Development of a concise and general enantioselective approach to 255-disubstituted-3-hydroxytetrahydrofurans

Article abstract of DOI:10.1021/ol802711s

Concise syntheses of 2,5-disubstituted-3-hydroxytetrahydrofurans have been developed that provide access to each configurational isomer of this scaffold from a single aldol adduct. Application of these methods to the rapid preparation of (6S,7S,9S,1QS)- a

Full text of DOI:10.1021/ol802711s

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1717-1720
Development of a Concise and General
Enantioselective Approach to
2,5-Disubstituted-3-hydroxytetrahydrofurans
Baldip Kang, Jeffrey Mowat, Thomas Pinter, and Robert Britton*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe,
Burnaby, BC, Canada V5A 1S6
rbritton@sfu.ca
Received February 13, 2009
ABSTRACT
Concise syntheses of 2,5-disubstituted-3-hydroxytetrahydrofurans have been developed that provide access to each configurational isomer of
this scaffold from a single aldol adduct. Application of these methods to the rapid preparation of (6S,7S,9S,10S)- and (6S,7S,9R,10R)-6,9-
epoxynonadec-18-ene-7,10-diol, two structurally related marine epoxylipids, is reported.
Oxygenated 2,5-disubstituted tetrahydrofurans are common
structural scaffolds in biologically active natural products.1
For example, the diastereomeric brown alga metabolites 12a
and 22b (Figure 1) possess a C3-oxygenated tetrahydrofuran
lective synthesis of oxygenated tetrahydrofurans.3,4 However,
these strategies often initiate with chiral pool materials and
are consequently designed for the synthesis of a single
configurational isomer and are not widely applicable to the
production of naturally occurring and stereochemically
(3) For recent reviews, see: (a) Wolfe, J. P.; Hay, M. B. Tetrahedron
2007, 63, 261. (b) Kang, E. J.; Lee, E. Chem. ReV. 2005, 105, 4348. (c)
Miura, K.; Hosomi, A. Synlett 2003, 143. (d) Norcross, R. D.; Paterson, I.
Chem. ReV. 1995, 95, 2041. (e) Harmange, J.-C.; Figade`re, B. Tetrahedron:
Asymmetry 1993, 4, 1711
.
(4) For recent examples, see: (a) Mitchell, T. A.; Zhao, C.; Romo, D.
Angew. Chem., Int. Ed. 2008, 47, 5026. (b) Parsons, A. T.; Campbell, M. J.;
Johnson, J. S. Org. Lett. 2008, 10, 2541. (c) Donohoe, T. J.; Williams, O.;
Churchill, G. H. Angew. Chem., Int. Ed. 2008, 47, 2869. (d) Chavre, S. N.;
Choo, H.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Cho, Y. S. Org. Lett. 2006,
8, 3617. (e) Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 2096.
(f) Chandler, C. L.; Phillips, A. J. Org. Lett. 2005, 7, 3493. (g) Mertz, E.;
Figure 1. Anthelmintic oxylipids 1 and 2 isolated from the Southern
Australian brown alga Notheia anomala.
Tinsley, J. M.; Roush, W. R. J. Org. Chem. 2005, 70, 8035
.
(5) For enantioselective syntheses of 1, see: (a) Gadikota, R. R.; Callam,
C. S.; Lowary, T. L. J. Org. Chem. 2001, 66, 9046. (b) Yoda, H.; Maruyama,
K.; Takabe, K. Tetrahedron: Asymmetry 2001, 12, 1403. (c) Garc´ıa, C.;
Soler, M. A.; Mart´ın, V. S. Tetrahedron Lett. 2000, 41, 4127.
(6) For enantioselective syntheses of 2, see: (a) de la Pradilla, R. F.;
Castellanos, A. Tetrahedron Lett. 2007, 48, 6500. (b) Mori, Y.; Sawada,
T.; Furukawa, H. Tetrahedron Lett. 1999, 40, 731. (c) Wang, Z.-M.; Shen,
M. J. Org. Chem. 1998, 63, 1414. (d) Chikashita, H.; Nakamura, Y.;
Uemura, H.; Itoh, K. Chem. Lett. 1993, 477. (e) Gurjar, M. K.; Mainkar,
P. S. Hetrocycles 1990, 31, 407. (f) Hatakeyama, S.; Sakurai, K.; Saijo,
K.; Takano, S. Tetrahedron Lett. 1985, 26, 1333. See also ref 5c.
