Gold-catalyzed synthesis of oxygen- and nitrogen-containing heterocycles from alkynyl ethers: Application to the total synthesis of andrachcinidine

Article abstract of DOI:10.1021/jo071225w

(Chemical Equation Presented) In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol.

Full text of DOI:10.1021/jo071225w

Gold-Catalyzed Synthesis of Oxygen- and Nitrogen-Containing
Heterocycles from Alkynyl Ethers: Application to the Total
Synthesis of Andrachcinidine
Hyung Hoon Jung and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
ReceiVed June 12, 2007
In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles
react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones.
Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration,
alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran
and piperidine formation are very good to excellent. This method has been applied to an efficient total
synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than
homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the
scope of products that can be accessed through this protocol.
Introduction
functional groups into various spatial arrangements for binding
to biological targets. Consequently new reactions in which
saturated heterocycles can be prepared in a chemo- and
stereoselective manner will be broadly applicable for endeavors
in natural product synthesis and medicinal chemistry.
Saturated heterocycles are ubiquitous in natural products and
pharmaceutical agents. For example, tetrahydrofuran subunits
can be found in the annonaceous acetogenins,1 tetrahydropyrans
are present in several cytotoxins,2 and larger oxygen-containing
rings are components of the marine ladder toxins.3 Substituted
piperidine rings are common structural features in numerous
alkaloids.4 Additionally piperidine rings serve as attractive
scaffoldings for medicinal agents because they can be converted
to derivatives such as sulfonamides and carbamates that project
The synthesis of structurally complex heterocycles often
requires selective manipulation of one functional group in the
presence of other moieties with similar reactivity patterns. While
this issue is commonly addressed through the judicious use of
protecting groups, an attractive alternative approach exploits
latent functional groups that can be revealed through highly
chemoselective transformations. Alkene and alkyne activation
by electrophilic transition metal catalysts is proving to be a
successful strategy for achieving this objective, with gold
reagents proving to be exceptionally effective and versatile.5
Recent literature reports have shown that, in the presence of
(1) (a) Bermejo, A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269. (b) Alali, F. Q.;
Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(2) Representative examples: (a) Searle, P. A.; Molinski, T. F. J. Am.
Chem. Soc. 1995, 117, 8126. (b) Pettit, G. R.; Herald, C. L.; Doubek, D.
L.; Herald, D. L.; Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1982, 104,
6846. (c) Tanaka, J.; Higa, T. 1996, 37, 5535. (d) Cichewicz, R. H.;
Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951.
(3) Marine Toxins: Origin, Structure, and Molecular Pharmacology; Hall,
S.; Strichartz, G., Eds.; ACS Symp. Ser. No. 418; American Chemical
Society: Washington, DC, 1990.
(4) (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Michael, J. P.
Nat. Prod. Rep. 2001, 18, 520.
(5) For recent reviews, see: (a) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333. (b) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896. (c) Hoffmann-Ro¨der, A.; Krause, N. Org.
Biomol. Chem. 2005, 3, 387.
10.1021/jo071225w CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/11/2007
J. Org. Chem. 2007, 72, 7359-7366
7359

Jung and Floreancig
SCHEME 2. Synthesis of Primary Alcohol Substratesa
SCHEME 1. Gold-Mediated Tetrahydropyran Synthesis
from a Homopropargylic Ether
a Reagents and conditions: (a) NaH, THF, 0 ˚C, then TBSCl; (b)
SO3‚pyridine, Et3N, DMSO, CH2Cl2; (c) propargyl bromide, Zn, 1,2-
diiodoethane, THF, sonication; (d) NaH, THF, 0 ˚C, then MeI; (e) HCl,
H2O, THF.
gold catalysts, alkynes can be converted to ketones,6 vinyl
esters,7 acetals,6,8 and heterocycles,9 serve as electrophiles in
carbon-carbon bond forming reactions,10 and undergo a diverse
range of sigmatropic11 and skeletal rearrangements.12 Alkenes
have been transformed into ethers,9a,13 esters,13 and amine
derivatives.14 Following our observation that homopropargylic
ether 1 can be converted to tetrahydropyran 2 (Scheme 1) in
the presence of gold catalysts15 we initiated a program directed
toward optimizing this mild heterocycle synthesis, exploring its
mechanism, and expanding its scope. In this paper we describe
our use of homopropargylic ethers that, through gold catalysis,
serve as latent R,â-unsaturated ketones and react with appended
nucleophiles en route to saturated oxygen- and nitrogen-
containing heterocycles. Mechanistic details of this multistep
process will be presented, as will its application as the key step
in the enantioselective total synthesis of the monocyclic alkaloid
andrachcinidine.
SCHEME 3. Preparation of Secondary Alcohol Substratesa
Results and Discussion
a Reagents and conditions: (a) PDC, CH2Cl2; (b) MeMgBr, THF, 0 ˚C;
(c) LDA, tert-butyl acetate, THF, -78 ˚C; (d) LiAlH4, Et2O, -78 ˚C.
Oxacycle Substrate Synthesis. We prepared a range of
substrates to study the mechanism and scope of the process.
These substrates were designed to examine the facility of
accessing multiple ring sizes, the capacity for diastereocontrol
in the cyclization step, and the ability to conduct chemoselective
cyclization reactions in the presence of other potentially reactive
functional groups.
The synthesis of the initial group of substrates is shown in
Scheme 2. Monosilylation16 of R,ω-diols 3a-c followed by
oxidation,17 Barbier-type propargyl addition,18 and methylation
provided silyl ethers 4a-c. Desilylation yielded substrate 1 and
its lower and higher homologues 5 and 6.
(6) (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729. (b) Teles,
J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415. (c)
Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed.
2002, 41, 4563.
