Highly stereoselective and modular syntheses of 10-hydroxytrilobacin and three diastereomers via stereodivergent [3 + 2]-annulation reactions

Article abstract of DOI:10.1021/ol801242d

(Chemical Equation Presented) A convergent synthesis of the annonaceous acetogenin, 10-hydroxytrilobacin (4a), was accomplished by using the [3 + 2]-annulation reaction of tetrahydrofuranyl carboxaldehyde 2a and allylsilane 3. The stereodivergency of the

Full text of DOI:10.1021/ol801242d

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3371-3374
Highly Stereoselective and Modular
Syntheses of 10-Hydroxytrilobacin and
Three Diastereomers via Stereodivergent
[3 + 2]-Annulation Reactions
Chan Woo Huh and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received June 2, 2008
ABSTRACT
A convergent synthesis of the annonaceous acetogenin, 10-hydroxytrilobacin (4a), was accomplished by using the [3 + 2]-annulation reaction
of tetrahydrofuranyl carboxaldehyde 2a and allylsilane 3. The stereodivergency of the [3 + 2]-annulation reaction made it possible to achieve
modular, highly stereoselective syntheses of three 10-hydroxytrilobacin diastereomers from the same precursors by using simple modifications
of reaction conditions.
The annonaceous acetogenins are fatty acid derived natural
products isolated from Annonaceae species (custard apple).1
As of 2005, more than 400 acetogenins had been reported.1a
The acetogenins are characterized by their ability to inhibit
mitochondria complex I of the mammalian and insect
mitochondrial electron transport system.1a
Among the numerous natural acetogenins, the stere-
ochemically diverse group of adjacent bis-THF acetogenins
(especially those with hydroxyl groups flanking both ends
of the bis-THF unit) have attracted the attention of many
synthetic laboratories2 because of their significant biological
activity against various human cancer cell lines.1b
activity of diastereomeric bis-THF acetogenins that the
stereochemistry of the bis-THF unit contributes substantially
to their biological profiles. For example, the LC50’s for
bullatacin and asimicin (which differ at a single stereocenter)
against MCF-7 are <10-12 µg/mL and 8.5 × 10-1 µg/mL,
respectively.3 However, the factors that govern the relation-
ship of acetogenin stereochemistry to biological activity are
unknown at present. Thus, generation of all possible dia-
stereomers of the bis-THF acetogenins would enable this
question to be addressed. Development of a modular and
stereochemically general synthesis of adjacent bis-THF
acetogenins amenable to SAR studies remains a major
While it has been stated in a review that the stereochem-
istry of the bis-THF core is not as important as the number
of THF units and the number of hydroxyl groups in
determining the biological potency of the various
acetogenins,1b it is readily apparent from comparison of the
(2) (a) Tinsley, J. M.; Mertz, E.; Chong, P. Y.; Rarig, R. A.; Roush,
W. R. Org. Lett. 2005, 7, 4245. (b) Tinsley, J. M.; Roush, W. R. J. Am.
Chem. Soc. 2005, 127, 10818. (c) Narayan, R. S.; Borhan, B. J. Org. Chem.
2006, 71, 1416. (d) Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee,
E. J. Am. Chem. Soc. 2005, 127, 10396. (e) Nattrass, G. L.; Dı´ez, E.;
McLachlan, M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2005,
44, 580. (f) Head, G. D.; Whittingham, W. G.; Brown, R. C. D. Synlett
2004, 1437. (g) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J.
Org. Chem. 2003, 68, 1780. (h) Emde, U.; Koert, U. Eur. J. Org. Chem.
2000, 2000, 1889.
(1) For recent reviews: (a) Bermejo, A.; Figade`re, B.; Zafra-Poloa, M.-
C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
(b) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(c) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087.
(3) He, K.; Shi, G.; Zhao, G.-X.; Zeng, L.; Ye, Q.; Schwedler, J. T.;
Wood, K. V.; McLaughlin, J. L. J. Nat. Prod. 1996, 59, 1029.
10.1021/ol801242d CCC: $40.75
Published on Web 06/28/2008
2008 American Chemical Society

