Diastereoselective ru-catalyzed cross-metathesis-dihydroxylation sequence. An efficient approach toward enantiomerically enriched syn-diols

Article abstract of DOI:10.1021/jo800145x

(Chemical Equation Presented) Sequential catalysis has evolved as a powerful concept within the past years and allows the more efficient use of catalytically active expensive transition metals in organic synthesis. In this paper we present the stereoselective cross-metathesis-dihydroxylation of various olefins with chiral auxiliary substituted acrylamides. The chiral information (i.e., the auxiliary) introduced in the metathesis reactions allows for a stereoselective subsequent RuO₄-catalyzed dihydroxylation. The sequence is concluded by an unusual kinetic resolution of the diastereomeric diols obtained in the oxidation reaction. As a consequence a variety of structurally diverse enantiomerically enriched diols are obtained. To the best of our knowledge the results summarized in this paper represent the first highly efficient diastereoselective RuO₄-catalyzed oxidation.

Full text of DOI:10.1021/jo800145x

Diastereoselective Ru-Catalyzed Cross-Metathesis-Dihydroxylation
Sequence. An Efficient Approach toward Enantiomerically Enriched
syn-Diols
N. Matthias Neisius and Bernd Plietker*
Institut fu¨r Organische Chemie, UniVersita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
bernd.plietker@oc.uni-stuttgart.de
ReceiVed January 21, 2008
Sequential catalysis has evolved as a powerful concept within the past years and allows the more efficient
use of catalytically active expensive transition metals in organic synthesis. In this paper we present the
stereoselective cross-metathesis-dihydroxylation of various olefins with chiral auxiliary substituted
acrylamides. The chiral information (i.e., the auxiliary) introduced in the metathesis reactions allows for
a stereoselective subsequent RuO4-catalyzed dihydroxylation. The sequence is concluded by an unusual
kinetic resolution of the diastereomeric diols obtained in the oxidation reaction. As a consequence a
variety of structurally diverse enantiomerically enriched diols are obtained. To the best of our knowledge
the results summarized in this paper represent the first highly efficient diastereoselective RuO4-catalyzed
oxidation.
Introduction
Transiton-metal-catalyzed reactions belong to the most pow-
erful transformations in modern organic chemistry. Despite the
achievements that have been made in this field of chemistry,
the number of transformations that managed to take the
crossover from academic into industrial application is compa-
rably low. Among others, the high price of the catalyst might
account for these difficulties. Within the past years sequential
FIGURE 1. Stereoselective sequential catalysis as a means to obtain
chiral Vic-diols.
(1) (a) Mu¨ller, T. J. J. Top. Organomet. Chem. 2006, 19, 149. (b)
Bruneau, C.; Derien, S.; Dixneuf, P. H. Top. Organomet. Chem. 2006, 19,
295.
catalysis has evolved as a probable solution for this dilemma.1
In these reaction cascades a given catalyst is transformed in
situ into a new catalytically active species once the first
transformation of the sequence has been completed. The junction
of two catalytic cycles by using one common metal catalyst
allows for a more efficient use of the expensive catalyst and
the avoidance of unnecessary purification procedures.
Due to the accessibility of eight different oxidation states,
Ru-based catalysts are predestined for applications in sequential
catalysis. Among the various catalytic reactions developed so
far, the Ru-catalyzed olefin metathesis appears to be an
interesting starting point for the development of these reaction
(2) (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312. (b) Lee, B. T.; Schrader, T. O.; Martin-Matute, B.;
Kauffman, C. R.; Zhang, P.; Snapper, M. L. Tetrahedron 2004, 60, 7391.
(c) Tallarico, J. A.; Malnick, L. M.; Snapper, M. L. J. Org. Chem. 1999,
64, 344. (d) Schmidt, B.; Pohler, M. J. Organomet. Chem. 2005, 690, 5552.
(e) Schmidt, B.; Pohler, M.; Costisella, B. J. Org. Chem. 2004, 69, 1421.
(f) Finnegan, D.; Seigal, B. A.; Snapper, M. L. Org. Lett. 2006, 8, 2603.
(g) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am.
