Regio- and diastereoselective allenylation of aldehydes in aqueous media: Total synthesis of (+)-goniofufurone

Article abstract of DOI:10.1021/jo9815610

The regio- and diastereoselectivities of metal-mediated allenylation of carbonyl compounds were investigated in aqueous media. Different metal mediators showed varied regioselectivities on product formation during propargylation-allenylation reactions of carbonyl compounds with simple propargyl bromide. Under the standard reaction conditions, the use of indium provided the highest regioselectivity, with a preference of formation of the homopropargyl alcohol. The use of tin and bismuth as the metal mediator provided slightly lower selectivities with the same preference. The use of zinc and cadmium as the mediators further lowered the product selectivity. The reactions of an alipathic aldehyde with simple propargyl bromide showed a lower selectivity than the reaction of an aromatic aldehyde in most cases, except for the use of tin or zinc (where comparable selectivities were observed). On the other hand, the reaction of terminal-substituted propargyl bromides with aldehydes mediated by indium showed a high regioselectivity in forming allenylation products. The indium-mediated allenylation of carbonyl compounds bearing an α-hydroxyl group also proceeded with a high diastereoselectivity, forming syn-diols predominantly in aqueous ethanol. The high diastereoselectivity in allenylation of α-hydroxyl-substituted aldehydes was attributed to the chelation effect exhibited by the α-hydroxyl substituent. Through the use of this highly diastereoselective allenylation, (+)-goniofufurone was synthesized from D'-glucurono-6,3-lactone.

Full text of DOI:10.1021/jo9815610

7472
J . Org. Chem. 1998, 63, 7472-7480
Regio- a n d Dia ster eoselective Allen yla tion of Ald eh yd es in
Aqu eou s Med ia : Tota l Syn th esis of (+)-Gon iofu fu r on e1
Xiang-Hui Yi, Yue Meng, Xiao-Gang Hua, and Chao-J un Li*
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118
Received August 3, 1998
The regio- and diastereoselectivities of metal-mediated allenylation of carbonyl compounds were
investigated in aqueous media. Different metal mediators showed varied regioselectivities on
product formation during propargylation-allenylation reactions of carbonyl compounds with simple
propargyl bromide. Under the standard reaction conditions, the use of indium provided the highest
regioselectivity, with a preference of formation of the homopropargyl alcohol. The use of tin and
bismuth as the metal mediator provided slightly lower selectivities with the same preference. The
use of zinc and cadmium as the mediators further lowered the product selectivity. The reactions
of an aliphatic aldehyde with simple propargyl bromide showed a lower selectivity than the reaction
of an aromatic aldehyde in most cases, except for the use of tin or zinc (where comparable selectivities
were observed). On the other hand, the reaction of terminal-substituted propargyl bromides with
aldehydes mediated by indium showed a high regioselectivity in forming allenylation products.
The indium-mediated allenylation of carbonyl compounds bearing an R-hydroxyl group also
proceeded with a high diastereoselectivity, forming syn-diols predominantly in aqueous ethanol.
The high diastereoselectivity in allenylation of R-hydroxyl-substituted aldehydes was attributed
to the chelation effect exhibited by the R-hydroxyl substitutent. Through the use of this highly
diastereoselective allenylation, (+)-goniofufurone was synthesized from D-glucurono-6,3-lactone.
In tr od u ction
goniofufurone (1)8 and (+)-7-epi-goniofufurone (2).9 The
Carbohydrates have long been a source of scientific
interest because of their abundance in nature, their wide
range of biological activities, and the synthetic challenges
posed by their polyhydroxylated structures.2 Methods
that could be used to transform and synthesize polyhy-
droxylated compounds in their underivatized states are
particularly desirable. In this respect, the Kiliani-
Fischer synthesis is the earliest carbohydrate chemical
synthesis without the use of a protecting group.3 The
recent development of Barbier-Grignard-type carbon-
carbon bond formations in aqueous media offers op-
portunities in the syntheses of various heavily oxygen-
ated, biologically important agents.4 Among the various
biologically important, polyhydroxylated compounds are
the ones recently isolated from the Asian trees of the
genus Goniothalamus. These trees have long been
recognized as a potential source of chemotherapeutic
agents. The extracts and leaves of Goniothalamus have
traditionally been used for the treatment of edema and
rheumatism,5 as a pain killer and a mosquito repellent,6
and as an abortifacient.7 From the constituents of these
plants, McLaughlin discovered a number of novel styryl
lactones which were found to possess moderate to sig-
nificant cytotoxicities against several human tumors.
Among the key components in the extracts are (+)-
absolute stereochemistry of (+)-goniofufurone was es-
tablished by Shing through the total synthesis of ent-(-
(4) For general reviews, see: Li, C. J . Chem. Rev. 1993, 93, 2023.
Lubineau, A.; Auge, J .; Queneau, Y. Synthesis 1994, 741. Li, C. J .
Tetrahedron 1996, 52, 5643. Li, C. J .; Chan, T. H. Organic Reactions
in Aqueous Media; J ohn Wiley & Sons: New York, 1997. For applica-
tions of aqueous metal-mediated reactions in carbohydrate syntheses,
see: Schmid, W.; Whitesides, G. M. J . Am. Chem. Soc. 1991, 113, 6674.
Chan, T. H.; Li, C. J . J . Chem. Soc., Chem. Commun. 1992, 747.
Gordon, D. M.; Whitesides, G. M. J . Org. Chem. 1993, 58, 7937. Gao,
J .; Harter, R.; Gordon, D. M.; Whitesides, G. M. J . Org. Chem. 1994,
59, 3714. Binder, W. H.; Prenner, R. H.; Schmid, W. Tetrahedron 1994,
50, 749. Chan, T. H.; Lee, M. C. J . Org. Chem. 1995, 60, 4228. Wang,
R.; Lim, C. M.; Tan, C. H.; Lim, B. K.; Sim, K. Y.; Loh, T. P.
Tetrahedron: Asymmetry 1995, 6, 1825. For accounts on Diels-Alder
type reactions in aqueous media, see: Breslow, R. Acc. Chem. Res.
1991, 24, 159. Grieco, P. A. Aldrichimica Acta 1991, 24, 59. Gajewski,
J . J . Acc. Chem. Res. 1997, 30, 219. For reviews on transition-metal-
catalyzed reactions in aqueous media, see: Herman, W. A.; Kohl-
painter, C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524. For an
account on Lewis acid catalysis in aqueous medium, see: Kobayashi,
S. Synlett 1994, 689. Recently, various Lewis acids were found to
catalyze aqueous Barbier-type reactions, see: Loh, T. P.; Cao, G. Q.;
Pei, J . Tetrahedron Lett. 1998, 39, 1457 and references therein.
(5) Wu, Y. C.; Duh, C. Y.; Chang, F. R.; Chang, G. Y.; Wang, S. K.;
Chang, J . J .; McPhail, D. R.; McPhail, A. T.; Lee, K. H. J . Nat. Prod.
1991, 54, 1077.
(1) Presented at the 215th ACS National Meeting, Dallas, April
1998. Taken in part from; Yi, X.-H. Ph.D. Dissertation, Tulane
University, 1998.
(6) Talapatra, S. K.; Basu, D.; Deb, T.; Goswami, S.; Talapatra, B.
Indian J . Chem., Sect. B 1985, 24, 29.
(2) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Press: Oxford, 1983.
(3) Webber, J . M. Advances in Carbohydrate Chemistry; Academic
Press: New York, 1962; Vol. 17.
(7) Sam, T. W.; Yeu, C. S.; Matsjeh, S.; Gan, E. K.; Razak, D.;
Mohamed, A. L. Tetrahedron Lett. 1987, 28, 2541.
(8) Fang, X. P.; Anderson, J . E.; Chang, C. J .; Fanwick, P. E.;
McLaughlin, J . L. J . Chem. Soc., Perkin Trans. 1 1990, 1655.
