Modular enantioselective synthesis of 8-aza-prostaglandin E1

Article abstract of DOI:10.1021/jo401412g

We report herein for the first time the enantioselective synthesis of 8-aza-PGE₁. The synthesis used the cross olefin metathesis reaction to connect the 5-vinyl-γ-lactam subunit, prepared from (R)-malic acid via the Ley's sulfone-based α-amidalkylation protocol (dr = 6.8:1), with the chiral pre-ω-chain. The latter was synthesized in high enantioselectivity from (E)-2-octenol by the Sharpless asymmetric epoxidation and the titanocene-mediated epoxide opening. This modular approach is quite concise and flexible, and requires only eight steps from commercially available reagents.

Full text of DOI:10.1021/jo401412g

Note
pubs.acs.org/joc
Modular Enantioselective Synthesis of 8‑Aza-prostaglandin E1
Xiao-Gang Wang, Ai-E Wang, Yi Hao, Yuan-Ping Ruan, and Pei-Qiang Huang*
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China
*
S Supporting Information
ABSTRACT: We report herein for the first time the
enantioselective synthesis of 8-aza-PGE . The synthesis used
1
the cross olefin metathesis reaction to connect the 5-vinyl-γ-
lactam subunit, prepared from (R)-malic acid via the Ley’s
sulfone-based α-amidalkylation protocol (dr = 6.8:1), with the
chiral pre-ω-chain. The latter was synthesized in high
enantioselectivity from (E)-2-octenol by the Sharpless asymmetric epoxidation and the titanocene-mediated epoxide opening.
This modular approach is quite concise and flexible, and requires only eight steps from commercially available reagents.
9
−11
rostaglandins (PGs) are a group of naturally occurring
lipid compounds found in trace amount in animals and in
interesting γ-lactam analogues discovered.
For example,
P
compound 2 was shown to be a potent and selective agonist of
the prostaglandin EP ; CP-734432 (3) is a highly selective EP
receptor agonist with an IC50 = 2 nM; PF-4475270 (4), the
isopropyl ester prodrug of 3, is a novel ocular hypotensive
compound capable of effectively lowering intraocular pressure
in dogs.
9
men. They are mediators and have a variety of strong
physiological effects, which has made them very promising
for the development of new therapeutic agents for a number of
4
4
10
1
diseases. Since the elucidation of their structures in the early
1
960s, and throughout 1970s, the total synthesis of
2
prostaglandins has attracted tremendous attention of numer-
ous chemists and pharmaceutical companies. These and the
following studies have led to the development of many
imaginative synthetic approaches and new chemistries, such
In spite of significant progress made in the chemistry and
9
−11
medicinal chemistry of 8-aza-analogues of PGs,
11-deoxy analogues of PGs have so far been reported; the 8-
aza-analogues of PGE with the 11-hydroxyl group retained has
never been reported. In light of the structure of PGE
(alprostadil), its medical usage, and side effects, it is
worthwhile to develop a method for the enantioselective
. Our group has long been interested in
the asymmetric synthesis of bioactive N-containing com-
pounds, and recently reported the synthesis of two aza-
prostaglandin analogues, namely, the 11-hydroxylated ana-
logues of the lead compounds CP-734432 (3) and PF-
only 8-aza-
1
3
as the three-component strategy. However, due to the
1
12
13
problems of the inherent instability, quick metabolism and
side effects, the development of PGs as medicinal agents has
2
been impeded. To tackle these problems, much effort has been
synthesis of 8-aza-PGE
1
devoted to the synthesis of prostaglandin analogues. Up until
14
1
984, over 5000 prostaglandin analogues have been synthesized
3a
and tested biologically. Those efforts resulted in the discovery
1
of several drugs currently in clinical use, which include
0
4475270 (4), by SmI -mediated intermolecular coupling of
prostaglandin E (PGE , alprostadil) and the analogues of
2
1
1
1
5
lactam N-α-radicals with activated alkenes. As a continuation
prostaglandins, such as Misoprostol (15-methyl-PGE , Cytotec;
1
of this study, we now report the synthesis of 8-aza-PGE by a
Anthrotec); Limaprost, Latanoprost (Xalatan), Carboprost
Hemabate), Bimatoprost (Lumigan), Travoprost (Travatan,
Travatan Z, Travo-Z), Tafluprost (Ziopta, Taflotan), and so
1
new strategy.
(
Among the strategies developed for the asymmetric synthesis
2
,3,5,7,8
of PGs, prostacyclins, and analogues,
metathesis-based strategy
the cross olefin
is quite flexible for the
installation of the chiral ω-chain. Inspired by this strategy,
our retrosynthetic analysis of 8-aza-PGE 7 is depicted in
forth. Four of these pharmaceuticals entered the list of top 200
7
c−e,8c
4
brand-name drugs by total US prescriptions in 2010. In this
context, many aza-analogues of PGE, in which a CH or a CH2
of the cyclopentane ring is replaced by a nitrogen atom, have
1
1
6
5
Scheme 1. A retro-cross olefin metathesis disconnection of
the protected 8-aza-PGE 8 suggested 5-vinyl-pyrrolidin-2-one
been synthesized. The diastereomeric mixture of the 15α and
1
5β analogues was found to effectively interrupt pregnancy in
1
9
and (S)-allylic alcohol 10 (pre-ω-chain) as the precursors. To
further enhance both the efficiency and flexibility of the cross
the hamster and displayed only minimal smooth muscle activity
5d
relative to PGF .
