The lyconadins: Enantioselective total syntheses of (+)-lyconadin A and (-)-lyconadin B

Article abstract of DOI:10.1021/ja804939r

A full account of the enantioselective total syntheses of (+)-lyconadin A (1) and (-)-lyconadin B (2) is presented. Central to this venture was recognition and deployment of a key strategy-level intramolecular aldol/conjugate addition cascade that led, in

Full text of DOI:10.1021/ja804939r

Published on Web 09/18/2008
The Lyconadins: Enantioselective Total Syntheses of
(+)-Lyconadin A and (-)-Lyconadin B
Douglas C. Beshore† and Amos B. Smith III*
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell
Chemical Senses Center, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received June 27, 2008; E-mail: smithab@sas.upenn.edu
Abstract: A full account of the enantioselective total syntheses of (+)-lyconadin A (1) and (-)-lyconadin
B (2) is presented. Central to this venture was recognition and deployment of a key strategy-level
intramolecular aldol/conjugate addition cascade that led, in a single operation, to two new carbon-carbon
σ-bonds, three new stereogenic centers, and two new rings, albeit with the incorrect stereogenicity at C(12)
for the lyconadins. Correction of the C(12) stereogenicity was achieved via innovative use of a protonated
intramolecular aminal. An aminoiodo olefin cyclization, in conjunction with R-pyridinone and 3,4-
dihydropyridinone annulation protocols, permitted completion of the syntheses of (+)-lyconadin A (1) and
(-)-lyconadin B (2), respectively.
Introduction
In 2001 and 2006, Kobayashi and co-workers reported the
isolation and structural elucidation of (+)-lyconadin A1 and (-)-
lyconadin B,2 respectively (1 and 2, Figure 1), from the methanol
extracts of Lycopodium complanatum, a new member within
this diverse family.3 Unique to the lyconadins is the unprec-
edented pentacyclic framework, involving either an R-pyridinone
or 3,4-dihydropyridinone ring annulated to a common tetracyclic
core, consisting of a central, highly substituted pyrrolidine ring,
which in turn is fused to three six-membered rings. From the
biomedical perspective, lyconadin A (1) possesses modest in
vitro cytotoxicity, when assayed against murine lymphoma
L1210 and human epidermoid carcinoma KB cells, while both
lyconadins A and B (1 and 2) induce enhanced mRNA
expression for neurotropic growth factor biosynthesis in 1321N1
human astrocytoma cells.1,2 Despite the intriguing structural
features, as well as the pharmacological properties of the
lyconadins, only a few reports have been directed toward their
syntheses.4 In 2007, we disclosed the first total syntheses of
(+)-lyconadin A (1) and (-)-lyconadin B (2);5 the synthesis of
lyconadin A in racemic form was subsequently reported by the
Sarpong group in early 2008.6 Presented here is a full account
of the evolution and successful execution of the Penn synthetic
venture.
Figure 1. Structures of the alkaloids (+)-lyconadin A (1) and (-)-lyconadin
B (2).
At the outset, we envisioned a late stage divergent approach
involving annulation of the requisite R-pyridinone7 or dihydro-
pyridinone ring onto ketone 3 (Scheme 1), the common
tetracyclic core, replete with a number of significant synthetic
challenges, including four cis-fused rings, punctuated with four
contiguous stereocenters [cf. C(6, 7, 12, and 13)]. To reduce
this complexity, we envisioned cleavage of the C(13)-N σ-bond
to furnish tricycle 4, formally a reductive amination in the
synthetic direction, albeit a violation of Bredt’s rule.8 Within
4, one next encounters a number of intriguing structural
elements, including a tricycle consisting of a 7- and two
6-membered rings, a 1,5-diketone (cf. highlighted bonds), an
equatorial C(16) methyl group anti to the C(6) carbon inscribed
within the cyclohexanone framework, and a piperidine ring
complete with cis-ring fusion at C(6) and C(10). Taken together,
† Present address: Merck Research Laboratories, Department of Medicinal
Chemistry, West Point, PA 19486.
(1) (a) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org. Chem.
2001, 66, 5901. (b) Hill, R. A.; Parker, M. C. Nat. Prod. Rep. 2001,
18, iii–v.
(4) (a) Tracey, M. R.; Hsung, R. Abstract of Papers, Presented at the 226th
National Meeting of the American Chemical Society, New York,
September 2003; paper ORGN-721. (b) Crich, D.; Neelamkavil, S.
Org. Lett. 2002, 4, 2573. (c) Castle, S. L. Presented at the 232nd
Meeting of the American Chemical Society, San Francisco, CA,
September 2006; paper ORGN-064. (d) Grant, S. W.; Zhu, K.; Zhang,
Y.; Castle, S. L. Org. Lett. 2006, 8, 1867.
(2) Ishiuchi, K.; Kubota, T.; Hoshino, T.; Obara, Y.; Nakahata, N.;
Kobayashi, J. Bioorg. Med. Chem. 2006, 14, 5995.
(3) For recent reviews of Lycopodium alkaloids, see: (a) Kobayashi, J.;
Morita, H. The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Elsevier Academic Press: New York, 2005; Vol. 61, p 1. (b) Ma, X.;
Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (c) Ayer, W. A.; Trifonov,
L. S. Lycopodium Alkaloids; Academic Press: San Diego, 1994. (d)
Ayer, W. A.; Trifonov, L. S. Alkaloids; Cordell, G. A., Brossi, A.,
Ed.; Academic Press: New York, 1994; Vol. 45, p 233. (e) Ayer, W. A.
Nat. Prod. Rep. 1991, 8, 455. (f) MacLean, D. B. The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1985; Vol. 26, p 241.
(5) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2007, 129, 4148.
(6) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222.
(7) For application: of a one-pot procedure for R-pyridinone ring
formation, see: Kozikowski, A. P.; Reddy, E. R.; Miller, C. P. J. Chem.
Soc., Perkin Trans. I 1990, 195.
(8) Shea, K. J. Tetrahedron 1980, 36, 1683.
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13778 J. AM. CHEM. SOC. 2008, 130, 13778–13789
10.1021/ja804939r CCC: $40.75
2008 American Chemical Society

Enantioselective Total Syntheses of the Lyconadins
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of (+)-Lyconadin A (1) and
(-)-Lyconadin B (2)
Scheme 2. Stereochemical Analysis of the Strategic Conjugate
Addition
these structural features led us to devise a strategy-level
transformation involving intramolecular conjugate addition of
the enolate derived from 5 to the R,ꢀ-unsaturated ketone to
access 4. According to Baldwin, such a 7-endo-trig cyclization
should prove favorable.9
hydrazone hydrolysis, oxidation at C(7), and generation of the
cyclohexenone ring via an intramolecular aldol condensation.
Since diketone 5 possesses four potentially enolizable centers,
three R- and one γ- to the two ketones, careful attention to the
various components of the proposed strategy-level tactic would
be required.10 From the stereoelectronic perspective, only the
C(6) E-enol can undergo a favorable intramolecular cyclization
(Scheme 2).9b Careful choice of the nitrogen protection was also
an issue; we selected the electron withdrawing N-carboxylbenzyl
(Cbz) group to enhance the required enolization. Additionally,
the stereogenicity at C(10) suggested formation of a cis-fused
7-membered ring; for such a process, two ring conformations
would be possible (i.e., 10 and 11). To minimize A1,3 strain,
favorable stereoelectronic axial attack should occur from the
top face of 10, in which the methyl group resides in the
equatorial position. Conversely, if the ring were to adopt an
alternate conformation (i.e., 11), favorable axial attack could
occur from the bottom face. Due to the expected steric repulsion
exerted by the axial methyl group on the incoming nucleophile,
the latter would presumably be unfavorable. Following this
reasoning, reaction via conformation 10 was expected. Proto-
nation of the resulting enol (9) at C(12) would then be
anticipated to occur axially to provide 4, possessing the required
relative stereogenicity of the three contiguous stereocenters
found in the lyconadins. For enone 5, construction would entail
C(11)-C(12) bond formation (Scheme 1), via union of the
kinetic enolate11 of hydrazone 6 with iodide 7, followed by
Results and Discussion
We began with construction of hydrazone 6 (Scheme 3),
employing commercially available methyl (R)-3-methylglutarate
(-)-14. While reduction of the carboxylic acid (-)-14 is known
to proceed with borane,12 a two-step activation/reduction
protocol was found to be more reliable on a larger scale.13 Under
these reaction conditions, partial lactone formation occurred to
furnish known lactone (+)-15; complete lactonization was
achieved upon treatment with acid.14 Direct installation of the
remaining carbon was next envisioned to occur via addition of
methyllithium, followed by silylation of the primary hydroxyl
group. However, all attempts to silylate the resulting hemiketal
Scheme 3. Construction of Hydrazone 6
(9) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939.
(10) While 7-endo-trig conjugate additions are known, their application to
the formation of a [5.4.0]undecane-2,7-dione is only precedented from
Tokoroyama′s studies toward the clerodane diterpenoids: Tokoroyama,
T.; Tsukamoto, M.; Iio, H. Tetrahedron Lett. 1984, 25, 5067.
(11) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178.
following the addition proved unsuccessful. We therefore turned
to a three-step protocol involving a Weinreb amide.15 Protection
of the hydroxyl as the TBS ether, installation of the requisite
carbon with methyl lithium, and conversion to the N,N-
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A R T I C L E S
Beshore and Smith
Scheme 5. Synthetic Approaches to Iodide 7
dimethylhydrazone delivered hydrazone 6 in 82% overall yield
for the seven-step sequence.
We next turned our attention toward the construction of iodide
7 from known acid16 (-)-17 (Scheme 4). Recognizing the
pseudo-C2 symmetry at C(10) in 18 and 20, either lactam
formation via Path A (18 f 19), or an SN2 displacement upon
interchange of the oxidation states of the acid and primary
alcohol via Path B (20 f 21), could lead to the requisite
piperidine.
Scheme 4. Synthetic Strategies to Construct Iodide 7
B. Antipode (-)-2622 was prepared in three steps from oxazo-
lidinone (+)-22 and acid (-)-17. Unfortunately, reduction of
the azide led spontaneously to exclusive formation of piperi-
dinone (-)-28, rather than the desired piperidine 27. We
reasoned that formation of the desired piperidine could however
be achieved if a properly substituted cyclization substrate were
employed.