S0022-3263(98)01561-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

Allenylation of Aldehydes in Aqueous Media
J . Org. Chem., Vol. 63, No. 21, 1998 7473
)-1.10 Subsequently, several synthetic studies have been
carried out on the synthesis of 1.11
Sch em e 1. Retr osyn th etic Rou te to
(+)-Gon iofu fu r on e
Our continued interests in metal-mediated carbon-
carbon bond formation in aqueous media12 led us to study
(+)-goniofufurone and the related styryl compounds.
Recently, we reported a highly regio- and diastereose-
lective indium-mediated allenylation of carbonyl com-
pounds in aqueous media, which led to a concise total
synthesis of (+)-goniofufurone from a readily available
starting material.13 Herein, we release our detailed study
on this research.
Resu lts a n d Discu ssion
During the assessment of the potential starting mate-
rial for the desired target, a special feature of the 5-5
fused heterocyclic ring system attracted our attention.
Such a structure is closely related to (+)-glucuronolac-
tone, an inexpensive and readily available compound.14
We could transform this 5-5 fused system into the target
if we could find a method to regioselectively attach a
benzyl alcohol unit to the hemiacetal carbon. For this
aim, an allenylation of the hemiacetal followed by
functional group transformations would generate the
desired styryl derivative. In addition, it would require
that the allenylation proceeds in a diastereoselective
fashion, generating a diol derivative with a syn relation-
ship. The initial assessment led us to derive the ret-
rosynthetic analysis of (+)-goniofufurone via a metal-
mediated allenylation reaction (Scheme 1).
Ta ble 1. Effect of Meta ls on th e
P r op a r gyla tion -Allen yla tion Rea ction a
entry
R
metal
8/9b
overall yield (%)
1
2
3
4
5
6
7
8
9
phenyl
n-hexyl
phenyl
n-hexyl
phenyl
n-hexyl
phenyl
n-hexyl
phenyl
n-hexyl
In
In
1:6
1:2
1:5
1:6c
1:3
1:4.4
1:5
1:1
1:1
1:1
72
85
60
60
64
65
83
60
60
20
Sn
Sn
Zn
Zn
Bi
Bi
Cd
Cd
10
P r op a r gyla tion -Allen yla tion . As illustrated in the
retrosynthetic analysis, the key connection of the pro-
posed synthetic approach is the metal-mediated carbon-
carbon bond formation between a carbonyl compound and
a propargyl halide. To evaluate the feasibility of the
proposed approach, we would be required to understand
the regiochemistry of the connection (e.g., allenylation
vs propargylation) and the diastereochemistry (syn vs
anti).15 In addition, other factors may also influence
these selectivities. Thus, the initial regiochemistry of the
carbon-carbon bond formation was investigated through
the reaction between various aldehydes (6) and propargyl
a
All reactions were carried out on 1 mmol scale at room
temperature in H2O/CH3OH (2:1) with aldehyde/propargyl bromide/
metal ) 1:3:3. Yields were referred to as the nonoptimized, isolated
ones after the column chromatography. The ratio based on 1H
b
NMR. c The allenyl alcohol is isomerized to a conjugated ketone
during isolation.
bromide (7) mediated by indium, zinc, tin, cadmium, and
bismuth (eq 1). The results are compiled in Table 1. The
(9) Fang, X. P.; Anderson, J . E.; Chang, C. J .; McLaughlin, J . L.;
Fanwick, P. E. J . Nat. Prod. 1991, 54, 1034.
(10) Shing, T. K. M.; Tsui, H. C. J . Chem. Soc., Chem. Commun.
1992, 432.
ratio of allenylation-propargylation (8/9) was determined
1
by H NMR measurement of peaks corresponding to the
terminal alkyne and the internal olefin in the crude
reaction mixture.
(11) Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H. J . Org. Chem. 1995,
60, 3121 and references therein. Shing, T. K. M.; Tsui, H. C.; Zhou, Z.
H. J . Chem. Soc., Chem. Commun. 1992, 810. Murphy, P. J .; Dennison,
S. T. Tetrahedron 1993, 49, 6695. Prakash, K. R. C.; Rao, S. P.
Tetrahedron 1993, 49, 1505. Tsubuki, M.; Kanai, K.; Honda, T. Synlett
1993, 653. Mukai, C.; Kim, I. J .; Hanaoka, M. Tetrahedron Lett. 1993,
34, 6081. Ye, J .; Bhatt, R. K.; Falck, J . R. Tetrahedron Lett. 1993, 34,
8007. For more recent efforts in the synthesis of related compounds,
see: Mereyala, H. B.; Reddy, R.; Krishnan, R. J . Chem. Soc., Perkin
Trans. 1 1997, 3567. Surivet, J .-P.; Vatele, J .-M. Tetrahedron Lett.
1997, 38, 819. Cagnolini, C.; Ferri, M.; Cox, B. Tetrahedron 1997, 53,
4815. Mukai, C.; Hirai, S.; Hanaoka, M. Tetrahedron 1996, 52, 6547.
(12) Li, C. J .; Chen, D. L.; Lu, Y. Q.; Haberman, J . X.; Mague, J . T.
Tetrahedron 1998, 54, 2347. Li, C. J .; Meng, Y.; Yi, X. H.; Ma, J . H.;
Chan, T. H. J . Org. Chem. 1997, 62, 8632. Haberman, J . X.; Li, C. J .
Tetrahedron Lett. 1997, 38, 4735. Yi, X. H.; Meng, Y.; Li, C. J .
Tetrahedron Lett. 1997, 38, 4731. Li, C. J .; Chen, D. L.; Lu, Y. Q.;
Haberman, J . X.; Mague, J . T. J . Am. Chem. Soc. 1996, 118, 4216. Lu,
Y. Q.; Li, C. J . Tetrahedron Lett. 1996, 37, 471. Chen, D. L.; Li, C. J .
Tetrahedron Lett. 1996, 37, 295. Li, C. J .; Lu, Y. Q. Tetrahedron Lett.
1995, 36, 2721. Li, C. J . Tetrahedron Lett. 1995, 36, 517.
(13) Yi, X. H.; Meng, Y.; Li, C. J . Chem. Commun. (Cambridge) 1998,
449.
The reaction of propargyl bromide with benzaldehyde
mediated by indium at room temperature in aqueous
methanol was found to be fairly regioselective16,17 with a
preference for the formation of the homopropargyl alco-
hol. On the other hand, the same reaction mediated with
tin18 and bismuth19 provided slightly lower selectivi-
(16) Isaac, M. B.; Chan, T. H. J . Chem. Soc., Chem. Commun. 1995,
1003. For an early example of allylation in aqueous media, see: Li, C.
J .; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017. For early examples
of indium reagents in organic solvents, see: Chao, L. C.; Rieke, R. D.
J . Org. Chem. 1975, 40, 2253. Araki, S.; Ito, H.; Butsugan, Y. Synth.
Commun. 1988, 18, 453. For more information on indium reagents,
see: Cintas, P. Synlett 1995, 1087. For the use of InCl3(cat.)/M systems
for aqueous Barbier-type reactions, see: Araki, S.; J in, S. J .; Idou, Y.;
Butsugan, Y. Bull. Chem. Soc. J pn. 1992, 65, 1736. Li, X. P.; Loh, T.
P. Tetrahedron: Asymmetry 1996, 7, 1535 and references therein.
(17) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. J . Org.
Chem. 1993, 58, 5500.
(14) Aldrich Chemical Co., 17.7 ¢/g.
(15) Preliminary studies were presented at the 213th ACS National
Meeting, San Francisco, April 15, 1997.
(18) For examples of allylation, see: Nokami, J .; Otera, J .; Sudo,
T.; Okawara, R. Organometallics 1983, 2, 191. Wu, S. H.; Huang, B.
