Formal total synthesis of oximidine II via a Suzuki-type cross-coupling macrocyclization employing potassium organotrifluoroborates

Article abstract of DOI:10.1021/ja047190o

A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the macrocyclization.

Full text of DOI:10.1021/ja047190o

Published on Web 07/30/2004
Formal Total Synthesis of Oximidine II via a Suzuki-Type
Cross-Coupling Macrocyclization Employing Potassium
Organotrifluoroborates
Gary A. Molander* and Florian Dehmel
Contribution from the Roy and Diana Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
Received May 13, 2004; E-mail: gmolandr@sas.upenn.edu
Abstract: A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling
approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this
goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for
the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a
diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage
was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the
macrocyclization.
Introduction
During the past few years, many structurally related ben-
zolactone enamides have been isolated from various natural
sources. This family of compounds includes the oximidines, the
lobatamides, the apicularenes, the salicylihalamides, and similar
natural products (Figure 1).1 Besides their common structural
features, namely a 12- or 15-membered ring macrolactone and
an R,â-unsaturated enamide side chain, they share a unique
pharmacology. In biological testing, the salicylihalamides 5a/b
showed astonishing potency in the 60 cell line human tumor
assay from the National Cancer Institute (NCI), with a mean
panel GI50 of 7 nM. Even more exciting, these compounds
revealed a novel mode of action unprecedented in the NCI’s
extensive database. Pharmacological studies showed that sali-
cylihalamide A inhibits vacuolar-type (H+)-ATPases (V-
ATPases) with unparalleled selectivity. Consequently, V-
ATPases may provide a novel molecular target for chemothera-
peutic anticancer agents as well as for the amelioration of other
serious afflictions (e.g., glaucoma, Alzheimer’s disease and
osteoporosis).1i
The oximidines, first isolated in 1999 from Pseudomonas sp.
Q52002, show similarly promising biological activity.1a Oxi-
midines I and II (1b/a) exhibit selective cytotoxicity at ng/mL
levels for ras and src oncogene transformed cells. This
Figure 1. Oximidines and related natural products.
(1) (a) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J. Org.
Chem. 1999, 64, 153-155. (b) Hayakawa, Y.; Tomikawa, T.; Shin-Ya,
K.; Arao, N.; Nagai, K.; Suzuki, H.-I.; Furihata, K. J. Antibiot. 2003, 56,
905-908. (c) Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J.
H., II.; Boyd, M. R. J. Org. Chem. 1997, 62, 8968-8969. (d) McKee, T.
C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H., II.; Laakso, J.; Ireland,
C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org. Chem. 1998, 63,
7805-7810. (e) Suzumura, K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.;
Setiawan, B.; Rantiatmodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron
Lett. 1997, 38, 7573-76. (f) Dekker: K. A.; Aiello, R. J.; Hirai, H.; Inagaki,
T.; Sakakibara, T.; Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima,
N. J. Antibiot. 1998, 51, 14-20. (g) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913-919. (h) Kunze, B.; Jansen,
R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075-
1080. (i) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II.; Boyd, M. R.
J. Org. Chem. 1997, 62, 8188-8192.
biological inhibition was determined to affect the cell cycle at
the G1 phase. As is the case with the salicylihalamides,
V-ATPases appear to be the cellular target of these molecules.2
Very recently, oximidine III (1c) was extracted from a Pseudomo-
nas sp. QN05727 bacterial strain.1b
The tremendously exciting biology of the salicylihalamides
5a/b, combined with their novel structural features and scarcity,
has attracted the attention of several prominent synthetic organic
and medicinal chemists. Most of these efforts have focused on
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J. AM. CHEM. SOC. 2004, 126, 10313-10318
10313

A R T I C L E S
Molander and Dehmel
the ring closing metathesis reaction (RCM) as the key step to
form the macrocyclic ring.3 Besides the RCM approaches,
macrocyclizations have been accomplished using intramolecular
Suzuki4a or Stille couplings.4b For related members of this class,
many total syntheses and synthetic approaches have also been
reported.5
Porco and Wang recently published the first and thus far only
total synthesis of oximidine II (1a).6 Their elegant synthesis
also leads to the macrolactone by a RCM approach and
introduces the enamide side chain as the last stage employing
Porco’s efficient coupling method of vinyl halides and amides.7
Although other macrolactonization routes and cross-coupling
entries to the macrocyclic ring of the oximidines have been
briefly explored,8 difficulties in the construction of the highly
strained 12-membered macrolactone have been encountered.8a,b
The syntheses and synthetic approaches toward this entire class
of natural products have been reviewed recently.9
Herein, we report a formal total synthesis of oximidine II
that overcomes problems associated with other cross-coupling
approaches to this molecule. The successful campaign employed
an intramolecular Suzuki-coupling reaction of a highly func-
tionalized potassium organotrifluoroborate for the macrocy-
clization.
