Domino aza-Claisen/Mannich cyclization reaction from a chiral α-alkoxy enamine or sequential alkylation of an α-alkoxy ester enolate or nitrile anion, followed by an intramolecular Wittig reaction: Two (3+2) annulation routes to homochiral 4-alkyl-4-hydroxy-2-cyclopentenone synthesis

Article abstract of DOI:10.1002/ejoc.200300045

A study on the enantioselective synthesis of 4-alkyl-4-hydroxyalkylidene-cyclopentenone prostaglandins is reported. Two (3+2) annulation processes allow the synthesis of homochiral 4-alkyl-4-hydroxy-2-cyclopentenones 4-5, 10-11, and 17. The first process involves a domino aza-Claisen/Mannich cyclization reaction, resulting from the alkylation of an α-alkoxy-enamine, derived from chiral α-alkoxy aldehydes 1, 9, or 16 with 3-iodo-2-(methoxymethoxy)prop-1-ene (3) as the acetonyl equivalent. The second process is based on the sequential alkylation of esters 21, 39, or nitrile 20 with acetonyl equivalents 3 or 25, followed by an intramolecular Wittig reaction. As an application, the synthesis of the naturally occurring alkylidene-cyclopentenone prostaglandin clavulone II from the spiro[cyclopentene-furan]one 5 and the formal total synthesis of (+/-)-untenone 19 has been carried out. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300045

FULL PAPER
Domino Aza-Claisen/Mannich Cyclization Reaction from a Chiral α-Alkoxy
Enamine or Sequential Alkylation of an α-Alkoxy Ester Enolate or Nitrile
Anion, Followed by an Intramolecular Wittig Reaction: Two (3؉2) Annulation
Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
Cyrille Kuhn,[a] Leandros Skaltsounis,[b] Claude Monneret,[a] and Jean-Claude Florent*[a]
Keywords: Annulation / Domino reactions / Natural products / Prostaglandins
A study on the enantioselective synthesis of 4-alkyl-4-hydro-
xyalkylidene-cyclopentenone prostaglandins is reported.
on the sequential alkylation of esters 21, 39, or nitrile 20 with
acetonyl equivalents 3 or 25, followed by an intramolecular
Two (3+2) annulation processes allow the synthesis of homo- Wittig reaction. As an application, the synthesis of the natur-
chiral 4-alkyl-4-hydroxy-2-cyclopentenones 4−5, 10−11, ally occurring alkylidene-cyclopentenone prostaglandin cla-
and 17. The first process involves a domino aza-Claisen/ vulone II from the spiro[cyclopentene-furan]one 5 and the
Mannich cyclization reaction, resulting from the alkylation of
an α-alkoxy-enamine, derived from chiral α-alkoxy alde-
hydes 1, 9, or 16 with 3-iodo-2-(methoxymethoxy)prop-1-ene
(3) as the acetonyl equivalent. The second process is based
formal total synthesis of (+/-)-untenone 19 has been carried
out.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The cyclopentenone prostaglandin (PG) A and J series
demonstrate potent antitumor effects in vitro and in vivo.[1]
Marine natural prostanoids with high antiproliferative ac-
tivities, such as clavulone, have been isolated from the Okin-
awan soft coral Clavularia viridis,[2] and natural halogenated
compounds such as chlorovulone[3] and punaglandin IV[4]
have been isolated from Telesto reisi (Figure 1).
These alkylidene-cyclopentenones have been the focus of
intense research because of their involvement in cell growth
regulation, cell differentiation,[5] and cellular defenses
against viral infection.[6] They modulate the expression of a
variety of gene and protein functions.[7]
The cross-conjugated dienone structure plays a major
role in the biological activities and the antitumor mecha-
nism involves reversible carrier-mediated transport across
the cellular and nuclear membranes, followed by covalent
attachment to the nuclear protein.[8]
Figure 1. Cyclopentenone prostaglandins
A new and very interesting mechanism of action has re-
cently been reported in the case of ∆7-PGA1, involving the
suppression of tumor cell growth through induction of the dependent pathway,[9] associated with its increased associ-
protein cyclin-dependent kinase inhibitor p21 by a p53 in- ation with a cyclin A-cyclin-dependent kinase (cdk) in the
form of a ternary complex, as well as a reduction of the
[a]
level of cyclin E.[10]
UMR 176 CNRS-Institut Curie, Section de Recherche,
26 rue dЈUlm, 75248 Paris Cedex 05 France
Although many syntheses of naturally occurring PGs
Fax: (internat.) ϩ33-1-42346631
have been described,[11] reported SAR studies geared
E-mail: jean-claude.florent@curie.fr
[b]
University of Athens, Department of Pharmacy, Division of
Pharmacognosy,
towards obtaining more simplified analogues, particularly
more hydrophilic or metabolically more stable ones, have
Panepistimiopolis-Zografou, Athens 157 71, Greece
Fax: (internat.) ϩ30-1-7238297
been limited, in spite of the potential therapeutic oppor-
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DOI: 10.1002/ejoc.200300045
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tunities presented by these compounds.[12] However, the ∆7-
PGA1 analogue TEI 9826 was recently reported to be an
effective agent capable of overcoming cisplatin resistance,
and is currently under clinical trial.[13] New biological ac-
tivities and cellular targets, including anti-inflammatory,
anti-neoplastic, and anti-viral activities, have recently been
reported.[14] Thus there was a need to develop new methods
to elaborate the 4-alkyl-4-hydroxy-2-cyclopentenone frame-
work of these compounds. For these reasons, we initiated a
program towards the synthesis of simplified analogues of
marine antitumor prostaglandin derivatives of structure I.
Results and Discussion
We envisioned the synthesis of these new cyclopen-
tenones I (R1 ϭ halogen, R2 ϭ H or OH, R3 ϭ variable
chain) through alkylation of chiral 4-alkyl-4-hydroxy cyclo-
pentenone II (R2 ϭ H) or IIЈ or (R2 ϭ OH), potentially
synthesizable from spiro-cyclopentenones III (for R2 ϭ H)
or IV (for R2 ϭ OH), respectively. These could in turn be
elaborated through two different (3 ϩ2) annulation se-
quences in order to create the quaternary stereogenic center.
The first route (A) studied involved a one-pot sequential
alkylation of a sugar enamine with an acetonyl equivalent
by way of a 3-aza-Claisen reaction (step I), followed by a
tandem Mannich reaction resulting in annulation (step II).
The second route (B) was based on the alkylation of a cya-
no- or urono-sugar with the same acetonyl equivalent (step
I) followed by an intramolecular Wittig reaction (step II;
see Figure 2).
Figure 2. Retrosynthetic analysis
Synthesis of Cyclopentenones Through a 3-Aza-Claisen/
Mannich Tandem Reaction
We first focused on the possible α-allylation of aldehydes
1[15] or 1Ј,[16] easily prepared from diisopropylidene glucose
through the use of a 3-aza-Claisen reaction to introduce the
allyl moiety,[17] as previously also reported for the synthesis
of cyclopentane[18] or cyclopentenone.[19] Thus, treatment
of aldehyde 1 with pyrrolidine, according to the conditions
described by Secrist III[20] for the C-4 allylation of nucleo-
side, afforded the pyrrolidino enamine intermediate 2 as a
mixture of Z/E diastereoisomers. The crude 2 obtained
after evaporation of the solvent was directly N-alkylated at
80 °C in MeCN, with freshly prepared 3-iodo-2-(methoxy-
methoxy)prop-1-ene (3).[21] Surprisingly enough, the prod-
uct obtained after conventional workup was not the ex-
pected C-4 allylated aldehyde resulting from the (3,3)-re-
Scheme 1. Reagents and conditions: (a) pyrrolidine, MeCN, 80 °C;
(b) CH2ϭCH(MOM)ϪCH2I (3), toluene
arrangement (3-aza-Claisen) but the target cyclopentenones transition state.[22] The resulting transient iminium ion 7
4 and 5 directly as a mixture of diastereoisomers, thus ob- generated during this reaction was then trapped in a Man-
tained in 40% yield but in one-pot fashion from aldehydes nich reaction involving the nucleophilic carbonyl-like com-
1 or 1Ј by a domino reaction (Scheme 1).