Chem. Soc. 2002, 124, 13390. (h) Schmidt, B. J. Org. Chem. 2004, 69,
7672. (i) Schmidt, B. Chem. Commun. 2004, 742. (j) Schmidt, B. Eur. J.
Org. Chem. 2003, 816. (k) Bielawski, C. W.; Louie, J.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 12872. (l) Schmidt, B.; Pohler, M. Org. Biomol.
Chem. 2003, 1, 2512. (m) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc.
2006, 128, 52.
10.1021/jo800145x CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/22/2008
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J. Org. Chem. 2008, 73, 3218-3227

Cross-Metathesis-Dihydroxylation Sequence
FIGURE 2. Auxiliary-induced asymmetric RuO4-catalyzed dihydroxylation.
cascades.2 Hence, it is not surprising that a variety of different
catalytic sequences involving Ru-catalyzed metathesis have been
developed within the past 5 years. However, to the best of our
knowledge, the combination of different catalytic reactions with
the aim of preparing enantiomerically enriched material has not
yet been reported. In the present paper we report on our initial
findings in the field of stereoselective sequential catalysis.
Our strategy is based on the experiences we gained in the
field of RuO4-catalyzed oxidations3 of olefins within the past 5
years.4 We envisioned such a reaction to be the final step in a
catalytic sequence. Since no asymmetric RuO4-catalyzed dihy-
droxylation has been reported so far, the combination of cross-
metathesis between an olefin and a chiral auxiliary substituted
acrylamide appears to be an interesting alternative to the
classical introduction of chiral information by reacting a fully
substituted carboxylic acid with the auxiliary.5 By employing
an enantiopure auxiliary substituted olefin in the cross-metathesis
with a second olefin, two important issues are addressed: (1)
A new CdC double bond is being formed, and (2) a chiral
auxiliary is introduced. The subsequent in situ generation of
RuO4 sets the stage for a diastereoselective syn-dihydroxylation.
See Figure 1.
Although at first sight the use of a chiral auxiliary appears
to be less elegant, two main reasons make this method favorable;
to date, all efforts to design chiral ligands for RuO4 have met
with failure. Since this metal oxide belongs to one of the
strongest oxidants in organic synthesis and displays a low
stability at pH > 7,6 the use of the common ligand motifs
(phosphines, amines, etc.) is not possible. At the moment, the
use of a chiral auxiliary is the most promising way to obtain
enantiomerically enriched products using RuO4, and by using
chiral auxiliaries, a stereochemical enrichment of the resulting
diastereomeric products by crystallization, distillation, or chro-
matography is possible.7
acrylamides plus subsequent diastereoselective dihydroxylation.
A new type of chiral auxiliary has been developed based upon
a rational design that allows for the first time for an efficient
diastereoselective RuO4-catalyzed dihydroxylation of olefins in
diastereomeric ratios up to 19:1. Moreover, an unusual kinetic
resolution of the diastereomeric diols by methanolysis is
reported, which allowed for the preparation of enantiomerically
enriched syn-diols in either optical form with enantomeric
excesses up to 99%.
Results and Discussion
Whereas OsO4-catalyzed olefin dihydroxylations have been
developed into one of the most powerful metal-catalyzed
reactions in organic chemistry,8 asymmetric oxidations involving
catalytic amounts of RuO4 have attracted considerably less
attention. It is only recently that more sophisticated oxidation
protocols for a selective oxygen transfer toward different
functional groups have been developed.4,9 We reported the rate
acceleration in RuO4-catalyzed dihydroxylation upon addition
of catalytic amounts of Lewis acids (e.g., CeCl3).4c Due to the
formation of a redox-active cerium(IV)-periodato complex that
acts as a redox mediator, a more efficient reoxidation of the
primarily formed intermediate ruthenium(VI) ester was possible.
The new protocol allowed for the selective dihydroxylation of
olefins without the side reactions that were usually observed
after prolonged reaction times (e.g., overoxidation, C-C bond
scission, etc.).10
Our investigation started with the search for a suitable chiral
auxiliary that can selectively direct the addition of RuO4 on
one of the diastereotopic faces of the double bond. Until now,
only one report on an auxiliary-based asymmetric RuO4-
catalyzed dihydroxylation has appeared in the literature.11
Oppolzer’s camphorsultame12 proved to induce moderate to
good diastereoselectivities in the oxidation of various R,â-
unsaturated carboxamides (eq 1, Figure 2). While this auxiliary
allows for the preparation of one enantiomeric series of syn-
In the present paper we report on the use of a cross-metathesis
between different olefins and auxiliary substituted enantiopure
(3) Plietker B. Synthesis 2005, 2453.
