Synthesis of amphidinolide e C10-C26 fragment

Article abstract of DOI:10.1021/ol801923y

(Equation Presented) The key C10-C26 fragment in a total synthesis of (-)-amphidinolide E has been prepared from an oxolane-containing C10-C17 segment (9, derived from L-glutamic acid) via a Julia-Kocienski reaction with aldehyde 3, followed by a Sharpless AD to obtain the desired diol. The C22-C26 fragment was installed by means of an efficient Suzuki-Molander coupling, with an organotrifluoroborate reagent (4, arising from a cross-metathesis reaction between a vinylboronate and 2-methyl-1,4-pentadiene).

Full text of DOI:10.1021/ol801923y

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4843-4846
Synthesis of Amphidinolide E C10-C26
Fragment
Jorge Esteban, Anna M. Costa,* and Jaume Vilarrasa*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Barcelona,
AV. Diagonal 647, 08028 Barcelona, Catalonia, Spain
amcosta@ub.edu; jVilarrasa@ub.edu
Received August 17, 2008
ABSTRACT
The key C10-C26 fragment in a total synthesis of (-)-amphidinolide E has been prepared from an oxolane-containing C10-C17 segment (9,
derived from L-glutamic acid) via a Julia-Kocienski reaction with aldehyde 3, followed by a Sharpless AD to obtain the desired diol. The
C22-C26 fragment was installed by means of an efficient Suzuki-Molander coupling, with an organotrifluoroborate reagent (4, arising from
a cross-metathesis reaction between a vinylboronate and 2-methyl-1,4-pentadiene).
Amphidinolides are a family of cytotoxic marine natural
products with diverse structures, isolated from Okinawa
dinoflagellates (Amphidinium sp.).1 Years ago we embarked
on a project aimed at synthesizing different amphidinolides.2
Among them, amphidinolide E (1), which features a 19-
membered macrolide with an embedded tetrahydrofuran ring,
eight stereogenic C(sp3) atoms, two conjugate diene units,
and an unprecedented side chain (which looks like a
monoterpene unit at first sight but contains 11 carbons)3 and
exhibits a strong activity in vitro against murine lymphoma
L1210. Its absolute stereochemistry was not established until
2002,3b when further amounts of sample became available
through repeated cultivation. In short, amphidinolide E was
and is an attractive target molecule.4,5 We report an approach
to amphidinolide E very different from those described to
date,4,5 which relies on a key C10-C26 fragment.
Our retrosynthetic analysis of 1 is shown in Scheme 1.
Reasonable, standard disconnections at C9-C10 and C1-O
bonds reveal two major segments.6 The NE fragment, which
is the subject of this communication, can be derived from the
coupling of a synthon of type 2 with aldehyde 3 via a
Julia-Kocienski reaction (henceforward, J-K reaction),7 fol-
lowed by an appropriate dihydroxylation of the C17-C18
double bond. Afterward, a C(sp2)-C(sp2) coupling, e.g., involv-
(4) Total syntheses: (a) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.;
Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int. Ed. 2006, 45, 8019.
(b) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960. For
diastereomers of amphidinolide E, see: (c) Va, P.; Roush, W. R. Org. Lett.
2007, 9, 307. (d) Va, P.; Roush, W. R. Tetrahedron 2007, 63, 5768.
(5) For syntheses of segments, see: (a) Marshall, J. A.; Schaaf, G.;
Nolting, A. Org. Lett. 2005, 7, 5331 (C6-C21). (b) Heitzman, C. L.;
Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J. M.; Va, P.; Roush,
W. R. Org. Lett. 2005, 7, 2405 (C6-C21). (c) Gurjar, M. K.; Mohapatra,
S.; Phalgune, U. S.; Puranik, V. G.; Mohapatra, D. K. Tetrahedron Lett.
2004, 45, 7899 (C12-C26).
(6) Two approaches were envisaged by us at the very beginning of this
project (ref 2f) for the key steps: (i) a macrolactonization under the mildest
possible conditions (to avoid epimerization at C2) as the last step, after a
J-K reaction (C9-C10 bond); (ii) a ring-closing metathesis under ap-
propriate conditions in the final step, after the ester formation.
(7) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26. For reviews, see: (b) Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563. (c) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr.
Chem. 2007, 275, 163.
(1) Very recent reviews: (a) Kobayashi, J.; Kubota, T. J. Nat. Prod.
