Controlling π-Facial Diastereoselectivity in the 1,3-Dipolar Cycloadditions of Diazomethane to Chiral Pentenoates and Furanones: Enantioselective Stereodivergent Syntheses of Cyclopropane Hydroxy Acids and Didehydro Amino Acids

Article abstract of DOI:10.1021/jo972219a

The title compounds have been synthesized in both enantiomeric forms and in good overall yields by using D-glyceraldehyde as the single chiral precursor. The efficiency and usefulness of the synthetic routes have been secured by performing controlled manipulations of the functional groups and by highly stereoselective transformations, namely Wittig-Horner condensations and cyclopropanations. Cyclopropane derivatives have been synthesized through 1,3-dipolar cycloaddition of diazomethane to chiral pentenoates or furanones obtained, in turn, from D-glyceraldehyde. Syn/ anti stereochemistry of the cycloadducts has been unequivocally assigned and rationalized. Since π-facial diastereoselectivity involved in these cycloadditions is the opposite for cyclic and open- chain structures, enantiomeric series of products can be derived.

Full text of DOI:10.1021/jo972219a

J . Org. Chem. 1998, 63, 3581-3589
3581
Con tr ollin g π-F a cia l Dia ster eoselectivity in th e 1,3-Dip ola r
Cycloa d d ition s of Dia zom eth a n e to Ch ir a l P en ten oa tes a n d
F u r a n on es: En a n tioselective Ster eod iver gen t Syn th eses of
Cyclop r op a n e Hyd r oxy Acid s a n d Did eh yd r o Am in o Acid s
Marta Mart´ın-Vila`,† Neuh Hanafi,† J ose´ M. J ime´nez,† Angel Alvarez-Larena,‡
J oan F. Piniella,‡ Vicenc¸ Branchadell,† Antonio Oliva,† and Rosa M. Ortun˜o*,†
Departament de Quı´mica and Unitat de Cristal.lografia, Universitat Auto`noma de Barcelona,
08193 Bellaterra, Barcelona, Spain
Received December 8, 1997
The title compounds have been synthesized in both enantiomeric forms and in good overall yields
by using D-glyceraldehyde as the single chiral precursor. The efficiency and usefulness of the
synthetic routes have been secured by performing controlled manipulations of the functional groups
and by highly stereoselective transformations, namely Wittig-Horner condensations and cyclo-
propanations. Cyclopropane derivatives have been synthesized through 1,3-dipolar cycloaddition
of diazomethane to chiral pentenoates or furanones obtained, in turn, from D-glyceraldehyde. Syn/
anti stereochemistry of the cycloadducts has been unequivocally assigned and rationalized. Since
π-facial diastereoselectivity involved in these cycloadditions is the opposite for cyclic and open-
chain structures, enantiomeric series of products can be derived.
In tr od u ction
tionships. Nevertheless, despite the growing discovery
of new and efficient methods in asymmetric synthesis,
there are still some difficulties in the preparation of
enantiomeric series of compounds when the achievement
of this goal involves the use of specific chiral precursors
or auxiliaries.
The cyclopropane moiety is a structural feature of
widespread compounds with interesting biological activi-
ties. Among them, 2,3-methano 2-amino acids have been
found from natural sources playing important roles in
the secondary metabolism of plants.1 Moreover, satu-
rated 2,3- and 3,4-methano amino acids have been used
replacing proteinogenic amino acids in conformationally
restricted peptide surrogates with enhanced properties
with respect to the normal peptides,2 and have also been
utilized as biological probes in mechanistic studies.3 In
particular, cyclopropane 2,3-didehydro 2-amino acids
(DDAAs) have also been found as subunits of natural
product structures,4 but their main interest lies on their
usefulness as synthetic precursors to other types of amino
acids, obtained by later transformations of the CdC
double bond, i.e. reduction, conjugate additions, or cy-
cloadditions.5
Therefore, consideration of this fact and the increasing
attention devoted to cyclopropane derivatives by special-
ists of different fields prompts us to report our results
on the enantioselective and stereodivergent synthesis of
different kinds of cyclopropyl compounds from a single
precursor. Thus, we present in this work the syntheses
of conveniently protected 2,3-didehydro-4,5-methano amino
acids 1 and ent-1, a new class of DDAA, and 4-hydroxy-
2,3-methano acids 2 and ent-2, using D-glyceraldehyde
acetonide7 as the only chiral precursor (Chart 1). The
success of the synthetic strategy is based on the combina-
tion of highly stereoselective cyclopropanation of conve-
nient substrates, stereoselective Wittig-Horner conden-
sations, and controlled manipulation of functional groups.
Among the currently used cyclopropanation methods,
we chose the one involving 1,3-dipolar cycloaddition of
diazomethane to chiral dipolarophiles followed by pho-
tolysis of the pyrazolines produced. We have already
employed this protocol in our laboratory to synthesize
several 2,3-methano 2-amino acids in a highly efficient
and stereoselective manner.8
In turn, cyclopropane hydroxy acid derivatives are also
relevant building blocks in the synthesis of several types
of products such as amino alcohols and cyclopropyl
carbocyclic nucleosides.6
The availability of chiral products in both enantiomeric
forms is crucial to the study of chirality-activity rela-
† Departament de Qu´imica. E-mail: iqor9@cc.uab.es.
‡ Unitat de Cristal.lografia. E-mail: angel@salduba.uab.es.
(1) See, for instance: (a) Sakamura, S.; Ichichara, A.; Shiraishi, K.;
Sato, H.; Nishiyama, K.; Sakai, R.; Furusaki, A.; Matsumoto, T. J . Am.
Chem. Soc. 1977, 99, 636. (b) Hoffman, N. E.; Yang, S. F.; Ichihara,
A.; Sakamura, S. Plant Physiol. 1982, 70, 195. (c) Mitchell, R. E.
Phytochemistry 1985, 24, 1485. (d) Pirrung, M. C.; McGeehan, G. M.
J . Org. Chem. 1986, 51, 2103.
We will show that the control of π-facial diastereose-
lectivity in the cycloadditions of diazomethane to chiral
furanones or to functionally equivalent pentenoates
(2) Burgess, K.; Ho, K.-K.; Moye-Sherman D. Synlett 1994, 575, and
references therein.
(3) For reviews on the isolation, synthesis, and biological properties
of cyclopropane amino acids, see: (a) Stammer, C. H. Tetrahedron
1990, 46, 2234. (b) Alami, A.; Calmes, M.; Daunis, J . J acquier, R. Bull.
Soc. Chim. Fr. 1993, 130, 5.
(4) Kotha, S. Tetrahedron 1994, 50, 3639. See p 3650 and references
therein.
(5) (a) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1988, 159.
(b) Duthaler, R. A. Tetrahedron 1994, 50, 1539.
(6) (a) Zhao, Y.; Yang, T.; Lee, M.; Lee, D.; Newton, M. G.; Chu, C.
K. J . Org. Chem. 1995, 60, 5236. (b) Lee, M. G.; Du, J . F.; Chun, M.
W.; Chu, C. K. J . Org. Chem. 1997, 62, 1991. These authors
synthesized enantiomeric nucleosides using D- and L-glyceraldehyde
as chiral precursors which, in turn, were obtained from D-mannitol
and L-gulono-γ-lactone, respectively.
(7) Mann, J .; Partlett, N. K.; Thomas, A. J . Chem. Res. (S) 1987,
369, and references therein. Although D-glyceraldehyde acetonide is
commercially available it can be easily prepared from D-mannitol
according to this work.
S0022-3263(97)02219-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/07/1998

3582 J . Org. Chem., Vol. 63, No. 11, 1998
Mart´ın-Vila` et al.
