Development of aliphatic alcohols as nucleophiles for palladium-catalyzed DYKAT reactions: Total synthesis of (+)-hippospongic acid A

Article abstract of DOI:10.1021/ja050340q

The ability to use aliphatic alcohols as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation of Baylis-Hillman adducts is explored. High yield and enantioselectivity is obtained for both the kinetic transformation a

Full text of DOI:10.1021/ja050340q

Published on Web 04/26/2005
Development of Aliphatic Alcohols as Nucleophiles for
Palladium-Catalyzed DYKAT Reactions: Total Synthesis of
(+)-Hippospongic Acid A
Barry M. Trost,* Michelle R. Machacek, and Hong C. Tsui
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received January 18, 2005; E-mail: bmtrost@stanford.edu
Abstract: The ability to use aliphatic alcohols as competent nucleophiles in the palladium-catalyzed dynamic
kinetic asymmetric transformation of Baylis-Hillman adducts is explored. High yield and enantioselectivity
is obtained for both the kinetic transformation and dynamic kinetic transformation. The absolute
stereochemistry of the products is used to explore the reactive conformation of 2-substituted π-allyl
complexes with DPPBA-based chiral ligands. The utility of this method is further demonstrated in the context
of a concise total synthesis of the gastrulation inhibitor (+)-hippospongic acid A. The synthesis features
three palladium-catalyzed allylic alkylation reactions to introduce three different bond types: C-S, C-H,
and C-O.
1. Introduction
alkoxide but also delivers the nucleophile in an intramolecular
fashion. Furthermore, excellent selectivity is achieved without
boron cocatalysis when the nucleophilic addition is otherwise
constrained to be intramolecular (ie 4).8
Palladium-catalyzed asymmetric allylic alkylation (AAA) has
become a powerful tool for the construction of stereogenic
centers. As such, it has been used to efficiently solve many
difficult problems in the context of natural product synthesis.1
A unique feature of this method that leads to its versatility is
the ability to form multiple types of bonds in the asymmetry-
inducing step: C-O, C-S, C-N, and C-C bonds have all
been successfully introduced.2 The unifying quality of these
reactions has been the use of “soft” functional groups as
nucleophilic partners. Limited success has been achieved with
“hard” nucleophiles, such as simple ketone enolates or aliphatic
alkoxides, through the corresponding tin,3 silicon,3a boron,4
zinc,5 or ammonium6 derivatives.
More recent developments have indicated that a select group
of nonstabilized nucleophiles are in fact compatible with
palladium AAA reactions. Simple ketone and amide enolates
afford excellent enantioselectivities in the alkylation of allyl
acetate derivatives.7 Furthemore, aliphatic alcohols are effective
nucleophiles when the addition is constrained to be intramolec-
ular.4a,8 For example, high selectivity is achieved with alcohol
1 and vinyl epoxides in the presence of triethyl boron (Scheme
1).9 Presumably, borate 2 forms which not only “softens” the
We were interested in exploring the versatility of aliphatic
alcohols as nucleophiles by extending this novel nucleophilic
class to other AAA processes, with a particular interest in the
dynamic kinetic asymmetric transformation of Baylis-Hillman
adducts. Enantiopure Baylis-Hillman adducts are versatile
synthetic intermediates; as a result, much research has been
devoted to designing catalytic asymmetric versions of this
reaction.10 A conceptually distinct approach was recently
developed in the Trost group wherein achiral Baylis-Hillman
derivatives are transformed to their chiral counterparts through
a palladium-catalyzed dynamic kinetic asymmetric transforma-
tion (DYKAT) (Scheme 2).11 Aryl alcohols were found to be
competent nucleophiles for this process. Access to the derace-
mized parent compounds was achieved through deprotection
of the chiral aryl ether products. Extension of this strategy to
include alkyl alcohols would significantly expand its versatility
and offer direct access to chiral alkyl ether products. Further-
more, the complex nature of this transformation represents a
challenging test for determining the generality of this novel class
of nucleophiles in AAA reactions.
The transformation outlined in Scheme 2 becomes most
impressive when one considers the degree of control exhibited
by the catalyst. Under the influence of a chiral catalyst, one
enantiomer of starting material ionizes via a matched pathway,
(1) Trost, B. M.; Crawley,M. L. Chem. ReV. 2003, 103, 2921. Also see Trost,
B. M. Chem. Pharm. Bull. 2004, 50, 1.
(2) Trost, B. M.; Fleming, I. Eds. ComprehensiVe Organic Synthesis; Pergam-
mon Press: Oxford, England, 1991; Vol. 4, Chapter 3.3.
(3) (a) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2927. (b) Trost,
B. M.; Self, C. R. J. Org. Chem. 1984, 49, 468. (c) Trost, B. M.; Keinan,
E. Tetrahedron Lett. 1980, 21, 2591.
(4) (a) Trost, B. M.; MacEachern, E.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 12702. (b) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R. A. J.
Org. Chem. 1982, 47, 3188.
(10) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem.
Soc. 1999, 121, 10219. (b) Iwama, T.; Tsukiyama, S.; Kinoshita, H.;
Kanematsu, K.; Tsurukami, Y.; Iwamura, T.; Watanabe, S.; Kataoka, T.
Chem. Pharm. Bull. 1999, 47, 956. (c) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533. (d) Hayase, T.; Shibata, T.;
Soai, K.; Wakalsuki, Y. Chem. Commun. 1998, 1271. (e) Marko, I. E.;
Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015.
(5) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369.
(6) Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31, 4747.
(7) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
(8) Trost, B. M.; Machacek, M. R. Angew. Chem., Int. Ed. 2002, 41, 4693.
(9) Trost, B. M.; Tang, W. Org. Lett. 2001, 3, 3409.
(11) Trost, B. M.; Tsui, H. C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534.
