A novel synthesis of functionalized tetrahydrofurans by an Oxa-Michael/Michael cyclization of γ-hydroxyenones

Article abstract of DOI:10.1021/jo020700h

An approach to highly functionalized tetrahydrofuran derivatives based upon a novel Oxa-Michael/ Michael dimerization of cis-γ-hydroxyenones is presented. The reaction begins with either 1,2-dioxines or trans-γ-hydroxyenones and proceeds by addition of on

Full text of DOI:10.1021/jo020700h

A Novel Syn th esis of F u n ction a lized Tetr a h yd r ofu r a n s by a n
Oxa -Mich a el/Mich a el Cycliza tion of γ-Hyd r oxyen on es
Ben W. Greatrex,† Marc C. Kimber,† Dennis K. Taylor,*,† and Edward R. T. Tiekink‡
Department of Chemistry, The University of Adelaide, South Australia 5004, Australia, and
Department of Chemistry, National University of Singapore, Singapore 117543
dennis.taylor@adelaide.edu.au
Received November 18, 2002
An approach to highly functionalized tetrahydrofuran derivatives based upon a novel Oxa-Michael/
Michael dimerization of cis-γ-hydroxyenones is presented. The reaction begins with either 1,2-
dioxines or trans-γ-hydroxyenones and proceeds by addition of one molecule of trans-γ-hydroxyenone
to another molecule of cis- or trans-γ-hydroxyenone catalyzed by an alkoxide or hydroxide base.
Subsequent intramolecular Michael addition of the keto-enolate gives the observed tetrahydro-
furans. Substitution at both the 2- and 4-positions of the γ-hydroxyenone is tolerated; however, for
4-substituted γ-hydroxyenones, selectivity issues arise due to the possibility of heterochiral or
homochiral dimerizations. The major products were those with all contiguous groups trans.
SCHEME 1
In tr od u ction
The tetrahydrofuran (THF) ring is a core constituent
of many bioactive molecules,1 and numerous methods for
its synthesis have been developed.2 One particular ap-
proach that has been used in the synthesis of several
natural products is the 1,4-addition of oxygen nucleo-
philes to conjugate acceptors. The reaction is normally
intramolecular and proceeds under base catalysis. Com-
patible conjugate acceptors include R,â-unsaturated es-
ters,3 ketones,4 and sulfonates.5 While R,â-unsaturated
ketones are better conjugate acceptors than R,â-unsatu-
rated esters, comparatively few examples of the 1,4-
addition of oxygen nucleophiles to R,â-unsaturated ke-
tones exist.
We have recently reported that cis-γ-hydroxyenones 1
undergo 1,4-addition exceedingly well with a variety of
nucleophiles including stabilized phosphorus ylides,6
stabilized phosphonates,7 and malonates.8 The γ-hydroxyl
group R to the site of “attack” within the cis-γ-hydroxy-
enone allows for interaction between the incoming nu-
cleophile and hydroxyl group to occur after initial attack
of the nucleophile. Furthermore, substitution at the
γ-position effectively blocks one face of the molecule,
leading to very high facial selectivity for 1,4-addition.6a
As the γ-hydroxy group may also act as a nucleophile
itself, cis-γ-hydroxyenones are unique electrophiles that
give highly selective addition products.
* To whom correspondence should be addressed. Phone: (+61) 8
8303 5495. Fax: (+61) 8 8303 4358.
† The University of Adelaide.
‡ National University of Singapore.
(1) For recent examples of THF-containing natural products, see:
(a) Araya, H.; Hara, N.; Fujimoto, Y.; Srivastava, A.; Sahai, M. Chem.
Pharm. Bull. 1994, 42 (2), 388. (b) Kim, E.; Tian, F.; Woo, M. J . Nat.
Prod. 2000, 63 (11), 1503. (c) Sekiguchi, M.; Shigemori, H.; Ohsaki,
A.; Kobayashi, J . J . Nat. Prod. 2002, 65 (3), 375.
(2) For examples of THF syntheses, see: (a) Maioli, A. T.; Civiello,
R. T.; Foxman, B. M.; Gordon, D. M. J . Org. Chem. 1997, 62 (21), 7413.
(b) J ung, M. E.; Fahr, B. T.; D’Amico, D. C. J . Org. Chem. 1998, 63,
2982. (c) Shim, J .-G.; Yamamoto, Y. J . Org. Chem. 1998, 63, 3067. (d)
Marshall, J .; J iang, H. J . Org. Chem. 1999, 64, 971.(e) Guindon, Y.;
Soucy, F.; Christiane, Y.; Ogilvie, W.; Plamondon, L. J . Org. Chem.
2001, 66, 8992. (f) Makasza, M.;, Przyborowski, J .; Klajn, R.; Kwast,
A. Synlett 2000, 1773. (g) Makasza, M.; J udka, M. Chem.sEur. J . 2002,
4234.
(3) (a) Ko, S.; Klein, L.; Pfaff, K.-P.; Kishi, Y. Tetrahedron Lett. 1982,
23, 4415. (b) Honda, T.; Ishikawa, F. J . Org. Chem. 1999, 64, 5542. (c)
J in, C.; J acobs, H. K.; Gopalan, A. S. Tetrahedron Lett. 2000, 41, 9753.
(d) Kubota, T.; Tsuda, M.; Kobayashi, J . Org. Lett. 2001, 3, 1363. (e)
Paquette, L. A.; Tae, J .; Arrington, M. P.; Sadoun, A. H. J . Am. Chem.
Soc. 2000, 122, 2742.
(4) (a) Ireland, R. E.; Wardle, R. B. J . Org. Chem. 1987, 52, 1780.
(b) Grigg, R.; Rasparini, M.; MacLachlan, W. Chem. Commun. 2000,
2241.
cis-γ-Hydroxyenones 1 may be conveniently generated
from 1,2-dioxines 2 by base catalysis or by employing a
(6) (a) Avery, T. A.; Taylor, D. K.; Tiekink, E. R. T. J . Org. Chem.
2000, 65, 5531. (b) Avery, T. D.; Greatrex, B. W.; Taylor, D. K.; Tiekink,
E. R. T. J . Chem. Soc., Perkin Trans. 1 2000, 1319. (c) Avery, T. D.;
Fallon, G.; Greatrex, B. W.; Pyke, S. M.; Taylor, D. K.; Tiekink, E. R.
T. J . Org. Chem. 2001, 66, 7955. (d) Palmer, F. N., Taylor, D. K. J .
Chem. Soc., Perkin Trans. 1 2000, 9, 1323.
(5) (a) Marot, C.; Rollin, P. Tetrahedron Lett. 1994, 35, 8377. (b)
Craig, D. C.; Edwards, G. L.; Muldoon, C. A. Synlett 1997, 1318. (c)
Ko, C.; Chou, T. J . Org. Chem. 1998, 63, 4645.
(7) Kimber, M. C.; Taylor, D. K. J . Org. Chem. 2002, 67, 3142.
(8) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Fallon, G.; Tiekink,
E. R. T. J . Org. Chem. 2002, 67, 5307.
10.1021/jo020700h CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003
J . Org. Chem. 2003, 68, 4239-4246
4239

Greatrex et al.
TABLE 1. Oxa -Mich a el/Mich a el Rea ction s of En on es Gen er a ted fr om 1,2-Dioxin es
yieldb (%)
entrya
dioxine
time
base
solvent, temp (°C)
6
7
8
9
1
2d
3
2a
2a
2a
2a
2b
2c
2c
2c
2d
2e
16 h
31 d
3 h
LiOH
LiOH
LiOH
NaOEt
LiOH
LiOH
NaOEt
NaOEt
LiOH
LiOH
THF, rt
THF, -15
THF, 65
CH3CN/EtOH, rt
THF, rt
THF, rt
THF/EtOH, rt
THF/EtOH, -10
THF, rt or 65
THF, rt or 65
50
(47)
(62)
57 (78)
46
67 (87)
57
(63)
29c
(53)
(38)
(22)
4e
5
1 h
72 h
72 h
1 h
1 h
72 h
16 h
11
22
6
7 (8)
6
(16)
(5)
18
(21)
7e
8e
9f
10f
a
b
Reactions were performed on a 1 mmol scale with 1 equiv of base in 5 mL of solvent. Isolated yield; the numbers in parentheses
indicate the ratio determined by 1H NMR. c An 11% yield of an additional unassignable THF also isolated. Assignment of stereochemistry
was not possible due to ambiguous NOE data. 79% complete by 1H NMR. e A 5:1 ratio of THF/ethanol was used. f Resulted in complete
d
decomposition of starting material.
