Formaldehyde SAMP-hydrazone as a neutral formyl anion equivalent: Asymmetric synthesis of substituted β-formyl δ-lactones and furofuran lactones

Article abstract of DOI:10.1002/(SICI)1099-0690(200003)2000:6<893::AID-EJOC893>3.0.CO;2-U

An efficient asymmetric synthesis of α-substituted β-formyl δ- lactones 5 (de ≥98%, ee = 80-95%) and 4-substituted furofuran lactones 6 (de ≥ 98%, ee = 80->98%) in acceptable overall yields is reported. Key steps of the new procedure are an asymmetric Michael addition of formaldehyde SAMP- hydrazone (1) to 5,6-dihydro-2H-pyran-2-one (2) under neutral conditions, followed by trans-selective α-alkylation and subsequent cleavage of the auxiliary by ozonolysis or a hydrolytic domino reaction protocol, respectively. The absolute configurations given for the title compounds are based on three X-ray structure analyses and NOE measurements.

Full text of DOI:10.1002/(SICI)1099-0690(200003)2000:6<893::AID-EJOC893>3.0.CO;2-U

FULL PAPER
Formaldehyde SAMP-Hydrazone as a Neutral Formyl Anion Equivalent:
Asymmetric Synthesis of Substituted β-Formyl δ-Lactones and Furofuran
Lactones
[a]
[a]
[a]
´
Dieter Enders,* Juan Vazquez, and Gerhard Raabe
Dedicated to Professor Günther Wulff on the occasion of his 65th birthday
Keywords: Asymmetric synthesis / Nucleophilic formylation / Michael addition / Lactones / Formyl anion equivalent /
Domino reactions
An efficient asymmetric synthesis of α-substituted β-formyl
δ-lactones 5 (de Ն 98%, ee = 80–95%) and 4-substituted furo-
ral conditions, followed by trans-selective α-alkylation and
subsequent cleavage of the auxiliary by ozonolysis or a hy-
furan lactones 6 (de Ն 98%, ee = 80–Ͼ98%) in acceptable drolytic domino reaction protocol, respectively. The absolute
overall yields is reported. Key steps of the new procedure
are an asymmetric Michael addition of formaldehyde SAMP-
hydrazone (1) to 5,6-dihydro-2H-pyran-2-one (2) under neut-
configurations given for the title compounds are based on
three X-ray structure analyses and NOE measurements.
The commercially available formaldehyde SAMP-hy-
drazone [(S)-1][3] has been successfully employed as a chiral
formyl-d1 reagent in the nucleophilic asymmetric formyl-
ation and cyanation of a variety of electrophilic substrates,
including nitroalkenes,[4] sugar aldehydes,[5] α,β-unsaturated
ketones,[6] and trifluoromethyl ketones.[7] Because this
methodology allows introduction of the versatile aldehyde
or nitrile functionality with a high level of stereoselectivity,
it has great synthetic potential as a tool for asymmetric car-
bon–carbon bond formation in the construction of complex
organic molecules.
This neutral chiral equivalent of the formyl anion H
should allow stereoselective introduction of the formyl
group at the β-position of lactones 2 through 1,4-addition
(Scheme 2). Moreover, subsequent alkylation with alkyl hal-
ides I should generate a second stereogenic centre with the
introduction of further groups α to the carbonyl group.
Therefore, a Michael addition/α-alkylation protocol should
allow a vicinal difunctionalization of lactone frameworks,
as indicated in the retrosynthetic analysis of Scheme 2.
Introduction
Nucleophilic formylation is an important C–C bond-for-
ming process in synthetic chemistry and a variety of re-
agents, including asymmetric analogues, have been de-
veloped in recent years.[1] In the late1960’s, Brehme et al.[2]
recognized that formaldehyde N,N-dialkylhydrazones A can
be regarded as azaenamines and reported electrophilic sub-
stitutions at the aldehyde hydrazone carbon on treatment
with reactive electrophiles (A B C). After transformation of
the hydrazone group to the aldehyde (C D) or nitrile func-
tion (C E), the overall result is a nucleophilic formylation
or cyanation under neutral conditions. Thus, formaldehyde
hydrazones A are indeed synthetic equivalents of the formyl
and cyanide anion synthons F (Scheme 1).[3]
Scheme 2. Retrosynthetic analysis of β-formyl γ- and δ-lactones
There have been several precedents for the vicinal difunc-
tionalization of 2-butenolide (2a), which have been directed
towards the synthesis of lignans.[8] Of note are the processes
involving the use of metallated dithianes,[9] O-silylcyanohy-
drins,[10] and α-aminonitriles[11] as nucleophiles and sub-
sequent trapping with various electrophiles. However, very
little has been reported on such processes employing unsat-
urated six-membered lactones as Michael acceptors.[12]
Scheme 1. Formaldehyde N,N-dialkylhydrazones as neutral formyl
anion and cyanide equivalents
[a]
Institut für Organische Chemie, Rheinisch-Westfälische
Technische Hochschule Aachen,
Professor-Pirlet-Strasse 1, D-52074 Aachen, Germany
Fax: (internat.) ϩ 49-(0)241/888-8127
E-mail: Enders@RWTH-Aachen.de
Eur. J. Org. Chem. 2000, 893Ϫ901
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0306Ϫ0893 $ 17.50ϩ.50/0
893

´
D. Enders, J. Vazquez, G. Raabe
FULL PAPER
Lactones[13] and their derivatives constitute important su-
bunits in many natural products, such as sesquiterpenes,[14]
α-methylene lactones,[15] and macrolides.[16] Moreover,
many exhibit important biological properties, for example
as semiochemicals, as flavours and fragrances, or as antibi-
otics or cytostatics. Therefore, the efficient and versatile
asymmetric synthesis of lactone building blocks is of great
interest.[17] With this in mind, we decided to extend the al-
ready well-established formaldehyde SAMP-hydrazone
methodology to α,β-unsaturated lactones.[18]
Scheme 4. Self-condensation of (S)-1 in the presence of Lewis acids
Results and Discussion
addition of formaldehyde 1-aminopyrrolidine hydrazone
to aldehydes.[20]
We wish to describe here in detail our protocol for the
stepwise Michael addition/α-alkylation of (S)-1 to lactones
2 (Scheme 3 and 5). The use of a Lewis acid proved neces-
sary in order to activate the α,β-unsaturated lactones 2 to-
wards attack by formaldehyde SAMP-hydrazone. Various
Lewis acids (AlCl3, BF3Et2O, TiCl4, ZnCl2, etc.) were
tested, but as has previously been observed with enones,[6]
only the use of trialkylsilyl triflates (TBS or TMS) as pro-
moters led to formation of the desired Michael adduct
(S,R)-3, the best results being obtained with TBS triflate.
These reactions were found to be very dependent on the
lactone ring size and hence it was not possible to establish
a general method for both lactones (2a,b). In the case of 5-
hydro-2H-furan-2-one (2a), the best results were achieved
when the hydrazone (S)-1 was slowly added to a solution
of the preformed trialkylsilyl lactone complex at Ϫ78 °C
(see Experimental Section). Under these conditions, al-
though the Michael product could only be obtained in poor
yield (20%), it was formed with an excellent diastereoisom-
eric excess (de Ͼ95%). In the case of 5,6-dihydro-2H-pyran-
2-one (2b), the best results were achieved by slow addition
of the promoter to the mixture of reactants (see Experi-
mental Section).
On the other hand, in the case of 2-pentenolide (2b) the
use of dichloromethane proved necessary as THF was
found to favour the formation of by-products, again arising
from the dual electrophilic and nucleophilic nature of form-
aldehyde SAMP-hydrazone. Furthermore, it also proved
necessary to carry out the reaction under dilute conditions
to avoid the formation of these by-products. Under optim-
ized conditions, it was possible to obtain the desired
Michael product 3 (n ϭ 2) in acceptable yield (54%) and
with good diastereomeric excess (de ϭ 80%). The corres-
ponding intermediate silyl ketene acetal was found to be
unstable to purification by chromatography, which obviated
the need for subsequent treatment of the Michael adduct
with tetrabutylammonium fluoride (TBAF). The reaction
was therefore quenched with pH 7 buffer or Et3N to neut-
ralize the triflic acid generated. The diastereomeric excess
1
of the Michael adduct 3 was determined by 13C- or H-
NMR spectroscopy.
