Total synthesis of sporolide B and 9-epi-sporolide B

Article abstract of DOI:10.1021/ja1048994

The total synthesis of the structurally unique secondary metabolite sporolide B (1b) is described. The total synthesis of 1b was developed on the basis of preliminary studies that revealed the reactivity of an appropriate o-quinone as a diene system toward a number of indene derivatives as dienophiles, first in intermolecular and thence intramolecular settings. Thus, substrates were devised (37 and 75) that underwent exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolide-type structures that were subsequently elaborated to a sporolide model system, 9-epi-sporolide B, and 1b. The requisite indene o-quinone precursor 75 was synthesized through a ruthenium-catalyzed [2+2+2] cycloaddition reaction between a propargylic alcohol and a chloroacetylenic cyclopentenyne, followed by elaboration and silver-promoted oxidation of the resulting chloroindene derivative. In addition to the total synthesis of 1b, this work demonstrated, for the first time, the power of the intramolecular hetero [4+2] cycloaddition reaction in the total synthesis of complex molecules and the application of the ruthenium-catalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue on the aromatic nucleus.

Full text of DOI:10.1021/ja1048994

Published on Web 07/22/2010
Total Synthesis of Sporolide B and 9-epi-Sporolide B
K. C. Nicolaou,* Jianhua Wang, Yefeng Tang, and Lorenzo Botta
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received June 7, 2010; E-mail: kcn@scripps.edu
Abstract: The total synthesis of the structurally unique secondary metabolite sporolide B (1b) is described.
The total synthesis of 1b was developed on the basis of preliminary studies that revealed the reactivity of
an appropriate o-quinone as a diene system toward a number of indene derivatives as dienophiles, first in
intermolecular and thence intramolecular settings. Thus, substrates were devised (37 and 75) that underwent
exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolide-
type structures that were subsequently elaborated to a sporolide model system, 9-epi-sporolide B, and 1b.
The requisite indene o-quinone precursor 75 was synthesized through a ruthenium-catalyzed [2+2+2]
cycloaddition reaction between a propargylic alcohol and a chloroacetylenic cyclopentenyne, followed by
elaboration and silver-promoted oxidation of the resulting chloroindene derivative. In addition to the total
synthesis of 1b, this work demonstrated, for the first time, the power of the intramolecular hetero [4+2]
cycloaddition reaction in the total synthesis of complex molecules and the application of the ruthenium-
catalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue
on the aromatic nucleus.
Introduction
in Figure 1, the conversion of the initially generated benzenoid
diradical 3 from the Bergman cycloaromatization of 2 required
The marine actinomycete Salinospora tropica is the producer
of salinosporamide A,1 a potent inhibitor of the 20S proteasome
that elicited considerable interest as a lead compound for cancer
chemotherapy.2 In addition to this natural product, the Fenical
group has recently disclosed the isolation, from the same species,
of sporolides A (1a) and B (1b) (Figure 1).3 Despite their
striking molecular architectures, the latter natural products
exhibited no biological activities for which they were tested.
Their conspicuous indanoid structural motif, however, gave rise
to the intriguing hypothesis4 that they are derived from the nine-
membered enediyne 2 (Figure 1), which was named pre-
sporolide,5 through a Bergman cycloaromatization.6 As shown
a hitherto unknown reaction, namely the sequential trapping of
the diradical with a chloride anion (ClQ) and a proton (Hx).
This mode of reactivity was later demonstrated by Perrin and
O’Connor through experimentation that included supporting
kinetic studies.7 Thus, it does appear that S. tropica produces,
in addition to salinosporamide A, a second, structurally distinct
cytotoxic agent, presporolide 2, whose rapid rearrangement and
subsequent reactions lead to the inactive, but revealing, sporolides
A (1a) and B (1b).
Fascinated by the unprecedented molecular structures of the
sporolides, and the interesting hypothesis regarding their origins,
we contemplated their total synthesis, an endeavor that we felt
could lead to new synthetic strategies and technologies and may
also serve as a prelude to a possible approach toward the more
challenging structure of presporolide (2) by virtue of its expected
strain and lability. In previous communications, we disclosed
preliminary results leading to the construction of a sporolide
model system (4, Figure 1)8 and sporolide B (1b).9 In this article,
we provide a full account of our investigation that led to the
(1) (a) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355–357.
(b) Williams, P. G.; Buchanan, G. O.; Feling, R. H.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. J. Org. Chem. 2005, 70, 6196–6203.
(2) (a) Macherla, V. R.; Mitchell, S. S.; Manam, R. R.; Reed, K. A.; Chao,
T.-H.; Nicholson, B.; Deyanat-Yazdi, G.; Mai, B.; Jensen, P. R.;
Fenical, W.; Neuteboom, S. T. C.; Lam, K. S.; Palladino, M. A.; Potts,
B. C. M. J. Med. Chem. 2005, 48, 3684–3687. (b) Palladino, M. A.;
Neuteboom, S. T. C.; Theodora, C.; Macherla, V. R.; Potts, B. C.
Patent WO 02005002572, 2005.
(3) (a) Buchanan, G. O.; Williams, P. G.; Feling, R. H.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731–2734. (b) Fenical,
W.; Jensen, P. R. Nature Chem. Biol. 2006, 2, 666–673. (c) Jensen,
P. R.; Williams, P. G.; Oh, D.-C.; Zeigler, L.; Fenical, W. Appl.
EnViron. Microbiol. 2007, 73, 1146–1152.
(6) (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
For selected reviews on naturally occurring enediynes exhibiting
Bergman cycloaromatization properties, see: (b) Nicolaou, K. C.; Dai,
W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387–1416. (c) Smith,
A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103–2117.
(7) Perrin, C. L.; Rodgers, B. L.; O’Connor, J. M. J. Am. Chem. Soc.
2007, 129, 4795–4799.
(4) (a) Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical,
W. Org. Lett. 2006, 8, 1021–1024. (b) McGlinchey, R. P.; Nett, M.;
Moore, B. S. J. Am. Chem. Soc. 2008, 130, 2406–2407. (c) Nett, M.;
Moore, B. S. Pure Appl. Chem. 2009, 81, 1075–1084.
(8) Nicolaou, K. C.; Wang, J.; Tang, Y. Angew. Chem., Int. Ed. 2008,
47, 1432–1435.
(5) Udwary, D. W.; Zeigler, L.; Asolkar, R. N.; Singan, V.; Lapidus, A.;
Fenical, W.; Jensen, P. R.; Moore, B. S. Proc. Natl. Acad. Sci. U.S.A.
2007, 104, 10376–10381.
(9) (a) Nicolaou, K. C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009,
48, 3449–3453. (b) Li, P.; Menche, D. Angew. Chem., Int. Ed. 2009,
48, 5078–5080.
9
11350 J. AM. CHEM. SOC. 2010, 132, 11350–11363
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Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Figure 1. Molecular structures of sporolide A (1a), sporolide B (1b),
presporolide (2), benzenoid diradical 3, sporolide model system 4, and 9-epi-
sporolide B (5).
Figure 2. Plausible synthetic approaches to sporolide B: path a, biomimetic
approach; path b, o-quinone [4+2] cycloaddition approach. P ) protecting
group.
total synthesis of sporolide B (1b) and its diastereoisomer, 9-epi-
sporolide B (5, Figure 1).
molecule. Path b reverses these two key steps and requires
substrate VI as an intermediate postulated to undergo an
intramolecular [4+2] cycloaddition11 involving its o-quinone
and indene structural motifs.
Results and Discussion
Initial Retrosynthetic Considerations and Model Studies.