SCHEME 2a
a
Key: (a) AcCl/pyridine/CH2Cl2.
transition metal such as Co(II), Ru(II), or Fe(II); however,
as they undergo ready dehydration to furans 3 under
acidic and neutral conditions they must be used immedi-
ately.6a,9 When amine bases are employed, cis-γ-hydroxy-
enones are also susceptible to further rearrangement to
their isomeric 1,4-diketones, Scheme 1.6a,10 We have
found that hydroxide and alkoxide bases do not favor the
rearrangement to 1,4-diketone but alternately promote
the 1,4-addition of oxygen nucleophiles. This leads to the
possibility of interesting tandem reactions of γ-hydroxy-
enones initiated by an oxa-Michael addition. In this paper
we describe the base-promoted self-condensation of γ-
hydroxyenones affording substituted THFs 5 by an oxa-
Michael/Michael ring-closing reaction as depicted in
Scheme 1.
of singlet oxygen.6a,8,10b The 1,2-dioxines 2a -e were
allowed to react with alkoxide and hydroxide bases under
various conditions, the results of which are summarized
in Table 1 and Scheme 2. 1,2-Dioxines 2a -c afforded the
substituted THFs 6a -c, 7a -c, 8b-c, and 9b as the sole
isolable products in good combined yields. The initial
discovery was made from 1,2-dioxine 2a , so the effects
of varying reaction conditions versus outcome were
examined for this example. Although not tabulated, the
reaction proceeded in the presence of both stoichiometric
and catalytic quantities of base with only the rate of
reaction being affected. Allowing these reactions to stand
under basic conditions for prolonged periods of time failed
to result in altered ratios. Additionally, reexposure of
either 6f or 8f to the basic reaction conditions over 16 h
resulted only in reisolation of starting material. These
observations indicate that these THFs are not undergoing
further isomerization once formed. When ethoxide in
ethanol/THF was employed to catalyze the reaction, the
outcome was not dramatically affected although reaction
times were reduced, entries 4, 7, and 8. Varying the
reaction temperature was found to mildly affect the
reaction outcome. Lower temperatures led to an increase
in the percentage of the minor isomer 7 with the reaction
times significantly increased, entries 2, 3, 7, and 8.
Substitution on the double bond at the site of nucleophilic
attack (2e, entry 10) prevented the reaction from occur-
ring at both ambient temperature and reflux. With the
Resu lts a n d Discu ssion
TH F Syn t h esis fr om 1,2-Dioxin es. 1,2-Dioxines
2a -e were initially employed as a source of cis-γ-
hydroxyenones and were prepared from their correspond-
ing 1,3-butadienes by the Rose Bengal sensitized addition
(9) (a) Boyd, J . D.; Foote, C. S.; Imagawa, D. K. J . Am. Chem. Soc.
1980, 102, 3641. (b) O’Shea, K. E. J . Org. Chem. 1989, 54, 3475. (c)
Avery, T. A.; J enkins, N. F.; Kimber, M. C.; Lupton, D. W.; Taylor, D.
K. J . Chem Soc., Chem. Commun. 2002, 28.
(10) (a) Kornblum, N.; De La Mare, H. J . Am. Chem. Soc. 1951, 73,
881. (b) Clennan, E. L. Tetrahedron 1991, 47, 1343.
4240 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Functionalized Tetrahydrofurans
SCHEME 3
SCHEME 4
TABLE 2. Syn th esis of tr a n s-Hyd r oxyen on es
yieldb of
14 (%)
yieldb of
14 (%)
entrya
ylide
entrya
ylide
TABLE 3. Rea ction of tr a n s-Hyd r oxyen on es w ith LiOH
c
1
2
3
13c
13f
13g
95
4
5
6
13h
13i
13j
yieldb (%)
86
61
93
c
entrya
enone
6
7
8
a
Reactions were performed by refluxing in THF for 4 h with
1
2
14a
14c
14f
14g
62 (82)
54 (90)
58
(18)
6 (10)
3
1.2 equiv of ylide. Isolated yield. c trans-γ-Hydroxyenones 14g
and 14h were not separable from TPPO but instead were allowed
to react with LiOH after filtering through Florisil.
b
3
15
9
4c
65
a
Reactions were performed on a 1 mmol scale in THF (5 mL).
Isolated yield; the numbers in parentheses indicate the ratio
b
possibility of so many stereoisomeric products, the mod-
erate diastereoselectivity observed for the major isomer
6 in all cases was an encouraging result and gave us
incentive to further investigate this reaction.
determined by 1H NMR. c A 15% yield of 1,4-dioxane 15 was also
isolated.
SCHEME 5a
THF Syn th esis fr om tr a n s-γ-Hyd r oxyen on es. The
isomerization of cis-γ-hydroxyenones
1 to trans-γ-
hydroxyenones 14 may be promoted by nucleophiles such
as triethylamine and triphenylphosphine.6a The isomer-
ization of the trans-enone back to the cis-enone has been
promoted by light and heat.6a,d It has been shown that
the cis-enone and not the trans-enone acts as the
conjugate acceptor in the conjugate addition of nucleo-
philes to this type of system. However, additions to cis-
γ-hydroxyenones afford R,S relative stereochemistry
between the initial site of addition and the R-chiral center
within the conjugate acceptor. As R,R relative stereo-
chemistry was found in the products from the reaction
of the 1,2-dioxine (vide infra), there exists the possibility
that the reaction was proceeding through the isomeric
trans-enone. To examine whether this was the case,
trans-enones 14a ,c,f-j were prepared.
The majority of the enones 14c,f-j were prepared by
allowing glycoaldehyde to react with the appropriate
stabilized keto ylide in refluxing CHCl3, Scheme 3 and
Table 2.6d,11 Both the alkyl-substituted enones 14g and
14h could not be readily separated from TPPO by
chromatography and so were used without rigorous
purification. Finally, treatment of 1,2-dioxine 2a with
Co(II) Salen and then exposure to triphenylphosphine
gave 14a according to a published literature procedure.6a
With a range of trans-enones in hand, their isomerization
and subsequent reactions could now be examined.
Treatment of trans-enones 14a ,c,f,g with lithium
hydroxide gave the THFs 6a ,c,f,g, 7a ,c,f,g, and 8a ,c,f,g
in good yield, Scheme 4 and Table 3. Reaction times were
a
Key: (a) LiOH.
significantly shorter than if starting from the appropriate
1,2-dioxine 2 due to the absence of the rate-limiting ring-
opening step. The major isomer was again 6 with all
contiguous groups trans, the same as that found when
starting from 1,2-dioxine 2. All isomers were readily
separable by flash chromatography on silica gel.
When starting with trans-enone 14g, in addition to
the expected THFs a 1,4-dioxane 15 was also isolated.
The formation of the 1,4-dioxane is a result of a sequen-
tial oxa-Michael-enolate quenching/proton-transfer oxa-
Michael addition sequence.
In the case of methyl ketone 14h further intramolecu-
lar Aldol condensation resulted in the formation of the
fused bicycle 16,12 which under the experimental condi-
tions underwent slow decomposition, Scheme 5. The
1
stereochemistry of 16 was determined by 2D H NMR;
the two rings were found to be cis-fused, which indicated
stereochemistry about the THF ring different from that
found for all other major isomers.
2-Methyl-substituted trans-enones 14i and 14j were
expected to afford THFs with further substitution about
the ring. trans-γ-Hydroxyenone 14i gave two diastereo-
meric products, both with identical stereochemistry about
the THF ring but isomeric at the tertiary center R to the
ring, Scheme 6.
