Catalytic enantioselective synthesis of (-)-prostaglandin E1 methyl ester based on a tandem 1,4-addition-aldol reaction

Article abstract of DOI:10.1021/jo025987x

Catalytic enantioselective 1,4-additions and tandem 1,4-addition-aldol reactions of dialkylzinc reagents to cyclopentene-3,5-dione monoacetals in the presence of an in situ generated Cu(OTf)₂/chiral phosphoramidite catalyst result in highly functionalized cyclopentane building blocks with ee's up to 97%. A new synthesis of cyclopentene-3,5-dione monoacetals is presented as well as its use in a tandem 1,4-addition-aldol protocol for the catalytic asymmetric total synthesis of (-)-PGE₁ methyl ester. This synthesis represents a new approach to this class of natural products. By using only 3 mol % of an enantiomerically pure catalyst in the key step, the absolute configurations at three stereocenters of the basic structure of the PGE₁ are established at once.

Full text of DOI:10.1021/jo025987x

Ca ta lytic En a n tioselective Syn th esis of (-)-P r osta gla n d in E1
Meth yl Ester Ba sed on a Ta n d em 1,4-Ad d ition -Ald ol Rea ction
Leggy A. Arnold, Robert Naasz, Adriaan J . Minnaard, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
feringa@chem.rug.nl
Received May 29, 2002
Catalytic enantioselective 1,4-additions and tandem 1,4-addition-aldol reactions of dialkylzinc
reagents to cyclopentene-3,5-dione monoacetals in the presence of an in situ generated Cu(OTf)2/
chiral phosphoramidite catalyst result in highly functionalized cyclopentane building blocks with
ee’s up to 97%. A new synthesis of cyclopentene-3,5-dione monoacetals is presented as well as its
use in a tandem 1,4-addition-aldol protocol for the catalytic asymmetric total synthesis of (-)-
PGE1 methyl ester. This synthesis represents a new approach to this class of natural products. By
using only 3 mol % of an enantiomerically pure catalyst in the key step, the absolute configurations
at three stereocenters of the basic structure of the PGE1 are established at once.
In tr od u ction
cally active enone 1 is treated with a functionalized
cuprate prepared from chiral vinyl iodide 2 and the in
situ generated enolate is trapped with aldehyde 3 as
electrophile.9 This sequence provides a convenient way
to introduce simultaneously the R and ω side chains
necessary for the elaborations into (-)-PGE1 5.
The versatility of organocopper reagents10 and the
possibility of enolate trapping resulting in R-functional-
ization11 (exemplified in Scheme 1), makes the 1,4-
addition one of the most versatile carbon-carbon bond
formation reactions in organic synthesis.12 In the past
decade, considerable progress has been achieved in the
development of a catalytic enantioselective 1,4-addition
to enones.13 In the copper-catalyzed 1,4-addition of di-
alkylzinc reagents to enones, full stereocontrol has been
observed using phosphoramidites as simple chiral ligands
for copper.14 The reaction of 6-, 7-, and 8-membered
2-cycloalkenones and (functionalized) dialkylzinc (R2Zn)
reagents gave, in the presence of 1 mol % of an in situ
prepared catalyst based on Cu(OTf)2 and phosphoramid-
Prostaglandins (PGs) belong to the family of polyoxy-
genated fatty acids that are produced by a cyclooxygenase
enzyme system widely distributed in mammalian tissue.1
Their biological functions are restricted locally because
of the rapid metabolism, but nevertheless, their phar-
macological effects are so diverse that they have become
the subjects of intensive research for the past decades.2
Several synthetic prostaglandin derivatives are currently
used as drugs, but their synthesis is often still the subject
of considerable improvement and innovation.3 Synthetic
routes are largely based on three strategies, the Corey
synthesis,4 the two-component coupling,5 and the three-
component coupling,6 although a number of other ap-
proaches have been reported.7 The latter method, devel-
oped by Noyori,8 is particular attractive because of the
limited number of steps in this convergent synthetic
approach. The key step of this route is the tandem 1,4-
addition-enolate-trapping reaction (Scheme 1). The opti-
(1) (a) Needleman, P.; Isakson, P. C. J . Rheumatol. 1997, 24, 6. (b)
Masferrer, J . L.; Seibert, K.; Zweifel, B.; Needleman, P. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 3917.
(2) Marks, F.; Fu¨rstenberger, G. Prostaglandins, Leukotrienes and
other Eicosanoids. From Biogenesis to Clinical Applications; Wiley-
VCH: Weinheim, 1999.
(3) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533.
(4) (a) Corey, E. J .; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J . Am. Chem. Soc. 1969, 91, 5675. (b) Corey, E. J .; Ensley, H. E. J .
Am. Chem. Soc. 1975, 97, 6908.
(5) (a) Alvarez, F. S.; Wren, D.; Prince, A. J . Am. Chem. Soc. 1972,
94, 7823. (b) Kluge, A. F.; Untch, K. G.; Fried, J . H. J . Am. Chem. Soc.
1972, 97, 7827. (c) Babiak, K. A.; Ng, J . S.; Dygos, J . H.; Weyker, C. L.
J . Org. Chem. 1990, 55, 3377.
(6) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn
Wiley & Sons: New York, 1994.
(7) (a) Corey, E. J .; Cheng, X.-M. The Logic of Chemical Synthesis;
J ohn Wiley & Sons: New York, 1989. (b) ApSimon, J . The Total
Synthesis of Natural Products; J ohn Wiley & Sons: New York, 1981;
Vol. 4.
(9) Suzuki, M.; Yanagishi, T.; Suziki, T.; Noyori, R. Tetrahedron Lett.
1982, 23, 4057.
(10) (a) Posner, G. H. Organic Reactions; J ohn Wiley & Sons, Inc.:
New York, 1972; Vol. 19, Chapter 1. (b) Lipshutz, B. H.; Sengupta, S.
Organic Reactions; J ohn Wiley & Sons, Inc.: New York, 1992; Vol.
41, Chapter 2.
(11) Chapdelaine, M. J .; Hulce, M. Organic Reactions; J ohn Wiley
& Sons, Inc.: New York, 1990; Vol. 38, Chapter 2.
(12) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Tetrahedron Organic Chemistry Series, No. 9; Pergamon:
Oxford, 1992.
(13) For the latest reviews, see: (a) De Vries, A. H. M.; Feringa, B.
L. Advances in Catalytic Processes; Doyle, M. P., Ed.; J AI: Greenwich,
CT, 1995; Vol. 1, pp 151-192. (b) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033. (c) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin/Heidelberg, 1999; Vol. 3, Chapter 31.1. (d)
Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (e) Feringa, B.
L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley VCH: Weinheim, 2002; Chapter 7.
(14) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(8) Suzuki, M.; Yanagisawa, A.; Noyori, R. J . Am. Chem. Soc. 1988,
110, 4718.
10.1021/jo025987x CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002
7244
J . Org. Chem. 2002, 67, 7244-7254

Synthesis of (-) Prostaglandin E1 Methyl Ester
SCHEME 1
a chiral oxazoline group. Recently, Hoveyda23 reported
ee values up to 97% using a chiral peptide-based phos-
phine ligand L6 in this conjugate addition reaction.
Although these ligands give excellent enantioselectivi-
ties in the copper-catalyzed 1,4-addition to 2-cyclopen-
tenone, the isolated yields for the corresponding 1,4-
addition products are often moderate compared to those
with other enones.24 When the reaction was performed
in the presence of an aldehyde, representing a three-
component coupling procedure, the yield increased con-
siderably.19,20,24 Despite the fact that 2-cyclopentenone is
frequently used as a model substrate, it is as such less
suitable as a starting material for natural products
including the prostaglandins. In the search for a suitable
prochiral enone as starting material for the total syn-
thesis of this class of natural products, we focused on
cyclopentene-3,5-dione monoacetals because of the fol-
lowing reasons:
(1) These compounds represent easy accessible highly
functionalized prochiral 2-cyclopentenones.
(2) The acetal functionality can be readily converted
into a ketone or alcohol.
(3) These enones are more sterically demanding than
2-cyclopentenone, which increases the steric interaction
with the catalyst.
(4) The two oxygen atoms of the acetal might induce
an electronic interaction with the catalyst during the
tandem 1,4-addition-aldol reaction, giving rise to a
higher selectivity.
We report here a new synthesis of cyclopentene-3,5-
dione monoacetals and their application as substrate for
highly enantioselective catalytic tandem 1,4-addition-
aldol reaction. Furthermore, we illustrate the practicality
of this new methodology in a short total synthesis of (-)-
PGE1 methyl ester including full experimental details.25
The new features of this strategy are the application of
a ca ta lytic three-component coupling, the use of only
a ch ir a l starting materials, and the observation that the
enantioselective introduction of the three stereocenters
with absolute stereocontrol is possible in a single key
step.
SCHEME 2
ite L1, the corresponding 1,4-addition products in high
yields and with ee’s up to >98% (Scheme 2).15
On the basis of this methodology, catalytic routes are
now available to enantiomerically pure products embed-
ding cyclohexane and larger rings in their structure.16
In addition to the enantioselective copper-catalyzed 1,4-
addition of organozinc reagents, a highly enantioselective
rhodium-catalyzed conjugate addition of aryl- and alk-
enylboronic acids to enones has been developed by
Hayashi.17 For cyclic and acyclic enones, ee’s between 92
and 99% have been found in the presence of 1.5 mol % of
a [Rh(OH)((S)-binap)]2 catalyst. For example, 3-phenyl-
cyclopentanone was obtained in 95% yield and 98% ee.