Sporolides A (1a) and B (1b) share the same molecular structure
except for the location of the chlorine atom on the benzenoid
nucleus. Of their 24 carbons, 22 are either oxygenated or sp2
hybridized, forming a web of unusual structural motifs, including
a highly substituted indane system, a [1,4]-dioxane ring, an
epoxy cyclohexenone hemiacetal, and a 13-membered macrolide
moiety.3a Considering the unprecedented and complex molecular
architectures of the sporolides, the discovery and development
of new synthetic strategies and technologies were essential
prerequisites for a serious attempt of their total synthesis. Figure
2 outlines, in retrosynthetic format, two plausible approaches
to sporolide B (1b). Based on the postulated biosynthesis of
the sporolides (I + II f 1b),4b the first approach (path a, Figure
2) was considered risky, despite the rather conventional steps
required for its implementation, due to the expected lability of
some of the obligatory intermediates. Therefore, the second
approach, based on the rarely employed [4+2] cycloaddition
reaction of o-quinones10 (III + IV f 1b, path b, Figure 2),
became our preferred choice for initial exploration.
In order to test the viability of these two synthetic strategies
(paths a and b, Figure 3a), we designed model systems 4 and
4′ and pursued their synthesis from an o-quinone derivative or
surrogate (6 or 8, respectively, Figure 3b) and hydroxy indene
fragments (7 or 9, respectively, Figure 3b). Our first task toward
this goal was to prepare o-quinone 6 and study its reactivity
toward suitable indene fragments. Scheme 1 summarizes the
synthesis of this o-quinone starting with 3-methylsesamol
(10).12a Thus, activation of phenol 10 with MeMgBr,12b followed
by addition of glyoxalate 11, led to phenolic hydroxy ester 12
(10) (a) Horner, L.; Merz, H. Justus Liebigs Ann. Chem. 1950, 570, 89–
120. (b) Finley, K. T. In The Chemistry of Quinoid Compounds; Patai,
S., Rappoport, Z., Eds.; John Wiley & Sons: New York, 1988; Vol.
II, pp 538-717. (c) Nair, V.; Kumar, S. Synlett 1996, 1143–1147. (d)
Kharisov, B. I.; Mendez-Rojas, M. A.; Garnovskii, A. D.; Ivakhnenko,
E. P.; Ortiz-Mendez, U. J. Coord. Chem. 2002, 55, 745–770. (e) Aly,
A. A.; Ehrhardt, S.; Hopf, H.; Dix, I.; Jones, P. G. Eur. J. Org. Chem.
2006, 335–350. (f) Varma, R. L.; Ganga, V. B.; Sureshc, E.; Suresh,
C. H. Tetrahedron Lett. 2006, 47, 917–921.
(11) For recent examples of macrocyclization by standard cycloadditions,
see: (a) Zapf, C. W.; Harrison, B. A.; Drahl, C.; Sorensen, E. J. Angew.
Chem., Int. Ed. 2005, 44, 6533–6537. (b) Johannes, J. W.; Wen-
glowsky, S.; Kishi, Y. Org. Lett. 2005, 7, 3997–4000. (c) Baran, P. S.;
Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908–3909. (d) Snyder,
S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740–742.
(12) (a) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J. J. Org. Chem. 2005,
70, 4397–4408. (b) Casiraghi, G.; Cornia, M.; Rassu, G. J. Org. Chem.
1988, 53, 4919–4922.
In contemplating the o-quinone-based strategy toward sporolide
B (1b), the two approaches shown retrosynthetically in Figure
3 (both relying on the same bond disconnections) came to mind.
Path a requires an intermolecular o-quinone [4+2] cycloaddition
with an indene partner, followed by a macrolactonization of
seco acid V to forge the main ring skeleton of the target
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Scheme 1. Construction of o-Quinone 6a
a Reagents and conditions: (a) 10, MeMgBr (3.0 M in Et2O, 1.2 equiv),
THF, 0 °C, 0.5 h; then 11 (50% in toluene, 1.5 equiv), THF, 0 °C, 0.5 h,
98%; (b) BnBr (3.0 equiv), Cs2CO3 (2.0 equiv), NaI (1.0 equiv), DMF, 0
f 25 °C, 3 h, 92%; (c) TMSCHN2 (2.0 M in hexanes, 2.0 equiv), HBF4
(49% in H2O, 1.0 equiv), CH2Cl2, 0 f 25 °C, 2 h, 81%; (d) Pb(OAc)4 (1.5
equiv), benzene, 80 °C, 16 h; (e) AcOH:THF:H2O (10:5:1), 25 °C, 6 h,
95% for the two steps; (f) Ag2O (2.5 equiv), CH2Cl2, 25 °C, 15 min, 94%.
Bn ) benzyl, TMS ) trimethylsilyl.
p-quinone in the presence of DMP or CAN, it reacted smoothly
with Ag2O to afford the desired o-quinone 6 in 94% yield.
Since the mode of [4+2] cycloaddition reactions of o-
quinones with dienophiles depends on the nature of their
substituents and is often unpredictable,10 an initial investigation
of the reactivity of o-quinone 6 toward indenes was deemed
important. Scheme 2 summarizes a number of illuminating
observations made in this model study. Thus, reaction of 6 with
indene (16) in toluene at 110 °C proceeded smoothly but
afforded 1,2-cyclohexadione system 17 as a mixture with its
facial diastereoisomer 17′ (ca. 1.5:1 dr), products of the
undesired reactivity mode for the o-quinone that involved its
all-carbon diene system. The precise structure of this cycload-
duct was evident from its NMR spectroscopic analysis, including
the NOE correlation between the methyl group and its adjacent
proton as indicated on its structure (see 17, Scheme 2). The
exquisite regioselectivity of this cycloaddition reaction may be
explained by assuming polarization10e of the two reactants as
indicated on transition state 6,16-TS (see Scheme 2) and the
relatively low steric demands associated with the olefinic bond
of indene 16. This leads to the engagement of the dienophile
with the apparently more reactive, all-carbon diene system of
o-quinone 6. This reasoning led us to believe that by increasing
the steric demands10f of the indene dienophile through fusion
of the additional cyclopentane ring as required for our target
molecule, we may be able to reverse the reactivity mode of the
o-quinone component from the all-carbon diene to the 1,2-
dicarbonyl moiety. Indeed, indene derivative 1815 reacted with
o-quinone 6 under the same conditions as above to afford,
presumably through transition state 6,18-TS (see Scheme 2),
1,4-dioxane derivative 19 (ca. 1:1 mixture with its facial
diastereoisomer 19′) exclusively and in 57% yield. Needless to
say, this was exciting news, but before we describe the next
Figure 3. Retrosynthetic analysis of sporolide B (1b) and sporolide model
systems 4′ and 4.
in 98% yield. Reaction of the latter compound with BnBr in
the presence of Cs2CO3 and NaI resulted in selective formation
of hydroxy benzyl ether 13 (92% yield), which was methylated
(TMSCHN2, HBF4)13 to afford fully protected derivative 14.
Cleavage of the rather robust dioxolane ring within 14 was
achieved through sequential treatment with Pb(OAc)4 (benzene,
with heating)14 and AcOH, furnishing diphenol 15 in 95%
overall yield. Interestingly, while 15 proved inert toward DDQ
oxidation at ambient temperature and led to the corresponding
(13) Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1990, 31, 5507–5508.
(14) Hussain, H. H.; Babic, G.; Durst, T.; Wright, J. S.; Flueraru, M.;
Chichirau, A.; Chepelev, L. L. J. Org. Chem. 2003, 68, 7023–7032.
(15) Halterman, R. L.; Zhu, C. Tetrahedron Lett. 1999, 40, 7445–7448.