Although initially the reaction proceeded quite quickly
(35% yield after 3 h), its rate decreased dramatically after
the first 3 h (40% after 8 h) and no improvement in the
yield was observed beyond 30 h (54% yield after 30 h and
after 48 h). Since scaling up of the reaction with 2-butenol-
ide did not allow the synthesis of reasonable amounts of γ-
lactones 3 (n ϭ 1), it was decided to use only the Michael
product 3 (n ϭ 2) obtained from the pentenolide. Unfortu-
nately, it was found that the mixture of β-epimers 3 could
only be separated by HPLC on chiral stationary phases.
This mixture was therefore used directly in the subsequent
deprotonation/α-alkylation step. Attempts to trap the silyl
ketene acetal intermediate using different alkyl halides
were unsuccessful.
Scheme 3. Asymmetric Michael addition of (S)-1 to α,β-unsatur-
ated lactones
A screening of various bases (lithium tetramethylpiperid-
ide, tert-butyllithium, and lithium diisopropylamide)
These reactions not only proved dependent on the order showed that LDA gave significantly better results compared
of addition of reactants, but were also found to be strongly to the other bases. Accordingly, lactone 3b was depro-
dependent on the solvent used. In the case of 2-butenolide tonated using LDA[21] at Ϫ78 °C, hexamethylphos-
(2a), it proved necessary to carry out the reaction in tetra- phoramide (HMPA, 2.5–5 equiv.) was added, and sub-
hydrofuran, since in dichloromethane the dimer K[19] was sequent addition of the requisite alkylating agent afforded
formed, owing to self-condensation of formaldehyde the α-substituted lactone hydrazones 4 (Scheme 5, Table 1)
SAMP-hydrazone via the intermediate J (Scheme 4). In this in moderate to excellent yields (44–90%) and with satisfact-
case, (S)-1 reacts both as a nucleophilic and as an elec- ory diastereomeric excesses (de ϭ 80–Ͼ98%). However, the
trophilic species. A similar outcome was observed in the reaction did not take place in the absence of the HMPA
894
Eur. J. Org. Chem. 2000, 893Ϫ901

Formaldehyde SAMP-Hydrazone as a Neutral Formyl Anion Equivalent
FULL PAPER
minimized. After several hours, TLC control indicated total
consumption of the starting materials in the case of more
reactive electrophiles (Table 1, entries a, b, e). However, in
the other cases (entries c, d) requiring longer reaction times,
a certain amount of starting material (2–5%) persisted. Ini-
tial reaction temperatures of –100 °C with subsequent
warming to –78 °C or –35 °C had little effect on the results
obtained previously. The only exception was in the case of
methyl iodide, where the de value of the alkylation increased
by 10%. Although optimal conditions involved the use of
relatively large quantities of HMPA (2.5–5 equivalents),
both the yield and the de value were found to increase by
up to 20%. The use of 5–10 equivalents of DMPU instead
of HMPA led to similar results. Under the optimized al-
kylation conditions, dialkylation (6%) was only observed in
the case of propyl iodide. Dialkylation also occurred using
allyl and benzyl bromides, when the reaction mixtures were
slowly allowed to warm to 0 °C.
Unfortunately, employing potassium diisopropylamide
(KDA) the use of additives could not be avoided and lower
yields were achieved. Interestingly, however, the use of this
base had an effect on the ratio of the trans/cis-alkylated
products in each case (see Table 2). The most drastic effect
was observed in the case of methyl iodide, where the cis-
configured lactone product became the major isomer. The
addition of tetrabutylammonium iodide to exchange the
counterion did not increase the ratio of the cis/trans prod-
ucts.
The relative trans-configuration of the α,β-disubstituted
lactones 4 was determined by 1H-NMR spectroscopy based
Scheme 5. Asymmetric synthesis of substituted β-formyl δ-lactones
and furofuran lactones
Table 2. α-Alkylation of lactone (S,R)-3b using LDA or KDA as
additive. In order to prevent self-condensation,[22] a THF
solution of the lactone (cooled to –78 °C) was slowly added
to a solution of the lithium amide base. Various experi-
ments indicated that an increase in the reaction temperature
led to decreases in both the de and the yield. Posner et al.
observed a similar reduction in yield at temperatures in ex-
cess of –30 °C.[21a] Therefore, by maintaining the reaction
temperature at –78 °C in the case of more reactive elec-
trophiles and warming to –35 °C in the case of less reactive
base
entry
RX
ratio trans/cis[a]
(HMPA/LDA)
ratio trans/cis[a]
(DMPU/KDA)
a
b
c
MeI
13 : 1
4.9 : 1
61 : 1
1 : 2.5
4.6 : 1
7 : 1
nPrI
AllylBr
BnBr
d
Ͼ99 : 1
10 : 1
[a] Determined by HPLC on chiral stationary phases [chiralpak AD
(4.6 ϫ 250 mm), (S,S)-Whelk-O (4 ϫ 250 mm), chiralcel OJ
1
electrophiles, the partial decomposition of the anion was (4.6 ϫ 250 mm)].
Table 1. Stepwise Michael addition/α-alkylation of (S)-1 to 2-pentenolide 2 and subsequent hydrazone cleavage to β-formyl δ-lactones 5
yield[a]
(%)
[α]D (c, CHCl3)
de[b]
(%)
yield 5
(%)
[α]D (c, CHCl3)
ee (%)
RT
RT
4,5
RX
[c]
a
b
c
d
e
AllylBr
MeI
nPrI
TBSO(CH2)2I
BnBr
90
89
67
44
77
Ϫ158.5 (1.20)
Ϫ126.4 (2.88)
Ϫ132.6 (1.44)
Ϫ99.7 (1.30)
Ϫ155.7 (0.97)
Ͼ98 (98)
80[d,e] (88)
88 (74)
–
–
70
68
50
59
ϩ36.4 (1.11)
ϩ21.5 (0.78)
Ϫ1.3 (0.77)
Ϫ9.0 (0.89)
82[f]
89[g]
95[h]
80[i]
94 (59)
80[e] (Ͼ98)
[a]
[b]
Yield after flash chromatography. – Determined by HPLC on chiral stationary phases [chiralpak AD (4.6 ϫ 250 mm), (S,S)-Whelk-
O 1 (4 ϫ 250 mm), chiralcel OJ (4.6 ϫ 250 mm)] after HPLC separation. Figures in brackets refer to the de values of the alkylation
reactions. – [c] 5a decomposes during ozonolysis. – [d] After flasch chromatography. – [e] Dieastereoisomers were not separable by HPLC. –
[f]
Determined from the de of the corresponding acetal derived from (R,R)-2,3-butanediol by GC on a chiral stationary phase (Lipodex
[g]
[h]
E 25 m). – Determined by shift experiments using (R)-1-(9-anthryl)-2,2,2-trifluoroethanol as co-solvent. – Determined as de of the
[i]
corresponding hydrazone 4. – Determined as de of the corresponding acetal by HPLC on chiral stationary phases [(S,S)-Whelk-O
1 (4 ϫ 250 mm)].
