Ru-catalyzed alkene-alkyne coupling. Total synthesis of amphidinolide P

Article abstract of DOI:10.1021/ja055967n

A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo- and regioselective fashion, despite the significant degree of unsaturation of the substrates. The resulting 1,4-diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne partner made use of an unusual anti-selective addition under chelation-control conditions of an allyltin reagent derived from tiglic acid. In addition, a remarkably E-selective E₂ process using the azodicarboxylate-triphenylphosphine system is featured. Also featured is the first example of the use of a β-lactone as a thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity to further probe the scope of the ruthenium-catalyzed alkene-alkyne coupling, in particular using enynes, and studies using various functionalized substrates are described.

Full text of DOI:10.1021/ja055967n

Published on Web 11/19/2005
Ru-Catalyzed Alkene-Alkyne Coupling. Total Synthesis of
Amphidinolide P
Barry M. Trost,* Julien P. N. Papillon, and Thomas Nussbaumer
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received August 30, 2005; E-mail: bmtrost@stanford.edu
Abstract: A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon
bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo- and
regioselective fashion, despite the significant degree of unsaturation of the substrates. The resulting 1,4-
diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner
was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential
three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne
partner made use of an unusual anti-selective addition under chelation-control conditions of an allyltin reagent
derived from tiglic acid. In addition, a remarkably E-selective E2 process using the azodicarboxylate-
triphenylphosphine system is featured. Also featured is the first example of the use of a â-lactone as a
thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive
protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity
to further probe the scope of the ruthenium-catalyzed alkene-alkyne coupling, in particular using enynes,
and studies using various functionalized substrates are described.
these two cell lines.3c The biological activity of these com-
pounds, along with their very limited availability and challenging
Introduction
Within the past decade, marine microorganisms have become
an important source of biologically active substances. Unicellular
eukaryotes known as dinoflagellates produce some of the most
structurally complex and most toxic substances known to man
such as brevetoxin, ciguatoxin, okadaic acid, and saxitoxin, all
of which are increasingly the source of human intoxication.1
Although 90% of these organisms are planktons, a number of
photosynthetic dinoflagellates take up residence within other
organisms as symbiotic partners. In 1986, the group of Koba-
yashi isolated a novel macrolide, named amphidinolide A, from
a strain of laboratory-cultured symbiotic dinoflagellates of the
genus Amphidinium sp., which are found inside the cells of the
Okinawan flatworm Amphiscolops sp.2 New members of this
structurally varied class of compounds have been continually
discovered by the group of Kobayashi ever since, and close to
40 amphidinolides have been isolated.3 These macrolides have
all demonstrated antineoplastic activity against murine lym-
phoma L1210 and human epidermoid carcinoma KB cells in
vitro. Although most of them have an IC50 in the low micromolar
range, amphidinolide N displays subpicomolar activity against
structures, has made them popular targets for total synthesis.
Numerous strategies have been disclosed,4 and several amphi-
dinolides have succumbed to total synthesis.5 A common feature
to the vast majority of amphidinolides is the presence of one,
or more commonly, several, exo-methylene units. We envisioned
that the ruthenium-catalyzed alkene-alkyne coupling reaction
developed in our laboratories6 would provide a tool to develop
convergent syntheses of these compounds (the proposed mech-
(4) For the most recent studies, see, Amphidinolide F: (a) Shotwell, J. B.;
Roush, W. R. Org. Lett. 2004, 6, 3865. Amphidinolides B1, B2, and B3:
(b) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69,
2569. Amphidinolide O: (c) Pang, J.-H.; Ham, Y.-J.; Lee, D.-H. Bull.
Korean Chem. Soc. 2003, 24, 891. Amphidinolide C: (d) Kubota, T.; Tsuda,
M.; Kobayashi, J. Tetrahedron 2003, 59, 1613.
(5) Amphidinolides T1 and T4: (a) Colby, E. A.; O’Brien, K. C.; Jamison, T.
F. J. Am. Chem. Soc. 2005, 127, 4297. Amphidinolide X: (b) Lepage, O.;
Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970. Amphidi-
nolide P: (c) Trost, B. M.; Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126,
13618. (d) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945.
Amphidinolide A, revised structure: (e) Trost, B. M.; Wrobleski, S. T.;
Chisholm, J. D.; Harrington, P. E.; Jung, M. J. Am. Chem. Soc. 2005, 127,
13589; Trost, B. M.; Harrington, P. E.; Chisholm, J. D.; Wrobleski, S. T.
J. Am. Chem. Soc. 2005, 127, 13598. (f) Trost, B. M.; Chisholm, J. D.;
Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420. (g)
Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III. Org. Lett.
2002, 4, 2841. (h) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002,
41, 508. Amphidinolide W: (i) Ghosh, A. K.; Gong, G. J. Am. Chem. Soc.
2004, 126, 3704. Amphidinolide T1: (j) Colby, E. A.; O’Brien, K. C.;
Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998. (k) Ghosh, A. K.; Liu,
C. Strategies Tactics Org. Synth. 2004, 5, 255. (l) Ghosh, A. K.; Liu, C. J.
Am. Chem. Soc. 2003, 125, 2374. Amphidinolide T1, T3, T4, and T5: (m)
Aiessa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003,
125, 15512. Amphidinolide T4: (n) Fu¨rstner, A.; Aissa, C.; Riveiros, R.;
Ragot, J. Angew. Chem., Int. Ed. 2002, 41, 4763. Amphidinolide K: (o)
Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765.
Amphidinolide J: (p) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc.
1998, 120, 11198.
(1) (a) Stommel, E. W.; Watters, M. R. Curr. Treat. Options Neurol. 2004, 6,
105. (b) Van Dolah, F. M. EnViron. Health Perspect. 2000, 108, 133.
(2) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Yamasu, T.;
Sasaki, T.; Hirata, Y. Tetrahedron Lett. 1986, 27, 5755.
(3) (a) Tsuda, M.; Kariya, Y.; Iwamoto, R.; Fukushi, E.; Kawabata, J.;
Kobayashi, J. Mar. Drugs 2005, 3, 1. (b) Kubota, T.; Sakuma, Y.; Tsuda,
M.; Kobayashi, J. Mar. Drugs 2004, 2, 83. (c) Kobayashi, J.; Tsuda, M.
Nat. Prod. Rep. 2004, 21, 77. (d) Chakraborty, T. K.; Das, S. Curr. Med.
Chem.: AntisCancer Agents 2001, 1, 131. (e) Kobayashi, J. In Compre-
hensiVe Natural Products Chemistry; Mori, K., Ed.; Elsevier: New York,
1999; Vol. 8, p 619. (f) Ishibashi, M.; Kobayashi, J. Heterocycles 1997,
44, 543. (g) Ishibashi, M.; Kobayashi, J. Chem. ReV. 1993, 93, 1753.
9
10.1021/ja055967n CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 17921-17937
17921

A R T I C L E S
Trost et al.
Figure 1. Proposed catalytic cycle for the ruthenium-catalyzed alkene-alkyne coupling reaction.
Scheme 1. Initial Retrosynthetic Analysis
1
anism is shown in Figure 1). Reciprocally, total synthesis of
judiciously chosen members of this family would provide a
stringent test for the chemoselectivity of this reaction and an
opportunity for further development. We have successfully
applied it, both inter- and intramolecularly, to the synthesis of
amphidinolide A.5e,f We now report in full details our efforts
which led to the completion of the synthesis of amphidinolide
P.5c Amphidinolide P (1), which was isolated by Kobayashi in
a yield of 0.0002%, exhibits cytotoxicity against murine
lymphoma L1210 and human epidermoid carcinoma KB cells
in vitro (IC50 ) 4.0 and 14.6 µM, respectively).7 The structure
and relative configuration of amphidinolide P was determined
by extensive H NMR and 13C NMR studies and molecular
mechanics calculations. These studies revealed a backbone
consisting of a 15-membered macrolactone with three exo-
methylene units, one hemiketal forming a tetrahydropyran
moiety, an epoxide moiety, and seven chiral centers. The
proposed structure and relative configuration of 1 was confirmed
by total synthesis.5d
Our initially envisioned retrosynthetic analysis is depicted
in Scheme 1. Amphidinolide P (1) was anticipated to derive
from precursor 2 via a thermal macrocyclization.8 Although
â-ketoesters also undergo thermal macrocyclization (via the
same acylketene intermediate),5d,9 the dioxenone can be con-
veniently carried through multiple synthetic steps. We therefore
initially envisioned 4 as the desired alkene addition partner. An
intriguing feature of 1, and of 2 by extension, is the presence
(6) (a) Trost, B. M.; Shen, H. C.; Pinkerton, A. B. Chem. Eur. J. 2002, 8,
2341. (b) Trost, B. M.; Machacek, M.; Schanderbeck, M. J. Org. Lett. 2000,
2, 1761. (c) Trost, B. M.; Indolese, A. F.; Mu¨ller, T. J. J.; Treptow, B. J.
Am. Chem. Soc. 1995, 117, 615. (d) Trost, B. M.; Probst, G. D.; Schoop,
A. J. Am. Chem. Soc. 1998, 120, 9228. (e) Trost, B. M.; Pinkerton, A. B.;
Toste, F. D.; Sperrle, M. J. Am. Chem. Soc. 2001, 123, 12504. For use in
natural product syntheses, see: (f) Trost, B. M.; Yang, H.; Probst, G. D. J.
Am. Chem. Soc. 2004, 126, 48. (g) Trost, B. M.; Gunzner, J. L. J. Am.
Chem. Soc. 2001, 123, 9449. (h) ref 5c, 5e, 5f. See also: (i) Trost, B. M.
Acc. Chem. Res. 2002, 35, 695. (j) Trost, B. M.; Toste, D. F.; Pinkerton,
A. B. Chem. ReV. 2001, 101, 2067.
(8) (a) Boeckman, R. K.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111, 8286. (b)
Quinn, E. K.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1993, 58,
5011. (c) ref 6g.
(9) (a) Witzeman, J. S.; Nottingham, W. D. J. Org. Chem. 1991, 56, 1713. (b)
Clemens, R. J.; Witzeman, J. S. J. Am. Chem. Soc. 1989, 111, 2186. (c)
Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431. (d) Hyatt, J. A.
J. Org. Chem. 1984, 49, 5102. (e) Hyatt, J. A.; Feldman, P. E.; Clemens,
R. J. J. Org. Chem. 1984, 49, 5105.
(7) Ishibashi, M.; Takahashi, J.; Kobayashi, J. J. Org. Chem. 1995, 60, 6062.
9
17922 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Scheme 2. Synthesis of Racemic Enyne Systemsa
a Reagents and conditions: (a) 1.5 equiv of NaI, AcOH, 70 °C, 13 h, Z/E > 49:1; (b) 0.01 equiv of HI(aq), benzene, 1.7 M, 80 °C, 8 h, E/Z 16:1; (c) 1.1
equiv of trimethylsilylacetylene, 0.005 equiv of CuI, 0.01 equiv of Pd(PPh3)2Cl2, Et3N, 50 °C, 13 h, 81% (3 steps); (d) 1.1 equiv of DIBAL-H, toluene, -95
°C, 1 h, 70%; (e) 1.1 equiv of BF3‚Et2O, 1.3 equiv of 12, CH2Cl2, -78 °C, 5 min, quant, syn/anti 2.6:1; (f) 1.1 equiv of BF3‚Et2O, 1.3 equiv of 13, CH2Cl2,
-78 °C, 5 min, quant, syn/anti 6.5:1; (g) 1.0 equiv of HMPA, 2.0 equiv of 14, CH2Cl2, -78 °C, 12 h, 23%, syn/anti 1:19.
of an exo-methylene unit in conjugation with an olefin, forming
a 1,3-diene moiety. Synthesis of this moiety by a ruthenium-
catalyzed alkene-alkyne coupling reaction would therefore
require enyne 5. This type of substrate had never been
investigated before, and it was unclear at the onset of this project
what the outcome would be. As shown in Figure 1, the alkyne
partner can adopt two orientations in the cationic ruthenium(II)
complex, leading to either a linear or a branched 1,4-diene
product (although the alternative orientation of the alkene may
also lead to a ruthenacycle, syn-â-hydrogen elimination would
in this case most likely be precluded for geometrical reasons).
Our results have shown that as the size of R increases, the
branched-to-linear ratio decreases, indicating that steric interac-
tion between the alkene and alkyne is an important factor in
determining the regioselectivity of the reaction. On the basis
of steric factors, the enyne was therefore expected to largely
favor the formation of the desired branched product. However,
on electronic grounds, one might expect that attack of the
ruthenium at the terminal carbon of the alkyne would be less
favorable since the conjugated olefin reduces the polarization
of the triple bond. Conversely, we have shown that increasing
the polarization of the triple bond, by appending a trimethylsilyl
group at the terminal carbon, improved the branched-to-linear
product ratio.6b On the basis of these considerations, TMS-
alkyne 5 was envisioned to be the desired addition partner.
Herein we disclose a detailed account of our studies, leading to
a synthesis of amphidinolide P.
