Chemoenzymatic synthesis of trans -tetrahydrofuran cores of annonaceous acetogenins from bromobenzene

Article abstract of DOI:10.1021/ol400650v

Two types of trans-THF cores, present in acetogenins, have been synthesized by an intramolecular iodoetherification reaction. The starting alkenol was obtained in a few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The cyclization gave complete stereoselectivity for trans-THF cores with either (S,S) or (R,R) configurations at the THF chiral carbons.

Full text of DOI:10.1021/ol400650v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Chemoenzymatic Synthesis
of trans-Tetrahydrofuran Cores
of Annonaceous Acetogenins
from Bromobenzene
Juan Carlos Ramos, Margarita Brovetto,* and Gustavo A. Seoane*
´
ꢀ
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de la Repuꢀblica,
C.C. 1157 Montevideo, Uruguay
mbrovetto@fq.edu.uy; gseoane@fq.edu.uy
Received March 11, 2013
ABSTRACT
Two types of trans-THF cores, present in acetogenins, have been synthesized by an intramolecular iodoetherification reaction. The starting
alkenol was obtained in a few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The cyclization gave complete
stereoselectivity for trans-THF cores with either (S,S) or (R,R) configurations at the THF chiral carbons.
Annonaceous acetogenins are a large family of natural
products isolated from tropical plants belonging to the
Annonaceaefamily, comprisingmorethan430 members,1,2
displaying an ample array of biological activity such as
antitumor, pesticidal, antimalarial, immunosuppressive,
and antifeedant activities.3À5 Structurally, acetogenins
are characterized by one to three tetrahydrofuran (THF)
ring(s) flanked by two R-hydroxylated, long hydrocarbon
chains, one of them containing an R,β-unsaturated γ-lactone
residue at the end, which is essential for activity (Figure 1).
The THF core has been considered the site for mitocondrial
membrane recognition, and SAR studies have shown
that bis-trans-THF acetogenins are among the most potent
compounds of this family,3a,4c the cytotoxicity being
modulated by the stereochemistry of the THF core.6
Although many synthetic methodologies have been devel-
oped for the preparation of mono- and bis-THF cores of
(1) For recent reviews on annonaceous acetogenins, see: (a) Spurr,
I. B. B.; Richard, C. D. Molecules 2010, 15, 460–501. (b) McLaughlin,
ꢀ
J. L. J. Nat. Prod. 2008, 71, 1311–1321. (c) Bermejo, A.; Figadere, B.;
Zafra-Polo, M C; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod.
Rep. 2005, 22, 269–303.
(2) (a) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 1998, 4175–4200.
(b) Elliott, M. C. J. Chem. Soc., Perkin Trans. 2000, 1, 1291–1318.
(c) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G. Chemtracts Org.
Chem 1998, 11, 803–827. (d) Elliott, M. C.; Williams, E. J. Chem. Soc.,
ꢀ
Perkin Trans. 1 2001, 2303–2340. (e) Figadere, B. Acc. Chem. Res. 1995,
28, 359–365.
(3) (a) Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin,
J. L. Biochemistry 1998, 37, 854–866. (b) Pomper, K. W.; Lowe, J. D.;
Crabtree, S. B.; Keller, W. J. Agric. Food Chem. 2009, 57, 8339–8343. (c)
ꢁ
Chavez, D.; Mata, R.; Iglesias-Prieto, R.; Lotina-Hennsen, B. Physiol.
Plant. 2001, 111, 262–268.
(4) (a) Wolvetang, E.; Johnson, K. L.; Kramer, K.; Linnane, A. W.
(5) Oberlies, N. H.; Croy, V. L.; Harrison, M. L.; McLaughlin, J. L.
Cancer Lett. 1997, 15, 73–79.
ꢀ
ꢀ
FEBS Lett. 1994, 339, 40–44. (b) Derbre, S.; Roue, G.; Poupon, E.;
Susin, S. A.; Hocquemiller, R. ChemBioChem 2005, 6, 979–982. (c)
Kuwabara, K.; Takada, M.; Iwata, J.; Tatsumoto, K.; Sakamoto, K.;
Iwamura, H.; Miyoshi, H. Eur. J. Biochem. 2000, 267, 2538–2546. (d)
Eskobar-Khondiker, M.; Hlloerhage, M.; Muriel, M.-P.; Champy, P.;
Bach, A.; Depienne, C.; Respondek, G.; Yamada, E. S.; Lannuzel, A.;
Yagi, T.; Hirsch, E. C.; Oertel, W. H.; Jacob, R.; Michel, P. P.; Ruberg,
M.; Hoglinger, G. U. J. Neurosci. 2007, 27, 7827–7837.
