Total synthesis of herboxidiene/GEX 1A

Article abstract of DOI:10.1021/ol701427k

A convergent enantioselective synthesis of herboxidiene/GEX 1A (1) is described that features a double stereodifferentiating crotylation, [4 + 2] annulation, and a silicon-based sp²-sp² cross-coupling to assemble the conjugated diene

Full text of DOI:10.1021/ol701427k

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3141-3143
Total Synthesis of Herboxidiene/GEX 1A
Yun Zhang and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity, 590
Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received June 18, 2007
ABSTRACT
A convergent enantioselective synthesis of herboxidiene/GEX 1A (1) is described that features a double stereodifferentiating crotylation, [4
2] annulation, and a silicon-based sp2 sp2 cross-coupling to assemble the conjugated diene.
+
−
Herboxidiene/GEX 1A (1), a secondary metabolite originally
isolated from Streptomyces sp. A7847, displayed selective
phytotoxicity against a range of broadleaf annual weeds while
remaining harmless to coplanted wheat.1 In a search for new
antitumor agents, 1 was reisolated from a fermentation
culture broth with five other structurally related GEX 1
members (2-6, Figure 1).2 While several members of this
family showed potent cytotoxicity (IC50 values ranging from
3.7 nM to 0.99 µM) against several human tumor cell lines
in vitro, GEX 1A is the only one possessing antitumor
activity in vivo. The entire family of GEX 1 compounds
displayed cytotoxicity via up-regulating luciferase reporter
gene expression as well as inducing both G1 and G2/M arrest
in human tumor cell line WI-38.3 The stereochemical
assignment of 1 was obtained through a combination of
degradation studies, partial synthesis, and crystallographic
analysis.4 The class of natural products possesses several
synthetically challenging structural features, including the
trisubstituted tetrahydropyran core, the conjugated diene
moiety, and the polyoxygenated side chain. Two total
syntheses and several synthetic approaches toward herboxi-
diene/GEX 1A have recently been published.5
Herein, we describe a convergent enantioselective syn-
thesis of herboxidiene/GEX 1A (1) that makes use of
(1) Isaac, B. G.; Ayer, S. W.; Elliott, R. C.; Stonard, R. J. J. Org. Chem.
1992, 57, 7220.
(2) Sakai, Y.; Yoshida, T.; Ochiai, K.; Uosaki, Y.; Saitoh, Y.; Tanaka,
F.; Akiyama, T.; Akinaga, S.; Mizukami, T. J. Antibiot. 2002, 55, 855.
(3) Sakai, Y.; Tsujita, T.; Akiyama, T.; Yoshida, T.; Mizukami, T.;
Akinaga, S.; Horinouchi, S.; Yoshida, M.; Yoshida, M. J. Antibiot. 2002,
55, 863.
(4) Edmunds, A. J. F.; Trueb, W.; Oppolzer, W.; Cowley, P. Tetrahedron
1997, 53, 2785.
Figure 1. Structures of GEX 1 family members (1-6).
10.1021/ol701427k CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

