Total syntheses of (+)-tedanolide and (+)-13-deoxytedanolide

Article abstract of DOI:10.1021/ja8063205

Convergent total syntheses of the potent cytotoxins (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) are described. The carbon framework of these compounds was assembled via a stereoselective aldol reaction that unifies the C(1)-C(12) ketone fragment 5 with a C(13)-C(23) aldehyde fragment 6 (for 13-deoxytedanolide) or 52 (for tedanolide). Multiple obstacles were encountered en route to (+)-1 and (+)-2 that required very careful selection and orchestration of the stereochemistry and functionality of key intermediates. Chief among these issues was the remarkable stability and lack of reactivity of hemiketals 33b and 34 that prevented the tedanolide synthesis from being completed from aldol 4. Key to the successful completion of the tedanolide synthesis was the observation that the 13-deoxy hemiketal 36 could be oxidized to C(11, 15)-diketone 38 en route to 13-deoxytedanolide. This led to the decision to pursue the tedanolide synthesis via C(15)-(S)-epimers, since this stereochemical change would destabilize the hemiketal that plagued the attempted synthesis of tedanolide via C(15)-(R) intermediates. However, use of C(15)-(S)-configured intermediates required that the side-chain epoxide be introduced very late in the synthesis, owing to the ease with which the C(15)-(S)-OH cyclized onto the epoxide of intermediate 50.

Full text of DOI:10.1021/ja8063205

Published on Web 11/04/2008
Total Syntheses of (+)-Tedanolide and
(+)-13-Deoxytedanolide
Joshua R. Dunetz,† Lisa D. Julian,‡ Jason S. Newcom,‡ and William R. Roush*,†
Departments of Chemistry, Scripps Florida, Jupiter, Florida 33458, and
UniVersity of Michigan, Ann Arbor, Michigan 41809
Received August 9, 2008; E-mail: roush@scripps.edu
Abstract: Convergent total syntheses of the potent cytotoxins (+)-tedanolide (1) and (+)-13-deoxytedanolide
(2) are described. The carbon framework of these compounds was assembled via a stereoselective aldol
reaction that unifies the C(1)-C(12) ketone fragment 5 with a C(13)-C(23) aldehyde fragment 6 (for 13-
deoxytedanolide) or 52 (for tedanolide). Multiple obstacles were encountered en route to (+)-1 and (+)-2
that required very careful selection and orchestration of the stereochemistry and functionality of key
intermediates. Chief among these issues was the remarkable stability and lack of reactivity of hemiketals
33b and 34 that prevented the tedanolide synthesis from being completed from aldol 4. Key to the successful
completion of the tedanolide synthesis was the observation that the 13-deoxy hemiketal 36 could be oxidized
to C(11,15)-diketone 38 en route to 13-deoxytedanolide. This led to the decision to pursue the tedanolide
synthesis via C(15)-(S)-epimers, since this stereochemical change would destabilize the hemiketal that
plagued the attempted synthesis of tedanolide via C(15)-(R) intermediates. However, use of C(15)-(S)-
configured intermediates required that the side-chain epoxide be introduced very late in the synthesis,
owing to the ease with which the C(15)-(S)-OH cyclized onto the epoxide of intermediate 50.
Introduction
The tedanolides are a group of 18-membered macrolactones
that display remarkable biological activity. (+)-Tedanolide (1,
Figure 1), reported by Schmitz and co-workers in 1984 after
isolation from the Caribbean fire sponge Tedania ignis, is highly
cytotoxic against human nasopharynx carcinoma (ED50 ) 250
pg/mL) and lymphocytic leukemia (ED50 ) 16 pg/mL) cell lines
and causes cell accumulation in the S phase at concentrations
as low as 10 ng/mL.1 In addition, tedanolide has been shown
to increase the lifespan of mice implanted with lymphocytic
leukemia by 23% at 1.5 µg/kg of body weight.2 The closely
related macrolide (+)-13-deoxytedanolide (2, Figure 1) was
isolated by Fusetani and co-workers in 1991 from the Japanese
sponge Mycale adhaerens and demonstrates potent cytotoxicity
against P388 murine leukemia cells (IC50 ) 94 pg/mL).3 In an
elegant study designed to probe the mechanism of 13-deoxy-
tedanolide activity, Fusetani and co-workers demonstrated that
the macrolide binds to the eukaryotic 60S ribosomal subunit4a
and identified the C(11)-C(23) region of the natural product
as the pharmacophore.4b,5 A third member of this macrolide
family, (+)-tedanolide C (3, Figure 1), was reported by Ireland
Figure 1. Tedanolide natural products.
and co-workers in 2006 from the extract of Papua New Guinea
marine sponge Ircinia sp.6 The reported structure of tedanolide
C has different stereochemistry and a different methylation and
oxygenation pattern than the two older congeners. Nevertheless,
tedanolide C exhibits strong activity (IC50 ) 57 ng/mL) against
the HTC-116 colorectal cancer cell line.
The impressive biological profiles and the synthetic challenges
presented by the tedanolides have encouraged researchers in
our laboratory7,8 and others to pursue their synthesis.9-17 The
complex architecture of tedanolide (1) is underscored by a
heavily oxygenated and methylated carbon skeleton containing
13 stereocenters and two polysubstituted olefinssone of which
† Scripps Florida.
‡ University of Michigan.
(5) Structure-activity relationship studies of the structurally related
myriaporones 3 and 4: Hines, J.; Roy, M.; Cheng, H.; Agapakis, C. M.;
Taylor, R.; Crews, C. M. Mol. BioSyst. 2006, 2, 371.
(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.;
van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) Schmitz, F. J.; Gunasekera, S. P.; Hossain, M. B.; van der Helm, D.;
Yalamanchili, G. U.S. Patent Application 87-7347, 1988.
