Indole diterpene synthetic studies. Total synthesis of (+)-nodulisporic acid F and construction of the heptacyclic cores of (+)-nodulisporic acids A and B and (-)-nodulisporic acid D

Article abstract of DOI:10.1021/jo062422i

(Chemical Equation Presented) A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.

Full text of DOI:10.1021/jo062422i

Indole Diterpene Synthetic Studies. Total Synthesis of
(+)-Nodulisporic Acid F and Construction of the Heptacyclic Cores
of (+)-Nodulisporic Acids A and B and (-)-Nodulisporic Acid D
Amos B. Smith, III,* Akin H. Davulcu, Young Shin Cho, Kazuyuki Ohmoto,
La´szlo´ Ku¨rti, and Haruaki Ishiyama
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure
of Matter, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
ReceiVed NoVember 24, 2006
A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The
strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol
developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable
acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation
of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid
F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-
nodulisporic acid D were achieved.
Introduction
evaluation against the bedbug Cimex lectularius also revealed
(+)-nodulisporic acid A, the most potent member of the
nodulisporane family, to display a 10-fold greater systemic
adulticidal efficacy (LD90 ) 1 ppm) over the currently
prescribed flea insecticide ivermectin (LD90 ) 10 ppm).3 Other
members of the nodulisporic acid family proved to be 5- to
>100-fold less active.4 Importantly, (+)-nodulisporic acid A
revealed no apparent toxicity to the host animal, while ef-
In 1997, as part of an ongoing screening program to identify
structurally unique, biologically active natural products having
insecticidal activity, Ondeyka and co-workers at the Merck
Research Laboratories reported the isolation of (+)-nodulisporic
acid A (1, Figure 1), the most complex member of the
nodulisporane class of indole diterpenoids.1 Nodulisporic acid
A (1) proved particularly effective against flea and tick
infestations in dogs and cats.2 Further in vitro and in vivo
(2) Sings, H.; Singh, S. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Elsevier Academic Press: San Diego, CA, 2003; Vol.
60, pp 51-163.
(3) Shoop, W. L.; Gregory, L. M.; Zakson-Aiken, M.; Michael, B. F.;
Haines, H. W.; Ondeyka, J. G.; Meinke, P. T.; Schmatz, D. M. J. Parasitol.
2001, 87, 419-423.
(1) Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goetz, M. A.; Zink,
D. L.; Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski, A. W.;
Polishook, J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B. J.
Am. Chem. Soc. 1997, 119, 8809-8816.
10.1021/jo062422i CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/19/2007
4596
J. Org. Chem. 2007, 72, 4596-4610

Total Synthesis and Construction of Nodulisporic Acids
indoles.9-14 The cornerstone of our modular synthetic strategy
was envisioned to entail the indole synthetic protocol developed
in our laboratory in the mid 1980s for the regiospecific
construction of 2-substituted indoles (Scheme 1).15,16 In simplest
SCHEME 1. The Modular Indole Synthesis Protocol
Developed in Our Laboratory
FIGURE 1. Representative nodulisporic acid congeners.
fectively killing the fleas subsequent to their ingestion of a blood
meal. The lack of mammalian toxicity is ascribed to the
observation that (+)-nodulisporic acid A is active only against
glutamate-gated ion channels that are specific to invertebrates
and not against glycine- and GABA-gated chloride ion channels
common in mammals.5,6 As a result, (+)-nodulisporic acid A
is capable of selectively killing insects, while having no adverse
effect on mammals.
Encouraged by the remarkable insecticidal activity against
fleas, Merck & Co. undertook the development of (+)-
nodulisporic acid A as a novel anti-flea agent for companion
animals. Extensive biological evaluation revealed that, while
nodulisporic acid A possessed good in vivo and in vitro activity,
the stability and pharmacokinetic profiles were not optimal.7 A
medicinal chemistry campaign was therefore launched to
optimize the profile of this lead compound. To date, more than
1000 analogues have been prepared using both chemical
mutagenesis and traditional medicinal chemistry; none of the
analogues, however, exhibit significantly greater potency than
(+)-nodulisporic acid A, although some improvement in phar-
macokinetic properties has been achieved.7,8 Our longstanding
interest in the total synthesis of indole diterpenoid natural
products led us to initiate a synthetic program to devise a
modular strategy that would permit the construction of not only
the nodulisporic acids but also a number of congeners not easily
accessed by direct chemical modification of the natural
form, this protocol calls for the union of an N-silylated dianion
6 with an ester or lactone 7 to afford an N-lithio keto amine 8
that subsequently undergoes an intramolecular heteroatom
Peterson olefination17 to furnish 2- or 2,3-substituted indoles
9. Experience shows (vide infra) that in structurally complex
esters and lactones the heteroatom Peterson olefination may not
proceed. In such cases, the corresponding ketoaniline is
produced upon protonation of intermediate 8. Acid-promoted
dehydration is then required to generate the indole nucleus. For
construction of (+)-nodulisporic acids A and B, the requisite
western and eastern hemispheres were envisaged to be 11 and
12, respectively (Scheme 2).18,19 After the union and subsequent
elaboration of the advanced heptacyclic intermediate (Scheme
2, cf. 10), we envisioned late-stage introduction of the highly
strained D-ring via a Hendrickson annulation tactic.20 The
dienoic acid side chain would then be installed via a Stille
(9) Smith, A. B., III; Davulcu, A. H.; Ku¨rti, L. Org. Lett. 2006, 8, 1665-
1668.
(10) Smith, A. B., III; Davulcu, A. H.; Ku¨rti, L. Org. Lett. 2006, 8, 1669-
1672.
(4) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha, S. N.;
Dahl-Roshak, A.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W.; Tkacz,
J. S. J. Nat. Prod. 2004, 67, 1496-1506.
(11) Smith, A. B., III; Cui, H. Org. Lett. 2003, 5, 587-590.
(12) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am.
Chem. Soc. 2000, 122, 11254-11255.
(5) Meinke, P. T.; Smith, M. M.; Shoop, W. L. Curr. Top. Med. Chem.
2002, 2, 655-674.
(13) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingerywood, J. J.
Am. Chem. Soc. 1990, 112, 8197-8198.
(6) Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y.; Hunt,
D. C.; Ayer, M. B.; Wallace, M. A.; Chaudhary, A. G.; Egan, M. A.;
Meinke, P. T.; Dean, D. C.; Garcia, M. L.; Cully, D. F.; Smith, M. M.
Biochemistry 2002, 41, 6548-6560.
(7) Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden,
C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W.
L.; Schmatz, D. M.; Wyvratt, M.; Fisher, M. H.; Meinke, P. T. Bioorg.
Med. Chem. Lett. 2003, 13, 147-150.
(8) Ok, D.; Li, C.; Shih, T. L.; Salva, S.; Ayer, M. B.; Colletti, S. L.;
Chakravarty, P. K.; Wyvratt, M. J.; Fisher, M. H.; Gregory, L.; Zakson-
Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Meinke, P. T. Bioorg. Med.
Chem. Lett. 2002, 12, 1751-1754.
(14) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769-
1771.
(15) Smith, A. B., III; Visnick, M. Tetrahedron Lett. 1985, 26, 3757-
3760.
(16) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957-2969.
(17) Krueger, C.; Rochow, E. G.; Wannagat, U. Chem. Ber. 1963, 96,
2132-2137.
(18) Smith, A. B., III; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3, 3971-
3974.
(19) Smith, A. B., III; Ishiyama, H.; Cho, Y. S.; Ohmoto, K. Org. Lett.
2001, 3, 3967-3970.
J. Org. Chem, Vol. 72, No. 13, 2007 4597

Smith et al.
SCHEME 2. First-Generation Retrosynthetic Analysis of
Nodulisporic Acid A (1)
SCHEME 3. Retrosynthetic Analysis of (-)-Nodulisporic
Acid F (4)
SCHEME 4. Retrosynthetic Analysis of (+)-Nodulisporic
Acid D (3)
cross-coupling reaction as the last major synthetic operation.21
As will be presented, the presence of several sensitive function-
alities, including the C(24) benzylic hydroxyl group, the C(2′)
epimerizable center, and the C(2)-C(14) electron-rich olefin,
in conjunction with the highly strained â-ketodihydropyrrole
moiety (i.e., D-ring), conspires to make the (+)-nodulisporic
acids (1 and 2) most formidable synthetic targets.
Subsequent to the initiation of our nodulisporic acid A and B
synthetic program, Merck and Co. disclosed a number of simpler
nodulisporic acid congeners D and F (3 and 4).4,22 We quickly
recognized that the simpler congeners would serve as excellent
early model systems to evaluate our nodulisporic acid A and B
synthetic program. As with nodulisporic acids A and B,
construction of D and F (Schemes 3 and 4) would again employ
our indole synthetic tactic that has proven highly successful for
the indole diterpenoids (-)-21-isopentenylpaxilline and (-)-
penitrem D.11,23 With this scenario in mind, tricyclic lactone
(+)-12 (or slightly modified congeners thereof) was envisioned
to serve as a common eastern hemisphere coupling partner.24
Our plan thus evolved to undertake first the total syntheses of
the simpler nodulisporic acid congeners D (3) and F (4), and
then to apply the lessons learned in these synthetic ventures to
the construction of (+)-nodulisporic acids A and B (1 and 2).25
(20) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1989, 54, 1144-
1149.
(21) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(22) Ondeyka, J. G.; Dahl-Roshak, A. M.; Tkacz, J. S.; Zink, D. L.;
Zakson-Aiken, M.; Shoop, W. L.; Goetz, M. A.; Singh, S. B. Bioorg. Med.
Chem. Lett. 2002, 12, 2941-2944.
Results and Discussion
(23) (a) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am.
Chem. Soc. 2000, 122, 11254-11255. (b) Smith, A. B., III; Kanoh, N.;
Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui,
H.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 8228-8237.
(24) (a) Smith, A. B., III; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3,
3971-3974. (b) For an improved scalable synthesis, see: Smith, A. B.,
III; Ku¨rti, L.; Davulcu, A. H.; Cho, Y. S. Org. Proc. Res. DeV. 2007, 11,
19-24.
Synthesis of (+)-Nodulisporic Acid F: Union of the
Eastern Hemisphere (+)-12 with o-Toluidine 14. Given that
(25) For a preliminary account of this work, see: (a) Smith, A. B., III;
Davulcu, A. H.; Ku¨rti, L. Org. Lett. 2006, 8, 1665-1668. (b) Smith, A. B.,
III; Davulcu, A. H.; Ku¨rti, L. Org. Lett. 2006, 8, 1669-1672.
4598 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
SCHEME 6. Elaboration of the C-Ring
the simplest member of the nodulisporane class of indole
diterpenoids, nodulisporic acid F (4), does not possess substit-
uents on the phenyl ring of the indole moiety, the commercially
available o-toluidine 14 could serve as the western hemisphere
coupling partner. To this end, o-toluidine 14 was converted to
N-trimethylsilyl-o-toluidine and then treated with s-BuLi (2.1
equiv) to afford the corresponding dianion. Addition of eastern
hemisphere lactone (+)-12 furnished ketoaniline 19 in almost
quantitative yield (Scheme 5). A large excess of the dianion
was employed to ensure complete conversion of the more
precious tricyclic lactone (+)-12. That the reaction failed to
complete construction of the desired 2-substituted indole
(+)-20, but rather terminated at the ketoaniline stage, was not
completely unexpected given our experience in the total
synthesis of (-)-21-isopentenylpaxilline11 and (-)-penitrem D.12
Presumably, the steric hindrance at the C(3) quaternary stereo-
center adjacent to the carbonyl group prevents the heteroatom
Peterson olefination from taking place. Pleasingly, acid-
promoted cyclodehydration of (+)-19 furnished the desired
indole (+)-20 in 95% yield.