(11) Ylides not commercially available were synthesized by reacting
the appropriate haloalkanone with triphenylphosphine in refluxing
toluene, collecting the precipitate, and deprotonating with Na2CO3 in
MeOH/H2O. (a) Bestmann, H. J .; Attygalle, A. B.; Glasbrenner, J .;
Riemar, R.; Vostrowsky, O.; Constantino, M. G.; Melikyan, G.; Morgan,
E. D. Liebigs Ann. Chem. 1988, No. 1, 55-60.
(12) Brown, P. M., Ka¨ppel, N., Murphy, P. J . Tetrahedron Lett. 2002,
43, 8707.
J . Org. Chem, Vol. 68, No. 11, 2003 4241

Greatrex et al.
SCHEME 6a
SCHEME 7
molecule existed in its isomeric furanol form 20 as
evidenced by a hemiketal signal in the 13C NMR spectra,
δ 100-110 ppm, Scheme 7. Only a single cyclic furanol
isomer was visible in the NMR spectra for all THFs 8
synthesized. The relative stereochemistry between the
hemiketal carbon and adjacent tertiary center was found
1
to be S,S on the basis of 2D H NMR. The alternative
R,S isomer does not form, presumably due to steric
crowding between the large Ph or tert-butyl groups and
the THF ring. The cyclization of THF 8b to its furanol
allowed for the determination of the relative stereochem-
istry of C6-C6a, the only furanol isolated which con-
tained a stereogenic center at C6. THF 8b was assigned
as having R,S relative stereochemistry at C6-C6a, which
is different from that found for all other THFs. These
furanol compounds were found to be very acid sensitive
and although stable in the solid state decomposed quickly
when dissolved in CDCl3 due to trace acid. Their spectra
were therefore more readily obtained in either d6-acetone
or d6-benzene.
Mech a n ism for th e F or m a tion of THF s. With a
broad range of THFs produced under a range of experi-
mental conditions from a range of isomeric starting
materials, it was now possible to propose a mechanism
for their formation, Scheme 8. Thus, when starting from
1,2-dioxines of type 2, initial ring opening by the base
affords the cis-γ-hydroxyenones 1. 1,4-Addition of the
hydroxide to the cis-enone followed by rotation about the
C2-C3 axis followed by elimination establishes an equi-
librium between the cis- and trans-enones. Once the
equilibrium has been established, there exist two possible
reaction pathways. Pathway 1 involves the cis-enone as
the initial conjugate acceptor. Pathway 2, represented
in Scheme 8, involves the trans-enone as the initial
conjugate acceptor. The relative stereochemistry between
C5 and C6 is established in the initial hetero-Michael
addition, and this is governed by the conformation of the
conjugate acceptor. As R,R relative stereochemistry is
found in the major product, pathway 2 is the more
dominant pathway in operation on the basis of previous
observations of the selectivity of nucleophilic additions
to cis-enones.6 Consideration must also be given to
whether it is the cis- or trans-enone that acts as the
initial nucleophile.16 To determine this, the intramolecu-
lar ring closure must be examined.
a
Key: (a) LiOH; (b) BzCl, pyridine/CH2Cl2.
The relative stereochemistry between C3 and C7 in
17a was found to be R,S as determined by X-ray crystal-
lographic structure analysis.13 The minor isomer 17b
when converted to its O-benzoyl derivative 18 also
afforded crystals suitable for X-ray analysis and again
allowed for confirmation of assignment.14 The reaction
of 14j afforded only a single isolable product, 19, with
undefined stereochemistry at the methyl R to the ring.
Small singlets at δ 5.8 in the crude spectra indicated the
presence of compounds of structure similar to that of 16;
however, these could not be isolated. Thus, 2-methyl
substitution in the trans-enone did not significantly affect
the reaction outcome as enones still afforded THFs with
contiguous large groups trans.
Tetrahydrofurans 6a -c,f-g were assigned on the basis
of COSY, ROESY, HMBC, and HMQC 2D NMR spectra.
A typical ROESY spectra for 6b (C6D6) showed cross-
peaks between the protons attached to C6 (δ 3.61) and
C7 (δ 2.72) and the proton at C4 (δ 4.15) as well as
between protons on C7 (δ 2.72) and that on C2 (δ 3.98),
confirming the trans relationship of contiguous groups
about the ring. THF 6a has previously been reported in
the reduction of trans-1,2-dibenzoylethylene with alumi-
num isopropoxide; however, in this study the stereo-
chemistry of the side chain was not determined.15 The
stereochemistry of the C6 hydroxyl center for THF 6 was
found by conversion of 6b to its corresponding acetate
10b and X-ray crystallographic structure determination,
Figure 2 in the Supporting Information.
Tetrahydrofurans 7a -c,f also showed characteristic
splitting patterns and cross-peaks in their 2D NMR
spectra. Specifically, the ROESY spectra for 7a showed
cross-peaks between the proton attached to C6 (δ 4.88)
and those at C4 (δ 4.48) and C3 (δ 3.14) as well as
between the protons on C7 (δ 2.84, 3.24) and that on C2
(δ 5.12). Further support for the structural assignment
came by conversion of 7a to the corresponding acetate
11a and X-ray crystallographic structure determination,
Figure 3 in the Supporting Information.
The intramolecular cyclization of enolates onto conju-
gate acceptors, giving rise to cyclopentanoid or tetra-
hydrofuranoid products, has been rationalized by invok-
ing secondary orbital interactions.17 It is easiest to
consider the unsubstituted case of 14c, for which all
possible cyclic transition states leading to the observed
When both the hydroxyl and adjacent ketone moieties
were on the same face of the THF as in the case of 8, the
(13) Greatrex, B W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T.
Z. Krystallogr., in press.
(14) Greatrex, B W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T.
Z. Krystallogr., in press.
(16) For examples of hetero-Michael addition to enones, see: (a)
Betancort, J . M.; Mart´ın. V. S.; Padro´n, J . M.; Palazo´n, J . M.; Ram´ırez,
M. A.; Soler, M. A. J . Org. Chem. 1997, 62, 4570. (b) Ram´ırez, M. A.;
V. S.; Padro´n, J . M.; Palazo´n, J . M.; Mart´ın. V. S. J . Org. Chem. 1997,
62, 4584.
(15) Inamura, Y. Nippon Kagaku Kaishi 1974, 2011.
4242 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Functionalized Tetrahydrofurans
SCHEME 8
products are drawn, Figure 1. Thus, if the nucleophile
were the trans-enone, then the dominant interaction for
cyclization proceeding through chair transition state 22a
to give 6 would involve the HOMO of the enolate and
the LUMO of the unsaturated ketone carbonyl.18 If the
nucleophile were the cis-enone, then a cyclic transition
state giving rise to the donor and acceptor being trans
would not be obtainable. Furthermore, the only possible
cyclic transition state involving the cis-enone as the
nucleophile 22d appears highly congested. Thus, if the
reaction does indeed involve cyclic transition states, then
the initial nucleophile must be the trans-γ-hydroxyenone.
Thus, the trans-enone appears to be the key intermediate
in this reaction sequence.19
When 1 contains a stereogenic center and is racemic,
as is the case when starting from 2a ,b and 14a , there
exist two possibilities for the initial heteroconjugate
addition; these are the homochiral and heterochiral
combinations yielding the two intermediates 21a and
21b, respectively, Scheme 8.
a variety of starting materials and is appreciably more
stable than the isomeric cis-enone. Further reactions
involving the addition of oxygen nucleophiles to cis- and
trans-γ-hydroxyenones are under development.
Exp er im en ta l Section
Gen er a l P r oced u r e for t h e Syn t h esis of tr a n s-γ-
Hyd r oxyen on es 14. To a solution of the appropriate stabi-
lized ylide (3.6 mmol) in THF (15 mL) was added glycoaldehyde
dimer (180 mg, 3 mmol), and the resulting solution was heated
under reflux for 3 h. The solution was cooled and the solvent
evaporated in vacuo. The product was purified by chromatog-
raphy (Florisil, 1:1 hexane/ethyl acetate) and was used im-
mediately. Decomposition of the trans-γ-hydroxyenones to the
corresponding furan was especially rapid in CDCl3 due to trace
acid.
