Structure of inumakilactone a, a bisnorditerpenoid

Tetrahedron Letters No.17, pp. 2065-2070, 1968.

Per-on

PresS*

printed in Great Britain.

STRUCTDRE OF IEDKAKILACTOBE A, A BISRCRDITERPEROID Sh8 It8, Mitsuaki Kodama and Rakoto Sunagawa Department of Chemistry, Tohoku University, Sendai and Toehio Takahashi, Hiroyuki Imamura and Osamu Honda Government Forest Experiment Station, Tokyo, Japan (Receivedin Japan 29 December 1967) Inumakilactone A is a bitter principle first isolated (1,2) by one of us (T. T.) from the wood of Podocarpus macroohyllua D. Don (Japanese name:

Inumaki) together with

the other constituents (3). We have isolated the same compound as the major constituent of seeds of the seme plant together with nagilactone C (4) and a few other related compounds, and now wish to provide here the evidence which permits the assignment of the novel bienorditerpenoid dilaotone structure I for this compound. Constitution Inumakilactone (I) (5)

(C1SH200S, m.p. 251-j' (dec.), [aJD+OO, Amax 220

mu (E IlOOC), Y 3460, 1760, 1705, 1640 cm'3 afforded the diacetate (II) (2) [m.p. 263-4" (dec.), u 1772, 1750-1700 cm*, no OH absorption, CaJD +34.7", [eJ263 -172003 by acetylation with Ao20-NaOAc, and, on catalytic hydrogenation (Pt02), yielded the dihydro derivative (III) (2) [m.p. 260-5*, Y 3460, 1760, 1740 cm').

The spectral properties of

these compounds confirmed the presence of two hydroxyl groups and a Y-lactone and an a,Punsaturated-6-lactone; the remaining two oxygen atoms were attributed to ether linkages. The EER spectrum of II (TABLE I), in conjunction with the RMDR experiments (FIG. I) (6), disclosed the arrangement of the hydrogens on Cl-C2-C3, C5-C6-C7, C14-C15-Cl6 and The position of the acetoxyl groups at C3 and Cl5 in II was suggested by the large c11' acotylation shift of II3 (1.11 ppm) and El5 (0.96 ppm) compared to the other hydrogen6 (TABLE I) and confirmed by the following experiments: The 15-acetate (IV) (m.p. 256-C" (dso.), Y 3510, 1768, 1735, 1715, 1644 cm*) obtained by mild acetylation of I was oxidized with Jones1 reagent to afford the j-ketone (V) (m.p. 270' (dec.), v 1797, 1745 sh, 1732, 1650 cm'J which clearly shoved RMR signala due to R1 and R2 as a pair of doublets (TABLE I).

On the other hand, similar oxidation of the j-acetate (VI) [m.p.

294-7. (deo.), Y 1757, 1736 sh, 1724, 1640 cm-')obtained by the mild acid hydrolysis of II, yielded the 15-ketone (VII) cm.p. 215-S' (dec.), v 1780, 1742, 1722, 1642 cm'J which exhibited three singlet methyl signals and a singlet due to R in its NMR spectrum. 14 These experiments also revealed that C6 and Cl4 are connected with the lactonic oxygens. Catalytic hydrogenation of II afforded the corresponding dihydro derivative (VIII) Cm.p. 247-fl"(dec.), Y 1776, 1746 cm+].

In the RER spectrum of VIII in CDC13-benzene,

No.17

I: 11%

R=Rl-H B=R~=Ac

III: VIII:

V

R=Rl=H R=Rl=Ac

IV: R=H, Rl-Ao VI:

R=Ac, Rl-H

IX: X: XIII;

FIG. I.

