Synthesis of (+)-bullatacin via the highly diastereoselective [3+2] annulation reaction of a racemic aldehyde and a nonracemic allylsilane

Article abstract of DOI:10.1021/ol051719k

(Chemical Equation Presented) A total synthesis of (+)-bullatacin has been accomplished via a diastereoselective [3+2] annulation reaction of the highly enantiomerically enriched allylsilane 3 and racemic aldehyde 4, which provides the key bis-tetrahydrof

Full text of DOI:10.1021/ol051719k

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4245-4248
Synthesis of (
Highly Diastereoselective [3
Annulation Reaction of a Racemic
+
)-Bullatacin via the
2]
+
Aldehyde and a Nonracemic Allylsilane
Jennifer M. Tinsley, Eric Mertz, Pek Y. Chong, Robert-Andre´ F. Rarig, and
William R. Roush*,‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received July 20, 2005
ABSTRACT
A total synthesis of (
+
)-bullatacin has been accomplished via a diastereoselective [3
+
2] annulation reaction of the highly enantiomerically
20:1 ds.
enriched allylsilane 3 and racemic aldehyde 4, which provides the key bis-tetrahydrofuran fragment 15 with
g
(+)-Bullatacin (1) is one of more than 350 Annonaceous
acetogenins isolated from the tropical plant family Annon-
aceae (Figure 1). Many members of this structurally diverse
family of natural products exhibit impressive antitumor
activity in human tumor cell lines.1 The acetogenins contain
a long aliphatic backbone bearing a terminal butenolide unit
and one or more tetrahydrofuran rings and hydroxyl groups
at internal positions of the aliphatic chain. These compounds
are intriguing synthetic targets owing to the variation of
stereochemistry around the tetrahydrofuran rings and at the
sites bearing additional hydroxyl groups.2,3
2,5-trans or 2,5-cis substituted tetrahydrofurans with excel-
lent selectivity, depending on the use of chelating or
nonchelating Lewis acids, respectively.6 We have recently
utilized this methodology in a highly stereoselective total
synthesis of asimicin (2).7
The [3+2] annulation reaction of aldehydes and chiral
allylsilanes is an important method for the stereocontrolled
synthesis of substituted tetrahydrofurans.4,5 â-Silyloxy-
substituted allylsilanes undergo [3+2] annulation reactions
with aldehydes and certain electrophilic ketones to give either
‡ Address correspondence to this author at Scripps Florida, Department
of Medicinal Chemistry, 5353 Parkside Drive, RF-2, Jupiter, FL 33485.
E-mail: roush@scripps.edu.
(1) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504.
Figure 1. Structures of bullatacin and asimicin.
10.1021/ol051719k CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