(E)-1-(4-Br om op h en yl)-4-h yd r oxy-2-bu ten -1-on e (14f):
white solid; mp 77-79 °C; Rf 0.58 (40:60 hexane/ethyl acetate);
1
IR (Nujol) 3427, 1665, 1614, 1586, 1302, 1012, 794 cm-1; H
NMR (200 MHz, d6-acetone) δ 2.96 (br s, 1H), 4.37-4.39 (m,
2H), 7.13 (ddd, J ) 15.4, 3.2, 1.4 Hz, 1H), 7.25 (ddd, J ) 15.4,
1.6, 1.6 Hz, 1H), 7.69-7.75 (m, 2H), 7.88-7.94 (m, 2H); 13C
NMR (d6-acetone, 50 MHz) δ 61.4, 122.7, 127.2, 130.3, 131.9,
137.0, 149.4, 188.6; MS (EI) m/z (rel intens) 242 (M+, 81Br, 20),
240 (M+, 79Br, 20), 213 (81Br, 40), 211 (79Br, 40), 185 (81Br, 100),
183 (79Br, 100).
The heterochiral combination of enones affords only the
observed major isomers 6a ,b with all contiguous groups
trans. For the homochiral combination, the Michael ring
closure yields 7 or 8 with poor selectivity.
(E)-4-Hyd r oxy-2-m eth yl-1-p h en yl-2-bu ten -1-on e (14i):
colorless oil; Rf 0.17 (1:1 hexane/ethyl acetate); IR (neat) 3429,
3058, 2925, 1644, 1597, 1446, 1332, 1267, 1014 cm-1; 1H NMR
(d6-acetone, 200 MHz) δ 1.88 (dt, J ) 1.2, 1.2 Hz, 3H), 4.14 (t,
J ) 5.5 Hz, D2O exch, 1H), 4.39 (ddq, J ) 5.5, 5.5, 1.2 Hz,
2H), 6.33 (tq, J ) 5.5, 1.2 Hz, 1H), 7.42-7.69 (m, 5H); 13C NMR
(50 MHz, d6-acetone) δ 12.5, 59.8, 128.9, 129.9, 132.2, 135.9,
139.3, 146.3, 198.3.
Con clu sion s
In summary, a novel synthesis of highly substituted
tetrahydrofuran building blocks has been described
starting either from trans-γ-hydroxyenones derived from
stabilized phosphorus ylides and R-hydroxy aldehydes or
from 1,2-dioxines. The discovery that the trans-enone and
not the cis-enone is the key intermediate in this reaction
is significant as it may be conveniently generated from
(E)-5-Hyd r oxy-3-m eth yl-3-p en ten -2-on e (14j): colorless
oil; Rf 0.42 (40:60 hexane/ethyl acetate); IR (neat) 3420, 2929,
1
1670, 1652, 1436, 1362, 1026 cm-1; H NMR (d6-acetone, 200
MHz) δ 1.66 (dt, J ) 1.0, 1.0 Hz, 3H), 2.62 (s, 3H), 4.14 (br s,
1H), 4.30-4.40 (br m, 2H), 6.71 (tq, J ) 5.6, 1.4 Hz, 1H); 13C
NMR (50 MHz, d6-acetone) δ 11.6, 25.3, 59.9, 136.6, 144.0,
199.0.
Gen er a l P r oced u r e for t h e Syn t h esis of THF s fr om
1,2-Dioxin e P r ecu r sor s. To 3,6-diphenyl-3,6-dihydro-1,2-
(17) (a) Sevin, A.; Tortaja, J .; Pfau, M. J . Org. Chem. 1985, 51, 2671.
(b) Bunce, R. A.; Dowdy, E. D.; J ones, P. B.; Holt, E. M. J . Org. Chem.
1993, 58, 7143. (c) Bunce, R. A.; Dowdy, E. D.; Childress, S.; J ones, P.
B. J . Org. Chem. 1998, 63, 144.
(18) (a) See ref 17. (b) d’Angelo, J .; Guinant, A. Tetrahedron Lett.
1988, 29, 2667. (c) Dumas, F.; d’Angelo, J . Tetrahedron: Asymmetry
1990, 1, 167.
(19) (a) See ref 6a. (b) Friedrich, L. E.; Cormier, R. A. J . Org. Chem.
1971, 36, 3011. (c) Coxon, J . M.; Hii. G. S. C. Aust. J . Chem. 1977, 30,
161.
F IGURE 1. Cyclic transition states leading to THFs for trans-
enone 14c.
J . Org. Chem, Vol. 68, No. 11, 2003 4243

Greatrex et al.
dioxine (2a ) (238 mg, 1 mmol) in THF (5 mL) was added
lithium hydroxide (23 mg, 1 mmol), and the resulting suspen-
sion was stirred for 16 h. The mixture was evaporated, and
the products were separated by flash chromatography (60:40
hexane/ethyl acetate) to afford the following compounds.
(d, J ) 6.6 Hz, 3H), 1.36 (d, J ) 6.0 Hz, 3H), 2.00 (s, 3H), 2.85
(dddd, J ) 8.5, 8.2, 7.4, 5.8 Hz,1H), 3.05 (dd, J ) 16.7, 7.4 Hz,
1H), 3.16 (dd, J ) 16.7, 5.8 Hz, 1H), 3.89 (dd, J ) 6.6, 8.5 Hz,
1H), 4.09 (dq, J ) 8.2, 6.0 Hz, 1H), 4.28 (dd, J ) 7.2, 4.7 Hz,
1H), 5.00 (dq, J ) 6.6, 4.7 Hz, 1H), 7.37-7.45 (m, 4H), 7.51-
7.56 (m, 2H), 7.75-7.79 (m, 2H), 7.88-7.91 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 16.1, 19.3, 21.1, 39.9, 48.2, 53.8, 70.9, 80.7,
83.2, 127.9, 128.3, 128.6, 128.7, 131.1, 133.2, 136.6, 137.2,
170.3, 198.0, 199.8; MS (EI) m/z (rel intens) 395 (MH+, 10),
335 (10), 159 (95), 105 (100). Anal. Calcd for C24H26O5: C,
73.07; H, 6.64. Found: C, 72.93; H, 6.77.
(()-2-{(2S ,3S ,4S ,5S )-4-B e n zo y l-5-[(S )-1-h y d r o xy -1-
p h en ylm eth yl]-2-p h en yltetr a h yd r o-3-fu r a n yl}-1-p h en yl-
1-eth a n on e (6a ): white solid; mp 150-152 °C; Rf 0.38 (60:40
hexane/ethyl acetate); IR (Nujol) 3411, 1683, 1667, 1043 cm-1
;
1H NMR (600 MHz) δ 2.89 (d, J ) 3.0 Hz, 1H), 3.00-3.07 (m,
2H), 3.15-3.19 (m, 1H), 4.11 (dd, J ) 8.4, 6.6 Hz, 1H), 4.69
(dd, J ) 7.2, 6.6 Hz, 1H), 4.78 (dd, J ) 7.2, 3.0 Hz, 1H), 4.96
(d, J ) 3.6 Hz, 1H), 7.12-7.37 (m, 13H), 7.44-7.48 (m, 5H),
7.59-7.61 (m, 2H); 13C NMR (150 MHz) δ 38.1, 50.1, 53.1, 75.6,
85.6, 87.4, 127.2, 127.5, 127.8, 128.1, 128.2, 128.4, 128.5, 128.5,
128.6, 132.7, 133.2, 136.5, 136.9, 138.9, 139.5, 197.9, 199.7 (1
masked aromatic); MS (EI) m/z (rel intens) 477 (M+, 5), 459
(25), 369 (80), 221 (100). 6a was converted to its acetate 10a
for comparison with literature data. 6a (36 mg, 0.075 mmol)
was dissolved in dichloromethane (1 mL), and acetyl chloride
(12 mg, 0.15 mmol) was added. Pyridine (1 drop) was added
and the reaction left to stir overnight. Evaporation of the
volatiles in vacuo, purification by flash chromatography, and
then recrystallization from hot hexane afforded a white solid
(14 mg, 36%): mp 190-192 °C (lit.14 mp 193-194 °C). The
spectral data were consistent with those reported.