ponent situated at the enol ether function. This produced
The postulated mechanism for this new reaction is de- the spiro[cyclopentane-furan]one 8, which subsequently
picted in Scheme 1. It involves N-alkylation of the E/Z en- underwent β-elimination of the piperidine moiety to afford
amines 2, giving access to the iminium 6 through an aza- the spiro diastereomers 4 (4S, threo) and 5 (4R, erythro),
Claisen rearrangement, accelerated by the charged am- isolated in 38% yield (2:1 molar ratio).
monium moiety and, possibly, by the rate-enhancing p-do-
The modest diastereoselectivity primarily reflects the two
nor effect of the vinyl oxygen atom (MOM) in the chair stereochemical factors that could govern the stereocontrol:
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Two (3ϩ2) Annulation Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
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(1) the Z/E N-alkyl olefin geometry determined during en- the presence of lead tetraacetate to give 16 (95% from 15).
amine formation, and (2) the contribution of the chair ver- Treatment of this under Claisen/Mannich conditions gave
sus the boat transition state (internal asymmetric induc- the cyclopentenone 17 in 38% yield, together with 12% of
tion). The sequence of a cationic aza-Claisen rearrangement recovered starting material 16 and 19% of methoxymethyl
and a Mannich cyclization to build a pyrrolidine ring has ester 18, probably resulting from the oxidation of the inter-
served many research groups as a key step in the total syn- mediary enamine (Scheme 3).
thesis of alkaloids.[23] The main characteristic feature of this
new domino reaction resides in the unusual β-elimination[24]
of the pyrrolidine nucleus occurring after the Mannich reac-
tion. The spiro carbon atom configurations in the cyclopen-
tenones 4 and 5 were determined with the aid of NOESY
experiments and further confirmed by the RX diagram ob-
tained from the crystalline (4S) major compound 4 stereo-
selectively prepared by the second route (vide infra).[25] We
focused on demonstrating the generality of this domino
cyclopentannulation with other aldehydes. Thus, the alde-
hyde 9 Ϫ easily obtained from ribose[26] Ϫ when treated
under the same conditions as described above, gave a 1:1
mixture of two diastereoisomers (4ЈR, 10 and 4ЈS, 11) in
36% overall yield. The absolute stereochemistry was unam-
biguously determined by NOESY experiments, since only in
the case of the minor S isomer was a strong cross-coupling
between H-5 and H-6 observed (Scheme 2).
Scheme 3. Reagents and conditions: (a) C16H33MgBr, Et2O, 0 °C;
(b) MOMCl, EtN(iPr)2, CH2Cl2, 0 °C (c) OsO4, NMO acetone/
H2O, 0 °C to room temp.; (d) [Pb(OAc)4], benzene, 0 °C to room
temp.; (e) pyrrolidine, MeCN/toluene, 50 °C then CH2ϭ
CH(MOM)ϪCH2I (3)
It therefore appears that the original domino 3-aza-
Claisen/Mannich reaction is an expeditious method by
which to prepare a 4-alkyl-4-hydroxy-2-cyclopentenone di-
rectly from an aldehyde. The main drawback of the reaction
is in the difficulties that we encountered in controlling the
enamine geometry, in the case of a chiral aldehyde. All at-
tempts to improve this diastereoselectivity, in particular by
use of calcium hydride Ϫ known to produce (Z)-enamines
preferably Ϫ were unsuccessful,[28] as was the use of other
additives (MgBr2). In consequence, we decided to focus on
a second strategy based on the alkylation of an ester enol-
ate, or nitrile anion, in which facial diastereoselectivity
should be much easier to control.
Scheme 2. Reagents and conditions: (a) pyrrolidine, MeCN, 80 °C;
(b) CH2ϭCH(MOM)ϪCH2I (3), toluene
Application to the Formal Total Synthesis of (؉/-)-
Untenone
As another extension of this reaction, a rapid formal to-
tal synthesis of natural (ϩ/Ϫ)-untenone, a natural cyclopen-
tenone prostaglandin with antiproliferative activity (IC50
ϭ
0.4 µg/mL) was carried out, based upon the preparation of
the cyclopentenone 17 and its conversion into the target
compound according to Yamada.[27] The starting aldehyde
was readily obtained as follows. Treatment of acrolein 12
Synthesis of 4-Alkyl-4-hydroxy-2-cyclopentenone by
Alkylation of α-Alkoxy Esters and Nitriles
We presumed that alkylation of an α-alkoxynitrile anion
with hexadecylmagnesium bromide at Ϫ78 °C to 0 °C in A or an α-alkoxy ester enolate B or C should be easily stere-
diethyl ether gave the allylic alcohol 13 (52%), which was ocontrolled through the remote stereogenic center present
protected as its p-methoxymethyl ether 14. Oxidation of the in the heterocycles (the tetrahydrofurans A and B or the
double bond to an aldehyde function was achieved in two dioxolan ring C). The allylated compounds D and E should
steps, involving conversion of the alkene into glycol 15 later give the spiro 4-hydroxycyclopentenones F and G by
(93%), followed by osmium tetraoxide oxidative cleavage in ring closure (Figure 3).
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formed during the reduction by use of Rochelle salt or mild
acid hydrolysis. Reduction with Raney Nickel by the pro-
cedure of Albrecht et al.[36] furnished the aldehyde in 30%
yield, with starting nitrile and methyl ketone. In the case of
the ester 23a, reduction with DIBAH produced 26 in 69%
yield, but the methyl ketone derivative 28 resulting from the
hydrolysis of the enol ether was also isolated (20%), as well
as the over-reduced compound 27 (5%). Fortunately, the
more stable 2-chloro-allylated ester 24 gave the aldehyde 29
in 70% yield, with only 13% of the other reduced product
30 (Scheme 4).
Figure 3. Synthesis of cyclopentenone by alkylation of α-alkoxy
esters and nitriles followed by annulation
We first studied the alkylation of the cyano sugar 20 and
of the ester 21, readily prepared from 1,2-O-isopropylidene-
-glucose by the procedure of Weidmann et al.[29] For the
alkylation, we initially used standard conditions involving
deprotonation of the nitrile or of the ester with LDA (1.2
equiv.) at Ϫ78 °C for 30 min, followed by addition of the
electrophilic 3-iodo-2-(methoxymethoxy)prop-1-ene (3).
However, the alkylated products 22 and 23a/b were only
obtained in low (15Ϫ20%) and irreproducible yields, to-
gether with large amounts of starting material. After many
experiments,[30] a dramatic increase in the yield was fortu-
nately obtained with the use of KHMDS as the base in an
internal quench procedure, as described by Williams et
al.[31] and, more recently, by Snyders et al.[32] Under these
conditions, a very good diastereoselectively (de Ͼ 95%) was
observed. Thus, (4S) isomer 22 was obtained in 84% yield
from the cyanide 20, while from ester 21 the (4S) esters 23a
and 24 were obtained in 61% and 70% yields, respectively,
with 3-iodo-2-(methoxymethoxy)prop-1-ene (3) and 2-
chloro-iodopropene (25) as the electrophiles. In the case of
the alkylation of 21, the minor (4R) isomer 23b was also
isolated (Ͻ 5%). The structure of the crystalline product 22
was unambiguously determined by X-ray analysis.[25]
Scheme 4. Reagents and conditions.: a) CH2ϭCH(OMOM)ϪCH2I
(3) or CH2ϭCH(Cl)ϪCH2I (25), KHMDS (0.5  in toluene), THF
at Ϫ78 °C; (b) for 22, 23, 24 DIBAH in toluene at Ϫ78 °C, or
Raney Nickel NaH2PO2, H2O, pyridine, CF3COOH for 22; (c) for
26: NBS in aqueous NaHCO3 in dioxane; for 29: NBS, HBr cat.,
MeCN/H2O (4:1); (d) Ph3P in CH2Cl2, propylene oxide, reflux
Alkylation of this sugar uronate derivative 21 was hence
easily performed in the internal quench condition. It is
worth noting that, in our case, alkylation by a sigmatropic
uronic acid-drived allyl ketene acetal Ireland Claisen re-
arrangement[33] could be obtained neither from the corre-
sponding 2-MOM compound nor from the 2-chloroallyl es-
In an attempt to achieve the cyclopentannulation reac-
ter, contrarily to the results reported by Rizzacasa[34] et al. tion, we first Ϫ unsuccessfully Ϫattempted an intramolecu-
and more recently by Thiem et al.[35] from a closely related lar ene reaction by treatment of aldehyde 26 with a Lewis
urono sugar, although unsubstituted allyl esters were used acid (Et2AlCl, BF3ϪEt2O, SnCl4) in dichloromethane at
in these two cases.
