A stereoselective synthesis of (+)-herboxidiene/GEX1A

Article abstract of DOI:10.1021/ol102549a

A stereoselective synthesis of (+)-herboxidiene is described. The convergent synthesis utilized a Suzuki cross-coupling reaction to assemble the key segments. The synthesis of the functionalized tetrahydropyran ring utilized an Achmatowicz reaction as the

Full text of DOI:10.1021/ol102549a

ORGANIC
LETTERS
2011
Vol. 13, No. 1
66-69
A Stereoselective Synthesis of
(+)-Herboxidiene/GEX1A
Arun K. Ghosh* and Jianfeng Li
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity, 560 OVal
DriVe, West Lafayette, Indiana 47907, United States
akghosh@purdue.edu
Received October 20, 2010
ABSTRACT
A stereoselective synthesis of (+)-herboxidiene is described. The convergent synthesis utilized a Suzuki cross-coupling reaction to assemble
the key segments. The synthesis of the functionalized tetrahydropyran ring utilized an Achmatowicz reaction as the key step. The synthesis
of the C10-C19 segment was accomplished using Brown’s crotylboration, asymmetric alkylation, and a stereoselective allylic chlorination
reactions.
Researchers at Monsanto (USA) isolated herboxidiene (1,
Figure 1) from Streptomyces chromofuscus in 1992.1 It
displayed highly potent and selective phytotoxicity against
a myriad of broad leaf weeds over coplanted wheat.1
Subsequently, in 2002, Yoshida and co-workers isolated six
structurally related compounds, including GEX1 from a
culture broth of Streptomyces sp.2 One of the compounds,
GEX1A was identified as herboxidiene (1), and it was shown
to reduce plasma cholesterol by up-regulating the gene
expression of low-density lipoprotein receptors.3 Further-
more, it induced both G1 and G2/M cell cycle arrest in a
human normal fibroblast cell line, WI-38.4 The initial
structural assignment of herboxidiene was carried out by
chemical degradation and spectroscopic studies.5 Ultimately,
the first total synthesis by Kocienski and co-workers6
confirmed the relative and absolute configuration of her-
boxidiene/GEX1A (1). Important biological properties, low
abundance, and the interesting structural features of 1 led to
considerable interest in its synthesis and biological studies.
Subsequently, three other total syntheses were accomplished
by Banwell, Panek, and Forsyth.7 Edmonds and co-workers
reported simplified aromatic hybrids of 1 with interesting
herbicidal activity.8 Herein we report an asymmetric syn-
thesis of (+)-herboxidiene that can be amenable to analog
preparation.
Our retrosynthesis of (+)-herboxidiene (1) is shown in
Figure 1. We planned to utilize a Suzuki cross-coupling
reaction similar to Murray and Forsyth7c to attach the vinyl
iodide 2 and boronate 3 at a late stage in the synthesis. The
functionalized tetrahydropyran ring 2 could be constructed
from furfural derivative 4 via oxidative Achmatowicz rear-
rangement followed by reduction of the resulting hemiketal.
The boronate segment 3 could be derived from cross-
metathesis of olefin 5 and vinyl pinacol boronate. Olefin 5
would be obtained by asymmetric alkylation with allylic
(1) Isaac, B. G.; Ayer, S. W.; Elliott, R. C.; Stonard, R. J. J. Org. Chem.
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10.1021/ol102549a  2011 American Chemical Society
Published on Web 12/02/2010

