Total syntheses of amphidinolide X and Y

Article abstract of DOI:10.1021/ja061918e

Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) and amphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. A pivotal step of the highly convergent routes to these structurally rather unusual secondary metabolites consists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 16 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 17 was then cyclized with the aid of Ag(I) to give dihydrofuran 19 containing the (R)-configured tetrasubstituted sp³ chiral center at C. 19, which was further elaborated into tetrahydrofuran 25 representing the common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configured stereodiad at C. 10 and C. 11 was generated by a palladium-catalyzed, Et ₂Zn-promoted addition of the enantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the corresponding C.1-C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an α-ketoester, a diastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination with suitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the end games of both total syntheses follow similar blueprints, involving key fragment coupling processes via the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction and final Yamaguchi esterifications to forge the 16-membered macrodiolide ring of amphidinolide X and the 17-membered macrolide frame of amphidinolide Y, respectively. This methodological convergence ensures high efficiency and an excellent overall economy of steps for the entire synthesis campaign.

Full text of DOI:10.1021/ja061918e

Published on Web 06/24/2006
Total Syntheses of Amphidinolide X and Y
Alois Fu¨rstner,* Egmont Kattnig, and Olivier Lepage
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/Ruhr, Germany
Received March 21, 2006; E-mail: fuerstner@mpi-muelheim.mpg.de
Abstract: Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) and
amphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. A
pivotal step of the highly convergent routes to these structurally rather unusual secondary metabolites
consists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of the
enantioenriched propargyl epoxide 16 (derived from a Sharpless epoxidation) with a Grignard reagent.
Allenol 17 was then cyclized with the aid of Ag(I) to give dihydrofuran 19 containing the (R)-configured
tetrasubstituted sp3 chiral center at C.19, which was further elaborated into tetrahydrofuran 25 representing
the common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configured
stereodiad at C.10 and C.11 was generated by a palladium-catalyzed, Et2Zn-promoted addition of the
enantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the corresponding
C.1-C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an R-ketoester, a
diastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination with
suitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the end
games of both total syntheses follow similar blueprints, involving key fragment coupling processes via the
“9-MeO-9-BBN” variant of the alkyl-Suzuki reaction and final Yamaguchi esterifications to forge the 16-
membered macrodiolide ring of amphidinolide X and the 17-membered macrolide frame of amphidinolide
Y, respectively. This methodological convergence ensures high efficiency and an excellent overall economy
of steps for the entire synthesis campaign.
Introduction
dinolide X (1), which displays none of these structural elements
on its eVen-numbered macrocycle.4 Moreover, 1 was the first
Marine dinoflagellates of the genus Amphidinium sp. living
in symbiosis with the Okinawan flatworm Amphiscolops spp.
have turned out to be exceptionally rich sources of bioactive
natural products with previously unknown structural character-
istics.1 To date, they have given rise to more than 30 novel
metabolites belonging to the “amphidinolide” class, all of which
exhibit potent cytotoxic properties against various cancer cell
lines in the standard assays.2 Despite their common origin and
this uniform activity profile, the individual members of the series
are quite dissimilar in structural terms. This diversity is the result
of a complex nonsuccessive polyketide biosynthesis pathway
that generates a host of frequently odd-numbered macrocyclic
skeletons of largely varying ring size that are decorated with
exo-methylene groups, vicinal one-carbon branches, and 1,3-
diene units.1,3 However, even these distinctive features are not
preserved throughout the family, as can be seen from amphi-
example of a natural product containing a macrodiolide ring
that embodies a diacid and a diol subunit rather than two
hydroxyacid entities.5
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77. (b) Ishibashi,
M.; Kobayashi, J. Heterocycles 1997, 44, 543. (c) Chakraborty, T. K.; Das,
S. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 131. (d) Kobayashi,
J.; Ishibashi, M. In ComprehensiVe Natural Products Chemistry; Mori, K.,
Ed.; Elsevier: Amsterdam, 1999; Vol. 8; pp 415-649.
(2) IC50 values as low as 0.00014 µg/mL were reported; hence, amphidinolides
H and N exhibit potencies similar to that of the spongistatins, cf. ref 1.
(3) (a) Review: Rein, K. S.; Borrone, J. Comp. Biochem. Physiol., B 1999,
124, 117. (b) For representative studies on the biosynthesis of the
amphidinolides see: Kobayashi, J.; Takahashi, M.; Ishibashi, M. J. Chem.
Soc., Chem. Commun. 1995, 1639. (c) Ishibashi, M.; Takahashi, M.;
Kobayashi, J. Tetrahedron 1997, 53, 7827. (d) Sato, M.; Shimbo, K.; Tsuda,
M.; Kobayashi, J. Tetrahedron Lett. 2000, 41, 503.
Yet another glimpse of the complex biochemical machinery
producing the individual amphidinolides was caught during a
9
9194
J. AM. CHEM. SOC. 2006, 128, 9194-9204
10.1021/ja061918e CCC: $33.50 © 2006 American Chemical Society

Total Syntheses of Amphidinolide X and Y
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of Amphidinolide X (1) and Y
(2), Converging to the Common Synthon Da
recent recollection of the Amphidinium Y-42 strain, which not
only provided 1 together with three other known amphidinolides
but also afforded tiny amounts of a novel congener, designated
amphidinolide Y (2); this product exists as an equilibrium
mixture of the dominant C.6-keto- and the minor C.6(9)-
hemiacetal form.6 Although 2 contains a 17-membered lactone
rather than the conspicuous 16-membered macrodiolide core
of its companion amphidinolide X (1), it is obviously closely
related to the latter and is thought to be its biogenetic pre-
cursor. In line with this notion, oxidative cleavage of the
R-hydroxyketone moiety with lead tetraacetate followed by
spontaneous lactonization of the resulting acid with the hy-
droxyl group in vicinity converted compound 2 into 1 in fair
yield.6
During our studies on the total synthesis7 and biological
evaluation8 of various natural products of marine or terrestrial
origin, a strong interest arose in the amphidinolide class.9,10
These compounds constitute obvious targets for an exploratory
program at the chemistry/biology interface because of their
challenging and diverse molecular architectures and because they
are extremely scare, thus rendering a detailed assessment of their
promising anticancer activities difficult if one relies on extraction
from the producing dinoflagellates only. As part of this program,
we now present the first total syntheses of amphidinolide X,11
its nonnatural stereomer 47, as well as of its biosynthetic
precursor amphidinolide Y. Moreover, from the purely chemical
perspective, this endeavor provided an excellent opportunity to
scrutinize methodology for catalytic C-C-bond formation
previously developed in this laboratory.
(4) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kawabata, J.;
Katsumata, K.; Horiguchi, T.; Kobayashi, J. J. Org. Chem. 2003, 68,
5339.
(5) For a recent review on macrodiolides see: Kang, E. J.; Lee, E. Chem.
ReV. 2005, 105, 4348.
(6) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kawabata, J.;
Kobayashi, J. J. Org. Chem. 2003, 68, 9109.