Secondary alcohol substrates were readily prepared from the
primary alcohols through straightforward sequences (Scheme
3). Oxidation followed by either Grignard reagent addition or
aldol reaction with the lithium enolate of tert-butyl acetate
provided substrates 7-9. Reducing 9 with LiAlH4 provided diol
substrate 10. No effort was made to control the stereochemical
outcomes of these reactions at this point in the study.
Reaction Optimization. Initial efforts at converting 1 to 2
in the presence of various gold catalysts in CH2Cl2 under
ambient conditions proved to be irreproducible. Noting the
apparent requirement for water to effect the desired transforma-
tion, we employed CH2Cl2 that had been presaturated with water
as the reaction solvent. Using this solvent and gentle heating
(7) (a) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt,
J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. (b) Harkat, H.;
Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2006, 47, 6273.
(8) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem.
Soc. 2005, 127, 9976.
(9) (a) Hashmi, A. S. K.; Schwartz, L.; Choi, J. H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (b) Zhu, J.; Germain, A. R.; Porco, J. A.,
Jr. Angew. Chem., Int. Ed. 2004, 45, 1239. (c) Hashmi, A. S. K.; Weyrauch,
J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391. (d) Gorin, D. J.; Davis,
N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (e) Nakamura, I.;
Mishizuma, Y.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473.
(10) (a) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485. (b)
Abbiatti, G.; Arcadi, A.; Bianchi, G.; Di Giusseppe, S.; Marinelli, F.; Rossi,
E. J. Org. Chem. 2003, 68, 6959. (c) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (d) Ferrer, C.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 1105. (e) Nieto-Oberhuber, C.;
Lo´pez, S.; Mun˜oz, M. P.; Jime´nez-Nu´n˜ez, E.; Ca´rdenas, D. J.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 1694.
(11) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(b) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925. (c) Zhang,
L. J. Am. Chem. Soc. 2005, 127, 16804. (d) Buzas, A. K.; Istrate, F. M.;
Gagosz, F. Org. Lett. 2007, 9, 985.
(12) Nieto-Oberhuber, C.; Mun˜oz, E.; Bun˜uel, E.; Nevado, C.; Ca´rdenas,
D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (b)
Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546. (c) Zhang, L.;
Kozmin, S. J. Am. Chem. Soc. 2004, 126, 11806. (d) Nieto-Oberhuber, C.;
Lo´pez, S.; Mun˜oz, M. P.; Ca´rdenas, D. J.; Bun˜uel, E.; Nevado, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1694.
(35 °C) with the cationic gold species that arises from mixing
10a,19
Ph3PAuCl and AgSbF6
as the catalyst (procedure A)
resulted in a reproducibly efficient conversion of 1 to 2, with
nearly quantitative yields of the volatile product being observed
by gas chromatography. Neither Ph3PAuCl nor AgSbF6 alone
promoted the transformation. The less expensive gold source
NaAuCl4 (procedure B) also promoted the process, albeit more
slowly, providing good yields of the desired product. The highest
(13) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (b)
Taylor, J. G.; Whittall, N.; Hii, K. K. M. Chem. Commun. 2005, 5103.
(14) (a) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128,
1798. (b) Han, X. Q.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006,
45, 1747. (c) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707.
(15) For a preliminary account of parts of this work, see: Jung, H. H.;
Floreancig, P. E. Org. Lett. 2006, 8, 1949.
(16) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
(17) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(18) Lee, A. S.-Y.; Chu, S.-F.; Chang, Y.-T.; Wang, S.-H. Tetrahedron
Lett. 2004, 45, 1551.
(19) Preisenberger, M.; Schier, A.; Schmidbaur, H. J. Chem. Soc., Dalton
Trans. 1999, 1645.
7360 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of O- and N-Containing Heterocycles
SCHEME 4. Proposed Cyclization Mechanism
FIGURE 1. Enone byproduct from the cyclization of 6.
TABLE 1. Scope of Oxacycle Forming Reactions
accumulate to a significant extent except when 6 was the
substrate. The cyclization of ester 9 resulted in the isolation of
the methyl ester as the major product, presumably due to
alcoholysis of the tert-butyl ester by the MeOH that is released
in the reaction, though the tert-butyl ester was also isolated as
a minor product.
The formation of tetrahydropyrans 15-17 as single stereoi-
somers from diastereomeric mixtures of starting materials
indicates that the stereogenic center that bears the methoxy group
is lost or is subjected to stereochemical mutation during the
course of the reaction. The possibility that the loss of stereo-
genicity is only relevant when secondary alcohols are used as
nucleophiles was discounted by preparing 1 in enantiomerically
enriched form through an asymmetric propargylation reaction20
and subjecting it to the reaction conditions. Racemic product
was isolated. The isolation of enone 13 from the cyclization of
6, and the ability to convert it to the oxepane through
resubjection to the reaction conditions, indicates that enone
intermediates are formed during the transformation. These
observations led us to propose the mechanistic pathway shown
for the cyclization of 1 in Scheme 4, in which the initial step is
ketone formation through alkyne hydration to yield 18, followed
by â-elimination of the methoxy group to form enone 19, and
gold-mediated conjugate addition of the nucleophilic hydroxyl
group to provide 2.
a Procedure A: Substrate in water-saturated CH2Cl2 (∼60 mM), Ph3PAuCl
(5 mol %), AgSbF6 (5 mol %), 35 °C. Procedure B: Substrate in water-
saturated CH2Cl2 (∼60 mM), NaAuCl4 (5 mol %), 35 °C. b Yields are
reported for isolated, purified products unless otherwise noted. c Yield
determined by GC. d The tert-butyl ester was also isolated in 10% yield.
Several aspects of this mechanism merit further discussion.
