1-Phenylprop-2-ynyl acetate: A useful building block for the stereoselective construction of polyhydroxylated chains

Article abstract of DOI:10.1021/ol0616539

(R)- or (S)-1-phenylprop-2-ynyl acetate was added stereoselectively to aldehydes to afford 4-hydroxy-1-phenylalk-2-ynyl acetates. The transformation of such adducts into the corresponding allylic 1,4-diacetates allowed a highly efficient transfer of chirality from C1 to C3 by a regio- and stereoselective [3,3]-sigmatropic rearrangement. The obtained unsaturated 1,2-diacetates were useful synthetic intermediates whose double bond and/or phenyl group were transformed in different aldehydes, acids, or esters.

Full text of DOI:10.1021/ol0616539

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4501-4504
1-Phenylprop-2-ynyl Acetate: A Useful
Building Block for the Stereoselective
Construction of Polyhydroxylated
Chains
Xavier Ariza,* Jordi Garcia,* Yohan Georges, and Mar Vicente
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, Mart´ı i Franque`s 1,
08028 Barcelona, Spain
xariza@ub.edu
Received July 6, 2006
ABSTRACT
(R)- or (S)-1-phenylprop-2-ynyl acetate was added stereoselectively to aldehydes to afford 4-hydroxy-1-phenylalk-2-ynyl acetates. The
transformation of such adducts into the corresponding allylic 1,4-diacetates allowed a highly efficient transfer of chirality from C1 to C3 by
a regio- and stereoselective [3,3]-sigmatropic rearrangement. The obtained unsaturated 1,2-diacetates were useful synthetic intermediates
whose double bond and/or phenyl group were transformed in different aldehydes, acids, or esters.
The stereoselective formation of 1,2-diols with the concomi-
tant C(1)-C(2) bond formation has been mainly studied by
addition of an enolate (either a glycolate or an R-hydroxy-
ketone) to aldehydes.1 However, very often only one of the
two relative stereochemistries can be achieved. In the course
of studies directed toward the construction of sugar-type
polyhydroxylated frameworks with independent control of
each chiral center, we envisaged a new approach to 1,2-diols
based on a two-step process (Scheme 1): (i) stereoselective
addition of an alk-1-yn-3-ol (or its acetate) to an aldehyde
and (ii) transfer of chirality from the new alcohol formed to
the vicinal C(2) position (via A in Scheme 1) or, alternatively,
transfer of chirality from the C(4) stereocenter arising from
the alkyne moiety to the C(2) position (via B in Scheme 1).
Our initial efforts according to the first strategy only allowed
us the preparation of 1,2-syn diols.2 Gratifyingly, the second
option has been demonstrated to be more versatile. Herein,
we wish to report our findings in this connection.
First, we evaluated 1-phenylprop-2-yn-1-ol (1) as starting
chiral alkynol since this compound can be prepared in
enantiomerically enriched form through a lipase-catalyzed
resolution. Thus, the kinetic resolution of racemic 1-phen-
ylprop-2-yn-1-ol3 using Novozym 435 (Candida antarctica
Scheme 1. Chirality Transfer
(1) (a) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley & Sons: New York, 1995. (b) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem. Soc. ReV. 2004, 33, 65. (c) Enders, D.; Voith, M.;
Lenzen, A. Angew. Chem., Int. Ed. 2005, 44, 1304.
(2) Georges, Y.; Allenbach, Y.; Ariza, X.; Campagne, J.-M.; Garcia, J.
J. Org. Chem. 2004, 69, 7387.
10.1021/ol0616539 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/08/2006