2
α
7
d,e,8c
olefin metathesis-based strategy,
and in view of the
7d,e,8c
In recent years, with the development of synthetic chemistry
problems in the creation of the stereogenic center at C15,
and progress in the identification and cloning of PG receptor
6
7,8
introduction of an efficient and flexible method for the
subtypes, there is renewed interest in the synthesis and
8
−11
medicinal chemistry
of PGs, prostacyclins, isoprostanes,
neuroprostanes, and their analogues. Highly efficient synthetic
strategies have been developed and several medicinal
Received: July 2, 2013
Published: August 19, 2013
7
©
2013 American Chemical Society
9488
dx.doi.org/10.1021/jo401412g | J. Org. Chem. 2013, 78, 9488−9493

The Journal of Organic Chemistry
Note
Scheme 2
Figure 1. Prostaglandin E and its 8-aza analogues.
1
Scheme 1. Retrosynthetic Analysis of 8-aza-PGE (7)
1
20
method is known for a long time, its advantage in yielding
21
racemization-free product was proven only very recently. The
desired malimide derivative 14 was thus produced in 79% yield
by heating the mixture of (R)-malic acid and 13 in the presence
of triethylamine in xylene at reflux for 8 h. The hydroxyl group
of 14 was then protected to give benzyl ether 11 (BnBr, Ag O,
2
EtOAc, rt, 72 h, yield: 95%). Treatment of malimide 11 with
2
2
NaBH in THF at −30 °C for 15 min gave hemiaminal 15
4
regio- and chemoselectively, as a separable 11:1 diastereomeric
mixture in a combined yield of 82%. Under the Ley conditions
19
(
PhSO H, CaCl , CH Cl , rt, 2 h), the diastereomeric
2 2 2 2
mixture of hemiaminal 15 was converted smoothly to sulfone
2 as a separable diastereomeric mixture in 84% yield. Since the
subsequent acid-catalyzed α-amidoalkylation reaction is known
1
23
to pass through the N-acyliminium ion intermediate, the
diastereomeric mixture of sulfone 12 was used for the next step
without separation. We have previously demonstrated that the
combination of α-phenylsulfonyllactams as the reactive
substrates with in situ generated organozinc reagents is efficient
for the trans-α-amidoalkylation of malimide-derived sulfones,
24
construction of the pre-ω-chain 10 in high enantioselectivity is
albeit the diastereoselectivities are modest. The application of
this method to the asymmetric synthesis of alkaloids has been
highly desirable. In light of our recent work on the total
14d
25
synthesis of (+)-awajanomycin,
the pre-ω-chain 10 was
recently nicely demonstrated by Martin. In the event, the
envisioned to be synthesized from commercially available (E)-
diastereomeric mixture of sulfone 12 in CH Cl was treated
with the zinc reagent, generated in situ from vinyl magnesium
2
2
17
2-octenol by a combination of Sharpless epoxidation with the
titanocene-mediated stereospecific epoxide opening, a method
bromide and a 1 M solution of anhydrous ZnCl in diethyl
ether, at rt for 2 h to produce the desired vinylated product 9 in
82% yield as a diastereomeric mixture (dr = 6.8:1). On the basis
2
18
developed by Yadav and co-workers. 5-Vinyl-pyrrolidin-2-one
could be accessible from malimide derivative 11 via α-
amidovinylation of α-phenylsulfonyllactam 12 with the method
9
of the observed small vicinal coupling constant between H and
4
19
developed by Ley and co-workers. Finally, malimide 11 can
be prepared by the condensation of commercially available (R)-
malic acid and ethyl 7-aminoheptanoate hydrochloride salt 13.
The synthesis started from the direct condensation of (R)-
malic acid with the commercially available α,ω-amino ester
hydrochloride salt 13 (Scheme 2). Although this condensation
H5 (J4,5 = 2.0 Hz), the stereochemistry of the major
22
diastereomer of 9 was assigned as trans. This assignement
was confirmed by NOESY experiments on the major
diastereomer 9. The NOE correlations between H and the
4
vinylic proton at C1′, as well as H and a benzylic proton were
5
observed, which indicate the 4,5-trans-stereochemistry.
9
489
dx.doi.org/10.1021/jo401412g | J. Org. Chem. 2013, 78, 9488−9493

The Journal of Organic Chemistry
Note
On the other hand, (S)-allylic alcohol 10 was synthesized
from (E)-2-octenol in two steps (Scheme 3). The Sharpless
Scheme 4
Scheme 3
17
asymmetric epoxidation of (E)-2-octenol (16) gave epoxy
alcohol 17 in 91% yield (99% ee), which was converted in 84%
yield to (S)-allylic alcohol 10 by treatment with Cp TiCl , Zn,
2
2
18
and ZnCl in THF at rt. To the best of our knowledge, this is
2
the first use of this method for the preparation of the pre-ω-
chain of PGs. In addition, the easy availability of other achiral
(
E)-allylic alcohols and versatility of both the Sharpless
asymmetric epoxidation reaction and the Yadav’s method
render this method flexible for preparing other analogues of
pre-ω-chain of PGs.
enantioselective construction of the ω-chain of PGs, which, in
combination with the cross olefin metathesis strategy,
constitutes a powerful strategy for the synthesis of PGs,
prostacyclins and analogues in general.
With vinylic compound 9 and allylic alcohol 10 in hand, their
cross olefin metathesis reaction was then attempted. However,
26
all the attempts using the Grubbs second generation catalyst
EXPERIMENTAL SECTION
were unsuccessful, with the starting vinyl lactam 9 remaining
intact.