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Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Scheme 2. Intermolecular [4+2] Cycloaddition Reaction between Indene Derivatives and o-Quinone 6a
a Reagents and conditions: indene derivatives 16, 18, 20 (1.0 equiv), o-quinone 6 (1.2 equiv), toluene, 115 °C, 4 h 17,17′, 82%, ca. 1.5:1 dr; 19,19′, 57%,
ca. 1:1 dr; and 21,21′, 80%, ca. 10:1 dr.
phase of the campaign we should note that indene derivative
20 (Scheme 2) reacted with o-quinone 6 in yet another exquisite
mode. Specifically, this [4+2] cycloaddition reaction led to
carbocyclic system 21 as the major product in high yield (80%,
ca. 10:1 mixture with its facial diastereoisomer 21′), presumably
through transition state 6,20-TS as shown in Scheme 2. In this
case, the regioselectivity exhibited by the o-quinone moiety of
6 toward indene (i.e., 16) is preserved, whereas that of the
dienophile is now reversed, apparently due to the presence of
the polarizing carbonyl group within the indene partner. The
higher reactivity of the latter component may explain its ability
to overcome its steric demands and reach the more reactive,
but more sterically shielded, all-carbon diene system of o-
quinone 6. The structure of the observed major product 21,
preferentially crystallized from EtOAc/hexanes (mp 210-212
°C, acetone/hexanes), was unambiguously proven through X-ray
crystallographic analysis16 (see ORTEP representation, Figure
4).
These studies suggested that hydroxy indene derivative 7
(Scheme 3) might be an appropriate partner, indeed, for
o-quinone 6 in our first strategy toward sporolide model system
4′. Its construction from benzoic acid derivative 2217 is
summarized in Scheme 3. Thus, reduction of the carboxylic acid
moiety of 22 with borane (80% yield), followed by protection
of the resulting alcohol (dihydropyran, TsOH ·H2O, 95% yield),
Figure 4. ORTEP of 21 derived from X-ray crystallographic analysis (non-
hydrogen atoms are shown as 30% ellipsoids).
furnished THP ether 23. This benzyl bromide derivative (23)
was then used to alkylate cyclopentanone (24, LDA) to afford
aryl iodide 25 (65% yield), whose intramolecular Nozaki-
Hiyama-Kishi reaction (CrCl2, NiCl2)18 led to tricyclic tertiary
alcohol 26 in 76% yield. Exposure of the latter compound to
TsOH·OH caused both elimination of water and cleavage of
the THP ether to afford the desired hydroxy indene 7 in 82%
yield. The other required indene derivative 9 for model system
4 (path b, see Figure 3b) was formed from 7 by one-carbon
homologation in 76% overall yield through the standard four-
step sequence summarized in Scheme 3.
With both required fragments now available, we proceeded
to explore the first approach to the designed sporolide model
(16) CCDC-773715 contains the supplementary crystallographic data for
compound 21. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://www.ccdc.
cam.ac.uk/data_request/cif and are also available as Supporting
Information.
(17) Shankar, S.; Vaidyanathan, G.; Affleck, D.; Welsh, P. C.; Zalutsky,
M. R. Bioconjugate Chem. 2003, 14, 331–341.
(18) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281–5284. (b) Nicolaou, K. C.; Sorensen,
E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; pp 711-
730. (c) Fu¨rstner, A. Chem. ReV. 1999, 99, 991–1046.
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Scheme 3. Construction of Indene Derivatives 7 and 9a
Scheme 4. Synthesis of Dihydroxy Acid 31 and Failed Attempts To
Form Macrocycle 32 through Macrolactonizationa
a Reagents and conditions: (a) BH3 ·THF (1.0 M in THF, 2.0 equiv),
THF, 25 °C, 2 h, 80%; (b) DHP (1.2 equiv), TsOH ·H2O (0.1 equiv), CH2Cl2,
0 °C, 0.5 h, 95%; (c) 24 (1.3 equiv), LDA (1.3 equiv), THF:HMPA (5:1),
-78 f 0 °C, 1 h; then 23 (1.0 equiv), -78 f 25 °C, 2 h, 65%; (d) CrCl2
(4.0 equiv), NiCl2 (0.02 equiv), DMF, 100 °C, 16 h, 76%; (e) TsOH ·H2O
(0.1 equiv), benzene, 80 °C, 0.5 h; then MeOH, 25 °C, 0.5 h, 82%; (f)
DMP (1.2 equiv), NaHCO3 (3.0 equiv), CH2Cl2, 25 °C, 0.5 h, 95%; (g)
MeOCH2PPh3Br (1.5 equiv), KHMDS (0.5 M in toluene, 1.5 equiv), THF,
0 f 25 °C, 2 h, 96%; (h) HCl (aq., 2.0 N, 4.0 equiv), THF, 60 °C, 3 h,
88%; (i) NaBH4 (1.1 equiv), THF:MeOH (5:1), 0 °C, 0.5 h, 95%. DHP )
3,4-dihydro-2H-pyran, DMP ) Dess-Martin periodinane, HMPA )
hexamethylphosphoramide, KHMDS ) potassium hexamethyldisilazane,
LDA ) lithium diisopropylamide, Ts ) p-toluenesulfonyl.
system 4′ involving, in that order, the [4+2] cycloaddition and
macrolactonization reactions, as outlined in Scheme 4. Thus,
heating hydroxyl indene derivative 7 with o-quinone 6 in toluene
at 115 °C led, as expected, and presumably through transition
state 6,7-TS, to 1,4-dioxa cycloadduct 27, together with its facial
diastereoisomer 27′, in 62% combined yield (ca. 1:1 dr). This
mixture was taken forward through the rest of the sequence in
order to test the key macrolactonization step. Oxidation of
27+27′ (DMP, 88% yield), followed by olefination of the
resulting aldehyde (28+28′, CH2dPPh3), furnished styrene
derivative 29 (together with its facial diastereoisomer 29′),
whose asymmetric dihydroxylation (AD-mix ꢀ)19 afforded diols
30+30′ (93% yield). Finally, saponification of the ethyl ester
moiety within 30+30′ (LiOH) furnished seco acids 31+31′
(98% yield). All attempts to macrolactonize 31+31′ through
either carboxyl20 or hydroxyl activation21 (see legend, Scheme
4) failed to produce any detectable amounts of the desired model
system 32 (or its facial diastereoisomer 32′), presumably due
to overwhelming strain within the expected transition state for
the macrolactonization reaction. These failures led us to the
second, and more daring, appoach involving the risky intramo-
lecular [4+2] cycloaddition as the means to forge the sporolide
framework.
a Reagents and conditions: (a) 6 (1.0 equiv), 7 (1.2 equiv), toluene, 115
°C, 3 h, 62% [27+27′ (not shown), ca. 1:1 dr]; (b) DMP (1.5 equiv),
NaHCO3 (5.0 equiv), CH2Cl2, 25 °C, 0.5 h, 88% [28+28′ (not shown), ca.
1:1 dr]; (c) MePPh3Br (4.5 equiv), KHMDS (0.5 M in toluene, 3.0 equiv),
THF, -78 f 25 °C, 0.5 h; then 28+28′ (ca. 1:1 dr, 1.0 equiv), THF, -78
f 25 °C, 0.5 h, 91% [29+29′ (not shown), ca. 1:1 dr]; (d) AD-mix ꢀ (1.4
g per 1.0 mmol of 29+29′), t-BuOH:H2O (1:1), 0 °C, 4 h, 93% [30+30′
(not shown), ca. 1:1 dr]; (e) LiOH (30 equiv), dioxane:H2O (5:1), 80 °C,
6 h, 98% [31+31′ (not shown), ca. 1:1 dr]; (f) carboxylic acid activation
methods (Corey-Nicolaou,22 Yamaguchi,23 cyanuric chloride,24 Mukaiyama
salt,25 Shiina26); alcohol activation method (Mitsunobu21).
Coupling of the latter intermediate with hydroxy indene 9 (see
Scheme 3 for preparation) through DCC/4-DMAP esterification
(19) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.