2007, 70, 451. (b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(2) (a) Mas, G.; Gonza´lez, L; Vilarrasa, J. Tetrahedron Lett. 2003, 44,
8805 (amphi K C1-C5 chiral blocks). (b) Andreou, T.; Costa, A. M.;
Esteban, L.; Gonza´lez, L.; Mas, G.; Vilarrasa, J. Org. Lett. 2005, 7, 4083
(amphi K C9-C22 fragment). (c) Rodríguez-Escrich, C.; Urpí, F.; Vilarrasa,
J. submitted for publication (amphi X total synthesis). (d) Rodríguez-Escrich,
C.; Olivella, A.; Urpí, F.; Vilarrasa, J. Org. Lett. 2007, 9, 989 (amphi X/Y
C12-C21 segments). (e) Esteban, J.; Costa, A. M.; Go´mez, A.; Vilarrasa,
J. Org. Lett. 2008, 10, 65 (amphi E C1-C5 chiroblocks). (f) Esteban, J.
Ph.D. Thesis in process (2005-2008).
(3) (a) Kobayashi, J.; Ishibashi, M.; Murayama, T.; Takamatsu, M;
Iwamura, M.; Ohizumi, Y.; Sasaki, T. J. Org. Chem. 1990, 55, 3421. (b)
Kubota, T.; Tsuda, M.; Kobayashi, J. J. Org. Chem. 2002, 67, 1651.
10.1021/ol801923y CCC: $40.75
Published on Web 10/07/2008
2008 American Chemical Society

of the resulting alcohol as its tert-butyldiphenylsilyl (TBDPS)
ether (see 8), and quantitative oxidation of the sulfide to the
sulfone, with H2O2 and catalytic amounts of
(NH4)6Mo7O24·4H2O in EtOH at room temperature,10 afforded
9 in 76% overall yield from 7 (around 30% from 5). Compound
9 is equivalent to synthon 2. As X of 2 may be Het′S or Het′SO2
(a heteroaromatic sulfone different from SO2Het of Scheme 1),
the approach should allow us to carry out independent
Julia-Kocienski reactions to link C17 and C18 and, later, C9
and C10.
Scheme 1. Retrosynthetic Analysis of Amphidinolide E (1)
With 9 in our hands, we turned our attention to its J-K
reaction with aldehyde 3.11 Although ꢀ-alkoxysulfonyl-
phenyltetrazoles have been utilized in some cases,7b,c,12
a
ꢀ-elimination reaction from the anionic intermediate and/or
a scarce stereoselectivity are always possible.13 To examine
this transformation in our particular case, we first tested the
stability of 9 under the conditions of the J-K reaction. When
9 was treated with LiHMDS in THF at -78 °C for 1 h and
then the solution was quenched by pouring it into aqueous
NH4Cl at 0 °C, a 70:30 mixture of 9 and its epimer at C16
(epi-9) was recovered; that is, 30% epimerization occurred
(Scheme 3). Conversely, under identical conditions with
ing organotrifluoroborate 4, could create the C21-C22 bond.
Several challenges were inherent in this strategy. Moreover, its
versatility (which should afford series of stereoisomers for future
screenings) encouraged us to go ahead with the initial project,2f
despite the publication of other syntheses.4
Scheme 3. Configurational Stability of Alkaline Salts of 9
The synthesis of the C10-C17 fragment (see Scheme 2)
Scheme 2. Synthesis of Fragment C10-C17 (9)
NaHMDS or KHMDS, 9 was recovered almost or fully
unchanged, respectively.
The influence of the base and solvent on the E/Z ratio was
also examined, on a model (an analogue of 9, see Table 1).
As a solution of KHMDS (solid) in DMF/HMPA afforded
the best E/Z ratio (entry 7), these conditions were applied to
(10) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
began from butyrolactone 5 (commercially available or readily
prepared from L-glutamic acid).8 By means of a known
intramolecular allylation (from the O-silyl derivative to the
TiCl4-generated oxocarbenium ion), the desired 2,5-disubstituted
oxolane was obtained as a 85:15 cis-trans mixture.9 Separation
by chromatography furnished 6 in ca. 50% overall yield from
5. Thioether 7 was then obtained under standard conditions (a
Mitsunobu reaction with 1-phenyltetrazole-5-thiol as the nu-
cleophile).7 Anti-Markovnikov hydration of the double bond
via hydroboration followed by oxidation with H2O2, protection
(11) We prepared 3 from the Li enolate of N-propanoyl-4(S)-benzylox-
azolidin-2-one and 2,3-dibromopropene. Its enantiomer is known: (a) Evans,
D. A.; Kim, A. S. J. Am. Chem. Soc. 1996, 118, 11323. (b) Evans, D. A.;
Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506.
