Sequencing of three-component olefin metatheses: Total synthesis of either (+)-gigantecin or (+)-14-deoxy-9-oxygigantecin

Article abstract of DOI:10.1021/ol061383u

An efficient, flexible, and highly convergent strategy for accessing skipped bis-THF containing Annonaceous acetogenins is demonstrated by the synthesis of each of (+)-gigantecin (1) and its constitutional isomer (+)-14-deoxy-9-oxygigantecin (11). The skeleton of each compound is produced, at will, from the same precursors via a three-component ring-closing/cross- metathesis sequence that differs only in the ordering of the RCM vs CM events. Another notable aspect is the use of in situ epoxide-closing and -opening of iodohydrins with dimethylsulfonium methylide to provide inverted allylic alcohols.

Full text of DOI:10.1021/ol061383u

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3383-3386
Sequencing of Three-Component Olefin
Metatheses: Total Synthesis of Either
(
+
)-Gigantecin or
)-14-Deoxy-9-oxygigantecin
(+
Thomas R. Hoye,* Brian M. Eklov, Junha Jeon, and Mila Khoroosi
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hoye@chem.umn.edu
Received June 6, 2006
ABSTRACT
An efficient, flexible, and highly convergent strategy for accessing skipped bis-THF containing Annonaceous acetogenins is demonstrated by
the synthesis of each of ( )-gigantecin (1) and its constitutional isomer ( )-14-deoxy-9-oxygigantecin (11). The skeleton of each compound
+
+
is produced, at will, from the same precursors via a three-component ring-closing/cross-metathesis sequence that differs only in the ordering
of the RCM vs CM events. Another notable aspect is the use of in situ epoxide-closing and -opening of iodohydrins with dimethylsulfonium
methylide to provide inverted allylic alcohols.
Here we describe an efficient, highly convergent chemical
synthesis of (+)-gigantecin (1)1,2 utilizing a one-pot, three-
component olefin metathesis coupling strategy. This potent
cytotoxic antitumor agent, a rare nonadjacent bis-THF-
containing acetogenin, was isolated both from the bark of
Goniothalamus giganteus (Annonaceae) in Southeast Asia1
and from the seeds of the Brazilian plant Annona coriacea.2
A synthesis of (+)-gigantecin was achieved by Crimmins
and She in 2004.3
Our retrosynthetic strategy (Scheme 1) relied upon two
staged metathesis eventssa bimolecular diene cross-meta-
thesis4,5 and a unimolecular, silicon-tethered ring-closing
metathesis6 to form the C7/C8 and C15/C16 bonds, respec-
tively. Fragments 3-5, all of similar structural complexity,
were identified as the building blocks. We envisioined that
the propinquity of the latter two would be enforced via the
mixed silaketal 6. Treatment with a ruthenium-based me-
tathesis initiator in the presence of alkene 3 would then
(4) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360-11370.
(1) (a) Alkofahi, A.; Rupprecht, J. K.; Liu, Y. M.; Chang, C.-J.; Smith,
D. L.; McLaughlin, J. L. Experientia 1990, 46, 539-541. (b) Rupprecht, J.
K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278 (c) Gu,
Z.-M.; Fang, X.-P.; Zeng, L.; Song, R.; Ng, J. H.; Wood, K. V.; Smith, D.
L.; McLaughlin, J. L. J. Org. Chem. 1994, 59, 3472-3479.
(2) Yu, J.-G.; Hu, X. E.; Ho, D. K.; Bean, M. F.; Stephens, R. E.;
Cassady, J. M. J. Org. Chem. 1994, 59, 1598-1599.
(5) For use of a related CM reaction in the synthesis of adjacent bis-
THF acetogenins, see: Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.;
Lee, E. J. Am. Chem. Soc. 2005, 127, 10396-10399.
(6) For application of a related RCM to the synthesis of the skipped
THP/THF acetogenin, mucocin, see: Evans, P. A.; Cui. J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702-14703.
For application to the skipped bis-THF, bullatanocin, see: Zhu, L.; Mootoo,
D. R. J. Org. Chem. 2004, 69, 3154-3157.
(3) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790-
12791.
10.1021/ol061383u CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

