Sequential Ru-Pd catalysis: A two-catalyst one-pot protocol for the synthesis of N- and O-heterocycles

Article abstract of DOI:10.1021/ja060812g

An atom economic, selective, and highly practical two-metal one-pot synthesis of heterocycles has been developed that efficiently affords enantio- and diastereopure N- and O-heterocyclic products. Furthermore, use of a chiral catalyst in the two-metal procedure allows formation of all possible diastereomers, even those that are traditionally difficult to access via cyclization routes due to thermodynamics. Interestingly, the nature of the enantiodiscriminating event differs between the use of amine versus alcohol nucleophiles. The method also affords heterocyclic products that are synthetically useful intermediates. Through the Z-vinylsilane a variety of stereodefined trisubstituted olefin products can be accessed including several all-carbon motifs. Finally, the utility of these heterocyclic products in total synthesis is demonstrated through concise syntheses of a kainoid intermediate, a constituent of oil of rose, and the ring B portion of bryostatin, a potent chemotherapeutic.

Full text of DOI:10.1021/ja060812g

Published on Web 04/25/2006
Sequential Ru-Pd Catalysis: A Two-Catalyst One-Pot
Protocol for the Synthesis of N- and O-Heterocycles
Barry M. Trost,* Michelle R. Machacek, and Brian D. Faulk
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received February 2, 2006; E-mail: bmtrost@stanford.edu
Abstract: An atom economic, selective, and highly practical two-metal one-pot synthesis of heterocycles
has been developed that efficiently affords enantio- and diastereopure N- and O-heterocyclic products.
Furthermore, use of a chiral catalyst in the two-metal procedure allows formation of all possible
diastereomers, even those that are traditionally difficult to access via cyclization routes due to thermodynam-
ics. Interestingly, the nature of the enantiodiscriminating event differs between the use of amine versus
alcohol nucleophiles. The method also affords heterocyclic products that are synthetically useful
intermediates. Through the Z-vinylsilane a variety of stereodefined trisubstituted olefin products can be
accessed including several all-carbon motifs. Finally, the utility of these heterocyclic products in total
synthesis is demonstrated through concise syntheses of a kainoid intermediate, a constituent of oil of rose,
and the ring B portion of bryostatin, a potent chemotherapeutic.
1. Introduction
group such as 3 and the yne partner contains a pendant
nucleophile (2), the product of coupling, 4, will contain a newly
formed allylic group. Since palladium catalysts are known to
promote ionization of allylic groups and induce asymmetry in
the cyclization, we surmised that the resulting π-allyl complex
could be trapped with the pendant nucleophile to form enan-
tioenriched heterocyclic products (6) without isolation of the
1,4-diene intermediate.
To realize this tandem process, there were several issues that
needed to be addressed. The first was the regioselectivity of
the ruthenium-catalyzed coupling reactions. In some instances,
two isomeric products are generatedsthe “linear” product 5 and
the “branched” product 4. While both diene intermediates can
undergo ionization, the trans double bond present in 5 precludes
cyclization to five- and six-membered heterocyclic rings.
Therefore, our initial goal was to control the regioselectivity of
coupling for essentially all cases. The answer was found by
utilizing silyl-substituted alkynes (7) wherein steric interactions
within the ruthenacycle intermediates favor reaction through 10
(Scheme 2).3 An additional feature of this strategy is that the
resulting vinyl silane offers a pathway for further structural
elaboration and differentiates the two resulting double bonds.4
With the first issue addressed, we focused on optimizing the
conditions to induce tandem coupling and cyclization. While
several metals are known to catalyze nucleophilic trapping of
π-allyl species, palladium is one of the most general, forming
Functionalized chiral heterocyclic rings such as tetrahydro-
furans, pyrans, pyrrolidines, and piperidines are found in a
diverse array of bioactive natural products, ranging in complex-
ity from the simple such as nicotine to the complex such as
bryostatin. While several methods are available for the synthesis
of these moieties, their formation often involves an intramo-
lecular ring closure of a chiral intermediate, necessitating lengthy
syntheses and isolation of the cyclization precursor. Furthermore,
methods that offer selective access to all possible diastereomers,
especially those that are thermodynamically disfavored, are less
common. For example, cyclization methods for the formation
of cis-2,6-substituted tetrahydropyrans are prevalent, but very
few methods offer direct access to the thermodynamically
unfavored trans pyrans in isomerically pure form.1 With these
challenges in mind, we envisioned developing a transition-metal-
catalyzed synthesis of heterocyclic products that was (1)
efficient, generating multiple bonds in one pot, (2) regio- and
stereoselective, allowing for all diastereomeric products to be
selectively generated, and (3) practical, being experimentally
simple and tolerant of multiple functional groups. The basis for
our synthesis centered on the ruthenium-catalyzed ene-yne
coupling reaction. Employing [RuCp(CH3CN)3]PF6 (1) to effect
alkene/alkyne cross-coupling is a highly versatile and efficient
strategy for diene synthesis.2 We envisioned utilizing the
coupling reaction to set up the necessary juxtaposition of reactive
groups to induce an in situ cyclization to form heterocycles
(Scheme 1). For example, when the ene partner is a homoallylic
(2) (a) Trost, B. M.; Surivet, J.-P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
15592. (b) Trost, B. M.; Shen, H. C.; Pinkerton, A. B. Chem. Eur. J. 2002,
8, 2341. (c) Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M. J.
Am. Chem. Soc. 2001, 123, 12504. (d) Trost, B. M.; Surivet, J.-P.; Toste,
F. D. J. Am. Chem. Soc. 2001, 123, 2897. (e) Trost, B. M.; Toste, F. D.;
Pinkerton, A. B. Chem. ReV. 2001, 101, 2067. (f) Trost, B. M.; Toste, F.
D. J. Am. Chem. Soc. 2000, 122, 714. (g) Trost, B. M.; Toste, F. D.
Tetrahedron Lett. 1999, 40, 7739.
(1) Some notable exceptions: (a) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle,
R. J. J. Am. Chem. Soc. 2003, 125, 11456. (b) Marcotte, S.; D’Hooge, F.;
Ramadas, S.; Feasson, C.; Pannecoucke, X.; Quirion, J.-C. Tetrahedron
Lett. 2001, 42, 5879. (c) McDonald, F. E.; Singhi, A. D. Tetrahedron Lett.
1997, 38, 7683. (d) Vares, L.; Rein, T. J. Org. Chem. 2002, 67, 7226. (e)
Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40,
2287. (f) Panek, J. S.; Huang, H. J. Am. Chem. Soc. 2000, 122, 9836.
