Radical-mediated construction of cyclopentane with concurrent formation of a well-defined quaternary center

Article abstract of DOI:10.1021/jo9822380

Synthetic efforts toward the total synthesis of clavulactone dealing with enantioselective construction of the cyclopentane moiety are reported. With a novel radical-mediated cyclization as key step, the current approach allows for concurrent enantioselective construction of a quaternary chiral carbon at the cyclization step. The stereochemistries of the newly formed chiral centers are dictated by the configuration of the C-1 (cf. numbering in 1). The high selectivity observed in this work is ascribed to the conformational advantage of the cyclic acetal, which results in a much better defined transition state than the previously used open-chain counterpart does.

Full text of DOI:10.1021/jo9822380

2428
J . Org. Chem. 1999, 64, 2428-2432
Ra d ica l-Med ia ted Con str u ction of Cyclop en ta n e w ith Con cu r r en t
F or m a tion of a Well-Defin ed Qu a ter n a r y Cen ter
Qiang Zhu, Li-Xin Qiao, Yikang Wu, and Yu-Lin Wu*,†
State Key Laboratory of Bio-organic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received November 10, 1998
Synthetic efforts toward the total synthesis of clavulactone dealing with enantioselective construction
of the cyclopentane moiety are reported. With a novel radical-mediated cyclization as key step, the
current approach allows for concurrent enantioselective construction of a quaternary chiral carbon
at the cyclization step. The stereochemistries of the newly formed chiral centers are dictated by
the configuration of the C-1 (cf. numbering in 1). The high selectivity observed in this work is
ascribed to the conformational advantage of the cyclic acetal, which results in a much better defined
transition state than the previously used open-chain counterpart does.
Sch em e 1
Clavulactone, isolated and structurally elucidated first
by us1 and later by Su2 et al., is a member of the naturally
occurring marine diterpene dolabellane3 compounds,
which are characterized by an unusual trans-bicyclo-
[9.3.0]tetradecane nucleus. Because of their remarkable
bioactivities4 and unique skeleton, this class of com-
pounds has attracted5 synthetic organic chemists’ inter-
ests over the last 5 years. Our initial effort toward the
total synthesis of clavulactone was based on the strategy
of developing a general method for the construction of
the skeleton of this type of compounds. We envisaged that
the trisubstituted cyclopentane segment 1 (Scheme 1),
with a quaternary center established at an early stage
of the synthesis, could be a key intermediate common to
many dolabellanes and other naturally occurring com-
pounds containing a similar segment.
carbocation methodologies is obvious, especially in con-
struction of sterically congested structures such as
quaternary and neopentyl centers or the fused rings.
Although radical-mediated syntheses7 of functionalized
cyclopentanes using carbohydrates as starting material
often appear in the literature, to the best of our knowl-
edge none of them allows for stereoselective construction
of a quaternary center in the radical-mediated cyclization
leading to cyclopentane framework. In this paper we wish
to disclose a chiron approach to multifunctionalized
cyclopentanes with stereoselective construction of a
quaternary carbon as the key step.
The synthesis starts from D-glucose (Scheme 2). Ferrier
rearrangement8 gave product 2, from which after steps
of transformations the radical precursor 8 was obtained
in moderate to good yields. The radical-mediated cycliza-
tion was carried out to afford the diastereomers 9a , 9b,
and 9c in a ratio of 24:53:18 in 95% total yield after
careful column chromatography on silica gel. Another
isomer 9d was not found in the reaction mixture. Because
the absolute configuration of C1 was retained from
natural glucose, the stereochemistries of these diaster-
eomers were established by 1H-1H COSY and 1H-1H
NOESY spectroscopy.
In last two decades, organic chemists have witnessed6
the prosperity of organic free radical chemistry, which
is now widely employed in the formation of C-C bonds
due to its high chemo-, regeio-, and stereoselectivity and
the advantage that the reaction can be carried out under
neutral conditions. Its superiority over carbanion or
† E-mail: YLWU@PUB.SIOC.AC.CN.
(1) Li, J .-C.; Zhang, Z.-M.; Xia, Z.-X.; Ni, C.-Z.; Wu, Y.-L. Acta Chim.
Sin. (Huaxue Xuebao) 1987, 45, 558.
(2) (a) Su, J .-Y.; Zhong, Y.-L.; Shi, K.-L.; Cheng, Q.; Snyder, J .; Hu,
S.-Z.; Huang, Y.-Q. J . Org. Chem. 1991, 56, 2337. (b) Su, J .-Y.; Zhong,
Y.-L.; Zeng, L.-M. J . Nat. Prod. 1991, 54, 380.
(3) (a) Ireland, C.; Faulkner, D. J .; Finer, J .; Clardy, J . J . Am. Chem.
Soc. 1976, 98, 4664. (b) Rao, C. B.; Pullaiah, K. C.; Surapeneni, R. K.;
Sullivan, B. W.; Albizati, K. F.; Faulkner, D. J .; Cun-heng, H.; Clardy,
J . J . Org. Chem. 1986, 51, 2736. (c) Matsuo, A.; Yoshida, K.; Uohama,
K.; Hayashi, S.; Connolly, J . D.; Sim, G. A. Chem. Lett. 1985, 935. (d)
Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye, Y. Tetrahedron
Lett. 1987, 28, 5673. (e) Rodriques, A. D. Tetrahedron 1995, 51, 4571.