Retrosynthesis
Our initial concept for the synthesis of the macrolactone is
outlined in Figure 2. The key step envisioned was the macro-
cyclization via an intramolecular Suzuki-coupling reaction using
potassium organotrifluoroborates.10 Protecting group manipula-
tions on the macrolactone would readily give alcohol 6, which
Figure 2. Retrosynthetic analysis of oximidine II (1a).
is an intermediate in Porco’s oximidine II synthesis. Inherent
in this strategy was the notion that Pd-catalyzed cross-coupling
reactions have a distinct advantage over macrolactonizations
in approaches to constrained systems.8b Thus, the postulated
intermediate for the former reactions, a metallacycle, contains
two additional long Pd-C bonds that would translate into
reduced strain in the transformation leading to the polyolefinic
system. Ring contraction by reductive elimination of the inter-
mediate organometallic generates the desired macrolactone. In
contrast to Sonogashira-Castro-Stephens type approaches,8b
which create added strain owing to the introduction of the linear
alkyne into the macrolactone, the Suzuki reaction precursor will
already have in place all of the double bonds in the required
geometry, which also represents the lowest energy configuration
of the final product.6,8a The two stereogenic centers of the sub-
strate would be created by a diastereoselective, chelation-con-
trolled addition of organometallic nucleophiles derived from 13
to an R-chiral aldehyde, establishing the two stereogenic centers
of the natural product.
(2) (a) Boyd, M. R.; Farina, C.; Befiore, P.; Gagliardi, S.; Kim, J. W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
J. J. Pharmacol. Exp. Ther. 2001, 297, 114-120. (b) Beutler, J. A.; McKee,
T. C. Curr. Med. Chem. 2003, 10, 787-796.
(3) (a) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81-89.
(b) Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129-813. (c) Yang,
K. L.; Blackman, B.; Diederich, W.; Flaherty, P. T.; Mossman, C. J.; Roy,
S.; Ahn, Y. M.; Georg, G. I. J. Org. Chem. 2003, 68, 10030-10039. (d)
Yang, K. L.; Haack, T.; Blackman, B.; Diederich, W. E.; Srinivas Pusuluri,
S. R.; Georg, G. I. Org. Lett. 2003, 5, 4007-4009. (e) Smith, A. B., III.;
Zheng, J. Y. Tetrahedron 2002, 58, 6455-6471. (f) Wu, Y. S.; Liao, X.
B.; Wang, R. F.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2002,
124, 3245-3253. (g) Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G.
Chem. Eur. J. 2001, 7, 5286-5298. (h) Smith, A. B., III.; Zheng, J. Y.
Synlett 2001, 1019-1023. (i) Snider, B. B.; Song, F. B. Org. Lett. 2001,
3, 1817-1820. (j) Wu, Y. S.; Esser, L.; De Brabander, J. K. Angew. Chem.
Int. Ed. 2000, 39, 4308-4310. (k) Labrecque, D.; Charron, S.; Rej, R.;
Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648.
(4) (a) Bauer, M.; Maier, M. E. Org. Lett. 2002, 4, 2205-2208. (b) Holloway,
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2204.
(5) (a) Graetz, B. R.; Rychnovsky, S. D. Org. Lett. 2003, 5, 3357-3360. (b)
Su, Q. B.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425-2430. (c) Lewis,
A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol.