organosilane-based bond construction methodology in three
crucial ways (Scheme 1). The first disconnection at C9-
Scheme 2. Synthesis of C10-C19 Fragment 8
Scheme 1. Retrosynthetic Analysis of Herboxidiene/GEX 1A
(1)
C10 leads to a functionalized pyran core and an oxygenated
side chain. We anticipated using a silicon-assisted sp2-sp2
cross-coupling for the union of intermediates 7 and 8. In
this plan, the conjugated (E,E)-diene could be accessed with
high levels of selectivity. Dihydropyran 7 could be obtained
from syn-silane reagent 9 and the silyl-substituted methac-
rolein 10 utilizing our stereoselective [4 + 2] annulation
strategy.6 Further, we hoped that side chain 11 could be
rapidly constructed from silane reagent (S)-12 and R-silyloxy
acetal (S)-13.
over two steps. Rearrangement of 14 followed by trapping
of the ketene with (+)-pseudoephedrine gave the homolo-
gated amide 15 in 80% yield. At this stage, the C12 methyl-
bearing stereocenter was introduced with high selectivity
using Myers’ pseudoephedrine-derived auxiliary11 and af-
forded 16 in 96% yield. The magnitude of diastereoselectivity
of the alkylation was determined to be >10:1 after reductive
removal of the auxiliary using lithium amidotrihydroborate
(LAB).12 The resulting primary alcohol 17 was then oxidized
to the corresponding aldehyde under Swern conditions,13
which was subjected to Takai iodoolefination to give the (E)-
vinyl iodide 8 (E/Z > 20:1, 75% yield).14
Synthesis of the C10-C19 fragment was initiated with a
double-stereodifferentiating crotylation7 based on the use of
a newly developed crotylsilane reagent (S)-12 that bears a
fully substituted stereocenter (Scheme 2).8 Since the C18
hydroxyl would be properly configured for a directed
epoxidation later in the synthesis, we chose (S)-silyloxy acetal
13 as the crotylation electrophile.9 Thus, a matched crotyl-
ation between (S)-12 and (S)-13 promoted by TMSOTf
provided the desired syn homoallylic ether 11 containing a
trans-trisubstituted olefin in 62% yield and high diastereo-
selectivity (dr >30:1). When subjected to Arndt-Eistert
conditions10 11 was converted to diazoketone 14 in 97% yield
The short sequence required for the elaboration of the cis-
2,6-trans-5,6-tetrahydropyran core is summarized in Scheme
3. A TMSOTf-promoted [4 + 2] annulation between syn-
Scheme 3. Synthesis of C1-C9 Fragment 20
(5) Total synthesis, see: (a) Blakemore, P. R.; Kocien˜ski, P. J.; Morley,
A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955. (b) Banwell, M.;
McLeod, M.; Premraj, R.; Simpson, G. Pure Appl. Chem. 2000, 72, 1631.
Diastereomeric synthesis, see: (c) Smith, N. D.; Kocien˜ski, P. J.; Street S.
D. A. Synthesis 1996, 652. Fragment synthesis, see: (d) Banwell, M. G.;
Bui, C. T.; Simpson, G. W.; Watson, K. G. Chem. Commun. 1996, 723. (e)
Banwell, M. G.; Bui, C. T.; Hockless, D. C. R.; Simpson, G. W. J. Chem.
Soc., Perkin Trans. 1 1997, 1261. (f) Banwell, M. G.; Bui, C. T.; Simpson,
G. W. J. Chem. Soc. Perkin Trans. 1 1998, 791. SAR studies, see: (g)
Edmunds, A. J. F.; Arnold, G.; Hagmann, L.; Schaffner, R.; Furlenmeier,
H. Med. Chem. Lett. 2000, 1365.
(6) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836.
(7) (a) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996,
118, 12475. (b) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1.
(8) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529.
(9) (S)-Silyloxy acetal 13 was prepared in two steps from the com-
mercially available (S)-ethyl lactate. See the Supporting Information for
details.
crotylsilane 9 and (E)-vinylsilyl aldehyde 1015 provided cis-
2,6-dihydropyran 18 in 65% yield and with high selectivity
(10) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
3142
Org. Lett., Vol. 9, No. 16, 2007