(4) (a) Amico, V.; Oriente, G.; Piattelli, M.; Tringali, C.; Fattorusso,
E.; Magno, S.; Mayol, L. Tetrahedron 1980, 36, 1409. (b) Rodriguez,
A. D.; Acosta, A. C.; Dhasmana, H. J . Nat. Prod. 1993, 56, 1843.
(5) (a) Corey, E. J .; Kania, R. S. J . Am. Chem. Soc. 1996, 118, 1229.
(b) Williams, D. R.; Coleman, P. J . Tetrahedron Lett. 1995, 36, 35. (c)
J enny, L.; Borschberg, H.-J . Helv. Chim. Acta 1995, 78, 715. (d) Corey,
E. J .; Kania, R. S. Tetrahedron Lett. 1998, 39, 741. (e) Miyaoka, H.;
Isaji, Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y. Tetrahedron Lett.
1998, 39, 6503. (f) Mehta, G.; Karra, S. R.; Krishnamurthy, N.
Tetrahedron Lett. 1994, 35, 2761. (g) Kato, N.; Higo, A.; Nakanishi,
K.; Wu, X.; Takeshita, H. Chem. Lett. 1994, 1967. (h) Luker, T.;
Whiteby, R. J . Tetrahedron Lett. 1996, 37, 7661.
(7) Some examples of radical mediated substituted cyclopentane
construction: (a) RajanBabu, T. V. J . Org. Chem. 1988, 53, 4522. (b)
RajanBabu, T. V. J . Am. Chem. Soc. 1987, 109, 609. (c) RajanBabu, T.
V.; Fukunaga, T.; Reddy, G. S. J . Am. Chem. Soc. 1989, 111, 1759. (d)
RajanBabu, T. V.; Fukunaga, T. J . Am. Chem. Soc. 1989, 111, 296. (e)
RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139. (f) Rondot, B.; et al.
Tetrahedron Lett. 1993, 34, 8245. (g) Rokach, J .; Khanapure, S. P.;
Hwang, S.-W.; Adiyaman, M.; Schio, L.; FitzGerald, G. A. Synthesis
1998, 569. (h) Bennett, S. M.; Biboutou, R. K.; Zhou, Z.-H.; Pion, R.
Tetrahedron 1998, 54, 4761. (i) Molander, G. A.; Harris, C. R. J . Org.
Chem. 1997, 62, 7418. (j) Grau, A. M.; Contelles, J . M. Chem. Soc.
Rev. 1998, 27, 155.
(6) (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J .; Thoma, G.;
Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301. (b) J asperse, C. P.;
Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237.
(8) (a) Roth, W, Pigman, W. Methods Carbohydr. Chem. 1963, II,
405. (b) Ferrier, R. J ., Prasad, N. J . Chem. Soc. C 1969, 570.
10.1021/jo9822380 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

Construction of Cyclopentane and Formation of a 4° Center
J . Org. Chem., Vol. 64, No. 7, 1999 2429
Sch em e 2a
Sch em e 3a
a
Reaction conditions: (a) Ph3PdCHCOCH3, THF, rt, 45%; (b)
H2/Pd, MeOH; ethyl vinyl ether, PPTS, CH2Cl2, 2 steps, 86%; (c)
(C2H5O)2P(O)CH2CO2Et, NaH, THF; (d) 1 N HCl, THF, 2 steps,
77%; (e) CS2, DBU, MeI, DMF, 93%; (f) Bu3SnH, AIBN, benzene,
reflux, 93%.
a
Sch em e 4
Reaction conditions: (a) MeOH-Et3N-H2O; H2, Pd/C; BnBr,
NaH, DMF, 80%; (b) aqueous HCl-HOAc, 95 °C; NaBH4, MeOH,
0 °C, 89%; (c) PvCl, Py, CH2Cl2, rt, 24 h, 95%; (d) ethyl vinyl ether,
PPTS, CH2Cl2; MeLi, ether, rt, 95%; (e) Swern oxidation; MeLi,
ether; Swern oxidation, 55%; (f) (EtO)2P(O)CH2CO2Et, NaH, THF,
reflux; aqueous HCl-THF, 74%; (g) DBU, CS2, MeI, DMF, 87%,
Bu3SnH, AIBN, reflux, 94%.
The stereoselectivity is consistent with Beckwith’s9
transition-state model. The two newly formed chiral
centers in the major products 9a and 9b are in an
unwanted cis arrangement, whereas the desired product
9c is obtained only in 18% yield, presumably due to the
flexibility of the chain radical reaction precursor, which
allows for several possible approaches for the radical to
attack the double bond. Later, we tried to protect the 1,3-
dihydroxyl functionality by forming a cyclic acetal with
paraldehyde. This was expected to lead to a more rigid
(Scheme 3) transition state during the radical cyclization.
Thus 2,4-O-ethylidene-D-erythrose 10 was prepared ac-
cording to known10 methods. Wittig reaction of 10 with
triphenylphosphoranylideneacetone provided unsatur-
ated ketone 11. The radical precursor 15 was prepared
in 5 steps using common transformations in good to
excellent yields. Two diastereomers 16a and 16b were
easily isolated by column chromatography on silica gel
after radical cyclization in 75% and 18% yields, respec-
tively. The diastereoselectivity was apparently improved.
The absolute configuration of the quaternary center in
16a was also correctly established. However, another
newly formed chiral center was of undesired configura-
tion. In fact the two rings are always cis fused, so that
the vicinal configuration is only decided by the hydroxyl
configuration at C-1.
formed according to literature11 procedures. Except for
hydrogenation of 18 and the following hydroxyl protection
as the vinyl ethyl ether, moderate to good yields were
obtained when similar reaction conditions were applied.