In contrast, the enantioselective copper-catalyzed 1,4-
addition of dialkylzinc reagents to 2-cyclopentenone
remained a major challenge, particularly because chiral
cyclopentane structures are ubiquitous in natural prod-
ucts such as prostaglandins. Surprisingly, the use of
phosphoramidite L1 as ligand for Cu(OTf)2 in the 1,4-
addition of diethylzinc to 2-cyclopentenone resulted in
hardly any selectivity at all (10% ee).16a Employing
TADDOL18-based phosphoramidite ligand L2, up to 62%
ee was obtained for the corresponding 1,4-addition prod-
uct when the reaction was run in the presence of
molecular sieves (Figure 1).19 Under the same conditions,
chiral bidentate phosphoramidite ligand L3 gave an
enantioselectivity of 83%.20 Chan21 reached 89% ee using
the diphosphite ligand L4 in the 1,4-addition of dieth-
ylzinc to 2-cyclopentenone, whereas Pfaltz22 enhanced the
enantioselectivity to 94% using phosphite L5 containing
Resu lts a n d Discu ssion
(15) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.
(16) (a) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa,
B. L. J . Am. Chem. Soc. 1999, 121, 1104. (b) Naasz, R.; Arnold, L. A.;
Minnaard, A. J .; Feringa, B. L. Chem. Commun. 2001, 735.
(17) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J . Am.
Chem. Soc. 2002, 124, 5052 and references cited herein.
(18) Seebach, D.; Beck, A.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92.
(19) Keller, E.; Maurer, J .; Naasz, R.; Schrader, T.; Meetsma, A.;
Feringa, B. L. Tetrahedron: Asymmetry 1998, 9, 2409.
(20) Mandoli, A.; Arnold, L. A.; Salvadori, P.; Feringa, B. L.
Tetrahedron: Asymmetry 2001, 12, 1929.
The preparation of monoacetals of cyclopentene-3,5-
dione has been described only in few cases in the
literature.26 The reported syntheses are not generally
applicable, which encouraged us to develop a new pro-
cedure for their preparation. Treatment of commercial
(23) Degrado, S. J .; Mizutani, H.; Hoveyda, A. H. J . Am. Chem. Soc.
2001, 123, 755.
(24) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron
Lett. 1996, 37, 5141.
(21) Yan, M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645.
(22) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(25) For a preliminary communication: Arnold, L. A.; Naasz, R.;
Minnaard, A. J .; Feringa, B. L. J . Am. Chem. Soc. 2001, 123, 5841.
J . Org. Chem, Vol. 67, No. 21, 2002 7245

Arnold et al.
F IGURE 1. Different ligands used for the catalytic asymmetric 1,4-addition of diethylzinc to 2-cyclopentenone.
TABLE 1. Mon oa ceta liza tion of 6 in th e P r esen ce of BF 3‚Et2O
entry
alcohol
time (h)
T (°C)
convna (%)
acetal
yieldb (%)
1
2
3
4
5
6
7
methanol
2,2-dimethyl-1,3-propanediol
ethylene glycol
2,2-diphenyl-1,3-propanediol
pinacol
isopropyl alcohol
1.5
1.5
1.5
3
72
48
0
0
0
50
58
45
71
76f
0f
7a
7b
7c
7d
7e
26 (+7)c
29
25
0
50 (64)d
29 (6)e
25
25
25
benzyl alcohol
48
0f
a
b
d
Determined by 1H NMR after 3 h. Isolated yield. c 4-Ethoxy-4-methoxy-2-cyclopenten-1-one. Purification by different purification
procedure.27 e Diacetal. f After 3 d at room temperature.
available cyclopentene-3,5-dione 6 with different alcohols
in the presence of boron trifluoride gave the correspond-
ing cyclopentene-3,5-dione monoacetals 7a -e summa-
rized in Table 1.
of BF3‚Et2O afforded 7e in 29% yield (76% conversion)
after 3 days at room temperature (Table 1, entry 5). In
addition, 6% yield of the diacetal was obtained. In the
case of 2-propanol and benzyl alcohol, no acetal formation
was observed even after 2 days at room temperature
(Table 1, entries 6 and 7).
The reactions were stopped after a certain conversion
to avoid the formation of side products. The reaction of
6 with methanol was stopped after 50% conversion, and
the acetal 7a could be isolated in 26% yield (Table 1,
entry 1). An interesting observation was made, namely
the formation of 4-ethoxy-4-methoxy-2-cyclopenten-1-one
in 7% yield. The EtO fragment of this compound origi-
nates from BF3‚Et2O. The acetals 7b and 7c were
obtained in 29% and 25% yield at conversions of 58% and
45%, respectively (Table 1, entries 2 and 3). The acetal-
ization of 6 with 2,2-diphenyl-1,3-propanediol gave 71%
conversion after 3 h at 0 °C and 50% yield of 7d (Table
1, entry 4). Employing a different purification method27
instead of column chromatography improved the isolated
yield to 64%. The reaction of 6 and pinacol in the presence
Ca ta lytic Asym m etr ic 1,4-Ad d ition . The monoac-
etals 7b and 7d were employed in the 1,4-addition with
dialkylzinc reagents catalyzed by different chiral copper
complexes. The copper catalyst was prepared in situ
using 2 mol % Cu(OTf)2 and 4 mol % phosphoramidite
L1 or L7 (for structures of ligands, see Scheme 2 and
Figure 3). The reactions were carried out in toluene at
-45 °C, and the results are summarized in Table 2.
Full conversions were reached in all reactions after 16
h affording the corresponding substituted ketones in
moderate yields (31-40%). The 1,4-addition of diethylzinc
to 7b in the presence of 2 mol % Cu(OTf)2/L1 catalyst
afforded 8 in 31% isolated yield (Table 2, entry 1).
Unfortunately, no separation of the enantiomers was
achieved by chiral HPLC. Derivatization with optically
pure (1S,2S)-diphenylethylenediamine28 was also unsuc-
cessful. Apart from the formation of 8, 8a and 8b were
(26) (a) Yoshida, Z.-I.; Kimura, M.; Yoneda, S. Tetrahedron Lett.
1975, 12, 1001. (b) Sugihara, Y.; Wakabayashi, S.; Murata, I. J . Am.
Chem. Soc 1983, 22, 6718. (c) Bauermeister, H.; Riechers, H.; Schom-
burg, D.; Washausen, P.; Winterfeldt, E. Angew. Chem., Int. Ed. Engl.
1991, 30, 191.
(27) See the Experimental Section.
7246 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (-) Prostaglandin E1 Methyl Ester
TABLE 2. Ca ta lytic En a n tioselective 1,4-Ad d ition w ith
Cyclop en ten e-3,5-d ion e Mon oa ceta ls
yielda
(%)
eeb
(%)
entry
enone
R′ Zn
ligand
product
2
1
2
3
4
5
7b
7d
7d
7d
7d
Et2Zn
Et2Zn
Et2Zn
Bu2Zn
Bu2Zn
L1
L1
L7
L7
L1
8
9
9
10
10
31 (42)c
40
37
32
37
d
90
0
5
94
a
b
Isolated yield. Determined by chiral HPLC. c Side product,
d
see: Figure 2. No separation by chiral HPLC.
F IGURE 3. Different phosphoramidite ligands.
SCHEME 3
F IGURE 2. Side products formed in the catalytic enantiose-
lective 1,4-addition of diethylzinc to 7b.
isolated in 42% combined yield (Figure 2). Similar
products, formed by an aldol reaction between a zinc
enolate prepared by a 1,4-addition and an enone, have
been reported.29 NMR analysis identified these diaster-
eomers, which differ in the configuration of the tertiary
alcohol. The presence of these products shows the dif-
ferent reactivity between the five-membered-ring zinc
enolate and the six-membered-ring zinc enolate.20,30 In
the case of the copper-catalyzed 1,4-addition of diethyl-
zinc to 2-cyclohexenone, the formation of this type of
products was not detected even at elevated temperature.
Much to our delight, the use of 2-cyclopentenone with
an additional acetal functionality increases the enant-
ioselectivity of the Cu(OTf)2/L1-catalyzed 1,4-addition
dramatically. The reaction of 7d and diethylzinc afforded
9 in 40% yield and 90% ee (Table 1, entry 2). Using L7
(Figure 3) instead of L1 as ligand for copper, no asym-
metric induction was observed and 9 was isolated in 37%
yield (Table 2, entry 3). The 1,4-addition of dibutylzinc
to 7d in the presence of Cu(OTf)2/L7 afforded 10 in 32%
yield and 5% ee (Table 2, entry 4). In contrast, catalyst
Cu(OTf)2/L1 gave in the same reaction 10 in 37% yield
with an ee of 94% (Table 2, entry 5). In all cases, the
1,4-addition suffers from considerable side product for-
mation (vide supra) resulting in modest isolated yields.
Ca ta lytic Ta n d em 1,4-Ad d ition -Ald ol Rea ction .
To circumvent the formation of 8a and 8b (Figure 2), an
aldehyde (more reactive than a ketone in an aldol
reaction) was added to the reaction mixture from the
start. This tandem 1,4-addition-aldol reaction procedure,
trapping the intermediate zinc enolate, was first reported
by Noyori.24 The reaction was carried out using enone
7d , p-bromobenzaldehyde, and dibutylzinc at -45 °C. We
were very pleased to find that only 2 mol % of the
catalyst, prepared in situ from Cu(OTf)2 and ligand L1,
was sufficient to obtain the â-hydroxy ketones 11a and
11b with three consecutive stereocenters in 64% yield
(Scheme 3 and Table 3, entry 14).