Eur. J. Org. Chem. 2000, 893Ϫ901
895

´
D. Enders, J. Vazquez, G. Raabe
FULL PAPER
on the trans-diaxial coupling constants (9.5–10.7 Hz) of the purification required the use of silica gel of particle size
protons at the new stereogenic centres.[23] The absolute con- 0.063–0.100 mm to avoid partial decomposition upon chro-
figuration of the major diastereoisomer (3S,4R)-4e was de- matography.
termined by X-ray crystal structure analysis. X-ray analysis
of 4e indicated that the lactone ring adopts a chair-like con-
formation with the C-3 and C-4 substituents adopting a
Table 3. Asymmetric synthesis of (1S,5R)-2,8-dioxabicy-
clo[3.3.0]octan-3-one derivatives 6
trans-diequatorial orientation (Figure 1). On the other
6
R
yield[a]
(%)
m.p.[b]
[α]RDT (c, CHCl3)
ee[c]
hand, the X-ray analysis of the minor diastereoisomer
(3R,4R)-4b revealed a boat-like conformation, similar to
that observed by Posner (Figure 1).[24]
(°C)
(%)
a
b
H
Me
66
oil
78–80
ϩ29.5 (0.96)
ϩ49.8 (0.95)
85
98 (75)[d]
80 (Ͼ98)[d]
c
d
e
nPr
Allyl
Bn
97
87
90
oil
52–54
oil
ϩ76.8 (0.80)
ϩ75.6 (0.80)
ϩ104.4 (0.91)
88
Ͼ98
80
[a]
Yield after flash chromatography (silica gel, Et2O/pentane). –[b]
[c]
Uncorrected, measured on a Büchi apparatus. – Determined by
[d]
GC on a chiral stationary phase (Chirasil dex 25 m). – Figures
in parentheses indicate values after recrystallization of the final
product.
The enantiomeric purities of the δ-lactones were deter-
mined from the de values of the corresponding (R,R)-di-
methylbutanediol acetals,[26] as measured by GC or HPLC
on chiral stationary phases (5b,e), by 1H-NMR shift experi-
ments using (R)-1-(9-anthryl)-2,2,2-trifluoroethanol as co-
solvent (5c), or from the de value of the corresponding hy-
drazone 4 (5d). In all cases, it was demonstrated that the
ozonolysis proceeds without racemization under the condi-
tions used.[27]
Decomposition of the aldehydes was observed upon pro-
longed standing, hence it was necessary to store these com-
pounds as their corresponding chemically and optically
stable acetals or to prepare them directly prior to use in
further reactions.
δ-Lactones 5 are interesting polyfunctional molecules,
which may be used as building blocks in the synthesis of
more complex compounds. One example of the potential
use of these materials may be seen from their behaviour
upon hydrolysis.[28] Acidic hydrolysis using 5  HCl in a
two-phase system rapidly initiated a domino reaction and
afforded furofuran lactone derivatives 6 in excellent yields
(87–98%) and with high stereoisomeric purities (de Ն 98%,
ee ϭ 80–98%, Table 3, reaction times 20–35 min.). Only in
the case of the unsubstituted compound 6a was the yield
lower, probably due to its sensitivity under the reaction con-
ditions. The final cascade steps involve cleavage of the hy-
drazone moiety, opening of the lactone ring, and formation
of the furofuran lactone system through the corresponding
hemiacetal intermediate. This final step has previously been
described by Yoshikoshi et al.,[29] who obtained 7-methylfu-
rofuran lactones by hydrolysis of 6-methyl-2-oxotetrahydro-
2H-pyran-4-carbaldehyde in the presence of p-toluenesul-
Figure 1. Crystal structures of (2ЈS,3R,4R)-4b and (2ЈS,3S,4R)-4c
Assuming a uniform reaction pathway in all cases, the
relative chair-like transition-state geometry for the nucleo-
philic attack of (S)-1 on the α,β-unsaturated δ-lactone 2 can
be explained in the same way as previously described for
1,4-additions to enones.[6] Fortunately, in some cases the
diastereoisomers of the lactone hydrazones 4 were found
to be separable by flash chromatography (4b) or by HPLC
(4a,c,d) and it was therefore possible to perform the cleav-
age of the chiral auxiliary using diastereomerically en-
riched hydrazones.
Cleavage of the Hydrazone Moiety
Finally, in order to confirm the previously demonstrated fonic acid.
equivalence of formaldehyde SAMP-hydrazone to the for-
These furofuran lactones 6 are particularly interesting be-
myl anion, diastereomerically enriched compounds 4 were cause a number of insect antifeedant clerodanes,[30] such as
converted in acceptable yields (50–70%) and with high dia- clerodin (R ϭ H) and caryoptin (R ϭ OAc) L or mycotox-
stereo- and enantiomeric excesses (de Ն 98%, ee ϭ 80–95%, ins such as aflatoxin B1 M (Figure 2), contain furo[2,3-b]fu-
Table 3) to their corresponding α-substituted β-formyl δ- ran moieties at various levels of oxidation.
lactones 5 by ozonolysis at –78 °C (Scheme 5).[25] These for-
Because the bicyclic lactone acetal 6a could easily be
myl δ-lactones 5 proved to be relatively unstable and their transformed into the alcohol and the 2,3-dihydrofurofu-
896
Eur. J. Org. Chem. 2000, 893Ϫ901

Formaldehyde SAMP-Hydrazone as a Neutral Formyl Anion Equivalent
FULL PAPER
Conclusion
In summary, our Michael addition/α-alkylation protocol
employing formaldehyde SAMP-hydrazone 1 as a neutral
chiral formyl anion equivalent in 1,4-additions to 2-penten-
olide extends the palette of electrophiles that may be used
for C–C bond formation with 1. The new procedure has
allowed an efficient and stereoselective synthesis of (4R)-
2-oxotetrahydro-2H-pyran-4-carbaldehyde and (1S,5R)-2,8-
dioxabicyclo[3.3.0]octan-3-one derivatives in acceptable
overall yields and with high diastereo- and enantiomeric
purities, the outcome being dependent on the hydrazone
cleavage method used. Both types of compound represent
useful building blocks in the asymmetric synthesis of bioac-
tive compounds, of which the corresponding enantiomers
would be obtained by employing the enantiomeric auxili-
ary RAMP.
Figure 2. Insect antifeedants and mycotoxins with furo[2,3-b]fu-
ran moieties
ran[31] derivatives, substructures encountered in the clerod-
ane family, these furofuran lactones may represent valuable
chiral building blocks for the synthesis of clerodane derivat-
ives. To the best of our knowledge, only a few methods exist
that allow access to furofuran lactones[32] or the furo-
[2,3-b]furan moiety[33] in such a short sequence.
Experimental Section
General: All solvents were dried and purified prior to use. – Col-
umn chromatography: Merck silica gel 60, 0.040–0.063 mm (230–
400 mesh). – Optical rotation values: Perkin–Elmer P 241 (254 nm);
solvents Merck Uvasol quality. – IR: Perkin–Elmer FT-IR 1750. –
NMR: Varian VXR 300 and Gemini 300; TMS as internal stand-
ard. – MS: Finnigan MAT 212 and Finnigan SSQ 7000 (70 eV). –
Microanalyses: Elementar vario EL. – Crystallographic data (ex-
cluding structure factors) for the structures 4b and 4e (Figure 1)
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC-115168 and 115169, respectively. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union
Road, Cambridge CB2 1EZ, U.K. [Fax: (internat.) ϩ44 (0)1223
336033; E-mail: deposit@ccdc.cam.ac.uk]. – THF was dried by dis-
tillation from K/benzophenone under Ar. CH2Cl2 was dried by dis-
tillation from CaH2 under Ar. All other reagents were purchased
and used as received. The diastereoisomeric excesses of δ-lactones
(S,R,S)-4 were determined by HPLC for 4a, and by HPLC on
chiral stationary phases [chiralpak AD (4.6 ϫ 250 mm) for com-
pounds 4c, (S,S)-Whelk-O 1 (4 ϫ 250 mm) for compounds 4d,e,
and chiralcel OJ (4.6 ϫ 250 mm) for compound 4b]. The enantiom-
eric excesses of α-substituted β-formyl δ-lactones 5 were deter-
mined in the case of 5b from the de of the corresponding acetal by
GC on a chiral stationary phase (Lipodex E 25m) and in the case
of 5e from the de of the corresponding acetal by HPLC on a chiral
stationary phase [(S,S)-Whelk-O 1 (4 ϫ 250 mm)]. The enantiom-
eric excesses of furofuran lactones 6 were determined by GC on a
chiral stationary phase (Chirasil dex 25m). The title reagent, form-
aldehyde SAMP-hydrazone (S)-1, may be purchased from Merck-
Schuchardt, Hohenbrunn, Germany.