(7) Recent examples: (a) Fu¨rstner, A.; Domostoj, M. M.; Scheiper, B. J. Am.
Chem. Soc. 2005, 127, 11620. (b) Fu¨rstner, A.; Turet, L. Angew. Chem.,
Int. Ed. 2005, 44, 3462. (c) Fu¨rstner, A.; Radkowski, K.; Peters, H. Angew.
Chem., Int. Ed. 2005, 44, 2777. (d) Scheiper, B.; Glorius, F.; Leitner, A.;
Fu¨rstner, A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11960. (e) Fu¨rstner,
A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. 2002, 41, 2097. (f)
Fu¨rstner, A.; Mu¨ller, C. Chem. Commun. 2005, 5583. (g) Fu¨rstner, A.;
Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J.
Am. Chem. Soc. 2002, 124, 7061. (h) Fu¨rstner, A.; Mamane, V. Chem.
Commun. 2003, 2112. (i) Fu¨rstner, A.; Wuchrer, M. Chem. Eur. J. 2006,
12, 76. (j) Fu¨rstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006.
(8) (a) Fu¨rstner, A.; Kirk, D.; Fenster, M. D. B.; A¨ıssa, C.; De Souza, D.;
Mu¨ller, O. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8103. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2003, 42, 3582. (c) Fu¨rstner, A. Eur. J. Org. Chem.
2004, 943. (d) Fu¨rstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Tetrahedron
2004, 60, 9543.
a Note the “shift” in the numbering scheme for the two natural products
caused by their different ring sizes and connectivities.
Results and Discussion
General Retrosynthetic Considerations. Because of the
identity of the tetrahydrofuran segments in 1 and 2, it should
be possible to use a common building block for both syntheses.
While the ester linkages forming the macrodiolide ring of
amphidinolide X constitute obvious sites for disconnection of
this target, it was envisaged to assemble the required C.7-C.22
diol entity B by metal-catalyzed cross coupling at the C.13-
C.14 bond (Scheme 1). This strategy employs building blocks
A, C, and D of similar size and ultimately ensures high
flexibility; more importantly, however, it allows one to address
the critical formation of the tetrasubstituted chiral center C.19
residing at the ether bridge in D in an early stage of the synthesis
campaign. Because D can be directly used for the envisaged
total synthesis of amphidinolide Y (2) as well by a similar
fragment-coupling process at the corresponding C.12-C.13
bond, an excellent overall “economy of steps”,12 a favorable
methodological redundancy, and hence a significant convergence
of the entire program should be secured. The C.1-C.12
fragment E to be embedded into 2, which carries another
(9) (a) A¨ıssa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003,
125, 15512. (b) Fu¨rstner, A.; A¨ıssa, C.; Riveiros, R.; Ragot, J. Angew.
Chem., Int. Ed. 2002, 41, 4763.
(10) For total syntheses of amphidinolides reported by other groups, see: (a)
Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198. (b)
Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945. (c) Williams,
D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765. (d) Lam, H. W.;
Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508. (e) Maleczka, R. E.,
Jr.; Terrell, L. R.; Geng, F.; Ward, J. S. Org. Lett. 2002, 4, 2841. (f) Ghosh,
A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374. (g) Trost, B. M.;
Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028. (h) Ghosh, A. K.;
Gong, G. J. Am. Chem. Soc. 2004, 126, 3704. (i) Colby, E. A.; O’Brien,
K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998. (j) Trost, B. M.;
Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126, 13618. (k) Trost, B. M.;
Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124,
12420. (l) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085. (m)
Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005,
127, 17921. (n) Trost, B. M.; Harrington, P. E.; Chisholm, J. D.; Wrobleski,
S. T. J. Am. Chem. Soc. 2005, 127, 13598. (o) Colby, E. A.; Jamison, T.
F. Org. Biomol. Chem. 2005, 3, 2675. (p) Colby, E. A.; O’Brien, K. C.;
Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297.
(11) Preliminary communication: Lepage, O.; Kattnig, E.; Fu¨rstner, A. J. Am.
Chem. Soc. 2004, 126, 15970.
(12) For a discussion see: Fu¨rstner, A. Synlett 1999, 1523.
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J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9195

A R T I C L E S
Fu¨rstner et al.
Scheme 2. Use of an Axially Chiral Allene J as a Relay for the
Envisaged Chirality Transfer from a Propargyl Epoxide K to
Fragment D Embodying the Tetrasubstituted Chiral Center C.19.
Scheme 3 a
tetrasubstituted chiral center at C.7, should be accessible by aldol
chemistry joining segments G and H, followed by elaboration
of the C.6/C.7 acyloin motif through suitable oxidation-state
management and a chelate-controlled addition of a methyl donor
to an adequately protected R-hydroxy ketone at C.7.
Preparation of the Common Tetrahydrofuran Segment.
Control over the absolute configuration of the tertiary ether
residing at C.19 of the tetrahydrofuran segment D (amphi-
dinolide X numbering) deemed crucial for the entire synthesis
campaign and was therefore addressed in an early stage.
The chosen route to this key structural element hinges upon
methodology recently developed in our laboratory (Scheme
2).13,14 Specifically, it was planned to use a chiral allene J as
latent progenitor of the tetrahydrofuran ring, which can be
formed stereoselectively by an iron-catalyzed reaction of a
propargyl epoxide K with a suitable Grignard reagent.13 This
sequence should enable an efficient chirality transfer from a
readily accessible epoxide to the quaternary chiral sp3 center
C.19 in D via the axial chirality of an allene relay.
a Reagents and conditions: [a] Catalyst 5 or 6 (5 mol %), CH2Cl2, rt;
[b] CBr4, PPh3; CH2Cl2, 0 °C; [c] n-BuLi, THF, -78 °C, then MeI, 0 °C,
66% (over both steps); [d] ketone 8 (25 mol %), MeCN/DMM, Bu4NHSO4
cat., aq K2CO3, Oxone, Na2ETDA, -10 °C, 33% (ee ) 83%).
To reduce this plan to practice, we initially pursued a cross
metathesis approach15 using complexes 516 or 617 as appropriate
catalysts (Scheme 3). Since only aldehyde 4a (R ) PMB) could
be obtained in isomerically pure form, this compound was
chosen for further elaboration into enyne 7 as the substrate for
a chemo- and enantioselective oxidation with Oxone mediated
by the D-fructose derivative 8.18 Although significant levels of
enantiocontrol could be reached, the conversion remained
unsatisfactory despite considerable experimentation. Since
catalyst 8 also leads to the wrong enantiomer of 9 and would
ultimately have to be replaced by (a surrogate for) nonnatural
L-fructose, we decided to abandon this very short entry and to
pursue a somewhat more conservative route to the required
building block.
To this end, monosilylation of propane-1,3-diol 10 followed
by oxidation and standard olefination of the resulting aldehyde
ensured the exclusive formation of (E)-12, which was reduced
with Dibal-H (Scheme 4).19 The allylic alcohol 13 thus obtained
was epoxidized by the Sharpless method20 to give product 1419
in excellent yield and decent optical purity (ee ) 83%).
