Regioselective and stereoselective cyclizations of chloropolyols in water: Rapid synthesis of hydroxytetrahydrofurans

Article abstract of DOI:10.1021/ol100260z

A concise, stereoselective synthesis of functionalized tetrahydrofuranols has been developed that involves heating readily available chloropolyols in water. These reactions are operationally straightforward and chemoselective for the formation of tetrahydrofurans, obviating the need for complicated protecting group strategies. The efficiency of this process is demonstrated in a short asymmetric synthesis of the natural product (+)-goniothalesdiol.

Full text of DOI:10.1021/ol100260z

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1716-1719
Regioselective and Stereoselective
Cyclizations of Chloropolyols in Water:
Rapid Synthesis of
Hydroxytetrahydrofurans
Baldip Kang, Stanley Chang, Shannon Decker, and Robert Britton*
Department of Chemistry, Simon Fraser UniVersity, Burnaby,
British Columbia V5A 1S6, Canada
rbritton@sfu.ca
Received February 2, 2010
ABSTRACT
A concise, stereoselective synthesis of functionalized tetrahydrofuranols has been developed that involves heating readily available chloropolyols
in water. These reactions are operationally straightforward and chemoselective for the formation of tetrahydrofurans, obviating the need for
complicated protecting group strategies. The efficiency of this process is demonstrated in a short asymmetric synthesis of the natural product
(+)-goniothalesdiol.
The prevalence of tetrahydrofuranols in biologically active
natural products1 continues to motivate the development of
Scheme 1. Naturally Occurring Tetrahydrofuranols and the
Silver-Promoted Cyclization of Unprotected Chlorodiols
new synthetic methods to access these substances.2,3 For
example, a number of syntheses of the cytotoxic Gonio-
thalamus styryllactones and their naturally occurring deriva-
tives (e.g., goniothalesdiol (1), Scheme 1) have been re-
(1) (a) Bermejo, A.; Figadere, 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) For a recent review, see: Wolfe, J. P.; Hay, M. B. Tetrahedron 2007,
63, 261
.
(3) For recent examples of tetrahydrofuran syntheses, see: (a) Friestad,
G. K.; Lee, H. J. Org. Lett. 2009, 11, 3958. (b) Mitchell, T. A.; Zhao, C.;
Romo, D. Angew. Chem., Int. Ed. 2008, 47, 5026. (c) Parsons, A. T.;
Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541. (d) Donohoe,
T. J.; Williams, O.; Churchill, G. H. Angew. Chem., Int. Ed. 2008, 47, 2869.
(e) Wang, J.; Pagenkopf, B. Org. Lett. 2007, 9, 3703
.
(4) For example, see: (a) Babjak, M.; Kapita´n, P.; Gracza, T. Tetrahedron
2005, 61, 2471. (b) Carren˜o, M. C.; Herna´ndez-Torres, G.; Urbano, A.;
Colobert, F. Org. Lett. 2005, 7, 5517. (c) Prasad, K. R.; Gholap, S. L. J.
Org. Chem. 2006, 71, 3643. (d) Ghosh, S.; Rao, C. N.; Dutta, S. K. Synlett
2007, 9, 1464. (e) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 9,
1532. (f) Yadav, J. S.; Raju, A. R.; Rao, P. P.; Rajaiah, G. Tetrahedron:
Asymm. 2005, 16, 3283. (g) Babjak, M.; Kapita´n, P.; Gracza, T. Tetrahedron
Lett. 2002, 43, 6983. (h) Murga, J.; Ruiz, P.; Falomir, E.; Carda, M.; Peris,
ported,4 and owing to a 100-fold increased potency over
mean toxicity toward a variety of cancer cell lines,5 varitriol
(2) has attracted the attention of several synthetic chemistry
groups.6 Recently, we reported a rapid and stereochemically
G.; Marco, J.-A. J. Org. Chem. 2004, 69, 1987
.
10.1021/ol100260z  2010 American Chemical Society
Published on Web 03/18/2010