(3) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1991, 56,
4971.
(6) Chevallier, C.; Bugni, T. S.; Feng, X.; Harper, M. K.; Orendt, A. M.;
Ireland, C. M. J. Org. Chem. 2006, 71, 2510.
(7) Total synthesis of (+)-13-deoxytedanolide: Julian, L. D.; Newcom,
J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 6186.
(8) Previous efforts toward tedanolide: (a) Dunetz, J. R.; Roush, W. R.
Org. Lett. 2008, 10, 2059. (b) Roush, W. R.; Newcom, J. S. Org.
Lett. 2002, 4, 4739. (c) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1,
95.
(4) (a) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.; Yokoyama,
S.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 449. (b) Nishimura,
S.; Matsunaga, S.; Yoshida, S.; Nakao, Y.; Hirota, H.; Fusetani, N.
Bioorg. Med. Chem. 2005, 13, 455.
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 16407–16416 16407

A R T I C L E S
Dunetz et al.
Scheme 1. Retrosynthetic Analysis of the Tedanolides
is incorporated into a ꢀ,γ-unsaturated ketone with the potential
to migrate into conjugation with the carbonyl. In addition,
tedanolide possesses a sensitive R-hydroxy trisubstituted epoxide
and four ꢀ-hydroxy ketone units that are potentially susceptible
to retro aldol decomposition. Total syntheses of tedanolide were
recently completed by Kalesse9a,b (2006) and Smith10a (2007);
a few years earlier, Smith10c,d (2003) and our group7 (2005)
reported total syntheses of 13-deoxytedanolide.
Results and Discussions
In planning our synthetic approach to tedanolide and 13-
deoxytedanolide, we initially envisioned that 4 would serve as
a common intermediate that would permit entry into both
macrolides (Scheme 1). We planned to assemble 4 from the
convergent aldol coupling of methyl ketone 5 and aldehyde 6,
which would establish the C(13)-alcohol stereochemistry of
tedanolide via Felkin addition of 5 to 6. We chose the (R)-
configuration for the C(15)-position of 6 after previous studies
from our group demonstrated that the lithium enolates of methyl
ketone models of 5 add to 2,3-anti aldehydes (e.g., 6) with
greater Felkin selectivity than additions to 2,3-syn aldehydes
(e.g., 39, vide infra).18 We envisaged that aldol 4 could be
converted to tedanolide via a sequence involving C(15)-
oxidation to the requisite carbonyl and macrolactonization. After
considerable experimentation,8b we decided to mask the C(1)-
(9) (a) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. Chem. Eur. J.
2008, 14, 2232. (b) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M.
J. Am. Chem. Soc. 2006, 128, 14038. (c) Hassfeld, J.; Eggert, U.;
Kalesse, M. Synthesis 2005, 1183. (d) Ehrlich, G.; Kalesse, M. Synlett
2005, 655. (e) Hassfeld, J.; Kalesse, M. Synlett 2002, 2007.
(10) (a) Smith, A. B., III.; Lee, D. J. Am. Chem. Soc. 2007, 129, 10957.
(b) Cho, C.-G.; Kim, W.-S.; Smith, A. B., III. Org. Lett. 2005, 7,
3569. (c) Smith, A. B., III.; Adams, C. M.; Lodise Barbosa, S. A.;
Degnan, A. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (d)
Smith, A. B., III.; Adams, C. M.; Lodise Barbosa, S. A.; Degnan,
A. P. J. Am. Chem. Soc. 2003, 125, 350. (e) Smith, A. B., III.; Lodise,
S. A. Org. Lett. 1999, 1, 1249.
acid in 5 as an allyl ester and the C(16)-hydroxymethyl group
in 6 as an allyl carbonate (Alloc), motivated by our desire to
remove both protection groups simultaneously prior to macro-
lactonization. We envisioned that aldol adduct 4 could also be
converted to 13-deoxytedanolide by using a similar sequence
that also included deoxygenation of the C(13)-alcohol.
(11) (a) Jung, M. E.; Zhang, T.-h. Org. Lett. 2008, 10, 137. (b) Jung, M. E.;
Yoo, D. Tetrahedron Lett. 2008, 49, 816. (c) Jung, M. E.; Yoo, D.
Org. Lett. 2007, 9, 3543. (d) Jung, M. E.; Lee, C. P. Org. Lett. 2001,
3, 333. (e) Jung, M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41, 9719.
(f) Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. (g) Jung, M. E.;
Marquez, R. Tetrahedron Lett. 1999, 40, 3129.
(12) (a) Wong, C.-M.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 4485. (b)
Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 6001. (c) Loh,
T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 3223.
We developed a convergent route that assembles the
C(1)-C(12) ketone 5 via the aldol reaction of ethyl ketone 7
and aldehyde 8. The synthesis of ethyl ketone 7 began with
asymmetric hydrogenation19 of ꢀ-keto ester 9, followed by
alkylation of the ꢀ-hydroxy ester under Fra´ter conditions20 to
access the 2,3-anti ester 10 (Scheme 2). The hydroxyl group of
10 was protected as a DMPM ether in 11 through a sequence
involving ester reduction with LiAlH4, conversion of the 1,3-
diol to the 3,4-dimethoxybenzylidene acetal, and regioselective
acetal reductive opening with DIBAL. The primary alcohol of
11 was oxidized under Swern conditions,21 and the resulting
aldehyde was treated with 3 equiv of γ-siloxy allylstannane 1222a
and BF3-OEt2 in CH2Cl2 at -78 °C22b to afford the 3,4-syn-
4,5-syn-homoallylic alcohol with >95:5 diastereomeric ratio
(dr). Methylation of the alcohol (MeOTf, 2,6-di-tert-butyl-4-
(13) (a) Matsui, K.; Zheng, B.-Z.; Kusaka, S.-i.; Kuroda, M.; Yoshimoto,
K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001, 3615. (b)
Zheng, B.-Z.; Yamauchi, M.; Dei, H.; Kusaka, S.-i.; Matsui, K.;
Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441. (c) Matsushima, T.;
Nakajima, N.; Zheng, B.-Z.; Yonemitsu, O. Chem. Pharm. Bull. 2000,
48, 855. (d) Zheng, B.-Z.; Maeda, H.; Mori, M.; Kusaka, S.-i.;
Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J.-i. Chem.