The unexpected poor yields were due to incomplete
reactions and formation of unidentified byproducts, prob-
ably because the hydroxyl group was in the axial position
in the chairlike conformation of the 1,3-dioxane. The
result of the radical cyclization was very surprising; only
one product was isolated and the yield was over 88%! The
good selectivity and yield are quite unusual in radical
chemistry. Although the two side chains are still cis
(instead of trans as we wished) to each other and with
the quaternary center of undesired configuration, it
should have great potential in asymmetric synthesis of
some other target molecules.
We chose D-galactose as the starting material (Scheme
4); the configuration of the 4-hydroxyl is opposite to that
in D-glucose. 2,4-O-Ethylidene-D-threose 17 was trans-
On the basis of the results of the two routes, possible
transition states were postulated to explain the high
stereoselectivity and the difference between them. As we
know, the transition state of the radical reaction is early,
reactant-like because of the high reactivity of radical. The
(9) (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073. (b) Beckwith,
A. L. J .; Easton, J . C.; Lawrence, T.; Serelis, A. K. Aust. J . Chem. 1983,
36, 545.
(10) Barker, R.; MacDonnald, D. L. J . Am. Chem. Soc. 1960, 82,
2301.
(11) (a) Ball, D. H.; J ones, J . K. N. J . Chem. Soc. 1958, 905. (b) Ball,
D. H. J . Org. Chem. 1966, 31, 220.

2430 J . Org. Chem., Vol. 64, No. 7, 1999
Zhu et al.
Sch em e 5
design better precursors (with two correct chiral centers)
to the desired product.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Flash column
chromatography was performed on silica gel H (10-40 µm)
and with a petroleum ethe-ethyl acetate system as eluant.
Microanalyses were carried out in the Microanalytical Labora-
tory at Shanghai Institute of Organic Chemistry.
(2R ,3S ,6S )-6-E t h o x y -3-p h e n y lm e t h o x y -2-p h e n y l-
m eth oxym eth yltetr a h yd r op yr a n (3). To a solution of tri-
acetyl glycal (81.6 g 0.30 mol) in benzene (280 mL) were added
absolute ethanol (30 mL) and BF3‚Et2O (12.1 mL).8 The
reaction mixture was stirred at 35 °C for 2.5 h. Anhydrous
sodium carbonate (27 g) was added, and the stirring was
continued for an additional 0.5 h. The reaction mixture was
filtered and concentrated under reduced pressure to give 2.
Methanol (650 mL), triethylamine (180 mL), and water (320
mL) were added to the residue, and the mixture was stirred
at room temperature for 18 h. The solvent was evaporated
under reduced pressure with addition of toluene (200 mL ×
4). To the solution of the resulting residue in ethyl acetate (500
mL) was added Pd/C (5%, 1.0 g). The mixture was treated with
atmospheric hydrogen at room temperature until no more
hydrogen was consumed. The catalyst was filtered off, and the
solvent was removed under reduced pressure. DMF (200 mL)
was added to the residue, followed by a suspension of NaH
(80%, 21.6 g) in DMF (300 mL) at 0 °C. When the evolution of
hydrogen stopped, a solution of benzyl bromide (85 mL 0.66
mol) in DMF (100 mL) was added dropwise and the mixture
was stirred overnight. The reaction mixture was poured into
water, extracted with ethyl ether, washed with water and
brine, dried (Na2SO4), and then concentrated. Triethylamine
(100 mL) was added to the residue, and the mixture was
heated to reflux for 1 h to destroy excess benzyl bromide. The
cooled reaction mixture was diluted with ethyl ether, washed
with water and brine, dried (Na2SO4), and concentrated to give
Sch em e 6
light yellow liquid 3 (85 g, 80% from triacetyl D-glycal): [R]20
D
+101.3 (c 0.99, CHCl3). 1H NMR (CDCl3, 300 MHz): 7.21-
7.36 (m, 10H), 4.84 (d, 1H, J ) 2.9 Hz), 4.40-4.70 (m, 4H),
3.76 (d, 2H, J ) 6.0 Hz), 3.69 (q, 2H, J ) 7.1 Hz), 3.44-3.49
(m, 2H), 1.80-2.00 (m, 4H), 1.21 (t, 3H, J ) 7.1 Hz). IR (film):
2950, 2850, 1455, 1130, 1090, 1060, 1030, 990, 740, 700 cm-1
.
EIMS: 255 (M - CH2Ph), 236, 219, 149, 129, 115, 105, 91.
R,â-unsaturated ester of 15 has two possible conforma-
tions relative to the chairlike 1,3-dioxane, endo and exo.
In the endo conformation, the vinyl methyl and the 1,3-
dioxygen atoms have spatial repulsion, thereby favoring
exo conformation, which results in 16a as the major
product (Scheme 5).
The situation in 22 is quite different. The thioester
group is probably too bulky to be in the axial position. It
is more likely that the 1,3-dioxane now assumes a boat-
like conformation. In this case, the endo conformation is
highly disfavored because of the strong steric interaction
between the vinyl methyl and the hydrogen atom. Such
an interaction can be avoided in the exo conformation,
which results in product 23 only (Scheme 6).
