Asymmetric synthesis of solenopsins A, B and C

Recueil des Travaux Chimiques des Pays-Bas, 114/4-5, Apri l /May 1995

Recl. Trav. Chim. Pays-Bas 114, 153-156 (1995) SSDI 0 1 6 5 -05 1 3 (95 ) O O O 1 9 -4

I53

0165-0513/95/4/5 153-04$9.50

Asymmetric synthesis of solenopsins A, B and C

Guy SolladiC * and Nathalie Huser

Ecole Europe'enne des Hautes Etudes des Industries Chimiques, (EHICS), Laboratoire de Ste're'o- chimie associe' au CNRS, Universite' L. Pasteur, 1, Rue Blaise Pascal, 67008 Strasbourg, France (Received October 28, 1994)

Abstract. Solenopsins A, B and C have been synthesized in enantiomerically pure forms from the corresponding anti-15-diols which have been obtained from glutaric anhydride by an asymmetric synthesis induced by chiral sulfoxides.

Solenopsins A, B and C belong to a family of 2-methyl-6- alkylpiperidines which have been isolated from the venom secreted by the fire ant Solenopsis inuicta'. The absolute configuration (2R,6R) of solenopsins A and I3 have been determined by comparison of synthetic with the natural products. Recently, the absolute stereochem- istry of natural solenopsins A, B and C has been determined by comparison of the MTPA aderivatives (Mosher's reagent) of the natural products and standards of estab- lished absolute configuration'. Solenopsin A has already been prepared by asymmetric synthesis: from a chiral 6-(oxazolo-2-yl-piperidine-2- carbonitril*, from a chiral sultam3, and from a chiral salt of 1-a~ylpyridinium~. Two other syntheses started from optically active precursors: (R)-a-methylbenzenemethan- amine' or L-aspartic acid6. Solenopsin B has also been prepared by asymmetric synthesis from the stereoselective reduction of an enantiomerically pure P-keto ester' and from L-glutamic acid'. Solenopsin C has never been synthesized. We report in this paper the enantioselective synthesis of solenopsins A, B and C from anti-1,5 diols which one readily prepared from p-keto sulfoxides. The retrosynthetic Scheme 1 shows that solenopsins can be obtained by cyclization of the deprotected anti-1,5-diol 2 with benzylamine. The different side-chains can easily be introduced by a Wittig reaction on the aldehyde 3 resulting from a Pummerer rearrangement of the protected dihydroxy sulfoxide 4. The synthesis of the P-keto sulfoxide 5 (Scheme 2) from glutaric anhydride has already been reported for the

Abbreviations and IUPAC names carbinol = tertiary alcohol de = diastereorneric excess DMSO = dimethylsulfoxide ee = enantiorneric excess DIBAL = diisobutylalurninium hydride LDA = lithium diisopropylamide mesyl = methylsulfonyl MTPA = Mosher's reagent = . . . TBAF = tetrabutylammonium fluoride TBDMS = tert-butyldirnethylsilyloxy TBDPS = terr-butyldiphenylsilyloxy

enantioselective synthesis of zearalenone''. Similarly the reduction of 5 with ZnCI,/DIBAL and the transforma- tion of the ester 6 into the hydroxy sulfoxide 8 was described in a short communication concerning the enantioselective synthesis of heptane-2,5-dio11'. The highly stereoselective reduction (de > 95%) of the P-keto sulfoxides 5 and 7 with ZnC12/DIBAL was expected from our previous results". We have shown indeed that chiral methyl carbinols could be efficiently obtained in both enantiomeric forms by reduction of P-keto sulfoxides, followed by desulfurization of the resulting P-hydroxy sulfoxides. DIBAL reduction of the (R)-P-keto sulfoxide gave the (R)-carbinol by an intramolecular hydride shift from an intermediate having aluminium chelated on the sulfoxide oxygen, while ZnCI,/DIBAL reduction af- forded the (S)-carbinol by hydride transfer from a zinc chelate between the sulfoxide and carbonyl oxygens' u. The hydroxyl group of 8 was then protected by a TBDPS group (Scheme 3) and the resulting compound 4 was submitted to a Pummerer rearrangement to give, in high yield after desulfurization, the acetate 9 which was trans- formed into the aldehyde 3 by a sequential reduction- oxidation process. The Wittig reactions with the appropri- ate phosphorus ylides gave 80/20 mixtures of E/Z olefinic adducts in very good yields which were finally reduced to compounds 2. After removing the protecting groups with TBAF, the resulting diols 11 (Scheme 4) were mesylated and allowed to react with benzylamine at room temperature to give the benzylated solenopsins in high yields. These were deprotected with Pd/C to give, respectively, solenopsins A, B and C which showed all the characteristics described in the literature2-'. The diastereoselectivities of the reaction products were checked by 'H and 13C-NMR and their rotatory powers were consistent with the highest values reported in the literature for solenopsins A and B. Solenopsin C has not yet been reported.

