Efficient and selective syntheses of (all-E)- and (6E,10Z)-2′-O- methylmyxalamides D via Pd-catalyzed alkenylation-carbonyl olefination synergy

Article abstract of DOI:10.1021/ol801115s

(Chemical Equation Presented) Highly efficient and selective syntheses of both (all-E) and (6E,10Z)-isomers of 2′-O-methylmyxalamide D (2 and 3), in which the crucial conjugated pentaene moieties were assembled in ≥98% stereoselectivity through the use of

Full text of DOI:10.1021/ol801115s

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3223-3226
Efficient and Selective Syntheses of
(all-E)- and
(6E,10Z)-2′-O-Methylmyxalamides D via
Pd-Catalyzed Alkenylation-Carbonyl
Olefination Synergy
Guangwei Wang, Zhihong Huang, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received May 14, 2008
ABSTRACT
Highly efficient and selective syntheses of both (all-E) and (6E,10Z)-isomers of 2′-O-methylmyxalamide D (2 and 3), in which the crucial
conjugated pentaene moieties were assembled in g98% stereoselectivity through the use of two Pd-catalyzed alkenylation reactions, the
Horner-Wadsworth-Emmons (HWE) olefination, and either the Corey-Schlessinger-Mills modified (CSM-modified) Peterson olefination for
2 or the Still-Gennari olefination for 3, are reported. Either 2 or 3 was prepared in 16% yield in seven steps from propargyl alcohol.
Ojika and co-workers reported in 2004 the isolation and
identification of three polyene antifungal agents 1-3 from
the myxobacterium Cystobacter fuscus.1 2′-O-Methylmyx-
alamide D (1a) is an O-methylated derivative of the
previously known myxalamide D (1b),2 and the other two
are its (6E)-isomer (2) and (6E,10Z)-isomer (3) (Figure 1).
Myxalamide D (1b), 2′-O-methylmyxalamide D (1a) and its
(6E)-isomer (2) have recently been synthesized by using the
Pd-catalyzed cross-coupling with (all-E)-1-stanna-6-bora-
1,3,5-hexatriene.3 To the best of our knowledge, however,
the (6E,10Z)-isomer (3) does not appear to have been
synthesized.
Over the past few decades, two methodologically discrete
routes to regio- and stereodefined alkenes have been devel-
oped as widely applicable and selective methods. Carbonyl
olefination,4 especially variants of the Wittig reaction4a
including the E-selective Horner-Wadsworth-Emmons
(HWE hereafter) reaction4b,c and its Z-selective Still-Gennari
modification,4d as well as the Corey-Schlessinger-Mills
modified Peterson olefination (CSM-modified Peterson
olefination hereafter),4e–g can in some cases be highly
stereoselective (g98%). Much more widely applicable and
(1) Kundim, B. A.; Itou, Y.; Sakagami, Y.; Fudou, R.; Yamanaka, S.;
Ojika, M. Tetrahedron 2004, 60, 10217–10221.
(2) Jansen, R.; Reifenstahl, G.; Gerth, K.; Reichenbach, H.; Ho¨fle, G.
Liebigs Ann. Chem. 1983, 1081–1095.
(3) Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129,
3826–3827.
10.1021/ol801115s CCC: $40.75
Published on Web 07/02/2008
2008 American Chemical Society

Scheme 1
strictly stereoselective (g98-99%) in most cases is the Pd-
catalyzed alkenylation.5Nevertheless, other synthetic require-
A case in point is the synthesis of allylically Me-branched
trisubstituted alkenes (4) that can be most readily and
selectively prepared by either the CSM-modified Peterson
olefination (E-isomers)4e–g or the Still-Gennari-modified
HWE reaction (Z-isomer).4d
Herein, we report highly efficient and selective syntheses
of both (all-E) and (6E,10Z)-isomers of 2′-O-methylmyx-
alamide D (2 and 3), in which the crucial conjugated
pentaene moieties are assembled in g98% stereoselectivity
through the use of two Pd-catalyzed alkenylation reactions
for the formation of the C3-C4 and C5-C6 bonds, the HWE
olefination for the C8-C9 double bond, and either the CSM-
modified Peterson olefination (for 2) or the Still-Gennari
olefination (for 3) for the formation of the C10-C11 double
bond. As summarized in Schemes 1 and 2, either 2 or 3 was
(4) For a review of the Wittig and related olefinations, see: (a) Maryanoff,
B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863–927. (b) Horner, L.; Hoffmann,
H.; Wippel, J. H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–2505. (c)
Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Soc. Chem. 1961, 83, 1733–
1738. (d) For a seminal work on the Still-Gennari olefination, see: Still,
W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408. (e) Corey, E. J.;
Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7–10. (f) Schlessinger,
R. H.; Poss, M. A.; Richardson, S.; Lin, P. Tetrahedron Lett. 1985, 26,
2391–2394. (g) Desmond, R.; Mills, S. G.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1988, 29, 3895–3898.
(5) For reviews on Pd-catalyzed alkenylation, see: (a) Negishi, E., Ed.
Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002; 2 Vols., pp 3279; Chap. III.2.6, pp 335-408;
Chap. III.2.14.2, pp 721-766; Chap. III.2.15, pp 767-789; Chap. III.2.17,
pp 807-823; Chap. III.2.18, pp 863-942. (b) Negishi, E.; Hu, Q.; Huang,
Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71–88.
Figure 1. Myxalamide D and its derivatives.
ments and restrictions have made it desirable to use both
(6) Negishi, E.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res., submitted.
methods, i.e., alkenylation-carbonyl olefination synergy.6
3224
Org. Lett., Vol. 10, No. 15, 2008