Z.; Gao, X. Synth. Commun. 1990, 20, 1279.

7474 J . Org. Chem., Vol. 63, No. 21, 1998
Yi et al.
ties with the same preference. The reaction with zinc20
further lowered the selectivity, and the use of cadmium
had no selectivity on the product formation. The reac-
tions of heptaldehyde with propargyl bromide in aqueous
methanol mediated by indium, bismuth, or cadmium all
gave low selectivity in the allenylation-propargylation.
However, mediation by tin and zinc showed slightly
higher selectivity favoring the propargylation product.
To study the regioselectivity of the reaction between
aldehydes and propargyl bromides bearing different
substituents, we prepared several bromo compounds. The
compound 11 was readily prepared from 1-pentyne (10).
Ta ble 2. Cou p lin g of Ald eh yd e w ith Su bstitu ted
P r op a r gyl Br om id esa
yield 15
entry
R
R′
solvent
(%)
1
2
3
phenyl
n-hexyl
phenyl
propyl
phenyl
p-MeO-
water
water
15a (69)
15b (53)
0.1 N HCl/95% 15c (77)
ethanol
0.1 N HCl/95% 15d (50)
ethanol
0.1 N HCl/95% 15e (57)
ethanol
phenyl
p-MeO-
phenyl
hydroxymethyl phenyl
4
5
n-hexyl
a
All reactions were carried out in an air atmosphere. Yields
were referred to as the isolated yields and were not optimized.
Sch em e 2
The starting material 10 was deprotonated with butyl-
lithium and treated with methyl chloroformate; subse-
quent diisobutylaluminum hydride (DIBAL) reduction
followed by mesylation and substitution (with lithium
bromide) afforded the desired 1-bromo-2-hexyne (11) (eq
2). For the preparation of 3-bromo-1-propynylbenzene
derivatives (eqs 3 and 4), iodobenzene (12) and 4-iodoani-
sole (13) were coupled with propargyl alcohol through a
palladium-catalyzed reaction in an aqueous medium.21
gylindium species in an aqueous medium (Scheme 2).
Both intermediates can react with the carbonyl com-
pounds, leading to carbon-carbon bond formation prod-
ucts. The selectivity was controlled by both steric and
electronic effects.16
The diastereoselectivity study was based on the results
of the highly regioselective indium-mediated allenylation
of aldehyde by substituent-bearing propargyl bromides.
Coupling between 1-phenyl-3-bromopropyne and the
R-hydroxyl substituted aldehydes 18 and 5 mediated by
indium was investigated in aqueous ethanol (eqs 6 and
7). The use of aqueous alcohol as the reaction solvent
Subsequent mesylation and bromination generated the
desired bromides 4 and 14. In contrast to the reaction
of propargyl bromide itself, the reaction of propargyl
bromides terminally substituted by an aliphatic or an
aromatic substituent with aldehydes gave the allenyla-
tion products 15, essentially as exclusive products (eq 5)
(Table 2). During the present study, a similar high
was desirable and provided a high diastereoselectivity.
The corresponding allenylation products (after peracety-
lation: 19a and 20a ) were obtained favoring the syn
diastereomer. The high diastereoselectivity of this in-
dium-mediated allenylation reaction can be attributed to
a chelation control (Figure 1). The allene unit was
regioselectivity was also reported by Isaac and Chan in
a more comprehensive investigation.16 In agreement
with the report by Isaac and Chan, the reaction of
propargyl bromide with indium was proposed to generate
an equilibrium between the allenylindium and propar-
primarily delivered from the least hindered face.
A
similar chelation-control model has been used exten-
(21) Calsalnuovo, A. L.; Calabreze, J . C. J . Am. Chem. Soc. 1990,
112, 4324. Genet, P. J .; Blart, E.; Savignac, M. Synlett 1992, 715.
Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Russ. J . Org. Chem.
1995, 31, 348. Li, C. J .; Chen, D. L.; Costello, C. W. Org. Process Res.
Dev. 1997, 1, 325. Li, C. J .; Slaven, W. T., IV; J ohn, V. T.; Banerjee, S.
Chem. Commun. (London) 1997, 1569; Li, C. J .; Slaven, W. T., IV;
Chen, Y. P.; J ohn, V. T.; Rachakonda, S. H. Chem. Commun. (Cam-
bridge) 1998, 1351.
(19) For allylation, see: Wada, M.; Ohki, H.; Akiba, K. Y. Bull.
Chem. Soc. J pn. 1990, 63, 1738; J . Chem. Soc., Chem. Commun. 1987,
708. Katritzky, A. R.; Shobana, N.; Harris, P. A. Organometallics 1992,
11, 1381. Minato, M.; Tsuji, J . Chem. Lett. 1988, 2049.
(20) For early examples of allylation, see: Petrier, C.; Luche, J . L.
J . Org. Chem. 1985, 50, 910. Wilson, S. R.; Guazzaaroni, M. E. J . Org.
Chem. 1989, 54, 3087.

Allenylation of Aldehydes in Aqueous Media
J . Org. Chem., Vol. 63, No. 21, 1998 7475
countered during attempts to effect a base-catalyzed
elimination. Instead of generating the desired R,â-
unsaturated γ-lactone 30, the reaction resulted in an
unidentifiable mixture.
After careful examination of the problems during the
first two approaches, we devised a third approach (Scheme
4). In this case, the starting material D-glucurono-6,3-
lactone (5) was protected with an isopropylidene group
following another literature procedure.26 Replacement
of toluenesulfonic acid with concentrated sulfuric acid
enabled us to carry out the transformation into 21
without the use of cupric sulfate and to scale up the
reaction. Following the same literature procedure,26 21
was converted into its corresponding triflate 31 by
treatment with triflic anhydride in the presence of
pyridine. Normally, a triflate is supposed to be reactive
and unstable, but in this case, the product was kinetically
stable enough to be stored at room temperature for a long
period. After being stirred with lithium bromide at room
temperature for 1 h, the triflate 31 was smoothly
transformed into the desired diastereomer of the corre-
ponding bromo analogue 23 stereospecifically. The ster-
eoconfiguration of the bromo at the R position of the
lactone is crucial for the reductive elimination at a later
stage. Treatment of 23 with trifluoroacetic acid and
water26 at room temperature cleanly afforded the desired
substrate 32 in almost quantitative yield. Initial at-
tempts to carry out the deprotection of the isopropylidene
group by heating 23 with Dowex-50w appeared less
satisfactory. Then, reaction of 32 with 3-bromo-1-pro-
pynylbenzene under the conditions of indium mediation
in aqueous ethanol generated a mixture of allenylation
products (56% yield) in which the desired allene com-
pound 33 was the major component together with de-
bromination and reductive elimination products. Again,
the allenylation reaction showed a very high diastereo-
selectivity (>10:1) favoring the syn diastereomer. Sub-
sequent ozonolysis of the allene compound 33 in methanol
followed by a diastereoselective reduction with sodium
borohydride27 generated the desired alcohol as the pre-
dominant product (de ) 3:1). The stereo configuration
was assigned after the target compound was synthesized.
To effect a reductive elimination, the crude polyol mixture
was directly treated with concentrated sulfuric acid in
acetic anhydride28 to afford the peracetylation product
34 (calculated 75% yield from 33), which showed decom-
position on silica gel. Subsequent treatment of the
peracetylation product 34 with sodium bisulfite/sodium
sulfite29 in aqueous methanol cleanly afforded the desired
R,â-unsaturated γ-lactone, as shown by the 1H NMR
measurement of the crude product. To remove the acetyl
protecting groups, the product was stirred in methanolic
HCl for 2 days. Surprisingly, the reaction resulted in
the deprotected product, which then cyclized, in situ,
providing the target (+)-goniofufurone (1) in 44% yield.