SCHEME 5. Coupling of o-Toluidine 14 with Lactone
(+)-12
product (+)-23 proved to be the major regioisomer. We also
explored the use of MeMgI, as demonstrated by Danishefsky27
in the total synthesis of staurosporine to furnish excellent C(3)
indole selectivity (entry 4, Table 1). These conditions led to an
improvement in the product ratio, albeit the observed modest
yield precluded significant material advancement.
TABLE 1. Elaboration of the C-Ring of Nodulisporic Acid F
ratio of
22:23
yield
(%)
entry
conditions
1
2
3
4
5
t-BuMgCl, toluene, 110 °C
Bu2Mg, toluene, 110 °C
Mg(HMDS)2, toluene, 110 °C
MeMgI, toluene, 110 °C
t-BuMgCl, Zn(OTf)2 (5 equiv),
toluene, 110 °C
2.5:1.0
2.8:1.0
1.0:1.8
7.7:1.0
6.3:1.0
48
42
21
41
63
Elaboration of Ring C of Nodulisporic acid F (4). With
indole (+)-20 in hand, we turned to construction of ring C
(Scheme 6), exploiting a tactic developed during the total
synthesis of (-)-21-isopentenylpaxilline for this purpose.11 Our
expectation was that C(3)-alkylation of the indole would
dominate over the undesired N-alkylation. The primary hydroxyl
of (+)-20 was therefore converted to the corresponding meth-
anesulfonate (+)-21 and in turn exposed to t-BuMgCl at reflux
in toluene (entry 1, Table 1), conditions successfully employed
in the total synthesis of (-)-21-isopentenylpaxilline.11 A mixture
of C- and N-alkylated products (+)-22 and (+)-23 (2.5:1.0,
respectively) resulted. At room temperature, the undesired
N-cyclized regioisomer (+)-23 predominated (22/23 ) 1.0:8.2),
consistent with the expected stereoelectronic bias favoring the
formation of the N-cyclized product.11 To increase both the
regioselectivity and yield, optimization studies were carried out
employing a number of different bases (Table 1). Inspired by
the reported C3-arylation of unprotected indoles by Sames et
al.,26 we explored magnesium bis(hexamethyldisilazide) [Mg-
(HMDS)2] as the base (entry 3, Table 1). High C3 regioselec-
tivity is attributed by Sames to the steric bulk of the hexame-
thyldisilazide anion in the Mg coordination sphere. Unfortunately,
when Mg(HMDS)2 was employed, the undesired N-cyclized
6
t-BuMgCl, Zn(OTf)2 (10 equiv),
toluene, 110 °C
9.0:1.0
72
At this juncture, we reasoned that the generation of a more
covalent indolyl nitrogen metal species (i.e., zinc) might favor
C-cyclization over the undesired N-cyclization, known to
predominate with metals that possess more ionic bonds (i.e.,
sodium, potassium, magnesium, etc.).28 To this end, transmeta-
lation of the initially formed indolyl N-magnesium species with
zinc triflate [Zn(OTf)2] furnished indole (+)-22 in 72% isolated
yield, with only 7% of the undesired (+)-23 congener.
Selective Removal of the Primary TBS Protecting
Group: A Difficult Transformation. With ample quantities
of indole (+)-22 in hand, we next attempted selective removal
of the primary C(1′) TBS group in the presence of the C(7)
secondary TBS ether. Subsequent elaboration of the side chain
would then complete the synthesis of (+)-nodulisporic acid F
(4). Despite extensive efforts employing a large number of
(27) Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky, S. J.; Chou, T.
C.; Ballas, L. M. J. Am. Chem. Soc. 1996, 118, 2825-2842.
(28) Bergman, J.; Venemalm, L. Tetrahedron 1990, 46, 6061-6066.
(26) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050-8057.
J. Org. Chem, Vol. 72, No. 13, 2007 4599

Smith et al.
conditions, selective removal of the C(1′) TBS group could not
be achieved (Scheme 7). We attribute this difficulty to the fact
that, although the C(1′) carbon is primary, it is also neopentyl.
(-)-27. We then turned to the coupling protocol employing the
dianion derived from 14 (Scheme 9). Ketoaniline (+)-28,
obtained in 85% yield, was subjected to cyclodehydration to
furnish the desired 2-substituted indole (+)-29. Conversion to
the corresponding mesylate was followed by closure of ring C
SCHEME 7. Failed Attempts to Selectively Remove the
C(1′) TBS Ether
SCHEME 9. Coupling of Modified Eastern Hemisphere
Lactone (-)-27 with Dianion Derived from 14
The failure to effect selective removal of the C(1′) TBS group
had serious consequences, vis-a`-vis our proposed endgame for
the total synthesis of both nodulisporic acids F and D [(+)-4
and (-)-3, respectively]. Specifically, modification of the C(1′)
carbon would be required prior to union with the appropriate
western hemisphere to avoid the selectivity issue. Accordingly,
we constructed a new eastern hemisphere lactone [(-)-27] from
(+)-12 in 83% yield over four steps (Scheme 8). In this case,
the TES group was selected to protect the secondary hydroxyl.
under the previously optimized conditions to complete construc-
tion of the pentacyclic indole (+)-30 in 59% yield. A small
amount of the undesired N-cyclized regioisomer (7.4:1.0) was
also obtained. The relatively modest yield of (+)-30 is attributed
to a competitive E2 elimination of the primary mesylate to gener-
ate the corresponding exocyclic olefin. Completion of the total
synthesis of (+)-4 would now require a B-alkyl Suzuki-
Miyaura cross-coupling to elaborate the side chain. Toward this
end, hydroboration of the vinyl side chain of (+)-30 employing
the crystalline dimer of 9-BBN in toluene at 80 °C, according
to the method described by Johnson et al.31 (Scheme 10), fur-
nished the corresponding alkylborane adduct. Other conditions
resulted only in a low yield of the adduct, presumably due to the
sterically encumbered olefin. The solvent was then exchanged
for DMF, followed by the addition of the requisite vinyl bromide
ester, Pd(dppf)Cl2 (10 mol %), and powdered K3PO4 (2 equiv).
Indole (+)-31 was isolated in 69% yield. After a thorough
optimization study we discovered that the morphology of the
K3PO4 was critical to achieve high yields. Specifically, the K3-
PO4 must be finely powdered, otherwise the reaction is both slow
and only furnishes (+)-31 in low yield. Completion of the total
synthesis of (+)-nodulisporic acid F (4) then proved straight-
forward; the methyl ester was saponified with LiOH (87%
yield), followed by acid removal of the C(7) TES ether to furnish
(+)-nodulisporic acid F (4) in 92% yield. The total synthesis
thus proceeded with a longest linear sequence of 28 steps from
Wieland-Miescher ketone and in an overall yield of 0.6%.
(-)-Nodulisporic Acid D: Preparation of the Western
Hemisphere (-)-17. We turned next to the synthesis of
(-)-nodulisporic acid D (3). Here a significantly more complex
western hemisphere aniline 17 was required (Schemes 4 and
11). At the time (vide infra), we had already developed a
synthetic route to the western hemisphere for nodulisporic acids
SCHEME 8. Preparation of a Modified Eastern
Hemisphere Lactone (-)-27
In the event, both TBS groups were removed with tetrabutyl-
ammonium fluoride (TBAF) to furnish the corresponding diol
(-)-25, which was then selectively oxidized at C(1′) employing
the 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO)
under biphasic conditions to yield hydroxyaldehyde (-)-26.29
Protection of the C(7) hydroxyl in (-)-26 (97% yield) was
followed by a one-carbon Wittig homologation30 of the derived
aldehyde to furnish the modified eastern hemisphere lactone
(29) De Nooy, A. E. J.; Besemer, A. C.; Van Bekkum, H. Synthesis 1996,
1153-1174.
(30) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318-1330.
(31) Sabat, M.; Johnson, C. R. Org. Lett. 2000, 2, 1089-1092.
4600 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
SCHEME 10. Completion of the Total Synthesis of
SCHEME 13. Enders Asymmetric Alkylation of Hydrazone
(+)-Nodulisporic Acid F
(+)-36
(Scheme 13), which could be conveniently purified by crystal-
lization. Hydrazone (+)-36 was then metalated with t-BuLi and
the resulting anion alkylated with benzylic bromide 33; adduct
(+)-37 was isolated in 72% yield as a single diastereomer, after
thermal equilibration of the initially formed mixture of (E)- and
(Z)-hydrazones. The requisite C(23) stereogenicity was con-
firmed by single-crystal X-ray analysis of the bromophthalimide
analogue of 40 (vide infra), exploiting the anomalous dispersion
tactic.10 Ozonolysis of (+)-37 next furnished ketone (-)-38 in
75% yield (Scheme 14). The excellent enantiomeric excess
(98%), determined by reverse-phase HPLC employing an
enantiomerically enriched stationary phase, revealed little or no
epimerization at C(23). Kinetic deprotonation of (-)-38, fol-
lowed by capture of the resulting lithium enolate with the
Comins reagent,34 then furnished enol triflate (+)-39 in 82%
yield. The requisite Pd-catalyzed ring closure was next explored
employing the conditions developed in the earlier synthesis of
western hemisphere subtarget (-)-11 (entry 1, Table 2).19 After
some optimization (entries 1-6, Table 2), the conditions of
Kelly et al.35 developed for intramolecular biaryl couplings
(entry 6, Table 2) furnished (+)-40 in near quantitative yield.
Treatment of (+)-40 with hydrazine revealed the aniline,
completing construction of the tricyclic aniline coupling partner
(-)-17 in six steps from 32 (Scheme 14).
A and B, namely (-)-11 (Scheme 2),19 structurally similar to
17, except incorporating the C(24) hydroxyl group (nodulisporic
acid A numbering). An overview of the retrosynthetic analysis
of 17 is illustrated in Scheme 11.
SCHEME 11. Retrosynthetic Analysis of Western
Hemisphere (-)-17
The synthesis of (-)-17, following the earlier developed route
to (-)-11,19 began with the preparation of benzylic bromide
33, required as the alkylating agent for an Enders asymmetric
SAMP hydrazone alkylation.32 Accordingly, treatment of known
benzylic alcohol 3419 with phosphorus tribromide furnished
benzylic bromide 33 in 85% yield (Scheme 12). The Enders
(-)-Nodulisporic Acid D: Assembly of the Heptacyclic
Core. With ample quantities of the structurally complex tricyclic
aniline (-)-17 in hand, we turned to assembly of the heptacyclic
core of (-)-nodulisporic acid D (3). The requisite tricyclic
lactone (-)-18 was prepared from known lactone (+)-12
(Scheme 4).24 Union was again achieved via generation of the
dianion derived from (-)-17, followed by addition of tricyclic
lactone (-)-18. Ketoaniline (+)-43 was obtained in 94% yield
(Scheme 15). Interestingly, despite the structural complexity of
SCHEME 12. Preparation of Benzylic Bromide 33
SAMP hydrazone/aldol protocol32 was then executed to intro-
duce the requisite stereocenter in (-)-37. Condensation of
tetrahydro-γ-pyrone 3233 with the Enders SAMP hydrazine (-)-
35 furnished hydrazone (+)-36 in near quantitative yield
(33) Magnus, P.; Mansley, T. E. Tetrahedron Lett. 1999, 40, 6909-
6912.
