem. Soc. Japan, 43, 824 (1970). (56) T. Hayashi and H. Kakisawa, ibid., 43, 1897 (1970). (57) K. K. Maheshwari, P. de Mayo and D. Wiegand, Can. J. Chem., 48, 3265 (1970). (58) W. Herz, R. C. Ligon, H. Kanno, W. H. Schuller and R. V. Lawrence, J. Org. Chem.,

35, 3338 (1970).

(59) M. Kitadani, A. Yoshikoshi, Y. Kitahara, J. de Paiva Campello, J. D. McChesney, D. J. Watts and E. Wenkert, Chem. Pharm. Bull. (Tokyo), 18, 402 (1970).

(60) A. Tahara and K. Hirao, ibid., 18, 1960 (1970). (61) J. W. Huffman, J. A. Alford and R. R. Sobti, J. Org. Chem., 35, 473 (1970). (62) J. W. Huffman, ibid., 35, 478 (1970). (63) J. W. Huffman, ibid., 35, 3154 (1970). (64) J. C. Sircar and G. S. Fisher, ibid., 35, 3090 (1970). (65) S. W. Pelletier, K. N. Iyer and C. W. J. Chang, ibid., 35, 3535 (1970). (66) P. Penczek, Rocz. Chem., 44, 1815 (1970). (Chem. Abstr., 74, 88163 s (1971).) (67) K. Mori and M. Matsui, Tetrahedron, 26, 3467 (1970). (68) T. Hayashi, H. Kakisawa, H-Y Hsu, and Y. P. Chen, Chem. Comm., 299 (1970). (69) J. F. Biellmann, R. Wennig, Ph. Daste and M. Faure-Raynaud, ibid., 346 (1970). (70) R. C. Cambie and R. A. Franich, ibid., 845 (1970). (71) J. C. Sircar and G. S. Fisher, Chem. and Ind. (London), 26 (1970). (72) M. N. Galbraith, D. H. S. Horn, J. M. Sasse and D. Adamson, Chem. Comm., 170 (1970). (73) B. Blessington, D. W. Mathieson and A. Karim, J. Chem. Soc. (C), 1703 (1970). (74) D. W. Mathieson and A. Karim, ibid., 1705 (1970). (75) A. Balmain and J. D. Connolly, Chem. Comm., 1244 (1970). (76) P. Sengupta, S. Roy and K. G. Das, Chem. and Ind. (London), 534 (1970).

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(77) S. von Kurten, P. Pachaly, F. Zymalkowski and G. Snatzke, Ann., 741, 142 (1970). (78) S. auf dem Keller, P. Pachaly and F. Zymalkowski, Arch. Pharm., 303, 249 (1970). (79) T. Okuno, N. Hamanaka, H. Miyakoshi and T. Matsumoto, Tetrahedron, 26, 4765

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1071 (1970). (81) H. Hikino, N. Shoji, S. Koriyama, T. Ohta, Y. Hikino and T. Takemoto, ibid., 18,

2357 (1970).

(82) H. Hikino, Y. Hikino, T. Takemoto and S. Takahashi, ibid., 18, 852 (1970). (83) Z. Kumazawa and R. Iriye, Tetrahedron Letters, 927 (1970). (84) Z. Kumazawa and R. Iriye, ibid., 931 (1970). (85) Y. Nakamura, J. Iwasa and H. Ono, Nippon Nogei Kagaku Kaishi, 44, 130 (1970). (86) P. Narayanan, M. ROhrl, K. Zechmeister and W. Hoppe, ibid., 3943 (1970). (87) M. Yasue, T. Kato and J. Sakakibara, Chem. Pharm. Bull. (Tokyo), 18, 854 (1970). (88) M. Yasue, T. Kato and J. Sakakibara, Yakugaku Zasshi, 90, 893 (1970). (89) S. Mori, K. Shudo, T. Ageta, T. Koizumi and T. Okamoto, Chem. Pharm. Bull. (To-

kyo), 18, 871 (1970). (90) E. Fujita, T. Fujita, H. Katayama and M. Shibuya, Chem. Comm., 252 (1967). (91) S. Mori, T. Koizumi, K. Shudo and T. Okamoto, ibid., 18, 884 (1970). (92) E. Fujita, T. Fujita, M. Shibuya and T. Shingu, Tetrahedron, 25, 2517 (1969). (93) E. Fujita, T. Fujita and H. Katayama, ibid., 26, 1009 (1970). (94) E. Fujita, T. Fujita, H. Katayama, M. Shibuya and T. Shingu, J. Chem. Soc. (C),

1674 (1970).