The spectroscopic data, the Rf value, and the melting
point of the compound are consistent with the reports of
(+)-goniofufurone in the literature.11
F igu r e 1.
sively, by Paquette and co-workers22 in explaining the
syn selectivity of aqueous allylation of carbonyl com-
pounds.
Syn th esis of (+)-Gon iofu fu r on e. The promising
results of the regio- and diastereoselectivity studies led
us to examine the synthesis of (+)-goniofufurone via the
indium-mediated allenylation reaction. In our first ap-
proach (Scheme 3), the commercially available D-glucu-
rono-6,3-lactone (5) was converted to 21 by treatment
with a catalytic amount of toluenesulfonic acid in acetone
in the presence of the hydroxyl group in the R position.
Following a literature procedure,23 the adduct 21 was
then reacted with toluenesulfonic chloride in the presence
of pyridine, yielding the corresponding tosylate 22. The
tosylate 22 was transformed to the bromide 23 (as a
diastereomeric mixture) with lithium bromide in DMF
solvent based on a literature procedure.24 Attempts to
effect a reductive elimination to generate the desired
aldehyde compound 24 were not successful. Only the
corresponding reduced product 25 was obtained.
To circumvent the problem associated with the reduc-
tive elimination, another synthetic route was designed.
In this case, the key step was the allenylation between
3-bromo-1-propynylbenzene (4) and the R-reduced ana-
logue of D-glucurono-6,3-lactone 27. Low-temperature
treatment of 21 with sulfuryl chloride yielded its R-chloro
analogue 26 stereospecifically according to a literature
procedure.25 Then, reaction of 26 with zinc in saturated
ammonium chloride solution mixed with tetrahydrofuran
gave the reduced adduct 25 (in about 30% yield, although
the reaction gave cleanly one product). The low isolated
yield can be attributed to the high solubility of the
accidentally deprotected adduct in water. Subsequent
deprotection of the isopropylidene group produced the
aqueous reaction substrate 27 quantitatively. After the
aqueous indium-mediated allenylation, the crude mate-
rial 28 was peracylated upon treatment with acetic
anhydride along with pyridine and a catalytic amount
of 4-(dimethylamino)pyridine (DMAP). The peracety-
lated product 29 was isolated in 49% yield after flash
column chromatography. However, problems were en-
(22) Paquette, L. A.; Mitzel, T. M. Tetrahedron Lett. 1995, 36, 6863.
Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc. 1996, 118, 1931.
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Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schomer, W.
W. J . Org. Chem. Soc. 1997, 62, 4293. Bernardelli, P.; Paquette, L. A.
J . Org. Chem. 1997, 62, 8284. Marshall, J . A. Chemtracts: Org. Chem.
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walla, A. J . Org. Chem. 1998, 63, 1836.
(23) Hall, L. D.; Hough, L.; Pritchard, R. A. J . Am. Chem. Soc. 1961,
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Tetrahedron 1987, 43, 415.
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(28) Abdel-Akher, M.; Hamilton, J . K.; Smith, F. J . Am. Chem. Soc.
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(29) Vekemans, J . A. M.; Franken, G. A. M.; Dapperens, C. W. M.;
Godefroi, E. F.; Chittenden, G. J . F. J . Org. Chem. 1988, 53, 627.
(25) Parolis, H. Carbohydr. Res. 1983, 114, 21.

7476 J . Org. Chem., Vol. 63, No. 21, 1998
Yi et al.

Allenylation of Aldehydes in Aqueous Media
J . Org. Chem., Vol. 63, No. 21, 1998 7477
1 N NH4Cl, and extracted with ether (4 × 10 mL). The
combined ethereal solution was dried over MgSO4 and con-
centrated. Measurement of the 8/9 ratio was then taken. The
propargylation and allenylation products (105 mg, 72%) were
isolated by column chromatography on silica gel (eluent:
hexane/ethyl acetate).
Sch em e 4. Syn th esis of (+)-Gon iofu fu r on e
3-Br om o-1-p r op yn ylben zen e (4). A solution of iodoben-
zene (4.08 g, 20 mmol), propargyl alcohol (1.8 mL, 31 mmol),
triethylamine (7 mL, 50 mmol), triphenylphosphine (270 mg,
1.03 mmol), palladium acetate (117 mg, 0.52 mmol), acetoni-
trile (30 mL), and water (15 mL) was stirred at room temper-
ature under nitrogen overnight.30 After filtration through
Celite, most of the acetonitrile was evaporated, and the
resulting suspension was extracted with ether (50 mL, 30 mL,
30 mL), washed with brine, dried over magnesium sulfate, and
filtered. The filtrate was concentrated to give a crude oil,
which was then purified by flash chromatography (70% me-
thylene chloride in hexanes) to give 3-phenyl-2-propyn-1-ol31
(1.47 g, 55% yield).
To a solution of the above product (1.47 g, 11.1 mmol) and
triethylamine (2.4 mL, 17.3 mmol) in methylene chloride (25
mL) cooled to 0 °C was slowly added methanesulfonic chloride
(1 mL, 13 mmol) over methylene chloride (10 mL). After being
stirred for 30 min, the reaction mixture was washed with cold
water, cold 5% hydrochloric acid, saturated sodium bicarbonate
solution, and brine. After being dried over magnesium sulfate
and filtered, the solution was concentrated to give a crude
material.
A solution of the above crude material and lithium bromide
(7.05 g, 81 mmol) in acetone (120 mL) was stoppered and
stirred at room temperature overnight. After evaporation of
acetone, the residue was dissolved in ether (100 mL), washed
with water (3 × 30 mL) and brine, dried over magnesium
sulfate, and filtered. The solution was concentrated to give
the crude product, which was filtered through a pad of silica
gel to produce 432 (1.65 g, quantitative). IR (film): 1203, 1271,
Con clu sion
In conclusion, different metal mediators show varied
regioselectivities on the product formation of propargy-
lation-allenylation reaction of carbonyl compounds with
propargyl bromide in aqueous media. The reaction of
terminal-substituted propargyl bromides with aldehydes
showed a high regioselectivity in forming allenylation
products. The allenylation of carbonyl compounds bear-
ing an R-hydroxyl group proceeded with a high diaste-
reoselectivity predominantly forming syn-diols. The
selectivity is attributed to chelation control. Through the
use of this highly diastereoselective allenylation, a total
synthesis of (+)-goniofufurone was completed. The scope
and applications of this highly regio- and diastereoselec-
tive allenylation reaction to the syntheses of other
polyhydroxylated compounds are presently under inves-
tigation.
1442, 1491, 1597, 2220 cm-1
.
1H NMR (400 MHz, CDCl3,
ppm): δ 4.16 (2H, s), 7.28-7.40 (3H, m), 7.40-7.50 (2H, m).
13C NMR (100 MHz, CDCl3, ppm): δ 131.95, 128.97, 128.43,
122.17, 86.80, 84.39, 15.53. The compound was used directly
in the coupling study.
1-Br om o-2-h exyn e (11). To a solution of 1-pentyne (10,
1.0 mL, 10.2 mmol) in anhydrous tetrahydrofuran (20 mL)
cooled to -78 °C under nitrogen was added dropwise a 1.6 M
solution of butyllithium (6.3 mL, 10.1 mmol). After being
stirred at the same temperature for 40 min, methyl chloro-
formate (0.8 mL, 10.4 mmol) in tetrahydrofuran (7 mL) was
slowly added. The reaction mixture was stirred at -78 °C for
4 h before being warmed to room temperature. After evapora-
tion of tetrahydrofuran under vacuum, the residue was dis-
solved in ether (20 mL) and washed with water (3 × 20 mL)
and brine. After drying over magnesium sulfate, the solution
was filtered and concentrated to provide methyl 2-hexynoate33
(1.05 g, 83% yield). The compound was used directly for the
next step without further purification.
