Total synthesis of GEX1A

Article abstract of DOI:10.1021/ol800902g

(Chemical Equation Presented) An efficient and readily modifiable synthesis of GEX1A/herboxidiene/TAN-1609 (1) was developed. This modular synthesis featured a Suzuki coupling to install the conjugated diene and a Ru-catalyzed lactonization and Roush crotylation to construct the functionalized tetrahydropyran moiety. Myers' alkylation, cross-metathesis, and Keck crotylation were employed for assembly of the biologically essential side-chain domain.

Full text of DOI:10.1021/ol800902g

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3429-3431
Total Synthesis of GEX1A
Timothy J. Murray† and Craig J. Forsyth*,‡
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210-1185, and GlaxoSmithKline, 553 Old CorVallis Road,
Hamilton, Montana 59840
forsyth@chemistry.ohio-state.edu
Received April 18, 2008
ABSTRACT
An efficient and readily modifiable synthesis of GEX1A/herboxidiene/TAN-1609 (1) was developed. This modular synthesis featured a Suzuki coupling
to install the conjugated diene and a Ru-catalyzed lactonization and Roush crotylation to construct the functionalized tetrahydropyran moiety. Myers’
alkylation, cross-metathesis, and Keck crotylation were employed for assembly of the biologically essential side-chain domain.
GEX1A (1, also known as herboxidiene and TAN-1609) is an
interesting microbial natural product that was first described in
the primary literature in 1992 by Isaac and co-workers.1
Thereafter, the absolute configuration of 1 was reported by a
group at Novartis in 1997.2 GEX1A induces an array of diverse
xenobiotic responses that include herbicidal activity,1 activation
of the LDL receptor,3 an increase of G1 and G2 cell phase
population,4–6 and antitumor activity in numerous cell lines.4–6
Recent publications characterized naturally occurring GEX1A
analogues that replicate several of these biological re-
sponses.5,6 However, the cellular mechanisms and modes of
action of 1 and its cogeners remain to be elucidated. The
provision of GEX1A and structural varaints and derived
cellular probes should enable studies to accomplish this.
Two initial synthetic entries to the GEX1A architecture were
reported by Kocienski and Banwell, respectively. Kocienski7
described the first total synthesis of 1 in 1999, whereas Banwell8
elaborated upon this benchmark in reporting a formal total
synthesis in 2000. Edmunds9 subsequently published the
syntheses of simpler, non-natural analogues of 1, whereas Panek
published a signature silane-based total synthesis of 1 in 2007.10
The combination of enticing structural features, ammenable
to convergent assembly, and opportunities to enable further
chemical biology studies compelled us to develop a flexible
synthetic entry to this unique class of natural products.11
Our synthetic plan for 1 focused on the construction of the
diene via a Suzuki coupling of vinyl iodide 2 and vinyl boronate
3 (Scheme 1).12 Disconnection of the C1-C2 acetate and the
C8 vinyl iodide of 2 revealed lactone 4 (Scheme 2). A Ru-
catalyzed carbonylation of homoallylic alcohol 5 was designed
† GlaxoSmithKline.
‡ The Ohio State University.
(1) Isaac, B. G.; Ayer, S. W.; Elliott, R. C.; Stonard, R. J. J. Org. Chem.
1992, 57, 7220.
(2) Edmunds, A. J. F.; Trueb, W.; Oppolzer, W.; Cowley, P. Tetrahedron
1997, 53, 2785.
(7) Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem.
Soc., Perkin Trans. 1 1999, 995.
(3) Koguchi, Y.; Nishio, M.; Kotera, J.; Omori, K.; Ohnuki, T.;
Komatsubara, S. J. Antibiot. 1997, 50, 970.
(4) Horiguchi, T.; Shirasaki, M.; Tanida, S. Takeda Kenkyushoho 1996,
(8) Banwell, M.; McLeod, M.; Premaj, R.; Simpson, G. Pure Appl.
Chem. 2000, 72, 1631.
55, 149
.
(9) Edmunds, A. J. F.; Arnold, G.; Hagmnaa, L.; Schaffner, R.;
Furlenmeier, H. Bioorg. Med. Chem. Lett. 2000, 10, 1365.
(10) Zhang, Y.; Panek, J. S. Org. Lett. 2007, 9, 3141.
(11) The work described here has been previously documented: Murray,
T. J. Ph.D. Thesis, 2006, University of Minnesota.
(12) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(5) Sakai, Y.; Yoshida, T.; Ochiai, K.; Uosaki, Y.; Saitoh, Y.; Tanaka,
F.; Akiyama, T.; Akinaga, S.; Mizukami, T. J. Antibiot. 2002, 55, 855
.
(6) Sakai, Y.; Tsujita, T.; Akiyama, T.; Yoshida, T.; Mizukami, T.;
Akinaga, S.; Horinouchi, S.; Yoshida, M.; Yoshida, T. J. Antibiot. 2002,
55, 863
.
10.1021/ol800902g CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society