9
7014
J. AM. CHEM. SOC. 2005, 127, 7014-7024
10.1021/ja050340q CCC: $30.25 © 2005 American Chemical Society

Nucleophiles for PD-Catalyzed DYKAT Reactions
A R T I C L E S
Scheme 1. AAA with Simple Aliphatic Alcohols
Scheme 2. Deracemization of Baylis-Hillman Adducts
Scheme 3. Syn and Anti π-Allyl Complexes
whereas the other ionizes via a mismatched pathway (Scheme
3). Direct attack onto the two diastereomeric intermediates
results in racemic product. However, if equilibration of the
diastereomers via a π-σ-π mechanism is faster than nucleo-
philic addition, then chiral product can be obtained. Substrates
such as 6 and 9 offer an additional challenge in that both syn
(C and D) and anti (A and B) π-allyl complexes need to be
considered. In general, the syn π-allyl complex is more stable
than the anti due to unfavorable A1,3 interactions in the anti
complex.12 However, 2-substitution on the allyl destabilizes the
syn complex through developing 1,2-steric interactions. De-
pending on the steric size of the substituent at C2, either π-allyl
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 7015

A R T I C L E S
Trost et al.
Scheme 4. Aliphatic Alcohol DYKAT
Table 2. Cyclization Optimization of 16
entry
ligand
solvent
additiveb
temp (
°
C)
% conv.c
% ee
Table 1. Cyclization Optimization of 14a
1
2
3
4
5
L-3
L-3
L-3
L-3
L-1
dioxane
dioxane
CH3CN
toluene
toluene
N(Hex)4Cl
N(Hex)4Cl
N(Hex)4Cl
N(Hex)4Cl
N(Hex)4Cl
25
80
80
80
60
52
100
100
100
100
98
68
67
81
91
a All reactions run in degassed solvent for 17 h. b 30 mol % additive
was added. c Conversions are based on 300 MHz 1H NMR ratios. Isolated
yields consistently ranged between 85% and 95% for 100% conversion.
entry
ligand
solvent
additiveb
temp (
°
C)
% conv.c
% ee
1
2
3
4
5
6
7
L-1
L-1
L-3
L-3
L-3
L-3
L-3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NEt3d N(Bu)4Cl
N(Hex)4Cl
N(Hex)4Cl
N(Hex)4Cl
N(Hex)4Cl
0
0
0
25
50
25
80
56
50
75
55
62
64
68
50
95
83
Bulky counterions are assumed to associate with the nucleophile,
increasing its effective steric bulk and slowing the rate of
attack.15 These changes resulted in a slight increase in selectivity,
although little change was noted in the conversion (entry 2).
100e
100
53
dioxane N(Hex)4Cl
dioxane N(Hex)4Cl
100
At this stage, we noted that reaction conversion was con-
sistently hovering around 50%, indicating that the ligand
environment was suppressing the mismatched ionization. For-
tunately, several DPPBA-based ligands with varying steric
environments have been developed. In particular, stilbene-based
L-3 contains a more flexible backbone than L-1, which should
“open” the pocket and facilitate mismatched ionization.16 In
practice, reactions utilizing L-3 showed improved conversion
and enantioselectivity (Table 1, entry 3). Increasing the reaction
temperature to 25 °C was also beneficial, affording complete
conversion and a small increase in enantioselectivity (entry 4).
Increasing the temperature further, led to reduced selectivity.
This trend with temperature points to the fact that, while heat
can lead to faster equilibration of the allyl complexes and
increased selectivity, it can also lead to faster nucleophilic
addition and decreased selectivity. Striking a balance between
these two competing processes is key. Finally, we looked at
the effect of solvent. Solvents that stabilize the charged
intermediates should slow nucleophilic attack and increase the
selectivity. Accordingly, reactions run in dioxane at 25 °C afford
15 in an excellent 95% ee (entry 6). Interestingly, the conversion
was a modest 53%, independent of the duration of the reaction,
and the starting material, 14, was recovered with 91% ee. These
observations indicate that a highly selective kinetic resolution
has been achieved wherein the mismatched ionization is not
occurring. Increasing the temperature above 25 °C allows the
mismatched ionization to proceed, such that full conversion with
83% ee (a DYKAT process) was obtained (entry 7).
a All reactions run in degassed solvent for 17 h. b 30 mol % additive
was added. c Conversions are based on 300 MHz 1H NMR ratios. Isolated
yields consistently ranged between 85% and 95% for 100% conversion.
d 100 mol % additive was added. e Required 21 h for complete conversion.
intermediate may predominate. The catalyst must effectively
control the relative population of these two isomers to achieve
high product enantioselectivity since matched nucleophilic attack
onto the syn complex leads to absolute configuration that is
opposite from that by matched attack onto the anti complex.13
2. DYKAT with Aliphatic Alcohol Nucleophiles
To design a system compatible with aliphatic alcohol nu-
cleophiles, we need to constrain the nucleophilic attack to be
intramolecular in nature. The tether length between electrophile
and nucleophile is of ultimate importance. Short tethers may
lead to fast trapping of the π-allyl intermediates, which will
decrease the enantioselectivity of the products. Long tethers may
lead to poor trapping of the π-allyl complexes due to unfavorable
entropic and ring strain effects, which can lead to decomposition
and undesirable side products. Our previous work with alkyl
alcohol nucleophiles indicated that both five- and six-membered
rings are efficiently formed, with pyran synthesis affording the
highest % ee. Adopting pyran formation as ideal, our model
substrate to test the DYKAT becomes 12 (Scheme 4).14
2.1. Development of the Method. We initiated our optimiza-
tion with conditions similar to those employed in the cyclization
of achiral substrate 4, but found both low conversion and
enantioselectivity (Table 1, entry 1). Under these conditions,
the rate of π-allyl complex equilibration is slower than the rate
of facile 6-exo nucleophilic attack. It is necessary to increase
the rate of equilibration while at the same time decreasing the
rate of nucleophilic attack. Removal of the triethylamine from
the reaction should decrease the effectiveness of the alcohol
nucleophile. Furthermore, since chloride ion has been shown
to promote equilibration of Pd-allyl complexes, we kept this
additive but switched to the tetrahexylammonium counterion.