(4) Ru-catalyzed dihydroxylation: (a) Plietker, B.; Niggemann, M. Org.
Lett. 2003, 5, 3353. (b) Plietker, B.; Niggemann, M.; Pollrich, A. Org.
Biomol. Chem. 2004, 2, 1116. (c) Plietker, B.; Niggemann, M. J. Org. Chem.
2005, 70, 2402. RuO4-catalyzed ketohydroxylation. (d) Plietker, B. J. Org.
Chem. 2003, 68, 7123. (e) Plietker, B. J. Org. Chem. 2004, 69, 8287. (f)
Plietker, B. Eur. J. Org. Chem. 2005, 1919.
(5) While this work was in progress, two independent reports on the
sequential cross-metathesis-dihydroxylation starting from methyl acrylate
and various olefins appeared. However, the syn-diols were obtained as a
racemate. (a) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew.
Chem. 2006, 119, 1933; Angew. Chem., Int. Ed. 2006, 45, 1900-1903. (b)
Scholte, A. A.; Snapper, M. L. Org. Lett. 2006, 8, 4759.
(8) (a) Schro¨der, M. Chem. ReV. 1980, 80, 187. (b) Kolb, H. C.; Van
Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2487. (c)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 357. (b)
Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 399.
(9) (a) Roth, S.; Stark, C. B. W. Angew. Chem. 2006, 118, 6364; Angew.
Chem., Int. Ed. 2006, 45, 6218-6221. (b) Roth, S.; Go¨hler, S.; Cheng, H.;
Stark, C. B. W. Eur. J. Org. Chem. 2005, 4109.
(10) This method was successfully applied in synthesis; for a prominent
example see: Tiwari, P.; Misra, A. K. J. Org. Chem. 2006, 71, 2911.
(11) Lee, A. W. U.; Chen, W. H.; Yuen, W. H.; Xia, P. F.; Wang, W.
Y. Tetrahedron: Asymmetry 1999, 10, 1421.
(6) (a) Griffith, W. P.; Suriaatmaja, M. Can. J. Chem. 2001, 79, 598.
(b) Mills, A.; Holland, C. J. Chem. Res. 1997, 368.
(7) Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
(12) Oppolzer, W.; Chapuis, C.; Bernadelli, G. HelV. Chim. Acta 1983,
67, 1397.
J. Org. Chem, Vol. 73, No. 8, 2008 3219

Neisius and Plietker
TABLE 1. Auxiliary Effects in Asymmetric RuO4-Catalyzed Dihydroxylations
a All reactions were performed on a 2 mmol scale using 1.0 mol % RuCl3 (as a 0.1 M stock solution in water), 20 mol % CeCl3‚7H2O, and 1.5 equiv of
NaIO4 in a solvent mixture of CH3CN/H2O (6 mL/1 mL) at 0 °C and stopped after full conversion. b Determined by 1H NMR integration. c Combined
isolated yield.
3220 J. Org. Chem., Vol. 73, No. 8, 2008

Cross-Metathesis-Dihydroxylation Sequence
diols, we wondered whether it was possible to identify another
class of auxiliaries that would allow for the synthesis of the
opposite enantiomeric series. Among the chiral auxiliaries that
have been used in organic chemistry within the past 30 years,
chiral oxazolidinones have attracted considerable attention.13 On
the basis of the simplified sketch shown in eq 2 (Figure 2), we
speculated that this class of chiral auxiliary could induce the
opposite sense of stereoinduction in the dihydroxylation reaction.
Hence, we started our investigation by analyzing the stere-
ochemical course of the oxidation of cinnamic acid derived
enantiopure oxazolidinones (Table 1).14 The configuration of
the main diastereomer was determined after methanolysis and
comparison of the obtained mixture of enantiomers with an
enantiopure sample obtained via asymmetric dihydroxylation
of methyl cinnamate.
ing sulfamidate exo-31 was obtained upon treatment of exo-30
with SOCl2 and subsequent oxidation using RuO4 (eq 3, Scheme
1).
