Total synthesis of muconin by efficient assembly of chiral building blocks

Full text of DOI:10.1021/jo9810765

4876
J . Org. Chem. 1998, 63, 4876-4877
Sch em e 1
Tota l Syn th esis of Mu con in by Efficien t
Assem bly of Ch ir a l Bu ild in g Block s
Scott E. Schaus, J onas Brånalt, and Eric N. J acobsen*
Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138
Received J une 8, 1998
Muconin (1) is a novel tetrahydropyran-bearing acetoge-
nin isolated from Rollinia mucosa that has exhibited potent
and selective in vitro cytotoxicities against pancreatic and
breast tumor cell lines.1 We considered the possibility of
preparing 1 by the convergent assembly of readily accessible
chiral units (Scheme 1). We describe herein the total
synthesis of muconinsthe first of any THP-bearing Annona-
ceous acetogenin2sby taking advantage of such a chiral
building block approach.
8
CH2Cl2 with MgBr2‚OEt2 at -78 °C provided the desired
allylic alcohol in 74% yield and >100:1 diastereoselectivity.
This material was converted to acid 11 in 92% yield by
alkylation with sodium iodoacetate in THF.
Our laboratories uncovered recently a highly effective
Pyranol 12 was constructed by the hetero-Diels-Alder
condensation of 1-methoxy-3-[(trimethylsilyl)oxy]-1,3-buta-
diene with p-bromobenzyloxyacetaldehyde catalyzed by 2
mol % (S,S)-9 followed by diastereoselective Luche reduc-
tion.9 The moderate enantioselectivity of the catalytic
reaction (80% ee) was reconciled by recrystallization of the
dihydropyranone condensation product to 99% ee and in
good yield. Esterification of 12 with acid 11 was effected
cleanly under EDC coupling conditions. The corresponding
silyl ketene acetal was generated with LDA in 4:1 THF/
HMPA and in situ trapping with TMSCl.10 Ireland-Claisen
rearrangement11 occurred upon elevation of the reaction
temperature to 50 °C, with formation of the 2,6-cis-disub-
stituted dihydropyran isolated as the methyl ester in 81%
yield and 5:1 diastereoselectivity at C(18). The observed
preferential formation of the threo stereoisomer is attribut-
able to sigmatropic rearrangement of the Z-silyl ketene
acetal through a boatlike transition state.12 The methyl
ester was converted to the terminal olefin 13 in 70% yield
by means of a one-pot DIBALH reduction/Wittig olefination
sequence.13 The MOM protecting group proved labile in
subsequent steps of the synthesis and was therefore ex-
changed for a TBS group at this stage. Ring-closing me-
tathesis14 yielded the desired dihydrofuran in excellent yield.
This material was reduced to the THF-THP derivative with
concomitant removal of the PBB protecting group by hydro-
genation using 10% Pd/C. The resulting primary alcohol
was oxidized with Dess-Martin periodinane15 to yield
aldehyde 2, which was used without purification.
method for the hydrolytic kinetic resolution (HKR) of
terminal epoxides catalyzed by cobalt complex 8 (eq 1).3 The
HKR provides practical access to both terminal epoxides and
1,2-diols in highly enantioenriched form. The commercial
availability on a bulk scale of racemic terminal epoxides such
as tetradecene oxide, epichlorohydrin, and propylene oxide
render these attractive starting materials for the synthesis
of muconin. The fourth requisite building block, dihydro-
pyran 5, is also readily accessed in enantioenriched form
using the recently discovered hetero-Diels-Alder condensa-
tion of 1-methoxy-3-[(trimethylsilyl)oxy]-1,3-butadiene with
aldehydes catalyzed by chromium complex 9 (eq 2).4
To synthesize fragment 2, the HKR of (()-tetradecene
oxide using 0.5 mol % of complex (S,S)-8 in TBME and 0.5
equiv of H2O afforded (R)-tetradecane-1,2-diol 4 in >99% ee
and in 90% of the theoretical yield.5 Selective protection of
the secondary hydroxyl group was effected by the method
of Yamamoto using trimethyl orthoformate and DIBALH.6
The resulting primary alcohol 10 was transformed to the
corresponding aldehyde without detectable epimerization by
means of TEMPO-catalyzed oxidation with hypochlorite.7
Chelation-controlled addition of vinylmagnesium bromide in
To synthesize fragment 3, (R)-epichlorohydrin 6 was
readily obtained in >99% ee and 82% of theoretical yield by
HKR of racemic epoxide using 0.5 mol % of (S,S)-8 and 0.55
equiv of water. Copper(I)-catalyzed16 epoxide ring-opening
(7) Leanna, M. R.; Sowin, T. J .; Morton, H. E. Tetrahedron Lett. 1992,
33, 5029.