(95) E. Fujita, T. Fujita and H. Katayama, ibid., 1681 (1970). (95) E. Fujita, T. Fujita and Y. Nagao, Chem. Pharm. Bull. (Tokyo), 18, 2343 (1970). (97) K. Wiesner, Z. I. Komlossy, A. Philipp and Z. Valenta, Experientia, 26, 471 (1970). (98) N. R. Krishnaswamy, T. R. Seshadri and T. N. C. Vadantham, Indian J. Chem., 8, 375

(1970). (Chem. Abstr., 73, 25693 y (1970).) (99) D. Mukherjee and A. Das Gupta, ibid., 8, 1045 (1970). (Chem. Abstr., 74, 87713 j

(1971).) (100) R. A. Appleton, P. A. Gunn and R. McCrindle, J. Chem. Soc. (C), 1148 (1970). (101) M. S. Yunusov, Va. V. Rashkes, S. Yu. Yunusov and A. S. Samatov, Khim. Prir.

Soedin., 6, 101 (1970). (Chem. Abstr., 73, 13178 u (1970).) (102) A. I. Kalinovskii, E. P. Serebryakov, B. M. Zolotarev, A. V. Simolin, V. F. Kucherov

and 0. S. Chizhov, Org. Mass Spectrum., 3, 1393 (1970). (Chem. Abstr., 74, 13294 b

(1971).) (103) S. C. Pakrashi, P. P. G. Dastidar and S. K. Gupta, Phytochemistry, 9, 459 (1970). (104) R. A. Appleton, R. McCrindle and K. H. Overton, ibid., 9, 581 (1970). (105) B. E. Cross and J. C. Stewart, ibid., 9, 1065 (1970). (106) E. Foresti, L. Riva di Sanseverino and F. Piozzi, Tetrahedron, 26, 2717 (1970). (107) J. R. Hanson and A. F. White, ibid., 26, 4839 (1970). (108) J. St. Pyrek, ibid., 26, 5029 (1970). (109) E. P. Serebryakov, A. V. Simolin, V. F. Kucherov and B. V. Rosynov, ibid., 26, 5215

(1970). (110) S. Huneck and 0. Vevle, Zeitsch. fur Naturforsch., 25 b, 227 (1970). (111) E. Fujita and Y. Nagao, Chem. Comm., 1211 (1970). (112) E. Fujita, T. Fujita, M. Taoka, H. Katayama and M. Shibuya, Tetrahedron Letters,

421 (1970). (113) K. Wiesner, A. Delijac, T. Y. R. Tsai and M. Przybylska, ibid., 1145 (1970). (114) P. R. Jefferies, J. R. Knox and T. Ratajczak, ibid., 3229 (1970). (115) K. Mori, Y. Nakahara and M. Matsui, ibid., 2411 (1970). (116) I. F. Cook and J. R. Knox, ibid., 4091 (1970). (117) A. Martin and R. D. H. Murray, J. Chem. Soc. (C), 2529 (1968). (118) A. Martin and R. D. H. Murray, ibid., 2023 (1970). (119) J. R. Hanson, Tetrahedron, 26, 2711 (1970).

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(120) K. Mori and M. Matsui, Tetrahedron Letters, 3287 (1970). (121) A. Tahara and Y. Ohtsuka, Chem. Pharm. Bull. (Tokyo), 18, 859 (1970). (122) I. A. Gurvich, N. S. Kobrina and V. F. Kucherov, Izv. Akad. Nauk SSSR, Ser. Khim.,

164 (1970). (Chem. Abstr., 72, 110888 q (1970).)

(123) J. C. Brown and B. E. Cross, J. Chem. Soc. (C), 71 (1970). (124) M. F. Barnes, R. C. Durley and J. MacMillan, ibid., 1341 (1970). (125) R. Evans, J. R. Hanson and A. F. White, ibid., 2601 (1970). (126) K. Schreiber, J. Weiland and G. Sembdner, Phytochemistry, 9, 189 (1970). (127) P. K. Sircar, B. Dey, T. Sanyal, S. N. Ganguly and S. M. Sircar, ibid., 9, 735 (1970). (128) K. Mori, M. Matsui and Y. Sumiki, Proc. of the Japan Academy, 46, 450 (1970). (129) K. Mori, M. Matsui and Y. Sumiki, Tetrahedron Letters, 429 (1970). (130) N. Takahashi, Shokubutsu no Kagaku-Chosetsu, (Chemical Regulation of Plants), 5, 192

(1970). (131) G. Adam, Zeitschr. fiir Chem., 10, 140 (1970). (132) N. Murofushi, T. Yokota and N. Takahashi, Agr. and Biol. Chem., 34, 1436 (1970). (133) I. Yamaguchi, T. Yokota, N. Murofushi, Y. Ogawa and N. Takahashi, ibid., 34, 1439

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Soc., 92, 3202 (1970).