The initial alkyne hydration is well-precedented.6 The elimina-
tion of the methoxy group has far less precedent. Utimoto and
Fukuda observed21 the gold-mediated conversion of propargylic
ethers to enones, but that process is potentially mechanistically
distinct as it proceeds through the formation of an enol
intermediate that is adjacent to an alkoxy leaving group. The
nucleophilic addition can simply be considered as the micro-
scopic reverse of the elimination reaction. Several reports of
gold-mediated additions of nucleophiles to alkenes have recently
appeared in the literature,9a,13,14 but these examples generally
employ alkenes that are far more electron rich than the electron-
deficient intermediates that appear in this work. Trost, however,
has postulated22 that ruthenium catalysts can promote tetrahy-
dropyran formation through a similar mechanism and Kobayashi
has reported23 carbamates undergo conjugate additions with R,â-
unsaturated carbonyl compounds in the presence of gold
catalysts. In consideration of the mild reaction conditions and
the apparent facility of the cyclization step (enones could not
be isolated, or even observed by TLC, in reactions that provided
tetrahydrofurans and tetrahydropyrans), these conditions should
be generally useful for ring constructions that proceed through
yields were observed when the catalyst was added in two
portions, suggesting the possibility that the active catalytic
species decomposed over time. Coordinating solvents such as
THF or CH3CN completely suppressed the reaction.
Cyclization Scope and Mechanism. To determine the scope
of the reaction and to gain insight into its mechanism we
subjected several substrates to procedures A and/or B. The
results are shown in Table 1. Primary alcohol substrates cyclized
smoothly to form tetrahydropyran and tetrahydrofuran structures
(entries 1 and 3), and with moderate efficiency to form oxepane
12 (entry 4). An appreciable amount of enone 13 (Figure 1)
was isolated in cyclization of 6. Silyl ether 4b also proved to
be a suitable substrate for the process (entry 2), indicating that
protected hydroxyl groups can serve as nucleophiles in the
cyclization event. Secondary alcohols 8-10, though prepared
as diastereomeric mixtures, provided products as single stere-
oisomers (entries 6-8), while 7 provided a diastereomeric
mixture of products (entry 5). Substrates that yielded tetrahy-
drofuran products showed faster starting material consumption
than substrates that yielded tetrahydropyran products, and
primary alcohols were generally consumed faster than secondary
alcohols. Intermediates along the reaction pathway did not
(20) Yu, C.-M.; Choi, H.-S.; Yoon, S.-K.; Jung, W.-H. Synlett 1997,
889.
(21) Fukuda, Y.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 2013.
(22) Trost, B. M.; Yang, H.; Wuitshik, G. Org. Lett. 2005, 7, 761.
(23) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319.
J. Org. Chem, Vol. 72, No. 19, 2007 7361

Jung and Floreancig
SCHEME 5. Product Equilibration under Cyclization
Conditions
SCHEME 6. Synthesis of Nitrogen-Containing Substratesa
heteroatom addition into R,â-unsaturated carbonyl compounds.24
Phosphine-catalyzed ring formation25 can be discounted because
of the ability of ligand-free NaAuCl4 to promote the process.
While Brønsted acid catalysis of the latter steps in the sequence26
cannot be rigorously ruled out, exposing 1 to HCl in wet CH2-
Cl2 at 35 °C resulted in the recovery of starting material,
confirming the essential role of gold in initiating the process.
Neither Ph3PAuCl nor AgSbF6 alone promoted the cyclization
from any of the proposed intermediates, though the combination
promoted cyclizations of enone and â-methoxy ketone inter-
mediates, indicating that Brønsted acid, should it be a relevant
catalyst, requires both catalysts to be generated. As noted above,
the rate of starting material consumption is related to the rate
of cyclization, even though the rate of alkyne hydration would
appear to be unaffected by downstream events. This suggests
that the gold catalyst is sequestered by an intermediate during
the course of the reaction and is liberated upon cyclization. Two
important advantages of this method from the perspective of
synthetic strategy are illustrated in this study. The ability to
use potent nucleophiles such as Grignard reagents or enolates
for substrate preparation highlights the utility of homopropar-
gylic ethers as enone surrogates, and the high selectivity of gold
catalysts for alkynes eliminates the need to protect remote
hydroxyl groups.
The stereochemical outcomes of these reactions could arise
from kinetic control or, because the products are â-alkoxy ethers
of the type that undergo elimination, through thermodynamic
control. To address whether stereochemical equilibration can
occur during the course of the reaction, we subjected a single
diastereomer of tetrahydrofuran 14 to the reaction conditions
(Scheme 5). After several hours a 55:45 mixture of diastereo-
mers was formed, which was identical with the results from
the initial reaction. Thus stereochemical outcomes from these
reactions can be predicted based on thermodynamic grounds,
with heightened A-values for substituents at the 2- and 6-posi-
tions of tetrahydropyrans27 accounting for the exceptional
diastereocontrol that is observed in their formation.
a Reagents and conditions: (a) NsNH2, Ph2PPy, DTBAD, CH2Cl2; (b)
PhSH, NaHCO3, CH3CN; (c) R′OC(O)Cl or R′OC(O)OC(O)OR′, NaHCO3,
THF, H2O; (d) Ph3P, DIAD, CH2Cl2.
carbamates to serve as nucleophiles in this process and to
determine whether the identity of the substituent on the nitrogen
would impact the diastereoselectivity of the cyclization.
The substrates for this process were prepared (Scheme 6) from
the corresponding alcohol substrates through facile sequences.
Sulfonamides 20 and 21 were accessed directly from alcohols
1 and 8 and o-nitrobenzene sulfonamide (NsNH2) under
modified Mitsunobu conditions29 by using di-tert-butyl azodi-
carboxylate (DTBAD) and Ph2PPy. Cleavage with basic thiophe-
nol30 provided amines 22 and 23 that were converted to
carbamates 24-28 with the appropriate chloroformates. Aniline
30 was constructed through a Mitsunobu reaction between 1
and phenyl sulfonamide 29 followed by cleavage with basic
thiophenol.
