Exploiting the Pd- and Ru-catalyzed cycloisomerizations: Enantioselective total synthesis of (+)-allocyathin B2

Article abstract of DOI:10.1021/ja051547m

Pd- and Ru-catalyzed cycloisomerizations of 1,6-enynes are compared and contrasted. Such considerations led to the enantioselective synthesis of a cyathin terpenoid, (+)-allocyathin B₂ (1). The synthesis features a Pd-catalyzed asymmetric allyl

Full text of DOI:10.1021/ja051547m

Published on Web 06/28/2005
Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations:
Enantioselective Total Synthesis of (+)-Allocyathin B2
Barry M. Trost,* Li Dong, and Gretchen M. Schroeder
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94301-5080
Received March 10, 2005; E-mail: bmtrost@stanford.edu
Abstract: Pd- and Ru-catalyzed cycloisomerizations of 1,6-enynes are compared and contrasted. Such
considerations led to the enantioselective synthesis of a cyathin terpenoid, (+)-allocyathin B2 (1). The
synthesis features a Pd-catalyzed asymmetric allylic alkylation (AAA) to install the initial quaternary center,
a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diaste-
reoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. We demonstrate for
the first time a mechanism-based stereochemical divergence in Pd- and Ru-catalyzed cycloisomerization
reactions as well as in creation of alkene geometry with alkynes bearing a carboalkoxy group. Mechanistic
rationalization is proposed for these observations.
Introduction
Cycloisomerizations represent atom economic approaches to
ring construction. As a result, we have pioneered metal-catalyzed
cycloisomerizations of enynes to form cyclic 1,3- and 1,4-
dienes.1-3 In the Pd-catalyzed reaction (Figure 1), a mechanistic
rationale invokes HPd+ formed by protonation of Pd(0) as the
catalytically active species.4 Preferential hydropalladation of the
alkyne and intramolecular carbapalladation of the alkene by the
in situ generated vinylpalladium species followed by â-hydrogen
elimination complete the cycle. â-Hydrogen elimination toward
Ha creates a 1,3-diene, whereas â-hydrogen elimination of Hb
provides a 1,4-diene. Experimentally, both pathways have been
observed and normally proceed with excellent regioselectivity
depending upon the substrate. On the other hand, a Ru-catalyzed
process proceeds via a completely different pathway, as shown
in Figure 2. This mechanism precludes the formation of 1,3-
dienes since â-hydrogen elimination within the metallacycle is
geometrically strongly disfavored. Further, the regioselectivity
in the â-hydrogen elimination to form 1,4-dienes, where such
exists (i.e., with trisubstituted alkenes), also has been comple-
mentary. Despite these facts, divergences of the two quite
distinct mechanisms remain to be elucidated.
Figure 1. Pd-catalyzed cycloisomerization mechanism.
earlei Lloyd, is distinguished by an angularly fused 5-6-7
tricyclic skeleton with a highly unsaturated trienal motif
embedded in the framework and 1,4-anti quaternary methyl
groups located at the ring junctions. These terpenoids exhibit
interesting biological activities against actinomycetes, Gram-
positive and Gram-negative bacteria, as well as some fungi.6
Metabolites of other fungi14-17 and liverworts18 also share the
In the course of a total synthesis project, the issue of the
differences between these two catalytic systems arose. In 1979,
Ayer et al. reported the isolation and structure of (+)-allocyathin
B2 (1, Scheme 1),5 a member of the cyathin terpenoids.5-13
Compound 1, a metabolite from the fruit bodies of Cyathus
(9) Ayer, W. A.; Lee, S. P.; Nakashima, T. T. Can. J. Chem. 1979, 57, 3338-
3343.
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Can. J. Chem. 1981, 59, 2665-2672.
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15592-15602.
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2113-2120.
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Lett. 1996, 37, 7399-7402.
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H.; Furukawa, S. Heterocycl. Commun. 1996, 2, 51-54.
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A R T I C L E S
Trost et al.
contrasting these two metal-catalyzed cycloisomerizations stimu-
lated by this total synthesis. A preliminary report describing
only the total synthesis has recently appeared.31
Herein, we report an enantioselective total synthesis of
(+)-allocyathin B2. The goal of this synthesis was to develop a
catalytic approach to enantioselectively install the first quater-
nary carbon and relay the stereochemical information to the
remaining two stereogenic centers. Strategically, we planned
to construct the cycloheptadiene unit of allocyathin B2 by a late-
stage intramolecular aldol condensation from aldehyde 4
(Scheme 1). A transition metal-catalyzed cycloisomerization was
envisioned to build the six-membered ring of the 5-6-7
tricyclic cyathin core (compound 5).32 At the outset, it was
recognized that this key disassembly allows several synthetic
parameters, such as catalyst, substrate geometry, and appendage
at the alkyne terminus, to be adjusted to achieve the requisite
stereochemistry as well as to prepare for subsequent transforma-
tions. This disconnection also provides a rare opportunity to
explore the Pd- and Ru-catalyzed cycloisomerizations related
to the methods developed in this laboratory in a complex setting.
The crucial intermediate, enyne 6, would be prepared through
a Pd-catalyzed asymmetric allylic alkylation (AAA) reaction
from ketone 7, another methodology recently developed in this
group.33-35
Figure 2. Ru-catalyzed cycloisomerization mechanism.
Scheme 1. Retrosynthetic Analysis
Results and Discussion
Pd-Catalyzed Cycloisomerization of 1,7-Enyne 14. Since
we had an efficient and reliable approach to enantioselectively
install the C17 methyl group using a Pd-catalyzed enolate AAA
reaction (8, Scheme 2),36 it was desirable to design a cyclization
substrate from this compound in such a way that both sides of
the resulting six-membered ring would be properly functional-
ized to allow the diastereoselective introduction of the C14
hydroxyl group as well as set the stage for the closure of the
final seven-membered ring. With these considerations in mind,
compound 14 was conceived as one of the viable substrates for
the pivotal transition metal-catalyzed cycloisomerization. It
should be noted that the Z-geometry of the olefin in compound
14 was chosen at this stage because of its ease of assembly,
although we do anticipate that the olefin geometry will be a
key factor to determine the stereochemical outcome of this
reaction.
Alkyne 6 was synthesized in satisfactory yield through the
addition of lithium dimethylcuprate to 8 followed by treatment
of the resulting ketone 9 with LDA and PhNTf236 followed by
a Sonogashira coupling reaction (Scheme 2).37 The elaboration
of the Z-alkene 14 involved a straightforward chain elongation
protocol38-40 involving a stereospecific conjugate addition of
lithium dimethylcuprate to ynoate 12.41
cyathane backbone, including a hydroxylated analogue, sar-
codonin A (2, Scheme 1) from Sarcodon scabrosus, which has
anti-inflammatory activity,19 and a D-xylose conjugate of
allocyathin B2, erinacine A (3, Scheme 1) from the mycelia of
Hericum erinaceum, which possesses potent stimulating activity
for nerve growth factor (NGF) synthesis in vitro.15 The imposing
structure and potential medicinal importance of these molecules
have attracted a great deal of attention from many research teams
since the disclosure of their structures,7,20-26 although only three
groups have completed the racemic syntheses of allocyathin
B227-29 and sarcodonin A.30 In this paper, we report our studies
(17) Lee, E. W.; Shizuki, K.; Hosokawa, S.; Suzuki, M.; Suganuma, H.; Inakuma,
T.; Li, J.; Ohnishi-Kameyama, M.; Nagata, T.; Furukawa, S.; Kawagishi,
H. Biosci. Biotechnol. Biochem. 2000, 64, 2402-2405.
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H.; Tada, T. Agric. Biol. Chem. 1989, 53, 3373-3375.