(12) (a) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am.
Chem. Soc. 2000, 122, 10033. (b) Sivaramakrishnan, A.; Nadolski, G. T.;
McAlexander, I. A.; Davidson, B. S. Tetrahedron Lett. 2002, 43, 213. (c)
Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.;
Reeves, J. T. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 12058. (d) Hara, S.;
Makino, K.; Hamada, Y. Tetrahedron Lett. 2006, 47, 1081. (e) Chang, S.-
K.; Paquette, L. A. Synlett 2005, 2915. (f) Lucas, B. S.; Gopalsamuthiram,
V.; Burke, S. D. Angew. Chem., Int. Ed. 2007, 46, 769
.
(13) (a) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685. (b)
Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573. (c) Compostella, F.; Franchini, L.; Panza, L.;
Prosperi, D.; Ronchetti, F. Tetrahedron 2002, 58, 4425. (d) Vicente, J.;
Huckins, J. R.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006, 45, 7258.
(e) Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi, T. J.
Org. Chem. 2008, 73, 5360.
(8) (a) Lehmann, J.; Pieper, B. Tetrahedron: Asymmetry 1992, 3, 1537.
(b) Figade`re, B.; Harmange, J.-C.; Laurens, A.; Cave´, A. Tetrahedron Lett.
1991, 32, 7539. (c) Also see ref 2b.
(9) Pilli, R. A.; Riatto, V. B. Tetrahedron: Asymmetry 2000, 11, 3675.
4844
Org. Lett., Vol. 10, No. 21, 2008

that the configuration of 11a was that shown in Scheme 4 on
the basis of the well-established Sharpless empirical rule for
the AD reaction of trans-disubstituted olefins (also see
below).15b On the other hand, AD-mix-ꢀ, that is, the
osmate-(DHQD)2PHAL complex,15 and 10 gave a 7:93 11a/
11b mixture, from which the desired diol 11b was obtained in
85% yield after column chromatography (only this last reaction
is shown in Scheme 4). Thus, these AD reactions took place
with full regioselectivitysthe CH2dCBr moiety did not react
at allsand excellent diastereofacial selectivity. Again, we relied
upon the Sharpless empirical rule to attribute the configuration
of the two newly created stereocenters of 11b. The NMR
coupling constants and a NOESY experiment agreed with the
prediction and indicated that the main conformer of 11b was
that shown in Figure 1.16
Table 1. Screening the Conditions for the J-K Reaction of 9
E/Z
ratiob
entry
base (soln), major solvent, tempa
1
2
3
4
5
6
7
NaHMDS (in THF), THF, -78 °C to rt
NaHMDS (in THF), DME, -78 °C to rt
NaHMDS (in THF), DMF, -60 °C to rt
KHMDS (in toluene), THF, -78 °C to rt
KHMDS (in toluene), DME, -78 °C to rt
KHMDS (in toluene), DMF, -60 °C to rt
15:85
58:42
85:15
60:40
85:15
90:10
KHMDS (solid), 4:1 DMF/HMPA, -78 °C to rt 93:07
a The sulfone and base were mixed at -78 °C (or -60 °C, in some
cases, to avoid freezing), for 10-15 min; after the addition of isobutyral-
dehyde and stirring for 1 h at the same temperature, the solution was allowed
to warm up to rt for 2 h. b The E/Z ratios were determined by 1H NMR
analysis of the crude product mixtures.
the coupling of substrates 9 and 3. To our delight, in this
way 10 was obtained always in good yields and with
excellent selectivities (>95:5 E/Z, Scheme 4).
Scheme 4. Synthesis and Dihydroxylation of 10
Figure 1. Relevant NMR data of 11b and 11a in CDCl3.