J. Org. Chem. 1992, 57, 2768–2771. (b) Kolb, H. C.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483–2547.
(20) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006, 106,
911–939.
Scheme 5 summarizes the intramolecular o-quinone [4+2]
cycloaddition approach to sporolide model system 4 from
fragments 15 and 9. Thus, catechol 15 was protected as
orthoester 33 [CH(OEt)3, TsOH ·H2O, 96% yield], which was
saponified (LiOH, 99% yield) to afford carboxylic acid 34.
(21) (a) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976,
17, 2455–2458. (b) Mitsunobu, O. Synthesis 1981, 1–28. (c) Hughes,
D. L. Org. React. 1992, 42, 335–656. (d) Hughes, D. L. Org. Prep.
Proced. Int. 1996, 28, 127–164.
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Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Scheme 5. Synthesis of Sporolide Model System 4a
a Reagents and conditions: (a) CH(OEt)3 (2.0 equiv), TsOH ·H2O (0.2
equiv), 4 Å MS (80 mg per mmol of 15), benzene, 80 °C, 16 h, 96%; (b)
LiOH (20 equiv), dioxane:H2O (5:1), 80 °C, 3 h, 99%; (c) 34 (1.25 equiv),
9 (1.0 equiv), DCC (1.3 equiv), 4-DMAP (0.2 equiv), CH2Cl2, 25 °C, 3 h,
84%; (d) TsOH ·H2O (0.05 equiv), MeOH, 25 °C, 24 h, 98%; (e) one-step
procedure: Ag2O (2.0 equiv), toluene (c ) 0.005 M solution), 120 °C, 1 h,
60%; two-step procedure: (i) Ag2O (2.0 equiv), CH2Cl2, 25 °C, 5 min, 99%;
(ii) toluene (c ) 0.005 M solution), 120 °C, 3 h, 50%; (f) H2 (balloon),
Pd(OH)2/C (20 wt %), EtOH, 25 °C, 14 h, 85%; (g) PIFA (1.05 equiv),
PMBOH (10.0 equiv), K2CO3 (5.0 equiv), MeCN, 0 f 25 °C, 5 min, 87%;
(h) DDQ (1.5 equiv), CH2Cl2:H2O (10:1), 25 °C, 15 h, 96%; (i) t-BuOOH
(5.0 equiv), DBU (0.2 equiv), CH2Cl2, 40 °C, 24 h, 60%. DBU ) 1,8-
diazabicyclo[5.4.0]undec-7-ene, DCC ) N,N′-dicyclohexylcarbodiimide,
DDQ ) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 4-DMAP ) 4-dim-
ethylaminopyridine, PIFA ) phenyliodine bis(trifluoroacetate), PMB )
p-methoxybenzyl.
Figure 5. Four possible diastereoisomers of macrolide 38 (a-d) and
rationale for the exclusive formation of the only isomer (i.e., 38a).
compound served as a precursor, first to o-quinone 37 and then
to the desired, doubly cyclized cycloadduct 38a. Thus, heating
the deep-red solution of 36 in toluene at 120 °C (oil bath) in
the presence of Ag2O afforded compound 38a, presumbly
through o-quinone 37, in 60% isolated yield. Indeed, the latter
intermediate was prepared from 36 by oxidation with Ag2O at
room temperature (99% yield) and, when heated in toluene at
120 °C, furnished compound 38a in 50% yield. This product
was obtained as a single diastereoisomer (out of the four possible
diastereoisomers, 38a-d, shown in Figure 5). Its structure was
consistent with its NMR spectral data, including the 13C NMR
chemical shifts for the two newly formed tertiary dioxane
led to ester 35 (84% yield), whose exposure to TsOH ·H2O
afforded catechol ester 36 in 98% yield. Pleasantly, the latter
9
J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010 11355

A R T I C L E S
Nicolaou et al.
Figure 7. ORTEP of sporolide model system 4 derived from X-ray
crystallographic analysis (atoms are shown as 30% ellipsoids).
Figure 6. ORTEP of compound 39 derived from X-ray crystallographic
analysis (atoms are shown as 30% ellipsoids).
yield), whose exposure to PIFA28 in the presence of PMBOH
and K2CO3 led to p-hemiquinone 40 in 87% yield. Treatment
of the latter intermediate with DDQ gave p-hydroxy hemiquinol
41 (96% yield), which underwent selective epoxidation (t-
BuOOH, DBU, 40 °C)29 under controlled conditions to afford
the targeted sporolide model system 4 in 60% yield. The regio-
and stereocontrol observed in the latter reaction was ensured
not only by the directing effect of the hemiacetal moiety but
also by the shielding effects imposed upon the top face of the
olefinic bond by the macrocyclic structural motif of the substrate
(41). That all structural motifs were present within 4 (mp
218-219 °C, acetone/hexanes) in their proper stereochemical
arrangements was proven through an X-ray crystallographic
analysis30 (see ORTEP representation, Figure 7)
Unsuccessful Forays toward Sporolide B. The successful
model study culminating in the synthesis of sporolide model
system 4 set the foundation for the next phase of the program
toward the total synthesis of 1b, the sporolide chosen as our
synthetic target molecule. The two approaches considered
toward sporolide B (1b) are shown retrosynthetically in Figure
8. Path a was based on the obvious disconnection of the ester
bond within advanced precursor VII obtained through disas-
sembly of the 1,4-dioxane ring of sporolide B (1b), as depicted.
This analysis led to key building blocks carboxylic acid VIII
and hydroxy chloroindene IX as the requisite fragments for the
projected synthetic strategy.
Although a synthesis of enantiopure carboxylic acid VIII (P
) Bn) could be secured (see below), repeated attempts to
construct hydroxy chloroindene IX through conventional meth-
ods were met with difficulties, presumably due to the sensitive
and crowded nature of this molecule. These failures let us to
consider the alternative strategy (path b) shown in Figure 8 as
a possible avenue to reach the desired precursor VII. In this
scenario, the chlorobenzenoid nucleus in VII was disassembled
through a metal-catalyzed [2+2+2] cycloaddition31 that led to
propargylic alcohol 42 and chloroacetylene enyne 43 as the
desired building blocks for sporolide B (1b). These building
blocks were then traced back to even simpler starting materials
through the disconnections indicated on their structures (see
Figure 8).
carbons (δ ) 101.5 and 98.3 ppm, 150 MHz, CDCl3). An X-ray
crystallographic analysis27 of the debenzylated derivative (39,
mp 233-234 °C, acetone/hexanes) of 38a provided unambigu-
ous proof of its structure as shown (see ORTEP representation,
Figure 6). This stereochemical outcome can be attributed to a
combination of electronic and steric effects, as shown in Figure
5. Electron donation from the benzyl ether oxygen toward the
C6′ carbonyl oxygen results in polarization of the o-quinone
system of substrate 37. The partial negative charge (δ-) on this
oxygen atom matches the partial positive charge (δ+) on the
C10 indene olefinic carbon, thereby providing guidance for
the regiochemical outcome of the ensuing [4+2] cycloaddition.
The other factors controlling the outcome of this reaction include
steric effects (1,3-allylic strain) and feasibility of bond formation
(ability of the two polarized ends to reach each other to form a
bond). As depicted in Figure 5, from the four possible transition
states (38a-d-TS), only 38a-TS, leading to the desired product
38a, is favored by both electronic matching and sterics. Indeed,
in this case the OMe group (front) resides opposite the OBn
(back), and the Oδ- is well positioned beneath the Cδ+ for
bonding interaction and ring formation. Transition state 38b-
TS suffers from 1,3-allylic strain (OBn group resides on the
same side as the OMe group, both in back). Transition state
38c-TS suffers from both 1,3-allylic strain (both OBn and OMe
in front) and a mismatch of the positions of the partial charges
(δ- front, δ+ back). Transition state 38d-TS suffers from a
mismatch of the positions of the partial charges (δ+ front, δ-
back). In view of these considerations, the fact that only product
38a is formed in this intramolecular [4+2] cycloaddition is no
surprise.