corresponding reaction in our asimicin synthesis that pro-
ceeded with g20:1 ds.7
The erythro stereochemistry of C(23)-C(24) of aldehyde
4 requires that a syn-â-silyloxy allylsilane 6 be used in a
chelate-controlled [3+2] annulation reaction with R-benzy-
loxy acetaldehyde (5). Initial attempts to develop an enan-
tioselective synthesis of syn-â-silyloxy allylsilanes related
to 6 focused on asymmetric allylboration reactions using (Z)-
γ-dimethylphenylsilyallylboronate 7 (Scheme 1). Thus, si-
Scheme 1. Synthesis of syn-â-Hydroxyallylsilanes via
Asymmetric Allylboration
Figure 2. Retrosynthetic analysis of bullatacin.
As part of ongoing studies focusing on the development
of a stereochemically general synthesis of members of the
acetogenin family, we have developed and report herein a
highly stereoselective synthesis of bullatacin (1),8 which
differs from asimicin (2) at a single stereocenter (C-24). We
envisaged that the bis-tetrahydrofuran core unit of bullatacin
could be synthesized from sequential chelate-controlled
[3+2] annulation reactions of allylsilanes 3 and 6 (Figure
2). The proposed [3+2] annulation of 3 and 4 is expected to
be a stereochemically matched double asymmetric reaction
under chelate-controlled conditions, by analogy with the
(2) Representative acetogenin total syntheses: (a) Marshall, J. A.; Jiang,
H. J. Org. Chem. 1999, 64, 971. (b) Kuriyama, W.; Ishigami, K.; Kitahara,
T. Heterocycles 1999, 50, 981. (c) Marshall, J. A.; Jiang, H. J. Nat. Prod.
1999, 62, 1123. (d) Hu, T.-S.; Wu, Y.-L.; Wu, Y. K. Org. Lett. 2000, 2,
887. (e) Emde, U.; Koert, U. Eur. J. Org. Chem. 2000, 1889. (f) Hoppen,
S.; Baurle, S.; Koert, U. Chem. Eur. J. 2000, 6, 2382. (g) Dixon, D. J.;
Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed. 2000, 39, 3622. (h)
Harcken, C.; Bruckner, R. New J. Chem. 2001, 25, 40. (i) D’Souza, L. J.;
Sinha, S. C.; Lu, S.-F.; Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57,
5255. (j) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002,
4, 1083. (k) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790.
(l) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004,
126, 36. (m) Nattrass, G. L.; Diez, E.; McLachlan, M. M.; Dixon, D. J.;
Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580.
(3) Previous syntheses of bullatacin: (a) Hoye, T. R.; Hanson, P. R.
Tetrahedron Lett. 1993, 34, 5043. (b) Hoye, T. R.; Tan, L. Tetrahedron
Lett. 1995, 36, 1981. (c) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.;
Sasaki, S. J. Org. Chem. 1995, 60, 4419. (d) Sinha, S. C.; Sinha-Bagchi,
A.; Yazbak, A.; Keinan, E. Tetrahedron Lett. 1995, 36, 9257. (e) Avedissian,
H.; Sinha, S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E.
J. Org. Chem. 2000, 65, 6035.
lylcupration9 of acetylene, addition of the intermediate
vinylcopper species to diisopropyl iodomethylboronate,10
hydrolysis of the crude alkylation product, and then esteri-
fication of the intermediate allylic boronic acid with diiso-
propyl (R,R)-tartrate provided (R,R)-7 in 57-60% yield. This
reagent underwent the expected11 syn-selective allylboration
reaction of achiral aldehydes in 74-95% yield. However,
the syn-â-hydroxyallylsilanes 8 were obtained with only 50-
64% ee. Because the synthesis of 7 proved difficult to scale-
up, alternative strategies for synthesis of the targeted
allylsilanes was pursued.
(4) For a review see: Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95,
1293.
(5) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b)
Panek, J. S.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Beresis, R.; Panek,
J. S. Bioorg. Med. Chem. Lett. 1993, 3, 1609. (d) Micalizio, G. C.; Roush,
W. R. Org. Lett. 2001, 3, 1949. (e) Smitrovich, J. H.; Woerpel, K. A.
Synthesis 2002, 2778. (f) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org.
Lett. 2003, 5, 1693.
(6) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461.
(7) Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818-
10819.
A more convenient route to (racemic) syn-â-hydroxyal-
lylsilanes 8 involves the γ-silylallylstannation of aldehydes
using γ-(dimethylphenylsilyl)allylstannane 9.12 Treatment of
cyclohexanecarboxaldehyde with 9 at -78 °C in CH2Cl2 in
the presence of BF3‚OEt2 provided 8d in 51% yield, along
(8) (a) Hui, Y.-H.; Rupprecht, J. K.; Liu, Y. M.; Anderson, J. E.; Smith,
D. L.; Chang, C.-J.; McLaughlin, J. L. J. Nat. Prod. 1989, 52, 463. (b)
Rieser, M. J.; Hui, Y.-H.; Rupprecht, J. K.; Kozlowski, J. F.; Wood, K. V.;
McLaughlin, J. L.; Hanson, P. R.; Zhuang, Z.; Hoye, T. R. J. Am. Chem.
Soc. 1992, 114, 10203. (c) Ahammadsahib, K. I.; Hollingworth, R. M.;
McGovren, J. P.; Hui, Y.-H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113.
(d) Morre´, D. J.; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin, J.
L. Life Sci. 1994, 56, 343. (e) Oberlies, N. H.; Croy, V. L.; Harrison, M.
L.; McLaughlin, J. L. Cancer Lett. 1997, 115, 73.
(9) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin Trans.
1 1981, 2527.
(10) (a) Matteson, D. S. Tetrahedron 1998, 54, 10555. (b) Soundararajan,
R.; Li, G.; Brown, H. C. J. Org. Chem. 1996, 61, 100.
(11) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 2, p 1.
(12) (a) Keck, G. E.; Romer, D. J. Org. Chem. 1993, 58, 6083. (b)
Yamamoto, Y.; Saito, Y.; Maruyama, K. J. Organomet. Chem. 1985, 292,
311.
4246
Org. Lett., Vol. 7, No. 19, 2005

