Total synthesis of (+)-tedanolide

Article abstract of DOI:10.1021/ja073329u

A convergent, stereocontrolled total synthesis of (+)-tedanolide (1), an architecturally complex marine antitumor macrolide, has been achieved in 31 steps (longest linear sequence). Highlights of the synthesis comprise a highly efficient dithiane union, f

Full text of DOI:10.1021/ja073329u

Published on Web 08/11/2007
Total Synthesis of (+)-Tedanolide
Amos B. Smith, III* and Dongjoo Lee
Contribution from the Department of Chemistry, Laboratory for Research on the Structure of
Matter, and Monell Chemical Senses Center, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
Received May 10, 2007; E-mail: smithab@sas.upenn.edu
Abstract: A convergent, stereocontrolled total synthesis of (+)-tedanolide (1), an architecturally complex
marine antitumor macrolide, has been achieved in 31 steps (longest linear sequence). Highlights of the
synthesis comprise a highly efficient dithiane union, followed by an Evans-Tishchenko “oxidation” to enable
formation of the seco-ester in the presence of an oxidatively labile dithiane, a highly refined protecting
group strategy, and a chemo- and stereoselective epoxidation at C(18,19).
Introduction
(E)-olefin encased in a 18-membered macrolide framework,
punctuated with 13 stereogenic centers. Not surprisingly, the
remarkable biological profile, in conjunction with the architec-
Tedanolide and the 13-deoxy-congener [(+)-1 and (+)-2]
comprise initial members of a small, architecturally intricate
family of sponge metabolites, reported respectively by the
tural complexity of (+)-1 and (+)-2, has triggered considerable
6
synthetic effort, culminating in the first total synthesis of a
1
2
Schmitz and Fusetani laboratories in 1984 and 1991 (Figure
). Both display exceptionally potent antitumor activities with
+)-tedanolide (1), increasing the life span of mice implanted
tedanolide, namely (+)-13-deoxytedanolide (2) by our labora-
1
7
tory in 2003, followed by a second total synthesis by Roush
(
8
and co-workers in 2005. More recently, Kalesse and co-
3
with lymphocytic leukemia by 23% at 1.5 µg/kg body weight,
and (+)-13-deoxytedanolide (2), lowering the growth rate of
P388 tumors with a T/C value of 189% at a dose level of 0.125
mg/kg. Although a detailed understanding of the mode of action
remains unknown, Fusetani and co-workers in an elegant study
9
workers achieved the first total synthesis of (+)-tedanolide (1)
exploiting a series of stereoselective aldol unions.
2
In keeping with our longstanding interest in the development
of unified synthetic strategies for members of architecturally
complex families of natural products, we initially devised a
4
recently disclosed the binding site of (+)-13-deoxytedanolide
(2) to be the 60S ribosomal subunit. A third equally potent
(
6) (a) Yonemitsu, O. J. Synth. Org. Chem., Jpn. 1994, 52, 946. (b) Matsushima,
T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett. 1996, 37,
385. (c) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda, H.; Uenishi, J.;
Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (d) Matsushima, T.;
Mori, M.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.; Yonemitsu,
O. Chem. Pharm. Bull. 1999, 47, 308. (e) Matsushima, T.; Zheng, B.-Z.;
Maeda, H.; Nakajima, N.; Uenishi, J. Yonemitsu, O. Synlett 1999, 780. (f)
Zheng, B.-Z.; Maeda, H.; Mori, M.; Kusaka, S.; Yonemitsu, O.; Mat-
sushima, T.; Nakajima, N. Uenishi; J. Chem. Pharm. Bull. 1999, 47, 1288.
congener, (+)-tedanolide C (3), bearing a different pattern of
oxygenation and methylation, was recently described by Ireland
and co-workers.5
(
g) Matsushima, T; Nakajima, N.; Zheng, B.-Z.; Yonemitsu, O. Chem.
Pharm. Bull. 2000, 48, 855. (h) Zheng, B.-Z.; Yamauchi, M.; Dei, H.;
Kusaka, S.; Matsui, K.; Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441.