Scheme 2
prepared in 16% overall yield in just seven steps from
1). Thus, the reaction of tiglic aldehyde with a crotylborane
reagent generated from trans-2-butene and (+)-B-methoxy-
diisopinocamphenylborane (Aldrich) according to the litera-
ture procedure7 afforded 5 in 84% yield. The observed
diastereomeric ratio of 96/4 indicates the overall enantiomeric
purity to be >99.9% by virtue of kinetic resolution operative
in the crotylboration. After protection of the hydroxyl group
with TBSOTf and 2,6-lutidine, the Sharpless dihydroxylation
with AD-mix-R12 (Aldrich) followed by oxidation with
NaIO4 provided 6, which was purified by chromatography
(Silica gel, 5% EtOAc in hexanes). The yield of g98% pure
6 was 81% over three steps. For the conversion of 6 to 7,
the CSM-modified Peterson olefination proved to be both
efficient requiring just one step and highly stereoselective.
The crudely isolated 7 was g98% E,E by 13C NMR after
simple chromatographic purification, and g98% pure 7 was
obtained in 81% yield (55% yield in five steps from tiglic
aldehyde). The Still-Gennari olefination of 6 with
(CF3CH2O)2P(O)CH(Me)CO2Me, KN(SiMe3)2, and 18-
crown-6 (1.5 equiv)4d proved to be g98% Z-selective. After
reduction with i-Bu2AlH, 8 was obtained as a g98% pure
compound in 66% yield over two steps (Scheme 1).
propargyl alcohol. In fact, the overall yield of 2 in the same
seven steps from tigilic aldehyde (g96%, Aldrich) is
significantly higher at 34%, while the overall yield of 3 in
eight steps in the longest linear sequence is 27%. Except in
the Brown crotylboration of tiglic aldehyde (g96%) produc-
ing a 96/4 diastereomeric mixture of 5 and requiring
chromatographic isomer separation after the conversion of
5 into 6, no isomer formation was detectable throughout
either of the two syntheses. The ready availability of 5 in
one step, its high yielding three-step conversion to 6, and
one- or two-step conversion of 6 into isomerically g98%
pure 7 or 8 dictated their HWE olefination with the trienoic
amide containing phosphonate (9) prepared in 26% yield in
five steps from propargyl alcohol (or in 33% yield in five
steps from methacrylic acid) via a series of two Pd-catalyzed
alkenylation reactions followed by phosphonation, as detailed
in Scheme 2.
Of various selective and asymmetric routes3,7–11 to two key
intermediates 7 and 8 tested and/or considered, the one via
the Brown crotylboration7 of tiglic aldehyde proved to be
the most efficient and selective, albeit noncatalytic (Scheme
In view of the current high cost of (CF3CH2O)2-
P(O)CH(Me)CO2Me and the variable Z-selectivity of the
Still-Gennari olefination, we initially considered the conver-
sion of 6 to 12 via Corey-Fuchs reaction,13 bromoalkyne
hydroboration-migratory insertion, zincation-iodinolysis,
and Pd-catalyzed alkenylation,11e as depicted in Scheme 3.
Even though a model transformation for converting
TBDPSOCH2CHdCH2 to 14 via 1314 was achieved in 30%
yield in seven steps, its application to the conversion of 6 to
(7) For the Brown crotylboration, see: (a) Brown, H. C.; Bhatt, K. S.
J. Am. Chem. Soc. 1986, 108, 5919–5923. (b) Brown, H. C.; Jadhav, P. K.;
Bhatt, K. S. J. Am. Chem. Soc. 1988, 110, 1535–1538
.
(8) For the T-to-H (tail-to-head) construction of natural products
containing (E)-4 via the CSM-modified Peterson olefination, see: (a)
Magnin-Lachaux, M.; Tan, Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6,
1425–1427. (b) Zeng, X.; Zeng, F.; Negishi, E. Org. Lett. 2004, 6, 3245–
3248
.
(9) For other T-to-H (tail-to-head) routes to (E)-4, see: (a) Tan, Z.;
Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2911–2914. (b) Zhu, G.;
Negishi, E. Chem.-Eur. J. 2008, 14, 311–318
(10) For the H-to-T (head-to tail) construction of (E)-4, see: Hoye, T. R.;
Temakoon, M. A. Org. Lett. 2000, 2, 1481–1483
.
.
(11) For the T-to-H (tail-to-head) construction of (Z)-4, see: (a) Panek,
J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912–4913. (b) Panek, J. S.; Hu, T.
J. Org. Chem. 1997, 62, 4914–4915. (c) Arefolov, A.; Panek, J. S. Org.
Lett. 2002, 4, 2397–2400. (d) Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am.
Chem. Soc. 2007, 129, 8960–8961. (e) Tanino, K.; Arakawa, K.; Satoh,
M.; Iwata, Y.; Miyashita, M. Tetrahedron Lett. 2006, 47, 861–864. (f) Tan,
Z.; Negishi, E. Angew. Chem., Int. Ed. 2006, 45, 762–765. (g) Huang, Z.;
(12) (a) AD-mix-R: Sharpless asymmetric dihydroxylation agent con-
taining hydroquinine 1,4-phthalazinediyl diether [(DHQ)2PHAL],
K3Fe(CN)6, K2CO3, and K2OsO4·2H2O. Sharpless, K. B.; Amberg, W.;
Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768–2771. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483–2547.
Negishi, E. J. Am. Chem. Soc. 2007, 129, 14788–14792
.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
Org. Lett., Vol. 10, No. 15, 2008
3225