(34) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
(32) (a) Enders, D.; Whitehouse, D. L. Synthesis 1996, 621-626. (b)
Also see: Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253-2329.
6302.
(35) Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161-
164.
J. Org. Chem, Vol. 72, No. 13, 2007 4601

Smith et al.
TABLE 2. Optimization of Stille-Kelly Coupling of Enol Triflate
(+)-39
SCHEME 14. Preparation of Tricyclic Aniline (-)-17
ratio of
40:41
yield
(%)
entry
1
conditions
PdCl2(PPh3)2 (10 mol %), TMSSnBu3
(3 equiv), Bu4NBr (3 equiv), Li2CO3
(1 equiv) toluene, 110 °C
2.0:1.0
<50
2
3
4
Pd(PPh3)4 (20 mol %), TMSSnBu3
(3 equiv), Bu4NBr (3 equiv),
Li2CO3 (1 equiv) xylenes, 140 °C
PdCl2(dppf) (5 mol %),
bis(pinacolato)boron, Bu4NBr (3 equiv),
Li2CO3 (1 equiv), DMF, 75 °C
Pd(PPh3)4 (15 mol %), Me3SnSnMe3
(2 equiv), Bu4NBr (3 equiv), Li2CO3
(1 equiv), xylenes, 140 °C
2.0:1.0
no rxn
1.0:2.5
<50
<50
5
6
Pd(PPh3)4 (10 mol %), Me3SnSnMe3
(2 equiv), LiCl (2 equiv), THF, 65 °C
Pd(PPh3)4 (20 mol %),
Me3SnSnMe3 (1.2 equiv), LiCl
(20 equiv), dioxane, 100 °C
no rxn
only (+)-40
96
preliminary form in 2001.19 As our synthetic program has pro-
gressed, we have engaged in the development of an improved,
scalable synthesis to support the coupling studies. At issue was
the number of required chromatographic purifications.
(-)-17, the resulting dianion 42 proved significantly more stable
than the dianion derived from o-toluidine 14. As a result, only
slightly more than 2-fold excess (2.38 equiv) of dianion 42 was
required for full conversion of tricyclic lactone (-)-18 to
ketoaniline (+)-43. Again, the union of (-)-17 and (-)-18
terminated at the ketoaniline stage. As before, indole formation
was readily achieved in this case by exposing (+)-43 to the
very weak acid trifluoroethanol at reflux. Use of stronger acids
such as p-toluenesulfonic acid for cyclodehydration led to facile
migration of the trisubstituted ∆18,19 double bond to the isomeric
tetrasubstituted ∆18,23 position. At this juncture, two additional
steps were required to complete construction of ring F and
thereby of the core of (-)-nodulisporic acid D (Scheme 16).
The first step entailed conversion of the primary hydroxyl group
to the corresponding mesylate (-)-45. Application of our now
optimized annulation conditions [e.g., t-BuMgCl, Zn(OTf)2 (10
equiv), toluene, reflux], developed during the total synthesis of
(+)-nodulisporic acid F,9 yielded (-)-46, albeit in modest yield
(ca. 30%). Pleasingly, the reaction proceeded with high regi-
oselectivity. Decreasing the amount of Zn(OTf)2 to only 1 equiv
improved the yield to 72%; the regioselectivity was now 20:1,
favoring the C-alkylated heptacyclic core of (-)-nodulisporic
acid D (46). In summary, the synthesis of the heptacyclic core
of (-)-nodulisporic acid D (46) was achieved with a longest
linear sequence of 10 steps beginning with (+)-36.
The sequence began with a five-step synthesis of aldehyde
49 from commercially available benzyl alcohol 47; the overall
yield was 70% (Scheme 17). The sequence proceeds with high
efficiency and without resort to chromatography (100 g of 47
produced ca. 200 g of aldehyde 49, the latter purified by
crystallization). The Enders SAMP hydrazone/aldol tactic32 was
next employed to introduce the two requisite stereogenic centers
in (-)-11 (Scheme 18). To this end, treatment of hydrazone
(+)-36 with 1 equiv of t-BuLi at -78 °C was followed by
stirring for 25 min, cooling to -100 °C, and addition of aldehyde
49. The stability of the anion derived from (+)-36 appeared to
be poor above -100 °C, leading to substantial decomposition.
A 2-fold excess of the nucleophile generated from (+)-36 was
therefore employed to maximize the yield of the corresponding
â-hydroxyhydrazone (-)-50. As anticipated from the work of
Enders,32 the syn aldol adduct (-)-50 proved to be the major
product (71%; syn:anti ) 5.5:1.0).
Removal of the chiral auxiliary via ozonolysis, followed by
protection of the secondary alcohol as the TES ether, furnished
(-)-51. Surprisingly, the ozonolysis step proved to be the most
challenging step in this sequence. Numerous combinations of
temperature, solvent, and reducing agents (e.g., PPh3, Me2S)
were explored; yields ranged from 45 to 63%.19 Analysis of
the ozonolysis reaction mixture by NMR suggested that the
initially formed product was not stable in the presence of ozone,
(+)-Nodulisporic Acids A and B: Development of a
Scalable Synthesis of the Western Hemisphere [(-)-11]. The
synthesis of the western hemisphere of nodulisporic acids A
and B (-)-11 was developed in our laboratory and reported in
4602 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
SCHEME 15. Coupling of Complex Aniline (-)-17 with
Lactone (-)-18
SCHEME 16. Preparation of the Heptacyclic Core of
(-)-Nodulisporic Acid D
thus providing a possible explanation for the modest yield.
Kinetic deprotonation of ketone (-)-51, followed by capture
of the resulting lithium enolate with the Comins reagent,34
furnished the requisite precursor (+)-52 for the proposed tandem
Stille cross-coupling event (Scheme 18). Initially, this two-step
cyclization-deprotection sequence, employing the conditions
developed by Shibasaki and Mori (Scheme 19),36 was followed
by removal of the phthalimide protecting group; only a modest
yield (ca. 40-48%) resulted, due to reductive deiodination of
(+)-52. We reasoned that deiodination was due to protonolysis
of the incipient organometallic species. When the reaction
mixture was rendered anhydrous prior to the addition of the Pd
catalyst, by performing vacuum azeotropic removal of water
with toluene, the yield of the two-step sequence was improved
to 59%. The preparation of the western hemisphere (-)-11 was
thus achieved via a 14-step sequence (9 steps in the longest
linear sequence); the overall yield was 21%.
Elaboration of the Heptacyclic Core of Nodulisporic Acids
A and B. Early on in our nodulisporic acid A and B synthetic
program, we recognized that the dianion of (-)-11 was not
stable. That is, conversion of (-)-11 to the N-trimethylsilyl
derivative, followed by exposure to sec-butyllithium to generate
dianion 53 at -78 °C (Scheme 20), led to rapid decomposition.
A plausible pathway for the observed decomposition might
comprise a 1,6-elimination of the OTES moiety resulting in the
formation of 54, capable of undergoing anionic polymerization.
The net result was rapid consumption of aniline (-)-11. Thus,
all attempts to couple dianion 53 with eastern hemisphere lactone
SCHEME 17. Preparation of Aldehyde 49 from Benzyl
Alcohol 47
(+)-12 proved unsuccessful. Undaunted, we reasoned that
removal of the TES protecting group from the C(24) benzylic
alcohol (nodulisporic acid A numbering) would lead to a more
stable coupling partner, albeit a trianion. Also significant, the
one-pot indole synthetic protocol involving N-silylation, fol-
lowed by bismetalation would no longer be feasible. A new
nitrogen protecting group would also be required. Screening a
variety of aniline protecting groups revealed that the use of the
tert-butoxycarbonyl (Boc) group led to the best coupling results
(vide infra). To that end, protection of aniline (-)-11 as the
Boc derivative, followed by removal of the TES group (TBAF),
furnished the modified western hemisphere (-)-55 (Scheme 21).
Treatment with a small excess of tert-butyllithium (ca. 3.3 equiv)
at -78 °C led to what is presumed to be the corresponding
trianion 56 (Scheme 21). Subsequent addition of an ethereal
solution of lactone (+)-12 containing 1 equiv of HMPA
(36) Mori, M.; Kaneta, N.; Shibasaki, M. J. Org. Chem. 1991, 56, 3486-
3493.
J. Org. Chem, Vol. 72, No. 13, 2007 4603

Smith et al.
SCHEME 18. Preparation of Coupling Precursor (+)-52
SCHEME 20. Conversion of Tricyclic Aniline (-)-11 to the
Corresponding Dianion 53
SCHEME 21. Preparation of a Modified Western
Hemisphere Coupling Partner (-)-55 from (-)-11 and
Coupling of Eastern Hemisphere (+)-12 with (-)-55
SCHEME 19. Preparation of Western Hemisphere
Subtarget (-)-11
furnished ketoaniline 57 in 67% yield, in conjunction with
oxidation product 55a as a mixture (8:1, respectively). Again,
a large excess of the western hemisphere aniline (-)-55 was
required to maximize the conversion of the eastern hemisphere
lactone (+)-12. Careful chromatographic purification permitted
recovery of nearly 84% of the valuable western hemisphere
coupling partner (-)-55, which could be reused in subsequent
coupling reactions. Mindful of the sensitivity of the C(24)
hydroxyl group to acidic conditions, we next attempted to
remove the Boc group under basic conditions (10% KOH/
MeOH/at reflux), as prelude to formation of ring F. We had
earlier demonstrated that these conditions removed the Boc
4604 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
group from (-)-55 in 94% yield. To our surprise, these
conditions failed. Equally disappointing, various mild acidic
conditions [e.g., montmorillonite K 20 in dichloroethane at
reflux37 or TFA/H2O (9:1) in CH2Cl2 at 0 °C] led only to
elimination of the C(24) hydroxyl, followed by indole formation
(Scheme 22). However, upon exposure of 57 to PPTS (1.4
equiv), cyclic enol ether (-)-59, a single isomer (geometric
isomerism unassigned), was produced in which both the Boc
group and the C(24) hydroxyl remained intact. Further treatment
of (-)-59 with p-toluenesulfonic acid furnished the indole, but
unfortunately loss of the C(24) hydroxyl also occurred. The yield
of indole (+)-58 was 70% (Scheme 22).
(-)-61 was obtained in 48% yield over two steps. Although
lacking the C(24) hydroxyl group, indole (-)-61 constitutes the
heptacyclic ABCEFGH skeleton of (+)-nodulisporic acids A
and B.
SCHEME 23. Elaboration of the F-Ring
SCHEME 22. Indole Formation Studies
In summary, the first total synthesis of (+)-nodulisporic acid
F (4), as well as the heptacyclic core of nodulisporic acid D
(-)-46 has been achieved. In addition, we completed an
effective union of the structurally complex western hemisphere
aniline (-)-55 with the eastern tricyclic lactone (+)-12 employ-
ing a modified version our modular indole synthetic protocol.