(7) For racemic syntheses of 1 and 2, see: (a) Capon, R. J.; Barrow,
R. A.; Skene, C.; Rochfort, S. Tetrahedron Lett. 1997, 38, 7609. (b)
Williams, D. R.; Harigaya, Y.; Moore, J. L.; D’sa, A. J. Am. Chem. Soc.
1984, 106, 2641.
core and have demonstrated nematocidal activity comparable
to that of commercially available nematocides.2a Not surpris-
ingly then, considerable effort has been invested in the
development of methods for the enantio- and diastereose-
(1) For reviews, see: (a) Bermejo, A.; Figade`re, B.; Zafra-Polo, M.-C.;
Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 269. (b)
Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod. Rep. 1995, 165.
(2) (a) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene,
C.; Lacey, E.; Gill, J. H.; Friedel, T.; Wadsworth, D. Tetrahedron 1998,
54, 2227. (b) Warren, R. G.; Wells, R. J.; Blount, J. F. Aust. J. Chem.
1980, 33, 891.
10.1021/ol802711s CCC: $40.75
Published on Web 03/26/2009
2009 American Chemical Society

differentiated tetrahydrofurans (e.g., 1 or 2).5-7 Herein we
report general synthetic methods that provide rapid access
to all possible configurational isomers of the 2,5-disubsti-
tuted-3-hydroxytetrahydrofuran scaffold, and the application
of these methods to short syntheses of both 1 and 2.
We recently reported a general method for the synthesis of
nonracemic trans-epoxides that relies on the diastereoselective
addition of organolithium reagents to enantioenriched R-chlo-
roaldehydes8 followed by KOH-promoted epoxide formation.9
As depicted in Scheme 1, we were pleased to find that lithium
Diastereoselective reductions of ketochlorohydrins are sum-
marized in Table 1. Treatment of 4 with NaBH4 at 0 °C
Table 1. Hydroxyl-Directed Reduction of Ketochlorohydrins
Scheme 1. Lithium Aldol Reaction of R-Chloroaldehydes and a
Stereodivergent Strategy for Tetrahydrofuran Synthesis
a A: Me4NBH(OAc)3, HOAc/MeCN (1:1.5), -40 °C. B: DIBAL-H,
THF, -78 °C. C: catecholborane, THF, -10 °C. b Isolated yield of the
chlorodiols, which were inseparable by flash chromatography. c Ratio
determined by 1H NMR spectroscopic analysis of crude reaction mixtures.
proceeded with poor diastereocontrol13 (dr ) 2.3:1); however,
we were encouraged by the apparent stability of the chlorohy-
drin function under these reaction conditions. Improvement of
this diastereomeric ratio was eventually realized through use
of NaBH(OAc)3 or Me4NBH(OAc)3,14 the latter of which
provided the 1,3-anti diol 10 as the major component of a 14:1
mixture of diastereomers (entry 1). After some experimentation
it was also found that both catecholborane15 and DIBAL-H
provide the epimeric 1,3-syn diol 11 in good yield (entries 2
and 3). Following these procedures, the ketochlorohydrins 5
and 6 were also reduced smoothly to afford 1,3-anti and 1,3-
syn chlorodiols 12-14 (entries 4-6).13
With the chlorodiols 10-14 in hand (Table 1), we turned
our attention to the key cyclization reaction. Unfortunately, after
surveying a wide variety of conditions we were unable to effect
the conversion of 10 or 11 into the desired tetrahydrofurans
via the direct 5-exo-tet cyclization outlined in Scheme 1. For
example, under basic conditions (e.g., KOH, KH, NaH, Et3N),
we observed only products of decomposition and/or varying
amounts of the corresponding epoxy alcohols (e.g., 15, Scheme
2). Notably, these latter substances were produced in near
quantitative yield by simply treating the chlorodiols with KOH
in EtOH. On the basis of this observation, we turned our
attention to a Lewis acid catalyzed cyclization of the readily
available epoxy alcohols, which would expectedly6b,16 give rise
enolates also couple smoothly with R-chloroaldehydes to
provide the corresponding aldol adducts in excellent diastere-
omeric ratios and yield.10 For example, treatment of the lithium
enolate derived from acetophenone (3) with (2S)-2-chloropen-
tanal9 cleanly affords the anti chlorohydrin 4 (>20:1 dr).