■
Ethyl 7-[(3R)-hydroxy-2,5-dioxopyrrolidin-1-yl]heptanoate
(
14). To a 150 mL round-bottom flask equipped with a Dean−Stark
The failure of cross olefin metathesis might be attributed to
the steric hindrance of the substrate 9. Thus the unprotected β-
hydroxy-γ-lactam 18 was envisioned as the substrate for the
cross olefin metathesis reaction. The benzyl group in
compound 9 was cleaved chemoselectively by treatment with
BBr in CH Cl at −10 °C. To our delight, the two alcoholic
apparatus were added successively (R)-malic acid (5.04 g, 37.3 mmol),
commercially available ethyl 7-aminoheptanoate hydrochloride salt 13
(
7
9.41 g, 44.8 mmol), xylene (94 mL), and triethylamine (10.4 mL,
4.6 mmol). The mixture was stirred and heated to reflux for 8 h. The
resulting mixture was diluted with EtOAc (30 mL) and washed
successively with water (20 mL) and brine (10 mL). The organic
phase was dried over anhydrous Na SO , filtered, and concentrated
3
2
2
diastereomers are separable and the major diastereomer 18 was
isolated in 80% yield. The subsequent cross olefin metathesis
between 18 and allylic alcohol 10 in the presence of the Grubbs
2
4
under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent:EtOAc/PE = 1:1) to afford
2
0
compound 14 (10.10 g, yield: 76%) as a colorless oil; [α]D +47.7 (c
second generation catalyst proceeded smoothly in CH Cl at 40
2
2
−1 1
1
.0, CHCl ); IR (film) ν : 3444, 1781, 1702, 1407, 1175 cm ; H
3 max
°
C to produce the desired olefin 19 in 53% yield. The
NMR (400 MHz, CDCl ) δ 1.15 (t, J = 7.2 Hz, 3H), 1.18−1.28 (m,
3
formation of (E)-olefins from the cross olefin metathesis
4
4
H), 1.41−1.53 (m, 4H), 2.18 (t, J = 7.6 Hz, 2H), 2.56 (dd, J = 18.0,
.8 Hz, 1H), 2.97 (dd, J = 18.0, 8.4 Hz, 1H), 3.38 (t, 7.4 Hz, 2H), 4.01
7
e,14d,16
reactions has been well documented in the literature.
The E-geometry of olefin 19 was also deduced from the
(
q, J = 7.2 Hz, 2H), 4.56 (dd, J = 8.4, 4.8 Hz, 1H), 4.75 (s, 1H, D O
2
13
characteristic olefinic vicinal coupling constant (J = 15.4 Hz)
exchangeable); C NMR (100 MHz, CDCl ) δ 14.0, 24.4, 26.1, 27.1,
vic
3
−1
and the absorption at 968 cm in its IR spectrum. Finally,
28.3, 33.9, 37.1, 38.5, 60.1, 66.6, 173.7, 174.4, 178.4; HRESIMS calcd
+
+
LiOH-catalyzed saponification of ester 19 gave the 8-aza-PGE1
for [C13H21NNaO ] (M+Na ): 294.1312; found: 294.1314.
5
Ethyl 7-[(3R)-benzyloxy-2,5-dioxopyrrolidin-1-yl]-
heptanoate (11). To a stirred suspension of compound 14 (4.7 g,
(
7) in 96% yield.
To determine the enantiomeric excess of the product, (R)-
1
7.38 mmol) and Ag O (12.0 g, 52.17 mmol) in EtOAc (30 mL) was
2
MTPA-Cl and (S)-MTPA-Cl were reacted respectively with
added BnBr (8.95 g, 52.4 mmol). The reaction was stirred at room
temperature for 3 days in dark. After that, the mixture was filtered
through a silica gel pad, and washed with EtOAc (35 mL × 3). The
filtrate was concentrated under reduced pressure and the residue was
purified by silica gel chromatography (EtOAc/PE = 1:8) to give
1
compound 18. The H NMR spectrum of each Mosher ester
shows only one diastereomer (according to the signal of OMe:
δ = 3.57 for (R,R)-diastereomer; δ = 3.60 for (R,S)-
diastereomer), which allows us to conclude that the ee of
compound 18 is higher than 95% (at the limit of the method).
In summary, starting from (R)-malic acid, the first synthesis
of 8-aza-prostaglandin E (8-aza-PGE , 7) was achieved by a
2
0
compound 11 (5.96 g, yield: 95%) as a colorless oil; [α]
.0, CHCl ); IR (film) νmax: 2934, 1710, 1620, 1542, 1399, 1179, 1105
+38.6 (c
D
1
3
−
1 1
cm ; H NMR (400 MHz, CDCl ) δ 1.23 (t, J = 7.1 Hz, 3H), 1.28−
3
1
1
1
.34 (m, 4H), 1.52−1.63 (m, 4H), 2.26 (t, J = 7.5 Hz, 2H), 2.62 (dd, J
18.2, 4.1 Hz, 1H), 2.91 (dd, J = 18.2, 8.3 Hz, 1H), 3.48 (t, J = 7.4
Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 4.33 (dd, J = 8.3, 4.1 Hz, 1H), 4.77
d, J = 11.7 Hz, 1H), 4.96 (d, J = 11.7 Hz, 1H), 7.29−7.37 (m, 5H);
longest linear sequence of eight steps with 17% overall yield.
The easy introduction of both the α-chain (by malimide
formation) and the ω-chain (by cross olefin metathesis
reaction) makes the method flexible. Importantly, the pre-ω-
chain (10) was synthesized from achiral allylic alcohol (16) in
only two steps. To the best of our knowledge, this is one of the
most convenient and flexible methods for the highly
=
(
13
C NMR (100 MHz, CDCl ) δ 14.2, 24.7, 26.4, 27.4, 28.6, 34.2, 36.2,
3
3
8.6, 60.2, 72.1, 72.9, 128.18 (2C), 128.22, 128.6 (2C), 136.8, 173.6,
+
+
174.2, 175.9; HRESIMS calcd for [C H NNaO ] (M+H ):
2
0
27
5
384.1781; found: 384.1784.
