4-Aryloxybutenolides as "chiral aldehyde" equivalents: An efficient enantioselective synthesis of (+)-brefeldin A

Article abstract of DOI:10.1021/ja026438b

4-(2′-Naphthoxy)-2-butenolide, readily available with high enantiopurity by a dynamic kinetic asymmetric transformation (DYKAT) of racemic 4-acyloxybutenolides (available in two steps from furfural), serves as an excellent chiral building block where the naphthoxy group strongly directs the stereochemistry of cycloadditions to the double bond. Notably, the cycloadditions of trimethylenemethanepalladium intermediates which do not exhibit good diastereoselectivity in additions to acceptors that possess many common and important chiral auxiliaries undergo cycloadditions with excellent regio- and stereocontrol. The utility of this process set the stage for an efficient new synthesis of (+)-brefeldin A, a compound of growing pharmacological significance. This synthesis also highlights the Pd-catalyzed DYKAT of crotyl carbonate to create the remote stereocenter. A new two-step method to convert aldehydes to δ-hydroxy-E-α,β-enoates is also outlined. Copyright

Full text of DOI:10.1021/ja026438b

Published on Web 07/18/2002
4-Aryloxybutenolides As “Chiral Aldehyde” Equivalents: An Efficient
Enantioselective Synthesis of (+)-Brefeldin A
Barry M. Trost* and Matthew L. Crawley
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received April 5, 2002
Scheme 1. Cycloaddition Reactions with 4-Naphthoxybutenolidea
Readily accessible “chiral aldehyde” equivalents play an impor-
tant role in organic synthesis.1 Enantiopure 4-aryloxybutenolides
are readily available using a palladium-catalyzed asymmetric allylic
alkylation (AAA) in a dynamic kinetic asymmetric transformation2
as shown in eq 1. In the previous examples, the aryloxy group acted
a (a) Ethyl diazoacetate, THF, ∆ (94%). (b) 1,3-cyclohexadiene, micro-
wave.
Table 1. TMM Cycloadditions to 4-Naphthoxybutenolide
entry
R )
conditions
yield
dra (epi)b
a1
a2
b1
b2
c
H
Toluene, 100 °C, 12 h
THF, 60 °C, 24 h
THF, 60 °C, 12 h
Toluene, 100 °C, 6 h
Toluene, 100 °C, 48 h
Toluene, 100 °C, 24 h
93
93
94
91
60
79
>98/2
>98/2
CNc
5.5/1
94/6
>98/2 (1/1)
>98/2 (4/1)
as a tether and was incorporated into the final product.3 A significant
aspect of the synthetic utility of γ-aryloxy or γ-alkoxybutenolides
relies on the ability to transfer the chirality from the γ-alkoxy center
to the R and â carbons in intermolecular reactions.4 We became
intrigued by this possibility in conjunction with our studies of
enantioselectivity of cycloadditions of trimethylenemethane-pal-
ladium complexes (TMM-PdL2) for asymmetric syntheses of
cyclopentanoids. Asymmetric catalysis of this cycloaddition as well
as using chiral auxiliaries on the acceptor has proven difficult.5 In
this work, we report the utility of the chiral acetal 3 for asymmetric
cycloadditions, notably those involving TMM-PdL2.
Previous reports have demonstrated the effectiveness of 5-men-
thyloxy-2-(5H)-furanone 5 in controlling diastereoselectivity of 1,3-
dipolar and Diels-Alder cycloadditions.6 For comparison, we
examined an example of each as shown in Scheme 1. In both cases,
as with 5, facial selectivity of the cycloaddition as well as
regioselectivity in the case of the 1,3-dipolar cycloaddition was
complete to give adducts 6 and 7. The yields were excellent,
significantly higher in the case of 3 compared to 5 for the Diels-
Alder reaction.6 While we performed the Diels-Alder reaction in
a normal thermal fashion (150 °C, 24 h, 68%), nearly quantitative
yields were obtained using a microwave at 150 °C (60 min) or 165
°C (20 min).
Me
Ph
d
a All diastereomeric ratios are of the crude mixture. All diastereomers
were separable by column chromatography. b Chiral center substituted with
R group. c Olefin isomerized into conjugation with the nitrile.
selectivity and excellent facial selectivity. In the case of the cyano-
substituted TMM reaction (entry b), the exocyclic double bond of
the initial product isomerized to the endocyclic position. The solvent
effect on the facial selectivity in this case is also noteworthy, that
is, higher diastereoselectivity in toluene than THF even though the
former is at considerably higher temperature. While the epimeric
ratio with respect to the methyl group in entry c was 1:1, the ratio
in the phenyl case increased to 4:1 (entry d).