The N-Boc ketoaniline coupled product 57 was then converted
to the corresponding indole (+)-58, albeit the acidic conditions
led via dehydration to the loss of the C(24) hydroxyl group.
Employing indole (+)-58, we were also able to elaborate ring
F, thereby successfully achieving a synthesis of the ABCEFGH
heptacyclic core skeleton (-)-61 of nodulisporic acids A and
B. In the following paper,38 we describe a second-generation
synthetic strategy, developed to circumvent the lability of the
C(24) hydroxyl group.
Elaboration of the F-Ring: Construction of the AB-
CEFGH Heptacyclic Skeleton of Nodulisporic Acids A and
B. Despite the loss of the C(24) hydroxyl in (+)-58, we decided
to explore the feasibility of F-ring construction to access the
ABCEFGH core of the nodulisporic acids (Scheme 23). To this
end, the primary hydroxyl was converted to the corresponding
mesylate (-)-60 and, again exposed to conditions developed
during the total synthesis of (-)-isopentenylpaxilline (i.e.,
t-BuMgCl in toluene at reflux) to construct ring F.11 In our
previous synthetic studies (i.e., isopentenylpaxilline,11 penitrem
D,12 nodulisporic acids D and F),9,10 ring F construction proved
to be one of the most challenging steps, due to competition
between nucleophilic attack by the indole nitrogen. In the case
of mesylate (-)-60, however, the desired C(14)-alkylated
compound proved to be the major product (4:1). Initially, the
undesired N-alkylation byproduct could not be separated from
the desired C(14) alkylated product, but upon removal of the
TBS protecting groups with trifluoroacetic acid (TFA), chro-
matographic separation proved possible; the heptacyclic indole
Experimental Section
Preparation of Ketoaniline (+)-19. To a flame-dried 100 mL
round-bottom flask equipped with a PTFE-coated stirbar were
charged o-toluidine 14 (516 mg, 4.82 mmol, 1.0 equiv) and freshly
distilled Et2O (30 mL). The resulting clear, light yellow solution
was cooled to -45 °C, treated with n-butyllithium (2.12 mL of a
2.5 M solution in hexanes, 5.29 mmol, 1.1 equiv) via syringe, and
then warmed to 6 °C over 15 min. The resulting orange solution
was cooled to -38 °C and treated with chlorotrimethylsilane (566.5
(37) Shaikh, N. S.; Gajare, A. S.; Deshpande, V. H.; Bedekar, A. V.
Tetrahedron Lett. 2000, 41, 385-387.
(38) Smith, A. B., III; Ku¨rti, L.; Davulcu, A. H.; Cho, Y. S.; Ohmoto,
K. J. Org. Chem. 2007, 72, 4611-4620.
J. Org. Chem, Vol. 72, No. 13, 2007 4605

Smith et al.
mg, 5.21 mmol, 1.05 equiv) via syringe, and then warmed to 5 °C
over 15 min. The resulting off-white slurry was cooled to -40 °C,
treated with sec-butyllithium (7.56 mL of a 1.4 M solution in
cyclohexane, 10.59 mmol, 2.2 equiv), warmed to 4 °C, and aged
at said temperature for 58 min to give a canary yellow slurry. This
mixture was cooled to -35 °C and treated with a solution of lactone
(+)-12 (195 mg, 0.382 mmol, 0.079 equiv) in freshly distilled Et2O
(10 mL) via syringe, and the resulting mixture was warmed to 12 °C
over 45 min. Upon quenching with saturated ammonium chloride
(50 mL), the mixture was diluted with brine (50 mL) and extracted
with Et2O (3 × 100 mL). The combined organic extract was washed
with brine (100 mL), dried over MgSO4, filtered through a coarse
frit, and concentrated in vacuo to a yellow oily residue. Flash
column chromatography (11.0 cm × 5.0 cm SiO2, hexanes/EtOAc
4:1 f 2:1) afforded ketoaniline (+)-19 (234 mg, 98%) as an off-
white foam: [R]D25 ) +8.33 (c 0.54, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.06 (dt, J ) 1.5, 7.4 Hz, 1H), 6.89 (dd, J ) 1.1, 7.4 Hz,
1H), 6.71 (dt, J ) 1.1, 7.4 Hz, 1H), 6.68 (br d, J ) 8.2 Hz, 1H),
3.88 (d, J ) 16.8 Hz, 1H), 3.74 (dd, J ) 5.2, 11.2 Hz, 1H), 3.59
(d, J ) 16.8 Hz, 1H), 3.38 (d, J ) 9.7 Hz, 1H), 3.27 (dd, J ) 6.3,
10.8 Hz, 1H), 3.14 (dd, J ) 7.4, 10.8 Hz, 1H), 3.13 (d, J ) 9.7
Hz, 1H), 2.68 (m, 1H), 1.98 (dd, J ) 3.7, 12.3 Hz, 1H), 1.90 (app
dt, J ) 4.1, 12.3 Hz, 1H), 1.58-1.72 (m, 4H), 1.30-1.40 (m, 5H),
1.22 (m, 2H), 1.00 (s, 3H), 0.99 (m, 2H), 0.95 (s, 9H), 0.88 (s,
9H), 0.64 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 214.1, 146.1, 130.9, 127.9,
121.4, 118.7, 116.7, 71.1, 66.0, 64.2, 57.4, 46.2, 43.8, 40.3, 40.0,
35.8, 32.9, 27.2, 25.9, 25.8, 24.9, 20.6, 18.1, 17.9, 17.2, 12.8, 11.4,
-3.7, -4.9, -5.4, -5.7; IR (neat) νmax 3367 (br m), 2946 (s), 2862
(s), 1693 (m), 1632 (m), 1466 (m), 1389 (m), 1308 (w), 1254 (m),
1088 (s), 841 (s), 768 (s) cm-1; HRMS (ESI-MS) calcd for C35H63-
NO4Si2Na+ [(M + Na)+] 640.4193, found 640.4187.
mixture was extracted with CH2Cl2 (3 × 50 mL), and the combined
organic extract was washed with brine (50 mL), dried over MgSO4,
filtered through a coarse frit, and concentrated in vacuo to a yellow
solid. Flash column chromatography (14.0 cm × 3.5 cm SiO2,
hexanes/EtOAc 9:1 f 5:1) afforded methanesulfonate (+)-21 (225
mg, >99%) as a light yellow oil: [R]D25 ) +6.63 (c 0.37, CHCl3);
1H NMR (500 MHz, CDCl3) δ 8.56 (br s, 1H), 7.55 (br d, J ) 7.8
Hz, 1H), 7.34 (br d, J ) 7.4 Hz, 1H), 7.14 (br t, J ) 7.1 Hz, 1H),
7.08 (br t, J ) 7.1 Hz, 1H), 6.28 (s, 1H), 4.18 (br s, 1H), 3.81 (br
t, J ) 9.7 Hz, 1H), 3.71 (dd, J ) 4.8, 10.8 Hz, 1H), 3.40 (d, J )
9.7 Hz, 1H), 3.17 (d, J ) 9.7 Hz, 1H), 2.87 (s, 3H), 2.75 (br m,
1H), 2.20 (m, 1H), 2.08 (br d, J ) 9.7 Hz, 1H), 1.42-1.66 (m,
7H), 1.34 (s, 3H), 0.96 (s, 6H), 0.86 (s, 9H), 0.63 (s, 3H), 0.08 (s
6H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
141.4, 135.2, 127.7, 121.2, 119.7, 119.6, 110.5, 102.8, 74.6, 71.5,
65.8, 64.1, 46.5, 43.7, 40.6, 39.1, 37.0, 36.7, 30.9, 27.2, 25.9, 25.8,
20.6, 18.0, 17.9, 17.2, 15.2, 12.8, -3.7, -4.9, -5.4, -5.7; IR (neat)
νmax 3416 (br m), 2953 (s), 2856 (m), 1459 (m), 1352 (m), 1252
(m), 1175 (m), 1091 (m), 949 (m), 836 (m), 774 (m) cm-1. HRMS
(ESI-MS) calcd for C36H63NO5SSi2Na+ [(M + Na)+] 700.3863,
found 700.3892.
Preparation of Pentacycle (+)-22. To a 100 mL round-bottom
flask equipped with a water-cooled reflux condenser and PTFE-
coated stirbar were charged mesylate (+)-21 (50.0 mg, 0.074 mmol,
1.0 equiv), zinc triflate (270 mg, 0.740 mmol, 10.0 equiv), and
anhydrous toluene (25 mL). The resulting mixture was heated to
110 °C and treated with tert-butylmagnesium chloride (555 µL of
a 2.0 M solution in Et2O, 1.11 mmol, 15.0 equiv) added dropwise
via syringe. Upon cooling, the mixture was quenched with saturated
ammonium chloride (50 mL) and extracted with Et2O (3 × 50 mL).
The combined organic extract was washed with brine (50 mL), dried
over MgSO4, filtered through a coarse frit, and concentrated in
vacuo to an off-white solid. Flash column chromatography (12.0
cm × 4.5 cm SiO2, hexanes/Et2O 20:1) afforded pentacycle (+)-22
Preparation of Indole (+)-20. To a 100 mL round-bottom flask
equipped with a water-cooled reflux condenser and PTFE-coated
stirbar were charged ketoaniline (+)-19 (220 mg, 0.356 mmol, 1.0
equiv), p-toluenesulfonic acid monohydrate (4.8 mg, 0.025 mmol,
0.07 equiv), and HPLC-grade benzene (50 mL), and the resulting
mixture was heated at reflux for 4 h. Upon cooling, the mixture
was diluted with saturated NaHCO3 (25 mL) and extracted with
Et2O (1 × 100, 2 × 50 mL). The combined organic extract was
washed with brine (50 mL), dried over MgSO4, filtered through a
coarse frit, and concentrated in vacuo to a yellow foam. Flash
column chromatography (11.5 cm × 4.5 cm SiO2, hexanes/EtOAc
20:1 f 5:1) afforded indole (+)-20 (202.5 mg, 95%) as a clear,
25
(41.2 mg, 96%) as a waxy, white residue: [R]D ) +15.43 (c
0.52, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.68 (br s, 1H), 7.42
(m, 1H), 7.30 (m, 1H), 7.06 (m, 2H), 3.76 (dd, J ) 5.2, 11.2 Hz,
1H), 3.44 (d, J ) 10.1 Hz, 1H), 3.15 (d, J ) 10.1 Hz, 1H), 2.76
(m, 1H), 2.66 (dd, J ) 6.3, 13.0 Hz, 1H), 2.32 (dd, J ) 10.8, 13.4
Hz, 1H), 2.02 (dd, J ) 3.0, 12.7 Hz, 1H), 1.67-1.93 (m, 4H),
1.46-1.61 (m, 4H), 1.10 (s, 3H), 1.01 (s, 3H), 0.94 (s, 9H), 0.89
(s, 9H), 0.63 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.06
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.9, 145.5, 130.8, 125.9,
125.1, 123.9, 123.8, 116.9, 77.4, 69.9, 58.5, 54.5, 49.3, 44.6, 42.6,
38.8, 33.4, 33.1, 31.5, 30.7, 28.3, 24.3, 23.7, 23.6, 20.0, 17.7, 2.1,
0.7, 0.4, -0.1; IR (neat) νmax 3460 (br w), 2927 (s), 2855 (s), 1471
25
1
colorless oil: [R]D ) +21.63 (c 0.49, CHCl3); H NMR (500
MHz, CDCl3) δ 8.07 (br s, 1H), 7.54 (br d, J ) 7.5 Hz, 1H), 7.31
(br d, J ) 7.3 Hz, 1H), 7.11 (br t, J ) 6.9 Hz, 1H), 7.06 (br t, J )
7.2 Hz, 1H), 6.28 (s, 1H), 3.71 (dd, J ) 5.7, 10.8 Hz, 1H), 3.55
(br d, J ) 9.0 Hz, 1H), 3.38 (d, J ) 9.6 Hz, 1H), 3.25 (br t, J )
9.7 Hz, 1H), 3.16 (d, J ) 9.6 Hz, 1H), 2.42 (m, 1 H), 2.14 (br d,
J ) 12.5 Hz, 1H), 2.08 (br d, J ) 11.6 Hz, 1H), 1.30-1.70 (m,
10H), 1.15 (br d, J ) 11.7 Hz, 1H), 0.97 (s, 3H), 0.95 (s, 9H),
0.85 (s, 9H), 0.62 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H),
0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.8, 135.0, 128.3,
127.8, 120.9, 119.7, 119.5, 110.4, 102.5, 71.7, 66.4, 64.2, 46.7,
43.7, 41.8, 40.5, 36.8, 31.2, 27.3, 26.5, 25.9, 25.8, 21.0, 18.1, 18.0,
17.4, 12.9, -3.7, -4.9, -5.3, -5.6; IR (neat) νmax 3359 (br s),
2947 (br s), 1462 (m), 1389 (m), 1244 (m), 1092 (s), 1003 (m),
845 (s), 775 (s), 671 (w) cm-1; HRMS (ESI-MS) calcd for C35H62-
(m), 1385 (m), 1255 (m), 1084 (s), 835 (s), 773 (s), 739 (m) cm-1
;
HRMS (ESI-MS) calcd for C35H60NO2Si2+ [(M + H)+] 582.4162,
found 582.4148.