silicon-based sp2-sp2 cross-coupling.17 Preactivation of
vinylsilane 20 with 2.2 equiv of TBAF18 followed by addition
of [AllyPdCl]2 and vinyl iodide 8, the desired product 21
was obtained in a good yield and exclusively as the (E,E)-
diene isomer. Nitrile 21 was then partially reduced to the
aldehyde by DIBAL-H. Pinnick oxidation19 followed by
methylation with TMS-stabilized diazomethane provided
methyl ester 22 in three steps, 59% yield. Removal of the
TBDPS group using TBAF was followed by a directed
epoxidation of the bishomoallylic alcohol 23.20 As reported,
C18 hydroxyl-directed epoxidation, catalyzed by VO(acac)2
gave a single diastereomer in 48% yield.5a Inversion of the
C18 hydroxyl under modified Mitsunobu conditions21 and
saponification of the resulting diester5 completed the total
synthesis of herboxidiene/GEX 1A (1).
Scheme 4. Completion of the Total Synthesis of 1
In summary, we have described a highly convergent and
enantioselective synthesis of herboxidiene/GEX 1A (1) in
16 steps from the crotysilane 12. The construction of pyran
fragment and oxygenated side chain and the utility of
vinylsilane in the union of 8 and 20 demonstrate the
versatility of organosilanes in natural product synthesis. This
work also illustrates the use of silicon-based cross-coupling
as an alternative to vinylstannane and other more sensitive
metal based cross-coupling reactions in complex molecule
synthesis.
Acknowledgment. Financial support for this research was
obtained from the NIH (NIGMS GM55740). We are grateful
to Dr. Qibin Su (AstraZeneca, Inc., Boston), Dr. Fredrik Lake
(AstraZeneca, Inc., So¨derta¨lje), and Dr. Frauke Pohlki
(Boston University) for useful suggestions and discussions.
(dr >30:1).6 Initially, this annulation was plagued with
significant amounts of protodesilylation giving terminal olefin
18a as the major product. After screening several bases and
solvent systems, we learned that with catalytic amounts of
2,6-di-tert-butylpyridine (DTBP) and 1.0 equiv of TMSOTf
in a mixture of CH2Cl2/MeCN (3:1, -20 °C), the reaction
proceeded smoothly to provide the desired product in a useful
yield. Reduction of 18, followed by a hydroxyl-directed
chemoselective hydrogenation using Wilkinson’s catalyst,16,20a
afforded the tetrahydropyran product 19 in 87% yield over
both steps. Alcohol 19 was then converted to a tosylate
followed by displacement with sodium cyanide to give the
desired nitrile 20, thereby reconstituting the oxidation state
of a carboxylate.
Note Added after ASAP Publication. There was an error
in Scheme 4 in the version published ASAP July 13, 2007;
the corrected version was published July 17, 2007.
Supporting Information Available: Experimental details
and new selected spectral for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL701427K
(17) For recent reports of Si-based X-couplings, see: (a) Denmark, S.
E.; Neuville, L.; Christy, M. E. L.; Tymonko, S. A. J. Org. Chem. 2006,
71, 8500. (b) Denmark, S. E.; Sweis, R. F.; Wehrli, D. J. Am. Chem. Soc.
2004, 126, 4865. (c) Rendler, S.; Oestreich, M. Synthesis 2005, 1727. (d)
Spivey, A. C.; Gripton, C. J. G.; Hannah, J. Curr. Org. Synth. 2004, 1,
211. (e) Denmark, S. E.; Liu, J. H. C. J. Am. Chem. Soc. 2007, 129, 3737.
(18) For examples using benzyldimethylsilyl group in cross-coupling,
see: (a) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Harrington, P.
E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666. (b) Trost,
B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895.
(19) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
With workable amounts of advanced intermediates 8 and
20 available, we were positioned to carry out the crucial
(11) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(12) For preparation of LAB reagent, see ref 11.
(13) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(14) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(15) (a) Mohamed, M.; Brook, M. A. HelV. Chim. Acta 2002, 85, 4165.
(b) Spino, C.; Gobdout, C. J. Am. Chem. Soc. 2003, 125, 12106.
(16) For a review of hydroxyl-directed hydrogenation, see: Brown, J.
M. Angew. Chem., Int. Ed. 1987, 26, 190.
(20) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer,
T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933.
(21) Martin, S. F.; Dodge, J. A.; Tetrahedron Lett. 1991, 32, 3017.
Org. Lett., Vol. 9, No. 16, 2007
3143