Ch a r t 1
Ch a r t 2
F igu r e 1. Stereochemical assignments of pyrazoline 7 and
cyclopropane 8, resultant from cycloaddition of diazomethane
to furanone 4.
of the stereogenic centers being the same in both dipo-
larophiles. In the last step of the synthetic plan, Wittig-
Horner condensations of the enantiomeric aldehydes with
suitable phosphonates bearing the preformed amino acid
moiety lead to the target molecules. Stereoselectivity in
the production of Z/E diastereoisomers was controlled
after investigation of the influence that base, tempera-
ture, and reaction time exert on the stereochemistry.
Furanone 3 (Scheme 1) was easily obtained from
D-glyceraldehyde acetonide through Wittig condensation
with (methoxycarbonylmethylidene)triphenylphosphorane,
chromatographic separation of Z/E isomers, and hydroly-
sis with concomitant lactonization of the (Z)-isomer.7
Reaction of 3 with tert-butyldiphenylsilyl chloride in the
presence of DMAP provided lactone 4 in 94% yield. This
compound was treated with excess ethereal diazomethane
to afford quantitatively pyrazoline 711 as a single stere-
oisomer, as a result of exclusive addition of diazomethane
to the C4-Si face of the CdC double bond.
Anti stereochemistry of 7 was assigned by NOE
experiments, as stated in Figure 1. Thus, significant
enhancement on H3′ was observed when H4 was selec-
tively irradiated. Moreover, presaturation of protons H7
and H7′ produced NOE on H3a and H6a in agreement with
the proposed configuration. This configuration was also
assigned to the pyrazolines produced from reaction
between diazomethane and both (S)-5-(hydroxymethyl)-
2(5H)-furanone12a and (S)-5-(pivaloyloxymethyl)-2(5H)-
furanone.12b ∆1-Pyrazoline 7 is a crystalline solid which
results in excellent de’s and provides alternative routes
to synthesize enantioselectively the target molecules.
Preferential π-facial diastereoselection of diazomethane
toward chiral pentenoates has been the subject of con-
tradictory interpretations.9,10 From our results the ste-
reoselectivity of these cycloadditions has been unambigu-
ously established. A discussion on these features is
presented below.
Resu lts a n d Discu ssion
Preliminary studies, carried out by our group, show
that facial diastereoselectivity in the reactions between
diazomethane and chiral 3-substituted furanones favors
preferential attack to the π-face opposite to the substitu-
ent, provinding anti adducts. On the contrary, when
chiral 4-alkoxy pentenoates are used, syn adducts are the
major stereoisomers produced. These findings allowed
us to design stereoselective syntheses of the target
molecules. A rationalization of the stereochemical out-
come of these cycloadditions follows the description and
discussion of the synthetic strategies.
1. Syn t h esis of Did eh yd r o Am in o Acid s 1 a n d
en t-1. Compounds 1 and ent-1 are retrosynthetically
related to enantiomeric aldehydes which provide the
absolute configuration of the stereogenic centers (Chart
2). These intermediates were obtained through diaste-
reoselective 1,3-dipolar cycloadditions of diazomethane
to a chiral furanone and a chiral pentenoate, respectively,
followed by photolysis of the resultant pyrazolines. The
furanone was obtained from the pentenoate, the chirality
(11) Hanessian, S.; Murray, P. J . Tetrahedron 1987, 43, 5055.
Pyrazoline 7 is depicted in this work with anti stereochemistry, but
this configuration is not justified. Although we have used polar
solvents to determine specific rotation for 7 due to the low solubility
of this crystalline compound in carbon tetrachloride, the latter was
the solvent used by those authors.
(12) (a) Ortun˜o, R. M.; Bigorra, J .; Font, J . Tetrahedron 1987, 43,
2199. In this work, pyrazoline from diazomethane and (S)-5-(hy-
droxymethyl)-2(5H)-furanone was used as intermediate in the syn-
thesis of (S)-5-(hydroxymethyl)-4-methyl-2(5H)-furanone (umbelac-
tone), but stereochemistry was not assigned. We have now confirmed
anti stereochemistry from NOE enhancements: 1.5% from H7/H7′ to
H3a and 3.4% from H4 to H3′. (b) Alibe´s, R.; Bourdelande, J . L.; Font,
J .; Gregori, A.; Parella, T. Tetrahedron 1996, 52, 1267.
(8) (a) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M. Tetrahedron: Asym-
metry 1996, 7, 537. (b) J ime´nez, J . M.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1996, 7, 3203. (c) J ime´nez, J . M.; Bourdelande, J . L.;
Ortun˜o, R. M. Tetrahedron 1997, 53, 3777.
(9) Galley, G.; Pa¨tzel, M.; J ones, P. G. Tetrahedron 1995, 51, 1631.
(10) Baskaran, S.; Vasu, J .; Prasad, R.; Kodukulla, K.; Trivedi, G.
K. Tetrahedron 1996, 52, 4515.

π-Facial Diastereoselectivity in 1,3-Dipolar Cycloadditions
Sch em e 1
J . Org. Chem., Vol. 63, No. 11, 1998 3583
Ta ble 1. P h otolysis of P yr a zolin e 7 To Affor d Cyclop r op a n e 8a
entry
solventb
photosensitizer (equiv)
temp (°C)c
time
4 h
1 h
3 h
% yield
ref
1
2
3
4
5
6
7
8
toluene
toluene
rt
-40
rt
-78
rt
58
86
35
42
51
84
12
5
this work
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
benzene-acetonitrile (1:1)
8 h
benzophenone (0.01)
benzophenone (0.01)
15 min
30 min
2 h
-78
14
14
benzophenone (0.1)
4 h
a
b
Irradiations were performed with a 125 W medium-pressure mercury-lamp. 0.02 M solutions were used in all cases. c Referred to
external temperature.
undergoes tautomerization to a ∆2-pyrazoline in trace-
acid-containing solutions. The observed tautomer is the
one in which the CdN bond is not conjugated to carbonyl,
stereochemistry of 8 was confirmed by NOE experiments
as shown in Figure 1.
Cyclopropanation of tosyloxy and iodo derivatives 5
and 613 was also attempted, but byproducts were obtained
due to elimination of p-TsOH or HI, respectively. These
results differ from those described by Mann et al.14 in a
work which appeared at the same time as a short
communication on our preliminary results.15 These
authors studied the photolysis of several pyrazolines
derived from furanones with 5-O substituents, such as
TBDMS, TBDPS, benzoyl, and tosyl (see Table 1, entries
7 and 8).
Deprotection of the primary alcohol was accomplished
by treatment of silyl ether 8 with n-Bu4NF to afford
alcohol 9 as a crystalline solid. Direct conversion of 9
into aldehyde 14 with Pb(OAc)4 in refluxing benzene-
methanol16 gave a low yield (10%) of the desired product
along with unreacted starting material 9 and methoxy-
furanone derived from 9. These products could not be
1
as deduced by H NMR.
Conditions for the photolysis of pyrazoline 7 were
crucial in order to obtain good yields of cyclopropane 8
and to prevent the formation of the olefinic insertion
product. Thus, solvent, temperature, and the use of
photosensitizers were investigated, results of selected
experiments being shown in Table 1. All reactions were
performed using 0.02 M solutions contained in a Pyrex
reactor by irradiation with a 125 W medium-pressure
mercury-lamp. Product remained unaltered when 1,4-
dioxane was used as a solvent at -40 °C and at room
temperature. The use of ether or benzene-acetonitrile
resulted in the exclusive production of byproducts, at
room temperature, or low yields of 8 at -40 or -78 °C.
Better results were found with toluene or dichlo-
romethane. Thus, irradiation of toluene solutions, at -40
°C for 1 h, afforded 86% of cyclopropane 8 (Table 1, entry
2). Similar results were obtained when benzophenone
was added to dichloromethane solutions, reaction being
much slower in absence of the photosensitizer as deduced
from comparison of entries 3/4 with 5/6 in Table 1.