Swern oxidation followed by treatment of the resulting aldehyde
with the Ohira-Bestmann reagent21 gave alkyne 15, which
could be methylated on treatment with LiHMDS/MeOTf at
-78°C. Gratifyingly, reaction of the resulting propargyl epoxide
16 with n-PrMgCl in the presence of cheap and benign Fe(acac)3
as the precatalyst furnished allenes 17 and 18 as an 8:1 mixture
in favor of the required syn isomer.13 The reaction is exception-
ally fast, requiring less than 5 min to go to completion. In
contrast to our original protocol, the iron salt was added to the
substrate as a solution in toluene. This simple modification
avoids some uncontrolled degradation of the labile oxirane
during the time it takes to dissolve the catalyst when added in
solid form, and therefore ensures good reproducibility and
respectable yields in this crucial step. The pronounced dia-
stereoselectivity favoring the syn-isomer 17 likely results from
a directed delivery of the nucleophile enforced by the preco-
(13) Fu¨rstner, A.; Me´ndez, M. Angew. Chem., Int. Ed. 2003, 42, 5355.
(14) (a) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (b) See also:
Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002,
124, 13856. (c) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43,
3955. (d) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3943. (e) Seidel, G.; Laurich, D.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3950. (f) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed.
2002, 41, 609. (g) Fu¨rstner, A.; Martin, R.; Majima, K. J. Am. Chem. Soc.
2005, 127, 12236.
(15) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (b) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012. (c) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (d) Connon, S. J.; Blechert,
S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(16) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.;
Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004,
2, 8.
(17) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.
J. Org. Chem. 2000, 65, 2204. (b) Fu¨rstner, A.; Ackermann, L.; Gabor,
B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R.
Chem. Eur. J. 2001, 7, 3236.
(19) Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55, 14013.
(20) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 231-280.
(21) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold, B.;
Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(18) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.
9
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Total Syntheses of Amphidinolide X and Y
A R T I C L E S
Scheme 4 a
Scheme 5 a
a Reagents and conditions: [a] Ethylene glycol, PTSA cat., benzene; [b]
Dibal-H, Et2O, 54% (over two steps); [c] Et2Zn, Pd(OAc)2 cat., PPh3 cat.,
THF, 65% (anti:syn ) 4.5:1); [d] PMBCl, NaH, TBAI, DMF, 94%; [e]
LiHMDS, MeI, THF, 95%; [f] (i) Cp2ZrHCl, C6H6; (ii) I2, CH2Cl2, 61%.
hydrines 20 and epi-20 as single stereomers each,24 which could
be separated by flash chromatography. Removal of the bromide
in 20 using (Me3Si)3SiH25 and AIBN followed by standard
protecting-group manipulations furnished product 25 as func-
tional surrogate of synthon D.26 The minor product epi-20 was
processed analogously to give epi-25 which was ultimately
converted into the first fully synthetic analogue of amphidinolide
X as outlined below.
Total Synthesis of Amphidinolide X. The preparation of
the second building block required for the total synthesis of
amphidinolide X started from acetoacetate 26, which was
transformed into acetal 2727 prior to reduction with Dibal-H
(Scheme 5). The resulting aldehyde 2828 was subjected to a
Et2Zn-mediated, palladium-catalyzed reaction with propargyl
mesylate 29,29,30 furnishing the desired anti-configured alcohol
30 in good yield, decent diastereoselectivity (dr ) 4.5:1) and
excellent optical purity (ee ) 94%); the fact that the minor syn-
isomer 31 could be readily separated by routine chromatography
turned out to be an additional bonus. Elaboration of alkyne 30
into product 33 followed by a hydrozirconation/iodination in
a Reagents and conditions: [a] TBDPSCl, Et3N, CH2Cl2, 92%; [b] (i)
oxalyl chloride, DMSO, Et3N, CH2Cl2; (ii) MeOOCCH2P(O)(OEt)2, NaH,
THF, 85% (over two steps); [c] Dibal-H, Et2O, 86%; [d] Ti(OiPr)4 cat.,
L-(+)-DET cat., t-BuOOH, MS 4 Å, CH2Cl2, 97% (ee ) 83%); [e] (i) oxalyl
chloride, DMSO, Et3N, CH2Cl2; (ii) (MeO)2P(O)C(N2)COMe, K2CO3,
MeOH, 67%; [f] LiHMDS, MeOTf, THF, 95%; [g] n-PrMgCl, Fe(acac)3
cat., toluene, 62% (syn:anti ) 8:1); [h] AgNO3, CaCO3, aq acetone, 90%;
[i] NBS, DMF/H2O (15/1), 65%; [j] AIBN, (TMS)3SiH, toluene; [k]
NaHCO3, MeOH, 90% (over both steps); [l] PMBOC(dNH)CCl3, PPTS,
CH2Cl2/C6H12, 76%; [m] TBAF, THF, 97%; [n] I2, PPh3, imidazole, MeCN/
Et2O, 92%.
(23) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M. Eur. J.
Org. Chem. 1998, 1675.
(24) Originally, it had been envisaged to install the missing -OH group at C.17
via hydroboration/oxidation or, alternatively, by a Wacker oxidation of the
olefin in 19 followed by reduction of the resulting ketone; however, both
sequences turned out to be unsatisfactory.
(25) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(26) For a recent alternative synthesis of a D-synthon surrogate see: Chen, Y.;
Jin, J.; Wu, J.; Dai, W.-M., Synlett 2006, 1177.
(27) Toluene should not be used as substitute for benzene in the acetalization
reaction because the separation of the volatile product is then much more
difficult and results in significantly lower yields.
(28) The literature reports that this Dibal-H reduction affords the corresponding
alcohol, cf: Langer, P.; Freifeld, I. Synlett 2001, 523; in our hands, however,
the reduction reproducibly stopped at the aldehyde stage even if an excess
Dibal-H was used.
ordination of the oxophilic catalyst and/or reagent to the epoxide
ring (Scheme 2) and hence nicely complements the anti-
selectivity of the standard copper-based methods for allenol
formation.13
Because the allene isomers 17 and 18, however, were not
readily separable, the mixture was treated with AgNO3/CaCO3
in aqueous acetone22 to afford the corresponding dihydrofurans
19 and epi-19 with strict chirality transfer. Subsequent bromo-
esterification with NBS in aqueous DMF23 gave the bromo-
(29) (a) Marshall, J. A. Chem. ReV. 2000, 100, 3163. (b) Marshall, J. A.; Adams,
N. D. J. Org. Chem. 1999, 64, 5201. (c) Marshall J. A.; Schaaf, G. M. J.
Org. Chem. 2001, 66, 7825.
(30) For a recent application see: Bes¸ev, M.; Brehm, C.; Fu¨rstner, A. Collect.
(22) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180.
Czech. Chem. Commun. 2005, 70, 1696.
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A R T I C L E S
Scheme 6 a
Fu¨rstner et al.