epoxide formation upon treatment with dimethylsulfonium
methylide (Me2SdCH2) followed by ring-opening provided
the inverted allylic alcohol 4.9 The synthesis of 5 (Scheme
2) began with DIBAL-H reduction of 9, the TIPS ether of a
known lactone.10 Wittig olefination of the lactol, reduction
to the corresponding allylic alcohol, and another trans-
selective iodoetherification provided 10. This iodohydrin was
also subjected to Me2SdCH2 to give the inverted allylic
alcohol 5. Finally, mixed silaketal 6 was prepared by
sequential loading of 5 and then 4 onto Ph2SiCl2.11
Scheme 1. Dual Metathetical Retrosynthetic Strategya
We first explored the ring-closing metathesis (RCM)
behavior of the mixed silaketal by itself. Namely, 6 (830
amu) was exposed to a metathesis initiator (the second-
generation Hoveyda-Grubbs complex12) to induce unimo-
lecular RCM. The resulting cyclic diene (830-28 amu) was
immediately treated with 3 (4 equiv) and G2 [RudCHPh-
(Cl)2 (PCy3)(DHIMes)]13 to induce cross-olefin methathesis
(CM), the successful outcome of which was evidenced by
an (molecular) ion at 1126 amu (ESI MS). Diimide reduction
(to 1130 amu)14 and desilylation (HF, MeCN), followed by
purification (SiO2), provided a compound having the mass
of gigantecin (1). However, critical inspection of its 1H and
13CNMRspectrarevealedsubtlebutnonignorabledifferencess
the product that had arisen from this “RCM then CM”
sequence was not gigantecin. Moreover, the melting point
(117-119 °C) of this isomer exceeded that of 1 (108-109
°C).
a Key: (a) hydrogenation; global desilylation; (b) three-
component olefin metathesis coupling. For alkene reactivity “types”,
see ref 4.
produce triene 2, which has the gigantecin (1) constitution.
We presumed that chemoselective saturation of the disub-
stituted alkenes and global desilylation would be straight-
forward and provide 1.
Butenolide fragment 3 was prepared7 by a precedented
sequence.7c Allylic alcohol 4 was synthesized (Scheme 2)
by Leighton asymmetric allylation of aldehyde 7,8 ester
reduction, and iodoetherification to give iodohydrin 8. In situ
Recalling that analysis of electron impact mass spectral
fragmentation patterns has played an important role in the
assignment of connectivity and constitution of new members
of the acetogenin family of natural products,1b we scrutinized
this isomer of 1 in that way, thereby deducing it to be 14-
deoxy-9-oxygigantecin (11). The diagnostic fragmentation
patterns for 11 (and 1)1b are summarized in Figure 1 (and
further detailed in the Supporting Information).
How 11 had arisen from the sequential RCM of 10 and
CM with 3 was revealed through analysis of the initial RCM
product. Instead of providing the seven-membered cyclic
silaketal, the RCM had yielded, instead, the 11-membered
silaketal 12 (Scheme 3). In retrospect, this can easily be
explained through preferential initiation of RCM at the least
hindered, type I,4 ∆8,8′-alkene in 10. The resulting alkylidene
Scheme 2. Construction of the Silaketal Triene 10a
(7) (a) Opening of (R)-1,2-epoxyhex-5-ene7b with the TBS ether of (S)-
1-lithiobut-1-yn-3-ol, TIPS protection, TBS removal, Red-Al reduction and
iodination of the alkyne, and carbonylative lactonization7c gave 3. (b)
Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 20,
6776-6777. (c) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801-
1802.
(8) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946-
948.
(9) (a) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall,
T.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449-5452. (b)
Whitehead, A.; McReynolds, M. D.; Moore, J. D.; Hanson, P. R. Org. Lett.
2005, 7, 3375-3378.
(10) Wang, Z.; Zhang, X.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi,
A.; Keinan, E. Tetrahedron Lett. 1992, 33, 6407-6410.
(11) (a) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-
6769. (b) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-
1432.
(12) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(13) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(14) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996-6000.
a Reagents and conditions: (a) Leighton allylation,8 CH2Cl2, -20
°C (87%); (b) DIBAL-H, PhMe, 0 °C to rt; (c) I2, K2CO3, THF,
-78 °C (33% yield from 7); (d) Me3S+I-, n-BuLi, THF, -45 °C
tort(71%);(e)DIBAL-H,hexanes,-78°C;(f)Ph3PCHCO2CH2CH3,
PhMe, 80 °C; (g) DIBAL-H, CH2Cl2, -78 °C to rt (87% yield
from 9); (h) I2, K2CO3, THF, -78 °C (63%); (i) Me3S+I-, n-BuLi,
THF, -45 °C to rt (81%); (j) 5, Ph2SiCl2, pyridine, PhMe, 0 °C to
rt, then 4, pyridine, PhMe, 0 °C to rt (52%).
3384
Org. Lett., Vol. 8, No. 15, 2006