(3) Trost, B. M.; Machacek, M. R.; Schnaderback, M. J. Org. Lett. 2000, 2,
1761.
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J. AM. CHEM. SOC. 2006, 128, 6745-6754
6745

A R T I C L E S
Trost et al.
Scheme 1. Tandem Coupling Cyclization
Scheme 2. Regioisomer Solution
rings that range in size from five-membered to large macrocyclic
structures.5 Furthermore, a diverse set of nucleophiles are
tolerated (C, N, S, O), thereby potentiating the type of products
that can be formed. Finally, several chiral ligands have been
developed for palladium-catalyzed allylic substitution, offering
the opportunity to develop an asymmetric process. However,
incorporating asymmetric transition-metal catalysis into a one-
pot process is a formidable goal.6 The key issue is compatibility
of the two catalyst systems. The reagents or catalysts may
interfere with each other by acting as nondissociating ligands
that shut down the catalytic cycle or distort the chiral pocket
which is crucial for high enantioselectivity. In addition to these
general issues, our system poses another challenge. To obtain
high enantioselectivity in the cyclization step, it is important
that only the chiral palladium catalyst effects ionization and
cyclization of 8. If the achiral ruthenium catalyst participates
in this step, the product enantioselectivity would degrade.7
To address the issue of selective ionization, we embarked
on finding a leaving group (X in 3) such that ionization only
occurred in the presence of the palladium catalyst. Initial studies
indicated that allyl carbonates, nitrobenzoates, and acetates were
readily ionized in the presence of ruthenium catalyst 1.
Furthermore, both coupling and ionization occurred at similar
rates, making them impractical for the one-pot process. Reac-
tions using less activated leaving groups such as phenol8 were
not general and failed with routine nucleophiles, presumably
due to the ability of phenol to also act as a nucleophile. Since
p-nitrophenyl ether can also be ionized by palladium but is less
nucleophilic, we chose this functional group as a starting point
for our studies. The ease of accessing such aryl ethers by
nucleophilic aromatic substitution further enhances the at-
tractiveness of these leaving groups.
2. Enantioselective Heterocyclization Reactions
2.1. Enantioselective N-Heterocyclization Reactions. Our
initial goal was the formation of N-heterocycles, utilizing
p-nitrobenzenesulfonamide as the nucleophile. This group was
desirable because of its compatibility with the ruthenium
catalyst9 and for the mild conditions under which it can be
removed.10 To induce asymmetry in the cyclization, we
employed the diphenylphosphinobenzoic acid based chiral
ligands (L-1-L-4). A first pass application of (R,R)-L-1
(7) Ru is known to catalyze allylic ionization and allylic substitution reac-
tions: (a) Renaud, J.-L.; Bruneau, C.; Demerseman, B. Synlett 2003, 3,
408. (b) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem., Int. Ed.
2002, 41, 1059. (c) Trost, B. M.; Fraisse, P. L. Unpublished results. (d)
Onitsuka, K.; Matsushima, Y.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi
2002, 60, 752. (e) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.;
Takahashi, S. J. Am. Chem. Soc. 2001, 123, 10405. (f) Zhang, S.-W.;
Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1993, 450,
197.
(8) (a) Takahasi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972, 45,
230. (b) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1973,
46, 1012. (c) Brady, D. G. Chem. Commun. 1970, 434. (d) Fiaud, J. C.;
Hibon de Gournay, A.; Larchevegere, M.; Kagan, H. B. J. Organomet.
Chem. 1978, 154, 175. (e) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi,
T. Tetrahedron Lett. 1980, 21, 3393.
(4) (a) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821. (b)
Hirabayashi, K.; Ando, J.; Mori, A.; Nishihara, Y.; Hiyama, T. Synlett 1999,
99. (c) Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309.
(d) Gouda, K.-I.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. J. Org. Chem.
1996, 61, 7232. (e) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1989, 54,
268. (f) Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30,
6051. (g) Hosomi, A.; Kohra, S.; Tominaga, T. Chem. Pharm. Bull. 1988,
36, 4622.
(5) (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (b) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921.
(6) Recent examples of dual transition-metal processes: (a) Jeong, N.; Seo, S.
D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220. (b) Doi, T.; Kobuko,
M.; Yamamoto, K.; Takahashi, T. Org. Synth. 1998, 63, 428. (c) Lopez,
F.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc. 2002, 124, 4218.
(9) Free amines are not compatible with the CpRu(CH3CN)3 catalyst.
(10) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831. (c) Wuts, P. G. M.; Northuis, J. M.
Tetrahedron Lett. 1998, 39, 3889.
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Two-Metal One-Pot Synthesis of Heterocycles
A R T I C L E S
Scheme 3. Catalyst Compatibility
Table 1. Optimization of the N-Heterocyclization Reaction
from the allyl intermediate. The type of base also had a dramatic
impact with amine bases such as DBU and TMG showing the
best yield and selectivity profiles. Fluoride bases such as TBAF
afforded excellent yield but poor enantioselectivity (entry 7).
Temperature also had an impact on the selectivity, with both
increases and decreases from ambient temperature being del-
eterious. Clearly, the enantioselectivity is a delicate balance
between the rate of ionization, π-allyl complex isomerization,
and nucleophilic attack. While all three of these variables are
affected by temperature, they may not all be cooperative. Finally,
the effect of solvent was investigated. Though the preferred
solvent for the ene-yne coupling is acetone, chlorinated solvents
such as methylene chloride afforded the highest selectivities for
the cyclization step (89% ee). While running the cross-coupling
reaction in chlorinated solvents led to significantly reduced
conversion, cyclization in a mixed solvent system (entry 13)
maintained high enantioselectivitysthereby allowing for a
simple injection of methylene chloride, base, and palladium
catalyst to the reaction mixture after ene-yne coupling was
complete. Lowering the ruthenium loading and accordingly the
fraction of acetone present in the cyclization afforded nearly
ideal selectivity, while slightly decreasing the yield (entry 14).
On the basis of these results, the two mixed solvent systems
were adopted as ideal.
Given our optimized conditions, we investigated the scope
of the asymmetric one-pot reaction sequence (Table 2). Both
pyrrolidines (17) and piperidines (13) are formed with good
yield and enantioselectivity under the optimized conditions.
Seven-membered rings (21) are formed with lower efficiency
accompanied by significant amounts of elimination to the triene
product. Since cyclization to seven-membered rings is kinetically
slower, elimination becomes competitive. Interestingly, the
enantioselectivity for formation of 21 also drops significantly.