(1) Shi, G.; Kozlowski, J . F.; Schwedler, J . T.; Wood, K. V.; MacDougal,
J . M.; McLaughlin, J . L. J . Org. Chem. 1996, 61, 7988.
(2) (a) Oberlies, N. H.; Chang, C.; McLaughlin, J . L. J . Med. Chem. 1997,
40, 2102. (b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J . L. Nat. Prod. Rep. 1996, 275. (c) Rupprecht, J . K.; Hui, Y.-
H.; McLaughlin, J . L. J . Nat. Prod. 1990, 53, 237.
(3) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N. Science
1997, 277, 936.
(4) Schaus, S. E.; Brånalt, J .; J acobsen, E. N. J . Org. Chem. 1998, 63,
403. For general reviews, see: (a) Danishefsky, S. J . Chemtracts 1989, 273.
(b) Danishefsky, S. J . Aldrichim. Acta 1986, 19, 59.
(8) Keck, G. E.; Andrus, M. B.; Romer, D. R. J . Org. Chem. 1991, 56,
417.
(9) (a) Luche, J .-L.; Gemal, A. J . Am. Chem. Soc. 1981, 103, 5454. (b)
Paterson, I.; Smith, J . D.; Ward, R. A. Tetrahedron 1995, 34, 9413.
(10) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(11) (a) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J . Org.
Chem. 1980, 45, 48. (b) Ireland, R. E.; Anderson, R. C.; Badoud, R.;
Fitzsimmons, B. J .; McGarvey, G. J .; Thaisrivongs, S.; Wilcox, C. S. J . Am.
Chem. Soc. 1983, 105, 1988.
(12) Ireland, R. E.; Wipf, P.; Xiang, J .-N. J . Org. Chem. 1991, 56, 3572.
(13) Wei, Z.-Y.; Knaus, E. E. Synthesis 1994, 1463.
(14) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 7325.
(15) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.
(16) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron
Lett. 1979, 20, 1503.
(5) The kinetic resolution yields provided in this paper are expressed as
a percentage of the theoretical maximum yield of 50%.
(6) Takasu, M.; Naruse, Y.; Yamamoto, H. Tetrahedron Lett. 1988, 29,
1947.
S0022-3263(98)01076-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/08/1998

Communications
J . Org. Chem., Vol. 63, No. 15, 1998 4877
Sch em e 2a
a
Reagents: (a) 0.5 mol % (S,S)-8, 0.5 equiv of H2O, TBME, 0 °C f rt, 90%, 99% ee; (b) (i) CH(OMe)3, cat. CSA, CH2Cl2, rt; (ii) DIBALH, CH2Cl2,
-78 °C, 84%; (c) (i) cat. TEMPO, NaBr, NaHCO3, NaOCl, PhMe/EtOAc 1:1, H2O, 0 °C; (ii) MgBr2‚OEt2, CH2dCHMgBr, CH2Cl2, -78 °C, 74%; (d)
(i) NaH, THF, 0 °C; (ii) ICH2CO2Na, 0 °C f rt, 92%; (e) (i) 2 mol % (S,S)-9, TBME, 4 Å molecular sieves, -30 °C; (ii) TFA, rt; (iii) recrystallization,
72% yield, 99% ee; (f) CeCl3‚H2O, MeOH, NaBH4, EtOH, -78 f 0 °C, 76%; (g) (i) EDC, cat. DMAP, CH2Cl2, 0 °C; (ii) LDA, TMSCl, THF/HMPA
4:1, -78 f +50 °C; (iii) CH2N2, 82%; (h) (i) DIBALH, PhMe, -78 °C; (ii) CH2dPPh3, THF, -78 f +40 °C, 70%; (i) TMSBr, 4 Å molecular sieves,
CH2Cl2, -30 °C, 82%; (j) TBSOTf, 2,6-lutidine, 0 °C, 99%; (k) 5 mol % Mo(CHMe2Ph)(NAr)(OCMe(CF3)2)2, PhH, rt, 99%; (l) 10% Pd/C, NaHCO3,
EtOH, H2 (5 atm), rt, 95%; (m) Dess-Martin periodinane, pyridine, CH2Cl2, rt, 95% (crude yield); (n) 0.5 mol % (S,S)-8, 0.55 equiv of H2O, 0 °C
f rt, 82%, 99% ee; (o) 1-(trimethylsilyl)-6-bromo-1-hexyne, Mg, CuI, THF, -78 °C, 88%; (p) (i) NaOH, Et2O, rt; (ii) TBAF, THF, rt; (iii) LiI, AcOH,
THF, rt; (iv) TBSCl, imidazole, DMF, rt, 75%; (q) 0.2 mol % (S,S)-8, 0.55 equiv of H2O, 0 °C f rt, 95%, 98% ee; (r) (i) LDA, THF, phenylthioacetic
acid, rt; (ii) pTsOH, benzene, rt, 99%; (s) LDA, THF, HMPA, rt, 81%; (t) (i) (cyclohexyl)2BH, hexane, rt; (ii) ZnEt2, hexane, 2, -78 f -15 °C, 73%;
(u) (i) Swern; (ii) Zn(BH4)2, Et2O, cyclohexene, CH2Cl2, -78 f 0 °C; (iii) 10 mol % PtO2, THF, H2 (1 atm), 63%; (v) (i) m-CPBA, CH2Cl2, 0 °C; (ii)
PhMe, ∆; (iii) 5% AcCl in MeOH, rt, 70%.