(
i) Zheng, B.-Z.; Yamauchi, M.; Dei. H.; Yonemitsu, O. Chem. Pharm.
Bull. 2000, 48, 1761. (j) Matsui, K.; Zheng, B.-Z.; Kusaka, S.; Kuroda,
M.; Yoshimoto, K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001,
3615. (k) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett.
1998, 39, 9361. (l) Taylor, R. E.; Hearn, B. R.; Ciavarri, J. P. Org. Lett.
2002, 4, 2953. (m) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem.
1999, 64, 663. (n) Jung, M. E.; Marquez, R. Tetrahedron Lett. 1999, 40,
3129. (o) Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. (p) Jung, M.
Figure 1. The tedanolide family of natural products.
E.; Lee, C. P. Tetrahedron Lett. 2000, 41, 9719. (q) Jung, M. E.; Lee, C.
P. Org. Lett. 2001, 3, 333. (r) Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.;
Masamune, S. Tetrahedron Lett. 1998, 39, 1873. (s) Roush, W. R.; Lane,
G. C. Org. Lett. 1999, 1, 95. (t) Roush, W. R.; Newcom, J. S. Org. Lett.
From the synthetic perspective, (+)-tedanolide (1) comprises
a significant challenge, given the four labile aldol units, a
sensitive trisubstituted R-hydroxy epoxide, and a trisubstituted
2
002, 4, 4739. (u) Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 3223.
(v) Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 6001. (w) Wong,
C.-M.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 4485. (x) Hassfeld, J.;
Kalesse, M. Synlett 2002, 2007. (y) Hassfeld, J.; Eggert, U.; Kalesse, M.
Synthesis 2005, 1183. (z) Ehrlich, G.; Kalesse, M. Synlett 2005, 655. (aa)
Iwata, Y.; Tanino, K.; Miyashita, M. Org. Lett. 2005, 7, 2341.
(
1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.; van
der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(
2) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1991, 56, 4971.
3) Schmitz, F. J.; Gunasekera, S. P.; Hossain, M. B.; van der Helm, D.;
Yalamanchili, G. (1988) U.S. Patent Application 87-7347.
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.
(
(7) (a) Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S. A.; Degnan, A. P.
J. Am. Chem. Soc. 2003, 125, 350. (b) Smith, A. B., III; Adams, C. M.;
Lodise Barbosa, S. A.; Degnan, A. P. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12042.
(8) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127,
6186.
(9) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. J. Am. Chem. Soc. 2006,
128, 14038.
(
(
5) Chevallier, C.; Bugni, T. S.; Feng, X.; Harper, M. K.; Orendt, A. M.; Ireland,
C. M. J. Org. Chem. 2006, 71. 2510.
10.1021/ja073329u CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 10957-10962
9
10957

A R T I C L E S
Smith and Lee
flexible approach envisioned to exploit a dithiane linchpin
tactic10 to access both (+)-tedanolide (1) and (+)-13-deoxy-
tedanoilde (2) from a common advanced intermediate (Vide
infra). Having achieved the total synthesis of (+)-13-deoxy-
tedanolide, we outline herein the culmination of this synthetic
venture with an effective total synthesis of (+)-tedanolide (1).
common, late-stage olefin such as (-)-8 would potentially serve
as a precursor for iodide (+)-9 and epoxide (+)-10, respectively,
for (+)-13-deoxytedanolide (2) and (+)-tedanolide (1) (Scheme
2). Although the first generation route to the southern
hemisphere subunit (-)-8 demonstrated the feasibility of
1
1
Scheme 2
Results and Discussions
Synthetic Analysis of (+)-Tedanolide (1). As with (+)-13-
deoxytedanolide (2), our synthetic strategy for (+)-tedanolide
(1) called for initial construction of the macrocyclic domain,
with stereoselective installation of the C(18,19) epoxide late in
the synthetic sequence to avoid the need to carry this potentially
unstable functionality through various synthetic steps required
for the construction of the complex backbone (Scheme 1). To
Scheme 1
utilizing an epoxide opening with a dithiane anion to construct
the (+)-tedanolide (1) framework, this synthesis required 22
steps from the commercially available (S)-(+)-Roche’s ester
(11). The lengthy sequence resulted primarily from an unfore-
seen synthetic inefficiency; a seven-step protocol to convert
olefin (-)-8 to the terminal epoxide (+)-10.