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(21) Thominiaux, C.; Chiaroni, A.; Desmaele, D. Tetrahedron Lett. 2002, 43,
4107-4110.
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2105-2108.
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A. Org. Lett. 1999, 1, 1535-1538.
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(27) Tori, M.; Toyoda, N.; Sono, M. J. Org. Chem. 1998, 63, 306-313.
(28) Snider, B. B.; Vo, N. H.; O’Neil, S. V. J. Org. Chem. 1998, 63, 4732-
4740.
(31) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am. Chem. Soc. 2005, 127,
2844-2845.
(32) Aubert, C.; Buisine, O.; Malacria, B. Chem. ReV. 2002, 102, 813-834.
(33) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759-6760.
(34) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002,
41, 3492-3495.
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(36) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am.
Chem. Soc. 2004, 126, 4480-4481.
(37) Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am.
Chem. Soc. 1988, 110, 649-651.
(38) Brown, C. A.; Coleman, R. A. J. Org. Chem. 1979, 44, 2328-2329.
(39) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-168.
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1996, 118, 7644-7645.
(30) (a) Piers, E.; Cook, K. L. Chem. Commun. 1996, 1879-1880. (b) Piers,
E.; Gilbert, M.; Cook, K. L. Org. Lett. 2000, 2, 1407-1410.
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Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations
A R T I C L E S
Table 1. Pd-Catalyzed Cycloisomerization of Compound 14a
Scheme 2. Synthesis of Substrate 14a
yield of
entry
ligand
acid (mol %)
T (°
C) time (h)
15 (%)
1
2
3
4
5
6
BBEDAb HOAc (25 mol %)
60
60
60
70
25
70
24
20
2
4 (82% 14)
18 (13% 14)
19 (8% 14)
none
none
none
none
none
HOAc (25 mol %)
TFA (20 mol %)
HCO2H (200 mol %)
HCO2H (200 mol %)
o-CF3BzOH (20 mol %)
0.8 23 (62% 16)
20
12
22 (64% 16)
60
a All reactions were performed in toluene (0.1 M) with 2 mol % of
Pd2(dba)3CHCl3 at the indicated temperature. b No conversion was observed
with other ligands, such as (o-Tol)3P.
Scheme 3. Synthesis of Epoxide 19a
a Conditions: (a) LDA, [(η3-C3H5)PdCl]2 (0.5 mol %), (S,S)-L* (1 mol
%), allyl acetate, Me3SnCl, t-BuOH, 83%, 95% ee; (b) Me2CuLi, -20 °C
to room temperature, 85%; (c) LDA, PhNTf2, 98%; (d) Pd2(dba)3CHCl3
(2.5 mol %), PPh3 (20 mol %), CuI (5 mol %), TMS-acetylene, n-BuNH2,
50 °C, 85%; (e) 9-BBN; H2O2, NaOH, 87%; (f) (COCl)2, DMSO, Et3N,
-78 °C to room temperature, 84%; (g) CBr4, PPh3, 94%; (h) n-BuLi,
ClCO2Me, -78 °C to room temperature, 99%; (i) Me2CuLi, -78 °C, 93%;
(j) DIBAL-H, -78 °C to room temperature, 94%; (k) TBAF, 97%.
a Conditions: (a) PhS(O)CH2CN, piperidine, 69%; (b) 10% Pd/C, H2 (1
atm), 98%; (c) mCPBA, 76% or NBS, water, 46% or VO(acac)2, TBHP,
80%.
Many transition metals have been reported to catalyze the
cycloisomerization of 1,6- and 1,7-enynes, notably Pd, Ru, Rh,
and Ti.1,32 However, 1,7-enynes with trisubstituted olefins are
challenges for most of the known methodologies, possibly due
to the poor substrate coordination to the catalyst. Not surpris-
ingly, [Rh(COD)Cl]2/BINAP/AgBF442,43 and Cp2Ti(CO)244 are
ineffective catalysts in the cycloisomerization of 14. Prior efforts
in our laboratory indicate that palladium systems are more
tolerant of olefin substitution than ruthenium in these reactions.45
Therefore, we decided to initially examine palladium catalysts
in our cycloisomerization reaction.
Although Pd2(dba)3‚CHCl3/HOAc is known to be effective
in catalyzing the formation of six-membered rings, only trace
amounts of the cyclization product were obtained along with a
significant amount of the starting material when 14 was exposed
to the standard conditions (entry 1, Table 1). Despite the low
conversion, a single diastereomer was obtained, as demonstrated
by NMR analysis. The obvious difficulty in the coordination
of this 1,7-enyne to the catalyst prompted us to use the
“ligandless” conditions developed in this group.46 Indeed, the
yield significantly improved without the addition of BBEDA
[bis(benzylidene)ethylenediamine]. Since the use of HOAc as
the cocatalyst led to the formation of an unidentified isomer-
ization product, other acids were surveyed to avoid this problem.
Among the acids assayed, o-trifluoromethylbenzoic acid was
identified as the best choice (Table 1). Although formic acid
was superior in terms of reactivity, the relatively sluggish
cycloisomerization reaction allowed the formation of a signifi-
cant amount of the reduced triene 16. Using the optimized
conditions, compound 15 was obtained in 60% yield as a single
diastereomer (entry 6, Table 1). The relative stereochemistry
of the newly formed quaternary center was determined at a later
stage (vide infra).
We then turned our attention to the construction of the final
seven-membered ring. An interesting methodology developed
by Nokami, the hydroxylative Knoevenagel reaction, seemed
well suited to our goal of installing the C14 hydroxy group with
concomitant extension of the carbon chain.47 Gratifyingly, after
some experimentation, the desired transformation was ac-
complished to afford alcohol 17 as a single diastereomer
(Scheme 3). Compound 17, which contains all three requisite
stereogenic centers, was submitted for X-ray crystallographic
structural determination. Unfortunately, the two quaternary
methyls are 1,4-syn, while the hydroxyl group possesses the
correct configuration (Figure 1). Despite this setback, we decided
to pursue our synthesis using compound 17 as a model study
and a possible intermediate to an epimer of (+)-allocyathin B2.
Surprisingly, the 1,4-reduction of the R,â-unsaturated nitrile
(C12-C13) of compound 17 did not occur under a variety of
conditions known for this purpose.48 On the other hand, by
taking advantage of the unique conformation of nitrile 17, a
chemoselective hydrogenation was achieved with heterogeneous
catalysis. Thus, by subjecting compound 17 to 10% Pd/C and
1 atm of hydrogen, a near quantitative yield of the desired
dihydro derivative 18 was obtained (Scheme 3).
Having established the requisite oxygen-bearing stereocenter,
we found ourselves faced with the task of homologating the
(42) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 3457-
3460.
(43) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104-4106.
(44) Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 1976-1977.
(45) Trost, B. M. Acc. Chem. Res. 1990, 23, 34-42.
(46) Trost, B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625-6633.
(47) Nokami, J.; Mandai, T.; Imakura, Y.; Nishiuchi, K.; Kawada, M.;
Wakabayashi, S. Tetrahedron Lett. 1981, 22, 4489-4490.