This was confirmed by a selective synthesis of anti-11.12 Various
enantioselective versions of the allylation reactions shown in
Scheme 2 have been reported. Addition of allyltin reagents to
aldehydes, which proceed through open transition states, are
usually syn-selective.13 An exception to this trend was discov-
ered by Yamamoto and co-workers, who showed that methallyl-
and crotyltrialkyltin reagents react with aldehydes in the
presence of AgOTf-BINAP to give the anti adduct, irrespective
of the geometry of the starting material.14 However, to the best
of our knowledge, the use of trialkyl-(â-methylcrotyl)stannane
has not been reported in this process. The reaction of 10 and
12 in the presence of 20 mol % AgOTf-(R)-Binap at -20 °C,
according to Yamamoto’s procedure,14b was attempted. Unfor-
tunately, the reaction was prohibitively slow, and only minute
traces of product could be detected. Warming the mixture to
room temperature did not afford any further conversion.
Yamamoto reported good yields with both crotyltributyltin and
methallyltributyltin,14b and it appears that substitution at both
the â- and γ-position is detrimental to the reactivity of the
allylmetal reagent. We found however that 13 reacted with
aldehyde 10 in the presence Yamamoto’s CAB catalyst15 to
afford scalemic syn-11. Without optimization, the reaction
proceeded in 80% yield and 5:1 syn/anti ratio. Conversion of
the mixture into the O-methyl mandelate esters,16 and 500 MHz
1H NMR spectroscopy analysis indicated a 6.5:1 enantiomeric
ratio (e.r.) for the syn isomer and 2:1 e.r. for the anti isomer.
This was not a viable route however, since, as one would
anticipate, inversion of stereochemistry at the alcohol carbon
using Mitsunobu conditions resulted in intractable mixtures of
SN2′ and elimination products, as well as the desired product.
Results and Discussion
Synthesis of the Alkyne Coupling Partner. Several routes
toward alkyne 5 were investigated in the course of this project.
We envisioned that 5 could be the product of the allylation of
the corresponding aldehyde, as depicted in Scheme 2. The
required aldehyde 10 was prepared by an unusual partial
reduction of known ester 9.10 The reaction of allyltin reagent
12 and 13 (obtained in two steps from commercially available
angelic acid methyl ester and tiglic acid, respectively)11 with
aldehyde 10 in the presence of a stoichiometric amount of BF3‚
Et2O provided syn-11 in quantitative yield, as a 2.6:1 and 6.5:1
mixture of diastereomers, respectively. Given literature prece-
dents, the major diastereomer was assumed to be the syn isomer.
(12) (a) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620. (b) Denmark,
S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59,
6161. For the preparation of 14, see the Supporting Information and: (c)
Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993, 49, 1783.
(d) Haynes, R. K.; Katsifis, A. G.; Vonwiller, S. C.; Hambleyf, T. W. J.
Am. Chem. Soc. 1988, 110, 5423.
(13) (a) Yanagisawa, A. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999;
Vol. 2, Chapter 27. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93,
2207. (c) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J.
Org. Chem. 1994, 59, 7889.
(14) (a) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem.
Soc. 1996, 118, 4723. (b) Yanagisawa, A.; Ishiba, A.; Nakashima, H.;
Yamamoto, H. Synlett 1997, 88.
(15) (a) Ishiara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 11490. (b) Marshall, J. A.; Tang, Y. Synlett
1992, 653.
(10) Iijima, T.; Endo, Y.; Tsuji, M.; Kawachi, E.; Kagechika, H.; Shudo, K.
Chem. Pharm. Bull. 1999, 47, 398.
(11) Weigand, S.; Bru¨ckner, R. Synthesis 1996, 475.
(16) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J.
M.; Baldwin, J. L.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer,
J. P. J. Org. Chem. 1986, 51, 2370.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17923

A R T I C L E S
Trost et al.
Scheme 3 Substrate-Controlled Approach to Alkyne 5
Scheme 4. Synthesis of Alcohol 16a
a Reagents and conditions: (a) added to 1.3 equiv of lithium acetylide, 1.3 equiv of AlMe3, then 1.3 equiv of BF3‚Et2O added, ether, -78 °C, 0.5 h; (b)
2.0 equiv of benzyl-2,2,2-trichloroacetimidate, 0.2 equiv of TfOH, dioxane, 24 °C, 0.5 h; (c) 1.3 equiv of DIBAL-H, CH2Cl2, -78 °C, 15 min; (d) 2.0 equiv
of oxalyl chloride, 4.0 equiv of DMSO, 5.0 equiv of Et3N, CH2Cl2, -78 °C to 0 °C, 71% (4 steps); (e) 1.0 equiv of SnCl4, 2.0 equiv of 17, CH2Cl2-pentane
1:1, -110 °C, 15 min, 77%, 9:1 d.r. at C-6.
The stereochemistry of the allylation product can usually be
dictated by the geometry of the starting allylmetal reagent when
the reaction goes through closed transition states, and axial-
axial interactions in a Zimmermann-Traxler transition state
become the controlling factor. This has been shown to be the
mode of reaction of allyltrichlorosilanes in the presence of
nucleophilic catalysts.17 Again, to the best of our knowledge,
the use of trichloro-(â-methylcrotyl)silane (14) has not been
reported in this process. Although trichlorosilanes, including
â-substituted crotylsilane,17c,e are known to be relatively stable,
off-the-shelf compounds, 14 appeared to be an exception. The
isolation of 14 proved to be problematic, and it showed poor
intrinsic stability, as decomposition was noted after overnight
storage at -15 °C under argon. Given the difficulties we
encountered with the preparation and handling of this compound,
we did not pursue the asymmetric synthesis of anti-11 using
this reagent. Instead, we decided to investigate a substrate-
controlled approach to the allylmetal addition problem, as
depicted in Scheme 3. This idea was based on previous results
disclosed by Mikami et al., who found that the addition of
trimethyl-(â-methylcrotyl)silane to scalemic R-benzyloxypro-
pionaldehyde under chelation-control conditions afforded the
unusual anti product in excellent selectivities, regardless of the
geometry of the starting silane reagent.18
was an excellent solvent for this reaction, giving clean and
complete conversion within 15 min, in the presence of 20 mol
% of trifluoromethanesulfonic acid and using crude, freshly
prepared acetimidate.21 DIBAL-H deprotection of the crude ether
21 gave alcohol 22, which was essentially clean. No purification
of the intermediates was found to be necessary, and after a
Moffat-Swern oxidation, aldehyde 18 was isolated in 71% yield
over the four steps. This aldehyde was stable to chromatography
on silica gel. A Kumada coupling between a 7:3 isomeric
mixture of 2-bromo-2-butene and trimethylsilylmagnesium
chloride, using a modified literature procedure, gave the silane
17 in 52% yield as a 1:1 mixture of diastereomers.15a We initially
conducted the reaction at -78 °C in neat CH2Cl2, and a 42%
1
yield of product was obtained. As judged from 500 MHz H
NMR spectroscopy analysis, only traces of nonchelation product
was detected, and the product resulting from chelation control
(16) was isolated as a 6:1 mixture, epimeric at C-6. The 4,5-
syn-5,6-anti relationship for the major product was tentatively
assigned on the basis of the coupling constants for H-6, H-5,
H-4, (dq, J 9.0, 7.0), (dd, J 9.0, 2.0), (ddd, J 8.0, 6.0, 2.0),
respectively. This assignment was later supported by NOE
studies on a cyclopentane derivative (vide infra). The corre-
sponding signals for the minor diastereomer were masked, but
the two methyl doublets, as well as one benzylic hydrogen
doublet, were resolved and could be integrated. With the use
of a CH2Cl2-pentane mixture, the temperature could be lowered
to -110 °C, and we found that using 2 equiv of silane and 1
equiv of SnCl4 in a 1:1 mixture of CH2Cl2-pentane, the product
could be isolated in 77% yield and 9:1 diastereomeric ratio (d.r.).
The optimized synthesis of 16 is described in Scheme 4. Use
of the aluminum ate-complex derived from lithium trimethyl-
silylacetylide19 resulted in a quantitative yield for the addition
reaction to commercially available (S)-glycidyl butyrate (19)
in the presence of BF3‚Et2O. The benzyl protection of alcohol
20 using benzyl-2,2,2-trichloroacetimidate in mixtures of
CH2Cl2-hexane20 was quite sluggish, and we found that dioxane
The alcohol was protected as the TIPS ether to give 23 in
good yield, and the two diastereomers were separated at this
stage. Cleavage of the benzyl group with lithium di-tert-
butylbiphenylide resulted in the partial migration of the TIPS
group. Both BCl3 and transfer hydrogenation gave complex
mixtures. Various Lewis acids were tested, and they all
(17) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021. (b) Denmark,
S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (c) Denmark, S. E.; Fu, J. Org.
Lett. 2002, 4, 1951. (d) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y.
Tetrahedron Lett. 1998, 53, 2767. (e) Marshall, J. A.; Liao, J. J. Org. Chem.
1998, 63, 5962.
(18) Mikami, K.; Kawamoto, K.; Loh, T. P.; Nakai, T. J. Chem. Soc., Chem.
Commun. 1990, 1161.
(19) (a) Skrydstrup, T.; Be´ne´chie, M.; Khuong-Huu, F. Tetrahedron Lett. 1990,
31, 7145. (b) Watanabe, H.; Watanabe, H.; Bando, M.; Kido, M.; Kitchara,
T. Tetrahedron 1999, 55, 9755.
(20) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1
1985, 2247.
(21) Clizbe, L. A.; Overman, L. E. Org. Synth. 1978, 58, 4.
9
17924 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Scheme 5. Debenzylation of Alkyne 16a
a Reagents and conditions: (a) 3.0 equiv of TIPSOTf, 4.0 equiv of 2,6-lutidine, CH2Cl2, 24 °C, 6 h, 82%; (b) 2.0 equiv of DDQ, dichloroethane-buffer
(pH 7) 9:1 v/v, reflux, 45 min, 82%; (c) 1.3 equiv of 9-Br-9-BBN, CH2Cl2, -78 °C, 5 min, 59%; (d) 1.3 equiv of 9-I-9-BBN, CH2Cl2, -78 °C, 5 min, 75%;
(e) 1.3 equiv of FeCl3, CH2Cl2, 0-24 °C, 30 min, 39%; (f) 2.0 equiv of SnCl4, CH2Cl2, 0 °C, 30 min, complete conversion.
Scheme 6. Conversion of Alcohol 15 to Alkene 5a
reaction time afforded no further conversion. Neither higher
temperatures nor the use of tert-butyl azodicarboxylate had any
effect on the selectivity and conversion. On scale-up, those
conditions reliably afforded 5 in 75-83% yield and 8-9:1 E/Z
ratios. We therefore had access to alkyne 5 in eight steps and
32% overall yield from commercially available (S)-glycidyl
butyrate (19). The TMS group could be removed using standard
conditions in 96% yield, to give alkyne 25.
a Reagents and conditions: (a) 3.0 equiv of PPh3, 3.0 equiv of diisopropyl
azodicarboxylate, toluene, 80 °C, 20 min, 75%, E/Z 8:1; (b) 1.0 equiv of
K2CO3, MeOH, 24 °C, 2 h, 96%.
Synthesis of the Alkene Coupling Partner. We initially
envisioned that alkene 4 could be prepared using the sequence
outlined in Scheme 7. The chirality in this fragment could be
introduced using an asymmetric allylation reaction, and this
chiral center could be used to induce additional asymmetry.
Alkyloxy-directed aldol reactions between propionate-derived
silylketene acetals and â-alkoxyaldehydes have been described
and shown to proceed with good simple diastereoselectivity, to
give 1,2-syn products, and high levels of 1,3-induction to give
predominantly the 2,4-anti-diastereomer.25 Although there has
been no reported precedent for the use of silyl dienolates derived
from ethyl dioxenone in this process, the substrate-controlled
reaction of a silyl dienolate derived from methyl dioxenone with
a â-alkoxyaldehyde was recently disclosed (it proceeded ste-
reorandomly).26
We studied this unprecedented reaction with racemic 28a27
and 28b.28 Silylketene acetal 27 was prepared following a known
procedure,29 as a 1.6:1 mixture of isomers, starting from 6-ethyl-
2,2-dimethyl-[1,3]-dioxin-4-one.30 Although Sato et al. reported
that the Z isomer was the major product of the reaction,29 NOE
studies established that the E isomer was the major product in
our hands.31
Treatment of 27 and the TBS-protected aldehyde 28b with
TiCl4 as Lewis acid in dichloromethane at -78 °C resulted in
decomposition of the starting material (Table 1, entry 1).
Applying the same conditions to the reaction of the PMB-
protected aldehyde 28a resulted in cleavage of the benzyl group
(entry 3), and the diols could be obtained in good yield in a
2.6:1 ratio for the 2,4-anti/syn diastereomers, which could be
separated by column chromatography. The 2,4-anti product was
found to be a 4:1 diastereomeric mixture, favoring the desired
promoted rapid cyclization to give the tetrahydrofuran derivative
24 (Scheme 5).
