Divergent routes to chiral cyclobutane synthons from (-)-α-pinene and their use in the stereoselective synthesis of dehydro amino acids

Article abstract of DOI:10.1021/jo991773c

Several polyfunctionalized cyclobutane derivatives have been synthesized using commercial (-)-α-pinene and (-)-verbenone as chiral precursors. Thus, oxidative cleavage of these compounds by using ruthenium trichloride afforded quantitatively (-)-cis-pinonic and (-)-cis-pinononic acids, respectively, without epimerization. These products were converted into several types of aldehydes, which are the key intermediates in the synthesis of cyclobutane dehydro amino acids via Wittig-Horner condensations with suitable phosphonates. These reactions are highly stereoselective, affording exclusively (Z) isomers, stereochemistry being assessed by NMR experiments. The obtained dehydro amino acids are polyfunctionalized molecules useful for the synthesis of other α-amino acids, with additional chiral centers, whose configuration must be induced by the chirality of the terpene employed as a precursor.

Full text of DOI:10.1021/jo991773c

3934
J . Org. Chem. 2000, 65, 3934-3940
Diver gen t Rou tes to Ch ir a l Cyclobu ta n e Syn th on s fr om
(-)-r-P in en e a n d Th eir Use in th e Ster eoselective Syn th esis of
Deh yd r o Am in o Acid s
Albertina G. Moglioni,† Elena Garc´ıa-Expo´sito,† Gemma P. Aguado,† Teodor Parella,†
Vicenc¸ Branchadell,† Graciela Y. Moltrasio,§ and Rosa M. Ortun˜o*,†
Departament de Quı´mica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain,
Servei de Ressona`ncia Magne`tica Nuclear, Universitat Auto`noma de Barcelona, 08193 Bellaterra,
Barcelona, Spain, and Departamento de Qu´ımica Orga´nica, Facultad de Farmacia y Bioqu´ımica,
Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
rosa.ortuno@uab.es
Received November 15, 1999
Several polyfunctionalized cyclobutane derivatives have been synthesized using commercial (-)-
R-pinene and (-)-verbenone as chiral precursors. Thus, oxidative cleavage of these compounds by
using ruthenium trichloride afforded quantitatively (-)-cis-pinonic and (-)-cis-pinononic acids,
respectively, without epimerization. These products were converted into several types of aldehydes,
which are the key intermediates in the synthesis of cyclobutane dehydro amino acids via Wittig-
Horner condensations with suitable phosphonates. These reactions are highly stereoselective,
affording exclusively (Z) isomers, stereochemistry being assessed by NMR experiments. The obtained
dehydro amino acids are polyfunctionalized molecules useful for the synthesis of other R-amino
acids, with additional chiral centers, whose configuration must be induced by the chirality of the
terpene employed as a precursor.
In tr od u ction
efforts have been devoted to the production of the natural
products and their modified and more active analogues.
It is interesing to note that these biologically active
products involve derivatives with both the amino and the
carboxyl groups directly attached to the cyclobutane ring
as well as other compounds in which the amino function
and/or the carboxyl are in a side chain. Among these last
CBAA, cyclobutylglycine (R-aminocyclobutylacetic acid)
can be used as an alternative substrate for valyl trans-
port RNA-synthetase.5 Moreover, certain (3-aminom-
ethyl-2,2-dimethyl)cyclobutylacetic acid derivatives, readily
available from pinonic and pinic acids,6 display antiviral
activity.7 At present, the studies are mainly focused on
the activity of compounds concerning the NMDA, H2-
H3, and GABA receptors.8
However, in an interesting review, Avotins remarked
that, despite the great diversity of CBAA known, the
majority of the syntheses described for these products
are neither enantio- nor diastereoselective.9 Among the
scarce stereoselective methodologies published, the recent
work of Burgess et al. on the synthesis of enantiopure
CBAA from (+)-R-pinene and their incorporation in some
peptide isosteres is noteworthy.10 Cyclopropanes have
been successfully incorporated in peptide surrogates in
order to constrain them conformationally, thus enhancing
their properties, or to investigate the topological require-
ments of the receptor interactions. Since, in certain cases,
The cyclobutane moiety is a structural feature present
in several natural or designed products with interesting
biological properties. Thus, for instance, the synthesis of
cyclobutane analogues of the nucleoside oxetanocin has
been the subjet of great interest during the last years
because of their activity against human immunodefi-
ciency viruses (HIV).1
Cyclobutane amino acids (CBAA) have also received
attention. Thus, in 1980, Bell et al., in pioneering work,
isolated 2,4-methanoglutamic acid and 2,4-methanopro-
line from the seeds of the plant Ateleia herbert smithii.2
Another nonprotein amino acid, cis-1-amino-3-hydroxym-
ethylcyclobutane-1-carboxylic acid, was isolated also from
the same plant.3 On the other hand, the antibiotic
dipeptide X-1092, (1S,2S)-1-hydroxy-2-[(S)-valylamino]-
cyclobutane-1-acetic acid, produced by the microorganism
Streptomyces species X-1092, was isolated in 1983.4 Since
then, other CBAA and related peptides have been ob-
tained from natural sources. Some of these compounds
display activities as antiviral or antimicrobial agents,
neurotropics, and analgesics. Therefore, great synthetic
† Departament de Qu´ımica, Universitat Auto`noma de Barcelona.