Results could be well reproduced when working in
multigram preparative scale using a 400 W lamp. Anti
(13) Camps, P.; Cardellach, J .; Font, J .; Ortun˜o, R. M.; Ponsat´ı, O.
Tetrahedron 1982, 38, 2359.
(14) Butler, P. I.; Clarke, T.; Dell, C.; Mann, J . J . Chem. Soc., Perkin
Trans. 1 1994, 1503. In this work, aldehyde 14 was synthesized in
20% from furanone 5, but their physical and spectroscopic data were
not described.
(15) Hanafi, H.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1994, 5,
1657.

3584 J . Org. Chem., Vol. 63, No. 11, 1998
Mart´ın-Vila` et al.
isolated by flash chromatography, and reaction of the
mixture with phosphonate 15a (R ) Cbz)17 afforded a
condensation product in very low yield. Oxidation of 9
18
with sodium periodate in the presence of 2 N H2SO4
only led to the recovery of the starting material.
The successful synthetic pathway to gain access to 14
is depicted in Scheme 1. Alcohol 9 was converted into
iodide 11 via tosylate intermediate 10 in 83% yield for
the two steps. Vinyl acid 12 was quantitatively obtained
by reductive â-elimination performed by exposure of
iodide 11 to powdered zinc in glacial acetic acid and
converted into methyl ester 13 by reaction with diaz-
omethane.
Ozonolysis of vinyl derivative 13 as a dichloromethane
solution at -40 °C, followed by treatment with dimethyl
sulfide, provided aldehyde 14 in 94% yield which was
obtained in 66% overall yield from furanone 4.14
The didehydro amino acid key intermediates 1a , 1b,
and 1c were accessible by Wittig-Horner condensation
of 14 with phosphonates 15a -c.17 Several bases, such
as LDA, tert-BuOK, BuLi, and NaH in THF or CH2Cl2,
were used to generate the anions derived from the
corresponding phosphonates. Condensation reactions
were conducted at room temperature, affording the
expected products in 61-81% yields. While (Z)-isomers
were exclusively obtained for 1a and 1c (Scheme 1),
mixtures of Z/E stereoisomers 1b were obtained in 65:
35 (BuLi) to 80:20 (the other bases) ratio.
F igu r e 2. Structure of pyrazoline 17a as determined by X-ray
structural analysis
Sch em e 2
(Z)-Stereochemistry was assigned to the exclusive or
major products on the basis of differential NOE experi-
ments. For instance, for (Z)-1a , 0.5% NOE was observed
on H2a when H4,H5 (chemical shifts for these protons are
very close) were irradiated. Furthermore, significant
NOE values were found for H7, but not for H2a, when H3
was selectively irradiated. In addition, NOE produced
between H3 and H7b suggests a conformation around C3-
C4 as represented in Scheme 1, in which these protons
are close. Similar results were obtained from (Z)-1b and
(Z)-1c. This high stereoselectivity of phosphonates 15a-c
to afford mainly (Z)-geometry diastereoisomers in Wit-
tig-Horner reactions had been previously observed in our
laboratory in the condensation with D-glyceraldehyde
acetonide, independently of the base, solvent, or temper-
ature used.8a Recently, Le Corre et al. reported the
synthesis of the trans-(1S,2S)-isomer of formyl ester 14,
from (S)-glutamic acid. They reported that the conden-
sation of this compound with 15a afforded a 70:30
mixture of Z/E stereoisomers in 65% yield19 which cor-
relates well with our previous finding.
more stereoselective. This behavior is similar to that
observed in the Diels-Alder cycloadditions of pen-
tenoates (Z)- and (E)-16a to several dienes.20a,c Thus,
treatment of (Z)-16a with ethereal diazomethane at room
temperature for 18 h led almost quantitatively to a >95:5
mixture of syn/anti pyrazolines from which major product
17a was isolated. Structural analysis by X-ray diffrac-
tion of a single crystal confirmed its syn stereochemistry
as shown in Figure 2.21 In turn, (E)-16a was reacted with
diazomethane at room temperature for 2 h to afford a
75:25 mixture of pyrazolines 17a being the major isomer.
In the optimal conditions, acetone solutions of pyra-
zoline 17a contained in quartz reactors were irradiated
with a 125 W medium-pressure mercury-lamp to give
(4R,5R)-2,3-Didehydro-4,5-methano amino acids (Z)-1
were thus synthesized in highly stereoselective and
efficient manner in 38-52% overall yields from chiral
furanone 4.
The synthesis of enantiomeric amino acids ent-1 was
undertaken from pentenoates 16, prepared from D-
glyceraldehyde acetonide7 (Scheme 2). (Z)-16a resulted
to be less reactive than (E)-16a toward diazomethane but
(16) Hamada, Y.; Iwai, K.; Shiori, T. Tetrahedron Lett. 1990, 31,
5041.
(17) (a) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1984, 53.
(b) Schmidt, U.; Lieberknecht, A.; Kazmaier, U.; Griesser, H.; J ung,
G.; Metzger, J . Synthesis 1991, 49.
(18) (a) Mulzer, J .; Kappert, M. Angew. Chem., Int. Ed. Engl. 1983,
22, 63. (b) Krief, A.; Dumont, W.; Pasau. P. Lecomte, Ph. Tetrahedron
1989, 45, 3039.
(19) Le Corre, M.; Hercouet, A.; Bessieres, B. Tetrahedron: Asym-
metry 1995, 6, 683.
(20) (a) Casas, R.; Parella, T.; Branchadell, V.; Oliva, A.; Ortun˜o,
R. M.; Guingant, A. Tetrahedron 1992, 48, 2659. (b) Sbai, A.;
Branchadell, V.; Oliva, A. J . Org. Chem. 1996, 61, 621. (c) Sbai, A.;
Branchadell, V.; Ortun˜o, R. M.; Oliva, A. J . Org. Chem. 1997, 62, 3049.
(21) The atomic coordinates and thermal parameters for structure
17a are available on request from the Director of the Cambridge
Crystallographic Data Centre. Any request should be accompanied
by a full literature citation for this paper. Please note that the
crystallographic numbering differs from that used in this article.

π-Facial Diastereoselectivity in 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 63, No. 11, 1998 3585
Ch a r t 3
Sch em e 4
Sch em e 3
data of enriched fractions. Subsequent saponification of
the mixture with methanolic 1 M NaOH gave hydroxy
acid 2 as a crystalline solid mp 60-61 °C, [R]D -1.9 (c
0.4, CHCl3) in 52% yield from 13 and 37% overall yield
from furanone 4.
cyclopropane 18 with yield ranging from 10% to 80%.
Instability of the pyrazoline in solution and the difficulty
of ∆2-pyrazolines to release nitrogen giving the cyclopro-
pane precursor-biradical22 may account for these erratic
results.
The synthesis of ent-2 started with reduction of ester
13 upon treatment with DIBAL followed by benzoylation
of the resultant primary alcohol, affording vinyl ester 22
in 65% for the two steps (Scheme 4). The synthesis of
acid 24 was undertaken by following two alternative
pathways. First, ozonolysis of 22 provided almost quan-
titatively aldehyde 23 which was oxidized to acid 24 with
PDC in DMF, in 49% yield. On the other hand, one-step
oxidation of 21 with catalytic RuO2 and NaIO4 was more
efficient and gave compound 24 in 56% yield. Finally,
saponification of the benzoyl ester by using 1 M NaOH
in methanol furnished hydroxy acid ent-2, mp 61-62, [R]D
+1.9 (c 0.4, CHCl3), in 26% yield from vinyl ester 13 and
18% overall yield from furanone 4.