using the Grignard reagent derived from 1-(trimethylsilyl)-
6-bromo-1-hexyne17 gave the corresponding chlorohydrin in
88% yield, and this product was converted to the TBS-
protected iodohydrin 14 in 75% yield. Lactone 1518 was
readily prepared in quantitative yield from phenylthioacetic
acid and (S)-propylene oxide, the latter obtained by a highly
efficient HKR with catalyst (R,R)-8. Alkylation of the
enolate derived from 15 with iodohydrin 14 afforded 16 in
81% yield.19 Elimination of the phenyl sulfide was deferred
to the end of the synthesis in order to avoid possible
epimerization of the base-sensitive butenolide in the inter-
vening steps.20
tion sequence to provide the desired diastereomer with 7:1
diastereoselectivity. Hydrogenation over PtO2 afforded dia-
stereomerically pure lactone 17 after isolation by flash
chromatography in 63% overall yield for the three-step
sequence. Oxidation of the phenyl sulfide with m-CPBA,
followed by thermally induced elimination to the butenolide
and a final deprotection step, provided muconin 1 with
spectral properties identical to those of the natural product.
With the ongoing development of powerful new asym-
metric catalytic reactions, the synthetic chemist’s reliance
on Nature’s pool of optically active building blocks is
diminishing. The synthesis of stereochemically complex
targets by assembly of chiral components24 becomes not only
more tenable, but also highly attractive from a strategic
standpoint since it is readily amenable to the preparation
of stereochemical and structural analogues.
The key fragment coupling was accomplished by hydrobo-
ration of 16 and transmetalation, followed by addition of
aldehyde 2 to the resulting vinylzinc derivative.21 The
addition product was obtained in 73% yield as a 3.6:1
mixture of diastereomers favoring the undesired C(12)
epimer.22 Exploration of a variety of reaction conditions
failed to uncover any effective method for the chelation-
controlled alkylation of 2, presumably as a result of the ion-
sequestering capabilities of the THF-THP unit in this
substrate. The desired C(12)-(S) stereochemistry was
Ack n ow led gm en t . This work was sponsored by the
NIH (GM-43214). We would like to thank Prof. J . L.
McLaughlin for providing spectral data of muconin. We
acknowledge predoctoral fellowship support to S.E.S. from
the Ford Foundation and postdoctoral fellowship support
to J .B. from the Knut and Alice Wallenberg Foundation.
23
installed by means of a Swern oxidation/Zn(BH4)2 reduc-
Su p p or tin g In for m a tion Ava ila ble: Complete experimental
procedures, chiral chromatographic analyses of racemic and enan-
tiomerically enriched 4-6, and 1H NMR spectra of key intermedi-
ates (47 pages).
(17) Fujikura, S.; Inoue, M.; Utimoto, K.; Nozaki, H. Tetrahedron Lett.
1984, 25, 1999.
(18) White, J . D.; Somers, T. C.; Reddy, G. N. J . Org. Chem. 1992, 57,
4991.
(19) Alkylation of the same enolate with the epoxide of 14 afforded
mixtures of trans-lactonization products.
(20) Duret, P.; Figade´re, B.; Hocquemiller, R.; Cave´, A. Tetrahedron Lett.
1997, 38, 8849.
J O9810765
(21) (a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. (b)
Oppolzer, W.; Radinov, R. N. J . Am. Chem. Soc. 1993, 115, 1593.
(22) The C12 stereochemical assignment is based on McLaughlin’s
analysis (ref 1) and has been confirmed by independent NMR studies carried
out in our laboratories on muconin and C12-epi-muconin. These will be
described in detail in a future full paper.
(23) (a) Gensler, W. J .; J ohnson, F. A.; Sloan, D. B. J . Am. Chem. Soc.
1960, 82, 6074. (b) Evans, D. A.; Miller, S. J .; Ennis, M. D. J . Org. Chem.
1993, 58, 471.
(24) Hanessian, S. In Total Synthesis of Natural Products: The ‘Chiron’
Approach; Baldwin, J . E., Ed.; Permagon Press: New York, 1983.