Ϫ78 °C.[37] We also did not succeed in producing a Man-
The nitrile derivative 22 was next transformed into the nich reaction by treatment of aldehyde 26 with pyrrolidine;
aldehyde 26 (34% yield) by treatment with DIBAH at Ϫ78 this could be attributable to the congested neopentylic posi-
°C in toluene. The low yield observed was attributed to dif- tion preventing the initial iminium formation. Finally, we
ficulties in the total hydrolysis of the iminoaluminate adopted an intramolecular Wittig reaction. The enol ethers
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Two (3ϩ2) Annulation Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
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26 and 29 were treated with N-bromosuccinimide under a high diastereoselectivity, an extension of this procedure to
basic (NaHCO3 in aqueous dioxane) or acidic (cat. HBr in the stereoselective synthesis of 2-cyclopentenone by dioxol-
aqueous CH3CN) conditions, respectively. The not isolated ane ester alkylation was further devised; this should provide
unstable bromoketone intermediate thus obtained (31), was a rapid and efficient way to prepare new cyclopentenone
directly treated with triphenylphosphane in the presence of prostaglandin analogues (Scheme 6).
propylene oxide as acid scavenger to give, via an intermedi-
ary ylide, the cyclopentenone Wittig product 4 (83% from
26 and 66% from 29).
In summary, by use of this strategy we successfully
achieved a stereocontrolled synthesis of the chiral target
spiro-furano cyclopentenone 4 in four steps either from ni-
trile 20 or from glucurono ester 21. This convenient strategy
to synthesize a chiral cyclopentenone was used to prepare
clavulone II, a naturally occurring cyclopentenone prostag-
landin.
Formal Total Synthesis of Clavulone from Spiro-Furano
Cyclopentenone
The reduction of cyclopentenone 5 with Luche reagent[38]
gave compound 32. Acidic hydrolysis of the isopropylidene
ring furnished the unsaturated sugar 33 (77%), which was
next reduced with sodium borohydride and then oxidized
with sodium periodate to give the hemiacetal 34 (66%). Fi-
nally, a Wittig reaction with (hexyl)triphenylphosphorane,
obtained from (hexyl)triphenylphosphonium bromide and
butyllithium at Ϫ78 °C, gave the cyclopentanediol 35 (42%).
Oxidation of the allylic hydroxy group with Jones reagent
furnished the cyclopentenone 36 ([α]2D0 ϭ Ϫ80; c ϭ 0.5,
CHCl3), identical to the cyclopentenone intermediate of
Yamada’s clavulone synthesis ([α]2D0 ϭ Ϫ84; c ϭ 0.31,
CHCl3)[11b,11e] (Scheme 5).
Scheme 6. Reagents and conditions. (a) CH2ϭCH(MOM)ϪCH2I
(3), KHMDS Ϫ78 °C, THF; (b) DIBAH Ϫ78 °C in toluene; (c)
1.1 equiv. NBS, aqueous CH3CN; (d) PPh3, propylene oxide in
aqueous dioxane at reflux
The dioxolane ester 39, easily prepared from commercial
ribonolactone in one step by Chittenden’s procedure,[39] was
treated with KHMDS in the presence of the 3-iodo-2-
(methoxymethoxy)prop-1-ene (3) at Ϫ78 °C under internal
quench conditions, as described previously. The alkylation
was very stereoselective and furnished the two products 40
and 41, in a 7:1 ratio, as determined from the NMR spec-
trum of the crude reaction mixture (87% de). These alkyl-
MeOH; (b) AcOH/H2O (5:2); (c) NaBH4, MeOH; (d) NaIO4, ated compounds were too difficult to separate well and to
Scheme 5. Reagents and conditions. (a) NaBH4, CeCl3·7H2O,
MeOH/H2O; (e) Ph3PϩC6H13BrϪ , BuLi, in THF/HMPA, Ϫ20 °C
characterize at this stage. In consequence, they were trans-
formed into cyclopentenones by the intramolecular Wittig
to room temp. (f) Jones, 0 °C
reaction sequence. The mixture of compounds (40 ؉41) was
Synthesis of Cyclopentenones by the Highly Stereoselec- treated with DIBAH to give aldehyde 42, which was cy-
tive Alkylation of Dioxolane Ester Enolate: Since the alky- clized as described previously for compound 26 to give,
lation route to 2-cyclopentenone from urono ester displayed after column chromatography, the two spiro-cyclopen-
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centrated. The obtained residue was purified by silica gel flash col-
umn chromatography (cyclohexane/EtOAc, 8:1 to 4:1) to afford an
oil (2.22 g, 38%) as a mixture of two diastereoisomers in a 3:2 ratio.
The pure cyclopentenones were obtained after a second purifi-
cation of 300 mg by preparative TLC, affording 4 (151 mg) and 5
(101 mg) as solids.
tenones 10 and 11. The structure of this rigid spiro skeleton
could now be determined unambiguously by NOESY
experiments. The major compound 10 had a stereogenic
quaternary carbon of (R) configuration, meaning that the
corresponding open-chain alkyl product was 41, corre-
sponding to an expected cis and ‘‘contrasteric’’ attack of
the alkylation, in accordance with Hoffmann’s obser-
vation.[40] The trans or ‘‘steric’’ attack was disfavored as a
consequence of the 1,3-steric interaction occurring with the
incoming electrophile and a methyl group of the dioxolane
ring in the sofa transition state.
Synthesis from Aldehyde 26: NaHCO3 (350 mg) and NBS (800 mg,
4.5 mmol) were successively added to a solution of aldehyde 26
(1.08 g, 4 mmol) in a CH3CN/H2O mixture (5:1, 70 mL). After the
mixture had been stirred for 1.5 h, water (20 mL) was added and
the mixture was extracted with CH2Cl2 (3 ϫ 50 mL). The collected
organic layers were washed with H2O and brine, dried (MgSO4),
and filtered. The filtrate was cooled to 0 °C; Ph3P (1.87 g,
7.2 mmol) and propylene oxide (2.5 mL) were then added, and the
reaction mixture was heated at reflux for 18 h. After addition of
water (100 mL), the mixture was extracted with CH2Cl2 (3 ϫ
50 mL). The organic layer was washed with H2O and brine, and
Conclusion
In conclusion, we have demonstrated that an unpre-
cedented tandem cationic aza-Claisen rearrangement and dried (MgSO4). Evaporation by flash column chromatography
(cyclohexane/EtOAc, 2:1) gave crystalline 4 (702 mg, 83%).
