Synthesis of enantiomerically pure dihydrofurans and dihydropyrans from common precursors using RCM and tandem RCM-isomerization

Article abstract of DOI:10.1055/s-2007-985606

Starting from glyceraldehyde, structurally and stereochemically diverse dihydrofurans and dihydropyrans with a 1,2-dihydroxyethylene side chain can be accessed in few steps via allyl metal addition, O-allylation and ring-closing metathesis (RCM) or tandem

Full text of DOI:10.1055/s-2007-985606

LETTER
2375
Synthesis of Enantiomerically Pure Dihydrofurans and Dihydropyrans from
Common Precursors Using RCM and Tandem RCM–Isomerization
D
B
ihydrofurans an
e
d Dihydrop
r
yrans fr
n
omCommon
d
Precursors Schmidt,* Anne Biernat
Institut für Chemie, Organische Chemie II, Universität Potsdam, Karl-Liebknecht-Straße 24-25, Haus 25, 14476 Golm, Germany
Fax +49(331)9775059; E-mail: bernd.schmidt@uni-potsdam.de
Received 6 June 2007
Abstract: Starting from glyceraldehyde, structurally and stereo-
chemically diverse dihydrofurans and dihydropyrans with a 1,2-di-
hydroxyethylene side chain can be accessed in few steps via allyl
metal addition, O-allylation and ring-closing metathesis (RCM) or
tandem RCM–isomerization, respectively. The synthesis of di-
hydrofurans requires a selective double-bond isomerization on the
homoallylic alcohol stage, prior to O-allylation and RCM or RCM–
isomerization.
OH
OH OH
HO
HO
HO
HO
OH
O
O
OR
1
2
OH
OH
OH
OH
Key words: carbohydrates, isomerizations, metathesis, ruthenium,
tandem reactions
O
O
OR
3
4
Partially or fully hydroxylated tetrahydrofuran building Figure 1 Interesting oxacyclic structures with dihydroxyethylene
blocks 1 and 2 with a dihydroxyethylene side chain have
side-chain
attracted considerable interest as constituents in certain
1
disaccharide alditols isolated from seaweed or as inter-
be considered as an assisted tandem catalysis in the taxon-
omy recently proposed by Fogg and dos Santos. The re-
mediates in the total synthesis of complex target mole-
25
2
3
cules such as avermectin, pyragonicin and other
quired switch from metathesis to isomerization reactivity
4
annonaceous acetogenins, and certain piperidine alka-
loids. HIV-1 protease inhibitors and nucleoside ana-
logues as potential cholesterol lowering agents have also
been synthesized using enantiopure building blocks 1 or
23
is achieved by certain additives, which cause a trans-
5
6
formation of the Ru-carbene species to the Ru-hydride
species. The objective of this contribution is: (i) to de-
monstrate the usefulness of the tandem RCM–isomeriza-
tion sequence for the synthesis of enantiopure glycal-type
7
2
. Normally, these intermediates are derived from hexitols
8
–11
by cyclization reactions
or from dianhydrohexitols by
26
structures and (ii) to illustrate that the combination of
1
2
ring-opening reactions. The analogous tetrahydropyrans
and 4 have also attracted attention from various points
of view, e.g. as precursors in the synthesis of the alkaloid
conhydrine or as a key structural pattern in various ace-
togenins. Syntheses based on the use of tartraric acid
metathesis and isomerization reactions in appropriate
order allows the selective synthesis of structurally diverse
heterocycles starting from a common precursor.
3
1
3
Addition of allyl metal compounds to the isopropylidene
analogue of 5 has been investigated some time ago. A sig-
nificant preference of the anti-(R,S)-isomer was observed
if the allylzinc reagent was used in THF.2 In our case
1
4
13
1
5
or hetero Diels–Alder reactions have been published in
the literature (Figure 1).
7,28
In this contribution we describe a route to the individual
diastereomers of regioisomeric dihydrofurans and di-
hydropyrans which can be elaborated to 1–4, starting from
a common precursor, the cyclohexylidene-protected
both homoallylic alcohols were required and therefore the
16,29,30
less selective Grignard reagent was chosen.
The re-
sulting homoallylic alcohols (R,R)-6 and (R,S)-6 are sep-
arable by column chromatography and were separately
converted into the known allyl ethers (R,R)-7 and (R,S)-7,
1
6
glyceraldehyde 5. We planned to convert 5 into allylic or
homoallylic alcohols by addition of suitable organometal-
29
respectively. Treatment of these dienes with the first-
1
7
lics. Subsequently, the alcohols should be allylated, and
31
generation Grubbs’ catalyst A gives the corresponding
1
8
the resulting dienes subjected to either RCM or tandem
dihydropyrans (R,R)-8 and (R,S)-8 in good to excellent
1
9,20
RCM–isomerization sequence.