The conditions that were successful for cyclization reactions
of the oxygen-containing substrates proved to be unsuitable for
promoting complete conversion of 20 to piperidine 31. After
extensive studies we discovered that changing the solvent from
CH2Cl2 to water-saturated toluene and using a 2:1 ratio of
AgSbF6 to Ph3PAuCl (procedure C) resulted in complete
conversions and reproducible reaction times. Notably, toluene
can be used directly from the bottle with no loss of yield. The
results of exposing the nitrogen-containing substrates to these
conditions are shown in Table 2. Also shown (entry 7) is the
result of exposing oxygen-containing substrate 8 to procedure
C. The reaction was complete within 1 h rather than the 48 h
that were required for the initial conditions (Table 1), highlight-
ing the dramatic rate enhancement that results from conducting
the reaction in toluene.
Application to Piperidine Synthesis. Our successful results
in the area of oxygen-containing heterocycle synthesis led us
to examine the potential for using the method to prepare
nitrogen-containing heterocycles. Nitrogen nucleophiles have
been used with great success in gold-catalyzed processes,14,28
with the vast majority of reactions utilizing sulfonamides or
carbamates rather than aliphatic amines. Our objective was to
test the capacity of aliphatic amines, anilines, sulfonamides, and
As shown in the table, sulfonamides and most carbamates
react smoothly to form piperidines in good to excellent yield,
though the tert-butyl carbamate 27 did not yield any cyclization
product. This is most likely due to steric interactions in the
cyclization transition state. Free amine 22 and aniline 30 also
failed to react, indicating that nitrogen basicity must be
modulated for successful cyclization. Tanaka has proposed31 that
amines react with gold catalysts to form complexes that should
(24) For examples of this approach to heterocycle formation, see: (a)
Bhattacharjee, A.; Soltani, O.; De Brabander, J. K. Org. Lett. 2002, 4, 481.
(b) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J. Am.
Chem. Soc. 1999, 121, 6816. (c) Negri, D. P.; Kishi, Y. Tetrahedron Lett.
1987, 28, 3463.
(25) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc.
2003, 125, 8696.
(26) (a) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141. (b) Li,
Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett.
2006, 8, 4175. (c) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsonomiya,
M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(29) Guisado, C.; Waterhouse, J. E.; Price, W. S.; Jorgensen, M. R.;
Miller, A. D. Org. Biomol. Chem. 2005, 3, 1049.
(30) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
(27) Eliel, E. L. Acc. Chem. Res. 1970, 3, 1.
(28) For a review, see: Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem.
2006, 4555.
(31) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
7362 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of O- and N-Containing Heterocycles
TABLE 2. Gold-Mediated Piperidine Synthesisa
FIGURE 2. Conformations of sulfonamide and carbamate products.
FIGURE 3. Andrachcinidine.
oriented by the half-chair ring conformation (Figure 2). An
examination of related structures in the Cambridge Crystal-
lographic Data Centre supported these conformational assign-
ments. Thus, while the relative stereochemical outcomes of these
reactions are not altered upon changing the group on nitrogen,
the product conformations are substantially different. With
respect to using this reaction for diversity oriented synthesis,
the ability to access different substituent orientations through
changing the group on nitrogen creates the opportunity to
explore a greater range of conformational space with minimal
effort.
Application to the Synthesis of (+)-Andrachcinidine.
Andrachcinidine (37) is a piperidine-containing alkaloid from
the beetle Andrachne aspera that has been implicated as a
chemical defense agent (Figure 3).34 Our ability to prepare 2,6-
cis-dialkylpiperidine rings through the gold-mediated hydration/
cyclization protocol led us to select 37 as a target for
demonstrating the capacity of the method to be a key step in
natural product total synthesis.
The synthesis of andrachcinidine is shown in Scheme 7. Lewis
acid-mediated propargylation35 of the commercially available
acetal 38 with allenyl tributyltin36 provided homopropargylic
ether 39 in excellent yield. Displacement of the bromide with
the metalloenamine derived from the cyclohexylimine of
acetone37 followed by condensing the resulting ketone with
Ellman’s sulfinamide 4038 provided sulfinylimine 41. We
selected this antipode of the auxiliary because it had previously
been prepared in our group for a different purpose. While its
use results in the synthesis of the enantiomer of the natural
product, the antipodes of the sulfinamide are now equally
accessible through an improved synthetic protocol.39 Thus this
sequence can be applied to the synthesis of the correct
enantiomer of the natural product. Deprotonation of 41 with
LDA, metal exchange with MgBr2, and addition to n-butanal
yielded alcohol 42.40 Reduction of the sulfinylimine with
catecholborane40 followed by a sequential protocol of acidic
sulfinyl group cleavage, basification, and sulfonamide formation
a Procedure C: Substrate in water-saturated toluene (∼25 mM), Ph3PAuCl
(5 mol %), AgSbF6 (10 mol %), 40 °C. b Yields are reported for isolated,
purified products unless otherwise noted. c Starting material was largely
unconsumed in these reactions.
be substantially less electrophilic than cationic Au(I) catalysts,
and Krause reported32 that utilizing aliphatic amines in gold-
catalyzed cyclization reactions results in substantially diminished
rates when compared to the corresponding sulfonamides (5 d
vs 1 h), though rates can be improved with appropriate catalyst
selection.33 As observed in the oxacycle syntheses, AgSbF6 alone
does not promote any of the steps in the sequence, suggesting
that excess silver in these reactions simply promotes more
efficient generation of the relevant cationic Au(I) catalyst.
Branched sulfonamides and carbamates react to form 2,6-
disubstituted piperidines, with the cis-isomer being the dominant,
though not exclusive, product in both cases. As determined by
2D NOESY spectroscopy and 1D homonuclear decoupling
experiments, the conformations of the cis-sulfonamide and
carbamate products are different, with the alkyl groups of
sulfonamide 35 existing in slightly distorted axial configurations
on a chair structure and the alkyl groups of carbamate 36 being
(34) Mill, S.; Hootele´, C. J. Nat. Prod. 2000, 63, 762.