Scheme 7. Possible Scenarios for the End Game
a Reagents and conditions: [a] (EtO)2P(O)CH2COOMe, LiCl, DBU,
MeCN, 94%; [b] HF‚pyridine, MeCN, quant.; [c] (i) oxalyl chloride, DMSO,
Et3N, CH2Cl2; (ii) NaClO2, NaH2PO4, (CH3)2CdCHCH3, t-BuOH, 92%.
benzene as the solvent of choice31,32 gave vinyl iodide 34 in
well reproducible 65% yield as the only regioisomer.33
The third fragment (Scheme 6) was obtained by olefination
of the known aldehyde 35 (ee ) 95%)34 under Masamune-
Roush conditions,35 providing ester (E)-36 in 85% yield.
Desilylation with HF‚pyridine gave alcohol 37 which was
converted to acid 38 by stepwise oxidation36 that was more
productive than the one-step protocol using PDC in DMF.37
With all required fragments in suitably protected form in
hand, the stage was set for the completion of the first total
synthesis of amphidinolide X (1). The assembly process itself,
however, deserves careful consideration.
Due to the “bifunctional” nature of each building block,
various scenarios for the assembly of 1 can be envisaged
(Scheme 7). Among them, the sequence AD + C (green line)
was ruled out because it implies rather severe selectivity issues
during the conversion of the leaving group X at C.14 of the
AD part into a suitable nucleophile as required for the envisaged
cross coupling with the alkenyl iodide residing on segment C.38
In contrast, the choice between the remaining two options, AC
+ D (red line) or CD + A (blue line), seemed less obvious.
Some exploratory studies, however, provided clear guidance.
Thus, it was found that the unprotected aldol substructure
extending from the keto group at C.8 to the -OH group at C.10
is fairly labile to acid as well as base, suffering from elimination
even under mild conditions. This observation spoke against a
late-stage manipulation of this site as required in the CD + A
scenario and certainly against attempted formation of the
macrocycle by lactonization at the fragile aldolic -OH. Since
the sequence AC + D projects formation of the crucial ester
linkage at C.10 in an early stage, it seemed less risky overall.
Furthermore, this particular assembly process has the subtle
advantage of introducing the most valuable building block, D,
last in the linear sequence and might therefore engender optimal
productivity. As a consequence, our attempts to complete the
first total synthesis of amphidinolide X gravitated toward this
option, which could in fact be successfully reduced to practice
as shown in Scheme 8.
To this end, the PMB-ether in 34 was cleaved with DDQ,39
and the resulting alcohol 39 was subjected to a Yamaguchi
esterification40,41 with acid 38, delivering the desired product
40 in excellent yield. The crucial coupling of this elaborate
alkenyl iodide with the tetrahydrofuran segment 25 was achieved
by recourse to the “9-MeO-9-BBN variant” of the Suzuki
reaction previously developed in this laboratory (Scheme 9).42
Rather than generating the required borate nucleophile by
complexation of an organoborane precursor with base (e.g.,
MeOM),43 the reactive species is formed from 9-MeO-9-BBN
on treatment with a suitable organolithium- or other polar
organometallic reagent RM,42 which can also be generated in
situ, e.g., by metal-halogen exchange.44
Application of this method to the present case resulted in
efficient alkyl-alkenyl cross coupling45 of the highly function-
(39) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(40) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Sakurai, Y.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
(41) (a) Review: Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006,
106, 911. (b) For a recent application from this laboratory, see: Mlynarski,
J.; Ruiz-Caro, J.; Fu¨rstner, A. Chem. Eur. J. 2004, 10, 2214.
(42) (a) Fu¨rstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165. (b) Fu¨rstner, A.;
Leitner, A. Synlett 2001, 290. (c) Fu¨rstner, A.; Nikolakis, K. Liebigs Ann.
1996, 2107. (d) Fu¨rstner, A.; Seidel, G. Synlett 1998, 161. (e) The method
was also independently reported by: Soderquist, J. A.; Matos, K.; Rane,
A.; Ramos, J. Tetrahedron Lett. 1995, 36, 2401.
(43) For general reviews on the Suzuki reaction see, inter alia: (a) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147. (b) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457.
(44) (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885. (b) Mickel,
S. J. et al. Org. Process Res. DeV. 2004, 8, 113-121.(c) Yuan, Y.; Men,
H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720.
(45) Reviews on the alkyl-Suzuki reaction and applications to total synthesis:
(a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4442. (c) For early applications of the alkyl-Suzuki
reaction from this laboratory, see: Fu¨rstner, A.; Konetzki, I. J. Org. Chem.
1998, 63, 3072. (d) Fu¨rstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071.
(e) Fu¨rstner, A.; Seidel, G. J. Org. Chem. 1997, 62, 2332. (f) Fu¨rstner, A.;
Seidel, G.; Gabor, B.; Kopiske, C.; Kru¨ger, C.; Mynott, R. Tetrahedron
1995, 51, 8875.
(31) (a) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15,
333. (b) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115
(32) Hu, T.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 11368.
(33) Thereby it was essential to dilute the mixture with CH2Cl2 prior to the
addition of iodine at low temperature (-15°C) to avoid freezing of the
reaction medium. Moreover, it is important to treat the mixture with aq
Na2S2O3 once the color of iodine starts to persist in order to ensure high
and reproducible yields, cf. Supporting Information.
(34) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410.
(35) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(36) (a) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(37) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(38) Such a transformation could be achieved via zinc insertion into the C-X
bond in the AD fragment followed by Negishi cross coupling. Exploratory
studies, however, invariably resulted in low yields and were abandoned in
favor of the Suzuki route.
9
9198 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Total Syntheses of Amphidinolide X and Y
A R T I C L E S
Scheme 10. Preparation of 19-epi-Amphidinolide Xa
Scheme 8 a
a Reagents and conditions: [a] t-BuLi, Et2O/THF, then 9-MeO-9-BBN;
[b] (dppf)PdCl2, Ph3As, K3PO4, aq DMF, 43%; [c] LiI, pyridine, 125 °C;
[d] aq HOAc, 57% (over both steps); [e] DDQ, CH2Cl2, pH 7 buffer; [f]
2,4,6-trichlorobenzoyl chloride, Et3N, THF; then DMAP, toluene, 39% over
both steps.
a Reagents and conditions: [a] DDQ, CH2Cl2, pH 7 buffer, 89%; [b]
acid 38, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene; then 39, DMAP,
96%; [c] t-BuLi, Et2O/THF, then 9-MeO-9-BBN; [d] (dppf)PdCl2, Ph3As,
K3PO4, aq DMF, 74%; [e] LiI, pyridine, 125 °C; [f] aq HOAc, 53% (over
both steps); [g] DDQ, CH2Cl2, pH 7 buffer, 84%; [h] 2,4,6-trichlorobenzoyl
chloride, Et3N, THF; then DMAP, toluene, 62%.