Solenopsln A Solenopsln B Solenopsln C

Figure I .

154 G. Solladit!, N. Huser /Asymmetric synthesis of solenopsins A, B and C

4 Scheme 1.

These results show clearly that any enantiomerically pure 2,6-dialkylpiperidines can be prepared from the corresponding 1,5-diols which are easily available from the P-keto sulfoxides 5 in any of the four possible configura- tions.

Experimental

( + )-/6S, S(R)]-6-(tert -Butyldimethyls i ly loxy)- l - (p- tolylsulf in- heptan-2-one (7)

A solution of (R)-(+)-methyl p-tolyl ~ulfoxide'~ (822 mg, 5.33 mmol, 2.05 eq) in THF (10 ml) was added at -40°C to a LDA solution [prepared from diisopropylamine (0.83 ml, 5.82 mmol, 2.2 eq), BuLi (3.68 ml of a 1.51M solution in hexane, 5.57 mmol, 2.1 eq), and THF (10 ml) at -4o"Cl. After stirring at -40°C for 15 min, the ester 6" (678.2 mg, 2.6 mmol, 1 eq) in THF (5 ml) was added. After 30 min, the reaction mixture was hydrolyzed with satd. NH4CI (30 ml) and the aqueous phase extracted with ethyl acetate (3x20 ml). The organic phases were washed with satd. NaCl (30 ml), dried (MgSO,) and evaporated. The product was purified by silica gel chromatography (AcO,Et/hexane: 30/70, Rf 0.27). Yield 94%, [aID + 129 (c 1.1, CHCI,). H-NMR (200 MHz, CDCI,): 6 0.00 and -0.01 [s, 6H, Me,Si], 0.84 [s, 9H, (CH,),C-Si], 1.06 (d, 3H, J 6Hz, H-7), 1.15-1.60 (m, 4H, H-4, H-9, 2.39 (s, 3H, Me of p-tol.), 2.45 (m, 2H, H-3), 3.70 (m, 1H, H-6), 3.77 (AB, 2H, JAB 13.5Hz, Au 21H2, H-l), 7.30 and 7.50 (AA'BB', 4H, J 8Hz, arom. H.). ',C-NMR (CDCI,): 6 -4.66 and -4.31 (Me,Si), 18.16 (Me$-%), 19.40 (C-41, 21.53 (CH, of p-tol.), 23.75 (C-71, 25.96 [(CH,), C-Si], 38.77 (C-5), 45.08 (C-31, 68.14 (C-0, 68.23 (C-6), 124.13 and 130.17 (arom C), 139.86 and 142.19 (arom. CHI, 201.62 (C-2). Anal. calcd. for C20H,40,SSi: C 62.78, H 8.96; found: C 62.89, H, 9.15%.

( + )-[2R,6S,S(R)]-6-(tert-Bu~ldimethylsilylo~)-1-(p-to1y1su1~ny1)- heptan-2-01 (8)

A solution of the P-keto sulfoxide 7 (480 mg, 1.25 mmol, 1 eq) and anhydrous ZnBr, (285 mg, 1.3 mmol, 1,05 eq) in THF (15 ml) was stirred at room temperature for 30 min. After cooling at -78°C a 1M DIBAL solution in toluene (1.5 ml, 1.5 mmol, 1.2 eq) was added. After stirring for 45 min, the reaction mixture was hydrolyzed with methanol (10 ml), concentrated, diluted with EtOAc (15 ml), and

9

I LDA

ZnClp. DIBAL I 0 OH OTBDMS

pTol 10,. E u R

.4

Scheme 2.

0 0 0 u: <lpTd M e 0

P 1) ZnC12. DIBAL 2) TBDMSCI. Im.. 3) Raney Ni I

MeO w h

4

1) Ac20. AcONa. 96% 2) Raney Ni. MeOH. 94%

OTBDPS OTBDMS

1 Hx .- A c o a

B 1) DIBAL M F . 88% 0 3 2) Swern oxidalion. 94%

EIOH

l&. R=CgHI9. 84% lL%,R=CI1Hn.85% lQc, A= CI3H27. 91%

Scheme 3.