This facile process is precedented,22 and could be due to the
presence of traces of water in the solvent, or of protic acid in
the commercial solution of Lewis acid. Hydrochloric acid has
been shown to promote this reaction,23 and although it has been
found that the CeCl3‚7H2O/NaI system was an efficient cy-
clization promoter,24 this might also be due to the presence of
1
Brønsted acid. In the event, although analysis of the H NMR
spectrum of tetrahydrofuran derivative 24 was ambiguous
(H-3, qd, J 7.5, 4.5; H-4, dd, J 4.5, 4.0; H-5, ddd, J 8.0, 5.5,
4.0) with regard to the relative stereochemistry, NOEs of 5.0%
(H-3 irradiation) and 4.1% (H-5 irradiation) were measured
between H-3 and H-5 (Scheme 5). Although NOEs between
H-4 and H-3, and H-4 and H-5 are less diagnostic in a five-
membered ring, the large values observed (7.2% and 8.8%,
respectively) also pointed to an all-syn arrangement in 24,
consistent with a (chelation-controlled) anti-selective silane
addition, and this was in agreement with Nakai’s precedent.18
Eventually, we found that the use of an excess of DDQ in a
boiling mixture of dichloroethane and aqueous buffer (pH 7)
rapidly cleaved the benzyl ether to give alcohol 15 in excellent
yields (82-86%) (Scheme 5). This easy oxidation might be
facilitated by the inductive effect of the neighboring silyl ether.
Initial elimination attempts focused on converting alcohol 15
into the sulfonate derivative, followed by base-promoted
elimination. DBU-promoted elimination of the mesylate deriva-
tive afforded the alkene 5 in 60% yield, albeit in an unacceptable
1.6:1 E/Z ratio. An attempt to improve this ratio by making the
triisopropylbenzenesulfonyl derivative failed, as the alcohol was
too unreactive toward trisyl chloride. We turned our attention
to the use of the azodicarboxylate-triphenylphosphine system.
We were pleased to find that DIAD-PPh3 (3 equiv) in toluene
at 80 °C gave a clean reaction to afford 5 in 83% yield (Scheme
6) and a very satisfying 9:1 E/Z ratio (E isomer: 2 d, δ 5.70
and 6.09, J 16.0, 5.0 and 16.0, 2.0; Z isomer: 1 d, δ 5.49, J
11.0 and 1 dd, δ 5.89, J 11.0, 9.0). The two isomers were
inseparable, and traces of starting material remained. Extended
(25) (a) Reetz, M.; Kessler, K.; Jung, A. Tetrahedron 1984, 40, 4327. (b)
Mahrwald, R. Chem. ReV. 1999, 99, 1095.
(26) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.; Tadano, K.
J. Am. Chem. Soc. 2003, 125, 14722.
(27) Racemic aldehyde 28a was prepared by dihydroxylation, followed by
oxidative cleavage of known PMB-protected hepta-1,6-dien-4-ol: Shepherd,
J. N.; Na, J.; Myles, D. C. J. Org. Chem. 1997, 62, 4558.
(28) Racemic aldehyde 28b was prepared in four standard steps (allylation, TBS
protection, DDQ-mediated PMB cleavage, and Moffat-Swern oxidation)
from known 3-(4-methoxy-benzyloxy)-propionaldehyde: Oka, T.; Marai,
A. Tetrahedron 1998, 54, 1.
(22) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena,
G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302.
(23) Paquette, L. A.; Balogh, D.; Engel, P. Heterocycles 1981, 15, 271.
(24) Marrota, E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.; Rosini,
G. Org. Lett. 2002, 4, 4451.
(29) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995, 41, 1435.
(30) (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087.
(b) Sato, M.; Ogasawara, H.; Komatsu, S.; Kato, T. Chem. Pharm. Bull.
1984, 32, 3848.
(31) See the Supporting Information for details.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17925

A R T I C L E S
Trost et al.
Scheme 7. Retrosynthetic Analysis for the Preparation of 4
Table 1. Addition of Silylketene Acetal 27 to Aldehydes 28a and 28b
entry
R
E/Z ratio 27
lewis acid
solvent
2,4-anti/syna
1,2-anti/synb
yieldc
1
TBS
TBS
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
10:1
10:1
1:2
TiCl4
BF3‚OEt2
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
decomp
78%
61%
76%
80%
89%
75%
73%
80%
72%
2
2:1
2.6:1
1.7:1
3.4:1
7.5:1
3:1
8:1
4:1
5:1
1:1
1:4e
1:1
1:1.3
1:1
2:1
3:1
1:1.4
1.1:1
3d
4
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
BF3‚OEt2
5
6
7
8
9
10
TiCl2(OiPr) 2
TiCl2(OiPr) 2
TiCl2(OiPr) 2
TiCl2(OiPr) 2
TiCl2(OiPr) 2
TiCl2(OiPr) 2
1:2
a All four diastereomers were inseparable; the ratio was determined by integration of the PMB benzylic protons, which gave one AB system for each pair
of 2,4-anti and 2,4-syn diastereomers. b Determined by integration of the protons of the methyl R to the hydroxyl, which gave one doublet for each pair of
1,2-anti and 1,2-syn diastereomers. c Combined yield of all diastereomers. d Loss of the PMB group was observed. e The 2,4-anti/syn diastereomers were
separable; the 1,2-anti/syn ratio is given for the desired 2,4-anti product.
Scheme 8. Retrosynthetic Analysis for a Hydrosylilation-Based Approach to Dioxenone 4
syn isomer. The yield of the desired product was however
unacceptably low, and we sought to improve on this result. Use
of BF3‚Et2O resulted in very poor selectivities (entries 2 and
4). The switch to TiCl2(OiPr)2 gave cleaner reactions, with no
PMB deprotection and improved 2,4-anti/syn ratios. Although
the four diastereomers were inseparable, only two AB systems
were observed for the methylene group of the PMB ether, which
corresponded to each pair of 2,4-anti and 2,4-syn diastereomers,
and these could be integrated. Likewise, the 1,2-anti/syn
diastereomeric ratio was determined by integration of proton
signals of the methyl group in the R position of the hydroxyl
group, which gave only two doublets corresponding to each pair
of 1,2-anti and 1,2-syn diastereomers.31 Replacing dichlo-
romethane with toluene consistently improved the 2,4-anti
selectivity (entries 6 vs 5, 8 vs 7, 10 vs 9). However, 1,2-anti/
syn ratios were poor, and we therefore investigated whether
modifying the isomeric ratio for 27 could lead to improved
results. When a 10:1 mixture was used, the 1,2-anti/syn ratio
increased (entries 7 and 8). It was possible to obtain a 1:2 E/Z
solution of 27 from a 10:1 E/Z solution by treating 27 with
iodine in dichloromethane. Unfortunately, no major improve-
ment of the 1,2-anti/syn ratio could be observed using this 1:2
E/Z solution of 27 (entries 9 and 10). The use of simple esters
and thioesters instead of the dioxenone did not provide any
satisfactory solution,32 nor did the use of chiral Lewis acids.29
Thus, we abandoned this route.
Capitalizing on a hydrosilylation reaction developed in our
laboratories,33 a different approach to dioxenone 4 was envi-
sioned using alkyne 31 (Scheme 8). Oxidation of the vinylsilane
29 to the corresponding ketone could lead to dioxenone 4. We
hoped that a regioselective addition to epoxide 32 would afford
alkyne 31.
Epoxide 32 was prepared as depicted in Scheme 9. Klunder
et al. reported that Grignard reagents reacted chemoselectively
with p-toluenesulfonic acid glycidyl ester (34) in the presence
of Li2CuCl4, although they reported incomplete conversions for
this reaction.34 Commercially available Z-1-bromoprop-1-ene
(33) could be converted at room temperature (r.t.) without
apparent loss of stereochemistry to the corresponding Grignard
reagent,35 which reacted with 34 in the presence of Li2CuCl4
(32) Use of a 1:5 E/Z mixture of silylketene acetal derived from ethyl propionate
in the presence of TiCl2(OiPr)2 in toluene gave a 2.5:1 1,2-anti/syn ratio
and a better than 10:1 2,4-anti/syn ratio. Use of a 1:6 E/Z mixture of
silylketene acetal derived from tert-butyl thiopropionate in the presence of
TiCl2(OiPr)2 in dichloromethane gave a 1:1 1,2-anti/syn ratio and an 8:1
2,4-anti/syn ratio. In both cases, alternative conditions gave higher 1,2-
anti/syn ratio.
(33) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2004, 126, 13942. (b) Trost,
B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
(34) Klunder, J. M.; Onami, T.; Sharpless, K. B. J. Org. Chem. 1989, 54, 1295.
(35) Kant, J. J. Org. Chem. 1993, 58, 2296 and references therein.
9
17926 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Scheme 9. Synthesis of Epoxide 32a
a Reagents and conditions: (a) 1.0 equiv of Mg, THF, 23 °C, 2 h, then added to 0.05 equiv of Li2CuCl4, THF, -35 °C, 35 min, then 0.7 equiv of 34, -35
°C, 10 min, 97%, Z/E > 49:1; (b) 1.2 equiv of KH, THF, 0-23 °C, 22 h, then added to 2.0 equiv of lithium trimethylsilylacetylide (prepared from
trimethylsilylacetylene and n-BuLi, THF, -78 °C, 10 min), THF-hexane, -78 °C, 10 min, then 1.1 equiv of BF3‚Et2O; (c) 0.07 equiv of VO(acac)2, 2.2
equiv of TBHP, CH2Cl2-decane, 23 °C, 16 h, 71%, d.r. 19:1; (d) 3.2 equiv of TMEDA, 2.0 equiv of TBSCl, DMF, 23 °C, 13 h; (e) 1.1 equiv of K2CO3,
MeOH, 23 °C, 6 h; (f) 1 atm of H2, 0.02 equiv of Lindlar catalyst, 2.1 equiv of quinoline, hexane, 23 °C, 15 min, 86% (3 steps).
Table 2. Opening of Epoxide with Alkynylmetal Reagents
entry
R
R
′
conditions
result
t
1
2
3
TBS
TBS
TBS
CO2 Bu
1.0 equiv of BF3‚Et2O
85%, 41a/42a 1.7:1
mixtures of epichlorhydrin
no conversion
t
CO2 Bu
1.0 equiv of Et2AlCl
1.0 equiv of AlMe3,
then 1.0 equiv of BF3‚Et2O
1.0 equiv of AlMe3,
then 1.0 equiv of BF3‚Et2O
i. Ti(OiPr)4
t
CO2 Bu
4
5
TBS
H
TMS
62%, 41b/42b 1:1.3
39%, 41c/42c 0:1
t
CO2 Bu
ii. BF3‚Et2O
t
6
7
H
H
CO2 Bu
1.0 equiv of BF3‚Et2O
i. aluminum tris(2,6-diphenylphenoxide)
ii. BF3‚Et2O
74%, 41c/42c 0:1
37%, 41c/42c 1.3:1
t
CO2 Bu
t
8
H
CO2 Bu
Sc(OTf)3
50%
t
9
10
H
H
CO2 Bu
SnCl4, Et3N
Mg(OTf)2
no reaction
no reaction
t
CO2 Bu
to give alcohol 35 in 97% yield. We found that simply using a
slight excess of Grignard reagent did afford complete conversion
in less than 5 min on a 20 g scale. Treating alcohol 35 with
KH for 7-22 h gave the corresponding epoxide, which was
not isolated, but rather was treated with the lithium salt of
trimethylsilylacetylene in the presence of BF3‚Et2O, to afford
alkyne 36. Crude 36 was directly treated with catalytic
VO(acac)2 and excess TBHP36 to afford epoxide 37 in an
hydrins (entry 2). We also tested the alane prepared from tert-
butylpropiolate (n-BuLi, AlMe3) in this reaction, but it was
unreactive (entry 3). The use of the alane derived from the
trimethylsilylacetylide also resulted in low selectivities, favoring
the undesired isomer 42b (entry 4).
We sought to increase the steric bulk on the alkoxy side of
the epoxide by preparing a TIPS analogue of epoxide 32.
However, this alcohol was unreactive toward TIPSCl, even
under forcing conditions, whereas TIPSOTf caused decomposi-
tion of the epoxide and TIPSH under rhodium catalysis gave
no reaction. A trityl analogue of 32 could be prepared (1.5 equiv
TrCl, 2.0 equiv DBU, CH2Cl2, 22 °C, 21 h), but the ratio of
products under the conditions of entry 1 was still only 2:1,
favoring the desired product (not shown). We then decided to
test the unprotected alcohol (40) in the presence of bidentate
Lewis acids, in the hope that a five-membered chelate should
favor alkylation at the desired position. To the best of our
knowledge there is no precedent for this reaction with â-(1,2-
disubstituted)-epoxy alcohols. Strong Lewis acids are required
to activate the oxirane toward attack by carbon nucleophiles,
and BF3‚OEt2 has been used extensively,37 with Et2AlCl being
1
excellent 80% yield over the two steps. Pleasingly, H NMR
spectroscopy analysis indicated a 19:1 diastereomeric ratio.
O-Silylation (TBSCl, TMEDA), followed with C-desilylation
(K2CO3 in methanol) and Lindlar reduction of the alkyne gave
the desired epoxide 32 in 86% overall yield for the three steps.