Scheme 1. Synthesis of Tetrahydropyran Segment 2
Figure 1. Retrosynthesis of (+)-herboxidiene.
iodide 6, which can be obtained from an asymmetric
crotylboration with an appropriate aldehyde.
The synthesis of vinyl iodide 2 (Scheme 1) commenced
by treatment of aldehyde 49 with allylmagnesium bromide
followed by lipase resolution of the resulting homoallylic
alcohol to provide 8 in 40% yield and 97% ee (by Mosher
ester analysis). The absolute stereochemistry of 8 was
predicted based upon the Kazlauskas model.10 Ultimately,
it was confirmed through its conversion to (+)-herboxidiene.
Reaction of alcohol 8 with t-BuOOH in the presence of a
catalytic amount of VO(acac)2 resulted in a rearranged
hemiketal.11 The resulting hemiketal was reduced according
to the procedure developed by Kishi and co-workers12 to
afford enone 9 in 65% yield, over two steps.
Our synthetic plan then required installation of the 6(S)-
methyl-bearing stereocenter. This was achieved by selective
ozonolysis of the terminal olefin of 9 using Sudan Red 7B13
as an indicator. The resulting aldehyde was oxidized with
NaClO2 to the corresponding acid which was esterified to
methyl ester 10. Reduction of 10 with NaBH4 in the presence
of CeCl3·7H2O in a mixture (1:1) of CH2Cl2 and MeOH at
-10 °C yielded the allylic alcohol as a single diastereomer.14
Directed cyclopropanation of the resulting allylic alcohol with
Et2Zn and CH2I2 at -10 °C to 23 °C furnished cyclopropane
15
1
derivative 11 as a single diastereomer (by H NMR).
Alcohol 11 was subjected to Barton’s deoxygenation
reaction16 to open the cyclopropane ring to give the corre-
sponding methyl group. Thus, reaction of 11 with thiocar-
bonyldiimidazole (TCDI) in the presence of 3 equiv of
DMAP in toluene at 110 °C for 10 min provided the
corresponding imidazole thiocarbonate. Subsequent radical
generation with n-Bu3SnH in the presence of AIBN at 80
°C in toluene provided the desired ring-opened product in
38% yield, and a small amount (ca. 5%) of starting material
was recovered. Interestingly, the use of (TMS)3SiH at 80
°C in place of n-Bu3SnH improved the yield and the desired
ring-opened product was obtained in 54% yield along with
a small amount of a deoxygenated cyclopropane derivative
(ca. 6%). Catalytic hydrogenation of the resulting olefin over
PtO2 followed by treatment with dilute methanolic HCl
yielded 12. Our initial attempt to use 10% Pd/C resulted in
a significant epimerization at the ring methyl stereocenter.
Oxidation of alcohol 12 with Dess-Martin periodinane17
(9) Celanire, S.; Marlin, F.; Baldwin, J. E.; Adlington, R. M. Tetrahedron
2005, 61, 3025–3032.
(10) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic
Synthesis; Wiley-VCH: Weinheim, 1999.
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4976–4978.
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Org. Lett., Vol. 13, No. 1, 2011
67

provided the corresponding aldehyde. Treatment of this
aldehyde with the Ohira-Bestmann reagent (13)18 in a
methanolic suspension of K2CO3 afforded the corresponding
alkyne. Exposure of the resulting alkyne to a catalytic amount
of HgSO4 (0.2 equiv) in aqueous THF and acid smoothly
tranformed the alkyne into ketone 14 in good yield.19 It was
reacted with a mixture of CrCl2 and CHI320 in THF to furnish
the requisite vinyl iodide 2 in excellent yield and good E/Z
selectivity (5.7:1, by HPLC analysis).
a substrate-reagent mismatch, the high diastereoselectivity
of 7 clearly demonstrated that the chiral borane reagent
overruled the stereodirecting effect of the R-stereogenic
center of 15. Similar diastereoselection was observed by
Armstrong and co-workers23 with tetrasubstituted borane
reagents and Masamune and co-workers with a chiral
Z-crotyldimethyl borane.24 Removal of the isopropylidene
group by exposure of 7 to Dowex-50W in MeOH followed
by regioselective tosylation of the resulting diol provided
monotosylate 16 in excellent yield.25 The reduction of 16
with LiAlH4 in THF followed by protection of the resulting
alcohol afforded TBS ether 17. This was converted to
The synthesis of allylic iodide 6 is shown in Scheme
2. We investigated the double diastereoselection of Brown’s
1
γ-lactone 18 in 81% yield over three steps. The H NMR
NOE experiments of 18 fully supported the stereochemical
assignment of the major diastereomer 7. Ozonolysis of 17
followed by reaction of the resulting aldehyde with isopro-
penyl magnesium bromide resulted in a mixture (2.6:1) of
alcohols 19. Treatment of 19 with thionyl chloride at 6 °C
provided the rearranged allylic chloride 20 as a single isomer
(by 1H NMR). Finkelstein reaction of 20 furnished iodide 6
in excellent yield. The high degree of stereoselection in favor
of the E-isomer in this allylic chlorination reaction can be
Scheme 2. Synthesis of Allylic Iodide 6
explained by an SN process26 through a chair-like six-
i
membered transition state shown in Figure 2. The large
Figure 2. Plausible chlorination transition states for 20.
R-group would likely induce a greater 1,3-diaxial interaction
in transition state 21b over 21a, resulting in 20 as the sole
product. The reaction can also proceed through a close ion-
pair mechanism as suggested by Cram.27 It is noteworthy to
mention that the TBS group was unaffected under the
reaction conditions. This was also observed by Paquette and
Taylor previously.28
crotylboration21 with (R)-isopropylidene glyceraldehyde 1522
at -78 °C. The crude product was directly treated with NaH
and methyl iodide to provide 7 in 63% overall yield and
good diastereoselectivity (dr ) 7.5:1). Interestingly, despite
(23) Ogawa, A. K.; DeMattei, J. A.; Scarlato, G. R.; Tellew, J. E.; Chong,
L. S.; Armstrong, R. W. J. Org. Chem. 1996, 61, 6153–6161.
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4831–4832.
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(18) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521–522.
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Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447–450.
(26) (a) Roberts, J. D.; Young, W. G.; Winstein, S. J. Am. Chem. Soc.
1942, 64, 2157–2164. (b) Goering, H. L.; Nevitt, T. D.; Silversmith, E. F.
J. Am. Chem. Soc. 1955, 77, 4042–4048. (c) Ireland, R. E.; Wrigley, T. I.;
Young, W. G. J. Am. Chem. Soc. 1958, 80, 4604–4605.
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1988, 66, 2805–2815.
(20) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410.
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(22) Prepared in two steps from D-mannitol, see: Organic Syntheses,
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68
Org. Lett., Vol. 13, No. 1, 2011