Based on the lessons learned in our first generation synthesis
of epoxide (+)-10, we therefore developed a second-generation
strategy employing the alternative â-stereogenicity C(15), vis-
a` -vis the (+)-13-deoxytedanolide synthetic venture (Scheme 3).
Importantly, the second-generation synthesis of the requisite
Scheme 3
this end, disconnection of (+)-tedanolide (1) at the macrolactone
and C(11-12) linkage gave rise to a common C(1-11) dithiane
epoxide [cf. 7(15â)] for the dithiane coupling reaction was
designed to produce this subunit efficiently and in suitable
quantities to achieve the goal of (+)-tedanolide (1). Careful
development of a viable protecting group strategy for the
southern hemisphere also appeared prudent at this juncture.
Indeed, the selection of the protecting groups for the C(15),
C(17), and C(29) hydroxyls proved to be one of the most critical
aspects of the (+)-tedanolide (1) synthetic venture. Further
recognition of the allylic alcohol system at C(17) prompted
construction of this structural array via a stereoselective union
tactic. That is, disconnection of the C(17-18) σ-bond in 7(15â)
revealed vinyl iodide 12 and aldehyde 13. In the synthetic sense
this scenario would make construction of a C(12-23) subtarget
considerably more convergent (Scheme 2). As with our (+)-
13-deoxytedanolide (2) synthesis, the stereogenecity at C(15)
7
a,b
(-)-5,
and in the case of (+)-tedanolide (1), a C(13-23)
epoxide 7(15R). The 13-deoxy congener called for iodide 6 or
a diastereomer thereof (Vide infra). In the synthetic direction,
we envisioned seco-acid 4a to be available via addition of
epoxide 7(15R) to the dianion derived from dithiane (-)-5,
followed by selective oxidation of the hydroxyl at C(1).
Highlights of the late stage of the synthesis would then entail
retention of the dithiane moiety until macrolactonization to
prevent potential intramolecular ketalization between the C(15)
and C(29) hydroxyl and ketone, respectively, as observed by
8
Roush, and installation of the requisite epoxide at the C(18,19)
trisubstituted olefin.
In initiating the synthetic program for the tedanolides, we
had outlined a unified synthetic strategy, anticipating that a
(10) Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249.
(11) Adams, C. M. Ph.D. Dissertation, University of Pennsylvania, 2003.
1
0958 J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007
9

Total Synthesis of (
+
)-Tedanolide
A R T I C L E S
would be of no consequence, since the C(15) hydroxyl would
eventually be oxidized to a ketone in the final product.
Elaboration of the C(18-21) Fragment: Vinyl Iodide (+)-
followed by reductive-removal of the oxazolidinone then
furnished homoallylic diol (+)-19, establishing the C(15) and
C(16) stereogenic centers with excellent diastereoselectivity. The
resulting C(15) and C(29) hydroxyls, which we anticipated could
be readily differentiated during the macrolactonization event
were protected as a cyclic ketal. Ozonolysis of the terminal
olefin in (-)-20 next provided aldehyde (+)-13, a substrate for
the coupling reaction.
1
2. Our point of departure for the construction of the C(18-
1) (E)-vinyl iodide was known aldehyde (+)-15, prepared
2
1
2
during the (+)-13-deoxytedanolide (2) synthesis (Scheme 4).
Aldehyde (+)-15 was then converted to alkyne (+)-17 via
Scheme 4
Construction of the C(12-23) Southern Hemisphere of
(
(
+)-Tedanolide (1). With both vinyl iodide (+)-12 and aldehyde
+)-13 in hand, we embarked on elaboration of the southern
hemisphere epoxide (+)-7(15â) (Scheme 6). The coupling
reaction was achieved by metal-halogen exchange of vinyl
iodide (+)-12 with t-BuLi in Et2O at -78 °C, followed by the
addition to aldehyde (+)-13 to furnish predominantly the desired
2
2
adduct (-)-21 as a diastereomeric mixture [6:1 at C(17)], in
a combined yield of 90%. Importantly, the diastereomers could
be separated chromatographically.