Unfortunately, regioselectivity for the epoxide opening using
BF3‚Et2O turned out to be very low (1.7:1 in favor of the desired
isomer), giving the two separable isomers 41a and 42a in 85%
combined yield (Table 2, entry 1). The two products were
unambiguously identified by the splitting pattern of the hydrogen
R to the alkyne, i.e., dq for 41a and dt for 42a. The use of
Et2AlCl instead of BF3‚Et2O gave only a mixture of epichlor-
(36) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17927

A R T I C L E S
Trost et al.
Scheme 10. Retrosynthetic Analysis for the Preparation of Dioxenone 4
Scheme 11. Synthesis of the Alkene Coupling Partnera
a Reagents and conditions: (a) 1.0 equiv of TBDPSCl, 1.3 equiv of imidazole, CH2Cl2, 23 °C, 0.5 h; (b) 1.15 equiv of DIBAL-H, CH2Cl2, -78 °C, 60
min, then 1.35 equiv of MeOH, -78 °C to 24 °C, then added to 2.5 equiv of CH3(CO)CHN2P(O)(OMe)2, 2.5 equiv of NaOMe, THF, -78 °C to 0 °C, 20
min, 83% (2 steps); (c) 2.0 equiv of 9-Br-9-BBN, CH2Cl2-hexane, 0 °C, 6 h, then 14 equiv of AcOH, 0 °C, 1 h, 96%; (d) 2.0 equiv of t-BuLi, ether, -78
°C, 1 h, then 1.3 equiv of ThCu(CN)Li, THF, -78 °C to -45 °C, -45 °C, 1 h, then 2.0 equiv of 34, THF, -45 to 0 °C, 0 °C, 5 h, then 2.0 equiv of
vinyllithium, 2.0 equiv of BF3‚Et2O, THF, -78 °C, 20 min, 71%; (e) 1.8 equiv of TBSOTf, 4.0 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 5 min; (f) 1.2 equiv of
TBAF‚3H2O, 1.2 equiv of AcOH, DMF, 23 °C, 13 h, 77% (2 steps); (g) 2.0 equiv of (COCl)2, 4.0 equiv of DMSO, 4.6 equiv of Et3N, CH2Cl2, -78 °C to
-20 °C, 20 min; (h) 4.0 equiv of t-BuOAc, 4.0 equiv of LDA, THF-hexanes, -78 °C, 1 h, then 45, THF, -78 °C, 10 min, 78% (2 steps); (i) 1.5 equiv
of TBAF, THF, 24 °C, 4 h, 89%.
the other metal complex of choice. The use of catalytic AlMe3
in conjunction with alkynyllithium reagents and â- or γ-epoxy
ethers results in an equilibrium between the aluminum ate-
complex and the chelate complex with the epoxide, to give good
yields of product.38 Crucially, however, this has only been
demonstrated with monosubstituted epoxides. First treating 40
with Ti(OiPr)4, and adding it to the lithiated propiolate and BF3‚
OEt2, resulted in the exclusive formation of the undesired isomer
42c in 39% yield (entry 5). The use of the same conditions, but
in the absence of Ti(OiPr)4, gave only the undesired isomer in
74% yield (entry 6). Precomplexation with a very bulky Lewis
acid39 gave the desired isomer 41c in low selectivity and low
yield (entry 7). Use of Sc(OTf)3 gave a product whose structure
was tentatively assigned as the tetrahydrofuran derivative 43
(entry 8). We also tested a variety of Lewis acids with alcohol
40 and trimethylacetylide but were not able to find conditions
that afforded the desired product. Although the BF3‚Et2O-
catalyzed reaction with tert-butylpropiolate (Table 2, entry 1)
represented an improvement (85% yield, 1.7:1 ratio of separable
isomers) over the results obtained with the aldol route (Table
1, entry 6), the remaining difficulties associated with this route
made it a dicey bet for a rapid access to the long-awaited
dioxenone 4. We therefore decided to settle for a safer, less
ambitious but nonetheless concise route, which we expected
would afford a straightforward access to 4.
Our third approach is depicted in Scheme 10, with com-
mercially available (R)-glycidyl tosylate (34) and (R)-hydroxy-
isobutyric acid methyl ester (Roche ester, 48) envisioned as
starting material. We planned to prepare vinyl bromide 47 from
alcohol 48. We envisioned that epoxide 34 would serve as a
linchpin to connect metalated 47 and vinyllithium, thus exploit-
ing the difference of reactivity between the two electrophilic
sites of 34. Alcohol 46 thus obtained would then be converted
in five steps to dioxenone 4, via 45 and 44.
The Roche ester (48) was protected with TBDPSCl in
quantitative yield (Scheme 11). Initially, the crude product 49
was reduced to the corresponding aldehyde with DIBAL-H,
which was converted to alkyne 50 using the Seyferth-Ohira-
Bestmann reagent.40 Bestmann’s conditions, using K2CO3 in
methanol at 0 °C to effect deacetylation of the reagent, induced
significant elimination and 50 was isolated in a modest 40%
yield. We found that the homogeneous conditions optimized
by Nicolaou et al. (1 equiv NaOMe/phosphonate, THF, -78
°C to r.t)41 were very efficient, allowing isolation of alkyne 50
in a very reproducible 76% yield over the three steps {[R]26
D
-5.3, c 4.1, CHCl3}. Only on an 80 mmol scale, did we observe
a drop in the yield (59%), and this was largely due to the
(37) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391. (b) Eis, M.
J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1994, 106, 3693.
(38) Ooi, T.; Kagoshima, N.; Ichikawa, H.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 3328.
(39) (a) Maruoka, K.; Imoto, H.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 4131. (b) Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585.
(40) (a) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(b) Ohira, S. Synth. Commun. 1989, 19, 561.
(41) Nicolaou, K. C.; Li, Y.; Fylaktadikou, K. C.; Mitchell, H. J.; Wei, H.-X.;
Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40, 3849.
9
17928 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Figure 2. 500 MHz 1H NMR spectroscopy analysis of the esters derived from 46 and (R)- and (S)-methoxyphenyl acetic acid (MPA) confirmed the absolute
stereochemistry of alcohol 46.
Scheme 12. Model Studies for Dioxenone Formationa
a Reagents and conditions: (a) 3 equiv of isopropenyl acetate, 3 equiv of LDA, -78 °C, 5 min; (b) 4 equiv of PCC, 1 equiv of NaOAC, 4 Å MS, CH2Cl2,
18 h, 24% (2 steps); (c) toluene-acetone (100 equiv) 2:1 v/v, 90 °C, 40 min, 77%.
formation of a larger amount of alcohol in the DIBAL-H reduc-
tion step. We surmised that aluminum salts should not prevent
the alkynylation reaction and that it should be possible to prepare
50 without isolating the intermediate aldehyde. After stirring
49 with 1.15 equiv of DIBAL-H in CH2Cl2 at -78 °C for 1 h,
1.35 equiv of MeOH was added, and the mixture was warmed
to r.t., and then added to 2.5 equiv of Seyferth-Ohira-Best-
mann reagent which had been premixed with 2.5 equiv of
NaOMe in THF at -78 °C. After warming to 0 °C over 20
min and standard workup, alkyne 50 was isolated in an improved
83% yield from 48 (Scheme 11). The drawback of this procedure
is the excess of Seyferth-Ohira-Bestmann reagent needed, as
2.2 equiv gave a 62% yield and 1.5 equiv afforded 50 in ca.
40% yield. Alkyne 50 could then be converted into 47 in excel-
lent yields, using 9-Br-9-BBN, followed by an acetic acid
quench. The standard hydrogen peroxide-sodium hydroxide
workup led to lower yields of product and was omitted. Al-
though this meant that the crude product was contaminated with
large amounts of material of very low solubility, it did not prove
to be detrimental to the purification of 47 by flash silica gel
chromatography. The coupling of 47 with (R)-glycidyl tosylate
34 required extensive optimization. We initially focused on
forming the Grignard reagent and found that it could only form
at the reflux temperature of THF, with 1,2-dibromoethane-
mediated activation of the magnesium, and this reaction was
always accompanied with the formation of unacceptable amounts
of debrominated alkene. We were able to effect clean bromine-
lithium exchange, providing that this reaction was carried out
in ether, using a fresh solution of t-BuLi. Formation of Lipshutz’
mixed cyanocuprate42 afforded epoxide 51, which upon treat-
ment with vinyllithium in the presence of BF3‚Et2O afforded
alcohol 46 in good yields. The two operations could be done in
one flask, without isolation of 51, with no detrimental effect
on the yield. The stereochemistry of 46 was confirmed by
preparing the corresponding (R) and (S)-O-methyl mandelate
showed a single diastereomer for each compound, and analysis
of the chemical shifts unambiguously confirmed the S config-
uration of the alcohol (Figure 2).
TBS protection of 46 afforded compound 52 which was used
in the next step without purification. Selective hydrolysis of
the primary silyl ether using TBAF in the presence of acetic
acid in DMF,43 gave alcohol 53 (Scheme 11). Moffat-Swern
oxidation, followed by addition of the lithium enolate of tert-
butyl acetate, gave ester 54 in 78% yield, and as a 2.8:1 mixture
of diastereoisomers (the presumably major Felkin-Anh product
is shown). As the formation of the dioxenone proved problem-
atic and the study of the alkene-alkyne coupling progressed
(vide infra), the desilylated substrate 55 became attractive and
could be obtained from 54 in 89% yield using TBAF in THF.
We were unable to find conditions that would allow us to
prepare 55 without resorting to intermediate TBS protection of
the secondary alcohol.
Conditions for the formation of the dioxenone were initially
examined on a model system. Precedents for this reaction stem
from studies by Eastman chemists, Clemens, Witzeman, and
Hyatt, who studied the formation and mechanism thereof of
acylketene from â-ketoesters and dioxenones.9 In particular, they
established that formation of acylketene was most favorable with
tert-butyl acetoacetate compared with methyl, ethyl, isopropyl,
and isobutyl9a and also that isopropenyl acetoacetate forms 2,2,6-
trimethyl-1,3-dioxen-4-one upon heating with excess acetone.9b
We prepared isopropenyl ester 57 from commercially available
methylpropionaldehyde (56) and submitted it to Clemens’ and
Witzeman’s conditions (Scheme 12).9b Upon heating with 100
equiv of acetone in toluene in a stoppered flask, 58 afforded
(42) (a) Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J. Organomet. Chem. 1985, 285, 437. (b) Organocopper
Reagents: A practical Approach; Taylor, R. J. K., Ed.; Oxford University
Press: Oxford, 1994.
(43) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.;
Nakata, M. Synlett 2000, 1306.
1
esters derivatives.16 500 MHz H NMR spectroscopy analysis
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17929

A R T I C L E S
Trost et al.
Scheme 13. Attempted Dioxenone Formationa
a Reagents and conditions: (a) 5 equiv of isopropenyl acetate, 5 equiv of LDA, -78 °C, 5 min, 45%; (b) 4 equiv of PCC, 1 equiv of NaOAC, 4 Å MS,
CH2Cl2, 4 h, 50%. (c) Conditions A: toluene-acetone (100 equiv) 2:1 v/v, 90 °C, 90 min. Conditions B: acetone, 56 °C, 3.5 h.
dioxenone 59 in 77% yield, although the purity of the product
was modest as judged by H NMR spectroscopy.
reaction (entry 10). Next we studied racemic alkynes 64e-g.
The result obtained with 64c (entry 5) was nicely reproduced
with the desired, more functionalized analogue 64e since the
coupling reaction with olefin 65a in a 1:1 ratio in acetone at
room temperature in the presence of 67 (10 mol %) yielded the
desired compound 66ea in 46% yield (brsm 65%) as well as
several unidentified byproducts (entry 11). Treatment of 66ea
in acetone in the presence of 20 mol % 67 led to a 95% recovery,
which pointed to the stability of the product. With the use of
dioxenone 65b, the reaction was carried out in acetone at r.t.,
and again rapid conversion and low yield of product was
observed (entry 12). Poor reactivity of alkene 65b might be
inferred from the facts that the alkyne was fully consumed and
that alkene recovery was excellent. Unlike what has been
occasionally observed,6c adding another portion of catalyst
resulted in no further conversion. Using 1 equiv of catalyst 67
gave worse conversion (entry 13) which might indicate the
formation of catalytically inactive aggregates, or self-catalyzed
decomposition, although poor mass recovery points to a possible
different reaction manifold. Curiously, when DMF was used,
no reaction was observed (entry 14). The reaction of 64g also
proceeded poorly (entry 16), while the addition of a bidentate
acid to the medium was detrimental to the conversion (entry
17). Again DMF was not a suitable solvent, affording no product
(entry 17).
1
We then prepared the isopropenyl ester (61) derived from
aldehyde 45 (Scheme 13), but when heated in the presence of
acetone, none of the desired dioxenone was formed. Instead,
two products were isolated (conditions A), methyl ketone 62
and dioxenone 63, presumably via the mechanism depicted in
Scheme 13. In neat acetone (conditions B), the reaction still
proceeded, although at a lower rate, and only the dioxenone 63
was observed by TLC. This was unanticipated as Williams used
a similar â-ketoester, going through a similar acylketene to
accomplish the macrocyclization.5d In the complete amphidi-
nolide P system, the acylketene got smoothly trapped by the
alcohol 12 carbons away to form the 15-membered ring (starting
from the methyl ester, 90 min, toluene, reflux). With alkenes
54 and 55 in hand, we could certainly envisage completing the
synthesis, and we did not do any further studies on dioxenone
synthesis.