lipase B)4 was very efficient at 60 °C,4a leading to (S)-(+)-1
alcohol and (R)-(+)-1-phenylprop-2-yn-1-yl acetate ((R)-2)
in up to 99% ee. Furthermore, acetylation of (S)-1 afforded
(S)-2, whereas hydrolysis of (R)-2 gave (R)-1 quantitatively.
Therefore, any stereoisomer of alcohol 1 or acetate 2 can be
obtained with high ee.
Table 1. Additions of (R)-2 to Aldehydes
Next, we focused our attention on the addition of 1 to
aldehydes. In 2000, Carreira et al. reported an efficient
enantioselective Zn-mediated addition of alkynes to alde-
hydes.5 Shortly thereafter, we extended this methodology to
alkynols.6 Based on these studies, we have explored the
addition of (R)-1 to cyclohexancarbaldehyde by using
commercially available Zn(OTf)2 (zinc triflate), (-)-N-
methylephedrine (NME), and Et3N in toluene (Scheme 2).
a 76% based on recovered starting material.
Scheme 2. Alkyne Addition
As result, a valuable matched case was observed for a
Felkin-Ahn addition to the protected lactaldehyde leading
to anti,anti-4d (Figure 1). More remarkably, Ley’s butane-
2,3-diacetal-protected glyceraldehyde proved to be an excel-
lent group in terms of reactivity and selectivity for both type
of additions (syn and anti).9
Since the reaction leading to diol syn-3a showed low
conversion (37% of recovered alkyne 1) and moderate
selectivity, we turned our attention to the corresponding
acetylated alkyne (R)-2. To our delight, alkynol syn-4a was
obtained in 94% yield and >99:1 dr7 in the addition of (R)-2
to cyclohexancarbaldehyde in the presence of (-)-NME.
Furthermore, the use of (+)-NME led to the anti isomer
(anti-4a) in 71% yield (Table 1).
As shown in Table 1, similar results were noted in the
addition of (R)-2 to a set of aldehydes. It should be mentioned
that the dominant stereochemical control was provided by
the NME employed (compare entries 2 and 3, or 6 and 7, in
Table 1) leading to >25:1 dr, with the resident stereogenic
center of 2 or of aldehyde playing a subordinate role.
The last entries in Table 1 concerning protected lactalde-
hyde and glyceraldehyde8 deserve special attention since the
good results suggested that highly polyhydroxylated species
could be obtained with a judicious choice of the stereochem-
istry of the aldehyde, the alkyne, and the NME (Figure 1).
To assess this assumption, we explored further additions to
such aldehydes using (S)-2.
Figure 1. Carreira’s additions to chiral aldehydes.
Keeping in mind the metal-catalyzed [3,3]-sigmatropic
rearrangement of allylic acetates,10 we then explored the
chirality transfer from the benzylic position (via B in Scheme
1). These rearrangements usually occur under thermody-
namical control and the more stable allylic acetate predomi-
nates (Scheme 3). Our hypothesis was that the conjugation
of the double bond to the phenyl group might shift the
equilibrium to the allylic acetate II.
(3) Prepared by addition of lithium acetylide to benzaldehyde: Mortier,
J.; Vaultier, M.; Carreaux, F.; Douin, J.-M. J. Org. Chem. 1998, 63, 3515.
(4) (a) Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343. (b)
Raminelli, C.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L. M.
Tetrahedron: Asymmetry 2004, 15, 3117.
(5) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687.
(6) (a) Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron Lett.
2002, 43, 2691. For propargyl acetate additions, see also: (b) El-Sayed,
E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3, 3017.
(7) Determined by HPLC analysis.
(8) (a) Michel, P.,; Ley, S. V. Angew. Chem., Int. Ed. 2002, 41, 3898.
(b) Michel, P.; Ley, S. V. Synthesis 2004, 147.
(9) Boyer, J.; Allenbach, Y.; Ariza, X.; Garcia, J.; Georges, Y.; Vicente,
M. Synlett 2006, 1895.
(10) For recent stereoselective applications, see: (a) Trost, B. M.; Lee,
C. B. J. Am. Chem. Soc. 2001, 123, 3687. (b) Saito, S.; Kuroda, A.;
Matsunaga, H.; Ikeda S. Tetrahedron 1996, 52, 13919.
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Org. Lett., Vol. 8, No. 20, 2006