Similarly, the aldol adducts 5 and 6 were produced in excellent
yield from the coupling of (2R)-2-chloroheptanal11 with trans-
4-phenylbuten-2-one and 11-dodecen-2-one, respectively. On
the basis of these results we envisaged the conceptually
straightforward strategy outlined in Scheme 1, whereby hy-
droxyl-directed reduction of the ketone function in the aldol
adducts, followed by cyclization, would provide rapid access
to stereochemically unique tetrahydrofurans (e.g., 8 or 9). While
cognizant of potential problems associated with the reactivity
of chlorohydrins,12 we set out to assess the viability of this
stereodivergent route to tetrahydrofuran synthesis.
(8) For the asymmetric R-chlorination of aldehydes, see: (a) Halland,
N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem.
Soc. 2004, 126, 4790. (b) Brochu, M. P.; Brown, S. P.; Macmillan, D. W.
J. Am. Chem. Soc. 2004, 126, 4108. (c) Marquez, C. A.; Fabbretti, F.;
Metzger, J. O. Angew. Chem., Int. Ed. 2007, 46, 6915.
(9) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083.
(10) For a theoretical investigation of nucleophilic addition to an
R-chloroaldehyde, see: Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem.
Soc. 2006, 128, 2920.
(13) The relative configuration of the formed carbinol stereocenter was
confirmed unequivocally by conversion to the corresponding acetonide and
subsequent analysis of the 13C NMR spectrum as reported in Rychnovsky,
S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945.
(11) (2R)-2-Chloroheptanal is available in 97% yield and 84% enan-
tiomeric excess through chlorination of heptanal (NCS, CH2Cl2, L-
prolinamide) following the procedure described in ref 8a.
(12) De Kimpe, N.; Verhe´, R. The Chemistry of R-Haloketones,
R-Haloaldehydes and R-Haloimines; Patai, S.; Rappoport, Z., Eds.; John
Wiley and Sons: New York, 1988.
(14) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(15) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190.
1718
Org. Lett., Vol. 11, No. 8, 2009

Scheme 2
.
Synthesis of Tetrahydrofurans 16 and 17
Table 2. AgOTf-Promoted Cyclization of Chlorodiol 11
entry
AgOTf (equiv)
additive (equiv)
% yield 19a
1
2
3
4
1.0
1.0
0.5
1.0
none
0b
55
45
90
Ag2O (1.0)
Ag2O (0.5)c
Ag2O (1.0)d
a Isolated yield of 19. b Considerable decomposition of starting material
and/or product was observed. c Complete consumption of 11 required 24 h.
d 0 °C to rt overnight.
contained none of the desired tetrahydrofuran 19. We were
encouraged, however, by resonances in the 1H NMR spectrum
of the crude reaction mixture (e.g., δ 5.73 (dd, J ) 6.5, 2.5
Hz)) that were consistent with the formation of dihydrofurans,
potentially produced via acid-catalyzed dehydration of 19.
Unfortunately, addition of a variety of organic or inorganic bases
failed to significantly improve the outcome of this reaction. As
AgOTf can be prepared from the reaction of Ag2O with triflic
acid,21 Ag2O was screened as a triflic acid scavenger and found
to facilitate the formation of 19 in good yield (entry 2).22 Use
of substoichiometric amounts of Ag2O and AgOTf required
extended reaction times and resulted in increased decomposition
of 11 and/or 19 and consequently lower isolated yields of the
latter substance (entry 3).23 The most favorable conditions for
the conversion of 11 into 19 involved the addition of 1 equiv
of both AgOTf and Ag2O to a THF solution of 11 at 0 °C,
followed by the gradual warming of this mixture to room
temperature over 12 h (entry 4). On the basis of these results
and the epoxide opening route detailed above, each configu-
rational isomer of the 2,5-disubstituted-3-hydroxytetrahydro-
furan scaffold can now be accessed in excellent overall yield
from a single aldol adduct.
