XIII

A more plausible biosynthetic route utilizing tryptophane (VI) or tryptamine (XI) with the geraniol

NA NM

derivative A-5 is outlined below. This scheme involves

MNV\

cleavage of the C2-C13 bond in intermediate XII followed

NNVt.

by

internal cyclization of XIII to give the desired skeleton

MMMA

of camptothecin (I).

M

2

H

> >

NNt.

XI

~ A-5

NNIN\ XII

>

References

1. M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, J. Am Chem, Soc,, 88, 3888 (1966).

,.;vo.

2. N. Kowanko, E. Leete, J. Am, Chem, Soc,, 84, 4919

(1962), ^NY'.

3, I, Menkovic: I, D. Spenser, Chem. Commun., 204 (1966).

4. T.

w.

Goodwin, "The Biosynthesis of Vitamins and Related Compounds," Academic Press, New York, 1963, Chap. 3.

5. H, J. Teas, E. G. Anderson, Proc. Nat, Acad. Sci,, Wash,, 37, 645 (1951)

NV\

6. T.

w.

Goodwin, ibid,, p. 80,

7, a, A. R, Battersby, R. T. Brown, R.

s.

Kapil, J. A.

Knight, J. A. Martin, A.

o.

Plunkett, Chem.

Commun,, 888 (1966).

b. P. Loew, H. Goeggel,

o.

Arigoni, Chem. Commun,, 347 (1966).

c. E.

s.

Hall, F. McCapra, T. Money, K. Fukumoto, J, R. Hanson, B.

s.

Mootoo, G. T. Phillips, A. I, Scott, Chem, Commun,, 348 (1966),

d, E, Leete,

s.

Ueda, Tetrahedron Lett,, 4915 (1966).

8, R.

c.

Elderfield, "Heterocyclic Compounds, Vol. IV,"

John Wiley and Sons, New York, 1950, p. 227.

9, E. Klingsberg, ed., "Pyridine and Its Derivatives, Part 3," Interscience, New York, 1962, p. 206.

Proposition 2

PROPOSEOa A general synthesis of 3-alkylfurans.

There are a variety of compounds of plant origin that contain a 3-monosubstituted furan nucleus (1), and more

recently this structural unit has been found in dendrolasin, an odorous substance isolated from ants (2). However,

while nature has supplied ample proof of her ability to

C)I

0

Perillene Clausenane Dendrolasin

create these outwardly simple systems, the laboratory

chemist is still quite restricted in his choice of methods available for constructing 3-alkylfurans. Other than two specific syntheses of 3-methylfuran (3), the literature contains only one report of an efficient route to 3-alkyl- furans. Recently, Gianturco and Friedel (4) prepared several 3-alkylfurans in approximately 50% overall yield by application of the Bamford-Stevens reaction to the tosylhydrazones of some 3-alkyl-tetrahydrofuran-4-ones.

As is well known, 3-alkylfurans unsubstituted at the 2- and 5-positions are exceedingly difficult to synthesize because substitution of the furan nucleus always occurs

preferentially at C-2 and C-5 (5). This order of reactivity implies that an efficient synthesis of a 3-alkylfuran must involve an indirect route in which the future 3-alkyl

group is properly situated prior to formation of the furan ring. Such a synthesis is proposed and is outlined in

Chart A. Besides providing an efficient route to a variety of 3-alkylfurans, this scheme has added value in that one of the intermediates is the 3-alkyl-4,5-dihydrofuran A-5.

~

Dihydrofurans have found commercial value in the production of polymers, pharmaceuticals, and pesticides (6).

The starting material for the proposed synthesis, the S-hydroxyketone A-1, can be obtained from any terminal

~

alkyne by the route outlined in Chart B (7). Compounds such as A-1 could also be synthesized by a base catalyzed

N'NW\

aldol condensation between a methyl ketone and f ormalde- hyde, however the efficiency of such a process is doubt- ful as much dehydrated product would be expected. In the conversion of B-3 to A-1 with potassium carbonate

N'N'VV\ NV'N\/\

in methanol, only trace amounts of vinyl ketone are observed, even for the· lower yields of 75-80%.

While i t may be satisfactory to form oxirane C-1

NNv'..

by allowing two equivalents of dimethylsulfonium methylide

CHART A

R'rJ

CH3 =NSiMe3 ^~SiMe3

^R~

^{+ -}

>

^Me2S-CH2

>

H 0

SiMe3

I

1 2

- -

:D ¹⁾

iPrOH, iPro-, ^R

> Hu

^SOCl2,

^PY1)>

2) H20 00

0 0

SiMe3

I

N. 4

N\ 3

1) NBS

2) Collidine )

R

D

⁰

5 ₆

No. No.

to react directly with hydroxy ketone A-1, there is a

N'NVY\

good chance that the initially formed alkoxide would undergo a retroaldol reaction before the second equi- valent of ylide could add to the carbonyl group. Use

CHART B

RCECH

l) Na

2) HCHO

>

1) HOAc, BF3-HgO,

>

l

2 (90%)

N\ N\

> A-1 (75-95%)

NNt/I.