Under these reaction conditions, virtually one stere-
oisomer out of the possible four diastereomers was
formed. A ratio of 97:3 between 11a trans-threo and 11b
trans-erythro was detected by 1H NMR based on different
absorptions of H1 (4.77 ppm 11a and 5.11 ppm 11b).
1
COSY-NMR and H NMR was used to assign the relative
configurations of the two compounds. The coupling
constant for 11a and 11b was J 2,3 ) 7.2 Hz. This value
is typical for a trans configuration of H2 and H3 (Scheme
4).31 In addition, 11a and 11b have different coupling
constants for their H1 and H2. The large difference is
probably due to strong hydrogen bonding between the
hydroxy and carbonyl group, thus preventing free rota-
(28) Alexakis, A.; Frutos, J . C.; Mangeney, P. Tetrahedron: Asym-
metry 1993, 4, 2431.
(29) Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett.
1985, 26, 4763.
(30) De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374.
J . Org. Chem, Vol. 67, No. 21, 2002 7247

Arnold et al.
TABLE 3. Ca ta lytic En a n tioselective Ta n d em 1,4-Ad d ition -Ald ol Rea ction of Dia lk ylzin c Com p ou n d s to
Cyclop en ten e-3,5-d ion e Mon oa ceta ls in th e P r esen ce of Ald eh yd es
entry
enone
R′ Zn
ligand
R′′CHO
aldol
convna (%)
yieldb (%)
diketone
eec (%)
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
7b
7b
7b
7b
7b
7b
7b
7b
7b
7d
7d
7d
7d
7d
7d
7e
7c
7a
Et
L1
L1
L1
L1
L8
L9
L7
L3
L2
L1
L1
L1
L1
L1
L1
L1
L1
L1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-BrC6H4
p-BrC6H4
n-C3H8
C6H5
C6H5
C6H5
13a
14a
14a
14a
14a
14a
14a
14a
14a
15a
15a
16a
17a
11a
18a
19a
20a
21a
100
100
40
100
70
62
93
59
0
67
64
23
67
13c
14c
14c
14c
14c
14c
14c
14c
14c
15c
15c
16c
17c
11c
g
87
87
84d
83e
38
56
13
5
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Et
Et
Bu
Et
Bu
Et
Et
76
68
69
69
64
94
94f
94
96
97
65
54
g
Et
Et
(75)h
(64)h
a
1
b
d
Determined by H NMR. Isolated yield. c Determined by chiral HPLC DAICEL CHIRALPAK AD. Reaction carried out in CH2Cl2.
e Reaction temperature -30 °C. f Reaction temperature -60 °C. g Oxidation with PCC and NMO/RuCl2(PPh3)334 was unsuccessful. Crude
tandem product identified by NMR; purification by column chromatography resulted in the formation of elimination product. See text.
h
i
tion of the R-substituent. The coupling constants found
were J 1,2 ) 7.8 Hz for 11a and J 1,2 ) 3.6 Hz for 11b
(Scheme 3). Further proof for the relative configuration
was given by NOESY-NMR measurements.32 No cis-threo
and cis-erythro products are formed. The proof of the
absolute stereochemistry was realized with the total
synthesis of (-)-PGE1 methyl ester and its comparison
with the natural compound (vide infra). The selectivity
of the aldol step can be explained by the stability of the
different transition states for 11a and 11b and can be
rationalized in terms of a Zimmerman-Traxler transi-
tion-state model (Scheme 4).33 In our case, transition
state 12a gives product 11a , which was formed almost
exclusively under these reaction conditions. The steric
interactions between the aromatic ring of the aldehyde
and the acetal functionality are less severe for the
addition that involves transition state 12a than for the
competing reaction via transition state 12b. The chiral
copper complex is presumed to have no influence in the
aldol bond formation step. In the case of 2-cyclopenten-
one, there is no significant difference between the two
diastereomeric transition states leading to a 50:50 mix-
ture of trans-threo/trans-erythro using various copper
complexes.19,20
tandem 1,4-addition-aldol products, it is necessary to
remove the stereocenter associated with the hydroxy
functionality. Therefore, oxidation to the corresponding
diketone was performed using PCC (pyridinium chloro-
chromate). The results are summarized in Table 3.
In the tandem 1,4-addition-aldol reaction with monoac-
etals 7a -e, catalyzed by Cu(OTf)2 and different phos-
phoramidites, good yields were obtained for the corre-
sponding aldol products 11a and 13a -21a . Oxidations
with PCC provide the diketones 11c and 13c-17c in
yields up to 76% with excellent ee values. In the presence
of 2 mol % of Cu(OTf)2 and 4 mol % of ligand L1, enone
7b, Et2Zn, and benzaldehyde gave the â-hydroxy ketone
13a in 67% yield and after oxidation diketone 13c with
87% ee (Table 3, entry 1). For the reaction with Bu2Zn,
similar results were found (Table 3, entry 2). Changing
the solvent from toluene to CH2Cl2 slowed the reaction
(40% conversion after 36 h) and resulted in an ee of 84%
for 14c (Table 3, entry 3). When the reaction was
performed with diethylzinc at -30 °C instead of -45 °C,
the enantioselectivity decreased from 87% to 83% (Table
3, entry 1 vs 4). For various phosphoramidite ligands,
the following results were achieved: for ligand L8 (Figure
3), 70% conversion of 7b after 36 h and 38% ee for
diketone 14c (Table 3, entry 5); the ligands L9 and L7
(Figure 3) gave 62% and 93% conversion of 7b after 36 h
and 56% ee and 13% ee for 14c, respectively (Table 3,
entries 6 and 7); bidentate ligand L3 (Figure 1) gave 59%
conversion of 7b after 36 h and 5% ee for 14c (Table 3,
entry 8); and TADDOL-derived phosphoramidite L2
(Figure 1) gave no conversion at all (Table 3, entries 9).
Using monoacetal 7d , diethylzinc or dibutylzinc, and
benzaldehyde in this reaction gave ee values of 94% for
15c and 16c (Table 3, entries 10 and 12). Performing the
reaction at lower temperature (-60 °C) has no influence
To explore the scope of the reaction, different monoac-
etals, aldehydes, and dialkylzinc reagents were used in
the catalytic asymmetric tandem 1,4-addition-aldol re-
action. In all cases, ratios (trans-threo/trans-erythro)
exceeding 95:5 for the corresponding hydroxy ketones
were found. To facilitate the ee determination of the
(31) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem. Soc.
J pn. 2000, 73, 999.
(32) See the Supporting Information.
(33) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.
7248 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (-) Prostaglandin E1 Methyl Ester
TABLE 4. Con ver sion of th e Elim in a tion P r od u cts to th e Cor r esp on d in g Dik eton e 23
ee of
23b
(%)
aldol
product
elimination
product
yielda
(%)
entry
R
R′
1
2
3
-CH2CH2-
CH3
-CH2C(CH3)2CH2-
Et
Et
Et
20a
21a
13a
20d
21d
13d
75
64
67
70
76
87
a
b
Isolated yield based on cyclopentene-3,5-dione monoacetal. Determined by chiral HPLC.
on the enantioselectivity (Table 3, entry 11). Further-
more, different aldehydes were used as electrophiles. In
the case of p-bromobenzaldehyde, the corresponding
hydroxy ketones 17a and 11a were isolated in 69% and
64% yield using Et2Zn and Bu2Zn, respectively (Table 3,
entries 13 and 14). After oxidation, excellent ee values
of 96% for diketone 17c and 97% for 11c were obtained.
Applying butanal resulted in the corresponding hydroxy
ketone in 65% yield, but attempts to oxidize 18a with
Table 4, entry 2). Furthermore, a control experiment was
carried out to make sure that epimerization does not
occur applying this protocol. For this purpose, 13a was
treated with acid undergoing an elimination reaction and
13d was obtained in quantitative yield (Table 3, entry
1, and Table 4, entry 3). The reduction/elimination and
oxidation reaction gave 23 with an ee of 87%, confirming
that no epimerization took place during these conversions
(Table 3, entry 1, and Table 4, entry 3).
34
PCC or NMO/RuCl2(PPh3)3 to determine the ee value
From these experiments using different phoshoramid-
ite ligands, cyclopentene-3,5-dione monoacetals, alde-
hydes, and dialkylzinc reagents, the following conclusions
can be drawn. The catalyst prepared in situ from Cu-
(OTf)2 and L1 gave the highest asymmetric induction in
these reactions. The nature of the acetal has a strong
influence on the stability of the tandem products. The
compounds with the 2,2-dimethyl- and 2,2-diphenyl-
substituted 1,3-dioxane acetal functionality are quite
stable resulting only in up to 10% elimination product
after column chromatography. The tandem products with
the 1,3-dioxolanes and acyclic acetal functionality, in
contrast, are converted completely during purification by
column chromatography (SiO2 and Al2O3). Furthermore,
the enantioselectivity of the tandem 1,4-addition-aldol
reaction was influenced by the nature of the acetal
functionality. The use of dioxolane 7c and dimethoxy
acetal 7a gave enantioselectivities of 70% and 76%,
respectively, whereas for the dioxane acetals 7d and 7b
ee values of 97% and 87% were found for the products of
the tandem 1,4-addition-aldol reaction. On the basis of
these results, 7d was used as starting material for the
natural product synthesis.
gave a complex reaction mixture (Table 3, entry 15). A
reduction strategy as it was used for the ee determination
of 35 (vide infra) offers a solution (Scheme 7). Enone 7e
was also successfully applied in the tandem 1,4-addition-
aldol reaction. The tandem product 19a was obtained in
54% yield (Table 3, entry 16). Like compound 18a , 19a
gave a complex reaction mixture during attempts to
oxidize it to the corresponding diketone. The application
of enones 7a and 7c resulted in the formation of the crude
tandem 1,4-addition-aldol products 20a and 21a (Table
3, entries 17 and 18) but during purification by column
chromatography an elimination reaction occurred (Table
4). The formation of these elimination products was also
observed using reaction temperatures above -30 °C.