We began with Path A (Scheme 5). Formation of the mixed
anhydride derived from (-)-17, followed by treatment with
lithiated oxazolidinone (-)-2217 obtained from L-phenylalanine,
furnished (+)-23 in 94% yield. A titanium-mediated aldol
reaction with s-trioxane then delivered (+)-24 as a single
diastereomer with the requisite stereogenicity at C(10) based
on the Evans precedent.18 Reduction of the azide furnished
amine 25, which underwent spontaneous lactam formation to
provide piperidinone (-)-19 in good yield. Surprisingly,
however, all attempts to reduce the lactam to the corresponding
secondary amine failed to deliver the piperidine.19,20 Attempts
to exploit the alternative thioamide21 resulted in either poor
conversion and/or erosion of the stereointegrity at C(10), the
latter likely due to the formation of the thermodynamically more
stable diequitorial thiopiperidinone. We therefore turned to Path
Toward that end, protection of the primary hydroxyl in (+)-
24 as the TBS ether followed by reductive removal of the
oxazolidinone furnished the corresponding primary alcohol,
which was subsequently converted to mesylate (+)-30 (Scheme
6). Hydrogenation of the azide led, as anticipated, to in situ
cyclization of the amine to furnish the required piperidine (-)-
31. Protection of the amino group as the Cbz carbamate, acidic
hydrolysis of the primary TBS ether, and conversion of the
resulting alcohol to the iodide completed construction of (+)-7
in 61% overall yield from known acid (-)-17. Importantly, this
sequence proved both reliable and scalable.
(19) The following conditions were examined: LiAlH4: (a) Meyers, A. I.;
Berney, D. J. Org. Chem. 1989, 54, 4673. Borane: (b) Herdeis, C.;
Kaschinshki, C.; Karla, R. Tetrahedron: Asymmetry 1996, 7, 867.
TiCl4/NaBH4: (c) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett.
1976, 10, 763. (d) Gribble, G. W Chem. Soc. ReV. 1998, 27, 395. Red-
Al: (e) Fre´ville, S.; Ce´le´rier, J. P.; Thuy, V. M.; Lhommet, G.
Tetrahedron: Asymmetry 1995, 6, 2651. AlH3: (f) Batistini, L.; Zanardi,
F.; Rassu, G.; Spanu, P.; Pelosi, G.; Fava, G. G.; Ferrari, M. B.;
Casiraghi, G. Tetrahedron: Asymmetry 1997, 8, 2975.
(12) (a) Cid, M. B.; Pattenden, G. Tetrahedron Lett. 2000, 41, 7373. (b)
Alvarez, E.; Cuvigny, T.; Herve du Penhoat, C.; Julia, M. Tetrahedron
1988, 44, 119.
(13) Kokotos, G.; Noula, C. J. Org. Chem. 1996, 61, 6994.
(14) Irwin, A. J.; Jones, J. B. J. Am. Chem. Soc. 1977, 99, 556.
(15) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989.
(20) Masking the hydroxyl as the TBS ether did not improve amide
reduction.
(16) Kottirsch, G.; Metternich, R.; New Derivatives of Beta-Amino Acids
with Anti-Thrombotic Activity. Eur. Patent EP 0 560 730 B1, 1996.
(17) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
(18) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
(21) Thioamide formation was accomplished utilizing Lawesson′s
Reagent: Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson,
S. O. Bull. Soc. Chim. Belg. 1978, 87, 223.
(22) See Supporting Information for preparation of (-)-26.
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Enantioselective Total Syntheses of the Lyconadins
A R T I C L E S
Scheme 6. Construction of Iodide (+)-7
entries 1 and 2) led either to decomposition or no reaction. Use
of the Stork pyrrolidinium acetate strategy also proved unfruitful
(entry 3),27 resulting in slow decomposition over several hours.
Acidic conditions initially appeared no better (entry 4); however,
treatment of (+)-34 in a two-phase system consisting of HCl
(12 N aqueous) and chloroform (1:25) at 40 °C for 2 h (entry
Table 1. Conditions Examined and Optimized to Affect
Intramolecular Aldol Condensation and Conjugate Addition
temp
(°C)
% yield % yield
(-)-5a
entry
conditions
time (h)
35a
1
2
3
4
5
6
7
8
9
NaOMe, MeOH
DBU, THF
Pyrrolidinium acetate, C6H6
HCl, MeOH
HCl, H2O/CHCl3
HCl (aq.), DMSO
HCl (aq.), DMSO
HCl (aq.), DMSO c ) 0.02M
HCl (aq.), DMSO c ) 0.01M
HCl (aq.), DMSO c ) 0.005M
23 1 min
-
-
-
-
24
5b
-
-
-
-
-
-
23
105
40
2
5
18
2
-
-
40
-
23
1
-
40
1
5b
43
54
84
50
70
18
3
10
70
3
With the key fragments in hand, union of hydrazone 6 with
iodide (+)-7 was achieved via the Stork11 metalloimine protocol
(Scheme 7). Specifically, the lithium anion23 derived from
hydrazone 6 was treated with iodide (+)-7 in the presence of
HMPA24 to furnish 32, the result of exclusive alkylation at the
less hindered carbon.25 Removal of the hydroxyl and carbonyl
protective groups with aqueous acid resulted in spontaneous
hemiketalization of the ketodiol to furnish 33 as a mixture of
diastereomers (ca. 3:1) in 74% overall yield for the two steps.
Oxidation of both hydroxyls could not be accomplished under
basic conditions (i.e., Parikh-Doering26 conditions). Rather, mild
acidic conditions were required (i.e., Dess-Martin periodinane
or pyridinium chlorochromate), suggesting that the pH of the
reaction mixture influences the ketone-hemiketal equilibrium.
In the end, the less expensive pyridinium chlorochromate proved
a Isolated yield. b Conversion based on 1H NMR analysis of the
reaction mixture.
Figure 2. Structure of diketone (-)-35.
5) led to enone (-)-5, albeit in a modest 24% yield. Attempts
to improve the conversion were not fruitful, as competitive
polymerization proved persistent. Fortunately, screening solvents
and temperature regimes led to more promising results. For
example, although treatment of (+)-34 with hydrochloric acid
in dimethyl sulfoxide (entry 6) at ambient temperature for 1 h
led to enone (-)-5 in low yield, at slightly elevated temperatures
Scheme 7. Fragment Union and Elaboration to Diketoaldehyde
(+)-34
1
(40 °C, entry 7) a new compound began to appear. Initial H
NMR analysis suggested the new entity to be the intramolecular
conjugate addition product 35 derived from enone (-)-5, the
next intermediate required in our synthetic sequence! Optimiza-
tion of this serendipitous result revealed that temperature, time,
and acid concentration were critical (Table 1). Best results
involved treatment of diketoaldehyde (+)-34 with aqueous
hydrochloric acid in a degassed solution of DMSO (25:1;
DMSO:HCl 12 N; v/v) for three hours at 70 °C to provide (-)-
35 as a crystalline solid (mp 134-138 °C; Figure 2); the yield
was 84%. Single crystal X-ray analysis revealed that although
(23) Stork, G.; Benaim, J. J. Am. Chem. Soc. 1971, 93, 5938.
(24) (a) Petersen, J. S.; To¨tenberg-Kaulen, S.; Rapoport, H. J. Org. Chem.
1984, 49, 2948. (b) Panek, J. S.; Beresis, R. T.; Celatka, C. A. J. Org.
Chem. 1996, 61, 6494.
(25) For a comprehensive review see: Whitesell, J. K.; Whitesell, M. A.
Synthesis 1983, 517.
more scalable (cf. 10 g), furnishing the double oxidation product
(+)-34 in 66% yield.
Diketo aldehyde (+)-34 proved to be somewhat unstable and
difficult to handle. For example, treatment with base (Table 1,
(26) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(27) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
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Scheme 8. Stereochemical Analysis of the Strategy-Level Conjugate Addition
the connectivity was correct, the relative stereochemical outcome
at C(12) was not that of the lyconadins. Not withstanding this
stereochemical issue, the intramolecular conjugate addition had
furnished two new carbon-carbon σ-bonds, two rings, and three
contiguous stereocenters in a single operation.
can be understood to occur under thermodynamic control,
as 4 is higher in energy than the observed product (-)-35
(∆∆G°f ) 1.21 kcal/mol). While we were gratified that the
7-endo-trig conjugate addition proceeded efficiently to furnish
a single diastereomer, we were now faced with the challenge
of correcting the stereogenicity at C(12) to construct the
tetracyclic core of the lyconadins.
Recognizing that the relative energy difference between the
C(12) epimers [4 and (-)-35] is small, we reasoned that
conditions might be found to correct the stereochemical issue.
Further analysis suggested the use of protonated hemiaminal
46, generated by acid-catalyzed epimerization, to trap the desired
diastereomer (Vida supra). With this scenario in mind, removal
of the Cbz group in (-)-35 to reveal the secondary amine 42
(Scheme 9) and treatment with methanolic hydrochloric acid
(12N) (10:1; MeOH:HCl; v/v) at reflux for 18 h, followed by
concentration and careful neutralization led to (-)-44 in 71%
yield.29 Pleasingly, this process permits facile epimerization of
(-)-42 to the higher energy epimer (-)-44. Support for
To understand this intriguing observation, as well as to
seek a solution to the unfavorable stereochemical outcome,
we carefully analyzed the reaction sequence (Scheme 8). The
aldol product (-)-5 has the opportunity to undergo a Baldwin
allowed 7-endo-trig intramolecular conjugate addition either
syn or anti to the C(16)-methyl group (Paths A and B). If
Path A were followed, equatorial attack via the conformation
depicted by 36 would result in formation of the C(6)-C(7)
bond cis to the C(16) methyl group, forming enol 37, which
in turn could undergo protonation either from the top or
bottom face to result in 38 or 39, respectively. Conversely,
following Path B, axial attack from the top face via what
would be a stereoelectronically favorable trajectory would
furnish the required stereogenicity at C(6) and C(7), relative
to both C(10) and the cyclohexenone C(16) methyl group.
Protonation of the resultant enol (41) could again occur either
from the top or bottom face to furnish 4 or (-)-35. In this
event, only (-)-35 was isolated in 84% yield.
Scheme 9. Correction of the Stereogenicity at C(12)
Structure calculations employing B3LYP/6-31G** level
of theory, performed on the four diastereomers (4, 35, 38,
and 39) using the Gaussian package,28 revealed the lowest-
energy diastereomer to be 39, which was not observed. The
sole isolated product (-)-35 proved intermediate in energy,
with the congener arising via the stereoelectronically pre-
ferred protonation pathway (i.e., 4) having the highest energy.