(35) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3925.
(36) Tanaka, H.; Hai, A. K. M. A.; Ogawa, H.; Torii, S. Synlett 1993,
835.
(37) Larcheveˆque, M.; Valette, G.; Cuvigny, T. Tetrahedron 1979, 35,
1745.
(38) (a) Liu, G.; Cogan, D.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984.
(39) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(40) (a) Kochi, T. P.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518. (b) Kochi, T. P.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276.
(32) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
(33) Morita, N.; Krause, N. Eur. J. Org. Chem. 2006, 4634.
J. Org. Chem, Vol. 72, No. 19, 2007 7363

Jung and Floreancig
SCHEME 7. Total Synthesis of (+)-Andrachcinidinea
SCHEME 8. Cyclization with an Internal Alkyne Substrate
to yield ketone 46. In contemplating approaches to controlling
hydration regiochemistry, we became intrigued by Utimoto’s
results21 in which propargylic ethers undergo hydration at the
distal carbon with respect to the alkoxy group, ultimately leading
to the formation of enones. Considering the presumed interme-
diacy of enones along our proposed mechanistic pathway, we
turned our attention to the cyclization of propargylic ether 47.
Gratifyingly, exposing 47 to the standard cyclization protocol
(procedure C) provided tetrahydrofuran 48 in 93% yield within
1 h. This result clearly demonstrates that internal alkynes can
be used as substrates in this reaction and also indicates that
any gold-mediated reaction that yields an R,â-unsaturated
carbonyl group can potentially serve as an entry into heterocycle
synthesis.42
a Reagents and conditions: (a) allenyl tributyltin, TiCl4, CH2Cl2, -78
˚C, 93%; (b) acetone cyclohexylimine, LDA, THF, HMPA, -78 ˚C to rt,
then H3O+, 41%; (c) 40, Ti(OEt)4, THF, 70 ˚C, 72%; (d) LDA, THF, then
MgBr2, then butyraldehyde, -78 ˚C, 65%; (e) catecholborane, THF, 0 ˚C,
78%, dr ) 84:16; (f) HCl, MeOH, then NsCl, NaHCO3, THF, H2O, 83%;
(g) Ph3PAuCl, AgSbF6, PhMe, H2O, 40 ˚C, 24 h, 89% (h) PhSH, K2CO3,
CH3CN, 95%.
Summary and Conclusions
We have developed a versatile and experimentally facile gold-
mediated protocol for the synthesis of heterocyclic ketones from
homopropargylic ethers. In these reactions hydroxyl, silyloxy,
sulfonamide, and carbamate groups can serve as nucleophiles
in the cyclization event. Mechanistic investigations indicated
that the reaction pathway proceeds through alkyne hydration,
alkoxy group elimination to form an enone, and nucleophilic
addition. The reactions can be highly stereoselective when one
diastereomer of the product is significantly more stable than
the other because product stereoisomers interconvert under the
reaction conditions. The method was applied to an efficient
enantioselective synthesis of (+)-andrachcinidine that high-
lighted the capacity of the reaction to proceed without interfer-
ence from a distal unprotected hydroxyl group. Our mechanistic
proposal led us to employ a propargylic ether as a substrate,
thereby expanding the scope of the reaction to include internal
alkynes. This result suggests that gold-mediated protocols
leading to the formation of an electrophilic alkene can be
adapted to heterocycle synthesis.
provided cyclization substrate 43. Mosher ester analysis showed
the enantiomeric excess of 43 to be 94%. The high enantiomeric
purity can be attributed to the sulfinyl auxiliary promoting good
diastereocontrol in both the aldehyde addition and reduction
steps.40 Exposing 43 to the standard cyclization conditions
resulted in the formation of protected andrachcinidine (44) as a
single diastereomer in 89% isolated yield. Direct cyclization of
the sulfinylamide intermediate was unsuccessful due to the
affinity of the sulfinyl group for the gold catalyst. Sulfonamide
cleavage proceeded efficiently with basic thiophenol to yield
the final product. Thus (+)-andrachcinidine can be prepared
with excellent enantio- and diastereocontrol through a brief
sequence in an 8% overall yield. This route compares quite
favorably with the previously reported41 synthesis of this
compound.
Reactions with Internal Alkynes. All substrates in this report
have been terminal alkynes. While this results in complete
regiocontrol for the initial hydration reaction it limits the scope
of the available products. Because of their exquisite nucleo-
philicity, metalated alkynes are highly versatile functional groups
for fragment coupling in complex molecule synthesis. The ability
to apply the mild gold-mediated cyclization conditions to internal
alkynes would dramatically enhance the scope of products that
can be accessed through the gold-mediated heterocycle synthe-
sis. Applying the standard reaction conditions to internal alkyne
45 (Scheme 8), however, provided a mixture of products with
the major pathway being simple alkyne hydration in which water
reacted at the distal carbon with respect to the methoxy group
Experimental Section
General Cyclization Procedure A. In a 2 dram (8 mL) screw-
capped vial containing a magnetic stir bar was placed homoprop-
argylic methyl ether and water-saturated CH2Cl2 (∼60 mM final
concentration). To the stirred solution at room temperature were
added Ph3PAuCl (5 mol %) and AgSbF6 (5 mol %). The resulting
white suspension was stirred at 35 °C until starting material
consumption was complete. The black reaction mixture was dried
over MgSO4 and the crude contents of the vial in an ice bath were
concentrated by using a N2 gas. Products were purified by silica
gel chromatography. For volatile products yields were determined
by GC in accord with the procedure defined above.