(137) E. J. Corey, M. Narisada, T. Hiraoka and R. A. Ellison, ibid., 92, 396 (1970). (138) S. N. Ganguly, T. Sanyal, P. K. Sircar and S. M. Sircar, Chem. and Ind. (London),

832 (1970). (139) J. MacMillan and N. Takahashi, ibid., 1115 (1970). (140) T. Yokota, N. Murofushi and N. Takahashi, Tetrahedron Letters, 1489 (1970). (141) L. M. Jackman, E. F. M. Stephenson and H. C. Yick, ibid., 3325 (1970). (142) S. W. Pelletier, L. H. Wright, M. G. Newton and H. Wright, Chem. Comm., 98 (1970). (143) L. H. Wright, M. G. Newton, S. W. Pelletier and N. Singh, ibid., 359 (1970). (144) S. K. Pradhan and V. M. Girijavallabhan, ibid., 644 (1970). (145) Y. Ichinohe, M. Yamaguchi, N. Katsui and S. Kakimoto, Tetrahedron Letters, 2323

(1970). (146) H. Shimanouchi, Y. Sasada and T. Takeda, ibid., 2327 (1970). (147) S. W. Pelletier, S. W. Page and M. G. Newton, ibid., 4825 (1970). (148) G. I. Birnbaum, Acta Cryst. B 26, 755 (1970). (149) K. Wiesner, E. W. K. Jay, C. Demerson, T. Kanno, J. Krepinsky, L. Poon, T. Y. R.

Tsai, A. Vilim and C. S. Wu, Experientia, 26, 1030 (1970). (150) M. S. Yunusov and S. Yu. Yunusov, Khim. Prim. Soedin., 6, 90 (1970). (Chem. Abstr.,

73, 35572 x (1970).) (151) M. S. Yunusov and S. Yu. Yunsov, ibid., 6, 334 (1970). (Chem. Abstr., 73, 77443 m

(1970).) (152) V. A. Telnov, M. S. Yunusov and S. Yu. Yunusov, ibid., 6, 583 (1970). (Chem. Abstr.,

74, 42527 k (1971).)

(153) M. S. Yunusov, V. A. Telnov and S. Yu. Yunusov, ibid., 6, 774 (1970). (Chem. Abstr., 74, 100248 h (1971).)

(154) D. P. Della Casa de Marcano, T. G. Halsall and G. M. Hornby, Chem. Comm., 216 (1970).

(155) D. P. Della Casa de Marcano, T. G. Halsall, A. I. Scott, and A. D. Wrixon, ibid., 582 (1970).

(156) D. P. Della Casa de Marcano, T. G. Halsall, ibid., 1381 (1970). (157) D. P. Della Casa de Marcano, T. G. Halsall, H. Castellano and O. J. R. Hodder, ibid.,

1382 (1970). (158) K. B. Birnbaum, K. Wiesner and P. T. Ho, Tetrahedron Letters, 1071 (1969). (159) K. B. Birnbaum, Ada Cryst., B 26, 722 (1970). (160) 0. Kennard, D. G. Watson, L. Riva di Sanseverino, B. Tursch, R. Bosmans and C.

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Djerassi, Tetrahedron Letters, 2879 (1968).

(161) O. Kennard, D. G. Watson and L. Riva di Sanseverino, Acta Cryst. B 26, 1038 (1970). (162) A. Ballio, C. G. Casinovi, G. Randazzo and C. Rossi, Experientia, 26, 349 (1970). (163) R. E. Ireland, P. S. Grand, R. E. Dickerson, J. Bordner and D. R. Rydjeski, J. Org.

Chem. 35, 570 (1970). (164) V. A. Raldugin, N. K. Kashtanova and V. A. Pentegova, Khim. Prir. Soedin, 6, 481

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Ponsinet, R. J. Pryce, T. S. Santhanakrishnan, L. G. Matyukhina and I. A. Saltikova, ibid., 2241 (1970).

(171) K. Zechmeister, M. Rohrl, B. Brandl, S. Hechtfischer, W. Hoppe, E. Hecker, W. Adolf and H. Kubinyi, ibid., 3071 (1970).

(172) K. Zechmeister, F. Brandt, W. Hoppe, E. Hecker, H. J. Opferkuch and W. Adolf, ibid., 4075 (1970).

(173) E. L. Ghisalberti, P. R. Jefferies, T. J. Payne and G. K. Worth, ibid., 4599 (1970). (174) G. H. Stout, W. G. Balkenhol, M. Poling and G. L. Hickernell, J. Am. Chem. Soc., 92,

1070 (1970).

(175) S. M. Kupchan, C. W. Sigel, M. J. Matz, J. A. Saenz Renauld, R. C. Haltiwanger and R. F. Bryan, ibid., 92, 4476 (1970).

(176) H. Kakisawa, Kagaku to Kogyo (Chemistry and Chemical Industry), 23, 1152 (1970). (177) M. Toda, H. Irikawa, S. Yamamura and Y. Hirata, Nippon Kagaku Zasshi 91, 103

(1970). (178) T. Kato and Y. Kitahara, Yuki Gosei Kyokai-shi (J. Synth. Org. Chem. Japan), 28,

559 (1970).

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