Excellent selectivity for a kinetic resolution was also obtained
for 16 when the reaction was run at 25 °C in dioxane (Table 2,
entry 1). However, the optimized DYKAT conditions for 14
did not transfer over to 16 (entry 2). Fortunately, reactions run
in toluene returned high product selectivity. Even more gratify-
ing was the combination of L-1 and toluene since 91% ee was
obtained at full conversion. The optimized conditions for both
the kinetic and dynamic kinetic transformations are outlined in
Scheme 5.
(12) (a) Faller, J. W.; Tully, M. T. J. Am. Chem. Soc. 1972, 94, 2676. (b) Faller,
J. W.; Thomsen, M. E.; Mattina, M. J.. J. Am. Chem. Soc. 1971, 93, 2642.
(13) Matched implies that the reaction pathway is favored by the given
enantiomer of chiral ligand.
(14) Full experimental details for all intermediates and products are reported in
the Supporting Information.
(15) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1998, 120, 70.
(16) L-3 has been successfully used to effect alkylations on bulky or otherwise
sterically encumbered substrates. For an example relating to DYKAT
reactions, see ref 11.
9
7016 J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005

Nucleophiles for PD-Catalyzed DYKAT Reactions
A R T I C L E S
Scheme 5. Optimized Conditions
Scheme 6. Analysis of the Linear Isomer
3. Determination of Absolute Stereochemistry
7). These substrates ionize directly to the anti complex. If the
anti complex is more reactive, this olefin geometry should be
preserved in the linear products. On the other hand, if the syn
complex is more reactive, then a scrambling of the olefin
geometry is expected. In practice, cyano substrate 24 affords a
mixture of linear products 25 and 20. The amount of scrambling
increases as an external chloride source is introduced, indicating
the ability of chloride to promote the anti-to-syn interconversion.
In contrast, substrate 26 affords exclusively linear product 23
independent of the amount of chloride added. This result again
indicates that substrates with C2-ester substitution preferentially
react through the anti π-allyl complex.
These results are curious at first glance since exo nucleophilic
attack onto the syn and anti π-allyl complexes should afford
products with opposite absolute stereochemistries (Scheme 8),
and yet both 22 and 19 were experimentally found to have the
same absolute configuration.11 Experimental work with cyclic
systems was used to shed light on this situation. In a recent
report, we noted that π-allyl complexes substituted at the
2-position with an ester afford the opposite selectivity than that
predicted by the working model.18 Furthermore, the absolute
stereochemistry is opposite to that observed for cyclic π-allyl
complexes bearing a cyano or hydrogen19 at C2 (Scheme 9).
To explain this change, we invoke a change in the cant of
the π-allyl complex due to coordination of the methyl ester to
palladium. Normally, the 2-position of the allyl cants away from
the palladium. Upon coordination of the ester, the allyl then
cants toward the metal (Scheme 10). Stereoelectronic arguments
dictate that the nucleophile approaches antiperiplanar relative
to palladium. Therefore, the preferred trajectory for addition is
via the right rear quadrant of the π-allyl-metal-ligand complex,
As noted in Scheme 3, both syn and anti complexes are
possible reactive intermediates in the DYKAT of 2-substituted
π-allyl substrates. Importantly, the absolute stereochemistry of
the products will differ, depending on the conformation of the
allyl intermediate. Given the high selectivity of the DYKAT
process, we assume the nucleophilic attack occurs predominantly
on one of the two possible conformations. Our efforts to identify
the reactive conformation of 2-substituted π-allyl complexes
participating in the intermolecular DYKAT reaction revealed
several interesting aspects. Unlike in the intramolecular cy-
clization reaction where the nucleophile is constrained to attack
only at the more substituted terminus of the π-allyl complex,
addition to both termini of the allyl is possible in an intermo-
lecular reaction.17 While the catalyst is effective at controlling
the regioselectivity of addition, small amounts of the linear
isomer can be isolated under unoptimized conditions. Analysis
of the linear isomer indicates that with cyano substrate 18, the
double bond geometry is exclusively Z (Scheme 6). This
stereochemistry is expected if the reactive π-allyl complex is
in the syn conformation. In contrast, with ester substrate 21,
the product olefin configuration is exclusively E, as expected
for nucleophilic addition occurring through the anti complex.
The change in allyl conformation is rationalized on the basis
of the different steric size of the two substituents. The linear
cyano group is sterically small, and as such, the unfavorable
A1,3 interactions of an anti π-allyl complex dominate. However,
the ester is sterically large enough that unfavorable 1,2-repulsion
between the ester and propyl group in the syn complex dominate.
Further evidence for a reactivity dichotomy is uncovered
through investigations of achiral substrates 24 and 26 (Scheme
(18) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262.
(19) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815.
(17) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc. 2002, 124, 11616.
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 7017

A R T I C L E S
Trost et al.
Scheme 7. Reactivities of 24 and 26
Scheme 8. Predictions Based on Exo Nucleophilic Addition
Scheme 9. Additions onto Cyclic 2-Substituted Allyls
cant and the syn/anti conformation of the π-allyl changes, the
same stereochemistry is predicted (Scheme 11) as is observed
experimentally.
These stereochemical arguments are also consistent with the
experimental observations of the cyclization DYKAT reaction.
The absolute stereochemistry of the tetrahydropyran products
was determined through derivitization. Ester 15 was saponified
under basic conditions to afford 34, and nitrile 17 was
transformed through a DIBAl-H reduction/20Pinnick oxidation21
sequence to afford 34 in an unoptimized 40% yield (Scheme
12). Comparison of the rotations indicates that both substrates
afford product with the same absolute stereochemistry. Utiliza-
tion of this DYKAT in the synthesis of a (+)-hippospongic acid
A (vide infra) was used to assign the (R) configuration arising
from (R,R)-ligand. These results are completely consistent with
the stereochemical assignment made for 19 and 22 and with
the working model (same analysis as Scheme 11). We can
therefore conclude that, in the cyclization DYKAT, alkylation
of 14 is occurring through the anti π-allyl complex with
coordination of the ester to the palladium center, whereas
alkylation of 16 is occurring through the syn complex with no
cyano coordination to the metal.
which predicts the observed stereochemistry. Interestingly, the
cyano substrate, which is electronically similar to the ester, but
is geometrically constrained from coordinating to the palladium
metal, affords stereochemistry consistent with the typical cant
of the allyl unit.