Studies of the Ruthenium-Catalyzed Enyne-Alkene Cou-
pling. As mentioned in the Introduction, enynes had never been
tested as substrates for the alkene-alkyne coupling, and we
therefore carried out some model studies. Enynes 64a-g and
alkenes 65a and 65b were prepared31 (we were not able to
identify conditions to convert ketone 65b into the desired olefin)
and coupled under various conditions using [CpRu(CH3CN)3]-
PF6 (67) or CpRu(COD)Cl (68), and the results are compiled
in Table 3.
At this point in time we had alkenes 54 and 55 in hand, and
the alkene-enyne coupling was then tested with those sub-
strates, as shown in Table 4. Alkene 54 was unstable in the
presence of the catalyst 67 in acetone (entry 1), and no reaction
occurred in DMF (entry 2), except under forcing conditions (100
°C), where the silyl ether was hydrolyzed, demonstrating the
Lewis acid character of the ruthenium(II) species. Surmising
that steric hindrance might preclude coordination of both
coupling partners to the ruthenium center, we removed the TMS
group and tested the reaction with alkyne 25, to no avail (entry
4). Pushing the idea further, we carried out the reaction with
diol 55 and alkyne 25 and were pleased to isolate the product
70 in 28% yield (entry 5). Using an excess of alkene was
essential in order to obtain good conversion. Importantly, no
linear isomer was detected by 500 MHz 1H NMR spectroscopy,
We first studied the reaction with methyl 10-undecenoate
(65a) in the presence of 10 mol % of catalyst 67. With TMS-
alkynes 64a-c fast conversions (<10 min) and low turnovers
were observed (Table 3, entries 1-5), although as expected,
1
only the branched product was detected by H NMR spectro-
scopic analysis. Removing the TMS group resulted in increased
turnover (entry 6 vs entry 1) although the linear product was
now the major product. Switching to DMF and increasing the
temperature improved the yield further and favored the branched
product (entries 7-9). The yield could be increased up to 56%
by heating the reaction mixture at 70 °C in DMF (preheated oil
bath), and an improved branched-to-linear ratio of 2.7:1 was
observed. The CpRu(COD)Cl (68) catalyst fared poorly in this
9
17930 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Table 3. Addition of Alkene 65a,b to Enynes 64a-g
catalyst
temp
branched-to-linear
ratio
entrya
alkyne
alkene
(mol %)
solvent
°
C
product % (brsm)b
1
2
3
4
5
6
7
8
64a
64a
64a
64b
64c
64d
64d
64d
64d
64d
64e
64f
64f
64f
64g
64g
64g
65a
65a
65a
65a
65a
65a
65a
65a
65a
65a
65a
65b
65b
65b
65b
65b
65b
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
68 (5)
67 (10)
67 (10)
67 (100)
67 (10)
67 (10)
67 (10)
67 (10)
acetone
DMF
DMF
acetone
acetone
acetone
DMF
24
24
55
24
24
24
24
55
70
65
24
24
24
60
24
24
65
66aa 31 (70)
66aa 5 (73)
66aa 5 (65)
1:0
n.d.
n.d.
no reaction
66ca 45 (75)
66da 26 (75)
66da 36 (78)
66da 50 (76)
66da 56 (68)
66da 13 (53)
66ea 46 (65)
66fb 27 (100)
66fb 10 (25)
66fb no reaction
66gb 10 (40)
66gb traces
1:0
1:2
1.8:1
1.8:1
2.7:1
2.3:1
1:0
DMF
DMF
9
10
11
12
13
14
15
16c
17
MeOH
acetone
acetone
acetone
DMF
acetone
acetone
DMF
n.d.
n.d.
n.d.
66gb no reaction
a All reactions were run at 0.1M for 1-4 h using a 1:1 ratio of alkene to alkyne. b brsm indicates the yield based on recovered alkene. c 1 equiv of
malonic acid was added.
and unreacted alkene recovery was good. To try and obtain full
conversion, we tested the CpRu(COD)Cl (68) catalyst.6c,d At
the reflux of methanol in the presence of ammonium ion and
using a 3-fold excess of alkene, full conversion was obtained
and product 70 was obtained in 57% yield (entry 6). Again, no
linear isomer was detected by 500 MHz 1H NMR spectroscopy,
and unreacted alkene recovery was good.
species. Similar results as those of entry 9 were obtained on a
small scale when acetone from a wash bottle was used, in which
case, at 0.06M, the molar ratio of water to ruthenium was at
least 15. More work will need to be done to understand the
effect of water in the alkene-alkyne coupling using catalyst
67. To this day, it remains unclear what the structure of the
active catalyst is. With the use of the optimized conditions (entry
9), the addition of 10 mol % of TBAC totally shut down the
reaction (entry 11, TBAC and 67 were mixed under argon,
acetone was added, followed with 55 and 25, which were both
recovered quantitatively after several hours). With the use of
the conditions of entry 7, but the replacement of 68 with 10
mol % of 67 and 10 mol % of TBAC, only traces of 70 were
observed (entry 12). These results would seem to indicate that
the active catalyst is different in acetone and methanol (not-
withstanding the role of the solvent as a ligand), with the
chloride remaining bound to the ruthenium when methanol is
used as solvent. Adding chloride to 67 in acetone shut down
the reaction (entry 11), and conversely, it could be that no active
chloride-bound ruthenium catalyst was formed when 67 and
TBAC were mixed in methanol (entry 12). Alkene-alkyne
couplings do proceed with catalyst 68 in methanol in the absence
of NH4PF6 (where presumably the active catalyst is a Cp-
ruthenium chloride species), and in fact NH4PF6 provides only
modest improvements.6d We did not however run this experi-
ment (entry 6 conditions) without NH4PF6.
Since the reaction was almost quantitative in alkene 55, and
significant decomposition of the alkyne occurs, the reaction was
attempted at lower catalyst loading and lower alkyne concentra-
tion (entries 7 and 8). Only a marginal improvement was
observed with 5 mol % of 68 using a 4.5:1 ratio of 55/25,
whereas using 2 mol % resulted in incomplete conversion,
although the yield based on recovered starting material was 66%.
The quality of the solvent was crucial in this process, since the
use of methanol purified using a column solvent purification
apparatus,44 which was most likely contaminated with basic
alumina, led to no conversion. We returned to catalyst 67 (10
mol %) using a 4.5:1 ratio of 55/25 at 0.06 M, and found that
the reaction proceeded slowly but cleanly in dry acetone at r.t.
to give 70 in 72% yield (entry 9). However, on scale-up, a lot
of decomposition was observed (entry 10). This difference of
catalyst activity might be due to a difference in water concentra-
tion between the small scale and large scale reactions, and we
hypothesized that water might be a ligand for the active catalytic
(44) (a) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H. Organometallics 1996,
15, 1518. (b) Alaimo, P. J.; Petrs, D. W.; Arnold, J.; Bergman, R. G. J.
Chem. Educ. 2001, 78, 64. (c) http://www.glasscontour.com/.
In view of the subsequent macrocyclization step, it was
interesting to find out whether the reaction could be carried out
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17931

A R T I C L E S
Trost et al.
Table 4. Studies of the Coupling Reaction between Alkynes 5, 25, and 69 and Alkenes 54 and 55
alkene/alkyne
ratio
catalyst
(mol %)
solvent
temp
reaction
time
product %
(recovered alkene, recovered alkyne)a
entry
alkene
alkyne
(alkyne concn)
°
C
1
2
3
4
5
6
7
8
54
54
54
54
55
55
55
55
55
55
55
55
55
55
55
55
5
5
5
1:1
1:1
2:1
1.1:1
2:1
2.7:1
4.5:1
4.5:1
4.5:1
4.5:1
4.5:1
4.5:1
1.3:1
5.5:1
3:1
67 (10)
67 (10)
67 (10)
67 (10)
67 (10)
68 (10)c
68 (5)c
68 (2)c
67 (10)
67 (10)
67 (10)h
67 (10)i
68 (5)c
68 (5)c
68 (10)c
67 (5)c
acetone (0.15)
DMF (0.15)
24
24 to 100
24
24
24
67
67
67
24
24
24
67
67
67
67
24
2 h
2 h
complex mixture
- (60,b 100)
- (100, 100)
- (57, n.d.)
28 (80, 45)
DMF-acetone 3:1 (0.20)
acetone (0.25)
acetone (0.15)
methanol (0.10)
methanol (0.06)
methanol (0.06)
acetone (0.06)
acetone (0.06)
acetone (0.06)
methanol (0.10)
methanol (0.10)
methanol (0.06)
methanol (0.05)
acetone (0.05)
16 h
1.5 h
2 h
20 min
75 min
2 h
15 h
13 h
3 h
25
25
25
25
25
25
25
25
25
69
69
69
69
57d (80, e)
61d (86, e)
43d (77, 35)
72 (95, e)
9f
10g
11
12
13
14
15
16
50 (42, e)
- (100, 100)
traces (n.d., n.d.)
17d (96, e)
3 h
48 h
16 h
3 h
20d (84, e)
30d (70, e)
2.5:1
3 h
traces (n.d., n.d.)
a In all the cases where the product was isolated, the branched-to-linear ratio was found to be >49:1 as judged by 500 MHz 1H NMR analysis. b Desilylation
was observed. c 2 equiv/Ru of NH4PF6 was added. d Yield adjusted for the amount of alkyne consumed in the [2 + 2 + 2] reaction with the COD ligand.
e Full alkyne conversion was observed. f 0.04 mmol scale. g 1 mmol scale. h 10 mol % tetra-n-butylammonium chloride was added. i 10 mol % tetra-n-
butylammonium chloride and 10 mol % NH4PF6 were added.
Scheme 14. Preparation of Seco-Acid 73 and Attempted Macrolactonizationa
a Reagents and conditions: (a) 4.0 equiv of TBAF, THF, 24 °C, 2 h, 94%; (b) 7.5 equiv of TMSOTf, 11.5 equiv of 2,6-lutidine, 0 °C, 3 h, 24 °C, 30 min,
quant.
with desilylated 69, which was obtained from 25 (3 equiv of
TBAF, THF, r.t., 15 min, 50% unoptimized). It turned out 69
afforded very low rates compared to 25, presumably because
69 is a better ligand than 25 and is not displaced easily by the
alkene (entries 13-16). None of it was recovered, and only low
yields of 71 were observed.
Completion of the Synthesis. With the full backbone of
amphidinolide P in hand (70), we could now focus on the final
steps of the synthesis. Without the dioxenone functionality, and
with the C-3 and C-7 alcohols both deprotected, macrocycliza-
tion through acylketene formation seemed precluded. Even if
we could selectively oxidize the C-3 alcohol, we thought that
formation of a stable hemi-acetal might considerably slow or
even shut down the formation of the acylketene. We thus
decided to test more standard macrocyclization techniques,
through acyl activation of the corresponding acid. Compound
70 was therefore treated with excess TBAF to afford alcohol
72 in excellent yield (Scheme 14), and 72 was subjected to a
variety of conditions to convert it to the acid, all leading to
extensive decomposition. In spectacular contrast, we found that
TMSOTf was an excellent Lewis acid for this transformation,45
and after an aqueous HCl workup, acid 73 was obtained in
quantitative yield and did not require additional purification.
Reversing the order of steps also gave acid 73 in good yield,
but purification was then required. We found that acid 73 was
a very unstable compound, which decomposed in a few days
upon standing, even at -20 °C. It was nonetheless submitted
to a variety of macrocyclization conditions. The macrolacton-
ization methods reported by the groups of Yamaguchi,46 Trost,47
Mukaiyama,48 Keck,49 and Mitsunobu50 all gave complex
(45) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.;
Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540.
9
17932 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Scheme 15. Novel End-Game for the Synthesis of 1, Using a â-Lactone Precursor
mixtures. With the use of Mukaiyama’s or Keck’s systems, some
residue could be isolated that displayed IR stretching frequencies
of 1720 and 1830 cm-1, indicative of a mixture of medium-
sized lactone and â-lactone, respectively. When the Corey-
Nicolaou methodology51 was employed, eight-membered ring
75 was isolated in 20-30% yields. Intrigued by the possibility
that â-lactone 76 was an intermediate in the formation of 75,
and rather than trying to optimize the reaction with this unstable
seco-acid, we wondered whether we could not use the â-lactone
functionality52 as an activated acyl system, stable enough to
undergo several synthetic steps, albeit reactive enough to
undergo transesterification to some larger, more stable ring
systems. This novel strategy for macrolactonization would not
require a redesign of our synthetic route since, in theory,
aldehyde 45 could undergo a [2 + 2] cycloaddition reaction to
form a â-lactone (Scheme 15), which would provide an
interesting substrate for our alkene-alkyne coupling reaction.
