Total synthesis of (-)-mucocin

Article abstract of DOI:10.1021/ol060704z

An enantioselective total synthesis of (-)-mucocin has been completed. A combination of asymmetric glycolate aldol additions and ring closing metathesis reactions were exploited to construct the C18-C34 and C7-C17 fragments. A selective cross-metathesis r

Full text of DOI:10.1021/ol060704z

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2369-2372
Total Synthesis of (−)-Mucocin
Michael T. Crimmins,* Yan Zhang, and Frank A. Diaz
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina, 27599
crimmins@email.unc.edu
Received March 22, 2006
ABSTRACT
An enantioselective total synthesis of (−)-mucocin has been completed. A combination of asymmetric glycolate aldol additions and ring
closing metathesis reactions were exploited to construct the C18
employed as the key step to couple two complex fragments.
−C34 and C7
−C17 fragments. A selective cross-metathesis reaction was
In 1995 mucocin (1), a novel member of the anonnaceous
acetogenin family, was isolated from the leaves of Rollinia
mucosa by McLaughlin and co-workers.1 The annonaceous
acetogenins are a series of polyethers with antimitotic and
cytotoxic properties, containing either adjacent or nonadja-
cent tetrahydrofuran (THF) rings. Mucocin was the first
member of this family reported to bear a tetrahydropyran
(THP) ring along with a THF ring.2 Mucocin is quite active
in the brine shrimp toxicity (BST) assay (IC50 1.3 µg/mL),
and shows remarkably selective inhibitory effects against
A-549 (lung cancer) and PACA-2 (pancreatic cancer) tumor
cell lines with potency 10 000 times that of the known
antitumor agent adriamycin.3 Mucocin’s mode of action is
believed to result from inhibition of both the mitochondrial
complex I (NADH-ubiquinone oxidoreductase) and the
plasma membrane NADH oxidase. Consequently, the ATP
level of the tumor cells decreases and apoptosis is induced.4
The potent antitumor activity and the unique structure of
mucocin have stimulated numerous synthetic endeavors; five
previous total syntheses of mucocin have been published.5
Herein we describe an enantioselective total synthesis of
(-)-mucocin. Mucocin was envisioned to derive from the
Scheme 1
coupling of advanced acetylene 2 and known butenolide 36
via a Pd(0) catalyzed Sonogashira reaction (Scheme 1). The
bis cyclic ether 2 would be generated by coupling fragments
4 and 5 through a cross-metathesis reaction, wherein both
fragments would be prepared via an asymmetric glycolate
aldol-ring closing metathesis (RCM) sequence.
(1) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao, G.-
X.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc. 1995,
117, 10409.
(2) (a) Rupprecht, J. K.; Hui, Y. H.; McLaughlin, J. L. J. Nat. Prod.
1990, 53, 237. (b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.;
He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275. (c) Alali, F. Q.;
Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(3) McLaughlin, J. L. In Methods in Plant Biochemistry; Hostettmann,
K., Ed.; Academic Press: London, UK, 1991; Vol. 6, p 1.
(4) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovern, J. P.;
Hui, Y.-H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113. (b) Morre, D. J.;
Cabo, R. D.; Farely, C.; Oberlies, N. H.; McLaughlin, J. L. Life Sci. 1995,
56, 343.
(5) (a) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, Sa. C.; Sinha,
Su. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279. (b) Baurle, S.;
Hoppen, S.; Koert, U. Angew. Chem. Int. Ed. 1999, 38, 1263. (c) Hoppen,
S.; Baurle, S.; Koert, U. Chem. Eur. J. 2000, 6, 2906. (d) Takahashi, S.;
Nakata, T. J. Org. Chem. 2002, 67, 5739 and references therein. (e) Evans,
P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H. J. Am. Chem.
Soc. 2003, 125, 14702. (f) Zhu, L.; Mootoo, D. R. Org. Biomol. Chem.
2005, 3, 2750.
(6) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790.
10.1021/ol060704z CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/26/2006