9
490
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The Journal of Organic Chemistry
Note
Ethyl 7-[(4R,5R/S)-4-benzyloxy-5-hydroxy-2-oxopyrrolidin-
1H), 3.61 (dt, J = 13.6, 8.0 Hz, 1H), 3.88 (ddd, J = 6.6, 3.2, 3.2 Hz,
1H), 4.05 (dd, J = 7.8, 3.2 Hz, 1H), 4.11 (q, 7.2 Hz, 2H), 4.52 (d, J =
12.0 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 5.24−5.31 (m, 2H), 5.63
1
1
1
-yl]heptanoate (15). To a cooled (−30 °C) solution of compound
1 (1.13 g, 3.13 mmol) in THF (7.8 mL) was added NaBH (0.48 g,
4
13
2.52 mmol) in one portion. The resulting suspension was stirred at
the same temperature for 15 min. Fifteen mL of saturated aqueous
(ddd, J = 17.6, 9.6, 7.8 Hz, 1H), 7.27−7.37 (m, 5H); C NMR (100
MHz, CDCl ) δ 14.3, 24.8, 26.4, 27.0, 28.8, 34.3, 37.0, 40.3, 60.2, 67.2,
3
solution of NaHCO and brine were added. The resulting mixture was
71.2, 118.8, 127.6 (2C), 127.9, 128.5 (2C), 135.1, 137.5, 172.3, 173.7;
3
+
+
extracted with CH Cl (3 × 25 mL). The combined extracts were
HRESIMS calcd for [C H NNaO ] (M+Na ): 396.2145; found:
2
2
22 31 4
dried over anhydrous Na SO , filtered, and concentrated under
396.2149.
2
4
reduced pressure to give hemiaminal 15 as a diastereomeric mixture
0.93 g, yield: 82%, cis/ trans = 11: 1). A sample of the major
diastereomer was obtained by flash chromatography on silica gel
Ethyl 7-[(4R,5S)-4-benzyloxy-2-oxo-5-vinylpyrrolidin-1-yl]-
heptanoate (18). To a vigorously stirred solution of the
diastereomeric mixture of 9 (cis/trans = 1:6.8, 60 mg, 0.16 mmol) in
(
(
1
EtOAc/PE= 1:3), which was confirmed to be the cis-diastereomer. cis-
CH Cl (1.6 mL) was slowly added BBr (1.0 M in CH Cl , 0.32 mL,
2 2 3 2 2
5 (major diastereomer): colorless oil; [α]D20 −15.2 (c 1.0, CHCl );
0.32 mmol) at −10 °C under an atmosphere of Ar. The mixture was
stirred at the same temperature for 10 min. The reaction was
3
IR (film) νmax: 3390, 2925, 2855, 1731, 1681, 1453, 1385, 1266, 1183,
−1 1
1
3
2
121, 1026 cm ; H NMR (400 MHz, CDCl ) δ 1.24 (t, J = 7.1 Hz,
quenched with a saturated aqueous solution of NaHCO
resulting mixture was extracted with CH Cl (3 mL × 3). The
combined organic phases were dried over anhydrous Na SO , filtered,
3
, and the
3
H), 1.30−1.38 (m, 4H), 1.49−1.65 (m, 4H), 2.27 (t, J = 7.4 Hz, 2H),
2
2
.50 (dd, J = 16.8, 5.6 Hz, 1H), 2.55 (dd, J = 16.8, 6.6 Hz, 1H), 3.22
2
4
(
ddd, J = 14.0, 8.8, 5.6 Hz, 1H), 3.41 (ddd, J = 14.0, 9.2, 6.8 Hz, 1H),
and concentrated under reduced pressure. The residue was purified by
3
4
5
1
.52 (d, J = 8.1 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.08−4.15 (m, 1H),
column flash chromatography eluting with ethyl acetate:petroleum
.59 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 11.6 Hz, 1H), 5.12 (dd, J = 8.1,
ether (2:1) to give diastereomer 18 as a colorless oil (37 mg, yield:
1
3
20
.6 Hz, 1H), 7.31−7.40 (m, 5H); C NMR (100 MHz, CDCl ) δ
80%). [α]
D
−25.6 (c 1.0, CHCl ); IR (film) νmax: 3386, 2921, 1735,
3
3
−1 1
4.3, 24.8, 26.6, 27.6, 28.8, 34.2, 35.9, 40.3, 60.2, 71.9, 72.2, 82.2, 128.0
1692, 1449, 1428, 1250, 1179, 1063, 968 cm ; H NMR (500 MHz,
CDCl ) δ 1.15 (t, J = 7.2 Hz, 3H), 1.18−1.26 (m, 4H), 1.36−1.1.46
(
2C), 128.4, 128.7 (2C), 136.6, 171.1, 173.8; HRESIMS calcd for
3
+
+
[
C H NNaO ] (M+Na ): 386.1938; found: 386.1935.
(m, 2H), 1.47−1.54 (m, 2H), 2.18 (t, J = 7.5 Hz, 2H), 2.23 (dd, J =
17.1, 3.1 Hz, 1H), 2.58 (dd, J = 17.1, 6.5 Hz, 1H), 2.74 (ddd, J = 14.8,
8.2, 5.5 Hz, 1H), 3.48 (dt, J = 14.8, 7.8 Hz, 1H), 3.85 (dd, J = 7.9, 2.2
Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 4.01−4.05 (m, 1H), 4.32 (d, 4.3 Hz,
20
29
5
Ethyl 7-[(4R,5S/R)-4-benzyloxy-5-(phenylsulfonyl)-2-oxopyr-
rolidin-1-yl] heptanoate (12). A suspension of the diastereomeric
mixture of compound 15 (1.25 g, 3.4 mmol), freshly prepared
benzenesulfinic acid (2.93 g, 20.7 mmol), and CaCl (2.27 g, 20.7
1H, D O exchangeable), 5.10−5.20 (m, 2H), 5.55 (ddd, J = 7.9, 9.6,
2
2
13
mmol) in CH Cl2 (86 mL) was stirred for 2 h at rt under an
17.6 Hz, 1H); C NMR (125 MHz, CDCl ); δ 14.0, 24.6, 26.1, 26.7,
2
3
atmosphere of nitrogen. The reaction was quenched with water and
extracted with dichloromethane. The combined extracts were washed
with saturated NaHCO , dried over anhydrous Na SO , filtered, and
28.5, 34.0, 39.3, 40.3, 60.1, 69.8 (2C), 118.4, 134.5, 172.9, 173.7;
+
+
HRESIMS calcd for [C H NNaO ] (M+Na ): 306.1676; found:
15
25
4
306.1673.
