Diastereoselective synthesis of protected syn 1,3-diols: preparation of the C16-C24 portion of Dolabelides.

Article abstract of DOI:10.1021/ol017122w

We have designed a new method to make synthons encompassing a protected syn 1,3-diol motif and an aldehyde alpha to the 1,3-dioxane ring. An additional stereocenter was also created, potentially leading to stereochemically defined 1,2,4-triols. This metho

Full text of DOI:10.1021/ol017122w

ORGANIC
LETTERS
2002
Vol. 4, No. 3
419-421
Diastereoselective Synthesis of
Protected syn 1,3-Diols: Preparation of
the C16−C24 Portion of Dolabelides
,‡
Laurence Grimaud,† Romain de Mesmay,† and Joe1lle Prunet*
Laboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure des Techniques AVance´es,
32 bouleVard Victor, F-75015 Paris, France, and Laboratoire de Synthe`se Organique,
UMR CNRS 7652, Ecole Polytechnique, DCSO, F-91128 Palaiseau, France
joelle.prunet@polytechnique.fr
Received November 26, 2001
ABSTRACT
We have designed a new method to make synthons encompassing a protected syn 1,3-diol motif and an aldehyde r to the 1,3-dioxane ring.
An additional stereocenter was also created, potentially leading to stereochemically defined 1,2,4-triols. This method was successfully applied
to the synthesis of the C16−C24 portion of Dolabelides.
In 1995, Dolabelides A and B were isolated from Japanese
specimens of the sea hare Dolabella auricularia (family
Apysiidae).1 Two parent compounds, Dolabelides C and D,
were extracted from the same source in 1997 (Figure 1).2
These macrolides exhibit cytotoxicity against HeLaSe3 cell
lines with IC50 values of 6.3, 1.3, 1.9, and 1.5 µg/mL,
respectively. Their structures were determined by spectro-
scopic techniques such as HRFABMS and 2D NMR, and
their absolute configuration was ascertained by applying the
modified Mosher method.3
by a macrolactonization involving the appropriate hydroxyl
function (C21 for the A, B series and C23 for the C, D
The retrosynthesis we envisioned is shown in Scheme 1.
Dolabelides can be disconnected in two roughly equal
fragments C1-C15 and C16-C30. The macrocycle would
be constructed by a Suzuki coupling4 between a vinyl iodide
at C15 and a borane derived from the olefin at C16, followed
† Ecole Nationale Supe´rieure des Techniques Avance´es.
‡ Ecole Polytechnique.
(1) Ojika, M.; Nagoya, T.; Yamada, K. Tetrahedron Lett. 1995, 36, 7491.
(2) Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada, K. J.
Nat. Prod. 1997, 60, 155.
(3) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(4) For a recent use of such a coupling reaction, see: Sawada, D.;
Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 209 and references therein.
Figure 1. Structures of Dolabelides A, B, C, and D.
10.1021/ol017122w CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/12/2002