(42) For an example of gold-mediated R,â-unsaturated ester formation,
see: Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4207.
(41) Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878.
7364 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of O- and N-Containing Heterocycles
General Cyclization Procedure B. In a 2 dram (8 mL) screw-
capped vial containing a magnetic stir bar was placed homoprop-
argylic methyl ether and water-saturated CH2Cl2 (∼60 mM final
concentration). To the stirred solution at room temperature was
added NaAuCl4‚2H2O (5 mol %). The reaction mixture was stirred
at 35 °C until starting material consumption was complete. The
dark yellow reaction mixture was dried over MgSO4 and the crude
contents of the vial in an ice bath were concentrated by using a N2
gas. Products were purified by silica gel chromatography. For
volatile products yields were determined by GC in accord with the
procedure defined above.
General Cyclization Procedure C. In a 4 dram (16 mL) screw-
capped vial containing a magnetic stir bar was placed homoprop-
argylic methyl ether and water-saturated toluene (∼25 mM final
concentration). To the stirred solution at room temperature were
added Ph3PAuCl (5 mol %) and AgSbF6 (10 mol %). The resulting
white suspension was stirred at 40 °C until starting material
consumption was complete. The crude contents of the vial were
directly purified by silica gel chromatography.
crude residue was purified by flash chromatography (4:1, hexanes/
EtOAc) to afford ketone (573 mg, 3.41 mmol, 41%) as a colorless
oil. H NMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.29 (m, 1H),
1
2.45 (t, J ) 6.4 Hz, 2H), 2.39 (m, 2H), 2.12 (s, 3H), 1.98 (t, J )
2.6 Hz, 1H), 1.73-1.54 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
208.6, 80.8, 79.0, 70.0, 57.0, 43.6, 33.0, 29.8, 23.0, 19.6; IR (neat)
3287, 2933, 2827, 2118, 1715, 1427, 1360, 1160, 1112 cm-1
;
HRMS (EI) m/z calcd for C7H13O2 (M - C3H3)+ 129.0915, found
129.0919.
(12R,E)-N-(6-Methoxynon-8-yn-2-ylidene)-2-methylpropane-
2-sulfinamide (41). To a solution of the appropriate ketone (500
mg, 2.97 mmol) in THF (3 mL) was added Ti(OEt)4 (3.10 mL,
14.9 mmol) at room temperature, followed by adding a solution of
40 (540 mg, 4.46 mmol) in THF (3 mL). The reaction mixture
was stirred at 70 °C for 12 h. The reaction was cooled to 0 °C
immediately and then poured into a brine solution with vigorous
stirring. The resulting white suspension was filtered through a Celite
pad and rinsed with EtOAc. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined organic
phase was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography (10:1 to 4:1, hexanes/EtOAc with 5%
Et3N) to afford 41 (584 mg, 2.15 mmol, 72%) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.30 (m, 1H), 2.40
(m, 4H), 2.31 (s, 3H), 1.98 (t, J ) 2.6 Hz, 1H), 1.67 (m, 4H), 1.22
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 185.0, 80.8, 79.0, 70.0,
57.0, 56.2, 43.2, 33.0, 23.1, 22.9, 22.2, 21.3; IR (neat) 3469, 3294,
1-(1-(2-Nitrophenylsulfonyl)piperidin-2-yl)propan-2-one (31).
General procedure C was followed with homopropargylic methyl
ether 20 (50.0 mg, 0.147 mmol), Ph3PAuCl (3.8 mg, 7.7 µmol),
and AgSbF6 (5.2 mg, 15 µmol) in water-saturated toluene (6.0 mL)
for 12 h. The residue was purified by flash chromatography (20:1,
1
CH2Cl2/EtOAc) to give 31 (41 mg, 84% isolated yield). H NMR
(300 MHz, CDCl3) δ 8.09 (m, 1H), 7.67 (m, 3H), 4.46 (m, 1H),
3.78 (dm, J ) 13.6 Hz, 1H), 3.00 (td, J ) 13.6 Hz, 1H), 2.87 (dd,
J ) 16.7, 9.1 Hz, 1H), 2.70 (dd, J ) 16.7, 4.3 Hz, 1H), 2.11 (s,
3H), 1.72-1.44 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 205.5,
147.7, 133.7, 133.4, 131.8, 131.2, 124.3, 49.2, 44.0, 41.8, 30.3,
28.1, 25.1, 18.3; IR (neat) 2944, 1716, 1544, 1342, 1372, 1160
cm-1; HRMS (ESI) m/z calcd for C14H18N2O5SNa (M + Na)+
349.0834, found 349.0811.
3235, 2928, 2826, 2118, 1624, 1475, 1362, 1189, 1112 cm-1
;
HRMS (EI) m/z calcd for C14H26NO2S (M + H)+ 272.1684, found
272.1685.