A potentially big advantage of intermediate 78 over 70 was the
presence of only one free hydroxyl, which could reduce
chemoselectivity problems in the end-game. Indeed, studies of
the hydroxyl-directed epoxidation of ester 70 led to complex
mixtures, partly due to lack of chemoselectivity. In this respect,
the â-lactone would act as a “productive protecting group”.
We investigated conditions to form â-lactone 79 from
aldehyde 45. The Lewis acid-catalyzed cycloaddition of ketene
and an aldehyde has been known for some time.53 However,
the generation of ketene requires burdensome equipment.
Alternatively, a stable ketene equivalent such as trimethylsi-
lyketene (80)54 or dichloroketene could be used, where the
stabilizing substituents could be removed in the product; another
alternative is to generate ketene in situ, by dehydrohalogenation
of acetyl halides with an amine base.55 We initially focused on
the latter, inspired by the work of Nelson et al.,56 who generated
ketene from Hu¨nig’s base and acetyl chloride and used Al(SbF6)3
(generated in situ from AgSbF6 and AlCl3) as a Lewis acid to
promote the cycloaddition. Although we had some degree of
success with this protocol, in our hands it was a very capricious
reaction that led to unreproducible results, and none of the
alternative Lewis acids tested gave satisfactory results (replacing
AlCl3 with GaCl3, InCl3, Al(OTf)3, or Me2AlCl). AcBr offered
no improvement, and various sulfonamide/trimethylaluminum
systems57 offered only modest amounts of â-lactone. The LiClO4
methodology reported by Lecea et al.58 was also inneffective.
We briefly studied the tandem aldol-lactonization reaction,59
using ketene triethylsilylthioacetal and 45 in the presence of
ZnCl2, but again only low yields of â-lactone were obtained.
We next turned our attention to the use of trimethylsilylketene
(80).54 This compound can be prepared very conveniently by
silylation of ethyl ethynyl ether to give ethyl trimethylsilyl-
ethynyl ether, which upon heating to 120 °C, undergoes a 1,5-
hydrogen shift to give off ethylene and 80 (bp 81-82 °C) in
70% yield. Ketene 80 was stored in the freezer and no
decomposition was observed after 6 weeks. The cycloaddition
of 80 and 45 did not proceed when catalyzed by MgBr2‚Et2O,60
whereas BF3‚Et2O gave the lactone (81) in 49% yield. Me2AlCl
however afforded 81 as an inconsequential 1.6:1 mixture of
diastereomers in a very reproducible 90% yield, using just 1.1
equiv of 80 (Scheme 16).61 This was consistent with literature
results that show that Al(III) is predominantly the metal catalyst
of choice for [2 + 2] reactions between aldehydes and
ketenes.56,57,61,62 Next, we looked for conditions that would
cleave both the O-Si bond and the C-Si bond in one pot.
TBAF gave the fully desilylated product 79 (υCdO 1827 cm-1
)
(56) Nelson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron Lett.
1999, 40, 6535.
(46) (a) Inanaga, J.; Hirata, H.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikato, M.; Sakurai, Y.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367. (c) Evans, D. A.; Kim,
A. S. J. Am. Chem. Soc. 1996, 118, 11323.
(47) Trost, B. M.; Chisholm, J. D. Org. Lett. 2002, 4, 3743.
(48) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(49) Keck, G. E.; Boden, E. P. J. Org. Chem. 1985, 50, 2394.
(50) Mitsunobu, O. Synthesis 1981, 1.
(51) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(52) (a) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403. (b) Pommier, A.;
Pons, J.-M. Synthesis 1995, 729. (c) Pommier, A.; Pons, J.-M. Synthesis
1993, 441. (d) Lowe, C.; Vederas, J. C. Org. Prep. Proced. Int. 1995, 27,
305.
(57) (a) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655.
(b) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Chem. Commun. 1996,
1053. (c) Tamai, T.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano,
S. J. Chem. Soc., Chem. Commun. 1994, 2281.
(58) Lecea, B.; Arrieta, A.; Arrastia, I.; Cossio, F. P. J. Org. Chem. 1998, 63,
5216.
(59) (a) Yang, H. W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471. (b)
Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344.
(60) Zemribo, R.; Romo, D. Tetrahedron Lett. 1995, 36, 4159.
(61) For the use of Et2AlCl and other aluminium-based Lewis acids, see:
Concepcion, A. B.; Maruoka, K.; Yamamoto, H. Tetrahedron 1995, 51,
4011.
(53) (a) Zaitseva, G. S.; Vinokurova, N. G.; Baukov, Y. I. Zh. Obshch. Khim.
1975, 45, 1398. (b) Brady, W. T.; Saidi, K. J. Org. Chem. 1979, 44, 733.
(54) (a) Ruden, R. A. J. Org. Chem. 1974, 39, 3607. (b) Shchukovskaya, L. L.;
Pal’chik, R. I.; Lazarev, A. N. Dokl. Akad. Nauk. SSSR 1965, 164, 357.
(55) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159.
(62) (a) Tamai, T.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin.
Trans. 1 1994, 1549. (b) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.;
Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg.
Med. Chem. 1998, 6, 1255. (c) Nelson, S. G.; Cheung, W. S.; Kassick, A.
J.; Hilfiker, M. A. J. Am. Chem. Soc. 2002, 124, 13654.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17933

A R T I C L E S
Trost et al.
Scheme 16. Synthesis of â-Lactone 79a
a Reagents and conditions: (a) 2.0 equiv of (COCl)2, 4.0 equiv of DMSO, 4.6 equiv of Et3N, CH2Cl2, -78 °C to 0 °C; (b) 1.0 equiv of Me2AlCl, 1.1
equiv of 80, CH2Cl2, -78 °C, 0.5 h; (c) 1.5 equiv of KF‚2H2O, CH3CN, 25 °C, 1 h, then 40% HF(aq), 0 °C, 0.5 h, 69% (3 steps), d.r. 1.6:1.
Table 5. Alkene-Alkyne Coupling of 79 and 25
scale
yield 78
recovered 79
entry
conditions
(mmol 25)
(%)
(%)
1a
2a
3a
4a
5a
6b
10 mol % 67, acetone, 0.05 M, r.t., 13 h, 25/79 1:3.5
10 mol % 67, acetone, 0.05 M, r.t., 10 h, 25/79 1:3.5
10 mol % 67, acetone, 0.05 M, r.t., 12 h, 25/79 1:3.3
10 mol % 67, acetone, 0.05 M, r.t., 12 h, 25/79 1:3.5
10 mol % 67, acetone, 0.05 M, r.t., 10 h, 25/79 1:2.8
10 mol % 67, acetone, 0.05 M, r.t., 22 h, 25/79 1:3.4
0.14
0.20
0.44
0.80
0.36
0.04
75
69
68
56
64
72
87
86
87
91
90
75
a Acetone was distilled from CaCl2. b Acetone was taken from a wash bottle.
Scheme 17. Attempted Formation of the Amphidinolide
in only 26% yield, and aqueous HF did not cleave the C-Si
bond. It is known that KF‚2H2O desilylates â-lactones,60 so 81
was first treated with KF‚2H2O until TLC analysis indicated
complete conversion, whereupon the mixture was cooled to 0
°C, and aqueous HF was added. With the use of this procedure,
79 was very reliably obtained in 69% yield over the three steps.
As an added bonus, the two diasteromers were separable, and
although this epimeric center would eventually be destroyed,
working with a single diastereomer simplified the studies of
the remaining steps.
15-Membered Ring Systema
Despite slight concerns about the compatibility of the
somewhat Lewis acidic (see for example Table 4, entry 2)
catalyst 67 and the â-lactone functionality, coupling between
alkene 79 and alkyne 25 proceeded well (Table 5, entry 1).
However, a steady decrease of the yield was observed as the
scale of the reaction was increased (entry 1 vs 2 vs3 vs 4). This
was accompanied with a higher recovery of the excess alkene
79, indicating a greater propensity for the alkyne 25 to
decompose. The use of 3.5 equiv of alkene seemed optimal,
since a slight decrease in yield was observed when only 2.8
equiv were used (68% vs 64%, entry 3 vs entry 5). It is worth
noting that a similar result was observed when acetone from a
wash bottle (entry 6) was used instead of distilled acetone (entry
1).
We then submitted 78 to TBAF and obtained 82 in 71% yield
(Scheme 17). When we heated oxetanone 82 at the reflux of
hexane in the presence of 10 mol % of Otera’s catalyst63 (85)
at 0.001 M for 20 min, we only isolated eight-membered lactone
83 in quantitative yield. Lowering the catalyst loading to 1 mol
% gave 83 in 88% yield after 45 min. We did not observe any
conversion to the 15-membered macrolide after 3 h using 10
a Reagents and conditions: (a) 4.0 equiv of TBAF, THF, 0 °C, 5 h, 71%;
(b) 0.1 equiv of 85, hexane, 0.001 M, reflux, 20 min, quant.
mol % catalyst, which would suggest, somewhat counterintu-
itively, that 83 is in fact more stable than the corresponding
15-membered ring (84). This somewhat unanticipated result
suggested, at the cost of one extra step, an excellent strategy to
differentiate between the three secondary alcohols. While the
two alcohols at C-3 and C-14 were protected as a â-lactone
and a TIPS ether (78, Scheme 17), respectively, the alcohol at
C-7 would be used to direct the epoxidation. Leaving the TIPS
group on, and after isomerization from the four- to the eight-
membered lactone, we could anticipate oxidizing the newly
unmasked alcohol at C-3. Removing the TIPS would then reveal
the C-14 allylic alcohol. We expected that with this substrate,
the 8- to 15-membered ring isomerization would be favored,
driven by concomitant hemi-acetal formation and giving the
natural product amphidinolide P (1). We briefly investigated
the substrate-directed epoxidation of alkene 78. It is well
established in the literature that E-1,2-disubstituted olefins are
poor substrates for hydroxyl-directed epoxidation with allylic
alcohols, since they sustain minimal A-1,2 and A-1,3 interac-
tions in the transition state, usually giving the syn product with
(63) (a) Otera, J.; Ioka, S.; Nozaki, H. J. Org. Chem. 1989, 54, 4013. (b) Otera,
J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307. (c) Orita, A.;
Sakamoto, K.; Hamada, Y.; Mitsutome, A.; Otera, J. Tetrahedron 1999,
55, 2899.
9
17934 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
Scheme 18. Final Stepsa
a Reagents and conditions: (a) 1.0 equiv of Ti(OiPr)4, 1.2 equiv of (-)-DET, 2.0 equiv of TBHP, 4 Å MS, CH2Cl2, -20 °C, 2 h, 83%; (b) 0.05 equiv
of 85, hexane, 0.002 M, reflux, 1 h, 93%; (c) 3.0 equiv of Dess-Martin periodinane, CH2Cl2, 23 °C, 1 h, 82%; (d) 5.0 equiv of TBAF, THF, 0-23 °C, 23
°C, 1 h, 95%; (e) 0.20 equiv of 85, hexane, 0.001 M, reflux, 8 h, 84%.
1
very poor selectivities.64 Only the VO(acac)2/TBHP system is
known to be anti-selective for this particular class of allylic
alcohols. We tested this system with syn-78 in various solvents
(dichloromethane, hexane, toluene, benzene, chlorobenzene), and
although mass recovery was good, close to 1:1 ratios were
obtained in all cases. The major product in the toluene, hexane,
CH2Cl2 experiment was assigned the anti configuration based
on literature precedent (the coupling constants are not diagnostic
in these systems), and later, on the result of the reagent-
controlled epoxidation (vide infra). A reversal of selectivity was
observed in chlorobenzene and benzene (which gave the highest
selectivity, 1:2). We then resorted to the Katsuki-Sharpless
tartrate/Ti(OiPr)4 system.65 On the basis of multiple literature
precedents,66 the use of (-)-tartrate was expected to be a
matched case. Indeed the reaction with anti-78 gave 3,4-anti-
77 in 87% yield, and a single diastereomer using (-)-diethyl
tartrate (diisopropyl tartrate gave a similar result but was
inseparable from the product). Reaction with the mixture of
diastereomers anti-78 and syn-78 gave a partially separable
mixture of 3,4-syn-77 and 3,4-anti-77 in 83% yield (Scheme
18). As anticipated, when we submitted 77 to catalyst 85, eight-
membered lactone 86 (υCdO 1732 cm-1) was obtained in 93%
yield using 5 mol % catalyst at 0.002 M in hexane. The C-3
alcohol could then be oxidized using Dess-Martin periodinane
to give ketone 87 in 83% yield (υCdO 1756 and 1715 cm-1).
Desilylation using excess TBAF in THF at r.t. gave alcohol 88
in near quantitative yield. This was a very clean reaction, and
no double-bond isomerization or epimerization were observed.
observed after 5 h of storage in methanol, and the H NMR
spectra of 1 in C6D6 and CD3OD were also unchanged. Williams
et al. reported a synthesis of 1 which relied on two Sharpless
asymmetric epoxidations to introduce the chirality, both of them
using the (+)-diethyl tartrate ligand, and which should give
synthetic 1 of opposite absolute configuration to the one reported
herein.5d Yet they also reported a negative optical rotation, [R]23
-30 (c 0.09, MeOH). Unfortunately, Professor Williams was
not able to provide us with a sample of synthetic 1, and no
direct comparative measurement could be done.