Treatment of 18 with a few drops of acetic acid in
methanol followed by an oxidative cleavage of the result-
ant diol with tetrabutylammonium periodate afforded
aldehyde ent-14, in 83% yield for the two steps. Con-
densation of this compound with phosphonate 15a in the
presence of LDA furnished (4S,5S)-didehydro-3,4-meth-
ano amino acid ent-(Z)-1a , whose specific rotation is in
excellent accordance with that found for (Z)-1a . This
result shows the usefulness of this synthetic route
starting from pentenoates to obtain enantiomeric prod-
ucts with respect to those resultant from furanones.
2. Syn th esis of Hyd r oxy Acid s 2 a n d en t-2. The
synthesis of these enantiomeric compounds was achieved
through stereodivergent routes from vinyl ester 13
obtained, in turn, from furanone 4 (Scheme 1). In this
case, selective manipulation of the functional groups led
to reverse the chirality of these molecules, allowing the
isolation of both enantiomeric products. Thus, hydroxy
acid 2 was obtained from degradation of the vinyl side-
chain to a hydroxymethyl group. Alternatively, oxidation
of the CdC double bond in 13 to a carboxylic acid and
reduction of the ester group to a primary alcohol afforded
ent-2 (Chart 3).
In this way, both enantiomeric hydroxy acids 2 and
ent-2 were synthesized in satisfactory overall yields from
vinyl ester 13 as a common intermediate.
3. π-F a cia l Dia ster eoselectivity in th e Cycloa d -
d ition s of Dia zom eth a n e to F u r a n on es 3 a n d 4, a n d
to P en ten oa tes 16. In a previous publication, we
showed and rationalized the opposite facial diastereose-
lectivity in the Diels-Alder cycloadditions of chiral
5-(hydroxymethyl)-2(5H)-furanone 3 and derivatives,
with respect to the one showed by its equivalent open-
chain hydroxy pentenoate (Z)-16a .20a In the case of alkyl-
monosubstituted furanones, the preferential attack of the
dienes occurs always on the less hindered C4-Si face, anti
to the substituent at the C-5 position, and the same result
is obtained for the diazomethane cycloadditions (Figure
1). The case of the pentenoates is complicated by the
conformational freedom of the molecules. Diastereose-
lection favors the C3-Re face, that is, the production of
The corresponding synthetic routes were carried out
as follows. Aldehyde 14 was reduced with methanolic
NaBH4 to afford a mixture of hydroxy ester 19 and
lactone 20 in 64% yield (Scheme 3). Although these
compounds could not be isolated by flash chromatogra-
phy, their identity was stablished by the spectroscopic
(22) March J . Advanced Organic Chemistry; J ohn Wiley and Sons:
New York, 1992; p 1046 and references therein.

3586 J . Org. Chem., Vol. 63, No. 11, 1998
Mart´ın-Vila` et al.
In our work, X-ray analysis of pyrazoline 17a confirms
unequivocally syn stereochemistry such as depicted in
Figure 2. Moreover, the preferential production of syn
adducts can be rationalized by considering the active
conformations for (Z)- and (E)-16 as shown in Figure 3.
In a previous study, we calculated conformational
enthalpies for (Z)- and (E)-16a by the AM1 method.20a
The position of the ester group with respect to the C-C
double bond was fixed to be s-cis and the rotation around
the C3-C4 bond was considered. In the case of (Z) isomer,
the only energy minimum corresponded to (Z)-B, in which
the C2-C3-C4-O dihedral angle is -153°. When the
structure is optimized at the BLYP/6-31G* level of
calculation, the value obtained for the dihedral angle is
-158°.
In the Diels-Alder reactions of (Z)-16a with buta-
diene20a and cyclopentadiene20c the conformation of the
enoate was maintained in the transition state corre-
sponding to the most favorable syn isomer. In the
transition state leading to the anti cycloadduct the
conformation of the enoate was (Z)-A. At the BLYP/6-
31G* level of calculation, the geometry optimization of
such conformer by keeping the C2-C3-C4-O dihedral
angle frozen leads to a structure 4.3 kcal/mol higher in
energy than (Z)-B. Contributing factors accounting for
such a large energy difference would include (Z)-A
suffering from destabilizing interaction between H3 and
H5 as well as dipole-dipole interactions which are
relieved in (Z)-B. Thus, the major stereoisomer, i.e. syn
adduct, results from the attack of diazomethane to the
less hindered C3-Re face in (Z)-B with the allylic hydrogen
pointing to the incoming diazomethane.
This facial diastereoselection is the opposite to that
accounting for the only observed anti stereoisomers
produced by C4-Si attack to chiral 5-alkyl or 5-heteroalky-
2(5H)-furanones, as described above. On the contrary,
C3-Si attack to conformer (Z)-A leads to minor anti
adduct. Thus, in the 1,3-dipolar cycloadditions of diaz-
omethane to the (Z) and (E) pentenoates 16, as well as
in their Diels-Alder cycloadditions,20 the antiperiplanar
attack with respect to the C-O bond (conformation (Z)-
A) is not the most favorable one to account for the isomer
ratio. For (E)-pentenoate 16a , two energy minima are
observed in the rotation around the C3-C4 bond: (E)-C
and (E)-D. The energy difference between these confor-
mations is only 0.1 kcal/mol at the BLYP/6-31G* level.
Conformation (E)-C is equivalent to (Z)-B, while the
thermodynamically most stable (E)-D shows a C2-C3-
C4-O dihedral angle of 7.5°. Again, C3-Re attack pro-
vides major syn stereoisomer, from (E)-C. In turn, minor
anti adduct results from C3-Si attack to (E)-D.
F igu r e 3. Stereochemical features in the production of syn/
anti adducts from diazomethane and active conformers for
pentenoates (Z)-16a [(Z)-A, (Z)-B] and (E)-16a [(E)-C, (E)-D],
determined at the BLYP/6-31G* level of calculation.
syn-adducts either in uncatalyzed20a,b or catalyzed Diels-
Alder reactions.20c
The facial diastereoselectivity in the 1,3-dipolar cy-
cloadditions of (E)-16a /b to several dipoles has previously
been reported.
Whereas azomethyne ylides,23a,b
nitrones,23a,c and nitrile oxides23a,d gave predominantly
anti adducts, syn isomers were found with nitrilimines,23e
silyl nitronates,23f and diazo compounds other than
diazomethane.9 Pa¨tzel et al. assigned syn stereochem-
istry to the adduct 17b, obtained from diazomethane and
pentenoate (E)-16b, by comparison with other studied
dipolarophiles.9 Later, Trivedi et al.10 reported anti
stereochemistry to be predominant in the cycloadditions
of this dipole to both (Z)- and (E)-16b, and they rational-
ized this stereoselectivity, in the case of the (Z)-pen-
tenoate, by preferential C3-Si attack to a conformer like
(Z)-A in Figure 3.
It is noteworthy that the same compound 17a is
obtained from both pentenoates, (Z)- and (E)-16, since
the obtained ∆1-pyrazolines must tautomerize rapidly to
the thermodynamically most stable ∆2-pyrazoline.
Con clu d in g Rem a r k s
In conclusion, as a result of the present work, the
stereochemical outcome of the cycloadditions of diaz-
omethane to 5-(alkoxymethyl)-2(5H)-furanones and the
functionally equivalent γ-alkoxy pentenoates has been
unequivocally established both by direct stereochemical
analysis and by chemical correlation. Moreover, a ra-
tionalization of the predominant diastereoselection has
been realized through computation of the energies and
geometries of the active conformers.
(23) (a) Annunziata, R., Benaglia, M.; Cinquini, M.; Raimondi, L.
Tetrahedron 1993, 49, 8629. (b) Galley, G.; Liebscher, J .; Pa¨tzel, M.