SCHEME 1. Preparation of Oxazolidinone exo-29 and
Sulfamidate exo-31
Indeed the use of oxazolidinones allowed for a reversal of
the π-facial selectivity in the oxidation reaction (entries 1-11,
Table 1). However, though the desired diols were obtained in
good yields, the diastereoselectivities were only moderate and
did not reach or surpass the selectivities obtained for the
oxidation of camphorsultame-bound cinnamic acid 23 (entry
12, Table 1).
At this point we were wondering whether we could construct
an auxiliary based on a rational design: a chiral compound
possessing similar topological characteristics that could be
referred to as a “pseudoenantiomeric camphorsultame”. Our idea
was guided by the following thoughts: The preferred formation
of one rotamer, I (or III), plus the steric properties of the
auxiliary build the base for a high degree of diastereoselectivity
in the oxidation reaction. If we were able to stabilize the
corresponding rotamer II, we would in principle be able to
obtain a topologically similar auxiliary that should induce the
opposite sense of stereoinduction starting from a unique
enantiopure source (i.e., D-camphor) (Figure 3).
The auxiliaries were coupled to cinnamic acid and subse-
quently subjected to the RuO4-catalyzed dihydroxlyation (Scheme
2). The first investigations concentrated on the use of oxazo-
lidinone exo-29 as the chiral auxiliary (eq 2, Scheme 2). Indeed
the rationally designed camphor-derived oxazolidinone
exo-29 proved to induce a similar degree of stereoselectivity
compared to the camphorsultame (eq 1 vs eq 2, Scheme 2).
However, the corresponding sulfamidate exo-31 proved to
be an even more powerful chiral inductor (eq 3, Scheme 2).
The simple exchange of the carbonyl group for SO2 led to a
significant increase in the diastereoselectivity from 4.1:1.0
to 12.0:1.0 (eqs 2 and 3, Scheme 2). Furthermore, the cam-
phor-derived sulfamidate-based auxiliary induces the de-
sired complementary sense of stereoselectivity and allows
for the formation of two new stereocenters with opposite
chirality compared to the camphorsultame (eq 1 vs eq 3, Scheme
2).
SCHEME 2. Diastereoselective Dihydroxylation Using
Camphor-Derived Auxiliaries
FIGURE 3. Rationale for the design of camphor-derived auxiliary
IV.
Hence, two chiral auxiliaries of type IV with two different
linker groups were prepared in a straightforward manner starting
from D-camphor. Diastereoselective R-hydroxylation was fol-
lowed by oxime formation to give oxime exo-27 as a key
intermediate (eq 1, Scheme 1), whereas reduction, carbamate
formation, and subsequent cyclization under basic conditions
led to oxazolidinone exo-29 (eq 2, Scheme 1). The correspond-
(13) Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(14) The â-substituent was shown to significantly decrease the stereo-
selectivity in auxiliary-induced RuO4-catalyzed dihydroxylations and was
therefore chosen as a suitable model compound. See ref 11.
J. Org. Chem, Vol. 73, No. 8, 2008 3221

Neisius and Plietker
TABLE 2. Stereoselective RuO4-Catalyzed Dihydroxylation
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Cross-Metathesis-Dihydroxylation Sequence
Table 2. (Continued)
a All reactions were performed on a 2 mmol scale using 1 mol % RuCl3 (as a 0.1 M solution in water), 20 mol % CeCl3‚7H2O, and 1.5 equiv of NaIO4
1
at 0 °C in a solvent mixture of acetonitrile/water (6 mL/1 mL). b Determined by H NMR, GC, or HPLC integration. c Isolated yields.
Having in hand these powerful chiral auxiliaries, we inves-
tigated their potential in the dihydroxylation of various substi-
tuted olefins.
The new chiral auxiliaries proved to be broadly applicable.