Mannich cyclization to the synthesis of 4-alkyl-4-hydroxy-
cyclopentenone is an efficient procedure. Application of this
reaction to the synthesis of natural prostanoids has been
demonstrated, and this reaction could be a good entry
point for preparations of series of 4-alkyl-4-hydroxy-2-
Synthesis from Aldehyde 29: NBS (562 mg, 3.16 mmol) was added
at 0 °C to a cold solution of aldehyde 29 (520 mg, 2.1 mmol) in a
CH3CN/H2O mixture (4:1, 50 mL), followed by a solution of HBr
(48%, 4 µL). The reaction mixture turned yellow and, after stirring
cyclopentenones. Concurrently, we have studied the stereo- for 15 min, the reaction was stopped by addition of a saturated
aqueous solution of NaHCO3 until decolorization. The reaction
mixture was extracted with CH2Cl2 (3 ϫ 30 mL). The collected
organic layers were washed with H2O and brine, dried (MgSO4),
and filtered. Ph3P (2.1 g, 8 mmol) and propylene oxide (1.5 mL)
were successively added to the filtrate. The reaction mixture was
treated at reflux as above and extracted. Purification by flash col-
umn chromatography (cyclohexane/ethyl acetate, 2:1) gave crystal-
line 4 (250 mg, 66%). Major Isomer 4 (4ЈS): [α]2D0 ϭ Ϫ17 (c ϭ 0.83,
CHCl3). M.p. 68 °C. IR (CDCl3): ν˜max (cmϪ1) ϭ 1680 (CϭC), 1723
selective alkylation of α-alkoxy esters or nitriles, followed by
internal Wittig reactions. This sequence of transformations
greatly increased the diastereoselectivity of the cyclopen-
tenones formed. These two methodologies are complemen-
tary to the one we recently reported in our currently efforts
towards the synthesis of new antitumor cyclopentenone
prostaglandin analogues.[41]
1
(CϭO). H NMR: (250 MHz, CDCl3): δ ϭ 7.81 (d, J ϭ 5.7 Hz, 1
Experimental Section
H), 6.09 (d, J ϭ 5.7 Hz, 1 H), 5.91 (d, J ϭ 4 Hz, 1 H), 4.88 (t, J ϭ
4 Hz, 1 H), 2.76 and 2.46 (2d, AB system, J ϭ 18.5 Hz, 2 H), 2.42
(d, J ϭ 14 Hz, 1 H) and 2.25 (dd, J ϭ 14, J ϭ 5 Hz, 1 H), 1.65 (s,
3 H) and 1.35 (s, 3 H) ppm. MS (CI/NH3): m/z ϭ 228 [M ϩ NH4]ϩ,
211 [M ϩ H]ϩ. C11H14O4 (210.23): calcd. C 62.83, H 6.72; found
C 62.74, H 6.72. Minor Isomer 5 (4ЈR): [α]2D0 ϭ Ϫ84 (c ϭ 1.14,
CHCl3). M.p. 94 °C. 1H NMR (250 MHz, CDCl3): δ ϭ 7.30 (d,
J ϭ 5.7 Hz, 1 H), 4.92 (t, J ϭ 5.7 Hz, 1 H), 2.92 and 2.82 (2d, AB
system, J ϭ 19 Hz, 2 H), 2.27 (d, J ϭ 13.7 Hz, 1 H), 2.17 (dd, J ϭ
13.7, J ϭ 5 Hz, 1 H), 1.61 (s, 3 H) and 1.37 (s, 3 H) ppm. 13C
NMR: (62.5 MHz, CDCl3): δ ϭ 206.2, 162.7, 135.6, 111.8, 106.4,
87.0, 80.9, 49.0, 42.9, 26.3 and 25.5 ppm. MS (CI/NH3): m/z ϭ 228
[M ϩ NH4]ϩ, 211 [M ϩ H]ϩ. C11H14O4 (210.23): calcd. C 62.83,
H 6.72; found C 62.66, H 6.57.
General Remarks: Measurements of NMR spectra (90, 250, and
1
300 MHz, H) were made in CDCl3 (which also provided the lock
signal at δ ϭ 7.26 ppm) with a Bruker 300 spectrometer. Mass spec-
tra were determined by CI (NH3 or CH4). Melting points are un-
corrected. Optical rotations were measured with a PerkinϪElmer
241 polarimeter at 25 °C. Silica gel 60 (35Ϫ70 µm) was used for
flash chromatography, with distilled cyclohexane, ethyl acetate, and
dichloromethane being used as eluents. Analytical plates (Merck
60 F254 aluminium sheets) were rendered visible by spraying with
p-anisaldehyde/H2SO4/AcOH/EtOH or with phosphomolybdic
acid (5% in ethanol), followed by heating. THF was distilled from
sodium/benzophenone prior to use. CH2Cl2 was distilled from P2O5
˚
prior to use. DMF was stored over 4-A molecular sieves under dry
argon atmosphere. Triethylamine was stored under argon atmos-
phere.
Compound 10 [5R,4R] and Isomer 11 [5S,4R]. From Aldehyde 9 by
3-Aza-Cope/Mannich Reaction:
A
solution of
9
(500 mg,
2.17 mmol) and pyrrolidine (0.27 mL, 3.28 mmol) in a mixture of
anhydrous CH3CN/toluene (1:1, 20 mL) was stirred at 50 °C for
1 h. The reaction solvents were evaporated under reduced pressure,
(3ЈaR,5ЈS,6ЈaR)-5: Synthesis from Aldehyde 1 by 3-Aza-Claisen/
Mannich Reaction: A solution of 1 (4.8 g, 27.8 mmol) and pyrroli-
dine (5.05 mL, 61.2 mmol) in a mixture of anhydrous CH3CN and and the obtained residue was dissolved in anhydrous CH3CN
toluene (1:1, 300 mL) was stirred under argon at 50 °C for 1 h. (20 mL). 3-iodo-2-(methoxymethoxy)prop-1-ene (3, 0.81 mL,
After evaporation of the solvents under reduced pressure, the resi-
due obtained, a mixture of the (E ϩ Z) enamine, was dissolved in °C for 18 h. After addition of H2O (10 mL) and extraction with
anhydrous CH3CN (20 mL). After addition of 3-iodo-2-(methoxy- EtOAc (3 ϫ 30 mL), the obtained organic layers were washed with
methoxy)prop-1-ene (3, 8.4 mL, 55.7 mmol), the reaction mixture brine, dried over MgSO4, and concentrated to furnish a residue,
5.40 mmol) was then added. The reaction mixture was stirred at 80
was heated at reflux under argon for 22 h at 80 °C. After addition
of water and extraction with EtOAc (2 ϫ 50 mL), the collected
organic layers were washed with brine, dried over MgSO4, and con-
which was purified by flash column chromatography (cyclohexane/
EtOAc, 4:1), giving a mixture of compounds 10 (100 mg) and 11
(107 mg) (36% overall yield from 9).
2590
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2585Ϫ2595

Two (3ϩ2) Annulation Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
FULL PAPER
From Aldehyde 42: The mixture of aldehyde 42 (160 mg,
1.92 mmol) was treated with NaHCO3 (160 mg) in dioxane (10 mL) hexane/acetone, 3:1), to give compound 15 (400 mg, 93%). 1H
and H2O (0.5 mL). NBS was then added (345 mg). After stirring NMR (90 MHz, CDCl3): δ ϭ 4.73 and 4.61 (2d, AB system, J ϭ
was purified by flash column chromatography on silica gel (cyclo-
for 3 h, the reaction mixture was diluted with H2O (20 mL) and 6.9 Hz, 2 H), 3.76Ϫ3.50 (m, 4 H), 3.43 (s, 3 H), 1.46 (s, 3 H), 1.28
extracted with EtOAc. The collected organic layers were washed
with H2O and with brine, dried (MgSO4), and filtered. The ob-
tained filtrate was evaporated and dissolved in dichloromethane
(20 mL). Propylene oxide (0.7 mL) and triphenylphosphane
(524 mg) were then added at 0 °C. After stirring for 18 h at room
temperature, the reaction mixture was extracted with CH2Cl2. The
organic layers were washed with H2O and with brine, and dried
(MgSO4). After filtration and evaporation under reduced pressure,
the residue obtained was purified by flash column chromatography
to give compounds 10 (80 mg, 57%) and 11 (11 mg). Major Isomer
(s), 0.88 (t) ppm. MS (DCI/NH3): m/z ϭ 378 [M ϩ NH4]ϩ, 361 [M
ϩ H]ϩ. C21H44O4 (360.57): calcd. C 69.95, H 12.30; found C 69.87,
H 12.32.
2-(Methoxymethoxy)octadecanal (16): A solution of compound 15
(390 mg, 1.05 mmol) in anhydrous benzene (40 mL) was cooled to
0 °C for 5 min, [Pb(OAc)4] (470 mg, 1.1. mmol) was then added,
and the mixture was stirred at room temperature. After 5 min, the
yellow suspension became limpid and was filtered through Celite.
The filtrate was evaporated, and co-evaporated twice with toluene.