J . Org. Chem. 1995, 60, 5005. (c) Busque´, F.; de March, P.; Figueredo,
M., Font, J .; Monsalvatje, M.; Virgili, A.; AÄ lvarez-Larena, A.; Piniella,
J . F. J . Org. Chem. 1996, 61, 8578. (d) J a¨ger, V.; Mu¨ller, I.; Schohe,
R.; Frey, M.; Ehrler, R.; Ha¨fele, B.; Schro¨ter, D. Lect. Heterocycl. Chem.
1985, 8, 79. (e) Grubert, L.; Galley, G.; Pa¨tzel, M. Tetrahedron:
Asymmetry 1996, 7, 1137. (f) Galley, G.; J ones, P. G.; Pa¨tzel, M.
Tetrahedron: Asymmetry 1996, 7, 2073.

π-Facial Diastereoselectivity in 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 63, No. 11, 1998 3587
(1R,4S,5S)-4-(Hydr oxym eth yl)-3-oxabicyclo[3.1.0]h exan -
2-on e (9). A mixture of compound 8 (8.0 g, 21.8 mmol) and
n-Bu4NF (32.7 mL of a 1.0 M solution in THF, 32.7 mmol) in
THF (20 mL) was stirred at room temperature for 10 min.
Then the solvent was removed, and the residue was flash
chromatographed (hexanes-EtOAc, 1:1) to afford 2.7 g (98%
yield) of alcohol 9 as a white solid. Crystals, mp 54-55.5 °C
(from CH2Cl2-hexane); [R]D +63.4 (c 1.4, CHCl3); IR (KBr)
3445-3409 (broad), 1730 cm-1; 400-MHz 1H NMR (CDCl3) 0.85
(m, 1H), 1.21 (m, 1H), 2.11 (m, 2H), 3.01 (broad s, 1H), 3.67
(dd, J ) 17.0, 12.1 Hz, 1H), 3.82 (dd, J ) 14.6, 12.1, 1H), 4.25
(t, J ) 3.6 Hz, 1H); 62.5-MHz 13C NMR (CDCl3) 11.5, 17.6,
19.4, 29.6, 64.5, 81.2, 176.4. Anal. Calcd for C6H8O3: C, 56.25;
H, 6.29. Found: C, 56.23; H, 6.19.
The opposite π-facial diastereoselectivity in the cy-
cloadditions to these chiral furanones and pentenoates
was revealed to be useful in the synthesis of enantiomeric
series of products, starting from D-glyceraldehyde as the
only source of chirality.
The cyclopropyl intermediates synthesized are small
molecules densely functionalized. Thus, selective trans-
formation of functional groups allows design of stereo-
divergent and efficient routes for the enantioselective
synthesis of hydroxy acids.
Both types of target molecules synthesized, namely 2,3-
didehydro-4,5-methano-2-amino acids and 3-hydroxy-2,3-
methano acids, are useful chiral building blocks for the
synthesis of a variety of enantiomerically pure cyclopro-
pane derivatives. Active investigation in this field is
being carried out in our laboratory.
(1R,4S,5S)-4-(Iod om eth yl)-3-oxa bicyclo[3.1.0]h exa n -2-
on e (11). Tosyl chloride (0.6 g, 3.1 mmol) was added in small
portions to an ice-cooled and stirred solution of alcohol 9 (0.2
g, 1.6 mmol) and freshly distilled pyridine (0.25 mL, 3.1 mmol)
in dry CH2Cl2 (10 mL). The mixture was stirred at room
temperature for 8 h. The reaction mixture was diluted with
CH2Cl2 (10 mL) and washed successively with 1% HCl and
water. The organic phase was dried (MgSO4), and solvent was
removed at reduced pressure. The residue was flash chro-
matographed (hexanes-EtOAc, 3:2) to give known tosylate
1014 as a white solid (0.4 g, 86% yield). A mixture of compound
10 (0.3 g, 0.9 mmol) and NaI (2.1 g, 13.9 mmol) in dry acetone
(15 mL) was heated to reflux for 2 h. Solution was evaporated
to dryness, and the residue was poured into EtOAc (20 mL)
and water (10 mL). The layers were separated, and the
organic phase was washed with 5% aq Na2S2O3. The aqueous
phase was extracted with EtOAc, the combined organic phases
were dried (MgSO4), and solvents were removed at reduced
pressure giving iodide 11 which was purified by flash chro-
matography (hexanes-EtOAc, 4:1) to afford pure 11 as a white
solid (0.2 g, 97% yield). Crystals, mp 68-70 °C (from hex-
Exp er im en ta l Section
Flash column chromatography was carried out on silica gel
(240-400 mesh). Melting points were determined on a hot
stage and are uncorrected. Distillation of small amounts of
material was effected in a bulb-to-bulb distillation apparatus,
with oven temperatures (ot) being reported. Electron impact
mass spectra were recorded at 70 eV. Chemical shifts in NMR
spectra are given on the δ scale.
Com p u ta tion a l Deta ils. Theoretical calculations have
been done at the density functional level using the gradient
corrected functionals of Becke24 and Lee, Yang, and Parr25
(BLYP) for exchange and correlation, respectively, and the
6-31G* basis set.26 All calculations have been done using the
Gaussian-94 program.27
(1R,5S,6S)-4-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-7-
oxa -2,3-d ia za bicyclo[3.3.0]h exa n -2-en -8-on e (7). Excess
ethereal diazomethane was distilled onto an ice-cooled and
stirred solution of furanone 4 (10 g, 28.4 mmol) in 25 mL of
THF. The resultant mixture was light-protected and stirred
at room temperature for 18 h. Then excess diazomethane was
destroyed, and solvents were removed to afford quantitatively
11.1 g of pyrazoline 7 as a white solid. Crystals, mp 105-106
°C (from ether-pentane), [R]D -182 (c 1.2, CHCl3) and -212
(c 1.7, acetone) [lit.11 mp 105-106 °C (from ether-pentane),
[R]D -215 (c 1.2, CCl4)]. Spectroscopic data are in good
agreement with those described for structure 7 in ref 11.
anes-EtOAc); [R]D +86.1 (c 1.8, CHCl3); IR (KBr) 1770 cm-1
;
250-MHz 1H NMR (CDCl3) 0.9 (m, 1H), 1.27 (m, 1H), 2.10-
2.24 (complex absorption, 2H), 3.21 (dd, J ) 10.9, 3.6 Hz, 1H),
3.54 (dd, J ) 10.9, 7.3 Hz, 1H), 4.31 (dd, J ) 8.3, 4.3 Hz, 1H);
62.5-MHz 13C NMR (CDCl3) 8.0, 12.0, 18.0, 23.2, 78.4, 174.8.
MS, m/z (%) 238 (M-1, 25), 111 (90), 97 (100), 55 (20), 41 (45).
Anal. Calcd for C6H7O2I: C, 30.28; H, 2.96. Found: C, 30.22;
H, 2.95.
(1R,2R)-1-(Meth oxycar bon yl)-2-vin ylcyclopr opan e (13).
A mixture of iodide 11 (175 mg, 0.7 mmol), powdered Zn (252
mg, 4.5 mmol), and two drops of glacial AcOH in ether (12
mL) was heated to reflux for 1 h. Then the mixture was
filtered through Celite, and solvent was removed. The residue
was flash chromatographed (hexanes-EtOAc, 1:1) to afford
quantitatively 80 mg of acid 12 as a yellowish and highly
volatile oil, IR (film) 3200-2945 (broad), 1696, 1644 cm-1. This
acid was treated with diazomethane in the usual way to
furnish quantitatively ester 13 as a extremely volatile liquid,
which was identified by its spectroscopic data. IR (film) 1729,
1645 cm-1; 250-MHz 1H NMR (CDCl3) 1.2 (m, 2H), 1.9 (m, 2H),
3.64 (s, 3H), 5.08 (dd, J ) 10.2, 2.9 Hz, 1H), 5.22 (dd, J )
17.5, 2.9 Hz, 1H), 5.75 (m, 1H); 62.5-MHz 13C NMR (CDCl3)
14.2, 20.7, 24.8, 51.6, 116.2, 135.3, 172.4; MS, m/z (%) 126 (M,
10), 95 (26), 67 (100), 55 (17), 41 (49).