(48) Reduction with in situ generated copper hydride, Mo-catalyzed hydrosilane
reduction, or Lindlar’s catalyst reduction gave no reaction.
9
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A R T I C L E S
Trost et al.
Scheme 4. Pd-Catalyzed Cycloisomerization of Compound 23a
a Conditions: (a) OsO4 (1 mol %), NMO, NaIO4, 84%; (b) NaBH4, 94%;
(c) PPh3, I2, ImH, 93%; (d) t-BuLi, ZnCl2, -78 °C to room temperature,
then Pd(PPh3)4 (5 mol %), 22; (e) TBAF, 72% from 21; (f) Pd2(dba)3CHCl3,
o-CF3BzOH, 70 °C, 54%.
Figure 3. X-ray crystallography of compound 17.
group, are generated. In intermediate 25, the C-Pd bond and
the π-bond of the acyclic alkene are syn-coplanar as required
for the carbametalation. Thus, this orientation is energetically
favorable and leads to the observed product. On the other hand,
the alternative conformation 26 has the C-Pd and π-bond
orthogonal. Such an unfavorable geometry for the carbameta-
lation disfavors this cyclization and precludes formation of the
desired stereochemistry. As this picture illustrates, the geometry
of the trisubstituted double bond with respect to the product
stereochemistry is irrelevant.
exocyclic olefin to an R,â-unsaturated aldehyde or equivalent.
An osmium-catalyzed dihydroxylation of 18 failed to proceed
with a number of co-oxidants [NMO, trimethylamine oxide, or
K3Fe(CN)6] and additives (methane sulfonamide or pyridine).49
On the other hand, exposure of 18 to sterically less sensitive
epoxidizing agents, such as mCPBA or NBS/water, generated
epoxide 19 due to an electron-rich nature of the tetrasubstituted
double bond (Scheme 3).50 As predicted by analysis of a
molecular model, a hydroxyl-directed epoxidation [VO(acac)2,
TBHP]51 afforded the same product. These results, although
discouraging, demonstrated the key role that the C6 stereo-
chemistry plays in affecting the chemoselectivity. We, therefore,
tried several approaches to reverse the diastereoselectivity of
the cycloisomerization.
Pd-Catalyzed Cycloisomerization of Compounds 23 and
28. As previously mentioned, we anticipate the olefin geometry
of the enyne to be a key factor in determining the stereochemical
outcome of the cycloisomerization reaction. Thus, E-isomer 23
was synthesized from compound 6 as detailed in Scheme 4.
The allyl side chain of compound 6 was oxidatively cleaved
(OsO4, NMO; NaIO4), reduced (NaBH4), and iodinated (PPh3,
I2, imidazole) to furnish compound 21. A Pd-catalyzed Negishi
sp3-sp2 coupling reaction of the zinc derivative of alkyl iodide
21 and vinyl iodide 2252 followed by TBAF-mediated desily-
lation provided the desired E-allylic alcohol 23.53-55 When
compound 23 was subjected to the established cycloisomeriza-
tion conditions, surprisingly, the same aldehyde 15 was obtained
in 54% yield.
To further test this mechanistic proposal and provide an
alternative strategy for our synthesis, we decided to prepare the
demethylated substrate 28 and subject this compound to the Pd-
catalyzed cycloisomerization reaction (Scheme 5). Toward this
end, Moffatt-Swern oxidation of compound 11 followed by a
Wittig reaction with PPh3CHCO2Et furnished E-olefin 27 as
the only product.39 Reduction of the ester and desilylation
produced alcohol 28. The Pd-catalyzed cycloisomerization of
enyne 28 proceeded smoothly under the previously established
conditions to afford aldehyde 29 in 54% yield as a single
diastereomer. As expected, the same stereoselectivity was
achieved as in the case of E-olefin 23.57 This result provides
further evidence to support our rationale that the interaction
between the fused five-membered ring and the vinyl substituent
dominates the stereo-determining step. It is also noteworthy that,
in this transformation, no 1,3-diene 30 was detected (Scheme
5). Previous studies show that Pd-catalyzed enyne cycloisomer-
izations of disubstituted olefins often generate mixtures of 1,4-
and 1,3-dienes.58 Further, the presence of an allylic hydroxyl
substituent tends to favor the 1,3-diene (i.e., 30).59 Presumably,
the overwhelming bias toward the formation of a nonconjugated
1,4-diene in this reaction is derived from the conformational
restriction of the bicyclic system and the strain associated with
placing a double bond exocyclic to a six-membered ring.58-60
We observed a similar effect in our application of this
cycloisomerization in our synthesis of saponaceolide.60
The outcome observed for both 14 and 23 in the Pd-catalyzed
cycloisomerization can be rationalized by the proposed mech-
anism (Figure 4).56 For the substrate 24, after the initial
hydropalladation, two intermediates 25 and 26, which place the
bulky Pd catalyst approximately perpendicular to the five-
membered ring to minimize steric interactions with the isopropyl
Ru-Catalyzed Cycloisomerization. Because the Pd-catalyzed
cycloisomerization only generated the cyclized product with
a 1,4-syn relationship, we considered employing CpRu-
(CH3CN)3PF6 as the catalyst.61,62 This choice was based on the
(49) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766-768.
(50) Sato, T.; Nagata, T.; Maeda, K.; Ohtsuka, S. Tetrahedron Lett. 1994, 35,
5027-5030.
(51) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981, 103,
7690-7692.
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6584.
(53) Gagneur, S.; Montchamp, J. L.; Negishi, E. Organometallics 2000, 19,
(57) The relative stereochemistry was assigned by comparison of the NMR
spectra of compound 29 with those of compound 15.
(58) Trost, B. M.; Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651-654.
(59) Trost, B. M.; Chung, J. Y. L. J. Am. Chem. Soc. 1985, 107, 4586-4588.
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38.
2417-2419.
(54) Negishi, E.-I.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102,
3298-3299.
(55) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406-
5409.
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4278.
2096.
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Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations
A R T I C L E S
Figure 4. Proposed rationale for the palladium-catalyzed cycloisomerization of compound 24.
Scheme 5. Pd-Catalyzed Cycloisomerization of Compound 28a
Scheme 7. Synthesis of Epoxide 40a
a Conditions: (a) CpRu(CH3CN)3PF6 (35 mol %), 29%; (b) PhS(O)CH2CN,
piperidine, 44%, dr > 20:1; (c) 10% Pd/C, H2 (1 atm), 87%; (d) VO(acac)2,
TBHP, 52%.
a Conditions: (a) (COCl)2, DMSO, NEt3, 88%; (b) Ph3PCHCO2Et, 98%;
(c) DIBAL-H, -78 °C to room temperature, 96%; (d) TBAF, 92%; (e)
Pd2(dba)3CHCl3, o-CF3BzOH, 70 °C, 54%.
Encouraged by this result, compounds 14 and 23 as well as
their silyl ethers were subjected to the Ru-catalyzed reaction.
Unlike the disubstituted model 31, the silyl-protected deriva-
tives of 14 and 23 did not give any desired product.64 With
some optimization, we found that exposure of compound 23 to
CpRu(CH3CN)3PF6 (20 mol %) in 2-butanone generated a
cyclization product in 15% yield. Gratifyingly, comparison of
NMR data of this product with those of compound 15 indi-
cates that only the desired diastereomer 33 was obtained
(Scheme 7). This result agreed with our observations in the
reactions of disubstituted substrates. The excellent diastereo-
selectivity was certainly exciting. However, improvement on
the conversion was desirable to render the reaction synthetically
practical.65 A yield of 29% was achieved by increasing the
catalyst loading to 35 mol %. Further increase of the catalyst
was detrimental due to significant decomposition of the starting
material. On the other hand, the best yield (41%) was obtained
upon addition of 100 mol % of DMF with 20 mol % of catalyst
(vide infra).