The residue obtained was purified by flash column chromatography
(cyclohexane/ethyl acetate, 8:1) to give compound 16 (330 mg,
1
10 (R): H NMR (300 MHz, CDCl3): δ ϭ 7.29 (d, J ϭ 5.5 Hz, 1
H), 6.19 (d, J ϭ 5.5 Hz, 1 H), 4.16Ϫ4.08 (m, 2 H), 3.98Ϫ3.90 (m,
2 H), 2.95 and 2.35 (2d, AB system, J ϭ 18 Hz, 2 H), 1.42, 1.41,
1.27 and 1.24 (4s) ppm. IR: ν˜max (cmϪ1) ϭ 1723 (CϭO) ppm. MS
(DCI/NH3): m/z ϭ 286 [M ϩ NH4]ϩ, 269 [M ϩ H]ϩ. C14H20O5
(268.31): calcd. C 62.67, H 7.51; found C 62.75, H 7.48. Minor
1
95%). H NMR (90 MHz, CDCl3): δ ϭ 9.58 (d, J ϭ 1.5 Hz, 1 H),
4.63 (s, 2 H), 3.80 (d, J ϭ 1.5 Hz, JЈ ϭ 6 Hz, 1 H), 1.66Ϫ1.06 (m,
30 H), 0.8 (t, 3 H) ppm. MS (DCI/NH3): m/z ϭ 346 [M ϩ NH]ϩ.
C20H40O3 (328.53): calcd. C 73.12, H 12.27; found C 72.90, H 2.36.
1
Isomer 11 (S): [α]2D0 ϭ ϩ6 (c ϭ 0.5, CHCl3). H NMR (300 MHz,
(؎)-4-Hexadecyl-4-(methoxymethoxy)cyclopent-2-enone (17): Pyr-
rolidine (0.3 mL, 3.6 mmol) was added under argon to a solution
of aldehyde 16 (330 mg, 1 mmol) in acetonitrile/toluene (1:1,
40 mL). The mixture was stirred at 50 °C for 3 h. After evaporation
of the solvents under reduced pressure, dry acetonitrile (30 mL)
and iodo compound 3 (0.40 mL, 2.38 mmol) were added. The reac-
tion was stirred at 80 °C for 18 h. The crude residue obtained after
evaporation of the solvents under reduced pressure was purified by
flash column chromatography (cyclohexane/ethyl acetate, 15:1) to
give compound 17 (369 mg, 38%), the starting aldehyde 16 (40 mg,
12%), and compound 18 (60 mg, 19%). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.47 (d, 1 H), 6.19 (d, J ϭ 5.7 Hz, 1 H), 4.65 (d, 1 H,
AB system) and 4.59 (d, AB system, J ϭ 7.5 Hz, 1 H), 3.34 (s, 3
H), 2.65 (d, AB system, J ϭ 18.6 Hz, 1 H) and 2.42 (d, AB system,
J ϭ 18.6 Hz, 1 H), 1.72 (t, J ϭ 6.4 Hz, 2 H), 1.24 (s, 28 H), 0.87
(t, J ϭ 6 Hz, 3 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 206.0,
164.8, 134.3, 91.5, 83.6, 55.0, 45.7, 38.7, 31.6, 29.9, 29.3, 29.2, 29.0,
23.7 and 22.4, 13.8 ppm. MS (DCI/NH3): m/z ϭ 384 [M ϩ NH4]ϩ,
367 [M ϩ H]ϩ. C23H42O3 (366.58): calcd. C 75.36, H 11.55; found
C 75.22, H 11.65.
CDCl3): δ ϭ 7.45 (d, J ϭ 5.5 Hz, 1 H), 6.25 (d, J ϭ 5.5 Hz, 1 H),
4.21Ϫ4.10 (m, 1 H), 4.05Ϫ3.87 (m, 3 H, H-6, H-7), 2.64 (s, 2 H),
1.50, 1.43, 1.36, 1.25 (4s, 12 H) ppm.
Nonadec-1-ene-3-ol (13): A solution of hexadecyl bromide (4.4 mL,
14.5 mmol) was added dropwise at 0 °C to a suspension of mag-
nesium (350 mg, 14.5 mmol) in anhydrous Et2O (75 mL), contain-
ing a crystal of iodine. The reaction mixture was heated at reflux
for 1 h, and was then transferred at 0 °C into a Et2O (30 mL) solu-
tion of acrolein (0.24 mL, 3.6 mmol) and stirred at this temperature
for 1 h. The reaction was quenched to neutrality by addition of a
2  aqueous HCl solution. After addition of water, the reaction
mixture was extracted with Et2O (3 ϫ 50 mL), and the organic
layers were washed with water and brine, and dried (MgSO4). After
filtration and evaporation under reduced pressure, a residue was
obtained, and this was purified by flash column chromatography
on silica gel (cyclohexane/ethyl acetate, 10:1) to give compound 13
1
(530 mg, 52%). H NMR (90 MHz, CDCl3): δ ϭ 6.00Ϫ5.66 (m, 1
H), 5.35Ϫ4.97 (m, 2 H), 4.26Ϫ3.97 (m, 1 H), 1.43Ϫ1.13 (s, 30 H),
0.86 (t, 3 H) ppm. MS (DCI/NH3): m/z ϭ 300 [M ϩ NH4]ϩ, 283
[M ϩ H]ϩ.
Methoxymethyl Heptadecanoate (18): Side-product obtained during
the preparation of 17. IR: ν˜max (cmϪ1) ϭ 1737. 1H NMR
(300 MHz, CDCl3): δ ϭ 5.23 (s, 2 H), 3.46 (s, 3 H), 2.35 (t, J ϭ
7.1 Hz, 2 H), 1.65 (t, J ϭ 7.1 Hz, 2 H), 1.26 (s, 26 H), 0.88 (t, J ϭ
6.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 173.3, 90.1,
57.4, 34.3, 31.8, 29.6, 29.4, 29.2, 29.1, 29.0, 24.7, 22.6, 14.0 ppm.
MS (DCI/NH3): m/z ϭ 332 [M ϩ NH4]ϩ, 315 [M ϩ H]ϩ.
3-(Methoxymethoxy)nonadec-1-ene (14): Compound 13 (500 mg,
1.77 mmol) was dissolved in CH2Cl2 (50 mL), and methoxymethyl
chloride (0.13 mL, 7 mmol) and iPr2NEt (0.3 mL, 7 mmol) were
then added. The reaction mixture was stirred at room temperature
for 24 h. After evaporation under reduced pressure, a residue was
obtained, and this was purified by flash column chromatography
on silica gel (cyclohexane/ethyl acetate, 15:1) to give compound 14
3-Deoxy-1,2-O-isopropylidene-4-C-[2-(methoxymethoxy)allyl]-β-L-
1
(400 mg, 69%). H NMR (90 MHz, CDCl3): δ ϭ 5.66Ϫ5.43 (m, 1
threo-pentofurano-urononitrile (22): A solution of KHMDS (0.5 ,
15 mL) was added under argon at Ϫ78 °C to a solution of com-
pound 20[29] (750 mg, 4.43 mmol) and 3-iodo-2-(methoxymeth-
oxy)prop-1-ene (3, 1.9 g, 8.38 mmol) in anhydrous THF (30 mL).
H), 5.30Ϫ4.96 (m, 2 H), 4.70 and 4.50 (m), 1.43Ϫ1.13 (s, 30 H),
0.86 (t, 3 H) ppm. MS (DCI/NH3): m/z ϭ 344 [M ϩ NH4]ϩ, 327
[M ϩ H]ϩ.
3-(Methoxymethoxy)nonadecane-1,2-diol (15): Compound 14 After stirring for 0.5 h, the reaction mixture was quenched by ad-
(390 mg, 1.2 mmol) was dissolved at 0 °C in a mixture of acetone/ dition of a saturated aqueous solution of ammonium chloride
H2O (8:1, 36 mL). A solution of OsO4 in tBuOH (1.2 mL, (5 mL). After addition of water (50 mL), the mixture was extracted
0.12 mmol) and NMO (140 mg, 1.2 mol) were successively added.