(2R,3S)-1,3-Dip h en ylm eth oxy-2,6-h exa n ed iol (4). A so-
lution containing 3 (85 g 0.24 mol), acetic acid (800 mL), and
1 N HCl (200 mL) was heated under reflux for 3 h before being
cooled, extracted with CH2Cl2, washed with water, saturated
aqueous NaHCO3 and brine, and dried (CaCl2). Removal of
the solvent under reduced pressure and flash chromatography
on silica gel gave the product and a small amount of recovered
reactant. The above procedure was repeated to give combined
product (61.8 g, 79%) after one cycle. To the solution of the
above product in methanol (500 mL) was added sodium
borohydride (30 g) at 0 °C. Stirring was continued for 2 h before
being quenched by adding diluted HCl. The mixture was
extracted with CH2Cl2 and dried (Na2SO4). Removal of the
solvent under reduced pressure followed by flash chromatog-
raphy on silica gel (1:1 petroleum ether/EtOAc) gave 4 (55 g,
89%): [R]20 +9.6 (c 0.40, CHCl3). 1H NMR (CDCl3, 300
D
It appears that making the chain conformation more
rigid by protecting the chain as a cyclic acetal is an
effective way to enhance the stereoselectivity at the
radical cyclization step. This effect is fully manifested in
the D-galactose case, where practically only one isomer
is formed. Although the latter two approaches of the three
we have examined afforded products with only one of the
two newly formed chiral centers in the desired configu-
ration, compound 16a and its enantiomer 23 can serve
as very useful building blocks for other synthetic tar-
gets. Based on the knowledge gained from this work,
especially the possible transition states, we are able to
MHz): δ 7.27-7.36 (m, 10H), 4.56, 4.55 (s, s; 2H, 2H), 3.91
(m, 1H), 3.67-3.53 (m, 5H), 2.00 (s, 2H), 1.68-1.76 (m, 4H).
IR (film): 3400, 1080, 740, 700 cm-1. EIMS: 331 (M + 1), 221,
181, 179, 133, 107, 91, 71.
(2R,3S)-2-(1-Eth oxyeth oxy)-1,3-diph en ylm eth oxy-6-h ex-
a n ol (6). To a solution of 4 (55 g, 0.15 mol) in CH2Cl2 (200
mL) were added pyridine (18 mL, 0.23 mol) and PvCl (22.7
mL, 0.19 mol). The reaction mixture was stirred for 24 h and
then quenched by addition of 1 N HCl (100 mL). The mixture
was washed with saturated aqueous NaHCO3 and brine and
then dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was dissovled in CH2-
Cl2 (500 mL). Ethyl vinyl ether (30 mL, 0.31 mol) and PPTS

Construction of Cyclopentane and Formation of a 4° Center
J . Org. Chem., Vol. 64, No. 7, 1999 2431
(200 mg) were added at 0 °C. The solution was warmed to room
temperature and stirred for 3 h. The reaction mixture was
washed with brine, dried (MgSO4), and then concentrated
under reduced pressure. To the solution of the residue in ethyl
ether (500 mL) was added dropwise methyllithium (180 mL,
1.68 M, 0.30 mol) at -78 °C with vigorous mechanical stirring.
The reaction mixture was stirred at this temperature for 3 h
and then allowed to warm to room temperature. The solution
was washed with brine and dried (Na2SO4). Removal of the
solvent under reduced pressure followed by flash chromatog-
raphy on silica gel (3:1 petroleum ether/EtOAc) gave 6 (51 g,
85% from 4). 1H NMR (300 MHz, CDCl3): δ 7.27-7.33 (m,
10H), 4.86 (m, 3/8 H), 4.64-4.68 (m, 5/8 H), 4.55 (m, 4H), 3.91
(m, 1H), 3.45-3.73 (m, 7H), 1.62-1.76 (m, 5H), 1.11-1.36 (m,
6H). IR (film, neat): 3400, 1080, 740, 700 cm-1. EIMS: 181,
167, 149), 133, 115, 107, 105, 91. Anal. Calcd for C24H34O5: C,
71.61; H, 8.51. Found: C, 71.51; H, 8.72.
(5S,6R)-6-(1-Eth oxyeth oxy)-5,7-diph en ylm eth oxy-2-h ep-
ta n on e (7). A solution of oxalyl chloride (14.5 mL, 0.166 mol)
in dry CH2Cl2 (100 mL) was cooled to -60 °C before a solution
of DMSO (22.5 mL, 0.31 mol) in dry CH2Cl2 (60 mL) was
introduced slowly. After stirring for 30 min, a solution of 6 in
dry CH2Cl2 (100 mL) was added dropwise. The mixture was
stirred at -60 °C for 2 h. A solution of triethylamine (100 mL)
in CH2Cl2 (100 mL) was added. The reaction mixture was
allowed to warm to room temperature slowly and stirred for
an additional 2 h before being poured into water (200 mL),
washed with saturated a NH4Cl solution and brine, dried (Na2-
SO4), and evaporated to give the crude aldehyde. To a solution
of the aldehyde in diethyl ether (200 mL) was added methyl-
lithium (110 mL, 1.68 M) at 0 °C with vigorous stirring. The
solution was stirred for 2 h and quenched by addition of a
saturated NH4Cl solution (100 mL). The mixture was washed
with brine and dried (Na2SO4). After removal of the solvent,
the residue was subjected to Swern oxidation again as
described above. After purification by flash chromatography
on silica gel (5:1 petroleum ether/EtOAc), 7 (28.6 g, 55% from
6) was obtained. 1H NMR (300 MHz, CDCl3): δ 7.27-7.33 (m,
10H), 4.87 (m, 1H), 4.41-4.65 (m, 4H), 3.92 (m, 1H), 3.45-
3.72 (m, 5H), 2.50 (m, 2H), 2.04 (d, 3H, J ) 3.5 Hz), 1.83 (m,
2H), 1.32 (m, 3H), 1.14 (q, 3H, J ) 7.0 Hz). IR (film, neat):
