Synthesis of functionalized 2,3- and 3,4-dihydropyrans starting from α- hydroxycarboxylic esters via RCM

Article abstract of DOI:10.1055/s-1999-2884

α-Hydroxy carboxylic acids and their derivatives are naturally occurring starting materials for the synthesis of functionalized tetrahydropyrans using ring closing metathesis and base induced epoxide rearrangement as key steps. (S)-Lactic acid methyl este

Full text of DOI:10.1055/s-1999-2884

LETTER
1591
Synthesis of Functionalized 2,3- and 3,4-Dihydropyrans Starting from
a-Hydroxycarboxylic Esters via RCM
Bernd Schmidt*, Holger Wildemann
Universität Dortmund, Fachbereich Chemie, Organische Chemie I, D-44221 Dortmund, Germany
Fax +49 (231) 7555363; e-mail: bschmidt@citrin.chemie.uni-dortmund.de
Received 17 June 1999
Abstract. a-Hydroxy carboxylic acids and their derivatives are nat-
urally occurring starting materials for the synthesis of functional-
ized tetrahydropyrans using ring closing metathesis and base
induced epoxide rearrangement as key steps. (S)-Lactic acid methyl
ester has been used as the starting material for the preparation of
enantiomerically pure 6-desoxy C-glycoside precursors.
Key words: metathesis, pyrans, glycals, epoxidation
Tetrahydropyrans with oxo substituents play an important
role in synthetic organic chemistry, as these substructures
are found in many natural products with interesting bio-
logical properties, such as annonaceous acetogenins,1
polyether ionophores,2 and C-glycosides.3-5 The latter
class of compounds has found increasing interest over the
past years, because many physiologically active natural
products with C-glycosidic structures have been identi-
fied, but there is also a continuous interest in the use of
non-natural C-glycosides as carbohydrate mimics.6 Thus,
organic chemists have developed a variety of syntheses
for these compounds, mostly starting from naturally oc-
curring carbohydrates. Probably the most useful de novo
synthesis of glycals and carbohydrates is the hetero-Diels-
Alder reaction of aldehydes and siloxydienes.7,8 Met-
al-catalyzed or -mediated ring closure reactions are less
common in this field. Among this group of reactions the
ring closing metathesis of dienes9 turned out to be a very
powerful tool over the last few years. Recent examples for
the utilization of olefin metathesis for the construction of
di- and tetrahydropyran frameworks include the synthesis
of spirocyclic dihydropyrans10 and the utilization of car-
bohydrates as starting materials for fused or spiroannellat-
ed dihydropyrans and -furans.11
i, allylbromide, Ag2O, Et2O, r.t.; ii, DIBAL-H, C2H3MgCl, Et2O,
-90°C; iii, Cl2P(Cy3)2Ru=CH-CH=CPh2 (3 mol%), DCM, r. t.; iv, Bu-
tOOH, VO(acac)2, toluene, 110°C; v, LDA, THF, r.t.
Scheme 1
similar systems, which have been prepared via a two-step
procedure, i. e. with isolation of the aldehyde.13 Thus, it is
likely that the formation of 3a via the one-pot procedure
involves the intermediate formation of a chelate complex
A of aluminum and the a-allyloxy aldehyde ("Cram's cy-
clic model") (Scheme 2).15
In this communication we wish to disclose our prelimi-
nary results on the utilization of naturally occurring a-hy-
droxy carboxylic acid12 derivatives as starting materials
for functionalized di- and tetrahydropyrans (Scheme 1).13
The a-allyloxy ester 2a was obtained in enantiomerically
pure form and very high yield from inexpensive (S)-meth-
yl lactate following a literature procedure.14 Allylation of
1a with sodium hydride and allyl bromide occurs with
Scheme 2
complete racemization to give rac-2a ([a]25D = 0°). Re- Ring closing metathesis of 3a gives dihydropyrans 4a as
duction of the ester functionality in 2a with DIBAL-H and an inseparable mixture of diastereomers (cis/trans = 4:1).
addition of one equivalent of vinylmagnesium chloride in The cis-configuration of the major diastereoisomer was
a one-pot procedure yields, with good diastereoselectivity elucidated by comparison of the coupling constants
(dr = 4:1), the allylic alcohol 3a. The relative configura- 3J(H2-H3), which is 2.3 Hz for the cis- and 7.3 Hz for the
tion of 3a is opposite to the one observed by us for very trans-diastereoisomer.
Synlett 1999, No. 10, 1591–1593 ISSN 0936-5214 © Thieme Stuttgart · New York