(()-2-[(2R,3S,3a S,4S,6S,6a R)-4-Hyd r oxy-2,6-d im eth yl-
4-p h en ylp er h yd r ofu r o[3,4-b]fu r a n -3-yl]-1-p h en yl-1-eth a -
n on e (8b): white solid; mp 148-150 °C; Rf 0.50 (60:40 hexane/
ethyl acetate); IR (neat) 3368, 2924, 1673, 1595, 1320, 1267
1
cm-1; H NMR (600 MHz) δ 0.95 (d, J ) 6.0 Hz, 3H), 1.33 (d,
J ) 6.6 Hz, 3H), 1.59 (dddd, J ) 9.6, 9.2, 8.2, 3.6 Hz, 1H),
2.43 (dd, J ) 15, 9.6 Hz, 1H), 2.71 (s, 1H), 2.74 (dd, J ) 15,
3.6 Hz, 1H), 2.89 (dd, J ) 8.2, 7.6 Hz, 1H), 3.64 (dq, J ) 9.2,
6.0 Hz, 1H), 4.36 (dq, J ) 6.6, 4.8 Hz, 1H), 4.58 (dd, J ) 7.6,
4.8 Hz, 1H), 7.01-7.13 (m, 6H), 7.67-7.69 (m, 2H), 8.12-8.14
(m, 2H); 13C NMR (150 MHz) δ 13.75, 18.6, 40.8, 46.3, 62.1,
75.3, 81.2, 83.2, 106.2, 126.8, 128.0, 128.3, 128.4, 128.5, 132.9,
136.3, 140.8, 198.7; MS (EI) m/z (rel intens) 335 (MH+ - H2O,
8), 316 (15), 290 (20), 105 (100). Anal. Calcd for C22H24O4: C,
74.97; H, 6.86. Found: C, 74.72; H, 6.70.
(()-2-{(2R,3R,4R,5R)-4-Ben zoyl-5-[1-h yd r oxyet h yl]-2-
m eth yltetr a h yd r o-3-fu r a n yl}-1-p h en yl-1-eth a n on e (9b):
isolated as a 75:25 mixture together with an unidentified
isomer not separable by chromatography; colorless oil; Rf 0.33
(60:40 hexane/ethyl acetate); 1H NMR (300 MHz, C6D6) δ 1.00
(d, J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.6 Hz, 3H), 2.00 (br d, J )
7.5 Hz, 1H), 2.74-2.90 (m, 2H), 3.44 (dq, J ) 6.6, 5.7 Hz, 1H),
3.56 (br m, 1H), 3.99-4.06 (m, 2H), 4.56 (dq, J ) 8.4, 6.6 Hz,
1H) 6.89-7.16 (m, 6H), 7.73-7.76 (m, 2H), 8.13-8.17 (m, 2H);
13C NMR (150 MHz) δ 16.7, 20.3, 38.1, 43.6, 52.8, 67.7, 76.8,
85.9, 127.9, 128.5, 128.5, 128.7, 133.2, 133.4, 136.6, 137.2,
198.4, 200.7; MS (EI) m/z (rel intens) 334 (MH+ - H2O, 20),
307 (30), 159 (90), 105 (100). 9b (46 mg, 0.19 mmol) was
converted to its corresponding acetate 12b as per 6a to give a
colorless oil as a single isomer (38 mg, 75%): IR (neat) 2980,
1732, 1682, 1597, 1448, 1372, 1242 cm-1; 1H NMR (600 MHz,
C6D6) δ 1.24 (d, J ) 6.0 Hz, 3H), 1.25 (d, J ) 6.0 Hz, 3H), 1.91
(s, 3H), 3.00 (dd, J ) 16.8, 8.4 Hz, 1H), 3.06-3.10 (m, 1H),
3.30 (dd, J ) 16.8, 6.0 Hz, 1H), 3.75 (dd, J ) 6.6, 4.2 Hz, 1H),
4.17 (dd, J ) 7.2, 4.2 Hz, 1H), 7.41-7.47 (m, 4H) 7.53-7.58
(m, 2H), 7.87-7.89 (m, 4H); LSIMS m/z (rel intens) 395 (MH+,
90), 393 (100), 377 (20), 215 (90); HRMS m/z calcd for 12b (+H)
(()-2-{(2S ,3S ,4R ,5R )-4-Be n zoyl-5-[(R )-1-h yd r oxy-1-
p h en ylm eth yl]-2-p h en yltetr a h yd r o-3-fu r a n yl}-1-p h en yl-
1-eth a n on e (7a ): white solid; mp 140-142 °C; Rf 0.56 (60:40
hexane/ethyl acetate); IR (Nujol) 1681, 1672, 1237, 1047, 1023
1
cm-1; H NMR (600 MHz) δ 2.84 (dd, J ) 18.0, 4.2 Hz, 1H),
3.06 (br s, 1H), 3.10-3.16 (m, 1H), 3.24 (dd, J ) 18.0, 10.2
Hz, 1H), 4.48 (dd, J ) 7.8, 4.8 Hz, 1H), 4.51 (dd, J ) 7.8, 4.8
Hz, 1H), 4.88 (d, J ) 7.8 Hz, 1H), 5.12 (d, J ) 9.6 Hz, 1H),
7.12-7.58 (m, 18H), 7.58-7.60 (m, 2H); 13C NMR (75 MHz) δ
35.8, 46.7, 49.0, 77.2, 77.3, 86.4, 126.9, 127.5, 127.6, 128.2,
128.2, 128.3, 128.4, 128.6, 128.7, 133.0, 136.4, 136.6, 139.5,
139.7, 198.3, 201.2 (2 masked aromatic); MS (EI) m/z (rel
intens) 477 (M+, 10), 459 (40), 440 (30), 369 (95), 105 (100).
Anal. Calcd for C32H28O4: C, 80.65; H, 5.92. Found: C, 80.21;
H, 5.98. 7a (81 mg, 0.17 mmol) was converted to its corre-
sponding acetate for X-ray diffraction studies as per 6a to give
11a as colorless crystals (46 mg, 52%): mp 184-186 °C; Rf
0.30 (80:20 hexane/ethyl acetate); IR (Nujol) 1743, 1670, 1591,
1576, 1232, 1207 cm-1; 1H NMR (300 MHz) δ 2.08 (s, 3H), 2.81
(dd, J ) 17.7, 7.2 Hz, 1H), 3.03 (dddd, J ) 10.2, 7.2, 8.7, 4.5
Hz, 1H), 3.12 (dd, J ) 17.7, 10.2 Hz, 1H), 4.44 (dd, J ) 8.4,
5.4 Hz, 1H), 4.78 (dd, J ) 6.0, 6.0 Hz, 1H), 5.02 (d, J ) 8.7 Hz,
1H), 6.09 (d, J ) 6.9 Hz, 1H), 7.16-7.57 (m, 20H); 13C NMR
(75 MHz) δ 21.1, 35.8, 47.1, 49.1, 77.3, 83.7, 86.1, 126.9, 127.5,
127.8, 128.2, 128.3, 128.5, 133.0, 133.1, 136.4, 136.8, 136.8,
139.8, 170.1, 198.2, 201.4; MS (EI) m/z (rel intens) 518 (M+,
5), 517 (10), 501 (30), 440 (50), 369 (100). Anal. Calcd for
C
24H27O5 395.1858, found 395.1864.