1715, 1080, 740, 700 cm-1. EIMS: 325 (M - CH2Ph), 191, 233,
181, 112, 107, 105, 91. Anal. Calcd for C25H34O5: C, 72.09; H,
8.71. Found: C, 72.40; H, 8.47.
(6S,7R,E)-7-Hyd r oxy-3-m eth yl-6,8-d ip h en ylm eth oxy-2-
octen oic Acid Eth yl Ester (8). To the suspension of NaH
(4.2 g, 80%, 0.14mol) in THF (50 mL) was added a solution of
triethyl phosphonoacetate (28 mL, 0.14 mol) in THF (50 mL)
dropwise at 0 °C. The mixture was stirred until it turned
transparent. A solution of 7 (28.3 g) in THF (100 mL) was
added, and the stirring was continued for an additional 48 h
at room temperature. The reaction mixture was diluted with
diethyl ether, washed with water and brine, and dried (Na2-
SO4). Removal of the solvent under reduced pressure followed
by flash chromatography on silica gel (10:1 petroleum ether/
EtOAc) gave a light yellow liquid, which was dissolved in THF
(100 mL) and then treated with 1 N HCl (150 mL). The
solution was stirred at room temperature for 6 h, before being
diluted with diethyl ether. The ether layer was washed with
a saturated NaHCO3 solution and brine and dried (Na2SO4).
Removal of the solvent under reduced pressure followed by
flash chromatography on silica gel (5:1 petroleum ether/EtOAc)
gave a colorless liquid, 18.4 g (74%): [R]20D 4.87 (c 0.60, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.31 (m, 10H), 5.65 (d, 1H, J )
1.0 Hz), 4.54 (m, 4H), 4.13 (q, 2H, J ) 7.1 Hz), 3.89 (m, 1H),
3.61 (m, 2H), 3.50 (m, 1H), 2.28 (m, 2H), 2.16 (bs, 1H), 2.14
(d, 3H, J ) 1.0 Hz), 1.78 (m, 2H), 1.29 (t, 3H, J ) 7.1 Hz). IR
(film, neat): 1710, 1640, 1100, 740, 700 cm-1. EIMS: 413 (M +
1), 367, 275, 215, 181, 169, 125, 91. Anal. Caldcd for
added CS2 (21 mL) and DBU (14.0 mL, 87.4 mmol) at 0 °C.
The solution was allowed to warm to room temperature and
stirred for 2 h before the addition of MeI (22 mL) at 0 °C. The
reaction mixture was stirred at room temperature for an
additional hour, followed by addition of 1 N HCl (100 mL),
extracted with diethyl ether, washed with water and brine,
and then dried (Na2SO4). Removal of the solvent under reduced
pressure followed by flash chromatography on silica gel (20:1
petroleum ether/EtOAc) gave a light yellow liquid, 19.1 g
(87%). To the solution of the thioester (19.1 g) and AIBN (160
mg) in benzene (300 mL) was added dropwise a solution of
Bu3SnH (15.8 mL, 57 mmol) in benzene (50 mL) under reflux.
The reaction was cooled after refluxing for 3 h. A saturated
KF solution (50 mL) was added, and the mixture was stirred
for another 2 h. The reaction mixture was extracted with
diethyl ether, washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. Flash chromatography on silica
gel of the residue (40:1 petroleum ether/EtOAc) gave 9a (3.67
g, 24%), 9b (7.98 g, 53%), and 9c (2.75 g, 18%).
(1S,2S,3S)-9 (9a ): [R]20 +32.4 (c 0.82, CHCl3). 1H NMR
D
(600 MHz,CDCl3): δ 7.28-7.31 (m, 10H), 4.57, 4,37 (d, d; 1H,
1H; J ) 12.1, 12.1 Hz), 4.51 (s, 2H), 4.10 (m, 3H), 3.76 (t, 1H,
J ) 8.7 Hz), 3.56 (dd, 1H, J ) 5.6 Hz, 9.0 Hz, OCH), 2.68,
2.15 (dd, AB system, 2H, J ) 14.1 Hz), 2.15 (m, 1H), 1.85-
1.91 (m, 3H), 1.42 (m, 1H), 1.24 (t, 3H, J ) 7.1 Hz), 1.20 (s,
3H). 13C NMR (75 MHz, CDCl3): 173.0, 139.4, 138.8, 128.4 ×
2, 128.3 × 2, 127.6 × 2, 127.5 × 2, 127.3 × 2, 81.4, 73.4, 71.1,
66.9, 59.9, 55.8, 41.8, 40.9, 37.1, 29.9, 27.1, 14.4. IR (film, neat):
2900, 1730, 1100, 1030, 740, 700 cm-1. CIMS: 425 (M+ + 29),
397 (M+ + 1), 351, 289, 199, 181, 107, 91. Anal. Calcd for
C
25H32O4: C, 75.73; H, 8.13. Found: C, 75.88; H, 8.16.
(1R,2R,3S)-9 (9b): [R]20D +46.8 (c 1.0, CHCl3). 1H NMR (600
MHz, CDCl3): δ 7.30-7.33 (m, 10H), 4.43-4.53 (dd, 2H, AB
system, J ) 11.9 Hz), 4.49-4.45 (dd, 2H of AB system, J )
11.8 Hz), 4.09 (q, 2H, J ) 7.1 Hz), 3.89 (m, 1H), 3.55 (d, 2H,
J ) 6.3 Hz), 2.32-2.23 (dd, 2H of AB system, J ) 14.0 Hz),
2.03 (m, 2H), 1.81 (m, 1H), 1.74 (CH), 1.61(m, 1H), 1.25 (m,
6H). IR (film, neat): 2900, 1730, 1100, 1030, 740, 700 cm-1
.