3
2
4
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent:EtOAc/PE = 1:1) to give a
diastereomeric mixture of sulfone compound 12 (1.41 g, yield: 84%)
as a colorless oil, which, upon standing at −20 °C for several weeks
epimerized to give trans-12 as a single diastereomer. trans-12: colorless
[(2S,3S)-3-Pentyloxiran-2-yl]methanol (17). Under a nitrogen
atmosphere, to a stirring and cooled (−25 °C) suspension of activated
powered 4 Å molecular sieves (950 mg) in anhydrous CH Cl (60
2
2
mL) were added successively L-DIPT (1.10 g, 4.7 mmol) in anhydrous
CH Cl (5 mL) and Ti(OPr-i) (1.10 g, 3.9 mmol) in anhydrous
2
2
4
oil; [α]D20 +17.3 (c 1.0, CHCl ); IR (film) νmax: 2859, 1714, 1449,
CH Cl (4 mL). The mixture was stirred for 15 min, and commercially
3
2 2
−1 1
1
407, 1316, 1150, 1092 cm ; H NMR (400 MHz, CDCl ) δ 1.25 (t,
available (E)-2-octenol (16) (2.0 g, 15.6 mmol) in anhydrous CH Cl
2 2
3
J = 7.2 Hz, 3H), 1.18−1.34 (m, 4H), 1.44−1.59 (m, 4H), 2.01 (dd, J =
(5 mL) was added. After stirring for 30 min, TBHP (2.20 mL, 21.9
mmol) was added slowly. The mixture was stirred at the same
temperature for 5 h before quenching with an aqueous solution (7
1
7.8, 6.3 Hz, 1H), 2.20−2.27 (m, 3H), 3.04 (ddd, J = 13.7, 7.8, 5.4 Hz,
1H), 3.81 (dt, J = 13.7, 7.8 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.32 (d,
J = 6.3 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H),
mL) containing FeSO (2.42 g) and citric acid (760 mg). The mixture
4
4
2
.74 (s, 1H), 7.22−7.26 (m, 2H), 7.28−7.36 (m, 3H), 7.55−7.62 (m,
was stirred for 15 min. The organic layer was separated, and the
13
H), 7.70−7.75 (m, 1H), 7.80−7.84 (m, 2H); C NMR (100 MHz,
aqueous layer extracted with CH Cl (15 mL × 3). The combined
2
2
CDCl ) δ 14.26, 24.73, 25.91, 26.22, 28.59, 34.15, 36.80, 41.91, 60.19,
7
organic extracts were washed with brine, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure. The
3
1.21, 72.63, 82.69, 127.80 (2C), 128.17, 128.59 (2C), 129.15 (2C),
2
4
1
29.82 (2C), 134.99, 135.57, 136.57, 173.61, 173.73; HRESIMS calcd
residue was purified by flash column chromatography on silica gel
+
+
for [C H NNaO S] (M+Na ): 510.1921; found: 510.1922.
(EtOAc/PE = 1:5) to give epoxide 17 (2.05 g, yield: 91%, ee = 99%) as
26
33
6
2
0
Ethyl 7-[(4R,5S/R)-4-benzyloxy-2-oxo-5-vinylpyrrolidin-1-yl]-
heptanoate (9). To a solution of anhydrous zinc chloride (1.0 M in
diethyl ether, 2.93 mL. 2.93 mmol) in dichloromethane (6.0 mL) was
a colorless oil. [α]
D
−38.0 (c 1.0, CHCl ); IR (film) νmax: 3427,
3
−1 1
2954, 2915, 2859, 1602, 1465, 1374, 1080, 1026, 889 cm ; H NMR
(500 MHz, CDCl ) δ 0.9 (t, J = 7.0 Hz, 3H), 1.28−1.36 (m, 4H),
3
added dropwise an Et O solution of the vinyl magnesium bromide (1.0
1.38−1.49 (m, 2H), 1.54−1.60 (m, 2H), 2.23 (t, J = 5.5 Hz, 1H, D O
2
2
M in diethyl ether, 4.9 mL, 4.90 mmol). The mixture was stirred at
room temperature under an atmosphere of nitrogen for 30 min. A
solution of the diastereomeric mixture of sulfone 12 (1.191 g, 2.44
mmol) in anhydrous dichloromethane (5 mL) was added and the
mixture was stirred at room temperature for another 14−16 h. The
reaction was quenched with water, and extracted with dichloro-
methane (3 × 25 mL). The combined organic phases were dried,
filtered, and concentrated under reduced pressure. The residue was
purified by chromatography (eluent:EtOAc/PE = 1:3−1:1) to give
vinyl lactam 9 as an inseparable diastereomeric mixture (896 mg, yield:
exchangeable), 2.92 (dt, J = 4.5, 2.5 Hz, 2H), 2.95 (td, J = 5.6, 2.3 Hz,
13
1H), 3.61 (m, 1H), 3.87−3.93 (m, 1H); C NMR (125 MHz,
CDCl ): δ 13.9, 22.5, 25.6, 31.5, 31.5, 56.1, 58.6, 61.8; HRESIMS calcd
3
+
+
for [C H NaO ] (M+Na ): 167.1043; found: 167.1064. The
8
16
2
enantiomeric excess (ee) of epoxide (2S,3S)-17 was determined by
HPLC analysis of the corresponding 3,5-dinitrobenzoyl ester (column:
Chiralpak AD-H; n-hexane/ethanol = 80:20; flow rate: 1.0 mL/min).
tR (min): (2S,3S)-17: 39.0 (99.5%); (2R,3R)-17: 41.3 (0.48%), ee =
99% (c.f. Supporting Information).