Figure 3. NOE connectivity in (1S,4S,5R)-6d
The relative configuration of the perhydrofurofuran lac-
tones 6 was confirmed by NOE experiments on (1S,4S,5R)-
6e (Figure 3) and the absolute configuration of this com-
pound was determined by the X-ray structure analysis of
its minor diastereoisomer (1S,4R,5R)-6e,[28] which could be
separated from the major isomer by HPLC. The absolute
configuration of the furofuran lactone 6a was confirmed
by comparison of its optical rotation value with literature
data.[34] Assuming uniform reaction pathways, the absolute
configurations of 6b,c and d were assigned by analogy with
6e and 6a.
The enantiomeric purities of all the compounds were de-
termined by gas chromatography on chiral stationary
phases, which indicated that no racemization took place
during this transformation. It was found that the enantiom-
eric purity of 6b could be increased by simple recrystalliza-
tion. Finally, we wish to mention that the use of vana-
dium(II) chloride or chromium(II) acetate also led to the
formation of furofuran lactones 6 from 3b, albeit in poor
yields.
(4R)-4({[2S-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]imino}-
methyl)tetrahydro-2H-2-furanone [3a (n ؍ 1)]: To a cooled (Ϫ78 °C)
solution of 2-butenolide (2a) (1 mmol) in dry THF (1 mL) under
argon were sequentially added TBSOTf (0.25 mL, 1.1 mmol) and
precooled (Ϫ78 °C) formaldehyde SAMP-hydrazone [(S)-1]
(0.18 mL, 1.25 mmol). After 3 h, the mixture was neutralized by
addition of pH 7 buffer at –78 °C and then allowed to warm to
room temperature. The resulting mixture was diluted with CH2Cl2
and washed with water. The organic layer was dried (MgSO4), con-
centrated, and the residue was purified by flash chromatography
It has been shown that perhydrofuro[2,3-b]furan derivat-
ives exhibit antifeedant activity even in the absence of the
trans-decalin system, although this activity is between 10
and 20 times lower than that of clerodin itself.[35] Taking
this into account, pentenolides with different substituents
at C-6 could allow access to potential insect antifeedants.
Extension of this methodology is currently under study in
our laboratory.
Eur. J. Org. Chem. 2000, 893Ϫ901
897

´
D. Enders, J. Vazquez, G. Raabe
FULL PAPER
(SiO2, Et2O/CH2Cl2/pentane, 2:2:3) to give 3a (n ϭ 1) as a yellow 2.03 (m, 6 H, 3Ј-H, 4Ј-H, 5-H), 2.41–2.51 (m, 1 H, 8a-H), 2.57–
oil. – Yield: 46 mg (20%). – IR (film): ν ϭ 2957, 2927, 2857, 1780, 2.68 (m, 1 H, 8b-H), 2.70–2.80 (m, 2 H, 4-H, 2Ј-H), 2.86 (dt, J ϭ
1745, 1670, 1461, 1407, 1379, 1341, 1300, 1283, 1256, 1170, 1118, 5.4 Hz, J ϭ 8.8 Hz, 1 H, 3-H), 3.30–3.43 (m, 2 H, 5Јa-H), 3.38 (s,
1017, 916, 838 cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 1.80–2.01 3 H, OMe), 3.48 (dd, J ϭ 5.8 Hz, J ϭ 9.1 Hz, 1 H, 5Јa-H), 3.54
(m, 4 H, 3Ј-H, 4Ј-H), 2.66 (dd, J ϭ 3.7 Hz, J ϭ 8.1 Hz, 2 H, 3-H), (dd, J ϭ 3.8 Hz, J ϭ 9.1 Hz, 1 H, 5Јb-H), 4.26 (m, 1 H, 6a-H),
2.71–2.82 (m, 1 H, 2Ј-H), 3.37 (s, 3 H, OMe), 3.29–3.55 (m, 5 H,
4-H, 5Ј-H, CH2OMe), 4.26 (dd, J ϭ 6.9 Hz, J ϭ 9.1 Hz, J ϭ 1 Hz, H, CHϭ), 6.49 (d, J ϭ 5.0 Hz, 1 H, CHϭN). – 13C NMR
1 H, 5b-H), 4.46 (dd, J ϭ 7.7 Hz, J ϭ 9.1 Hz, 1 H, 5a-H), 6.45 (d, (75 MHz, CDCl3): δ ϭ 22.6, 27.0, 28.0, 34.6 (C-3Ј, C-4Ј, C-5, C-
J ϭ 4.9 Hz, 1 H, HCϭN). – 13C NMR (75 MHz, CDCl3): δ ϭ 8), 38.6, 43.8 (C-4, C-3), 50.2 (C-4Ј), 59.8 (C-1Ј), 63.9 (OMe), 67.7,
4.35 (m, 1 H, 6b-H), 5.08–5.14 (m, 2 H, CH2ϭ), 5.81–5.84 (m, 1
22.7, 27.1 (C-3Ј, C-4Ј), 33.5 (C-5Ј), 39.3 (C-4), 50.1 (C-3), 59.8 (C-
74.9 (C-6, C-5Ј), 118.6 (CH2ϭ), 135.6, 136.0 (HCϭN, CHϭ), 174.0
2Ј), 63.7 (OMe), 72.1 (CH2OMe), 75.0 (C-5), 132.0 (HCϭN), 177.0 (C-2). – MS (EI, 70 eV): m/z (%) ϭ 280 [Mϩ] (5), 235 (100), 207
(C-2). – MS (EI, 70 eV): m/z (%): 226 [Mϩ] (15), 181 (100), 123 (7), (3), 123 (7), 70 (25), 55 (8). – HRMS: calcd. 280.17855; found
97 (2), 80 (4), 70 (13), 55 (3). – It was not possible to obtain a
correct combustion analysis.
280.17843. – C15H24O3N2 (280.37): calcd. C 64.26, H 8.63, N 9.99;
found C 63.42, H 8.69, N 10.04.
(4R)-4-({[(2S)-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]imino}-
methyl)tetrahydro-2H-pyran-2-one [(S,R)-3b]: To a cooled (–78 °C)
solution of 2-pentenolide (2b) (10 mmol) and (S)-1 (20 mmol) in
CH2Cl2 (80 mL), TBSOTf (12 mmol) precooled at –30 °C was ad-
ded dropwise. The mixture was stirred for 30 h, then neutralized
with Et3N at –78 °C, and allowed to warm to 0 °C. The resulting
mixture was washed with water, dried (MgSO4), and purified by
(3S,4R)-4({[2S-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]imino}-
methyl)-3-methyltetrahydro-2H-pyran-2-one (4b): According to
GP1, 4b was obtained as a colourless oil after purification by col-
umn chromatography (SiO2, Et2O/pentane, 3:1). Yield: 0.51 g
(89%). The trans diastereoisomers (74%) were eluted first, followed
by the cis diastereoisomers (15%). – [α]2D5 ϭ –126.4 (c ϭ 2.88,
CHCl3). – IR (film): ν ϭ 3447, 2972, 2931, 2878, 2828, 1739, 1458,
flash chromatography (SiO2, Et2O/pentane, 3:1, Et2O) to give 1402, 1383, 1340, 1304, 1285, 1252, 1220, 1188, 1162, 1110, 1037,
1
(S,R)-3b as a yellow oil. – Yield: 1.3 g (54%). – IR (film): ν ϭ 3490,
991, 973 cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 1.30 (d, J ϭ
2925, 2829, 1737, 1600, 1475, 1461, 1449, 1402, 1340, 1253, 1199, 6.9 Hz, 3 H, 8-H), 1.80–2.12 (m, 6 H, 3Ј-H, 4Ј-H, 5-H), 2.45–2.55
1156, 1120, 1078, 972 cm–1. – 1H NMR (500 MHz, C6D6): δ ϭ (m, 1 H, 4-H), 2.70 (dt, J ϭ 6.9 Hz, J ϭ 9.6 Hz, 1 H, 3-H), 2.75–
1.17–1.25 (m, 1 H, 5a-H), 1.32–1.39 (m, 1 H, 5b-H), 1.46–1.55 (m, 2.83 (m, 1 H, 1Ј-H), 3.30–3.56 (m, 4 H, 5Ј-H, CH2OMe), 3.37 (s,
1 H, 4Јa-H), 1.66–1.75 (m, 3 H, 4Јb-H, 3Ј-H), 2.27–2.34 (m, 1 H, 3 H, OMe), 4.24–4.41 (m, 2 H, 6-H), 6.51 (d, J ϭ 5.3 Hz, 1 H,
4-H), 2.40 (ddd, J ϭ 1 Hz, J ϭ 6.3 Hz, J ϭ 17.0 Hz, 1 H, 3a-H),
2.40–2.48 (m, 1 H, 5Јa-H), 2.53 (ddd, J ϭ 0.5 Hz, J ϭ 8.0 Hz, J ϭ 28.2 (C-3Ј, C-4Ј, C-5), 39.1 (C-3), 42.1 (C-4), 50.3 (C-5Ј), 59.8
CHϭN). – 13C NMR (75 MHz, CDCl3): δ ϭ 16.0 (C-8), 22.7, 27.0,
17.0 Hz, 1 H, 3b-H), 2.87–2.94 (m, 1 H, 5Јb-H), 3.16 (s, 3 H, OMe),
3.41 (dd, J ϭ 6.8 Hz, J ϭ 9.0 Hz, 1 H, CH2OMe), 3.46–3.51 (m, 1
(OMe), 63.8 (C-2Ј), 67.5 (C-6), 74.4 (CH2OMe), 136.3 (CHϭN),
175.3 (C-2). – MS (EI, 70 eV): m/z (%): 254 [Mϩ] (9), 213 (13), 209
H, 1Ј-H), 3.58 (dd, J ϭ 3.3 Hz, J ϭ 9.0 Hz, 1 H, CH2OMe), 3.64 (100), 70 (17), 68 (13), 41 (14). – C13H22O3N2 (254.33): calcd. C
(ddd, J ϭ 4.2 Hz, J ϭ 8.0 Hz, 11.3 Hz, 1 H, 6a-H), 3.84 (ddd, J ϭ 61.39, H 8.72, N 11.01; found C 61.32, H 8.86, N 10.83.