Having secured key intermediate 38a, its further elaboration,
requiring dearomatization and appropriate functionalization, was
undertaken (Scheme. 5). Thus, hydrogenolysis of the benzyl
ether within 38a [H2, Pd(OH)2/C] furnished phenol 39 (85%
(22) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–
5616.
(23) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(24) Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1980, 21, 1893–
1896.
(28) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52,
3927–3930.
(25) Mikaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49–50.
(26) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535–
7539.
(29) Zilbeyyaz, K.; Sahin, E.; Kilic, H. Tetrahedron: Asymmetry 2007, 18,
791–796.
(27) CCDC-667552 contains the supplementary crystallographic data for
compound 39. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://www.ccdc.
cam.ac.uk/data_request/cif and are also available as Supporting
Information.
(30) CCDC-669253 contains the supplementary crystallographic data for
compound 4. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://www.ccdc.
cam.ac.uk/data_request/cif and are also available as Supporting
Information.
9
11356 J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010

Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Scheme 6. Construction of Propargylic Alcohol 42a
a Reagents and conditions: (a) MePPh3Br (1.5 equiv), KHMDS (1.0 M
in toluene, 1.2 equiv), THF, -78 f 0 °C, 0.5 h; then 44, THF, -78 f 0
°C, 0.5 h, 98%; (b) AD-mix ꢀ (1.4 g per mmol of 45), t-BuOH:H2O (1:1),
25 °C, 8 h, 96%, 98% ee by chiral HPLC; (c) TBSCl (1.5 equiv), Et3N
(1.5 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 25 °C, 8 h, 99%; (d) t-BuOK
(3.0 equiv), MeI (4.0 equiv), MeCN, 0 f 25 °C, 16 h, 95%; (e) n-Bu4NF
(1.0 M in THF, 1.5 equiv), THF, 25 °C, 16 h, 99%; (f) DMP (1.5 equiv),
NaHCO3 (5.0 equiv), CH2Cl2, 25 °C, 1 h, 78%; (g) NaClO2 (4.5 equiv),
NaH2PO4 ·2H2O (3.0 equiv), 2-methyl-2-butene (2.5 equiv), t-BuOH:H2O
(1:1), 25 °C, 0.5 h, 96%; (h) 49 (1.3 equiv), EDCI (1.2 equiv), 4-DMAP
(0.2 equiv), CH2Cl2, 25 °C, 3 h, 73%; (i) Pb(OAc)4 (1.5 equiv), benzene,
75 °C, 1 h, 89%. EDCI ) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride.
and removal of the TBS group (TBAF, 99% yield). Generation
of the corresponding aldehyde from primary alcohol 47 (DMP,
78% yield) followed by Pinnick oxidation (96% yield, 98% ee,
chiral HPLC) then led to carboxylic acid 48. This intermediate
proved rather sensitive to racemization even on standing, and,
therefore, was freshly prepared and coupled with acetylenic diol
4933 in the presence of EDCI and 4-DMAP to afford hydroxy
ester 50 in 73% yield. At this point, it was necessary to partially
(31) (a) Shore, N. E. Chem. ReV. 1988, 88, 1081–1119. (b) Saito, S.;
Yamamoto, Y. Chem. ReV. 2000, 100, 2901–2916. (c) Varela, J. A.;
Sa, C. Chem. ReV. 2003, 103, 3787–3802. (d) Henry, G. D. Tetrahe-
dron 2004, 60, 6043–6061. (e) Yamamoto, Y. Curr. Org. Chem. 2005,
9, 503–509. (f) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 70, 4741–4761. (g) Chopade, P. R.; Louie, J. AdV. Synth.
Catal. 2006, 348, 2307–2327. (h) Tanaka, K. Synlett 2007, 1977–
1993. (i) Heller, B.; Hapke, M. Chem. Soc. ReV. 2007, 36, 1085–
1094. (j) Agenet, N.; Busine, O.; Slowinski, F.; Gandon, V.; Aubert,
C.; Malacria, M. Org. React. 2007, 68, 1–302. (k) Shibata, T.;
Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317–1323. (l) Galan,
B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830–2834.
(32) Saito, N.; Tashiro, K.; Maru, Y.; Yamaguchi, K.; Kubo, A. J. Chem.
Soc., Perkin Trans. 1 1997, 53–69.
Figure 8. Retrosynthetic analysis (path a, top; path b, bottom) of sporolide
B (1b).
The hydroxy ester fragment 42 was synthesized through
coupling and elaboration of carboxylic acid 48 and acetylenic
diol 49, starting with benzaldehyde derivative 44,32 as sum-
marized in Scheme 6. Thus, methylenation of aldehyde 44
(Ph3PdCH2, 98% yield) followed by asymmetric dihydroxyla-
tion (AD-mix ꢀ)19 of the resulting styrene 45 furnished 1,2-
diol 46 in 96% yield and 98% ee (chiral HPLC). Conversion
of the latter compound to methoxy primary alcohol 47 required
temporary silylation of the primary alcohol (TBSCl, 99% yield),
methylation of the secondary alcohol (t-BuOK, MeI, 95% yield),
(33) Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett. 1988,
29, 2737–2740.
9
J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010 11357

A R T I C L E S
Nicolaou et al.
Scheme 7. Construction of Chloroacetylenic Enyne 43a
oxidize the methylene protecting moiety within 50 in order to
facilitate its pending rupture under mild conditions at a later
stage. This was accomplished through the action of Pb(OAc)4
in benzene14 at 75 °C, which afforded acetoxy derivative 42 in
89% yield.
The readily available iodocyclopentenone 5134 served as an
excellent precursor to the desired chloroacetylenic enyne
fragment 43, as shown in Scheme 7. Thus, Luche reduction
(NaBH4, CeCl3 ·7H2O)35 of 51 followed by benzylation (BnBr,
NaH, n-Bu4NI) of the resulting secondary alcohol furnished
vinyl iodide 52 in 95% overall yield. Carboxymethylation36 of
the latter compound [CO, Pd(PPh3)2Cl2, MeOH] afforded methyl
ester 53 in 95% yield. A sequence of four steps was then
employed to convert ester 53 to enone 54 [(i) DIBAL-H, 95%
yield; (ii) DHP, TsOH ·H2O; (iii) TBAF, (iv) DMP, 83% overall
yield for the three steps]. Iodination (I2, 80% yield) of this enone
(54) afforded iodoenone 55, whose CBS reduction [(S)-CBS-
Me]37 and TBS protection of the so-obtained alcohol (ca. 10:1
dr) led to the intended TBS ether 56 in 97% overall yield for
the two steps. Incidently, reduction of iodoenone 55 under
standard Luche reduction conditions35 led, as expected on steric
grounds, to the corresponding 1,4-syn diol. Sonogashira cou-
pling38 of vinyl iodide 56 with TMS acetylene (79% yield) then
furnished, after THP cleavage (Et2AlCl) and DMP oxidation
(73% yield for the two steps), aldehyde 57. This aldehyde was
added to lithio chloroacetylene, generated in situ from cis-1,2-
dichloroethylene and MeLi,39 to give propargylic alcohol 58
(ca. 7:1 dr, chelation-controlled, see path a in 57-TS, Scheme
7) in 79% yield. Pure 58 was obtained at this stage by
chromatographic removal of all other minor diastereoisomers
obtained in the CBS reduction (55 f 56) and the lithio
chloroacetylene addition (57 f 58). Finally, the TMS group
was removed from intermediate 58 with K2CO3 in MeOH to
afford compound 59, whose hydroxy group was acetylated,
leading to the targeted fragment chloroacetylenic enyne 43 in
93% yield for the two steps.