Alkyne 22 was synthesized to increase the cyclization rate;
however, no ene-yne coupling was observed even under
extended reaction times.
cyclization
T ( C)
cyclization
solvent
entry % 1
°
base
% yielda % eeb
1
2
3
10
5
5
25
25
25
DBU
DBU
acetone
acetone
74
80
14
72
78
10
AcOH/NBu4OAc acetone
(2:1)
AcOH
TMG
quinuclidine
TBAF
DBU
DBU
DBU
DBU
DBU
4
5
6
7
8
9
10
11
12
13
5
5
5
5
5
5
5
5
5
5
25
25
25
25
60
0
25
25
25
25
acetone
acetone
acetone
acetone
acetone
acetone
DCM
dioxane
DCE
DCM/acetone
(3:1)d
0c
74
77
80
84
88
82
80
66
90
71
46
54
68
70
89
78
83
84
DBU
14
2
25
DBU
DCM/acetone
(10:1)d,e
83
88
a All reactions run with a 1.7:1 ratio of 15:14 with 1 in acetone at 0.2 M
for 2 h at room temperature followed by addition of DBU, [Pd(η3-C3H5)Cl]2,
and (R,R)-L-1 in the given solvent to afford 0.08 M and stirring for 2 h at
the given temperature. Yields represent isolated yields after chromatography.
b The ee was determined by HPLC. c Only elimination to triene was
observed. d Ru-catalyzed reaction run in acetone only. Cyclization run in
noted solvent mixture. e Ruthenium coupling run at 0.5 M in acetone.
afforded piperidine 13 in 72% yield and 74% ee. Even more
encouraging was that the enantioselectivity and yield were
similar regardless of whether the reaction was performed in two
separate operations or in one pot. This similarity implied that
the intrinsic reactivity and enantioselectivity of the palladium-
catalyzed cyclization were not affected by the presence of the
ruthenium catalyst. Furthermore, no background reaction was
seen when 12 was subjected to conditions for cyclization without
palladium. These results indicate that the dual-catalyst concept
is viable (Scheme 3).
A screen of chiral ligands L-1-L-4 showed that L-1 reliably
afforded product with higher enantioselectivity. Catalyst loading
had mild effects on yield with either 2% or 5% 1 and 2% (Pd-
(η3-C3H5)Cl)2 being ideal. Choice of reaction pH was crucial
for the success of the cyclization. Reactions conducted under
acidic or buffered conditions (Table 1, entry 3 and 4) led to
significant amounts of triene products formed by elimination
The absolute configuration of these heterocyclic products is
assigned based upon correlation to a product of known absolute
configuration (vide supra). On the basis of our working model,11
ionization constitutes the enantiodiscriminating event. The
predictions are based on literature precedent as well as
experimental results. For example, chloride ion is known to
(11) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (b)
Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
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A R T I C L E S
Trost et al.
Table 2. Enantioselective Cyclization Reactions: Nitrogen
Table 3. Optimizing Pyran Formation
Nucleophiles
entry
Pd source
solvent
base
T (
°
C) % yielda % eeb
1
2
3
4
5
6
7
8
9
[Pd(η3-C3H5)Cl]2 DCM TBAF
[Pd(η3-C3H5)Cl]2 DCM TMG
Pd2(dba)3‚CHCl3 THF NEt3
Pd2(dba)3‚CHCl3 THF NEt3
Pd2(dba)3‚CHCl3 THF NEt3
Pd2(dba)3‚CHCl3 THF NEt3
Pd2(dba)3‚CHCl3 DCM NEt3
[Pd(η3-C3H5)Cl]2 DCM NEt3
Pd2(dba)3‚CHCl3 DCM 0.2 equiv NEt3
25
25
60
25
0
42
61
73
86
83
27
80
71
85
NAc
NAc
72
77
81
89
94
92
86
-35
0
0
0
a All reactions run in degassed solvent under argon with 1 equiv of base
for 2 h at 0.08 M at the given temperature. Yields represent isolated yields
after chromatography. b The ee was determined by HPLC. c Racemic dppp
ligand used.
conditions that would yield an enantioselective cyclization of
1,4-diene intermediate 23 (Table 3).
Gratifyingly, the palladium-catalyzed cyclization proceeds
smoothly under several conditions. Similar to the sulfonamide
cases, methylene chloride was found to be the optimum solvent
both in terms of yield and selectivity. It was also apparent that
Pd2(dba)3‚CHCl3 afforded better yield and selectivity than the
π-allyl chloride dimer. Furthermore, of all the bases tested,
triethylamine gave the best yield and selectivity. Interesting
temperature effects were also noticed, with the enantioselectivity
displaying a prominent inverse dependence on temperature. As
the temperature of the cyclization was lowered from 60 to 0
°C, there was a continuous increase in the selectivity of (+)-
24. Temperatures below zero led to poor conversions, and as
such 0 °C was chosen as optimal, affording product in 94% ee.
With our optimized conditions in hand, we again tested the
one-pot process for scope (Table 4). Furans and pyrans both
form in good yield, with pyrans affording the highest selectivi-
ties. Attempted seven-membered ring formation was unsuc-
cessful affording only the triene elimination product. The
absolute configuration of these heterocyclic products was
assigned to be opposite of that found in the sulfonamide cases,
based upon subsequent correlation in one case to a known
stereochemistry (vide infra). On the basis of our working
model,11 now the nucleophilic addition constitutes the enantio-
discriminating event. This prediction is supported by the fact
a All reactions run with a 1.7:1 ratio of 15 to alkyne under inert
atmosphere under the conditions listed below. Condition A, for a 0.2 mmol
scale: (i) 5% 1, 1.0 mL of acetone, room temperature, 2 h; (ii) 2% [[Pd(η3-
C3H5)Cl]2, 6% (R,R)-L-1, 1 equiv of DBU, 3.0 mL of DCM, room
temperature, 2 h. Condition B, for a 0.2 mmol scale: (i) 2% 1, 0.4 mL of
acetone, room temperature, 2 h; (ii) 2% [Pd(η3-C3H5)Cl]2, 6% (R,R)-L-1,
1 equiv of DBU, 3.6 mL of DCM, room temperature, 2 h. Condition C, for
a 0.2 mmol scale: (i) 10% 1, 1.0 mL of acetone, room temperature, 2 h;
(ii) 2% [Pd(η3-C3H5)Cl]2, 6% (R,R)-L-1, 1 equiv of DBU, 3.0 mL of DCM,
room temperature, 2 h. b Isolated yields after chromatography. c Percent ee
was measured by chiral HPLC. d Thirty-six percent of triene elimination
product was also observed.
increase the rate of isomerization of the palladium π-allyl
intermediate, which should decrease the selectivity if ionization
is the enantiodiscrimination event. In support of this, addition
of tetrabutylammonium chloride to the cyclization reaction
causes a precipitous drop in the selectivity.
