An Improved Synthesis of 1α, 3β-Dihydroxycholesta-5, 7-Diene

This article was downloaded by: [Carnegie Mellon University] On: 09 November 2014, At: 00:42 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/lsyc20 An Improved Synthesis of 1α, 3β- Dihydroxycholesta-5, 7-Diene A. Mouriño a a Department of Chemistry , University of California , Riverside, California, 92521 Published online: 05 Dec 2006. To cite this article: A. Mouriño (1978) An Improved Synthesis of 1α, 3β-Dihydroxycholesta-5, 7-Diene, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 8:2, 117-125, DOI: 10.1080/00397917808062105 To link to this article: http://dx.doi.org/10.1080/00397917808062105 PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/ page/terms-and-conditions http://www.tandfonline.com/loi/lsyc20 http://www.tandfonline.com/action/showCitFormats?doi=10.1080/00397917808062105 http://dx.doi.org/10.1080/00397917808062105 http://www.tandfonline.com/page/terms-and-conditions http://www.tandfonline.com/page/terms-and-conditions SYNTHETIC COMMUNICATIONS, 8(2), 117-125 (1978) A SYNTHETIC PRECURSOR OF VEFWJCARIN A Barry B . Snider* and S h a n t i l a l G . Amin Department of Chemistry, Pr inceton Universi ty Pr inceton, New Jersey 08540 The t r ichothecane a n t i b i o t i c s , produced by t h e fungi Trichothecium, Trichoderma, Myrothecium and Fusarium c o n s t i t u t e an important c l a s s of an t i funga l , cytotoxic and phytotoxic sesquiterpenes. ' These com- pounds a r e a l l oxygenated der iva t ives of the t e t r a - cyc l i c 12,13-epoxytrichothec-9-ene (;) skeleton. Verrucarin A ( Z ) , a potent cytotoxin w i t h s i g n i f i c a n t anti-tumor a c t i v i t y , gives the t r ichothecane verru- ca ro l on hydrolysis . I n add i t ion t o ver rucar in A , severa l o ther macrolides a l s o contain a ver rucaro l moiety. u 3 15 2 N * To whom correspondence should be addressed. 117 Copyright 0 1978 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 118 SNIDER AND AMIN W e w i s h t o r epor t here a synthes is of a key i n t e r - mediate, (2),3 f o r the t o t a l synthes is of ver rucaro l . Lactone 2 i s a very a t t r a c t i v e syn the t i c intermediate s i n c e i t has the appropr ia te stereochemistry (C-6 and C-11 of the t r ichothecane nucleus) and has a r i g i d ske le ton which w i l l al low establishment of t he des i red stereochemistry a t o the lac tone carbonyl (C-5 of the t r ichothecane nucleus) . 3 w a s based on a Diels-Alder r eac t ion s ince this route i s adaptable t o preparat ion of o the r na tu ra l ly occur- r i ng t r ichothecanes and ver rucaro l analogs. Our approach t o u Diels-Alder r eac t ion of 3-methyl-1-acetoxybuta- diene (&) with i t a c o n i c anhydride should g ive , i n one s t e p , a compound with the carbon ske le ton and approp- r i a t e func t iona l i t y f o r conversion t o 5. i s a known c o m p ~ u n d , ~ previous syntheses a r e not amenable t o the preparat ion of the l a r g e q u a n t i t i e s needed f o r use a s a s t a r t i n g mater ia l . The prepara t ion of & from 3-methyl-2-butenal i s imprac t ica l due t o the i n a c c e s s i b i l i t y of this aldehyde. We chose in s t ead t o i n v e s t i g a t e the direct rearrangement of propargyl ic esters t o acyloxy b ~ t a d i e n e s . ~ r6 Saucy, e t a l . , have reported t h a t treatment of 2-methyl-3-butyn-2-yl a c e t a t e w i t h s i l v e r carbonate i n a c e t i c a c i d and a c e t i c anhydride a t r e f lux y i e l d s the a l l e n e , 3-methyl-l- a ce t oxy -1 ,2-buta diene and 1 , 1 - dia ce t oxy -3 -me thy 1- 2 - butene (z).6 y i e l d any a l l e n e but ins tead gives 3-methyl-1-acetoxy- 1,3-butadiene H 4 i n 224 y i e l d and the d i a c e t a t e 5- i n