Taken together, these results suggest that the reaction
sequence is not solely under thermodynamic control. Given
that the product derived via the stereoelectronically preferred
axial protonation (i.e., diastereomer 4) was not observed, the
reaction also cannot be considered to be solely under kinetic
control. Rather, the observed product is the result of both
kinetic and thermodynamic processes operating at different
points along the reaction sequence. Since neither 38 nor 39
were formed during the reaction, we conclude that formation
of the C(6)-C(7) σ-bond is irreversible. With Path B the
only way forward, the protonation event at C(12) of enol 41
(28) Frisch, M. J. Gaussian 03, revision C.01; Gaussian, Inc.: Wallingford,
CT, 2004. See Supporting Information for details regarding the
described calculations.
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A R T I C L E S
intermediacy of the hemiaminal salt was obtained by treatment
of (-)-44 with hydrochloric acid (12N) in d7-DMF; a new
resonance at 97.6 ppm in the 13C NMR, characteristic of a
tertiary carbinol salt (cf. 46), was observed.30 Upon neutraliza-
tion with sodium bicarbonate, diketoamine (-)-44 is regener-
ated.31 Given the facile formation of the hemiaminal salt 46,
we reasoned that direct reduction or capture of the hemiaminal
might be possible (cf. 3, Scheme 1). Unfortunately, all efforts
to achieve such transformations failed, presumably due to the
relative unreactivities of both the sterically congested, non-
nucleophilic tertiary alcohol of the aminal and the hindered
nitrogen in the corresponding aminoketone. We were therefore
forced to revise our strategy. Interconversion of aminoketone
(-)-44 and hemiaminal salt 46 would however play a significant
role in our modified tactic to deliver the tetracyclic core for the
lyconadins (Vida infra).
ing group (cf. Cbz) would be required to complete the synthetic
venture. Thus, in similar fashion, (-)-35 was converted to (-)-
50 in 51% yield for the four-step sequence (Scheme 11). In
this case, a diastereomeric mixture of diols (i.e., 51; 29% yield)
was also formed, the result of incomplete epimerization at C(12)
and nonselective reduction of the C(13) and C(5) carbonyl
groups. Fortunately, 51 could be recycled via Dess-Martin
periodinane32 oxidation to afford (-)-35 in 92% yield, thereby
permitting efficient material utilization. The overall yield for
the four-step sequence was 80%.33
Scheme 11. Four-Step Sequence to Correct the C(12)
Stereogenicity
Unable to affect direct formation of the critical N-C(13)
σ-bond, we explored differentiation of the two carbonyl groups
in diketoamine (-)-44 (Scheme 10), by taking advantage of
the hemiaminal salt 46, to act as an in situ mask for the C(13)
ketone. Toward this end, treatment of 46 with lithium borohy-
dride led with high selectivity to the equatorial alcohol 47, which
without isolation was protected with tert-Boc anhydride (Boc2O)
to furnish the N-Boc derivative (-)-49 as a crystalline solid;
single crystal X-ray analysis verified both the structure and
relative stereochemistry.
Scheme 10. Hemiaminal Mask for the C(13) Ketone
Formation of the C(13)-N σ-bond (Scheme 12) was the next
priority. Recognizing that the C(13) ketone could not be
employed directly, we reasoned that if (-)-50 could be
converted to the trisubstituted olefin 52 (Scheme 12), treatment
with a suitable electrophile might induce intramolecular cy-
clization to forge the long-sought σ-bond, and thereby the
tetracyclic core of the lyconadins (i.e., 53).
Scheme 12. Synthetic Strategy to Construct the Tetracyclic Core
We began with TBS protection of the secondary hydroxyl34
(Scheme 13) followed by L-Selectride reduction to provide (-)-
(29) Single crystal X-ray crystallographic analysis unambiguously confirmed
the structural identity of compound (-)-42. See Supporting Information
for details.
(30) Similar 13C-NMR shifts have been observed for hemiaminal salts; see:
Hext, N. M.; Hansen, J.; Blake, A. J.; Hibbs, D. E.; Hursthouse, M. B.;
Shishkin, O. V.; Mascal, M. J. Org. Chem. 1998, 63, 6016.
(31) See Supporting Information for details.
(32) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer,
S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(33) Increasing reaction time for the epimerization of (-)-42 to 46 did not
effect the ratio after 18 h (1:3, respectively), suggesting that this
represents the equilibrium mixture for the specified conditions.
(34) Protection of the secondary hydroxyl employing standard conditions
(i.e., TBSCl, imidazole, DMAP, CH2Cl2) afforded a mixture of
silylated secondary hydroxyl, the epimeric C(12) protected silylated
secondary hydroxyl, as well as the bissilylated secondary hydroxyl
C(5) and C(12) enol ether. These reaction byproducts were minimized
by employing 2,6-di-tert-butyl-4-methylpyridine (DtBMP) as a base.
While preparation of (-)-49 led to invaluable structural
information, we anticipated that a more robust nitrogen protect-
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A R T I C L E S
Beshore and Smith
were obtained. We turned instead to a report by Mulzer,40 in
which the ketone is first converted to a ꢀ-ketoester and then
subjected to Michael addition with acrylonitrile. Use of a
ꢀ-ketoester was expected to enhance reaction with propiola-
mide.41 At this point, we had also come to recognize the volatile
nature of aminoketone (-)-3. Use of the less volatile iodoamine
(cf. 53, X ) I), in conjunction with the Mulzer protocol, thus
appeared desirable.
Scheme 13. Construction of the Tetracyclic Core of the Lyconadins
Beginning with aminoolefin (-)-52 (Scheme 14), treatment
with N-iodosuccinimide to promote olefin cyclization, followed
by removal of the silyl group, furnished (-)-58 as a crystalline
solid in 93% for the two steps. Single crystal X-ray diffraction,
in conjunction with the anomalous dispersion technique, pro-
vided unambiguous assignment of the structure, including
confirmation of the absolute stereochemistry.42 Dess-Martin
oxidation then furnished ketone (-)-59, now a nonvolatile
compound that could be readily handled. Installation of the
ꢀ-ketoester, achieved via the Mander43 protocol, followed by
reductive removal of the iodine and conjugate addition with
propiolamide furnished unsaturated amide (-)-60, the envi-
sioned common intermediate for both lyconadins.
Scheme 14. Preparation of the Penultimate Intermediate for
(+)-Lyconadin A (1)
54 with high stereoselectivity (>95:5). Removal of the Cbz
group then led to amino alcohol (-)-55, which was readily
dehydrated with the Martin sulfurane,35 notably in the presence
of the unprotected secondary amine, to generate exclusively
trisubstituted olefin (-)-52 in 82% yield. To construct the
tetracyclic core, we initially explored an acid-induced cycliza-
tion;36 however, no reaction was observed. We turned next to
N-iodosuccinimide (NIS) as a source of iodonium ion.37
Pleasingly, upon treatment of (-)-52 with NIS, the requisite
5-endo cyclization occurred at ambient temperature to generate
53 (X ) I). Reductive removal of the tertiary iodide38 then
furnished (-)-56 in 75% yield for the two steps. Completion
of the tetracyclic core entailed removal of the silyl group to
furnish secondary alcohol (-)-57, which upon Dess-Martin
periodinane oxidation led to (-)-3.
At this juncture, we only required installation of the C(1-3)
carbon fragment, in conjunction with formation of the R-pyri-
dinone and dihydropyridinone rings to complete the lyconadins.
From the outset, we had envisioned use of the one-pot protocol
developed by Kozikowski,39 employing methyl propiolate and
ammonia to access (+)-lyconadin A (1). Unfortunately, this
approach was not successful; only unreacted starting materials
Initial attempts to construct the pyridinone ring with sodium
hydroxide in DMSO (Table 2, entry 1) led only to polymeri-
zation. Milder conditions employing sodium cyanide were
therefore investigated (entry 2). Formation of R-pyridinone (-)-
61 occurred, albeit with incorporation of the nitrile group in
the ring (20% yield).44 Use of even less nucleophilic reagents,
such as tetramethylammonium acetate45 (entries 3 and 4),
(40) Ho¨genauer, K.; Baumann, K.; Enz, A.; Mulzer, J. Bioorg. Med. Chem.
Lett. 2001, 11, 2627.
(35) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
(36) (a) Ruggeri, R. B.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3714.
(b) Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem.
1992, 57, 2554. (c) Heathcock, C. H.; Kath, J. C.; Ruggeri, R. B. J.
Org. Chem. 1995, 60, 1120.
(41) Hay, L. A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell, D. J.
Org. Chem. 1998, 63, 5050.
(42) See Supporting Information for details.
(43) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(44) Formation of compound (-)-61 can be understood as a conjugate
addition of cyanide to the unsaturated amide prior to ring closure,
followed by ring closure, and then oxidation, thermodynamically driven
by aromatization to the R-pyridinone ring. See the following reference
for a similar eliminative, aromatization event: Donohue, T. J.; Fishlock,
L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285.
(37) Diaba, F.; Ricou, E.; Bonjoch, J. Org. Lett. 2007, 9, 2633.
(38) Boukherroub, R.; Chatgilialoglu, C.; Manuel, G. Organometallics 1996,
15, 1508.
(39) (a) Kozikowski, A. P.; Ding, Q.; Saxena, A.; Doctor, B. P. Bioorg.
Med. Chem. Lett. 1996, 6, 259. (b) Camps, P.; Mun˜oz-Torrero, D.;
Simon, M. Synth. Commun. 2001, 31, 3507. (c) Kozikowski, A. P.;
Reddy, E. R.; Miller, C. P. J. Chem. Soc., Perkin Trans I 1990, 195.
(45) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4743.
9
13784 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Enantioselective Total Syntheses of the Lyconadins
A R T I C L E S
Table 2. Conditions Explored to Affect Formation of (+)-Lyconadin
A (1)
lyconadin B were in complete agreement with those reported
for the natural products, confirming the Kobayashi structural
and absolute stereochemical assignments.48 Overall, (+)-ly-
conadin A (1) and (-)-lyconadin B (2) were prepared both in
2.2% overall yield, with longest linear sequences of 27 and 28
steps, respectively.