Performing the tandem 1,4-addition-aldol reaction at 0
°C gave these products exclusively. To establish an ee
determination method that is applicable for these elimi-
nation products a protocol comprising a reduction/
elimination and oxidation reaction was used. Part of this
protocol was actually developed for the synthesis of
2-cyclohexenones.35 Applying this protocol to the elimina-
tion products resulted in the formation of 23 in all cases.
The results are given in Table 4.
The elimination product 20a resulting from the copper-
catalyzed tandem 1,4-addition-aldol reaction of dieth-
ylzinc to 7c in the presence of benzaldehyde was obtained
in 75% yield after column chromatography (Table 3, entry
17, and Table 4, entry 1). Reduction of 20a with LiAlH4
and subsequent acid workup gave 22 in 65% yield.
Oxidation with PCC afforded 23 in 68% yield and 70%
ee. Compound 21d was obtained in 64% yield after
column chromatography, and after conversion to 23 an
ee value of 76% was measured (Table 3, entry 18, and
Ca ta lytic En a n tioselective Syn th esis of P r osta -
gla n d in E1 Meth yl Ester . The results of the asymmetric
1,4-addition-aldol reactions of diorganozinc reagents to
cyclopentene-3,5-dione monoacetals enabled us to employ
the optimal conditions for the asymmetric synthesis of a
prostaglandin. The initial approach we followed for this
catalytic asymmetric total synthesis is reminiscent of the
three-component coupling reaction introduced by Noyori
(Scheme 1).9 However, the application of the required
dialkenylzinc reagents, corresponding to the organocop-
per reagents in Scheme 1, did not lead to product
formation. These reagents can be prepared, like dialkyl-
zinc reagents, by a boron-zinc exchange reaction in a
(34) Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976,
17, 2503.
(35) Gannon, W. F.; House, H. O. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 294.
J . Org. Chem, Vol. 67, No. 21, 2002 7249

Arnold et al.
SCHEME 4
SCHEME 5a
a
Key: (a) (1) Red-Al, THF, 5 h; (2) I2, -78 °C; (b) DMPSCl,
Et3N, DMAP, CH2Cl2, 0 °C; (c) t-BuLi, 2 equiv, THF, -78 °C; (d)
(COCl)2, Me2SO, Et3N, -78 °C.
salt-free procedure from organoboranes.36 Using this type
of reagent in a model 1,4-addition with 2-cyclohexenone
in the presence of an in situ generated catalyst from Cu-
(OTf)2/L1, no product was formed after 24 h at -20 °C.
Employing an in situ generated mixed alkylalkenylzinc
reagent,37 it was found that only the saturated carbon
nucleophile was transferred to the enone.
SCHEME 6a
These results indicate that the ω side chain, appar-
ently, cannot be introduced using an unsaturated dior-
ganozinc reagent in a catalytic asymmetric 1,4-addition
protocol. This is the reason for the new approach outlined
in the retrosynthetic analysis in Scheme 4.
a
Key: (a) MeOH, p-TSA, CCl4, 10 h; (b) (1) Et2BH, THF, 0 °C,
3 h, (2) Et2Zn neat, 0-25 °C, 3 h.
procedure proceeds with 100% cis selectivity because of
the intramolecular coordination of the aluminum center
with the hydroxy functionality. Using chlorodimeth-
ylphenylsilane, allylic alcohol 30 was converted to the
silyl ether 31 in excellent yield. This compound under-
went a 1,4-O f sp2C silyl migration using 2 equiv of
t-BuLi.39 The corresponding (Z)-vinylsilane 32 was ob-
tained in 74% yield. Subsequently, Swern oxidation gave
the unsaturated aldehyde 25 with an E/Z ratio of 6:94.
The overall yield of this sequence was 51%.
The zinc reagent 24 was prepared following a Knochel
procedure (Scheme 6).43 Therefore, commercially avail-
able 6-heptenoic acid 33 was converted to the methyl
ester 34. Subsequently, hydroboration of the olefin gave
the functionalized borane, which underwent a borane-
zinc exchange reaction in the presence of neat Et2Zn.
After evaporation of the excess of Et2Zn, the correspond-
ing functionalized zinc reagent 24 was obtained in high
yield.
For the total synthesis of PGE1 methyl ester enone 7d ,
aldehyde 25 and the functionalized zinc reagent 24 were
converted in a catalytic enantioselective 1,4-addition-
aldol procedure (Scheme 7).
In the presence of 3 mol % of an in situ generated chiral
Cu(OTf)2/L1 catalyst, compound 26 was obtained in 60%
yield as a mixture (not separable at this stage) of
diastereomers with high stereoselectivity (trans-threo/
trans-erythro ratio 83:17). Reduction of the ketone moiety
of 26 proceeded with 95% stereoselectivity using Zn(BH4)2
in ether at -30 °C. All diastereomers (79% yield) could
be isolated by column chromatography, and the major
diastereomer 35 was obtained in 63% yield with an ee of
The preparation of PGE1 methyl ester 28 would involve
cleavage of the acetal and an allylic transposition38
starting from 27. To carry out the allylic transposition,
conversion of the diol 27 to the corresponding diacetate
would be necessary. Protodesilylation39 and stereoselec-
tive reduction of 26 could afford 27. Formation of 26
would involve the tandem 1,4-addition-aldol reaction of
7d , 24, and 25 in the presence of a chiral copper catalyst.
In this new three-component coupling approach, the
saturated R-chain of the PGE1 methyl ester would be
introduced with a functionalized zinc reagent and the
ω-chain via an unsaturated aldehyde involving the
simultaneous presence of an enone and enal. To discrimi-
nate between them, 25 is equipped with a silyl substitu-
ent, exploiting the fact that 3-substituted enones are not
reactive under the condition of the catalytic 1,4-addi-
tion.40 The phenyldimethylsilyl group is chosen because
of its easier removal in comparison with other silyl
groups. For the synthesis of aldehyde 25, a protocol
described by Magriotis for similar compounds was fol-
lowed (Scheme 5).39
Commercially available 2-octyn-1-ol 29 was converted
in a stereoselective manner to 30 by the Masamune
modification41 of the Corey reductive iodination.42 This
(36) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449. For an earlier
report dealing with the alkenyl transfer from boron to zinc, see:
Molander, G. A.; Zinke, P. W. Organometallics 1986, 5, 2161.
(37) (a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75,
170. (b) For a stereoselective version, see: Soai, K.; Takahashi, K. J .
Chem. Soc., Perkin Trans. 1 1994, 1257.
(38) (a) For the Pd(II)-mediated allylic acetate transposition in a
modified prostaglandin intermediate, see: Grieco, P. A.; Takigawa, T.;
Bongers, S. L.; Tanaka, H. J . Am. Chem. Soc. 1980, 102, 7588. (b) The
Pd(II)-catalyzed allylic acetate transposition was first described by:
Meyer, K. DOS 2513198 1975; Chem. Abstr. 1976, 84, 89629s. (c) For
a full review of Pd(II)-catalyzed [3,3]-sigmatropic rearrangements,
see: Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(39) Kim, K. D.; Magriotis, P. A. Tetrahedron Lett. 1990, 31, 6137.
(40) De Vries, A. H. M. Catalytic Enantioselective Conjugate Addi-
tion of Organometallic Reagents. Ph.D. Thesis, University of Gronin-
gen, 1996.
(41) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Somfai, P.;
Whritenour, D. C.; Masamune, S. J . Org. Chem. 1989, 54, 2824.
(42) Corey, E. J .; Katzenellenbogen, J . A.; Posner, G. H. J . Am.
Chem. Soc. 1967, 89, 4245.
(43) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (b)
Langer, F.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. Synlett
1994, 410.
7250 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (-) Prostaglandin E1 Methyl Ester
SCHEME 7a
a
Key: (a) 3 mol % Cu(OTf)2, 6 mol % L1, toluene, -45 °C, 18 h; (b) Zn(BH4)2, ether, -30 °C, 3 h; (c) (1) 3 equiv of Bu4NF (1 M in THF),
methyl propionate, DMSO, 80 °C, 20 min, (2) Ac2O, DMAP, pyridine, 20 min; (d) 5 mol % Pd(CH3CN)2Cl2, THF, 3 h; (e) K2CO3, MeOH,
18 h; (f) (NH4)2Ce(NO3)6, MeCN, borate-HCl buffer (pH ) 8), 60 °C, 2 h.
94%. In the next step, the silyl substituent was removed
using Bu4NF in THF/DMSO to give compound 27. This
comprises a novel protection and deprotection sequence
for enones/enals suitable for the catalytic 1,4-addition
with dialkylzinc reagents. The cleavage of vinyl carbon-
silicon bonds with Bu4NF was developed by Nozaki.44
However, under the normal reaction conditions, hydroly-
sis of the ester moiety of compound 27 was observed
caused by water in the commercial THF solution of Bu4-
NF. Adding first sacrificial methyl propionate to remove
the water by hydrolysis and only afterward 35 gave the
desilylated compound 27 as the only product. Diacetyl-
ation of crude 27 afforded 36 in 71% yield over two steps.