4.4 Hz, J ϭ 6.6 Hz, J ϭ 11.3 Hz, 1 H, 6b-H), 5.98 (d, J ϭ 3.9 Hz,
(3S,4R)-4-({[2S-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]imino}-
1 H, 1-H). – 13C NMR (125 MHz, C6D6): δ ϭ 22.2 (C-4Ј), 27.1
methyl)-3-propyl)tetrahydro-2H-pyran-2-one (4c): According to
(C-3Ј), 27.3 (C-5), 34.1 (C-3), 34.4 (C-4), 49.1 (C-5Ј), 58.9 (OMe),
GP1, 4c was obtained as a yellow oil after purification by column
63.3 (C-1Ј), 66.8 (C-6), 75.1 (CH2OMe), 133.8 (C-1), 169.3 (C-2). –
chromatography (SiO2, Et2O/pentane, 4:1). Yield: 0.38 g (67%).
MS (EI, 70 eV): m/z (%) ϭ 241 [Mϩ ϩ 1] (2), 240 [Mϩ] (10), 195
(100), 110 (7), 70 (13), 68 (10), 55 (7). – C12H20O3N2 (240.31):
calcd. C 59.98, H 8.39, N 11.66; found C 59.66, H 8.53, N 11.74.
This mixture of diastereoisomers was separated by HPLC and the
major isomer was used in the next step. – [α]2D5 ϭ –132.6 (c ϭ 1.44,
CHCl3) – IR (film): ν ϭ 3455, 2958, 2828, 1735, 1599, 1460, 1341,
General Procedure for the α-Alkylation of δ-Lactone [(S,R)-3b]
(GP1): At –78 °C, a solution of (S,R)-3b (2 mmol) in THF (4 mL)
was treated with a precooled solution of LDA (2.2 mmol) in THF
1260, 1199, 1116 cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 0.92
(t, J ϭ 7.1 Hz, 3 H, 9-H), 1.30–1.60 (m, 2 H, 8-H), 1.67–2.12 (m,
8 H, 3Ј-H, 4Ј-H, 5-H, 7-H), 2.61–2.82 (m, 3 H, 4-H, 5Јa-H), 3.28–
(4 mL). After stirring for 3 h, HMPA (0.87 mL or 1.74 mL) was 3.36 (m, 5 H, 2Ј-H, 3-H, 5Јb-H, CH2OMe), 3.37 (s, 3 H, OMe),
added dropwise. The mixture was then treated with the appropriate
alkyl halide (2.6 mmol) and kept at –78 °C or allowed to warm to –
35 °C until TLC indicated consumption of the starting material
[the most reactive electrophiles required about 8 h (4a,b,e) and the
less reactive required 24 h (4c) and 48 h (4d)]. After hydrolysis with
saturated aqueous NH4Cl solution, the aqueous phase was ex-
tracted with Et2O and the combined organic phases were extracted
with water and dried (MgSO4). The crude material was purified by
flash chromatography as indicated below.
4.26 (ddd, J ϭ 4.1 Hz, J ϭ 7.1 Hz, J ϭ 11.3 Hz, 1 H, 6a-H), 4.36
(ddd, J ϭ 3.8 Hz, J ϭ 7.4 Hz, J ϭ 11.3 Hz, 1 H, 6b-H), 6.50 (d,
J ϭ 5 Hz, 1 H, CHϭN). – 13C NMR (75 MHz, CDCl3): δ ϭ 14.67
(C-9), 20.71, 22.62, 26.96, 28.05, 33.01 (C-3Ј, C-4Ј, C-5, C-7, C-8),
39.64, 43.82 (C-3, C-4), 50.22 (C-5Ј), 59.79 (OMe), 63.85 (C-2Ј),
67.38 (C-6), 74.87 (CH2OMe), 136.44 (CHϭN), 174.67 (C-2). – MS
(EI, 70 eV): m/z (%): 282 [Mϩ] (8), 267 (6), 237 [Mϩ – 45] (100),
193 (12), 149 (10), 99 (13), 83 (13), 70 (34), 55 (41). – C15H26O3N2
(283.39): calcd. C 63.80, H 9.28, N 9.92; found C 63.41, H 9.30,
N 10.26.