For the sake of comparison, the main NMR data of 11a
are also included in Figure 1.17
The diol moiety of 11b was protected as the acetal 12
(see Scheme 4, PMP ) p-methoxyphenyl, ca. 1:1 mixture
of epimers). We examined here if it would be possible, later,
to deprotect selectively one of the hydroxy groups of the
1,2-diol moiety. Treatment of 12 with DIBALH gave rise
to a very selective cleavage, as p-methoxybenzyl (PMB) ether
13 was isolated in 80% yield (91% brsm).18
Finally, organotrifluoroborate 4 was prepared by cross
metathesis (CM) as shown in Scheme 5, namely, from
The catalytic dihydroxylation of 10 with encapsulated OsO4
(Os EnCat 40) and NMO in acetone/H2O gave a 85% yield of
two diols in a 2:1 ratio.14 Sharpless asymmetric dihydroxyla-
tion15 of 10 with AD-mix-R provided the same diols (11a/11b)
in 97:3 ratio; a 93% yield of pure 11a was isolated. We assumed
(16) See Supporting Information for the corresponding spectra. The
largest HCCH coupling constant in the key moiety of 11b indicates an
almost antiperiplanar arrangement of H18 and H19, whereas the very small
gauche 3J(H17H18) suggests a dihedral angle closer to 90° than to 60° (see
the Newman projection through the C18-C17 bond in Figure 1, left). The
value of 3J(H17COH) is also worth noting. The most relevant NOEs agree
with these observations (with H16, H17, H18, Me29, and H20 in the same,
rear face). The depicted hydrogen bondings likely help to fix the conforma-
tion shown in Figure 1 (left).
(17) A full conformational study of this “byproduct” is outside the scope
of our work. However, the 3J(H17H18) value for 11a, the (small) cross peak
between H16 and H17, and the intense cross peak between H17 and Me29
may be accounted for by the main conformation depicted in Figure 1 (right);
other possible minor rotamers (by counterclockwise 60° rotation of the
C19-C18 bond and/or by clockwise rotation of the C18-C17 bond) cannot
be ruled out.
(14) According to the Kishi rule (Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron 1984, 40, 2247), they should be 11a and 11b, respectively.
(15) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
4263. Very recent reviews: (b) Kolb, H. C.; Sharpless, K. B. In Transition
Metals for Organic Synthesis; 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2004; Vol. 2, p 275. (c) Zaitsev, A. B.; Adolfsson, H.
Synthesis 2006, 1725. (d) Franc¸ais, A.; Bedel, O.; Haudrechy, A. Tetra-
hedron 2008, 64, 2495.
Org. Lett., Vol. 10, No. 21, 2008
4845

We hope to report the assembly of appropriately substi-
tuted C10-C26 (NE) and C1-C9 (SW) fragments, as well
as alternative but less successful routes to our NE segment(s),
in a future full paper.
Scheme 5. Preparation of 4 via Cross Metathesis
In conclusion, a fragment has been achieved that is key
for our planned synthesis of 1 since both approaches2f,6 go
across this C10-C26 fragment. To obtain it in practical
overall yields, a fine-tuning of some protocols to our case
was essential. Thus, the J-K reaction(s) with the C10-C17
segment required an optimization, to avoid ꢀ-elimination and/
or epimerization reactions and to attain the highest stereo-
selectivity during the formation of the C17-C18 double
bond; with solid KHMDS in 4:1 DMF/HMPA, E/Z ratios
equal to or higher than 20:1, without epimerization at all,
have been achieved in all batches. On the other hand, AD-
mix-ꢀ gave directly the desired dihydroxylation of this double
bond, with excellent regioselectivity and diastereofacial
selectivity. Regarding the C18-C26 triene moiety, among
the methods examined by us to date the very efficient
combination of a Grubbs CM (with only 2 mol % of H-G
II, to prepare the boronate precursor of trifluoroborate 4) with
a Suzuki-Molander-type cross-coupling (of 4 with 12) is
remarkable.
commercially available vinylboronic acid pinacol ester,19
2-methyl-1,4-pentadiene(140mol%),andtheHoveyda-Grubbs
II initiator20 (H-G II, only 2 mol %), to give the corre-
sponding boronate, which was treated immediately with
KHF2 in 3:1 CH3CN/H2O to give 4.21 Salt 4 has not been
reported to the best of our knowledge; it was isolated as a
pale yellow powder, in 70% overall yield.22
The synthesis of fragment C10-C26 was completed as
shown in Scheme 6. The Suzuki cross-coupling reaction
Scheme 6. Cross-Coupling Reaction of 12 and 4
Acknowledgment. Support from the Ministerio de Educa-
cio´n y Ciencia, through grants SAF2002-02728 and CTQ-2006-
15393, is acknowledged. The Universitat de Barcelona con-
tributed with a studentship to J.E. (from February 2004 till
January 2008). Our group is a member of the IBUB (Institut
de Biomedicina de la Universitat de Barcelona). Thanks are
due to a reviewer for bringing to our attention ref 14.