Xq?OH, aH, R=H X+OAc,

UR, R=Ac

XI: XII:

X'$OH, UH XQ

X=0, R=Ac

BMR and RlfDRSpectra Of Inumakilactone A diaoetste (II) (100 RHZ, c~G1~)

2~67

No.17

a new proton only with

(Hq) appeared

indicating

(6 2.34,

incorporated

presence

of 1,2-epoxide

The number C15H2C08

of atoms

double

one more oxide

formula,

in such

situated

close

to and in the same plane

satisfy with

be in the proximity effect

Since no indication

rings

are concluded.

the

to

of the presenoe carbons,

The two carbocyclic

the following

as the double

(0.2 ppm or more)

proximity.

all of the foregoing

requirements:

The

bond.

Moreover,

of the double

15

is I.

extremum

(NMR of II and VIII).

upon acetylation

group

indicating

of the partial

The presence

"5' H7

they also are subjected

bond

-hydroxyl

The only arrangement

evidence

of the first

of the C

Me20,

structure

of a C 7, C8-oxide

in the ORD of the keto ester

(VI-II)

the two which

is consistent

XII described

(8).

the Cotton

The absolute

effect

configuration

of the C 7, C8-epoxide

in the ORD of the keto ester

XII:

When

to

(X) [amorphous,

v CHC13

dihydro

hydroxy

ester

chromic

acid oxidation XII displayed

the epoxide

1733

(XI) [m.p. afforded

cm’).

Cotton

keto

give

the

to alkaline

trihydroxy

ester

the hydroxy-diacetoxJ-

c>-ter

(Pt02) hydrogenation

of X to the

v 3390, 1766, 1733, 1689 cm') followed

265-7'.

an o-configuration the hydroxy

Catalytic

the keto ester

a negative

to have

acetylation,

3320,

from

ring was deduced

I was submitted

(Na CO ) methanolysis, the Y-lactone opened preferentially 2 3 (IX) (m.p. 259-260° (dec.)], acetylation of which yielded

after

of the Y-

of three quaternary

of the doubl e bond because

(VI--*VII), respectively,

Configuration

CU4].

a part

so far in I amounts

(0.64 and 0.81 ppm) of H7 were observed

shifts

the position

below

C6 forms

Cl4 is

of Hl and Ii2 suggested

the presence

a way to fulfill

difference

to be in close

signal

14

(0.54 ppm) of H1 in II and VIII means that Hl must be

shift

and oxidation

6.2 Hz)

of the H

(NMR of II and VII),

established

C18H2008.

and two carbocyclic

must be constructed

to the paramagnetic

carbon

constants

in the part structures

chemical

Large up-field

the multiplicity

part; hence

and coupling

bond in I was observed,

linkage

and H14 should

6.2 HZ) coupled

Jx12.2,

at Cl and C2.

out of the molecular

of a further

groups

Since

with a quaternary

shifts

(6 1.72,

12.2 Hz and 6 2.60, Jd4.8,

in the a,g-unsaturated-&-lactone

(7). The chemical

lactone

of doublets

J=l4.8,

both C8 and Cl0 are quaternary. that Cl4 was connected

revealed

rings

as a doublet

the Cll-methylene

(XII) [m.p.

257-q"

(dec.),

effect

((~)~;~ugh-1180,

(@):;Tk+

(10).

Similar

methanolysis

ester

(XIII)

alkaline

(m.p.

Z29-2jo'

by

v 1730-1728

3060) showing

(dec.),

cf V yielded,

Y 3360, 1735,

1713 cm'). As shown

'56

equal

in diterpene In these molecular

in TABLE

to 4.6-5.5

is in accord

of known

configuration

lactones

derivatives model

J67 remains

with H /H

Hz if the two hydrogens

'67'

Thus,

I, all inumakilactone

Hz, which

56-

are a, 5

figures

and H 6 is a.

d

being

function

(5.5-8 Hz) for show J=ll-13

The dihedral

Jcalcs=3-4 Hz if R

the latter of R

with a Y-lactone

(trans hydrogens

less than 1.5 Hz.

cis suggests

the configuration

derivatives

with the values

angle

have

-cis

hydrogen3

HZ)

(11). from the

obtained

A7 is &

and Jcalc

=0.7-1-C .