flexible synthesis of 2,5-disubstituted 3-hydroxytetrahydro-
furans that involves a silver-promoted cyclization of unpro-
tected chlorodiols (e.g., 3).7 While this process affords the
corresponding tetrahydrofurans (e.g., 4) in excellent yield,
a notable drawback is the requirement for stoichiometric
quantities of both AgOTf and Ag2O. During our efforts to
expand the scope of this reaction and investigate the
cyclizations of unprotected chlorotriols (e.g., 5 f 6), we
found that a variety of chloropolyols undergo direct cycliza-
tion to the corresponding tetrahydrofuranol by simply heating
them in water. Herein we describe the discovery, optimiza-
tion, and scope of this environmentally friendly and economic
process as well as its application in the concise asymmetric
synthesis of goniothalesdiol (1).
aqueous H2SO4 (0.5 M) for 18 h, a mixture of the triol 9
and its C1 epimer (dr ) 3:1, 40% combined yield) were
produced along with the tetrahydrofuran 10 and its C2 epimer
(dr ) 3:1, <5% combined yield). This observation prompted
us to re-examine the epoxide opening, whereupon it was
eventually discovered that heating the epoxychlorohydrin 8
in aqueous H2SO4 (0.5 M) afforded the 3:1 mixture of
tetrahydrofurans in 67% yield (not shown). Moreover,
repetition of this reaction without added acid (i.e., simply
heating 8 in water) provided the tetrahydrofuranol 10 in 90%
yield. As tetrahydrofuran formation presumably proceeds via
the triol 9, this later material was also heated in water (8 h),
which resulted in clean formation of the expected tetrahy-
drofuran 10 as a single stereoisomer (89% yield).
The chlorotriols required for this work were readily
available from alkenyl chlorohydrins,8 prepared through the
addition of vinyllithium reagents to R-chloro aldehydes.9
For example, hydroxyl-directed epoxidation10 of chlorohy-
drin 7 afforded epoxide 8 (Scheme 2), the treatment of which
In an effort to reduce the reaction time required for
tetrahydrofuran formation and assess the importance of water
to this process, cyclization of the chlorotriol 9 was repeated
in a variety of solvents using microwave heating. As
indicated in Table 1, tetrahydrofuran 10 was produced in
Table 1. Microwave-Assisted Cyclization of the Chlorotriol 9a
Scheme 2. Synthesis of the Dihydroxytetrahydrofuran 10
entry
solvent
H2O
time (min)
tempb (°C)
yieldc (%)
1
2
3
4
5
6
7
8
10
5
120
180
120
120
120
120
120
120
91
90
82
0
H2O
DMSO
PhCH3
DMF
CH3CN
CH3OH
pH 7 buffer
15
30
10
25
10
20
25d
55d
90
86
with dilute acid provided chlorotriol 9 as the major diaste-
reomer (dr ) 8:1).11 Alternatively, triol 9 could be accessed
directly from the alkenylchlorohydrin 7 via hydroxyl-directed
dihydroxylation (dr ) 20:1). While it was gratifying to find
that our optimized conditions (AgOTf, Ag2O)7 effected the
desired cyclization (i.e., 9 f 10), surprisingly, the spectral
data derived from the resultant tetrahydrofuranol 10 were
identical to those of a minor byproduct observed during
optimization of the epoxide opening (i.e., 8 f 9). For
example, when the epoxychlorohydrin 8 was treated with
a A 0.1 M solution of 9 was heated as indicated in a sealed vial in a
Biotage Initiator 2.5 (400 W magnetron) microwave reactor. b Internal
temperature measured with a vertically focused IR temperature sensor.
c Isolated yield of 10. d Product formation accompanied by decomposition
of 9 and/or 10.
moderate to excellent yield in all solvents except toluene,
although no significant quantities of product were observed
within 1 h at temperatures below 100 °C. Notably, the
cyclization can also be carried out in aqueous pH 7 buffer
in nearly identical yield (86% yield) to that obtained in pure
water, conditions that may be beneficial for acid-sensitive
substrates. To demonstrate the practical utility of this process,
0.5 g of the chlorotriol 9 was heated for 20 min at 120 °C
in 3 mL of water to provide, after simple decantation, 0.39 g
(91%) of the tetrahydrofuranol 10.
In order to explore the scope of this reaction, a number
chlorodiols, triols, and tetrols12 were subjected to brief
microwave heating in water (Table 2). In general, these
microwave-assisted cyclizations proceeded in excellent yield
regardless of the configuration or functionalization of the
starting material. As indicated in entries 1 and 2, cyclization
of the silyl-protected chlorotetrols 12 and 14 led to the
(5) (a) Malmstrøm, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.;
Justica, J.; Rosales, A. J. Nat. Prod. 2002, 65, 364. (b) Mayer, A. M. S.;
Gustafson, K. R. Eur. J. Cancer 2004, 40, 2676.
(6) (a) McAllister, G. D.; Robinson, J. E.; Taylor, R. J. K. Tetrahedron
2007, 63, 12123. (b) Clemens, R. T.; Jennings, M. P. Chem. Commun. 2006,
2720. (c) Kumar, V.; Shaw, A. K. J. Org. Chem. 2008, 73, 7526. (d) Pal´ık,
M.; Karlub´ıkova´, O.; Lasikova´, A.; Koz´ızek, J.; Gracza, T. Eur. J. Org.
Chem. 2009, 709.
(7) Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett. 2009, 11, 1717.
(8) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083.
(9) (a) Brochu, M. P.; Brown, S. P.; Macmillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108. (b) Halland, N.; Braunton, A.; Bachmann, S.; Marigo,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (c) Amatore, M.;
Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2009, 48, 5121.
(10) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(11) That this process involves double inversion at C1 suggests the
intermediacy of a tetramethylenechloronium ion. See: Olah, G. A.; Peterson,
P. E. J. Am. Chem. Soc. 1968, 90, 4675.
Org. Lett., Vol. 12, No. 8, 2010
1717