Scheme 6. Ru-Catalyzed Cycloisomerization of Compound 31a
a Conditions: (a) TBSCl, ImH, 99%; (b) CpRu(CH3CN)3PF6 (10 mol
%), 53%; (c) TFA, H2O, 0 °C to room temperature, 83%.
notion that Pd- and Ru-catalyzed cycloisomerizations undergo
different reaction mechanisms.32 Unfortunately, precedent in-
dicated that this cycloisomerization is sensitive to olefin
substitution, and that 1,7-enynes with trisubstituted olefins are
not particularly good substrates. Consequently, we first carried
out a model study with compound 31 to establish the diaste-
reoselectivity of this process and as proof of concept. Previous
efforts in our group suggested the use of an allylic silyl ether
as the substrate.2 Indeed, no reaction occurred with compound
28 under standard conditions with CpRu(CH3CN)3PF6 (10 mol
%), while the reaction of silyl ether 31 cleanly generated an
enol ether,63 which was hydrolyzed (TFA, H2O) to deliver
aldehyde 32 as a single diastereomer (Scheme 6). To our delight,
comparison of the spectral data of compound 29 with those of
32 clearly indicated that the opposite diastereoselectivity was
achieved with Ru catalysis. This result provided support to our
hypothesis that different reaction mechanisms might induce
complementary diastereoselectivity in transition metal-catalyzed
cycloisomerization reactions.
(63) The enol ether was obtained as a single E-isomer based on the NMR
analysis.
(64) A rapid decomposition was observed with TBS-protected compounds in
the presence of CpRu(CH3CN)3PF6 in acetone, while a clean desilylation
occurred in DMF after 4 h. On the other hand, TBDPS derivatives are
very stable and were quantitatively recovered in both solvents. Protection
of the free hydroxyl group as an acetate led to no reaction.
(65) We attempted to use CpRu(COD)Cl, which is an effective catalyst in the
intermolecular Alder-ene reaction. There was no reaction with this catalyst
alone, and a complex mixture was obtained with the addition of AgOTf as
the cocatalyst. Since the free allylic alcohol was perceived as a potential
problem due to its possible coordination with Ru, some additives were
added to tentatively mask the hydroxyl group. However, no reaction
occurred when the substrate was premixed with AlMe3 before the addition
of the catalyst. On the other hand, TMS-protected starting material was
isolated if BSA was added.
(62) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 714-715.
9
J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005 10263

A R T I C L E S
Trost et al.
Figure 5. Mechanistic rationale for the Ru-catalyzed cycloisomerization of compounds 14 and 23.
Scheme 8. Mechanistic Rationale for the Hydroxylative
Knoevenagel Reaction to Form 38
Although there was no difference in reactivity or diastereo-
selectivity in the Pd-catalyzed cycloisomerization of Z- and
E-isomers 14 and 23, this was the not case in the Ru-catalyzed
reaction. In fact, only a small amount of cyclization product
(5%) was obtained when compound 14 was subjected to the
optimized cycloisomerization conditions (20 mol % of cata-
lyst).66 More surprisingly, examination of the NMR spectra
revealed that a 1:1 mixture of both diastereomers, compounds
33 and 15, was obtained.
To explain our observations in the Ru-catalyzed cycloisomer-
ization of compounds 14 and 23, especially the difference in
diastereoselectivity, the following mechanistic rationale was
proposed (Figure 5). Presumably, after the initial chelation of
the coordinatively unsaturated Ru catalyst to the enyne, the rate-
limiting formation of a ruthenacyclopentene intermediate oc-
curs.3,61 Between the two conformers 34 and 35, the syn-
coplanar orientation of the alkene and alkyne in the former
compared to an orthogonal orientation in the latter should favor
formation of ruthenacycle 36 over 37. In the case of Z-substrate
14, the intermediates derived from the corresponding to the
Z-geometrical isomer of 34 and 35 lead to bad steric interac-
tions in both 36 and 37, leading to both being disfavored. Thus,
the reaction is poorer and both products are observed. With the
E-substrate 23, the upper pathway via 36 is now favored since
it is devoid of most bad inter-reactions.
compound 18 (vide supra), no reaction occurred under osmium-
catalyzed dihydroxylation conditions. We anticipated that, by
changing the stereochemistry at C6, the chemoselectivity of the
hydroxyl-directed epoxidation would be different since the
tetrasubstituted olefin is no longer accessible from the bottom
face. Indeed, treatment of compound 39 with VO(acac)2/TBHP
furnished the desired epoxide 40 as the only product. However,
our attempts to open the epoxide with a cyanide source (KCN;
TMSCN)68 were thwarted by the poor stability of the substrate.
In appraisal of the difficulty of this route, we decided to pursue
a more feasible alternative.
With these results, we demonstrate for the first time a
mechanism-based stereochemical divergence in Pd- and Ru-
catalyzed cycloisomerizations. By varying substrate geometry
and, more importantly, catalyst choice, we can enable access
to all four diastereomers with excellent stereocontrol. The
complementarity of Pd and Ru catalysts revealed by our study
further broadens the scope of transition metal-catalyzed cyclo-
isomerization reactions and provides valuable insight into the
mechanistic aspects of these interesting transformations.
With aldehyde 33 available, it was subjected to the hydroxy-
lative Knoevenagel reaction to furnish nitrile 38 with excellent
diastereoselectivity (dr > 20:1, Scheme 7).67 On the basis of
previous results, the stereochemistry of the hydroxyl group was
assigned as R and would have to be inverted at a later stage.
After the selective hydrogenation of the C13-C14 double bond
to produce diene 39, we were again in a position to address the
homologation of the exocyclic olefin. As observed with
Before discussing the revised approach, it is necessary to
examine the unusual diastereoselectivity in the formation of
compound 38. The accepted mechanism of the transformation
from 42 to 43 involved the initial Knoevenagel reaction followed
by double bond migration, sulfoxide-sulfenate 2,3-sigmatropic
rearrangement, and desulfurization.69 We believe that, in this
case, the double bond migration generates an olefin that is
oriented perpendicular to the plane of the bicyclic system to
avoid the steric interaction with the exocyclic olefin (Scheme
8). By analogy to previous studies in this group, a quickly
equilibrating mixture of roughly equal amounts of two diaster-
eomers 42 and 43 is expected.70 Since the nitrile group has to
be situated to lead to an E double bond, each diastereomer can
only rearrange as depicted in Scheme 8.71 Intermediate 42
rearranges much faster to 44 from the front than from the back
due to the steric interaction with the exocyclic olefin. Since
(68) Chini, M.; Crotti, P.; Favero, L.; Macchia, F. Tetrahedron Lett. 1991, 36,
4775-4778.
(66) The rest of the mass is recovered starting material along with some of the
corresponding allylic aldehyde. Rigorous exclusion of oxygen from the
solvent minimized the formation of the oxidation byproduct. This is also
true for the reaction of compound 23.
(67) Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Wakabayashi,
S. J. Am. Chem. Soc. 1984, 106, 7890-7893.
(69) Trost, B. M.; Flemming, I.; Paquette, L. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Elsevier: Oxford, 1991; Vol. VI,
pp 899-904.