Corey-Fuchs protocol13 in 76% overall yield. To construct the
key structural element of fragment (+)-12, the (E)-vinyl iodide
moiety, we initially explored a palladium-catalyzed hydrostan-
nylation approach,14 followed by iodination; the result proved
to be a mixture of regioisomeric vinyl iodides (6:1, 89%,
Scheme 6
15
BORSM ). Radical initiated hydrostannylation (AIBN, (n-
Bu)3SnH)1 and hydrozirconation resulted in similar selectivi-
ties. Pleasingly, however, stannylcupration of (+)-17 employing
the conditions of Pancrazi18 and co-workers [i.e., 2 equiv of
the mixed cyanocuprate (n-Bu)3Sn(n-Bu)CuCNLi2], followed
by iodination afforded the desired (E)-trisubstituted vinyl iodide
6
17
The favorable stereochemical outcome of this substrate-
controlled reaction can be understood in terms of transoid
conformer 13, that would minimize dipole-dipole interactions
between carbonyl and the oxygens in the dioxolane ring, thereby
leading to preferential nucleophilic attack from the less hindered
face of the carbonyl group to furnish the R-isomer as a major
diastereomer (Figure 2). This result is also consistent with a
(
+)-12 as a single stereoisomer in excellent yield (91% over
15
two steps, BORSM ), without compromise of regioselectivity.
Fragment (+)-12 was thus available in four steps and 69%
overall yield from (+)-15.
Construction of the C(12-17) Fragment: Aldehyde (+)-
1
3. Elaboration of aldehyde (+)-13 began with known aldehyde
1
9
23
(
-)-18 bearing two contiguous stereogenic centers generated
Cram-Felkin-Anh model.
20
via a Brown asymmetric crotylboration (Scheme 5). A syn-
2
1
aldol condensation employing the Evans’s crotonate imide,
Scheme 5
Figure 2. Conformational analysis of vinyl anion addition to C(17)
aldehyde.
Completion of epoxide (+)-7(15â) was achieved in a
straightforward fashion (Scheme 7). After separation, the C(17)
hydroxyl group in (-)-21 was protected as the SEM ether and
the PMB group oxidatively removed to afford (-)-22. The
(
19) Ramachandran, P. V.; Prabhudas, B.; Pratihar, D.; Chandra, J. S.; Reddy,
(
12) (a) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 1995, 117, 12011. (b) Smith, A. B., III; Beauchamp, T. J.; LaMarche,
M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 2000, 122, 8654.
M. V. R. Tetrahedron Lett. 2003, 44, 3745.
(20) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(21) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron Lett.
1986, 27, 4957.
(
(
(
(
13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
14) Zhang, H. X.; Guib e´ , F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
15) Based on recovered starting materials.
(22) The absolute stereochemistry of the newly generated stereocenter in (-)-
21 was assigned by the modified Mosher ester analysis of the derived esters.
For a complete discussion of the Mosher analysis for assignment of the
stereochemistry of secondary alcohol, see: (a) Kusumi, T.; Fujita, Y.;
Ohtani, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2923. (b) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Org. Chem. 1991, 56, 1296.
(c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
16) (a) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Vel’der, Y. L.
Synthesis 1986, 496. (b) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982,
2
3, 3851.
(17) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
9
7, 679. For a review, see: (b) Wipf, P.; Jahn, H. Tetrahedron 1996, 52,
2853. (c) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
1
(23) (a) Ch e´ rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (b)
Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61. (c) Anh, N. T. Top.
Curr. Chem. 1980, 88, 145.
(18) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J. J. Org. Chem.
1
997, 62, 7768.
J. AM. CHEM. SOC.
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A R T I C L E S
Scheme 7
Smith and Lee
We also investigated iodide (-)-25, an equally attractive
coupling partner, as an alternative coupling strategy to assemble
the C(11-13) aldol unit in (+)-tedanolide (1) (Scheme 9). We
Scheme 9
required (Z)-olefin was then installed by Dess-Martin oxida-
tion,24 followed by Wittig ethylidenation of the resulting
aldehyde, to yield (-)-23. Removal of both TBS groups, and
in turn conversion of the resultant hydroxyl groups to the desired
2
5
epoxide was achieved via the Fraser-Reid protocol, thereby
completing the construction of epoxide (+)-7(15â). The overall
sequence from (-)-18 required 11 steps and proceeded in 22%
overall yield.