(1R,4S,5S)-4-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-3-
oxa bicyclo[3.1.0]h exa n -2-on e (8). A stirred solution of
pyrazoline 7 (10.5 g, 26.5 mmol) in anhydrous toluene (500
mL), contained in a Pyrex reactor under argon atmosphere,
cooled at -78°, was irradiated with a 400 W medium-pressure
lamp for 2.5 h. Solvent was removed to afford a yellowish solid
that was crystallized to afford pure 8 (23.6 g, 86%). Crystals,
mp 110-111.5 °C (from CH2Cl2-pentane); [R]D -163.1 (c 3.2,
1
CHCl3); IR (KBr) 1771 cm-1; 250-MHz H NMR (CDCl3) 0.82
(m, 1H), 1.01 (s, 9H), 1.21 (m, 1H), 2.08-2.20 (complex
absorption, 2H), 3.70 (dd, J ) 10.9, 8.0 Hz, 1H), 3.82 (dd, J )
10.9, 7.3, 1H), 4.35 (t, J ) 3.6 Hz, 1H), 7.4 (m, 5H), 7.65 (m,
5H); 62.5-MHz 13C NMR (CDCl3) 11.3, 17.6, 19.1, 19.7, 26.6,
65.1, 80.2, 127.7, 129.8, 132.8, 135.5, 175.9. Anal. Calcd for
(1R,2S)-2-For m yl-1-(m eth oxycar bon yl)cyclopr opan e 14.
Ozone was bubbled through a stirred solution of vinyl ester
13 (180 mg, 1.4 mmol) in CH2Cl2 at -40 °C for 10 min, and
then three drops of Me2S were added. After stirring for 3 h
at room temperature, the mixture was diluted with CH2Cl2
(10 mL) and washed with five portions of water. The combined
aqueous phases were extracted twice with CH2Cl2, the com-
bined organic phases were dried (Na2SO4), and solvent was
removed at reduced pressure to afford aldehyde 1414 as a
highly volatile liquid (174 mg, 94% yield); [R]D +94.2 (c 2.8,
CHCl3); IR (film) 1736 cm-1; 250-MHz 1H NMR (CDCl3) 1.2
(m, 1H), 1.5 (m, 1H), 2.0 (m, 2H), 3.68 (s, 3H), 9.3 (d, J ) 6.5
Hz, 1H); 62.5-MHz 13C NMR (CDCl3) 12.4, 21.1, 22.2, 52.3,
170.4, 175.5; MS, m/z (%) 128 (M, 1), 100 (100), 97 (80), 96
(36), 69 (84), 68 (72), 55 (72), 41 (95).
C
22H26O3Si: C, 72.09; H, 7.15. Found: C, 72.11; H, 7.13.
(24) Becke, A. D. Phys. Rev. A 1988, 38, 3098.
(25) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. A 1988, 37, 785.
(26) Hehre, W. J .; Radom, L.; Schleyer, P. v. R.; Pople, J . A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(27) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T. A.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andre´s, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . J .; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, Revision B.3; Gaussian Inc.: Pittsburgh, PA, 1995.

3588 J . Org. Chem., Vol. 63, No. 11, 1998
Mart´ın-Vila` et al.
Gen er a l P r oced u r e for Wittig-Hor n er Con d en sa tion s.
A typical experiment was run as follows for the obtention of
1b. Methyl 2-(tert-butoxycarbonylamino)-2-(dimethoxyphos-
phonyl)acetate17 (705 mg, 2.4 mmol) in THF (5 mL) was added
to a solution of LDA, prepared from diisopropylamine (364 µL,
2.5 mmol) and n-BuLi (1.63 mL of a 1.6 M solution in hexane,
2.5 mmol), in anhydrous THF (5 mL) at -78 °C, under nitrogen
atmosphere. After stirring for 40 min, aldehyde 14 (254 mg,
2.0 mmol) was added, and the mixture was allowed to reach
room temperature and then stirred for 5 h. The solution was
evaporated to dryness, and the residue was flash chromato-
graphed (hexanes-EtOAc, increasing polarity) to afford (E)-
1b and (Z)-1b. Yield, physical constants, and spectroscopic
data for 1a -c and ent-1a are described below.
Dim et h yl (Z)-(4R,5R)-2-(Ben zyloxyca r b on yla m in o)-
4,5-m eth a n o-2-h exen ed ioa te (Z)-1a . Yield: 143 mg (61%).
Dense oil, ot 190 °C (0.01 Torr); [R]D -72.9 (c 3.6, CHCl3); IR
(film) 3325 (broad), 1721, 1651 cm-1; 250-MHz 1H NMR
(CDCl3) 1.2 (m, 1H), 1.4 (m, 1H), 2.10 (m, 2H), 3.68 (s, 3H),
3.72 (s, 3H), 5.12 (s, 2H), 6.29 (broad s, 1H), 6.7 (d, J ) 10.3
Hz, 1H), 7.47 (m, 5H); 62.5-MHz 13C NMR (CDCl3) 15.81,
20.44, 21.86, 51.95, 52.39, 67.36, 126.20, 128.14, 128.47,
134.75, 135.90, 154.19, 164.72, 172.04; MS, m/z (%) 334 (M+1,
1), 225 (14), 166 (17), 139 (63), 107 (55), 91 (100), 79 (92), 51
(33). Anal. Calcd for C17H19NO6: C, 61.25; H, 5.75; N, 4.20.
Found: C, 61.18; H, 5.72; N, 4.13.
1H); 62.5-MHz 13C NMR (CDCl3) 24.9, 26.1, 46.5, 50.9, 51.6,
68.1, 73.7, 108.7, 140.2, 162.9. Anal. Calcd for C10H16N2O4:
C, 52.62; H, 7.07; N, 12.27. Found: C, 52.67; H, 7.12; N, 12.30.
Meth yl (1S,2R,4′S)-2-(2′,2′-Dim eth yl-1′,3′-d ioxola n -4′-
yl)cyclop r op a n eca r boxyla te (18). A stirred solution of
pyrazoline 17a (100 mg, 0.4 mmol) in freshly distilled acetone
(40 mL) contained in a quartz reactor was irradiated with a
125 W medium-pressure lamp under argon atmosphere. The
reaction was monitored by GC until total consumption of the
starting material. Then solvent was removed to afford a bright
red oil that was flash chromatographed (mixtures of hexanes-
EtOAc) affording 69 mg of a yellowish oil identified as 18 by
its specroscopic data but contaminated by unidentified byprod-
ucts. Since it decomposed under distillation conditions, this
product was used in subsequent transformations without
1
further purification. IR (film) 1739 cm-1; 250-MHz H NMR
(CDCl3) 1.19 (dd, J ) 7.3, 5.1 Hz, 1H), 1.30 (s, 3H), 1.28 (m,
1H), 1.41 (s, 3H), 1.50 (dd, J ) 9.5, 5.1 Hz, 1H), 1.62 (m, 1H),
3.60 (s, 3H), 3.70 (m, 1H), 3.90 (dd, J ) 9.5, 5.1 Hz, 1H), 4.10
(m, 1H); 62.5-MHz 13C NMR (CDCl3) 14.1, 2.5, 24.8, 26.4, 28.7,
52.7, 69.3, 75.5, 109.0, 172.0.
(1S,2R)-2-F or m yl-1-(m et h oxyca r b on yl)cyclop r op a n e
(en t-14). A solution of compound 18 (143 mg, 0.7 mmol) and
3 drops of 90% AcOH in MeOH (5 mL) was stirred at room
temperature for 6 h and then evaporated to dryness. The
residue was washed with methanol and dried under vacuo.