(70) Trost, B. M.; Mallert, S. Tetrahedron Lett. 1993, 34, 8025-8028.
(71) Hoffmann, R. W. Angew. Chem., Int. Ed. 1979, 18, 563-572.
9
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Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations
A R T I C L E S
Scheme 9. Preparation of Substrates 47 and 48a-c and Their
Table 2. Ru-Catalyzed Cycloisomerization of Compounds 48a-ca
Cycloisomerization Reactionsa
entry
substrate
additive
yield (49
+
50) (%)b
ratio (49/50)c
1
2
3
4
5
6
7
48a
48a
48a
48a
48a
48b
48c
none
4Å mol. sieves
23 (30% 51a)
1.8:1
1:8.2
1.2:1
1.2:1
1.2:1
1.5:1
6.7:1
14
54
29
62
60
55
water (100 mol %)
DMF (50 mol %)
DMF (100 mol %)
DMF (100 mol %)
DMF (100 mol %)
a All reactions were performed with 20 mol % of CpRu(CH3CN)3PF6 in
2-butanone (0.1 M) at room temperature for 2 h. b Yields of 51a-c were
not determined except entry 1. c Ratio was determined upon isolation. Both
geometric isomers were obtained as single diastereomers.
47 was subjected to the standard Ru-catalyzed cycloisomeriza-
tion conditions, no reaction occurred, presumably due to the
conformation rigidity associated with amides and the coordina-
tion of the amide moiety to the ruthenium catalyst.72 Reaction
of ester 48a produced three compounds along with some
recovered starting material. We identified two separable cy-
clization products 49a and 50a in a ratio of 1.8:1 as well as a
hydroxyl group transposition product 51a (Scheme 9). Satis-
factorily, both 49a and 50a constitute only the desired diaste-
reomer. It is worth noting that this is the first reported double
bond isomerization in enyne cycloisomerization reactions to
form six-membered rings.73
While we were certainly delighted to observe the excellent
diastereoselectivity and the isomerization of the exocyclic double
bond, the poor yield and the low geometric selectivity represent
two major hurdles to overcome. The issue of conversion was
addressed first using compound 48a as a model. Previous
experiences in this laboratory with CpRu(CH3CN)3PF6 indicate
that the reaction can be sensitive to the water content of the
solvent. However, no significant change was observed when
freshly distilled 2-butanone was used. Interestingly, the conver-
sion deteriorated with the addition of 4 Å molecular sieves, and
the ratio of compound 48a to 49a was completely reversed
(entry 2, Table 2). On the other hand, adding water (100 mol
%) to the reaction actually doubled the yield, although the
selectivity of the two geometric isomers dropped slightly (entry
3, Table 2). We ascribe the beneficial effect of water to its
function as a weak ligand. Following this lead, we assayed a
variety of ligands74 and improved the yield to 62% with DMF
as an additive (100 mol %), although the product ratio is still
poor (entry 5, Table 2).75 It is noteworthy that the conversion-
promoting effect of DMF was also observed in the reaction of
compound 23 as the yield increased from 29% with 35 mol %
of catalyst to 41% with 20 mol % of catalyst with 100 mol %
of DMF as the additive.
a Conditions: (a) t-BuLi, ZnCl2, -78 °C to room temperature, then
Pd(PPh3)4 (5 mol %), 22; (b) K2CO3, MeOH, 68% from 21; (c) n-BuLi,
ClCO2NEt2 (47); ClCO2CH3 (48a); ClCO2i-Pr (48b); ClCO2, t-Bu (48c),
99%; (d) TBAF, 52-55%; (e) CpRu(CH3CN)3PF6 (20 mol %).
only the final S-O bond cleavage by piperidine is irreversible,
it does not matter which intermediate, 44 or 45, is favored in
the equilibrium. Only the relative rate of the sigmatropic
rearrangement controls the diastereoselectivity, which represents
a Curtin-Hammett situation (Scheme 8). It is worth noting that
in similar instances, only 50-75% de was obtained through the
â-chiral carbon induction.70
Revised Strategy. To avoid the difficulty in the homologation
of the exocyclic double bond, we decided to introduce the
requisite carbon as an alkynyl substituent before the cyclization.
However, this strategy has several potential drawbacks. First,
after the initial ruthenacyclopentene formation, significant steric
interaction between the extra carbon at the terminus of the
alkyne and the isopropyl group might slow the already sluggish
reaction. Furthermore, the mechanism of both the Pd- and
Ru-catalyzed cycloisomerizations indicates that the E-geometry
of the exocyclic olefin should form exclusively, which will
require a subsequent isomerization in some way to allow the
intramolecular aldol reaction to form a seven-membered ring.
On the other hand, the introduction of an alkynyl substituent
might benefit the cycloisomerization. The presence of a terminal
alkyne in the substrate slows the Ru-catalyzed cyclization since
the Ru catalyst gets tied up in formation of a vinylidene
complex. While this is reversible, the rates of these steps are
not so fast compared to the cycloisomerization. Preventing such
a pathway should, therefore, speed up the cycloisomerization
as well as shut down decomposition pathways via the reactive
vinylidene intermediates. While the cycloisomerization might
suffer from the strain between the substituent at the alkyne and
the isopropyl group, the same strain might promote the
isomerization of the resulting exocyclic olefin to give the desired
Z-product. The fact that the initial C-bound Ru enolate can slip
to form an O-bound enolate may provide a kinetic pathway for
equilibration (see Scheme 9).3,61
As E-isomer 50 is not a viable candidate for the intramo-
lecular aldol cyclization to form a seven-membered ring, we
attempted to further increase the ratio of compound 49.76 Using
the proposed rationale as a guide, we reasoned that by increasing
(72) We also synthesized the corresponding unsaturated nitrile and aldehyde.
The reaction of the nitrile derivative gave recovered starting material
because of its strong coordination with Ru and subsequent deactivation of
the catalyst. The aldehyde derivative generated a cyclization product which
is too labile to be isolated.
(73) For complete double bond isomerization in seven-membered ring formation,
see ref 61.
(74) Other weak phosphorus-containing ligands, such as triphenylphosphine
oxide and phosphonate, suppressed the conversion to less than 3%.
(75) No reaction was observed with DMF as solvent.
(76) Attempts to isomerize the double bond by treatment with diphenyl disulfide
in the presence of light led to decomposition of the starting material.
Four derivatives of compound 23 were prepared in a
straightforward fashion by monodesilylation of the Negishi
coupling product followed by acylation and deprotection to
remove the TBDPS group (47,48a-c, Scheme 9). When amide
9
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A R T I C L E S
Trost et al.
a
Scheme 10. Synthesis of (+)-Allocyathin B2
this asymmetric route also constitutes a formal synthesis of this
natural product. An alternative approach for the asymmetric
synthesis of allocyathin B2 also appeared recently.79
Summary. We demonstrate for the first time a mechanism-
based stereochemical divergence in Pd- and Ru-catalyzed
cycloisomerizations. Building upon these enyne cycloisomer-
izations, we have achieved an efficient enantioselective synthesis
of a cyathin diterpene, (+)-allocyathin B2 (1). Additional
highlights of this route include a Pd-catalyzed enolate AAA
reaction to build the first quaternary carbon and a unique
hydroxylative Knoevenagel reaction to stereoselectively intro-
duce the oxygen-bearing center. The unusual olefin isomeriza-
tion in the Ru-catalyzed cycloisomerization was also investigated
and exploited. The synthesis consists of a longest linear sequence
of 17 steps and a total of 19 steps from 2-methylcyclopentanone.
a Conditions: (a) PhS(O)CH2CN, piperidine, 75%; (b) 10% Pd/C, H2,
83%; (c) DIBAL-H; (d) KOH, MeOH, 60 °C, 51% from 55.
