Diastereoselective Acetalization of Pseudo-C2-Symmetric 1,3,5-Triols: A New Strategy for the Synthesis of Polyacetates and Polypropionates

Full text of DOI:10.1021/jo970808a

4558
J . Org. Chem. 1997, 62, 4558-4559
Dia ster eoselective Aceta liza tion of
P seu d o-C2-Sym m etr ic 1,3,5-Tr iols: A New
Str a tegy for th e Syn th esis of P olya ceta tes
a n d P olyp r op ion a tes
J ennifer N. Shepherd, J im Na, and David C. Myles*
Department of Chemistry and Biochemistry, UCLA,
Los Angeles, California 90095-1569
F igu r e 1.
Received May 8, 1997
In this paper, we describe a new, highly general
approach to the synthesis of 1,3-polyol and polypropi-
onate structures based on the oxidative acetalization of
p-methoxybenzyl (PMB) ethers of pseudo-C2-symmetric
1,3,5-triols. Polyhydroxylated carbon chains, such as
those found in polyacetates (1,3...n-polyols) and polypro-
pionates (2,4...n-polymethyl-1,3,5...n-polyols), are ubiq-
uitous substructures found in many important natural
products. The control of stereochemistry in the context
of such structures has spawned many novel synthetic
strategies often based on reiterative application of dia-
stereoselective methodology1 or simultaneous two-direc-
tional chain synthesis.2 Our strategy combines elements
of both of these approaches to achieve rapid access to
differentially protected 1,3-polyol and polypropionate
precursors with high diastereoselectivity.
described by Sharpless7 to furnish tetrol 6. Through this
dihydroxylation, the pseudo-C2-symmetry was estab-
lished in one operation. Oxidation of the PMB ether of
6 to the corresponding acetals using DDQ afforded 7 and
8 in greater than 90% yield. Under standard conditions
(DDQ, room temperature, CH2Cl2), we found that the
oxidative acetalization gave a mixture of two acetals in
a ratio of ca. 95:5. Only two acetal-containing products
were observed for this cyclization. We determined the
stereochemistry of the major diastereomer by examina-
tion of the NOESY spectrum of triacetate 9, prepared by
acetylation of 7 (Ac2O, Et3N, CH2Cl2, DMAP). Close
contacts were observed between all axial methine protons
on the newly established acetal ring. The diastereo-
selectivity of this cyclization shows a dramatic temper-
ature dependence. At 25 °C, we found that the diaster-
eomeric ratio was 95:5, at 0 °C the ratio was 98:2, and
at -30 °C, the ratio of acetal isomers was >99:1.8 Under
these conditions, the oxidative acetalization is an ir-
reversible process, and therefore, the product ratio is
representative of ∆∆Gq. From these ratios, we are able
to estimate that the ∆∆Gq for the two cyclization path-
ways is 2.0 ( 0.3 kcal/mol. This value is consistant with
the 2.3 kcal/mol energy difference, ∆E, between the
products of cyclization as determined by MM2.9 Having
succeeded in effectively differentiating the pseudohomo-
topic alcohols of the starting polyol 6, a potential precur-
sor for the synthesis of 1,3-polyols, we next examined the
cyclization of polypropionate precursors.
The oxidative cyclization of mono-PMB ethers of 1,3-
diols to afford the corresponding p-methoxyphenyl (PMP)
acetals is well known.3 The oxidation of the aromatic
ring with DDQ under anhydrous conditions gives the
benzylic cation, which undergoes cyclization via a 6-exo-
trig4 -like ring closure. In the case of the 1,3-diol
monoethers, there is only one possible regioisomer of
cyclization. In contrast, C-3 PMB ethers of pseudo C2-
symmetric 1,3,5-triols may cyclize to afford either the
(1,3) or (3,5) acetal isomers. We evaluated the factors
that govern which of these two isomers will predominate
in the oxidative cyclization in the context of transition
structures A and B (Figure 1). Cyclization via A places
all substituents of the forming ring in pseudoequatorial
locations, whereas in B at least one is placed in an axial
We prepared polypropionate precursor 11 via a short
sequence from readily available 3-[(p-methoxybenzyl)-
oxy]-2,4-dimethyl-1,4-pentadiene (10) (Figure 3).10 Di-
astereoselective hydroboration of diene 1011 afforded
pseudo-C2-symmetric diol 11 as the major component of
a 23:5:1 mixture of diastereomeric products. We obtained
11 in high diastereomeric purity by recrystallization of
the bis(4-nitrobenzoate). As before, oxidation of the PMB
ether to the corresponding acetals using DDQ afforded
the expected products in greater than 90% yield. At 25
°C, we found that the oxidative acetalization gave a
q
location. Therefore, we expect that the energy of A (∆GA )
would be less than that of B (∆GBq), and the product
mixtures obtained from the oxidative acetalization of 1
should favor acetal 2 arising from transition structure
A.5
To test our hypothesis, we first examined the cycliza-
tion of polyhydroxylated PMB ether 6, a precursor for
the synthesis of 1,3-polyols (Figure 2). We prepared 6
via a short, two-directional synthesis from readily avail-
able 4-[(p-methoxybenzyl)oxy]-1,6-heptadiene (4).6 Ozo-
nolysis of 4, followed by homologation with triethyl
phosphonoacetate and NaH afforded the dienoate 5. This
material was then dihydroxylated under the conditions
(7) (a) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,
J .; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibati, T.;
Ukita, T. J . Org. Chem. 1991, 56, 4585. (b) Corey , E. J .; J ardine, P.