Physical Data for Undesired Cyclization Regioisomer (+)-23.
25
Colorless needles; mp ) 107-108.5 °C; [R]D ) +8.12 (c 0.60,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.53 (br d, J ) 8.6 Hz,
1H), 7.19 (br d, J ) 7.4 Hz, 1H), 7.09 (br t, J ) 7.1 Hz, 1H), 7.03
(br t, J ) 7.4 Hz, 1H), 6.04 (s, 1H), 4.00 (br t, J ) 7.8 Hz, 1H),
3.77 (dd, J ) 4.8, 10.1 Hz, 1H), 3.59 (br t, J ) 10.1 Hz, 1H), 3.46
(d, J ) 9.7 Hz, 1H), 3.15 (d, J ) 9.7 Hz, 1H), 2.84 (m, 1H), 2.17
(dd, J ) 2.6, 13.0 Hz, 1H), 1.00-1.75 (m, 8H), 1.27 (s, 3H), 1.14
(s, 3H), 0.94 (s, 9H), 0.90 (s, 9H), 0.64 (s, 3H), 0.10 (s, 3H), 0.08
(s, 3H), 0.07 (s, 3H), 0.06 (s, 3 H); 13C NMR (125 MHz, CDCl3)
δ 151.4, 132.1, 125.5, 120.4, 120.1, 118.8, 108.9, 91.5, 71.9, 64.3,
50.9, 46.8, 45.9, 43.7, 38.8, 36.8, 31.9, 30.4, 29.7, 27.7, 25.9 (2),
22.9, 21.9, 18.1, 15.7, 12.2, -3.5, -4.9, -5.2, -5.7; IR (neat) νmax
2953 (s), 2928 (s), 2857 (m), 1458 (m), 1387 (w), 1251 (m), 1089
(s), 836 (s), 771 (s) cm-1. HRMS (ESI-MS) calcd for C35H60NO2-
+
NO3Si2 [(M + H)+] 600.4268, found 600.4293.
Preparation of Methanesulfonate (+)-21. To a 50 mL round-
bottom flask equipped with a PTFE-coated stirbar were charged
indole (+)-20 (200 mg, 0.333 mmol, 1.0 equiv), 4-dimethylami-
nopyridine (1.02 g, 8.33 mmol, 25.0 equiv), and anhydrous CH2Cl2
(40 mL). The clear, colorless solution was cooled to 0 °C and then
treated with methanesulfonyl chloride (381.8 mg, 3.33 mmol, 10.0
equiv) via syringe. The thin white slurry that resulted was aged at
0 °C for 40 min and then poured into a mixture of saturated
ammonium chloride (75 mL) and brine (75 mL). The resulting
Si2 [(M + H)+] 582.4163, found 582.4158.
+
Preparation of Diol (-)-25. To a 150 mL round-bottom flask
equipped with a PTFE-coated stirbar were charged lactone (+)-12
(968 mg, 1.89 mmol, 1.0 equiv) and freshly distilled THF (10 mL).
The resulting clear, colorless solution was cooled to 0 °C and then
4606 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
25
1
treated with a solution of tetrabutylammonium fluoride (5.87 mL
of a 1.0 M solution in THF, 5.87 mmol, 3.1 equiv). The dark orange
solution that resulted was warmed to 24 °C over the course of 35
min and then aged at 24 °C for 40 h. The reaction mixture was
concentrated in vacuo to a dark orange residue. Flash column
chromatography (16.0 cm × 5.0 cm SiO2, EtOAc, 100% f EtOAc/
MeOH, 9:1) afforded the diol (-)-25 (482 mg, 90%) as a waxy,
103 °C; [R]D ) -14.77 (c 0.68, CHCl3); H NMR (500 MHz,
CDCl3) δ 9.29 (s, 1H), 4.13 (dd, J ) 8.2, 10.4 Hz, 1H), 3.87 (dd,
J ) 8.2, 11.2 Hz, 1H), 3.72 (dd, J ) 4.8, 11.2 Hz, 1H), 2.56 (m,
1H), 2.09 (ddd, J ) 3.3, 3.3, 13.5 Hz, 1H), 1.82 (m, 1H), 1.50-
1.75 (m, 5H), 1.28-1.41 (m, 2H), 1.17 (s, 3H), 1.09 (s, 3H), 1.06
(s, 3H), 0.87 (t, J ) 8.6 Hz, 9H), 0.48 (q, J ) 8.6 Hz, 6H); 13C
NMR (125 MHz, CDCl3) δ 206.8, 179.1, 73.7, 69.0, 55.4, 49.4,
39.8, 38.9, 37.5, 29.5, 26.9, 23.8, 21.2, 17.8, 10.9, 9.0, 6.6, 4.9; IR
(neat) νmax 2952 (s), 2876 (m), 2345 (w), 1769 (s), 1724 (s), 1453
25
1
white residue: [R]D ) -11.38 (c 0.67, CHCl3); H NMR (500
MHz, CDCl3) δ 4.17 (dd, J ) 7.1, 8.2 Hz, 1H), 3.91 (dd, J ) 8.2,
11.2 Hz, 1H), 3.66 (br d, J ) 10.4 Hz, 1H), 3.63 (dd, J ) 5.9, 11.2
Hz, 1H), 3.37 (br d, J ) 10.4 Hz, 1H), 2.62 (dddd, J ) 3.4, 3.4,
7.1, 11.2 Hz, 1H), 2.47 (br s, 2H), 2.14 (ddd, J ) 3.4, 3.4, 13.4
Hz, 1H), 1.65-1.76 (m, 3H), 1.54-1.64 (m, 3H), 1.34-1.47 (m,
2H), 1.17 (s, 3H), 1.13 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 179.7, 75.3, 70.0, 69.2, 49.8, 42.4, 39.9, 39.7, 38.4, 29.7,
26.9, 21.8, 21.5, 18.1, 11.2, 11.1; IR (neat) νmax 3394 (br s), 2942
(s), 1763 (s), 1454 (w), 1385 (w), 1238 (w), 1165 (w), 1045 (s),
(m), 1384 (m), 1241 (m), 1106 (s), 1050 (w), 1009 (w) cm-1
.
HRMS (CI-MS) calcd for C22H39O4Si+ [(M + H)+] 395.2618, found
395.2615.
Preparation of Revised Eastern Hemisphere Subtarget (-)-27.
To a flame-dried 50 mL round-bottom flask equipped with a PTFE-
coated stirbar were charged methyltriphenylphosphonium bromide
(597.5 mg, 1.67 mmol, 3.0 equiv) and freshly distilled THF (20
mL). The resulting mixture was cooled to 0 °C, treated with
potassium hexamethyldisilazide (3.34 mL of a 0.5 M solution in
toluene, 1.67 mmol, 3.0 equiv) via syringe, and warmed to 24 °C
over 30 min to give a lemon yellow slurry. The reaction mixture
was then cooled to 0 °C and treated with a solution of aldehyde
(-)-S1 (220 mg, 0.557 mmol, 1.0 equiv) in freshly distilled THF
(15 mL) via syringe, and the resulting mixture was again warmed
to 24 °C over 30 min. Upon quenching with saturated ammonium
chloride (25 mL), the mixture was diluted with brine (50 mL) and
extracted with Et2O (1 × 100, 2 × 50 mL). The combined organic
extract was washed with brine (50 mL), dried over MgSO4, filtered
through a coarse frit, and concentrated in vacuo to an orange oily
residue. Flash column chromatography (15.0 cm × 3.5 cm SiO2,
hexanes/EtOAc 18:1 f 9:1) afforded compound (-)-27 (208.5 mg,
95%) as a colorless oil that crystallizes on standing: mp 74-76 °C;
[R]D25 ) -16.28° (c 0.78, CHCl3); 1H NMR (500 MHz, CDCl3) δ
5.43 (dd, J ) 10.4, 17.1 Hz, 1H), 5.04 (d, J ) 10.4 Hz, 1H), 4.91
(d, J ) 17.1 Hz, 1H), 4.12 (dd, J ) 7.7, 8.2 Hz, 1H), 3.87 (dd, J
) 8.6, 11.7 Hz, 1H), 3.28 (dd, J ) 4.8, 11.7 Hz, 1H), 2.58 (dddd,
J ) 4.2, 4.2, 8.7, 11.9 Hz, 1H), 2.09 (ddd, J ) 3.3, 3.3, 13.4 Hz,
1H), 1.76-1.66 (m, 1H), 1.64-1.48 (m, 4H), 1.39-1.25 (m, 3H),
1.15 (s, 3H), 1.11 (s, 3H), 0.91 (s, 3H), 0.90 (t, J ) 7.8 Hz, 9H),
0.51 (q, J ) 7.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 179.6,
148.9, 113.7, 77.6, 69.2, 49.9, 46.5, 43.7, 40.2, 37.9, 29.7, 27.6,
22.9, 21.5, 18.2, 11.0, 10.9, 6.8, 5.1; IR (neat) νmax 2949 (s), 2877
(s), 1774 (s), 1637 (w), 1456 (m), 1412 (m), 1235 (m), 1107 (s),
1072 (s), 1049 (s), 1003 (s), 914 (m), 877 (m), 826 (m), 737 (s)
cm-1. HRMS (CI) calcd for C23H41O3Si+ [(M + H)+] 393.2825,
found 393.2816.
+
984 (m) cm-1. HRMS (CI-MS) calcd for C16H27O4 [(M + H)+]
283.1909, found 283.1909.