D
Conclusion
The synthesis of amphidinolide P demonstrated that â-lac-
tones could be used as a handle for the construction of medium-
sized rings and as an alternative macrolactonization strategy.
The use of a â-lactone in this work also allowed for the
differentiation of three secondary alcohols, thereby minimizing
the use of protecting groups in the end-game and increasing
the efficiency of the synthesis. This work also highlighted the
chemo- and regioselectivity of the ruthenium-catalyzed addition
of alkene to alkynes. In the course of these studies, we showed
that this reaction was compatible with silyl ethers, esters,
â-lactones, allylic alcohols, and disubstituted alkenes and that
enynes gave perfect regioselectivity for the branched product
to give 2-allylated-1,3-dienes. As a result, a novel highly
convergent synthetic strategy emerged for the synthesis of
amphidinolide P. Indeed the required alkene was prepared in
nine steps and 30% yield, and the alkyne also in nine steps and
26% yield, both from readily available and inexpensive chiral
building blocks.
1
No enol was detected in CDCl3, as judged from the H NMR
spectroscopy spectrum. Finally, when 88 was submitted to 20
mol % 85 for 8 h at 0.001 M in hexane at reflux, amphidinolide
P (1) was isolated in an excellent 84% yield.
Experimental Section
(E)-(5S,6S)-6,7-Dimethyl-5-triisopropylsilanyloxy-1-trimethylsi-
lanyl-octa-3 ,7-dien-1-yne (5). To a solution of 15 (1.73 g, 4.36 mmol)
and triphenylphosphine (3.46 g, 13.19 mmol) in dry toluene (20 mL)
was added diisopropyl azodicarboxylate (2.67 g, 13.20 mmol), and the
flask was lowered into a preheated oil bath (80 °C). After stirring at
this temperature for 20 min, the volatiles were removed in vacuo and
the residue was purified by flash silica gel column chromatography
(petroleum ether) to give alkyne 5 (1.37 g, 3.61 mmol, 83%) as a
colorless oil and an 8:1 inseparable E/Z mixture (Found: C, 69.59; H,
11.14. C22H42OSi2 requires C, 69.77; H, 11.18%); [R]23D +1.7 (c 3.41,
CHCl3); Rf 0.40 (petroleum ether); νmax/cm-1 2945, 2868, 2361, 2134,
1464, 1250, 1059, 958, 883, 843, 760, 679, 654; E isomer: δH (500
MHz, CDCl3) 0.18 (9 H, s), 0.97 (3 H, d, J 7.0), 1.07 (21 H, s), 1.76
(3 H, s), 2.40 (1 H, br. quin., J 6.0), 4.46 (1 H, td, J 5.0, 2.0), 4.75 (1
Data for synthetic 1 was identical to the data reported for
the natural product, except for the optical rotation: [R]23D -27.4
(c 0.17, MeOH), lit.7 [R]20D +31 (c 0.098, MeOH). Four optical
rotation measurements in absolute methanol at slightly different
concentrations gave consistent values. Concentrations of 0.09,
0.17, 0.19, 0.23 gave [R]23 values of -27.2, -27.4, -31.7,
D
and -28.3, respectively. No change of optical rotation was
(64) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(65) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981,
103, 464.
(66) For an excellent example demonstrating the exquisite selectivity of the
Katsuki-Sharpless reagent, see: Ahmed, A.; Hoegenauer, E. K.; Enev,
V. S.; Hanbauer, M.; Kaehlig, H.; O¨ hler, E.; Mulzer, J. J. Org. Chem.
2003, 68, 3016.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17935

A R T I C L E S
Trost et al.
H, s), 4.85 (1 H, s), 5.70 (1 H, dd, J 16.0, 2.0), 6.09 (1 H, dd, J 16.0,
5.0); δC (125 MHz, CDCl3) 0.0, 12.3, 12.5, 18.1, 22.2, 47.1, 74.1, 94.1,
103.8, 110.0, 111.9, 144.5, 146.0; Z isomer: δH (500 MHz, CDCl3)
0.17 (9 H, s), 0.97 (3 H, d, J 7.0), 1.06 (21 H, s), 1.80 (3 H, s), 2.40
(1 H, masked), 4.46 (1 H, masked), 4.75 (1 H, s), 4.85 (1 H, s), 5.49
(1 H, d, J 11.5), 5.89 (1 H, dd, J 11.5, 9.0).
4.93 (1 H, s), 4.98 (1 H, s), 4.99 (1 H, s), 5.04 (5.02) (1 H, s), 5.53-
5.58 (1 H, m), 5.62 (1 H, dd, J 16.0, 7.0), 5.73-5.79 (1 H, m), 6.16 (1
H, d, J 16.0); δC (125 MHz, CDCl3, minor diastereomer in brackets)
12.5, 13.3, 14.9 (15.6), 18.1 (18.1), 21.8, 28.1(29.7), 35.0, 39.9 (39.5),
44.0 (43.9), 44.2 (45.3), 47.8, 70.3 (71.2), 70.4 (70.9), 75.5, 81.2, 111.5,
113.8 (114.1), 115.7, 129.2 (128.8), 130.5, 131.9, 133.8 (133.9), 143.9,
146.9, 148.2 (148.3), 172.5.
(4S,7S)-8-(tert-Butyl-diphenyl-silanyloxy)-7-methyl-6-methylene-
oct-1-en-4 -ol (46). To a solution of thiophene (0.76 g, 9.03 mmol) in
THF (8 mL) at -30 °C was added n-BuLi (2.58 M, 3.50 mL, 9.03
mmol) dropwise. The mixture was stirred for 30 min, whereupon it
was cannulated into a slurry of CuCN (99.99%, 809 mg, 9.03 mmol)
in THF (8 mL) at -78 °C. The cooling bath was removed, and upon
reaching r.t., a clear brown solution was obtained. This solution was
kept at ca. -20 °C until the vinyllithium reagent was ready (vide infra).
Conditions of Table 4, entry 9: To a solution of alkyne 25 (13 mg,
0.042 mmol) and alkene 55 (2.8:1 d.r., 54 mg, 0.190 mmol) in dry
acetone (0.7 mL) at 0 °C was added [CpRu(CH3CN)3]PF6 (1.8 mg,
0.004 mmol). The mixture was warmed to r.t. and stirred for 15 h,
whereupon it was concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether-ethyl acetate, 30%)
to afford some recovered alkene 55 (43 mg, 0.151 mmol) and the ester
70 (18 mg, 0.030 mmol, 72%) as a yellow oil and an inseparable 2.8:1
mixture of C-3 epimers.
To a solution of vinyl bromide 47 (2.79 g, 6.91 mmol) in ether (28
mL) was added t-BuLi (1.44 M, 10 mL, 14.4 mmol) at -78 °C over
10 min. After another 45 min, the freshly prepared solution of
2-thienyllithiumcyanocuprate was cannulated into it. The pale brown
heterogeneous mixture was warmed to -45 °C (chlorobenzene/dry ice
bath) and stirred at this temperature for 1 h. A solution of (R)-glycidyl
tosylate (34) (3.1 g, 13.58 mmol) in THF (11 mL) was then cannulated
into the mixture, and the resulting slurry was warmed to 0 °C over 10
min. After an additional 5 h at 0 °C, the mixture was recooled to -78
°C and a vinyllithium solution (13.93 mmol, prepared from n-BuLi
and tetravinyltin at -78 °C, 45 min then warming to 24 °C) in THF
(14 mL) was added, followed after 5 min, with BF3‚Et2O (1.97 g, 13.93
mmol). The resulting mixture was stirred for 20 min, then quenched
with a 9:1 solution of saturated aqueous NH4Cl solution/NH4OH and
diluted with ether. After 20 min of vigorous stirring followed by
filtration through Celite, the organic phase was washed with brine. The
combined aqueous phase was back-extracted twice with ether. After
drying the combined organic phase over MgSO4, the volatiles were
removed in vacuo to give a residue that was purified by silica gel flash
chromatography (petroleum ether-ethyl acetate, 19:1 to 9:1) to afford
the alcohol 46 (2.01 g, 4.92 mmol, 71%) as a colorless oil (Found: C,
76.43; H, 9.02. C26H36O2Si requires C, 76.42; H, 8.88%); [R]22D -13.1
4-((1S,4S)-4-Hydroxy-1-methyl-2-methylene-hept-6-enyl)-oxetan-
2-one (79). To a solution of DMSO (1.68 g, 21.56 mmol) in CH2Cl2
(75 mL) at -78 °C was added oxalyl chloride (1.36 g, 10.77 mmol),
and the mixture was stirred for 20 min, whereupon a solution of alcohol
53 (1.54 g, 5.41 mmol) was added dropwise. After another 20 min at
-78 °C, triethylamine (3.26 g, 32.29 mmol) was added and the cooling
bath was removed. Upon reaching 0 °C, the mixture was partitioned
between ether and saturated aqueous NH4Cl. The organic phase was
washed with saturated aqueous NH4Cl, brine, dried over MgSO4, and
concentrated in vacuo. The crude aldehyde (45), which was obtained
as a yellow oil (1.55 g), was immediately redissolved in CH2Cl2 (50
mL) and cooled to -78 °C. Me2AlCl (1.0 M in hexanes, 5.4 mL, 5.4
mmol) was added over 5 min. The bright yellow mixture was stirred
for 3 min, whereupon neat trimethylsilylketene (0.65 g, 5.72 mmol)
was added dropwise. After another 30 min, 0.5 M aqueous NaHSO4
(20 mL) and ether (100 mL) were added and the mixture was allowed
to warm to r.t. with vigorous stirring. Additional 0.5 M aqueous
NaHSO4 (150 mL) and ether (100 mL) were added, and the two clear
phases were separated. The organic phase was washed with brine (100
mL), and the combined organic phase was back-extracted with ether
(2 × 50 mL), dried over MgSO4, and concentrated in vacuo. The yellow
residue (81, 2.15 g) was taken up in acetonitrile (60 mL) and KF‚
2H2O (0.76 g, 8.06 mmol) was added. The mixture was vigorously
stirred for 1 h, whereupon it was cooled to 0 °C. Aqueous 49% HF
(13 mL, 364 mmol) was added dropwise, and the mixture was stirred
at 0 °C for 30 min. After dilution with ether (100 mL), solid NaHCO3
(30 g) was added portionwise over 5 min. After stirring for another 5
min, the mixture was filtered through a sintered funnel packed with
MgSO4. The solids were well rinsed with ether and the combined filtrate
was concentrated in vacuo. The residue was purified by silica gel flash
chromatography (petroleum ether-ethyl acetate, 7:3 to 3:2) to afford
the lactone 79 (0.78 g, 3.71 mmol, 69%) as a yellow oil and a 1.6:1
mixture of separable diastereomers (Found: M+, 210.1254. C12H18O3
requires M 210.1256, 0.7 ppm, EIMS);
One C-3 Epimer: [R]26D +20.8 (c 1.73, CHCl3); Rf 0.19 (petroleum
ether-ethyl acetate, 7:3); νmax/cm-1 3417, 2924, 1827, 1642, 1412,
1278, 1127, 914, 867; δH (400 MHz, CDCl3) 1.22 (3 H, d, J 7.0), 2.14-
2.35 (4 H, m), 2.50 (1 H, br. quin, J 7.0), 3.15 (1 H, dd, J 16.5, 4.5),
3.45 (1 H, dd, J 16.5, 6.5), 3.77-3.83 (1 H, m), 4.45 (1 H, ddd, J 8.5,
6.5, 4.5), 4.94 (1 H, s), 5.04 (1 H, s), 5.16 (1 H, d, J 18.0), 5.17 (1 H,
d, J 11.0), 5.33 (1 H, dddd, J 18.0, 11.0, 7.5, 7.0); δC (100 MHz, CDCl3)
16.1, 41.6, 41.8, 43.1, 43.7, 68.9, 73.8, 113.9, 118.6, 134.2, 146.5, 168.1.
Other C-3 Epimer: [R]26D -14.4 (c 1.4, CHCl3); Rf 0.13 (petroleum
ether-ethyl acetate, 7:3); νmax/cm-1 3417, 2933, 1827, 1642, 1412,
1278, 1127, 913, 869; δH (500 MHz, CDCl3) 1.10 (3 H, d, J 7.0), 2.16-
2.26 (3 H, m), 2.29-2.34 (2 H, m), 2.52-2.58 (1 H, m), 3.13 (1 H,
dd, J 16.5, 4.5), 3.48 (1 H, dd, J 16.5, 6.0), 3.78-3.83 (1 H, m), 4.46
(1 H, ddd, J 8.0, 6.0, 4.5), 5.05 (1 H, s), 5.06 (1 H, s), 5.12-5.17 (2
H, m), 5.80-5.89 (1 H, m); δC (125 MHz, CDCl3) 14.7, 41.4, 41.6,
43.0, 43.1, 68.6, 73.4, 114.0, 118.2, 134.4, 146.3, 167.8.