With both fragments acetylenic ester 42 and chloroacetylenic
enyne 43 in hand, their [2+2+2] cycloaddition to form the
desired indene structural motif became the next task. As shown
in Scheme 8, it was found that reaction of these compounds in
the presence of catalytic amounts of Cp*RuCl(COD)40 at
ambient temperature furnished a single regioisomer (77% yield)
whose structure was determined to be that depicted as 60 (for
a mechanistic rationale for this outcome, see below). Acetylation
of the lone hydroxyl group within the latter intermediate (Ac2O,
4-DMAP, Et3N, 81% yield), followed by treatment with aqueous
HF, caused desilylation and liberation of the catechol moiety
(50% yield, unoptimized) to afford diphenolic hydroxy diacetate
61, in which the C-11 stereocenter had apparently epimerized
a Reagents and conditions: (a) NaBH4 (1.2 equiv), CeCl3 ·7H2O (1.2
equiv), MeOH, -78 °C, 1 h; (b) NaH (60% in mineral oil, 1.5 equiv),
THF, 0 °C, 0.5 h; then BnBr (1.5 equiv), n-Bu4NI (0.2 equiv), THF, 0 f
25 °C, 16 h, 95% for the two steps (ca. 10:1 dr); (c) Pd(PPh3)2Cl2 (0.05
equiv), Et3N (5.0 equiv), CO (balloon), MeOH, 70 °C, 3 h, 95%; (d)
DIBAL-H (1.0 M in toluene, 2.5 equiv), toluene, -78 f -10 °C, 1 h,
95%; (e) DHP (1.5 equiv), TsOH ·H2O (0.1 equiv), CH2Cl2, 0 °C, 0.5 h;
(f) n-Bu4NF (1.0 M in THF, 1.5 equiv), THF, 25 °C, 3 h; (g) DMP (1.2
equiv), NaHCO3 (5.0 equiv), CH2Cl2, 25 °C, 0.5 h, 83% for the three steps;
(h) I2 (3.0 equiv), CH2Cl2:pyridine (1:1), 25 °C, 15 h, 80%; (i) (S)-CBS-
Me (1.0 M in toluene, 0.1 equiv), BH3 ·THF (1.0 M in THF, 1.3 equiv),
THF, -30 °C, 2 h, 99%; (j) TBSCl (2.0 equiv), imidazole (2.0 equiv),
4-DMAP (0.1 equiv), CH2Cl2, 25 °C, 16 h, 97%; (k) TMS acetylene (1.5
equiv), Pd(PPh3)2Cl2 (0.02 equiv), CuI (0.04 equiv), Et2NH, 25 °C, 16 h,
79%; (l) Et2AlCl (1.8 M in toluene, 2.0 equiv), CH2Cl2, -25 f 25 °C, 3 h;
(m) DMP (1.5 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 25 °C, 0.5 h, 73% for
the two steps; (n) cis-1,2-dichloroethylene (4.5 equiv), MeLi (1.6 M in Et2O,
3.0 equiv), Et2O, 0 °C, 0.5 h; then 57, Et2O, 0 °C, 15 min, 79% of pure 58
(ca. 7:1 dr, all the undesired diastereoisomers were chromatographically
removed at this stage); (o) K2CO3 (1.5 equiv), MeOH, 25 °C, 1 h, 99%;
(p) Ac2O (1.5 equiv), Et3N (2.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0
°C, 0.5 h, 93%. (S)-CBS-Me ) (S)-(-)-2-methyl-CBS-oxazaborolidine.
(34) (a) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014–
11015. (b) Curran, T. T.; Hay, D. A.; Koegel, C. P. Tetrahedron 1997,
53, 1983–2004.
(35) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(36) Pichlmaira, S.; de Lera Ruiza, M.; Basua, K.; Paquette, L. A.
Tetrahedron 2006, 62, 5178–5194.
(37) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012.
(38) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467–4470. (b) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997,
62, 1582–1583.
(ca. 1:1 dr). This mixture was oxidized with Ag2O to furnish
o-quinone 62 in 89% yield (mixture of C-11 diastereoisomers,
ca. 1:1 dr). Attempts to induce the desired intramolecular [4+2]
cycloaddition of substrate 62 (heating in toluene up to 120 °C),
however, failed, leading to either no reaction or decomposition,
(39) Phillips, D.; Wickham, P.; Potts, G.; Arnold, A. J. Med. Chem. 1968,
11, 924–928.
(40) (a) Yamamoto, Y.; Ogawa, R.; Itoh, K. Chem. Commun. 2000, 549–
550. (b) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am.
Chem. Soc. 2003, 125, 12143–12160. (c) Oshima, N.; Suzuki, H.;
Moro-oka, Y. Chem. Lett. 1984, 13, 1161–1164.
9
11358 J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010

Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Scheme 8. Synthesis of o-Quinone 62 and Failed Attempt To
Induce Its Intramolecular [4+2] Cycloaddition Reactiona
Scheme 9. Synthesis of Chloro Enediyne 64a
a Reagents and conditions: (a) NaBH4 (1.2 equiv), CeCl3 ·7H2O (1.2
equiv), MeOH, -78 °C, 1 h, 99%, ca. 10:1 dr; (b) TBSCl (2.0 equiv),
imidazole (2.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 25 °C, 3 h, 95%; (c)
TMS acetylene (1.2 equiv), Pd(PPh3)2Cl2 (0.02 equiv), CuI (0.04 equiv),
Et2NH, 25 °C, 16 h, 98%; (d) Et2AlCl (1.8 M in toluene, 2.0 equiv), CH2Cl2,
-25 f 25 °C, 2 h, 99%; (e) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2,
25 °C, 1 h, 79%; (f) cis-1,2-dichloroethylene (4.5 equiv), MeLi (1.6 M in
Et2O, 3.0 equiv), Et2O, 0 °C, 0.5 h; then 68, Et2O, 0 °C, 10 min, ca. 5:1 dr;
(g) DMP (1.5 equiv), NaHCO3 (5.0 equiv), 25 °C, 0.5 h, 93% for the two
steps; (h) DIBAL-H (1.0 M in toluene, 1.5 equiv), toluene, -78 °C, 0.5 h,
81% of pure 70 (ca. 7:1 dr, all the undesired diastereoisomers were
chromatographically removed at this stage); (i) K2CO3 (1.5 equiv), MeOH,
25 °C, 1 h, 99%; (j) Ac2O (1.5 equiv), Et3N (1.5 equiv), 4-DMAP (0.1
equiv), CH2Cl2, 0 °C, 0.5 h, 98%.
a Reagents and conditions: (a) 42 (1.0 equiv), 43 (1.0 equiv),
Cp*RuCl(COD) (0.10 equiv), DCE, 25 °C, 0.5 h, 77%; (b) Ac2O (2.0 equiv),
Et3N (2.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0 °C, 0.5 h, 81%; (c) HF
(48% aqueous solution, excess), MeCN, 25 °C, 0.5 h; then MeOH (excess),
25 °C, 3 h, 50%; (d) Ag2O (2.5 equiv), CH2Cl2, 25 °C, 0.5 h, 89%. COD
) 1,5-cyclooctadiene, Cp* ) pentamethylcyclopentadienyl, DCE )
1,2-dichloroethane.
cycloaddition imposed by this substituent. The new strategy
required chloroacetylene 64 (Scheme 9) as a key building block.
Its synthesis from the readily available iodoenone 6541 is
summarized in Scheme 9.
with no detectable amounts of the expected cycloadduct 63. The
steric clash encountered by the approaching o-quinone moiety
with the OBn group (see transition state 62-TS, Scheme 8) is
apparently prohibitive.
