Concise total syntheses of palominol, dolabellatrienone, β-araneosene, and isoedunol via an enantioselective Diels-Alder macrobicyclization

Article abstract of DOI:10.1021/ja0576379

Concise total syntheses of four members of the dolabellane family of diterpenoid natural products are reported. Key features of the developed route include the first demonstration of an enantioselective, intramolecular Type I Diels-Alder macrobicyclization, the first example of a stereoselective π-allyl Stille coupling reaction involving a farnesyl-derived intermediate, a powerful new reagent for the formation of dithianes with acid-sensitive molecules, and a unique and highly efficient ring-contraction sequence based on a modified Wolff photochemical rearrangement. Copyright

Full text of DOI:10.1021/ja0576379

Published on Web 12/24/2005
Concise Total Syntheses of Palominol, Dolabellatrienone, â-Araneosene, and
Isoedunol via an Enantioselective Diels-Alder Macrobicyclization
Scott A. Snyder and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received November 9, 2005; E-mail: corey@chemistry.harvard.edu
Although 75 years of study have proven that the Diels-Alder
reaction is one of the most powerful tools for the construction of
complex molecules, particularly natural products, its full potential
has not yet been reached.1 For instance, no chiral, small molecule
catalyst has yet proven capable of coaxing an achiral precursor to
undergo an enantioselective Type I Diels-Alder-based macrobi-
cyclization. In this Communication, we report the first solution to
this problem as part of a broader research program to develop
effective synthetic pathways to bioactive dolabellane-type marine
natural products,2,3 including the parents â-araneosene (1, Figure
1),4 dolabellatrienone (2),5 and palominol (3).6
The overall approach to these targets is summarized retrosyn-
thetically in Figure 1, for the case of dolabellatrienone (2).
Retrosynthetic 5 f 6 ring expansion and functional group introduc-
tion serve to convert this structure to one suitable for retrosynthetic
Diels-Alder disconnection. Since this disconnection would produce
an achiral precursor, any enantioselective synthesis would require
the application of a chiral catalyst. We surmised that this key step
could proceed asymmetrically with the chiral cis-fused oxazaboro-
lidinium cation 47 by way of endo-transition state assembly 5, whose
organization involves a formyl hydrogen bond and π-π stacking
between the dienophile and the catalyst. Such a reaction course
would result in the required macrocyclic enantiomer.1a
The manner in which this general plan was reduced to practice
is shown in Scheme 1. Synthetic efforts began with the stereospe-
cific coupling of building blocks 68 and 79 through a π-allyl Stille
Figure 1.
reaction induced by catalytic Pd2dba3, to form 8 in 96% yield.
Although this type of reaction has been employed on a number of
occasions to fashion similar diene systems with high stereospeci-
ficity,10 to our knowledge, this example represents the first case in
which a farnesyl-derived fragment has been utilized successfully.11
Subsequent exposure of this intermediate to HIO4 (1.1 equiv) and
NaIO4 (0.6 equiv) in aqueous THF at 25 °C for 1 h generated an
aldehyde that was then combined with the anion derived from the
reaction of phosphonate 9 (3.0 equiv) with KOt-Bu (2.5 equiv), to
provide methyl ketone 10 in 92% overall yield. This product was
then converted into Diels-Alder precursor 11 in 78% overall yield
via (1) TBAF-mediated deprotection of the tert-butyldiphenylsilyl
(TBDPS) ether, (2) MnO2 oxidation of the resultant alcohol, and
(3) triisopropylsilyl (TIPS) enol ether formation by brief exposure
of the intermediate methyl ketone to TIPSOTf (1.1 equiv) and i-Pr2-
NEt (4.0 equiv) in CH2Cl2 at -78 °C for only 3 min.
With the key Diels-Alder substrate in hand, we next undertook
the study of Diels-Alder macrocyclization. To our delight, effecting
this reaction required little scouting since in the first experiment
we found that the slow addition of a solution of 20 mol % of the
(S)-catalyst 4 in toluene to a stirred solution of the highly acid
sensitive 11 in toluene at -93 °C, followed by 3 h at -93 °C and
10 h at -78 °C, resulted in the formation of macrocycle 12 in 74%
yield and 90% enantiomeric excess (ee). The structure and absolute
configuration of 12 were verified by X-ray crystallographic analysis
of the tosylhydrazone derivative. Both the structure and absolute
configuration of 12 are as predicted by the transition state model
5.12 Remarkably, catalyst 4 was unique in its ability to effect this
[4 + 2]-cycloaddition. Exposure of 11 to standard achiral initiators,
such as Me2AlCl, MeAlCl2, EtAlCl2, or heat deprotected and/or
polymerized 11, without detectable conversion to 12 or any other
Diels-Alder-type product.