‡ Servei de Ressona`ncia Magne`tica Nuclear, Universitat Auto`noma
de Barcelona.
§ Universidad de Buenos Aires.
(1) Norbeck, D. W.; Kern, E.; Hayashi, S.; Broder, S.; Mitsuya, H.
J . Med. Chem. 1990, 33, 1281.
(2) Bell, E.; Qureshi, M.; Pryce, R.; J anzen, D.; Lemke, P.; Clardy,
J . J . Am. Chem. Soc. 1980, 102, 1409.
(3) Austin, G. N.; Baird, P. D.; Chow, H. F.; Fellows, L. E.; Fleet, G.
W. J .; Nash, R. J .; Peach, J . M.; Pryce, R. J .; Stirton, C. H. Tetrahedron
1987, 43, 1857.
(4) (a) Adlington, R. M.; Baldwin, J . E.; J ones, R. H.; Murphy, J . A.;
Parisi, M. F. J . Chem. Soc., Chem. Commun. 1983, 1479. (b) Baldwin,
K. A.; Adlington, R. M.; Parisi, M. F.; Ting, H.-H. Tetrahedron 1986,
42, 2575.
(5) Anderson, J . W.; Fowden, L. Biochem. J . 1970, 119, 691.
(6) See, for instance: (a) Parkin, B. A.; Hendrick, G. W. J . Am. Chem.
Soc. 1958, 80, 2899. (b) Pearl, I. Forest. Prod. J . 1958, 8, 39.
(7) Gudriniece, E.; Avotins, F. Izv. Latv. Akad. Nauk 1990, 101.
(8) Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C.-K.; J ane, D.
E.; Watkins, J . C. J . Med. Chem. 1994, 37, 4288.
(9) Avotins, F. Russ. Chem. Rev. 1993, 62, 897.
(10) Burgess, K.; Li, S.; Rebenspies, J . Tetrahedron Lett. 1997, 38,
1681. See also references therein.
10.1021/jo991773c CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/07/2000

Divergent Routes to Chiral Cyclobutane Synthons
J . Org. Chem., Vol. 65, No. 13, 2000 3935
Sch em e 1
the highly rigid cyclopropane moiety difficults the suit-
able folding, it is assumed at present that the more
flexible cyclobutane rings can provide peptides with more
convenient structural features.11
Terpenes are convenient chiral precursors due to their
availability and low cost, and among them, R-pinene
(both enantiomers) and verbenone are prominent. For
instance, pinene has been used as starting material for
the production of some compounds of industrial interest12
and as chiral solvent in the resolution of enantiomers by
direct crystallization.13
As a part of our research program on the synthesis and
structural study of cyclobutane amino acids and related
peptides,14 we have recently reported our preliminary
results on the synthesis of chiral polyfunctionalized
cyclobutane building blocks as precursors of dehydro
amino acids.14a In the present paper, we describe several
divergent synthetic routes to prepare different aldehydes,
which are versatile synthons, and their use in the
stereoselective synthesis of novel dehydro amino acids
whose stereochemical assignment is provided and dis-
cussed. In all cases, (-)-R-pinene was the only starting
material affording the cyclobutane ring, as well as two
chiral centers with unambiguous absolute configuration
and several chemical functions suitable to prepare the
target molecules.
dition reactions. Actually, the stereochemical outcome of
such processes must be presumably influenced by the
bulkiness and the chirality of the cyclobutyl moiety
contributing to the diastereoselection of the two double-
bond faces and, in consequence, to the configuration of
the new chiral centers. With the purpose to confirm this
hypothesis in connection with the synthesis of polyfunc-
tionalized amino acids with constrained structures, we
have prepared the dehydro amino acids depicted in
Scheme 1. In 6 and 8 the double bond is directly attached
to a stereogenic center of the cyclobutane ring, whereas
in 7 the double bond is separated from the carbocycle by
a methylene group. Both features coexist in 5. Moreover,
6 and 8 show reverse chirality.