(()-2-[(3S,4S,5S)-4-Ben zoyl-5-(h yd r oxym et h yl)t et r a -
h yd r o-3-fu r a n yl]-1-p h en yl-1-eth a n on e (6c): colorless oil;
Rf 0.30 (50:50 hexane/ethyl acetate); IR (neat) 3459, 2874,
1681, 1596, 1448, 1213 cm-1; 1H NMR (600 MHz) δ 2.21 (br s,
1H), 3.17 (dd, J ) 17.4, 8.4 Hz, 1H), 3.1 (dd, J ) 17.4, 6.0 Hz,
1H), 3.35 (m, 1H), 3.57 (br d, J ) 12.0 Hz, 1H), 3.78 (dd, J )
9.0, 5.4 Hz, 1H), 3.86 (dd, J ) 12.0, 3.0 Hz, 1H), 3.96 (dd, J )
7.8, 6.6 Hz, 1H), 4.14 (ddd, J ) 8.4, 3.0, 3.0 Hz, 1H), 4.30 (dd,
8.4, 7.2 Hz, 1H), 7.40-7.43 (m, 2H), 7.46-7.49 (m, 2H), 7.52-
7.55 (m, 1H), 7.57-7.60 (m, 1H), 7.86-7.87 (m, 2H), 7.99-
8.01 (m, 2H); 13C NMR (150 MHz) δ 40.7, 41.9, 52.1, 62.3, 73.6,
83.5, 127.9, 128.5, 128.6, 128.8, 133.2, 133.5, 136.4, 137.1,
198.2, 199.9; MS (EI) m/z (rel intens) 325 (MH+, 15), 305 (20),
145 (40), 105 (100); HRMS m/z calcd for 6c (+H) C20H21O4
325.1439, found 325.1434.
C
34H30O5: C, 78.74; H, 5.83. Found: C, 78.72; H, 5.85.
(()-2-{(2S,3R,4R,5R)-4-Ben zoyl-5-[(1R)-1-h ydr oxyeth yl]-
2-m eth yltetr ah ydr o-3-fu r an yl}-1-ph en yl-1-eth an on e (6b):
colorless oil; Rf 0.21 (60:40 hexane/ethyl acetate); IR (neat)
3468, 2973, 1681, 1596, 1448, 1366, 1265, 1214, 1074 cm-1
;
1H NMR (600 MHz, C6D6) δ 1.07 (d, J ) 6.0 Hz, 3H), 1.35 (d,
J ) 6.6 Hz, 3H), 1.80-2.20 (br s, 1H), 2.72-2.73 (m, 2H), 3.16
(dddd, J ) 8.4, 7.6, 6.8, 6.8 Hz, 1H), 3.61 (dq, J ) 6.6, 3.3 Hz,
1H), 3.98 (dq, J ) 7.6, 6.0 Hz, 1H), 4.15 (dd, J ) 8.2, 8.4 Hz,
1H), 4.23 (dd, J ) 8.2, 3.3 Hz, 1H), 7.01-7.13 (m, 6H), 7.67-
7.69 (m, 2H), 8.12-8.14 (m, 2H); 13C NMR (150 MHz, CDCl3)
δ 19.8, 19.9, 40.5, 48.2, 54.1, 68.1, 80.8, 85.7, 127.9, 128.4,
128.5, 128.6, 133.2, 133.3, 136.5, 137.4, 198.1, 200.0; MS (EI)
m/z (rel intens) 353 (M+, 8), 335 (10), 307 (20),159 (100). 6b
was converted to its acetate 10b for X-ray diffraction studies.
6b (83 mg, 0.23 mmol) was treated as per 6a to give colorless
crystals of 10b (69 mg, 74%): mp 99-101 °C (CH3CN/H2O);
Rf 0.38 (60:40 hexane/ethyl acetate); IR (Nujol) 1741, 1683,
1667, 1596, 1246, 1216 cm-1; 1H NMR (300 MHz, C6D6) δ 1.21
(()-2-[(3S,4R,5R)-4-Ben zoyl-5-(h yd r oxym et h yl)t et r a -
h yd r o-3-fu r a n yl]-1-p h en yl-1-eth a n on e (7c): colorless oil;
Rf 0.29 (ethyl acetate); IR (neat) 3402, 2918, 1680, 1596, 1448,
1
1379, 1219 cm-1; H NMR (600 MHz) δ 1.90 (br s, 1H), 2.88
(dd, J ) 17.9, 5.1 Hz, 1H), 3.11 (dd, J ) 17.9, 9.7 Hz, 1H),
3.37 (m, 1H), 3.62 (dd, J ) 11.9, 4.0 Hz, 1H), 3.77 (dd, J )
8.9, 5.5 Hz, 1H), 3.87 (dd, J ) 11.9, 3.6 Hz, 1H), 4,29 (dd, J )
8.1, 8.1 Hz, 1H), 4.33 (dd, J ) 8.7, 6.2 Hz, 1H), 4.54 (ddd, J )
4244 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Functionalized Tetrahydrofurans
8.1, 4.0, 3.6 Hz, 1H), 7.36-7.58 (m, 6H), 7.76-7.77 (m, 2H),
7.98-8.00 (m, 2H); 13C NMR (150 MHz) δ 37.6, 39.1, 49.3, 63.3,
74.2, 81.1, 127.8, 128.3, 128.5, 128.8, 133.2, 133.7, 136.5, 137.0,
198.2, 199.6; MS (EI) m/z (rel intens) 325 (MH+, 15), 305 (20),
145 (40),105 (100); HRMS m/z calcd for 7c (+H) C20H21O4
325.1439, found 325.1449.
1H), 2.65-2.69 (m, 2H), 2.72-2.77 (m, 1H), 3.24 (dd, J ) 7.2,
4.8 Hz, 1H), 3.54-3.57 (br d, 1H), 3.99 (ddd, J ) 6.6, 3.6, 3.0
Hz, 1H), 4.11 (dd, J ) 6.8, 6.0 Hz, 1H); 13C NMR (150 MHz) δ
25.8, 26.2, 40.2, 42.0, 43.9, 44.7, 51.1, 62.5, 73.8, 84.3, 214.2,
216.4; MS (EI) m/z (rel intens) 285 (MH+, 10), 267 (100), 253
(10), 209 (20). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92.
Found: C, 67.83; H, 9.63.
(()-2-[(3R,3a R,4R,6a S)-4-Hyd r oxy-4-p h en ylp er h yd r o-
fu r o[3,4-b]fu r a n -3-yl]-1-p h en yl-1-eth a n on e (8c). Although
stable as a solid, 8c slowly decomposed in CDCl3 solution:
white solid; mp 134-135 °C; Rf 0.50 (ethyl acetate); IR (Nujol)
3384, 1678, 1596, 1265, 1228 cm-1; 1H NMR (600 MHz) δ 2.08
(ddddd, 1H), 2.53 (s, 1H), 2.59 (dd, J ) 16.2, 10.2 Hz, 1H),
2.80 (dd, J ) 16.2, 5.1 Hz, 1H), 2.80 (dd, J ) 6.6, 6.6 Hz, 1H),
3.36 (dd, J ) 9.0, 6.6 Hz, 1H), 3.62 (dd, J ) 9.0, 6.0 Hz, 1H),
4.12 (d, J ) 10.2 Hz, 1H), 4.27 (dd, J ) 10.2, 4.5 Hz, 1H), 4.88
(dd, J ) 6.6, 4.5 Hz, 1H), 7.32-7.54 (m, 8H), 7.65-7.68 (m,
2H); 13C NMR (150 MHz) δ 39.5, 41.2, 59.9, 72.4, 73.5, 83.5,
107.8, 126.5, 127.9, 128.3, 128.5, 128.6, 128.9, 133.0, 140.6,
(()-1-[(3S ,3a S ,4S ,6a R )-4-(t e r t -Bu t yl)-4-h yd r oxyp e r -
h ydr ofu r o[3,4-b]fu r an -3-yl]-3,3-dim eth yl-2-bu tan on e (8g):
colorless solid; mp 92-94 °C; Rf 0.55 (ethyl acetate); IR (Nujol)
1
3346, 1698, 1137, 1083, 997 cm-1; H NMR (600 MHz) δ 1.12
(s, 9H), 1.23 (s, 9H), 2.43 (s, 1H), 2.53 (dd, J ) 7.5, 1.2 Hz,
1H), 2.63-2.70 (m, 2H), 3.23-3.26 (m, 1H), 3.76 (d, J ) 8.4,
3.0 Hz, 1H), 4.04 (dd, J ) 9.6, 6.0 Hz, 1H), 4.13 (dd, J ) 9.6,
4.2 Hz, 1H), 4.62 (dd, J ) 9.0, 6.0 Hz, 1H), 4.65 (ddd, J ) 6.6,
6.6, 4.2 Hz, 1H); 13C NMR (75 MHz) δ 25.0, 26.1, 37.5, 38.5,
40.7, 43.8, 53.6, 70.9, 75.7, 83.5, 109.7, 213.0; MS (EI) m/z (rel
intens) 285 (MH+, 5), 267 (80), 227 (15), 125 (40), 83 (100).
Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found: C, 67.48;
H, 9.79.
-
189.5; MS (EI) m/z (rel intens) 306 (M+ H2O, 5), 288 (20),
168 (10), 105 (100). Anal. Calcd for C20H20O4: C, 74.05; H, 6.21.
Found: C, 73.80; H, 6.21.
1-[(2R,5S)-5-(3,3-Dim eth yl-2-oxobu tyl)-1,4-d ioxa n -2-yl]-
3,3-d im eth yl-2-bu ta n on e (15): colorless solid; mp 125 °C
(sublimes); Rf 0.77 (60:40 hexane/ethyl acetate); IR (Nujol)
(()-2-[(3S,4S,5S)-4-(4-Br om oben zoyl)-5-(h yd r oxym eth -
y l)t e t r a h y d r o -3-fu r a n y l]-1-(4-b r o m o p h e n y l)-1-e t h a -
n on e (6f): white solid; mp 63-65 °C; Rf 0.57 (40:60 hexane/
ethyl acetate); IR (Nujol) 3445, 2955, 2871, 1681, 1674, 1584,
1
1708, 1127, 1083, 1054 cm-1; H NMR (300 MHz) δ 1.12 (s,
9H), 2.32 (dd, J ) 17.4, 5.7 Hz, 1H), 2.78 (dd, J ) 17.4, 5.4
Hz, 1H), 3.33 (dd, J ) 11.4, 10.5 Hz, 1H), 3.79 (dd, J ) 11.4,
2.4 Hz, 1H), 3.99 (dddd, J ) 10.5, 5.7, 5.4, 2.4 Hz, 1H); 13C
NMR (75 MHz) δ 26.0, 38.4, 44.2, 70.8, 71.0, 212.6; MS (EI)
m/z (rel intens) 285 (MH+, trace), 143 (20), 125 (100), 57 (80),
41 (40). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found:
C, 67.60; H, 9.66.
1397, 1070, 1007 cm-1 1H NMR (600 MHz) δ 3.13 (dd, J )
;
17.0, 7.6 Hz, 1H), 3.18 (dd, J ) 17.0, 6.8 Hz, 1H), 3.31 (m,
1H), 3.52 (dd, J ) 3.1, 12.5 Hz, 1H), 3.77 (dd, J ) 9.0, 5.4 Hz,
1H), 3.87 (dd, J ) 12.5, 2.7 Hz, 1H), 3.89 (dd, J ) 8.0, 6.8 Hz,
1H), 4.08 (ddd, J ) 7.8, 3.2, 3.2 Hz, 1H), 4.29 (dd, J ) 8.8, 7.3
Hz, 1H), 7.56-7.63 (m, 4H), 7.71-7.73 (m, 2H), 7.84-7.87 (m,
2H); 13C NMR (75 MHz) δ 40.7, 41.9, 52.1, 62.1, 73.6, 83.7,
128.6, 128.9, 129.4, 130.0, 132.0, 132.1, 135.1, 135.8, 197.2,
198.9; MS (EI) m/z (rel intens) 465 (MH+ - H2O - H2, 2 × 81Br,
5), 463 (MH+ - H2O - H2,79Br, 81Br, 10), 461 (MH+ - H2O - H2,
2 × 79Br, 5), 225 (81Br, 20), 223 (79Br, 20), 185 (81Br, 100), 183
(79Br, 100).
(()-(3 S ,3 a R ,7 a R )-3 -(H y d r o x y m e t h y l )-6 -m e t h y l -
1,3,3a ,4,7,7a -h exa h yd r o-4-isoben zofu r a n on e (16): colorless
oil; Rf 0.48 (ethyl acetate); IR (neat) 3435, 2935, 1651, 1435,
1381, 1054 cm-1; 1H NMR (600 MHz) δ 1.99 (s, 3H), 2.31 (dd,
J ) 18.6, 6.6 Hz, 1H), 2.43 (br s, 1H), 2.49 dd, J ) 18.6, 6.6,
1H), 2.76 (dd, J ) 7.2, 7.2 Hz, 1H), 2.89 (ddddd, J ) 7.2, 6.6,
6.6, 6.6, 6.6 Hz, 1H), 3.63-3.68 (m, 2H), 3.81 (br d, J ) 11.4
Hz, 1H), 3.99 (dd, J ) 8.1, 5.4 Hz, 1H), 4.14 (ddd, J ) 6.6, 4.8,
4.8 Hz, 1H), 5.96 (d, J ) 0.6 Hz, 1H); 13C NMR (150 MHz) δ
24.5, 30.5, 38.2, 49.1, 64.7, 72.9, 81.2, 125.5, 160.7, 197.6; MS
(EI) m/z (rel intens) 183 (MH+, 40), 152 (40),152 (40), 69 (100);
HRMS m/z calcd for 16 (+H) C10H15O3 183.1021, found
183.1020.
(()-2-[(3S,4R,5R)-4-(4-Br om oben zoyl)-5-(h yd r oxym eth -
y l)t e t r a h y d r o -3-fu r a n y l]-1-(4-b r o m o p h e n y l)-1-e t h a -
n on e (7f): colorless solid; mp 130-132 °C; Rf 0.55 (40:60
hexane/ethyl acetate); IR (neat) 3442, 2931, 1681, 1584, 1567,
1
1484, 1398, 1071, 732 cm-1; H NMR (600 MHz) δ 1.80-2.00
(br s, 1H), 2.95 (dd, J ) 18.0, 6.6 Hz, 1H), 3.03 (dd, J ) 18.0,
8.4 Hz, 1H), 3.30-3.36 (m, 1H), 3.59 (dd, J ) 12.0, 3.6 Hz,
1H), 3.76 (dd, J ) 8.4, 6.0 Hz, 1H), 3.85 (dd, J ) 12.0, 3.6 Hz,
1H), 4.27 (dd, J ) 8.4, 8.4 Hz, 1H), 4.30 (dd, J ) 8.4, 6.0 Hz,
1H), 4.46 (ddd, J ) 8.4, 3.6, 3.6 Hz, 1H); 13C NMR (150 MHz)
δ 37.5, 39.1, 49.0, 63.2, 74.2, 81.5, 128.5, 129.1, 129.3, 129.8,
131.8, 132.1, 135.1, 135.7; MS (EI) m/z (rel intens) 464 (M+ -
(()-(2R)-2-[(3S,4S,5S)-4-Ben zoyl-5-(h yd r oxym eth yl)-4-
m eth yltetr ah ydr o-3-fu r an y l]-1-ph en ylpr opan -1-on e (17a):
colorless solid; mp 102-104 °C; Rf 0.42 (1:1 hexane/ethyl
1
acetate); IR (neat) 3394, 1673, 1248, 1051, 964, 723 cm-1; H
NMR (600 MHz) δ 1.05 (d, J ) 7.2 Hz, 3H), 1.39 (s, 3H), 1.80
(br s, 1H), 3.44 (dd, J ) 9.6, 9.0 Hz, 1H), 3.53 (dq, J ) 10.2,
7.2 Hz, 1H), 3.64 (dd, J ) 12.0, 5.4 Hz, 1H), 3.76 (dd, J ) 12.0,
7.2 Hz, 1H), 3.83 (ddd, J ) 9.6, 9.6, 9.6 Hz, 1H), 4.26 (dd, J )
8.4, 8.4 Hz, 1H), 4.61 (dd, J ) 6.6, 4.8 Hz, 1H), 7.43-7.51 (m,
5H), 7.56-7.58 (m, 1H), 7.78-7.80 (m, 2H), 7.89-7.90 (m, 2H);
13C NMR (150 MHz) δ 12.1, 17.6, 40.7, 50.9, 58.2, 61.8, 71.0,
86.1, 128.2, 128.3, 128.4, 128.8, 131.4, 133.4, 135.7, 138.1,
202.0, 205.8; MS (EI) m/z (rel intens) 353 (MH+, trace), 321
(10), 238 (20), 201 (40), 105 (100). Anal. Calcd for C22H24O4:
C, 74.97; H, 6.86. Found: C, 74.68; H, 7.14.