Chem. 2003, 1, 104. (d) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S.
A.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 5549-5552. (e) Nicolaou,
K. C.; Kim, D. W.; Baati, R. K.; O’Brate, A.; Giannakakou, P. Chem.
Eur. J. 2003, 9, 6177-6191. (f) Nicolaou, K. C.; Kim, D. W.; Baati, R.
Angew. Chem., Int. Ed. 2002, 41, 3701-3704. (g) Bhattacharjee, A.; Seguil,
O. R.; De Brabander, J. K. Tetrahedron Lett. 2001, 42, 1217-1220. (h)
Shen, R. C.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. J.
Am. Chem. Soc. 2003, 125, 7889-7901. (i) Shen, R. C.; Lin, C. T.; Porco,
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Synthetic Efforts
The diene-yne nucleophile 14 was readily available in four
steps employing a double Sonogashira coupling on cis-1,2-
dichloroethylene 15 (Scheme 1).11 The TMS-group in 16 was
converted to the bromide, and a regioselective reduction of the
brominated alkyne to the (Z,Z)-diene according to Brown12
provided 13 in good overall yield. Bromine-lithium exchange
(6) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040-6041.
(7) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333-1336.
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7209-7212. (d) Scheufler, F.; Maier, M. E. Synlett 2001, 1221-1224.
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Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313-4327.
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Harwig, C. W.; Fallis, A. G. Can. J. Chem. 1995, 73, 2253-2262.
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9
10314 J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004

Formal Total Synthesis of Oximidine II
A R T I C L E S
Scheme 1. Diastereoselective 1,2-Diol Formationa
Scheme 2. Diene-yne Formationa
a Conditions: (a) triisopropylsilylacetylene, CuI, Pd(PPh3)4, NEt3, Et2O,
rt, 93%; (b) trimethylsilylacetylene, CuI, Pd(PPh3)4, NEt3, Et2O, rt, 96%;
(c) NBS, AgNO3, acetone, rt, 99%; (d) c-Hex2BH, pentane/THF, 0 °C, then
AcOH, 45-60%; (e) K2CO3, MeOH/C6H6, 0 °C, 96%; (f) 12, (+)-NME,
Zn(OTf)2, NEt3, toluene, rt, 77%, dr >98:2. (+)-NME: N-Methylephedrine.
a Conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, rt, 86%; (b) H2 (1 bar),
Lindlar’s cat. (70 w/w%), quinoline, hexanes, rt, 98%; (c) DIBALH, CH2Cl2,
0 °C, 69%; (d) i. NaHMDS, THF, 0 °C, then 23, rt; ii. TBAF, THF, 0 °C,
58% (2 steps); (e) Tf2O, pyr, 0 °C, 85%; (f) NaH, BnBr, DMF, 0 °C, 96%.
yielded the nucleophile 14. However, addition of 14 to (2R,4S)-
2-phenyl-[1,3]dioxane-4-carbaldehyde (12)13 suffered from low
yields (<20%) and low diastereoselectivities (dr < 2:1) under
several reaction conditions.
One of the most efficient methods to form esters of salicylates
is the nucleophilic transesterification of the corresponding
acetonides.4b,5c-g,6,17 This transformation was incorporated into
the current approach to oximidine II.
The application of alkynyllithium or alkynylmagnesium com-
pounds derived from 18 did not improve the diastereoselectivity
of the carbonyl addition reaction to 12. However, using the
method developed by Carreira for the enantioselective addition
of terminal alkynes to aldehydes,14 the desired diastereoselective
addition was achieved in good yield and excellent diastereose-
lectivity to afford 19. An additional advantage of this reaction
over the reaction employing the sensitive bromodiene 13 is the
relative robustness of the alkyne precursor to standard laboratory
conditions.
The addition product 19 was protected, and selective hydro-
genation15 of the sterically less hindered alkyne in the ene-diyne
unit afforded the benzylidene acetal 11 (Scheme 2). Reductive
cleavage of the benzylidene acetal was facilitated by coordina-
tion of DIBALH to the MOM protecting group of the substrate
and provided selectively the secondary alcohol 9.16
Thus, 9 was deprotonated and the resulting anion was reacted
with benzyl protected 23 followed by desilylation to give 21.