Depending on the substitution pattern, good to excellent
diastereoselectivities were observed. In general, the sulfamidate-
based auxiliary proved to induce the highest degree of stereo-
selectivity (entries 15-21, Table 2). Only in the case of a
substituent at the R-position of the carboxylic acid moiety did
the oxazolidinone-based auxiliary prove to be superior (entries
12 and 13 vs entries 19 and 20, Table 2). With regard to the
diastereoselectivity trends, it appears indeed worthwhile to refer
to the camphorsulfamidate as a pseudoenantiomeric camphor-
sultame: The trends for either diastereomer are comparable;
however, the stereoinduction in the case of the sulfamidate
auxiliary is significantly higher.
Having developed a new generation of auxiliaries that allow
for the preparation of either enantiomeric series of diols, we
J. Org. Chem, Vol. 73, No. 8, 2008 3223

Neisius and Plietker
TABLE 4. Dihydroxylation of Olefin 33: Influence of the Catalyst
and Additive
subsequently turned our attention toward the development of
the sequential catalysis. Therefore, the initial cross-metathesis
reaction was investigated in detail. Several catalysts were used
in the present study (Figure 4).
yieldc
entrya catalyst
additive
time (min) 41-A:41-Bb (%)
1
2
3
4
5
77
75
60
e
NH4PF6
60
60
30
15
1.0:5.1
1.0:5.1
1.0:5.1
1.0:5.1
64
65
73
85
NH4PF6,e Bu4NIO4
TBAIO4,e acetonef
e
a All reactions were performed on a 1 mmol scale using 2.5 mol %
catalyst in a solvent mixture of CH3CN/EtOAc/H2O (1.5 mL/1.5 mL/0.5
mL). b Determined by 1H NMR integration. c Combined isolated yield.
d Determined by chiral HPLC. e A 1 equiv portion of additive based on the
amount of catalyst was added. f A 1.5 mL volume of acetone was added.
FIGURE 4. Catalysts employed in the present cross-metathesis study.
(i.e., the reaction between the Ru-alkylidene complex and
NaIO4). Very much to our delight, the addition led to a
significant increase in reactivity (entry 2, Table 4); the corre-
sponding diol 41 was obtained as a mixture of diastereoiosmers
in moderate yield. Catalytic amounts of complex 75 on the other
hand furnished the oxidation product 41 in moderate yield in
the absence of any additive (entry 3, Table 4). The addition of
NH4PF6 led to a further increase in the yield (entry 4, Table 4).
Exchanging the chloride ligand in the presence of catalytic
amounts of Bu4NIO4 in acetone finally led to the formation of
the oxidation product 41 in a good isolated yield and moderate
diastereoselectivity (entry 5, Table 4).
Apart from the nature of the catalyst, a strong focus was
placed upon the use of exact stoichiometric amounts of either
olefin employed in the reaction. Although the cross-metathesis
between acrylic amides and olefins has been known for some
time, in most cases the less electron rich olefin is used in excess
to suppress undesired homocoupling between the electron rich
olefins.15 Since in our attempted sequential catalysis the less
electron rich olefin is also enantiopure, we designed a special
“dilution apparatus” that allowed for an exact stoichiometric
cross-metathesis reaction between olefins of different electronic
properties (Table 3).16
Having found optimum conditions for the dihydroxylation,
we set out to combine both processes in a sequential manner.
We were delighted to find that the asymmetric cross-metathe-
sis-dihydroxylation sequence proceeded equally well for cam-
phorsultame-derived 36 and camphorsulfamidate-derived 60.
The Vic-diols 41 and 65 were obtained in good yields and
diastereoselectivities. However, within the subsequent metha-
nolysis of the diastereomeric diol 41 or 65, an unusual kinetic
differentiation between the two stereoisomers was observed. As
a result the syn-diol 80 was obtained in either enantiomeric form
with more than 99% ee (Scheme 3). Moreover, the reaction stops
at full conversion of the major diastereomer; a full set of signals
for the minor isomer was observed in the crude 1H NMR spectra.
To the best of our knowledge, this is the first observation of an
efficient kinetic separation within the cleavage of a chiral
auxiliary.