To assess the scope of these cyclization protocols, the
syntheses of several 2,5-disubstituted-3-hydroxytetrahydrofurans
were undertaken. As summarized in Table 3, alkyl, alkenyl,
and phenyl substituents were well tolerated by these processes,
and a variety of stereoisomeric tetrahydrofurans were prepared
in good to excellent yield. As indicated in eqs 1 and 2, the
styryltetrahydrofurans 21-24 readily epimerize when treated
with BF3·OEt2 at room temperature, and consequently, the
BF3·OEt2-catalyzed rearrangement of epoxyalcohols derived
from 12 or 13 (entries 3 and 5) were carried out at -35 °C to
minimize epimerization.24 Notably, the tetrahydrofuran 25 (entry
6), a C-10 deshydroxy analogue of the marine oxylipid 1, is
to the stereoisomeric tetrahydrofurans 16 and 17. Following
this revised strategy, treatment of 15 with BF3·OEt2 (10 mol
%) at low temperature (-78 °C) effected clean transforma-
tion to 16, albeit with low conversion.17 Repetition of this
experiment at room temperature, however, provided the
desired tetrahydrofuran 16 in excellent yield (92%). Like-
wise, treatment of the epoxy alcohol derived from 11 (not
shown) under similar conditions resulted in clean transforma-
tion to 17. Mechanistically, both 16 and 17 are derived from
direct opening of the epoxide and inversion of configura-
tion.18 In both cyclizations, none of the C2 epimer that would
arise from an SN1-type process or the intermediacy of a
halohydrin16d,18 were observed.
While it could be shown that Mitsunobu inversion19/hydroly-
sis of 16 or 17 provides access to the two remaining diastere-
omers of the 2,5-disubstituted-3-hydroxytetrahydrofuran scaf-
fold,20 these additional synthetic steps detract from the overall
appeal of this route. Thus, we refocused efforts on the direct
5-exo-tet cyclization outlined in Scheme 1. Bearing in mind
that base-promoted cyclizations of 10 and 11 led exclusively
to epoxide formation, we envisaged that treatment of the
chlorodiols with silver triflate (AgOTf) may lead to a silver
alkoxide (e.g., 18) in which coordination between silver and
chlorine would favor a noncompetent conformation for epoxide
formation and activate the chloromethine to nucleophilic attack
by the distal alcohol function. Table 2 summarizes our efforts
toward the realization of this process. As indicated in entry 1,
treatment of 11 with AgOTf led to a complex mixture that
(16) For examples of 5-endo cyclizations of epoxy alcohols, see: (a)
Doan, H. D.; Gallon, J.; Piou, A.; Vate´le, J.-M. Synlett 2007, 6, 983. (b)
Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416. (c) Smith, A. B.,
III; Fox, R. J. Org. Lett. 2004, 6, 1477. (d) Karikomi, M.; Watanabe, S.;
Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495. (e) Jung, M. E.;
D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (f) Mukai, C.;
Sugimoto, Y.-i.; Ikeda, Y.; Hanaoka, M. J. Chem. Soc., Chem. Commun.
1994, 1161.
(17) Use of other Lewis acids (e.g., AlCl3 or EtAlCl2) resulted in
complex mixtures that contained only minor (<10%) amounts of 16.
(18) For a theoretical investigation of the 5-endo cyclization of epoxy
alcohols, see: Coxon, J. M.; Morokuma, K.; Thorpe, A. J.; Whalen, D. J.
Org. Chem. 1998, 63, 3875.
(21) Whitesides, G. M.; Gutowski, F. D. J. Org. Chem. 1976, 41, 2882.
(22) For AgOTf/Ag2O promoted oxetane formation from a bromohydrin,
see: Popsavin, V.; Radic, J.; Popsavin, M.; Cirin-Novta, V. J. Serb. Chem.
Soc. 2004, 69, 117.
(23) When 11 was treated with Ag2O (1 equiv) in THF without AgOTf,
none of the desired tetrahydrofuran 19 was formed.
(19) Mitsunobu, O. Synthesis 1981, 1.
(20) Mitusnobu inversion of 16, 17, and 19 provided access to ent-
19, ent-20, and ent-16, respectively (see Supporting Information
for details).