Combining these observations, we can rationalize for the
acyclic cases why the selectivity does not change between the
methyl ester and cyano-substituted substrates. When both the
(20) Campi, E.; Fitzmaurice, N. J.; Jackson, W. R.; Perlmutter, P.; Smallridge,
A. J. Synthesis 1987, 1032.
(21) (a) Bal, B. S.; Childers, W. E., Jr; Pinnick, H. W. Tetrahedron 1981, 37,
2091. (b) Yung-Son, H.; Wei-Chih, L. Tetrahedron Lett. 1995, 35, 7693.
9
7018 J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005

Nucleophiles for PD-Catalyzed DYKAT Reactions
A R T I C L E S
Scheme 10. Cyclic Substrates: Changing the Cant
Scheme 11. Acyclic Cases: Stereochemical Rationale
Scheme 12. Derivitization
4. Synthesis of (+)-Hippospongic Acid A
derm, mesoderm and germ layer occurs. Inhibition of this
developmental pathway would permit study of the individual
stages; however, very few inhibitors are known. Recently, 35
has also been found to be a modest inhibitor of both DNA
polymerase (IC50 ) 5.9-17.5 µM) and DNA topoisomerase I/II
(IC50 ) 15-20 µM), both crucial enzymes for DNA replica-
tion.23 Furthermore, 35 is effective at inducing apoptosis in the
human gastric cancer cell line NUGC-3 by arresting the cell
cycle at G1/G2.23 Because of these properties, there has been
considerable interest in the terpene-based natural product and
During the course of our methodology studies, we became
interested in the natural product (+)-hippospongic acid A (35)
(Figure 1).22 This compound shows considerable activity for
inhibiting gastrulation in starfish embryos. Gastrulation is a
fundamental process in the development of all multicellular
organisms during which differentiation of the ectoderm, endo-
(22) Ohta, S.; Uno, M.; Tokumasu, M.; Hiraga, Y.; Ikegami, S. Tetrahedron
Lett. 1996, 37, 7765.
(23) Mizushima, Y.; Murakami, C.; Takikawa, H.; Kasai, N.; Xu, X.; Mori, K.;
Oshige, M.; Yamaguchi, T.; Saneyoshi, M.; Shimazaki, N.; Koiwai, O.;
Yoshida, H.; Sugawara, F.; Sakaguchi, K. J. Biochem. 2003, 133, 541.
Figure 1. Structure of (+)-hippospongic acid A.
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 7019

A R T I C L E S
Trost et al.
Scheme 13. Retrosynthetic Analysis
Scheme 14. Selective Ozonolysis
We next planned to couple the geranyl subunit to farnesyl
bromide using nucleophilic displacement. To transform 44 into
a nucleophilic moiety, we envisioned directly transforming the
allyl acetate to an allyl sulfone using palladium catalysis. Alde-
hyde 44 was protected as a dioxolane acetal and used without
purification in the allylic alkylation step. Using phenyl sulfinic
acid and conditions developed for sulfone nucleophiles30 resulted
in incomplete conversion even under extended reaction times
and a 10:1 mix of SN2- and SN2′-like products as well as a 4:1
mix of E:Z isomers 46 and 47 (Table 3). Reasoning that too
much π-σ-π isomerization of the allyl intermediate was
causing the formation of both 47 and 48, we investigated the
effect of various conditions on the reaction. Increasing the
temperature allowed for full conversion but increased the
formation of isomer 48. Using the less hindered tetramethyl-
ammonium bromide as a phase transfer catalyst slightly
increased the E:Z olefin ratio of the products. Ligand electronics
had promising effects on selectivity (entry 5), but ligand sterics
had the largest impact. Bulky ligands are known to decrease
the rate of π-allyl isomerization since formation of the σ
complex is disfavored. Consistent with this idea, moving from
dppp to dppb to dppf systematically improved ratios of 46:47
and completely eliminated the formation of 48 (entries 2-4).
The isomeric mixture was then smoothly deprotonated with
LDA and coupled with farnesyl bromide in the presence of
DMPU to yield monoalkylated product 49 in good yield
(Scheme 15). The presence of DMPU is crucial for this coupling
as lower yield and bisalkylation product was observed in its
absence. Attempts to remove the resulting allyl sulfone under
traditional dissolving metal conditions (Li/NH3 or Na/Hg)
afforded modest yields of desulfonylated product accompanied
by varying amounts of olefin regio- and stereochemical scram-
bling. Literature precedent indicated that allyl sulfones can be
removed with retention of olefin stereochemistry in the presence
of catalytic Pd and a hydride source.31 The mechanism involves
ionization of the allyl sulfone followed by trapping of the
resulting η3-intermediate with a hydride nucleophile. Reaction
temperature was found to be very important since no reaction
is seen at 0 °C and mixtures of olefin regioisomers are obtained
at 65 °C. Running the reaction at 25 °C affords an excellent
yield of desulfonylated product 50 with no observable olefin
scrambling.
its derivatives. Several groups have completed racemic syntheses
of hippospongic acid.24 However, only two syntheses have
addressed the one stereocenter: introducing the chirality through
a late-stage resolution25 and an enzyme-mediated asymmetric
reduction,26 respectively. While these syntheses provided the
absolute stereochemistry of 35, both are lengthy, requiring 23
and 33 steps, respectively.