Scheme 2
The synthesis of the C18-C34 fragment 4 started with
Preparation of the C7-C17 fragment 5 began by protecting
the terminal alkyne of 5-hexyn-1-ol (13) with a TIPS group
(Scheme 4).13 Swern oxidation of the resultant primary
alcohol and a subsequent Grignard reaction with vinylmag-
nesium bromide delivered allylic alcohol 14 in 66% yield
over three steps. Allylic alcohol 14 was then exposed to the
standard Sharpless kinetic resolution conditions14 [(+)-
dicyclohexyl tartrate (DCHT), Ti(i-PrO)4, t-BuOOH, 4 Å
molecular sieves]. The reaction was quenched at 52%
conversion to provide alcohol 15 in 92% ee.15 Alkylation of
the secondary alcohol with sodium bromoacetate and coup-
ling of the resultant acid to (R)-3-lithio-4-benzyl-2-oxazo-
lidinone gave glycolate 16 in 77% yield. Once again, the
NMP-promoted asymmetric aldol reaction was utilized.
Exposure of glycolate 16 to these conditions with acrolein
provided the aldol adducts in 82% yield (93% based on
recovered starting material), with a 4:1 dr favoring the desired
syn adduct 17. Silylation of the mixture of diastereomers as
TES ethers and reductive removal of the auxiliary afforded
the primary alcohol 18 in 89% yield.
the protection of the known compound (2R,3R)-1-oxiranyl-
undecan-1-ol (6)7 as its THP ether, followed by epoxide
opening8 to afford the homologated allylic alcohol 7 in 87%
yield (Scheme 2). The resulting secondary alcohol was
protected as a benzyl ether, and the THP group was removed
under acidic conditions to deliver alcohol 8 in 86% yield
over the two steps. Alkylation of the sodium alkoxide of
alcohol 8 with sodium bromoacetate gave a glycolic acid,
which was converted to its mixed pivalic anhydride and
treated with (R)-3-lithio-4-benzyl-2-oxazolidinone to generate
the N-glycolyloxazolidinone 9 in 69% yield (2 steps). Our
recently developed aldol reaction protocol9 was then ex-
ploited, where the chlorotitanium enolate of glycolate 9 was
formed by treatment with TiCl4 (1.0 equiv), i-Pr2NEt (2.5
equiv), and N-methyl-2-pyrrolidinone (1.0 equiv). Addition
of acrolein to the enolate solution gave the desired syn aldol
adduct 10 in good yield and diastereoselectivity (77%, 11:1
dr). Other aldol protocols gave significantly lower yields and
diastereoselectivity. Protection of the resulting alcohol 10
as its TES ether and reductive removal of the chiral auxiliary
afforded primary alcohol 11 in 93% yield. The subsequent
Swern oxidation10-Wittig reaction sequence delivered triene
12 in 83% yield. Triene 12 was exposed to the Grubbs second
generation catalyst11 [Cl2(PCy3)(IMes)RudCHPh], followed
by acidic workup to remove the TES protecting group in
the same pot, regioselectively generating dihydropyran 4 in
good yield.12 The use of the triethylsilyl ether as the alcohol
protecting group in triene 12 resulted in less than 5% of the
corresponding seven-membered-ring metathesis product.
With the desired stereocenters established, efforts focused
on the regioselective formation of the five-membered ring.
Previous studies from our laboratory showed that the RCM
reaction of simple triene 19 with the ruthenium alkylidene
catalysts gave a poor regioselectivity of five-membered and
six-membered cyclic ethers (Scheme 3).16 We rationalized
that the unexpected result was due to indiscriminate insertion
of the ruthenium carbene into all three alkenes of triene 19,
followed by fast ring closure to generate both regioisomers.
To circumvent this problem, Hoye’s “activation” strategy
was utilized, where the RCM substrate 20 was modified to
contain an allyloxymethyl side chain.17 In this case, the
ruthenium carbene complex preferentially inserts in the
(7) Mori, K.; Otsuka, T. Tetrahedron 1983, 39, 3267.
(8) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall,
T.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
(9) Crimmins, M. T.; She, J. Synlett 2004, 8, 1371.
(10) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem. 1978, 43,
2480.
(11) Morgan, J. P.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(12) When the secondary allylic alcohol of triene 12 was protected as
its MOM ether rather than the TES ether, a 2:1 mixture of six-membered
and seven-membered cyclic ethers was produced under the same RCM
conditions.
(13) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc.
2002, 124, 773.
(14) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(15) The ee was determined by first converting alcohol 15 to UV active
glycolate 16, followed by HPLC of 16.
2370
Org. Lett., Vol. 8, No. 11, 2006