Exp er im en ta l Section
Unless otherwise noted, all reagents were obtained from
commercial sources and used without further purification. All
organic solvents were freshly distilled prior to use. Air-
sensitive reactions were generally conducted under a positive
pressure of dry N2 within glassware which had been oven-
dried. Anhydrous solvents were obtained by distillation from
the indicated drying agents: tetrahydrofuran (sodium, ben-
zophenone ketyl) and methylene chloride (calcium hydride).
Flash chromatography employed silica gel (40 µm). Mass
spectra were obtained at the Center of Instrumental Facility
of Tulane University and at the Biomedical Mass Spectrometry
Unit of Medical School of McGill University. Elemental
analyses were performed at the Center of Instrumental
Facility of Tulane University.
To a solution of the above product (747 mg, 5.9 mmol) in
anhydrous ether (20 mL) cooled to -78 °C under nitrogen was
added diisobutylaluminum hydride (8.2 mL, 12.4 mmol) drop-
wise. After being stirred at -78 °C for 2 h, the reaction
mixture was warmed to room temperature, and methanol (8
mL) was added; the solution turned into a gel. After being
diluted with ether (30 mL), the mixture was stirred with
potassium sodium tartrate (30 mL) for 1.5 h before the gel
disappeared. After separation, the aqueous layer was ex-
tracted with ether (2 × 10 mL). The combined ethereal
solution was washed with brine and dried over magnesium
(30) Claesson, A.; Sahlberg, C. Tetrahedron 1982, 38, 363.
(31) Pelter, A.; Ward, R. S.; Little, G. M. J . Chem. Soc., Perkin Trans.
1 1990, 2775.
(32) Padwa, A.; Rodriguez, A.; Tohidi, M.; Fukunaga, T. J . Am.
Chem. Soc. 1983, 105, 933.
(33) Boger, D. L.; Brotherton, C. E. J . Am. Chem. Soc. 1986, 108,
6695.
Gen er a l P r oced u r e for th e Effect of Meta ls on th e
P r op a r gyla tion -Allen yla tion Rea ction . To a suspension
of benzaldehyde (106 mg, 1 mmol) in 10 mL of H2O/CH3OH
(2:1) was added indium powder and 7 (228 mg, 2 mmol). The
reaction mixture was stirred vigorously for 12 h, diluted with

7478 J . Org. Chem., Vol. 63, No. 21, 1998
Yi et al.
sulfate. Subsequent filtration and removal of solvent fur-
nished 2-hexyn-1-ol34 (590 mg, 89% yield).
tography on silica gel (eluent: 8% ether and 1% triethylamine
in hexane) to give the title compound (15a )39 (224 mg, 69%).
3-P h en yl-1,2-d eca d ien -4-ol (15b). A suspension of hep-
taldehyde (228 mg, 2.0 mmol), 3-bromo-1-propynylbenzene
(754 mg, 3.87 mmol), and indium (520 mg, 4.52 mmol) in water
(10 mL) was stirred at room temperature overnight. After
treatment with 2% hydrochloric acid (30 mL), the reaction
mixture was extracted with ether. The ethereal solution was
washed with water, saturated sodium bicarbonate, and brine,
dried over magnesium sulfate, and filtered. The solution was
concentrated to give a crude product, which was purified with
flash chromatography on silica gel to produce 15b (245 mg,
To a solution of the above crude product (496 mg, 5.06 mmol)
and triethylamine (1.05 mL, 7.45 mmol) in methylene chloride
(25 mL) cooled to 0 °C was slowly added methanesulfonyl
chloride (0.45 mL, 5.83 mmol) over methylene chloride (5 mL)
under nitrogen. After being stirred at 0 °C for 1 h, the solution
was washed successively with cold water (20 mL), 5% cold
hydrochloric acid (25 mL), cold water (20 mL), a saturated
sodium bicarbonate solution (20 mL), and brine. After drying
over magnesium sulfate, the solution was filtered and con-
centrated to give 2-hexyn-1-yl methanesulfonate35 (717 mg,
80% yield).
53%). IR (film): 3390, 1940 cm-1 1H NMR (400 MHz, CDCl3,
.
ppm): δ 0.90 (t, J ) 6.7 Hz, 3H), 1.20-1.58 (m, 8H), 1.58-
1.82 (m, 2H), 2.05-2.25 (br, 1H), 4.60-4.67 (m, 1H), 5.19-
5.27 (m, 2H), 7.20-7.27 (m, 1H), 7.35 (t, J ) 7.9 Hz, 2H), 7.47
(d, J ) 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm): δ 14.1,
22.5, 25.8, 29.3, 31.8, 36.4, 70.0, 80.4, 110.0, 126.8, 128.6, 131.7,
134.8, 207.2. Anal. Calcd for C13H18O: C, 83.43; H, 9.63.
Found: C, 83.17; H, 9.69.
A solution of the above crude product (698 mg, 3.97 mmol)
and anhydrous lithium bromide (3.50 g, 40.2 mmol) in acetone
(50 mL) was stirred at room temperature under nitrogen
overnight. After vacuum filtration through Celite and evapo-
ration of acetone, the residue was dissolved in ether (60 mL)
and washed with water (50 mL, 20 mL, 20 mL) and brine.
After being dried over magnesium sulfate and filtered, the
solvent was removed, thus providing crude 1-bromo-2-hexyne
(11),36 which was purified by column chromatography on silica
gel (eluent: 5% ethyl acetate in hexane) (296 mg, 46% yield).
3-(4-Meth oxyp h en yl)-4-p h en yl-1,2-bu ta d ien -4-ol (15c).
A solution of 1-(3-bromo-1-propynyl)-4-methoxybenzene (225
mg, 1 mmol), benzaldehyde (318 mg, 3 mmol), and indium
powder (402 mg, 3.5 mmol) in 0.1 N aqueous HCl/95% ethanol
(1:9; 6 mL) was stoppered and stirred at room temperature
overnight. After evaporation of the ethanol, the mixture was
extracted with ethyl ether (2 × 30 mL). The combined organic
phase was washed with saturated sodium bicarbonate and
brine, dried over magnesium sulfate, and filtered. After
evaporation of the solvent, the crude material was purified by
column chromatography on silica gel (eluent: 17% ethyl
acetate in hexane) to afford 3-(4-methoxyphenyl)-4-phenyl-1,2-
IR (film): 1209, 2234 cm-1
.
1H NMR (400 MHz, CDCl3,
ppm): δ 0.98 (t, J ) 7.4 Hz, 3H), 1.48-1.59 (m, 2H), 2.22 (tt,
J ) 7.0, 2.3 Hz, 2H), 3.93 (t, J ) 2.3 Hz, 2H). 13C NMR (100
MHz, CDCl3, ppm): δ 88.04, 75.40, 21.83, 20.89, 15.77, 13.42.
1-(3-Br om o-1-pr opyn yl)-4-m eth oxylben zen e (14). A mix-
ture of 4-iodoanisole (20 g, 85.5 mmol), propargyl alcohol (14.36
g, 14.9 mL, 256.15 mmol), triethylamine (25.89 g, 35.66 mL,
255.86 mmol), triphenylphosphine (1.1207 g, 4.27 mmol),
palladium acetate (479 mg, 2.13 mmol), copper(I) iodide (814
mg, 4.27 mmol), acetonitrile (210 mL), and water (40 mL) was
stirred at room temperature under nitrogen for 29 h. After
evaporation of the bulk of acetonitrile, the resulting suspension
was extracted with ether (200 mL, 100 mL, 100 mL). The
ethereal solution was washed with brine, dried over magne-
sium sulfate, and filtered. After evaporation of the solvent,
the crude material was purified by column chromatography
on silica gel (eluent: 17% ethyl acetate in hexane) to afford
3-(4-methoxyphenyl)-2-propyn-1-ol37 (12.83 g, 93%).
butadien-4-ol (15c) (195 mg, 77%). IR (film): 3410, 1940 cm-1
.