CIMS: 425 (M + 29, 6.97), 395 (M - 1, 1.25), 351 (3.47), 289
(100, M - OBn), 191(28.9), 107 (110.1), 91 (22.6).
(1S,2R,3S)-9 (9c): [R]20 +31.0 (c 1.61, CHCl3). 1H NMR
D
(600 MHz,CDCl3): δ 7.31-7.34 (m, 10H), 4.53, 4.43 (dd, 2H
of AB system, J ) 11.9 Hz), 4.51-4.48 (dd, 2H of AB system,
J ) 12.0 Hz), 4.10 (q, 2H, J ) 7.2 Hz), 3.78 (m, 1H), 3.56 (m,
2H), 2.66, 2.37 (dd, 2H of AB system, J ) 14.0 Hz), 2.16 (q,
1H, J ) 7.0 Hz), 1.59 (m, 2H), 1.74 (m, 1H), 1.58 (m, 1H), 1.25
(t, 3H, J ) 7.2 Hz), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 172.38, 139.09, 138.81, 128.35 × 2, 128.05 × 2, 127.66 × 2,
127.57 × 2, 127.45 × 2, 82.68, 73.19, 71.34, 69.85, 59.91, 54.33,
47.03, 37.60, 29.62, 21.05, 14.38. IR (film, neat): 2900, 1730,
1100, 1030, 740, 700 cm-1. EIMS: 397 (M + 1, 3.61), 307 (2.26),
289 (7.81), 275 (3.70), 261 (5.36), 243 (5.67), 199 (17.91), 181
(34.78), 153 (25.96), 122 (39.65), 105 (95.36), 91(100).
(2R,4S,5R)-4-(3-Bu ten on e-1-yl)-5-h yd r oxy-2-m eth yl-1,3-
d ioxa n e (11). To the solution of aldehyde 10 (36 g, 0.25 mol)
in THF (700 mL) was added triphenylphosphoranylideneac-
etone (94 g, 0.31 mol). The reaction was stirred for 8 h at room
temperature before being refluxed for an additional 5 h. The
solvent was removed under reduced pressure. To the residue,
water was added with vigorous stirring for 10 min and then
filtered. The residue was extracted for another 2 to 3 times.
The combined filtrate was evaporated under reduced pressure
below 45 °C. The residue was dried under vacuum followed
by flash chromatography on silica gel (3:1 petroleum ether/
EtOAc) to give 11 (20.7 g, 45%, E:Z ) 2:1).
Z-11: [R]17 + 49.5 (c 1.59, EtOH). 1H NMR (300 MHz,
D
CDCl3): δ 6.45 (d, 1H, J ) 11.8 Hz), 6.07 (dd, 1H, J ) 11.8,
8.0 Hz), 4.65 (q, 1H, J ) 5.0 Hz), 4.61 (dd, 1H, J ) 8.0, 1.4
Hz), 4.17 (m, 2H), 3.44 (m, 1H), 3.42 (s, 1H), 2.28 (s, 3H), 1.28
(d, 3H, J ) 5.0 Hz). IR (KBr): 3480, 1682, 1402, 1193, 1161,
1136 cm-1. EIMS: 187 (M + 1, 6.73), 169 (100.00), 143 (10.31),
125 (53.27), 109 (41.80), 100 (60.82), 87 (63.06).
C
25H32O5: C, 72.79; H, 7.82. Found: C, 73.08; H, 7.83.
(Characterization of other minor components in the product
mixture was not attempted.)
1-Meth yl-3-p h en ylm eth oxy-2-p h en ylm eth oxym eth yl-
cyclop en ta n ea cetic Acid Eth yl Ester (9). To a solution of
the above alcohol (18.0 g, 43.7 mmol) in DMF (100 mL) were
E-11: [R]17 -80.3 (c 1.61, EtOH). 1H NMR (300 MHz,
D
CDCl3): δ 6.89 (dd, 1H, J ) 16.0, 4.6 Hz), 6.35 (dd, 1H, J )
16.0, 1.5 Hz), 4.71 (q, 1H, J ) 5.0 Hz), 4.11 (m, 1H), 3.99 (m,

2432 J . Org. Chem., Vol. 64, No. 7, 1999
Zhu et al.
1H), 3.45 (m, 3H), 2,25 (s, 3H), 1.32 (d, 3H, J ) 5.0 Hz). IR
(film, neat): 3440, 1676, 1410, 1161, 1117, 1065 cm-1. EIMS:
186 (M+, 8.66), 169 (69.08), 141 (16.18), 125 (25.96), 109
(13.47), 97 (55.16), 43 (100.00). Anal. Calcd for C9H14O4: C,
58.05; H, 7.58. Found: C, 58.05; H, 7.78.
(2R,4S,5R)-5-(1-E t h oxyet h oxy)-4-(3-b u t a n on e-1-yl)-2-
m eth yl-1,3-d ioxa n e (12). Hydrogenation (following the same
procedure described for 3, except in this case methanol was
used as a solvent) and EE protection (following the procedure
for 6) of the hydroxyl group of 11 (15.0 g, 81 mmol) gave 12
(18.0 g, 86% from 11). 1H NMR (300 MHz, CDCl3): δ 4.66,
4.62 (q, q; 1H; J ) 5.2, 5.2 Hz), 4.55 (q, 1H, J ) 5.1 Hz), 4.13
(m, 1H), 3.18-3.63 (m, 5H), 2.37-2.66, 1.97-2.17, 1.55-1.69
(m, 4H), 2.08 (s, 3H), 1.22 (d, 6H, J ) 5.2 Hz), 1.12, 1.11 (t, t;
3H; J ) 7.1, 7.1 Hz). IR (film, neat): 2990, 2956, 2855, 1717,
1412, 1381, 1370, 1151, 1096, 1061 cm-1. EIMS: 207, 141, 125,
77, 73.