We envisioned developing the first catalytic asymmetric route
to 35 by utilizing our cyclization DYKAT reaction. A further
advantage of this strategy is the simultaneous formation of both
the pyran ring and the one stereocenter, which should improve
the synthetic efficiency and decrease the overall step count. The
DYKAT cyclization substrate was envisioned to arise through
two Baylis-Hillman27 couplings and one Claisen rearrangement
(Scheme 13). The terpene side chain was disconnected through
an allyl-allyl coupling sequence leading back to commercially
available farnesyl bromide and geranyl acetate.
The synthesis begins with a selective oxidation of the more
electron-rich olefin of geranyl acetate. While dihydroxylation
and epoxidation led to mixtures of mono- and bisoxidation
products, a highly selective oxidation was achieved through
ozonolysis in a methylene chloride/pyridine mixed-solvent
system.28 Nucleophilic agents such as pyridine and pyridine
oxide have been proposed to react with ozone to form
compounds such as 42 and 43 (Scheme 14).29 Ozonolysis using
these less electrophilic agents slows the oxidation rate, allowing
for small electronic differences in the olefins to impact the
chemoselectivity. These conditions reliably afforded clean
monooxidation product 44 in good yield.
(24) (a) Hiraga, Y.; Ago, M.; Tokumasu, M.; Kaku, K.; Ohkata, K. Aust. J.
Chem. 2000, 53, 909. (b) Tokumasu, M.; Ando, H.; Hiraga, Y.; Kojima,
S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1999, 489. (c) Takikawa,
H.; Koizumi, J.; Kato, Y.; Mori, K. J. Chem. Soc., Perkin Trans. 1 1999,
2271. (d) Hioki, H.; Hamano, M.; Mimura, Y.; Kodama, M.; Ohta, S.;
Yanai, M.; Ikegami, S. Tetrahedron Lett. 1998, 39, 7745.
At this stage, we needed to reveal the aldehyde functionality
for the first of our two planned Baylis-Hillman reactions.
However, deprotection of the dioxolane was nontrivial. Both
(25) Ichihashi, M., Takikawa, H.; Mori, K. Biosci. Biotechnol. Biochem. 2001,
65, 2569.
(26) Hioki, H.; Ooi, H.; Hamano, M.; Mimura, Y.; Yoshio, S.; Kodama, M.;
Ohta, S.; Yanai, M.; Ikegami, S. Tetrahedron 2001, 57, 1235.
(27) Reviews: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV.
2003, 103, 811. (b) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653. (c) Ciganek, E. Org. React. 1997, 51, 201. (d) Basavaiah, D.; Rao,
P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(29) Meinwald, J. Chem. Ber. 1955, 88, 1886.
(30) Trost, B. M.; Crawley, M. L.; Lee, C. B. J. Am. Chem. Soc. 2000, 122,
6120
(31) (a) Mori, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Chem. Lett. 1985,
451. (b) Kotake, H.; Yamamoto, T.; Kinoshita, H. Chem. Lett. 1982, 1331.
(c) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380.
(28) Corey, E. J.; Achiwa, K.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969,
91, 4318.
9
7020 J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005

Nucleophiles for PD-Catalyzed DYKAT Reactions
A R T I C L E S
Table 3. Optimizing Formation of 46
entry
ligand
PTCa
temp (°C)
ratio 46:47
ratio 46
+47:48
total yield (%)b
1
2
3
4
5
dppp
dppp
dppb
dppf
N(Hex)4Brc
N(Me)4Br
N(Me)4Br
N(Me)4Br
N(Me)4Br
0
25
25
25
25
4:1
5:1
7:1
12:1
7:1
10:1
2.5:1
>23:1
>23:1
6:1
53
63
75
98
70
P(furyl)3
a 9% PTC (phase transfer catalyst) was added. b Represents isolated yields after chromatography of all isomers. c 20% N(Hex)4Br was added.
Scheme 15. Synthesis of 51a
oxidation state, thereby eliminating a reduction step. In practice
the coupling reaction worked quite well, affording a quantitative
yield of addition product 57. The choice of the TBDPS
protecting group on 56 was crucial to avoid the formation of
inseparable mixtures of products resulting from silyl transfer
to the neighboring alkoxide.
Allyl alcohol 57 was then subjected to a Johnson ortho ester
Claisen rearrangement at 100 °C, affording 58 as 16:1 Z:E olefin
mixture in excellent yield (Scheme 18). Higher temperatures
showed decreased selectivity, whereas lower temperatures
showed slightly increased selectivity but decreased yields. The
small amount of undesired double bond isomer is a result of
reaction through the alternate chair form, which removes steric
a Reactions and conditions: a) LDA, DMPU, then farnesyl bromide; b)
interactions with the bulky TBDPS ether. Reduction of 58 with
LiBHEt3, 12% dppp, 4% (Pd(π-allyl)Cl)2.
DIBAl-H followed by oxidation with Dess-Martin periodinane
afforded 59 in 75% yield. Direct formation of 59 from 57 via
an ethyl vinyl ether Claisen rearrangement was appealing, yet
protic and nonprotic acid conditions caused decomposition of
starting material and product. Since acyclic acetals are much
low yielding due to the formation of multiple products under
less stable than their cyclic counterparts, switching to a diethoxy
simple heating. Many transition metals are known catalyze this
acetal was expected to avoid the problems we were facing.
rearrangement, but substitution in the beta position of the allyl
Importantly, the diethoxy acetal behaved similarly to the dioxo-
alcohol is not well tolerated in the reaction.37,38 Consistent with
lane in the steps preceding deprotection (Scheme 16). Further-
these observations, reaction of 57 with ethyl vinyl ether
more, clean deprotection of 54 to aldehyde 51 was achieved in
catalyzed by either Hg(OAc)2 or (PhCN)2PdCl2 or organic
91% yield under mild conditions using Amberlist-15.
catalysts such as dimethoxyphenol38a led to no aldehyde
The Morita-Baylis-Hillman reaction of 51 with either
methyl acrylate or acrylonitrile was exceedingly slow and
products.