sulted in selective formation of the corresponding C-linked
pentoses 26 and 27, respectively. This result is consistent
with the fact that the structurally simplified chlorodiol 22
(entry 10) failed to produce appreciable amounts of tetrahy-
dropyran or epoxide. Thus, this experimentally straightfor-
ward process obviates the need for protecting groups on
ancillary alcohol functions.15 Tertiary alcohols were also
readily converted to tetrahydrofurans (entry 3), as were a
variety of configurationally and structurally unique chlo-
rodiols (entries 4-9). Notably, both allylic and propargylic
alcohols (entries 9 and 11) were compatible with the reaction
conditions, and all cyclizations proceeded in yields better
than those obtained employing our AgOTf/Ag2O protocol
and in much less time (20 min vs 12 h). As indicated in
entries 11 and 12, the hydroxymethyltetrahydrofuran subunit
37, common to many of the potently cytotoxic annonaceous
acetogenins,1a is accessible through this cyclization strategy.
It was also found that the 3-hydroxy-γ-lactone 38 (entry 13)
could be prepared as a single configurational isomer through
briefly heating the readily available aldol adduct 25.
Table 2. Microwave-Assisted Cyclization of Chloropolyolsa
While we were pleased with the generality and efficiency
of the cyclization reactions summarized in Table 2, access
to the chlorohydrin starting materials 11-25 via the addition
of lithium enolates or vinyl lithium reagents to R-chloroal-
dehydes invariably leads to 1,2-anti-chlorohydrins.7,8 Con-
sequently, the cyclizations of chloropolyols derived from
these substances are limited to the production of 2,3-syn-
tetrahydrofuranols (e.g., 29-34). Due to this limitation, we
were inspired by Jamison’s work on 6-endo-selective epoxide
opening reactions in aqueous media16 to explore the 5-endo-
epoxide opening of epoxydiols, readily available from
chloropolyols through treatment with base. For example,
reaction of the chlorotriol 9 with KOH in EtOH afforded
the epoxydiol 39. We were delighted to find that brief heating
(120 °C) of this material in water effected smooth conversion
to the corresponding tetrahydrofuranol 40, which was
produced as a single diastereomer (Scheme 3). Overall, this
Scheme 3. Microwave-Assisted Cyclization of Epoxydiol 39
epoxide formation/5-endo-epoxide opening sequence results
in net retention of configuration at C5 and is thus a
stereochemically complementary process to the direct cy-
a A solution/suspension of chlorohydrin in H2O (0.1 M) was heated in
a sealed vial at 120 °C in a CEM Discover LabMate microwave reactor for
20 min. b Isolated yield. c Reaction carried out at 80 °C in CH3OH-H2O.
(12) See the Supporting Information for the preparation of chloropolyols
depicted in Table 1 and the stereochemical assignment of all compounds.
(13) For selected examples, see: (a) Morihira, K.; Hara, R.; Kawahara,
S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am. Chem.
Soc. 1998, 120, 12980. (b) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D.
J. Am. Chem. Soc. 2007, 129, 2269.
C-linked pentoses 26 and 27, respectively, whereby con-
comitant removal of the silyl protecting group occurs under
the reaction conditions (i.e., generation of HCl). Remarkably,
simply heating the chlorotetrols 11 or 13 (entries 1 and 2)
in water, which could lead to formation of epoxides,8
oxetanes,13 tetrahydrofurans,14 and/or tetrahydropyrans, re-
(14) For selected examples of tetrahydrofuran formation via displacement
of secondary alkyl chlorides see refs 7, 13b, and: (a) Cekovic, Z.; Cvetkovic,
M. Tetrahedron Lett. 1982, 23, 3791. (b) Sato, M.; Uchimaru, F. Chem.
Pharm. Bull. 1981, 29, 3134.
1718
Org. Lett., Vol. 12, No. 8, 2010