1H NMR (400 MHz, CDCl3, ppm): δ 7.46 (d, J ) 7.7 Hz, 2H),
7.26-7.37 (m, 5H), 6.81 (d, J ) 8.4 Hz, 2H), 5.68 (s, 1H), 5.20-
5.30 (m, 2H), 3.75 (s, 3H), 2.40-2.60 (br, 1H). 13C NMR (100
MHz, CDCl3, ppm): δ 55.2, 72.5, 81.3, 109.4, 113.9, 126.1,
127.0, 127.8, 128.1, 128.4, 142.1, 158.7, 207.4. Anal. Calcd
for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.72; H, 6.50.
3-(4-Meth oxyp h en yl)-1,2-d eca d ien -4-ol (15d ). A mix-
ture of heptaldehyde (114 mg, 1 mmol), 1-(3-bromo-1-propy-
nyl)-4-methoxybenzene (674.7 mg, 3 mmol), and indium pow-
der (402 mg, 3.5 mmol) in 0.1 N aqueous HCl/95% ethanol (1:
9) (6 mL) was stoppered and stirred at room temperature
overnight. After evaporation of the ethanol, the mixture was
extracted with ethyl ether (2 × 30 mL). The combined organic
phase was washed with saturated sodium bicarbonate and
brine, dried over magnesium sulfate, and filtered. After
evaporation of the solvent, the crude material was purified by
column chromatography on silica gel (eluent: 9% ethyl acetate
in hexane) to afford 3-(4-methoxyphenyl)-1,2-decadien-4-ol
A solution of 3-(4-methoxyphenyl)-2-propyn-1-ol (8.28 g, 51.1
mmol), triphenylphosphine (16.08 g, 61.3 mmol), and carbon
tetrabromide (20.33 g, 61.3 mmol) in methylene chloride (150
mL) was stoppered and stirred at room temperature overnight.
The solvent was evaporated to give the crude material.
Column chromatography purification on silica gel (eluent: 9%
ethyl acetate in hexane) gave 1-(3-bromo-1-propynyl)-4-meth-
oxybenzene (14)38 (8.37 g, 73%). IR (film): 2220, 1606, 1512,
1465 cm-1 1H NMR (400 MHz, CDCl3, ppm): δ 7.38 (d, J )
.
8.5 Hz, 2H), 6.83 (d, J ) 9.1, 2H), 4.17 (s, 2H), 3.79 (s, 3H).
13C NMR (100 MHz, CDCl3, ppm): δ 160.05, 133.45, 114.14,
113.98, 86.94, 83.03, 55.32, 16.01.
(15d , 130 mg, 50%). IR (film): 3440, 1940 cm-1
.
1H NMR
(400 MHz, CDCl3, ppm): δ 7.37 (d, J ) 8.8 Hz, 2H), 6.88 (d, J
) 88 Hz, 2H), 5.20 (s, 2H), 4.54-4.60 (m, 1H), 3.80 (s, 3H),
1.8-1.9 (br, 1H), 1.2-1.8 (m, 10H), 0.87 (t, J ) 6.6 Hz, 3H).
13C NMR(100 MHz, CDCl3, ppm): δ 14.1, 22.6, 25.8, 29.2, 31.8,
36.2, 55.3, 69.9, 80.6, 109.5, 114.0, 126.7, 127.9, 158.7, 206.7.
Anal. Calcd for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.24;
H, 9.38.
3-P h en yl-3,4-p en ta d ien e-1,2-d iol (15e). A solution of
2-butene-1,4-diol (1.28 g, 14.5 mmol) in methanol was cooled
to -78 °C and bubbled with ozone until the solution turned
blue. Subsequently, the excess ozone was flushed out with
oxygen. After sodium bisulfite (9.16 g) was added, the suspen-
sion was allowed to warm to room temperature slowly and
stirred overnight. Subsequent filtration provided a crude oil
(1.02 g, 58%).
3-(1-P h en yl-1-h yd r oxym eth yl)-1,2-h exa d ien e (15a ). A
mixture of 1-bromo-2-hexyne (276 mg, 1.71 mmol), benzalde-
hyde (261.1 mg, 2.46 mmol), and indium (350 mg, 3.0 mmol)
in water (2.2 mL) was stoppered and stirred vigorously at room
temperature for 2 days. After being stirred with 0.1 N HCl
(4.0 mL) for 1 h, the solution was extracted with ether (3 × 20
mL). The ethereal solution was washed with saturated sodium
bicarbonate aqueous solution (2 × 20 mL) and brine, dried over
magnesium sulfate, and filtered. After evaporation of the
solvent, the crude material was purified by column chroma-
(34) Mori, K.; Nakazono, Y. Tetrahedron 1986, 42, 6459.
(35) Hall, S. E.; Han, W. C.; Haslanger, M. F.; Harris, D. N.;
Ogletree, M. L. J . Med. Chem. 1986, 29, 2335.
(36) Couffignal, R.; Gaudemar, M.; Perriot, P. Bull. Soc. Chim. Fr.
1967, 10, 3909.
(37) Wadsworth, D. H.; Geer, S. M.; Detty, M. R. J . Org. Chem. 1987,
52, 3662.
(38) Wrobel, J . E.; Li, Z.; Dietrich, A. J . (American Home Products
Corp.). PCT Int. Appl. WO95 24, 400(Cl. C07D277/36), Sept 14, 1995;
U.S. Appl. 207,980, Mar 8 1994; 51 pp.
A suspension of the above product (120 mg, 2.0 mmol),
3-bromo-1-propynylbenzene (1.16 g, 6.0 mmol), and indium
(465 mg, 4.0 mmol) in 0.1 N hydrochloric acid/ethanol (1:9, 12
mL) was stoppered and stirred at room temperature overnight.
After being diluted with methanol (50 mL), the reaction
(39) Kulkarni, S. V.; Brown, H. C. Tetrahedron Lett. 1996, 37, 4125.

Allenylation of Aldehydes in Aqueous Media
J . Org. Chem., Vol. 63, No. 21, 1998 7479
.
1750 cm-1 1H NMR (400 MHz, acetone-d6, ppm): δ 2.50 (d,
J ) 18.4 Hz, 1H), 2.84 (dd, J ) 18.4, 8.4 Hz, 1H), 3.20-3.90
(br, 2H), 4.21 (s, 1H), 4.81 (d, J ) 5.6 Hz, 1H), 5.01-5.06 (m,
1H), 5.31 (s, 1H). 13C NMR (100 MHz, acetone-d6, ppm): δ
175.16, 103.45, 87.02, 78.21, 77.70, 37.23.
mixture was neutralized with a 6 N aqueous sodium hydroxide
solution and filtered through Celite under vacuum. Removal
of solvent provided a crude product, which was purified by
flash chromatography (eluent: 40% ethyl acetate in hexane)
to give 15e (202 mg, 57%). IR (film): 3250, 1940 cm-1
.
1H
NMR (400 MHz, acetone-d6, ppm): δ 3.60-3.76 (m, 2H), 4.00
(t, J ) 5.8 Hz, 1H), 4.35 (d, J ) 5.6 Hz, 1H), 4.64-4.72 (m,
1H), 5.18 (d, J ) 2.0 Hz, 2H), 7.17-7.23 (m, 1H), 7.28-7.35
(m, 2H), 7.47-7.52 (m, 2H). 13C NMR (100 MHz, acetone-d6,
ppm): δ 65.5, 70.3, 79.2, 106.6, 126.7, 128.4, 132, 135.3, 208.1.
HRMS Calcd for C11H11O (M + H - H2O): 159.0810; found,
159.0810.
