Iterative Cr-mediated catalytic asymmetric allylation to synthesize syn/syn- and anti/anti-1,3,5-triols

Article abstract of DOI:10.1021/ol801094e

(Chemical Equation Presented) Iterative use of Cr-mediated catalytic asymmetric allylation could give a simple access to 1,3-polyols. Using syn/syn- and anti/anti-1,3,5-triols as representative examples, the feasibility of this approach is studied, thereby demonstrating that (1) the pre-existing TMS-protected alcohol at the β-position does not give a significant effect on the Cr-mediated catalytic asymmetric allylation and (2) this synthetic route furnishes the expected syn/syn- and anti/anti-1,3,5-triols at the useful level of asymmetric induction and yield.

Full text of DOI:10.1021/ol801094e

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3077-3080
Iterative Cr-Mediated Catalytic
Asymmetric Allylation To Synthesize
syn/syn- and anti/anti-1,3,5-Triols
Zhiyu Zhang, Sylvain Aubry, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received May 12, 2008
ABSTRACT
Iterative use of Cr-mediated catalytic asymmetric allylation could give a simple access to 1,3-polyols. Using syn/syn- and anti/anti-1,3,5-triols
as representative examples, the feasibility of this approach is studied, thereby demonstrating that (1) the pre-existing TMS-protected alcohol
at the ꢀ-position does not give a significant effect on the Cr-mediated catalytic asymmetric allylation and (2) this synthetic route furnishes the
expected syn/syn- and anti/anti-1,3,5-triols at the useful level of asymmetric induction and yield.
In the preceding paper,1 we reported Cr-mediated catalytic
asymmetric 2-haloallylation and allylation in the presence
Scheme 1. Co/Cr-Mediated Catalytic Asymmetric
of sulfonamide-based ligand A (Scheme 1). Many natural
products are known to contain a 1,3-polyol as a structure
cluster. Interestingly, this structure cluster is found in a
wide range of natural products, with a great diversity of
stereochemistry arrangement.2 In addition, some natural
products are known to possess the permethylated form of
1,3-polyol.3 We notice that an iterative use of the Cr-
2-Iodoallylation and Cr-Mediated Catalytic Asymmetric
Allylation in the Presence of Sulfonamide Ligand Aa
(1) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett. 2008, 10, 3073.
(2) The 1,3-polyol structure cluster is present in numerous natural
products ranging from antibiotics to marine natural products. A substructure
search with SciFinder gave 87 and 35 natural products bearing one or more
of 1,3,5,7,9-pentaol(s) and 1,3,5,7,9,11,13-heptaol(s), respectively.
(3) For example, see: (a) Mynderse, J. S.; Moore, R. E Phytochemistry
1979, 18, 1181. (b) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Mori,
Y.; Suzuki, M J. Org. Chem. 1990, 55, 4431. (c) Mori, Y.; Kawajiri, N.;
Furukawa, H.; Moore, R. E Tetrahedron 1994, 50, 11133, and references
cited therein. (d) Nakata, T.; Suenaga, T.; Nakashima, K.; Oishi, T
Tetrahedron Lett. 1989, 30, 6529 and the preceding paper. (e) Rychnovsky,
S. D.; Griesgraber, G. J. Org. Chem. 1992, 57, 1559. (f) Rao, M. R.;
Faulkner, D. J. J. Nat. Prod. 2002, 65, 1201.
aFor the structure of A, see Scheme 2.
mediated catalytic asymmetric allylation might give us a
stereocontrolled synthetic access to this structure cluster.
In this letter, using syn/syn- and anti/anti-1,3,5-triols as
representative examples, we demonstrate the feasibility
of this approach.
10.1021/ol801094e CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