With aldehyde 59 in hand, we were not surprised to see that
the Morita-Baylis-Hillman reaction gave similarly poor results
as with 51. We therefore turned to an alternative originally
explored by Tsuda who noticed that, when DIBAl-H is
precomplexed with HMPA, propiolate esters undergo 1,4- rather
than 1,2-reduction.39,40 Furthermore, NMR studies indicated that
the resulting organoaluminum species is carbon-bound rather
than oxygen-bound, indicating the possibility of forming
accompanied by large amounts of decomposition products under
either DABCO or trialkylphosphine-catalyzed32 conditions
(Scheme 17). Lewis acid/Lewis base catalysis33 resulted in rapid
dimerization of 51 to its self-aldol condensation product.
Furthermore, aqueous conditions34 failed with 51 presumably
due to the high hydrophobicity of the substrate. An alternative
to the Morita-Baylis-Hillman reaction is to add the vinyl
moiety through metal-mediated coupling. Chromium/nickel-
mediated coupling of vinyl halides with aldehydes to yield allylic
alcohols has been demonstrated to be a mild method for carbon-
carbon-carbon bonds by quenching with electrophiles. When
aldehydes are used as electrophiles, the resulting products are
equivalent to Morita-Baylis-Hillman adducts, yet they are
carbon bond formation.35 Using vinyl bromide 5636 has the
added advantage that the side chain comes in at the correct
(36) Vinyl bromide 56 is made by simple Markovnikov addition of dry hydrogen
bromide gas across propargyl alcohol, followed by silyl protection:
Marshall, J. A.; Sehon, C. A. Org. Synth. 1999, 76, 263.
(37) (a) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579. (b) Lutz,
R. P. Chem. ReV. 1984, 84, 205.
(38) (a) Mikami, K.; Takahashi, K.; Nakai, T.; Uchimaru, T. J. Am. Chem. Soc.
1994, 116, 10948. (b) Hiersemann, M. Synlett 1999, 1823.
(39) (a) Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1987,
52, 1624. (b) Tsuda, T.; Yoshida, T.; Saegusa, T. J. Org. Chem. 1988, 53,
1037.
(40) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem. Commun.
1999, 1979.
(32) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
2404.
(33) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org. Chem.
1998, 63, 7183.
(34) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org. Chem.
2002, 67, 510.
(35) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron
Lett. 1983, 24, 5281. (b) Jin, H.; Uenishi, J.; Christ, W. J., Kishi, Y. J.
Am. Chem. Soc. 1986, 108, 5644.
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 7021

A R T I C L E S
Trost et al.
Scheme 16. Diethoxyacetal as Protecting Groupa
a Reactions and conditions: a) O3, pyridine, then PPh3; b) EtOH, PPTS; c) 2%(Pd(π-allyl)Cl)2, 6% dppf, PhSO2Na, 9% TMAB; d) LDA, DMPU, then
farnesyl bromide; e) LiBHEt3, 12% dppp, 4% (Pd(π-allyl)Cl)2; f) Amberlist-15.
Scheme 17. First Baylis-Hillman
Scheme 18. Setting up the Cyclization DYKAT Reactiona
a Reactions and conditions: a) CH3C(OEt)3; b) DIBAl-H; c) Dess-Martin-periodinane, pyridine; d) methyl propiolate, HMPA, DIBAl-H; e) AcCl; f)
TBAF, AcOH.
formed with significantly shortened reaction times and under
mild temperatures. In our hands, the transformation was quite
successful, affording good yields of coupled product 60.
All that remained to set up the key DYKAT cyclization step
was to install the allylic leaving group and reveal the pendant
nucleophile. Both steps proceeded smoothly to afford palladium
cyclization precursor 61 in 75% overall yield. Both the
optimized kinetic transformation and dynamic kinetic transfor-
mation conditions were applied to 61 (Table 4). While the
optimized conditions were successful for obtaining a kinetic
transformation (entry 1), the conditions for a dynamic kinetic
transformation afforded only 55% conversion to 62 with 91%
enantioselectivity. Recovered 61 was enriched, indicating that
the mismatched isomer was not ionizing under these conditions.
Presumably, the bulk of the geranylgeranyl side chain prohibits
the mismatched ionization at temperatures that afford clean
ionization for the model substrate (14). Unfortunately, heating
the reaction to 100 °C afforded full conversion, but at the cost
of selectivity. Again, the bulk of the side chain is assumed to
be the cause since the necessary π-σ-π isomerization may be
slowed by the bulk of the side chain. The rate of mismatched
ionization can be increased through the use of more activated
allylic leaving groups such as trichloroethyl carbonate and tert-
butyl carbonate (entries 4 and 5). Unfortunately, the selectivity
in these cases decreased, presumably due to an increase in the
background reaction.
Nevertheless, 62 can be obtained in a satisfying 50% isolated
yield and 91% ee. To finish the synthesis the methyl ester is
saponified with LiOH in aqueous THF to afford the natural
product in 98% yield (Scheme 19).41 The absolute stereochem-
(41) Our spectral data matched those previously reported in refs 25 and 26.
9
7022 J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005

Nucleophiles for PD-Catalyzed DYKAT Reactions
A R T I C L E S
Table 4. Optimizing the Key Cyclizationa
tion affords products that result from reaction through the anti
π-allyl with ester coordination to the metal center. In contrast,
cyano substitution affords products that result from reaction
through the syn π-allyl with no cyano coordination to the metal
center.
We have further demonstrated the utility of this cyclization
DYKAT through a concise and high-yielding synthesis of
(+)-hippospongic acid A. Specifically, we employed three
palladium-catalyzed alkylation reactions to form three different
types of bonds: C-S, C-H, and C-O. Furthermore, these
alkylation reactions address important selectivity issues in the
synthetic sequence. Palladium-catalyzed reductive desulfony-
lation allowed for selective removal of an allyl sulfone without
concomitant isomerization of the delicate tetraene system. The
palladium-catalyzed DYKAT cyclization allowed an efficient
approach to the one chiral center present in (+)-hippospongic
acid A. Using the described synthetic sequence, we completed
the shortest synthesis to date of (+)-hippospongic acid A, which
demonstrates the power of palladium-catalyzed allylic alkylation
reactions in total synthesis.
entry
X
temp (
°
C)
% conv.b
% ee
1
2
3
4
5
OAc
OAc
OAc
OTroc
OBOC
25
80
100
25
45
55c
100d
47
94
91
65
87
23
25
53
a All reactions run in degassed solvent under argon for 17 h. b Conver-
sions based on 300 MHz 1HNMR ratios. c Isolated yield 50%. d Isolated
yield 93%.