3 ( 50%)

N\

of the trimethylsilyl group to protect the alcohol function will preclude the possibility of a retroaldol reaction.

Bis(trimethylsilyl)acetamide should quantitatively silylate hydroxy ketone ~ under extremely mild con- ditions (~ room temperature, several minutes) (8, 9) to provide siloxy ketone A-2. While the silyl group can

MANY\

be hydrolyzed easily in the presence of alcohol or water, i t is expected to be quite stable under the anhydrous conditions employed in the subsequent oxirane formation

(9, 10).

The conversion of siloxy ketone A-2 to siloxy oxirane

MMN\.

A-3 is to be accomplished with dimethylsulfonium methylide.

-

This ylide, initially described by Corey and Chaykovsky (11), has been used to selectively add methylene to the carbonyl group of cycloheptanone (97%), carvone (89%),

and eucarvone (93%). The aqueous workup procedure used to isolate A-3 may result in some hydrolysis of the

,..,.,,_,,.

silyl group, although it should be minor (10, 12, 13, 14).

In any event, partial hydrolysis at this time poses no problem as the silyl group is to be hydrolyzed in the next step.

The crux of the proposed synthesis, the conversion of siloxy oxirane A-3 to hydroxy tetrahydrofuran A-4, is ,.,,,.,.,,,.. MNNi.

to be effected in one step by refluxing a solution of

~iniso-propyl alcohol containing 1% sodium iso- propoxide as catalyst. These reaction conditions are expected to bring about the desired hydrolysis and ring closure as illustrated in Chart

c.

Alcoholysis of

CHART C

A-3 iPrOHi iPrO-;

> ~

^iPrO-

^>

/'NAM.

<

⁰ _H

<

N. 1

R

~ _~ ^> -ot:J

^iPrOH

_{< >}

^{A-4 ~ + iPrO-}

2 3

N.

N.

compounds of the type Me3SiOR is an equilibrium process normally slow in the absence of catalysts~ however, this equilibrium is rapidly established in the presence of acids or bases (13). Using iso-propyl alcohol as solvent favors formation of hydroxy oxirane C-1, and the hydroly-

~

sis should be complete within a half-hour (10, 12, 13).

In this brief time, the oxirane should easily remain intact. Opening of epoxides by alcohols in the presence of basic catalysts requires on the order of five to six

hours~ however when iso-propyl alcohol is employed for this purpose, the time for complete reaction is increased to fifteen to twenty '}';ours ( 15). The equilibrium between C-1 and iso-propoxide is an equilibrium between a primary

~

and secondary alcohol and would favor the formation of alkoxide C-2. This alkoxide is made to order for an

NWVI.

intramolecular SN2 attack on the oxirane moiety to generate the tetrahydrofuran system

.s.;;..i:

This intramolecular

process to form the five-membered ring is expected to occur much faster than intermolecular attack of iso- propoxide on the epoxide (15, 16). As the tertiary alkoxide C-3 is generated, i t would abstract a hydrogen

l'olVVW\

from the solvent, a secondary alcohol ( 17). Thus, the differences in acidity among primary, secondary, and

tertiary alcohols fav¹:>r the overall process in converting

~ to hydroxytetrahydrofuran ~·

The tertiary alcohol A-4 can dehydrate in three

N'NVtA

different directions: however, by employing mild conditions

(~ thionyl chloride in pyridine at

o

^{0 ),} i t is expected that the two possible dihydrofurans would be formed in high yield. Between the two dihydrofurans, the 4,5-di-

hydrofuran ~ should be the dominate one as the relatively acidic C-2 hydrogens, being adjacent to the ether oxygen, are more easily removed than the non-activated C-4 hydro- gens. Actually, either dihydrofuran can be converted to the same furan by the bromination--dehydrobromination sequence described below.

Bromination of dihydrofuran ~with N-bromosuccinimide should give the allylic bromide I, which can be dehydro-

,.,..

brominated with collidine to afford the desired 3-alkylfuran

..,..

I

~· With this procedure, 3,5-dialkylisoxazoles have been prepared in high yield from their 4,5-dihydro derivatives

(75-95%) (18), which indicates that side chain bromination is not an important side reaction in this process. Actually,

i t is not anticipated that the allylic bromide I need be

~

isolated, as elimination of hydrogen bromide is often a spontaneous process when increased conjugation or aromati- zation results (19).