Finally, the electrophilic moiety was introduced in the form of
a triflate.
With 24 in hand, the substructure was established for a
selective hydroboration of the terminal alkyne of the diene-yne
subunit. Although precedented in related systems,18 no efficient
hydroboration conditions could be found to obtain any (E,Z,Z)-
trienylboronic acid derivative that could be converted into the
potassium organotrifluoroborate of 7 (Scheme 3). The investi-
gated hydroboration reagents either lacked reactivity (cat-
echolborane under various conditions;18 pinacolborane and cata-
lytic amounts of Cp2Zr(H)Cl19), afforded extensive decomposi-
tion of the starting material (HBBr2 and HBCl220) or exhibited
difficulties during selective oxidation to the boronic acids
(disiamylborane,21 c-Hex2BH22 or i-PP2BH23).
(13) (a) Isobe, M.; Ichikawa, Y.; Bai, D.-l.; Goto, T. Tetrahedron Lett. 1985,
26, 5203-5206. (b) Pawlak, J.; Nakanishi, K.; Iwashita, T.; Borowski, E.
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Asymmetry 1991, 2, 191-194. (d) Guo, Z.; Padmakumar, R.; Hollingsworth,
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2003, 7, 1067-1069. (e) Flo¨gel, O.; Amombo, M. G. O.; Reissig, H.-U.;
Zahn, G.; Bru¨dgam, I.; Hartl, H. Chem. Eur. J. 2003, 9, 1405-1415.
(14) (a) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-
2606. (b) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3,
3017-3020. (c) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz, D. E.; Carreira,
E. M. Org. Lett. 2000, 2, 4233-4236. (d) Frantz, D. E.; Fa¨ssler, R.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 1806-1807. (e) Frantz, D. E.; Fa¨ssler,
R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373381. (f)
Maezaki, N.; Kojima, N.; Tominaga, H.; Yanai, M.; Tanaka, T. Org. Lett.
2003, 5, 1411-1414.
(17) See also: (a) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072-
3080. (b) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron
Lett. 2001, 42, 1217-1220.
(18) (a) de Lera, A. R.; Torrado, A.; Iglesias, B.; Lo´pez, S. Tetrahedron Lett.
1992, 33, 6205-6208. (b) Torrado, A.; Lo´pez, S.; Alvarez, R.; de Lera,
A. R. Synthesis 1995, 285-293. (c) Nicolaou, K. C.; Ramphal, J. Y.;
Palazon, J. M.; Spanevello, R. A. Angew. Chem., Int. Ed. Engl. 1989, 28,
587-588.
(19) (a) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127-3128. (b)
Batt, D. G.; Houghton, G. C.; Daneker, W. F.; Jadhav, P. K. J. Org. Chem.
2000, 65, 8100-8104.
(15) (a) Schmidt, H. M.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1967, 86,
1138-1142. (b) Corey, E. J.; Ritter, K.; Yus, M.; Najera, C. Tetrahedron
Lett. 1987, 28, 3547-3550. (c) Gueugnot, S.; Alami, M.; Linstrumelle,
G.; Mambu, L.; Petit, Y.; Larcheveque, M.; Tetrahedron 1996, 52, 6635-
6646. (d) Hansen, T. V.; Stenstroem, Y. Tetrahedron: Asymmetry 2001,
12, 1407-1409. (e) Marquez, M. D. de; Thaller, V. J. Chem. Res. Miniprint
1985, 4, 1268. (f) Nicolaou, K. C.; Ladduwahetty, T.; Elisseou, E. M. J.
Chem. Soc. Chem. Commun. 1985, 1580-1581.
(20) (a) Soundararajan, R.; Matteson, D. S. J. Org. Chem. 1990, 55, 2274-
2275. (b) Brown, H. C.; Basavaiah, D.; Bhat, N. G. Organometallics 1983,
2, 1309-1311.