2a R=CgHI9. 96%

Zk, R=CllH23,93% &. R= CI3Hz7, 92%

acidified with 1M HCI (15 ml). The aqueous phase was extracted with EtOAc (3 X 15 ml). The organic phases were washed with satd. NaCl (15 ml), dried (MgSO,) and evaporated. The product was purified by chromatography on silica gel (EtOAc/CH ,CI, 30/70, f f 0.25) yield 79.5%, m.p. 98-99°C; [a],, + 137.5 (c 0.92, CHCI,). H-NMR (200 MHz, CDCI,): only one diastereomer was detected

(de > 95%): 6 0.03 (s, 6H, Me,%), 0.86 (s, 9H, Me,C-Si), 1.10 (d, 3H, J 6Hz, H-7), 1.35-1.60 (m, 6H, H-3, H-4, H-51, 2.41 (s, 3H, Me of p-tol.), 2.83 (AB of ABX, 2H, JAB 13Hz, JAx 2.5Hz, JBx 9Hz, A u 33Hz, H-l), 3.76 (m, lH, H-6), 3.83 (d, lH, J 2Hz, OH), 4.27 (m, lH, H-2), 7.33 and 7.53 (AA'BB', 4H, J 8Hz, arom. H). I3C-NMR (CDCI,): 6 -4.6 and -4.29 (Me& 18.22 (Me,C-Si), 21.35 (C-4), 21.54 (Me of p-tol.), 23.81 (C-71, 26.00 [(CH,),C-Si], 37.42 and 39.51 (C-3, C-5), 62.56 (C-1). 68.48 (C-6), 68.94 (C-2), 123.99 and 130.24 (arom. CH), 140.76 and 142.07 (arom. C).

( + )-(2R ,6S)-6-( tert -Butyldimethylsilyloxy)-2-( tert -butyldiphenylsilyloxy)-l- (p -tolylsulfinyl)heptane (4)

A mixture of the P-hydroxy sulfoxide 8 (2.01 g, 5.22 mmol, 1 eq) imidazole (1.09 g, 15.66 mmol, 3 eq), tert-butyldiphenylsilyl chloride (2.71 ml, 10.44 mmol, 2 eq) in DMF (25 ml) was stirred at room temperature for 72 h. After adding satd. NH4CI (30 ml), the mixture was extracted with hexane/ether 70/30 (3 X 20 ml). The organic phases were washed with sat. NaCl (20 ml), dried (MgSO,) and evaporated to give after silica gel chromatography (EtOAc/hexane 10/90, Rf 0.2) pure compound 4 in 94% yield, [aID +67.5 (c 1.1, CHCI,). 'H-NMR (200 MHz, CDCI,): 6 -0.01 and 0.01 (s, 6H, Me,%), 0.86 (s, 9H, t-BuSi), 1.02 (d, 3H, J 6Hz, H-7), 1.08 (s, 9H,

OTBDPS OTBOMS OH &,), TBAF.THF, R

I Bn

la, R=CI Hm 89% a, R= C13H27. 88% l!,~ R=CI5 quanl.

Ua. R=CllHm 96% l2Il. R= C13H2p 73%

R=CI5 HglI 74%

H2, PUC. AcOH. 5 alm. l - 7 - 7 Solenopsin A, 82% Solenopsin 6 . 84% Solenopsln C, 86%

Scheme 4.

Recueil des Trauaux Chimiques des Pays-Bas, 114/4-5, April / May 1995

r-BuSi), 0.85-1.45 (m, 4H, H-4, H-51, 1.67 (m, 2H, H-3), 2.36 (s. 311, Me of p-tol), 2.90 (AB of ABX, 2H, JAB lOHz, JAx 6Hz, J , , 5Hz, Av 58Hz, H-11, 3.62 (m, IH, H-61, 3.99 (m, IH, H-2), 7.18-7.70 (m, 14H, arom. H). ',C-NMR (CDCI,): 6 -4.58 and -4.31 (Me,Si), 18.20 and 19.42 (Me,C-Si), 21.01 (C-4), 21.48 (Me of p-Tol), 23.78 (C-71, 26.01 and 27.09 [(CH,),C-Si)], 36.76 and 39.51 (C-3, C-5), 64.67 (C-I), 68.48 (C-61, 69.06 (C-21, 124.27 and 129.90 (CH of p-tol.), 127.64, 127.70, 135.99 and 136.14 (arom. CHI, 133.72 and 133.80 (arom. C), 141.32 and 141.44 (C of p-tol). Anal. calcd. for C,,HS,O,SSi,:C 69.40, H 8.74; found: C 69.35, H, 8.68%.

( + )-(2R,6S)-l-Acetoxy-6(tert-butyldimerhylsilyloxy)-2-(tert-biityl- diphenylsilyloxy-heptane 9

155

( I ) Pummerer reurrangement. A mixture of sulfoxide 4 (695 mg, 1.1 1 mmol) and sodium acetate (1 g) in acetic anhydride (20 ml) was refluxed for 17 h. After evaporating most of the acetic anhydride, the residue was dissolved in toluene and evaporated again. This opera- tion was repeated four times. Finally the residue was filtered on celite with ether as eluent and used in the next step without any other purification.