Resu lts a n d Discu ssion
The retrosynthetic pathways connecting the target
dehydro amino acids 5-8 with the cyclobutyl aldehydes
1-4, as the key intermediates, are shown in Scheme 1.
Compounds 5-8 result from Wittig-Horner condensa-
tions of these aldehydes with phosphonates affording the
amino acid function conveniently protected. It is remark-
able that dehydro amino acids 5-8 bear two asymmetric
carbons with determined absolute configuration, provided
by (-)-R-pinene, and two or four prochiral centers at the
olefinic carbons. In turn, dialdehyde 1 and monoalde-
hydes 2 and 3 were obtained by functional-group ma-
nipulation starting from (-)-cis-pinonic acid as a common
precursor. (-)-Verbenone is the precursor to aldehyde 4,
which is homologous with 3. The carbaldehyde group is
directly linked to the cyclobutane in compounds 2 and 4,
whereas in 3 this group is separated from the ring by a
methylene unit.
Dehydro amino acids are, in general, molecules of
interest to be used as precursors to saturated amino acids
through hydrogenation, conjugate addition, or cycload-
(11) For an example of the incorporation of cyclobutane amino acids
in unnatural bioactive peptides, see: Gershonov, E.; Granoth, R.;
Tzehoval, E.; Gaoni, Y.; Fridkin, M. J . Med. Chem. 1996, 39, 483.
(12) (+)-R-Pinene as synthetic precursor to methyl (+)-trans-chry-
santhemate: Mitra, R. B.; Khanra, A. S. Synth. Commun. 1977, 7,
245.
(13) (-)-R-Pinene as a chiral solvent: Groen, M. B.; Schadenberg,
H.; Wynber, H. J . Org. Chem. 1971, 36, 2797.
(14) (a) Moglioni, A. G.; Garc´ıa-Expo´sito, E.; Moltrasio, G.; Ortun˜o,
R. M. Tetrahedron Lett. 1998, 39, 3593. (+)-R-Pinene was used as
starting material in this work. (b) Martı´n-Vila`, M.; Minguillo´n, C.;
Ortun˜o, R. M. Tetrahedron: Asymmetry 1998, 9, 4291.
Both precursors are easily prepared from (-)-R-pinene
as the only primary source of chirality. This compound
affords commercially available (-)-verbenone by allylic
oxidation. On the other hand, we realized that early
classical procedures in the literature for the oxidation of

3936 J . Org. Chem., Vol. 65, No. 13, 2000
Moglioni et al.
pinene15 provided cis-pinonic acid with substantial epimer-
ization of the cyclobutane carbon linked to the ketone
carbonyl. This is, indeed, a secondary process concomi-
tant with the oxidation of the double bond under basic
or acid conditions, leading to a mixture of two diastere-
omers whose separation requires tedious successive
recrystallizations with the consequent yield decrease. The
presence of these isomers was evidenced by the absorp-
tion signals for the CH3 protons of the gem-dimethyl
substitution, which shows two sets of singlets at 0.84/
Sch em e 2a
1
1.31 ppm (major) and 0.99/1.21 ppm (minor) in the H
NMR spectrum of the crude mixture. In contrast, we
found that the use of ruthenium trichloride is more
convenient since it affords the desired product in high
yield without epimerization as confirmed by the presence
1
of only one set of signals both in the H and in the 13C
NMR spectra. This method had been previously used in
the oxidation of verbenone and verbenol,10 but not for
pinene.
1. Syn th eses of Ald eh yd es 1-4. The divergent
synthetic routes toward aldehydes 1-3 from (-)-cis-
pinonic acid are depicted in Scheme 2. Lieben degrada-
tion of the methyl ketone function by using aqueous
sodium hypobromite furnished (-)-cis-pinic acid 9.16
Compound 9 also resulted when benzyl ester 20, obtained
from the reaction between the potassium salt of (-)-cis-
pinonic acid and benzyl chloride, was submitted to Lieben
degradation. This concomitant deprotection of the benzyl
ester under the basic reaction conditions had not been
mentioned by Burgess in his earlier work employing a
similar protocol.10
Reduction of diacid 9 to diol 1 was attempted with
diborane or 9-BBN without satisfactory results. There-
fore, 9 was methylated with diazomethane to afford
diester 10.17 Direct reduction of 10 to dialdehyde 1 by
using DIBAL was not successful either. Finally, 10 was
reduced with LiBH4 to provide the new alcohol 11 which
was oxidized to aldehyde 1. Among the most common
methods, Swern oxidation is very convenient to afford
aldehydes from primary alcohols in high yield without
epimerization. Dialdehyde 1 was obtained following this
procedure, in 70% yield, as an unstable oil which was
used immediately in the Wittig-Horner condensation.