in accord

with

observed

Consequently,

the

the Y-lactone

function

has B-configuration. The /3-orientation

of Me2o was established

in the following

ways:

Scale models

con-

1.40 1.31

1.53

1.56

Py

Py

I

II

1.29

CDC13 1.52

Py

VII

coc13 1.29

CDC13 1.39

CDC13 1.39 1.73

XI

XII

XIII

H2 '3

1.40d

1.60d (6.2) 1.3Yd (6.0) 1.37d (6.2) 1.36d (6.0)

H5

'6

3.3-, 3.5 3.7 3.5-,

3.48*

(4.2) 3.77d

3.77d 3.6Sd (4.0) (4.0) 3.77d 4.07d (4.1) (4.1) 3.53.53.S* 3.8'

3.51d ~3.6~ (3.6)

2.92d (4.0) 3.04d (4.0)

3.41s

3.63.63.e5+ 3.05*

_

***

t-2 1

4.49b,t

4.94d -1.80 + -4.75* (2.1) 5.01s -2.1* 4.4Sdd 3.418 (2.5) l ** 3.27d 5.008 4.41t (4.0) (-2) 3.27dd 5.04d 2.05~ (4.0,~1) (1.0)

l.%5d 4.76d (5.3) (5.3)

(5. 0) (5 . 0 , 1 . 3) 2.2Vd 5.12dd

(6. 2) 5.76d

l

**

6.44s

6.81s

6.96s

6.45s

6.41s

6.40s

6.89s

6.73s

H1l

1.97 2.12

A0

2.12 5.53s

-

2.14

2.14

2.00

2.00

4.76d 4.1-, (8.5) 4*5 4.905 -

-5.35* -5.3*

4*77d 4.t'-, (5.0) 5.0

4.7Sd 4.97d,q 2.06 (4.9) (4.996.3) 2.12 2.11 .75d 4.95.5) 5.1+

4

H15 H14 4.72d 4.31m (8.5) 5.27+ 5.27*

-3.8 l

3.51s

6.28s

2.6-* 2.9

3.53d 2.3(2.1) 2.9*

3.73d 6.20s (-2.5)

2.07 2.18

4.8Od 4.8-* (4.0) 5.2

2.10

4.50d 4.73d,q 2.04 (2.7) (6.0,2.7) 2.15

4.55d 4.86d,q 2.04 (2.8) (6.2,2.8) 2.18

4.76d 4.0(4.0) 5.1')

4.51d 4.86d,q 2.04 3.74s 2.6Bdd (15.5,11.5) (3.5) (6.5,3.5) 2.11 2.88dd (15.597.2) 3.92 6.64~ 4.81d 4.2-• (8.0) 4.6 b,s

. !i'$

2.04 4.79dd 4.01d (5.0) (5.0,1.5) (1.5)

5.45m

5.75d (6.0)

-

-

.

q;4;;

5.08+

B7

3.99d (1.3) 4.00 b,s 2.66d -.4.06* 4.03d (5.0) (-1) 4.55d 3.03d 5.27dd (5.0) (5.0.1.5) (1.5) 2.2Sd -5.14* 5.11s (4.6)

3.62d 3.5ldd 4.65d 2.13d 5.08* (4.0) (4.096.0) (6.0) (5.5) 3.74d 3.62dd 5.76d 2.27d 5.13dd (4.0) (6.2.4.0) (6.2) (5.0) (5.091.5) 3.4s* 3.45* 5.46m -2.07* 4.86dd (4.891.3) J-4-, 3.4-, 4.4- -2.02 * -4.93* 3.6 3.6 4.6~0

Hl

NMN Signals of Inumakilactone A Derivatives**

1.38d 2.94d 3.34&d 5.3Sd (6.5) (3.9) (6.013.9) (6.0)

2.39s

2.409

1.43d (6.2) 1.54d (6.5) 1.58d (6.0)

1.56d (6.5) 1.53d (6.4) 1.41d (6.3) 1.43d (6.2)

Mel6

TABLE I.