Preparation of Hydroxyaldehyde (-)-26. To a 150 mL round-
bottom flask equipped with a PTFE-coated stirbar were charged
diol (-)-25 (479 mg, 1.89 mmol, 1.0 equiv), TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy free radical, 2.3 mg, 0.015 mmol,
0.008 equiv), potassium bromide (3.5 mg, 0.029 mmol, 0.016
equiv), saturated NaHCO3 solution (25 mL), and dichloro-
methane (50 mL). With vigorous stirring, the resulting biphasic
mixture was cooled to 0 °C and then treated with sodium
hypochlorite (commercial bleach, 2.47 mL of a ca. 0.72 M solution,
1.05 equiv) to give a vivid orange solution (the orange color is
due to the persistent oxoammonium salt derived from TEMPO and
serves as a visual indicator of the reaction endpoint). The resulting
mixture was diluted with brine (50 mL) and saturated NaHCO3
solution (50 mL) and subsequently extracted with EtOAc (3 × 75
mL). The combined organic extract was washed with brine (100
mL), dried over MgSO4, filtered through a coarse frit, and
concentrated in vacuo to give analytically pure hydroxyaldehyde
(-)-26 (480 mg, quantitative yield) as a white solid: mp 106-
25
1
108 °C; [R]D ) -10.35 (c 0.77, CHCl3); H NMR (500 MHz,
CDCl3) δ 9.41 (s, 1H), 4.18 (dd, J ) 7.4, 8.6 Hz, 1H), 3.93 (dd, J
) 8.6, 11.2 Hz, 1H), 3.76 (dd, J ) 4.8, 11.2 Hz, 1H), 2.62 (m,
1H), 2.19 (ddd, J ) 3.4, 3.4, 13.4 Hz, 1H), 1.89 (m, 1H), 1.11-
1.86 (m, 8H), 1.22 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 206.4, 179.1, 72.4, 69.1, 54.8, 49.5, 39.9,
39.3, 37.7, 29.6, 26.4, 24.0, 21.3, 17.9, 11.1, 8.6; IR (neat) νmax
3402 (br s), 2943 (m), 1728 (s), 1446 (w), 1354 (w), 1254 (w),
1061 (w), 968 (w), 733 (w) cm-1. HRMS (CI-MS) calcd for
Preparation of Ketoaniline (+)-28. To a flame-dried 100 mL
round-bottom flask equipped with a PTFE-coated stirbar were
charged o-toluidine 14 (532.2 mg, 4.96 mmol, 1.0 equiv) and freshly
distilled Et2O (40 mL). The resulting clear, light yellow solution
was cooled to -30 °C, treated with n-butyllithium (2.18 mL of a
2.5 M solution in hexanes, 5.46 mmol, 1.1 equiv) via syringe, and
then warmed to 24 °C over 10 min and aged at said temperature
for an additional 5 min. The resulting orange solution was cooled
to -10 °C and treated with chlorotrimethylsilane (566.5 mg, 5.21
mmol, 1.05 equiv) via syringe and then warmed to 24 °C over 10
min. The resulting white slurry was cooled to -30 °C, treated with
sec-butyllithium (7.8 mL of a 1.4 M solution in cyclohexane, 10.92
mmol, 2.2 equiv), warmed to 0 °C and aged at said temperature
for 50 min to give a canary yellow slurry. This mixture was cooled
to -50 °C and treated with a solution of lactone (-)-27 (170 mg,
0.433 mmol, 0.10 equiv) in freshly distilled Et2O (10 mL) via
syringe, and the resulting mixture was warmed to 8 °C over 90
min. Upon quenching with saturated ammonium chloride (10 mL),
the mixture was diluted with brine (25 mL) and extracted with Et2O
(4 × 30 mL). The combined organic extract was dried over MgSO4,
filtered through a coarse frit, and concentrated in vacuo to a yellow
oily residue. Flash column chromatography (14.0 cm × 3.5 cm
SiO2, hexanes/EtOAc 4:1 f 1:3) afforded ketoaniline (+)-28 (184
C16H24O4 [(M)+] 280.1674, found 280.1671.
+
Preparation of TES Ether (-)-S1.
To a 200 mL round-bottom flask equipped with a PTFE-coated
stirbar were charged hydroxyaldehyde (-)-26 (170 mg, 0.606 mmol,
1.0 equiv), 2,6-lutidine (162 mg, 1.52 mmol, 2.5 equiv), and
anhydrous dichloromethane (25 mL). The resulting clear, colorless
solution was cooled to 0 °C, treated with triethylsilyl triflate (168
mg, 0.636 mmol, 1.05 equiv), warmed to 24 °C over 35 min, and
then aged at 24 °C for 30 min. The reaction was then quenched
with saturated ammonium chloride solution (20 mL) and
subsequently extracted with dichloromethane (3 × 25 mL). The
combined organic extract was washed with brine (25 mL), dried
over MgSO4, filtered through a coarse frit, and concentrated in
vacuo to a yellow solid residue. Flash column chromatography (13.0
cm × 3.5 cm SiO2, hexanes/EtOAc 4:1 f 2:1) afforded the TES
ether (-)-S1 (231 mg, 97%) as a waxy white residue: mp ) 101-
25
1
mg, 85%) as a colorless oil: [R]D ) +64.2 (c 2.12, CHCl3); H
J. Org. Chem, Vol. 72, No. 13, 2007 4607

Smith et al.
NMR (500 MHz, CDCl3) δ 7.06 (dt, J ) 1.1, 7.8 Hz, 1H), 6.88
(br d, J ) 7.4 Hz, 1H), 6.71 (dt, J ) 1.1, 7.4 Hz, 1H), 6.67 (br d,
J ) 7.8 Hz, 1H), 5.49 (dd, J ) 10.8, 17.4 Hz, 1H), 5.07 (d, J )
10.8 Hz, 1H), 4.94 (d, J ) 17.4 Hz, 1H), 3.88 (d, J ) 16.7 Hz,
1H), 3.58 (d, J ) 16.8 Hz, 1H), 3.34 (dd, J ) 4.5, 11.5 Hz, 1H),
3.24 (dd, J ) 6.3, 10.6 Hz, 1H), 3.11 (dd, J ) 7.1, 10.6 Hz, 1H),
3.6-3.0 (br s, 2H), 2.65 (m, 1H), 1.93 (m, 1H), 1.78-1.58 (m,
3H), 1.47-1.22 (m, 9H), 1.01 (s, 3H), 0.97 (s, 3H), 0.95 (t, J )
7.7 Hz, 9H), 0.56 (q, J ) 7.6 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 213.6, 149.2, 146.0, 130.8, 127.9, 121.4, 118.6, 116.7, 113.7,
77.3, 65.8, 57.2, 46.6, 46.1, 46.0, 42.7, 40.1, 33.1, 27.6, 24.9, 21.4,
16.9, 11.8, 11.4, 6.9, 5.1; IR (neat) νmax 3366 (br s), 2950 (s), 2876
(s), 1691 (m), 1631 (m), 1459 (m), 1384 (m), 1303 (m), 1237 (m),
1112 (s), 1007 (s), 912 (w), 827 (w), 742 (m) cm-1. HRMS (ESI-
MS) calcd for C30H49NO3NaSi+ [(M + Na)+] 522.3379, found
522.3377.
Protocol for Recycling of Diol (+)-S2.
Preparation of Indole (+)-29. To a 100 mL round-bottom
flask equipped with a water-cooled reflux condenser and PTFE-
coated stirbar were charged ketoaniline (+)-28 (240 mg, 0.481
mmol, 1.0 equiv), p-toluenesulfonic acid monohydrate (6.04 mg,
0.024 mmol, 0.05 equiv), and HPLC-grade benzene (50 mL), and
the resulting mixture was heated at reflux for 4 h. Upon cooling,
the mixture was diluted with saturated NaHCO3 (25 mL) and
extracted with Et2O (1 × 100, 2 × 50 mL). The combined organic
extract was washed with brine (50 mL), dried over MgSO4, filtered
through a coarse frit, and concentrated in vacuo to a yellow oil.
Flash column chromatography (11.5 cm × 4.5 cm SiO2, hexanes/
EtOAc 20:1 f 5:1) afforded indole (+)-29 (220 mg, 95%) as a
clear, colorless oil and diol (+)-S2 (11.6 mg, 5%) as a white solid.
Physical data for indole: [R]D25 +10.8 (c 1.60, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 8.11 (br s, 1H), 7.54 (app d, J ) 7.4 Hz,
1H), 7.32 (app d, J ) 7.8 Hz, 1H), 7.12 (dt, J ) 1.5, 7.8 Hz, 1H),
7.07 (dt, J ) 1.1, 7.5 Hz, 1H), 6.29 (s, 1H), 5.53 (dd, J ) 10.8,
17.1 Hz, 1H), 5.08 (dd, J ) 1.5, 10.8 Hz, 1H), 4.96 (dd, J ) 1.5,
17.1 Hz, 1H), 3.56 (br d, J ) 9.3 Hz, 1H), 3.33 (dd, J ) 5.2, 10.8
Hz, 1H), 3.24 (dd, J ) 8.2, 10.4 Hz, 1H), 2.41 (m, 1H), 2.11 (m,
1H), 1.12-1.65 (m, 9H), 1.32 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H),
0.91 (t, J ) 8.2 Hz, 9H), 0.53 (q, J ) 8.2 Hz, 6 H); 13C NMR (125
MHz, CDCl3) δ 149.6, 142.5, 135.0, 127.8, 121.0, 119.8, 119.5,
113.7, 110.4, 102.6, 77.9, 66.4, 46.8, 46.7, 43.7, 41.9, 40.4, 31.6,
27.7, 26.6, 21.9, 17.2, 14.8, 11.9, 6.9, 5.2; IR (neat) νmax 3431 (br
s), 2950 (s), 2877 (s), 1723 (w), 1636 (w), 1525 (w), 1457 (m),
1411 (m), 1379 (m), 1344 (m), 1291 (m), 1238 (m), 1109 (s), 1004
(s), 909 (m), 825 (m), 735 (s) cm-1. HRMS (ESI-MS) calcd for
C30H48NO2Si+ [(M + H)+] 482.3454, found 482.3431. Physical
Data for Diol (+)-S2:
Preparation of Bis-TES Ether (+)-S3.