In summary, construction of the lyconadin alkaloids A and
B (1 and 2) has been achieved. A strategy-level cascade was
devised and executed to assemble a common, tricyclic ring
system (-)-35, during which two new carbon-carbon σ-bonds,
three stereogenic centers and two new rings were formed in a
single operation, albeit possessing the incorrect stereogenicity
at C(12) for the lyconadin skeleton. Isomerization through aegis
of an aminal salt corrected this stereochemical issue. Application
of a 5-endo aminoiodo olefin cyclization then permitted access
to the lyconadin tetracyclic core. Final elaboration to the
R-pyridinone and 3,4-dihydropyridinone rings was achieved via
a three- and four-step reaction sequence, respectively, to
complete the total syntheses of (+)-lyconadin A (1) and (-)-
lyconadin B (2).
entry
conditions
temp (°C)
time (h)
% yield (+)-1a
1
2
3
4
NaOH (1 N aq), DMSO
NaCN, HMPA
Me4NOAc, HMPA
Me4NOAc, MeCN
150
100
100
135
1
2
2
-
b
-
44c
71
16
a Isolated yield. b Compound (-)-61 was isolated in 20% yield.
c Yield based on recovered starting material.
provided moderate success employing HMPA as solvent; the
optimal protocol, however, entailed use of acetonitrile to provide
(+)-lyconadin A (1) in 71% yield.
For (-)-lyconadin B, we sought formation of the dihydro-
pyridinone ring (Table 3). Hydrogenation of (-)-60 furnished
saturated amide (-)-62. However, unlike (+)-lyconadin A (1),
tetramethylammonium acetate (entry 1) did not lead to the
dihydropyridinone, albeit several presumed intermediates (1H
NMR), such as 63 and 64, were encountered that had not been
observed during construction of the R-pyridinone ring system.
However, all attempts to convert either 63 or 64 to (-)-
lyconadin B (2) proved unsuccessful.46 Ultimately, the combina-
tion of lithium chloride in HMPA at 125 °C for 17.5 h proved
optimal to provide (-)-lyconadin B (2) in 68% yield (entry 4).47
Experimental Section
Selected experimental procedures for the preparation of (+)-
lyconadin A (1) and (-)-lyconadin B (2) appear below. Full
experimental details for all compounds are given in the Supporting
Information.
Preparation of Hemiketal 33. Hydrazone 6 (1.12 g, 4.22 mmol,
1.1 equiv) was dissolved in tetrahydrofuran (10 mL) and cooled to
-78 °C. n-Butyllithium (2.20 mL, 1.7 M in tetrahydrofuran, 3.90
mmol, 1.02 equiv) was added dropwise, and the mixture was stirred
for 1 h at -78 °C. Hexamethylphosphoramide (1.0 mL, 10% v/v)
was added dropwise, and the mixture was stirred for an additional
15 min at -78 °C, warmed to -60 °C for 15 min, and then cooled
to -78 °C. In a separate flask, iodide (+)-7 (1.88 g, 3.84 mmol)
was dissolved in tetrahydrofuran (5 mL), cooled to -78 °C, and
added dropwise via syringe to the hydrazone anion. After stirring
for 1 h at -78 °C, the dry ice/acetone bath was removed and the
reaction mixture was warmed to ambient temperature. After stirring
for 30 min at ambient temperature, the reaction mixture was treated
with sodium bicarbonate (5 mL, aqueous saturated) and poured into
a separatory funnel containing sodium bicarbonate (75 mL, aqueous
saturated). The aqueous layer was extracted with ethyl acetate (3
× 100 mL) and the combined organic extracts were dried with
sodium sulfate, filtered and concentrated in Vacuo. The coupling
product 32 was used without further purification in the next reaction.
High resolution mass spectrum (ES+) m/z 648.4610 [(M + H)+;
calculated for C35H66N3O4Si2: 648.4592].
Table 3. Conditions Examined to Affect Formation of
(-)-Lyconadin B (2)
entry
conditions
temp (°C)
time (h)
result
The above prepared coupling product 32 was dissolved in
tetrahydrofuran (25 mL) and treated with water (10 mL) and
hydrochloric acid (2 mL, 12 N aqueous). The mixture was stirred
vigorously for 14 h at ambient temperature, poured into water (100
mL), and extracted with ethyl acetate (3 × 100 mL). The combined
organic extracts were dried with sodium sulfate, filtered, and
concentrated in Vacuo. The residue was purified by silica gel
gradient chromatography (1:1 to 0:1; hexanes/ethyl acetate), provid-
ing the hemiketal 33 (1.07 g, 74% yield over 2 steps) as a colorless
1
2
3
4
Me4NOAc, MeCN
LiBr, DMA
LiBr, DMA
135
150
150
125
15
5
15
17.5
only 63
2 + 64
2 (26%)a
2 (68%)a
LiCl, HMPA
a Isolated yield.
Pleasingly, the spectral data (1H and 13C NMR, HRMS, IR,
chiroptic properties) for synthetic (+)-lyconadin A and (-)-
1
oil: H NMR (500 MHz, CDCl3; spectrum contains a mixture of
ketone and hemiketal diastereomers, which exhibit rotameric
signals) δ 7.35-7.27 (5H, m), 5.19-5.05 (2H, br m), 4.06-3.81
(br m), 3.63 (br ddd, J ) 11.2, 4.5, 1.1 Hz), 3.59 (br t, J ) 6.3
Hz), 3.44-3.34 (br m), 3.27-3.19 (br m), 3.10 (br dd, J ) 13.6,
2.0 Hz), 2.91-2.52 (br m), 2.52-2.31 (br m), 2.30-2.08 (br m),
1.99-1.80 (br m), 1.67 (br d, J ) 11.2 Hz), 1.64-1.55 (br m),
1.52 (br d, J ) 13.0 Hz), 1.45 (br dd, J ) 13.4, 7.1 Hz), 1.32 (br
tt, J ) 11.2, 2.8 Hz), 1.14 (br dq, J ) 12.8, 4.5 Hz), 1.01 (br t, J
(46) Conditions examined to convert 63 or 64 to (-)-lyconadin B (2)
included: Resubjection to reaction conditions. Treatment with acid: (a)
Kan, W. M.; Cheng, C.-L.; Chern, C.-Y Synth. Commun. 2004, 34,
4257. Thermal dehydration: (b) Citterio, A.; Carnevali, E.; Farina, A.;
Meille, V.; Alini, S.; Cotarca, L. Org. Prep. Proced. Int. 1997, 29,
465. Chemical dehydration: (c) Pawlowski, M.; Maurin, J. K.;
Leniewshki, A.; Wojtasiewicz, K.; Czarnocki, Z. Heterocycles 2005,
65, 9.
(47) A rationale for differences in the conditions required for optimal
formation of (+)-lyconadin A (1) and (-)-lyconadin B (2) is not
apparent to the authors.
(48) See Supporting Information for details.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13785

A R T I C L E S
Beshore and Smith
) 12.6 Hz), 0.91 (d, J ) 6.7 Hz), 0.89 (d, J ) 6.3 Hz), 0.86 (d, J
) 6.7 Hz) ppm; high resolution mass spectrum (ES+) m/z 400.2086
[(M + Na)+; calculated for C21H31NaNO5: 400.2100].
and concentrated in Vacuo to provide compound (-)-42, which was
used without purification in the next reaction. However, purification
by silica gradient gel chromatography (99:1 to 94:6; dichlo-
romethane/methanol containing 10% by volume ammonium hy-
Preparation of Diketoaldehyde (+)-34. Hemiketal 33 (10.3 g,
27.3 mmol) was dissolved in dichloromethane (400 mL) and treated
with freshly activated 4 Å molecular sieves (20.0 g, 2 weight equiv).
To the vigorously stirring mixture was added pyridinium chloro-
chromate (14.7 g, 68.2 mmol, 2.5 equiv) in several portions over
5 min. After stirring for 1 h, additional pyridinium chlorochromate
(14.7 g, 68.2 mmol, 2.5 equiv) was added, the reaction mixture
was stirred an additional 1 h and then diluted with diethylether (1
L) and Celite (∼60 g). The mixture was stirred vigorously for 1 h
and poured directly onto a silica gel column, eluting with diethyl
ether (1.5 L), then ethyl acetate, providing aldehyde (+)-34 (6.76
droxide) provided amine (-)-42: [R]20 -163° (c 0.90, CH2Cl2);
D
IR (NaCl plate, neat): 3364 (br m), 2953 (m), 2921 (s), 2866 (m),
1708 (s), 1446 (w), 1403 (w), 1380 (w), 1339 (w), 1285 (w), 1232
(w), 1213 (w), 1181 (w), 1113 (w), 1032 (w), 948 (w), 915 (w),
886 (w), 770 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 3.16 (d, J
) 11.2 Hz, 1H), 3.08 (dd, J ) 11.3, 4.3 Hz, 1H), 3.04 (s, 1H),
2.73 (dt, J ) 12.3, 4.2 Hz, 1H), 2.57 (dd, J ) 13.4, 5.9 Hz, 1H),
2.53-2.44 (m, 2H), 2.44-2.40 (m, 2H), 2.21-2.12 (m, 3H),
1.96-1.81 (br m, 1H), 1.87 (dt, J ) 12.3, 3.7 Hz, 1H), 1.58 (d, J
) 13.4 Hz, 1H), 1.50 (dd, J ) 14.9, 12.3 Hz, 1H), 0.95 (d, J ) 7.1
Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 212.7, 212.6, 66.7,
50.4, 47.4, 44.8, 44.3, 42.6, 37.7, 31.7, 30.7, 27.2, 19.8 ppm; high
resolution mass spectrum (CI+) m/z 221.1411 [(M+)+; calculated
for C13H19NO2: 221.1416].
g, 66%) as a light-green oil: [R]20 +10.6° (c 1.15, CH2Cl2); IR
D
(NaCl plate, neat): 2959 (m), 2930 (m), 2878 (m), 2721 (w), 1700
(s), 1454 (w), 1419 (m), 1367 (w), 1320 (w), 1216 (m), 1117 (m),
971 (w), 914 (w), 762 (w), 734 (w), 699 (w) cm-1; 1H NMR (500
MHz, CDCl3; spectrum contains an ∼1:10 mixture of rotamers, *
denotes minor rotamer signals) δ 9.72 (br s), *9.63 (br s), 7.40-7.29
(br m), 4.10 (br d, J ) 17.5 Hz), 4.04-3.76 (br m), 3.27-3.14 (br
m), 2.59 (br d, J ) 4.8 Hz), 2.58 (br d, J ) 4.1 Hz), 2.55-2.34 (br
m), 2.33 (br dd, J ) 7.1, 1.5 Hz), 2.30 (br dd, J ) 7.1, 1.9 Hz),
2.16 (dd, J ) 16.4, 9.7 Hz), 2.09-2.00 (br m), 1.69-1.51 (br m),
*1.33 (d, J ) 7.1 Hz), 0.98 (d, J ) 6.3 Hz) ppm; 13C NMR (125
MHz, CDCl3) δ 208.6, 204.4, 201.8, 155.3, 136.4, 128.7, 128.4,
128.2, 67.8, 54.2 br, 50.5, 49.3, 47.3 br, 45.0 br, 40.1, 34.0, 26.9,
24.2, 20.5 ppm; high resolution mass spectrum (ES+) m/z 396.1781
[(M + Na)+; calculated for C21H27NNaO5: 396.1787].