(S)-Oct-1-en-3-ol (10). To a red solution of Cp TiCl (9.71 g, 39.0
2
2
82%, cis/trans = 1:6.8). A sample of pure trans-diastereomer (trans-9)
mmol) in anhydrous THF (45 mL) were added anhydrous zinc
was obtained via O-debenzylation-diastereomers separation and re-O-
chloride (18.6 mL, 0.7 M in Et O, 13.0 mmol) and zinc powder (2.50
2
benzylation. trans-9: colorless oil; [α]D20 −16.3 (c 1.0, CHCl ); IR
g, 39 0.0 mmol). The mixture was stirred for 1 h at room temperature
while the solution turned green. To the resultant mixture was added
epoxide 17 (1.87 g, 13.0 mmol) in anhydrous THF (7 mL), and the
resultant mixture was stirred for 30 min. The reaction was quenched
with aqueous HCl (1.0 M, 5 mL), and the mixture was extracted with
3
(
film) νmax: 2929, 2855, 1735, 1694, 1457, 1179, 1092, 1063, 968
−1 1
cm ; H NMR (400 MHz, CDCl ) δ 1.24 (t, J = 7.2 Hz, 3H), 1.21−
1
=
3
.36 (m, 4H), 1.41−1.63 (m, 4H), 2.26 (t, J = 7.6 Hz, 2H), 2.46 (dd, J
17.2, 3.2 Hz, 1H), 2.65 (dd, J = 17.2, 6.6 Hz, 1H), 2.75−2.85 (m,
9
491
dx.doi.org/10.1021/jo401412g | J. Org. Chem. 2013, 78, 9488−9493

The Journal of Organic Chemistry
Note
Et O (10 mL × 3). The organic layers were successively washed with
2
AUTHOR INFORMATION
Corresponding Author
E-mail: pqhuang@xmu.edu.cn
■
*
water, 10% aqueous NaHCO , water, and brine; dried over anhydrous
3
Na SO ; filtered; and concentrated under reduced pressure. The
2
4
residue was purified by flash column chromatography on silica gel
Et O/PE = 1:5) to give compound 10 (1.40 g, yield: 84%) as a
(
Notes
2
20
colorless oil. [α]D +10.0 (c 1.0, CHCl ); IR (film) ν : 3423, 2958,
2
The authors declare no competing financial interest.
3
max
−1 1
925, 2851, 1653, 1590, 1348, 1270, 1121, 1080, 1017 cm ; H NMR
(
400 MHz, CDCl ) δ 0.86 (t, J = 6.8 Hz, 3H), 1.22−1.41 (m, 6H),
ACKNOWLEDGMENTS
3
■
1
4
1
.42−1.55 (m, 2H), 2.00 (d, J = 2.4 Hz, 1H, D O exchangeable),
2
The authors are grateful to National Basic Research Program
973 Program) of China (Grant No. 2010CB833200) and the
NSF of China (21072160; 20832005) for financial support.
.01−4.09 (m, 1H), 5.05 (dt, J = 10.4, 1.3 Hz, 1H), 5.18 (dt, J = 17.0,
(
.3 Hz, 1H), 5.83 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H); 13C NMR (100
MHz, CDCl ) δ 14.0, 22.6, 25.0, 31.8, 37.0, 73.2, 114.4, 141.4;
HRESIMS calcd for [C H NaO] (M+Na ): 151.1093; found:
1
3
+
+
8
16
REFERENCES
51.1086.
■
Ethyl 7-{(4R,5S)-4-hydroxy-5-[(3S,E)-3-hydroxyoct-1-en-1-
(1) Marks, F.; Furstenberger, G. Prostaglandins, Leukotrienes and
Other Eicosanoids. From Biogenesis to Clinical Application; Wiley-VCH:
Weinheim, 1999.
yl]-2-oxopyrrolidin-1-yl} heptanoate (19). To a stirred solution
of compound 18 (45 mg, 0.16 mmol) and compound 10 (100 mg,
0
.80 mmol) in CH Cl (1.6 mL) was added Grubbs second generation
(2) For a recent review on the chemistry of prostaglandins, see:
Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533−1564 and
references cited therein..
2
2
catalyst (27 mg, 0.03 mmol). After being stirred at 40 °C for 24 h, the
mixture was concentrated under reduced pressure. The residue was
purified by column flash chromatography on silica gel (eluent:EtOAc/
PE = 2:1) to give compound 19 as a colorless oil (32 mg, yield: 53%).
(
3) (a) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984, 23,
47−876. (b) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439−
4486.
8
́
[
1
α]D20 −7.0 (c 0.2, CHCl ); IR (film) νmax: 3375, 2929, 2855, 1739,
3
−1
1
(4) J. Chem. Educ. 2010, 87, 1348; http://cbc.arizona.edu/
njardarson/group/top-pharmaceuticals-poster.
660, 1457, 166, 1179, 968 cm ; H NMR (400 MHz, CDCl ) δ 0.88
3
(
1
(
t, J = 6.4 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.15−1.39 (m, 10H),
.40−1.55 (m, 4H), 1.55−1.64 (m, 2H), 2.27 (t, J = 7.4 Hz, 2H), 2.34
dd, J = 17.0, 3.6 Hz, 1H), 2.69 (dd, J = 17.0, 6.4 Hz, 1H), 2.80 (ddd,
(
5) For selected syntheses of 11-deoxy-8-aza-prostaglandin E1
analogues, see: (a) Smith, R. L.; Lee, T.; Gould, N. P.; Cragoe, E. J.,
Jr.; Oien, H. G.; Kuehl, F. A., Jr. J. Med. Chem. 1977, 20, 1292−1299.