(2) Desulfurization of the Pummerer product. The crude product obtained in the preceeding step was dissolved in methanol (25 ml) and Raney Nickel was added. After 24 h at room temperature the mixture was filtered on celite, the solvent was evaporated and the product purified on silica gel (CH,CI, /hexane 50/50). Yield 90%; [a], + 6 (c 1.4, CHCI,); Rf 0.7 (hexane/ether 80/20). 'H-NMR (200 MHz, CDCI,): 6 0.04 and 0.05 (s, 6H, Me,Si), 0.9 (s, 9H, t-BuSi), 1.08 (s, 9H, t-BuSi), 1.09 (d, 3H, J 5Hz, H-7), 1.21-1.55 (m, 6H, H-3, H-4, H-5), 1.79 (s, 3H, CH,COO), 3.71 (m, 1H, H-61, 3.93-4.03 (m, 3H, H-I, H-2), 7.35-7.75 (m, 10H, arom. H). "C-NMR (CDCI,): 6 -4.58 and -4.28 (Me,!%), 16.22 and 1930 (Me,C-Si), 20.72 (C-7), 21.18 (C-4). 23.67 (MeCOO), 26.03 and 27.08 [(CH,),C- Si], 34.53 (C-9, 39.96 (C-31, 66.17 (C-11, 68.55 (C-61, 71.27 (C-21, 127.51, 127.67, 129.59, 129.76, 135.87 and 136.04 (arom. CH), 133.89, 134.42, 141.32 and 141.44 (arom. C), 170.92 (ester C). Anal. calcd. for C,,H,,O,Si,: C 68.58, H 9.28; found: C 68.67, H 9.38%.

(2 R ,6 S) -6- (tert -Buryldimethylsilyloxy)-2- (tert -butyldiphenylsilyloxyl)- heptanul (3)

( I ) Acerate reduction. To the acetate 9 (1.26 g, 2.33 mmol, 1 eq) in THF (50 ml) was added at - 78°C a IM DIBAL solution in toluene (5.2 ml, 5.2 mmol, 2.2 eq). After stirring for 30 min at - 78°C and 15 min at O"C, the reaction mixture was hydrolyzed with satd. NH,CI and extracted with EtOAc (3x50 ml). The organic phases were washed with satd. NaCI, dried (MgSO,) and evaporated before purification on silica gel (hexane/ether 90/10); 88% yield, [a],, - 17 (c 1, CHCI,); Rf 0.45 (hexane/ether 80/20).

(2) Oxidation of the primary alcohol. DMSO (0.616 ml, 8.68 mmol, 6 eq) was dropwise added at - 78°C to oxalyl chloride (0.379 ml, 4.34 mmol, 3 eq) in CH,CI, (8 ml). After 15 min, the above-mentioned alcohol (725 mg, 1.44 mmol, 1 eq) in CH,CI, (10 ml) was slowly added and the reaction mixture stirred at - 78°C for 30 min, before adding Et,N (2.5 ml, 17.36 mmol, 12 eq) and stirred at - 78°C for 30 min and at 0°C for 1 h. Satd. NH,CI (15 ml) was finally added and the mixture extracted with CH,CI, (3x20 ml). The organic layers were washed with satd. NaCI, dried (MgSO,) and evaporated. The crude aldehyde was purified by silica gel column chromatography $hexane/ether: 95/5). 94% yield, Rf 0.7 (hexane/ether: 90/10). H-NMR (200 MHz, CDCI,): 6 0.09 and 0.10 (s, 6H, Me,Si), 0.94 (s,

9H, t-BuSi), 1.14 (d, 3H, J 6H2, H-71, 1.19 (s, 9H, t-BuSi:), 1.31-1.74 (m, 6H, H-3, H-4 and H-51, 3.77 (m, 1H, H-6), 4.10 (m, IH, H-2), 7.36-7.74 (rn, 10H, arom. HI, 9.52 (d, lH, J 1.5 Hz, H-I). %NMR (CDCI,): 6 -4.54 and -4.22 (Me,Si), 18.23 and 19.50 (Me,C-Si), 20.62 (C-41, 23.98 (C-71, 26.07 and 27.12 [(CH,),C-Si], 33.27 (C-5), 39.86 (C-31, 68.47 (C-61, 78.19 (C-21, 127.93, 130.13 and 135.93 (arom. CH), 133.19 and 133.28 (arom. C), 203.79 (C-I).