2.2. Enantioselective O-Heterocyclization Reactions. Since
many complex natural products contain chiral pyrans and furans,
we were interested in extending the enantioselective mixed-
metal process to oxygen-containing heterocycles. However, in
contrast to their phenolic and carboxylate counterparts, simple
alkyl alcohols are known to be poor nucleophiles for enanti-
oselective palladium π-allyl substitutions.12 The poor nucleo-
philicity is attributed to the mismatch between the “hard” alcohol
nucleophile and “soft” palladium π-allyl complex. To overcome
the inherent mismatch presented by alkoxy nucleophiles, previ-
ous solutions have relied on intramolecular closures,13 large
excesses of alcohol, or using tin,14 boron,15 silyl,16 or zinc17
ethers to “soften” the nucleophile. Furthermore, to our knowl-
edge there were no reports of an asymmetric allylic substitution
using simple alcohol nucleophiles without boron cocatalysis.18,19
Despite this significant challenge, we began a search for
(13) (a) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2927. (b)
Lakhmiri, R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1989, 30, 4669. (c)
Thorey, C.; Wilken, J.; Henin, F.; Martens, J.; Mehler, T.; Muzart, J.
Tetrahedron Lett. 1995, 36, 5527. (d) Fournier-Nguefack, C.; Lhoste, P.;
Sinou, D. Tetrahedron 1997, 53, 4353. (e) Hamada, Y.; Seto, N.;
Takayanagi, Y.; Nakano, T.; Hara, O. Tetrahedron Lett. 1999, 40, 7791.
(f) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650.
(14) (a) Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 8277. (b) Trost,
B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931.
(15) (a) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 12702. (b) Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999,
121, 8649. (c) Trost, B. M.; Brown, B. S.; McEachern, E. J.; Kuhn, O.
Chem. Eur. J. 2003, 9, 4442.
(16) Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31, 4747.
(17) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369.
(18) Enantioselective cyclization using boron cocatalysis has been achieved, see
ref 15.
(19) Low enantioselectivity has been reported: (a) Fournier-Nguefack, C.;
Lhoste, P.; Sinou, D. J. Chem. Res. 1988, 105A. Enantioselective allylic
cyclizations of alkoxy nucleophiles were developed independently and
concurrently with this work: (b) Jiang, L.; Burke, S. D. Org. Lett. 2001,
3, 1953. (c) Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411.
(12) (a) Takahashi, K.; Miyaki, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972, 45,
230. (b) Stork, G.; Poirier, J. M. J. Am. Chem. Soc. 1983, 105, 1073. (c)
Keinan, E.; Roth, Z. J. Org. Chem. 1983, 48, 1769. (d) Stanton, S. A.;
Felman, S. W.; Parkhurst, C. S.; Godleski, S. A. J. Am. Chem. Soc. 1983,
105, 1964. (e) Keinan, E.; Sahai, M.; Poth, Z.; Nudelman, A.; Herzig, J. J.
Org. Chem. 1985, 50, 3558.
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Two-Metal One-Pot Synthesis of Heterocycles
A R T I C L E S
Table 5. Diastereoselective Furan and Piperidine Synthesis
Table 4. Enantioselective O-Heterocyclization Reactions
a All reactions run with a 6:1 ratio of 15 to alkyne under inert atmosphere
under the conditions listed below. Condition D, for a 0.2 mmol scale: (i)
10% 1, 1.0 mL of acetone, room temperature, 2 h; (ii) concentrate in vacuo,
then add 2% [Pd(η3-C3H5)Cl]2, 6% (R,R)-L-1, 1 equiv of DBU, 4.0 mL of
DCM, 0 °C, 2 h. b Isolated yields after chromatography. c Percent ee was
measured by chiral HPLC. d Thirty percent NBu4Cl was added.
that addition of tetrabutylammonium chloride as a cocatalyst
slightly increases the selectivity for furan formation (entry 2)
and has no effect on the selectivity of pyran formation.
3. Diastereoselective Heterocyclization Reactions
a All reactions run with a 1.7:1 ratio of 15 to alkyne under inert
atmosphere under the conditions listed below. Condition A, for a 0.2 mmol
scale: (i) 5% 1, 1.0 mL of acetone, room temperature, 2 h; (ii) 2% [Pd(η3-
C3H5)Cl]2, 6% ligand, 1 equiv of DBU, 3.0 mL of DCM, room temperature,
2 h. Condition B, for a 0.2 mmol scale: (i) 2% 1, 0.4 mL of acetone, room
temperature, 2 h; (ii) 2% [Pd(η3-C3H5)Cl]2, 6% ligand, 1 equiv of DBU,
3.6 mL of DCM, room temperature, 2 h. Condition C, for a 0.2 mmol scale:
(i) 10% 1, 1.0 mL of acetone, room temperature, 2 h; (ii) 2% [Pd(η3-
C3H5)Cl]2, 6% ligand, 1 equiv of DBU, 3.0 mL of DCM, room temperature,
2 h. Condition D: use a 6:1 ratio of 15/alkyne. For a 0.2 mmol scale: (i)
10% 1, 1.0 mL of acetone, room temperature, 2 h; (ii) concentrate in vacuo,
add 2% Pd2(dba)3‚CHCl3, 6% ligand, 1 equiv of NEt3, 4.0 mL of DCM, 0
°C, 2 h. b Isolated yields. c The dr was measured by 1H NMR. d Yield based
on recovered starting material is 80%. e The dr was measured by HPLC.
Palladium catalysis allows for diastereo- as well as enantio-
control. Given chiral starting materials, we investigated whether
the chiral catalyst could control the diastereoselectivity in the
cyclization, either by enhancing or overcoming the intrinsic
substrate-controlled preference. Gratifyingly, good diastereo-
control is exhibited by the catalyst (Table 5). With matched
ligand/substrate pairs,20 the selectivity is universally excellent.
Furthermore, in every mismatched case, the nonnatural diaste-
reomer predominates indicating that the catalyst is able to
override and control the geometry of cyclization. For example,
utilizing an achiral ligand affords 38 as a 2:1 cis/trans diaster-
eomeric ratio (entry 8). Employing the matched chiral ligand
leads to exclusive formation of the cis isomer (entry 10), whereas
when the mismatched ligand is used, the trans isomer predomi-
nates (entry 9). The advantage of catalyst control is clear as
both diastereomers can be accessed from a single enantiomer
of starting material simply by switching the ligand. Similar levels
of control are seen for furan formation (entries 1-3). Increasing
the steric demands of the substrate leads to increased selectivity
in both the matched (23:1) and mismatched cases (1:4.5) (entries
4-6). Interestingly, the achiral dppp ligand consistently affords
lower conversions than its chiral counterpart regardless of
whether the chiral reaction involved a “matched” or “mis-
matched” stereochemical event indicating that the DPPBA-based
ligand plays a dual role in the reactionsimparting selectivity
and organizing the substrate such that cyclization is facilitated.