Pharm. Bull. 1999, 47, 1288. (e) Matsushima, T.; Mori, M.; Zheng,
B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.-i.; Yonemitsu, O. Chem.
Pharm. Bull. 1999, 47, 308. (f) Matsushima, T.; Zheng, B.-Z.; Maeda,
H.; Nakajima, N.; Uenishi, J.-i.; Yonemitsu, O. Synlett 1999, 780. (g)
Matsushima, T.; Mori, M.; Nakajima, N.; Maeda, H.; Uenishi, J.-i.;
Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (h) Matsushima,
T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 385.
(14) Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S. Tetrahedron
Lett. 1998, 39, 1873.
(15) Iwata, Y.; Tanino, K.; Miyashita, M. Org. Lett. 2005, 7, 2341.
(16) (a) Taylor, R. E.; Hearn, B. R.; Ciavarri, J. P. Org. Lett. 2002, 4,
2953. (b) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett.
1998, 39, 9361.
(19) (a) Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227.
For a review: (b) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed.
2001, 40, 40.
(17) (a) Nyavanandi, V. K.; Nadipalli, P.; Nanduri, S.; Naidu, A.; Iqbal, J.
Tetrahedron Lett. 2007, 48, 6905. (b) Nyavanandi, V. K.; Nanduri,
S.; Dev, R. V.; Naidu, A.; Iqbal, J. Tetrahedron Lett. 2006, 47, 6667.
(18) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett.
1995, 36, 3443.
(20) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269.
(21) For a review: Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(22) (a) Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1987,
28, 139. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.
J. Am. Chem. Soc. 1996, 118, 4322.
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Total Syntheses of (+)-Tedanolide and (+)-13-Deoxytedanolide
Scheme 2. Preparation of Allyl Ester 15
A R T I C L E S
Scheme 3. Synthesis of Unsaturated Aldehyde 8
available anti-ꢀ-hydroxy-R-methylbutyrate 1728 as shown in
Scheme 3. Ester 17 was converted to aldehyde 18 via ester
reduction with LiAlH4, dimethoxybenzylidene acetal formation,
regioselective acetal reductive opening, and Swern oxidation
of the resulting primary alcohol. Wittig olefination of 18 with
the stabilized ylide Ph3PdC(Me)CO2Et provided the R,ꢀ-
unsaturated ester 19 with excellent selectivity (>95:5 E/Z).
Reduction of 19 to the allylic alcohol, followed by Parikh–
Doering oxidation21 of the primary alcohol, furnished aldehyde
8 in 70% yield over three steps.
methylpyridine)23 and oxidative cleavage of the olefin provided
aldehyde 14, which in turn was converted to allyl ester 15 via
chlorite oxidation to the carboxylic acid24 and esterification with
allyl alcohol under Mitsunobu conditions.25
The stereoselective aldol coupling of ethyl ketone 7 and
aldehyde 8 was effected by using TiCl4 and i-Pr2NEt and
provided 20 in 73% yield with 10:1 diastereoselectivity (Scheme
4).29 The selectivity of this transformation stems from a
transition state, TS, in which the C-O bond of the titanium
enolate eclipses the R′-C-H bond, allowing the aldehyde to
approach from the less-hindered face of the enolate.29 Extensive
optimization was required to minimize the formation of 21 via
intramolecular cyclization of the titanium enolate onto the allyl
ester. This competitive pathway was suppressed by treating
ketone 7 with TiCl4 and i-Pr2NEt for a maximum of 8 min at
-78 °C longer exposure times led to substantially lower yields
(<30%) of 20 and correspondingly increased amounts of 21.
The synthesis of C(1)-C(12) ketone 5 was completed in three
steps with the silylation of the C(7)-alcohol of 20, DDQ cleavage
of the dimethoxybenzyl ether,26 and TPAP oxidation30 of the
liberated secondary alcohol.
The conversion of allyl ester 15 to the ethyl ketone 7 was
complicated by the competitive formation of lactone 16 when
15 was treated with dichlorodicyanoquinone (DDQ)26 followed
by oxidation of the resulting secondary alcohol via the
Parikh-Doering method (eq 1).21 Lactone 16 is produced during
isolation of the C(5)-alcohol after DDQ-mediated benzyl ether
cleavage. This side reaction became more prominent when the
debenzylation-oxidation sequence was performed on a gram
scale. The alcohol intermediate proved very sensitive to acid,27
and great care was taken to minimize the formation of lactone
16 by removing the mildly acidic dihydroquinone (DDQ
byproduct) with aqueous sodium bicarbonate extractions.