Total Synthesis of 9-epi-Sporolide B. Having failed to induce
the intramolecular [4+2] cycloaddition reaction with the
o-quinone-indene substrate possessing the desired C-9 con-
figuration for sporolide B, we resorted to a modified strategy
involving a substrate with the C-9 inverted stereochemistry in
order to remove the steric barrier to the intended [4+2]
Thus, Luche reduction35 of iodoenone 65 furnished hydroxy
compound 66 (ca. 10:1 dr), which was converted to its TBS
ether 67 (TBSCl) in 94% overall yield. Sonogashira coupling
of 67 with TMS acetylene (Pd(PPh3)2Cl2 catalyst, CuCl catalyst,
(41) Iodoenone 65 was prepared following the same chemical transforma-
tion steps as depicted in Scheme 7 (51 f 56), starting from the
opposite enantioisomer of 51.
9
J. AM. CHEM. SOC. VOL. 132, NO. 32, 2010 11359

A R T I C L E S
Nicolaou et al.
Scheme 10. Synthesis of o-Quinone 75a
Et2NH, 98% yield), followed by THP removal (Et2AlCl, 99%
yield) and DMP oxidation (79% yield), led to aldehyde 68.
Addition of the latter substrate to the lithio derivative of
chloroacetylene, generated from 1,2-cis-dichloroethylene, re-
sulted in the formation of propargylic alcohol 69 as the major
product (ca. 5:1 dr, chelation-controlled, see transition state 68-
TS, Scheme 9), possessing the undesired 11(R) configuration.
Attempts to invert the C-11 stereocenter through the Mitsunobu
reaction failed, prompting us to adopt an oxidation (DMP)-
reduction (DIBAL-H) protocol, which led to the 11(S) propar-
gylic alcohol 70 in a ca. 7:1 dr (steric effect, see depiction 69a,
Scheme 9) and 95% combined yield. Chromatographic purifica-
tion at this stage led to pure isomer 70 (81% yield), from which
the TMS group was removed (K2CO3, MeOH, 99% yield) to
afford hydroxy acetylene 71, whose acetylation under standard
conditions furnished the coveted chloroacetylenic enyne frag-
ment 64 (98% yield).
As previously (see Scheme 8 above), the [2+2+2] fusion of
acetylenic fragments 42 and 64 under the influence of
Cp*RuCl(COD) catalyst40 was expected to proceed regioselec-
tively toward the desired meta-substituted chlorobenzyl alcohol
system 72 (see Scheme 10). This expectation was based on the
established mechanism of the reaction (see Figure 9),40 which
dictated a preference, due to steric control, for only one
orientation (out of the four possible) for the approach of the
propargylic component (i.e., 42) to the initially formed metal-
locycle (see transition state XI, Figure 9). As seen from
inspection of the alternative transition state XI′ (Figure 9), this
orientation of the two reacting species suffers from severe steric
clash between the bulky R group and the ruthenium and its
ligand entourage, and, therefore, does not provide a productive
pathway. Similarly, the other two orientations (not shown) of
the propargylic component on the side of the metallocycle
chlorine residue are disfavored due to steric repulsion, from
either the ruthenium moiety or the chlorine residue, and are,
therefore, nonproductive. Indeed, exposure of a mixture of
chloroacetylenic enyne 64 (1.1 equiv) and propargylic alcohol
ester 42 (1.0 equiv) to Cp*RuCl(COD) catalyst in 1,2-dichlo-
roethane at room temperature for 0.5 h led to chloroindene 72
in 87% yield. The ortho-substituted product 72′ that would have
been formed through transition states XI′ and XII′ (Figure 9)
was not observed. The impressively short reaction time of this
process was attributed to a possible coordination of the free
hydroxyl group onto the ruthenium nucleus that may help in
the initial anchoring of the hydroxy acetylene onto the metal
(see XI, Figure 9). Supporting this notion was the observation
that the corresponding acetyl-protected propargylic substrate (not
shown) reacted with chloroacetylenic enyne 64 in the presence
of Cp*RuCl(COD) catalyst under the same conditions signifi-
cantly slower (ca. 10-fold) and with eroded regioselectivity (ca.
10:1). Erosion of regioselectivity (meta:ortho regioisomers, ca.
20:1 f 10:1) was also observed in the rhodium-catalyzed
reaction (Wilkinson’s catalyst) of 42 and 64, which, however,
proceeded equally well to afford the desired chloroindene 71
(85% combined yield). Proceeding toward the targeted o-
quinone 75 (Scheme 10), the exclusively obtained hydroxy
chloroindene product 72 was acetylated (Ac2O, 4-DMAP, Et3N,
92% yield), and the resulting product 73 was treated initially
with aqueous HF in MeCN and then with MeOH to cleave both
the silyl ether and the acetoxy acetal moiety, furnishing hydroxy
catechol 74 in 74% yield. The latter compound was then
smoothly oxidized with Ag2O to afford the desired o-quinone
75 in 94% yield.
a Reagents and conditions: (a) 42 (1.0 equiv), 64 (1.1 equiv),
Cp*RuCl(COD) (0.07 equiv), DCE, 25 °C, 0.5 h, 87%; (b) Ac2O (2.0 equiv),
Et3N (2.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0 °C, 0.5 h, 92%; (c) HF
(48% aqueous solution, excess), MeCN, 25 °C, 0.5 h; then MeOH (excess),
25 °C, 3 h, 74%; (d) Ag2O (2.5 equiv), CH2Cl2, 25 °C, 0.5 h, 94%.
With o-quinone 75 in hand, we were now ready to attempt
the much anticipated intramolecular [4+2] cycloaddition reac-
tion (which had failed previously with the correct C-9 sporolide
stereochemistry as discussed above, see Scheme 8). This time,
and much to our delight, heating 75 at 110 °C in toluene for
1.5 h resulted in the formation of the desired cycloadduct 76 as
a single isomer and in 40% yield (based on 50% consumed
starting material, Scheme 11). Repeated attempts to improve
the yield of this reaction (e.g., prolonged or shortened reaction
times, lower or higher temperatures, Lewis acid catalysts,
microwaves) proved fruitless, apparently due to the sensitivity
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Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
Figure 9. Mechanistic rationale for the exclusive regioselectivity of the ruthenium-catalyzed [2+2+2] cycloaddition reaction of acetylenic components 42
and 64 to afford indene 72.
of both the substrate 75 and the product 76. Due to the
robustness of the sequence leading up to o-quinone 75, however,
sufficient quantities of sporolide scaffold 76 could be secured
Scheme 11. Intramolecular Hetero [4+2] Cycloaddition Reaction of
o-Quinone 75a
for further elaboration. The impressive exclusivity by which
cycloadduct 76 is formed from 75 can be explained, as in the
case of model system 4 (see above, Scheme 5 and Figure 5),
upon inspection (manual molecular models) of postulated
transition states [75-TS and 75-TS′ (generated by 180° rotation
around the C2′-C3′ bond), see Scheme 11] that reveals the
difficulties with 75-TS′ (inhibitive 1,3-allylic strain) and the
impossibility of the other two diastereofacial arrangements (not
shown).