Finally, entry 7 indicates that biaryl alkynes afford little to no
conversion in the ene-yne coupling, potentially due to deac-
tivation of the catalyst from bidentate coordination.
importantly, the trans isomer is formed exclusively in the
mismatched cases (Table 6).21 This is significant because while
cyclization methods for the formation of cis 2,6-tetrahydropyrans
are prevalent, very few methods offer direct access to the
thermodynamically unfavorable trans pyran in isomerically pure
form.1 For this class of substrates the ability of the chiral ligands
to control the relative stereochemistry is impressive and indicates
the potential of this catalyst system.22 For example, several
prominent and bioactive natural products such as the phorbox-
azoles, salinomycin, and swinholide A contain a trans-2,6-
disubstituted pyran and illustrate the possible utility of this
method. Furthermore, we have successfully performed the two-
metal one-pot procedure on large scale (as high as 20 mmol)
indicating its practical nature and potential easy incorporation
into total synthesis.23
(21) For all substrates in Tables 5 and 6, the relative stereochemistry was
determined by 1H NMR techniques. In particular, the presence of a strong
NOE (generally between 5% and 10%) for cis 2,6- and 2,5-disubstituted
compounds was observed between protons adjacent to the heteroatom. The
corresponding absence of this NOE confirmed the trans stereochemical
assignment of the opposite diastereomer. Furthermore, since the absolute
stereochemistry of the starting substrate is known, the absolute configuration
of the newly created allylic stereogenic center is also known.
Dramatically, for pyran formation the selectivity is completes
the cis isomer is formed exclusively in matched cases and, more
(20) Matched implies that the catalyst reinforces the natural diastereoselectivity
of the substrate, and mismatched implies that the catalyst contradicts the
natural diastereoselectivity.
(22) For a preliminary account of this work: Trost, B. M.; Machacek, M. R.
Angew. Chem., Int. Ed. 2002, 41, 4693.
(23) See compound 85 in the Supporting Information.
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Scheme 4. Sulfonamides: Ionization Is Enantiodetermining
Table 6. Diastereoselective THP Synthesis
Scheme 5. Oxygen Nucleophiles: Nucleophilic Addition as
Enantiodetermining
with 92% ee, while the enantioselectivity drops to 88% and
17% for closure to six- and seven-membered rings, respec-
tively. Moreover, addition of 30% tetrabutylammonium chloride
to the cyclization of 52 causes a precipitous drop in the enantio-
selectivity. Since chloride ion is known to increase the rate of
equilibration of the intermediate π-allyl species, the rate of
equilibration can become competitive with nucleophilic trapping,
causing a decrease in the selectivity. Finally, if ionization is
enantiodetermining, conditions in which the sulfonamide is fully
deprotonated should show the highest selectivity. Experimen-
tally, DBU afforded the best selectivity, whereas weakly basic
amines or buffered conditions resulted in poor selectivity.
a All reactions run under inert atmosphere under the conditions listed.
Condition D: use a 6:1 ratio of 15/alkyne. For a 0.2 mmol scale: (i) 10%
1, 1.0 mL of acetone, room temperature, 2 h; (ii) concentrate in vacuo, add
2% Pd2(dba)3‚CHCl3, 6% ligand, 1 equiv of NEt3, 4.0 mL of DCM, 0 °C,
1
2 h. b Isolated yields after chromatography. c The dr was measured by H
NMR.
4. Absolute Stereochemical Analysis: Prediction and
Proof
Given the mechanism of palladium-catalyzed allylic alkyla-
tion, there are multiple steps that can be considered enantio-
determining. Both the substrate and the reaction conditions
define which step or steps will be operating. Applying literature
precedent to the sulfonamide substrates, ionization is expected
to be enantiodetermining.24 Matched ionization25 to form syn
complex 53 is followed by fast intramolecular mismatched
nucleophilic addition (Scheme 4). By tethering the nucleophile,
and using conditions where the sulfonamide is fully deproto-
nated, the rate of mismatched attack becomes faster than
equilibration and the (S)-stereochemistry is predicted from the
(R,R)-ligand even though ring closure involves a “mismatched”
event.
Interestingly, cyclizations involving alcohol nucleophiles
display the opposite selectivity pattern. For example, improved
selectivity is obtained for pyrans over furans. Furthermore, the
addition of exogenous chloride has a small but measurable
positive effect on the overall selectivity. And finally, strong
amine bases such as DBU afford lower selectivity than does
the weakly basic triethylamine. This experimental evidence
indicates that the nature of the nucleophile is crucial in defining
the enantiodetermining step in asymmetric intramolecular cy-
clization reactions. Simple alcohols are notoriously poor nu-
cleophiles for palladium-catalyzed allylic substitutions. There-
fore, the rate of addition is slower than equilibration of the
palladium-allyl diastereomers and nucleophilic addition be-
comes enantiodetermining. Applying this model to 1,4-diene
54, a matched ionization is followed by rapid equilibration of
55 and 56. Matched nucleophilic attack through 56 leads to (R)-
26 when utilizing (R,R)-ligand (Scheme 5).
Further support for this interpretation comes from both opti-
mization studies and substrate scope. If ionization is enantio-
determining, reactions in which the cyclization of the heteroatom
onto the allylpalladium intermediate is kinetically fast should
give the highest selectivity. Indeed, pyrrolidine formation occurs
(24) (a) Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339. (b) Trost,
B. M.; Patterson, D. E. Chem. Eur. J. 1999, 5, 3279.
(25) For definitions of matched and mismatched with respect to the working
model see ref 11.
Unambiguous stereochemical proof was achieved through
analogue synthesis. Several proline derivatives have been used
9
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Scheme 6. Synthesis of the 4-Oxyproline Derivative
Scheme 7. Completion of Rose Oil Oxide
as building blocks for total synthesis. We envisioned intersecting
a synthesis of the kainoids, a class of nonproteinogenic amino
acids with activity as glutamate agonists,26 through a concise
synthesis of the known 4-oxoproline derivative 6027 (Scheme
6). The one-pot heterocyclization process using (R,R)-L-1
proceeds very smoothly to afford pyrrolidine 58 in 94% ee.