D.; Virgil, S.; Yuen, P.; Connell, R. D. J . Am. Chem. Soc. 1989, 111,
9243.
(1) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
(2) See (inter alia): Ho, T. L. Tactics of Organic Synthesis Wiley:
New York, 1994; pp 33-38 and references cited therein.
(3) Oikiawa, Y.; Toshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
(4) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(5) Hoye and co-workers have investigated structurally analogous
6-exo-trig cyclizations of functionalized pseudo-C2 hydroxy diacids and
esters to form valerolactones and found that the selectivity for the all-
equatorially functionalized lactone was high. See: Hoye, T. R.; Peck,
D. R.; Swanson, T. A. J . Am. Chem. Soc. 1984, 106, 2748.
(6) Ether 4 was prepared from commercially available 1,6-heptadien-
4-ol by benzylation (PMB-Cl, NaH, THF).
(8) Diastereomeric ratios were determined by integration of the
acetal proton in the 1H NMR spectra.
(9) Molecular modeling was carried out on
a Silicon Graphics
workstation using MacroModel V5.0 (Richards, N. G. J .; Guida, W.
C.; Liskamp. R.; Lipton, M.; Caulfield, C.; Chang, G.; Hendrickson,
T.; Still, W. C. J . Comput. Chem. 1990, 11, 440). For compounds 7
and 8, Monte Carlo conformational searches were carried out using
Batchmin (500 MC steps, MM2, energy window ) 25 kJ /mol, 2000
maximum iterations). Calculated energies are global minima.
(10) Ether 10 was prepared from methacrolein and 2-propenylmag-
nesium bromide followed by benzylation.
(11) Harada, T.; Matsuda, Y.; Uchimura, J .; Oku, A. J . Chem. Soc.,
Chem. Commun. 1990, 21.
S0022-3263(97)00808-6 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 14, 1997 4559
F igu r e 2.
F igu r e 3.
mixture of acetals 12 and 13 in a ratio of ca. 75:25. Only
two acetal-containing products were observed for this
cyclization. We determined the stereochemistry of the
precursors for the preparation of complex polyoxygenated
natural products. The similarity of the calculated ∆E of
the products and the experimentally determined ∆∆Gq
suggests that the transition state is late. Furthermore,
the similarity of these energy values suggests that
computational analysis of potential substrates to predict
product ratios should be useful in the optimization of this
reaction for use in synthesis. We are currently develop-
ing this methodology in the context of 1,3-polyol and
polypropionate synthesis.
1
major diastereomer by examination of the indicated H-
1H coupling constants of benzyl ether 14, prepared by
benzylation of 12 with benzyl bromide and sodium
hydride in THF (Figure 2). Like the previously described
cyclization, the diastereoselectivity of this cyclization also
shows a temperature dependence. At 25 °C, we found
that the diastereomeric ratio was 75:25, at 0 °C the ratio
was 79:21, and at -30 °C the ratio of acetal isomers was
82:18. From these ratios, we are able to estimate that
the ∆∆Gq for the cyclization pathways leading to 12 and
13 is 0.7 ( 0.1 kcal/mol. Computational analysis (MM2)
of the energies of 12 and 13 gave a ∆E for these
compounds of 0.7 kcal/mol.
Ack n ow led gm en t. Financial support was provided
by the Alfred P. Sloan Foundation, the Academic Senate
of University of California, and the Office of the
Chancellor. We thank Prof. K. N. Houk and Ms. C. S.
McKnight for assistance with the computational analy-
sis of the oxidative acetalization and Mr. S. G. Hegde
for assistance in obtaining the NOESY spectrum of 9.
End differentiation of pseudo-C2-symmetric chains is
a powerful strategy for the rapid synthesis of stere-
ochemically complex structures. The results presented
in Figures 2 and 3 demonstrate that oxidative acetaliza-
tion can be used to differentiate the end groups in 1,3,5-
triol systems having pseudo-C2-symmetry. These reac-
tions can be used to synthesize highly dissymmetric
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data for compounds 4-14 and copies
of 1H and 13C NMR spectra and depictions of minimized
structures of 7, 8, 12, and 13 (32 pages).
J O970808A