situ from i-Bu2AlH-ZrCp2Cl2,17 and (iii) iodinolysis all in
one pot. Ethynylation18 of (E)-3-iodoallyl alcohol was
performed in 78% yield by (i) OH protection with Et2Zn
and (ii) ethynylation with (HCt C)2Zn in the presence of 5
mol % of Pd(DPEphos)Cl2. Hydrozirconation of (E)-2-
penten-4-yn-1-ol performed as in the first step followed by
Pd-catalyzed cross-coupling with 10 and 5 mol % of PEPPSI-
IPr (98%, Aldrich)19 provided 11 of g98% isomeric purity
in 62% yield. The required intermediate 10 was prepared in
three steps in 79% yield by ꢀ-bromination of methacrylic
acid20 and amidation with (S)-H2NCH(Me)CH2OMe (98%
pure, Alpha Aesar). As detailed in an upcoming publication,
an N-heterocyclic carbene-containing PEPPSI-IPr proved to
be distinctly superior to Pd(PPh3)4, Pd(PPh3)2Cl2, or Pd-
(DPEphos)Cl2. Thus, 11 was prepared as a g98% isomeri-
cally pure compound in just three steps either from propargyl
alcohol (39% overall yield) or from methacrylic acid (49%
overall yield) via a series of two Pd-catalyzed alkenylation
reactions. Conversion of 11 to 9 via bromination with PBr3
and pyridine followed by phosphonation with P(OEt)3
according to the literature21 proceeded in 67% yield over
two steps (26% from propargyl alcohol or 33% from
methacrylic acid in five steps). All isolated compounds were
g98% isomerically pure by 13C NMR either as crude
products or as purified compounds. With 7, 8, and 9 in hand,
the final assembly of 2 and 3 proceeded smoothly as shown
in Scheme 1 and described earlier. The spectral data for 2
and 3 are in excellent agreement with those reported in the
literature.1,3
Scheme 3
In summary, combined use of the Pd-catalyzed alkenyla-
tion and carbonyl olefination reactions, such as the HWE
olefination, its Still-Gennari modification, and the CSM-
modified Peterson olefination, permits efficient and selective
synthesis of various oligoenes containing E- and/or Z-
trisubstituted alkenes. This protocol has been applied to the
synthesis of (all-E)- and (6E,10Z)-2′-O-methylmyxalamides
D (2 and 3).
12 encountered an unexpected and as yet unsolved difficulty
in the attempted conversion of the bromoalkyne intermediate
to the corresponding iodoalkene. We therefore opted for the
conversion of 14 to 12, which was achieved in 25% yield in
seven steps. In the absence of external chiral reagents, the
reaction of R-methylaldehyde derived from 14 with (E)-2-
butenylmethylzinc gave nearly 1:1 C7 epimers of 12 which
was converted to 12 of g98% purity via Dess-Martin
oxidation15 and Corey-Bakshi-Shibata reduction.16 At this
point, however, it became unmistakably clear that the route
summarized in Scheme 1 would be superior to that shown
in Scheme 3.
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research. We also thank Sigma-Aldrich for samples of
PEPPSI-IPr and Albemarle for organoaluminum compounds.
Supporting Information Available: Detailed experimen-
tal procedures and 1H and 13C NMR spectra of isolated pure
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
For the construction of the C1-C8 fragment 9, propargyl
alcohol was converted to 3-iodoallyl alcohol of g99% E in
80% yield via (i) in situ OH protection with i-Bu2AlH, (ii)
hydrozirconation with HZrCp2Cl-ClAl(i-Bu)2 generated in
OL801115S
(17) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675–3678.
(18) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979–2017.
(19) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768–2813.
(14) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006,
128, 2770–2771.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(16) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861–2863.
(20) Dzierba, C. D.; Zandi, K. S.; Mo¨llers, T.; Shea, K. J. J. Am. Chem.
Soc. 1996, 118, 4711–4712.
(21) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 533–536.
3226
Org. Lett., Vol. 10, No. 15, 2008