(21) (a) Miyaura, N.; Suginome, H.; Suzuki, A. Tetrahedron Lett. 1984, 25,
761-764. (b) Miyaura, N.; Satoh, Y.; Hara, S.; Suzuki, A. Bull. Chem.
Soc. Jpn. 1986, 59, 2029-2031.
(22) Vaultier, M.; Truchet, F.; Carboni, B.; Hoffmann, R. W.; Denne, I.
Tetrahedron Lett. 1987, 28, 4169-4172.
(16) For DIBALH deprotection on similar systems, see: (a) Mikami, T.; Asano,
H.; Mitsunobu, O. Chem. Lett. 1987, 2033-3036. (b) Sulikowski, G. A.;
Lee, W.-M.; Jin, B.; Wu B. Org. Lett. 2000, 2, 1439-1442.
(23) i-PP2BH) Di(isopropylprenyl)borane; Kalinin, A. V.; Scherer, S.; Snieckus,
V. Angew. Chem., Int. Ed. 2003, 42, 3399-3404.
9
J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004 10315

A R T I C L E S
Molander and Dehmel
Scheme 3. Attempted Hydroboration of 24
Scheme 4. Formation of 29a
a Conditions: (a) 32, (+)-NME, Zn(OTf)2, NEt3, toluene, rt, 89%, dr
91:9; (b) MOMCl, i-Pr2NEt, CH2Cl2, rt, 86%; (c) K2CO3, MeOH, 0 °C;
(d) H2 (1 bar), Lindlar’s cat. (70 w/w%), quinoline, hexanes, rt, 81% (3
steps); (e) IBX, DMSO, rt, 97%; (f) CBr4, PPh3, NEt3, CH2Cl2, 0 °C, 84%;
(g) n-Bu3SnH, Pd(PPh3)4, C6H6, rt, 88%; (h) DIBALH, CH2Cl2, 0 °C, 75%.
(+)-NME: N-Methylephedrine.
Revised Retrosynthesis
Because of the difficulties encountered with the selective
hydroboration on the polyene-yne system, the proposed synthesis
of oximidine II was revised (Figure 3). Another strategic
disconnection for a Suzuki coupling approach lies between the
(E)- and (Z)-configured olefin moieties in the ring (C9/C10),
which would require the hydroboration of an arylated alkyne
in the presence of a (Z,Z)-bromodiene. This precursor would
again come from an esterification, this time between the
secondary alcohol 29 and acetonide 30. Although the salicylic
acid precursor 30 could be derived in one step from 10, the
bromodiene unit in 29 would originate from an olefination of
the enal 31, which eventually would be obtained from the
diastereoselective addition of propargyl acetate 32 to the chiral
aldehyde 12.14a
the Carreira protocol. The reaction took place with good yield
and high diastereoselectivity. After protection of the alcohol,
removal of the acetate, and partial reduction of the alkyne, allyl
alcohol 36 was obtained in good overall yield. The installation
of the (Z,Z)-bromodiene unit was achieved via a three-step
protocol previously employed in similar systems.24 The required
secondary alcohol function was finally obtained by regioselec-
tive reductive cleavage of the benzylidene acetal.
Having succeeded in synthesizing the diene 29, our attention
turned to the synthesis of the salicylate subunit. This requisite
partner was easily derived from the protected triflate 10 in a
Sonogashira type coupling with trimethylsilylacetylene (Scheme
5). After desilylation, the terminal alkyne was hydroborated
using Snieckus’ i-PP2BH.23 The resulting organoborane was
converted directly into the corresponding potassium trifluo-
roborate 41. Other boranes, such as catecholborane, were
ineffective as hydroborating agents. This serves to highlight the
utility of the Snieckus reagent as a precursor to trifluoroborates.
This borane exhibits the reactivity and selectivity characteristics
of most dialkylborane reagents, but has the added advantage of
being easily transformed to boronic acids and their derivatives.