Amine (-)-42 was dissolved in an 80:15:5 mixture (1 L) of
water:methanol:hydrochloric acid (12 N aqueous) and placed into
an oil bath preheated to 100 °C for 18 h. The mixture was cooled
to ambient temperature and concentrated in Vacuo to provide the
hemiaminal salt 46, which was used without purification in the next
1
reaction: H NMR (500 MHz, d7-DMF) δ 4.20 (ddd, J ) 13.0,
3.9, 2.8 Hz, 1H), 3.96 (d, J ) 5.6 Hz, 1H), 3.03 (d, J ) 11.9 Hz,
1H), 2.69 (dd, J ) 14.1, 5.6 Hz, 1H), 2.65-2.60 (m, 2H), 2.47
(dd, J ) 10.0, 5.2 Hz, 1H), 2.31-2.23 (m, 1H), 2.12 (s, 1H), 1.89
(br d, J ) 13.4 Hz, 1H), 1.76 (d, J ) 14.1 Hz, 1H), 1.64 (dd, J )
14.0, 12.1 Hz, 1H), 1.32 (t, J ) 11.9 Hz, 1H), 0.96 (d, J ) 6.3 Hz,
3H) ppm; 13C NMR (125 MHz, d7-DMF) δ 204.9, 97.6, 69.5, 47.8,
47.3, 44.5, 43.7, 42.3, 38.2, 29.9, 26.1, 25.1, 21.6 ppm.
Preparation of Tricycle (-)-35. Aldehyde (+)-34 (183 mg,
0.490 mmol) was dissolved in dimethylsulfoxide (100 mL) and was
sparged under an argon atmosphere. Hydrochloric acid (4 mL) was
added, and the vessel was placed into an oil bath preheated to 70
°C for 3 h. The mixture was cooled to ambient temperature, poured
into water (300 mL), and extracted with ethyl acetate (3 × 200
mL). The combined organic extracts were dried with sodium sulfate,
filtered, and concentrated in Vacuo. The residue was purified by
silica gel chromatography (1:1; hexanes/ethyl acetate), providing
tricycle (-)-35 (147 mg, 84% yield) as a white solid. X-ray quality
crystals were prepared via vapor diffusion from hexanes/dichlo-
romethane; melting point 134-138°: [R]20D -83.9° (c 2.8, CH2Cl2);
IR (NaCl plate, thin film, CH2Cl2): 2954 (m), 2927 (m), 1702 (s),
1448 (w), 1409 (s), 1346 (m), 1310 (w), 1285 (s), 1233 (m), 1216
(m), 1155 (w), 1110 (m), 1079 (w), 1030 (w), 969 (w), 917 (w)
Hemiaminal salt 46 was dissolved in methanol (300 mL), cooled
to 0 °C and treated with sodium borohydride (600 mg, 15.9 mmol,
3.15 equiv) portionwise over 90 min. Hydrochloric acid (10 mL,
12 N aqueous) was added and the mixture was stirred vigorously
for 30 min. The mixture was concentrated in Vacuo to provide the
alcohol as a light yellow foam, which was dissolved in ethyl acetate
(100 mL), treated with sodium bicarbonate (50 mL, aqueous
saturated) and cooled to 0 °C with vigorous stirring. An ethyl acetate
solution (20 mL) of benzyl chloroformate (2.00 mL, 11.5 mmol,
2.27 equiv) was added slowly to the solution over 5 min. The
reaction mixture was slowly warmed to ambient temperature over
2 h and then stirred for an additional 14 h. The mixture was poured
into water (200 mL) and extracted with ethyl acetate (3 × 250
mL). The combined organic extracts were dried with sodium sulfate,
filtered and concentrated in Vacuo. The residue was purified by
silica gel gradient chromatography (10:0 to 25:75; hexanes/ethyl
acetate), providing alcohol (-)-50 (919 mg, 51% yield). Upon
further elution (25:75 to 0:1; hexanes/ethyl acetate), the diol 51
was obtained (526 mg, 29% yield). The alcohol (-)-50 was obtained
1
cm-1; H NMR (500 MHz, CDCl3; spectrum contains a mixture
of rotamers) δ 7.40-7.31 (m), 5.23-5.11 (m), 4.61 (s), 4.47 (s),
3.62 (br t, J ) 11.7 Hz), 3.53 (br dd, J ) 12.1, 3.9 Hz), 2.68-2.62
(br m), 2.62-2.55 (br m), 2.53-2.34 (br m), 2.26-2.18 (br m),
2.16-2.09 (br m), 2.16 (s), 2.06 (br d, J ) 4.5 Hz), 2.03 (s), 2.00
(br dd, J ) 11.9, 2.6 Hz), 1.93 (br d, J ) 9.3 Hz), 1.81 (br d, J )
12.6 Hz), 1.63 (br d, J ) 8.6 Hz), 1.53-1.46 (m), 0.94 (d, J ) 7.4
Hz), 0.91 (d, J ) 7.1 Hz) ppm; 13C NMR (125 MHz, CDCl3;
spectrum contains a mixture of rotamers) δ 211.1, 210.7, 207.8,
207.6, 156.4, 155.8, 136.4, 136.1, 128.7, 128.5, 128.4, 128.2, 67.9,
67.9, 66.1, 65.5, 50.3, 50.3, 47.4, 47.3, 47.3, 47.1, 47.0, 44.0, 43.9,
43.7, 37.5, 30.5, 30.4, 30.3, 26.1, 25.7, 19.5, 19.4 ppm; high
resolution mass spectrum (ES+) m/z 378.1686 [(M + Na)+;
calculated for C21H25NNaO4: 378.1681].
Preparation of Alcohol (-)-50. Tricycle (-)-35 (1.80 g, 5.1
mmol) was dissolved in a 1:1 mixture of methanol/ethyl acetate
(500 mL). The solution was sparged under an argon atmosphere
and then treated with Pd(OH)2/C (180 mg, 20% weight Pd). The
vigorously stirring mixture was sparged under an atmosphere of
hydrogen (1 atm, balloon) and stirred for 90 min. Additional
Pd(OH)2/C (90 mg, 20% weight Pd) was added, and the mixture
was sparged under an atmosphere of hydrogen and stirred for an
additional 45 min. The reaction mixture was sparged under an
atmosphere of argon and filtered through a pad of Celite. The Celite
was washed with a 1:1 mixture of methanol/ethyl acetate (500 mL)
as a white foam: [R]20 -26.6° (c 0.70, CH2Cl2); IR (NaCl plate,
D
thin film, CH2Cl2): 3434 (br m), 2927 (m), 2873 (m), 1699 (s),
1452 (m), 1411 (m), 1354 (w), 1312 (m), 1255 (w), 1212 (w), 1114
(m), 1070 (w), 1015 (w), 916 (w), 734 (m), 702 (w) cm-1 1H
;
NMR (500 MHz, CDCl3; spectrum contains an ∼3:1 mixture of
rotamers, * denotes minor rotamer signals) δ 7.39-7.28 (m),
*5.27-5.22 (br m), 5.14 (br d, J ) 12.7 Hz), 5.08 (br d, J ) 12.7
Hz), *4.69 (br s), 4.19 (br d, J ) 2.6 Hz), *4.05-4.00 (br m),
3.96-3.89 (br m), 3.47 (br d, J ) 11.2 Hz), *3.40 (br d, J ) 17.1
Hz), *3.19-3.13 (br m), 3.07 (br d, J ) 11.5 Hz), 2.97-2.91 (br
m), *2.82-2.75 (br m), 2.68-2.59 (br m), 2.56-2.48 (br m),
2.46-2.37 (br m), 2.33 (br dd, J ) 14.9, 4.5 Hz), 2.26-2.14 (br
m), 1.86 (br dd, J ) 14.8, 10.0 Hz), 1.79 (br d, J ) 13.8 Hz),
*1.75-1.65 (br m), 1.61 (br ddd, J ) 13.3, 10.0, 3.5 Hz), 1.54-1.49
(br m), 1.46-1.42 (br m), 0.95 (d, J ) 6.7 Hz), *0.86-0.81 (br
m) ppm; 13C NMR (125 MHz, CDCl3; spectrum contains an ∼3:1
mixture of rotamers, only the major rotamer signals are reported)
δ 211.4, 156.5, 136.9, 128.6, 128.0, 127.7, 68.1, 67.4, 58.1, 47.9,
47.7, 46.6, 38.4, 37.4, 34.7, 32.9, 29.2, 22.2 ppm; high resolution
9
13786 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Enantioselective Total Syntheses of the Lyconadins
A R T I C L E S
mass spectrum (CI+) m/z 357.1943 [(M+)+; calculated for
C21H27NO4: 357.1940].