Synthesis of boronate 3 is shown in Scheme 3. Asym-
metric alkylation29 of (R)-4-benzyl-3-propionyloxazolidin-
Scheme 4. Completion of (+)-Herboxidiene/GEX1A
Scheme 3. Synthesis of Boronate 3
0.29, MeOH)} and the synthetic (+)-herboxidiene/GEXA1
{[R]2D2 ) +4.9 (c 0.02, MeOH)} reported by Zhang and
Panek7b and {[R]2D2 ) +4.0 (c 0.02, MeOH)} by Murray and
Forsyth7c are identical.
2-one (23) with 6 afforded 24 as a single diastereomer in
64% isolated yield. Reductive cleavage of the chiral auxiliary
with LiBH4 furnished the primary alcohol. Dess-Martin
oxidation17 afforded the corresponding aldehyde, which was
converted to terminal alkene 5 by a Wittig reaction. Cross-
metathesis of the resulting olefin with vinyl pinacol boronate
25 catalyzed by Hoveyda-Grubbs II catalyst 2630 provided
3 predominantly (E/Z selectivity >16:1, by 1H NMR), in 43%
yield, over three steps.
With vinyl iodide 2 and boronate 3 in hand, our synthetic
plan was to utilize a Suzuki cross-coupling reaction, previ-
ously carried out by Murray and Forsyth.7c As shown in
Scheme 4, coupling of 2 and 3 was conducted in the presence
of Cs2CO3 and Pd(PPh3)4 (5 mol %) at 55 °C to give the
corresponding coupled product in 71% yield.31 Treatment
of this coupled product with dilute methanolic HCl solution
at 0 °C gave alcohol 27. Regio- and stereoselective directed
epoxidation of 27 was carried out as described in previous
syntheses.7 Thus, treatment of 27 with t-BuOOH and
VO(acac)2 furnished the corresponding epoxide. Methyl ester
hydrolysis with Me3SnOH using a protocol described by
Nicolaou and co-workers32 provided synthetic (+)-1. The
spectroscopic data of our synthetic (+)-1 {[R]2D0 ) +4.2 (c
In summary, we have accomplished a stereoselective
synthesis of (+)-herboxidiene/GEX1A. The synthesis fea-
tures an Achmatowicz reaction, a lipase resolution, stereo-
selective construction of the tetrahydropyran ring, and
stereoselective installation of the ring methyl group through
a radical-promoted opening of a cyclopropane derivative for
subunit 2. Segment 3 utilized Brown’s crotylboration of (R)-
isopropylidene glyceraldehyde as one of the key steps.
Interestingly, the product showed high diastereoselectivity
despite that there was a substrate-reagent mismatch. These
results indicated that the chiral borane reagent overruled the
stereodirecting effect of the R-stereogenic center. The
synthesis also utilized a highly stereoselective allylic chlo-
rination reaction, asymmetric alkylation, and Suzuki coupling
reaction. The present synthesis could be utilized in the
synthesis of structural variants of (+)-herboxidiene/GEX1A.
Acknowledgment. Financial support of this work was
provided in part by the National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
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OL102549A
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