Rearrangement of homoallylic alcohols induced by DAST

Article abstract of DOI:10.1021/ol060529m

Treatment of β,γ-unsaturated monoprotected 1,2-diols with diethylaminosulfur trifluoride (DAST) allows the stereoselective formation of β,γ-unsaturated aldehydes in good yields and with a good transfer of chirality.

Full text of DOI:10.1021/ol060529m

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2091-2094
Rearrangement of Homoallylic Alcohols
Induced by DAST
Sophie Canova,† Ve´ronique Bellosta,† Serge Mignani,‡ Antony Bigot,‡ and
Janine Cossy*,†
Laboratoire de Chimie Organique, Associe´ au CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and Sanofi-AVentis, 13 quai Jules Guesde,
94403 Vitry-sur-Seine, France
janine.cossy@espci.fr
Received March 3, 2006
ABSTRACT
Treatment of
â,γ-unsaturated monoprotected 1,2-diols with diethylaminosulfur trifluoride (DAST) allows the stereoselective formation of
â,γ
-unsaturated aldehydes in good yields and with a good transfer of chirality.
The introduction of fluorine in organic molecules strongly
modifies their physical, chemical, and biological properties.1
Although a variety of fluorinating reagents and methodolo-
gies have been developed to fulfill the increasing demand
for site-selective fluorination of organic compounds, appli-
cations of bis(2-methoxyethyl)aminosulfur trifluoride
(Deoxofluor) and diethylaminosulfur trifluoride (DAST)
continue to be used widely.2 Simple alcohols are readily
converted to the corresponding monofluorinated products
using these reagents. Moderate to excellent yields were
obtained with a variety of structurally diverse substrates such
as primary, secondary, tertiary, allylic, and benzylic alcohols
(Scheme 1).
(SN2 mechanism). In some hindered substrates, products with
retained configuration may be obtained.3 Retention of con-
figuration and/or rearrangements have also been reported,4
Scheme 1
The fluorination of optically active alcohols by using
DAST generally proceeds with inversion of configuration2
especially in substrates having an electron-rich group at a
vicinal position (e.g., in carbohydrates,4a in compounds with
pyrrole4b or indole4c moieties, with azido4a or acetate4d groups,
† Laboratoire de Chimie Organique, Associe´ au CNRS.
‡ Sanofi-Aventis.
(1) (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
Y., Eds.; Elsevier: Amsterdam, 1982. (b) Mann, J. Chem. Soc. ReV. 1987,
16, 381-436. (c) Welch, J. T. Tetrahedron 1987, 43, 3123-3197. (d)
Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley: New York, 1991. (e) SelectiVe Fluorination in Organic and Bio-
organic Chemistry; Welch, J. T., Ed.; ACS Symposium Series 456;
American Chemical Society: Washington, DC, 1991. (f) Abeles, R. H.;
Alston, T. A. J. Biol. Chem. 1990, 265, 16705-16708. (g) Special issue on
fluorine chemistry. Tetrahedron: Asymmetry 1994, 5, 955-1126. (h)
O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645-652.
(2) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561-2578. (b)
Hudlicky´, M. Org. React. 1988, 35, 513-637.
(3) Zhou, G.-C.; Zhu, D.-Y. Bioorg. Med. Chem. Lett. 2000, 10, 2055-
2057.
(4) (a) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Carmona,
A. T.; Go´mez-Guille´n, M. Tetrahedron: Asymmetry 2004, 15, 429-444.
(b) Boiadjiev, S. E.; Lightner, D. A. J. Org. Chem. 1997, 62, 399-404. (c)
Giannini, G.; Marzi, M.; Moretti, G. P.; Penco, S.; Tinti, M. O.; Pesci, S.;
Lazzaro, F.; De Angelis, F. Eur. J. Org. Chem. 2004, 2411-2420. (d)
Shiuey, S.-J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic´, M. R. J. Org. Chem.
1990, 55, 243-247. (e) Burnell-Curty, C.; Faghih, R.; Pagano, T.; Henry,
R. F.; Lartey, P. A. J. Org. Chem. 1996, 61, 5153-5154.
10.1021/ol060529m CCC: $33.50
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or with a double bond4e). These results can be explained in
terms of neighboring group participation2b and are due to
the carbonium ion character of the reaction of alcohols with
DAST, as mentioned previously.5
Table 1. Rearrangement of â,γ-Unsaturated Monoprotected
1,2-Diols Induced by DAST9
To prepare homoallylic fluorides, the corresponding ho-
moallylic alcohols were treated with DAST. When homoal-
lylic alcohol 1 was treated with DAST (3 equiv) at -45 °C
for 45 min in CH2Cl2, the homoallylic fluoride 2 was
obtained as the major product in 50-60% yield (Scheme
2). Furthermore, compound 4 was isolated in 45-50% yield
when the monoprotected 1,3-diol 3 was treated with DAST.
Scheme 2
However, when the unsaturated monoprotected 1,2-diols
of type A (Table 1) were treated with DAST, the expected
fluoro compounds of type A′ were not observed; instead,
the â,γ-unsaturated aldehydes of type B were isolated in good
yields. The reaction has been tested on several â,γ-unsatur-
ated 1,2-diols, and the results are reported in Table 1.6
Diol (+)-5 was first treated with DAST (5 equiv)7 in
dichloromethane from -45 °C to room temperature during
5 h. After workup, the reaction mixture was stirred with silica
gel for 30 min at room temperature in CH2Cl2 and aldehyde
14 was isolated in 80% yield after filtration (Table 1, entry
1). Under the same conditions, compound (+)-6, a diaste-
reomer of (+)-5, led to the enantiomeric vinyl aldehyde
ent-14. In this case, the obtained â,γ-unsaturated aldehyde
ent-14 was isolated as an inseparable mixture with its
isomerized R,â-unsaturated aldehyde 158 (Scheme 3), with
a global yield of 90% and a ratio ent-14/15 ranging from
2:1 to 1:1 (Table 1, entry 2).
To determine the enantioselectivity of the rearrangement
process, compounds 14 and ent-14 were transformed,
respectively, to the corresponding lactones (-)-29 and
(+)-2910 (Scheme 3). Aldehyde 14 was first reduced to
(5) Middleton, W. J. J. Org. Chem. 1975, 40, 574-578.
(6) The unsaturated aldehydes 14-21 formed during the rearrangement
process could not be purified because of their instability. â,γ-Unsaturated
aldehydes 14, ent-16, and 18-21 were directly reduced into the corre-
sponding primary alcohols 22-27 which were fully characterized.
(7) When less than 5 equiv was used, low conversion was observed
possibly due to DAST decomposition during the reaction.
(8) The isomerization of the double bond of the â,γ-unsaturated aldehydes
ent-14, 16, and ent-16 leading to the conjugated aldehyde 15 and 17 was
impossible to avoid. For compounds 18-21, the isomerization of the double
bond seems to take place much more slowly and was avoided by controlling
the treatment with silica gel.
a Crude isolated yields.
alcohol (-)-22 (NaBH4, MeOH, 44%) which was trans-
formed to the lactone (-)-29 after treatment with acryloyl
chloride (DIPEA, CH2Cl2, quantitative) and ring-closing
metathesis (RCM) with the second-generation Grubbs’
catalyst 28, [(4,5-dihydroIMES)(PCy3)Cl2RudCHPh]11 (10
mol %, CH2Cl2, 80%). The analytical data of the isolated
(9) In the case of the silyl protecting group, no deprotection was observed
in the presence of DAST. See, for example: Shiuey, S. J.; Kulesha, I.;
Baggiolini, E. G.; Uskokovic, M. R. J. Org. Chem. 1990, 55, 243-246.
2092
Org. Lett., Vol. 8, No. 10, 2006