The reaction mixture was stirredat room temperature for 18 h , and
was then quenched by addition of an aqueous solution of NaHSO3
(10%, 5 mL). After stirring for 1 h, the reaction mixture was ex-
with EtOAc (3 ϫ 30 mL). The collected organic layers were washed
with brine, and dried with MgSO4. After filtration and evaporation
under reduced pressure, a residue was obtained. Purification by
flash column chromatography (cyclohexane/EtOAc, 3:1), gave com-
tracted with EtOAc (3 ϫ 30 mL). The organic layers were washed pound 22 (1 g, 84%) as white crystals; m.p. 37Ϫ38 °C. [α]2D0 ϭ Ϫ36
with H2O and brine, and dried (MgSO4). After filtration and evap-
oration under reduced pressure, a residue was obtained, and this
(c ϭ 1, CHCl3). IR (CDCl3): ν˜max (cmϪ1) ϭ 1249. 1H NMR
(270 MHz, CDCl3): δ ϭ 5.80 (d, J ϭ 4 Hz, 1 H), 4.87 (s, 2 H), 4.75
Eur. J. Org. Chem. 2003, 2585Ϫ2595
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2591

C. Kuhn, L. Skaltsounis, C. Monneret, J.-C. Florent
(t, J ϭ 5 Hz, J ϭ 4 Hz, 1 H), 4.35 and 4.20 (2d, AB system, J ϭ From Nitrile 22 by Reduction with Raney Nickel: A Raney nickel
FULL PAPER
2 Hz, 2 H), 3.40 (s, 3 H), 2.70 and 2.45 (2d, AB system, J ϭ 14 Hz,
2 H), 2.60 (d, J ϭ 14 Hz, 1 H) and 2.10 (dd, J ϭ 14, JЈϭ 5 Hz, 1
suspension (40%, 10 g) and sodium hypophosphite (1.1 g,
10 mmol) were successively added to a solution of 22 (296 mg, 1.1.
H), 1.61 (s, 3 H) and 1.25 (s, 3 H) ppm. MS: (DCI/NH3): m/z ϭ mmol) in a pyridine/AcOH/H2O mixture (2:1/1, v/v, 15 mL). The
287 [M ϩ NH4]ϩ. C13H19NO5 (269.29): calcd. C 57.98, H 7.11;
found C 58.12, H 7.18.
reaction mixture was stirred under argon at room temp. for 6 h.
The filtrate obtained after filtration through Celite was extracted
with EtOAc (3 ϫ 30 mL). The collected organic layers were washed
with H2O and with brine, and dried (MgSO4). After filtration and
purification under reduced pressure, the obtained residue was puri-
fied by flash column chromatography to give compound 26 (90 mg,
34%), together with the starting cyano compound 22 (95 mg, 39%)
and the more polar ketone 28 (63 mg, 25%).
Methyl
allyl]-β-
3-Deoxy-1,2-O-isopropylidene-4-C-[2-(methoxymethoxy)-
L-threo-pentofurano-uronate (23a) and the Corresponding er-
ythro Isomer (23b): The iodo compound 3 (1.5 mL, 4.6 mmol) was
added at Ϫ78 °C, under argon, to a solution of 21[29] (460 mg,
2.3 mmol) in anhydrous THF (30 mL). A solution of KHMDS in
toluene (0.5 , 5 mL) was then added dropwise to the mixture.
After 0.5 h, the reaction was quenched by addition of a saturated
aqueous solution of NH4Cl (5 mL) and the reaction mixture was
extracted with EtOAc (3 ϫ 30 mL). The collected organic layers
were washed with water and brine, and dried with MgSO4. After
evaporation under reduced pressure, a residue was obtained. Purifi-
cation by flash chromatography (cyclohexane, EtOAc, 3:1) gave a
mixture (420 mg, 61%) of diastereoisomer compounds (4S)-threo-
23a (major) and (4R)-erythro-23b (minor) (96% de), as shown by
crude NMR spectroscopy. Analytical samples of each diastereoiso-
mer were obtained by preparative median pressure liquid chroma-
tography. (4S)-threo-23a: [α]2D0 ϭ ؊56 (c ϭ 1.7, CHCl3). IR
(CDCl3): ν˜max (cmϪ1) ϭ 1742. 1H NMR (90 MHz, CDCl3): δ ϭ
5.82 (d, J ϭ 3.6 Hz, 1 H), 4.87 (s, 2 H), 4.69 (dd, J ϭ JЈ ϭ 3.6 Hz,
1 H), 4.24 and 4.07 (2d, AB system, J ϭ 2.4 Hz, 2 H), 3.70 (s, 3
H), 3.38 (s, 3 H), 2.82 (d, J ϭ 14 Hz, 1 H), 2.50 (s, 2 H), 1.98 (dd,
From Ester 23a by Reduction with DIBAH: A solution of DIBAH
(1.5 , 3 mL) was added at Ϫ78 °C to a solution of 23a (450 mg,
15 mmol) in anhydrous toluene (50 mL). After stirring for 2 h, the
reaction mixture was quenched by addition of MeOH (5 mL), and
was then stirred for 0.5 h at 0 °C. A saturated solution of Rochelle
salt (10 mL) was added and the mixture was stirred overnight. The
reaction mixture was extracted with EtOAc and the collected or-
ganic layers were washed with H2O and with brine, and dried
(MgSO4). After filtration and evaporation under reduced pressure,
the residue obtained was purified by flash column chromatography
(cyclohexane/EtOAc, 3:1) to give compound 26 (280 mg, 69%),
compound 28 (70 mg, 20%) and alcohol 27 (15 mg, 5%).
Compound 26: [α]2D0 ϭ Ϫ48 (c ϭ 0.9, CHCl3). IR (CDCl3): νmax
(cmϪ1) ϭ 1249 (ether), 1733 (CϭO aldehyde), 2956 (ϭCH2). 1H
˜
J ϭ 14, JЈ ϭ 3.6 Hz, 1 H), 1.40 (s, 3 H), 1.25 (s, 3 H) ppm. MS NMR (250 MHz, CDCl3): δ ϭ 9.85 (s, 1 H), 5.97 (d, J ϭ 4 Hz, 1
(DCI/NH3): m/z ϭ 320 [M ϩ NH4]ϩ, 303 [M ϩ H]ϩ. C14H22O7 H, H-1), 4.98 and 4.95 (2d, AB system, J ϭ 14 Hz, 2 H), 4.75 (dd,
(302.32): calcd. C 55.62, H 7.33; found C 55.48, H 7.15. (4R)-er-
ythro-23b: [α]2D0 ϭ Ϫ40 (c ϭ 1, CHCl3). 1H NMR (90 MHz,
J ϭ 4, JЈϭ 3 Hz, 1 H), 4.31 and 4.14 (2d, AB system, J ϭ 2 Hz, 2
H), 3.46 (s, 3 H), 2.86 and 2.45 (2d, AB system, J ϭ 14 Hz, , 2 H),
CDCl3): δ ϭ 5.86 (d, J ϭ 3.75 Hz, 1 H), 4.86 (s, 2 H), 4.73 (m, 1 2.73 (d, J ϭ 14 Hz, 1 H) and 2.05 (dd, J ϭ 14, J ϭ 3 Hz, 1 H),
H), 4.21 and 4.07 (2d, AB system, J ϭ 2.25 Hz, 2 H), 3.75 (s, 3 H),
3.40 (s, 3 H), 2.90 (s, 2 H), 2.40 (m, 2 H), 1.60 (s, 3 H), 1.33 (s, 3
H) ppm. MS (DCI/NH3): m/z ϭ 320 [M ϩ NH4]ϩ, 303 [M ϩ H]ϩ.
1.49 (s, 3 H) and 1.32 (s, 3 H) ppm. MS (DCI/NH3): m/z ϭ 290
[M ϩ NH4]ϩ, 273 [M ϩ H]ϩ.
3-Deoxy-1,2-O-isopropylidene-4-C-[2-(methoxymethoxy)allyl]-β-L-
Methyl 4-C-(2-Chloroallyl)- 3-deoxy-1,2-O-isopropylidene)-β-L-
threo-pentofuranose (27): Side-product of the DIBAH reduction of
23a. [α]2D0 ϭ Ϫ23 (c ϭ 1, CHCl3). IR (CDCl3): ν˜max (cmϪ1) ϭ 1072,
threo-pentofurano-uronate (24): A mixture of compound 21 (2 g,
10 mmol) and iodo derivative 25 (4 mL, 20 mmol) in anhydrous
THF (30 mL) was treated at Ϫ78 °C with KHMDS (0.5  in tolu-
ene, 20 mL). After 0.5 h, the reaction was worked up as for com-
pound 23a and 23b, giving starting ester 21 (0.270 g) and com-
pound 24 (1.33 g, 49%). [α]2D0 ϭ Ϫ53 (c ϭ 1, CHCl3). IR (CDCl3):
ν˜max (cmϪ1) ϭ 1740. 1H NMR (90 MHz, CDCl3): δ ϭ 5.86 (d, J ϭ
4.5 Hz, 1 H), 5.31 (d, J ϭ 3.75 Hz, 2 H), 4.75 (dd, J ϭ JЈ ϭ 4.5 Hz,
1 H), 3.80 (s, 3 H), 2.93 (d, J ϭ 15 Hz, 1 H), 2.83 (s, 2 H), 2.10
(dd, J ϭ 4.5, JЈ ϭ 15 Hz, 1 H), 1.46 (s, 3 H), 1.31 (s, 3 H) ppm. MS
(DCI/NH3): m/z ϭ 294 [M ϩ NH4]ϩ, 277 [M ϩ H]ϩ. C12H17ClO5
(276.71): calcd. C 52.09, H 6.19; found C 52.20, H 6.15.
1
1262, 2952, 3570. H NMR (250 MHz, CDCl3): δ ϭ 5.80 (d, J ϭ
4.5 Hz, 1 H), 4.90 (s, 2 H), 4.74 (dd, J ϭ 4.5, JЈ ϭ 4.5 Hz, 1 H),
4.22 and 4.09 (2d, AB system, J ϭ 2 Hz, 2 H), 3.69 (m, 2 H), 3.39
(s, 3 H), 2.49 and 2.30 (2d, AB system, J ϭ 14 Hz, 2 H), 2.40 (m,
1 H), 2.19 (dd, J ϭ 4.5, JЈ ϭ 15 Hz, 1 H), 2.03 (d, J ϭ 15 Hz, 1
H), 1.52 (s, 3 H), 1.27 (s, 3 H) ppm. 13C NMR (62.5 MHz,
CD3OD): δ ϭ 158.7, 113.2, 107.5, 94.8, 89.6, 88.8, 82.8, 67.2, 56.6,
43.0, 38.0, 27.2 and 26.1 ppm. MS (DCI/NH3): m/z ϭ 292 [M ϩ
NH4]ϩ. C13H22O6 (274.31): calcd. C 56.92, H 8.08; found C 56.85,
H 8.12.
3-Deoxy-5-formyl-1,2-O-isopropylidene-4-C-(2-oxopropyl)-β-L-
3-Deoxy-5-formyl-1,2-O-isopropylidene-4-C-[2-(methoxymethoxy)-
allyl]-β-L-threo-pentofuranose (26). From Nitrile 22 by Reduction
threo-pentofuranose (28): Side-product of the DIBAH reduction of
23a or 24, as well as of the reduction with Raney Nickel of 22. IR
(CDCl3): ν˜max (cmϪ1) ϭ 1249, 1723. 1H NMR (250 MHz, CDCl3):
δ ϭ 10.00 (s, 1 H), 5.90 (d, J ϭ 3.6 Hz, 1 H), 4.70 (t, J ϭ 4.8 Hz,
JЈ ϭ 3.6 Hz, 1 H), 3.13 and 2.82 (2d, AB system, J ϭ 17 Hz, 2 H),
2.58 (d, AB system, J ϭ 14 Hz, 1 H), 2.05 (dd, J ϭ 14, JЈ ϭ 4.8 Hz,
ABX system, 1 H), 1.51 (s, 3 H) and 1.29 (s, 3 H) ppm. MS (DCI/
NH3): m/z ϭ 246 [M ϩ NH4]ϩ, 229 [M ϩ H]ϩ.
with DiBAH: A solution of DIBAH in toluene (0.5 mL, 0.75 mmol)
was added at Ϫ78 °C to a solution of 22 (33 mg, 0.12 mmol) in
anhydrous toluene (30 mL). After stirring for 50 min, the reaction
was quenched by addition of MeOH (1 mL), a saturated solution
of Rochelle salt (5 mL) was then added, and the medium was
stirred for 4 h. The reaction mixture was extracted with EtOAc (3
ϫ 20 mL). The collected organic layer were washed with H2O and
with brine, and dried (MgSO4), and the solvents were evaporated
under reduced pressure after filtration. The residue obtained was
purified by flash chromatography (cyclohexane, EtOAc) to give
compound 26 (11.6 mg, 34%) as a colorless oil.
4-C-(2-Chloroallyl)-3-deoxy-5-formyl-1,2-O-isopropylidene-β-L-
threo-pentofuranose (29): A solution of DIBAH (1.5 ) in toluene
(7 mL, 10.5 mmol) was added dropwise at Ϫ78 °C to a solution of
compound 24 (1.33 g, 4.8 mmol) in anhydrous toluene (30 mL).
2592
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2585Ϫ2595

Two (3ϩ2) Annulation Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
FULL PAPER
After stirring for 1 h, the reaction was stopped by addition of
MeOH (5 mL). Then, after 1 h, a solution of Rochelle salt (30 mL) 34 (110 mg) in solution in THF (2 mL) were added at 0 °C to a
was added and the mixture was stirred overnight. After addition of red solution of (hexyl)triphenylphosphorane in THF [prepared
H2O (50 mL), the reaction was extracted with ethyl acetate (3 ϫ from (n-hexyl)triphenylphosphonium bromide (1.27 g, 2.9 mmol in
Wittig Reaction of Compound 34: HMPA (1 mL) and compound
50 mL). The collected organic layers were washed with brine, dried
(MgSO4), and filtered. Evaporation and purification by flash chro-
matography (cyclohexane/ethyl acetate 6:1) gave compound 29
(0.83 g, 70%) and alcohol 30 (170 mg, 13%). [α]2D0 ϭ Ϫ54 (c ϭ 1,
10 mL of THF at Ϫ78 °C), by addition of BuLi (2.5  in 1.2 mL
of THF)]. The reaction mixture was stirred at Ϫ20 °C for 15 h and
then at room temp. for 6 h. After addition of water (30 mL), the
reaction mixture was extracted with Et2O (3 ϫ 20 mL), and the
CHCl3). IR (CDCl3): ν˜max (cmϪ1) ϭ 1733. 1H NMR (300 MHz, organic layers were washed with H2O (5 ϫ 10 mL) and with brine,
CDCl3): δ ϭ 9.89 (s, 1 H), 5.93 (d, J ϭ 4 Hz, 2 H), 5.34 (s, 2 H), and dried (MgSO4). Purification by flash column chromatography
4.72 (dd, J ϭ 4, JЈ ϭ 5 Hz, 1 H), 2.66 (d, J ϭ 14 Hz, 1 H), 2.83 (cyclohexane/acetone, 5:1) furnished compound 35 (115 mg, 42%).
and 2.64 (2d, AB system, J ϭ 15 Hz, 2 H), 2.10 (dd, J ϭ 5, JЈ ϭ
1H NMR (250 MHz, CDCl3): δ ϭ 5.91 (m, 2 H, H-4), 5.56 and
15 Hz, 1 H), 1.47 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (75 MHz, 5.38 (2m, 2 H), 4.97 (m, 0.33 H), 4.66 (m, 0.66 H), 2.50Ϫ2.30 (m,
CDCl3): δ ϭ 203.6, 135.2, 117.7, 111.9, 106.2, 89.8, 79.9, 44.9, 40.0, 3 H), 2.08Ϫ2.02 (m, 2 H), 2.87Ϫ1.69 (m, 3 H), 1.26 (m, 6 H), 0.88
26.3 and 25.4 ppm. MS (DCI/NH3): m/z ϭ 264 [M ϩ NH4]ϩ, 246 (t, J ϭ 8 Hz, 3 H) ppm. MS (DCI/NH3): m/z ϭ 228 [M ϩ NH4]ϩ.
[M ϩ H]ϩ.
(4R)-(Z)-4-Hydroxy-4-(oct-2-enyl)cyclopent-2-enone (36): Jones re-
4-C-(2-Chloroallyl)-3-deoxy-β-1,2-O-isopropylidene-
L
-threo-
agent (0.1 mL) was added to a solution of compound 35 (102 mg,
pentofuranose (30): This compound is a side-product of the re-
0.48 mmol) in acetone (5 mL). The reaction mixture was stirred for
duction of 24 with DIBAH. Cf. preparation of 29. IR (CDCl3): 15 min at room temperature, and the reaction was then stopped by
1
ν˜max (cmϪ1) ϭ 1072Ϫ1155, 1262, 2952, 3570. H NMR (250 MHz,
CDCl3): δ ϭ 5.80 (d, J ϭ 4.5 Hz, 1 H), 4.90 (s, 2 H), 4.74 (dd, J ϭ EtOAc (25 mL) was then added to the reaction mixture. The or-
4.5, JЈ ϭ 4.5 Hz, 1 H), 4.22 and 4.09 (dd, J ϭ 2 Hz, 2 H), 3.69 (m, ganic layers were neutralized with aqueous NaOH (0.1 ⁾, washed
2 H), 3.39 (s, 3 H), 2.49 and 2.30 (dd, J ϭ 14 Hz, 2 H), 2.40 (m, 1 with brine, and dried (MgSO4), and the solvents were evaporated
addition of dry sodium bisulfite until a green color was obtained.