The synthesis of C(13)-C(23) aldehyde 6 is summarized in
Scheme 5. Wittig olefination of the known aldehyde 2231 with
the stabilized ylide Ph3PdC(Me)CO2Et furnished the R,ꢀ-
unsaturated ester in excellent selectivity (97:3 E/Z), and DIBAL
reduction provided the allylic alcohol. Subsequent Sharpless
epoxidation32 of the allylic alcohol (>18:1 dr) and Parikh-
Dosering oxidation of the hydroxyl group afforded epoxyalde-
hyde 23. Evans aldol reaction33a of 23 with the chiral crotonate
Aldehyde 8 (to be coupled with ethyl ketone 7 en route to
C(1)-C(12) ketone 5) was synthesized from the readily
(28) Available from methyl acetoacetate (see ref 20) via a sequence of
asymmetric hydrogenation and alkylation that parallels the conversion
of 9 to 10 (Scheme 2).
(23) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171.
(24) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
For a modification using 2-methyl-2-butene as chlorine scavenger: (b)
Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(25) For a review: Mitsunobu, O. Synthesis 1981, 1.
(26) Oikawa, Y.; Tanaka, T.; Horita, K.; Yoshioka, T.; Yonemitsu, O.
Tetrahedron Lett. 1984, 25, 5393.
(29) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(30) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625. For a review: (b) Ley,
S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(27) A sample of secondary alcohol in CDCl3 (treated with K2CO3)
completely converted to lactone 16 within 20 min, as observed by 1H
NMR analysis.
(31) Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D. C. J.
Org. Chem. 2003, 68, 6646.
(32) For a review: Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
9
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A R T I C L E S
Dunetz et al.
Scheme 4. Completion of the Synthesis of C(1)-C(12) Ketone 5
Scheme 5. Synthesis of C(13)-C(23) Aldehyde 6
imide 24,33b silylation of the newly formed alcohol, and
reduction of the acyl oxazolidinone with LiBH4 in aqueous
tetrahydrofuran (THF)34 provided homoallylic alcohol 25a. The
primary alcohol of 25a was temporarily protected as a 2-bro-
moethyl carbonate (BEC); unfortunately, the Alloc group we
desired at this position in 6 could not be directly installed due
to its incompatibility with subsequent olefin oxidative cleavage
steps. Standard oxidative cleavage of the vinyl group of BEC-
protected 25b furnished an aldehyde that was converted to 27
via asymmetric crotylboration with (S,S)-26.35
The conversion of 27 to the targeted aldehyde 6 required the
installation of the C(21)-C(22) (Z)-olefin and conversion of
the terminal C(13)-alkene to the aldehyde. Our initial efforts to
chemoselectively functionalize the C(13)-alkene in the presence
of the C(21)-C(22) olefin were unsuccessful; as a result, it was
necessary to functionalize the terminal alkene before introducing
the C(21)-C(22) olefin. This was accomplished by silylation
of the secondary alcohol of 27, dihydroxylation of the terminal
alkene, and protection of the resulting diol as two R-methoxy-
acetate esters in 28. The C(21)-C(22) (Z)-olefin was installed
upon DDQ oxidative cleavage of the PMB ether of 28,
Dess-Martin oxidization36 of the primary alcohol, and Wittig
olefination of the resulting aldehyde. Treatment of 29 with allyl
alcohol and MeMgBr, which generates the magnesium alkoxide
in situ, converted the BEC to the Alloc and also cleaved the
two R-methoxyacetate esters. Treatment of the liberated diol
with Pb(OAc)4 then furnished the targeted C(13)-C(23) alde-
hyde 6.
diastereomer37 in 59% yield, along with recovered ketone 5
(27%) and aldehyde 6 (11%). Surprisingly, our efforts to protect
the newly formed C(13)-alcohol as a trimethylsilyl (TMS) or
triethylsilyl (TES) ether or as an acetate ester (Ac or AcOMe)
were unsuccessful, and we carried the unprotected aldol 4
forward. Cleavage of the allyl ester and allyl carbonate units
by treatment with Pd(PPh3)4 and n-Bu3SnH38 liberated the seco-
acid for macrolactonization;39 however, efforts to obtain mac-
rolactone 30were complicated by the formation of 14-membered
macrolactone 31 via competitive cyclization onto the unprotected
C(13)-alcohol. We did not observe equilibration of 30 and 31 upon
treatment of these macrolactones with titanium isopropoxide.
In an attempt to circumvent the competitive formation of 31,
we tried to alter the conformation of the seco-acid by installing
the C(15)-ketone prior to macrolactonization. Selective cleavage
of the C(15)-TES ether of 4 with aqueous AcOH in THF led to
secondary alcohol 32a that cyclized onto the C(11)-carbonyl
to form hemiketal 33a (Scheme 7). Silylation of the C(13)-
alcohol of 33a with TESCl provided the hemiketal 33b, which
proved to be remarkably stable and unreactive toward oxidants.
Extensive efforts to intercept the ring-opened isomer 32b with
oxidants (Dess-Martin periodinane,36 SO3-pyridine in di-
methylsulfoxide (DMSO),21 H2CrO6 (Jones oxidation),40 PDC,41
Completion of the synthesis of the tedanolide backbone was
accomplished by converting methyl ketone 5 to its lithium
enolate with LHMDS followed by the addition of aldehyde 6
(Scheme 6). This aldol reaction provided adduct 4 as a single
(37) The stereochemistry was assigned by using NMR methods: Roush,
W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwehnze, M. S.; Gustin,
D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W. J., III. J.
Org. Chem. 2002, 67, 4284.
(33) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L.
Tetrahedron Lett. 1986, 27, 4957.
(34) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
(35) Roush, W. R.; Palkowitz, A. D.; o, K. J. Am. Chem. Soc. 1990, 112,
6348.
(38) Dangles, O.; Guibe´, F.; Balavoine, G.; Lavielle, S.; Marquet, A. J.
Org. Chem. 1987, 52, 4984.
(39) For a macrolactonization review: Parenty, A.; Moreau, X.; Campagne,
J.-M. Chem. ReV. 2006, 106, 911.