challenge.4 Current approaches to the synthesis of libraries
of bis-THF acetogenin analogues require use of multiple
complex starting materials5 or additional steps to install
flanking hydroxyl groups after establishment of the bis-THF
core.6
Scheme 1. Retrosynthetic Analysis of 10-Hydroxytrilobacin (4a)
Preliminary studies in our laboratory demonstrated the
potential for use of the [3 + 2]-annulation reaction7 for
synthesis of adjacent bis-THF acetogenin analogues.8 The
stereochemistry of the two THF rings is set by using either
a nonchelate (BF3·OEt2 catalyzed) or a chelate controlled
(SnCl4 catalyzed) [3 + 2]-annulation reaction of a chiral
allylsilane with the appropriate aldehyde coupling partner.
Although we previously reported syntheses of asimicin and
bullatacin using the [3 + 2]-annulation reaction,2a,b these
syntheses were too linear and correspondingly lengthy. This
prevented us from using these routes to capitalize on the
implicit stereodivergency of the [3 + 2]-annulation reaction
for generation of stereochemically diverse bis-THF aceto-
genin analogues. Therefore, we have developed and report
herein a convergent, highly stereoselective and stereodiver-
gent synthesis of four representative adjacent bis-THF
acetogenins using [3 + 2]-annulation reactions of chiral,
nonracemic ꢀ-alkoxy allylsilanes 1 and 3.
Scheme 2. Synthesis of the Allylsilane Fragment 3
We targeted the synthesis of 10-hydroxytrilobacin3 (4a),
a natural acetogenin with a cis/erythro/trans bis-THF core
unit which displays high cytotoxicity toward two human
cancer cell lines, A-549 (LC50 ) 1.0 × 10-8 µg/mL) and
MCF-7 (LC50 ) 1.9 × 10-8 µg/mL).3 We anticipated 10-
hydroxytrilobacin (4a) could be generated by Sonogashira
coupling9 of the bis-THF alkyne fragment 5a and the
butenolide-containing vinyl iodide 6 (Scheme 1). The bis-
THF unit of 5a would be accessed by a nonchelate-controlled
[3 + 2]-annulation of cis-THF aldehyde 2a and allylsilane
3. On the basis of earlier studies, it was anticipated that this
[3 + 2]-annulation would be stereochemically mismatched8
and therefore synthetically challenging. The cis-THF alde-
hyde 2a would be derived from allylsilane 1 by a nonchelate-
controlled [3 + 2]-annulation.7c The allylsilane subunit of 3
would be introduced by using an asymmetric γ-silylallylbo-
ration reaction,10 whereas the chiral propargyl alcohol center
of 3 would be generated by transfer hydrogenation of a
propargyl ketone precursor.11 We anticipated that the buteno-
lide 6 could be obtained from the ꢀ-hydroxy-γ-lactone 8,
which in turn would be assembled via the aldol reaction of
ester 9 and aldehyde 10.
The synthesis of allylsilane 3 began with nucleophilic
addition of trimethylsilylethynyl lithium to methyl adipoyl
chloride (7),12 followed by a Noyori asymmetric transfer
hydrogenation using chiral catalyst 1213 which provided
propargyl alcohol 13 with 97% ee and 76% yield for two
steps (Scheme 2). After protection of 13 as the TBS ether
(97%), the ester unit of 14 was reduced by treatment with
DIBAL-H to yield aldehyde 15 (68%). Asymmetric allylation
of 15 with γ-silylallylborane 1610 and then protection of the
new hydroxyl group as a TBS ether afforded 3 in 65% yield
for the two steps, and with 95% ee.
The synthesis of the butenolide fragment 6 was initiated
by B-iododicyclohexylborane-mediated aldol reaction14 of
ester 9 and chiral aldehyde 10,15 followed by lactonization
triggered by treatment of the aldol mixture with HF (Scheme
3). Lactone 8 was obtained as the major component of a
mixture of diastereomers (4.7:1, ratio of 8 to the sum of three
(4) (a) Kojima, N.; Maezaki, N.; Tominaga, H.; Yanai, M.; Urabe, D.;
Tanaka, T. Chem.-Eur. J. 2004, 10, 672. For library approaches to mono-
THF acetogenins: (b) Kojima, N.; Maezaki, N.; Tominaga, H.; Asai, M.;
Yanai, M.; Tanaka, T. Chem.-Eur. J. 2003, 9, 4980. (c) Curran, D. P.;
Zhang, Q.; Richard, C.; Lu, H.; Gudipati, V.; Wilcox, C. S. J. Am. Chem.
Soc. 2006, 128, 9561.
(5) Das, S.; Li, L. S.; Abraham, S.; Chen, Z.; Sinha, S. C. J. Org. Chem.
2005, 70, 5922.
(6) Wysocki, L. M.; Dodge, M. W.; Voight, E. A.; Burke, S. D. Org.
Lett. 2006, 8, 5637.
(7) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. (b) Panek,
J. S.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Micalizio, G. C.; Roush,
W. R. Org. Lett. 2000, 2, 461.
(8) Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem. 2005, 70,
8035.
(12) Carbery, D. R.; Reignier, S.; Myatt, J. W.; Miller, N. D.; Harrity,
J. P. A. Angew. Chem., Int. Ed. 2002, 41, 2584.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(13) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 285.
(10) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett.
2000, 41, 9413.
(14) Ganesan, K.; Brown, H. C. J. Org. Chem. 1994, 59, 2336.
(15) Bongini, A.; Camerini, R.; Hofman, S.; Panunzio, M. Tetrahedron
Lett. 1994, 35, 8045.
(11) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
3372
Org. Lett., Vol. 10, No. 15, 2008