(3S,4R)-3-Allyl-4-({[2S-(methoxymethyl)tetrahydro-1H-1-pyrrolyl]-
imino}methyl)tetrahydro-2H-pyran-2-one (4a): According to GP1,
4a was obtained as a yellow oil after purification by column chro-
matography (SiO2, Et2O/pentane, 3:1). – Yield: 0.51 g (90%). This
mixture of diastereoisomers was separated by HPLC and the major
isomer was used in the next step. – [α]2D5 ϭ –158.5 (c ϭ 1.20,
CHCl3). – IR (film): ν ϭ 3438, 3076, 2925, 2829, 1731, 1640, 1598,
(3S,4R)-4-({[2S-(Methoxymethyl)tetrahydro-1H-1-pyrrolyl]imino}-
methyl)-3-(2-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}ethyl)tetrahydro-
2H-pyran-2-one (4d): According to GP1, 4d was obtained as a yel-
low oil after purification by column chromatography (SiO2, Et2O/
pentane, 3:1). Yield: 0.35 g (44%). This mixture of diastereoisomers
was separated by HPLC and the major isomer was used in the next
1442, 1403, 1386, 1341, 1302, 1260, 1196, 1164, 1120, 1003, 973, step. – [α]2D5 ϭ –99.7 (c ϭ 1.30, CHCl3). – IR (film): ν ϭ 3346,
958, 919, 876, 803 cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 1.81– 2928, 2856, 1739, 1682, 1471, 1463, 1387, 1255, 1198, 1103, 837
898
Eur. J. Org. Chem. 2000, 893Ϫ901

Formaldehyde SAMP-Hydrazone as a Neutral Formyl Anion Equivalent
FULL PAPER
cm–1. – 1H NMR (400 MHz, CDCl3): δ ϭ 0.02 (s, 6 H, Me2Si), Yield: 116 mg (68%). – [α]2D8 ϭ ϩ21.5 (c ϭ 0.78, CHCl3). – IR
0.86 (s, 9 H, tBu), 1.75–2.08 (m, 8 H, 3Ј-H, 4Ј-H, 5-H, 7-H), 2.64– (film): ν ϭ 3408, 2961, 2874, 1784, 1731, 1446, 1323, 1120, 1078,
2.78 (m, 3 H, 5Ј-H, 4-H), 3.26–3.31 (m, 1 H, 3-H), 3.34 (s, 3 H,
OMe), 3.36–3.52 (m, 3 H, 2Ј-H, CH2OMe), 3.70–3.80 (m, 2 H, 8-
949 cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 0.94 (t, J ϭ 7.2 Hz,
3 H, 9-H), 1.20–1.88 (m, 4 H, 7-H, 8-H), 2.00–2.21 (m, 2 H, 5-H),
H), 4.25 (ddd, J ϭ 4.1 Hz, J ϭ 7.2 Hz, J ϭ 11.2 Hz, 1 H, 6a-H), 2.73–2.84 (m, 1 H, 3-H), 2.94–3.01 (m, 1 H, 4-H), 4.18–4.34 (m, 2
4.33 (ddd, J ϭ 3.9 Hz, J ϭ 7.2 Hz, J ϭ 11.2 Hz, 1 H, 6b-H), 6.47 H, 6-H), 9.75 (s, 1 H, CHO). – 13C NMR (75 MHz, CDCl3): δ ϭ
(d, J ϭ 5.0 Hz, 1 H, CHϭN). – 13C NMR (100 MHz, CDCl3):
δ ϭ –5.4, –5.3 (Me2Si), 22.2, 26.6, 27.9, 32.7 (C-3Ј, C-4Ј, C-5, C-
14.2 (C-9), 20.5–22.6 (C-7, C-8), 33.1, 37.9 (C-3, C-4), 47.7 (C-5),
64.8 (C-6), 171.8 (C-2), 198.6 (CHO). – MS (EI, 70 eV): m/z (%):
7), 26.0 (tBu), 39.2, 40.2 (C-3, C-4), 49.7 (C-5Ј), 59.3, 63.3 (C-2Ј, 171 [Mϩ ϩ 1] (1), 141 [Mϩ – CHO] (3), 128 (11), 99 (100), 83 (13),
OMe), 60.7, 66.9 (CH2OMe, C-8), 76.8 (C-6), 135.9 (CHϭN), 174.1 71 (10), 55 (46). – HRMS: 170.09429 (C9H14O3 calcd. 170.09448).
(C-2). – MS (EI, 70 eV): m/z (%): 398 [Mϩ] (1), 353 [Mϩ – 45] (10),
(3S,4R)-3-(2-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}ethyl)-2-oxo-
tetrahydro-2H-pyran-4-carbaldehyde (5d): According to GP2, 5d
was obtained as a yellow oil after purification by column chromato-
229 (18), 228 (100), 149 (25), 128 (48), 96 (12), 91 (42), 73 (47), 57
(34). – HRMS: calcd. 353.22605; found 353.22610. – C20H38O4N2Si
(398.63): calcd. C 60.26, H 9.61, N 7.03; found C 59.62, H 9.76,
graphy (SiO2, Et2O/pentane, 1:1 3:1). Yield: 144 mg (50%). –
N 7.00.
[α]2D7 ϭ –1.3 (c ϭ 0.77, CHCl3). – IR (film): ν ϭ 3381, 2928, 2856,
(3S,4R)-3-Benzyl-4-({[2S-(methoxymethyl)tetrahydro-1H-1-
pyrrolyl]imino}methyl)tetrahydro-2H-pyran-2-one (4e): According
to GP1, 4e was obtained as a colourless solid after purification by
1779, 1732, 1682, 1471, 1379, 1257, 1099, 951, 837 cm–1. – 1H
NMR (300 MHz, CDCl3): δ ϭ 0.05 (s, 6 H, Me2Si), 0.88 (s, 9 H,
tBuSi), 1.85–2.20 (m, 4 H, 5-H, 7-H), 2.91–3.01 (m, 1 H, 3-H),
column chromatography (SiO2, Et2O/pentane, 1:1 3:1). Yield: 3.07–3.14 (m, 1 H, 4-H), 3.71–3.85 (m, 2 H, 8-H), 4.20–4.36 (m, 2
0.51 g (77%). – m.p. 59–60 °C – [α]2D5 ϭ –155.7 (c ϭ 0.97,
CHCl3). – IR (film): ν ϭ 3420, 2927, 2829, 1732, 1603, 1496, 1454,
H, 6-H), 9.74 (d, J ϭ 1.4 Hz, 1 H, CHO). – 13C NMR (75 MHz,
CDCl3): δ ϭ –5.8 (Me2Si), 17.9 (CMe3), 22.9, 32.6, 35.3 (C-3, C-
1404, 1386, 1341, 1303, 1245, 1217, 1193, 1153, 1121, 1098, 1075, 5, C-7), 25.6 (tBu), 47.3 (C-4), 60.1, 65.6 (C-6, C-8), 172.7 (C-2),
1030, 972 cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 1.83–2.02 (m, 199.2 (CHO). – MS (EI, 70 eV): m/z (%): 287 [Mϩ ϩ 1] (1), 271
6 H, 3Ј-H, 4Ј-H, 5-H), 2.65–2.69 (m, 2 H, 4-H, 5Јa-H), 3.10–3.20
(m, 3 H, 3-H, 5Јb-H, 8a-H), 3.21–3.29 (m, 1 H, 2Ј-H), 3.40 (s, 3 H, (45).
[Mϩ – 15] (3), 229 [Mϩ – tBu] (100), 199 (10), 171 (8), 109 (13), 75
–
HRMS: [Mϩ
271.13669).
– 15]; 271.13656 (C14H26O4Si calcd.
OMe), 3.39–3.59 (m, 3 H, CH2OMe, CH2Ph), 4.11 (ddd, 1 H, J ϭ
3.9 Hz, J ϭ 7.4 Hz, J ϭ 11.2 Hz, 6a-H), 4.32 (ddd, 1 H, J ϭ 3.9 Hz,
J ϭ 7.2 Hz, J ϭ 11.2 Hz, 6b-H), 6.39 (d, 1 H, J ϭ 4.7 Hz, CHϭ
N), 7.21–7.30 (m, 5 H, Ph). – 13C NMR (75 MHz, CDCl3): δ ϭ
22.12 (C-4Ј), 26.60 (C-3Ј), 27.61 (C-5), 35.95 (CH2Ph), 38.25, 45.30
(C-3, C-4), 49.56 (C-5Ј), 59.33 (OMe), 63.26 (C-2Ј), 66.99 (C-6),
74.49 (CH2OMe), 126.47, 128.44, 129.80, 139.13 (Ph), 135.34 (C-
7), 173.66 (C-2). – MS (EI, 70 eV): m/z (%): 330 [Mϩ] (4), 286 (17),
285 [Mϩ – 45] (100), 131 (7), 115 (7), 91 (41), 70 (31). – C19H26O3N2
(330.43): calcd. C 69.09, H 7.88, N 8.48; found C 69.12, H 7.97,
N 8.76.
(3S,4R)-3-Benzyl-2-oxotetrahydro-2H-pyran-4-carbaldehyde
(5e):
According to GP2, 5e was obtained as a yellow oil after purifica-
tion by column chromatography (SiO2, Et2O/pentane, 1:2 1:1).