3,5,6-Tr i-O-a cet yl-2,7,8,9-t et r a d eoxy-7-p h en yl-D-id o-
n on a n e-7,8-d ien oic Acid , 1,4-La cton e (29). A suspension
of 27 (98.9 mg, 0.62 mmol), 3-bromo-1-propynylbenzene (647.7
mg, 3.32 mmol), and indium (286 mg, 2.49 mmol) in 0.1 N
hydrochloric acid/ethanol (1:9; 4 mL) was stoppered and stirred
vigorously at room temperature overnight. The mixture was
vacuum filtered and concentrated to provide a crude product,
which was then mixed with 4-(dimethylamino)pyridine (9.2
mg), anhydrous pyridine (8 mL, 104 mmol), and acetic
anhydride (5 mL, 49 mmol). After being stirring at room
temperature under nitrogen overnight, the solvent was re-
moved under vacuum. Filtration of the reaction mixture
through silica gel produced a crude oil, which was subse-
quently purified by flash chromatography (eluent: 35% ethyl
acetate in hexane) to give 29 (121.6 mg, 49%). IR (film): 1940,
1,2,3-Tr i-O-acetyl-4-ph en yl-er yth r o-h exa-4,5-dien e (19a).
A suspension of glyceraldehyde (100 mg, 1.11 mmol), 3-bromo-
1-propynylbenzene (550 mg, 2.82 mmol), and indium (260 mg,
2.26 mmol) in 0.1 N hydrochloric acid/ethanol (1:9; 5 mL) was
stirred at room temperature for 6 h. Vacuum filtration
provided a crude product, which was stirred with anhydrous
triethylamine (20 mL, 144 mmol), 4-(dimethylamino)pyridine
(7.5 mg), and acetic anhydride (2 mL, 20 mmol) overnight.
Subsequent purification by flash chromatography on silica gel
(eluent: 15% ethyl acetate in hexane) produced 19a (210 mg,
1790, 1750, 1200 cm-1 1H NMR (400 MHz, CDCl3, ppm): δ
.
2.01 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 2.61 (dd, J ) 18.4, 6.0
Hz, 1H), 2.86 (dd, J ) 18.0, 7.8 Hz, 1H), 4.85 (dd, J ) 6.4, 4.0
Hz, 1H), 5.20-5.33 (m, 2H), 5.42 (dt, J ) 8.0, 6.0 Hz, 1H),
5.51 (dd, J ) 7.2, 4.0 Hz, 1H), 5.95 (d, J ) 7.2 Hz, 1H), 7.23-
7.28 (m, 1H), 7.32-7.37 (m, 2H), 7.43-7.47 (m, 2H). 13C NMR
(100 MHz, CDCl3, ppm): δ 20.5, 20.9, 30.30, 34.8, 69.1, 69.9,
70.4, 78.5, 80.9, 103.4, 126.8, 127.8, 128.8, 133.1, 169.1, 169.7,
170.2, 172.4, 209.3. HRMS Calcd for C21H23O8 (M + H):
403.1393; found, 403.1394.
5-Br om o-5-d eoxy-1,2-O-isop r op ylid en e-â-L-id o-fu r a -
n u r on o-6,3-la cton e (23a ). A solution of 31 (4.38 g, 12.6
mmol) and lithium bromide (4.96 g, 57 mmol) in acetone (110
mL) was stoppered and stirred at room temperature for 1 h.
After the solvent was removed, the residue was suspended in
ether (100 mL) and washed with water (3 × 100 mL) and brine.
After being dried over magnesium sulfate and filtered, the
solution was concentrated to produce 23a 23 (3.40 g, 97% yield)
63% yield). IR (film): 1940, 1740 cm-1 1H NMR (400 MHz,
.
CDCl3, ppm): δ 1.91 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 4.06
(dd, J ) 12.0, 5.5 Hz, 1H), 4.27 (dd, J ) 12.0, 3.2 Hz, 1H),
5.21 (s, 2H), 5.34-5.42 (m, 1H), 5.95 (d, J ) 7.4 Hz, 1H), 7.20
(t, J ) 7.2 Hz, 1H), 7.30 (t, J ) 7.6 Hz, 2H), 7.41 (d, J ) 7.6
Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm): δ 20.5, 20.7, 20.9,
62.5, 70.5, 71.5, 80.5, 103.7, 126.8, 127.6, 128.6, 131.6, 133.4,
169.9, 170.0, 170.3, 209.3. HRMS Calcd for C18H21O6 (M +
H); 333.1338; found, 333.1339.
2,3,5,6-Tet r a -O-a cet yl-7,8,9-t r id eoxy-7-p h en yl-D-glyc-
er o-L-gu lo-n on a -7,8-d ien oic Acid , 1,4-La cton e (20a ).
A
suspension of D-glucurono-6,3-lactone (90 mg, 0.51 mmol),
3-bromo-1-propynylbenzene (390 mg, 2.0 mmol), and indium
(202 mg, 1.76 mmol) in 0.1 N hydrochloric acid/ethanol (1:9;
10 mL) was stirred vigorously at room temperature overnight.
After removal of solvent under vacuum, the residue was mixed
with 4-(dimethylamino)pyridine (6.8 mg), acetic anhydride (6
mL, 60 mmol), and pyridine (20 mL, 259 mmol). The mixture
was stirred at room temperature under nitrogen overnight
before solvent was removed. Filtration of the reaction mixture
through silica gel gave the crude product, which was then
purified by flash chromatography to afford 20a (148 mg, 63%
as a white solid. IR (film): 1792, 1377, 1169, 1061, 1018 cm-1
.
1H NMR (400 MHz, CDCl3, ppm): δ 1.34 (s, 3H), 1.52 (s, 3H),
4.25 (s, 1H), 4.84 (d, J ) 3.5 Hz, 1H), 4.93 (d, J ) 2.9 Hz, 1H),
5.07 (d, J ) 2.8 Hz, 1H), 5.97 (d, J ) 3.5 Hz, 1H). 13C NMR
(100 MHz, CDCl3, ppm): δ 170.55, 113.60, 106.87, 84.04, 83.57,
81.32, 38.03, 27.01, 26.48.
yield). IR (film): 1940, 1820, 1750 cm-1 1H NMR (400 MHz,
.
5-Br om o-5-d eoxy-â-L-id o-fu r a n u r on o-6,3-la cton e (32).
A solution of 23a (2.51 g, 9 mmol) in trifluoroacetic acid/water
(3:1; 25 mL) was stirred at room temperature for 4.5 h.
Removal of solvent under vacuum provided 32 (2.138 g, 98%
CDCl3, ppm): δ 1.93 (s, 3H), 2.00 (s, 3H), 2.06 (s, 3H), 2.08 (s,
3H), 4.76-4.82 (m, 1H), 5.13-5.22 (m, 2H), 5.57 (dd, J ) 7.7,
3.6 Hz, 1H), 5.66-5.71 (m, 3H), 7.19-7.35 (m, 5H). 13C NMR
(100 MHz, CDCl3, ppm): δ 20.0, 20.1, 20.5, 20.7, 67.9, 69.0,
69.2, 69.7, 76.4, 80.4, 103.6, 127.0, 127.9, 128.8, 133.3, 166.3,
169.0, 169.1, 169.2, 169.5, 208.3. HRMS Calcd for C23H25O10
(M + H): 461.1448; found, 461.1449.
yield). IR (film): 3400, 1750 cm-1
.
1H NMR (400 MHz,
acetone-d6, ppm): δ 4.28 (s, 1H), 4.46 (s, 1H), 5.05 (d, J ) 5.3
Hz, 1H), 5.08 (d, J ) 5.0 Hz, 1H), 5.40 (s, 1H). 13C NMR (100
MHz, CDCl3, ppm): δ 171.53, 103.74, 85.39, 84.84, 77.17,
41.40. Mp: >125 °C dec. Anal. Calcd for C6H7BrO5: C, 30.15;
H, 2.95. Found: C, 30.54; H, 2.94.