With this critical operation complete, the task of deoxygenating
the aldehyde function that had enabled the enantioselective Diels-
Alder reaction was undertaken. After numerous unsuccessful
attempts, for example, involving reduction of arylsulfonylhydra-
zones, the required reduction was accomplished in two steps using
novel methodology that depended on dithiolane formation using
13
12 and the reagent Me2AlSCH2CH2SAlMe2 (3 equiv, prepared
in situ from ethanedithiol and Me3Al) at 60 °C in dichloroethane
solution for 12 h. After silyl ether cleavage, the dithiolane was
treated with deactivated Raney Ni (formed by stirring Raney Ni in
acetone for 30 min at 25 °C prior to reaction) in THF at 25 °C for
10 h to afford the required product 13 in 65% overall yield from
12.15 Many other reagents and methods were screened for thioacetal
formation, but all failed because of vinyl ether cleavage and further
reaction. As indicated by the additional examples in Table 1, this
method of nonacidic thioacetalization is quite general and mild as
ketones (17), aryl aldehydes (19), and hindered aldehydes containing
tert-butyldimethylsilyl (TBS) ether subunits (25) are all smoothly
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10.1021/ja0576379 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
converted into the thioacetals in good yields. Additionally, it should
be noted that alternative protocols, such as Wolff-Kishner reduction
and Barton-McCombie deoxygenation, failed to convert 12 into
13.
ation, and (3) diol formation upon exposure to excess LiAlH4 and
subsequent cleavage using NaIO4 on silica gel. Beyond accomplish-
ing the enantioselective total syntheses of these four natural product
targets, the developed sequence could also be employed to access
the parent structures of several additional dolabellanes. For instance,
the transformation of palominol (3) into the corresponding meth-
oxymethyl ether (MOM) using MOMI (4 equiv) and i-Pr2NEt (6
equiv) in refluxing THF for 12 h followed by Li-NH3 reduction
[excess Li in NH3/THF (1:1), -40 °C, 2 h] provided triene 29 (95%
yield),22 a regioisomer of â-araneosene (1) and the core element
of several more highly oxidized dolabellane diterpenoids, such as
30.3
The next strategic operation, ring contraction,14 was achieved in
a single step by an unusual application of the Wolff rearrangement.16
In the first stage, the synthesis of R,â-unsaturated diazoketone 14
was carried out in 62% overall yield by the following sequence:
(1) R,â-desaturation using the oxidation conditions developed by
Nicolaou;17 and (2) a phase-transfer-induced diazo transfer reaction
as described by the Mander group.18 Photoirradiation of 14 in
MeOH for 2 h at 25 °C, followed by solvent removal and heating
in neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 115 °C for
18 h, generated the required ring-contracted ester 15 in 68% yield.19
The success of this ring-contraction process, given the number of
potential side reactions of an intermediate carbene generated so
close to a neighboring olefinic linkage and ring junction, is note-
worthy; an additional example, 27 f 28, is shown in Scheme 2.20
The chiral dolabellane derivative 15 was readily converted to
palominol (3) and dolabellatrienone (2) as indicated in Scheme 1.2c,5c
In addition to these target molecules, synthetic routes to both
â-araneosene (1) and isoedunol2a were established by the successful
conversion of 15 into ketone 16 by a three-step sequence in 51%
overall yield (following earlier studies):21 (1) conjugate reduction
of 15 using L-Selectride (4 equiv) in THF at 0 °C, (2) R-oxygen-
In summary, concise and stereoselective total syntheses of four
members of the dolabellane family of diterpenoids, as well as the
carbocyclic core of several more highly oxygenated natural
products, have been achieved by an efficient synthetic strategy
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C O M M U N I C A T I O N S
Table 1. Me2AlSCH2CH2SAlMe2-Induced Dithiane Formationa
Supporting Information Available: Experimental procedures and
characterization data for all new products, list of abbreviations, selected
1H NMR spectra of key intermediates and synthetic natural products,
and X-ray diffraction data (CIF). This material is available free of charge
via the Internet at http://pubs/acs.org.
References
(1) For reviews, see: (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vasillikogiannakis,
G. E. Angew. Chem., Int. Ed. 2002, 41, 1668.
(2) For other approaches from our group, see: (a) Kingsbury, J. S.; Corey,
E. J. J. Am. Chem. Soc. 2005, 127, 13813. (b) Hu, T.; Corey, E. J. Org.
Lett. 2002, 4, 2441. (c) Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998,
39, 741. (d) Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118,
1229.