clizations highlighted in Table 2. Further investigations that
address the scope and utility of this microwave-assisted
5-endo-epoxide opening reaction are currently ongoing in
our laboratory.
Finally, the efficiency of this chloropolyol cyclization
strategy was demonstrated in a short synthesis of goniotha-
lesdiol (1)17 that initiated with the asymmetric R-chlorination
of commercially available methyl 5-oxopentanoate (41)
(Scheme 4). Unfortunately, the prolinamide-catalyzed orga-
the imidazolidinone catalyst 46, chosen in part for its lack
of reactivity with the R-chloro products,9c provided the
desired R-chloro aldehyde 42 in good yield and enantiomeric
excess (91% ee). Treatment of the resultant chloroaldehyde
42 with the lithium anion derived from (Z)-2-phenyl-1-
iodoethene (43) and subsequent dihydroxylation (dr ) 8:1)
afforded the chlorotriol 45 as the major diastereomer in 74%
isolated yield. Microwave heating of this material in metha-
nol gave (+)-goniothalesdiol (1) as a single configurational
isomer. The spectral data (1H NMR, 13C NMR, HRMS, [R]D,
IR)19 derived from (+)-1 were in complete agreement with
those reported for the natural product.4,17 It is noteworthy
that this four-step synthesis of (+)-1 compares well with
those reported in the literature that range in length from 10
to 16 linear steps.4
Scheme 4. Total Synthesis of (+)-Goniothalesdiol (1)
In summary, we have developed a concise and stere-
ochemically flexible approach to functionalized tetrahydro-
furanols that involves simply heating readily available
chloropolyols in water. Notably, this operationally straight-
forward reaction is both high yielding and regioselective for
the formation of tetrahydrofurans. Thus, complicated protect-
ing group strategies can be avoided, as displacement of the
chloride by ancillary alcohol functions does not occur at any
appreciable rate under these reaction conditions. The ef-
ficiency of this approach to functionalized tetrahydrofuranols
was also demonstrated in a short (four-step) synthesis of the
natural product goniothalesdiol (1). The application of this
methodology to the synthesis of more structurally complex
tetrahydrofuran-containing natural products is currently
underway in our laboratory, and the results of these efforts
will be reported in due course.
nocatalytic R-chlorination method developed by Jørgensen9b
and effectively employed by us in previous natural product
syntheses7,8,18 proved sluggish on the oxoester 41 and
provided the desired R-chloro aldehyde 42 in modest yield
and enantioselectivity (40% ee). Presumably, epimerization
of the R-chloro product 42 occurs during the extended
(20 h) reaction times required for full conversion of 41. We
were delighted to find, however, that MacMillan’s SOMO-
actiVated aldehyde R-chlorination reaction,9c that employs
Acknowledgment. Research supported by NSERC-
Canada and Merck Frosst Canada Ltd., Michael Smith
Foundation for Health Research (B.K.), and NSERC CGS
(B.K.). We thank Prof. Glenn Sammis (UBC) for generously
allowing us use of his microwave reactor.
Supporting Information Available: Characterization data
and detailed experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) The formation of oxepane was also inefficient following this
protocol. For example, microwave heating of 6-chloro-1-hexanol in H2O
provided oxepane (10%), 1,6-hexanediol (20%), and 7-oxa-1,13-tride-
canediol (30%).
(16) See, for example: (a) Simpson, G. L.; Heffron, T. P.; Merino, E.;
Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1056. (b) Heffron, T. P.;
Jamison, T. F. Synlett 2006, 14, 2329. (c) Morten, C. J.; Jamison, T. F.
J. Am. Chem. Soc. 2009, 131, 6678. (d) Morten, C. J.; Byers, J. A.; Van
Dyke, A. R.; Vilotijevic, I.; Jamison, T. F. Chem. Soc. ReV. 2009, 3175.
(17) Isolation of goniothalesdiol: Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.;
Tan, B. K. H.; Pereira, J. T.; Goh, S.-H. Tetrahedron 1998, 10, 2143.
(18) Mowat, J.; Gries, R.; Gries, G.; Khaskin, G.; Britton, R. J. Nat.
OL100260Z
(19) Certain resonances in the 13C NMR spectrum of (+)-1 recorded in
CDCl3 were found to shift slightly depending on concentration. The 13C NMR
spectrum of a 0.04 M solution of (+)-1 was identical to that reported for both
natural17 and synthetic4 goniothalesdiol. The specific rotation for synthetic (+)-1
([R]25 +7.2 (c 0.2, EtOH)) was consistent with the value reported in ref 17
D
Prod. 2009, 72, 772
.
for natural goniothalesdiol ([R]25D +7.5 (c 0.23, EtOH)).
Org. Lett., Vol. 12, No. 8, 2010
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