Scheme 3. Synthesis of Vinyl Iodide Fragment 6
Scheme 4. Stereodivergent Syntheses of Bis-THF Fragments 25a-d
minor isomers, 81% combined yield). The ꢀ-hydroxyl group
of 8 was protected as a p-methoxybenzyl ether (PMB) by
using p-methoxylbenzyl 2,2,2-trichloroacetimidate and cata-
lytic CSA.16 One-pot oxidative cleavage17 of the terminal
vinyl group then afforded aldehyde 18 in 78% yield for the
two steps. Asymmetric allylation18 of 18 provided allylation
product 19 with >20:1 ds (93% yield). Homoallylic alcohol
19 was then protected as a TBS ether, and the terminal vinyl
group was subsequently oxidatively cleaved17 to furnish
aldehyde 21 (81% yield). The vinyl iodide was then installed
under modified Takai alkenylation conditions,19 and the PMB
ether was removed using DDQ to give alcohol 23 (74% for
two steps). Finally, ꢀ-elimination of the hydroxyl group of
23 by treatment with MsCl and Et3N afforded butenolide
fragment 6 (86%).20
3 mediated by SnCl4 provided cis/erythro/trans bis-THF 25a
in 77% yield and with 15:1 diastereoselectivity. It was
previously determined that the bulky TBS ether side chain
in cis-THF aldehyde 2a prevents the chelation with SnCl4
in the stereochemically mismatched [3 + 2]-annulation
reaction of 2a with chiral, nonracemic allylsilanes homo-
chirally related to 3.8
We synthesized the three additional bis-THF diastereomers
by simple modification of the conditions for the two [3 +
2]-annulation reactions summarized in Scheme 4. Use of an
acetyl protecting group in 2b allows chelation of 2b and
SnCl4 in the stereochemically mismatched double asymmetric
[3 + 2]-annulation reaction with allylsilane 3,8 from which
the cis/threo/cis bis-THF 25b was obtained in 52% yield and
with 20:1 diastereoselectivity.
The bis-THF fragment 25a, needed for synthesis of 10-
hydroxytrilobacin, was synthesized as summarized in Scheme
4. Cis-THF aldehyde 2a was obtained from allylsilane 1 via
a known five-step sequence.8 The stereochemically mis-
matched8 [3 + 2]-annulation reaction of 2a and allylsilane
Allylsilane 1 was also used in the modular synthesis of
trans-THF 24b by the chelate-controlled [3 + 2]-annulation
with R-benzyloxyacetaldehyde, followed by protiodesilyla-
(20) The dehydration of 8 by treatment with MsCl and Et3N was studied
to determine if epimerization of the butenolide occurs under the mildly
basic elimination conditions. As shown below, the dehydration of 8 via
mesylate elimination proceeds without detectable racemization.
(16) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(17) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(18) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(19) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
Org. Lett., Vol. 10, No. 15, 2008
3373