Clearly, the central issue concerned with this iterative
approach is how to eliminate, or reduce, the effect from the
pre-existing alcohol, or its protected form, at the ꢀ-position
on the catalytic asymmetric allylation.7 As reported in the
preceding paper, a significant effect from a methyl group at
the ꢀ-position was detected for allylation of (R)-(+)-
citronellal with allyl and methallyl bromides, whereas only
an insignificant effect was detected for allylation with γ,γ-
dimethylallyl and 2-haloallyl bromides.1 Despite these
somewhat confusing results, we decided to study the feasibil-
ity of this approach, with the hope that a suitable protecting
group could be found, to override the pre-existing alcohol
at the ꢀ-position on the Cr-mediated catalytic asymmetric
allylation.
Scheme 2. Iterative Synthesis of syn/syn- and anti/
anti-1,3,5-Triols via Cr-Mediated Catalytic Asymmetric
Allylation in the Presence of Ligands A and ent-Aa
To avoid the technical difficulty associated with high
volatility of substrates, we chose to use heptanal (1) for this
demonstration. Thus, 1 was subjected to the Cr-mediated
catalytic asymmetric allylation in the presence of sulfonamide
ligand A, followed by TMS protection, to furnish the an-
ticipated, protected allylic alcohol 2 in 83% yield (Scheme
3).8 The enantiomeric excess (ee) of 2 was estimated to be
aOne cycle of iteration is composed of oxidative cleavage of the olefin
to form an aldehyde, catalytic asymmetric allylation, and protection of the
resultant alcohol.
Scheme 3
.
The First Cr-Mediated Catalytic Asymmetric
Allylation
Various methods are known effectively to synthesize 1,3-
polyols.4 Among them, the method by Cossy and co-workers5
is most relevant to the current work; they iteratively utilized
enantioselective allyltitanation with (R,R)- or (S,S)-cyclo-
pentadienyldialkoxy allyltitanium complex developed by
Hafner, Duthaler, and co-workers.6 An impressive level of
stereochemistry control was achieved, although it utilized a
stoichiometric amount of (R,R)- or (S,S)-titanium complex.
Scheme 2 outlines our iterative approach for a synthesis
of syn/syn- and anti/anti-1,3,5-triols. One cycle of iteration
is composed of a three-step operation, i.e., oxidative cleavage
of the olefin to form an aldehyde, catalytic asymmetric
allylation, and protection of the resultant alcohol. Conceptu-
ally, this iterative approach is the same as the method used
by Cossy, with two exceptions. First, Cossy utilized the Ti-
based asymmetric allylation, whereas we intend to utilize
the Cr-based asymmetric allylation. Second, Cossy used a
stoichiometric amount of the chiral Ti reagent, whereas we
attempt to employ a catalytic amount of the chiral Cr reagent.
97% from the 1H NMR spectra of (R)- and (S)-Mosher esters
of the allylic alcohol.9
We then conducted a preliminary study on the protecting-
group effect on the next round of catalytic asymmetric
allylation. Among three types of protecting groups tested:
(1) silyl ethers (TMS, TES, and TBS), (2) ether (PMB), and
(3) esters (Ac and MeOAc), sterically least demanding TMS
was found to give the most satisfactory result on both
asymmetric induction and yield.10
With this result in hand, we subjected the TMS-protected
allylic alcohol 2 to the first cycle of iteration (Scheme 4).
(4) For reviews on this subject, see: (a) Bode, S. E.; Wolberg, M.; Mu¨ller,
M. Synthesis 2006, 557. (b) Schneider, C. Angew. Chem., Int. Ed. 1998,
37, 1375. (c) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (d) Norcross,
R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041. (e) Hoveyda, A. M.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (f) Oishi, T.; Nakata, T.
Synthesis 1990, 635. (g) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984,
23, 556.
(7) For a review on this subject, see: (a) Masamune, S.; Choy, W.;
Peterson, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
(8) With use of TMS-Cl as the dissociating agent, the transformation
of 1 into 2 could be achieved in a single step. Under this condition, however,
the rate of coupling was significantly slower and the yield was lower.
(9) For the determination of absolute configuration, see the Supporting
Information for (a) Kurosu, M.; Lin, M.-H.; Kishi, Y J. Am. Chem. Soc.
2004, 126, 12248.
(5) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501. (b) BouzBouz,
S.; Cossy, J Tetrahedron Lett. 2000, 41, 3361. (c) BouzBouz, S.; Cossy, J
Org. Lett. 2000, 2, 3975. (d) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz,
S J. Org. Chem. 2002, 67, 1982. (e) Amans, D.; Bellosta, V.; Cossy, J.
Org. Lett 2007, 9, 1453. (f) Ferrie´, L.; Boulard, L.; Pradaux, F.; Bouzbouz,
S.; Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864.
(6) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(10) Protection with an ether (PMB) or silyl ether (TES and TBS) group
made the rate of allylation to be significantly slower. Protection with an
acyl (Ac and MeOAc) group gave an excellent result in terms of asymmetric
induction, but products were often accompanied with the corresponding
elimination by-products. In addition, the rate of allylation with an aldehyde
bearing a free alcohol was found to be very slow.
3078
Org. Lett., Vol. 10, No. 14, 2008