This method has been
and Snapper et al.
32
23
yields. Under RCM–isomerization conditions, howev-
er, the regioisomeric dihydropyrans (R,R)-9 and (R,S)-9
were obtained. In both cases, enol ethers 9 were obtained
as single regio- and diastereoisomers and the use of 2-
propanol and NaOH as additives was found to give the
shortest reaction times and highest yields of the desired
enol ethers. This indicates that the isomerization step of
the tandem sequence is highly regioselective and does
not result in any stereochemical scrambling. The a,b-un-
2
1–23
24
independently developed by us
over the past few years. It relies on the conversion of an
olefin-metathesis catalyst into an isomerization catalyst
via an organometallic transformation in situ and can thus
SYNLETT 2007, No. 15, pp 2375–2378
1
7
.0
9
.2
0
0
7
Advanced online publication: 23.08.2007
DOI: 10.1055/s-2007-985606; Art ID: G18007ST
©
Georg Thieme Verlag Stuttgart · New York

2
376
B. Schmidt, A. Biernat
LETTER
i
O
O
O
O
O
+
O
+
O
O
O
O
O
O
vi
O
O
OH
OH
(R,S)-6
ii
O
5
(
R,R)-6
cis-(R,S)-12
trans-(R,S)-12
ii
iii
iii
O
O
O
O
O
O
O
O
O
O
O
O
(R,R)-8
(R,R)-7
(R,S)-7
iv
(R,S)-8
iv
v
PCy3
Ph
Cl
Cl
O
O
O
O
Ru
O
O
O
O
O
PCy3
+
O
O
O
O
A
O
(R,R)-9
(R,S)-9
(R,S)-10
(R,S)-11
Scheme 1 Reagents and conditions: (i) H C=CHCH MgBr, Et O, –78 °C, H O; column chromatography [42% of (R,R)-6 and 45% of (R,S)-
2
2
2
2
6
]; (ii) H C=CHCH Br, THF, 65 °C [81% of (R,R)-7 and 99% of (R,S)-7]; (iii) A (5 mol%), CH Cl [75% of (R,R)-8 and 96% of (R,S)-8]; (iv)
2
2
2
2
A (5 mol%), toluene, 25 °C, then 2-propanol–KOH, 110 °C [60% of (R,R)-9 and 66% of (R,S)-9]; (v) PDC (2.0 equiv), CH Cl , [10/11 = 10:1,
2
2
5
4% of (R,S)-10]; (vi) MCPBA, CH Cl , [cis-(R,S)-12/trans-(R,S)-12 = 1:1, 35% of cis-(R,S)-12 and 35% of trans-(R,S)-12].
2
2
saturated lactones 10 are also potentially very useful recovery of unchanged dihydropyran 8. In the case of di-
building blocks. The isopropylidene analogues of 10 have hydropyran (R,S)-8 the oxidative functionalization of the
previously been obtained as a diastereomeric mixture by C=C double bond was demonstrated by dihydropyran ox-
3
3
ring-closing metathesis of acrylates.
ide formation with MCPBA. The resulting diastereomeric
dihydropyran oxides 12 were easily separated by column
chromatography and were isolated in good overall yield
Although significant progress has been made for olefin
metathesis reactions involving electron-deficient double
bonds, this process is still hampered by the necessity to
(
Scheme 1).
work at low concentrations. Often Lewis acid additives34 Next, we planned to synthesize the analogous series of
or the more active second generation catalysts are re- regio- and diastereomeric dihydrofurans. Unfortunately,
3
5
quired to obtain useful rates of conversion, which is a upon addition of vinyl magnesium chloride to 5, an insep-
further drawback of the RCM of acrylates. One approach arable mixture of allylic alcohols was obtained. Various
to overcome these difficulties is to convert dihydropyrans methods of derivatization were then applied to the
8
into lactones 10 by allylic oxidation, e.g. using Cr(VI) mixture, but it was not possible to separate the diastereo-
3
6,37
reagents.