+ Chemical shifts are approximate because of serious overlapping. I+ Multiplicity of the signals is abbreviated to 8, d, dd, t, q, m and b for singlet, doublet, double doublet, triplet, quartet, multiplet and broad. +*ICMeans the signal hidden under the other signals.

1.26

1.29

CDC13 1.213 1.56

X

1.52

Py

1.79

CDC13 1.50 0.92

IX

VIII

1.16

1.57

w

VI

1.55

1.09

1.66

Py 1.34

1.00

cycle 1.56

V

1.23

cycle 1.46

IV

CDC13 1.52 1.13

Me20

MeI8

Compd No. Solv.

3.81

3.68

3.78

3.79

3.69

neoco

5tructed with a B-orientation of the Y-lactone grouping require the methyl group to be p-axial in order for Hl to be situated in the plane of the A9'11 double bond. This is in accord with the resistance of the 6/j-hydroxylgroup to ecetylation (1X+X, V-+XIII), the up-field shift of the Me20 signal upon the oxidation of the 6g-hydroxgl group (XI-+ XII) and the inhibition of ketal formation from XII a5 was observed by the lack of change in its ORD curve on the addition of acid (12). The large doun-field ehift of Me2o (TABLE I) observed on the cleavage of the Y-lactone (e.g. 11+X,

VdXIII) can be

explained by the anisotropic effect of the Y-lactone ring replaced by that of an ester grouping (which may be freely rotating) and by the creation of a new 1,3-diaxial interaction between the methyl group and 6P-hydroxyl group which waa masked a5 modified acetate in II (13). The orientation of the oxygen functions on the A-ring was establiehed as follows: Observation of intramolecular hydrogen bonding between the 3-hydroxyl and the Y-lactone CHC13 3534 cm* (concentration independent), $$lJ carbonyl group5 [IV, uOH vEz13

1740 CP4, II,

1793 cm'] and a large nuclear Overhaueer effect (14) between Mel8 and H3 (17%

increase of area) means that H 3 is a-oriented.

The axial nature of the 3g-hydroxyl,

suggested by the above-mentioned intramolecular hydrogen bonding was supported by the fact that up-field shifts of the MepO signal upon acetylation (IV-bII) and oxidation (IV+V) were observed in the derivative5 with a 'Y-lactone,in contrast to the downfield shift5 observed by corresponding chemical modifications of the 30 hydroxy+a steroids (13). The coupling constant J23 in the NMR spectra of all compounda with the Y-lactone fall5 in the range of 6+1 Hz.

This large value is markedly decreased to O-l.0

Hz when the Y-lactone is cleaved (TABLE I).

This change can be reconciled only when

these lactones have 3g-axial-hydroxy-1,2*-epoxide structures with the ring A in a twisted boat conformation which changes to a half-chair conformation when the lactone is opened8 inspection of models shows that the dihedral angle between H 2 and H

changes 3 from ca. 40' to 85" during the conversion of ring A from a twisted boat to a half-chair. Finally, the stereochemistry at C and Cl5 was elucidated as follower a-orienta14 tion of the aide chain, suggested by the close proximity of H and the C15-hydroxyl 7 group as described earlier, received further support from the negative Cotton effect supra) of the enelactone chromophore in II, assuming that the side chain ha5 an The S-configuration for C was established by the applica15 tion of the bensoate rule [(MJ,+99" for VI and [M)D+226' for it5 bensoate, m.p. 292-4O

equatorial orientation (15).

(dec.)J (16) and Horeau's asymmetric synthesis (17). Author5 are deeply indebted to Dr. M. C. Woods, Varian Associates, and Mr. I. Hiura, Tohoku University, for measurements of NMDR and nuclear Overhauser effect, to Professor T. Sakan, Osaka City University, for hi5 helpful discussion and generous gift of samples of nagilactones. Author5 are also thankful to Professors W. Cocker, University of Dublin, M. Takahashi, Tohoku College of Pharmacy, K. Mori, Tokyo University. for their donation of various samples, to Drs. Y. Inoue, H. Hikino, Tohoku University, K. Kuriyama, Shionogi Research Laboratory, for the measurement of ORD, CD and [aJ,s.