1592
B. Schmidt, H. Wildemann
LETTER
Compound 4a was used to check whether the reduction-
vinylation sequence leading to 3a occurred without race-
mization. This was achieved by NMR-shift experiments
using Eu(tfc)3 (europium(III)-[3-(trifluoromethyl-hy-
droxymethylene)camphorate) and CDCl3 as solvent. For
reasons of comparison, rac-4a (obtained from rac-2a by
the sequence described above for the enantiomerically
pure material) was also employed in shift experiments.
Most conveniently, the doublet for the methyl group is ob-
served: Under conditions where the signals for the enanti-
omers of rac-4a are baseline-separated, enantiomerically
pure 4a gives only one doublet, indicating that no racem-
ization occurs during the reaction sequence.
Starting from DL-methyl mandelate, rac-4b (cis/trans =
5:1) becomes accessible analogously. In this case it was
possible to remove the minor diastereoisomer by careful
column chromatography. Dihydropyrans 4 can be readily
elaborated into cyclic enol ethers with additional hydroxy
functions in the 3- and 4-position. Thus, cis-rac-4b was
subjected to a highly diastereoselective substrate directed
epoxidation16 using t-BuOOH and VO(acac)2 (dr > 95:5,
as only the all-cis-diastereoisomer was detected from the
H-NMR spectra of the reaction mixture). Base-induced
isomerization17 of rac-5b in the presence of three equiva-
lents of LDA gives rac-6b as a single diastereoisomer, in-
dicating that no deprotonation of the benzylic ether
occurs.
i, C2H3MgCl (exc.), Et2O, -78°C; ii, allylbromide, NaH, THF, 0°C;
iii, Cl2P(Cy3)2Ru=CH-CH=CPh2 (3 mol%), DCM, r. t.; iv, ButOOH,
VO(acac)2, toluene, 110°C; v, LDA, THF, r. t.
Scheme 3
a-Hydroxy esters 1 may also serve as starting materials
for the construction of tetrahydropyrans with a quaternary
centre, a structural element which is very common in the
polyether ionophores (e. g. salinomycin or lasalocid)
(Scheme 3).2
In conclusion, we have shown that a-hydroxy carboxylic
acids are promising naturally occurring starting materials
for functionalized di- and tetrahydropyrans using the ring
closing metathesis reaction and base induced rearrange-
ments of dihydropyran oxides as key steps. It is notewor-
thy that the rearrangement of epoxides 5 and 10 can be
carried out without protection of the hydroxyl group. Ap-
plication of the methodology described herein and its ex-
tension to other, natural and non-natural a-hydroxy acid
derivatives is currently under investigation.
Thus, esters 2 were treated with two equivalents of vinyl
magnesium chloride leading to the formation of trienes 7,
along with minor amounts of 1,4-addition product 12,
which was only observed for the lactic acid derivative.
Formation of the 1,4-adduct 12 can be completely avoided
if ester 1a is first treated with an excess of vinyl magne-
sium chloride to give the diol 8a.18 In the presence of so-
dium hydride and allyl bromide at 0°C the secondary
hydroxyl group is selectively allylated to give triene 7a.
Both routes leading to 7a occur without racemization,
which was proven by NMR shift experiments (using the
Eu(tfc)3 reagent and observing the doublets for the methyl
group) of the ring closing metathesis products 9a and
rac-9a. Ring closing metathesis of 7 is a moderately dias-
tereoselective process:19,20 For both 9a (dr = 2.5:1) and 9b
(dr = 4:1) the formation of the cis-isomer is preferred; elu-
cidation of the relative configuration was achieved by
NOESY-experiments.
Acknowledgment
Generous support of this work by the Fonds der Chemischen Indu-
strie (Liebig-fellowship) and the Deutsche Forschungsgemein-
schaft is gratefully acknowledged. The authors thank C. Hollmann
for NMR-shift experiments. B.S. thanks Prof. Dr. P. Eilbracht for
encouragement and support.
References and Notes