(6) (a) Kuwabara, K.; Takada, M.; Iwata, J.; Tatsumoto, K.; Sakamoto,
K.; Iwamura, H.; Miyoshi, H. Eur. J. Biochem. 2000, 267, 2538–2546. (b)
Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin, J. L. Biochem-
istry 1998, 37, 854–866. (c) Yang, H.; Zhang, N.; Li, X.; Chen, J.; Cai, B.
Bioorg. Med. Chem. Lett. 2009, 19, 2199–2202. (d) Sinha, S. C.; Chen, Z.;
Huang, Z.-Z; Nakamaru-Ogiso, E.; Pieytaszkiewicz, H.; Edelstein, M.;
Valeriote, F. J. Med. Chem. 2008, 51, 7045–7048.
r
10.1021/ol400650v
XXXX American Chemical Society

these compounds;7 there is still interest in the development
of new methodologies for synthetic routes with high
selectivity and divergency.
Scheme 1
Figure 1. Representative structure of annonaceous acetogenins.
Our group has been working on the enantioselective
synthesis of THF rings, in connection with our ongoing
efforts to prepare marine natural products.8 Also, as part
of a continuous program to employ microbially derived
and enantiomerically pure cis-cyclohexadienediols such as
1 as synthons for organic synthesis, herein we present an
efficient synthetic sequence that enables the preparation
of trans-THF cores with either (S,S) or (R,R) configura-
tion at the THF chiral carbons, in arrangements similar to
those found in natural acetogenins.
The sequence for both THF cores started with the
toluenedioxygenase-mediated oxidationofbromobenzene
to produce enantiopure cis-diol 1, usingPseudomonas putida
F39/D as a whole-cell biocatalytic system (Scheme 1).9,10
Reduced diol 2 was obtained in 90% through selective
hydrogenation with diimide generated in situ.11 Protection
of the diol functionality as acetonide followed by ozonolysis
in the presence of NaHCO3, using DMS in the reductive
step, afforded esterÀaldehyde 4 in 76% combined yield.8
Wittig reaction of 4 using Boden conditions8 gave
alkenol 5, which is a common precursor in both synthetic
routes for (R,R) and (S,S) trans-THF rings. Compound 5
was obtained in an overall yield of 58% through a five-step
sequence starting from bromobenzene.
For the key cyclization step we chose the simple halo-
etherification methodology12 over protected 3-butenyl-
carbinol 5. The reaction can be performed on a free
alkenol, but it is known that the presence of protecting
groups on the alcohol dramatically affects the stereo-
chemical outcome.13 In particular, the presence of cyclic
protecting groups at the vic-diol system in these structures
induces a complete trans diasteroselectivity in the forma-
tion of THF rings.12a,b Pursuing the idea of using con-
formationally restrictedalkenolsasa template for thetrans
selective halocyclization, we performed the reaction under
different conditions, changing the halonium source, base,
solvent, temperature, and also using complexing agents
for the diol system .14 After some experimentation with
different halonium sources (NIS, NBS, I2), best results in
terms of yield and selectivity were obtained with iodonium
dicollidine perchlorate (I(Coll)2ClO4, IDCP) for the pro-
tected vic-diol 5. Thus, treatment of 5 with IDCP in wet
acetonitrile at different temperatures, led to the formation
of diastereomeric mixtures of THF rings with high trans
selectivity, but contaminated with variable amounts of
iodohydrin 7 (Table 1, entries 1À3).
(7) (a) Hoppen, S.; Baurle, S.; Koert, U. Chem.-Eur. J 2000, 6, 2382–
2396. (b) Wang, Z. M.; Tian, S. K.; Shi, M. Eur. J. Org. Chem. 2000, 349–
356. (c) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc.
Rev. 2000, 29, 109–118. (d) Dixon, D. J.; Ley, S. V.; Reynolds, D. J.
Angew. Chem., Int. Ed. 2000, 39, 3622–3626. (e) Avedissian, H.; Sinha,
S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org.
Chem. 2000, 65, 6035–6051. (f) Ruan, Z. M.; Dabideen, D.; Blumenstein,
M.; Mootoo, D. R. Tetrahedron 2000, 56, 9203–9211. (g) Albarella, L.;
Musumeci, D.; Sica, D. Eur. J. Org. Chem. 2001, 997–1003. (h) Hu, T. S.;
Yu, Q.; Wu, Y. L.; Wu, Y. K. J. Org. Chem. 2001, 66, 853–861. (i) Dixon,
D.; Ley, S.; Reynolds, D. Chem.;Eur. J. 2002, 8, 1621–1636. (j)
Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002, 4,
1083–1085. (k) Wang, F.; Kawamura, A.; Mootoo, D. Bioorg. Med.