H, OH), 2.19 (dd, J ϭ 4.5, JЈ ϭ 15 Hz, 1 H), 2.03 (d, J ϭ 15 Hz,
under reduced pressure to give a residue, which was purified by
1 H), 1.52 (s), 1.27 (s) ppm. 13C NMR (62.5 MHz, CD3OD): δ ϭ flash column chromatography on silica gel (cyclohexane/acetone,
158.7, 113.2, 107.5, 94.8, 89.6, 88.8, 82.8, 67.2, 56.6, 43.0, 38.0, 27.2 7:1). Compound 36 was obtained as an amorphous gum (87 mg,
and 26.2 ppm. MS (DCI/NH3): m/z
ϭ
266 [M
ϩ
NH4]ϩ.
86%). [α]2D0 ϭ Ϫ80 (c ϭ 0.5, CHCl3). {ref.[11e] [α]2D0 ϭ Ϫ84 (c ϭ
0.31, CHCl3); ref.[11b] [α]2D0 ϭ Ϫ54 (c ϭ 1.52, CHCl3)}. IR (CDCl3):
ν˜max (cmϪ1) ϭ 1712. 1H NMR (300 MHz, CDCl3): δ ϭ 7.43 (d,
J ϭ 5.8 Hz, 1 H), 6.15 (d, J ϭ 5.8 Hz, 1 H), 5.67 and 5.37 (2m, 2
H), 2.57 and 2.45 (2d, AB system, J ϭ 18.4 Hz, 2 H, 2.61Ϫ2.38
(m, 2 H) ppm. MS: (DCI/NH3): m/z ϭ 226 [M ϩ NH4]ϩ, 209 [M
ϩ H]ϩ. C13H20O2 (208.30): calcd. C 74.96, H 9.68; found C 74.71,
H 9.59.
C11H17ClO4 (248.70): calcd. C 53.12, H 6.89; found C 53.01, H
6.80.
(3R/S,3ЈaR,5ЈR,6ЈaR)-6Ј,6Јa-Dihydro-2Ј,2Ј-dimethylspiro[4-cyclo-
pentene-1,5Ј(3ЈaH)-furo[2,3-d][1,3]dioxol]-3-ol (32): Compound 5
(500 mg, 2.4 mmol) was dissolved in a solution of CeCl3·7H2O
(2.5 mmol) in MeOH (6.25 mL), and NaBH4 (94.5 mg, 2.4 mmol)
was added dropwise. The reaction mixture was stirred for 5 min at
room temperature and then quenched by addition of an saturated
aqueous solution of NH4Cl (5 mL). After addition of water
(5R)- and (5S)-(1R,4R) Esters 40 and 41: A solution of ester 39[39]
(2.06 g, 7.9 mmol) and iodopropene 3 (2 mL, 13.2 mmol) in THF
(30 mL), the mixture was extracted with CH2Cl2 (3 ϫ 20 mL). The (50 mL) was treated at Ϫ78 °C with KHMDS (0.5 , 16 mL) under
organic layers were washed with brine and dried (MgSO4), and the
solvents were evaporated under reduced pressure to give compound
32 (390 mg, 77%) as a mixture of 3R/S diastereoisomers. 1H NMR
the same conditions as used for compound 21. After usual workup,
compounds 40 (5S) and 41 (5R) were obtained as an inseparable
mixture of two diastereoisomers (ratio 1:7, respectively). H NMR
1
(90 MHz, CDCl3): δ ϭ 5.94 (m, 1 H), 5.77 (d, J ϭ 3 Hz, 1 H), 5.61 (90 MHz, CDCl3): δ ϭ 4.88 and 4.78 (2d, AB system, J ϭ 6 Hz, 2
(d, J ϭ 4.5 Hz, 1 H), 4.71 (m, 2 H), 2.80 (dd, J ϭ 15, JЈ ϭ 7.5 Hz, H), 4.22Ϫ3.89 (m, 6 H), 3.69 (s, 3 H), 3.37 (s, 3 H), 2.97 and 2.31
ABX system, 1 H), 2.31Ϫ1.81 (m, 3 H), 1.56 (s, 3 H), 1.30 (s, 3 H) (2d, AB system, J ϭ 15 Hz, 2 H), 1.46, 1.43, 1.41 and 1.35 (4s, 12
ppm. MS: (DCI/NH3): m/z ϭ 230 [M ϩ NH4]ϩ, 213 [M ϩ H]ϩ.
H) ppm. MS (DCI/NH3): m/z ϭ 378 [M ϩ NH4]ϩ, 361 [M ϩ H]ϩ.
C17H28O8 (360.40): calcd. C 56.65, H 7.83; found C 56.73, H 7.80.
(1R,3R/S)-1-(Oct-2-enyl)cyclopent-4-ene-1,3-diol (35): Compound
32 (270 mg, 1.27 mmol) was dissolved in a mixture of AcOH/H2O
Carbaldehyde 42: A mixture of 40/41 (920 mg, 2.55 mmol) in tolu-
(5 mL/3 mL) and stirred for 1 h at 80 °C. Successive evaporations ene (10 mL) was treated at Ϫ78 °C with DIBAH (1.5 , 2.5 mL)
with toluene afforded a residue, which was purified by flash column
chromatography on silica gel (MeCN/MeOH, 3%). The crude com-
pound 33 obtained (230 mg) was dissolved in MeOH (10 mL).
and kept stirring for 1.5 h. The reaction mixture was then quenched
by addition of MeOH (3 mL) and a saturated aqueous solution of
Rochelle salt and extracted with EtOAc (3 ϫ 50 mL). The collected
NaBH4 (50 mg, 1.3 mmol) was added at 0 °C, and after stirring organic layers were washed with H2O and with brine, and dried
for 15 min, the reaction mixture was neutralized by addition of
Amberlite IRC-50S resin. After co-evaporation with MeOH (3 ϫ
10 mL) under reduced pressure, a residue was obtained. This was
dissolved in MeOH/H2O (3:2, 10 mL) and cooled to 0 °C, NaIO4
(278 mg, 130 mmol) was then added, and the mixture was stirred
(MgSO4). After filtration and evaporation under reduced pressure,
a residue was obtained and purified by flash column chromatogra-
phy (cyclohexane/ethyl acetate, 4:1) to furnish 42 as a mixture of
(2R) and (2S) diastereoisomers (500 mg, 59%) immediately treated
1
(cf. 10 and 11 preparation). H NMR (90 MHz, CDCl3): δ ϭ 9.57
for 1 h at room temperature. After filtration through a Celite pad (s, 1 H), 4.90 and 4.80 (2d, AB system, J ϭ 6 Hz, 2 H), 4.29Ϫ3.72
and evaporation of MeOH under reduced pressure at 30 °C
(10 Torr), an aqueous solution of the aldehyde 34 was obtained,
giving, after lyophilization, an amorphous solid (110 mg).
(m, 6 H), 3.34 (s, 3 H), 3.03 and 2.40 (2d, AB system, J ϭ 15 Hz,
2 H), 1.45, 1.36, 1.33 and 1.30 (4s, 12 H) ppm. MS: (DCI/NH3):
m/z ϭ 348 [M ϩ NH4] ϩ, 331 [M ϩ H]ϩ.
Eur. J. Org. Chem. 2003, 2585Ϫ2595
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2593

C. Kuhn, L. Skaltsounis, C. Monneret, J.-C. Florent
FULL PAPER
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Eur. J. Org. Chem. 2003, 2585Ϫ2595

Two (3ϩ2) Annulation Routes to Homochiral 4-Alkyl-4-hydroxy-2-cyclopentenone Synthesis
FULL PAPER
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Received January 23, 2003
Eur. J. Org. Chem. 2003, 2585Ϫ2595
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2595