Scheme 11. Mechanistic Rationale for the Hydroxylative
Knoevenagel Reaction to Form 54
Experimental Procedures
[(5S,7aS)-3-Isopropyl-5,7a-dimethyl-4-methylene-2,4,5,6,7,7a-
hexahydro-1H-inden-5-yl]acetaldehyde (15). To a solution of com-
pound 14 (55.0 mg, 0.224 mmol) in toluene (2.2 mL) were added
Pd2(dba)3‚CHCl3 (3.5 mg, 0.00335 mmol) and o-trifluoromethylbenzoic
acid (6.3 mg, 0.0335 mmol) at room temperature. The mixture was
stirred at 70 °C for 15 h and cooled to room temperature. The mixture
was directly purified by column chromatography (5% ether in petroleum
the size of the ester we might be able to accentuate the strain
and thus promote the double bond isomerization. Indeed, we
observed a drastic improvement in the ratio of compound 49
by changing methyl ester (48a) to tert-butyl ester (48c) as the
most relief was achieved in the latter case (Table 2). In the event,
a 55% combined yield of the 6.7:1 ratio of products 49c and
50c was obtained, and the pure diastereomer 49c was isolated
in 48% yield.
ether) to afford compound 15 as a clear oil (33.1 mg, 60%): [R]D
)
+206.3° (c 3.1, 24.4 °C, CH2Cl2); IR (neat) 2959, 1723, 1459, 1370,
900 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.60 (dd, J ) 4.4, 4.0 Hz, 1
H), 5.02 (d, J ) 1.6 Hz, 1 H), 4.79 (d, J ) 1.6 Hz, 1 H), 2.81 (sept,
J ) 7.2 Hz, 1 H), 2.56 (dd, J ) 14.8, 1.2 Hz, 1 H), 2.04 (dd, J ) 14.4,
4.8 Hz, 1 H), 1.79 (m, 1 H), 1.64-1.57 (m, 6 H), 1.49 (m, 1 H), 1.22
(s, 3 H), 1.00 (dd, J ) 6.8, 1.6 Hz, 3 H), 0.93 (m, 6 H); 13C NMR
(CDCl3, 125 MHz) δ 204.2, 148.4, 142.3, 139.1, 110.2, 50.0, 48.7,
39.6, 39.5, 37.8, 36.8, 28.2, 26.4, 25.1, 23.1, 21.6, 21.4. HRMS calcd
for C17H26O [M+]: 246.1984. Found: 246.1990.
In the next hydroxylative Knoevenagel reaction, we obtained
lactone 54 in good yield as one diastereomer instead of the
expected alcohol (Scheme 10).67 Although tert-butyl esters have
been used to block the possible lactonization, the rigid confor-
mation of our substrates greatly accelerated the cyclization
process. The C12-C13 double bond was then selectively
hydrogenated to generate compound 55 in satisfactory yield.
The absolute configuration of the oxygen-bearing stereocenter
was later shown to be S by comparison to the final product.
This stereochemical outcome is the opposite of what was
expected based on the results of compound 38. The rationale
for this unusual observation is outlined in Scheme 11. We
propose that the E-vinyl ester forces the migrated olefin to be
parallel to the plane of the bicycle instead of perpendicular, as
in the previous case shown in Scheme 8. The preferred route
of sigmatropic rearrangement would be from the bottom
(intermediate 56) instead of from the top (intermediate 57),
where a quaternary methyl group interferes (Scheme 11). The
altered rearrangement trajectory leads to a reversal from the
stereoselectivity predicted by previous experiments.
(E)-(S)-4-Hydroxy-4-[(5S,7aR)-3-isopropyl-5,7a-dimethyl-4-
methylene-2,4,5,6,7,7a-hexahydro-1H-inden-5-yl]but-2-ene nitrile
(17). To a solution of compound 15 (30.0 mg, 0.122 mmol) in benzene
(1 mL) was added phenylsulfinyl acetonitrile (24.1 mg, 0.146 mmol)
followed by piperidine (12.5 mg, 0.146 mmol) at room temperature.
The mixture was stirred at room temperature for 15 h and was directly
purified by column chromatography (30% ether in petroleum ether) to
afford compound 17 as white crystals (23.9 mg, 69%): mp 181-182
°C; [R]D ) +102.3° (c 0.72, 23.5 °C, CH2Cl2); IR (neat) 3455, 2232,
1
1630, 1458 cm-1; H NMR (CDCl3, 500 MHz) δ 6.70 (dd, J ) 16.0,
3.0 Hz, 1 H), 5.67 (dd, J ) 16.0, 2.5 Hz, 1 H), 5.02 (d, J ) 1.5 Hz, 1
H), 4.85 (d, J ) 1.5 Hz, 1 H), 4.46 (m, 1 H), 2.82 (sept, J ) 7.0 Hz,
1H), 2.33 (m, 2 H), 1.85 (m, 1 H), 1.78 (m, 1 H), 1.65 (m, 1 H), 1.56-
1.53 (m, 3 H), 1.01 (d, J ) 7.0 Hz, 3 H), 0.93 (m, 9 H); 13C NMR
(CDCl3, 125 MHz) δ 155.5, 147.0, 142.5, 139.5, 118.0, 112.4, 99.4,
71.7, 49.0, 45.5, 39.9, 36.7, 33.6, 28.4, 26.7, 23.3, 21.8, 21.6, 18.7.
HRMS calcd for C19H27NO [M+]: 285.2093. Found: 285.2083.
(E)-(R)-5-(2-Ethynyl-3-isopropyl-1-methylcyclopent-2-enyl)-3-
methylpent-2-en-1-ol (23). To a solution of the compound 21 (110
mg, 0.293 mmol) and anhydrous ZnCl2 (39.8 mg, 0.293 mmol) in THF
(3 mL) was added t-BuLi (1.4 M in pentane, 0.627 mL, 0.818 mmol)
at -78 °C in 10 min. The mixture was stirred for 5 min at this
temperature and warmed to room temperature for 1 h. The resulting
yellow solution was transferred through cannular to a mixture of vinyl
iodide 22 (100.4 mg, 0.322 mmol) and Pd(PPh3)4 (16.9 mg, 0.146
mmol) at room temperature. The reaction mixture was stirred overnight
before the addition of ether (30 mL) and water (15 mL). After separation
of the layers, the aqueous layer was extracted with ether (2 × 10 mL).
The combined organic layers were washed with brine (10 mL), dried
With the stage set for the endgame, we attended to the closure
of the final seven-membered ring through an intramolecular
aldol condensation of lactol-aldehyde 4, as summarized in
Scheme 10.77,78 The spectroscopic properties of the synthetic
sample were in full agreement with those reported in the
literature.27-29 Since the preparation of erinacine A (3) through
the glycosidation of 1 has been described by Snider et al.,28,29
(77) Various conditions were attempted, including CSA/benzene reflux, L-proline,
pyrrolidine/acetic acid, as well as alumina.
(78) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-1626.
(79) Takano, M.; Umino, A.; Nakada, M. Org. Lett. 2004, 6, 4897-4990.