of aldehydes 18 and 19 were established by transformation
of these compounds to the known alcohols (-)-31 and
(+)-3313 by addition of phenylmagnesium bromide, as the
major isomers should be the result of a Felkin-Anh attack
of the nucleophile to the R-substituted aldehydes.
Scheme 3
After treatment of 18 by phenylmagnesium bromide,
alcohols (-)-31 and 32 were isolated in 70% yield in a ratio
of 75:25. The analytical and spectroscopic data of the major
product (-)-31 were in perfect agreement with those reported
in the literature,13 allowing us to attribute the anti/syn
stereochemistry for the substituents present in (+)-31 and
the (R) configuration of the C2 stereogenic center of aldehyde
18. When aldehyde 19 was treated with phenylmagnesium
bromide, alcohols (+)-33 and (-)-34 were isolated in 57%
yield in a ratio of 80:20. The major isomer (+)-33 corre-
sponds to the product issued from the Felkin-Anh addition
of phenylmagnesium bromide to aldehyde 19. The analytical
and spectroscopic data of (+)-33 match perfectly with those
described in the literature.13 The chemical transformation of
19 to the syn/syn product (+)-33 allowed us to attribute the
(S) configuration at the C2 position in aldehyde 19 (Scheme
4).
material were in agreement with those reported in the
literature.10 The comparison of the optical rotations allowed
us to attribute the (R) configuration to the stereogenic center
present in aldehyde 14 which was obtained with no apparent
loss of chirality.12 The same sequence of reactions was also
applied to the mixture of compounds ent-14 and 15; lactone
(+)-29 was isolated with a global yield of 30% from ent-
14, whereas acryloyl ester 30 did not react under RCM
conditions.
Scheme 4
When the primary alcohol is protected by a benzyl group
as in compounds (+)-7 and (+)-8, instead of by a TBDPS
group as in (+)-5 and (+)-6, the â,γ-unsaturated aldehydes
16 and ent-16 were obtained as well as was the conjugated
aldehyde 17 (16/17 ) 2.4:1 and ent-16/17 ) 2:1) with a
global yield of, respectively, 76% and 87% (Table 1, entries
3 and 4).
To study the influence of the stereogenic centers on the
stereoselectivity of the rearrangement, compounds (+)-9 and
(-)-10 were treated with DAST. These two epimers, whose
configurations differ only at the carbon bearing the methoxy
group, were transformed to the same â,γ-unsaturated alde-
hyde 18, obtained as a single diastereomer, in 86% and 80%
yields, respectively (Table 1, entries 5 and 6). Furthermore,
the homoallylic alcohol (+)-11, a diastereomer of (+)-9 and
(-)-10, was transformed to aldehyde 19 in 90% yield, and
this compound was revealed to be the diastereomer of 18
(Table 1, entry 7). The relative and absolute configurations
The results obtained for the rearrangement of
â,γ-unsaturated monoprotected 1,2-diols of type A (Table
1) and particularly the comparison of the transformation of
compound (+)-5 and (+)-6 to the enantiomer 14 and
ent-14, respectively, in addition to the transformation of
compounds (+)-9, (-)-10, and (+)-11 to the corresponding
aldehydes 18 and 19, proved that the hydroxy group may
be the directing element in the rearrangement induced by
DAST and that the methoxy group has no influence on it.
Diols (-)-12 and (+)-13 were also treated with DAST
and led, respectively, to the â,γ-unsaturated aldehydes 20
(90%) and 21 (79%) in good yields (Table 1, entries 8 and
9).
(10) Lactone (+)-29 of (S) configuration is described as enantiomerically
pure ([R]19D ) +50.6 (c 0.54, CHCl3)): Tanaka, D.; Yoshino, T.; Kouno,
I.; Miyashita, M.; Irie, H. Tetrahedron 1993, 49, 10253-10262.
(11) Scholl, M.; Ding, S.; Woo Lee, S.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
It is worth noting that a fluorine intermediate can be
isolated before treatment with silica gel. Compounds (+)-5
and (+)-9 were transformed quantitatively to the fluoroethers
35 and 36, respectively. Each fluoroether was isolated as a
mixture of two diastereomers in an equimolar ratio and was
(12) Diol (+)-5 was obtained with an enantiomeric excess of 85%
(determined from the corresponding (S)- and (R)-O-methoxymandelic esters).
Optical rotation obtained for lactone (-)-29, synthesized from (+)-5
([R]25 ) -38.4 (c 0.50 CHCl3)), is consistent with more than 75% ee,
D
confirming a good transfer of chirality. For the lactone of (S) configuration,
(13) Mulzer, J.; Kattner, L.; Strecker, A. R.; Schro¨der, C.; Bushmann,
see ref 9.
J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 4218-4229.
Org. Lett., Vol. 8, No. 10, 2006
2093