Scheme 1
Scheme 3
series). The order of events could also be reversed. The C16-
C30 portion would be made from aldehyde 1, using a Wittig
reaction to install the trisubstituted double bond between C24
and C25.
We report here the synthesis of the C16-C24 synthon 1
of Dolabelides, which involves a new method for the
construction of the C21-C23 stereotriad.
We planned to introduce the hydroxyl group at C23 by
an intramolecular conjugate addition of a hemiacetal anion
made in situ from homoallylic alcohol 3 and benzaldehyde
in the presence of a catalytic amount of potassium tert-
butoxide, which would lead to compound 4 (Scheme 2).
the corresponding sulfone was carried out with hydrogen
peroxide in the presence of a catalytic amount of ammonium
molybdate tetrahydrate. Deprotection of the TES ether gave
carbamate sulfone (()-7 in 89% yield.
The key conjugate addition proceeded in very good yield
and selectivity, affording protected syn diol (()-8 as a single
diastereomer. The diastereoselectivity at the diol level was
not unexpected; all the substituents on the 1,3-dioxane ring
are equatorial and thus (()-8 is the thermodynamically
favored product. However, we were surprised to see that the
diastereoselectivity was also excellent for the formation of
the stereocenter bearing the carbamate and the sulfone
groups. The configuration of this carbon has not been
determined, since it is destroyed in the next step, but could
be exploited by performing a nucleophilic substitution of the
sulfone group.
Scheme 2
A conjugate addition of this type has been reported by
Evans and Prunet,5 where X is an ester or a Weinreb amide
(and Y is a proton). In our case, X and Y should be easily
converted into an aldehyde moiety, and one of them should
be a Michael acceptor. To that aim, a sulfone was selected
to be the electron-withdrawing group X; Y could then be a
protected alcohol. We chose the carbamate group designed
by Hoppe, because precursors of 3 (such as 5, see Scheme
3) could be prepared diastereoselectively and enantioselec-
tively by a homoaldol reaction,6 which installs both stereo-
centers at C21 and C22.
The feasibility of the methodology was tested on model
compound (()-5.7 Sulfide (()-6 was obtained in excellent
yield from the triethylsilyl ether derived from (()-5 by
treatment with tert-butyllithium and diphenyl disulfide in the
presence of TMEDA (Scheme 3). Subsequent oxidation to
Attempts to hydrolyze the carbamate moiety under acidic
conditions failed to produce aldehyde (()-9 or the corre-
sponding deprotected lactol (()-11.8,9 Transformation of the
key intermediate into the desired aldehyde was effected in
10
two steps: reduction of the carbamate with LiAlH4 pro-
duced aldehyde (()-9 by elimination of benzenesulfinate,11
but this aldehyde was subsequently reduced to the primary
alcohol in 81% yield. This alcohol could be reoxidized to
the desired aldehyde (()-9 by o-iodoxybenzoic acid (IBX)12
in 74% yield. Aldehyde (()-9 could be transformed into
olefin (()-10 with phosphorane 2 in 89% yield.13
(8) Prolonged exposure to 3 N HCl/THF at 65 °C cleanly gave alcohol
7.
(9) Lactol 11 was also prepared by diasteresoselective epoxidation (73%,
>95:5) followed by acidic hydrolysis (74%), according to: (a) Hoppe, D.;
Lu¨bmann, J.; Jones, P. G.; Schmidt, D.; Sheldrick, G. M. Tetrahedron Lett.
1986, 27, 3591. (b) Hoppe, D.; Tarara, G.; Wilckens, M. Synthesis 1989,
83.
(10) Hoppe, D.; Tebben, P.; Reggelin, M.; Bolte, M. Synthesis 1997,
183.
(11) For a similar elimination, see ref 9.
(5) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
(6) Hoppe, D.; Zshage, O. Angew. Chem., Int. Ed. 1989, 28, 69. Zshage,
O.; Hoppe, D. Tetrahedron 1992, 48, 5657.
(7) Hoppe, D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg, F.; Van Hulsen,
E. Chem. Ber. 1985, 118, 2822.
420
Org. Lett., Vol. 4, No. 3, 2002

Having in hand a route to a model compound of the C16-
C24 fragment of Dolabelides, we addressed the synthesis of
this fragment. Aldehyde 13 was prepared in 3 steps from
known alcohol 12 (Scheme 4).14 The required carbamate was
peroxide was used in excess. The key step again proceeded
with excellent diastereoselectivity to furnish 17 in 86% yield.
Conversion of 17 to the required aldehyde 18 was
uneventful (Scheme 6), and the C16-C24 fragment of
Dolabelides was obtained in two steps: LiAlH4 reduction
(79%), followed by IBX oxidation (61%).
Scheme 4
Scheme 6
In conclusion, we have designed a new method to make
synthons encompassing a protected syn 1,3-diol motif and
an aldehyde R to the 1,3-dioxane ring. Moreover, an
additional stereocenter is created during this sequence,
potentially leading to stereochemically defined 1,2,4-triols.
This methodology was successfully applied to the synthesis
of the C16-C24 portion of Dolabelides.
obtained as a 1:1 inseparable mixture of diastereomers 14
and 14dia by performing a Hoppe homoaldol with TMEDA
at 0 °C.15 Fortunately, sulfides 15 and 15dia were separable
by flash chromatography (Scheme 5). Oxidation to the
sulfone was accompanied by TES deprotection if hydrogen
Acknowledgment. We gratefully acknowledge the CNRS
(UMR 7652) and the Ecole Polytechnique for financial sup-
port. Wilfried Nassiet, Marion Kopec, and Claire Thoumazet
are thanked for preliminary experiments.
Scheme 5
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 6-9 and
15-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL017122W
(12) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem.
1995, 60, 7272.
(13) Lactol 11 was also converted to compound 10 by Wittig coupling
with phosphorane 2 (95%), followed by protection of the resulting diol
(52%).
(14) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000,
39, 4308.
(15) Kinetic resolution with 2 equiv of the crotyl carbamate at -78 °C
(according to Berque, I.; Le Me´nez, P.; Razon, P.; Anies, C.; Pancrazi, A.;
Ardisson, J.; Neuman, A.; Prange´, T.; Brion, J.-D. Synlett 1998, 1132)
produced a 1.5:1 mixture of diastereomers favoring the undesired 14dia.
Org. Lett., Vol. 4, No. 3, 2002
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