Although 5 I n our hands this r eac t ion does not D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 PRECURSOR OF VERRUCARIN A 119 45% y i e l d . sium a c e t a t e i n acetic anhydride a t r e f l u x p a r t i a l l y converts 2 t o $ giving the des i red butadiene i n 53% o v e r a l l y i e l d from 2-methyl-3-butyn-2-01. T h i s i s an e f f i c i e n t rou te t o a u s e f u l diene proceeding i n good y i e l d from very inexpensive s t a r t i n g mater ia l s . Treatment of th is crude mixture w i t h potas- Treatment of 2 w i t h i t acon ic anhydride i n toluene f o r 8 hours a t 120° gives the Diels Alder adducts 5 and 2 a s a 3 : l mixture i n 81% y i e l d . isomer 6, i n which the conjugated carbonyl group has added endo p red~mkna tes . ' , ~ None of the o the r regio- isomer i s formed i n the D i e l s Alder r eac t ion . Reduc- t i o n of the mixture of 5 and A s expected the w i t h sodium borohydride H 6 R = O , R ' = A c Z R = O , R ' = A c 3 R = H 8 R = H2, R' = A c 2 R = H,, R ' = A c & R = H,, R ' = H U R = H,, R ' = H - 12 R = H,, R' = CONHPh - 13 R = CONHPh i n THF followed by a c i d i f i c a t i o n gives lactones and N 9 a s a 3 : l mixture i n quan t i t a t ive ~ i e l d . ~ , ~ Saponi- f i c a t i o n of this mixture w i t h methanolic sodium D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 120 SNIDER AND AMIN hydroxide followed by a c i d i f i c a t i o n y i e lds a 3 : l mix- ture of lac tone 2 and the des i red lactone Sl0 i n 95% y i e l d . Presumably both the ace ta t e s and the lactones of 8 and 5 a r e hydrolyzed. - cis fused y-lactone 5 forms i n preference t o the sp i ro fused lactone 2. On the o the r hand, t h e s p i r o fused lactone 2 forms i n preference t o a t r ans fused y - l ac tone . Upon a c i d i f i c a t i o n the H I n order f o r this route t o be of value f o r the preparat ion of 5 it was necessary t o convert 2 t o 2, hopefully without p r i o r separa t ion of these isomers. Treatment of t h e 3 : l mixture of 2 and 2 w i t h t r i e t h y l - amine and phenyl isocyanate gives a 3:l mixture of phenyl carbonates 2 and 2. hydrolyzed by treatment w i t h potassium bicarbonate i n re f lux ing methanol. Under these conditions t h e car- boxylate derived from 2 disp laces the a l l y l i c car- banatel ' g iving 2 which then hydrolyzes. l a t e der ived from 2 does not d i sp lace the carbamate under these condi t ions. The carbamate i s hydrolyzed by add i t ion of sodium hydroxide t o the re f luxing methanol. Ac id i f i ca t ion of the r eac t ion mixture y i e l d s lactone 5 i n 75% y i e l d from the mixture of 2 and 2 w h i c h contained only 25% of 2. T h i s procedure gives lactone 2 i n 50% y i e l d from 3-methyl-l-acetoxy-l,3-butadiene i n a sho r t procedure t h a t allows the u t i l i z a t i o n of both the endo and exo Diels-Alder adducts. Since this synthes is requi res no chromatography it i s amenable t o the prepara t ion These lactones were The carboxy- D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 PRECURSOR OF VERRUCARIN A 121 of the l a r g e amounts of 2 which w i l l b e needed f o r f u r t h e r syn the t i c s tud ie s . W e are cur ren t ly inves- t i g a t i n g methods f o r converting lac tone 5 t o verru- ca ro l . Experimenta 1 1 -a cet oxy -3 - m e thy 1 -1 ,3 -buta diene : A so lu t ion of 84.0 g (1 mol) of 2-methyl-3-butyn- ( $) 2-01 and 1.75 g of phosphoric a c i d i n 122 g a c e t i c anhydride was s t i r r e d a t room temperature under n i t r o - gen f o r 18 hours. sodium carbonate (3.05 g ) , and si lver carbonate (0 .5 were added, and the r eac t ion was heated a t l l O o f o r 3% hours , Af t e r cooling t o room temperature, the reac t ion mixture was poured i n t o