(R,Z)-N-((4R)-4-Hydroxy-10-methoxytridec-12-yn-6-ylidene)-
2-methylpropane-2-sulfinamide (42). To 1.0 M solution of LDA
in THF (2.2 mL, 2.2 mmol) at -78 °C was added a cooled solution
of 41 (502 mg, 1.85 mmol) in THF (8 mL). The mixture was stirred
for 30 min and anhydrous MgBr2 (670 mg, 3.70 mmol) was added
in one portion. The mixture was stirred at -78 °C for 1 h. To the
light yellowish metalloenamine solution was added n-butyraldehyde
(0.25 mL, 2.8 mmol) dropwise. The reaction mixture was stirred
at -78 °C for 24 h. After reaction was complete, a cooled 2.0 N
solution of AcOH in THF (10 mL) was added dropwise and the
resulting mixture was then stirred at -78 °C for 20 min. Brine and
saturated aqueous NaHCO3 solution were added and the reaction
was allowed to warm to room temperature. The organic layer was
separated and the aqueous layer was extracted with EtOAc. The
combined organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude was purified by
flash chromatography (4:1 to 2:1, hexanes/EtOAc with 5% Et3N)
to afford 42 (410 mg, 1.19 mmol, 65%) as a colorless oil, which
was immediately used for the next step because of the instability
6-Bromo-4-methoxyhex-1-yne (39). To a solution of 3-bro-
mopropionaldehyde dimethyl acetal (38) (2.31 g, 11.4 mmol) in
CH2Cl2 (15 mL) at -78 °C was added allenyltributyltin (5.2 mL,
17. mmol), followed by the dropwise addition of TiCl4 (13.6 mL,
1.0 M solution in CH2Cl2, 13.6 mmol). The dark brown mixture
was stirred at -78 °C for 3 h. The reaction was quenched with
saturated aqueous NaHCO3 at -78 °C and then was allowed to
warm to room temperature. The reaction mixture was poured into
saturated aqueous NaHCO3 solution. The crude material was
extracted with EtOAc (2×). The combined organic phase was
washed with brine (2×), dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude residue was purified by
flash chromatography (20:1, hexanes/EtOAc) to afford 39 (2.10 g,
1
10.5 mmol, 93%) as a colorless oil. H NMR (300 MHz, CDCl3)
δ 3.54 (m, 3H), 3.43 (s, 3H), 2.45 (dd, J ) 5.4, 2.7 Hz, 2H), 2.14
(m, 2H), 2.03 (t, J ) 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
80.1, 76.8, 70.5, 57.4, 37.1, 29.8, 22.8; IR (neat) 3298, 2931, 2828,
2120, 1433, 1360, 1260, 1109 cm-1; HRMS (EI) m/z calcd for C4H9-
OBr (M - C3H3)+ 151.9837, found 151.9824.
1
of 42. H NMR (300 MHz, CDCl3) δ 4.32 (d, J ) 9.4 Hz, 1H),
3.77 (m, 1H), 3.38 (s, 3H), 3.31 (m, 1H), 3.11 (t, J ) 11.4 Hz,
1H), 2.40 (m, 4H), 1.99 (t, J ) 2.5 Hz, 1H), 1.71-1.33 (m, 8H),
1.26 (s, 9H), 0.92 (t, J ) 6.8 Hz, 3H).
6-Methoxynon-8-yn-2-one. To a 1.0 M solution of LDA in THF
(10 mL, 10 mmol) with HMPA (3.5 mL, 20 mmol) at -45 °C was
added a cooled solution (-78 °C) of acetone cyclohexylimine43
(1.40 g, 10.1 mmol) in THF (5 mL) dropwise. The yellow mixture
was stirred at -45 °C for 1.5 h. To a solution of metalloenamine
was added a cooled solution (-78 °C) of bromide 39 (1.58 g, 8.27
mmol) in THF (10 mL) dropwise. The resulting mixture was stirred
at -45 °C for 2 h and allowed to warm to room temperature. The
reaction mixture was then stirred at room temperature for 12 h.
The reaction was quenched with water and acidified with 10%
aqueous HCl solution at 0 °C (pH 6). The organic layer was
separated and the aqueous layer was extracted with EtOAc (2×).
The combined organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
(S)-N-((4R,6S)-4-Hydroxy-10-methoxytridec-12-yn-6-yl)-2-
methylpropane-2-sulfinamide. To a solution of 42 (404 mg, 1.18
mmol) in THF (8 mL) at -50 °C was added catecholborane (0.38
mL, 3.5 mmol) dropwise. The reaction mixture was stirred at
-50 °C for 2 h. MeOH (10 mL) and saturated aqueous sodium
potassium tartrate solution (10 mL) were added. The resulting
mixture was stirred for an additional 20 min and allowed to warm
to room temperature. The white solution was washed with brine
and extracted with EtOAc. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined organic
phase was dried over MgSO4, filtered, and concentrated. The crude
mixture was purified by flash chromatography (1:1, hexanes/EtOAc
to 100% EtOAc) to afford pure syn-hydroxy sulfinamide (258 mg,
1
0.75 mmol, 64%) as a colorless oil. H NMR (300 MHz, CDCl3)
δ 3.89 (m, 1H), 3.72 (m, 1H), 3.36 (s, 3H), 3.30 (m, 2H), 2.90 (dd,
J ) 6.8, 2.9 Hz, 1H), 2.39 (m, 2H), 1.98 (t, J ) 2.6 Hz, 1H), 1.80
(43) Perez, A. L.; Gries, R.; Gries, G.; Oehlschlager, A. C. Bioorg. Med.
Chem. 1996, 4, 445.
J. Org. Chem, Vol. 72, No. 19, 2007 7365

Jung and Floreancig
(m, 2H), 1.65-1.30 (m, 10H), 1.20 (s, 9H), 0.90 (t, J ) 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 80.9, 79.0, 78.9, 71.5, 69.9,
57.0, 56.9, 56.8, 55.8, 43.1, 43.0, 40.9, 35.8, 35.7, 33.2, 23.0, 22.6,
21.6, 21.5, 18.5, 14.0; IR (neat) 3400 (br), 3311, 2932, 2870, 2119,
1645, 1457, 1364, 1106, 1043 cm-1; HRMS (ESI) m/z calcd for
7.68 (m, 3H), 4.43 (ddm, J ) 9.8, 3.2 Hz, 1H), 4.25 (m, 1H), 3.59
(m, 1H), 3.01-2.85 (m, 2H), 2.98 (dd, J ) 16.5, 3.4 Hz, 1H), 2.89
(dd, J ) 16.5, 9.8 Hz, 1H), 2.20 (s, 3H), 1.89 (ddd, J ) 13.8, 9.3,
3.2 Hz, 1H), 1.83 (ddd, J ) 13.8, 9.6, 4.2 Hz, 1H), 1.69 (d, J )
6.9 Hz, 1H), 1.65-1.34 (m, 10H), 0.95 (t, J ) 6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 206.0, 147.7, 133.4, 131.9, 131.4, 124.5,
69.5, 50.1, 48.8, 48.1, 43.1, 40.5, 30.3, 27.7, 27.2, 18.8, 14.0, 13.3;
IR (neat) 3400, 2955, 2871, 1714, 1544, 1373, 1340, 1168, 1136
cm-1; HRMS (EI) m/z calcd for C16H23N2O5S (M - C3H5O)+
C18H35NO3SNa (M + Na)+ 368.2235, found 368.2217; [R]23
D
-29.0 (c 0.700, CHCl3).