syn- and anti-diols was readily achieved by silica gel
chromatography. The optical purity of syn- and anti-diols
was then examined by 1H NMR spectroscopy of their Mosher
esters, thereby confirming the predicted optical purity.12
Overall, these experiments demonstrated that the pre-
existing TMS-protected ꢀ-alcohol does not give a significant
effect on the Cr-mediated catalytic asymmetric allylation in
the terms of asymmetric induction.
Scheme 4
.
First Cycle of Iterative Synthesis in the Presence of
Ligand A or Its Enantiomer ent-Aa
We then proceeded to the second cycle of iteration. As
before, after oxidative cleavage of the olefin, syn-3 (de >
99%) and anti-3 (de > 99%) were subjected to catalytic
asymmetric allylation in the presence of sulfonamide ligand
A. After the resultant alcohol protected as a TMS ether, the
products were isolated by passing through a short silica gel
column to furnish syn/syn-4 and anti/anti-4, respectively
(Scheme 5). The diastereomeric purity of syn/syn-4 (de )
a One cycle of iteration is composed of a three-step sequence: (1) OsO4/
NMO, followed by Pb(OAc)4 treatment (85% yield); (2) Cr-mediated
catalytic asymmetric allylation in the presence of ligand A or ent-A; (3)
TMS-Cl/Et3N (81% yield for two steps). These transformations were also
performed with 2 (ee ) 97%) to furnish syn-3 (de ) 92%) and anti-3 (de
) 95%), respectively.
Scheme 5
.
Second Cycle of Iterative Synthesis in the Presence
of Ligand Aa
After oxidative cleavage of the olefin, 2 was subjected to
the Cr-mediated catalytic asymmetric allylation in the
presence of sulfonamide ligand A or its enantiomer ent-A,
followed by TMS protection and product isolation by passing
through a short silica gel column.11 The H NMR analysis
1
revealed that the diastereomeric purity of resultant syn-3 and
anti-3 was de ) 92% and de ) 95%, respectively, thereby
showing that the pre-existing TMS ether group at the
ꢀ-position gave a small match/mismatch effect for this
transformation.
We should note that the optical purity of 2 used for this
study was ee ) 97%. Taking account of the optical purity
of 2 and assuming that the aldehyde derived from 2 and
contaminated enantiomer reacted with allyl bromide in the
same rate, we could estimate the degree of asymmetric
induction for 2fsyn-3 and 2fanti-3 to be de f 95% and
de f 98%, respectively.
aOne cycle of iteration is composed of a three-step sequence: (1) OsO4/
NMO, followed by Pb(OAc)4 treatment (85% yield); (2) Cr-mediated
catalytic asymmetric allylation in the presence of ligand A; (3) TMS-Cl/
Et3N (two-step yield: 64% in the syn/syn-series and 70% in the anti/anti-
series).11
We naturally wished to confirm this estimation experi-
mentally. For this reason, we looked for a method to enrich
the optical purity of 2 and eventually found that the optical
purity of 2 can be enriched via a 3-step operation, i.e.,
(1) preparation of crystalline p-acetylphenylcarbamate, (2)
recrystallization, and (3) NaOH/MeOH.12 With use of the
optically pure 2 (ee >99%), the anticipated degree of
asymmetric induction was experimentally verified (Scheme
4).12
It is also worthwhile commenting on the optical purity of
syn-3 and anti-3. Even for the case where 2 with ee ) 97%
was used, we expected that the optical purity of products
should be enhanced in this process; based on the same
considerations, we anticipated the optical purity of both syn-3
and anti-3 should exceed 99%. Because of the low polarity,
chromatographic separation of syn-3 and anti-3 was not
practical. However, after TMS-deprotection, separation of
97%) and anti/anti-4 (de ) 95%) was estimated from their
1H NMR spectra. Like the first cycle of iteration, we once
again detected only a small match/mismatch effect from the
pre-existing TMS ether groups. Interestingly, contrary to the
first cycle, a better asymmetric induction was observed for
the path leading to syn-product than the path to anti-product
for this cycle.13
Overall, the second cycle of iteration once again demon-
strated that the pre-existing TMS-protected alcohol does not
give a significant effect on the Cr-mediated catalytic asym-
metric allylation in the terms of asymmetric induction and
chemical yield.
Up to this stage, we assigned the stereochemistry of
allylation product, based on the sulfonamide-based ligand
A or ent-A employed for a given allylation.9 In this
connection, we should mention our NMR database relevant
to the current case; the central carbon of an acyclic 1,3,5-
triol exhibits a distinctive chemical shift dependent on its
(11) The oxidative cleavage could be done in one step (O3, followed
by PPh3 treatment or OsO4/NaIO4) or two steps (OsO4/NMO, followed by
NaIO4 treatment or by Pb(OAc)4 treatment). Among them, the procedure
of OsO4/NMO, followed by Pb(OAc)4 treatment, gave the best yield.
(12) For details, see the Supporting Information.
(13) These transformations were first studied with syn-3 (de ) 92%)
and anti-3 (de ) 95%). The diastereomeric purity of resultant syn/syn-4
and anti/anti-4 was estimated to be de ) 93% and 91%, respectively.
Org. Lett., Vol. 10, No. 14, 2008
3079