Supporting Information Available: Experimental pro-
1
cedures, copies of the H and 13C NMR spectra of 7, 8, 9,
10, 11b, 11a, 13, 4, and 15, and copies of 2D NMR spectra
of 11b, 11a, 13, and 15. This material is available free of
charge via the Internet at http://pubs.acs.org.
between 12 and 4 under the conditions of Molander et al.23
afforded 14 (epimer mixture) in 76% yield.24
OL801923Y
As expected (in the light of the conversion of 12 to 13),
the treatment of 14 with DIBALH gave the C18-OPMB-
protected NE fragment (15) in 83% yield, with recovery of
10% of 14. With AcOH/H2O at room temperature, the
cleavage of the acetal group of 14 was quick and practically
quantitative to give the unprotected diol.25
(22) Attempts to prepare 4 directly, from potassium trifluoro(vinyl)borate
(ethenyltrifluoroborate, KF3BCHdCH2), 2-methyl-1,4-pentadiene, and H-G
II, in refluxing CH2Cl2/acetone, were unsuccessful (no reaction).
(23) Five mole percent of Pd(OAc)2, 10 mol % of PPh3, and 300 mol
% of Cs2CO3. See: (a) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005,
70, 3950. For an example in anhydrous THF, see: (b) Fu¨rstner, A.; Larionov,
O.; Flu¨gge, S. Angew. Chem., Int. Ed. 2007, 46, 5545. For reviews, see:
(c) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49. (d)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(18) (a) The structure of 13 was assigned on the basis of 2D-NMR
spectra (COSY, HSQC, and HMBC). Cross peaks between C18 and the
methylene protons of OPMB (3JC-H) and between H17 and the OH proton
(3JHH) are relevant. (b) The oxygen atom of the oxolane ring may play a
role in this selective cleavage. We would have preferred the reverse cleavage,
to obtain mainly the C17-OPMB isomer, saving two steps, since later we
need C18-OH free (and, in principle, C17-OH protected).
(24) The reaction of 12 and 4 (Scheme 6, ref 23) was complete within
1.5 h. Monoprotected diol 13 can be coupled with 4 in the same way, but
the attempted coupling of unprotected diol 11b led mainly to decomposition.
For the sake of comparison, the coupling of 12 with the boronate of Scheme
5 was only partial even after overnight heating in a bath at 70 °C (as in
Scheme 6), under the following conditions for the Suzuki-Miyaura reaction:
PdCl2(dppf) (10 mol %) and Ba(OH)2·8H2O (300 mol %) in DMF. Compare:
(a) Gopalarathnam, A.; Nelson, S. G. Org. Lett. 2006, 8, 7. (b) Fu¨rstner,
A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.; Teply, F.; Aissa,
C.; Moulin, E.; Mu¨ller, O. J. Am. Chem. Soc. 2007, 129, 9150. (c) Most
recent review: Doucet, H. Eur. J. Org. Chem. 2008, 2013.
(19) Several CM of this etheneboronate ester (2-ethenyl-4,4,5,5-tetram-
ethyl-1,3,2-dioxaborolane), with the Grubbs II reagent, have been reported:
(a) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031 (and refs 13
and 14 therein). (b) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett.
2005, 7, 187. For other alkenylboronates, see: (c) Morrill, C.; Funk, T. W.;
Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733.
(20) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(25) Oxidative removal (e.g., with DDQ) of PMP and PMB groups is
counterindicated as conjugate dienes are too sensitive; for an overview,
see: Wutts, P. G. M.; Greene, T. W. ProtectiVe Groups in Organic Synthesis,
4th ed.; Wiley: Hoboken, 2007, p 124.
(21) Very recent review of potassium organotrifluoroborates: Darses,
S.; Genet, J.-P. Chem. ReV. 2008, 108, 288.
4846
Org. Lett., Vol. 10, No. 21, 2008