N-((4R,6S)-4-Hydroxy-10-methoxytridec-12-yn-6-yl)-2-nitroben-
zenesulfonamide (43). To a solution of syn-hydroxy sulfinamide
(246 mg, 0.71 mmol) in CH3OH (10 mL) was added a 4.0 M HCl
solution in 1,4-dioxane (0.36 mL, 1.42 mmol) at room temperature.
The reaction mixture was stirred for 1 h. After the desulfinylation
was complete, excess HCl and solvents were evaporated under
reduced pressure. A mixture of THF/H2O (v/v 1:1, 10 mL) was
added, followed by the addition of NaHCO3 (180 mg, 2.14 mmol)
and 2-nitrobenzenesulfonyl chloride (181 mg, 0.85 mmol) at room
temperature. The resulting mixture was stirred for 2 h. The crude
mixture was extracted with EtOAc (2×). The combined organic
phase was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography (1:2 to 1:1, hexanes/EtOAc) to afford 43
(252 mg, 0.59 mmol, 83%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ 8.15 (m, 1H), 7.85 (m, 1H), 7.73 (m, 2H), 5.52 (d, J )
7.3 Hz, 1H), 3.64 (m, 2H), 3.31 (s, 1.5H), 3.29 (s, 1.5H), 3.17 (m,
1H), 2.29 (m, 2H), 1.97 (m, 1H), 1.65-1.18 (m, 12 H), 0.87 (t, J
) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 147.8, 135.0, 133.2,
132.7, 130.6, 125.2, 125.1, 80.8, 78.9, 78.8, 70.0, 69.3, 56.9, 53.6,
53.5, 42.6, 42.5, 40.1, 35.2, 33.2, 33.1, 23.0, 22.9, 18.5, 13.9; IR
(neat) 3541, 3294, 3097, 2932, 2872, 2118, 1732, 1541, 1418, 1365,
1165 cm-1; HRMS (ESI) m/z calcd for C20H30N2O6SNa (M + Na)+
355.1337, found 355.1328; [R]23 -44.0 (c 0.425, CHCl3).
D
(+)-Andrachcinidine (37). To a solution of 44 (50.0 mg, 0.121
mmol) in acetonitrile (3.0 mL) were added K2CO3 (83.7 mg, 0.606
mmol) and thiophenol (37 µL, 0.36 mmol). The yellowish reaction
mixture was stirred at room temperature for 1 h. The solvent was
evaporated under reduced pressure. The crude residue was purified
by flash chromatography (EtOAc to 10:1, EtOAc/methanol with
5% Et3N) to afford (+)-37 (26.3 mg, 0.116 mmol, 95%) as a
1
colorless oil. H NMR (500 MHz, CDCl3) δ 3.80 (m, 1H), 2.97
(dtd, J ) 11.2, 6.3, 2.7 Hz, 1H), 2.74 (tt, J ) 10.3, 2.5 Hz, 1H),
2.49 (dd, J ) 16.5, 6.7 Hz, 1H), 2.43 (dd, J ) 16.5, 5.8 Hz, 1H),
2.11 (s, 3H), 1.82 (dm, J ) 13.5 Hz, 1H), 1.66 (dm, J ) 13.1 Hz,
1H), 1.62 (dm, J ) 13.1 Hz, 1H), 1.52 (m, 1H), 1.49 (m, 1H),
1.40 (m, 2H), 1.32 (m, 2H), 1.21 (dt, J ) 14.2, 10.2, 1H), 1.08-
0.96 (m, 2H), 0.89 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 207.2, 72.5, 58.2, 53.0, 50.5, 43.1, 40.4, 33.5, 32.5, 30.6, 24.5,
18.6, 14.1; IR (neat) 3299 (br), 2929, 2859, 1713, 1457, 1360, 1107
cm-1; HRMS (EI) m/z calcd for C13H25NO2 (M+) 227.1885, found
227.1882; [R]23 +24.1 (c 0.390, CHCl3).
D
Acknowledgment. We thank the NIH (GM62924) for
generous support of this work and Dr. Steven Geib for assistance
with crystal structure searches.
449.1722, found 449.1699; [R]23 +26.2 (c 0.480, CHCl3).
D
1-((2R,6S)-6-((R)-2-Hydroxypentyl)-1-(2-nitrophenylsulfonyl)-
piperidin-2-yl)propan-2-one (44). To a solution of 43 (70.0 mg,
0.164 mmol) in water-saturated toluene (6.6 mL, 0.025 M) were
added PPh3AuCl (4.1 mg, 0.008 mmol) and AgSbF6 (5.6 mg, 0.016
mmol). The reaction mixture was stirred at 40 °C for 24 h. The
reaction solution was directly purified by chromatography on silica
gel (10:1, CH2Cl2/EtOAc) to afford 44 (60.5 mg, 0.147 mmol, 89%)
Supporting Information Available: Experimental procedures
for all cyclization reactions and spectral characterization of all
cyclization starting materials, and products, and 1H and 13C NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
as a colorless oil. H NMR (300 MHz, CDCl3) δ 8.09 (m, 1H),
JO071225W
7366 J. Org. Chem., Vol. 72, No. 19, 2007