(36) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(40) For a review: Luzzio, F. A. Org. React. 1998, 53, 1.
9
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Total Syntheses of (+)-Tedanolide and (+)-13-Deoxytedanolide
Scheme 6. Aldol Coupling and Macrolactonization
A R T I C L E S
Scheme 7. Hemiketal Formation of C(11,15)-Hydroxy Ketone
Scheme 8. Hemiketal Stability in the Macrolactone
TPAP/NMO30) en route to the C(15)-ketone failed. We postu-
lated that converting these intermediates to the macrolactone
34 might shift the hemiketal/hydroxy ketone equilibrium to the
hydroxy ketone isomer 35 and permit C(15)-oxidation (Scheme
8). Therefore, conversion of 33b to the seco-acid and then
macrocyclization as described for 4 provided macrocyclic
hemiketal 34. However, the hydroxy ketone tautomer 35 could
not be intercepted with oxidants to afford the targeted C(11,15)-
dione, and under various oxidation conditions the hemiketal 34
was recovered intact. As a result, we were unable to elaborate
34/35 to tedanolide, even though these intermediates are only
two synthetic steps from the natural product (i.e., C(15)-
oxidation and global desilylation).
Although it was not possible to convert hemiketal 33b or 34
to tedanolide, we were able to use 33a for the synthesis of 13-
deoxytedanolide (Scheme 9). By analogy to the principles of
the Thorpe-Ingold effect,42,43 which stipulates that increased
numbers of substituents (typically in a geminal arrangement)
between two reactive termini lead to an increased rate of ring
formation, we speculated that removal of the C(13)-alcohol
would decrease the stability of the hemiketal relative to the
hydroxy ketone tautomer and enable oxidation of C(15)-OH to
the C(11,15)-dione. Excision of C(13)-OH of 33a was ac-
complished via conversion of the alcohol to the pentafluoro-
phenylthiocarbonate44 and subsequent treatment with Et3B and
n-Bu3SnH.45 Although the resulting hemiketal 36 did not appear
to be in equilibrium with hydroxy ketone isomer 37 according
1
to H NMR analysis, we were gratified that treatment of 36
with Dess-Martin periodinane furnished the triketone 38 in 71%
yield. Ketone 38 was converted to 13-deoxytedanolide (2) in
three steps via seco-acid formation and Yonemitsu-modified
Yamaguchi lactonization,39 followed by removal of the three
TBS ethers with Et3N-buffered Et3N-3HF (thereby generating
Et3N-2HF in situ).46 Synthetic 13-deoxytedanolide was identi-
cal in all respects (1H NMR, 13C NMR, IR, optical rotation,
HRMS) to an authentic sample.
Having completed the synthesis of the 13-deoxy congener,
we continued our efforts to synthesize tedanolide, which had
been thwarted by the stability of hemiketal intermediates 33b
and 34. We hypothesized that inversion of the C(15)-(R)-alcohol
stereochemistry in our first-generation intermediates to the
C(15)-(S)-configuration would destabilize the corresponding
(41) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(42) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107,
1080.
(43) Implicit to this assumption is the recognition that the equilibrium
constant for cyclization of the hydroxy ketone to the hemiketal is
determined by the ratio of the rates of formation and breakdown of
the hemiketal intermediate. Thus, while the Thorpe-Ingold effect is
kinetic in nature, it may also impact the equilibrium constant of
reversible processes.
(44) Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett. 1989, 30, 2619.
(45) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 6125.
(46) (a) Giudicelli, M. B.; Picq, D.; Veyron, B. Tetrahedron Lett. 1990,
31, 6527. (b) McClinton, M. A. Aldrichimica Acta 1995, 28, 31.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16411

A R T I C L E S
Dunetz et al.
Scheme 9. Synthesis of (+)-13-Deoxytedanolide (2)
Scheme 10. Proposed Effect of C(15)-Configuration on Hemiketal
Stability
Scheme 11. Unsuccessful Efforts toward Aldehyde 39
hemiketal B via increased 1,3-diaxial interactions and permit
the requisite C(15)-oxidation (Scheme 10).47,48 Thus, we
targeted aldehyde 39 containing the (S)-configuration at the
C(15)-position.
and subsequent reduction of the acyl oxazolidinone provided
1,3-diol 47. The primary alcohol of 47 was temporarily protected
as a methoxyacetate ester before silylation of the secondary
alcohol. Subsequent cleavage of the methoxyacetate ester fol-
lowed by oxidation of the resulting alcohol completed the
synthesis of aldehyde 49 with the desired (S)-configuration at
the C(15)-position.
The aldol reaction of the lithium enolate generated from
C(1)-C(12) ketone 5 and C(13)-C(23) aldehyde 49 led to the
Felkin adduct 50 as the major product37 with 78:22 diastereo-
selectivity (Scheme 13). The diminished diastereoselectivity
(compared to >95:5 dr from the aldol coupling of 5 and 2,3-
anti aldehyde 6) was expected due to the mismatched 1,3-
induction imparted by the 2,3-syn aldehyde 49.18,50 Specifically,
the expected Felkin chair-like transition state (TS-1) for the aldol
reaction of 5 with 2,3-syn aldehyde 49 is destabilized relative
to the Felkin chair-like transition state (TS-2) for the 2,3-anti
aldehyde 6 due to the stereoelectronic repulsion of interacting
dipoles of the aldehyde carbonyl and C(15)-hydroxy TES
ether.50 In an attempt to move the synthesis forward, aldol
product 50 was treated with aqueous AcOH in THF to cleave
We were unable to install the C(15)-(S)-OH of 39 via
crotylboration (Scheme 11) of 40 (the immediate precursor to
27, Scheme 5), which was surprising since a similar crotyl-
boration reaction set the C(15)-(R)-OH of aldehyde 6 (vide
supra). The reactions of (R,R)-tartrate crotylboronate35 or (-)-
Ipc2-(Z)-crotylboronane49 with aldehyde 40 did not provide 41
but rather gave either the undesired C(15)-(R)-OH diastereomer
(i.e., 27) or unidentified products lacking the diagnostic olefin
1
protons in the H NMR spectrum. Alternatively, we pursued
this key stereocenter using an Evans aldol approach.33a Reaction
of aldehyde 40 with chiral imide 42 provided the aldol adduct
43 with excellent yield and selectivity. Treatment of the alcohol
with TESCl afforded the silyl ether. However, efforts to cleave
the acyl oxazolidinone unit of 43 led to competitive reduction
of the 2-bromoethyl carbonate, and so we looked to replace the
carbonate protection group with a silyl ether, as shown in
Scheme 12. Aldol reaction of chiral imide 42 with aldehyde 45
(47) Julian, L. D. Studies toward the total synthesis of the tedanolides:
Total synthesis of 13-deoxytedanolide. Ph.D. thesis, University of
Michigan, 2005.