14.5, 8.0, 5.6 Hz, 1H), 3.29 (s, 1H, D O exchangeable), 3.58 (dt, J =
2
(
1
b) Barco, A.; Benetti, S.; Pollini, G. P. J. Org. Chem. 1979, 44, 1734−
1
4.5, 8.0 Hz, 1H), 3.87−3.94 (dd, J = 8.2, 1.9 Hz, 1H), 4.12 (q, J = 7.1
736. (c) Wang, C.-L. J Tetrehedron Lett. 1982, 23, 1067−1070.
Hz, 2H), 4.08−4.16 (m, 2H), 4.28 (br, 1H, D O exchangeable), 5.47
2
(d) Zoretic, P. A.; Bhakta, C.; Jardin, J. J. Heterocyclic Chem. 1983, 20,
13
(
(
dd, J = 15.4, 8.2 Hz, 1H), 5.73 (dd, J = 15.4, 6.4 Hz, 1H); C NMR
100 MHz, CDCl ) δ 14.0, 14.2, 22.6, 24.7, 25.1, 26.2, 26.9, 28.6, 31.6,
4
65−466 and references cited therein..
3
(6) Jones, R. L.; Giembycz, M. A.; Woodward, D. F. Br. J. Pharmacol.
3
4.2, 37.2, 39.4, 40.4, 60.3, 68.9, 70.7, 71.9, 126.9, 138.0, 172.4, 174.0;
2
009, 158, 104−145 and references cited therein..
+
+
HRESIMS calcd for [C H NNaO ] (M+Na ): 406.2564; found:
(7) For representative novel and efficient strategies, see: (a) Furstner,
21
37
5
̈
A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000,
122, 11799−11805. (b) Arnold, L. A.; Naasz, R.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841−5842. (c) Schrader,
T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 10998−11000.
(d) Jacobo, S. H.; Chang, C.-T.; Lee, G.-J.; Lawson, J. A.; Powell, W.
S.; Pratico, D.; FitzGerald, G. A.; Rokach, J. J. Org. Chem. 2006, 71,
1370−1379. (e) Sheddan, N. A.; Mulzer, J. Org. Lett. 2006, 8, 3101−
3104. (f) Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature 2012, 489,
4
06.2564.
-{(4R,5S)-4-Hydroxy-5-[(3S,E)-3-hydroxyoct-1-en-1-yl]-2-ox-
opyrrolidin-1-yl} heptanoic acid (7). To a solution of compound
7
1
3
9 (98 mg, 0.26 mmol) in a mixture of MeOH/THF/H O (2.5 mL,
2
/3/ 1) was added LiOH (30 mg, 1.28 mmol) at 0 °C. After being
stirred overnight at room temperature, the reaction was quenched with
an aqueous solution of HCl (2.0 M), and pH adjusted to 2. The
mixture was extracted with EtOAc (3 × 4 mL). The combined organic
phases were dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by column flash
chromatography (eluent: EtOAc) on silica gel to give compound 7 (87
mg, yield: 96%) as a white waxy solid. [α]D20 −12.0 (c 0.27, MeOH);
IR (film) νmax: 3382, 2925, 2855, 1710, 1664, 1640, 1485, 1387, 1258,
2
5
(
78−281. (g) Hayashi, Y.; Umemiya, S. Angew. Chem., Int. Ed. 2013,
2
4
2, 3450−3452.
8) For a review on recent developments in the synthesis of
prostaglandins and analogues, see: (a) Das, S.; Chandrasekhar, S.;
Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286−3337. For selected
recent examples on the synthesis of bioactive analogues of PGs, see:
−1 1
1
3
051, 968 cm ; H NMR (400 MHz, CD OD) δ 0.91 (t, J = 6.6 Hz,
3
(
b) Jahn, U.; Dinca, E. J. Org. Chem. 2010, 75, 4480−4491. (c) Patel,
H), 1.27−1.43 (m, 10H), 1.44−1.65 (m, 6H), 2.24 (dd, J = 17.2, 2.8
P.; Lee, G. J.; Kim, S.; Grant, G. E.; Powell, W. S.; Rokach, J. J. Org.
Chem. 2008, 73, 7213−7218.
Hz, 1H), 2.28 (t, J = 7.2 Hz, 2H), 2.73 (dd, J = 17.2, 6.4 Hz, 1H), 2.90
(
(
ddd, J = 13.4, 7.8, 5.2 Hz, 1H), 3.54 (dt, J = 13.4, 7.8 Hz, 1H), 3.96
dd, J = 8.2, 1.2 Hz, 1H), 4.05−4.13 (m, 2H), 5.51 (dd, J = 15.4, 8.2
(9) (a) Billot, X.; Chateauneuf, A.; Chauret, N.; Denis, D.; Greig, G.;
Mathieu, M. C.; Metters, K. M.; Slipetz, D. M.; Young, R. N. Bioorg.
Med. Chem. Lett. 2003, 13, 1129−1132. (b) Young, R. N.; Billot, X.;
Han, Y.; Slipetz, D. A.; Chauret, N.; Belley, M.; Metters, K.; Mathieu,
M. C.; Greig, G. M.; Denis, D.; Girard, M. Heterocycles 2004, 64, 437−
446.
13
Hz, 1H), 5.73 (dd, J = 15.4, 6.4 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 14.4, 23.7, 26.0, 26.2, 27.5, 28.0, 29.8, 32.9, 34.8, 38.2, 40.3,
3
41.6, 71.0, 71.2, 72.6, 127.5, 139.4, 175.3, 177.5; HRESIMS calcd for
−
+
[
C H NO ] (M−H ): 354.2286; found: 354.2277.
19
32
5
(10) Cameron, K. O.; Lefker, B. A.; Chu-Moyer, M. Y.; Crawford, D.