With subunits 29 and 41 in hand, both a macrolactonization
strategy and the Suzuki cross-coupling approach to the macro-
lactone were accessible for comparison. An examination of the
macrolactonization route was carried out first. This involved
an initial intermolecular cross-coupling reaction between the
two components. This was achieved under the conditions
established for the reaction of vinyl halides and potassium
vinyltrifluoroborates,25 providing triene 42 in high yield. As
expected, however, the macrolactonization using the esterifi-
cation method (42 to 43) successfully employed in the inter-
molecular reaction (see Scheme 2) did not succeed. Presumably,
this is due to the steric strain of the 12-membered ring as alluded
to previously. Thus, it is likely that the constraints afforded by
Figure 3. Revised retrosynthesis of 6.
Formal Total Synthesis
(24) (a) Boger, D. L.; Ichikawa, S. Zhong, W. J. Am. Chem. Soc. 2001, 123,
4161-4167. (b) Uemura, I.; Miyagawa, H.; Ueno, T. Tetrahedron 2002,
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J. Org. Chem. 1996, 61, 5716-5717. (d) Uenishi, J.-i.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965-8975.
The successful reaction sequence began with a diastereose-
lective addition to the enantiopure aldehyde 12 (Scheme 4). In
this case, propargyl acetate 32 was used as the nucleophile in
(25) Molander, G. A.; Felix, L., unpublished results.
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10316 J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004

Formal Total Synthesis of Oximidine II
A R T I C L E S
Scheme 5. Formation of 41 and Coupling Reaction
Scheme 6. Formation of 27a
a Conditions: (a) triisopropylsilylacetylene, CuI, Pd(PPh3)4, i-Pr2NEt,
THF, rt, 97%; (b) 29, NaHMDS, THF, 0 °C; (c) TBAF, THF, 0 °C, 98%
(2 steps); (d) TBDMSOTf, imidazole, DMAP, DMF, rt, 79%.
Scheme 7. Macrocyclization to 6a
a Conditions: (a) i. 2,5-dimethylhexa-2,4-diene, BH3‚DMS, THF, 0 °C,
then 28, rt, then H2O, then aq. CH2O, ii. KHF2, acetone, MeCN, H2O, rt,
∼99%; (b) Pd(PPh3)4, Cs2CO3, THF/H2O (10:1), 1 mM, reflux, 42% (2
steps); (c) TBDMSCl, imidazole, DMF, rt, 84%, (d) DDQ, CH2Cl2/pH)7-
buffer (10:1), rt to reflux, 86%.
trifluoroborate, the secondary alcohol 29 was reacted with the
protected alkyne 30 under the established conditions (THF
solvent), providing 47 in high yields (Scheme 6). The more
robust TIPS protection of the acetylene in 30 instead of the
TMS-protected 39 proved to be beneficial under the nucleophilic
reaction conditions. The TIPS group was removed and the
phenol 47 was protected to afford the precursor for the
hydroboration.
a Conditions: (a) trimethylsilylacetylene, CuI, Pd(PPh3)4, i-Pr2NEt, THF,
rt, 98%; (b) TBAF, THF, 0 °C, 99%; (c) 2,5-dimethylhexa-2,4-diene,
BH3‚DMS, THF, 0 °C, then 31, rt, then H2O, then aq. CH2O, ii. KHF2,
acetone, MeCN, H2O, rt, 66%; (d) 29, 41, Pd(PPh3)4, Cs2CO3, THF/H2O
(10:1), reflux, 93%; (e) 29, 41, NaHMDS, DMF, 0 °C, then Pd(PPh3)4,
Cs2CO3, THF/H2O (10:1), reflux, 7%.
the conjugated triene prevented attack of the alkoxide on the
lactone from the proper trajectory. Several attempts to activate
the system toward macrolactonization were also unsuccessful.
Again, application of the Snieckus reagent, i-PP2BH, allowed
selective hydroboration of the terminal alkyne, and the potassium
trifluoroborate 27 was isolated in virtually quantitative yield as
a slightly impure wax that was stable for weeks at ambient
temperature in the air (Scheme 7). The ability to isolate and
store a stable boron reagent allowed several reaction conditions
to be tested for comparison in the crucial cyclization.