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10266 J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005

Exploiting the Pd- and Ru-Catalyzed Cycloisomerizations
A R T I C L E S
(MgSO4), filtered, and concentrated under reduced pressure. The residue
was immediately purified with column chromatography (3% ether in
petroleum ether) to furnish the coupled product as a light yellow liquid,
which was contaminated with traces of unreacted vinyl iodide: 1H NMR
(CDCl3, 300 MHz) δ 7.62 (m, 4 H), 7.36 (m, 6 H), 5.27 (t, J ) 4.2
Hz, 1 H), 4.15 (d, J ) 6.0 Hz, 2 H), 2.92 (sept, J ) 7.0 Hz, 1H), 2.27
(m, 2 H), 1.90 (m, 1 H), 1.77 (m, 1 H), 1.44 (m, 1 H), 1.38 (s, 3 H),
1.21-1.06 (m, 3 H), 1.00 (m, 3 H), 0.99 (s, 9 H), 0.98 (m, 6 H), 0.15
(s, 6 H).
temperature for 2 h and concentrated under reduced pressure. The crude
material was purified by column chromatography (4% ether in
petroleum ether) to give compounds 49c (less polar) and 50c (more
polar). Compound 49c (88.6 mg, 48%, light yellow oil): [R]D
)
+266.0° (c 1.80, 23.7 °C, dichloromethane); IR (neat) 2959, 1750, 1708,
1
1456, 1368, 1143 cm-1; H NMR (CDCl3, 400 MHz) δ 9.83 (t, J )
3.6 Hz, 1 H), 5.51 (s, 1 H), 3.06 (dd, J ) 18.0, 4.0 Hz, 1 H), 2.91 (dd,
J ) 18.0, 4.0 Hz, 1 H), 2.86 (sept, J ) 6.8 Hz, 1H), 2.34 (m, 2 H),
1.71 (m, 2 H), 1.62 (m, 2 H), 1.51 (m, 1 H), 1.48 (s, 9 H), 1.42 (m, 1
H), 1.32 (s, 3 H), 1.01 (m, J ) 6.4 Hz, 3 H), 0.99 (s, 3 H), 0.98 (d, J
) 6.4 Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ 203.3, 166.4, 154.2,
145.8, 140.9, 118.7, 80.6, 51.1, 48.2, 40.3, 38.9. 36.2, 35.3, 28.5, 28.1,
26.5, 25.5, 24.5, 21.6, 21.4. HRMS calcd for C22H34O3 [M+]: 346.2508.
Found: 346.2508.
To a solution of the above product in THF (2 mL) was added TBAF
(1 M in THF, 0.585 mL, 0.585 mmol) at room temperature. The mixture
was stirred for 1 h and treated with brine (5 mL) and ether (15 mL).
After separation of the layers, the aqueous phase was extracted with
ether (20 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified with column chromatography (25% ether in petroleum ether)
to provide compound 23 (51.8 mg, 72%) as a light yellow liquid: [R]D
) + 2.26 (c 0.53, 23.3 °C, dichloromethane); IR (neat) 2960, 2137,
1458, 1249 cm-1; 1H NMR (CDCl3, 300 MHz) δ 5.40 (t, J ) 4.2 Hz,
1 H), 4.11 (d, J ) 6.9 Hz, 2 H), 3.08 (s, 1H), 2.94 (sept, J ) 6.6 Hz,
1H), 2.39 (t, J ) 7.8 Hz, 2 H), 1.94 (m, 2 H), 1.82 (m, 1 H), 1.67 (s,
3 H), 1.62-1.41 (m, 4 H), 1.07 (s, 3 H), 1.01 (d, J ) 1.5 Hz, 3 H),
0.98 (d, J ) 1.5 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 157.9, 140.7,
123.6, 122.9, 81.8, 79.6, 59.4, 49.9, 38.3, 34.8, 34.7, 29.2, 28.8, 26.0,
21.0, 20.8, 16.4. HRMS calcd for C17H26O [M+]: 246.1984. Found:
246.1975.
(E)-(3S,3aR,5aR)-3-(1-Isopropyl-3a,5a-dimethyl-8-oxo-
2,3,3a,4,5,5a,6,8-octahydro-7-oxacyclopenta[a]naphthalen-6-yl)-
acrylonitrile (54). To a solution of compound 49c (20.7 mg, 0.060
mmol) and phenylsulfinyl acetonitrile (13.8 mg, 0.084 mmol) in benzene
(0.6 mL) was added piperidine (7.1 mg, 0.084 mmol) at room
temperature. The mixture was stirred for 36 h and directly purified by
column chromatography (petroleum ether/ether, 2:1) to give compound
54 as a white solid (13.9 mg, 75%): mp 130-131 °C, [R]D ) +667.9°
(c 0.57, 24.6 °C, dichloromethane); IR (neat) 2957, 2227, 1724, 1678,
1
1451, 1247 cm-1; H NMR (CDCl3, 500 MHz) δ 6.71 (dd, J ) 16.0,
3.5 Hz, 1 H), 5.95 (dd, J ) 16.0, 2.0 Hz, 1 H), 5.77 (s, 1 H), 4.75 (dd,
J ) 4.0, 2.0 Hz, 1 H), 2.89 (sept, J ) 6.5 Hz, 1 H), 2.48 (m, 2 H),
1.84 (m, 2 H), 1.76 (m, 2 H), 1.65 (m, 2 H), 1.57 (s, 3 H), 1.05 (d, J
) 7.0 Hz, 3 H), 0.99 (s, 3 H), 0.98 (s, 3 H); 13C NMR (CDCl3, 100
MHz) δ 163.8, 160.0, 153.1, 146.3, 133.8, 130.3, 116.7, 113.7, 103.1,
82.8, 48.4, 40.1, 39.0, 35.4, 32.3, 29.3, 27.1, 23.4, 21.6, 21.4, 17.8.
HRMS calcd for C20H25NO2 [M+]: 311.1885. Found: 311.1865.
(5S,7aR)-(3-Isopropyl-5,7a-dimethyl-4-methylene-2,4,5,6,7,7a-
hexahydro-1H-inden-5-yl)acetaldehyde (33). To a solution of com-
pound 23 (165 mg, 0.67 mmol) and DMF (49.0 mg, 0.67 mmol) in
2-butanone (7 mL) was added CpRu(CH3CN)3PF6 (58 mg, 0.134 mmol)
in one portion at room temperature. The mixture was stirred for 2 h
and concentrated under reduced pressure. The crude material was
purified by column chromatography (8% ether in petroleum ether) to
provide compound 33 (67.6 mg, 41%) as a clear liquid: [R]D ) +120.0°
(+)-Allocyathin B2 (1). To a solution of compound 55 (10.0 mg,
0.032 mmol) in CH2Cl2 (0.5 mL) was added DIBAL-H (1 M in hexanes,
0.128 mL, 0.128 mmol) at -78 °C. The mixture was stirred at this
temperature for 2 h and quenched with the addition of 1 M NaHSO4
(0.4 mL). The suspension was warmed to room temperature for 15
min and extracted with ether (2 × 5 mL). The organic layer was washed
with brine (2 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude aldehyde 4 was used directly for the next