( + ) - (2 S, 6 R ) -2- ( te rt -Butyldimethylsilyloxy) -6- ( te rt -buryldiphenyl- sily1oxy)heptadecane (2a)

(1) Decyltriphenylphosphonium bromide. To a solution of 1- bromodecane (2.07 ml, 10 rnmol, 1 eq) in toluene (50 ml) was added triphenylphosphine (7.88g, 30 mmol, 3 eq). After refluxing for 3 days, the solvent was evaporated and the residue crystallized from ether. The solid was then washed with ether to eliminate the excess triphenylphosphine and used in the next step without further purification; yield 79%.

(2) BuLi (1.5 ml of a 1.36M solution in hexane, 2.05 mrnol, 1.5 eq) was added to the above-mentioned phosphonium bromide (1.4 g, 2.72 mmol, 2 eq) in THF (30 ml) at 0°C. The orange solution was stirred at 0°C for 15 min and aldehyde 3 (679 mg, 1.36 mmol, 1 eq) in THF (5 ml) was added. The orange colour of the solution disap- peared slowly and after 30 min, two spatulas of silica gel were added and stirring was maintained for 15 min After filtration, the solution was concentrated and the crude product purified by silica gel chromatography; yield 84% of a 80/20 Z / E mixture of 10a; Rf 0.6 (hexane/ether 90/10). 'H-NMR (200 MHz, CDCI,): 6 0.03 and 0.04 (s, 6H, Me,Si), 0.89 (s, 9H, Me,C-Si), 0.90 (t, 3H, J 6Hz, H-171, 1.06 (s, 9H, Me,C-Si), 1.08 (d, 3H, J 6Hz, H-l), 1.10-1.88 (m, 22H, H-3 to H-5 and H-9 to H-16), 3.70 (m, lH, H-2), 4.09 (m, lH, H-6, E ) , 4.45 (m, IH, H-6, Z), 5.14-5.45 (rn, 2H, H-7, H-8), 7.31-7.72 (m, 10H, arom. H).

(3) The olefin 10a (100 mg, 0.16 mmol) in EtOH (3 ml) was hydro- genated on Pd/C (22 mg) under 1 atm at room temperature overnight. The product was purified by column chromatography on silica gel (hexane/CH,CI 90/10) to give 2a in 98% yield; Rf 0.55;

0.06 (s, 6H, Me,Si), 0.91 (s, 9H, t-BuSi), 0.92 (m, 3H, H-17). 1.09 (s, 9H, t-BuSi), 1.10 (d, 3H, J 6Hz, 1.17-1.47 (m, 26H, H-3 to H-5 and H-7 to H-161, 3.74 (m, 2H, H-2 and H-61, 7.34-7.73 (m, IOH, arom. H). ',C-NMR (CDCI,): 6 -4.56 and -4.28 (Me,Si), 14.27 (C-17), 18.26 and 19.53 (Me,C-Si), 21.35, 22.84, 24.98, 29.51, 29.70, 29.80, 32.08, 36.36, 36.62 and 40.12 (C-3 to C-5 and C-7 to C-161, 23.88 (C-l), 26.06 and 27.24 [(CH,),C-Si], 68.79 and 73.41 (C-2 and C-6), 127.49, 129.48 and 136.07 (arom. CHI, 134.93 (arom. C).

[a], + 8 (c 1.2, CHCI,). 3 H-NMR (200 MHz, CDCI,): 6 0.05 and

( + ) - (2 S ,6 S ) -2- ( t ert -Bury ldimethy lsily loxy ) -6- ( t e rt -butyldiphenylsily - 1oxy)nonadecane (2b)

(I). Dodecanyltriphenylphosphonium bromide was prepared as the decanyl isomer from triphenylphosphine and 1 -bromododecane; yield 80%.

(2). Following the procedure used for 10a, the olefinic compound 10b was obtained in 85% yield; Rf 0.6 (hexane/ether 90/10). 'H- NMR (200 MHz, CDCI,): 6 0.04 and 0.06 (s, 6H, Me,Si), 0.90 (s, 9H, t-BuSi), 0.92 (m, 3H, H-191, 1.07 (s, 9H, f-BuSi), 1.11 (d, 3H, J 6Hz, H-l), 1.10-1.90 (m, 26H, H-3 to H-5 and H-9 to H-18), 3.71 (m, IH, H-2), 4.10 (m, IH, H-6 E) , 4.42 (m, IH, H-6 Z), 5.19-5.48 (m, 2H, H-7, H-81, 7.26-7.74 (m, IOH, arom. H).