(3) For a review, see: Rodr´ıguez, A. D.; Gonza´lez, E.; Ram´ırez, C.
Tetrahedron 1998, 54, 11683.
(4) Isolation: (a) Shin, J.; Fenical, W. J. Org. Chem. 1991, 56, 3392. (b)
Jenny, L.; Borschberg, H.-J. HelV. Chim. Acta 1995, 78, 715. Total
syntheses: (c) See ref 2a.
(5) Isolation: (a) See ref 4a. Total syntheses: (b) See ref 2c. (c) See ref 2d.
(d) Miyaoka, H.; Isaji, Y.; Mitome, H.; Yamada, Y. Tetrahedron 2003,
59, 61.
(6) Isolation: (a) Look, S. A.; Fenical, W. J. Org. Chem. 1982, 47, 4129. (b)
Rodrguez, A. D.; Acosta, A. L.; Dhasmana, H. J. Nat. Prod. 1993, 56,
1843. Total syntheses: (c) See ref 2c. (d) See ref 5d.
(7) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 9992. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
6388. (d) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 4800. (e) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 13708. For selected examples of enantioselective, intramolecular
Diels-Alder reactions, see: (f) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org.
Lett. 2003, 5, 3979. (g) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 11616.
(8) See Supporting Information for the preparation of this compound.
(9) See ref 2d for the synthesis of this fragment.
(10) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am.
Chem. Soc. 2003, 125, 5393.
(11) Previous studies in these laboratories indicated that related farnesyl
couplings using several different palladium sources and reaction conditions
afforded only isomeric mixtures. See: Kania, R. S. Ph.D. Thesis, Harvard
University, 1997.
a With 3 equiv of sulfide reagent at 60 °C in 1,2-dichloroethane for 2-12
h.
(12) See Supporting Information for further details on the optimization of this
step and the determination of the absolute configuration of 12.
Scheme 2
(13) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1973, 95, 5829.
(14) For an excellent review on the formation of cyclopentyl rings via ring
contraction reactions of six-membered carbocycles, see: Silva, L. F.
Tetrahedron 2002, 58, 9137.
(15) The use of other solvents, reaction temperatures, and untreated Raney Ni
in the desulfurization step caused olefinic reduction.
(16) For reviews, see: (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2193. (b)
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons: New
York, 1998; p 652.
(17) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed.
2002, 41, 993. (b) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.;
Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996. All other protocols,
such as Saegusa oxidation, provided markedly inferior yields.
featuring a highly enantioselective intramolecular Diels-Alder
macrobicyclization of an achiral precursor in combination with
several key reactions: (1) the first example of a stereoselective
π-allyl Stille coupling reaction involving a farnesyl-derived inter-
mediate, (2) a powerful new reagent for the formation of dithiolanes
with acid-sensitive molecules, and (3) a unique and highly efficient
ring-contraction sequence based on a modified Wolff photochemical
rearrangement. Additional synthetic studies pertaining to more
complex members of this class of diterpenoids, as well as studies
into the general ability of chiral oxazaborolidinium cations to
orchestrate enantioselective, intramolecular Diels-Alder macro-
cyclizations, are underway.
(18) Lombardo, L.; Mander, L. N. Synthesis 1980, 368.
(19) Milder conditions, such as DBU (5 equiv) in CH2Cl2 at 25 °C (Smith, N.
B.; Derrien, N.; Lloyd, M. C.; Taylor, S. J. C.; Chaplin, D. A.; McCague,
R. Tetrahedron Lett. 2001, 42, 1347) afforded only recovered the â,γ-
unsaturated isomer of 15, while exposure to DBU/toluene (1:1) at 110 °C
effected only partial conversion to 15 after 18 h of reaction time.
(20) The only side product in this conversion is that bearing a tetrasubstituted
olefin adjoining the A and B rings; such a side product has been formed
from 28 before through a thermal reaction: Fuchs, B.; Loewenthal, H. J.
E. Tetrahedron 1960, 11, 199.
(21) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(22) The selectivity in this event appears to be unique, as related model
compounds derived from 5R-cholestan-3-one afforded products corre-
sponding to â-araneosene (1). We ascribe the unique reactivity to
destabilizing steric interactions between the isopropylidene methyl groups
and the adjoining 11-membered ring that are relieved upon tertiary radical
formation followed by rapid H-atom abstraction from THF. Use of the
proton source tert-butyl alcohol afforded a 1:1 mixture of 29 and
â-araneosene (1).
Acknowledgment. We thank the National Institutes of Health
(Postdoctoral Fellowship to S.A.S.) and Dr. Robin A. Weatherhead-
Kloster for X-ray structure determination.
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