Yield: 129 mg (59%). – [α]2D3 ϭ –9.0 (c ϭ 0.89, CHCl3). – IR
(film): ν ϭ 3417, 2929, 1726, 1454, 1269, 1159, 1074, 756 cm–1. –
1H NMR (300 MHz, CDCl3): δ ϭ 1.91–2.13 (m, 2 H, 5-H), 2.74–
2.82 (m, 1 H, 4-H), 3.06 (dd, J ϭ 6.6 Hz, J ϭ 14.0 Hz, 1 H,
CHaPh), 3.20 (dd, J ϭ 5.7 Hz, J ϭ 14.0 Hz, 1 H, CHbPh), 3.28–
3.35 (m, 1 H, 3-H), 4.12–4.25 (m, 2 H, 6-H), 7.20–7.33 (m, 5 H,
Ph), 9.46 (d, J ϭ 1.0 Hz, 1 H, CHO). – 13C NMR (75 MHz,
CDCl3): δ ϭ 23.1 (C-5), 36.5 (CH2Ph), 40.5, 47.1 (C-3, C-4), 66.1
(C-6), 127.2, 128.9, 129.7, 137.7 (Ph), 172.4 (C-2), 199.1 (CHO). –
MS (EI, 70 eV): m/z (%): 218 [Mϩ] (35), 189 [Mϩ – CHO] (25), 149
(32), 131 (100), 115 (23), 103 (19), 91 (84), 70 (61). – HRMS:
218.09429 (C13H14O3 calcd. 218.09396).
General Procedure for the Ozonolysis of the δ-Lactones (S,R,S)-4
(GP2): Ozone was bubbled through a solution of 4 (1 mmol) in dry
CH2Cl2 (25 mL) at –78 °C until a blue colour persisted (TLC con-
trol). Me2S (1.1 mmol) was then added, the mixture was allowed
to warm to room temperature, and concentrated in vacuo. The res-
idue was purified by flash chromatography (SiO2, 0.063–0.100 mm)
as indicated below.
General Procedure for the Acetalation of α-Alkyl β-Formyl δ-Lac-
tones (5) (GP3): The appropriate aldehyde 5 (1 mmol) was dissolved
in anhydrous CH2Cl2 (10 mL) at 0 °C under an atmosphere of ar-
gon. (R,R)-Butanediol bis(trimethylsilyl) ether (468 mg, 2 mmol)
was then added, followed by a catalytic amount of TMSOTf (1
drop). The resulting mixture was stirred for 2 h at 0 °C, then poured
(3S,4R)-3-Methyl-2-oxotetrahydro-2H-pyran-4-carbaldehyde (5b):
According to GP2, 5b was obtained as a colourless oil after puri-
fication by column chromatography (SiO2, Et2O/pentane, 3:1).
Yield: 99 mg (70%). – [α]2D8 ϭ ϩ36.4 (c ϭ 1.11, CHCl3). – IR
(film): ν ϭ 3423, 2975, 2931, 2856, 1727, 1448, 1385, 1258, 1168, into water, and extracted with CH2Cl2. The combined extracts were
1
1082, 993 cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 1.31 (d, J ϭ dried (NaSO4) and concentrated in vacuo. The crude material was
6.8 Hz, 3 H, Me), 2.01–2.23 (m, 2 H, 5-H), 2.61–2.69 (m, 1 H, 4-
H), 2.89–2.99 (m, 1 H, 3-H), 4.21 (ddd, J ϭ 3.8 Hz, J ϭ 9.1 Hz,
J ϭ 11.5 Hz, 1 H, 6a-H), 4.31 (dt, J ϭ 4.9 Hz, J ϭ 11.5 Hz, 1 H,
6b-H), 9.75 (d, J ϭ 1.1 Hz, 1 H, CHO). – 13C NMR (75 MHz,
CDCl3): δ ϭ 15.2, 22.4 (C-5, Me), 33.0, 49.4 (C-4, C-3), 65.5 (C-
6), 173.4 (C-2), 198.9 (CHO). – MS (EI, 70 eV): m/z (%): 143 [Mϩ
ϩ 1] (2), 142 [Mϩ] (2), 114 (6), 99 (35), 86 (17), 83 (46), 69 (100),
purified by column chromatography as indicated below.
(3S,4R)-4-[(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-yl]-3-methyl-
tetrahydro-2H-pyran-2-one: According to GP3, the acetal derived
from 5b was obtained as a colourless solid after purification by
column chromatography (SiO2, Et2O/pentane, 1:4 1:1). Yield:
172 mg (80%); m.p. 55–57 °C. – IR (film): ν ϭ 2983, 2880, 1735,
1459, 1387, 1254, 1171, 1115, 1056, 969 cm–1. – 1H NMR
(300 MHz, CDCl3): δ ϭ 1.23–1.36 (m, 9 H, 3CH3), 1.83–2.00 (m,
3 H, 4-H, 5-H), 2.63–2.72 (m, 1 H, 3-H), 3.58–3.70 (m, 2 H,
2HCO), 4.22–4.29 (m, 1 H, 6a-H), 4.34–4.42 (m, 1 H, 6b-H), 5.14
(d, J ϭ 2.0 Hz, 1 H, HCO2). – 13C NMR (75 MHz, CDCl3): δ ϭ
55 (73). – HRMS: [Mϩ ϩ 1]: 143.07082 (C7H10O3, calcd. [Mϩ
ϩ
1]: 143.07054).
(3S,4R)-3-Propyl-2-oxotetrahydro-2H-pyran-4-carbaldehyde
(5c):
According to GP2, 5c was obtained as a colourless oil after puri-
fication by column chromatography (SiO2, Et2O/pentane, 1:1 3:1). 15.9, 16.7, 17.5 (3 CH3), 23.1 (C-5), 35.3, 41.1 (C-3, C-4), 67.1 (C-
Eur. J. Org. Chem. 2000, 893Ϫ901 899

´
D. Enders, J. Vazquez, G. Raabe
FULL PAPER
6), 79.4, 79.9 (2HCO), 103.4 (HCO2), 175.3 (C-2). – MS (EI, C9H14O3 (170.21): calcd. C 63.51, H 8.29; found C 63.22, H 8.46.
70 eV): m/z (%): 215 [Mϩ ϩ 1] (4), 213 (3), 101 (100), 83 (7), 73
(42), 55 (50). – C11H18O4 (214.26): calcd. C 61.66, H 8.47; found
C 62.06, H 8.65.
(1S,4S,5R)-4-Allyl-2,8-dioxabicyclo[3.3.0]octan-3-one (6d): Accord-
ing to GP4, 6d was obtained as a white solid after purification by
column chromatography (SiO2, Et2O/pentane, 1:1). Yield: 148 mg
(87%); m.p. 52–54 °C. – [α]2D0 ϭ ϩ75.6 (c ϭ 0.80, CHCl3). – IR
(film): ν ϭ 2979, 2925, 1769, 1360, 1171, 1113, 971, 910 cm–1. – 1H
NMR: (300 MHz, CDCl3): δ ϭ 1.81–1.93 (m, 1 H, 6b-H), 1.98–
2.10 (m, 1 H, 6a-H), 2.15–2.27 (m, 1 H, 9b-H), 2.73–2.81 (m, 1 H,
9a-H), 2.91–2.99 (ddd, J ϭ 4.7 Hz, J ϭ 8.5 Hz, J ϭ 11.0 Hz, 1 H,
4-H), 3.08–3.18 (m, 1 H, 5-H), 4.06 (t, J ϭ 7.1 Hz, 2 H, 7-H), 5.10–
5.18 (m, 2 H, H2Cϭ), 5.77–5.91 (m, 1 H, HCϭ), 6.00 (d, J ϭ
4.7 Hz, 1 H, 1-H). – 13C NMR (300 MHz, CDCl3): δ ϭ 24.4, 30.6
(C-6, C-9), 42.7, 43.1 (C-4, C-5), 68.8 (C-7), 106.4 (C-10), 116.9
(C-11), 134.4 (C-1), 175.1 (C-3). – MS (EI, 70 eV): m/z (%): 169
[Mϩ ϩ 1] (100), 145 (7). – C9H12O3 (168.19): calcd. C 64.27, H
7.19; found C 64.24, H 7.48.