byproduct and leaving the metal carbene in the desired
position to construct the five-membered cyclic ether selec-
tively.
Scheme 3
This successful strategy was applied to the synthesis of
fragment 5 (Scheme 4). Alcohol 18 was subjected to Swern
oxidation, followed by Wittig olefination with Ph3PdCHCO2-
Me in the same pot (no evidence of epimerization of the
aldehyde was detected). The resultant R,â-unsaturated ester
21 underwent selective 1,2-reduction with i-Bu2AlH, where-
upon the primary alcohol was O-alkylated with allyl bromide
to deliver tetraene 22 in excellent yield. Exposure of tetraene
22 to the Grubbs second generation catalyst provided
excellent regioselectivity, giving a 7:1 ratio of the five- and
six-membered rings. After removal of the TES group with
acidic workup of the RCM reaction, cyclic ether 23 was
isolated in 87% yield. No byproduct from any metathesis
reaction of the acetylene was identified. The alcohol 23 was
then converted to its MOM ether 5 in 89% yield.
With fragments 4 and 5 in hand, the key cross-metathesis
reaction was undertaken (Scheme 4). The disubstituted
internal olefin of each fragment was expected to be unre-
active under cross-metathesis conditions, allowing for
chemoselective reactions between the remaining two terminal
terminal alkene of the allyloxymethyl group for both steric
and electronic reasons, generating 2,5-dihydrofuran as a
Scheme 4
Org. Lett., Vol. 8, No. 11, 2006
2371

vinyl groups of these compounds. The MOM protecting
group on fragment 5 was anticipated to modify the steric
accessibility of the nearby allylic olefin, making it less
reactive than the structrually similar unprotected allylic olefin
on fragment 4. The difference in reactivities of the two
alkenes would lead to a selective cross-metathesis reaction.18
Exposure of a 1:1 mixture of alkenes 4 and 5 to the
Hoveyda-Grubbs second generation catalyst [Cl2(IMes)Rud
CH-o-Oi-PrC6H4]19 yielded the desired cross-coupling prod-
uct 24 in 68% yield (6:1 E:Z by HPLC), along with 13% of
alkene 5 recovered and 23% of the homodimer of 4.20 Using
the Grubbs second generation catalyst gave a lower yield of
53% under similar reaction conditions. Mootoo recently
reported a similar cross-metathesis approach to mucocin5e
as well as other acetogenins,21 but utilizing different allylic
alcohol protecting groups. The terminal TIPS group was then
readily removed. The resultant alkyne 2 was coupled with
known vinyl iodide 36 under Sonogashira coupling conditions
[Pd(PPh3)2Cl2, CuI, NEt3]22 to provide polyenyne 25. The
use of Pd(PPh3)2Cl2 as a precatalyst proved superior to Pd-
(PPh3)4 (82% vs 50% yield). Selective hydrogenation of the
pentaenyne moiety with diimide generated in situ from
tosylhydrazide23 afforded butenolide 26 in 77% yield. The
total synthesis of (-)-mucocin was completed by removal
of the protecting groups with BF3‚OEt2 and Me2S.6 Synthetic
1 was identical in all aspects (1H, 13C, MS, [R]24D) to the
natural product.5
In summary, the enantioselective total synthesis of (-)-
mucocin has been accomplished in 19 linear steps from
commerically available 5-hexyn-1-ol. This approach high-
lights a combination of asymmetric glycolate aldol additions
and RCM metatheses to construct the cyclic ethers. In
addition, Hoye’s “activation” strategy was applied to the
regioselective formation of a dihydrofuran. The synthesis also
employed a selective cross-metathesis reaction for the
coupling of two complex alkene fragments.
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM60567)
is acknowledged with thanks.
(16) She, J. Ph.D. Dissertation, University of North Carolina at Chapel
Hill, Chapel Hill, NC, 2004.
(17) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210.
(18) Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(19) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 122, 8168.
Supporting Information Available: Experimental pro-
cedures as well as 1H and 13C spectra for all new compounds
and synthetic (-)-mucocin. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL060704Z
(20) No cross-metathesis product was obtained under the same reaction
conditions when the allylic alcohol of fragment 5 was protected as the TES
ether, and only the homodimer of 4 was identified as a product.
(21) (a) Zhu, L.; Mootoo, D. R. Org. Lett. 2003, 5, 3475. (b) Zhu, L.;
Mootoo, D. R. J. Org. Chem. 2004, 69, 3154.
(22) Sonogashira, R. K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
12, 4467.
(23) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996.
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