Experimental Section
All reactions were performed under an atmosphere of dry argon in
flame-dried glassware. Solvents were distilled under an atmosphere of
argon before use and transferred via an oven-dried syringe.
Scheme 19. Completion of the Synthesisa
Compound 15. A solution of (Pd(π-allyl)Cl)2 (0.00084 g, 0.0023
mmol) and (R,R)-L-3 (0.0055 g, 0.0071 mmol) in 0.5 mL of degassed
dioxane was added via cannula to a solution of 14 (0.030 g, 0.12 mmol),
and tetrahexylammonium chloride (0.014 g, 0.036 mmol) in degassed
dioxane (0.7 mL). The reaction was stirred at 80 °C under argon for
17 h. The resulting light-yellow solution was purified directly via flash
chromatography (silica, ether/petroleum ether, gradient) to yield 0.022
g (92%) of 15 as a colorless oil. [R]D +69.28 (c ) 0.67, CH2Cl2). The
enantiomeric excess was determined to be 95% via chiral GC analysis.
(Cyclosil B column, 120 °C isotherm, flow rate ) 2.0 mL/min, tr: 26.19
(major), 27.47 (minor).) Rf ) 0.70 in 25% ether/petroleum ether. IR
1
(film from CDCl3) 1721, 1382 cm-1. H NMR (400 MHz, CDCl3) δ
6.23 (s, 1H), 5.80 (s, 1H), 5.27 (app q, J ) 6.8 Hz, 1H), 4.71 (d, J )
12.8 Hz, 1H), 4.31 (d, J ) 10.8 Hz, 1H), 3.86 (d, J ) 12.8 Hz, 1H),
3.75 (s, 3H), 2.32 (m, 2H), 2.00 (m, 1H), 1.60 (d, J ) 8.4 Hz, 3H),
1.35 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 166.4, 141.5, 133.6,
124.6, 118.9, 75.4, 66.7, 51.8, 33.9, 33.1, 12.6. HRMS calculated for
C11H16O3 (M+): 196.1099. Found: 196.1089.
a Reactions and conditions: a) 2% (Pd(π-allyl)Cl)2, 6% (R,R)-L-3, 30%
N(Hex)4Cl, dioxane; b) LiOH, THF/H2O.
Compound 17. A solution of (Pd(π-allyl)Cl)2 (0.00084 g, 0.0023
mmol) and (R,R)-L-3 (0.0050 g, 0.0071 mmol) in 0.5 mL of de-
gassed toluene was added via cannula to a solution of 16 (0.027 g,
0.12 mmol), and tetrahexylammonium chloride (0.014 g, 0.036 mmol)
in degassed toluene (0.7 mL). The reaction was stirred at 80 °C under
argon for 17 h. The resulting light-yellow solution was purified directly
via flash chromatography (silica, ether/petroleum ether, gradient) to
yield 0.018 g (94%) of 17 as a colorless oil. [R]D +45.74 (c ) 0.82,
CH2Cl2). The enantiomeric excess was determined to be 98% via chiral
GC analysis. (Cyclosil B column, 110 °C isotherm, flow rate ) 2.0
mL/min, tr: 37.97 (major), 45.06 (minor).) The enantiomeric excess
can also be determined via HPLC analysis. (Chiralcel OD column,
99.9:0.1 heptane:iPrOH, flow rate ) 1.0 mL/min, 220 nm, tr: 15.08
(major), 16.87 (minor)). Rf ) 0.60 in 25% ether/petroleum ether. IR
(film from CDCl3) 2227, 1622, 1442 cm-1. 1H NMR (300 MHz, CDCl3)
δ 6.01 (s, 1H), 5.97 (s, 1H), 5.34 (m, 1H), 4.72 (d, J ) 12.9 Hz, 1H),
4.03 (d, J ) 11.1 Hz, 1H), 4.85 (d, J ) 12.6 Hz, 1H), 2.36 (m, 2H),
2.02 (m, 1H), 1.62 (d, J ) 6.9 Hz, 3H), 1.55 (m, 1H). 13C NMR (75
MHz, CDCl3) δ 132.2, 129.9, 124.5, 112.0, 117.1, 76.4, 66.5, 32.5,
32.3, 12.7. Anal. calcd for C10H13NO: C, 73.59; H, 8.03. Found: C,
73.38; H, 8.00.
ical assignment of the DYKAT cyclization was confirmed by
comparison of the rotation of 35 to natural (+)-hippospongic
acid. This synthesis is the shortest to date, furnishing the natural
product in only 15 longest linear and 17 total steps with an
8.5% overall yield.
5. Conclusions
Chiral Baylis-Hillman adducts represent an important class
of asymmetric building blocks. We have demonstrated a concise
and highly selective deracemization of achiral Baylis-Hillman
adducts using aliphatic alcohol nucleophiles. Both a kinetic
transformation and a dynamic kinetic transformation were
developed to afford substituted pyran products with high yields
and selectivities. Furthermore, we have shown the generality
of aliphatic alcohols to function as competent nucleophiles in
palladium-catalyzed AAA reactions. We also contributed to the
body of knowledge on AAA with 2-substituted π-allyl com-
plexes. As in previous cases, the orientation of the π-allyl
complex is determined by the substitution at C2. Ester substitu-
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 7023

A R T I C L E S
Trost et al.