(3S,4R)-3-Benzyl-4-[(4R,5R)-4,5-dimethyl-1,3-dioxolan-2yl]tetra-
hydro-2H-pyran-2-one: According to GP3, the acetal derived from
5e was obtained as a colourless oil after purification by column
chromatography (SiO2, Et2O/pentane, 1:5 1:1). Yield: 205 mg
(71%). – IR (film): ν ϭ 3028, 2924, 2854, 1771, 1732, 1497, 1454,
1384, 1260, 1160, 1083, 968, 893 cm–1. – 1H NMR (300 MHz,
CDCl3): δ ϭ 1.15 (d, J ϭ 5.7 Hz, 3 H, CH3), 1.22 (d, J ϭ 5.8 Hz,
3 H, CH3), 1.64–1.84 (m, 1 H, 5-H), 2.00–2.11 (m, 1 H, 4-H), 2.89–
2.95 (m, 1 H, 3-H), 3.02–3.19 (m, 2 H, CH2Ph), 3.49–3.59 (m, 2
H, 2CHO), 3.83–3.91 (m, 1 H, 6a-H), 4.22–4.29 (m, 1 H, 6b-H),
4.95 (d, J ϭ 3.0 Hz, 1 H, HCO2), 7.12–7.27 (m, 5 H, Ph). – 13C
NMR (75 MHz, CDCl3): δ ϭ 16.3, 17.0 (2CH3), 22.7 (C-5), 36.5
(CH2Ph), 37.5, 41.6 (C-3, C-4), 66.8 (C-6), 78.8, 79.4 (2CHO),
103.4 (HCO2), 126.3, 128.2, 129.3, 138.2 (Ph), 173.5 (C-2). – MS
(EI, 70 eV): m/z (%): 290 [Mϩ] (11), 218 (7), 140 (17), 131 (14),
115 (14), 101 (100), 91 (47), 83 (46), 70 (55). – HRMS: 290.15181
(C17H22O4 calcd. 290.15177).
(1S,4S,5R)-4-Benzyl-2,8-dioxabicyclo[3.3.0]octan-3-one (6e): Ac-
cording to GP4, 6e was obtained as a colourless oil after purifica-
tion by column chromatography (SiO2, Et2O/pentane, 4:1). Yield:
197 mg (90%). – [α]2D5 ϭ ϩ104.4 (c ϭ 0.91, CHCl3). – IR (film):
ν ϭ 3028, 2960, 1769, 1497, 1454, 1316, 1184, 1116, 969, 893
1
cm–1. – H NMR: (500 MHz, CDCl3): δ ϭ 1.92–2.07 (m, 2 H, 6-
General Procedure for the Hydrolytic Cleavage of δ-Lactone (S,R)-
4 (GP4): To a cooled (0 °C) solution of hydrazone 4 (1 mmol) in
Et2O (20 mL) was added 5  HCl (4 mL) and the mixture was
stirred vigorously until TLC indicated total consumption of the
starting material (ca. 20 min.). The aqueous layer was then ex-
tracted with CH2Cl2 (3 times). The combined organic layers were
neutralized (NaHCO3, 0.1 g), dried (MgSO4), and concentrated.
The resulting residue was purified by flash chromatography as in-
dicated below.
H), 2.70 (dd, J ϭ 11.4 Hz, J ϭ 14.9 Hz, 1 H, CHaPh), 2.92–2.98
(m, 1 H, 5-H), 3.21 (ddd, J ϭ 4.2 Hz, J ϭ 7.9 Hz, J ϭ 11.9 Hz, 1
H, 4-H), 3.42 (dd, J ϭ 4.1 Hz, J ϭ 14.9 Hz, 1 H, CHbPh), 4.02–
4.07 (m, 1 H, 7a-H), 4.11–4.16 (m, 1 H, 7b-H), 5.95 (d, J ϭ 4.6 Hz,
1 H, 1-H), 7.21–7.35 (m, 5 H, Ph). – 13C NMR (125 MHz, CDCl3):
δ ϭ 25.0 (C-6), 32.7 (CH2Ph), 43.3 (C-5), 46.1 (C-4), 69.5 (C-7),
106.8 (C-1), 126.9, 128.4, 128.9, 138.5 (Ph), 175.2 (C-3). –
C13H14O3 (218.25): calcd. C 71.54, H 6.47; found C 71.31, H 6.57.
(1S,5R)-2,8-Dioxabicyclo[3.3.0]octan-3-one (6a): According to GP4,
6a was obtained as a colourless oil after purification by column
Acknowledgments
chromatography (SiO2, Et2O). Yield: 84 mg (66%). – [α]2D7
ϭ
Our work was generously supported by the Deutsche Forschungs-
gemeinschaft (Leibniz award, Sonderforschungsbereich 380) and
the Fonds der Chemischen Industrie. We thank the Ministerio de
ϩ29.5 (c ϭ 0.96, CHCl3). The spectroscopic data were in accord-
ance with previously published data.[33]
(1S,4S,5R)-4-Methyl-2,8-dioxabicyclo[3.3.0]octan-3-one (6b): Ac-
cording to GP4, 6b was obtained as a colourless solid after puri-
fication by column chromatography (SiO2, Et2O/pentane, 4:1).
Yield: 140 mg (98%). The solid was recrystallized from Et2O/hex-
ane (107 mg, 75%); m.p. 78–80 °C – [α]2D5 ϭ ϩ49.8 (c ϭ 0.95,
CHCl3). – IR (film): ν ϭ 3447, 2923, 2888, 1766, 1454, 1382, 1361,
´
Educacion y Cultura, Spain, for a postdoctoral fellowship to J. V.
We also thank Degussa-Hüls AG, BASF AG, Bayer AG, and the
former Hoechst AG for donations of chemicals.
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1
1189, 1098, 968 cm–1. – H NMR (300 MHz, CDCl3): δ ϭ1.27 (d,
J ϭ 7.1 Hz, 1 H, CH3), 1.83–2.08 (m, 2 H, 6-H), 2.89–2.99 (m, 1
H, 4-H), 3.09–3.19 (m, 1 H, 5-H), 3.95–4.11 (m, 2 H, 7-H), 6.00
(d, J ϭ 4.9 Hz, 1 H, 1-H). – 13C NMR (75 MHz, CDCl3): δ ϭ 11.2
(CH3), 24.6 (C-6), 37.7, 43.7 (C-4, C-5), 68.5 (C-7), 106.2 (C-1),
176.7 (C-3). – MS (EI, 70 eV): m/z (%): 143 [Mϩ ϩ 1] (3), 98 (51),
83 (100), 68 (35), 55 (31). – C7H10O3 (142.16): calcd. C 59.14, H
7.09; found C 58.92, H 7.18.
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(1S,4S,5R)-4-Propyl-2,8-dioxabicyclo[3.3.0]octan-3-one (6c): Ac-
cording to GP4, 6c was obtained as a colourless oil after purifica-
tion by column chromatography (SiO2, Et2O/pentane, 3:1). Yield:
165 mg (97%). – [α]2D5 ϭ ϩ76.75 (c ϭ 0.80, CHCl3). – IR (film):
ν ϭ 2961, 2935, 2874, 1775, 1180, 1113, 971, 938 cm–1. – 1H NMR
(300 MHz, CDCl3): δ ϭ 1.10 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.53–165
(m, 3 H, 9-H, 8a-H), 1.90–2.22 (m, 3 H, 8b-H, 6-H), 2.91–2.98 (m,
1 H, 4-H), 3.19–3.29 (m, 1 H, 5-H), 4.11–4.23 (m, 2 H, 7-H), 6.10
(d, J ϭ 4.9 Hz, 1 H, 1-H). – 13C NMR (75 MHz, CDCl3): δ ϭ 15.5
(C-10), 20.6, 24.1, 28.4 (C-6, C-8, C-9), 42.7, 43.2 (C-4, C-5), 68.6
(C-7), 106.3 (C-1), 176.0 (C-3). – MS (EI, 70 eV): m/z (%): 171 [Mϩ
ϩ 1] (1), 126 (10), 97 (37), 83 (100), 81 (11), 67 (8), 55 (31). –
25, 1159–1163.
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D. Enders, M. Bolkenius, J. Vazquez, J. M. Lassaletta, R. Fer-
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Eur. J. Org. Chem. 2000, 893Ϫ901

Formaldehyde SAMP-Hydrazone as a Neutral Formyl Anion Equivalent
FULL PAPER
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[O99544]
Eur. J. Org. Chem. 2000, 893Ϫ901
901