19-epi-Amphidinolide X. As outlined above, our total
synthesis of amphidinolide X is based on the assembly of three
building blocks of similar size. With a reliable protocol for the
coupling of these subunits at hand, a first attempt to exploit the
flexibility inherent to this synthesis blueprint was made as a
prelude for more detailed future investigations of the structure/
activity relationships of this particular target.
Scheme 9. Preparation of the Borate Donor Necessary for Suzuki
Cross-Coupling Reactions Either via the Conventional Route or by
the “9-MeO-9-BBN” Variant42
The epimeric tetrahydrofuran epi-25 derived from the iron-
catalyzed allenol formation/cyclization strategy shown in Scheme
4 was chosen for this exploratory study (Scheme 10). Metal-
halogen exchange with excess t-BuLi and interception of the
resulting organolithium species with 9-MeO-9-BBN42 delivered
the required borate which underwent productive alkyl-Suzuki
cross coupling45 with iodide 40. The subsequent elaboration of
the resulting product 44 could also be performed in close
analogy to the amphidinolide X case and proceeded in similar
yields, thus affording 19-epi-amphidinolide X 47 as a first
example of a fully synthetic analogue of the natural lead. Further
investigations on the synthesis and biological evaluation of
congeners and isomers of this cytotoxic macrolide antibiotic
are in progress and will be disclosed in due course.
alized segments 40 and 25. Specifically, alkyl iodide 25 was
treated with t-BuLi at -78°C followed by addition of excess
9-MeO-9-BBN to give the corresponding borate which transfers
its functionalized alkyl group to the organopalladium species
derived from alkenyl iodide 40 and (dppf)PdCl2/AsPh3, thus
delivering product 41 in 74% isolated yield. Selective cleavage
of the methyl ester in diester 41 with LiI in pyridine46 followed
by successive removal of the remaining dioxolane moiety and
the PMB ether gave seco-acid 43. Not unexpectedly, the acetal
cleavage in 42 was somewhat delicate due to the lability of the
released aldol subunit (see above). The use of dilute AcOH,
however, furnished the desired product 43 in 53% over two
steps. The final macrocyclization of seco-acid 43 under Yamagu-
chi conditions40,41 gave amphidinolide X 1 in 62% yield, thus
completing the first total synthesis of this unusual macro-
diolide.11,47 The analytical and spectroscopic data of the synthetic
samples are in excellent agreement with those reported for the
natural product.4
Amphidinolide Y: Preparation of the Building Blocks.
The reliability and excellent chemoselectivity profile of the “9-
(47) For other macrodiolide syntheses from this laboratory see: (a) Fu¨rstner,
A.; Albert, M.; Mlynarski, J.; Matheu, M.; DeClercq, E. J. Am. Chem.
Soc. 2003, 125, 13132. (b) Fu¨rstner, A.; Ruiz-Caro, J.; Prinz, H.; Waldmann,
H. J. Org. Chem. 2004, 69, 459. (c) Fu¨rstner, A.; Thiel, O. R.; Ackermann,
L. Org. Lett. 2001, 3, 449. (d) Fu¨rstner, A.; Mlynarski, J.; Albert, M. J.
Am. Chem. Soc. 2002, 124, 10274. (e) Fu¨rstner, A.; Albert, M.; Mlynarski,
J.; Matheu, M. J. Am. Chem. Soc. 2002, 124, 1168.
(46) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447.
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9199

A R T I C L E S
Fu¨rstner et al.
Scheme 11 a
MeO-9-BBN variant” of the alkyl-Suzuki reaction experienced
in the amphidinolide X and 19-epi-amphidinolide X series
recommend the use of this transformation as a late-stage
maneuver for the projected synthesis of amphidinolide Y (2)
as well. As already mentioned, the tetrahydrofuran embedded
into 2 is identical to that of 1, which makes any adaptation of
the corresponding synthon D unnecessary. The required coupling
partner E, however, is entirely different because of the macro-
lidic rather than macrodiolidic nature of the target. For the sake
of convergence, it was desirable to generate E bearing the
complementary vinyl iodide motif from two subunits, G and
H, of similar size and complexity (Scheme 1). Although various
transformations can be envisaged for such a purpose, an aldol
strategy seemed highly appropriate, not least because it allows
for control over the stereochemistry of the emerging chiral
center, and because the carbonyl group of the resulting product
F also provides a handle for the installation of the tertiary
alcohol group residing at C.7 of the chain. We therefore set out
to prepare surrogates of synthons G and H in adequately
functionalized form.
a Reagents and conditions: [a] PMBOC(dNH)CCl3, PPTS cat., CH2Cl2,
84%; [b] Dibal-H, CH2Cl2, -78 °C, 78%; [c] CBr4, PPh3, CH2Cl2, -78
°C, 90%; [d] n-BuLi, MeI, THF, -78 °C f rt, 91%; [e] Cp2Zr(H)Cl, THF,
I2, 66%; [f] (i) DDQ, CH2Cl2/pH 7 buffer (10/1), 0 °C f rt; (ii) Dess-
Martin periodinane, CH2Cl2, 0°C, cf. text; [g] (Me2PhSi)2Cu(CN)Li2, THF,
-78 °C f 0 °C, 92%; [h] DDQ, CH2Cl2/pH 7 buffer (10/1), then NaBH4,
MeOH, 0 °C f rt, 92%; [i] Dess-Martin periodinane, CH2Cl2, 0 °C, 92%.
Our synthesis started from Roche ester 48, which was
protected as O-PMB ether 49. Subsequent reduction with
Dibal-H delivered aldehyde 50 which was homologated in
excellent overall yield to alkyne 51 using the Corey-Fuchs
protocol48 followed by C-methylation with n-BuLi/MeI.49 In a
first run, alkyne 52 was converted into alkenyl iodide 53 by
hydrozirconation/iodination. Unfortunately, however, 53 and
aldehyde 54 derived thereof turned out to be difficult to work
with, as they were found to be highly sensitive as well as rather
volatile. Therefore a more appropriate substitute was searched
for and found in the corresponding vinylsilane 57, which was
accessible on a multigram scale, by regioselective silylcupra-
tion50 of alkyne 52 followed by cleavage of the PMB group in
55 with DDQ39 and oxidation of the resulting alcohol 56 to
aldehyde 57 with Dess-Martin periodinane.51 Although 57 is
also somewhat sensitive, it can be stored in the freezer for
extended periods of time if care is taken to avoid any residual
traces of acid or base (Scheme 11).
The preparation of the ketone building block commenced with
the enantiomeric Roche ester ent-48, which was converted to
the known O-TBDPS-protected aldehyde 5952 by routine
manipulations. Reaction of the latter with phosphonate 6053
readily afforded the R-acetoxy-enoate 61 which could be
hydrolyzed to give R-ketoester 62 in high yield, provided that
the cleavage of the acetate group was performed at low
temperature; more conventional conditions for this saponification
led to significantly poorer results. Although the catalytic
hydrogenation of R-ketoesters is less common than that of their
â-ketoester analogues,54,55 we were pleased by the outcome of
this transformation: thus, reduction of 62 in the presence of
[((S)-binap)2Ru2Cl5]- [Et2NH2]+ (67)56 as the catalyst in MeOH
under H2 atmosphere (20 bar) worked exquisitely well, deliver-
ing the desired alcohol 63 in 92% isolated yield with a
diastereomeric ratio of g23:1 (NMR) (Scheme 12).57 Mosher
analysis provided an independent and unambiguous proof for
the configuration assigned to the newly created stereocenter (cf.