The 1,3-allylic transposition of 36 with a catalytic amount
of Pd(CH3CN)2Cl2 in THF proceeded with reasonable
yield (63%) and full retention of configuration38 to provide
allylic acetate 37 with the required stereochemistry. After
deacetylation in the presence of K2CO3 in MeOH, com-
pound 38 was obtained in excellent yield. The final step
comprises the mild deprotection of the ketone functional-
ity to provide the labile â-hydroxy ketone moiety of the
prostaglandin E1. This conversion was realized using a
catalytic amount of (NH4)2Ce(NO3)6 under nearly neutral
conditions.45 In this way (-)-PGE1 methyl ester 28,46 in
all respect identical with an independent sample, was
obtained in 7% overall yield with 94% optical purity in 7
steps from 7d .
Con clu sion s. A new general synthesis of rather labile
cyclopentene-3,5-dione monoacetals with yields up to 64%
was introduced. Furthermore, we demonstrated that
these compounds could be successfully applied as sub-
strates for the catalytic enantioselective 1,4-addition and,
in particular, for the catalytic enantioselective tandem
1,4-addition-aldol reaction. In the presence of 2 mol %
of the in situ generated catalyst Cu(OTf)2/phosphoramid-
ite L1, enantioselectivities up to 94% could be obtained
for the 1,4-addition products, whereas 97% ee was
achieved in the tandem 1,4-addition-aldol reaction. In
the latter procedure, excellent stereoselectivity is also
observed in the subsequent aldol step achieving nearly
complete stereocontrol in the formation of the consecutive
stereocenters, which provides an efficient route to enan-
tiomerically pure multifunctional cyclopentanones. In
addition, it was shown that the stability toward elimina-
tion of the tandem 1,4-addition-aldol products depends
strongly on the nature of the acetal moiety; 1,3-dioxolanes
and acyclic monoacetals of cyclopentene-3,5-dione un-
dergo elimination even during purification by column
chromatography, whereas 2,2-disubstituted 1,3-dioxane
monoacetals can be purified without any difficulties. The
versatility of this catalytic methodology was demon-
(45) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J .-M.;
Quesnel, Y.; Vanherck, J .-C. Angew. Chem., Int. Ed. Engl. 1999, 38,
3207.
(46) The analytical and spectral data (TLC, HPLC, 1H NMR, 13C
(44) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron 1985, 41, 3257.
NMR, CD, MS) [R]23 -51 (c 1.0, CH3OH) of 28 were identical with
D
those of authentic material (Sigma) [R]23 -54 (c 1.0, CH3OH).
D
J . Org. Chem, Vol. 67, No. 21, 2002 7251

Arnold et al.
mined by HPLC on
CHIRALPAK AD, i-PrOH/hexane 10:90, 1 mL/min, rt, tR
6.03 min, tR ) 12.77 min).
a
chiral stationary phase (DAICEL
strated in the application as the key step in a short asym-
metric synthesis of a PGE1 methyl ester comprising a new
route to this natural product. We showed in this synthesis
that except for 3 mol % of an enantiomerically pure
catalyst, only achiral materials are required to prepare
an PGE1 methyl ester in a highly effective manner.
)
Gen er a l P r oced u r e for th e Ta n d em 1,4-Ad d ition -
Ald ol Rea ction (11a ,b, 13a -21a ). A solution of Cu(OTf)2 (3.6
mg, 0.01 mmol) and phosphoramidite47 (0.02 mmol) in toluene
(7 mL) was stirred under a nitrogen atmosphere at ambient
temperature for 1 h. Cyclopentene-3,5-dione monoacetal (0.5
mmol) and the aldehyde (0.5 mmol) were added. After the
reaction mixture was cooled to -45 °C, the dialkylzinc reagent
(0.6 mL, 1 M solution in toluene) was added, and stirring at
-45 °C was continued for 18 h. After complete conversion, the
reaction mixture was poured in 25 mL of NH4Cl (aq), the
organic layer was separated, and the aqueous layer was
extracted two times with diethyl ether. The combined organic
layers were dried over MgSO4, filtered, and concentrated in
vacuo.
(3S ,4R )-4-Bu t yl-3-[(R )-h yd r oxy(p h e n yl)m e t h yl]-8,8-
d ip h en yl-6,10-d ioxa sp ir o[4.5]d eca n -2-on e (16a ). Purifica-
tion by column chromatography (SiO2 pentane/diethyl ether,
2:1, Rf ) 0.18) gave 158 mg (69%) of 16a as a colorless oil which
solidified upon standing: 1H NMR (300 MHz) δ 7.33-7.06 (m,
15H), 4.81 (dd, J ) 8.1 Hz, J ) 1.8 Hz, 1H), 4.54-4.44 (m,
2H), 4.32-4.17 (m, 2H), 3.85 (d, J ) 1.8 Hz, 1H(OH)), 3.04 (d,
J ) 18.0 Hz, 1H), 2.53 (d, J ) 17.4 Hz, 1H), 2.44 (t, J ) 8.1
Hz, 1H), 2.02 (q, J ) 6.6 Hz, 1H), 1.35 (m, 1H), 0.70 (m, 5H),
0.52 (t, J ) 6.6 Hz, 3H); 13C NMR (200 MHz) δ 216.3, 143.4,
143.2, 140.9, 129.9, 128.6, 128.4, 128.3, 128.1, 127.9, 126.9,
126.6, 126.4, 104.0, 75.2, 70.1, 68.9, 59.8, 460.8, 45.4, 44.8, 29.6,
27.7, 22.7, 13.8; HRMS calcd for C31H34O4 477.245, found
477.243.
Gen er a l P r oced u r e for th e Oxid a tion to a Dik eton e
(11c, 13c-17c). To hydroxy ketone (0.2 mmol) in CH2Cl2 (5
mL) were added molecular sieves (4 Å, 0.5 g) and PCC (215
mg, 1 mmol) at 0 °C. The reaction mixture was stirred for 4 h
at room temperature, diluted with diethyl ether, filtered over
Celite, and evaporated to dryness.
(3R,4R)-3-Ben zoyl-4-bu tyl-8,8-diph en yl-6,10-dioxaspir o-
[4.5]d eca n -2-on e (16c). Purification by column chromatog-
raphy (SiO2 pentane/diethyl ether, 5:1, Rf ) 0.32) gave 64 mg
(69%) of 16c as a colorless oil which solidified upon standing:
1H NMR (300 MHz) δ 8.01 (d, J ) 6.0 Hz, 2H), 7.57-7.05 (m,
13H), 4.68 (d, J ) 11.6 Hz, 2H), 4.49-4.21 (m, 3H), 3.38 (d, J
) 18.0 Hz, 1H), 3.16 (m, 1H), 2.56 (d, J ) 16.2 Hz, 1H), 1.55
(m, 1H), 1.32-0.88 (m, 5H), 0.66 (t, J ) 6.9 Hz, 3H); 13C NMR
(200 MHz) δ 206.6, 194.7, 143.3, 143.0, 137.0, 133.5, 129.4,
128.7, 128.6, 128.1, 127.0, 126.9, 126.3, 103.1, 71.4, 68.6, 62.7,
49.1, 47.6, 45.0, 44.8, 30.2, 27.1, 22.8, 13.7; HRMS calcd for
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Unless otherwise noted, all
materials were obtained from commercial suppliers and used
without further purification. Toluene, diethyl ether, and THF
were distilled from sodium benzophenone ketyl and stored
under nitrogen. DCM, hexane, pentane, and CHCl3 were
distilled from P2O5 and MeOH from MeONa. BF3‚Et2O, benzyl
alcohol, and triethylamine were distilled before use. Cu(OTf)2
was dried before use. Enantiomeric ratios were determined
by chiral HPLC (DAICEL CHIRALPAK AD) in comparison
with racemic material. Spectra are referenced internally to the
residual resonance in CDCl3 (δ 7.24 ppm) for hydrogen and (δ
) 77 ppm) for carbon atoms. Chemical shifts (δ) are denoted
as part per million (ppm) starting from downfield to upfield.
Gen er a l P r oced u r e for th e Aceta liza tion of 2-Cyclo-
p en ten e-1,3-d ion e (7a -e). To a cooled solution (0 °C) of
cyclopentene-3,5-dione (1.92 g, 20 mmol) and BF3‚Et2O (2.52
mL, 20 mmol) in chloroform (50 mL) was added the alcohol
(40 mmol, 20 mmol for diol). After being stirred for 3 h, the
reaction mixture was poured into NH4Cl (aq) and extracted
three times with 25 mL of diethyl ether. The combined organic
layers were dried over MgSO4, filtered, and concentrated in
vacuo. Column chromatography (SiO2 ether/pentane) gave the
corresponding acetals.
8,8-Dip h en yl-6,10-d ioxa sp ir o[4.5]d ec-3-en -2-on e (7d ).
Purification by column chromatography (SiO2 hexane/diethyl
ether, 1:1, Rf ) 0.43) gave 3.06 g (50%) of 7d as a white solid.
Alternative workup for large-scale reaction (52 mmol) (only
starting materials and product present in the crude reaction
mixture): The reaction mixture was poured into NH4Cl (aq)
and diluted with CH2Cl2 (150 mL). The organic layer was
separated, washed with 1 M NaOH solution to remove the
cyclopentene-3,5-dione, dried over MgSO4, filtered, and con-
centrated in vacuo. The unreacted diol can be removed by
crystallization from hexane/CHCl3, and 7d (10.2 g) could be
obtained in 64% yield after evaporation of the solvents: mp
75-76 °C; 1H NMR (300 MHz) δ 7.51 (d, J ) 6.0 Hz, 1H), 7.41-
7.20 (m, 10H), 6.21 (d, J ) 6.0 Hz, 1H), 4.65 (d, J ) 11.7 Hz,
2H), 4.35 (d, J ) 11.7 Hz, 2H), 2.70 (s, 2H); 13C NMR (200
MHz) δ 203.3, 156.5, 143.4, 143.2, 135.1, 128.4, 128.2, 127.6,
126.7, 126.7, 126.4, 104.0, 70.2, 44.4, 44.0; MS (CI) for C20H18O3
m/z ) 306 (M+), 324 (M + NH4+).