sparged under an argon atmosphere. Pd/C (200 mg, 5% Pd weight,
catalytic) was added and the mixture was sparged under a hydrogen
atmosphere (1 atm, balloon). The mixture was stirred vigorously
for 90 min and then sparged under an argon atmosphere and filtered
through a pad of Celite. The Celite was washed with absolute
ethanol (50 mL), and the filtrate was concentrated in Vacuo. The
residue was dissolved in toluene (100 mL) and concentrated in
Vacuo to provide the aminoalcohol (-)-55 (529 mg, 99% yield) as
Preparation of Alcohol (-)-54. Alcohol (-)-50 (1.26 g, 3.52
mmol) was dissolved in dichloromethane (70 mL), treated with 2,6-
di-tert-butyl-4-methylpyridine (1.62 g, 7.91 mmol, 2.25 equiv) and
cooled to -78 °C. tert-Butyldimethylsilyl trifluoromethanesulfonate
(1.01 mL, 4.39 mmol, 1.25 equiv) was added dropwise and the
reaction mixture was stirred for 1 h at -78 °C. The reaction mixture
was quenched with sodium bicarbonate (5 mL, aqueous saturated)
and warmed to ambient temperature. The mixture was poured into
water (100 mL) and extracted with dichloromethane (3 × 200 mL),
and the combined organic extracts were dried with sodium sulfate,
filtered, and concentrated in Vacuo. The residue was purified by
silica gel gradient chromatography (10:0 to 85:15; hexanes/ethyl
acetate), providing the TBS ether (1.17 g, 70% yield) as a colorless
a white solid, which did not require further purification: [R]20
D
-28.8° (c 0.25, CH2Cl2); IR (NaCl plate, thin film, CH2Cl2): 3300
(br m), 3231 (br m), 2953 (s), 2927 (s), 2858 (s), 1541 (w), 1471
(m), 1461 (m), 1388 (m), 1307 (w), 1119 (m), 1093 (s), 1048 (m),
1006 (w), 909 (m), 899 (w), 867 (w), 836 (s), 776 (m), 734 (m),
668 (w), 643 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 3.98-3.94
(m, 1H), 3.72 (br dd, J ) 7.6, 4.7 Hz, 1H), 2.95-2.90 (br m, 2H),
2.67-2.64 (br m, 1H), 2.60 (dd, J ) 9.3, 4.8 Hz, 1H), 2.17-2.11
(m, 2H), 2.08-2.03 (m, 1H), 1.98 (ddd, J ) 14.3, 9.3, 4.8 Hz,
1H), 1.89-1.82 (m, 2H), 1.77 (br d, J ) 12.7 Hz, 1H), 1.48-1.42
(m, 2H), 1.27-1.21 (m, 2H), 1.16 (ddd, J ) 12.7, 10.4, 2.6 Hz,
1H), 0.89-0.88 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR
(125 MHz, CDCl3; spectra contains conformational isomers) δ 70.0,
69.9, 59.2, 45.4, 42.9, 41.4, 38.3, 36.2, 36.0, 35.9, 30.4, 29.9, 26.0,
22.9, 22.1, 18.1, -4.3, -4.6 ppm; high resolution mass spectrum
(ES+) m/z 340.2656 [(M + H)+; calculated for C19H38NO2Si:
340.2672].
oil: [R]20 -30.1° (c 1.65, CH2Cl2); IR (NaCl plate, neat): 2951
D
(s), 2929 (s), 2859 (m), 1701 (s), 1453 (m), 1405 (m), 1351 (w),
1309 (m), 1258 (m), 1213 (w), 1088 (s), 941 (w), 889 (m), 862
(w), 837 (m), 777 (m), 697 (w), 668 (w) cm-1 1H NMR (500
;
MHz, CDCl3; spectrum contains a ∼3:1 mixture of rotamers, *
denotes minor rotamer signals) δ 7.38-7.29 (m), 5.17 (br d, J )
12.3 Hz), 5.08 (br d, J ) 12.7 Hz), 4.15-4.10 (br m), *4.10-4.05
(br m), 3.94-3.84 (br m), 3.45 (br d, J ) 11.9 Hz), *3.37 (br d, J
) 12.3 Hz), *3.16 (br d, J ) 12.6 Hz), 3.08 (br d, J ) 11.5 Hz),
2.95-2.89 (m), *2.82-2.75 (br m), *2.66-2.59 (br m), 2.53 (br
dd, J ) 11.0, 5.4 Hz), 2.48-2.37 (br m), 2.33 (br dd, J ) 14.9, 4.5
Hz), *2.27-2.21 (br m), 2.21-2.11 (br m), *1.94-1.90 (br m),
1.86 (br dd, J ) 14.5, 9.7 Hz), 1.75-1.64 (br m), 1.60-1.43 (br
m), 0.94 (br d, J ) 6.3 Hz), 0.91-0.87 (br m), 0.80-0.03 (br m)
ppm; 13C NMR (125 MHz, CDCl3; spectrum contains a ∼3:1
mixture of rotamers, * denotes minor rotamer signals) δ 211.8,
156.3, 137.1, *128.7, 128.6, *128.3, 128.0, 127.8, 68.4, 67.2, 57.8,
*48.5, 47.9, 47.7, 46.9, *46.6, 37.6, 37.3, *35.3, *35.1, *33.8, 33.2,
*29.9, 29.5, *29.2, *28.9, 28.5, 25.9, 22.0, *20.9, 18.1, -4.4, *-4.5,
-4.6 ppm; high resolution mass spectrum (ES+) m/z 494.2719 [(M
+ Na)+; calculated for C27H41NNaO4Si: 494.2703].
Preparation of Aminoalkene (-)-52. Aminoalcohol (-)-55
(529 mg, 1.56 mmol) was dissolved in dichloromethane (20 mL)
and cooled to 0 °C. In a separate flask, a dichloromethane (10 mL)
solution of Martin sulfurane reagent (2.09 g, 3.11 mmol, 2.0 equiv),
which was weighed out and stored in a glovebox,49 was prepared.
From this solution, Martin sulfurane reagent (5 mL, 1.0 equiv) was
added dropwise to the aminoalcohol. After stirring for 30 min,
additional Martin sulfurane reagent (0.5 mL, 0.10 equiv) was added
and the mixture stirred for an additional 20 min at 0 °C. The reaction
mixture was quenched with sodium carbonate (10 mL, aqueous
saturated) and poured into water (100 mL). The aqueous layer was
extracted with dichloromethane (2 × 100 mL), and the combined
organic extracts were dried with sodium sulfate, filtered, and
concentrated in Vacuo. The residue was purified by silica gel
gradient chromatography (10:0 to 9:1; dichloromethane/methanol
containing 10% by volume ammonium hydroxide), providing
aminoalkene (-)-52 (410 mg, 82% yield) as a light-yellow oil:
The above prepared TBS ether (2.50 g, 5.3 mmol) was dissolved
in tetrahydrofuran (80 mL) and cooled to -78 °C. L-Selectride (14
mL, 1.0 M in tetrahydrofuran, 2.5 equiv) was added dropwise over
5 min and the reaction mixture stirred for 1 h at -78 °C, warmed
to 0 °C and then stirred for an additional 1 h. To the reaction mixture
was added additional L-Selectride (5.0 mL, 1.0 M in tetrahydrofuran,
1 equiv) and the mixture stirred for 1 h at 0 °C. The mixture was
treated with sodium bicarbonate (10 mL, aqueous saturated), stirred
vigorously for 15 min, and then poured into sodium bicarbonate
(300 mL, aqueous saturated). The aqueous layer was extracted with
ethyl acetate (2 × 300 mL), and the combined organic extracts
were dried with sodium sulfate, filtered, and concentrated in Vacuo.
The residue was purified by silica gel gradient chromatography
(10:0 to 1:1; hexanes/ethyl acetate), providing alcohol (-)-54 (2.50
[R]20 -28.8° (c 0.25, CH2Cl2); IR (NaCl plate, neat): 3360 (w),
D
2953 (s), 2926 (s), 2855 (s), 1649 (w), 1538 (w), 1464 (m), 1387
(m), 1253 (m), 1101 (m), 1076 (m), 873 (w), 837 (m), 777 (m),
664 (w), 567 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.59-5.57
(m, 1H), 4.15 (ddd, J ) 9.3, 6.3, 4.8 Hz, 1H), 2.95-2.82 (m, 2H),
2.80 (dd, J ) 12.1, 2.0 Hz, 1H), 2.73 (d, J ) 4.5 Hz, 1H), 2.39
(dd, J ) 14.5, 6.0 Hz, 1H), 2.37-2.34 (m, 1H), 2.30 (ddd, J )
17.3, 8.2, 5.4 Hz, 1H), 2.19 (d, J ) 17.1 Hz, 1H), 1.96-1.91 (m,
1H), 1.78-1.71 (m, 1H), 1.65-1.59 (m, 1H), 1.57 (dd, J ) 14.3,
6.5 Hz, 1H), 1.51-1.42 (m, 2H), 0.94 (d, J ) 6.7 Hz, 3H), 0.90 (s,
9H), 0.08 (s, 3H), 0.06 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ 137.4, 123.2, 68.5, 62.4, 45.9, 44.2, 39.4, 38.0, 35.2, 33.5, 29.9,
26.0, 25.9, 21.1, 18.2, -4.3, -4.5 ppm; high resolution mass
spectrum (ES+) m/z 322.2569 [(M + H)+; calculated for
C19H36NOSi: 322.2566].
g, 99% yield) as a colorless oil: [R]20 -47.6° (c 0.30, CH2Cl2);
D
IR (NaCl plate, neat): 3388 (br m), 2928 (s), 2861 (m), 1697 (m),
1458 (w), 1415 (m), 1359 (w), 1301 (m), 1255 (w), 1113 (m), 1074
(s), 891 (w), 836 (w), 769 (w), 641 (m) cm-1; 1H NMR (500 MHz,
CDCl3; spectrum contains a mixture of rotamers) δ 7.40-7.28 (br
m), 5.21-5.10 (m), 4.71-4.47 (br m), 4.45-4.37 (br m), 4.28 (br
q, J ) 6.0 Hz), 4.16 (br q, J ) 6.0 Hz), 4.14 (br q, J ) 6.3 Hz),
4.13-4.00 (br m), 3.36-3.23 (br m), 2.70-1.91 (br m), 1.77-1.19
(br m), 1.10-0.84 (br m), 0.08-0.05 (br m) ppm; 13C NMR (125
MHz, CDCl3; spectrum contains a mixture of rotamers) δ 156.6,
156.1, 137.3, 137.2, 128.7, 128.6, 128.1, 128.0, 128.0, 128.0, 127.9,
83.0, 68.3, 68.2, 68.1, 68.0, 67.9, 67.1, 67.1, 67.0, 67.0, 56.1, 55.6,
50.9, 50.5, 37.1, 36.9, 36.5, 35.4, 35.3, 34.7, 34.5, 34.3, 34.2, 34.0,
33.9, 26.1, 26.0, 25.9, 25.5, 19.0, 18.9, 18.8, 18.2, 18.1, 18.0, 15.9,
15.3, 14.7, 9.8, -4.4, -4.4, -4.5, -4.6, -4.7, -4.8 ppm; high
resolution mass spectrum (ES+) m/z 496.2854 [(M + Na)+;
calculated for C27H43NNaO4Si: 496.2859].
Preparation of Alcohol (-)-58. Alkene (-)-52 (51 mg, 0.16
mmol) was dissolved in dichloromethane (20 mL), and a dichlo-
romethane (5 mL) suspension of N-iodosuccinimide (59 mg, 0.16
mmol, 1.01 equiv) was added dropwise over 5 min. After stirring
for 20 min, the reaction mixture was treated with a 1:1 mixture (5
mL) of sodium thiosulfate/sodium carbonate (aqueous saturated),
stirred vigorously for 10 min, and then poured into water (15 mL)
and extracted with dichloromethane (2 × 50 mL). The combined
organic extracts were dried with sodium sulfate, filtered, and
(49) Martin sulfurane was handled and stored according to the procedures
described herein: Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972,
94, 5003.