At this stage and with sporolide B scaffold 76 in hand, we
opted to explore the pending sequence to 9-epi-sporolide B (5,
see Scheme 12) not only to obtain a new sporolide entity, but
also as a means to scout the chemistry ahead in preparation for
the final drive toward our ultimate target, sporolide B (1b)
(which required inversion of configuration at C-9). Only five
steps were needed to reach 9-epi-sporolide B (5) from inter-
mediate 76. Thus, and as shown in Scheme 12, hydroxy
compound 76 was acetylated (Ac2O, 4-DMAP, Et3N) to afford
triacetate 77 (92% yield), from which both benzyl groups were
removed through hydrogenolysis [H2, Pd(OH)2/C, 92% yield],
leading to hydroxy phenol 78. The phenol moiety of the latter
compound was dearomatized by reaction with PIFA in MeCN
in the presence of H2O and K2CO3 at 0 °C to afford p-
hemiquinol 79 in a regio- and stereoselective manner (66%
yield). All three acetates were then removed from 79 through
the action of DBU in CH2Cl2:MeOH (3:1) at 40 °C, leading to
3′,4′-deoxy-9-epi-sporolide B (80) in 77% yield. Finally, the
remaining oxygen atom was successfully installed onto the latter
intermediate regio- and stereoselectively, as expected on steric
a Conditions: (a) toluene, 110 °C, 1.5 h, 40% (based on 50% recovered
grounds, through the use of t-BuOOH and DBU in CH2Cl2 at
starting material).
40 °C, furnishing 9-epi-sporolide B (5) in 72% yield.
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A R T I C L E S
Nicolaou et al.
Scheme 12. Synthesis of 9-epi-Sporolide B (5)a
Scheme 13. Total Synthesis of Sporolide B (1b)a
a Reagents and conditions: (a) Ac2O (2.0 equiv), Et3N (2.0 equiv),
4-DMAP (0.10 equiv), CH2Cl2, 0 °C, 0.5 h, 92%; (b) H2 (balloon), Pd(OH)2
(10% on carbon, 2.0 equiv), EtOAc, 25 °C, 4 h, 92%; (c) PIFA (2.0 equiv),
H2O (2.0 equiv), K2CO3 (5.0 equiv), MeCN, 0 °C, 0.5 h, 66%; (d) DBU
(10.0 equiv), CH2Cl2:MeOH (3:1), 40 °C, 4 h, 77%; (e) t-BuOOH (10.0
equiv), DBU (5.0 equiv), CH2Cl2, 40 °C, 3 h, 72%.
Total Synthesis of Sporolide B. Armed with the confidence
gained through the successful synthesis of 9-epi-sporolide B
(5), we turned our attention toward the final stage of the total
synthesis of sporolide B itself (1b, Scheme 13). This task
required inversion of the C-9(S) configuration within 76, which
was intentionally and temporarily introduced as such for the
sole purpose of facilitating the otherwise unattainable intramo-
lecular o-quinone [4+2] cycloaddition reaction. To this end,
the hydroxyl group of 76 was ephemerally protected with a TES
group (TESOTf, 95% yield), and the benzyl groups were cleaved
by hydrogenolysis [H2, Pd(OH)2/C, 92% yield] to afford hydroxy
phenol 82 through bis-benzyl ether TES derivative 81 (see
Scheme 13). Oxidative dearomatization of phenolic substrate
82 with PIFA in the presence of PMBOH furnished p-
hemiquinone 83 (75% yield). Attempts to employ SN2 displace-
ment reactions (e.g., Mitsunobu reaction21 or mesylate displace-
ment42) as a means to achieve the desired inversion at C-9 failed,
forcing us to adopt an oxidation-reduction protocol with the
thought to exploit the 1,3-directing power of the C-7 ꢀ-hydroxyl
group within a hydroxy carbonyl substrate. Thus, oxidation of
83 with DMP produced ketone 84 in 90% yield. Desilylation
of the latter compound (aqueous HF, 85% yield) yielded
a Reagents and conditions: (a) TESOTf (1.5 equiv), Et3N (2.0 equiv),
CH2Cl2, 0 °C, 0.5 h, 95%; (b) H2 (balloon), Pd(OH)2 (10% on carbon, 2.0
equiv), EtOAc, 25 °C, 4 h, 92%; (c) PIFA (1.5 equiv), PMBOH (10.0 equiv),
K2CO3 (5.0 equiv), MeCN, 0 °C, 0.5 h, 75%; (d) DMP (2.0 equiv), CH2Cl2,
25 °C, 1 h, 90%; (e) HF (48% aqueous solution, excess), MeCN, 25 °C,
2 h, 85%; (f) Me4NBH(OAc)3 (10.0 equiv), MeCN:AcOH (10:1), 25 °C,
2 h, 85%; (g) DDQ (5.0 equiv), CH2Cl2:H2O (10:1), 25 °C, 5 h, 70%; (h)
DBU (10.0 equiv), CH2Cl2:MeOH (3:1), 40 °C, 4 h, 78%; (i) t-BuOOH
(10.0 equiv), DBU (5.0 equiv), CH2Cl2, 40 °C, 3 h, 63%. Tf )
trifluoromethanesulfonyl.
3′,4′-deoxysporolide B (87, 78% yield), whose intended regio-
and stereoselective epoxidation was achieved through the use
of t-BuOOH-DBU to afford sporolide B (1b) in 63% yield. The
spectral data of synthetic 1b were in accord with those reported
for the natural product.44
43
ꢀ-hydroxy ketone 85, whose reduction with Me4NBH(OAc)3
Conclusion
provided inverted [9(R)] diol 86 in 85% yield as a single
diastereoisomer, apparently through the expected intramolecu-
larly assisted hydride delivery from the ꢀ-face of the molecule.
Cleavage of the PMB group from 86 with DDQ (70% yield),
followed by methanolysis of the acetate groups from the
resulting hemiacetal diacetate (DBU, MeOH, 40 °C), afforded
A stereocontrolled total synthesis of sporolide B (1b) has been
achieved through a designed strategy that also delivered 9-epi-
sporolide B (5) and sporolide model system 4. In addition to
delivering the latter compound, the undertaken model studies
revealed the sensitivity of the intermolecular [4+2] cycloaddi-
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Total Synthesis of Sporolide B and 9-epi-Sporolide B
A R T I C L E S
tion reaction of o-quinones and indene-type dienophiles and its
dependence on the substituents on both partners with regard to
regioselectivity and diastereofacial selectivity. The intelligence
gathered from these studies proved decisive in guiding the design
of the eventually adopted synthetic strategy toward sporolide
B (1b) and may prove useful in future explorations of the
chemistry of o-quinones. The ultimately evolved synthetic
strategy toward sporolide B involved a thermally induced
intramolecular hetero [4+2] cycloaddition reaction with an
appropriately designed substrate that proceeded with exquisite
regio- and stereoselectivity. As a result of these investigations,
this unprecedented intramolecular o-quinone [4+2] cycloaddi-
tion process may now be added to the repertoire of synthetic
tools for future employment in complex molecule construction.
In addition, the described chemistry demonstrated the power
of the ruthenium-catalyzed [2+2+2] cycloaddition of acetylenic
substrates for the construction of highly substituted indenes,
including chlorinated systems, that may prove useful in chemical
and medicinal synthetic endeavors.
Acknowledgment. We thank Drs. D.-H. Huang, R. Chadha,
and G. Siuzdak for NMR spectroscopic, X-ray crystallographic,
and mass spectrometric assistance, respectively. We also gratefully
acknowledge Dr. R. Hungate and Mr. R. Jensen of Amgen,
Thousand Oaks, CA, for the preliminary 13C NMR study of
synthetic sporolide B. Financial support for this work was provided
by National Institutes of Health and the Skaggs Institute for
Research grants, an Andrea Elizabeth Vogt Memorial Fellowship
(to J.W.), and a Univeristy of Siena Scholarship (to L.B.).
Supporting Information Available: Experimental procedures,
list of abbreviations, and compound characterization (PDF);
crystallographic information files (CIF) This material is available
free of charge via the Internet at http://pubs.acs.org.
(42) Torisawa, Y.; Okabe, H.; Ikegami, S. Chem. Lett. 1984, 13, 1555–
1556.
(43) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
(44) We thank Prof. William Fenical for a sample of natural sporolide B.
JA1048994
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