Having exhausted nearly all other possibilities, our efforts
finally focused on the Suzuki strategy utilizing trifluoroborate
27. Surprisingly, intermolecular transesterification of 41 with
the secondary alcohol 29 was unsuccessful under conditions
previously established using THF as solvent (Scheme 5). The
low solubility of the reacting partners was deemed to be
problematic. Upon switching the solvent to DMF, a transes-
terification reaction of the acetonide was observed. The resulting
product was directly subjected to the cross-coupling conditions.
Interestingly, the only pure material isolated from the complex
mixture proved to be the 11-membered macrolactone 44 bearing
an exo-methylene moiety. The formation of this product can
be attributed to the base lability of 29 in DMF, wherein the
vinyl bromide is prone to dehydrohalogenation. The resulting
enyne 45 appeared to have undergone an intramolecular
carbometalation to form 46, which, after protonation, led to the
contracted macrolactone 44.
We were pleased to find that the cross coupling under
previously developed reaction conditions gave the desired
cyclized product 49 in 42% overall yield from alkyne 28
(Scheme 7). It is noteworthy that the reaction outcome depends
on concentration, the palladium-catalyst precursor, and solvent
(Table 1).
To complete the formal total synthesis, phenol 49 was then
reprotected and the benzyl protecting group was removed with
DDQ26 to give 6, which had been carried on by Porco to
oximidine II. The synthesized product 6 showed identical NMR
spectra to that quoted in the literature and a nearly identical
optical rotation ([R]20 -153.2; literature -151.86).
589
The final, successful campaign employed an intermolecular
transesterification of lactone 30, with formation of the trifluo-
roborate left to the penultimate step. To access the requisite
(26) For DDQ-deprotection of benzyl groups on olefinic substrates, see: (a)
Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009-3011. (b)
Meng, D.; Tan, Q.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1999,
38, 3197-3201.
9
J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004 10317

A R T I C L E S
Molander and Dehmel
Table 1. Macrocyclization Conditionsa
to the molecule and other cross-coupling strategies as well. The
stereocontrolled formation of the subunit possessing the two
stereocenters was accomplished using the Carreira protocol in
a diastereoselective, reagent controlled addition to a chiral
aldehyde. Advantage was taken of the Snieckus hydroborating
reagent to gain access to the key trifluoroborate needed for the
macrocyclization. Finally, potassium organotrifluoroborates were
applied for the first time to natural product synthesis, underscor-
ing their promising characteristics in complex molecule syn-
thesis.
entry
reaction conditionsa
yieldb (%)
1
Pd(PPh3)4 (10 mol %), Cs2CO3 (5 equiv),
THF/H2O (10:1), 5mM
16
2
3
4
5
Pd(PPh3)4 (10 mol %), Cs2CO3 (5 equiv),
THF/H2O (10:1), 2mM
Pd(PPh3)4 (10 mol %), Cs2CO3 (5 equiv),
THF/H2O (10:1), 1mM
Pd(PPh3)4 (10 mol %), Cs2CO3 (5 equiv),
DMF/H2O (10:1), 2mM
Pd(dppf)Cl2‚CH2Cl2 (10 mol %), Cs2CO3 (5 equiv),
THF/H2O (10:1), 2mM
29c
42c
8c
18c
Acknowledgment. We thank Professor John Porco and Xiang
Wang for graciously providing us with copies of the H and
a The reaction mixture was heated at reflux for 20 h. b Isolated yield of
1
49. c Yield over 2 steps from 28.
13C NMR spectra of 6. We gratefully acknowledge the National
Institutes of Health (GM 35249), Johnson & Johnson, and
Amgen for generous support of this work. F.D. thanks the
Deutsche Forschungsgemeinschaft for a postdoctoral stipend.
We also thank Dr. R. Kohli for performing HRMS.
Conclusion
We have completed a formal total synthesis of oximidine II
employing a novel approach to construct the highly strained,
polyunsaturated 12-membered macrolactone. To achieve this
goal, benefit was derived from the stability of potassium
alkenyltrifluoroborates to establish conditions for the macro-
cyclization via a Suzuki-type cross-coupling reaction. This has
a demonstrated advantage over a macrolactonization approach
Supporting Information Available: Detailed experimental
procedures including characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org
JA047190O
9
10318 J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004