Desilylation and oxidation of both olefins through ozonolysis
followed by an oxidative workup yielded the keto-acid with
complete retention of stereochemistry at the 2-position. The
crude acid was then directly capped as a tert-butyl ester.
Comparison of the optical rotation unambiguously determined
the stereochemistry to be (S),28 which matches the predictions
made by our working model for ionization being the enantio-
discriminating event.
lective cross-metathesis of 24 with 2-methylpropene30 to afford
61. Subsequent desilylation31 (Scheme 7) provided 62, whose
optical rotation unambiguously confirmed our predictions.32
Finally, chemoselective hydrogenation with Wilkinson’s catalyst
completed the simple three-step approach to rose oil oxide. Thus,
the nucleophilic addition is confirmed as the enantiodiscrimi-
nating event.
5. Synthetic Utility: A Concise Synthesis of Ring B of
Bryostatin
The two-metal, one-pot ene-cyclization method described
above provides a unique entry into enantio- and diastereopure
substituted heterocycles. There are several key structural features
associated with the products of this methodology that make them
convenient building blocks for complex total synthesis includ-
ing: a stereodefined trisubstituted exocyclic vinyl silane, two
sterically differentiated olefins, and differentiated substituents
on either side of the heteroatom. Given these features, a host
of further synthetic transformations can be performed after the
To establish the absolute stereochemistry of the products
wherein an alcohol is involved in the nucleophilic addition, we
turned to a synthesis of the important fragrance materials, the
rose oil oxides.29 Our synthesis began with a highly chemose-
(26) Kainic Acid as a Tool in Neurobiology; McGreer, E. G., Olney, J. W.,
McGreer, D. L., Eds.; Raven Press: New York, 1978 and references therein.
(27) Barraclough, P.; Hudhomme, P.; Spray, C. A.; Young, D. W. Tetrahedron
1995, 51, 4195.
(28) We are very grateful to Douglas W. Young for sending a copy of his original
spectra.
(29) Seidel, F.; Stoll, M. HelV. Chim. Acta 1959, 42, 1830.
(30) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939.
(31) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahderon
Lett. 1983, 24, 2877.
(32) Ohloff, G.; Giersch, W.; Schulte, E.; Karl, H.; Enggist, P.; Demoule, E.
HelV. Chim. Acta 1980, 63, 1582.
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A R T I C L E S
Trost et al.
Scheme 8. Representative Further Synthetic Transformationsa-f
Scheme 9. Bryostatin 1 and 2
The last feature of our heterocyclic products is the 2,4,6-
substitution pattern, a motif that is found in a variety of complex
natural products. Of these natural products, the bryostatin family
was of particular interest to us given the importance of these
compounds in both the biological and chemical community
(Scheme 9).40 The bryostatins are potent antitumor agents against
leukemia, B-cell lymphoma, ovarian carcinoma, and melanoma
cell lines. In addition, they show interesting stimulatory effects
on the immune and hematopoetic systems. Therefore, the
bryostatins are attractive targets for total synthesis, and three
total syntheses as well as several fragment syntheses have been
accomplished.41 Most striking from the standpoint of the one-
pot cross-coupling and cyclization reaction we developed was
the B ring portion (C10-C16). This highly conserved feature
in the bryostatin family consists of a 2,6-disubstituted pyran
ring with a stereodefined exocyclic olefin at the 4-position.
Though a small portion of the molecule, this ring embodies two
of the major synthetic challenges present in the molecule: the
stereoselective installation of the trisubstituted exocyclic olefin
and the enantioselective synthesis of pyran rings. Our method
nicely addresses both of these issues, and as such we saw this
ring as an excellent testing ground to explore its generality.
Our synthesis began with protection of commercially available
(S)-glycidol as the p-methoxybenzyl ether (Scheme 10). The
epoxide was then opened with lithium trimethylsilylacetylide
to yield the alkyne coupling partner 71 for the ruthenium-
catalyzed ene-yne cross-coupling reaction. The diene interme-
diate was cyclized to pyran 72 with complete syn selectivity in
52% yield over two steps. In this sequence, we opted to isolate
the 1,4-diene intermediate because of purification issues as 72
coeluted with the excess 15.
b
a SiR3 ) TMS, n ) 1; TFA, DCM, 92%. SiR3 ) TMS, n ) 1; NIS,
c
d
96%. SiR3 ) TMS, n ) 0; AcCl, AlCl3, 50%. SiR3 ) TMS, n ) 1; 3%
e
RhCl(PPh3)3, catecholborane, NaBO3, 78%. SiR3 ) DMPS, n ) 1; 2%
Grubbs II, isobutylene, 63%. fSiR3 ) Bn(Me)2Si, n ) 1; 2% Pd2(dba)3‚CHCl3,
TBAF, PhI, 85%.
cyclization to afford highly functionalized compounds (Scheme
8). Several transformations can be envisioned that take advan-
tage of the stereodefined trisubstituted exocyclic vinyl silanes
the most powerful feature of these heterocyclic products. Ipso-
substitution reactions such as Freidel-Crafts acylation33 (path
c) and iodination34 (path b) proceed smoothly to afford products
as single geometrical isomers. The stereodefined vinyliodide
products are useful intermediates for metal-catalyzed cross-
coupling reactions;35 however, the starting vinylsilane can also
be used as a cross-coupling partner.36 When vinylbenzyldim-
ethylsilane is utilized as the activated silane partner, smooth
cross-coupling to form all-carbon trisubstituted olefins is
achieved (path f).37 Furthermore, the exocyclic vinylsilane
differentiates the two olefins such that chemoselective trans-
formations can be achieved. For example, both cross-metathesis
with isobutylene (path e) and a hydroboration (path d)38 are
highly selective for the monosubstituted alkene (path e). In
contrast, oxidizing reagents such as mCPBA and osmium
tetroxide preferentially oxidize the silyl-substituted olefin with
osmium tetroxide affording mixtures of hydroxy and aldehyde
products. Finally, the vinyl silane can ultimately be converted
to the parent methylene by protodesilylation without olefin
isomerization (path a).39
Stereospecific transformation of the vinylsilane into the
desired enoate was accomplished through iodination and
subsequent palladium-catalyzed carbonylation. Functionalization
of the exocyclic vinyl group was accomplished through a
hydroboration-oxidation sequence.42 This route afforded the
fully functionalized ring B portion of bryostatin (74) in a short
seven-step sequence with 12% overall yield. More importantly,
the stereochemical integrity of the trisubstituted olefin created
(33) (a) Pillot, J.-P. Bull. Soc. Chim. Fr. 1975, 2143. (b) Colvin, E. W. J. Chem.