water (500 m l ) and ex t rac ted w i t h petroleum ether (8 x 150 ml). combined petroleum e t h e r f r a c t i o n s were washed w i t h water ( 2 x 150 m l ) , s a tu ra t ed NaHCO, so lu t ion ( 2 x 120 m l ) , b r i n e ( 3 x 120 m l ) and d r i ed (MgSO,). solvent was removed i n vacuo af ford ing 80% of yellow o i l which i s a 7:3 mixture of 2 and 6. d i s t i l l a t i o n provided 28.0 g (22%) of 2: bp 60-62 OC (20 m m ) ( l i t bp 69 O C (30 NMR (CDC1,)G: 1.85 (d, 3 H , J = 2 Hz), 2.5 ( s , 3 H ) , 4.95 (bd s , 2 H ) , 5.12 ( d , 1 H , J = 13 Hz), 7.35 ( d , 1 H, J = 13 Hz). T h e mixture contained 5% of the c i s isomer: NMR (CDC1,)G: 5.35 ( d , 1 H, J = 7 Hz) and 7.02 ( d , 1 H, J = 7 Hz). Acetic a c i d (303 m l ) , anhydrous The The F rac t iona l l-acetoxy-3-methyl-1,3-butadiene from 4 and 5 A mixture of potassium a c e t a t e (5 .2 g ; 0.05 mol), a c e t i c anhydride (20 m l ) , acetic a c i d (10 m l ) and D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 122 SNIDER AND AMIN crude mixture of & and 5 (5.65 g ) w a s hea ted a t r e f l u x f o r 2 hours . Water (30 m l ) w a s added and the s o l u t i o n was ex t r ac t ed w i t h ether (5 x 50 m l ) . T h e combined organic l aye r s were washed w i t h water (2 x 110 m l ) , s a t u r a t e d NaHCO, s o l u t i o n (2 x 50 m l ) , sodium ch lo r ide s o l u t i o n (2 x 100 ml) and d r i e d (MgS04). Removal of so lvent i n vacuo followed by d i s t i l l a t i o n gave 2.6 g of l-acetoxy-3-methyl-l,3-butadiene ( 4 ) . Diels-Alder Reaction of & and i t a c o n i c anhydride u A mixture of 4 (10 g , 71 mmol), i t a c o n i c anhydride LI (7.3 g, 65 m o l ) and hydroquinone (100 mg) i n to luene (50 ml) w a s hea ted f o r 8 hours a t 120° under N2. The so lven t was removed i n vacuo and the crude product was r e c r y s t a l l i z e d from a mixture of e ther /petroleum ether (2:l V/V) t o give a 3:l mixture of 5 and (12.5 g , 81%) : c o l o r l e s s needles , mp 91-93 O C ; NMR (CDC1,) 6: 1.75 (s, 3 H), 2.1 (s, 3 H ) , 2.15 (my 4 H ) , 3.1 and 2.75 (AB q , .25 x 2 H ) , 2.85 (s, .75 x 2 H ) , 5.43 (s, 1.75 H ) and 5.65 ( b r , .25 H ) ; I R ( n e a t ) 1850, 1780, 1725 and 1880 cm-'. Reduction of Anhydrides fi and Z A suspension of sodium borohydride (0.74 g , 20 mmo1)in THF (20 m l ) was s t i r r e d a t Oo w h i l e a s o l u t i o n of anhydrides ( 5 and 1, 4.76 g , 20 mmol) m l ) was added dropwise over a 30 min. per iod . The r e a c t i o n w a s s t i r r e d 1 hour a t O o , then 7 hours a t 20-30°. T h e r eac t ion mixture was poured onto ice , a c i d i f i e d w i t h 6N H C 1 , and ex t r ac t ed w i t h CH2C12 (3 x 100 m l ) . The combined CH2C12 l a y e r s w e r e washed with i n THF (50 D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 PRECURSOR OF VEFWJCARLN A 123 water ( 3 x 50 m l ) , s a tu ra t ed NaCl so lu t ion ( 2 x 50 m l ) and d r i ed (MgS04). reduced pressure gave g and 2 ( 3 : l ) as a viscous o i l ( 4 . 5 g , 100%): NMR (CDC1,)G: 1.73 ( s , 3 H ) , 2 . 1 ( s , 3 a) , 2.05 ( m , 4 H ) , 2 . 4 ( s , .75 x 2 H ) , 2.25 and 2.7 (A6 (I, .25 x 2 H ) , 3.9-4 .5 ( m , 2 H ) and 5.0-5 .6 ( m , 2 H ) ; I R ( n e a t ) 1730 and 1780 c m - l . Hydrolysis of Lactones 3 and 2 Removal of t h e so lvent under A mixture of crude lactones and 2 ( 4 . 5 g , 20 mmol) and sodium hydroxide ( 3 . 3 g) i n aqueous (25%) methanol so lu t ion was s t i r r e d f o r 12 hours a t room temperature and ref luxed a t 60° f o r 30 min. Af t e r cooling t o room temperature, the r eac t ion mixture was ex t rac ted w i t h ether ( 3 x 75 m l ) . The aqueous l a y e r w a s separa ted , a c i d i f i e d w i t h 6 N H C 1 (25 m l ) , s t i r r e d f o r 30 min and ex t r ac t ed w i t h CH,C12 ( 4 x 100 m l ) . The CH,C1, e x t r a c t s w e r e combined, washed w i t h H 2 0 ( 2 x 100 m l ) , b r i n e ( 3 x 75 m l ) and d r i e d (MgS04). Removal of the solvent i n vacuo gave crude lactones 10 and 2 ( 3 . 