C
31H32O4 468.230, found 648.231. The ee of 94% was deter-
mined by HPLC on chiral stationary phase (DAICEL
a
Gen er a l P r oced u r e for th e 1,4-Ad d ition (8-10). A solu-
tion of Cu(OTf)2 (3.6 mg, 0.01 mmol) and phosphoramidite
(0.02 mmol) in toluene (7 mL) was stirred under a nitrogen
atmosphere at ambient temperature for 1 h. The cyclopentene-
3,5-dione monoacetal (0.5 mmol) was added, and after the
reaction mixture was cooled to -45 °C, the diorganozinc
compound (0.6 mL of a 1 M solution in toluene) was added
and stirring at -45 °C was continued for 18 h. The conversion
was determined by TLC. After complete conversion, the reac-
tion mixture was poured into 25 mL of NH4Cl (aq), the organic
layer was separated, and the aqueous layer was extracted two
times with diethyl ether. The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo.
(4R)-4-Bu tyl-8,8-d ip h en yl-6,10-d ioxa sp ir o[4.5]d eca n -2-
on e (10). Purification by column chromatography (SiO2 pen-
tane/diethyl ether, 3:1, Rf ) 0.30) gave 67 mg (37%) of 10 as
a colorless liquid: 1H NMR (300 MHz) δ 7.50-7.05 (m, 10H),
4.57 (d, J ) 12.0 Hz, 2H), 4.26 (d, J ) 11.7 Hz, 2H), 3.06 (d,
J ) 18.3 Hz, 1H), 2.53-2.05 (m, 4H), 1.59 (m, 1H), 1.25-1.05
(m, 5H), 0.80 (t, J ) 7.4 Hz, 3H); 13C NMR (200 MHz) δ 213.3,
143.6, 143.3, 128.7, 128.5, 128.1, 126.9, 126.4, 126.3, 104.7,
70.8, 68.8, 45.9, 44.8, 44.7, 43.3, 30.1, 27.3, 22.9, 13.8; HRMS
calcd for C24H28O3 364.203, found 364.203. The ee was deter-
CHIRALPAK AD, i-PrOH/hexane 50:50, 1 mL/min, rt, tR
5.11 min, tR ) 10.71 min).
)
(4R,5S)-4-Eth yl-5-[(R)-h ydr oxy(ph en yl)m eth yl]-3-m eth -
oxy-2-cyclop en ten -1-on e (21d ). Purification by column chro-
matography (SiO2 hexane/diethyl ether, 1:1, Rf ) 0.18) gave
79 mg (64%) of 21d as a colorless liquid: 1H NMR (300 MHz)
δ 7.35-7.21 (m, 5H), 5.26 (s, 1H), 4.56 (d, J ) 9.9 Hz, 1H),
3.79 (s, 3H), 2.38 (m, 2H), 1.20 (m, 1H), 0.90 (m, 1H), 0.43 (t,
J ) 7.2 Hz, 3H); 13C NMR (200 MHz) δ 208.1, 193.4, 141.4,
128.4, 128.2, 127.0, 130.2, 76.2, 58.9, 55.8, 44.0, 22.6, 8.9;
HRMS calcd for C15H18O3 246.126, found 246.125.
(4S,5R)-4-Ben zoyl-5-eth yl-2-cyclopen ten -1-on e (22). Un-
der an argon atmosphere, a solution of the aldol product (0.9
mmol) in diethyl ether (10 mL) was added dropwise to a
solution of LiAlH4 (34 mg, 0.9 mmol) in diethyl ether (30 mL).
After complete addition, the reaction mixture was boiled under
reflux for an additional 30 min and allowed to cool to rt. The
complex was hydrolyzed, and excess lithium aluminum hy-
dride was destroyed by the cautious addition, dropwise and
(47) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
7252 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (-) Prostaglandin E1 Methyl Ester
with stirring, of 10 mL of water. The resulting reaction mixture
was poured into 70 mL of cold aqueous 10% sulfuric acid. The
organic layer was separated, the aqueous layer was extracted
two times with diethyl ether, and the combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2 diethyl ether/
hexane, 1:1, Rf ) 0.31) gave 124 mg (64%) of 22 as a colorless
liquid: 1H NMR (300 MHz) δ 7.75 (dd, J ) 5.7 Hz, J ) 2.1
Hz, 1H), 7.37-7.30 (m, 5H), 6.19 (dd, J ) 5.4, 2.1 Hz, 1H),
4.60 (dd, J ) 6.9, 2.7 Hz, 1H), 2.93 (m, 1H), 2.21 (d, J ) 2.1
Hz, OH), 2.07 (m, 1H), 1.35 (m, 2H), 0.67 (t, J ) 6.9 Hz, 3H);
13C NMR (200 MHz) δ 211.5, 164.1, 142.5, 134.8, 128.7, 128.3,
126.1, 76.5, 54.5, 48.9, 23.1, 10.4; MS (CI) for C114H16O2 m/z )
216 (M+), 234 (M + NH4+).
(4S,5R)-5-E t h yl-4-[(R)-h yd r oxy(p h en yl)m et h yl]-2-cy-
clop en ten -1-on e (23). General procedure for the oxidation
to a diketone was used in this case: Purification by column
chromatography (SiO2 hexane/diethyl ether, 2:3, Rf ) 0.31)
gave 23 in 65% yield as yellow oil: 1H NMR (300 MHz) δ 8.02
(m, 2H), 7.65-7.50 (m, 4H), 6.22 (m, 1H), 4.52 (m, 1H), 2.90
(m, 2H), 1.86 (m, 1H), 1.64 (m, 1H), 0.89 (t, J ) 7.2 Hz, 3H);
13C NMR (200 MHz) δ 210.1, 196.4, 159.7, 134.7, 133.9, 129.0,
128.5, 55.2, 48.8, 23.1, 11.0; MS (EI) for C14H14O2 m/z ) 214
(M+). The ee was determined by HPLC on a chiral stationary
phase (DAICEL CHIRALPAK AD, i-PrOH/hexane 2:98, 1 mL/
min, rt, tR ) 20.6 min, tR ) 25.0 min).
(Z)-3-Iod o-2-octen -1-ol (30). Under an argon atmosphere,
Red-Al (3.4 M in toluene, 49 g, 338 mmol) was dissolved in
diethyl ether (600 mL). To this mechanically stirred solution,
maintained at 0 °C, was added dropwise 2-octyn-1-ol (25 mL,
169 mmol) in ether (50 mL). After 4 h at room temperature,
the reaction mixture was re-cooled to 0 °C and quenched by
addition of ethyl acetate (16.5 mL, 169 mmol). After the
mixture was cooled to -78 °C, iodine (64 g, 254 mmol) was
added in one portion, and the reaction mixture was allowed
to warm to room temperature over 2 h. The reaction mixture
was quenched by slow addition of saturated Na2SO3 (aq), and
the organic layer was separated and washed with Na2SO3 (aq),
water, and saturated NaCl (aq). The resulting organic solution
was dried over MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2 diethyl ether/
pentane, 1:6, Rf ) 0.30) gave 40.3 g (94%) of 30 as a light
purple colored oil (100% cis): 1H NMR (300 MHz) δ 5.78 (t, J
) 5.9 Hz, 1H), 4.14 (d, J ) 5.9 Hz, 2H), 2.44 (t, J ) 7.4 Hz,
2H), 1.48 (m, J ) 7.0 Hz, 2H), 1.24 (m, 4H), 0.84 (t, J ) 6.6
Hz, 3H); 13C NMR (200 MHz) δ 133.2, 111.0, 67.3, 45.1, 30.4,
28.8, 22.4, 14.0; MS (CI) for C8H15IO m/z ) 254 (M)+, 272 (M
+ NH4+).
(Z)-1-Dim eth yl(p h en yl)siloxy-3-iod o-2-octen e (31). To
a solution of 30 (14 g, 59 mmol) in CH2Cl2 (300 mL) were added
Et3N (8.3 mL, 60 mmol) and a catalytic amount of DMAP. At
0 °C, chlorodimethylphenylsilane (10 mL, 59 mmol) in CH2-
Cl2 (20 mL) was added over a period of 1 h. After an additional
1 h, the reaction mixture was poured into NH4Cl (aq), and the
organic layer was filtered and concentrated in vacuo. The
residue was dissolved in pentane (300 mL), washed with water
and NaCl (aq), dried over MgSO4, filtered, and concentrated
in vacuo. The colorless oil (20.6 g, 92%) of 31 was used without
further purification: 1H NMR (300 MHz) δ 7.60-7.50 (m, 2H),
7.40-7.32 (m, 3H), 5.71 (t, J ) 5.4 Hz, 1H), 4.17 (d, J ) 5.4
Hz, 2H), 2.39 (t, J ) 6.8 Hz, 2H), 1.45 (m, J ) 6.6 Hz, 2H),
1.24 (m, 6H), 0.87 (t, J ) 6.5 Hz, 3H), 0.39 (s, 6H); 13C NMR
(200 MHz) δ 142.3, 133.9, 133.4, 129.7, 127.8, 108.4, 68.2, 45.0,
31.9, 30.4, 22.4, 14.0, -1.7; MS (CI) for C16H25IOSi m/z ) 388
(M)+, 406 (M + NH4+).