Supporting Information). This excellent selectivity was decisive
for the further course of the total synthesis because the secondary
alcohol at C.6 set by asymmetric hydrogenation was planned
to serve as a crucial relay, transferring stereochemical informa-
tion to the chiral centers to be generated at C.7 (via chelate-
controlled addition) as well as C.9 (via diastereoselective
aldolization), before it will ultimately be oxidized to the ketone
group residing on the aliphatic chain of amphidinolide Y
(Scheme 13). This concept also dictated the choice of the
protecting group for this secondary alcohol, which must impart
donor properties yet withstand basic conditions and organo-
metallic reagents. A PMB-ether seemed optimal, which was
installed in the usual fashion prior to conversion of the ester
moiety in the resulting product 64 to methyl ketone 66 via the
Weinreb amide intermediate 65.
(54) Reviews: (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Ohkuma, T.; Noyori, R. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 1; pp 199-246. (c) Noyori, R. Angew. Chem,.
Int. Ed. 2002, 41, 2008. (d) Tang, W.; Zhang, X. Chem. ReV. 2003, 103,
3029.
(55) For precedence on enantioselective hydrogenations of R-ketoesters with
Ru-based catalysts, see the following for leading references and literature
cited therein: (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am.
Chem. Soc. 1988, 110, 629. (b) Mashima, K.; Kusano, K.; Sato, N.;
Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki,
T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064. (c) Jeulin,
S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Geneˆt, J. P.; Champion,
N.; Dellis, P. Proc. Natl. Acad. Sci. U. S.A. 2004, 101, 5799. (d) Benincori,
T.; Piccolo, O.; Rizzo, S.; Sannicolo`, F. J. Org. Chem. 2000, 65, 8340. (e)
Transfer hydrogenation: Sˇterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron
Lett. 2004, 45, 535.
(48) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(49) The enantiomer of 52 is known, see: Organ, M. G.; Wang, J. J. Org. Chem.
2003, 68, 5568.
(50) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin Trans. 1
1981, 2527.
(51) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer, S.
D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549. (c) Boeckman, R. K.,
Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141.
(52) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112,
6348.
(53) (a) Nakamura, E. Tetrahedron Lett. 1981, 22, 663. (b) Schmidt, U.; Langner,
J.; Kirschbaum, B.; Braun, C. Synthesis 1994, 1138.
(56) The catalyst was prepared as described in: King, S. A.; Keller, J. Org.
Synth. 2005, 81, 178.
(57) For precedence on the diastereoselective hydrogenation of
a chiral
R-ketoester see: Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem. 1998,
63, 2133.
9
9200 J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006

Total Syntheses of Amphidinolide X and Y
A R T I C L E S
Scheme 14. Fragment Coupling by Aldol Reaction; for the
Scheme 12 a
Conditions and Results, See Table 1
Table 1. Aldol Reaction According to Scheme 14
entry
reagents
solvent
T (C°
)
dr
yield (%)
1
2
3
4
5
6
7
8
Cy2BCl, EtN(iPr)2
Et2O
-78 2.0:1
-78 2.4:1
-78 2.0:1
46
41
71
18a
41a
44
38
32a
69
84
75
65
toluene
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
(-)-DIPCl, EtN(iPr)2
(+)-DIPCl, EtN(iPr)2
(+)-DIPOTf, EtN(iPr)2
Bu2BOTf, EtN(iPr)2
Et2BOTf, EtN(iPr)2
-78
1:3.0
-78 4.3:1
-78
b
-78 3.0:1
pentane -110 5.5:1
9
toluene
toluene
THF
-78 3.3:1
-90 4.0:1
-78 1.5:1
10
11
12
LiHMDS
TMSCl, Et3N, LiHMDS; THF
then BF3.Et2O
-78
1:30c
a
Incomplete conversion. b Partial decomposition makes an accurate
determination of the dr difficult. c The crude NMR seems to indicate
formation of an additional product, which was not characterized any further.
tion in the case of the more reactive (+)-DIPOTf (entries 4-6).
A satisfactory solution, however, was found by changing the
size of the spectator alkyl groups on boron.62 Thus, replacement
of Cy2BCl by (n-Bu)2BOTf or, preferably, Et2BOTf resulted in
improved levels of stereochemical communication. In the latter
case, an isolated yield of 84% and a dr g 4:1 in favor of the
1,4-anti-isomer could be reproducibly achieved on a >2 g scale,
provided that the reaction was performed in toluene at -90°C
(entry 10). Although the individual isomers were not separable
at this stage, a Mosher analysis unequivocally indicated the
required (S)-configuration of the newly created secondary
a Reagents and conditions: [a] TBDPSCl, imidazole, DMAP cat.,
CH2Cl2, 90%; [b] Dibal-H, hexanes, -78 °C, 79%; [c] phosphonate 60,
LiHMDS, THF, -78 °C f rt, 91% (E:Z ) 6:1); [d] NaOMe, MeOH, -40
°C, 86%; [e] catalyst 67, HCl cat., H2 (20 bar), MeOH, 92% (dr g 23:1);
[f] PMBOC(dNH)CCl3, BF3‚Et2O cat., CH2Cl2/cyclohexane (1:2), 0 °C,
84%; [g] (i) LiOH, MeOH/THF/H2O (4:1:1); (ii) HN(OMe)Me hydro-
chloride, DCC, EtN(iPr)2, DMAP cat., CH2Cl2, 0 °C f rt, 86% (over both
steps); [h] MeMgBr, THF, 0 °C, 91%.
Scheme 13. Envisaged Stereochemical Relay
(58) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J.
A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. To the best of our
knowledge, this is the only report showing 1,4-induction by R-alkoxy
substitutents in methyl ketones without any superimposed 1,5-induction
and/or directing effects exerted by substituents in the aldehyde component.
For further examples in which such effects might be operative in addition
to 1,4-induction see: (b) Crimmins, M. T.; Katz, J. D.; McAtee, L. C.;
Tabet, E. A.; Kirincich, S. J. Org. Lett. 2001, 3, 949. (c) Paterson, I.; Coster,
M. J.; Chen, D. Y.-K.; Acen˜a, J. L.; Bach, J.; Keown, L. E.; Trieselmann,
T. Org. Biomol. Chem. 2005, 3, 2420.
Amphidinolide Y: Elaboration of the Western Domain.