5-Deoxy-1,2-O-isop r op ylid en e-r-D-glu cofu r a n u r on o-
6,3-la cton e (25). A suspension of 26 (0.9925 g, 4.24 mmol)
and zinc (2.70 g, 41.5 mmol) in a mixed-solvent system of
tetrahydrofuran/aqueous saturated ammonium chloride (1:1;
30 mL) was stirred overnight. After evaporation of tetrahy-
drofuran, the mixture was extracted with methylene chloride
(3 × 30 mL). The organic solution was washed with brine,
dried over sodium sulfate, and filtered. Subsequent filtration
through silica gel provided 2540 (250 mg, 30% yield). IR
2-Br om o-7-p h en yl-2,7,8,9-tetr a d eoxy-D-glycer o-L-id o-
n on a n e-7,8-d ien oic Acid , 1,4-La cton e (33). A suspension
of 32 (102 mg, 0.39 mmol), 3-bromo-1-propynylbenzene (312
mg, 1.6 mmol), and indium (92 mg, 0.8 mmol) in a mixed-
solvent system of 0.1 N hydrochloric acid/ethanol (1:9; 6 mL)
was stoppered and stirred vigorously at room temperature
overnight. After being diluted with ether, the reaction mixture
was filtered through Celite and concentrated to give a crude
oil (401 mg). Part of the crude oil (60 mg) was purified by
preparatory thin-layer chromatography to collect 33 (6 mg,
(film): 1790, 1387, 1165 cm-1
.
1H NMR (400 MHz, CDCl3,
ppm): δ 1.33 (s, 3H), 1.50 (s, 3H), 2.66-2.74 (m, 2H), 4.81 (d,
J ) 3.6 Hz, 1H), 4.83 (d, J ) 4.0 Hz, 1H), 4.95-5.02 (m, 1H),
5.96 (d, J ) 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, ppm):
δ 174.29, 112.67, 106.19, 85.48, 82.43, 78.03, 35.85, 26.93,
26.47.
5-Deoxy-r-D-glu cofu r a n u r on o-6,3-la cton e (27). A sus-
pension of 25 (194 mg, 0.97 mmol) and Dowex-50w (1.85 g) in
water (15 mL) was heated in an oil bath at 70 °C overnight.
After vacuum filtration, the filtrate was concentrated to give
2740 (0.155 g, 100%) as an off-white solid. IR (KBr): 3380,
32% yield). IR (film): 3430, 1938, 1779, 1743 cm-1 1H NMR
.
(400 MHz, acetone-d6, ppm): δ 4.27 (br, 1H), 4.40 (d, J ) 7.0
Hz, 1H), 4.56 (d, J ) 4.4 Hz, 1H), 4.67 (d, J ) 3.8 Hz, 1H),
4.80 (d, J ) 3.2 Hz, 1H), 5.26 (s, 2H), 5.67 (br, 1H), 7.21 (t, J
) 7.4 Hz, 1H), 7.31 (t, J ) 7.7 Hz, 2H), 7.51 (d, J ) 7.9 Hz,
2H). 13C NMR (100 MHz, acetone-d6, ppm): δ 44.7, 69.2, 70.4,
75.2, 80.0, 81.9, 106.7, 126.8, 127.0, 128.4, 134.7, 171.1, 208.7.
HRMS Calcd for C15H14O4Br (M + H - H2O), 337.0075; found,
337.0075.
2-Br om o-2-d eoxy-7-p h en yl-D-er yth r o-L-id o-h ep t a n o-
ic Acid , 1,4-La cton e (34). A solution of 33 (160 mg) in
(40) Paulsen, H.; Stoye, D. Chem. Ber. 1966, 99, 908.

7480 J . Org. Chem., Vol. 63, No. 21, 1998
Yi et al.
methanol (15 mL) cooled to -78 °C was bubbled with ozone
until the solution turned blue. After the ozone was flushed
out with oxygen, dimethyl sulfide (0.4 mL) was added. The
reaction mixture was warmed to room temperature gradually
and stirred overnight. Removal of solvent under vacuum
provided the crude product (160 mg).
hydrogen chloride (1.5 M, 10 mL) was stirred for 2 days
followed by neutralization with sodium bicarbonate powder.
The mixture was then diluted with ether and filtered. After
removal of solvent, the residue was suspended in ethyl acetate
and filtered again. Concentration of the filtrate gave the crude
product, which was then purified by preparatory thin-layer
chromatography to afford 111 (8.0 mg, 44% yield). Mp: 150-
To a solution of the crude product (160 mg) in methanol (15
mL) cooled to -10 °C was added sodium borohydride (45 mg)
in one portion. After being stirred for 30 min, the reaction
mixture was then quenched with acetic acid (0.6 mL). Re-
moval of solvent under vacuum provided a residue. Without
isolation of the product, the residue was stirred with acetic
anhydride (15 mL) and concentrated sulfuric acid (0.6 mL) for
5 h before neutralization with a saturated sodium bicarbonate
solution (20 mL). The reaction mixture was then extracted
with ether (100 mL). The ethereal solution was washed with
brine, dried over sodium sulfate, filtered, and concentrated to
give 34 (232 mg, 100% yield), in which the two diastereomers
were in a ratio of 3:1. An attempt to purify the crude product
by flash chromatography led to partial decomposition of the
compound. 1H NMR (400 MHz, CDCl3, ppm): δ 1.87 (s, 3H),
2.06 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 4.25 (d, J ) 2.0 Hz,
1H), 4.84 (dd, J ) 7.6, 4.4 Hz, 1H), 5.30 (dd, J ) 8.8, 1.2 Hz,
1H), 5.43 (dd, J ) 4.0, 2.0 Hz, 1H), 5.65 (d, J ) 8.8 Hz, 1H),
5.77 (dd, J ) 7.6, 1.6 Hz, 1H), 7.26-7.38 (m, 5H). The
compound was used directly in the next reaction.
152 °C (lit.:11 152-154 °C). IR (film): 3424, 1786, 1047 cm-1
.
1H NMR (400 MHz, CDCl3 + D2O, ppm): δ 2.68 (d, J ) 18.8
Hz, 1H), 2.76 (dd, J ) 5.6, 18.8 Hz, 1H), 4.09 (dd, J ) 2.6, 4.7
Hz, 1H), 4.38 (d, J ) 2.6 Hz, 1H), 4.87 (d, J ) 4.1 Hz, 1H),
5.11 (dd, J ) 4.4, 5.0 Hz, 1H), 5.20 (d, J ) 4.7 Hz, 1H), 7.34-
7.45 (m, 5H). 13C NMR (400 MHz, CDCl3 + D2O, ppm): δ 36.1,
73.5, 74.4, 82.9, 87.4, 125.8, 128.5, 128.8, 138.7, 175.3.
Ack n ow led gm en t. The research was supported by
an NSF CAREER Award (to C.-J .L., 1998-2002). Ac-
knowledgment is also made to the donors of the Petro-
leum Research Fund (administered by the ACS), LEQSF,
and the NSF-EPA joint program for partial support of
the research. Initial examination of the regiochemistry
was carried out by Y. Q. Lu and D. T. Tran. We thank
Prof. H. Ensley for discussions.
(+)-Gon iofu fu r on e (1). To a solution of 34 (49 mg, 70%
pure) in methanol/water (9:1; 2 mL), was added sodium
bisulfite (7.1 mg) and bisodium sulfite (17.4 mg). The suspen-
sion was stirred for 3 h before quenching with 1 N hydrochloric
acid (1 mL). The mixture was then extracted with methylene
chloride (10 mL). The organic solution was washed with water
and brine, dried over magnesium sulfate, filtered, and con-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 21-23, 26, and 31;
copies of 13C NMR spectra of 15e, 19a , 20a , 29, and 33 (8
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
centrated to provide a crude product (39 mg, 70% pure).
A
solution of the crude product (39 mg, 70% pure) in methanolic
J O9815610