According to another synthetic pathway (Scheme 2),
ester 12 was obtained by methylation of (-)-cis-pinonic
acid with diazomethane. Treatment of 12 with ethylene
glycol and pyridinium p-toluenesulfonate (PPTS) in boil-
ing benzene afforded ketal 13.18 Reduction of 13 with
LiBH4 gave alcohol 14 which was oxidized to aldehyde 3
alternatively by PDC or Swern reagent. Attempted
purification of aldehydes from Swern oxidation by column
chromatography resulted in decomposition of the product.
On the contrary, treatment with PDC followed by re-
moval of chromium salts by stirring the reaction mixture
with Florisil and subsequent filtration afforded pure
dialdehyde 3. Then, this procedure was also used in the
synthesis of aldehydes 2 and 4 (see below).
a
Reagents: (a) aqueous NaOBr; (b) CH2N2; (c) LiBH4; (d) PDC
or (COCl)2, DMSO, Et3N; (e) (CH2OH)2, PPTS; (f) BnBr, NaH,
DMF; (g) acetone, PPTS.
of ketal in 15 followed by Lieben degradation of the
resultant methyl ketone 16 afforded acid 17. Methylation
to ester 18 and conversion into aldehyde 2, through
alcohol 19, allowed us to achieve the synthetic goal.
Scheme 3 shows the synthesis of aldehyde 4 from (-)-
verbenone. Thus, this compound was treated with RuCl3
to produce (-)-cis-pinononic acid 21, which was reacted
with diazomethane to afford methyl ester 22. Ketone was
protected as described above for 12, affording ketal ester
23, which was reduced with LiBH4. Finally, the resultant
alcohol 24 was oxidized by PDC to aldehyde 4.
2. Syn th esis a n d Ster eoch em ica l Assign m en t of
Deh yd r o Am in o Acid s 5-8. The respective Wittig-
Horner condensations of aldehydes 1-4 with phospho-
nates 25a ,b19 (Scheme 3), in the presence of KO-t-Bu,
provided dehydro amino acids 5a ,b-8a ,b in which the
amino function is protected as a Cbz-carbamate or as an
acetamide. It is noteworthy the high stereoselectivity of
the reaction, since (Z)-isomers were exclusively produced.
Alcohol 14 is also precursor of aldehyde 2 after protec-
tion as a benzyl ether to give 15. Subsequent hydrolysis
(15) (a) Delepine, M. Bull. Soc. Chim. Fr. 1936, 5, 1369. (b) Berson,
J . A.; Dervan, P. B.; Malherbe, R.; J enkins, J . A. J . Am. Chem. Soc.
1976, 98, 5937.
(16) Webster, F. X.; Rivas-Enterrios, J .; Silverstein, R. M. J . Org.
Chem. 1987, 52, 689.
(17) Subramanian, L. R.; Rao, G. S. Tetrahedron 1969, 25, 1749.
(18) Sterkycki, R. Synthesis 1979, 724.
(19) (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.

Divergent Routes to Chiral Cyclobutane Synthons
J . Org. Chem., Vol. 65, No. 13, 2000 3937
Sch em e 3a
solutions for 2 days. These results agree with the
determined long-range heteronuclear coupling constant
between the carbonyl carbon and the olefinic proton
(Figure 1): the value 3J [13C]1H ) 4.5 Hz is consistent
with (Z) geometry for dehydro amino acids 5-8.21
Con clu d in g Rem a r k s
(-)-R-Pinene has been shown to be a convenient
starting material for the synthesis of a variety of poly-
functionalized cyclobutane synthons, according to diver-
gent synthetic routes which involve selective manipula-
tions of functional groups. These compounds are very
attractive for use in the synthesis of different cyclobutane
derivatives with, at least, two stereogenic centers of
determined absolute configuration. In this paper, we have
shown the efficiency of aldehydes 1-4 to synthesize
dehydro amino acids in stereoselective manner. It is
noteworthy that the Wittig-Horner condensations of
these aldehydes with phosphonates 25a ,b confirm the
ability of such reagents to afford (Z)-olefins as the
exclusive or predominant stereoisomers. This fact had
been already observed by us for condensations of 25 with
other aldehydes. Finally, we must mention the interest
of the obtained molecules for the synthesis of other types
of cyclobutane-containing compounds. For instance, our
preliminary results on the hydrogenation and on the
cyclopropanation of these dehydro amino acids show a
high diastereoselectivity allowing the production of satu-
rated amino acids which contain one or two additional
stereogenic centers with determined absolute configura-
tion. Further investigation in this field is being currently
carried out in our laboratories.