relative stereochemistry, but independent of the functional-
ities present outside of the structure cluster.14 In practice,
the central carbon of anti/anti-, anti/syn- or syn/anti-, and
syn/syn-1,3,5-triols gives a 13C NMR resonance in CD3OD
at 66.3 ( 0.5 ppm, 68.6 ( 0.5 ppm, and 70.7 ( 0.5 ppm,
respectively.15 In the case of 1,3,5-triols derived from syn/
syn-4 and anti/anti-4, the chemical shift of central carbon
was observed at 70.5 and 66.3 ppm, respectively, thereby
confirming the stereochemistry assigned based on the sul-
fonamide-based ligands A or ent-A employed for a given
allylation.
syn- and anti/anti-1,3,5-triols. This study has demonstrated
that (1) the pre-existing TMS-protected alcohol at the
ꢀ-position does not give a significant effect on the Cr-
mediated catalytic asymmetric allylation and (2) this synthetic
approach furnishes the expected syn/syn- and anti/anti-1,3,5-
triols at the useful level of asymmetric induction and yield.
Acknowledgment. Financial support from the National
Institutes of Health (CA 22215) and Eisai Research Institute
is gratefully acknowledged. S.A. gratefully acknowledges a
postdoctoral fellowship from the Association pour la Re-
cherche sur le Cancer (ARC).
In summary, iterative Cr-mediated catalytic asymmetric
allylation has been shown to give a simple access to syn/
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. HelV. Chim. Acta 2000, 83,
2562.
(15) In DMSO-d6, anti/anti-, anti/syn-, and syn/syn-1,3,5-triols give the
characteristic chemical shift at 63.9 ( 0.5 ppm, 66.2 ( 0.5 ppm, and 68.2
( 0.5 ppm, respectively.
OL801094E
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Org. Lett., Vol. 10, No. 14, 2008