T.; Jardine, P. D.; DeNinno, S. L.; Gilbert, S.; Grasser, W. A.; Ke, H.;
Lu, B.; Owen, T. A.; Paralkar, V. M.; Qi, H.; Scott, D. O.; Thompson,
D. D.; Tjoa, C. M.; Zawistoski, M. P. Bioorg. Med. Chem. Lett. 2006,
ASSOCIATED CONTENT
Supporting Information
Chiral HPLC chromatogram of 3,5-dinitrobenzoate derivative
of compound 17; NOESY spectral of compound 9; H and C
NMR spectra of all new compounds, H NMR spectra of two
diastereomeric Mosher esters prepared from (R) and (S)-
MTPA-Cl and compound 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
*
S
1
6, 1799−1802.
1
13
(11) (a) Kambe, T.; Maruyama, T.; Nakai, Y.; Oida, H.; Maruyama,
1
T.; Abe, N.; Nishiura, A.; Nakai, H.; Toda, M. Bioorg. Med. Chem.
2
012, 20, 3502−3522. (b) Kambe, T.; Maruyama; Nakai, Y.; Yoshida,
H.; Oida, Hi.; Maruyama, T.; Abe, N.; Nishiura, A.; Nakai, H.; Toda,
M. Bioorg. Med. Chem. 2012, 20, 2235−2251. (c) Arns, S.; Gibe, R.;
Moreau, A.; Morshed, M. M.; Young, R. N. Bioorg. Med. Chem. 2012,
9
492
dx.doi.org/10.1021/jo401412g | J. Org. Chem. 2013, 78, 9488−9493

The Journal of Organic Chemistry
Note
2
0, 2131−2140. (d) Kambe, T.; Maruyama, T.; Nagase, T.; Ogawa, S.;
Minamoto, C.; Sakata, K.; Maruyama, T.; Nakai, H.; Toda, M. Bioorg.
Med. Chem. 2012, 20, 702−713. (e) Kambe, T.; Maruyama, T.;
Nakano, M.; Nakai, Y.; Yoshida, T.; Matsunaga, N.; Oida, H.; Konaka,
A.; Maruyama, T.; Nakai, H.; Toda, M. Bioorg. Med. Chem. 2012, 20,
396−401. (f) Nair, S. K.; Matthews, J. J.; Cripps, S. J.; Ma, C.-R.;
Dovalsantos, E. Z.; Grubbs, A. W.; Sach, N. W.; Hoeve, W. T.; Koster,
H.; Flahive, E. J.; Tanis, S. P.; Renner, M.; Wiltenburg, J. V.
Tetrahedron Lett. 2010, 51, 1451−1454. (g) Elworthy, T. R.; Brill, E.
R.; Chiou, S. S.; Chu, F.; Harris, J. R.; Hendricks, R. T.; Huang, J.;
Kim, W.; Lach, L. K.; Mirzadegan, T.; Yee, C.; Walker, K. A. M. J. Med.
Chem. 2004, 47, 6124−6127. (h) Elworthy, T. R.; Kertesz, D. J.; Kim,
W.; Roepel, M. G.; Quattrocchio-Setti, L.; Smith, D. B.; Tracy, J. L.;
Chow, A.; Li, F.; Brill, E. R.; Lach, L. K.; Mcgee, D.; Yang, D. S.;
Chiou, S. S. Bioorg. Med. Chem. Lett. 2004, 14, 1655−1659.
(
12) Togo, S.; Chen, H.-C.; Takahashi, T.; Kubota, T.; Matsuo, K.;
Morioka, D.; Watanabe, K.; Yamamoto, H.; Nagashima, Y.; Shimada,
H. J. Surg. Res. 2008, 146, 66−72.
(
13) Haubrich, D. R.; Cruet, J. P.; Reid, W. D. Br. J. Pharmacol. 1973,
4
(
8, 80−87.
14) (a) Huang, S.-Y.; Chang, Z.; Tuo, S.-C.; Gao, L.-H.; Wang, A.-E;
Huang, P.-Q. Chem. Commun. 2013, 49, 7088−7090. (b) Huo, H.-H.;
Xia, X.-E.; Zhang, H.-K.; Huang, P.-Q. J. Org. Chem. 2013, 78, 455−
465. (c) Luo, S.-P.; Guo, L.-D.; Gao, L.-H.; Li, S.; Huang, P.-Q.
Chem.Eur. J. 2013, 19, 87−91. (d) Fu, R.; Ye, J.-L.; Dai, X.-J.; Ruan,
Y.-P.; Huang, P.-Q. J. Org. Chem. 2010, 75, 4230−4243.
(
15) Hu, K.-Z.; Ma, J.; Qiu, S.; Zheng, X.; Huang, P.-Q. J. Org. Chem.
2
013, 78, 1790−1801.
16) For a review on the recent developments in olefin cross-
metathesis, see: Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
2, 1900−1923.
17) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−
976 and references cited therein..
18) Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem.
Commun. 1990, 843−844.
19) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron
991, 47, 1311−1328.
20) Bhat, K. L.; Flanagan, D. M.; Joullie,
985, 15, 587−598 and references cited therein..
21) Zheng, J.-L.; Liu, H.; Zhang, Y.-F.; Zhao, W.; Tong, J.-S.; Ruan,
Y.-P.; Huang, P.-Q. Tetrahedron: Asymmetry 2011, 22, 257−263.
22) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.; Villa, R.
Tetrahedron Lett. 1990, 31, 4949−4952.
23) For recent reviews on α-amidoalkylation via N-acyliminium
ions, see: (a) Yazici, A.; Pyne, S. G. Synthesis 2009, 339−368.
b) Yazici, A.; Pyne, S. G. Synthesis 2009, 513−541.
24) Huang, P.-Q.; Tang, X.; Chen, A.-Q. Synth. Commun. 2000, 13,
259−2268.
25) David, G. W.; Richard, W. H., Jr.; Martin, S. F. Org. Lett. 2003,
, 3523−3525.
26) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360−11370.
(
4
(
5
(
(
1
(
́
M. M. Synth. Commun.
1
(
(
(
(
(
2
(
5
(
9
493
dx.doi.org/10.1021/jo401412g | J. Org. Chem. 2013, 78, 9488−9493