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McLaughlin, J. L. Nat. Prod. Rep. 1996, 275-306.
(2) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362.
(3) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599.
(4) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913-9959.
(5) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Pergamon: Oxford, 1995.
(6) Chapleur, Y. Carbohydrate Mimics; Wiley-VCH: Weinheim,
1998.
(7) Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250-259.
3,4-Dihydropyrans 9 have been subjected to the vanadium
catalyzed epoxidation, which is both regio- (as exclusive-
ly the endocyclic double bond is attacked) and stereose-
lective (only the epoxides with cis-configuration relative
to the hydroxyl group are formed). Base induced rear-
rangement of epoxides 10 opens up a path to highly func-
tionalized cyclic enol ethers 11.21
Synlett 1999, No. 10, 1591–1593 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Functionalized Dihydropyrans from a-Hydroxycarboxylic Esters via RCM
1593
(8) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem. 1996, 108,
1482-1522; Angew. Chem. Int. Ed. Engl. 1996, 35, 1380-
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Tetrahedron Lett. 1998, 39, 6061-6064; Leeuwenburgh, M.
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Synlett 1997, 1263.
(12) Coppola, G. M.; Schuster, H. F. a-Hydroxy acids in
enantioselective synthesis; Wiley-VCH: Weinheim, 1997.
(13) Schmidt, B.; Sattelkau, T. Tetrahedron 1997, 53, 12991-
13000.
(14) Aurich, H. G.; Biesemeier, F.; Boutahar, M. Chem. Ber.
1991,124, 2329-2334.
(15) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc. 1963, 85, 1245-
1249.
(16) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307-1370.
(17) Schmidt, B. Tetrahedron Lett. 1999, 40, 4319-4320.
(18) Yoshimitsu, T.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1994, 2197-2199.
(20) For diastereoselectivity in the formation of carbacycles via
RCM, see: Lautens, M.; Hughes, G. Angew. Chem. 1999, 111,
160-162; Angew. Chem. Int. Ed. Engl. 1999, 38, 129-131.
(21) Representative procedure for the base-induced rearrangement
of epoxides 5 and 10: To a solution of LDA (31 mmol) in THF
(40 mL) under an atmosphere of dry argon was added a
solution of epoxide 10a (1.60 g, 10 mmol) in dry THF (15
mL). The mixture was heated to 65°C until the starting
material was fully consumed as judged by TLC. Aqueous
workup yields 1.58 g (99%) of crude material which consists
mainly of 11a. Purification was only possible with partial
decomposition by Kugelrohr distillation (0.60 g, 38%). 11a:
1H NMR (400 MHz, CDCl3) d 6.39 (dd, 1, J = 6.3, 1.5 Hz),
5.59 (dd, 1, J = 17.3, 10.8 Hz), 5.45 (dd, 1, J = 17.3, 1.8 Hz),
5.29 (dd, 1, J = 10.8, 1.8 Hz), 4.71 (dd, 1, J = 6.3, 2.0 Hz), 4.17
(s(br.), 1), 3.86 (q, 1, J = 6.5 Hz), 2.10 (s(br.), 1), 1.18 (d, 3, J
= 6.5 Hz). 13C NMR (100 MHz, CDCl3) d 144.6 (1), 137.6 (1),
116.8 (2), 103.3 (1), 75.6 (1), 71.6 (0), 67.6 (1), 14.2 (3).
Compound 6b: 1H NMR (400 MHz, C6D6) d 7.24 (d, 2, J =
7.5 Hz), 7.09 (dd, 2, J = 7.5, 7.3 Hz), 7.00 (t, 1, J = 7.3 Hz),
6.20 (d, 1, J = 6.0 Hz), 4.54 (ddd, 1, J = 6.3, 1.8, 1.8 Hz), 4.47
(s, 1), 4.18 (m, 1), 3.62 (d, 1, J = 4.0 Hz), 3.30 (s(br), 2).
13C NMR (100 MHz, C6D6) d 144.8 (1), 138.6 (0), 128,4 (1),
127.9 (1), 127.0 (1), 103.4 (1), 78.7 (1), 68.6 (1), 65.3 (1).
(19) For highly diastereoselective ring closing metathesis reactions
for the construction of 2,5-disubstituted five-membered
azacycles see: Huwe, C. M.; Velder, J.; Blechert, S. Angew.
Chem. 1996, 108, 2542-2544; Angew. Chem. Int. Ed. Engl.
1996, 35, 2376-2378.
Article Identifier:
1437-2096,E;1999,0,10,1591,1593,ftx,en;G16099ST.pdf
Synlett 1999, No. 10, 1591–1593 ISSN 0936-5214 © Thieme Stuttgart · New York