(48) While this work was in progress, Kalesse reported experimental
evidence for this hypothesis (refs 9a and 9b). Kalesse credits us for
this analysis (ref 9b).
(49) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(50) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322.
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Total Syntheses of (+)-Tedanolide and (+)-13-Deoxytedanolide
Scheme 12. Synthesis of C(13)-C(23) Aldehyde 49
A R T I C L E S
C(13)-C(23) fragment 52 maintains the (S)-configuration at the
C(15)-position but lacks the epoxide. This revision to our
approach to tedanolide would now require a late-stage, C(17)-
OH-directed epoxidation of the C(18)-C(19) olefin,12c,52
a
strategy utilized by Smith10c,d in the synthesis of 13-deoxy-
tedanolide and by Kalesse9a,b and Smith10a in their syntheses
of tedanolide. Aldehyde 52 was designed with protecting groups
for the C(15)- and C(17)-alcohols that could be selectively
removed prior to C(15)-alcohol oxidation and C(17)-directed
epoxidation, respectively, at appropriate junctions of the syn-
thesis following the aldol coupling with 5.
We sought to construct the C(13)-C(23) framework of
aldehyde 52 via the anti-aldol reaction of aldehyde 53 and ketone
54 (eq 2) using conditions developed by Paterson (enol borinate
formation with c-Hex2BCl, Et3N in Et2O at 0 °C followed by
aldehyde addition).53 This convergent assembly would set the
C(16)- and C(17)-stereocenters in a single operation through a
transition state believed to minimize electronic repulsion
between the oxygen lone pairs of the enol borinate and the
benzyl ether.53b We were encouraged by literature precedent
showing that ꢀ-siloxy ethyl ketones participate in the anti-aldol
reaction under Paterson’s conditions without ꢀ-elimination of
the siloxy substituent.12c Furthermore, after the completion of
this work,8a Kalesse and co-workers reported the successful anti-
aldol coupling of aldehyde 53 with the C(13)-OPMB analogue
of ketone 54 under similar conditions.9a
Scheme 13. Aldol Coupling of Ketone 5 and Aldehyde 49
Fragments 53 and 54 were synthesized by using easily
scalable routes (Scheme 14). The synthesis of 539a,d commenced
with the Wittig olefination of trityl-protected aldehyde 55,
followed by cleavage of the trityl ether under acidic conditions.
Swern oxidation of alcohol 56 afforded ꢀ,γ-unsaturated aldehyde
57. The stabilized ylide Ph3PdC(Me)CO2Et was added directly
to the Swern reaction mixture to generate R,ꢀ-unsaturated ester
58 in a one-pot oxidation-olefination sequence. Reduction of
the ester and subsequent MnO2 oxidation of the allylic alcohol
then provided aldehyde 53. Ketone 54 was prepared from the
DMPM-protected 6054 in four synthetic steps. Addition of the
lithium enolate of tert-butyl acetate to 60 resulted in a ꢀ-hydroxy
ester that was reduced to a 1,3-diol with LiAlH4. Selective
silylation of the primary alcohol and oxidation of the secondary
alcohol furnished the requisite ketone 54.
the TES ether. Unfortunately, these desilylation conditions led
to the 5-exo-cyclization of the liberated C(15)-alcohol onto the
epoxide51 to form tetrahydrofuran 51. The analogous cyclization
was not obserVed during manipulation of aldol 4 deriVing from
the 2,3-anti-aldehyde 6 (Scheme 7). We hoped that cleavage
of the C(15)-TES ether under buffered or basic conditions
(Et3N-3HF, tetrabutylammonium fluoride, TAS-F) might avoid
the epoxide-opening, but these efforts led to competitive
desilylation of the various TBS ethers. Nevertheless, even when
these neutral or weakly basic conditions were used, evidence
for cyclization of C(15)-OH onto the epoxide was observed (e.g.,
51 and desilylated versions of 51 were detected). Thus, the
change in stereochemistry of C(15)-OH significantly affected
the reactivity of intermediate 50 (Scheme 13). As a result, we
were unable to elaborate these intermediates to tedanolide.
At this point, we targeted aldehyde 52 as a third-generation
coupling partner for ketone 5 en route to tedanolide (eq 2). The
Our early efforts to unify aldehyde 53 and ketone 54 using
Paterson’s anti-aldol conditions led to 61 as the major of two
diastereomers with 80:20 selectivity (Scheme 15). Literature
precedent9a,12c suggested that 62 would be the minor product;
however, Mosher ester analysis55 revealed that the C(17)-
alcohols of the major and minor aldols both have identical (S)-
(52) For a review of hydroxy directed epoxidations of allylic alcohols: Adam,
W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(53) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. Mechanistic discussion: (b) Vulpetti, A.; Bernardi, A.;
Gennari, C.; Goodman, J. M.; Paterson, I. Tetrahedron 1993, 49, 685.