(2R,4S,5R,E)-5-Hyd r oxy-4-((3-m eth yl-2-p en ten oic a cid
eth yl ester )-5-yl)-2-m eth yl-1,3-d ioxa n e (14). Wittig-Horn-
ner reaction (following the procedure described for 8) of 12
(15.0 g, 57.7 mmol) followed by removal of EE gave 14, 11.5 g
(77% from 12): [R]17D -47.4 (c 1.49, EtOH). 1H NMR (300 MHz,
CDCl3): δ 5.68 (s, 1H), 4.64 (q, 1H, J ) 5.1 Hz), 4.13 (q, 2H,
J ) 7.1 Hz), 4.08 (m, 1H), 3.49-3.23 (m, 3H), 2.50-2.48,
2.38-1.97, 1.69-1.55 (m, m, m; 1H, 2H, 1H), 2.16 (s, 3H),
1.31 (d, 3H, J ) 5.0 Hz), 1.26 (t, 3H, J ) 7.1 Hz). IR (KBr):
3516, 2991, 2977, 2941, 2916, 2874, 1701, 1646, 1452, 1415,
1236, 122 cm-1. EIMS: 259 (M + 1, 11.74), 213 (100.00), 197
(8.96), 171 (36.46), 151 (41.59), 125 (47.06). Anal. Calcd for
2872, 1732, 1649, 1462, 1409 cm-1. EIMS: 241 (M - 1, 6.08),
227 (24.78), 197 (44.28), 181 (96.75), 169 (16.42), 153 (94.97),
107 (100.00).
(2S,4R,5R)-4-(3-Bu ten on e-1-yl)-5-h yd r oxy-2-m eth yl-1,3-
d ioxa n e (18). Treatment of 17 (following the procedure for
preparing for 11) gave 18 as an E,Z mixture in 75% total yield.
IR (film): 3379, 1678, 1667, 1453, 1411, 1363 cm-1. EIMS: 187
(M+ + 1, 2.89) 169 (5.12) 143 (8.03) 125 (16.25) 43 (100.00).
Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.25;
H, 7.72.
(2S,4R,5R,E)-5-Hyd r oxy-4-((3-m eth yl-2-p en ten oic a cid
eth yl ester )-5-yl)-2-m eth yl-1,3-d ioxa n e (21). Hydrogenation
of 18 (2.6 g, 14 mmol) in methylene dichloride (100 mL) was
performed in the presence of Pd/C (10%, 300 mg). After
removal of Pd/C, concentration of the filtrate, followed by
purification on silica gel, gave 1.84 g (70%) of the saturated
ketone. Protection of the hydroxy group with vinyl ethyl ether
following the procedure for preparing 6 yielded intermediate
19 in only 59% yield after flash chromatography on silica gel.
The relatively low yield was due to the incomplete conversion
of the starting material and the acetal formation as byproduct.
The separated acetal was hydrolyzed with 1 N HCl in THF to
give the starting material in a total yield of 40% (together with
the unreacted one recovered from the above chromatography).
Wittig-Hornner reaction of 19 with triethyl phosphonoacetate
followed by deprotection with 1 N HCl in THF gave 21 in 77%
yield (following the procedure for preparing 8 and 14). 21:
[R]25 -14.0 (c 1.77, CHCl3). 1H NMR (300 MHz, CDCl3): δ
D
5.67 (q, 1H, J ) 1.1 Hz), 4.71 (q, 1H, J ) 5.1 Hz), 4.11 (q, 2H,
J ) 7.0 Hz), 4.03, 3.82 (d, d; 1H, 1H; J ) 11.9, 11.9 Hz), 3.60
(m, 1H), 3.33 (s, 1H), 2.15 (s, 3H), 2.20-2.10, 1.90-1.60 (m,
4H), 1.33 (d, 3H, J ) 5.2 Hz), 1.26 (t, 3H, J ) 7.2 Hz). IR:
3485, 1714, 1648, 1449 cm-1. EIMS: 259 (M+ + 1, 100.00) 241
(2.83) 213 (47.21) 197 (12.96). Anal. Calcd for C13H22O5: C,
60.45; H, 8.58. Found: C, 60.71; H, 8.70.
C
13H22O5: C, 60.45; H, 8.58. Found: C, 60.18; H, 8.75.
(2R,4S,5R,E)-2-Met h yl-5-(m et h ylt h io)t h ioca r b on yl-4-
((3-m eth yl-2-p en ten oic a cid eth yl ester )-5-yl)-1,3-d ioxa n e
(15). Treatment of 14 following the procedure for preparing
the precursor for 9 gave 15 (93%) as a light yellow syrup: [R]17
D
1
-40.2 (c 1.71 EtOH). H NMR (300 MHz, CDCl3): δ 5.67 (s,
1H), 5.48 (m, 1H), 4.70 (q, 1H, J ) 5.1 Hz), 4.36 (1H, dd, J )
10.7, 5.3 Hz), 4.14 (q, 2H, J ) 7.1 Hz), 3.69 (dt, 1H, J ) 9.1,
3.0 Hz), 3.44 (t, 1H, J ) 10.3 Hz), 2.56 (s, 3H), 2.36, 2.21, 1.80,
1.68 (m, m, m, m; 1H, 1H, 1H, 1H), 2.15 (d, 3H, J ) 1.1 Hz),
1.34 (d, 3H, J ) 5.0 Hz), 1.27 (t, 3H, J ) 7.1 Hz). IR (film,
neat): 2863, 1716, 1650, 1412, 1375, 1212, 1149, 1119, 1068
cm-1. EIMS: 349 (M + 1, 11.82), 305 (24.35), 287 (4.45), 259
(100.00), 241 (10.04), 197 (68.59), 151 (53.67). (Characteriza-
tion of other minor components in the product mixture was
not attempted.)