TABLE 3. Development of Cross-Metathesis: Influence of the
Catalyst
time
(h)
yieldc
(%)
entrya
catalyst
40:79b
1
2
3
4
5
6
72
73
74
75
76
77
24
24
24
12
24
10
only 79
26:74
only 79
91:9
only 79
91:9
nd
28
nd
89
nd
90
a All reactions were performed on a 1 mmol scale in ethyl acetate (1
mL) at reflux temperature using 2.5 mol % Ru catalyst. b Determined by
GC integration. c Isolated yield.
With these results in hand, we subsequently investigated the
reaction scope and were delighted to find this catalytic sequence
to be broadly applicable (Table 5). The moderate to excellent
selectivities obtained in the dihydroxylation improved signifi-
As can be seen from Table 3 the Grubbs-Hoveyda complex
7517 and the Grela catalyst 7718 displayed the highest catalytic
activity in the cross-metathesis (CM). Only minor amounts of
the homocoupling products were obtained. With these results
in hand, we turned our attention to the dihydroxylation (Table
4). Unfortunately, we found the most active CM catalyst 77 to
be unreactive in the oxidation reaction.19
To destabilize the Ru-alkylidene complex 77, we tried to
perform an anion exchange using catalytic amounts of NH4PF6
prior to the addition of NaIO4. The anion exchange was thought
to facilitate the initial oxidation event in the dihydroxylation
(15) (a) Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem.
2001, 113, 1317; Angew. Chem., Int. Ed. 2001, 40, 1277. (b) Hart, A. C.;
Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 1094. (c) Phillips, A. J.; Hart,
A. C.; Henderson, J. A. Tetrahedron Lett. 2006, 47, 3743.
(16) A figure of the apparatus is shown in the Supporting Information.
(17) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9073.
(18) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem. 2002,
114, 4210; Angew. Chem., Int. Ed. 2002, 41, 4038.
(19) The observed stability of Grela’s catalyst underlines its reported
extraordinary stability toward oxidation. See ref 18.
(20) Howe, N. R.; Sheikh, Y. M. Science 1975, 189, 386.
3224 J. Org. Chem., Vol. 73, No. 8, 2008

Cross-Metathesis-Dihydroxylation Sequence
TABLE 5. Preparation of Enantiomerically Enriched Wic-Diols
a All reactions were performed as indicated in Scheme 3. b Determined by chiral HPLC. c Combined isolated yield. d The auxiliary was recovered in good
yield. e CM was performed with 3 equiv of olefin I in refluxing CH2Cl2 without the dilution apparatus. f CM was performed in refluxing CH2Cl2 with 3
equiv of olefin I without the dilution apparatus using 5 mol % catalyst 75 and 5 mol % MeI.
J. Org. Chem, Vol. 73, No. 8, 2008 3225

Neisius and Plietker
SCHEME 3. Cross-Metathesis Dihydroxylation of Olefin 78 and Amides 36 and 60a
a Reagents and conditions (1 mmol scale): (a) 75 (2.5 mol %), EtOAc (3 mL), reflux, 12 h, then Bu4NIO4 (5 mol %), CeCl3‚7H2O (20 mol %), NaIO4
(2 equiv), CH3CN/acetone/H2O (3 mL/3 mL/1 mL), 0 °C, 30 min; (b) MeMgBr (4.0 equiv), MeOH (3 mL), 0 °C, 10 min.
SCHEME 4. Two-Step Synthesis of Anthopleurine and ent-Anthopleurine 88
cantly within the methanolysis step. Various diols were obtained
in high enantiomeric excesses ranging from 91% to 99%. A
thorough control of the conversion is not necessary; the reaction
stops at full conversion of the major stereoisomer. The kinetic
resolution allowed for simple access to enantiomerically pure
Vic-diols in both enantiomeric forms. The methanolysis was
performed on the crude mixture of diastereomeric alcohols
obtained after the cross-metathesis-dihydroxylation reaction.