(54) PreparedinanalogousfashiontotheknownPMB-protectedaldehyde:Organ,
M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568.
(55) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. For
a useful explanation and examples of Mosher ester analysis: (b) Ohtani,
I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
(51) Loh and co-workers induced a similar cyclization to analyze epoxide
stereochemistry in their tedanolide fragment synthesis (ref 12c).
9
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A R T I C L E S
Dunetz et al.
Scheme 14. Synthesis of Aldehyde 53 and Ketone 54
observation that only one diastereomer is formed from the aldol
coupling of ketones 54 or 67 with methacrolein under identical
conditions (eq 3). Furthermore, Mosher ester analysis of the
primary alcohol 59 (precursor to aldehyde 53, Scheme 14)
reVealed an 80:20 ratio of diastereomers at the C(20)-bisallylic
stereocenter. We concluded that C(20)-epimerization was oc-
curring during the oxidation-olefination sequence used in the
conversion of alcohol 56 (>95:5 enantiomeric ratio (er) as
determined by Mosher ester analysis) to R,ꢀ-unsaturated ester
58. After vigorously investigating different oxidation and
olefination conditions,8a we found that treatment of 56 with
Dess-Martin periodinane at 0 °C, followed by ylide addition
and olefination at 0 °C, provided ester 58 (and subsequently
aldehyde 53) with 94:6 er. When aldehyde 53 (of 94:6 er) was
used in the anti-aldol reaction with 54, we obtained a 94:6
mixture of aldol diastereomers 61 and 63 (eq 4). It is remarkable
that the aldol selectivity perfectly matched the enantiomeric
purity of aldehyde 53. These experiments were also crucial to
our ability to bring sufficient material forward en route to
tedanolide.
Scheme 15. Aldol Coupling of 53 and 54
The synthesis of C(13)-C(23) aldehyde 52 from 61 was
completed in five steps (Scheme 16). Reduction of the ꢀ-hy-
droxy ketone 61 to the syn-1,3-diol with DIBAL and selective
silylation57 of the allylic alcohol provided TES ether 70. The
dimethoxybenzyl ether of 70 was transferred to the secondary
alcohol via benzylidene acetal formation, followed by regiose-
lective acetal reductive opening with DIBAL. Finally, oxidation
of primary alcohol 71 using the Dess-Martin periodinane
provided aldehyde 52 in excellent yield.
Addition of the lithium enolate of ketone 5 to aldehyde 52
provided Felkin adduct 72 (as determined by NMR analysis37
and Mosher ester analysis55) in 77% yield with 75:25 selectivity
(Scheme 17). The diastereomeric ratio for this transformation
is similar to that observed previously for the aldol reaction of
configurations. Independent conversion of the two aldol products
to their corresponding benzylidene acetals (of type 65) and
acetonides (of type 66) revealed, through spectroscopic analy-
sis,56 that both aldol adducts have identical stereochemistry
within the C(14)-C(17) positions; that is, both aldol diastere-
omers are anti-aldol products with (S)-configurations at C(17)-
OH.
Scheme 16. Completion of the Synthesis of Aldehyde 52
We speculated that 63 (Scheme 15) might be the correct
structure of the minor aldol product and that it might arise from
epimerization of the bisallylic C(20)-stereocenter during the
synthesis of aldehyde 53. This hypothesis was supported by our
(56) Acetonide analysis: Rychnovsky, S. D.; Rogers, B. N.; Richardson,
T. I. Acc. Chem. Res. 1998, 31, 9.
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Total Syntheses of (+)-Tedanolide and (+)-13-Deoxytedanolide
Scheme 17. Aldol Coupling of Ketone 5 and Aldehyde 52
A R T I C L E S
Scheme 18. Attempted C(15)-Oxidation of Hemiketal 75
OH was observed),59 and the macrolactone was obtained in 32%
overall yield from 72 (four steps). Finally, the C(17)-OH was
protected as a SEM ether to provide 78.
2,3-syn aldehyde 49 (vide supra), and variations to the stoichi-
ometry of aldehyde 52 (0.8-1.4 equiv) relative to ketone did
not affect the yield (based on limiting reagent) or selectivity.
At this point, we looked to protect the C(13)-alcohol of 72 before
further elaborating the intermediate to the natural product.
Treatment of 72 with TBSOTf and 2,6-lutidine in CH2Cl2 led
to the product 73 as a mixture of TES and TBS ethers at the
C(17)-position. It seemed unlikely that this substitution is due
to the direct silylation of the C(17)-OTES oxygen, as the TES:
TBS ratio at this position was unchanged when a mixture of
products 73-TES and 73-TBS was resubjected to the silylation
reaction conditions. However, attempts to suppress the scram-
bling of the silyl ether protecting group at this position were
unsuccessful.
Instead, protection of the C(13)-OH of 72 as a SEM ether
proceeded without complication in quantitative yield (Scheme
18). At this point, we planned to convert the C(15)-dimethoxy-
benzyl ether to the C(15)-ketone via cleavage of the DMPM
group and subsequent oxidation. Treatment of SEM-protected
72 with DDQ liberated the C(15)-(S)-OH of 74; however,
hemiketal 75 was observed as the exclusive product by spec-
troscopic analysis. Furthermore, efforts to intercept the hydroxy
ketone isomer 74 with oxidants (e.g., DMP, SO3-pyridine in
DMSO) were unsuccessful, and we were unable to obtain the
desired C(15)-ketone 76.