This approach is also in line with the com- isomers at this stage. Therefore the possibility was inves-
mon precursor concept proposed in this contribution and tigated to use the homoallylic alcohols 6 also as starting
was therefore investigated for dihydropyran (R,S)-8. In materials for the dihydrofuran series. To this end, a selec-
the presence of two equivalents of pyridinium dichromate tive isomerization of the terminal double bond in both iso-
(
PDC), (R,S)-8 led to the desired lactone (R,S)-10 without mers of 6 was required. Defined Ru-hydride complexes
stereochemical scrambling. However, enone (R,S)-11 was have been efficiently used to isomerize double bonds in a
3
8,39
formed as an inseparable side product in small amounts. number of cases.
However, with respect to ‘catalyst
40
The enone 11 was identified by its characteristic signals in economy’, we thought that it would be advantageous to
1
the H NMR spectrum (two doublets at d = 7.29 and d = use the well-established and commercially available
5
.38 with a vicinal coupling constant of 6.0 Hz). As RCM metathesis precatalyst A as a precursor for an active
and allylic oxidation were conducted in the same solvent, isomerization catalyst.2 This approach has been inves-
0,41
4
2
it was an obvious extension to check if both steps could be tigated for some examples over the past few years by us
conducted as a one-pot sequence. Interestingly this ap- and by others.43 In our experiments we used ethyl vinyl
proach failed completely and resulted in the quantitative ether as a reagent to convert Ru-benzylidene complex A
Synlett 2007, No. 15, 2375–2378 © Thieme Stuttgart · New York

LETTER
Dihydrofurans and Dihydropyrans from Common Precursors
2377
4
4
into the hydride complex [RuHCl(CO)(PCy ) ]. The In conclusion, we have shown that oxacyclic products
3
2
homoallylic alcohols 6 were then treated separately with with diverse relative stereochemistries, substitution pat-
the in situ generated hydride complex. In a different terns, and ring sizes can be obtained from just two diaste-
context we had previously discovered that reomeric precursors by using olefin metathesis,
[
RuHCl(CO)(PCy ) ] is only moderately active in isomer- isomerization, tandem RCM–isomerization and allylic
3 2
2
3
ization reactions and therefore we expected a high selec- oxidation as key transformations. Further work to explore
tivity for terminal double bonds. However, isomerization the potential of this concept is currently under progress in
of homoallylic alcohols 6 to allylic alcohols was not as our laboratory.
straightforward as expected. Not fully unexpected was the
formation of ketone 13 from homoallylic alcohol (R,S)-6
4
5
upon prolonged heating, a process which has often been
4
6
O
O
referred to as redox isomerization. Quite interestingly,
the diastereomer (R,R)-6 reacted under identical condi-
tions to a fragmentation product 14 (Scheme 2).
i
O
O
OH
OH
ii
(R,R)-6
(R,R)-15
O
O
i
O
O
O
iii
O
O
O
OH
O
(R,R)-6
13
O
O
(R,R)-17
(R,R)-16
O
i
O
iv
O
HO
OH
R,S)-6
O
(
14
O
Scheme 2 Reagents and conditions: (i) A (5 mol%), toluene,
(R,R)-18
H C=CHOEt, then (R,S)-6 or (R,S)-6 (42% of 13, 56% of 14).
2
Scheme 3 Reagents and conditions: (i) A (5 mol%), toluene,
H C=CHOEt, then (R,R)-6 or (R,S)-6 [74% of (R,R)-15, 58% of (R,S)-
2
Formation of 14 is a subject of speculation. Obviously,
cleavage of the acetal moiety occurs and an oxocarbenium
ion is formed, which is subsequently attacked by the vinyl
1
5]; (ii) H C=CHCH Br, THF, 65 °C [62% of (R,R)-16 and 57% of
2 2
(
(
R,S)-16]; (iii) A (5 mol%), CH Cl [70% of (R,R)-17 and 56% of
R,S)-17]; (iv) A (5 mol%), toluene, 25 °C, then 2-propanol–NaOH,
2 2
moiety. We assume that a volatile C3-aldehyde is formed 110 °C [58% of (R,R)-18 and 39% of (R,S)-18].
as the second cleavage product; however, this could not be
detected. Intramolecular transfer of an allyl moiety from
homoallylic alcohol (R,S)-6 to the oxocarbenium ion, fol-
Acknowledgment
Generous financial support of this work by the Deutsche For-
schungsgemeinschaft is gratefully acknowledged.
lowed by isomerization, appears to be much more likely
because such reactions have precedence in the literature.47
However, such a scenario can be ruled out in this particu-
lar case, because monitoring of the progress of the reac-
tion revealed that after one hour (R,S)-6 was completely
converted into the desired allylic alcohol (R,S)-15, and
that 14 resulted from (R,S)-15 in a consecutive step.