(3). Compound 10b was reduced following the procedure used for 10a to give 2b in 93% yield; Rf 0.55 (hexane/CH,CI, 90/10), [a], + 7 (c 1, CHCI,). 'H-NMR (CDCI,, 200 MHz): 6 0.05 and 0.06 (s, 6H, Me,Si), 0.91 (s, 3H, t-BuSi), 0.92 (m, 3H, H-19), 1.09 (s, 9H, f-BuSi), 1.10 (d, 3H, J 6Hz, H-I), 1.11-1.47 (m, 30H, H-3 to H-5 and H-7 to H-18), 3.74 (m, 2H, H-2 and H-6), 7.33-7.74 (m, 10H, arom. H). ',C-NMR (CDCI,): 6 -4.58 and -4.29 (Me,Si), 14.25 (C-191, 18.24 and 19.52 (Me,C-Si), 21.32, 22.83, 24.97, 29.51, 29.80, 32.07, 36.35, 36.61 and 40.11 (C-3 to C-5 and C-7 to C-18), 23.87 (C-l), 26.05 and 27.22 [(CH,),C-Si], 68.77 and 73.39 (C-2 and C-6), 127.47, 129.45 and 136.04 (arom. CH), 134.92 (arom. C). Anal. calcd. for C,,H,20,Si,: C 75.39, H 11.11; found: C 75.54, H 11.31%.

( + - (2 S ,6 S) - 2- ( t er t -Bury ldimethy lsily loxy) -6- ( t er t - bu tyldiphenylsily- 1oxy)heneicosane (2c)

(1). Tetradecyltriphenylphosphonium bromide was prepared following the procedure described for the decyl isomer, in 74% yield.

(2). Following the procedure used for 10a, olefinic compound 1Oc was obtained in 91% yield; Rf 0.6 (hexane/ether 90/10). 'H-NMR (200 MHz, CDCI,): 6 0.05 and 0.07 (s, 6H, Me,Si), 0.91 (s, 9H, t-BuSi), 0.93 (t, 3H, J 6Hz, H-21), 1.09 (s, 9H, t-BuSi), 1.10 (d, 3H, J 6Hz, H-0, 1.09-1.91 (m, 30H, H-3 to H-5 and H-9 to H-20), 3.72 (m, lH, H-2), 4.10 (m, IH, H-6 El, 4.45 (m, lH, H-6 Z ) , 5.16-5.48 (m, 2H, H-7 and H-8), 7.25-7.75 (m, 10H, arom. H).

(3). Compound 1Oc was reduced following the procedure used for 10a to give 2c in 9?% yield; Rf 0.55 (hexane/CH,CI, 90/10); [a], + 7 (c 1, CHCI,). H-NMR (200 MHz, CDCI,): 6 0.07 and 0.09 (s, 6H, Me,Si), 0.93 (s 9H, t-BuSi), 0.94 (m, 3H, H-21), 1.11 (s, 9H, t-BuSi), 1.12 (d, 3H, J 6Hz, H-I), 1.13-1.49 (m, 34H, H-3 to H-5 and H-7 to H-20), 3.76 (m, 2H, H-2 and H-6), 7.35-7.76 (m, 10H: arom. H). "C-NMR (CDCI,): 6 -4.55 and -4.27 (Me,Si), 14.27 (C-191,

156 G. Solladie', N. Huser /Asymmetric synthesis of solenopsins A, B and C

18.25 and 19.54 (Me,C-Si), 21.35, 22.84, 24.99, 29.53, 29.66, 29.73, 32.09, 36.36, 36.64 and 40.13 (C-3 to C-5 and C-7 to C-181, 23.90 (C-I), 26.07 and 27.25 [(CH,),C-Si], 68.78 and 73.41 (C-2 and C-61, 127.49, 129.47 and 136.06 (arom CH), 134.93 (arom. C). Anal. calcd. for C,,H,,O,Si,: C 75.81, H 11.24; found: C 75.85, H 11.35%.

( + ) - (2 S , 6 S ) -Heptadecane-2,6-diol (1 1 a)

To a solution of 2a (98 mg, 0.16 mmol, 1 eq) in THF (5 ml) at 0°C was added TBAF (0.712 ml of a 1.1 M solution in THF, 0.78 mmol, 5 eq). After stirring for 4 days, the solvent was evaporated. The residue was dissolved in EtOAc (10 ml), acidified with 10% HCI (5 ml) and extracted with EtOAc (3x15 ml). The organic layers were washed with satd. NaCI, dried (MgSO,) and evaporated. The diol was finally purified by silica gel chromatography (hexane/EtOAc 50/50); yield 96%; Rf 0.3; m.p. 55-56°C; [aID + 11 ( c 1, CHCI,). 'H-NMR (200 MHz, CDCI,): S 0.85 (t, 3H, J 7Hz, H-171, 1.19 (d, 3H, J 6Hz, H-11, 1.20-1.46 (m, 26H, CH,), 1.63 (broad s, 2H, OH), 3.59 and 3.83 (m, 2H, H-2 and H-6). I3C-NMR (CDCI,): S 14.19 (C-17), 21.90, 22.76, 25.78, 29.43, 29.73, 31.99, 37.15, 37.71 and 39.11 (CH,), 23.66 (C-l), 67.87 and 71.78 (C-2 and C-6). Anal. calcd. for C,,H360,: C 74.94, H 13.31; found: C 74.92, H 14.07%.