The obtained crude diol was poured into THF (10 mL), and
n-Bu4IO4 (340 mg, 0.8 mmol) was added to the ice-cooled
resultant solution. The mixture was stirred for 2 h, the solvent
was removed, and the residue was poured into ether. The
precipitated solid was filtered, and the filtrate was evaporated
to dryness to afford 75 mg (83% yield) of an oil identified as
ent-14 by their spectrocopic data which agree with those
described above for 14. [R]D -92.7 (c 3.0, CHCl3).
Dim eth yl (Z)-(4S,5S)-2-(Ben zyloxyca r bon yla m in o)-4,5-
m eth a n o-2-h exen ed ioa te en t-(Z)-1a . Yield: 294 mg (66%).
[R]D +72.3 (c 3.2, CHCl3). Spectroscopic and analytical data
are in good agreement with those described above for (Z)-1a .
Dim eth yl (Z)-(4R,5R)-2-(ter t-Bu toxyca r bon yla m in o)-
4,5-m eth a n o-2-h exen ed ioa te (Z)-1b. Yield: 340 mg (58%).
Crystals, mp 76-78 °C (from EtOAc-pentane); [R]D -94.1 (c
3.0, CHCl3); IR (KBr) 3400-3100 (broad), 1730, 1664 cm-1
;
250-MHz 1H NMR (CDCl3) 0.79 (m, 1H), 1.40 (s, 9H), 1.30 (m,
2H), 2.10 (m, 1H), 3.60 (s, 3H), 3.80 (s, 3H), 6.21 (broad s, 1H),
6.55 (d, J ) 8.8 Hz, 1H); 62.5-MHz 13C NMR (CDCl3) 19.0,
20.4, 22.0, 28.1, 52.4, 52.5, 80.2, 126.7, 128.1, 156.0, 164.5,
172.0; MS, m/z (%) 300 (M+1, 2), 255 (28), 139 (63), 107 (55),
91 (100), 79 (92), 53 (30). Anal. Calcd for C14H21NO6: C, 56.18;
H, 7.07; N, 4.68. Found: C, 56.23; H, 7.10; N, 4.72.
(1R,2S)-1-Car boxy-2-(h ydr oxym eth yl)cyclopr opan e (2).
NaBH4 (182 mg, 4.8 mmol) was added to an ice-cooled solution
of aldehyde 14 (475 mg, 3.7 mmol) in MeOH (5 mL), and the
mixture was stirred for 1 h. Solvent was removed, and the
residue was poured into saturated aqueous NH4Cl (2 mL). The
resultant solution was extracted with CH2Cl2, the combined
organic extracts were dried (MgSO4), and solvent was removed.
The residue was flash chromatographed (hexanes-ether, 1:1)
affording a 1:1 mixture of hydroxy ester 19 and lactone 20 (300
mg, 64% yield) which were identified from enriched fractions.
(1R,2S)-2-(H yd r oxym et h yl)-1-(m et h oxyca r b on yl)cyclo-
Dim eth yl (E)-(4R,5R)-2-(ter t-Bu toxyca r bon yla m in o)-
4,5-m eth a n o-2-h exen ed ioa te (E)-1. Yield: 131 mg (23%).
Crystals, mp 62-64 °C (from EtOAc-pentane); [R]D +54.4 (c
1.2, CHCl3); IR (KBr) 3400-3100 (broad), 1725, 1667 cm-1
;
1
250-MHz 1H NMR (CDCl3) 1.31 (m, 1H), 1.40 (s, 9H), 1.96 (m,
2H), 2.95 (m, 1H), 3.60 (s, 3H), 3.80 (s, 3H), 6.48 (broad s, 1H),
6.52 (d, J ) 3.6 Hz, 1H); 62.5-MHz 13C NMR (CDCl3) 19.0,
20.2, 22.0, 28.1, 52.6, 52.5, 81.1, 125.9, 127.9, 156.1, 164.0,
172.1. Anal. Calcd for C14H21NO6: C, 56.18; H, 7.07; N, 4.68.
Found: C, 56.09; H, 7.13; N, 4.77
p r op a n e (19): IR (film) 3444, 1722 cm-1; 400-MHz H NMR
(MeOH-d4) 0.99 (m, 1H), 1.14 (m, 1H), 1.60 (m, 1H), 1.85 (ddd,
J ) 8.4, 7.9, 5.5, 1H), 3.62 (dd, J ) 11.6, 8.5 Hz, 1H), 3.71 (s,
3H), 3.83 (dd, J ) 11.6, 6.1 Hz, 1H); 100-MHz 13C NMR
(MeOH-d4) 12.1, 18.1, 24.1, 52.1, 71.1, 174.7. GC-MS, m/z (%)
113.1 (M, 1), 98.1 (36), 87.1 (77), 74.1 (67), 68.1 (22), 55.1 (100),
41.1 (40). (1R,5S)-3-Oxa bicyclo[3.1.0]h exa n -2-on e (20): IR
Dim eth yl (Z)-(4R,5R)-2-(Acetyla m in o)-4,5-m eth a n o-2-
h exen ed ioa te (Z)-1c. Yield: 264 mg (79%). Crystals, mp
82-84 °C (from EtOAc-pentane); [R]D +62.0 (c 2.6, CHCl3);
IR (KBr) 3500-3000 (broad), 1730, 1678 cm-1; 250-MHz 1H
NMR (CDCl3) 1.30 (m, 1H), 1.40 (s, 9H), 2.09 (m, 2H), 2.90
(m, 1H), 3.60 (s, 3H), 3.80 (s, 3H), 6.51 (broad s, 1H), 6.55 (d,
J ) 8.8 Hz, 1H); 62.5-MHz 13C NMR (CDCl3) 19.1, 20.2, 21.6,
23.5, 52.18, 52.9, 125.3, 130.0, 164.6, 169.9, 172.02; MS, m/z
(%) 242 (M+1, 2), 164 (21), 136 (60), 107 (55), 91 (100), 79 (92),
51 (33). Anal. Calcd for C11H15NO5: C, 54.77; H, 6.27; N, 5.81.
Found: C, 54.67; H, 6.32; N, 5.83.
1
(film) 1771 cm-1; 400-MHz H NMR (MeOH-d4) 0.85 (m, 1H),
1.34 (m, 1H), 2.10 (m, 1H), 2.36 (m, 1H), 4.27 (d, J ) 9.2 Hz,
1H), 4,39 (dd, J ) 9.2, 4.9 Hz, 1H); 100-MHz 13C NMR (MeOH-
d4) 12.7, 18.5, 30.5, 60.6, 177.9; GC-MS, m/z (%) 281.1 (M, 1),
98.1 (75), 70.1 (36), 68.1 (59), 42.1 (100), 41.1 (46).
A solution of the mixture 19/20 (150 mg) in 1 M methanolic
NaOH (6 mL) was stirred at room-temperature overnight and
then neutralized with 5% HCl and extracted with ethyl
acetate. The combined organic extracts were dried (MgSO4),
and solvent was removed to afford a yellowish oil that was
crystallized to afford pure 2 (115 mg, 86% yield). Crystals,
60-61 °C (from EtOAc-pentane); [R]D -1.9 and [R]365 -2.7 (c
0.4, CHCl3); IR (KBr) 3343-3339 (broad), 1623 cm-1; MS, m/z
116 (M, 1), 99 (20), 73 (100), 70 (39), 60 (40), 55 (97), 44 (73),
43 957); 400-MHz 1H NMR (acetone-d6) 0.89 (m, 1H), 1.08 (dt,
J ) 8.8, 4.4 Hz, 1H), 1.27 (broad s, 1H), 1.56 (m, 1H), 1.73 (m,
1H), 3.6, (dd, J ) 11.7, 7.3 Hz, 1H), 3.77 (dd, J ) 11.7, 5.8 Hz,
1H); 100-MHz 13C NMR (acetone-d6) 10.8, 16.5, 23.1, 59.0,
173.4; MS, m/z (%) 116 (M, 9), 99 (28), 73 (58), 71 (68), 57 (100).