4 9 g , 9 4 $ ) , a s a 3 : l mixture. graphy on s i l i c a g e l a f forded pure lac tone 2: mp 92- 93'; NMR (CDC1,)G: 1 . 7 ( s , 3 H ) , 1.95 ( m , 5 H ) , 2.35 ( s , 2 H ) , 3.95 ( m y 1 H ) , 3.98 and 4 . 5 1 (AB q , 2 H , JAB = 10 Hz) and 5.52 (m, 1 H ) ; I R ( n e a t ) 3427, 1763 and 1666 cm-l. Lactone 5 w a s a l s o obtained by chromato- graphy: mp 83-84 O C ( l i t mp 83-84 OC''); NMR ( C D C 1 , ) S : 1.8 ( s , 3 H ) , 2 . 0 ( m , 4 H ) , 2.35 and 2.65 (AB q , 2 H , Chromato- -4- = 18 Hz), 2.45 ( s , 1 H , O H ) , 3.58 ( s , 2 H ) , 4 . 7 J~~ ( m , 1 H ) , and 5 .52 ( m y 1 H ) ; I R ( n e a t ) 3440, 1745 and 1670 cm-'. D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 124 SNIDER AND AMIN Conversion of t o 3 A s o l u t i o n of t r ie thylamine (0.9 g , 9 mmo1) , phenyl isocyanate (1.07 g , 9 mmol) and lac tones 2 and 10 (0.546 g , 3 mmol) i n benzene w a s s t i r r e d f o r 48 hours . The so lvent w a s removed i n vacuo. The residue, KHC03 (600 mg, 6 mmo1),H20 (5 m l ) and methanol (30 m l ) wexeheated a t 60° f o r 12 hours . Sodium hydroxide (480 mg, 12 mol) w a s added and the mixture w a s hea ted a t 60° f o r 8 hours , The reac t ion mixture was a c i d i f i e d w i t h 6 N H C 1 a t Oo and s t i r r e d f o r 20 min. l a y e r was ex t r ac t ed w i t h methylene ch lo r ide (3 x 100 m l ) . The methylene ch lo r ide e x t r a c t s were combined, washed w i t h water (2 x 50 m l ) , s a t u r a t e d N a C l s o l u t i o n ( 2 x 50 m l ) and d r i e d (MgS04). Removal of the so lven t a f forded crude 2. by t r i t u r a t i o n w i t h ether (diphenyl urea i s in so lub le ) followed by r e c r y s t a l l i z a t i o n from ether-hexane gave 408 mg of pure 2, mp 83-84O, (75% y i e l d ) . .w The aqueous Removal of r e s i d u a l diphenyl urea References 1. J . R . Bamburg and F .M. Strong i n Microbial Toxins , V I I , S . Kadis, A . Ciegler and S . A j l , ed s . , Academic Press , New York, 1971 , pp. 207-292. 2. A.T. McPhail and G . A . S i m , J. Chem. SOC., C , 1394 (1966). 3. R. Raphael , e t a l . , have synthesized 2 by another rou te ; M . Cur r i e , J. C h e m . SOC. , Perkin Trans. 2, 240 (1973). 4 . J. Castells and J.F. Sanchez, An. Quim., 70, 567 (1974); J.F.W. Keana, e t a l . , J. Org. Chem., 4 l , 2124 (1976). D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14 PRECURSOR OF VEXRUCARIN A 125 5 . Such rearrangements have been used f o r the prepara- t i o n of 1-aminobutadienes: L.E. Overman and L.A. C l i zbe , J . Am. Chem. SOC. 98, 2352 (1976). 6. G . Saucy, e t a l . , Helv. C h i m . Ac ta , 4 2 , 1945 (1959). M . Appam and R. G lena t , C.R. Acad, S c i . , P a r i s , S e r . C , 265, 400 (1967). With some p r o p a r g y l i c a l c o h o l s Saucy observes formation of acetoxybuta- dienes . 7. R.K. H i l l and T . V . van Auken, J. Org. C h e m . , 23, 626 (1958); K. Alder , e t a l , , C h e m , Ber., 86, 1373 (1953). 8. J. Haslouin and F. Rouessac, Tetrahedron L e t t . , 4651 (1976). 9. D.M. Ba i l ey and R.E. Johnson, J . Org. C h e m . , 35, 3574 (1970). 10. We thank P r o f e s s o r Raphael and D r . Colvin f o r s p e c t r a l data and a sample of 2. i d e n t i c a l t o t h e i r sample3 by I R , NMR, and mass s p e c t r a l comparison and mmp. Our compound i s 11. A s i m i l a r displacement t o form a l a c t o n e has been r epor t ed ; E . J . Corey and G . Moinet, J . Am. C h e m . SOC. , 95, 6831 (1973). Received: November 22, 1977 D ow nl oa de d by [ C ar ne gi e M el lo n U ni ve rs ity ] at 0 0: 42 0 9 N ov em be r 20 14