Preparation of Aminoalcohol (-)-55. Alcohol (-)-54 (731 mg,
1.54 mmol) was dissolved in absolute ethanol (60 mL) and was
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13787

A R T I C L E S
Beshore and Smith
concentrated in Vacuo. The residue was purified by silica gel
gradient chromatography (100:0 to 96:4; dichloromethane/methanol
containing 10% by volume ammonium hydroxide), providing the
tetracycle (65 mg, 93% yield) as a light-yellow solid: [R]20D -2.0°
(c 0.50, CH2Cl2); IR (NaCl plate, thin film, CH2Cl2): 2930 (s), 2855
(m), 1458 (m), 1253 (m), 1102 (s), 877 (m), 837 (m), 777 (m),
664 (w), 568 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.20 (dt, J
) 8.6, 4.5 Hz, 1H), 3.36 (d, J ) 4.5 Hz, 1H), 3.19 (d, J ) 13.4
Hz, 1H), 3.13-3.10 (m, 1H), 2.97 (dd, J ) 13.8, 5.6 Hz, 1H),
2.78-2.75 (br m, 1H), 2.73 (ddd, J ) 13.4, 3.0, 1.9 Hz, 1H), 2.54
(br d, J ) 13.4 Hz, 1H), 2.24 (td, J ) 13.8, 8.9 Hz, 1H), 1.99-1.89
(m, 2H), 1.86 (br d, J ) 13.4 Hz, 1H), 1.84-1.74 (m, 3H), 1.46
(ddd, J ) 13.6, 8.4, 1.5 Hz, 1H), 0.96 (d, J ) 6.0 Hz, 3H), 0.89 (s,
9H), 0.06 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 75.4, 64.7,
64.1, 56.3, 53.7, 45.0, 42.4, 39.4, 36.6, 32.4, 29.9, 25.9, 23.3, 21.8,
18.2, -4.4, -4.6 ppm; high resolution mass spectrum (ES+) m/z
448.1545 [(M + H)+; calculated for C19H35INOSi: 448.1533].
mass spectrum (ES+) m/z 332.0509 [(M + H)+; calculated for
C13H21INO: 332.0511].
Unsaturated Amide (-)-60. Iodoketone (-)-59 (143 mg, 0.432
mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to
-78 °C. Freshly prepared lithium di-iso-propylamide50 (1.4 mL,
0.39 M solution in tetrahydrofuran, 1.3 equiv) was added dropwise,
and the solution was stirred for 10 min at -78 °C. Freshly distilled
hexamethylphosphoramide (1.0 mL, 10% v/v) was added dropwise
over 5 min. The mixture was stirred for an additional 5 min at
-78 °C, warmed to -60 °C for 10 min, and then cooled to -78
°C. Methyl cyanoformate (55 µL, 0.691 mmol, 1.6 equiv) was added
in one portion, and the reaction mixture was stirred an additional
1 h at -78 °C. The reaction mixture was quenched with sodium
bicarbonate (5 mL, aqueous saturated), warmed to ambient tem-
perature, poured into water (50 mL), and extracted with chloroform
(3 × 100 mL). The combined organic extracts were dried with
sodium sulfate, filtered, and concentrated in Vacuo. The mixture
of ꢀ-ketoester diastereomers was used without purification in the
next reaction. High resolution mass spectrum (ES+) m/z 390.0573
[(M + H)+; calculated for C15H21INO3: 390.0566].
The above prepared ꢀ-ketoester was dissolved in 2,6-lutidine (2.5
mL) and triethylsilane (2.5 mL). The mixture was stirred vigorously
and palladium(II)chloride (150 mg, 0.84 mmol, 1.9 equiv) was
added in three portions over 90 min. The mixture was stirred an
additional 30 min and then carefully treated with sodium bicarbonate
(15 mL, aqueous saturated). The mixture was stirred for 30 min,
poured into water (20 mL), and extracted with dichloromethane (3
× 100 mL). The combined organic extracts were dried with sodium
sulfate, filtered and concentrated in Vacuo. The residue was
dissolved in chloroform (50 mL) and washed twice with hydro-
chloric acid (20 mL, 1 N aqueous). The pH was adjusted to 8 with
solid sodium bicarbonate and extracted with chloroform (3 × 100
mL). The combined organic extracts were dried with sodium sulfate,
filtered, and concentrated in Vacuo. The residue passed through a
silica gel plug (100:0 to 96:4; dichloromethane/methanol containing
10% by volume ammonium hydroxide), providing a mixture of
desiodo-ꢀ-ketoester diastereomers (71 mg, 74% yield). High
resolution mass spectrum (ES+) m/z 264.1600 [(M + H)+;
calculated for C15H22NO3: 264.1600].
The above prepared tetracycle (20 mg, 0.045 mmol) was
dissolved in methanol (5 mL), treated with hydrochloric acid (12
N aqueous, 5 drops from a 9” pipet), and stirred for 18 h at ambient
temperature. The reaction mixture was poured into sodium hydrox-
ide (10 mL, 5 N aqueous) and extracted with dichloromethane (2
× 15 mL), and the combined organic extracts were dried with
sodium sulfate, filtered, and concentrated in Vacuo. The residue
was purified by silica gel gradient chromatography (100:0 to 90:
10; dichloromethane/methanol containing 10% by volume am-
monium hydroxide), providing the alcohol (-)-58 (15 mg, 99%
yield) as an oily solid. X-ray quality crystals were obtained via
vapor diffusion from pentane/diethyl ether. Upon slow evaporation
of most of the solvent, the mixture was placed into a refrigerator
for 24 h and then warmed to ambient temperature; melting point
124-126°: [R]20 -7.33° (c 2.10, CH2Cl2); IR (NaCl plate, thin
D
film, CH2Cl2): 2925 (s), 2967 (s), 1715 (s), 1454 (m), 1405 (w),
1378 (w), 1346 (w), 1334 (w), 1312 (w), 1281 (w), 1251 (m), 1202
(m), 1161 (m), 1117 (w), 1089 (w), 1068 (m), 1039 (w), 1000 (w),
985 (w), 969 (w), 943 (w), 925 (m), 896 (m), 866 (m), 838 (w),
1
821 (w), 803 (m), 791 (w), 767 (w), 749 (w), 686 (w) cm-1; H
NMR (500 MHz, CDCl3) δ 4.19 (dt, J ) 8.9, 4.5 Hz, 1H), 3.99
(br s, 1H), 3.38 (d, J ) 4.1 Hz, 1H), 3.15 (dd, J ) 13.4, 1.5 Hz,
1H), 3.10 (d, J ) 1.9 Hz, 1H), 2.97 (dd, J ) 13.6, 5.4 Hz, 1H),
2.74-2.69 (m, 2H), 2.54 (br d, J ) 13.8 Hz, 1H), 2.32 (td, J )
13.8, 8.8 Hz, 1H), 1.94-1.77 (m, 6H), 1.45 (ddd, J ) 13.8, 8.9,
1.5 Hz, 1H), 0.95 (d, J ) 5.2 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 75.2, 64.3, 63.8, 60.2, 56.2, 53.7, 44.8, 42.4, 39.2, 35.2,
32.2, 23.4, 21.8 ppm; high resolution mass spectrum (ES+) m/z
334.0679 [(M + H)+; calculated for C13H21INO: 334.0668].
Preparation of Iodoketone (-)-59. Alcohol (-)-58 (30 mg,
0.090 mmol) was dissolved in dichloromethane (7 mL) to which
sodium bicarbonate (57 mg, 0.67 mmol, 7.5 eqiuv.) and Dess-Martin
periodinane (96 mg, 0.22 mmol, 2.5 equiv) were added and the
mixture stirred vigorously for 1 h. The mixture was treated with a
1:1 mixture (3 mL) of sodium carbonate/sodium thiosulfate
(aqueous saturated) and stirred for 30 min. The mixture was poured
into water (30 mL) and extracted with dichloromethane (3 × 100
mL). The combined organic extracts were dried with sodium sulfate,
filtered, and concentrated in Vacuo. The residue was purified by
silica gel gradient chromatography (100:0 to 96:4; dichloromethane/
methanol containing 10% by volume ammonium hydroxide),
providing iodoketone (-)-59 (27 mg, 93% yield) as a white solid:
[R]20D -2.50° (c 1.35, CH2Cl2); IR (NaCl plate, thin film, CH2Cl2):
2925 (s), 2867 (s), 1715 (s), 1454 (m), 1405 (w), 1346 (w), 1334
(w), 1312 (w), 1281 (w), 1251 (m), 1202 (m), 1161 (m), 1099 (w),
1068 (m), 1039 (w), 987 (w), 943 (w), 925 (m), 896 (m), 866 (m),
The above prepared desiodo-ꢀ-ketoester (9.7 mg, 0.0368 mmol)
was dissolved in dimethylsulfoxide (2 mL) and treated with cesium
carbonate (120 mg, 0.368 mmol, 10 equiv), followed by the addition
of propiolamide (5 mg, 0.0737 mmol, 2 equiv). The mixture was
stirred for 24 h at ambient temperature, poured into water (15 mL),
and extracted with chloroform (3 × 15 mL). The combined organic
extracts were dried with sodium sulfate, filtered, and concentrated
in Vacuo. The residue was purified by silica gel gradient chroma-
tography (100:0 to 92:8; dichloromethane/methanol containing 10%
by volume ammonium hydroxide), providing the unsaturated amide
(-)-60 (10 mg, 82% yield) as a light-yellow solid: [R]20D -80.3°
(c 0.12, CDCl3); IR (NaCl plate, thin film, CH2Cl2): 3424 (br m),
3363 (br m), 3192 (br m), 2924 (s), 2849 (m), 1740 (s), 1710 (m),
1682 (s), 1455 (m), 1394 (m), 1291 (w), 1268 (w), 1230 (s), 1123
(w), 1070 (m), 1012 (w), 919 (w), 890 (w), 797 (w), 733 (w), 667
1
(w) cm-1; H NMR (500 MHz, CDCl3) δ 6.76 (d, J ) 15.6 Hz,
1H), 6.17 (d, J ) 15.6 Hz, 1H), 5.90 (br s, 1H), 5.83 (br s, 1H),
3.74 (s, 3H), 3.64 (s, 1H), 3.13 (dd, J ) 14.5, 3.7 Hz, 1H), 3.09
(br t, J ) 1.9 Hz, 1H), 3.06 (dd, J ) 14.3, 1.3 Hz, 1H), 2.75 (d, J
) 3.7 Hz, 1H), 2.24 (dd, J ) 6.3, 3.7 Hz, 1H), 2.16 (ddd, J )
15.1, 6.5, 3.1 Hz, 1H), 1.87 (br d, J ) 13.4 Hz, 1H), 1.81 (br t, J
) 3.0 Hz, 1H), 1.79-1.76 (m, 1H), 1.74 (dd, J ) 9.5, 5.0 Hz,
1H), 1.70 (br d, J ) 15.6 Hz, 1H), 1.05 (t, J ) 13.0 Hz, 1H), 1.01
1
803 (m), 749 (w), 686 (w) cm-1; H NMR (500 MHz, CDCl3) δ
(50) Lithium di-iso-propylamide was prepared as follows: Freshly distilled
di-iso-propylamine (1.4 mL, 10 mmol, 1.1 equiv) was dissolved in
tetrahydrofuran (15 mL) and cooled to 0 °C. n-Butyl lithium (6.6 mL,
1.37 M solution in tetrahydrofuran) was added dropwise over 5 min,
and the mixture was stirred for 1 h at 0 °C. The resulting lithium
di-iso-propylamide solution (0.39 M) was then used immediately in
the reaction.