The utility of the chiral aldehyde equivalent in the TMM-PdL2
cycloaddition is demonstrated in the access it gives to a wide range
of cyclopentane-containing natural products. Interest in the biologi-
cal properties of (+)-brefeldin A 25,8 which continues to grow
significantly,9 provides a continuing stimulation for new synthetic
strategies.10 The chemistry reported herein provides a new op-
portunity to enhance the efficiency of a synthesis of this significant
target.
As shown in Scheme 2, the TMM cycloadduct 9a was trans-
formed to ketone 10 in 84% yield, utilizing a one-pot dihydroxy-
lation-oxidative cleavage protocol.11 Ketone 10 was chemo- and
diastereoselectively (dr 96:4) reduced to alcohol 11 by the method
of Yamamoto.12 Without purification, the alcohol is silyl-protected
to afford intermediate 12 in 74% yield (two steps.) Using a Merck
protocol,13 the lactone 12 is opened to the Weinreb amide/aldehyde,
liberated 2-naphthol is removed (94% recovered), and the aldehyde
is epimerized to afford the functionalized core 13 in 72% yield
(two steps).
These results prompted us to examine the regio- and diastereo-
7
selectivity of cycloadditions via TMM-PdL2 (eq 2). As sum-
marized in Table 1, a range of TMM precursors (8a-8d) were
examined. All reacted well and gave complete control of regio-
Introduction of the upper side chain envisioned use of a new
protocol for formation of trans-alkenes from alkynes. Addition of
the lithium anion of ethyl propiolate to the core 13 in 5/1 THF/
* To whom correspondence should be addressed. E-mail: bmtrost@
stanford.edu.
9
9328
J. AM. CHEM. SOC. 2002, 124, 9328-9329
10.1021/ja026438b CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Completion of the Total Synthesisa
Scheme 2. Synthesis of the (+)-Brefeldin A Corea
a (a) KHMDS, DME, then 17 to rt (E/Z > 12/1, 81%). (b) C.A.N., 4:
1 ) acetone: water. (c) 1 N aq NaOH, THF, MeOH (76%, two steps). (d)
MsCl, Et3N, 2,4,6-trichlorobenzoyl chloride, xs. 4-DMAP, toluene, ∆ (61%).
(e) TBAF, THF, rt (77%).
The spectral data as well as the sign and magnitude of rotation
matched those of an authentic sample of (+)-brefeldin A. Thus,
(+)-brefeldin A is available in a convergent fashion from three
components: aldehyde-amide 13, ethyl propiolate, and sulfone 22.
All of the stereochemistry evolves from two palladium-catalyzed
AAA reactions. The effectiveness of the introduction of the upper
side chain via the new methodology described which achieves a
clean chemoselective reduction of an alkyne to a trans-alkene is
noteworthy. This work demonstrates the utility of 3, which is
available via a catalytic asymmetric route, as a “chiral aldehyde”
equivalent, especially in TMM-PdL2 cycloadditions.
a (a) NaIO4, 5% OsO4, THF/H2O (84%). (b) DIBAL-H, B. H. T., Toluene
(>96/4 dr).(c) TBDMSOTf, pyridine (74%, two Steps). (d) (iPr)2MgCl,
MeO(Me)NH-HCl, THF, -10 °C. (e) DBU, CH2Cl2 (72%, two Steps). (f)
LiCCCO2Et, THF/HMPA ) 5/1, -78 °C (>6:1 dr, 88%). (g) (EtO)3SiH,
1% Cp*Ru(CH3CN)3PF6, CH2Cl2 (92%). (h) TBDMSOTf, pyridine, CH2Cl2.
(i) DIBAL-H, THF, -78 °C (81%, two Steps).
Scheme 3. Lower Side Chain Synthesisa
Acknowledgment. We thank the National Science Foundation
and the General Medical Sciences Institute of the National Institutes
of Health (GM 13598) for their generous support of our work. Mass
spectra were provided by the Mass Spectrometry Regional Center
of the University of California-San Francisco, supported by the NIH
Division of Research Resources.
a p-Methoxyphenol, 0.25% Pd2dba3-CHCl3, 0.75% ligand 4, toluene
(>96/4 regio., up to 90% ee, 95%). (b) 9-BBN, THF, then H2O2, aq NaOH.
(c) PCC, CH2Cl2, Celite, 4Å MS then EtO2CC(H)PPh3 (65% two steps).