asimicin synthesis.7,14 Specifically, initial batches of allyl-
silane 3 were prepared that contained significant amounts
of the diastereomer 11 (Scheme 3). When these mixtures
were subjected to the [3+2] annulation reaction with trans-
tetrahydrofuran aldehyde 12 (>95% ee), only one diaster-
eomeric bis-tetrahydrofuran 13 was obtained. This result
implied that the reaction of the (R)-allylsilane 3 with 12 is
stereochemically matched and that the reaction of these two
components is substantially faster and/or chemically more
efficient than the mismatched reaction of the diastereomeric
(S)-allylsilane 11 with 12.15 This conclusion is supported by
studies in our laboratory on double asymmetric reactions of
chiral tetrahydrofuran aldehydes and chiral allylsilanes.16
The synthesis of bullatacin commenced with the synthesis
of racemic tetrahydrofuran carboxaldehyde 4 (Scheme 4).
Scheme 2. Synthesis of Racemic syn-â-Hydroxyallylsilanes
via γ-Silylallylstannation
Scheme 4. Synthesis of Erythro (()-Tetrahydrofuryl
Carboxaldehyde 4
with 11% of homoallylic alcohol 10. The latter compound
presumably arises from a secondary reaction of 8d with
cyclohexanecarboxaldehyde via an oxonia-Cope process.13
Production of the vinylsilane byproducts can be minimized
by using an excess of 9 (tyically 2 equiv) in the allylstan-
nation reaction, and by maintaining the reaction temperature
at -78 °C. This method consistently provides the targeted
(racemic) syn-â-hydroxyallylsilanes 8 in 51-68% yield with
g20:1 ds (Scheme 2). Efforts to accomplish these reactions
by using a chiral Lewis acid catalyst are in progress.
Allylsilane 6 was readily prepared from the BF3‚OEt2
catalyzed reaction of silylallylstannane 9 and undecanal,
followed by protection of the resulting secondary alcohol as
a TBS ether.17 The chelate controlled [3+2] annulation
reaction of allylsilane (()-6 and R-benzyloxy acetaldehyde
(5) in the presence of SnCl4 at -45 °C afforded the 2,5-
trans tetrahydrofuran (()-14 in 80% yield and g20:1
diastereoselectivity. Hydrogenolysis of the benzyl ether using
Pd(OH)2 and subsequent oxidation of the alcohol with SO3-
pyridine and DMSO provided (()-4.18
Scheme 3. Kinetic Diastereomer Resolution in the Asimicin
Synthesis
Treatment of highly enantiomerically enriched allylsilane
37 with 1 equiv of racemic aldehyde 4 in the presence of
SnCl4 (1 equiv) at 0 °C provided the bis-tetrahydrofuran 15
as a single diastereomer in 25% yield (Scheme 5).19 When
2 equiv of the aldehyde were used in the annulation reaction,
the yield of 15 increased to 50%, and a 76% yield was
obtained when 3 equiv of (()-4 was employed. In each case,
bis-tetrahydrofuran 15 was obtained as a single diastereomer.
(14) Tinsley, J. M., Ph.D. Thesis, University of Michigan, 2005.
(15) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
(16) Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem. Submittted
for publication.
(17) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(18) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(19) Aldehyde 4 recovered from this reaction was reduced with NaBH4
to give the corresponding primary alcohol. Moster ester analysis of this
intermediate indicated that the recovered 4 had an enantiomeric purity of
ca. 20% ee.
We decided to pursue a kinetic resolution strategy in the
bullatacin synthesis based on observations made in our
(13) (a) Roush, W. R.; Dilley, G. J. Synlett 2001, 955. (b) Sumida, S.;
Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310.
Org. Lett., Vol. 7, No. 19, 2005
4247

Scheme 5. Kinetic Resolution in the [3+2] Annulation
Reaction of 3 and (()-4
Scheme 6. Completion of the Total Synthesis of Bullatacin
The high selectivity of this reaction is attributed to the
matched facial selectivity of the chiral allylsilane and the
(2R,4R,5S)-enantiomer of the SnCl4-chelated chiral aldehyde
in the favored syn-synclinal transition state 16.6,16,20
Woerpel and co-workers have previously described a
kinetic resolution in a double asymmetric [3+2] annulation
reaction of a racemic allylsilane and a chiral auxiliary-bearing
R-keto ester to prepare highly substituted tetrahydrofurans
as single enantiomers.21 Our methodology is complementary
in that it takes advantage of the stereochemistry inherent in
the annulation substrates. In principle, our approach may be
expanded to other reaction partners.
Protiodesilylation of the bis-tetrahydrofuran 15 was ac-
complished by treatment with TBAF in a 1:1 mixture of THF
and DMF at 90 °C;22 this provided tetraol 17 in 49% yield
(Scheme 6). The butenolide ring was then installed by using
a procedure developed by Marshall and co-workers.7,23 Thus,
per-trifluoroacetylation of 17 followed by Pd(0)-catalyzed
hydroxycarbonylation and Ag(I)-promoted cyclization of the
intermediate allenyl carboxylic acid gave the tris-trifluoro-
acetate ester of bullatacin. Deprotection of the three trifluo-
roacetates by treatment of the tri-ester with KCN in MeOH
then provided synthetic (+)-bullatacin (1) in 60% yield for
this four-step sequence. The spectroscopic properties of
synthetic (+)-bullatacin were in excellent agreement with
literature data (see the Supporting Information).
In summary, the total synthesis of (+)-bullatacin has been
accomplished via a highly diastereoselective [3+2] annula-
tion reaction of allylsilane 3 and racemic aldehyde 4 in the
kinetic resolution manifold. Applications of the [3+2]
annulation sequence to the synthesis of other members of
the Annonaceous acetogenin family will be reported in due
course.
Acknowledgment. This work is supported by a grant
from the National Institutes of Health (GM 38907). E.M. is
grateful for fellowship support from the National Cancer
Institute (CA 103507).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all intermediates in the
bullatacin synthesis. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J.
Org. Chem. 1994, 59, 7889.
(21) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945.
(22) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley,
J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
(23) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62, 5989.
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