Union of the Northern and Southern Hemispheres. Having
secured scalable routes for both the preparation of (-)-5 and
reasoned that the union with dithiane (-)-5 would prove to be
a viable tactic, and in turn extend the utility of our dithiane
coupling strategy. However, reaction of the lithium dianion
derived from (-)-5 with iodide (-)-25, under the same
conditions that proved successful with epoxide (+)-7(15â), led
predominantly to elimination product (+)-27 (50-60%), in
conjunction with a low yield of the desired adduct (-)-26 (20-
(
+)-7(15â), we began to investigate assembly of the carbon
framework of (+)-tedanolide (1). For the critical union, epoxide
(
+)-7(15â) was added to the lithium dianion derived from the
2
6
dithiane (-)-5, the latter generated by the Williams protocol
[
e.g., t-BuLi in a 10% HMPA/THF solution] to furnish diol
3
0%). Although the desired tedanolide framework was obtained,
15
(-)-24 in 80% yield (BORSM) (Scheme 8). In contrast to
adventitious formation of the elimination product prohibited
further investment in this route.
Scheme 8
Construction of Macrocycle (+)-31. Having achieved the
critical union, and thereby the complete carbon skeleton of (+)-
tedanolide (1), we next addressed oxidation of the primary
hydroxyl to the requisite seco-acid for subsequent macrocy-
clization. To this end, bis-silylation of (-)-24, followed by
selective removal of the primary TBS ether employing HF·
pyridine in THF furnished (-)-26 (Scheme 10). Access to the
Scheme 10
relatively simple 1,3-dithianes, which readily undergo depro-
tonation with n-BuLi, metalation of structurally complex
dithianes such as (-)-5 often require a variety of stronger
bases,27 solvent additives, and time and temperature regimes.
We have found that t-BuLi in a THF solution of HMPA at -78
°
C comprises the optimal conditions for generation of the
dianion corresponding to (-)-5. Addition of the electrophile
immediately following metalation also proved important, since
prolonged maintenance of the dianion at -78 °C results in loss
of reactivity.
(
24) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess, D.
B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(
(
(
25) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
26) Williams, D. R.; Sit, S.-Y. J. Am. Chem. Soc. 1984, 106, 2949.
27) Lipshutz, B. H.; Garcia, E. Tetrahedron Lett. 1990, 31, 7261.
10960 J. AM. CHEM. SOC.
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Total Synthesis of (
+
)-Tedanolide
A R T I C L E S
seco-acid would now require the nontrivial conversion of the
primary hydroxyl to the corresponding seco-acid in the presence
of the oxidatively labile dithiane. For this conversion we turned
Scheme 12
2
8,29
to the SmI2-promoted Evans-Tishchenko “oxidation”,
a
protocol developed specifically for this transformation in our
7a,b
1
3-deoxytedanolide synthesis.
Toward this end, Parikh-
30
Doering oxidation of (-)-26 provided the corresponding
aldehyde, which upon treatment with SmI2 in the presence of
â-hydroxy ketone 282 furnished a diastereomeric mixture of
esters (29), effectively achieving oxidation at C(1) in 75% yield
over two steps.
8,29
Acid-catalyzed methanolysis (PPTS, MeOH) of the C(15,
29) acetonide in 29 furnished the diol in good yield (72%,
BORSM) (Scheme 11). At this juncture, the presence of two
Scheme 11
2
4
oxidation of the two free hydroxyls then led to triketone (+)-
hydroxyl groups was not viewed as an issue, as we anticipated
that Yamaguchi lactonization31 would prove highly chemose-
3
3
33.
85%), employing the conditions of Kim (MgBr2, EtSH),
known to remove selectively the SEM group in the presence of
Next, the desired diol was cleanly obtained in high yield
3
4
(
lective for the C(29) primary hydroxyl as in the 13-deoxy-
tedanolide synthesis, thereby affording the desired macrolactone.