2070

No.17

References

and

1) T. Takshashi, J. Japan Wood Res. Sot., 2,

2)

Abstracts of 11th Ann. Meeting

w.,

Footnotes 105 (1959).

of Japan Wood Res. Sot., 215 (1961).

3) S. M. Bocks, R. C. Cambie and T. Takahashi, Takahashi, M. Yaeue, $9 217 (1964).

H. Imamura,

M.

Hiyazaki

Tetrahedron, &z, 1109 (1963). T. and 0. Honda, J. Japan Wood Res. Sot.,

4) Y. Hayashi, Chea.

3. Takshashi, H. Ona and T. Sakan, Abstracts Sot. Japan, Part III, 627 (1967) and the following

of 20th Ann. Meeting paper.

of

5) Correct

analytical figures were obtained for all compounds described in this paper. DV and IR spectra were refered to methanol solution, and KBr disk, respectively, unless otherwise stated. All [a),s were maasured in pyridine and CD and ORD in

u

methanol.

6) All NMR data are listed in TABLE I. Measurement was carried out at 60 and/or 100 MHz. 7) Of the two possible Y-la&one part-structures, the one involving c in a part of the lactone was discarded because this structure is inconsistent with zany evidences described below. 8) The bathochromic effect of a a-axial hydroxyl or acetoryl group on the first extremum of the n-rfltransitionin ORD of ketones is well known (9)g the similar effect of epoxy

ring has been

observed

(10).

9) C. Djerassi, 0. Halpern, V. Halpern, 0. Schindler and C. Tamm, Helv. Chim. Aota, Q, 250 (1958).

10) C. Djerassi, W. Klyne, T. Norin, C. Ohloff and E. Klein, Tetrahedron, 22, 163 (1965). K. Kuriyama, H. Tada, Y. K. Sawa, S. It6 and I. Itoh, to be published. 11) E. Wenkert and B. L. Mylari, J. Or Rieke and D. M. S. Wheeler, i-i;

t!b6475y7 5:'~:',an:o,f:'T~s~~~~r~; ';2 ;a, 927 (1967). K. Mori :nx=' 1701 (1966). C. R. Bennett and;: C:'Cambie, ibid., M. Matsui, Tetrahedron Letters, 1633 (1966). R. Henderson, R. KcCrindle, K. H. Overton and A. Melera, ibid., 3969 (1964). R. Henderson, R. MoCrindle, K. H. Overton, M. Harris and D. W. Turner, Proc. Chem. K. Hirao, Chem. Pharm. Bull., &z, 1145 (1967).

12) C. Djerassi, L. A. Mitscher and B. J. Mitscher,

Sot.,

269 (1963).

A. Tahara

and

J. Am. Chem. Sot., EL, 947 (1959). Y. Kawazoe, T. Okamoto and K.

13) R. F. Ziircher,Helv. Chim. Acta, @, 2054 (1963). Tsuda, Chem. Pharm. Bull., $, 338 (1962).

M. C. Woods, 14) F. A. L. Anet and A. J. R. Bourn, J. Am. Chem. Sot., E+;5, 5250 (1965). I. Miura, Y. Nakadaira, A. Terahara, M. Maruysma and K. Nakanishi, Tetrahedron Letters, 321 (1967). 15) G. Snatske, H. Schwang and P. Welzel , Some Newer Physical Methods in Structural Chemistry, ed. by R. Bonnet and J. 0. Davis, p. 159. United Trade Press (19671. 16) J. II. Brewster, 17) A. Horeau

Tetrahedron,

and H. B. Kagan,

&s, 106 (1961). ibid.,

29, 2431

(1964).