(24) At temperatures below -35 °C these reactions required several days.
Repetition of these reactions at temperatures above -20 °C led to serious
erosion in diastereomeric purity.
Org. Lett., Vol. 11, No. 8, 2009
1719

Table 3. Synthesis of 3-Hydroxytetrahydrofurans
Scheme 3. Synthesis of Marine Oxylipids (+)-1 and (+)-2
sequence of reactions carried out on the tetrahydrofuran 23
afforded the C9/C10 epimeric natural product (+)-2. The
spectral data derived from these substances were in complete
agreement with those reported in the literature.5,6,28
In summary, we have developed efficient routes to all
configurational isomers of the 2,5-disubstituted-3-hydroxy-
tetrahydrofuran scaffold that initiate with a single aldol adduct.
Key to the success of this work is a high yielding, chemose-
lective, AgOTf-promoted cyclization of chlorodiols that rep-
resents a stereochemical compliment to epoxy alcohol forma-
tion-Lewis acid catalyzed rearrangement. In addition we have
applied these processes to concise syntheses of the anthelmintic
marine oxylipids 1 and 2. Notably, the overall yield for 1 (37%)
and 2 (26%) from heptanal and the total number of synthetic
steps required compare well with the reported asymmetric
syntheses of these substances.5,6 Importantly, the functional
group tolerance and stereochemical flexibility of this new
approach should allow rapid access to derivatives of 1 and
2 as well as a wide variety of naturally occurring and
biologically active oxygenated tetrahydrofurans, work that
is currently underway in our laboratory.
a A: AgOTf, Ag2O, THF, 0 °C to rt, 12 h. B: (i) KOH, EtOH, rt, 1.5 h;
(ii) BF3·OEt2 (10 mol %), CH2Cl2, -35 °C, 24 h. C: (i) KOH, EtOH, rt,
1.5 h; (ii) BF3·OEt2 (10 mol %), CH2Cl2, rt, 24 h. b Isolated yield. c Produced
as a separable 5:1 mixture of 22:24. d Produced as a separable 8:1 mixture
of 24:22.
available in four steps (64% overall yield) from heptanal
following this strategy.
Acknowledgment. This research was supported by NSERC-
Canada, Merck Frosst Canada, NSERC CGSD (B.K.), NSERC
PGSD (J.M.), and Michael Smith Foundation for Health
Research (B.K., J.M.). We thank Regine Gries (SFU) for
assistance with chiral GC analysis and Matthew Michaleski
(SFU) and Graeme Piercy (SFU) for carrying out some
preliminary experiments.
Finally, this concise approach to 3-hydroxytetrahydrofurans
was exploited in short total syntheses of the marine oxylipids
(+)-1 and (+)-2. As depicted in Scheme 3, oxidative cleavage
of the alkene function in 21 with ozone followed by reductive
workup with polymer-supported triphenylphosphine (PS-PPh3)
and filtration provided the crude aldehyde 27.25 Direct reaction
of 27 with an excess of 8-nonenylmagnesium bromide (29)26
in DCE at reflux27 provided (+)-1 as the major component of
a separable 5.5:1 mixture of C10 epimeric alcohols. A similar
Supporting Information Available: Experimental and
characterization details. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802711S
(25) The aldehydes 27 and 28 decomposed on silica gel, and conse-
quently the crude aldehydes were used without further purification.
(26) For the addition of 29 to derivatives of 27 and 28 in which the
alcohol function is protected, see refs 5a, 6b, 6c and 7b.
(27) Addition of Grignard reagents to 27 at lower temperatures required
extended reaction times and proceeded with lower diastereoselectivity,
resulting in decreased production of 1.
(28) The specific rotation for synthetic (+)-1 ([R]D ) +20.0, c 0.5,
CHCl3) was consistent with the value reported in ref 5a ([R]D ) +24.3, c
0.3, CHCl3), and the specific rotation for synthetic (+)-2 ([R]D ) +14.5, c
1.1, CHCl3) was consistent with the value reported in ref 6d ([R]D ) +15.0,
c 0.46, CHCl3)
.
1720
Org. Lett., Vol. 11, No. 8, 2009