With this proposed synthetic route i t should be possible to obtain 3-alkylfurans in better than 50%

overall yield with no stringent limitation on the identity of the alkyl group.

References

1. a. A. P. Dunlop, F. N. Peters, ¹¹The Furans, ¹¹ Reinhold, New York, 1953.

2.

b. P. Bosshard,

c.

H. Eugster, ¹¹The Development of the Chemistry of Furans, 1952-1963¹¹ in Advances in Heterocyclic Chemistry, Vol. 7, A. R. Katritzky, ed., Academic Press, New York 1966, p. 377.

A. Ouilico, F. Piozzi, M. Pavon, Tetrahedron, 1,

177 (1957). ^.M

3. a.

J. w.

Cornforth,

J.

Chern. Soc., 1310 (1958).

4.

s.

b. D. N. Burness, Org. Syn. Coll, Vol. 4, 628 (1963).

M. Gianturco, P. Friedel, Can. J , Chern., 44, 1083 (1966).

MA

R. M. Acheson, "An Introduction to the Chemistry of Heterocyclic Compounds," 2nd Ed,, Interscience, New York, 1967, p. 104.

6, a. M. A. Gianturco, P. Friedel,

v.

Flanagan, Tetra- hedron Lett., 1847 (1965).

b. British Patent 849,192: German Patent 1,064.957.

7. a. E. Royals, ¹¹Advanced Organic Chemistry, ¹¹ Prentice- Hall, New York, 1954, p. 521,

8.

9.

10.

11.

12.

b, M. Koulkes, Bull. Soc, Chim, Fr., 127 (1957), J. Klebe, J. Am. Chern. Soc,, 86, 3399 (1964).

Ml\

L. Birkofer, A. Ritter, Angew. Chem. Internat. Ed., 4, 417 (1965).

-.

L. Birkofer, A. Ritter, F, Bentz, Chem. Ber., 97,

2196 (1964). ,._,

E.

J.

Corey, M. Chaykovsky, J. Am. Chem. Soc., 87,

1353 (1965). ^NV\.

s.

Friedman, M. Kaufman, Anal, Chem., 38, 144 (1966). ,._,

13.

c.

Eaborn, "Organosilicon Compounds," Academic Press, New York, 1960, p. 295.

14. G. Stork, P. F. Hudrlik,

J. Am.

Chem. Soc., 90,

4462 (1968). ,_.

15. H.

c.

Chitwood, B. T. Freure, J. Am. Chem. Soc., 68, 680 (1946).

,_.

16. E. L. Eliel, ¹¹Stereochemistry of Carbon Compounds, ¹¹ McGraw-Hill, New York, 1962, p. 198.

17. H.

o.

House, "Modern Synthetic Reactions,"

w.

^A.

Benjamin, New York, 1965, p. 164.

18. G. Bianchi, P. Grunanger, Tetrahedron, 21, 817 (1965).

""""'

19.

w.

Forest, ed., ¹¹Newer Methods of Preparative Organic Chemistry, Vol 3, ¹¹ Academic Press, New York, 1964, p. 151.

Proposition 3

PROPOSEDs A synthesis of 3-bromomethyl-5-methoxy-1,2- benzisothiazole (A-7), an alkylating agent which can

Nl/'N.

be used with strongly basic enolates to introduce a functionalized ~-phenylethyl group (1).

As outlined in Chart A, the previously reported

synthesis (1) of methoxy bromide A-7, based on the concept

l"NVtNi.

of functionalizing the C-5 position of benzisothiazole A-2, suffered from the almost total lack of discrimination

NV\No.

between positions C-5 and C-7 during the initial nitration reaction. The proposed synthesis of A-7, depicted in

~

Chart B, avoids this shortcoming by introducing the necessary functionality prior to formation of the 1,2- benzisothiazole ring system. The heart of the synthetic scheme involves the efficient, step-wise conversion of thiocyano acetate B-3 to keto thioether B-6 under mild

NVV'A NV\No.

conditions.

The hydroxy ether B-2 can be obtained quite routinely

~

by sodium borohydride reduction of the commercially avail- able ketone B-1 (2). The subsequent transformation of B-2

NV'Nt. MNV\

to the thiocyano acetate B-3 makes use of the fact that

NN<NI.

aryl ethers, which are unreactive to thiocyanogen, react readily with thiocyanogen chloride in acetic acid to give para-substituted thiocyano derivatives in high yield (3, 4).

5 steps>

>

~ l

+ 02N

(55145)

3 4

Nt. ~

l

> >

5 6

,,,..

_M

M 7