To a 100 mL round-bottom flask equipped with a PTFE-coated
stirbar were charged diol (+)-S2 (40 mg, 0.108 mmol, 1.0 equiv),
2,6-lutidine (58.4 mg, 0.545 mmol, 5.0 equiv), and anhydrous
dichloromethane (50 mL). The clear, colorless solution was cooled
to 0 °C, treated with triethylsilyl triflate (63.3 mg, 0.239 mmol,
2.20 equiv), and subsequently warmed to 24 °C over 30 min. The
reaction was then quenched with saturated ammonium chloride
solution (20 mL) and subsequently extracted with dichloromethane
(3 × 25 mL). The combined organic extract was washed with brine
(25 mL), dried over MgSO4, filtered through a coarse frit, and
concentrated in vacuo to a yellow oily residue. Flash column
chromatography (17.5 cm × 3.5 cm SiO2, hexanes) afforded
25
(+)-S3 (59.2 mg, 91%) as a light yellow oil: [R]D ) -0.71 (c
1.50, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.19 (br s, 1H), 7.57
(br d, J ) 7.4 Hz, 1H), 7.32 (br d, J ) 7.8 Hz, 1H), 7.14 (br t, J
) 7.1 Hz, 1H), 7.09 (br t, J ) 7.4 Hz, 1H), 6.31 (s, 1H), 5.56 (dd,
J ) 10.8, 17.5 Hz, 1H), 5.11 (d, J ) 10.8 Hz, 1H), 4.98 (d, J )
17.5 Hz, 1H), 3.53 (br d, J ) 8.9 Hz, 1H), 3.37 (dd, J ) 5.6, 10.4
Hz, 1H), 3.18 (dd, J ) 7.3, 9.7 Hz, 1H), 2.39 (m, 1H), 2.18 (br d,
J ) 13.8 Hz, 1H), 1.32 (s, 3H), 1.28-1.70 (m, 8H), 0.98 (s, 3H),
0.97 (s, 3H), 0.95 (t, J ) 7.8 Hz, 9H), 0.92 (t, J ) 7.8 Hz, 9H),
0.56 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 149.7, 142.8, 134.9,
127.9, 120.9, 119.7, 119.4, 113.6, 110.3, 102.6, 77.9, 66.2, 46.8,
46.7, 43.8, 42.3, 40.4, 31.5, 27.8, 26.8, 22.1, 17.1, 15.1, 11.8, 6.9,
6.7, 5.2, 4.3; IR (neat) νmax 3488 (br w), 3440 (br w), 2952 (br s),
2875 (s), 1636 (w), 1526 (w), 1457 (m), 1411 (m), 1289 (m), 1236
(m), 1094 (s), 1004 (s), 811 (m), 734 (s) cm-1. HRMS (ESI-MS)
+
calcd for C36H62NO2Si2 [(M + H)+] 596.4319, found 596.4335.
Preparation of Indole (+)-29 from Bis-TES Ether (+)-S3. To
a 50 mL round-bottom flask equipped with a water-cooled reflux
condenser and PTFE-coated stirbar were charged bis-TES ether
(+)-S3 (50.0 mg, 0.084 mmol, 1.0 equiv), p-toluenesulfonic acid
monohydrate (2.11 mg, 0.0084 mmol, 0.1 equiv), methanol (10 µL),
and HPLC-grade benzene (10 mL), and the resulting mixture was
heated at reflux for 30 min. Upon cooling, the mixture was diluted
with saturated NaHCO3 (25 mL) and extracted with Et2O (3 × 50
mL). The combined organic extract was washed with brine (50 mL),
dried over MgSO4, filtered through a coarse frit, and concentrated
in vacuo to a yellow oil. Flash column chromatography (11.0 cm
× 5.0 cm SiO2, hexanes/EtOAc 9:1 f 2:1) afforded indole (+)-29
Colorless needles, mp 208 - 209 °C; [R]D25 +63.6 (c 0.50, MeOH);
1H NMR (500 MHz, CDCl3) δ 7.92 (br s, 1H), 7.48 (br d, J ) 7.8
Hz, 1H), 7.36 (br d, J ) 7.8 Hz, 1H), 7.05 (dt, J ) 1.1, 7.4 Hz,
1H), 6.98 (dt, J ) 1.1, 7.4 Hz, 1H), 6.28 (s, 1H), 5.69 (dd, J )
10.8, 17.5 Hz, 1H), 5.19 (d, J ) 10.8 Hz, 1H), 5.07 (d, J ) 17.5
Hz, 1H), 3.57 (br s, 1H), 3.38 (dd, J ) 4.8, 11.2 Hz, 1H), 3.15 (br
t, J ) 8.9 Hz, 1H), 2.49 (br m, 1H), 2.21 (br d, J ) 11.9 Hz, 1H),
1.17 (br m, 1H), 1.37 (s, 3H), 1.3-1.7 (m, 8H), 1.17 (br s, 1H),
1.05 (s, 3H), 1.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 150.7,
143.7, 137.2, 129.2, 121.5, 120.5, 119.8, 114.6, 111.7, 102.9, 79.6,
78.2, 66.8, 48.1, 47.5, 45.2, 42.9, 41.6, 33.2, 27.6 (2), 23.2, 17.9,
12.3; IR (neat) νmax 3300 (br m), 2932 (br m), 1455 (m), 1005
25
(34.4 mg, 85% (98% BORSM)) as a clear, colorless oil: [R]D
+
(m), 750 (m) cm-1. HRMS (ESI-MS) calcd for C24H34NO2 [(M
+10.8 (c 1.6, CHCl3). Spectral data were identical to that reported
previously (vide supra).
+ H)+] 368.2589, found 368.2583.
4608 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis and Construction of Nodulisporic Acids
Preparation of Methanesulfonate (-)-S4.
Physical Data for Undesired Cyclization Regioisomer (+)-
S5.
Yield 3.31 mg (8.0% yield), light yellow oil: [R]D25 +6.32 (c 0.53,
To a 100 mL round-bottom flask equipped with a PTFE-coated
stirbar were charged indole (+)-29 (200 mg, 0.416 mmol, 1.0
equiv), 4-dimethylaminopyridine (1.26 g, 10.38 mmol, 25.0 equiv),
and anhydrous CH2Cl2 (40 mL). The clear, colorless solution
was cooled to 0 °C and then treated with methanesulfonyl chloride
(476 mg, 3.33 mmol, 10.0 equiv) added dropwise via syringe. The
thin white slurry that resulted was aged at 0 °C for 60 min and
then poured into a mixture of saturated ammonium chloride (25
mL) and brine (25 mL). The resulting mixture was extracted
with CH2Cl2 (3 × 50 mL), and the combined organic extract
was washed with brine (50 mL), dried over MgSO4, filtered
through a coarse frit, and concentrated in vacuo to a yellow oil.
Flash column chromatography (14.0 cm × 5.0 cm SiO2, hexanes/
EtOAc 9:1 f 4:1) afforded methanesulfonate (-)-S4 (230 mg,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.54 (br d, J ) 7.4 Hz,
1H), 7.21 (br d, J ) 7.2 Hz, 1H), 7.11 (app br t, J ) 7.8 Hz, 1H),
7.04 (app br t, J ) 7.4 Hz, 1H), 6.06 (s, 1H), 5.54 (dd, J ) 10.4,
17.5 Hz, 1H), 5.10 (d, J ) 10.4 Hz, 1H), 4.98 (d, J ) 17.5 Hz,
1H), 4.01 (dd, J ) 7.1, 9.7 Hz, 1H), 3.59 (dd, J ) 9.7, 10.8 Hz,
1H), 3.40 (dd, J ) 4.1, 10.1 Hz, 1H), 2.82 (m, 1H), 1.20-1.80 (m,
9H), 1.17 (s, 3H), 1.16 (s, 3H), 0.98 (s, 3H), 0.97 (t, J ) 7.8 Hz,
9H), 0.58 (q, J ) 7.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
151.4, 149.6, 132.8, 132.0, 120.5, 120.1, 118.8, 113.6, 108.9, 91.6,
77.8, 51.1, 46.9, 46.7, 45.9, 43.7, 38.7, 32.1, 28.0, 23.3, 22.9, 17.8,
15.8, 10.9, 6.9, 5.2; IR (neat) νmax 2949 (br s), 2874 (s), 1456 (s),
1261 (m), 1095 (br s), 1017 (br s), 876 (m), 799 (m), 743 (s) cm-1
.
HRMS (ESI-MS) calcd for C30H46NOSi+ [(M + H)+] 464.3348,
found 464.3353.
25
1
Preparation of Coupled Adduct (+)-31. To a 50 mL round-
bottom flask equipped with a water-cooled reflux condenser and
PTFE-coated stirbar were charged pentacycle (+)-30 (50.0 mg,
0.108 mmol, 1.0 equiv), 9-BBN dimer (72.3 mg, 0.296 mmol, 2.75
equiv), and anhydrous toluene (8.0 mL). The resulting mixture was
heated at 80 °C for 5 h. Upon cooling, volatiles were removed by
vacuum transfer, and the resulting off-white solid residue was taken
up in anhydrous N,N-dimethylformamide (8.0 mL). Upon treatment
with PdCl2(dppf) (8.8 mg, 0.011 mmol, 0.10 equiv), methyl-(E)-
3-bromo-2-methylpropenoate 16 (38.6 mg, 0.216 mmol, 2.0 equiv),
and powdered potassium phosphate (45.8 mg, 0.216 mmol, 2.0
equiv), the resulting magenta solution was heated at 65 °C for 6 h
to yield a dark orange mixture. This was diluted with brine (150
mL) and extracted with Et2O (3 × 50 mL). The combined organic
extract was washed with brine (3 × 50 mL), dried over MgSO4,
filtered through a coarse frit, and concentrated in vacuo to an orange
oil. Flash column chromatography (16.0 cm × 3.5 cm SiO2,
hexanes/Et2O 30:1 f 15:1) afforded adduct (+)-31 (41.9 mg, 69%)
as a clear, colorless oil: [R]D +19.1 (c 0.33, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.39 (dd, J ) 1.9, 6.3 Hz,
1H), 7.31 (dd, J ) 1.9, 6.7 Hz, 1H), 7.06 (app dt, J ) 1.5, 6.7 Hz,
1H), 7.03 (app dt, J ) 1.5, 6.3 Hz, 1H), 6.75 (app br t, J ) 7.2 Hz,
1H), 3.73 (s, 3H), 3.61 (dd, J ) 4.8, 9.7 Hz, 1H), 2.78 (m, 1H),
2.68 (dd, J ) 6.3, 13.2 Hz, 1H), 2.34 (dd, J ) 10.8, 13.2 Hz, 1H),
2.12 (m, 2H), 1.89 (m, 1H), 1.88 (br s, 3H), 1.38-1.82 (m, 7H),
1.28 (m, 3H), 1.14 (s, 3H), 1.04 (s, 3H), 1.01 (t, J ) 8.2 Hz, 9H),
0.84 (s, 3H), 0.65 (br q, J ) 8.2 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 169.0, 151.6, 143.2, 140.6, 127.7, 125.8, 120.8, 119.9,
118.8, 111.9, 74.5, 53.7, 52.1, 49.5, 42.4, 40.5, 39.8, 36.4, 33.9,
30.3, 28.6, 27.9, 25.7, 23.6, 23.1, 19.5, 17.3, 14.9, 12.8, 7.4, 6.0;
IR (neat) νmax 3391 (br m), 2949 (br s), 2874 (m), 1698 (s), 1646
(m), 1455 (m), 1385 (w), 1283 (m), 1099 (s), 1010 (m), 824 (m),
739 (s) cm-1. HRMS (ESI-MS) calcd for C35H53NO3SiNa+ [(M +
Na)+] 586.3692, found 586.3687.