Our next course of action was to form the macrolactone prior
to C(15)-oxidation (Scheme 19). We postulated that conforma-
tional constraints imposed by the macrocycle might destabilize
the hemiketal or even disfavor hemiketal formation from the
hydroxy ketone. Therefore, the C(13)-alcohol of aldol adduct
72 was protected as a SEM ether, and the seco-acid was liberated
via stepwise cleavage of the primary TBS ether (along with
the C(17)-TES ether58) to provide 77, followed by removal of
the allyl ester. Macrolactonization of this seco-acid was effected
at room temperature using the Yonemitsu modification of the
Yamaguchi protocol.39 The cyclization was completely selective
for the primary alcohol (no reaction at the secondary C(17)-
Treatment of 78 with DDQ liberated the C(15)-alcohol.
Spectroscopic analysis reVealed that 79 exists as the open-chain
hydroxy ketone, and we did not detect the hemiketal isomer.
We were gratified that treatment of 79 with Dess-Martin
periodinane afforded the C(11,15)-dione 80 in 71% yield over
two steps from DMPM ether 78. The synthesis of (+)-tedanolide
(1) was then completed in three steps. Removal of the two SEM
ethers was accomplished by using MgBr2 and EtSH in Et2O60
(as previously demonstrated by Smith10a). C(17)-Hydroxyl-
directed epoxidation of the C(18)-C(19) olefin with m-CPBA12c
gave a single epoxide diastereomer in 54% yield. Finally, global
desilylation of the penultimate intermediate with Et3N-buffered
Et3N-3HF46 provided synthetic (+)-tedanolide. The spectro-
scopic data (1H NMR, 13C NMR, IR, optical rotation, HRMS)
from our synthetic tedanolide were in excellent agreement with
data published for an authentic sample,1 as well as with data
reported by Kalesse9a,b and Smith10a for synthetic tedanolide.
Summary
Convergent, stereocontrolled total syntheses of (+)-tedanolide
and (+)-13-deoxytedanolide have been accomplished. A key
transformation for the assembly of both natural products is the
aldol coupling of the C(1)-C(12) methyl ketone 5 with a
C(13)-C(23) aldehyde partner. Aldehyde 6, with 2,3-anti
stereochemistry, was initially employed, and its aldol reaction
with the lithium enolate generated from 5 proceeded with >95:5
selectivity for the Felkin aldol 4. However, it proved impossible
to elaborate 4 to tedanolide owing to the remarkable stability
of hemiketals 33b and 34 and especially their lack of reactivity
toward oxidants. Deoxygenation of hemiketal 33a provided the
13-deoxy hemiketal 36, which was successfully oxidized to the
C(11,15)-diketone 38 by using the Dess-Martin periodinane
reagent. The later intermediate was smoothly elaborated to (+)-
13-deoxytedanolide.
Recognition that 13-deoxy hemiketal 36 could be oxidized
by way of its hydroxy ketone tautomer 37 suggested that the
remarkable stability and lack of reactivity of hemiketals 33b
(57) Hicks, J. D.; Huh, C. W.; Legg, A. D.; Roush, W. R. Org. Lett. 2007,
9, 5621.
(59) Similar selectivity was also observed by Smith and co-workers in their
syntheses of tedanolide and 13-deoxytedanolide (refs 10a, 10c, 10d).
(60) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183.
(58) We were unable to remove the primary TBS ether without also cleaving
the TES ether.
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A R T I C L E S
Dunetz et al.
Scheme 19. Completion of the Total Synthesis of (+)-Tedanolide (1)
and 34 might be due to the equatorial conformation of ring
substituents in 33b and 44, which stabilizes the hemiketal
relative to the acyclic hydroxy ketone isomer. This then led to
the decision to redesign the synthesis of tedanolide to proceed
by way of the stereochemically inverted C(15)-(S)-alcohol
intermediates, since hemiketal intermediates with C(15)-(S)
series would be destabilized by having at least one large
substituent in an axial position (Scheme 10). However, use of
C(15)-(S)-configured intermediates also required that the side-
chain epoxide unit be introduced very late in the synthesis,
owing to the ease with which C(15)-(S)-OH cyclized onto the
epoxide in intermediate 50 (Scheme 13).
Therefore, 2,3-syn aldehyde 52 was employed in the aldol
coupling with methyl ketone 5 which gave the Felkin aldol 72
with 75:25 selectivity. Elaboration of Felkin aldol 72 to macro-
lactone 78 set the stage for removal of the C(15)-DMPM ether
and oxidation of the C(15)-OH to the required ketone in 80.
Fortunately, the hemiketal that plagued the unsuccessful tedano-
lide syntheses via C(15)-(R)-configured intermediates 33b and
34 was not observed for the C(15)-(S)-hydroxy ketone 79
derived from 78. Intermediate 80 was smoothly elaborated to
tedanolide via deprotection of C(17)-OH, which was used to
direct the epoxidation of the adjacent C(18,19)-olefin. Final,
global cleavage of all silyl ethers then completed the total
synthesis of (+)-tedanolide.
Acknowledgment. Support from the National Institutes of
Health (GM 038436) and a Bristol-Myers Squibb Graduate Fel-
lowship to L.D.J. are gratefully acknowledged. We thank Gregory
C. Lane for preliminary work8c involving the synthesis of alcohol
25a from aldehyde 22 (Scheme 5). We also thank Professor Schmitz
for supplying an authentic sample of (+)-tedanolide, and Professors
Fusetani and Matsunaga for supplying an authentic sample of (+)-
13-deoxytedanolide.
Supporting Information Available: Experimental procedures,
spectroscopic data, and spectra for selected intermediates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA8063205
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16416 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008