Scheme 1
.
Major Retrosynthetic Dissection
Scheme 3. Preparation of Lactone 4
to provide 4.13,14 Resident in 5 is the necessary C6,C7-anti
stereochemistry installed via crotylation of aldehyde 6.15 The
Suzuki coupling partner boronate 3 would arise from allylic
three steps (Scheme 3). Lactate derivative 6 was then subjeted
to crotylation to furnish the anti,syn stereochemistry in homoal-
lylic alcohol 5.15 Heating alcohol 5 with Ru3(CO)12, NMO, and
pyridyl formate 11 primarily yielded the six-membered lactone
4 and lesser amounts of the related five-membered lactone 12.14
The acetate side chain of 2 was installed by addition of the
lithium enolate of ethyl acetate followed by reduction of the
resultant hemiketal with boron trifluoride etherate and trieth-
ylsilane20 to yield 13 (Scheme 4). Cleavage of the benzyl ether
Scheme 2. Detailed Retrosynthesis
Scheme 4
iodide 7 via the key operations of Myers alkylation and Takai
olefination (Scheme 2).16,17 The trisubstituted (E)-olefin of
7 could be obtained by cross metathesis of precursor 8 with
methacrolein.18 Keck crotylation of 9 was recognized to
provide the syn,synstereochemistry within 8.19
of 13 and oxidation of the resultant alcohol provided ketone
14. Finally, Takai olefination of ketone 14 installed the vinyl
iodide of 2 in high E/Z selectivity.21
The synthesis of 1 thus began with the assembly of 2. For
this, (S)-methyl lactate 10 was converted into aldehyde 6 in
To synthesize boronate 3, (R)-isobutyl lactate 15 was
converted into aldehyde 16 (Scheme 5) via a three step sequence
similar to that used for the generation of 6. With 16 in hand,
Keck crotylation installed the necessary syn,syn stereochemistry
at carbons 16-18 in intermediate 8.19,22
Next, the C17 methyl ether was formed from 8 and
subsequent cross metathesis with methacrolein using the
Grubbs-Hoyveda catalyst was found to produce the best results
(13) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750
(14) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 4207
(15) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186.
(16) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T.
Synlett 1995, 963–964
.
.
.
(17) (a) Myers, A. G.; Yang, B. H. Org. Synth. 1999, 77, 22. (b) Myers,
A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116,
9361
.
(18) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) BouzBouz, S.; Cossy,
J. Org. Lett. 2001, 3, 1451
.
(19) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 1879
(20) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976
.
(21) Takai, K.; Nitta, K.; Utimeto, K. J. Am. Chem. Soc. 1986, 108,
7408.
.
(22) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
3430
Org. Lett., Vol. 10, No. 16, 2008

primary alcohol 21 was best performed with Dess-Martin
periodinane. Finally, Takai olefination with the bis-chloroboro-
lane installed vinyl boronate 3 ready for the Suzuki coupling.16
The complete carbon skeleton of 1 was ultimately assembled
via a successful palladium-mediated Suzuki coupling (Scheme
8).12 Boron trifluoride-mediated cleavage of the BOM acetal
Scheme 5
Scheme 8. Completion of the Total Synthesis of 1
for homologation to aldehyde 18 (Scheme 6).18 Aldehdye 18
was reduced with NaBH4, and iodination of the resultnt alcohol
gave allylic iodide 7. The iodide was then reacted with Myers’
pseudoephedrine propionate enolate to set the C12 configuration
in 20.17
Scheme 6
masking the C18 hydroxyl required careful control of reaction
temperature. When the reaction was performed at 0 °C, the C17
methyl ether also suffered cleavage. Initiating the reaction at
-78 °C and gradually warming to 0 °C led to selective cleavage
of the BOM acetal without scission the methyl ether. Thereafter,
the C14,15 oxirane was regio- and stereoselectively installed
via an established vanadyl-oxo epoxidation to produce epoxide
23 with only a small amount of the undesired C14,15 diste-
reomeric epoxide produced.8 Finally, saponification of the ester
yielded carboxylic acid 1, the spectroscopic data of which
matched those previously reported.1,7
This total synthesis of GEX1A was completed in a longest
linear sequence of 16 steps (26 total steps) and a 3.4% overall
yield from methyl lactate. This improves upon the statistical
efficiencies of the previously reported total syntheses of
GEX1A.7,8 It also offers an additional platform for the
generation of probes to elucidate the cellular targets and
mechanism(s) of action of GEX1A and congeners.
To elaborate the boronate coupling partner, the pseudoephe-
drinechiralauxiliaryof20wasremovedvialithiopyrrolidide-borane
induced reduction (Scheme 7).17a Oxidation of the resultant
Scheme 7
Acknowledgment. This research was sponsored by a
Bristol-Meyers Squibb Unrestricted Grant in Synthetic Organic
Chemistry (C.J.F.) and generous unrestricted financial support
from The Ohio State University. We thank L. Weyer, The Ohio
State University, for editorial assistance.
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR and spectra for 1-5, 7,
8, 13, 14, 16, 18, 22-24. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800902G
Org. Lett., Vol. 10, No. 16, 2008
3431