(d) NaBH4, MeOH, 5% NiCl2, 0 °C. (e) DIBAL-H, THF (92%, two steps).
(f) DIAD, PPh3, 1-phenyl-5-thioltetrazole, THF. (g) Oxone, MeOH, H2O,
60 °C (88%, two steps).
Supporting Information Available: Experimental procedures for
7, 9a-9d, 14, 15, 19, and 25 and characterization data for all
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
HMPA at -78 °C afforded propargyl alcohol 14 in 6:1 dr (88%
yield) with Felkin-Ahn control, whereas the epimer was also
available in 1:6 dr (92% yield) by simply using DME, presumably
under chelation control. Exposing this adduct 14 to ruthenium-
catalyzed trans-hydrosilylation14 followed by addition of cesium
fluoride and ethanol gave enoate 15 directly in one step in 92%
yield. Thus, the upper side chain was introduced in two steps, and
this sequence constitutes a convenient and general entry to
γ-hydroxy-R,â-trans-enoates. After silyl protection, the amide 16
was chemoselectively reduced to aldehyde 17 in 81% yield in the
presence of the enoate by utilizing one equivalent of DIBAL-H.
Scheme 3 summarizes the synthesis of the lower side chain. An
enantio- and regioselective palladium-catalyzed AAA of crotyl
carbonate 18 afforded the C(4) fragment 19 with 96:4 regioselec-
tivity and 90% ee in 93% yield.15 Olefin 19 was transformed to
enoate 20 via hydroboration-oxidation followed by one-pot oxida-
tion to the aldehyde and in situ Wittig reaction with an overall
yield of 65%. Nickel dichloride-catalyzed sodium borohydride 1,4-
reduction followed by DIBAL-H reduction converted the enoate
20 directly to saturated alcohol 21 in 92% yield (two steps).
Completion of the sulfone component 22 involved Mitsonobu
coupling of 1-phenyl-5-thioltetrazole followed by Oxone oxidation16
in 88% yield.
References
(1) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2000, 122, 6120 and
references therein.
(2) For a review on dynamic kinetic transformations, see: Ward, R. S.
Tetrahedron: Asymmetry 1995, 6, 1475.
(3) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543.
(4) Krief, A.; Lecomte, P.; Demounte, J. P.; Dumont, W. Synthesis 1990,
275.
(5) Trost, B. M.; Yang, B.; Miller, M. L. J. Am. Chem. Soc. 1989, 111, 6842.
(6) (a) Feringa, B. L.; de Jong, J. C.; van Bolhuis, F. Tetrahedron: Asymmetry
1991, 2, 1247. (b) Feringa, B. L.; Rispens, M. T.; Keller, E.; de Lange,
B.; Zijlstra, R. W. J. Tetrahedron: Asymmetry 1994, 5, 607.
(7) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105, 2326.
(8) Singleton, V. L.; Bohonos, N.; Ullstrupp, J. Nature 1958, 181, 1072.
(9) Cushman, M.; Fox, B. M.; Vroman, J. A.; Fanwick, P. E. J. Med. Chem.
2001, 44, 3915 and references cited therein.
(10) For most recent syntheses: (a) Kim, D.; Lee, J.; Shim, P. J.; Lim, J. I.;
Doi, T.; Kim, S. J. Org. Chem. 2002, 67, 772. (b) Ibid., 764. (c) Suh,
Y.-G.; Seo, S. Y.; Jung, J.-K.; Park, O.-H.; Jeon, R. A. Tetrahedron Lett.
2001, 42, 691. (d) previous Trost-group synthesis: Trost, B. M.; Lynch,
J.; Renaut, P.; Steinman, D. H. J. Am. Chem. Soc. 1986, 108, 284.
(11) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem.
1956, 21, 478.
(12) Yamamoto, H.; Iguchi, S.; Nakai, H.; Hayashi, M. J. Org. Chem. 1979,
44, 1363.
(13) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchegini, G.; Dolling, U.
H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461
(14) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
(15) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(16) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(17) Yamaguchi, M.; Innaga, J.; Hirata, K. Saeki, H.; Katsuki, T. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
Julia olefination proved nontrivial. Optimization involved use
of KHMDS in DME at -78 °C, whereby a 12:1 E:Z selectivity for
formation of alkene 23 was obtained (see Scheme 4). Completion
of the synthesis proceeded uneventfully and employed the Yamagu-
chi method for macrolactonization.17
JA026438B
9
J. AM. CHEM. SOC. VOL. 124, NO. 32, 2002 9329