With the two required components in hand, the crucial fragment
coupling by an aldol reaction was investigated. Encouraged by
a report by Evans et al. describing high levels of 1,4-anti-
selectivity in the addition of boron enolates derived from methyl
ketones bearing alkoxy substituents at the nonreacting R-
position,58-60 compound 66 was treated with Cy2BCl, EtN(iPr)2
and aldehyde 57 (Scheme 14, Table 1). Although good yields
could be obtained when CH2Cl2 was chosen as the solvent (entry
3), the observed diastereoselectivity was low. Attempts to
improve on this outcome by recourse to chiral IPC enolates61
was only partly successful, as the improved selectivity in the
matched case was overcompensated by low conversions when
(+)-DIPCl was used as the reagent or by significant decomposi-
(59) For pertinent discussions on the related 1,5-induction observed in reactions
of â-alkoxy substituted methyl ketone enolates with (chiral) aldehydes see
the following for leading references: (a) Gustin, D. J.; VanNieuwenhze,
M. S.; Roush, W. R. Tetrahedron Lett. 1995, 36, 3443. (b) Evans, D. A.;
Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc. 2003, 125,
10893. (c) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187.
(d) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.;
Scheidt, K. A. J. Org. Chem. 2002, 67, 4275 and literature cited therein.
(60) Review: Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(61) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Ramachandran, P.
V.; Xu, W.; Brown, H. C. Tetrahedron Lett. 1996, 37, 4911.
(62) For precedence see: Bhattacharjee, A.; Soltani, O.; De Brabander, J. K.
Org. Lett. 2002, 4, 481.
9
J. AM. CHEM. SOC. VOL. 128, NO. 28, 2006 9201

A R T I C L E S
Scheme 15 a
Fu¨rstner et al.
Scheme 16 a
a Reagents and condtions: [a] TESCl, imidazole, CH2Cl2, 0 °C f rt,
91%; [b] MeMgBr, Et2O, -78 °C, 96% (dr ) 15:2.6:1, NMR), cf. text.
alcohol in the major product 68 (cf. Supporting Information).
As expected, the use of the lithium enolate derived from 66
displayed poor selectivity (entry 11), while application of the
Mukaiyama conditions afforded the 1,4-syn product preferen-
tially (entry 12).
Next, the aldol products were reacted with TESCl and
imidazole (Scheme 15). This particular protecting group was
chosen under the premise that bulky silyl ethers at the â-position
to a carbonyl group are known to be poor ligands to Lewis acidic
metal cations and hence “nonchelating” substituents, exerting
directing effects in carbonyl addition reactions via 1,3-dipol
minimization in the transition state.63 In contrast, -OPMB
groups R to a ketone readily engage in chelation in carbonyl
addition reactions of, e.g., methylmagnesium halide, strongly
favoring the formation of the corresponding “chelate-Cram”
products.64 With these established patterns in mind, one may
forecast a matched situation for the major product 70, whereas
the companion minor isomer, 71, should experience opposing
effects and therefore constitute a mismatched case.
In line with this analysis,65 treatment of the inseparable 1,4-
anti/1,4-syn aldol mixture with MeMgBr in Et2O at -78°C
furnished only three of the four possible tertiary alcohols in a
15/2.6/1 ratio. This outcome parallels the diastereomeric purity
of the starting material (dr g 4/1; 15:3.6 ≈ 4.2:1), lending
credence to the notion that the major isomer 70 affords the
desired chelate-Cram product 72 diastereoselectively, whereas
the minor aldol 71 furnishes a mixture of both possible addition
products 73 and 74 due to the mismatched influences of its
substituents.
a Reagents and conditions: [a] TESOTf, 2,6-lutidine, -78 °C f rt, 92%;
[b] (i) DDQ, CH2Cl2/pH 7 buffer (1:1), 0 °C, 92%; (ii) Dess-Martin
periodinane, pyridine, CH2Cl2, 0 °C f rt., 93%; [c] camphorsulfonic acid
(cat.), MeOH/THF (5:1), 0 °C, 65% (R:â ) 3:1); separation of the major
isomer followed by reequilibration of the minor â-isomer with p-toluene-
sulfonic acid (cat.), MeOH, 86%; [d] (i) NIS, MeCN, 0 °C; (ii) TBAF,
THF, 72% (over both steps); [e] Dess-Martin periodinane, pyridine,
CH2Cl2; [f] (i) TMSCl, imidazole, CH2Cl2, 0 °C f rt, 94%; (ii) oxalyl
chloride, DMSO, Et3N, CH2Cl2, -78 °C f 0 °C; [g] LiHMDS,
(EtO)2P(dO)CH2COOMe, THF, -78 °C f 0 °C, 76% (over both steps).
tertiary alcohol, subsequent cleavage of the PMB-group in 75
with DDQ in buffered medium, oxidation of the liberated
hydroxyl group to the corresponding ketone 76, and cyclization
with formation of methyl glycoside 77 (Scheme 16). Impor-
tantly, the major product 77 could be separated without
difficulties at this leVel by routine flash chromatography and
was obtained in a satisfactory overall yield over five routine
steps, starting from the aldol products.
With a pure isomer in hand, it was possible to investigate
the stereochemical pattern of the product by extensive NOESY
spectroscopy which clearly supported the assignments made
above (cf. Supporting Information); the final proof then came
by the successful completion of the total synthesis. From the
strategic point of view it is worth mentioning that the “internal
protection” of the ketone in form of a glycoside also seems
highly advantageous, given the known lability of the R-hydroxy-
ketone entity embedded into the amphidinolide Y frame under
oxidative conditions. As will be outlined below, the final stages
However, no attempt was made to rigorously confirm this
tentative stereochemical assignment at this stage; rather, priority
was given to find a practical method for the separation of the
major isomer to keep the synthesis workable. After testing
several conceivable options, it was found that the mixture can
be processed into furanoside 77 by temporary protection of the
(63) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc.
1996, 118, 4322.
(64) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462.
(65) For pertinent examples in the ketone (rather than much more closely
investigated aldehyde series) see: (a) “chelate controlled” MeMgI addition
to R-alkoxyketone: Nakamura, S.; Inagaki, J.; Sugimoto, T.; Kudo, M.;
Nakajima, M.; Hashimoto, S. Org. Lett. 2001, 3, 4075. (b) “Dipole
controlled” addition of MeMgBr to â-silyloxy ketones: Ukaji, Y.; Kanda,
H.; Yamamoto, K.; Fujisawa, T. Chem. Lett. 1990, 19, 597.
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Total Syntheses of Amphidinolide X and Y
A R T I C L E S
Scheme 17 a
of the synthesis confirmed the notion that the chosen “glycoside
strategy” is preferable over other conceivable protecting-group
regimens.66
With the supply, constitution, and stereochemistry of this key
synthetic intermediate being secured, the conversion of the
vinylsilane into the alkenyl iodide moiety as required for the
envisaged fragment coupling via the Suzuki protocol was
performed on exposure of 77 to NIS in MeCN in the dark;67
cleavage of the remaining silyl ether of the crude product then
afforded diol 78 in 72% isolated yield over two steps.