Scheme 4. “CM then RCM” Sequence (to 1)a
Figure 1. Comparative and diagnostic EI mass spectrometric
fragmentation patterns for gigantecin (1)2 vs 14-deoxy-9-oxygi-
gantecin (11).
Scheme 3. “RCM then CM” Sequence (to 11)a
a Reagents and conditions: (a) G2 (20 mol %), CH2Cl2, 45 °C,
syringe pump addition (9 h) (63%); (b) TsNHNH2, NaOAc, H2O,
DME, ∆ (79%); (c) 5% HF/MeCN, CH2Cl2, rt (87%).
combined and exposed to G2. The major products were 2
(63%, from CM of 3 with 10) and the self-metathesis dimer
of 3 (which could be recycled by metathesis cleavage in the
presence of ethylene). A small amount of 13 (ca. 10%) was
competitively produced. Diimide reduction and global depro-
tection gave 1 (69%, mp 108-109 °C2). It should be
emphasized that 2 was produced, now in a one-pot operation,
from precisely the same pair of precursors as was used to
generate 13 via “RCM then CM.”
A side comment about the 1H NMR spectra of our samples
of 1 vs 11 is in order. These are presented in Figure 2. Not
surprisingly, they are quite similar. In fact, if we compare
the data set for each of these isomerssat the level of a
standard, tabulated listing of chemical shifts and discernible
coupling constantsswith the sets reported for natural gigan-
tecin (1),1c,2 we cannot conclude which is the better match.15
However, Visual comparison of the two vis-a`-vis that of
natural 1 (see Figure 2 as well as the Supporting Information
for ref 2) clearly permits this distinction to be made. This
underscores the value, for comparison purposes, of having
access to “pictures” of authentic spectra whenever possible.
a Reagents and conditions: (a) second-generation Hoveyda-
Grubbs initiator (15 mol %), PhMe, 80 °C (67%); (b) G2 (20 mol
%), 3, CH2Cl2, 45 °C; (c) TsNHNH2, NaOAc, H2O, DME, ∆; (d)
5% HF/MeCN, CH2Cl2, rt (48% from 12).
then closed onto the distal, ∆16,16′-alkene to produce the
bicyclo[8.2.0] framework. This outcome is perhaps somewhat
surprising given the 2,5-trans-substituted THF ring that is
embedded within that new skeleton. The subsequent CM with
3 had given, rather than 2, its constitutional isomer 13.
Following alkene reduction and desilylation, this turn of
events expressed itself in the apparent relocation of the
carbinol center from C14 to C9 (cf., 11 vs 1).
In summary (Scheme 5), we have shown that either
gigantecin (1) or its constitutional isomer 11 can be as-
sembled efficiently (13 or 14 linear steps, respectively) via
a highly convergent, three-component metathetical coupling
from the same precursors (i.e., 3 and 6) simply by reversing
the order of the two metathesis events. Specifically, RCM
of 6 followed by CM with 3 gave 11, whereas initial CM of
To overcome this obstacle and to successfully construct
(+)-gigantecin (1), we simply reversed the order of the two
metathesis reactions (Scheme 4). Namely, we changed to
the “CM then RCM” sequence. Triene 10 and alkene 3 (1:4
molar ratio), each of which contains a type I alkene, were
(15) For two other examples, see: (a) Trost, B. M.; Dirat, O.; Gunzner,
J. L. Angew. Chem., Int. Ed. 2002, 41, 841-843. (b) Zhang, Q.; Lu, H.;
Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004, 126, 36-37.
Org. Lett., Vol. 8, No. 15, 2006
3385

Figure 2. Proton NMR spectra (500 MHz, CDCl3) for (a) 14-deoxy-9-oxygigantecin (11) and (b) (+)-gigantecin (1) samples prepared in
the work described here.
These results underscore the importance of properly se-
quencing multistage metathesis processes.
Scheme 5. Summary of the Complementary Sequences
Acknowledgment. This investigation was supported by
a grant awarded by the DHHS (CA76497). We also
acknowledge with appreciation earlier guiding studies in our
laboratories by Andrew S. Judd, Michele A. Promo, and
Tricia J. Vos.
Supporting Information Available: Spectroscopic char-
acterization data and procedures for preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
3 with 6 followed by RCM (of intermediate 14) gave 1.
OL061383U
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Org. Lett., Vol. 8, No. 15, 2006