( + )-(2S, 6S)-Nonadecane-2,6-diol ( l lb)

Compound l l b was prepared following the procedure used for Ha; yield: 74%; Rf 0.3 (hexane/EtOAc 50/50); m.p. 63-65°C; [a],, + 9 ( c 1, CHCI,). 'H-NMR (200 MHz, CDCI,): S 0.87 (t, 3H, J 7Hz, H-191, 1.17 (d, 3H, J 6Hz, H-l), 1.19-1.44 (m, 30H, CH,), 1.90 (broad s, 2H, OH), 3.57 and 3.78 (m, 2H, H-2 and H-6). I3C NMR

37.17, 37.71 and 39.13 (CH,), 23.67 (C-l), 67.88 and 71.80 (C-2 and C-6). Anal. calcd. for C,,H4,,O2: C 75.94, H 13.42; found: C 75.92, H 13.64%.

(CDCI,): S 14.20 (C-19), 21.91, 22.77, 25.78, 29.44, 29.75, 32.00,

( + )- (2 S , 6S)Heneicosane-2,6-diol (1 lc)

Compound l l c was prepared following the procedure used for l l a ; yield 74%; R f 0.3 (hexane/EtOAc 50/50); m.p. 67-69°C; [a]D + 11 ( c 1, CHCI,) 'H-NMR (CDCI,): 6: 0.87 (t, 3H, J 7Hz, H-211, 1.17 (d, 3H, J 6Hz, H-l), 1.19-1.45 (m, 34H, CHh), 1.82 (broad s, 2H, OH), 3.58 and 3.79 (m, 2H, H-2 and H-6). C-NMR (CDCI,): S 14.20 (C-211, 21.92, 22.77, 25.77, 29.44, 29.77, 32.00, 37.20, 37.71 and 39.16 (CH,), 23.67 (C-11, 67.94 and 71.84 (C-2 and C-6). Anal. calcd. for C,,H,O,: C 76.76, H 13.49; found: C 76.95, H 13.74%.

(-)-(2 R,6 R)-trans-2-undecyl-6-methylpiperidine (solenopsin A )

( I ) Dimesylate of the diol lla. To a solution of diol lla (125 mg, 0.43 mmol, 1 eq) in CH,CI, (10 ml) were added at -20°C triethylamine (0.144 ml, 1 mmol, 2.3 eq) and mesyl chloride (0.072 ml, 0.9 mmol, 2.1 eq). After stirring at room temperature for 20 min, water was added and the reaction mixture extracted with CH,CI, (3 X 15 ml). The organic phases were washed with sat. NaCI, dried (MgSO,) and evaporated. The crude product (quant. yield) was used in the next step without further purification.

(2) (2R,6R)- trans- N-benlyl-2-undecyl-6-methylpiperidine (la). The above mentioned mesylate (183 mg, 0.43 mmol) dissolved in benzylamine (0.8 ml) was stirred at room temperature for 16 days. Then 10% NaOH (2 ml) was added followed by extraction with pentane (3 X 10 ml). The organic phases were washed with satd. NaCl (10 ml) and dried (MgSO,). The excess benzylamine was separated by distil- lation. The NMR of the crude product (89% yield) showed the presence of 5% of the cis isomer (from the benzylic methylene signals). This crude mixture was used in the next step without purification.

(3) Solenopsin A The crude product la (130 mg, 0.378 mmol) in acetic acid solution (3 ml) was debenzylated overnight on Pd/C (30 mg), (5 atm of hydrogen and room temperature). After filtration of the catalyst, 10% NaOH (10 ml) was added, the aqueous phase extracted with CH,CI, (3X 10 ml), the organic phase washed with satd. NaCl (10 ml), dried (Na,CO,) and evaporated. The crude product was purified by silica gel chromatography (ether, then ether containing 1% of 'PrNH,) to separate the cis isomer; yield 82%;

de > 95%; Rf 0.25 (ether); [a],, -2 ( c 1.1, methanol)'-'. 'H-NMR

6.5Hz, H-181, 1.14-1.64 (m, 27H, CH, and NH), 2.83 and 3.03 (m, 2H, H-2 and H-6). "C-NMR (CDCI,): S 14.03 (C-17), 19.53, 22.62, 26.41, 29.29, 29.57, 29.61, 29.73, 30.78, 31.86, 32.97, 34.05 (CH,), 21.21 (C-18), 45.76, and 50.78 (C-2, C-6).