100 mL of diethyl ether. The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication by column chromatography (SiO2 diethyl ether/pen-
tane, 1:6, Rf ) 0.35) gave 14.8 g (74%) of 32 as a colorless oil
(100% cis): 1H NMR (300 MHz) δ 7.54-7.50 (m, 2H), 7.37-
7.28 (m, 3H), 6.21 (t, J ) 5.7 Hz, 1H), 3.94 (d, J ) 5.7 Hz,
2H), 2.19 (t, J ) 6.9 Hz, 2H), 1.41-1.19 (m, 8H), 0.88 (t, J )
6.8 Hz, 3H), 0.40 (s, 6H); 13C NMR (200 MHz) δ 142.4, 141.4,
139.5, 133.5, 129.0, 128.0, 62.3, 38.3, 31.9, 30.1, 22.5, 14.0,
-1.0; MS (CI) for C16H26OSi m/z ) 262 (M)+, 280 (M + NH4+).
(Z)-3-Dim eth yl(p h en yl)silyl-2-octen a l (25). To a solution
of (COCl)2 (3.7 mL, 42 mmol) in THF (20 mL) was added Me2-
SO (6 mL, 84 mmol) in CH2Cl2 (10 mL) at -78 °C, and the
resulting solution was stirred for 5 min. To this solution was
slowly added alcohol 32 (10 g, 38 mmol) in THF (20 mL), and
the mixture was stirred for 30 min, followed by the addition
of Et3N (26 mL, 190 mmol) in CH2Cl2 (300 mL). The reaction
mixture was warmed to room temperature and quenched with
NH4Cl (aq). The organic layer was separated, and the aqueous
layer was extracted two times with diethyl ether. The com-
bined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(SiO2 diethyl ether/pentane, 1:50, Rf ) 0.34) gave 7.8 g (79%)
of 25 as a bright yellow oil (mixture of E/Z ratio, 7:93 deter-
mined by 1H NMR): 1H NMR (300 MHz) δ 9.68 (d, J ) 8.5
Hz, 1H), 7.50-7.43 (m, 2H), 7.35-7.30 (m, 3H), 6.45 (d, J )
8.5 Hz, 1H), 2.33 (t, J ) 8.0 Hz, 2H), 1.35-1.20 (m, 6H), 0.83
(t, J ) 6.7 Hz, 3H), 0.50 (s, 6H); 13C NMR (200 MHz) δ 192.8,
170.8, 141.5, 138.9, 133.4, 129.4, 128.0, 39.0, 31.3, 28.6, 22.2,
13.7, -0.70; MS (CI) for C16H24OSi m/z ) 260 (M)+, 278 (M +
NH4+).
Meth yl 6-Hep ten oa te (34). A mixture of commercially
available 6-heptenoic acid (5 mL, 37 mmol), MeOH (7 mL),
p-toluenesulfonic acid (0.5 g), and CCl4 (15 mL) was refluxed
for 16 h. After cooling, the mixture was diluted with CH2Cl2
and washed with NaHCO3 (aq). The organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. Purification
by column chromatography (SiO2 diethyl ether/pentane, 1:15,
Rf ) 0.78) gave 4.94 g (94%) of 34 as a colorless oil: 1H NMR
(300 MHz) δ ) 5.82-5.73 (m, 1H), 4.96-4.91 (m, 2H), 3.65 (s,
3H), 2.30 (t, J ) 7.3 Hz, 2H), 2.05 (q, J ) 7.3 Hz, 2H), 1.62
(m, 2H), 1.41 (m, 2H).
Bis(m eth yl-6-h ep a n oa te)zin c (24). Compound 34 (2.84
g, 20 mmol) was cooled (degassed using a freeze/thaw tech-
nique under vacuum/argon) to 0 °C, and HBEt2 [freshly
prepared from BH3‚Et2O (2 M in diethyl ether) and BEt3 (1 M
in THF)] were added via a syringe (1 min). The volatiles were
removed after complete conversion (GC) under vacuum (0.1
mmHg, 0 °C, 1 h). The resulting organoborane was treated at
0 °C with 2 mL of Et2Zn (neat) and stirred at room tempera-
ture for 2 h. The formed BEt3 and the excess Et2Zn were
removed under vacuum (0.1 mmHg, 3 h) giving 3 g (85%) of
24 as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 3.63 (s,
6H), 2.27 (t, J ) 7.8 Hz, 4H), 1.62-1.47 (m, 8H), 1.28-1.25
(m, 8H), 0.31 (t, J ) 7.8 Hz, 4H); 13C NMR (200 MHz, CDCl3)
δ 174.3, 51.4, 36.0, 34.1, 28.9, 26.1, 24.9, 15.9.
Meth yl 7-[(1R,2S)-2-[(1R,2Z)-3-[Dim eth yl(p h en yl)silyl]-
1-h yd r oxy-2-octen yl]-3-oxo-8,8-d ip h en yl-6,10-d ioxa sp ir o-
[4.5]d ec-1-yl]h ep ta n oa te (26). A solution of Cu(OTf)2 (32.4
mg, 0.09 mmol) and phosphoramidite L1 (97 mg, 0.18 mmol)
in toluene (20 mL) was stirred under a nitrogen atmosphere
at ambient temperature for 1 h, whereupon 7d (918 mg, 3
mmol) and 25 (780 mg, 3 mmol) were added. After the reaction
mixture was cooled to -45 °C, 24 (6 mL, 1 M solution in
toluene) was added, and stirring at -45 °C was continued for
18 h. The conversion was determined by TLC. After complete
conversion, the reaction mixture was poured into NH4Cl (aq)
(25 mL), the organic layer was separated, and the aqueous
layer was extracted two times with diethyl ether. The com-
bined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(SiO2 diethyl ether/pentane, 2:1, Rf ) 0.35) gave 1.28 g (60%
(Z)-3-Dim eth yl(p h en yl)silyl-2-octen -1-ol (32). Under ar-
gon atmosphere, 31 (30 g, 77 mmol) was dissolved in THF (400
mL). At -78 °C, 2.2 equiv of t-BuLi (100 mL, 1.7 M pentane)
was added dropwise over a period of 10 min, and the mixture
was stirred for 2 h at the same temperature. The reaction mix-
ture was quenched with NH4Cl (aq) (250 mL), the organic layer
was separated, and the aqueous layer was extracted twice with
J . Org. Chem, Vol. 67, No. 21, 2002 7253

Arnold et al.
yield) of 26 as a colorless oil (mixture of threo/erythro ratio of
83:17): 1H NMR (300 MHz) δ 7.44-7.42 (m, 4H), 7.39-7.12
(m, 9H), 7.01-6.96 (m, 2H), 6.33 (d, J ) 10.0 Hz, 1H) threo,
5.91 (d, J ) 10.0 Hz, 1H) erythro, 4.53 (m, 2H), 4.23-4.05 (m,
3H), 3.64 (s, 3H), 3.06 (d, J ) 17.0 Hz, 1H), 2.32-1.92 (m,
7H), 1.52-0.79 (m, 19H), 0.35 (s, 3H), 0.33 (s, 3H); 13C NMR
(200 MHz) δ 214.4, 174.1, 143.3, 143.1, 142.9, 142.2, 139.3,
133.5, 129.0, 128.5, 128.3, 128.1, 128.0, 127.9, 126.8, 126.2,
103.4, 70.6, 70.1, 68.3, 57.9, 51.3, 47.7, 44.9, 44.6, 38.2, 34.0,
31.7, 29.9, 29.6, 28.9, 27.9, 27.2, 24.9, 22.4, 13.9, -0.9; MS (EI)
for C44H58O6Si m/z ) 710 (M+).
Meth yl 7-[(1R,2R,3S)-2-[(Z)-3-[Dim eth yl(p h en yl)silyl]-
1-h y d r o x y -2-o c t e n y l]-3-h y d r o x y -8,8-d ip h e n y l-6,10-
d ioxa sp ir o[4.5]d ec-1-yl]h ep ta n oa te (35). Under argon at-
mosphere, a solution of 26 (1420 mg, 2 mmol) in diethyl ether
(40 mL) was treated with Zn(BH4)2 (8 mL, 0.5 M in diethyl
ether) at -30 °C. After being stirred for 3 h at the same
temperature, the reaction mixture was quenched with NH4Cl
(aq) in a beaker (250 mL) and stirred for 30 min. The reaction
mixture was diluted with diethyl ether (50 mL), and the
organic layer was separated. The aqueous layer was extracted
two times with diethyl ether, and the combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2 diethyl ether/
mmol) in THF (5 mL). The reaction mixture was stirred at rt
for 3 h, whereupon it was filtered over silica gel (20 g). The
solvent was evaporated at reduced pressure. Purification by
column chromatography (SiO2 diethyl ether/pentane, 3:1, Rf
) 0.35) gave 167 mg (63%) of 37 as a colorless oil: [R]D -39.5
1
(c ) 2.6, CDCl3); H NMR (300 MHz) δ 7.41-6.97 (m, 10H),
5.41 (m, 2H), 5.13 (m, 1H), 4.77 (m, 1H), 4.55 (d, J ) 11.7 Hz,
1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.29 (d, J ) 11.7 Hz, 1H), 4.16
(d, J ) 11.7 Hz, 1H), 3.62 (s, 3H), 2.52 (dd, J ) 14.3, 8.8 Hz,
1H), 2.27 (m, 1H), 2.19 (t, J ) 7.7 Hz, 2H), 2.05 (dd, J ) 14.3,
5.7 Hz, 1H), 1.97 (s, 3H), 1.95 (s, 3H), 1.55-0.84 (m, 19H),
0.81 (t, J ) 6.6 Hz, 3H); 13C NMR (200 MHz) δ 174.3, 170.8,
170.2, 143.6, 143.4, 133.1, 131.2, 128.7, 128.1, 126.8, 126.3,
126.1, 105.9, 75.7, 74.1, 70.4, 68.1, 51.7, 51.4, 44.8, 37.4, 34.2,
34.1, 31.5, 29.7, 28.9, 27.7, 26.4, 25.0, 24.7, 22.5, 21.5, 21.0,
14.0; MS (CI) for C40H54O8 m/z ) 662 (M+).