HF provided 10-hydroxy-trilobacin (4a). The enantiomeric
purity of the butenolide unit of 4a was determined to be
g98% ee by NMR analysis on the bis-Mosher ester species
derived from the 2′,4-diol obtained by protection of 4a as
the tetra-TBS ether followed by LiAlH4 reduction.24 The
spectroscopic properties of synthetic 10-hydroxytrilobacin,
as well as of the tetra-Mosher esters prepared from 4a, were
in complete agreement with literature values.3 The longest
linear sequence of this synthesis of 10-hydroxytrilobacin was
13 steps, originating from commercially available methyl-
4-pentenoate (9).
Scheme 5
.
Synthesis of 10-Hydroxytrilobacin and Three
Diastereomeric Acetogenins
The diastereomeric bis-THF fragments 25b-d were
subjected to the same synthetic sequence as described for
25a, leading to the successful synthesis of three analogues
of 10-hydroxytrilobacin: unnatural 4,10-dihydroxysquamo-
cin-N (4b),25 10-hydroxyasimicin (4c),3 and the unnatural
acetogenin 4d. Spectroscopic properties for 4c were in
excellent agreement with literature values.3 Results of
biological evaluation of these compounds will be reported
elsewhere.
In conclusion, we have developed a convergent and highly
stereoselective synthesis of 10-hydroxytrilobacin (4a). By
utilizing nonchelate- and chelate-controlled [3 + 2]-annu-
lation reaction conditions, we also achieved the modular
synthesis of three diastereomers of 10-hydroxytrilobacin from
the same precursors 1, 3, and 6. We anticipate that this
strategy for synthesis of adjacent bis-THF acetogenins can
be expanded to include use of the enantiomer 1, both
enantiomers of the syn diastereomer of 1,26 and allylsilane
diastereomers of 3. This chemistry has the potential to
provide a stereochemically diverse library of bis-THF
acetogenins. Studies along these lines will be reported in
due course.
tion.21 Further elaboration of trans-THF 24b to aldehyde 2c
followed by stereochemically matched double asymmetric
[3 + 2]-annulation reactions with 3 led to the trans/threo/
trans (25c) and the trans/erythro/cis (25d) bistetrahydro-
furans via SnCl4-mediated chelate-controlled and BF3·OEt2-
mediated nonchelate-controlled annulations, respectively,
both with >20:1 dr.
With four diastereomeric bis-THF fragments (25a-d) in
hand, their conversion to natural and unnatural acetogenins
4a-d was completed (Scheme 5). First, bis-THF 25a, the
precursor to 10-hydroxytrilobacin, was subjected to pro-
tiodesilylation conditions (TBAF, DMF, 80-85 °C).21 These
conditions effected removal of the C-phenyldimethylsilyl
group as well as the three TBS ethers and the alkynyl silane
and gave alkyne 5a in 64% yield. Sonogashira coupling9 of
alkyne 5a and butenolide 622 was followed by enyne
reduction using a large excess of TsNHNH2 and NaOAc.23
Finally, removal of the TBS ether of 26a by treatment with
Acknowledgment. This work was supported by the
National Institutes of Health (GM038436)
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801242D
(23) Dewey, R. S.; van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83,
3729.
(21) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley,
J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
(24)
(22) Our original plan was to deprotect the C(4)-OTBS ether of 6 prior
to the Sonogashira reaction with 5a. This sequence provided i uneventfully
(55% yield). However, reduction of the enyne unit of i provided 10-
hydroxytrilobacin contaminated with an inseparable impurity. This problem
required that we use the TBS ether protected vinyl iodide 6 in Scheme 5.
(25) References for the closely related natural product squamocin-N,
see: (a) Sahai, M.; Singh, S.; Singh, M.; Gupta, Y. K.; Akashi, S.; Yuji,
R.; Hirayama, K.; Asaki, H.; Araya, H.; Hara, N.; Eguchi, T.; Kakinuma,
K.; Fujimoto, Y. Chem. Pharm. Bull. 1994, 42, 1163. (b) Araya, H. Bull.
Natl. Inst. Agro-EnViron. Sci. 2004, 23, 77.
.
(26) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 4315.
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