Chem. 2008, 16, 8413–8418. (l) Brown, L.; Spurr, I.; Kemp, S.; Camp, N.;
Gibson, K.; Brown, R. Org. Lett. 2008, 10, 2489–2492.
(8) Brovetto, M.; Seoane, G. J. Org. Chem. 2008, 73, 5776–5785.
(9) Brovetto, M.; Schapiro, V.; Cavalli, G.; Padilla, P.; Sierra, A.; Seoane,
G.; Suescun, L.; Mariezcurrena, R. New J. Chem. 1999, 23, 549–555.
(10) (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichimica Acta
1999, 32, 35–62. (b) Banwell, M.; Edwards, A. J.; Harfoot, G. J.; Jolliffe,
K. A.; McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vogtle, M. Pure
Appl. Chem. 2003, 75, 223–229. (c) Johnson, R. A. Org. React 2004, 63,
117–264.
To diminish the formation of this compound, the reac-
tion was carried out at lower temperature and also in the
absence of water. However, under these conditions the
reaction did not proceed (entries 4À5). Regarding the
(12) (a) Zhang, H.; Seepersaud, M.; Seepersaud, S.; Mootoo, D. R.
J. Org. Chem. 1998, 63, 2049–2052. (b) Zhang, H.; Mootoo, D. R. J. Org.
Chem. 1995, 60, 8134–8135. (c) Maezaki, N.; Kojima, N.; Sakamoto, A.;
Iwata, C.; Tanaka, T. Org. Lett. 2001, 3, 429–432.
(13) Bartlett, P. A. Tetrahedron 1980, 36, 3–72.
(14) Cyclization studies were carried out using compound 5 and its
deprotected diol, with different halonium sources (NIS, NBS, I2, IDCP),
bases (K2CO3, DBU, NaH, KHMDS), carbonate counterions (Na2CO3,
Cs2CO3, CaCO3, PbCO3, CdCO3), complexing diol sources (CuCl2,
PhB(OH)2, CuSO4, montmorillonite), solvents (MeCN, toluene, THF,
DMF, CH2Cl2, hexanes), and temperatures(À20°C to rt) (see Supporting
Information).
(11) Fonseca, G.; Seoane, G. Tetrahedron: Asymmetry 2005, 16,
1393–1402.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Cyclization Studies
entry
1
conditions
time (h)
0.2
yield
70%
6 trans:6 cis:7a
IDCP, CH3CN:H2O
(99:1), rt
10:1:5
2
3
4
5
IDCP, CH3CN:H2O
(99:1), À10 °C
IDCP, CH3CN:H2O
(99:1), À20 °C
IDCP, CH3CN:H2O
(95:5), À40 °C
IDCP, CH3CN
À20 °C f rt
24
48
48
48
70%
65%
10:1:3
10:1:2
No reaction
No reaction
Figure 2. Proposed rationale for the diminished trans selectivity
observed when an ester group is present.
a Determined by 1H NMR
Scheme 2
stereochemical assignments, they are not easy for 2,5-
disubstituted THFs, due to the small NOE enhancements
observed in these systems; hence, we decided to take
advantage of the functionalities present in the substituents
and use chemical means for this task. Thus, treatment of
the isomeric mixture of THFs with DBU in CH2Cl2 led to
the cyclization of the cis-isomer to obtain a bicyclic
compound, leaving the trans-isomer unchanged and con-
firming the high trans selectivity of the THF-forming
cyclization (see Supporting Information). Despite pre-
vious reports on this type of system that mentioned a
complete stereoselection,12a,b with our compound both
cis- and trans-THF rings were obtained, suggesting that
the iodonium intermediate was formed through electro-
philic attack on both faces of the double bond. These
results, together with halocyclization studies performed in
our laboratory using I2-K2CO3 on compound 5 and its
deprotected analogue14 which gave always diastereomeric
mixtures, led us to believe that there is a stabilizing
interaction (involving electron-deficient and electron-rich
orbitals) between the iodonium and the carbonyl group of the
ester, respectively.15 Inspection of models for both modes of
cyclization is in agreement with such type of interaction
taking place only in the conformation leading to the cis-
isomer, decreasing the net unfavorable steric hindrance pro-
duced by the protecting group of the diol and thus lowering
the overall trans selectivity of the reaction (Figure 2).
To our delight, upon reduction of the ester group the
reaction of the alcohol substrate with electrophilic iodine
generated the trans-THF ring with complete stereoselec-
tivity. This selectivity was also maintained for the different
protecting groups tested (8À10), although the cyclization
yields varied. Best results were obtained using the benzyl
ether, yielding 80% of the trans-THF 14. Interestingly,
when cyclization was performed on the unprotected alco-
hol 8, diol 11 was formed in 32%, and not surprisingly,
acetonide 12 was also obtained in 37% yield, resulting
from acetonide migration. This result, coupled to the need
of a suitable protection for the terminal vic-diol system, led
us totestthe cyclization in the absenceofwater (Scheme 3).