This indeed proved to be the case. However, an initial attempt
at saponification of the resultant triol-ester 30, employing KOH
at room temperature, only proceeded with low conversion. Use
of LiOH in dioxane/H2O at reflux, followed by the macrocy-
clization employing the Yamaguchi protocol was more effective,
affording the desired macrocycle (+)-31 in an acceptable yield
of 46% over two steps.
Completion of the (+)-Tedanolide (1) Total Synthesis.
Having achieved the crucial macrocyclization, we turned to final
elaboration of (+)-tedanolide (1). The PMB group was removed
oxidatively using DDQ to produce diol (+)-32 in good yield
3
5
the TIPS and TBS silyl ethers. Hydroxyl-directed epoxidation
employing m-CPBA buffered with NaHCO3,
7
a,b
which had
proven successful in our total synthesis of (+)-13-deoxytedano-
lide (2), furnished the desired epoxide (+)-34 as a single
diastereomer (70%, BORSM). Global deprotection exploiting
8
Et3N·3HF and Et3N as described by Roush, completed the total
synthesis of (+)-tedanolide (1), identical in all respects (i.e.,
1
13
36
500 MHz H and 125 MHz C NMR, HRMS, chiroptical
3
7
properties, and single crystal X-ray analysis) to the data
reported for the natural and the Kalesse synthetic (+)-tedanolide
1
,9
(1).
(
84%) (Scheme 12). Removal of the dithiane with PhI(CF3CO2)2
32
(32) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
employing the Stork protocol followed by Dess-Martin
(
33) Alternatively, N-iodosuccinimide (NIS) was also explored for the removal
of dithiane in (+)-32 but showed no improvement (20% overall yield from
(+)-32).
(28) (a) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447. (b)
Tormakangas, O. P.; Koskinen, A. M. P. Rec. Res. DeV. Org. Chem. 2001,
(34) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183.
(35) (a) Hoveyda, A. H.; Evans, D. A.; Fu. G. C. Chem. ReV. 1993, 93, 1307.
(b) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
5
, 225.
(
29) Smith, A. B., III; Lee, D.; Adams, C. M.; Kozlowski, M. C. Org. Lett.
002, 4, 4539.
2
(36) Synthetic sample was found to undergo decomposition in CDCl
3
during a
1
3
(
30) Parikh, J. R.; von E. Doering, W. J. Am. Chem. Soc. 1967, 89, 5505.
31) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
6 6
C NMR experiment, but is stable in C D .
(
6 6
(37) Crystallization during an NMR experiment in C D yielded crystals suitable
for X-ray analysis.
J. AM. CHEM. SOC.
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VOL. 129, NO. 35, 2007 10961

A R T I C L E S
Smith and Lee
Summary
of his 70th birthday: innovative chemist, exceptional scholar,
and true gentleman. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant
Stereocontrolled total syntheses of both (+)-tedanolide (1)
and the 13-deoxy congener (2), exploiting a unified dithiane
linchpin strategy, have now been achieved. Highlights of this
synthetic venture include the development of Evans-Tishchenko
2
9028. We also thank Dr. Robert Udal for providing samples
for the synthesis of (-)-5 used in this work, Drs. George T.
Furst and James E. Hall (AstraZeneca) for NMR expertise, Dr.
Patrick J. Carroll for the X-ray analysis, and Professor Francis
“
oxidation” to generate a seco-ester in the presence of oxida-
tively labile dithiane, a highly refined protecting group strategy,
and the stereocontrolled epoxidation at C(18,19). As for the total
synthesis of (+)-tedanolide (1), the longest linear sequence
comprised 31 steps and proceeded in 0.31% overall yield from
1
J. Schmitz for the H spectrum of (+)-tedanolide (1).
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-(+)-glyceraldehyde acetonide.
Acknowledgment. With great pleasure, we dedicate this work
to Professor Yoshito Kishi (Harvard University) on the occasion
JA073329U
10962 J. AM. CHEM. SOC.
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VOL. 129, NO. 35, 2007