(c 3.22, CHCl3); Rf 0.30 (petroleum ether-ethyl acetate, 9:1); νmax
/
cm-1 3448, 2960, 2931, 2858, 1472, 1428, 1121, 1080, 823, 740, 702,
614; δH (400 MHz, CDCl3) 1.05 (9 H, s), 1.07 (3 H, d, J 7.0), 2.04 (1
H, dd, J 14.0, 9.5), 2.19-2.23 (3 H, m), 2.35 (1 H, broad sex, J 7.0),
3.49 (1 H, dd, J 10.0, 7.0), 3.62 (1 H, dd, J 10.0, 6.0), 3.71 (1 H, dddd,
J 9.5, 6.0, 6.0, 4.5), 4.93 (1 H, s), 4.94 (1 H, s), 5.09-5.14 (2 H, m),
5.83 (1 H, ddt, J 17.0, 10.5, 7.0), 7.35-7.43 (6 H, m), 7.64-7.68 (4
H, m); δC (100 MHz, CDCl3) 16.7, 19.2, 26.8, 41.4, 43.6, 68.2, 68.5,
112.7, 117.5, 127.6, 129.6, 133.6, 133.7, 134.9, 135.6, 135.6, 148.8.
(8E,12E)-(4S,7R,14R,15S)-3,7-Dihydroxy-4,15,16-trimethyl-5,11-
dimethyle ne-14-triisopropylsilanyloxy-heptadeca-8,12,16-trienoic
acid tert-butyl ester (70). Conditions of Table 4, entry 7: A dry flask
was charged with alkene 55 (2.8:1 d.r., 83 mg, 0.292 mmol) and alkyne
25 (20 mg, 0.065 mmol) and flushed with argon. Methanol (1.1 mL)
was added, followed with CpRu(COD)Cl (1.0 mg, 0.003 mmol) and
NH4PF6 (1.0 mg, 0.006 mmol), and the mixture was heated to reflux
over 10 min. After 75 min, the mixture was allowed to cool and
concentrated in vacuo. Purification by flash silica gel column chro-
matography (petroleum ether-ethyl acetate, 4:1 to 7:3) afforded some
recovered alkene 55 (72 mg, 0.252 mmol) and the ester 70 (24 mg,
0.040 mmol, 61%) as a yellow oil and an inseparable 2.8:1 mixture of
C-3 epimers (Found: C, 71.01; H, 10.77. C35H62O5Si requires C, 71.14;
H, 10.57%); [R]22 -6.0 (c 4.06, CHCl3); Rf 0.39 (petroleum ether-
D
ethyl acetate, 7:3); νmax/cm-1 3427, 2966, 2942, 2867, 1729, 1462, 1368,
1255, 1154, 1059, 970, 884; δH (500 MHz, CDCl3, minor diastereomer
in brackets) 0.97 (3 H, d, J 7.0), 1.05 (21 H, s), 1.10 (3 H, d, J 7.0),
1.45 (1.46) (9 H, s), 1.75 (3 H, s), 2.21 (1 H, dd, J 14.5, 9.0), 2.18-
2.40 (3 H, m), 2.36 (1 H, dd, J 16.0, 9.0), 2.42 (2.49) (1 H, dd, J 16.0,
3.5 (2.5)), 2.90 (2 H, d, J 6.5), 3.97 (1 H, ddd, J 9.0, 5.5, 3.5), 4.21-
4.30 (1 H, m), 4.36 (1 H, broad t, J 5.5), 4.70 (1 H, s), 4.78 (1 H, s),
9
17936 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Total Synthesis of Amphidinolide P
A R T I C L E S
4-((5E,9E)-(1S,4R,11R,12S)-4-Hydroxy-1,12,13-trimethyl-2,8-di-
methylene-11-triisopropylsilanyloxy-tetradeca-5,9,13-trienyl)-oxetan-
2-one (78). To a solution of alkyne 25 (42 mg, 0.137 mmol) and alkene
79 (1.6:1 d.r., 100 mg, 0.475 mmol) in dry acetone (2.5 mL) at 0 °C
was added [CpRu(CH3CN)3]PF6 (6.0 mg, 0.0138 mmol). The mixture
was warmed to r.t. and stirred for 13 h, whereupon it was concentrated
in vacuo. The residue was purified by silica gel flash chromatography
(petroleum ether-ethyl acetate, 20 to 40%) to afford some recovered
79 (62 mg, 0.295 mmol, 87%) and the lactone 78 (52 mg, 0.100 mmol,
75%) as a yellow oil and a 1.6:1 mixture of C-3 epimers (Found: [M
+ Na]+, 539.3517. C31H52O4Si requires M + Na 539.3533, 2.9 ppm,
ESIMS); [R]26D -0.2 (c 0.85, CHCl3); Rf 0.40 (petroleum ether-ethyl
acetate, 7:3); νmax/cm-1 3441, 2943, 2866, 1831, 1645, 1462, 1374,
1125, 1059, 970, 882; δH (500 MHz, CDCl3, minor diastereomer in
brackets) 0.97 (3 H, d, J 7.0), 1.05 (21 H, s), 1.20 (1.09) (3 H, d, J
7.0), 1.75 (3 H, s), 2.18-2.33 (2 H, m), 2.38 (1 H, br quin., J 7.0),
2.90 (2 H, d, J 6.5), 3.12 (3.13) (1 H, dd, J 16.5, 4.5), 3.42 (3.45) (1
H, dd, J 16.5, 5.5), 4.20-4.25 (1 H, m), 4.35-4.38 (1 H, m), 4.43
(4.46) (1 H, ddd, J 7.0, 5.5, 4.5), 4.69 (1 H, s), 4.78 (1 H, s), 4.91 (2
H, s), 4.98 (5.03) (1 H, s), 5.02 (5.06) (1 H, s), 5.53 (5.55) (1 H, dd,
J 15.0, 7.0), 5.61 (5.62) (1 H, dd, J 16.0, 6.5), 5.76 (5.76) (1 H, dt, J
15.0, 7.0), 6.16 (1 H, d, J 16.0); δC (125 MHz, CDCl3, minor
diastereomer in brackets) 12.4, 13.2 (13.3), 16.0, 18.1, 21.8, 35.0, 41.6
(41.2), 43.4 (42.9), 43.8 (43.6), 47.7, 71.1 (70.6), 73.8 (73.3), 75.3
(75.4), 111.4, 113.9 (114.1), 115.7, 129.6 (129.3), 130.5 (130.4), 131.8
(131.9), 133.7 (133.6), 143.7 (143.8), 146.0 (145.7), 146.9, 168.1
(167.8).
16.0, 6.5), 6.20 (1 H, d, J 16.0); δC (125 MHz, CDCl3) 12.4, 13.0,
18.1, 21.9, 34.17, 37.9, 41.2, 42.7, 45.0, 47.6, 56.4, 58.4, 73.3, 75.1,
81.1, 111.5, 116.7, 118.9, 130.64, 131.8, 140.8, 144.9, 146.8, 171.7.
Other C-3 Epimer: δH (500 MHz, CDCl3) 0.98 (3 H, d, J 7.0),
1.05 (21 H, s), 1.23 (3 H, d, J 7.0), 1.76 (3 H, s), 2.01 (1 H, dq, J 9.5,
7.0), 2.37-2.54 (4 H, m), 2.49 (1 H, dd, J 12.5, 5.0), 2.61 (1 H, dd, J
14.0, 1.5), 2.91 (1 H, dd, J 5.0, 2.0), 2.97 (1 H, dd, J 12.5, 4.0), 3.14
(1 H, ddd, J 6.0, 5.0, 2.0), 4.10 (1 H, m), 4.40 (1 H, br. t, J 6.0), 4.59
(1 H, ddd, J 11.0, 5.0, 2.5), 4.68 (1 H, br. s), 4.78 (1 H, br. s), 5.07 (2
H, br. s), 5.12 (1 H, br. s), 5.21 (1 H, br. s), 5.60 (1 H, dd, J 16.0, 6.5),
6.20 (1 H, d, J 16.0); δC (125 MHz, CDCl3) 12.4, 13.0, 18.1, 21.9,
34.21, 37.9, 41.2, 42.8, 43.7, 47.6, 55.8, 58.5, 73.3, 75.1, 79.3, 111.5,
116.1, 118.9, 130.68, 131.8, 140.8, 144.9, 147.4, 172.2.
Amphidinolide P (1). Lactone 88 (14.0 mg, 0.037 mmol) and
distannoxane 85 (9 mg, 0.007 mmol) were placed in a dry flask, and
dry hexane (37 mL) was added. The mixture was stirred at reflux for
8 h, cooled, and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether-ether, 17:3) to afford
amphidinolide P (1) (11.7 mg, 0.031 mmol, 84%) as a colorless oil;
[R]23D -27.4 (c 0.17, MeOH); Rf 0.35 (petroleum ether-ethyl acetate,
17:3); νmax/cm-1 3482, 3084, 2971, 2942, 1712, 1650, 1433, 1376, 1361,
1291, 1243, 1189, 1111, 988, 967, 896; δH (500 MHz, C6D6) 0.91 (3
H, d, J 7.0), 0.92 (3 H, d, J 7.0), 1.67 (3 H, br. s), 1.93-1.96 (1 H, m),
2.10 (1 H, dd, J 12.7, 11.5), 2.17 (1 H, br. dd, J 13.5, 9.5), 2.27 (1 H,
d, J 12.0), 2.36 (1 H, d, J 12.0), 2.43 (1 H, dq, J 9.5, 7.0), 2.48 (1 H,
dt, J 9.5, 1.5), 2.52 (1 H, dd, J 12.7, 2.7), 2.62 (1 H, dd, J 8.5, 1.5),
2.68 (1 H, br. d, J 13.5), 3.47 (1 H, ddd, J 11.5, 8.5, 2.7), 4.27 (1 H,
d, J 2.0), 4.77 (1 H, m), 4.81 (1 H, br. s), 4.81-4.82 (1 H, m), 4.87-
4.89 (1 H, m), 4.89-4.90 (1 H, m), 4.94 (1 H, m), 5.29 (1 H, br. t, J
8.5), 5.60 (1 H, dd, J 16.2, 7.5), 6.20 (1 H, d, J 16.2); δC (125 MHz,
C6D6) 11.8, 16.1, 19.5, 36.3, 39.4, 45.0 (-2), 45.2, 58.2, 62.7, 73.5,
78.5, 99.2, 110.0, 112.3, 118.2, 129.1, 133.6, 142.2, 143.7, 146.5, 172.4.
(5S,8R)-8-[(2S,3R)-3-((E)-(5R,6S)-6,7-Dimethyl-2-methylene-5-tri-
isopropyl silanyloxy-octa-3,7-dienyl)-oxiranyl]-4-hydroxy-5-methyl-
6-methylene-oxocan -2-one (86). Lactone 77 (1:1 mixture of C-3
epimers, 128 mg, 0.240 mmol) and distannoxane 85 (14 mg, 0.011
mmol) were placed in a dry flask, and dry hexane (120 mL) was added.
The mixture was stirred at reflux for 1 h, cooled and concentrated in
vacuo. The residue was purified by silica gel flash chromatography
(petroleum ether-ethyl acetate, 17:3) to afford the lactone 86 (119 mg,
0.223 mmol, 93%) as a pale yellow oil and an inseparable 1:1 mixture
of C-3 epimers (Found: M+, 532.3567. C31H52O5Si requires M
Acknowledgment. We thank the National Institutes of Health
(GM-33049) and the National Science Foundation for their
generous support of our programs. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University
of California-San Francisco supported by the NIH Division
of Research Resources.
532.3584, 3.2 ppm, EIMS); [R]25 +26.0 (c 1.93, CHCl3); Rf 0.21
D
(petroleum ether-ethyl acetate, 7:3); νmax/cm-1 3448, 2943, 2886, 1732,
1644, 1462, 1373, 1251, 1162, 1127, 1102, 1059, 1014, 992, 987, 884;
EIMS m/z 532 (M+, 3), 463 [(M - C5H9]+, 100);
One C-3 Epimer: δH (500 MHz, CDCl3) 0.98 (3 H, d, J 7.0), 1.05
(21 H, s), 1.18 (3 H, d, J 7.0), 1.76 (3 H, s), 2.10 (1 H, dq, J 9.5, 7.0),
2.37-2.54 (4 H, m), 2.52 (1 H, dd, J 11.5, 7.0), 2.55 (1 H, dd, J 13.5,
3.0), 2.71 (1 H, dd, J 11.5, 5.0), 2.89 (1 H, dd, J 5.5, 2.5), 3.11 (1 H,
td, J 5.5, 2.0), 3.66 (1 H, m), 4.25 (1 H, ddd, J 11.0, 5.5, 2.0), 4.40 (1
H, br. t, J 6.0), 4.68 (1 H, br. s), 4.78 (1 H, br. s), 5.03 (1 H, br. s),
5.06 (1 H, br. s), 5.07 (1 H, br. s), 5.12 (1 H, br. s), 5.60 (1 H, dd, J
Supporting Information Available: Experimental procedures
and characterization data for compounds 6-11, 14-28, 32, 35-
42, 44-47, 49, 50, 52-55, 64-66, 70, 77-79, 82, 83, 86-88
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA055967N
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17937