In these conditions (S,S)-trans-THF 12 was obtained as a
single isomer in 96% yield, resulting from intramolecular
attack of the primary OH to the oxonium cation formed
during the cyclization. The reasons to explain the lack of
reactivity of 5 compared to that of 8 are not clear.
We reasoned that the stabilizing interaction would be
eliminated by reduction of the ester, allowing a complete
selectivity in the formation of the preferred trans-THF
ring. With this hypothesis in mind, the ester group in
compound 5 was reduced using LiAlH4 and then protected
with different groups to try the cyclization (Scheme 2).
(15) (a) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, P. J. Am.
Chem. Soc. 1988, 110, 4533–4540. (b) Chamberlin, A. R.; Mulholland,
R. L., Jr.; Scott, D. K.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672–677.
(c) aBedford, S. B.; Fenton, G.; Knight, D. W.; Shaw, D. Tetrahedron Lett.
1992, 33, 6505–6506. (d) Bennett, F.; Bedford, S. B.; Bell, K. E.; Fenton, G.;
Knight, D. W.; Shaw, D. Tetrahedron Lett. 1992, 33, 6507–6510.
At this point we were able to synthesize (S,S)-trans-THF
12 with complete stereoselectivity and 47% overall yield, in
six steps from bromodiol 1.
Org. Lett., Vol. XX, No. XX, XXXX
C

With both trans-THF cores in hand, the next step is the
conversion of the iodomethyl substituent in a formyl
group, needed to prepare the R-hydroxyalkyl chain of
the acetogenins via an organometallic addition. Therefore,
alcohol formation by reaction withpotasium superoxide in
DMSO,17 in both (S,S)-trans-THF 12, and (R,R)-trans-
THF 16, followed by Swern oxidation afforded aldehydes
17 and 18 in 49% overall yield (Scheme 5). The alde-
hydes can be used not only to form the side chain of
the annonaceous acetogenins but also to prepare an ad-
jacent THF ring by addition of an homoallylic residue and
further halocyclization of the resulting 3-butenylcarbinol
in an iterative fashion.
Scheme 3
On the other hand, for the (R,R)-trans-THF rings an
inversion of configuration at the alcohol participating in
the cyclization is necessary. Thus, deprotection of the diol
functionality in compound 5, followed by Mitsunobu
inversion16 and further hydrolysis of the resulting p-nitro-
benzoate ester, affored diol 15 in 39% yield for the three steps.
It is noteworthy that the inversion protocol, performed on
the free diol, gave exclusively the product of inversion at the
C3-OH, probably due to the inductive effect of the ester group
lowering the nucleophilicity of the R-OH. Also, best yields
were obtained using the more reactive tributyl phosphine and
DIAD, compared to triphenyl phosphine and DEAD.
Scheme 5
In conclusion, we have developed a highly stereoselec-
tive synthesis of both trans-THF cores present in aceto-
genins, starting from a chiral cis-diol obtained from
microbial oxidation of bromobenzene. As THF rings of
type 17 and 18 can be functionalizedat both substituents to
form R-hydroxyalkyl chains, our strategy can be easily
applicable to the synthesis of a series of natural aceto-
genins. Also, the extension of this methodology to the
preparation of bis- and tris-THF cores present in aceto-
genins is currently being developed in our laboratory.
Scheme 4
Acknowledgment. Financialsupport from thefollowing
organizations is kindly acknowledged: ANII (Agencia
ꢀ
Nacional de Investigacion e Innovacion, Uruguay) Project
FCE 2009-1-3094, PEDECIBA (Programa de Desarrollo
ꢀ
ꢀ
de las Ciencias Basicas, PNUD), Facultad de Quımica-
´
Under those conditions, the sequence performed on the
free diol afforded a higher overall yield than that using a
compound monoprotected selectively on the R-OH. After
inversion, the syn-diol was reprotected as acetonide, the
ester group was reduced, and the cyclization with IDCP in
CH3CN gave the trans-THF in high yield (96%) with
complete stereoselectivity (Scheme 4). The entire sequence
for (R,R)-trans-THF cores of type 16 can be performed
with complete stereoselectivity and 20% overall yield in
10 steps from bromodiol 1.
ꢀ
Universidad de la Republica. J.C.R thanks ANII for a
fellowship.
Supporting Information Available. 1H and 13C NMR
spectra of compounds 3À18 and experimental procedures
for 4 to 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Brimble, M. A.; Carley, S. Org. Lett. 2009, 11, 563–566.
(16) Mitsunobu, O. Synthesis 1981, 1.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX