Studies directed towards the total synthesis of (±)-himbacine

Tctrddrrm Letters. Vol. 36. No. 41. pp. 7515-7518. 1995 Ekviakiarc~

Pergamon

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Studies Directed Towards the Total Synthesis of (k)-Himbacine Covert De Baecke and Pierre J. De Clercq* State.Uninnity

of Gcn~DepanmcntorOrganii Chanistry. Krij~srSm. 281 (St). B-9tNO GENT (Bclgiun)

Absnocl: 7%~syntJ~&rof sldehydc1la is qortcd bpseduponthe irmamolecularDick-Akkr reaction of tricnc 10. the butenolidcdicae part of which wu obtainedin one ste+~via the con&nsation af the enotatcdcrivcd from the (Z)uuWc ester5 with 2-acemxypfopaI. Aldchydc 11s possesses the con-03 stavochemisuyd IIUtricyclicpt d himbecinc.an immt mus&nc nsptor antagonist.

In 1956 the alkaloid himbacinc was first isolated from the bark of the tree only encountered

in New-Guinea

and in parts of Australia.

Galbulimima befgraveana species. a 1 Via an X-ray diffraction study of the

corresponding hydrobromic acid salt its relative and absolute configuration

were dctermined.g

Interestingly,

himbacine has been reported to be one of the more potent muscarine receptor antagonists that displays selectivity for M2 and M4 receptors, as compared to Ml and M3 receptors. 3 As such it could be an important lead structutc in the development of drugs for the treatment of Alr.heimer’s disease.4, k

Quite surprisingly,

despite its attractive

structure and biological importance. no total synthesis of this interesting alkaloid has been reported so far.5 In this communication we wish to report a preliminary synthetic study in this area.

H

2

himgmvine $

N'

G

I

Scheme

1

In the context of a rttrosynthetic analysis we will further concentrate on himgravine. one of a few similar alkaloids that have been isalatal fmm the same sounx (Scheme I).6 Himgravine can be selectively hydrogenated to himbacine.7 A convergent approach calls for the coupling of the pip&dine D-ring to the uicyclic ABC-ring

7515

7516

system via formation

of the connecting

(E)-double

bond through e.g. a Wittig

type olcfination

coupling.%+ b For that purpose a tricyclic aldchydc such as I (2 = CHO) is an ideal intermediate. us that the rrons-fused decalin system present in I could result from the Diels-Alder

or a Julia

It occurred to

reaction of ttienc II.

Also,

the correct nlative configuration at the five contiguous stereogcnic centres is expected from the cycloaddition in which the (&)-dicnophilc adds to the

leasthindered face of the diene in the c&mode.g

OAC'

CwH

VI

V

Scheme 2 Following the above approach the synthesis of a butcnolide such as VII carrying a side-chain with an Qconjugated double bond is necessary. For that purpose the following one-flask process shown in Scheme 2 was envisioned. The

tirst stage of the process is based on the known deconjugative protonation/alkylation of (Z)-2-

enoates to the corresponding (&)-3-cnoates. 9 Following upon further

reaction

with

2-acetoxypropanal,

this protocol (Z)-enoate

to alkoxide

IV.

III

would lead to IIIe

and,

In a second stage two consecutive

transestctifications would generate the ylactone VI in the presence of methoxide, which, in the last stage, should eliminate acetic acid to form butcnolide VII. The eventual synthesis along these two key-steps is outlined in Scheme 3. Following a straightforward sequence 6-bromo-I-hexanol

is converted to (Z)-enoate 5. to After some experimentation the crucial conversion

of the latter ester to butenolide 7 was realized in 65% yield: after deprotonation of Me ester 5 at -78’C with LDA in THF-HMPA

aldchyde 6 is added, after which the reaction mixture is kept between -78’C

days.’ 1. t* The conversion of butcnolide 7 into the required Diels-Alder (48% aqueous HF in CH3CN),t3 modification

iminc is hydrolyud

approach: t4. 1s Aldehyde

and 1 equiv of zinc(Il)bro

9 is treated with 6 equiv of N-rerr-butyl-2.2in THF (10°C. 16 h), after which the intermediate

with oxalic acid (65% yield). 10 The cycloaddition of IO required heating at 170°C for 24 h

(toluene, steel vessel) and gave a mixture of the four possible diastereomeric adducts 11 -epi-I Ib (ratio 8:5:6:1. respectively) separation by HPLC. COSY).le

for 3

Swem oxidation and elongation of the resulting aldehyde 9 using Claudemar’s

of Corey’s aldimine

bis(trimethylsilyl)acetaldimine

and -53’C

precursor 10 proceeded via desilylation

in 85% combined yield.

The configurational

Both I

lla. llb, 1 I-epi-lla

and

Ia and llb were obtained pure after

assignments rest on the analysis of the *H-NMR

spectra (2D

As expected the observed stereoselectivity is in favour of the [runs-fused decalins. with the desired

IIa as major isomer.17 The utility of I Ia was checked by subjecting it to a coupling reaction with 13t8 which led successfully to 14 as a mixture of diastereomers (55% yield).

7517

-

7R-TED 6R.“,=-jr

I

h

0

llb

I

11m

(a) tBuMc2SiCl. EIJN, CH2Cl2 (95%); (b) HC=CLiNH2(CH2)2NH2, DMSO. 8’C (92%); (c) n-BuLi. CO2. Et2Q CH2N2. Et20 (75%); (d) H2, Pd(BaSO4)chinoline. Et20 (90%); (c) LDA, THF. -78’C; HMPA (1 cq); 6 in THF, -78°C -> -53’C. 3 days (65%); (f) HF (48% in H20). CH$N (96%); (g)(COCl)2. DMSO. EtsN, CH2CI2(84%); (h) ((CH3)3Si)2CHCH=N+Bu (6 q). ZnBr2 (1 q). THF. 10°C. 16 h; (COOH)2. 16 h (66%); (i) PhCH3. 170°C (di-t-Bu-p-crcsol), 24 h (85%); (j) LDA (1 eq), THF, -78°C; (EtO)2POCI. THF. -78’C; LDA (I cq). -78’C. 3 h; lla. -78’C -> r.t.. 16 h (55%). Scheme 3 G. Lk Baeckc is indebted to the IWONL for a fellowship. The National Fund for Scientific Research and the “Ministcric voor Wetcnschapsbcleid” arc thanked for financial support Dr. M. Hibcrt of Merrcll-Dow/Marion (Strasbourg) is thanked for drawing our attention to this molcculc as synthetic target.

Acknowledgements:

References 1. Brown,

2. 3. 4. 5.

R. F. C.; Drummond. R.; Fogcrty, A. C.; Hughes, G. K.; Pinhcy. J. T.; Ritchic, E.; Taylor, W. C., Aust. /. Gem. 1956.9. 283-287 Fridrichsons. J.; Mathicson. A., Acru Crysr. 1962.15. 119-128. Miller. J. H.; Aagaard, P. J.; Gibson, V. A.; McKinncy. M., /. Pharmocol. Exp. Ther. 1992,263.663667 and rcfcrcnccs cited therein. Svcnsson. A.-L.; Alafuzoff, I.; Nordbcrg, A., Brain Res. 1992.5%. 142-145. For the synthesis of simplified analogs, see: (a) Kozikowski. A. P.; Fauq, A. H.; Miller. J. H.; McKinncy. M.. BioMed. Chem. Len. 1992.2. 797-802; (b) Malaska, M.; Fauq. A. H.; Kozikowski. A. P.; Aagaatd, P. J.; McKinncy. M.. BioUed. Chem. Lerr. 1993.3, 1247-1252; (c) ibid., 1995.5. 61-66.

7518

6.

Ritchie. E; Taylor. W. C.. “The Galbulimima

Alkaloids” in Tk

Afkufoidr, Ed. Man&e R. H. F.,

Academic Press, New Yoric (1%7). Vol. 9. pp. S29-543.

7. 8.

9. 10.

1 1. 12. 13. 14. 15. 16.

17.

18.