step. Aldehyde 4: 1H NMR (CDCl3, 500 MHz, mixture of two
diastereomers) major: δ 9.88 (s, 1 H), 5.88 (m, 1 H), 5.22 (m, 1 H),
3.85 (d, J ) 6.5 Hz, 1 H), 3.74 (m, 1 H), 3.66 (m, 1 H), 2.86 (m, 1 H),
2.57-2.39 (m, 4 H), 2.33 (m, 2 H), 1.98 (m, 1 H), 1.72 (m, 1 H), 1.67
(m, 2 H), 1.52 (m, 3 H), 1.35 (m, 2 H), 1.03 (m, 3 H), 0.99-0.96 (m,
6 H), 0.94 (s, 3 H); minor: δ 9.88 (s, 1 H), 5.37 (m, 1 H), 5.09 (m, 1
H), 3.87 (d, J ) 6.5 Hz, 1 H), 3.75 (m, 1 H), 3.58 (m, 1 H), 2.86 (m,
1 H), 2.33 (m, 2 H), 1.98 (m, 1 H), 1.72 (m, 1 H), 1.67 (m, 2 H), 1.52
(m, 3 H), 1.35 (m, 2 H), 1.03 (m, 3 H), 0.99-0.96 (m, 6 H), 0.92 (s,
3 H).
(c 1.2, 26.3 °C, dichloromethane); IR (neat) 2927, 1727, 1451 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 9.88 (m, 1 H), 4.78 (d, J ) 1.0 Hz, 1
H), 4.65 (d, J ) 1.0 Hz, 1 H), 2.77 (sept, J ) 7.0 Hz, 1 H), 2.50 (dd,
J ) 15.5, 3.0 Hz, 1 H), 2.42 (dd, J ) 15.5, 3.0 Hz, 1 H), 2.27 (m, 2
H), 1.80 (m, 2 H), 1.69 (m, 1 H), 1.54 (m, 3 H), 1.42 (m, 1 H), 1.03
(s, 3 H), 0.92 (d, J ) 7.0 Hz, 3 H), 0.88 (d, J ) 7.0 Hz, 3 H), 0.86 (s,
3 H); 13C NMR (CDCl3, 125 MHz) δ 204.2, 149.9, 142.5, 139.3, 108.9,
53.5, 39.9, 39.4, 37.0, 35.8, 29.9, 28.5, 26.7, 25.3, 23.4, 21.8, 21.6.
HRMS calcd for C17H26O [M+]: 246.1984. Found: 246.1990.
(E)-(R)-4-Hydroxy-4-[(5S,7aR)-(3-isopropyl-5,7a-dimethyl-4-
methylene-2,4,5,6,7,7a-hexahydro-1H-inden-5-yl)]but-2-enenitrile (38).
To a solution of compound 33 (66.0 mg, 0.268 mmol) and phenyl-
sulfinyl acetonitrile (53.1 mg, 0.322 mmol) in benzene (2.7 mL) was
added piperidine (27.4 mg, 0.322 mmol) dropwise at room temperature.
The mixture was stirred for 24 h and purified directly by column
chromatography (2:1, petroleum ether/ether) to give compound 38 as
a pale yellow solid (33.6 mg, 44%): [R]D ) +150.6° (c 1.16, 22.7 °C,
To a solution of the crude dialdehyde 4 in MeOH (1.0 mL) was
added 5% KOH in MeOH (1.0 mL). The mixture was stirred at 60 °C
for 1 h. The reaction was quenched with the addition of 10% citric
acid solution (3 mL) and was concentrated under reduced pressure.
The aqueous residue was extracted with ether (2 × 5 mL). The
combined organic layers were washed with brine (2 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (5:1 EtOAc/petroleum
ether) to give (+)-allocyathin B2 (1, 4.9 mg, 51%) as a pale yellow
oil: [R]D ) +482.3° (c 0.18, 23.6 °C, methanol); lit. [R]D ) +144° (c
0.18, methanol);15,79 IR (neat) 3442, 1668, 1571, 2959 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 9.45 (s, 1 H), 6.82 (dd, J ) 8.0, 6.5 Hz, 1 H),
5.94 (d, J ) 8.0 Hz, 1 H), 3.73 (m, 1 H), 3.16 (dd, J ) 18.5, 6.0 Hz,
1 H), 2.83 (sept, J ) 6.5 Hz, 1 H), 2.55 (br, d, J ) 18.5 Hz, 2 H), 2.53
(m, 1 H), 2.42 (dd, J ) 9.5, 2.5 Hz, 1 H), 2.41 (d, J ) 13.5 Hz, 1 H),
1.74 (ddd, J ) 12.5, 7.5, 5.0 Hz, 1 H), 1.69-1.65 (m, 3 H), 1.61 (br,
m, 1 H), 1.34 (dt, J ) 14.0, 3.5 Hz), 1.05 (d, J ) 7.0 Hz, 3 H), 1.00
1
dichloromethane); IR (neat) 3476, 2225, 1678, 1450, 1257 cm-1; H
NMR (CDCl3, 500 MHz) δ 7.09 (dd, J ) 16.0, 4.0 Hz, 1 H), 5.79 (dd,
J ) 16.0, 2.5 Hz, 1 H), 4.98 (s, 1 H), 4.79 (s, 1 H), 4.54 (m, 1 H), 2.83
(sept, J ) 7.0 Hz, 1H), 2.34 (m, 2 H), 1.96 (d, J ) 5.0 Hz, 1 H), 1.74
(m, 2 H), 1.59 (m, 3 H), 1.03 (s, 3 H), 0.99 (d, J ) 7.0 Hz, 3 H), 0.95
(d, J ) 7.0 Hz, 3 H), 0.91 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
154.4, 148.0, 142.6, 139.3, 117.6, 109.1, 100.6, 76.1, 48.6, 48.2, 45.4,
43.1, 39.0, 36.2, 31.3, 28.4, 26.5, 26.3, 25.0, 24.1, 23.1, 21.6, 21.4,
20.4. Anal. Calcd for C19H27NO: C, 79.95; H, 9.53; N, 4.91. Found:
C, 80.12; H, 9.54; N, 4.78.
(E)-[(5S,7aR)-3-Isopropyl-5,7a-dimethyl-5-(2-oxoethyl)-1,2,5,6,7,7a-
hexahydroinden-4-ylidene]acetic acid tert-butyl ester (49c). To a
solution of compound 48c (184.5 mg, 0.533 mmol) in 2-butanone (5.3
mL) and DMF (38.9 mg, 0.533 mmol) was added CpRu(CH3CN)3PF6
(46.3 mg, 0.107 mmol). The yellow solution was stirred at room
9
J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005 10267

A R T I C L E S
Trost et al.
(s, 3 H), 0.97 (d, J ) 7.0 Hz, 3 H), 0.96 (s, 3 H); 13C NMR (CDCl3,
125 MHz) δ 194.2, 155.1, 146.5, 144.4, 151.8, 137.7, 119.3, 74.0, 49.1,
48.2, 38.2, 36.5, 33.9, 29.2, 29.0, 27.0, 26.5, 23.9, 21.5, 21.5. HRMS
calcd for C20H28O2 [M+]: 300.2089. Found: 300.2077.
grateful to Prof. H. Kawagishi for sharing the optical rotation
and NMR spectra of (+)-allocyathin B2.
Supporting Information Available: Full experimental pro-
cedures and characterization data as well as copies of the NMR
spectra (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Institutes of Health
and the National Science Foundation for their generous support
of our program. Mass spectra were provided by the Mass
Spectrometry Facility, University of California, San Francisco,
supported the NIH Division of Research Resources. We are
JA051547M
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10268 J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005