Meth yl 7-[(1R,2R,3R)-3-Hyd r oxy-2-[(E,3S)-3-h yd r oxy-
1-octen yl]-8,8-d ip h en yl-6,10-d ioxa sp ir o[4.5]d ec-1-yl]h ep -
ta n oa te (38). Acetate 37 (320 mg, 0.46 mmol) was dissolved
in MeOH (2 mL), and potassium carbonate (32 mg, 0.23 mmol)
was added. The reaction was monitored by TLC, and after 3 h
full conversion was reached. The reaction mixture was treated
with NH4Cl (aq) and extracted two times with diethyl ether,
and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by column
chromatography (SiO2 diethyl ether/MeOH, 50:1, Rf ) 0.41)
gave 119 mg (90%) of 38 as a white solid: [R]D -24.5 (c ) 0.9,
CDCl3); 1H NMR (300 MHz) δ 7.41-7.00 (m, 10H), 5.48 (dd, J
) 15.0, 6.7 Hz, 1H), 5.36 (dd, J ) 15.0, 6.7 Hz, 1H), 4.52 (m,
2H), 4.25 (m, 2H), 4.00 (m, 1H), 3.81 (m, 1H), 3.62 (s, 3H),
2.42 (dd, J ) 13.6, 8.4 Hz, 1H), 2.19 (t, J ) 7.7 Hz, 2H), 2.04
(m, 2H), 1.64-0.85 (m, 19H), 0.81 (t, J ) 6.6 Hz, 3H); 13C NMR
(200 MHz) δ 174.3, 143.7, 143.5, 135.8, 132.9, 128.6, 128.0,
126.8, 126.3, 126.1, 106.2, 74.3, 73.0, 70.3, 68.2, 55.8, 52.6, 51.4,
50.8, 44.8, 39.2, 37.2, 34.1, 31.7, 29.6, 28.8, 27.7, 26.8, 25.1,
24.9, 22.6, 14.0; MS (CI) for C36H50O6 m/z ) 578 (M+).
Meth yl 7-[(1R,2R,3R)-3-Hyd r oxy-2-[(E,3S)-3-h yd r oxy-
1-octen yl]-5-oxocyclop en tyl]h ep ta n oa te or P r osta gla n -
d in E1 Meth yl Ester (28). Solid cerium ammonium nitrate
(18 mg, 0.045 mmol) was added to a solution of 38 (87 mg,
0.15 mmol) in MeCN (2 mL) and borate-HCl buffer (Merck,
pH 8, 2 mL). The faintly yellow solution was heated at 60 °C
for 2 h. After the mixture was cooled to room temperature,
H2O (5 mL) and 5 mL of ether were added. The organic layer
was separated, and the aqueous layer was extracted with CH2-
Cl2 (2 × 15 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. Column chroma-
tography (SiO2 diethyl ether/MeOH, 100:3, Rf ) 0.42) gave 26
mg (45%) of 28 as a colorless oil: [R]D -51 (c ) 1.00, CH3OH);
1H NMR (500 MHz) δ 5.64 (dd, J ) 15.0, 7.3 Hz, 1H), 5.51
(dd, J ) 15.0, 8.8 Hz, 1H), 4.09 (m, 1H), 4.00 (m, 1H), 3.63 (s,
3H), 2.70 (dd, J ) 18.6, 7.3 Hz, 1H), 2.32 (dt, J ) 12.1, 8.8 Hz,
1H), 2.26 (t, J ) 7.7 Hz, 2H), 2.20 (dd, J ) 18.3, 9.9 Hz, 1H),
1.96 (dt, J ) 12.1, 5.9 Hz, 1H), 1.60-1.24 (m, 19H), 0.86 (t, J
) 6.9 Hz, 3H); 13C NMR (300 MHz) δ 214.6, 174.3, 136.8, 131.8,
73.0, 71.8, 54.8, 54.4, 51.5, 45.8, 37.3, 34.0, 31.6, 29.3, 28.8,
27.6, 26.5, 25.1, 24.8, 22.6, 14.0; MS (CI) for C36H50O6 m/z 368
(M+), 386 (M + NH4+).
pentane, 5:4, Rf ) 0.30) gave 897 mg (63%) of 35 as colorless
1
oil: [R]23 -31 (c ) 0.9, CHCl3); H NMR (300 MHz) δ 7.47-
D
6.99 (m, 15H), 6.03 (d, J ) 10.0 Hz, 1H), 4.53-4.42 (m, 2H),
4.31-4.24 (m, 2H), 3.94 (m, 2H), 3.63 (s, 3H), 2.44 (d, J ) 5.6
Hz, 1H) OH, 2.23-2.04 (m, 6H), 1.57-0.80 (m, 22H), 0.38 (s,
3H), 0.33 (s, 3H); 13C NMR (200 MHz) δ 174.3, 144.0, 143.7,
143.6, 143.2, 139.8, 133.4, 129.2, 128.6, 128.5, 128.1, 128.0,
126.8, 126.4, 126.1, 107.3, 72.9, 72.1, 70.0, 68.7, 56.8, 51.4, 49.2,
44.8, 38.4, 37.8, 34.1, 31.8, 30.2, 29.8, 29.0, 28.6, 27.9, 25.0,
22.5, 14.0, -0.9, -1.0; MS (EI) for C44H60O6Si m/z ) 712 (M+).
The ee of 94% was determined by HPLC on a chiral stationary
phase (DAICEL CHIRALPAK AD, iPrOH/heptane 25:75, 1 mL/
min, rt, tR ) 4.9 min, tR ) 9.0 min).
Meth yl 7-[(1R,2R,3R)-3-(Acetyloxy)-2-[(1S,2E)-1-(acetyl-
oxy)-2-octen yl]-8,8-d ip h en yl-6,10-d ioxa sp ir o[4.5]d ec-1-yl]-
h ep ta n oa te (36). Under argon atmosphere, a solution of
Bu4NF (6 mL, 1 M THF) was added to a solution of methyl
propionate (176 mg, 2 mmol) in DMSO (3 mL), and the reaction
mixture was refluxed for 2 h. After addition of a solution of
35 (0.6 mmol, 427 mg) in DMSO (3 mL), the reaction mixture
was heated again for an additional 20 min. After full conver-
sion (indicated by TLC), the mixture was poured into NH4Cl
(aq) and diluted with diethyl ether (50 mL), and the organic
layer was separated. The aqueous layer was extracted two
times with diethyl ether, and the combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The
crude products were dissolved in pyridine (4 mL), and acetic
anhydride (2 mL) was added at room temperature together
with a catalytic amount of DMAP. After 20 min, the reaction
mixture was poured into NH4Cl (aq) and extracted two times
with ether, and the combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. Purification by
column chromatography (SiO2 diethyl ether/pentane, 1:1, Rf
) 0.69) gave 282 mg (71%) of 36 as a colorless oil: 1H NMR
(300 MHz) δ 7.39-6.99 (m, 10H), 5.61 (m, 1H), 5.25 (m, 2H),
5.07 (m, 1H), 4.54 (d, J ) 12.0 Hz, 1H), 4.44 (d, J ) 12.0 Hz,
1H), 4.34 (d, J ) 12.0 Hz, 1H), 4.14 (d, J ) 12.0 Hz, 1H), 3.62
(s, 3H), 2.37-1.89 (m, 6H), 1.97 (s, 3H), 1.96 (s, 3H), 1.62-
0.99 (m, 18H), 0.81 (t, J ) 6.5 Hz, 3H); 13C NMR (200 MHz) δ
174.3, 170.6, 170.0, 143.7, 143.4, 134.4, 128.6, 128.3, 128.1,
126.8, 126.5, 126.2, 126.0, 106.7, 73.3, 72.2, 70.3, 68.2, 51.7,
51.4, 47.6, 44.7, 37.2, 34.1, 32.1, 31.3, 29.7, 28.9, 28.5, 27.7,
27.3, 25.0, 22.4, 21.2, 21.1, 14.0; MS (EI) for C40H54O8 m/z )
662 (M+).
Ack n ow led gm en t. Financial support by the Min-
istry of Economic Affairs (EET grant) is gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Characterization of
compounds 7a -c,e, 8, 8a ,b, 9, 11a ,b, 13a -15a , 17a -21a , 11c,
13c-15c, 17c, 13d , and 20d ; NOESY-NMR of compounds
11a ,b and 28 and CD spectra of compound 28; 13C NMR
spectra of compounds: 7a -e, 8-10, 11a ,b, 13a -21a , 11c,
13c-17c, 13d , 20d , 21d , and 22-38. This material is available
free of charge via the Internet at http://pubs.acs.org.
Meth yl 7-[(1R,2R,3R)-3-(Acetyloxy)-2-[(E,3S)-3-(a cetyl-
oxy)-1-octen yl]-8,8-d ip h en yl-6,10-d ioxa sp ir o[4.5]d ec-1-yl]-
h ep ta n oa te (37). Bis(acetonitrile)palladium(II) chloride (18
mg, 0.07 mmol) was added to a solution of 36 (264 mg, 0.4
J O025987X
7254 J . Org. Chem., Vol. 67, No. 21, 2002