Analogously, isomerization of (R,R)-6 under carefully
References and Notes
(
1) Goncalves, A. G.; Ducatti, D. R. B.; Duarte, M. E. R.;
Noseda, M. D. Carbohydr. Res. 2002, 337, 2443.
2) Williams, D. R.; Klingler, F. D.; Dabral, V. Tetrahedron
Lett. 1988, 29, 3415.
(
48
controlled conditions gave the diastereomer (R,R)-15 as
an E/Z mixture without formation of ketone 13. Interest-
(3) Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett.
2005, 7, 2783.
4
8
(
4) Zanardi, F.; Battistini, L.; Rassu, G.; Auzzas, L.; Pinna, L.;
ingly, (R,S)-15 was formed as a single E-isomer. Both
diastereomers of 15 were subsequently allylated to the
allyl ethers (R,R)-16 and (R,S)-16, respectively. Both
Marzocchi, L.; Acquotti, D.; Casiraghi, G. J. Org. Chem.
2000, 65, 2048.
(
(
5) Herdeis, C.; Telser, J. Eur. J. Org. Chem. 1999, 1407.
6) Ghosh, A. K.; McKee, S. P.; Thompson, W. J. J. Org. Chem.
(
R,R)-16 and (R,S)-16 gave, in the presence of Ru catalyst
A, the corresponding dihydrofurans (R,R)-17 and (R,S)-
7, while under tandem RCM–isomerization conditions
the enol ethers (R,R)-18 and (R,S)-18 become selectively
1991, 56, 6500.
1
(7) Giovanninetti, G.; Cavrini, V.; Garuti, L.; Roveri, P.;
Amorosa, M.; Gaggi, R.; Defaye, J. Eur. J. Med. Chem.
1980, 15, 23.
4
9
available (Scheme 3).
(
8) Lundt, I.; Frank, H. Tetrahedron 1994, 50, 13285.
Synlett 2007, No. 15, 2375–2378 © Thieme Stuttgart · New York

2
378
B. Schmidt, A. Biernat
LETTER
(38) Krompiec, S.; Kuznik, N.; Krompiec, M.; Penczek, R.;
(
9) Kurszewska, M.; Skorupowa, E.; Madaj, J.; Konitz, A.;
Wojnowski, W.; Wisniewski, A. Carbohydr. Res. 2002, 337,
Mrzigod, J.; Tórz, A. J. Mol. Catal. A: Chem. 2006, 253,
132.
1261.
(
(
(
(
(
10) van Delft, F. L.; Valentijn, A. R. P. M.; van der Marel, G. A.;
van Boom, J. H. J. Carbohydr. Chem. 1999, 18, 165.
11) van Delft, F. L.; Valentijn, A. R. P. M.; van der Marel, G. A.;
van Boom, J. H. J. Carbohydr. Chem. 1999, 18, 191.
12) Ceré, V.; Mazzini, C.; Paolucci, C.; Pollicino, S.; Fava, A.
J. Org. Chem. 1993, 58, 4567.
13) Masaki, Y.; Imaeda, T.; Nagata, K.; Oda, H.; Ito, A.
Tetrahedron Lett. 1989, 30, 6395.
14) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod.
(39) van Otterlo, W. A. L.; Morgans, G. L.; Madeley, L. G.;
Kuzvidza, S.; Moleele, S. S.; Thornton, N.; de Koning, C. B.
Tetrahedron 2005, 61, 7746.
(40) Faulkner, J.; Edlin, C. D.; Fengas, D.; Preece, I.; Quayle, P.;
Richards, S. N. Tetrahedron Lett. 2005, 46, 2381.
(41) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
(42) Schmidt, B. Synlett 2004, 1541.
(43) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem. Int. Ed. 2002, 41, 4732.
1
999, 62, 504.
(44) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153.
(45) Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001, 42,
3633.
(
(
15) Jurczak, J.; Bauer, T. Tetrahedron 1986, 42, 5045.
16) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995,
6
0, 585.
(46) Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1993, 115,
2027.
(47) Lee, C.-L. K.; Lee, C.-H. A.; Tan, K.-T.; Loh, T. P. Org.
Lett. 2004, 6, 1281.
(
(
(
(
(
(
(
(
17) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
18) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
19) Schmidt, B. Pure Appl. Chem. 2006, 78, 469.
20) Schmidt, B. J. Mol. Catal. A: Chem. 2006, 254, 53.
21) Schmidt, B. Eur. J. Org. Chem. 2003, 816.
22) Schmidt, B. Chem. Commun. 2004, 742.
23) Schmidt, B. J. Org. Chem. 2004, 69, 7672.
24) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390.
25) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248,
(48) Suzuki, M.; Sugiyama, T.; Watanabe, M.; Murayama, T.;
Yamashita, K. Agric. Biol. Chem. 1987, 51, 1121.
(49) Synthesis of Cyclic Enol Ethers 9 and 18: To a solution of
the corresponding diene (1.0 mmol) in toluene (10 mL) was
added [Cl (PCy ) Ru=CHPh] (41 mg, 5 mol%). The solution
2
3 2
was stirred at 40 °C until the starting material was fully
consumed (approximately 30 min, TLC), and 2-propanol (1
mL/mmol) and NaOH (0.25 equiv) were added. The solution
was then heated to reflux until the RCM product was
completely converted into the enol ether. The reaction
(
(
(
2
365.
26) Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. Rev. 1993,
2, 579.
27) Mulzer, J.; Angermann, A. Tetrahedron Lett. 1983, 24,
843.
6
mixture was diluted with MTBE and washed with H O. The
2
2
organic layer was separated, dried with MgSO , filtered, and
4
(
(
28) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
29) Goekjian, P. G.; Lugo-Mas, P.; Cable, S. L.; Cole, J. O.;
White, J. W.; Thompson, D. J.; Dudley, T. P.; Jirousek, M.
R.; Dixon, J. T.; Ballas, L. M. J. Fluorine Chem. 1999, 98,
evaporated. Column chromatography on silica yielded the
2
3
dihydropyrans or the dihydrofurans. (R,R)-9: [a] –45 (c =
D
1
0.9, CH Cl ). H NMR (300 MHz, CDCl ): d = 6.41 (d, J =
6.0 Hz, 1 H, H6), 4.69 (m, 1 H, H5), 4.18 (ddd, J = 6.6, 6.6,
2
2
3
137.
6.6 Hz, 1 H, OH CCHO), 4.03 (dd, J = 6.6, 8.2 Hz, 1 H,
2
(
(
30) Brar, A.; Vankar, Y. D. Tetrahedron Lett. 2006, 47, 9035.
31) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
OH CCHO), 3.82 (ddd, J = 2.7, 6.6, 9.3 Hz, 1 H, H2), 3.75
2
(dd, J = 7.1, 8.2 Hz, 1 H, OH CCHO), 1.90–2.17 (2 H, H4),
2
1
3
1996, 118, 100.
1.22–1.78 [12 H, H3, (CH ) ]. C NMR (75 MHz, CDCl3):
2 5
(
(
32) RCM of dienes 7 has very recently been described in a
d = 143.6, 110.2, 100.4, 77.0, 75.7, 65.1, 35.9, 34.9, 25.1,
+
different context, while our work was in progress. See ref.
23.9, 23.8, 23.5, 19.4. HRMS: m/z [M + Na] calcd for
3
0.
33) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998,
9, 4651.
C H O Na: 247.1310; found: 247.1308.
1
3
20
3
2
4
1
(R,R)-18: [a] 51 (c = 0.9, CH Cl ). H NMR (300 MHz,
D
2
2
3
CDCl ): d = 6.25 (ddd, J = 2.4, 2.4, 2.4 Hz, 1 H, H5), 4.89
3
(
34) Fürstner, A.; Langemann, K. Synthesis 1997, 792.
35) Fürstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B.
J. Org. Chem. 2000, 65, 7990.
(ddd, J = 2.4, 2.4, 2.4 Hz, 1 H, H4), 4.48 (ddd, J = 6.8, 6.8,
(
10.3 Hz, 1 H, H2), 4.03–4.13 (2 H, OH CCHO), 3.86 (m, 1
2
H, OH CCHO), 2.72 (dddd, J = 2.4, 2.4, 10.3, 15.4 Hz, 1 H,
2
(
(
36) Patel, S.; Mishra, B. K. Tetrahedron 2007, 63, 4367.
37) Marco, J. A.; Carda, M.; Rodríguez, S.; Castillo, E.;
Kneeteman, M. N. Tetrahedron 2003, 59, 4085.
H3), 2.55 (dddd, J = 2.4, 2.4, 6.9, 15.4 Hz, 1 H, H3¢), 1.40–
1
3
1.70 [10 H, (CH ) ]. C NMR (75 MHz, CDCl ): d = 144.9,
2
5
3
109.9, 99.3, 81.2, 76.4, 66.5, 36.4, 34.8, 31.7, 25.2, 24.0,
+
2
3.8. HRMS: m/z [M + H] calcd for C H O : 211.1334;
12 19 3
found: 211.1331.
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