Anal. Calcd for C5H8O3: C, 51.72; H, 6.94. Found: C, 51.48;
H, 7.00.
(4R,4′S)-4-(2′,2′-Dim eth yl-1′,3′-d ioxola n -4′-yl)-3-(m eth -
oxyca r b on yl)-4,5-d ih yd r o-1H -p yr a zole
(17a ).
From
(Z)-16a : Excess ethereal diazomethane (ca. 15 equiv) was
distilled onto a solution of pentenoate (Z)-16a (3 g, 16 mmol)
in ether (5 mL). The mixture was light-protected and stirred
at room temperature for 18 h. Excess reagent and solvent
were removed, and the solid residue was washed with ether-
hexane to afford pure isomer 17a (3.3 g, 90% yield); crystals,
mp 144-146 °C (from ethyl acetate-pentane); [R]D +24.8 (c
1.4, CHCl3); IR (KBr) 3402 (broad), 1707 cm-1; 250-MHz 1H
NMR (CDCl3) 1.2 (s, 3H), 1.3 (s, 3H), 3.28 (m, 1H), 3.58 (m,
2H), 3.67 (s, 3H), 3.72 (dd, J ) 10.2, 7.3 Hz, 1H), 3.95 (dd, J
) 8.8, 6.6 Hz, 1H), 4.25 (dd, J ) 12.4, 6.6 Hz, 1H), 6.4 (br s,
(1R,2R)-1-(Ben zoyloxym eth yl)-2-vin ylcyclopr opan e (22).
A 1.0 M dichloromethane solution of DIBAL (2.0 mL, 2.0 mmol)

π-Facial Diastereoselectivity in 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 63, No. 11, 1998 3589
was added via syringe to a stirred solution of vinyl ester 13
(100 mg, 0.8 mmol) in dry CH2Cl2 (5 mL) cooled at -78 °C,
under nitrogen atmosphere. After stirring for 30 min, water
(5 mL) was added dropwise, and the mixture was extracted
with CH2Cl2. The combined organic phases were dried (Mg-
SO4), and solvent was removed. The residue was chromato-
graphed on silica gel to afford 55 mg (70% yield) of alcohol 21
as a yellowish liquid. Freshly distilled benzoyl chloride (0.2
mL, 1.8 mmol) was added to a stirred an ice-cooled solution of
21 (150 mg, 1.5 mmol) and anhydrous pyridine (0.7 mL, 9.2
mmol) in dry CH2Cl2 (5 mL), under nitrogen atmosphere.
After stirring for 15 min, water (5 mL) was added, and the
mixture was extracted with CH2Cl2. The combined organic
phases were washed successively with 5% HCl and 10%
Na2CO3 and dried (MgSO4). Solvent was removed, and the
residue was chromatographed on silica gel (hexane-CH2Cl2,
6:1) to afford pure 22 (290 mg, 94% yield) as a colorless oil, ot
75-80 °C (0.05 Torr); [R]D +1.5 (c 1.3, CHCl3); IR (film) 1721,
1637 cm-1; MS, m/z 105 (100), 81 (54), 77 (41), 51 (26), 41 (19);
250-MHz 1H NMR (CDCl3) 0.54 (dd, J ) 11.0, 5.8 Hz, 1H),
0.98 (m, 1H), 1.45 (m, 1H), 1.67 (m, 1H), 4.09 (dd, J ) 11.7,
8.0 1H), 4.38 (dd, J ) 11.7, 4.4 Hz, 1H), 5.03 (m, 2H), 5.6 (m,
1H), 7.4 (dd, J ) 8.0, 7.3, 2H), 7.50 (m, 1H), 8.00 (m, 2H); 62.5-
MHz 13C NMR (CDCl3) 14.3, 16.8, 19.6, 65.3, 115.6, 128.3,
129.5, 130.4, 132.7, 136.2, 166.6. Anal. Calcd for C12H14O2:
C, 77.20; H, 6.98. Found: C, 77.14; H, 6.99.
(1S ,2R )-1-Ca r b oxy-2-(b e n zoyloxym e t h yl)cyclop r o-
p a n e (24). Meth od 1. Catalytic RuO2 × n H2O (30 mg) and
NaIO4 (2.1 g, 9.8 mmol) were added to a solution of vinyl
compound 22 (360 mg, 1.8 mmol) in a 2:2:3 mixture of CCl4/
CH3CN/H2O (7 mL). After stirring for 30 min at room
temperature, ether (10 mL) was added and the mixture was
stirred for 5 min. The layers were separated, and the aqueous
layer was extracted with ether. The combined organic extracts
were washed with saturated aqueous NaHCO3, and the
resultant aqueous phases were acidified with 10% HCl and
extracted with ether. All the combined organic phases were
dried (MgSO4), and solvent was removed to afford a residue
which was washed with pentane and dried under vacuo to
afford acid 24 as a solid (220 mg, 56% yield). Meth od 2,
th r ou gh a ld eh yd e 23. Vinyl compound 22 (110 mg, 0.5
mmol) in CH2Cl2 (10 mL) at -78 °C underwent ozonolysis
following the same procedure than that described above for
the preparation of 14, affording aldehyde 23 (110 mg, 98%
yield) as a liquid which was identified by its spectroscopic data
and used in the next step without further purification. Alde-
hyde 23 (110 mg, 0.5 mmol) and pyridinium dichromate (467
mg, 1.1 mmol) in anhydrous DMF (10 mL) were stirred at room
temperature for 48 h. The mixture was filtered, and the
filtrate was evaporated to dryness under vacuo. The residue
was poured into CH2Cl2 and washed with saturated aqueous
Na2CO3. The organic phase was subsequently acidified with
10% HCl and extracted with CH2Cl2. The combined organic
phases were dried (MgSO4), and solvent was removed to afford
57 mg (49% yield) of acid 24. Crystals, mp 85-87 °C; [R]D
+1.7 (c 0.8, CHCl3); IR (KBr) 3058, 2960, 1728 cm-1; 250-MHz
1H NMR (CDCl3) 1.19 (t, J ) 7.3 Hz, 2H), 1.81 (m, 2H), 4.25
(m, 1H), 4.70 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.96 (d, J )
8.0 Hz, 2H); 62.5-MHz 13C NMR (CDCl3) 13.0, 17.4, 20.5, 63.1,
128.3, 129.5, 132.8, 166.4, 178.1. Anal. Calcd for C12H12O4:
C, 65.44; H, 5.49. Found: C, 65.40; H, 5.57.
(1S,2R)-1-Ca r b oxy-2-(h yd r oxym et h yl)cyclop r op a n e
(en t-2). Compound 24 (220 mg, 1 mmol) in methanolic 1 M
NaOH (10 mL) was stirred at room temperature for 2 days.
Then the mixture was subsequently neutralized with 5% HCl
and extracted with EtOAc. The combined organic extracts
were dried (MgSO4), and solvent was removed to afford a
yellow oil that became a white solid after crystallization. The
solid was recrystallized to afford pure ent-2 (82 mg, 70% yield).
Crystals, mp 61-62 °C (from EtOAc-pentane); [R]D +1.9 and
[R]365 +2.6 (c 0.4, CHCl3). Spectroscopic and analytical data
are in good agreement with those described above for 2.
Ack n ow led gm en t. M. M.-V. thanks the Ministerio
de Educacio´n for a predoctoral fellowship. Financial
support from Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica (DGICYT) through the project PB94-
0694 is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: An ORTEP draw-
ing, as well as the atomic coordinates and thermal parameters
for structure 17a (6 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O972219A