-
H2O - H2, 2 × 81Br, 5), 462 (M+ H2O - H2, 79Br, 81Br, 10),
460 (M+ - H2O - H2, 2 × 79Br, 5), 453 (2 × 81Br, 5), 451 (79Br,
81Br, 10), 449 (2 × 79Br, 8), 225 (81Br, 25), 223 (79Br, 25), 185
(81Br, 100), 183 (79Br, 100); HRMS m/z calcd for 7f (-H2O -
H2) C20H14O3Br2 459.9310, found 459.9278.
(()-2-[(3S,3a S,4S,6a R)-4-Hyd r oxy-4-(4-br om op h en yl)-
p er h yd r ofu r o[3,4-b]fu r a n -3-yl]-1-(4-br om op h en yl)-1-eth -
a n on e (8f): white solid; mp 149.5-155 °C; Rf 0.69 (40:60
hexane/ethyl acetate); IR (Nujol) 3353, 1683, 1584, 1068, 1008,
975 cm-1; 1H NMR (300 MHz, d6-acetone) δ 1.90-2.00 (m, 1H),
2.75-2.90 (m, 2H), 3.28 (dd, J ) 8.4, 6.3 Hz, H), 3.83 (dd, J )
8.7, 6.3 Hz, 1H), 3.95 (d, J ) 9.9 Hz, 1H), 4.18 (dd, J ) 9.9,
4.5 Hz, 1H), 4.81 (dd, J ) 6.9, 4.5 Hz, 1H), 7.49-7.65 (m, 8H);
MS (EI) m/z (rel intens) 465 (MH+ - H2O - H2, 2 × 81Br, 15),
463 (MH+ - H2O - H2, 79Br, 81Br, 20), 461 (MH+ - H2O - H2,
2 × 79Br, 10), 225 (81Br, 20), 223 (79Br, 20), 185 (81Br, 100),
183 (79Br, 100). Anal. Calcd for C20H18O4Br2: C, 49.82; H, 3.76.
Found: C, 49.76; H, 3.62.
(()-(2S)-2-[(3S,4S,5S)-4-Ben zoyl-5-(h yd r oxym eth yl)-4-
m eth yltetr ah ydr o-3-fu r an yl ]-1-ph en ylpr opan -1-on e (17b):
colorless oil; Rf 0.20 (ethyl acetate); IR (neat) 3455, 2976, 2878,
1
1681, 1596, 1251, 974, 733 cm-1; H NMR (600 MHz) δ 1.05
(s, 3H), 1.15 (d, J ) 7.2 Hz, 3H), 2.28 (br s, 1H), 3.53 (dd, J )
12.0, 4.2 Hz, 1H), 3.56 (dq, J ) 10.2, 7.6 Hz, 1H), 3.67 (dd, J
) 12.0, 7.8 Hz, 1H), 3.76 (ddd, J ) 10.2, 9.6, 8.4 Hz, 1H), 3.85
(dd, J ) 9.6, 8.4 Hz, 1H), 4.34 (dd, J ) 8.4, 8.4 Hz, 1H), 4.60
(dd, J ) 7.2, 4.2 Hz, 1H), 7.38-7.46 (m, 5H), 7.55-7.57 (m,
1H), 7.84-7.85 (m, 2H), 7.89-7.91 (m, 2H); 13C NMR (150
MHz) δ 13.5, 18.1, 40.5, 50.1, 57.8, 61.7, 70.6, 86.4, 128.0,
128.2, 128.3, 128.7, 130.7, 133.3, 135.2, 138.1, 201.8, 204.3;
MS (EI) m/z (rel intens) 353 (MH+, 15), 345 (15), 321 (50), 238
(()-1 -[(3 S ,4 S ,5 S )-4 -(2 ,2 -d i m e t h y l p r o p a n o y l )-5 -
(h yd r oxym et h yl)t et r a h yd r o-3-fu r a n yl]-3,3-d im et h yl-2-
bu ta n on e (6g): colorless oil; Rf 0.25 (60:40 hexane/ethyl
acetate); IR (neat) 3454, 2968, 1702, 1479, 1367, 1067 cm-1
;
1H NMR (600 MHz) δ 1.12 (s, 9H), 1.15 (s, 9H), 2.19 (br s,
J . Org. Chem, Vol. 68, No. 11, 2003 4245

Greatrex et al.
(55), 201 (55), 105 (100). 17b (40 mg, 0.11 mmol) was dissolved
in CH2Cl2 (1 mL), then benzoyl chloride (31 mg, 0.22 mmol)
and triethylamine (2 drops) were added, and the reaction was
stirred for 3 h. The solvent was removed under reduced
pressure and the residue purified by flash chromatography
(dichloromethane) to give 18 as colorless crystals suitable for
X-ray structure analysis (28 mg, 56%): mp 132-135 °C; Rf
0.11 (CH2Cl2); IR (Nujol) 1723, 1673, 1664, 1595, 1280, 1114,
971, 716 cm-1; 1H NMR (300 MHz) δ 1.17 (s, 3H), 1.19 (d, J )
6.9 Hz, 3H), 3.64 (dq, J ) 9.6, 6.9 Hz, 1H), 3.85-4.01 (m, 2H),
4.27 (dd, J ) 11.4, 5.1 Hz, 1H), 4.44-4.52 (m, 2H), 4.98 (dd, J
Hz, 1H), 3.17 (ddd, J ) 10.4, 9.6, 8.4 Hz, 1H), 3.39 (dd, J )
9.6, 8.4 Hz, 1H), 3.52 (dd, J ) 11.4, 6.0 Hz, 1H), 3.71 (dd, J )
11.4, 6.0 Hz, 1H), 4.14 (dd, J ) 6.6, 6.0 Hz, 1H), 4.71 (dd, J )
8.4, 8.4 Hz, 1H); 13C NMR (150 MHz) δ 10.1, 15.8, 26.4, 28.2,
47.2, 49.3, 57.9, 61.4, 70.8, 85.7, 210.2, 210.7; MS (EI) m/z (rel
intens) 229 (MH+, 20), 211 (10), 197 (10), 157 (20), 97 (100);
HRMS m/z calcd for 19 (+H) C12H21O4 229.1439, found
229.1441.
Ack n ow led gm en t. B.W.G. thanks the Faculty of
Science, University of Adelaide, for support in the form
of a scholarship. We also thank the Australian Research
Council for financial support and Prof. J . Bowie for
helpful discussion involving mass spectrometry.
) 7.5, 5.1 Hz, 1H), 7.35-7.60 (m, 9H), 7.85-7.95 (m, 6H); 13
C
NMR (75 MHz) δ 13.5, 18.2, 40.6, 50.2, 58.3, 63.5, 71.1, 83.7,
128.1, 128.2, 128.3, 128.3, 128.8, 129.6, 129.7, 130.9, 133.0,
133.3, 135.3, 137.8, 166.2, 201.7, 203.3; MS (EI) m/z (rel intens)
439 (MH+ - H2O, 10), 397 (20), 351 (20), 105 (100). Anal. Calcd
for C29H28O5: C, 76.12; H, 6.38. Found: C, 76.14; H, 6.33.
(()-2-[(3S,4S,5S)-4-Acetyl-5-(h yd r oxym eth yl)-4-m eth yl-
tetr a h yd r o-3-fu r a n yl]bu ta n -2-on e (19): colorless oil; Rf 0.50
(ethyl acetate); IR (neat) 3436, 2979, 2881, 1697, 1657, 1358,
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, ORTEP diagrams of THFs 10b (Figure 2) and
11a (Figure 3), and general X-ray crystallography data for 10b
and 11a . This material is available free of charge via the
Internet at http://pubs.acs.org.
1047 cm-1
;
1H NMR (600 MHz) δ 0.98 (d, J ) 6.6 Hz, 3H),
1.13 (s, 3H), 2.13 (s, 3H), 2.29 (s, 3H), 2.51 (dd, J ) 10.4, 6.6
J O020700H
4246 J . Org. Chem., Vol. 68, No. 11, 2003