elegantissima (Scheme 3).20 This compound is a subunit of a
larger polypeptidic structure and functions as an ion channel
binder. With regard to its biological activity, our modular
approach would allow the preparation of either enantiomer of
anthopleurine in just three steps (Scheme 4). Indeed, applying
the cross-metathesis-diastereoselective dihydroxylation condi-
tions to sultame 36 or sulfamidate 60 in the presence of (Z)-
1,4-dichlorobut-2-ene (86) followed by methanolysis yielded
the enantiopure Vic-diols (2R,3R)-87 and (2S,3S)-87 in good
yields with excellent enantiopurity. Substitution of chloride by
trimethylamine under standard conditions and saponification of
The catalytic sequence was finally applied to the total
synthesis of anthopleurine 88, a sea anemone alarm pheromone
that was isolated in 1975 from the sea anemone Anthopleura
3226 J. Org. Chem., Vol. 73, No. 8, 2008

Cross-Metathesis-Dihydroxylation Sequence
added a solution of MeMgBr (1.5 mmol, 500 µL, 3 M in THF) in
1 mL of MeOH (prepared at 0 °C prior to use). After the addition
stirring was contiunued for 5-10 min at 0 °C. The reaction mixture
was hydrolyzed by addition of a saturated aq NaHSO4 solution (1
mL). The organic phase was separated and the aqueous layer
extracted with CH2Cl2 (2 × 5 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuum. The crude
diol was purified by column chromatography.
the methyl esters led to target compounds (2S,3R)-88 and
(2R,3S)-88 in nearly quantitative yield (Scheme 4). A compari-
son of the optical rotations revealed the natural product to
possess the (2R,3S)-configuration in accordance with Rap-
poport’s earlier structural suggestion.21
Conclusion
(2S,3S)-87 was obtained in 40% yield (67 mg) starting from
sulfamidate 60 and cis-1,4-dichlorobutene (86): [R]2D0 16.9 (c 0.3,
CHCl3). (2R,3R)-87 was obtained in 45% yield (76 mg) starting
from sultame 36 and 86: [R]D20 -17.1 (c 0.25, CHCl3); colorless
solid; mp 31 °C; Rf 0.15 (1:1 isohexanes/ethyl acetate); enantiomeric
excess determined by chiral HPLC (Chiralcel OJ, heptane/2-
propanol (88:12), flow 0.9 mL/min, 215 nm), tR(2S,3S) ) 11.96
Sequential catalysis has emerged as a powerful new concept
which allows for the efficient use of one catalytically active
metal for various transformations, avoiding unnecessary workup
and purification procedures. In the present paper we summarize
our results on the development of a diastereoselective cross-
metathesis-dihydroxylation-methanolysis sequence. Within
this development several problems were successfully ad-
dressed: (i) Two powerful camphor-based chiral auxiliaries have
been identified, allowing for the first diastereoselective RuO4-
catalyzed dihydroxylation of olefins. (ii) An unusual kinetic
separation of diastereomeric diols was observed, allowing for
the selective methanolysis of the major diol formed within the
oxidation event giving rise to Vic-diols in either optical form
and in good to excellent enantiomeric excess. (iii) Additives
simplifying the in situ generation of RuO4 from various
metathesis catalysts were identified. (iv) The reaction scope was
explored, and the catalytic sequence was applied toward the
structural elucidation and determination of the absolute con-
figuration of anthopleurine, a natural product.
1
min, tR(2R,3R) ) 14.16 min; H NMR (400 MHz, CDCl3) δ 4.40
(d, J ) 1.5 Hz, 1H), 4.14 (ddd, J ) 7.0, 1.5 Hz, 1H), 3.86 (s, 3H),
3.67 (dd, J ) 11.0, 7.0, 1H), 3.64 (dd, J ) 11.0, 7.0 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl3) δ 173.1, 72.3, 70.2, 53.1, 44.8 ppm;
IR (KBr) ν 3427 (s), 1740 (s), 1440 (w), 1293 (w), 1254 (w), 1118
(m) cm-1; HRMS (EI-HR) m/z calcd for C5H9ClO4 168.0166, found
168.0184.