Soc. ReV. 1978, 7, 15. (c) Pillot, J.-P. Synth. Commun. 1979, 9, 395.
(34) (a) Miller, R. B.; Reichenbach, T. Tetrahedron Lett. 1974, 15, 543. (b)
Piscopio, A. D.; Minowa, N.; Chakraborty, T. K.; Koide, K.; Bertinato,
P.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1993, 7, 617.
(35) Metal Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinhein, Germany, 1998.
(36) (a) Colvin, E. W. Silicon in Organic Synthesis; Buttherworths: London,
1981. (b) Weber, W. P. Silicon Reagents for Organic Synthesis; Springer-
Verlag: Berlin, 1983.
(37) Vinyl BDMS cross-coupling: Trost, B. M.; Machacek, M. R.; Ball, Z. T.
Org. Lett. 2003, 5, 1895. Other activated vinyl silanes are not compatible
with the CpRu(CH3CN)3PF6 catalyst and thus are incompatible with our
mixed-metal methodology.
(38) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114,
6671.
(39) (a) O’Neil, S. V.; Quickley, C. A.; Snider, B. B. J. Org. Chem. 1997, 62,
1970. (b) Kano, S.; Yuasa, Y.; Mochizuki, N.; Shibuya, S. Heterocycles
1990, 30, 263. (c) Wenkert, E.; Bookser, B. C.; Arrhenius, T. S. J. Am.
Chem. Soc. 1992, 114, 644. (d) Honda, T.; Hoshi, M.; Tsubuki, M.
Heterocycles 1992, 34, 1515. (e) Keusenkothen, P. F.; Smith, M. B. J.
Chem. Soc., Perkin Trans. 1 1994, 2485. (f) Wang, C.; Gu, X.; Yu, M. S.;
Curran, D. P. Tetrahedron 1998, 54, 8355.
(40) (a) Petit, G. R.; Day, J. P.; Hartwell, J. L.; Wood, H. B. Nature 1970, 227,
962. (b) Petit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold,
E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846.
(41) Total syntheses: (a) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J.
C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990,
112, 7407. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (c)
Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yama-
mura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
(42) Higher overall yields were obtained when the hydroboration was performed
before carbonylation.
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Two-Metal One-Pot Synthesis of Heterocycles
A R T I C L E S
Scheme 10. Synthesis of Ring B
was stirred for 1 h at room temperature at which point the mixture
was concentrated in vacuo. The resulting oily residue was purified via
flash chromatography (silica, ether/petroleum ether, gradient).
Condition B. [CpRu(CH3CN)3]PF6 (1.7 mg, 0.004 mmol) was added
to a flame-dried test tube under argon. A solution of alkyne (0.20 mmol)
and alkene (0.35 mmol) in degassed acetone (0.4 mL) was added to
the catalyst via cannula. The reaction was stirred at room temperature
under argon for 3 h at which time it was diluted with 3.6 mL of
degassed DCM. DBU (32 mg, 0.21 mmol) was added followed by a
solution of (Pd(π-allyl)Cl)2 (1.5 mg, 0.004 mmol) and (R,R)-L-1 (8
mg, 0.012 mmol) in 0.5 mL of DCM. The resulting yellow solution
was stirred for 1 h at room temperature at which point the mixture
was concentrated in vacuo. The resulting oily residue was purified via
flash chromatography (silica, ether/petroleum ether, gradient).
Condition C. [CpRu(CH3CN)3]PF6 (5 mg, 0.012 mmol) was added
to a flame-dried test tube under argon. A solution of alkyne (0.12 mmol)
and alkene (0.19 mmol) in degassed acetone (0.6 mL) was added to
the catalyst via cannula. The reaction was stirred at room temperature
under argon for 3 h at which time it was diluted with 1.3 mL of
degassed DCM. DBU (18 mg, 0.12 mmol) was added followed by a
solution of (Pd(π-allyl)Cl)2 (0.9 mg, 0.0024 mmol) and (R,R)-L-1 (5
mg, 0.007 mmol) in 0.5 mL of DCM. The resulting yellow solution
was stirred for 1 h at room temperature at which point the mixture
was concentrated in vacuo. The resulting oily residue was purified via
flash chromatography (silica, 0-75% ether/petroleum ether, gradient).
Condition D. [CpRu(CH3CN)3]PF6 (8 mg, 0.02 mmol) was added
to a flame-dried test tube under argon. A solution of alkyne (0.20 mmol)
and alkene (1.2 mmol) in degassed acetone (1.0 mL) was added to the
catalyst via cannula. The reaction was stirred at room temperature under
argon for 3 h at which time it was directly concentrated in vacuo. The
resulting oily residue was purged with argon and dissolved in 1.3 mL
of degassed DCM. NEt3 (0.22 mmol) was added followed by a solution
of Pd2(dba)3‚CHCl3 (0.004 mmol) and (R,R)-L-1 (0.012 mmol) in 0.5
mL of degassed DCM. The resulting red solution was stirred for 2 h
at 0 °C at which point the mixture was concentrated in vacuo. The
resulting oily residue was purified via flash chromatography (silica,
0-75% ether/petroleum ether, gradient).
during the ene-yne cross-coupling reaction was completely
transferred to the stereochemistry of the exocyclic enoate. This
synthesis represents the shortest route to the B ring of bryosta-
tin43 and introduces a novel approach to the stereospecific
installation of the vinyl ester.
6. Conclusion
An atom economic, selective, and highly practical one-pot
synthesis of heterocycles has been developed that efficiently
affords enantio and diastereopure N- and O-heterocyclic prod-
ucts. Furthermore, use of a chiral palladium catalyst allows
formation of all possible diastereomers, even those that are
thermodynamically disfavored. This two-metal procedure also
affords heterocyclic products that are synthetically useful
intermediates. Through the Z-vinylsilane a variety of trisubsti-
tuted olefin substitution products can be accessed. Finally, the
utility of these heterocyclic products was demonstrated through
a concise synthesis of the ring B portion of bryostatin, a potent
chemotherapeutic. In addition, through a combination of ex-
perimental evidence, application of the working model for
palladium-catalyzed AAA, and stereochemical proof, we dem-
onstrated that the nature of the nucleophile is important for
defining the enantiodetermining step of the asymmetric allylic
cyclization reaction. Kinetic trapping of the initially generated
π-allyl complex determines the stereochemistry for “soft”
nucleophiles such as sulfonamides. In contrast, slow trapping
of equilibrating π-allyl diastereomers, determines the selectivity
for “hard” nucleophiles such as nonstabilized alcohols.