Unfortunately, attempted conversion of this compound into
enoate 81 (R ) H) by selective oxidation of the primary alcohol
followed by olefination met with failure due to spontaneous
hemiacetal formation at the aldehyde level68 and further
oxidation to the corresponding lactone 79, which was of no avail
for the synthesis.
This unproductive path, however, could be avoided by
silylation of 78 with TMSCl and imidazole followed by
oxidation of the resulting bis-silyl ether with formation of
aldehyde 80. Horner-Wadsworth-Emmons reaction then gave
enoate 81 as the fully functional building block required for
the ensuing end game of the total synthesis.
Amphidinolide Y: Completion of the Total Synthesis. In
line with our expectations, the coupling between the highly
functionalized alkenyl iodide 81 and the tetrahydrofuran segment
via the “9-MeO-9-BBN variant”42 of the alkyl-Suzuki reaction
proceeded smoothly under the conditions worked out in the
amphidinolide X series, affording product 82 in 79% isolated
yield (Scheme 17). Although an excess of t-BuLi and 9-MeO-
9-BBN has to be used, it is noteworthy that this reaction employs
both valuable components 25 and 81 exactly in a 1:1 ratio and
is therefore highly adequate as a late-stage maneuver. The
subsequent removal of the PMB-group with DDQ occurred
readily, but the isolated yields of the resulting alcohol 83 were
somewhat variable, ranging between 51 and 75%. This outcome
is deemed to reflect the sensitivity of the product toward
uncontrolled over-oxidation in case of adventitious opening of
the tertiary methyl glycoside locking the furanose ring; since
this functional group is somewhat labile, however, the DDQ
oxidation must be carried out in buffered medium to keep such
uncontrolled oxidative degradations to a minimum.
This sensitivity must also be taken into consideration during
the very end game. While the saponification of the methyl ester
in 83 with LiOH in aqueous THF/MeOH per se poses no
problem, the extractive work up is a critical phase because the
medium has to be made weakly acidic to allow for the isolation
of the resulting seco-acid. This very fragile product should be
immediately transformed into the corresponding triethylammo-
nium salt 84 to avoid self destruction and, as such, should be
subjected to cyclization under modified Yamaguchi conditions69
without delay. The resulting crude lactone 85 was finally
deprotected with dilute HOAc in aqueous THF. This sequence
a Reagents and conditions: [a] t-BuLi, Et2O/THF, then 9-MeO-9-BBN;
[b] (dppf)PdCl2, Ph3As, K3PO4, aq DMF, 79%; [c] DDQ, CH2Cl2/pH 7
buffer (1:1), 0 °C, 51-75%, cf. text; [d] LiOH, MeOH/THF/H2O (4:1:1),
then Et3N; [e] 2,4,6-trichlorobenzoyl chloride, Et3N, THF; then DMAP,
toluene; [f] HOAc/THF/H2O (4:1:1), 56% (over three steps).
avoids flash chromatography of any of the labile intermediates
and afforded amphidinolide Y (2) in well reproducible 56% over
three steps as a 5:1 mixture of the keto- and the corresponding
hemiacetal form. The spectra of the synthetic samples are
superimposable with those of the natural product isolated from
the Amphidinium Y-42 strain, and their analytical properties,
including the [R]D, are also in excellent agreement with the
literature data (cf. Supporting Information).6
With the first total synthesis of this bioactive marine natural
product completed, some additional comments on the final
stages of the successful route seem appropriate. As mentioned
above, the methyl glycoside plays a crucial role, providing
proper “internal protection” of the sensitive R-hydroxyketone
(66) For a related example see: Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M.
J. Am. Chem. Soc. 2005, 127, 10028.
(67) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8647.
(68) Note that this spontaneous cyclization provides further evidence for the
cis-orientation of the alkyl group at the anomeric center and the tertiary
alcohol group generated through chelate-Cram addition.
(69) In this modification, the slightly acidic Et3NH+ salts formed as byproducts
in the generation of the mixed anhydride are filtered off prior to
concentration of the solution and subsequent macrocyclization. This protocol
is highly advisable for very acid-sensitive compounds, cf: Evans, D. A.;
Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899.
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A R T I C L E S
Fu¨rstner et al.
motif of the synthesis intermediates against undue oxidative
degradation. It should be mentioned, however, that the adjacent
TMS-ether at C.7 was also indispensable. Although this group
had originally been introduced only because no direct way for
the elaboration of the primary alcohol in 78 to the required
enoate of type 81 (R ) H) could be found, we noticed later
that this silyl ether is more than just a quiet bystander.
Specifically, samples of 84 devoid of the protecting groups were
not amenable to regular Yamaguchi lactonization;70 even though
the tertiary -OH at C.7 is sterically encumbered, it interferes
by 1,4-additon to the R,â-unsaturated acid segment of the
starting material, its activated mixed anhydride form, and/or the
resulting lactone under the basic reaction conditions, thus leading
to a dreadful mixture of which the desired product is only a
minor component. Hence, the silylation of 78, originally
regarded as a detour, unintentionally turned out to be key to
success.
detailed mapping of the structure/activity relationships through
“diverted total synthesis”. Finally, these investigations constitute
the first application of the iron-catalyzed formation of allenol
derivatives13,14 to natural product chemistry. This benign
procedure not only complements existing methodologies in
stereochemical terms and allows for substantial structural
variations if desirable, but also provides a convenient solution
for the problem posed by the delicate tetrasubstituted chiral ether
bridge embedded into 1 and 2 via a straightforward relay
strategy. We are currently in the stage of further optimizing
the underlying synthesis blueprints, trying to expand our studies
in the field beyond the total synthesis stage, and intending to
cover other members of the amphidinolide family as well.
Progress along these lines and on the accompanying biochemical
investigations will be reported in due course.
Acknowledgment. Generous financial support by the MPG,
the Chemical Genomics Center (CGC Initiative of the MPG),
the Fonds der Chemischen Industrie, the Deutsch-Israelische
Projektkooperation (DIP project), and the Merck Research
Council is gratefully acknowledged. O.L. thanks the Alexander-
von-Humboldt Foundation and FQRNT for a fellowship. We
thank Dr. R. Mynott and Mrs. P. Phillips for recording several
high-field NMR spectra.
Conclusions
Concise, modular, and efficient total syntheses of the bio-
genetically related marine natural product amphidinolide X (1),
and its ring-expanded congener, amphidinolide Y (2), have been
developed which unravel many chemical characteristics of these
structurally unique macrolides. The flexibility inherent to the
chosen route is illustrated by the efficient preparation of 19-
epi-amphidinolide X 47 as a first fully synthetic analogue, thus
encouraging further synthesis-driven explorations of these
cytotoxic agents. The robustness and excellent chemoselectivity
profile recommends the chosen assembly process based upon
the “9-MeO-9-BBN” variant of the Suzuki coupling for a more
Supporting Information Available: Full experimental details,
complete ref 44b, spectroscopic and analytical data of all new
compounds, and copies of the NMR spectra of key synthetic
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
(70) Unprotected samples of the crude seco-acid were obtained by lowering
the pH during the extractive work to <5.
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