Compound 31. A test tube containing 4-methoxyphenol (45 mg,
0.37 mmol), Pd2dba3‚CHCl3 (3.8 mg, 0.004 mmol), and (S,S)-L-3 (7.7
mg, 0.012 mmol) was evacuated and filled with argon three times. The
test tube was charged with a solution of 30 (66 mg, 0.37 mmol) in
methylene chloride (3.7 mL). The resulting orange solution was stirred
at 0 °C for 3 h and directly chromatographed eluting with 6:1 petroleum
ether:diethyl ether to afford 31 (67 mg, 80%, 40%ee) as a colorless
film. Enantiomers were separated by HPLC using Chiralcel OD column
eluting with 95:5 heptanes:2-propanol at 1.0 mL/min. Retention
times: minor enantiomer (S) 37.20 min and major enantiomer (R) 41.86
min. IR (film) 2221, 1749, 1595, 1442, 1035 cm-1. 1H NMR (300 MHz,
CDCl3) δ 6.80-7.02 (m, 4H), 6.82 (br s, 1H), 3.77 (s, 3H), 2.31-2.41
(m, 1H), 2.12-2.30 (m, 1H), 1.92-2.06 (m, 1H), 1.61-1.90 (m, 4H).
13C NMR (75 MHz, CDCl3) δ 154.8, 151.4, 150.6, 149.1, 118.6 (2C),
114.6 (2C), 113.9, 72.2, 55.5, 26.9, 25.9, 16.5 HRMS for C14H15NO2
and tetrahexylammonium chloride (0.007 g, 0.018 mmol) in degassed
dioxane (0.3 mL). The reaction was stirred at 80 °C under argon for
17 h. The resulting light-yellow solution was purified directly via flash
chromatography (silica, ether/petroleum ether, gradient) to yield 0.014
g (50%) of 62. [R]D +20.38 (c ) 0.42, CH2Cl2) for 91% ee as
determined via chiral HPLC analysis. (Chiralcel AD column, 400:1
heptane:iPrOH, flow rate ) 0.5 mL/min, 230 nm, tr: 13.64 (minor),
1
17.22 (major).) The obtained spectral data [IR, H, 13C] matched the
literature values.24a IR (film from CDCl3) 1722, 1633, 1439, 955, 819
cm-1. 1H NMR (500 MHz, CDCl3) δ 6.23 (t, J ) 1.5 Hz, 1H), 5.88 (t,
J ) 1.5 Hz, 1H), 5.18 (t, J ) 7.0 Hz, 1H), 5.12-5.06 (m, 4H), 4.67
(d, J ) 12.5 Hz, 1H), 4.31 (d, J ) 11.5 Hz, 1H), 3.86 (d, J ) 12.5 Hz,
1H), 3.75 (s, 3H), 2.36-2.27 (m, 2H), 2.15-1.94 (m, 17H), 1.66 (d, J
) 1.5 Hz, 3H), 1.58 (s, 3H), 1.57 (s, 9H), 1.33 (m, 1H). 13C NMR
(125 MHz, CDCl3) δ 166.3, 141.5, 135.2, 134.9, 134.4, 132.9, 131.3,
124.8, 124.6, 124.5, 124.4, 124.2 (2C), 75.4, 67.1, 51.8, 39.8, 39.7,
33.9, 33.0, 29.7, 28.2 (2C), 26.7, 26.6, 25.7, 25.6, 17.7, 16.1, 16.0 (2C).
(M+) Calcd: 229.1103. Found: 229.1092. [R]22 -48.2 (c ) 0.78,
D
CH2Cl2, 48% ee, (R,R)-L-1).
Compound 33. A test tube containing 4-methoxyphenol (15 mg,
0.121 mmol), Pd2dba3‚CHCl3 (1.0 mg, 0.001 mmol), and (S,S)-L-3 (2
mg, 0.003 mmol) was evacuated and filled with argon three times. The
test tube was charged with a solution of 32 (25 mg, 0.117 mmol) in
methylene chloride (1.0 mL). The resulting orange solution was stirred
at 0 °C for 3 h and directly chromatographed eluting with 6:1 petroleum
ether:diethyl ether to afford 33 (24 mg, 78%, 86%ee) as a colorless
film. Enantiomers were separated by HPLC using Chiralcel OD column
eluting with 98:2 heptanes:2-propanol at 1.0 mL/min. Retention
times: minor enantiomer (R) 8.38 min and major enantiomer (S) 10.25
Acknowledgment. We thank the National Institutes of Health
(GM13598) and the National Science Foundation for their
generous support of our programs. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University
of California-San Francisco, supported by the NIH Division of
Research Resources. We thank Professor Shinji Ohta of the
Nagahama Institute of Bio-science and Technology for providing
copies of the original spectra of (+)-hippospongic acid A. We
also thank Bristol-Meyers Squibb and Eli-Lilly for predoctoral
support of M.R.M.
1
min. IR (film) 1717, 1506, 1436, 1069 cm-1. H NMR (CDCl3, 500
MHz) δ 7.24 (m, 1H), 6.99 (dm, J ) 9.0 Hz, 2H), 6.81 (dm, J ) 9.0
Hz, 2H), 5.01 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.38 (dt, J ) 19.8,
4.6 Hz, 1H), 2.20-2.09 (m, 2H), 1.89-1.79 (m, 1H), 1.66-1.60 (m,
1H), 1.43 (tt, J ) 14.0, 3.4 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ
166.9, 154.4, 152.0, 144.8, 129.7, 118.9 (2C), 114.5 (2C), 70.1, 55.6,
51.7, 26.3, 25.9, 15.8. HRMS Calcd for C15H18O4: 262.1205. Found:
262.1198.
Compound 62. A solution of (Pd(π-allyl)Cl)2 (0.00044 g, 0.0012
mmol) and (R,R)-L-3 (0.0028 g, 0.0036 mmol) in 0.3 mL of degassed
dioxane was added via cannula to a solution of 61 (0.03 g, 0.06 mmol),
Supporting Information Available: Detailed procedures and
full characterization of all synthetic intermediates and prod-
ucts, along with spectral comparison of natural and synthetic
(+)-hippospongic acid A. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA050340Q
9
7024 J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005