(PhCN)2 in different solvents: CH3CN (0%), THF (25%),
toluene (65%), and CH2Cl2 (83%). Therefore, CH2Cl2 was
chosen as standard solvent.
Scheme 3. [3,3]Sigmatropic Rearrangement
The partial hydrogenation of the triple bond of either syn-
or anti-4a followed by acetylation afforded (Z)-6a (syn or
anti). In sharp contrast with their E isomers, (Z)-6a did not
rearrange in CH2Cl2 under Pd(II) catalysis. As shown in
Scheme 5, the rearrangement only occurred with lower
stereoselectivity at higher temperature (CHCl3 at reflux).12
Scheme 6. Isomerization of Monoacetate (E)-syn-10a
To confirm this assumption, the propargylic acetate syn-
4a was first converted into the corresponding (E)-allylic
diacetate [(E)-syn-6a] and then treated with PdCl2(PhCN)2.11
We were gratified to observe the expected rearrangement
with complete transfer of chirality to afford the diacetate (E)-
syn-7a (Scheme 4). Very interestingly, only the benzylic
Scheme 4. Allylic Isomerization
Finally, looking for bearing different protecting groups in
the final 1,2-diols (Scheme 6) we explored other protectors
for the free hydroxyl group in adducts 4.
acetate isomerizes. The same behavior was observed for the
isomer (E)-anti-6a (96% yield).
Scheme 5. Isomerization of (Z)-6a
Figure 2. Pd(II)-catalyzed rearrangements.
Thus, syn-4a was protected as a benzyl ether and then
transformed into the corresponding allylic acetate (E)-syn-
10a (Scheme 6). When (E)-syn-10a was treated with Pd(II)
The effect of the solvent was next tested. Samples of (E)-
anti-6 were stirred (6 h, rt) in the presence of 5% of PdCl2-
(11) The catalytic activity of other Lewis acids (BF3‚Et2O, Sc(OTf)3,
TsOH, ...) was also explored but no reaction was observed after 2 h at rt in
CH2Cl2 in any case.
(12) The lower reactivity of (Z)-isomers was already reported for related
substrates (ref 10b).
Org. Lett., Vol. 8, No. 20, 2006
4503

catalysis the expected product [(E)-syn-11a] was obtained
in 85% yield (100% brsm) with perfect transfer of chirality.
However, rearrangements failed in analogous substrates with
the hydroxyl group unprotected or protected as TBS ether.
Having in hand this methodology, we undertook the
preparation of D-arabitol pentaacetate (17, Scheme 8).
Scheme 8. Arabitol Pentaacetate
Under our optimized conditions [5% PdCl2(PhCN)2 in
CH2Cl2 at reflux], several allylic 1,4-diacetates were rear-
ranged to 1,2-isomers (Figure 2). In all cases, complete
chirality transfer was observed being the starting material
the only other compound detected. Despite the fact that allylic
equilibrium is shifted toward the products, in some cases a
significant amount of starting material was recovered.
At this point several transformations were attempted to
convert these allylic acetates in convenient precursors for
subsequent additions (Scheme 7). Thus, the unsaturated
Oxidative cleavage of the olefin of (E)-anti,syn-7e to
triacetate 16 followed by hydrolysis and in situ acetylation
gave 17.14
In summary, we have developed a new procedure for the
stereoselective preparation of 1,2-diols, with independent
control of both stereocenters. The above methodology can
be potentially used for stepwise enantioselective synthesis
of polyhydroxylated chains as exemplified in the preparation
of D-arabitol pentaacetate.
Scheme 7. Useful Transformations of the Styryl Moiety
Acknowledgment. This work has been supported by the
Ministerio de Ciencia y Tecnologia (BQU2003-01269). We
thank to the Generalitat de Catalunya and Universitat de
Barcelona for doctorate studentships to Y.G. and M.V.,
respectively. We also acknowledge a generous gift of
Novozym 435 from Novozymes Spain SA.
Supporting Information Available: Experimental pro-
cedures and analytical data for all of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
moiety in diacetate syn-7a was transformed in either a
carbaldehyde (syn-12a) by an OsO4/NaIO4 oxidation or a
methyl ester (syn-13a) by RuCl3/NaIO4 oxidation,13 followed
by methylation. On the other hand, syn-7a was hydrogenated
to syn-14a and the phenyl group could be oxidized to methyl
ester syn-15a in a two-step process.
OL0616539
(14) As expected, compound 17 showed identical spectral data as that
reported in the literature: (a) Jarosz, S.; Sko´ra, S.; Szewczyk, K.; Ciunik,
Z. Tetrahedron: Asymmetry 2001, 12, 1895. (b) Nakagawa, I.; Aki, K.;
Hata, T. J. Chem. Soc., Perkin Trans. 1 1983, 1315. (c) Hirai, A.; Tonooka,
T.; Tanino, K.; Miyashita, M. Chirality 2003, 15, 108.
(13) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
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Org. Lett., Vol. 8, No. 20, 2006