3.67 (m, 1H), 3.29-3.27 (m, 1H), 3.25-3.20 (m, 2H), 3.11 (d, J
) 14.1 Hz, 1H), 2.68 (d, J ) 14.5 Hz, 1H), 2.57-2.52 (m, 3H),
2.14-2.08 (m, 1H), 1.96-1.74 (m, 5H), 0.96 (d, J ) 5.6 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 210.9, 74.4, 70.6, 58.4, 58.2,
54.1, 52.2, 44.7, 41.1, 38.9, 32.5, 23.4, 21.4 ppm; high resolution
9
13788 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Enantioselective Total Syntheses of the Lyconadins
A R T I C L E S
(ddd, J ) 13.4, 11.9, 1.9 Hz, 1H), 0.87 (d, J ) 6.3 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 206.2, 170.2, 166.7, 142.5, 126.5,
74.1, 70.9, 64.3, 55.2, 53.2, 46.3, 44.4, 40.2, 39.1, 35.4, 32.7, 24.9,
21.9 ppm; high resolution mass spectrum (ES+) m/z 333.1818 [(M
+ H)+; calculated for C18H25N2O4: 333.1814].
MHz, CDCl3) δ 209.8, 174.6, 172.5, 74.6, 71.1, 60.6, 55.4, 52.6,
45.8, 44.7, 40.4, 39.2, 37.0, 33.8, 33.4, 31.7, 24.9, 22.0 ppm; high
resolution mass spectrum (ES+) m/z 335.1984 [(M + H)+;
calculated for C18H27N2O4: 335.1971].
In a screw-cap vial, the above prepared saturated amide (4.0 mg,
0.012 mmol) was dissolved in freshly distilled hexamethylphos-
phoramide (2.5 mL). Lithium chloride (5.0 mg, 0.12 mmol, 10
equiv) was added, the vessel was sealed, and the mixture was placed
into an oil bath preheated to 125 °C for 17.5 h. The mixture was
cooled to ambient temperature and poured into hydrochloric acid
(5 mL, 1 N aqueous). The aqueous layer was extracted with
chloroform (2 × 15 mL), and the combined organic layers were
washed with hydrochloric acid (5 mL, 1 N aqueous). The organic
extracts were discarded, and the pH of the combined aqueous layers
was carefully adjusted to 12 with sodium carbonate (15 mL, aqueous
saturated) and then extracted with chloroform (3 × 15 mL). The
combined organic extracts were dried with sodium sulfate, filtered,
and concentrated in Vacuo. The residue was purified by silica gel
gradient chromatography (100:0 to 92:8; dichloromethane/methanol
containing 10% by volume ammonium hydroxide), to provide (-)-
lyconadin B (2; 2.1 mg, 68% yield) as a white solid: [R]20D -64.0°
(c 0.025, MeOH); IR (NaCl plate, neat): 3221 (w), 2922 (s), 2849
(m), 1671 (s), 1456 (m), 1373 (m), 1315 (w), 1233 (w), 1175 (w),
1093 (w), 1053 (w), 948 (w), 913 (w), 791 (w), 669 (w) cm-1; 1H
NMR (600 MHz, CD3OD) δ 3.50 (s, 1H), 3.31 (m, 1H), 3.28 (m,
1H), 2.86 (d, J ) 12.1 Hz, 1H), 2.52-2.29 (m, 4H), 2.27 (d, J )
4.8 Hz, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.95 (s, 1H), 1.95 (m,
1H), 1.85 (d, J ) 13.4 Hz, 1H), 1.74 (m, 1H), 1.69 (d, J ) 13.3
Hz, 1H), 1.06 (ddd, J ) 13.4, 12.4, 2.0 Hz, 1H), 0.95 (t, J ) 13.0
Hz, 1H), 0.89 (d, J ) 6.5 Hz, 3H) ppm; 13C NMR (125 MHz,
CD3OD) δ 173.3, 135.8, 120.7, 72.6, 63.7, 61.9, 49.9, 48.2, 41.1,
40.9, 34.5, 33.3, 31.5, 26.2, 25.0, 22.1 ppm; high resolution mass
spectrum (ES+) m/z 259.1818 [(M + H)+; calculated for
C16H23N2O: 259.1810].
Preparation of (+)-Lyconadin A (1). Unsaturated amide (-)-
60 (2.8 mg, 0.0084 mmol) was dissolved in anhydrous acetonitrile
(1.5 mL) and transferred to a screw cap vial. Tetramethylammonium
acetate (11.2 mg, 0.084 mmol, 10 equiv) was added; the vial was
sealed and then placed into an oil bath preheated to 135 °C. The
reaction mixture was stirred for 16 h, cooled to ambient temperature,
and poured into sodium bicarbonate (5 mL, aqueous saturated). The
aqueous layer was extracted with dichloromethane (2 × 15 mL)
and chloroform (1 × 15 mL). The combined organic extracts were
dried with sodium sulfate, filtered, and concentrated in Vacuo. The
residue was purified by silica gel gradient chromatography (100:0
to 90:10; dichloromethane/methanol containing 10% by volume
ammonium hydroxide), providing (+)-lyconadin A (1, 1.5 mg, 71%
yield) as a light-yellow solid: [R]20 +33° (c 0.13, MeOH); IR
D
(NaCl plate, neat): 3116 (w), 2921 (s), 2855 (m), 1653 (s), 1611
(m), 1559 (w), 1457 (m), 1262 (w), 1192 (w), 1099 (m), 1065 (m),
1
1024 (w), 946 (w), 797 (w), 678 (m) cm-1; H NMR (600 MHz,
CD3OD) δ 7.42 (d, J ) 9.0 Hz, 1H), 6.36 (d, J ) 8.9 Hz, 1H),
4.27 (s, 1H), 3.60 (m, 1H), 3.59 (m, 1H), 2.93 (d, J ) 13.2 Hz,
1H), 2.85 (m, 1H), 2.27 (br d, J ) 4.2 Hz, 1H), 2.11 (ddd, J )
14.0, 5.6, 4.0 Hz, 1H), 2.11 (m, 1H), 2.08 (m, 1H), 1.94 (br d, J )
13.3 Hz, 1H), 1.86 (m, 1H), 1.76 (d, J ) 13.8 Hz, 1H), 1.19 (t, J
) 12.8 Hz, 1H), 1.06 (t, J ) 13.0 Hz, 1H), 0.95 (d, J ) 6.3 Hz,
3H) ppm; 13C NMR (125 MHz, CD3OD) δ 165.4, 149.3, 141.8,
126.3, 116.6, 72.6, 64.0, 61.7, 50.8, 48.1, 41.0, 40.5, 34.3, 33.9,
26.2, 22.0 ppm; high resolution mass spectrum (ES+) m/z 257.1648
[(M + H)+; calculated for C16H21N2O: 257.1654].
Preparation of (-)-Lyconadin B (2). Unsaturated amide (-)-
60 (24 mg, 0.030 mmol) was dissolved in methanol (10 mL), and
the solution was sparged under an argon atmosphere. The mixture
was treated with Pd/C (5 mg, 10% weight Pd/C), sparged under a
hydrogen atmosphere (1 atm, balloon), and then stirred for 3 h.
The reaction mixture was sparged under an argon atmosphere and
filtered through a pad of Celite. The Celite was washed with
methanol (10 mL), and the filtrate was concentrated in Vacuo to
provide the saturated amide (-)-62 (24 mg, 99% yield), which was
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant CA-
19033 and Merck & Co., Inc. for D.C.B. We thank Drs. George
W. Furst and Sangrama Sahoo for NMR expertise, Dr. Patrick M.
Carroll for X-ray analyses, Dr. Rahesh Kohli for mass spectra, Dr.
Constantine Kreatsoulas (Merck & Co., Inc) for computational
studies, and Professor Jun’ichi Kobayashi (Hokkaido University)
for spectra of natural (+)-1 and (-)-2.
used without purification in the next reaction: [R]20 -61.3° (c
D
0.14, CH2Cl2); IR (NaCl plate, neat): 3430 (br m), 3363 (br m),
3203 (br s), 2923 (s), 2849 (m), 1734 (s), 1710 (m), 1669 (s), 1453
(m), 1268 (m), 1227 (m), 1068 (m), 1024 (w), 948 (w), 919 (w),
890 (w), 803 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.60 (br s,
1H), 5.44 (br s, 1H), 3.75 (s, 3H), 3.55 (s, 1H), 3.23 (dd, J ) 14.5,
1.9 Hz, 1H), 3.13 (dd, J ) 14.3, 3.9 Hz, 1H), 3.10-3.08 (m, 1H),
2.89-2.84 (m, 1H), 2.73 (br d, J ) 3.0 Hz, 1H), 2.27-2.16 (m,
2H), 2.10 (ddd, J ) 14.9, 6.3, 3.0 Hz, 1H), 2.03-1.98 (m, 1H),
1.96 (dd, J ) 6.0, 3.7 Hz, 1H), 1.90-1.85 (m, 1H), 1.79 (br t, J )
3.0 Hz, 1H), 1.76-1.71 (m, 2H), 1.67 (br d, J ) 14.9 Hz, 1H),
1.05-0.92 (m, 2H), 0.86 (d, J ) 6.3 Hz, 3H) ppm; 13C NMR (125
Supporting Information Available: Experimental procedures,
crystallographic information files, complete ref 28, and spec-
troscopic and analytical data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA804939R
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13789