(2S,4R,5R,E)-5-(Meth ylth io)th ioca r bon yl-4-((3-m eth yl-
2-p en t eoic a cid et h yl est er )-5-yl)-2-m et h yl-1,3-d ioxa n e
(22). Treatment of 21 following the procedure for preparing
the precursor for 9 gave 22 (74%) as a light yellow syrup: [R]23
D
1
-28.2 (c 1.58, EtOH). H NMR (300 MHz, CDCl3): δ 5.66 (q,
1H, J ) 1.2 Hz), 5.50 (t, 1H, J ) 1.5 Hz), 4.78 (q, 1H, J ) 5.0
Hz), 4.29 (dd, 1H, J ) 13.1, 1.5 Hz), 4.14 (q, 2H, J ) 7.2 Hz),
3.90 (dd, 1H, J ) 13.2, J ) 1.6 Hz), 3.82 (dt, 1H, J ) 5.2, J )
1.5 Hz), 2.59 (s, 3H), 2.15 (s, 3H), 2.30-2.10, 1.90-1.60 (m,
4H), 1.38 (d, 3H, J ) 5.0 Hz), 1.27 (t, 3H, J ) 7.1 Hz). IR:
1714, 1650, 1447, 1413 cm-1. EIMS: 349 (M+ + 1) 348 (M+ ),
347 (M+ - 1) 315, 302. Anal. Calcd for C15H24O5S2: C, 51.70;
H, 6.94. Found: C, 51.76; H, 6.93. (Characterization of other
minor components in the product mixture was not attempted.)
Ra d ica l-Med ia ted Cycliza tion of 22 (23). Treatment of
22 (following the procedure for preparing for 9) gave 23 as
the only product (88% yield obtained after purification twice
on silica gel). The 1H NMR and IR spectra were absolutely
identical with those of 16a . 23: [R]22D -7.1 (c 1.98, EtOH). Anal.
Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C, 64.02; H,
8.90.
R a d ica l-Med ia t ed Cycliza t ion of 15 (16a a n d 16b ).
Treatment of 15 following the procedure for preparing for 9
gave 16a (75%) and 16b (15%).
16a : a colorless oil; [R]27D +9.3 (c 1.25, EtOH). 1H NMR (300
MHz, CDCl3): δ 4.61 (q, 1H, J ) 5.1 Hz), 4.22 (dt, 1H, J )
5.3, 1.2 Hz), 4.10 (q, 2H, J ) 7.1 Hz), 4.08 (d, 1H, J ) 12.1
Hz), 3.95 (dd, 1H, J ) 12.6, 4.4 Hz), 2.84, 2.42 (d, d; 1H, 1H;
J ) 4.8, J ) 4.8 Hz), 2.24, 1.96, 1.78, 1.37 (m, m, m, m; 1H,
1H, 1H, 1H), 1.25 (d, 3H, J ) 5.4), 1.24 (t, 3H, J ) 7.2 Hz),
1.23 (m, 1H), 1.12 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 14.29,
21.26, 26.38, 30.56, 37.16, 41.63, 41.88, 48.55, 59.72, 64.21,
79.57, 97.27, 173.04. IR (film, neat): 2956, 2872, 1732, 1454,
1407, 1369, 1325 cm-1. EIMS: 243 (M + 1, 5.84), 213 (6.52),
196 (89.39), 181 (13.68), 171 (49.55), 151 (47.00), 141 (35.03),
95 (100.00). Anal. Calcd for C13H22O4: C, 64.44; H, 9.15.
Found: C, 64.35; H, 9.36.
Ack n ow led gm en t. This project was supported by
a grant from the National Natural Science Foundation
of China (No. 29132038). We thank Prof. Hou-Ming Wu
for helpful discussions about the configuration.
16b: a colorless oil; [R]27 +12.6 (c 1.64, EtOH). 1H NMR
D
(300 MHz, CDCl3): δ 4.61 (q, 1H, J ) 5.1 Hz), 4.21 (m, 1H),
4.09 (q, 2H, J ) 7.0 Hz), 4.08 (d, 1H, J ) 12.9 Hz), 3.96 (dd,
1H, J ) 12.5, 4.3 Hz), 2.32, 2.21 (d, d; 1H, 1H; J ) 13.8, 13.8
Hz), 1.88-1.68 (m, 4H), 1.54 (t, 1H, J ) 4.3 Hz), 1.29 (s, 3H),
1.26 (d, 3H, J ) 5.1 Hz), 1.23 (t, 3H, J ) 7.1 Hz). 13C NMR (75
MHz, CDCl3): δ 14.27, 21.34, 24.61, 30.55, 38.82, 41.49, 44.89,
47.33, 60.08, 64.88, 79.95, 97.21, 172.22. IR (film): 2989, 2939,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
9a , 9b, 9c, 16a , 16b, and 23. 13C NMR spectra of 9a , 9c, 16a ,
and 16b. NOESY and COSY spectra of 9a , 9b, and 9c. NOE
difference spectra of 16a and 16b. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9822380