>99%) as a light yellow oil: [R]D -13.10 (c 1.31, CHCl3); H
NMR (500 MHz, CDCl3) δ 8.60 (br s, 1H), 7.56 (d, J ) 7.7 Hz,
1H), 7.36 (d, J ) 7.9 Hz, 1H), 7.15 (t, J ) 7.5 Hz, 1H), 7.09 (t, J
) 7.4 Hz, 1H), 6.30 (s, 1H), 5.54 (dd, J ) 10.7, 17.4 Hz, 1H),
5.12 (d, J ) 10.8 Hz, 1H), 4.99 (d, J ) 17.3 Hz, 1H), 4.16 (br m,
1H), 3.82 (dd, J ) 9.7, 9.7 Hz, 1H), 3.36 (dd, J ) 6.1, 9.4 Hz,
1H), 2.87 (s, 3H), 2.74 (br m, 1H), 2.17 (br m, 1H), 1.70-1.39
(m, 8H), 1.37 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.92 (t, J ) 7.9
Hz, 9H), 0.53 (q, J ) 7.9 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 149.3, 141.0, 135.2, 127.6, 121.3, 119.8, 119.6, 113.9, 110.6,
102.5, 77.7, 74.5, 46.6, 46.5, 43.5, 40.5, 39.2, 37.1, 31.5, 30.3, 27.6,
25.8, 21.4, 16.9, 11.8, 6.9, 5.2; IR (neat) νmax 3412 (br m), 2951
(br s), 2874 (m), 1717 (w), 1457 (m), 1348 (s), 1236 (m), 1174
(s), 1110 (s), 1002 (m), 948 (s), 824 (m), 744 (m) cm-1. HRMS
(ESI-MS) calcd for C31H49NO4SSiNa+ [(M + Na)+] 582.3049,
found 582.3045.
Preparation of Pentacycle (+)-30. To a 50 mL round-bottom
flask equipped with a water-cooled reflux condenser and PTFE-
coated stirbar were charged mesylate (50.0 mg, 0.089 mmol, 1.0
equiv), zinc triflate (324.6 mg, 0.893 mmol, 10.0 equiv), and
anhydrous toluene (25 mL). The resulting mixture was heated to
110 °C and treated with tert-butylmagnesium chloride (670 µL of
a 2.0 M solution in Et2O, 1.34 mmol, 15.0 equiv) added dropwise
via syringe. Upon cooling, the mixture was quenched with saturated
ammonium chloride (50 mL) and extracted with Et2O (3 × 25 mL).
The combined organic extract was washed with brine (50 mL), dried
over MgSO4, filtered through a coarse frit, and concentrated in
vacuo to a yellow oil. Flash column chromatography (12.0 cm ×
3.5 cm SiO2, hexanes/Et2O 100:1 f 75:1) afforded pentacycle
(+)-30 (24.4 mg, 59%) as a light yellow oil: [R]D25 +2.38 (c 0.81,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.79 (br s, 1H), 7.40 (br d,
J ) 7.7 Hz, 1H), 7.30 (br d, J ) 7.7 Hz, 1H), 7.00-7.08 (m, 2H),
5.56 (dd, J ) 10.8, 17.3 Hz, 1H), 5.10 (dd, J ) 1.5, 10.8 Hz, 1H),
4.97 (dd, J ) 1.5, 17.3 Hz, 1H), 3.43 (dd, J ) 4.5, 11.2 Hz, 1H),
2.76 (m, 1H), 2.67 (dd, J ) 6.3, 13.4 Hz, 1H), 2.33 (dd, J ) 10.8,
13.4 Hz, 1H), 1.84-1.99 (m, 2H), 1.68-1.77 (m, 2H), 1.52-1.66
(m, 4H), 1.33-1.46 (m, 1H), 1.14 (s, 3H), 1.05 (s, 3H), 0.99 (t, J
) 8.0 Hz, 9H), 0.98 (s, 3H), 0.60 (q, J ) 8.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 151.4, 149.9, 140.5, 125.6, 120.6, 119.8,
118.6, 118.6, 113.7, 111.7, 78.1, 53.5, 49.6, 47.1, 44.3, 39.2, 33.7,
28.5, 27.8, 25.7, 24.6, 19.2, 14.6, 11.1, 7.2, 5.6; IR (neat) νmax 3433
(br m), 2948 (br s), 1456 (s), 1299 (m), 1099 (s), 1002 (m), 826
(m), 739 (s) cm-1. HRMS (ESI-MS) calcd for C30H46NOSi+ [(M
+ H)+] 464.3349, found 464.3351.
25
1
Preparation of Acid (+)-S6.
To a 50 mL round-bottom flask equipped with a PTFE-coated
stirbar were charged ester (+)-31 (30.2 mg, 0.054 mmol, 1.0 equiv),
aqueous LiOH (6.0 mL of a 1.0 M solution), methanol (12 mL),
and THF (HPLC grade, 6.0 mL), and the resulting mixture was
vigorously stirred at 25 °C for 48 h. The resulting mixture was
J. Org. Chem, Vol. 72, No. 13, 2007 4609

Smith et al.
subjected to rotary evaporation to remove volatiles and then adjusted
to pH 2 with saturated citric acid solution. The resulting hetero-
geneous mixture was extracted with EtOAc (3 × 25 mL), and the
combined organic extract was washed with brine (3 × 50 mL),
dried over MgSO4, filtered through a coarse frit, and concentrated
in vacuo to a light yellow oil. Flash column chromatography (12.0
cm × 3.5 cm SiO2, hexanes/EtOAc 4:1 f 1:1) afforded adduct
112.8, 74.2, 54.5, 50.4, 42.7, 41.6, 40.6, 37.2, 33.9, 28.5, 28.4, 26.5,
24.2, 23.6, 19.6, 17.4, 15.0, 12.6; IR (neat) νmax 3424 (br s), 2939
(br s), 1685 (s), 1642 (m), 1455 (m), 1385 (m), 1299 (m), 1221
(m), 1095 (w), 1072 (m), 1024 (m), 918 (w), 754 (s) cm-1; UV-
vis λmax ) 230, 282 nm (MeOH). HRMS (ESI-MS) calcd for
C28H37NO3Na+ [(M + Na)+] 458.2671, found 458.2661.
Physical Data for Natural (+)-Nodulisporic Acid F. Amor-
phous off-white powder: [R]D25 +7.20 (c 1.70, MeOH); 1H NMR
(500 MHz, CDCl3) δ 7.32 (br d, J ) 7.8 Hz, 2H), 6.99 (dt, J )
1.5, 7.1 Hz, 1H), 6.96 (dt, J ) 1.5, 7.4 Hz, 1H), 6.88 (br t, J ) 7.4
Hz, 1H), 3.59 (dd, J ) 4.5, 10.4 Hz, 1H), 2.82 (m, 1H), 2.66 (dd,
J ) 6.3, 13.0 Hz, 1H), 2.34 (dd, J ) 10.8, 13.4 Hz, 1H), 2.26 (m,
1H), 2.19 (m, 1H), 1.91 (s, 3H), 1.66-1.88 (m, 9H), 1.54 (m, 1H),
1.42 (m, 1H), 1.17 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.9, 152.4, 144.7, 142.2, 128.6, 126.4,
120.9, 119.9, 118.8, 118.2, 112.8, 74.2, 54.5, 50.4, 42.7, 41.6, 40.6,
37.2, 33.9, 28.5, 28.4, 26.5, 24.2, 23.6, 19.6, 17.4, 15.0, 12.6; UV-
vis λmax ) 230, 282 nm (MeOH).
25
(+)-S6 (25.5 mg, 86.7%) as a waxy, white solid: [R]D +20.20
1
(c 0.27, CH2Cl2); H NMR (500 MHz, CDCl3) δ ca. 9 ppm (br s,
1H), 7.79 (br s, 1H), 7.38 (br d, J ) 6.3 Hz, 1H), 7.29 (br dd, J )
1.8, 6.7 Hz, 1H), 7.05 (br dd, J ) 1.5, 7.1 Hz, 1H), 7.02 (br dd, J
) 1.5, 7.4 Hz, 1H), 6.90 (br t, J ) 7.4 Hz, 1H), 3.60 (dd, J ) 4.8,
10.1 Hz, 1H), 2.77 (m, 1H), 2.67 (dd, J ) 6.7, 13.4 Hz, 1H), 2.33
(dd, J ) 10.8, 13.4 Hz, 1H), 2.15 (m, 2H), 1.89 (br s, 3H), 1.40-
1.91 (m, 8H), 1.21-1.38 (m, 3H), 1.13 (s, 3H), 1.04 (s, 3H), 1.00
(t, J ) 8.2 Hz, 9H), 0.84 (s, 3H), 0.64 (br q, J ) 8.2 Hz, 6H); 13
C
NMR (125 MHz, CDCl3) δ 173.6, 151.6, 146.1, 140.6, 127.1, 125.8,
120.8, 119.9, 118.8, 118.7, 111.9, 74.5, 53.7, 49.5, 42.5, 40.5, 39.8,
36.3, 33.8, 28.6, 27.9, 25.7, 23.6, 23.4, 19.5, 17.3, 14.9, 12.5, 7.4,
6.0; IR (neat) νmax 3426 (br m), 2933 (br s), 2874 (s), 1683 (s),
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM-29028 and by the Bristol-
Myers Squibb Pharmaceutical Research Institute (for stipend
support of A.H.D.). We are also grateful to Eli Lilly and
Company for the graduate fellowship to L.K., the Merck
Research Laboratories for generous financial support of this
research program, and to Dr. P.T. Meinke for providing generous
samples of natural (+)-nodulisporic acid F and (-)-nodulisporic
acid D. Finally, we thank Dr. G. Furst, Dr. R.K. Kohli, and Dr.
P. Carroll for assistance in obtaining NMR spectra, high-
resolution mass spectra, and X-ray crystallographic data,
respectively.
1455 (m), 1299 (m), 1098 (s), 1012 (m), 824 (m), 740 (s) cm-1
.
HRMS (ESI-MS) calcd for C34H52NO3Si+ [(M + H)+] 550.3716,
found 550.3709.
Preparation of Synthetic (+)-Nodulisporic Acid F (4). To a
25 mL round-bottom flask equipped with a PTFE-coated stirbar
were charged acid (+)-S6 (25.0 mg, 0.046 mmol, 1.0 equiv),
p-toluenesulfonic acid monohydrate (0.87 mg, 0.005 mmol, 0.10
equiv), and methanol (HPLC grade, 10 mL). The resulting mixture
was stirred at 25 °C for 1 h and then subjected to rotary evaporation
to yield a light yellow residue. Flash column chromatography (12.5
cm × 3.5 cm SiO2, EtOAc/MeOH 20:1 f 10:1) afforded (+)-
nodulisporic acid F (4) (22.0 mg, 92.4%) as a waxy, off-white
residue: [R]D25 +7.31 (c 1.70, MeOH); 1H NMR (500 MHz, CDCl3)
δ 7.32 (br d, J ) 7.8 Hz, 2H), 6.99 (dt, J ) 1.5, 7.1 Hz, 1H), 6.96
(dt, J ) 1.5, 7.4 Hz, 1H), 6.88 (br t, J ) 7.4 Hz, 1H), 3.59 (dd, J
) 4.5, 10.4 Hz, 1H), 2.82 (m, 1H), 2.66 (dd, J ) 6.3, 13.0 Hz,
1H), 2.34 (dd, J ) 10.8, 13.4 Hz, 1H), 2.26 (m, 1H), 2.19 (m, 1H),
1.91 (s, 3H), 1.66-1.88 (m, 9H), 1.54 (m, 1H), 1.42 (m, 1H), 1.17
(s, 3H), 1.07 (s, 3H), 0.90 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
171.9, 152.4, 144.7, 142.2, 128.6, 126.4, 120.8, 119.8, 118.8, 118.2,
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data for all other new compounds.
1
Copies of H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO062422I
4610 J. Org. Chem., Vol. 72, No. 13, 2007