(200 MHz, CDCI,): S 0.85 (t, 3H, J 6.5Hz, H-171, 1.04 (d, 3H, J

( - )-(2R,6 R)- trans-2-Tridecyl-6-methylpiperidine (solenopsin B)

Obtained by the procedure described for solenopsin A: dimesylate of diol l l b , cyclization with benzylamine to the I-benzylpiperidine l b and finally debenzylation to solenopsin B. Overall yield 70%, de > 95%, [a],, -2 ( c 1.1, methanol)'-'. 'H-NMR (200 MHz, CDCI,): 6:

(m, 31H, CH, and NH), 2.82 and 3.02 (m, 2H, H-2 and H-6). I3C-NMR (CDCI,): 6: 14.03 (C-191, 19.52, 22.62, 26.41, 29.29, 29.61, 29.73, 30.75, 31.86, 32.95 and 34.03 (CH,), 21.18 (C-20), 45.76 and 50.77 (C-2 and C-6).

0.84 (t, 3H, J 6.5Hz, H-19), 1.03 (d, 3H, J 6.5HZ, H-20), 1.13-1.63

( - )-(2R,6R)- trans-Pentadecyl-6-methylpiperidine (solenopsin C )

Obtained by the procedure described for solenopsin A: dimesylate of diol l l c , cyclization with benzylamine to the 1-benzyl piperidine l b and finally debenzylation to solenopsin C. Overall yield 86%, de > 95% Rf 0.25 (ether); [a],, -2 ( c 0,9, methanol). 'H-NMR (200

H-22), 1.13-1.68 (m, 35H, CH, and NH), 2.83 and 3.02 (m, 2H, H-2 and H-6). I3C NMR (CDCI,): S 14.06 (C-211, 19.56, 22.65, 26.43,

45.76 and 50.79 (C-2 and C-6).

MHz, CDCI,): S 0.85 (t, 3H, J 6.5HZ, H-21), 1.04 (d 3H, J 6.5Hz,

29.32, 29.64, 29.76, 30.80, 31.89, 32.99, 34.07 (CH,), 21.23 (C-22),

Acknowledgements

We thank the 'Action IntCgrCe Franco-Espagnole' (Picasso n"94123) for financial support.

References

la J.G. MacConneN, M.S. Blum, H.M. Fales, Tetrahedron 27, 1129 (1971);

b T.H. Jones. M.S. Blum. H.M. Fales. Tetrahedron 38. 1949 (1982); C

2

3

4

5

6 7

X

9

10

11

12d

b

C

d

e

13

A.B. Attygalle, E.D. Morgan, Chem. SOC. Rev. 13, 245 (1984). '

D.S. Grierson, J. Royer, L. Guerrier, H-P. Husson, J. Org. Chem. 51, 4475 (1986). W. Oppolzer, C. G. Bochet, E. Merifeld, Tetrahedron Lett. 35, 7015 (1994). D. L. Comins, N.R. Benjelloun, Tetrahedron Lett. 35, 829 (1994). Y. Ukaji, T. Wakai, T. Sumi, T. Fujisawa, Chem. Lett. 1555 (1 991 1. C. W. Jeflord, J. Bo Wang, Tetrahedron Lett. 34, 2911 (1993). D. F. Taber, P.B. Deker, H.M. Fales, T.H. Jones, H.A. Lloyd, J. Org. Chem. 53, 2968 (1988). H. Kotsuki, T. Kusumi, M. Inoue, Y. Ushio, M. Ochi, Tetrahedron Lett. 32, 4159 (1991). S. Leclercq, I. Thirionet, F. Broeders, D. Daloze, R. Vander Meer, J.C. Braekman, Tetrahedron 50, 8465 (1994). G. Solladit!, M.C. Maestro, A . Rubio, C. Pedregal, M.C. Carreio, J.L. Garcia-Ruano, J. Org. Chem. 56, 2317 (1991). G. Solladit!, N. Huser, J.L. Garcia-Ruano, A. Jauier, C. Carreiio, A. Tito, Tetrahedron Lett. 35, 5797 (1994). G. Solladit!, G. Demailly, C. Greck, Tetrahedron Lett. 26, 435 (1985); G. Solladii, C. Fre'chou, G. Demailly, C. Greck, J. Org. Chem. 50, 1552 (1985); G. Solladit!, C. Fre'chou, G. Demailly, C. Greck, J. Org. Chem. 51, 1912 (1986); A. Solladie'-Cauallo, J. Suffert, A. Adib, G. Solladie', Tetrahedron Lett. 31, 6649 (1990); G.Solladie', A. Rubio, M.C. Carreno, J. L. Garcia-Ruano, Tetrahe- dron Asym. 1, 187 (1990). G. Solladie', J . Hutt, A. Girardin, Synthesis 173 (1987).

Documents

Asymmetric synthesis of solenopsins A, B and C