then transformed to the corresponding aldehyde, 14 from
(+)-5 and 18 from (+)-9, after treatment with silica gel
(Scheme 5).
induced by DAST, the formation of â,γ-unsaturated alde-
hydes of type B can be explained either by a homoallylic
participation14 of the double bond present in compounds of
type A (path a) or by a pinacolic-type rearrangement (path
b). Both pathways could explain the formation of the
fluoroethers of type C via the formation of an oxonium
intermediate which could react with a fluoride anion present
in the reaction media (Scheme 6).
Scheme 5
To verify the participation of the double bond in the
rearrangement, compound (+)-11 was hydrogenated and the
resulting saturated product 37 was treated with DAST
(3 equiv) and then with silica gel (chromatography). In this
case, no traces of aldehyde 38 or fluorinated compound 39
were detected but the reaction led to a complex mixture of
unidentified products (Scheme 7). The mechanism is cer-
tainly more complex than the one depicted in Scheme 6.
Current efforts are underway to elucidate the mechanism of
the rearrangement process.
As the methoxy group present in compounds 5-13 does
not seem to influence the stereoselectivity of the rearrange-
ment of unsaturated monoprotected 1,2-diols of type A
Scheme 7
Scheme 6
We have shown that DAST can induce a stereo- and
enantioselective rearrangement of unsaturated monoprotected
1,2-diols and that R-substituted â,γ-unsaturated aldehydes
can be formed stereoselectively in good yields.
Acknowledgment. One of us (S.C.) thanks the CNRS
and Aventis Pharma for a grant.
Supporting Information Available: General experimen-
tal procedure and characterization data of the described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060529M
(14) Nagasawa, T.; Handa, Y.; Onogushi, Y.; Suzuki, K. Bull. Chem.
Soc. Jpn. 1996, 69, 31-39.
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Org. Lett., Vol. 8, No. 10, 2006