2,3-Dihydroxy-4-(trimethylammonium)butanoate (88). Diol
87 (20 mg, 0.12 mmol) and NMe3 (2 mL, 50% aq solution) were
stirred in a 5 mL round-bottomed flask, heated to 45 °C, and stirred
overnight. After the solution was cooled to room temperature, NMe3
and H2O were removed in vacuum. The residue was taken up in
methanol (4 mL), and a basic ion exchanger (250 mg, Dowex 550
A (OH)) was added. The suspension was stirred at room temperature
overnight. The ion-exchange resin was filtered off, and the solvent
was evaporated to yield 18.3 mg (87%) of the desired betaine 88:
1
Experimental Section
colorless solid; H NMR (300 MHz, MeOH-d4) δ 4.27 (dd, J )
9.6, 1.1 Hz, 1H), 3.72 (d, J ) 3.4 Hz, 1H), 3.46 (dd, J ) 13.5, 1.5
Hz, 1H), 3.33 (dd, J ) 13.6, 9.7 Hz, 1H), 3.12 (s, 9H) ppm; 13C
NMR (100 MHz, MeOH-d4) δ 177.5, 74.3, 70.6, 69.0, 54.8 ppm;
IR (KBr) ν 3342 (s), 2945 (w), 2832 (w), 1606 (s), 1409 (w), 1198
Total Synthesis of Anthopleurine 88 and ent-Anthopleurine
ent-88. Methyl 4-Chloro-2,3-dihydroxybutanoate (87). In a 10
mL round-bottomed flask catalyst 75 (42 mg, 0.05 mmol, 5 mol
%) was dissolved in dichloromethane (1.5 mL) under an argon
atmosphere. CuCl (5 mg, 0.05 mmol, 5 mol %) and o-(isopropy-
loxy)styrene (8 mg, 0.05 mmol, 5 mol %) were added. The reaction
mixture was stirred at 50 °C for 1 h until the solution turned deep
green. The olefin 36 or 60 (1 mmol) was added followed by addition
of (Z)-1,4-dichlorobutene (86) (187 mg, 1.5 mmol, 1.5 equiv). The
mixture was heated to reflux and stirred until no more starting
material could be detected (12 h). After complete conversion the
slurry was cooled to room temperature and the solvent removed in
vacuum. Bu4NIO4 (21.6 mg, 0.05 mmol, 5 mol %) and acetonitrile
(1.5 mL) were added, and stirring was continued for 5 min.
Meanwhile, NaIO4 (427.8 mg, 2 mmol) and CeCl3‚7H2O (74.5 mg,
0.2 mmol) were stirred in water (0.5 mL) in a 10 mL round-
bottomed flask until the color of the suspension turned bright
yellow. After the suspension was cooled to 0 °C, acetone (1.5 mL)
and the metathesis reaction mixture were added. The resulting slurry
was stirred at 0 °C until the oxidation was complete (10-30 min).
Solid Na2SO4 and ethyl acetate were added, and the mixture was
filtered through a plug of silica into a saturated aq Na2SO3 solution.
The organic phase was separated, dried with Na2SO4, and concen-
trated in vacuum. The crude diol was then subjected to the standard
methanolysis conditions: To a stirred solution of the diastereomeric
diols (0.5 mmol) in a 1:1 mixture of CH2Cl2/MeOH (2 mL) was
(w), 1026 (w) cm-1
.
Data for anthopleurine (2R,3S)-88: optical rotations measured
as a solution in 1 M HCl, [R]2D0 -25.0 (c 0.72, 1 M HCl); HRMS
(ESI-HR) m/z calcd for C7H15NNaO4 200.0899, found 200.0896.
Data for ent-anthopleurine (2S,3R)-88: optical rotations mea-
sured as a solution in 1 M HCl, [R]2D0 24.4 (c 0.25, 1 M HCl);
HRMS (ESI-HR) m/z calcd for C7H15NNaO4 200.0899, found
200.0898.
Acknowledgment. We thank Prof. Dr. N. Krause for
generous support. B.P. thanks the Fonds der Chemischen
Industrie (Liebig fellowship) and the Deutsche Forschungsge-
meinschaft (Emmy-Noether fellowship). Further financial sup-
port by the Dr.-Otto-Ro¨hm-Geda¨chtnisstiftung is gratefully
acknowledged. N.M.N. thanks Mrs. Sandra Hauler and cand.-
chem. Johannes Klein for preparation of some starting materials.
Supporting Information Available: Experimental procedures
for the preparation of all starting materials (R,â-unsaturated
carboxylic acid derivatives) and the auxiliaries and 1H NMR spectra
of all reported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Musich, J. A.; Rapoport, H. J. Am. Chem. Soc. 1978, 100, 4865.
JO800145X
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