7. Experimental Section
General procedures for the mixed-metal synthesis of heterocycles
are as follows.
Condition A. [CpRu(CH3CN)3]PF6 (4.3 mg, 0.01 mmol) was added
to a flame-dried test tube under argon. A solution of alkyne (0.20 mmol)
and alkene (0.35 mmol) in degassed acetone (1.0 mL) was added to
the catalyst via cannula. The reaction was stirred at room temperature
under argon for 3 h at which time it was diluted with 2.5 mL of
degassed DCM. DBU (32 mg, 0.21 mmol) was added followed by a
solution of (Pd(π-allyl)Cl)2 (1.5 mg, 0.004 mmol) and (R,R)-L-1 (8
mg, 0.012 mmol) in 0.5 mL of DCM. The resulting yellow solution
Compound 58. [CpRu(CH3CN)3]PF6 (9 mg, 0.02 mmol) was added
to a flame-dried test tube under argon. A solution of 57 (56 mg, 0.20
mmol) and 15 (67 mg, 0.35 mmol) in degassed acetone (1.0 mL) was
added to the catalyst via cannula. The reaction was stirred at room
temperature for 4 h at which time it was directly concentrated in vacuo.
The resulting oily residue was purged with argon and dissolved in 3.0
mL of degassed dichloromethane. DBU (0.032 mL, 0.21 mmol) was
added followed by a solution of (Pd(π-allyl)Cl)2 (1.5 mg, 0.004 mmol)
and (R,R)-L-1 (8.3 mg, 0.012 mmol) in 1.0 mL of DCM. The resulting
yellow solution was stirred for 1 h at room temperature at which point
the mixture was concentrated in vacuo. The resulting oily residue was
(43) Other routes have accomplished syntheses of similar pieces with the
exocyclic olefin stereochemistry installed in 14 steps: (a) Vakalopoulos,
A.; Lampe, T. F. J.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 929. In 18
steps: (b) Hale, K. J.; Hummersome, M. G.; Bhatia, G. S. Org. Lett. 2000,
2, 2189. In 8 steps: (c) Munt, S. P.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1989, 8, 480.
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1
purified via flash chromatography (silica, 0-60% ether/petroleum ether,
gradient) to yield 65 mg (92%) of 58 as a light yellow oil. The
enantiomeric excess was determined to be 94% by chiral HPLC analysis
(Chiralcel AD column, 99:1 heptane/iPrOH, flow rate ) 0.5 mL/min,
254 nm, tr: 39.31 (major), 48.46 (minor)). [R]D +99.46 (c ) 0.81,
CHCl3). Rf ) 0.61 in 25% diethyl ether/petroleum ether. IR (neat):
2955, 1639, 1351, 1163, 840 cm-1. 1H NMR (300 MHz CDCl3) δ 7.70
(d, J ) 8.1 Hz, 2 H), 7.32 (d, J ) 8.1 Hz, 2 H), 5.76 (ddd, J ) 6.9,
10.2, 17.1 Hz, 1 H), 5.40 (br s, 1 H), 5.21 (d, J ) 17.1 Hz, 1 H), 5.09
(d, J ) 10.2 Hz, 1 H), 4.11 (m, 1 H), 3.93 (m, 2 H), 2.43 (m, 2 H),
2.44 (s, 3 H), 0.05 (s, 9 H). HRMS Calcd for C17H25NO2SSi: 335.1375.
Found: 335.1380.
Compound 72. CpRu(CH3CN)3PF6 (0.15 g, 0.34 mmol) was added
to a cooled (0 °C) solution of 71 (0.99 g, 3.4 mmol) and 15 (3.6 g,
18.6 mmol) in 17 mL of acetone. The resulting solution was stirred at
0 °C for 5 min and then at room temperature for 3 h. The reaction was
directly concentrated in vacuo and purified via flash chromatography
(silica, ether/petroleum ether gradient) to yield 0.98 g of 1,4-diene
coupling product. The 1,4-diene (0.99 g, 2.14 mmol) was dissolved in
42 mL of degassed DCM and cooled to 0 °C. Triethylamine (0.24 g,
2.4 mmol) was added followed by a solution of Pd2dba3‚CHCl3 (44
mg, 0.04 mmol) and (S,S)-L-1 (88 mg, 0.13 mmol) in 5 mL of degassed
DCM. The resulting solution was stirred for 2 h at 0 °C at which time
it was directly concentrated in vacuo. The resulting oily residue was
purified via flash chromatography (silica, ether/petroleum ether gradient)
to yield 0.64 g (86%) of 72 as a colorless oil. The diastereoselectivity
was determined to be >97:3 cis by 1H NMR analysis. Rf ) 0.8 in 25%
ether/petroleum ether. [R]D +5.35 (c ) 6.90, CH2Cl2). IR (film from
CH2Cl2): 2953, 2895, 1622, 1514, 1248, 1100, 1038, 878 cm-1. H
NMR (500 MHz, CDCl3) δ 7.31 (d, J ) 8.5 Hz, 2 H), 6.91 (d, J ) 9.0
Hz, 2 H), 5.93 (ddd, J ) 17.0, 10.5, 5.5 Hz, 1 H), 5.32 (s, 1 H), 5.29
(d, J ) 17.0 Hz, 1 H), 5.15 (d, J ) 10.5 Hz, 1 H), 4.58 (d, J ) 12.0
Hz, 1 H), 4.55 (d, J ) 12.0 Hz, 1 H), 3.90 (m, 1 H), 3.83 (s, 3 H), 3.55
(m, 3 H), 2.48 (d, J ) 13.5 Hz, 1 H), 2.24 (m, 2 H), 2.02 (t, J ) 12.0
Hz, 1 H), 0.14 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ 159.09, 152.68,
138.54, 130.37, 129.22 (2 C), 123.64, 115.21, 113.68 (2 C), 79.31,
77.29, 72.98, 72.80, 55.20, 45.19, 36.59, 0.26 (3 H). Anal. Calcd for
C20H30OSi: C, 69.32%; H, 8.73%. Found: C, 69.15%; H, 8.55%.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM33049) for their
generous support of our programs. Mass spectra were provided
by the Mass Spectrometry Regional Center for the University
of California, San Francisco, supported by the NIH Division of
Research Resources. We thank Bristol-Meyers Squibb and Eli-
Lilly for predoctoral support of M.R.M. We are indebted to
Johnson-Matthey who generously provided palladium salts.
Supporting Information Available: Detailed procedures and
full characterization of all synthetic intermediates and products,
along with spectral comparison of natural and synthetic ana-
logues. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA060812G
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6754 J. AM. CHEM. SOC. VOL. 128, NO. 20, 2006