Rinhey. J. T.; Ritchic. E.; Taylor, W. C.. Ausr. /. Ckm. 1961.14. 106134. For reviews on the intramolecular Dick-Alder reaction, see: (a) Fallis. A. G.. Con. 1. Ckm. 1984.62, 183-234; (b) Brieger, G.; Bennett, J. N.. Ckm. Rev. 1980.80. 63-97; (c) Ciganek. E.. Org. Rcoct. 1984.32. 1; (d) Craig, D.. Ckm. SOC.Rev. 1987.16. 187-201; (e) Roush. W. R. in Comprehensive Orgunic Syntksis, Eds. B. Trost, I. Fleming, Pergamon Press (1991). Vol. 5. pp. 513550. Kende. A. S.; Toder, B. H.. 1. Org. Ckm. 1982.47. 163-167. Satisfactory attaJytkaJ and spectroscopic (JR. JH NMR. MS) data welt obtained. Relevant lH-NMR data (500 MHr. CDCl3) of5 (360 MHz): 8 6.23 (1H. dt: 11.5.7.5 Hz). 5.76 (1H. d: 11.5 Hz). 3.70 (3H. s). 3.59 (2H. t: 6.6 HZ), 2.64 (2H. dt: 7.5, 7.4 HZ), 0.88 (9H. s). 0.04 (6H. s) ppm; 7: 8 7.03 (1H. d: 1.5 Hz), 6.78 (IH, dt: 16.0.7.0 Hz). 6.09 (IH. d: 16.0 Hz). 5.02 (IH, br q: 6.6 Hz), 3.59 (2H, t: 6.6 Hz), 2.18 (xH. dt: 7.1. 7.0 Hz). 1.42 (3H. d: 6.6 Hz). 0.88 (9H. s). 0.04 (6H, s) ppm; 9: 8 9.75 (IH, t: 1.6 Hz). 7.04 (IH. d: I.5 HZ). 6.78 (1H. dt: 16.0. 7.0 Hz). 6.09 (lH, d: 16.0 Hz). 5.02 (IH, br q: 6.6 Hz), 2.44 (2H. td: 7.3, 1.6 HZ), 2.18 (2H. dt: 7.1. 7.0 Hz). 1.42 (3H. d: 6.6 Hz) ppm; 10: 8 9.50 (lH, d: 7.9 Hz). 7.03 (lH, d: 1.7 Hz). 6.85 (!H, dt: 15.6. 6.8 Hz), 6.80 (1H. dt: 15.8, 7.0 Hz), 6.13 (1H. ddd: 15.6, 7.9. 1.4 Hz), 6.10 (IH, br d: 15.8 Hz), 5.03 (1H. br q: 6.8 Hz). 2.35 (2H. dtd: 7.0, 6.3, 1.3 HZ), 2.20 (2H. dt: 7.0.6.7 HZ), 1.42 (3H. d: 6.8 Hz) ppm; lla: 6 9.74 (!H, d: 4.4 Hz), 6.72 (lH, dd: 3.8, 3.2 Hz), 4.15 (IH, dq: 9.2, 6.1 Hz), 2.93 (!H, ddd: 9.3, 9.2, 3.2 Hz), 2.55 (IH, ddd: 10.9, 9.3, 4.4 Hz), 2.46 (1H. m: C = 29.0 Hz), 1.41 (3H, d: 6.1 Hz) ppm; llb: S 9.69 (!H, d: 4.3 Hz), 6.74 (1H. dd: 3.4, 3.0 Hz), 4.42 (1H. dq: 9.2, 6.1 Hz). 2.88 (1H. ddd: 10.4, 9.2, 3.4 Hz), 2.73 (IH. ddd: 10.6. 10.4, 4.3 Hz). 2.12 (1H. m: L: = 25.0 Hz), 1.45 (3H. d: 6.1 Hz) ppm; 1I-epi-lla: (admixed with 1I-epi-lib; only the H’s of the major isomer are given): 8 9.80 (IH. d: 3.3 Hz), 6.80 (IH. dd: 3.7, 3.6 Hz). 4.85 (!H, dq: 6.8, 6.6 Hz), 3.44 (1H. ddd: 10.7, 8.0. 2.9 Hz), 2.68 (IH. ddd: 11.0. 10.9, 3.3 Hz), 2.47 (1H. m). 2.31 (m: Z = 30.1 Hz) ppm; 14: 8 6.72 (lH, dd: 3.8,3.2Hz). 6.20(IH, d: 16.1Hz), 5.83(1H. dd: 16.1. 7.2 Hz), 4.15 (1H. dq: 9.2, 6.1 Hz), 3.53 (1H. m). 3.20 (1H. m). 2.93 (IH, ddd: 9.3, 9.2, 3.3 Hz), 1.41 (3H. d: 6.1 Hz). 1.28 (3H. d: 6.9 Hz) ppm. Aldchyde 6 is obtained from 3-buten-2-01 via esterification (Ac20, Et3N. CH2Cl2. 80%) and oxidation (03. CH2Cl2. Me2S. 65%). At highertempcmture a compkx mixture results. Upon shorter reaction times a condensation product in which lactone formation has not yet occuned is isolated. Collington, E. W.; Finch, H.; Smith, I. J.. Terruk&on far. 1985.26. 681684. Corey, E. J.; Enders, D.; Bock, M., Terrakdron far. 1976, 17.7-10. Gaudcmar, M.; Bellasoued, M.. Tefrukdron L&r. 1990.3 1.349-352. The rruns-fused isomers 1la and 11cpi-l la show a larger sum of vicinal coupling constants for H-3 (2930 Hz) than the cis-fused 1lb (25 Hz). Further distinction rests on the magnitude of J(H IO-H1 1): 9.2 Hz for lla and lib. and 6.8 Hz for 1I-epi-lla, in almost perfect agteemcnt with the calculated values: 9.39.6 Hz and 5.9 Hz, respectively. Calculations were performed using the MacroModel program (Still, W. C.; Mohamadi. F.; Richards, N. G. J.; Guida. W. C.; Lipton, M.; Liskamp. R.; Chang, G.; Hendrickson, T.: DeGunst, F.; Hasel, W.. MacroModel V3.0, Department of Chemistry, Columbia University, New York, NY 10027. USA). In most cases the cycloaddition of (E,E,E)- 1.3,9-decatriems occurs with low (or no) steteoselectivity. The use of an aldehyde as dienophile activating group favors the formation of rrans-adducts. For a thorough discussion, see ref. Se. Obtained from 12 (see: Jones, T. H.; Blum, M. S.; Fales. H. M.. Tetrahedron Lerr. 1979,20, 10311034) via deprotonation (LDA). treatment with diethyl chlorophosphatc. followed by a second LDA deprotonation. Purifwation of protonatcd 13 was unsuccessful. See: Highet. R. J.; Jones, T. H.. 1. Org. Chem. 1992.57. 4038-4040.

(Received in UK 14 July 1995; uccepted 11 August 1995)