a
Reagents: (a) RuCl3; (b) CH2N2; (c) (CH2OH)2, PPTS; (d)
LiBH4; (e) PDC; (f) KOt-Bu.
Exp er im en ta l Section
F igu r e 1. Determined 3J [13C]1H and significant %NOE
enhancements used for the stereochemical assignment of 5-8
(see Table 1).
Commercial (1S)-(-)-R-pinene (97% ee/GLC) and (1S)-(-)-
verbenone (99+%) were used as starting materials without
purification. Flash column chromatography was carried out
on silica gel (240-400 mesh) unless otherwise stated. Baker-
silica (40 µm) was used for the chromatography of acid-
sensitive products. 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,
Ta ble 1. Sign ifica n t % NOE En h a n cem en ts for
Com p ou n d s 5-8a
(Z)-5a (Z)-6a (Z)-7a (Z)-7b (E)-7b (Z)-8a (E)-8a
dCH/OCH3 0.24
dCH/NH
0.21
0.25
0.35
0.24
1
with oven temperatures (ot) reported. Standard H NMR and
0.95
1.80
13C NMR spectra were recorded at 250 and 62.5 MHz,
respectively. Long-range heteronuclear coupling constants,
3J [13C]1H, were determined in a 400 MHz spectrometer from
SDEPT-1D spectra.22 NOE data were extracted from DPFGE-
NOE 1D experiments using a mixing time of 800 ms according
to ref 23.
a
See Figure 1.
The same diastereoselectivity had been previously ob-
served in our laboratory for the condensations of other
aldehydes with phosphonates 25.20
(1′R,3′R)-2-(3′-Acet yl-2′,2′-d im et h ylcyclob u t yl)a cet ic
Acid [(-)-cis-P in on ic Acid ]. Catalytic RuCl3 hydrate (120
mg) and NaIO4 (13.4 g, 63 mmol) were added to a stirred
solution of (-)-R-pinene (2.5 mL, 16 mmol) in 2:2:3 carbon
tetrachloride-acetonitrile-water (130 mL). After the mixture
was stirred at room temperature for 24 h, ether (100 mL) was
added and the mixture was stirred for 5 min and extracted
with ether. The combined organic extracts were dried (MgSO4)
and concentrated under reduced pressure. The residue was
diluted with 50 mL of ether, filtered through Celite, and
evaporated to afford quantitatively crude (-)-cis-pinonic acid,
which can be crystallized but used without purification for
The Z geometry of the double bond was determined
by NMR techniques by means of NOE experiments. The
most significant data are collected in Table 1. Thus,
selective irradiation of the olefinic proton (triplet at 6.5
ppm) resulted in enhancement of the absorption due to
the methoxyl protons (Figure 1) but NOE on NH protons
was not observed in any case. In contrast, separate
experiments performed on (E)-7b and (E)-8a showed
NOE on the NH proton when the olefinic one (triplet at
6.2 ppm) was selectively irradiated. Diastereomers (E)-
7b and (E)-8a were obtained by epimerization of (Z)-7b
and (Z)-8a , respectively, on standing as chloroform
(21) This constant is in good agreement with that reported for a
closely related system: Le Corre, M.; Hercouet, A.; Bessieres, B.
Tetrahedron: Asymmetry 1995, 6, 683.
(20) (a) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1996, 7, 537. (b) Mart´ın-Vila`, M.; Hanafi, N.; J ime´nez, J .
M.; Alvarez-Larena, A.; Piniella, J . F.; Branchadell, V.; Oliva, A.;
Ortun˜o, R. M. J . Org. Chem. 1998, 63, 3581.
(22) Parella, T.; Sa´nchez-Ferrando, F.; Virgili, A. Magn. Reson.
Chem. 1994, 32, 343.
(23) Stott, K.; Stonehouse, J .; Keeler, J .; Hwang, T. L.; Shaka, A. J .
J . Am. Chem. Soc. 1995, 117, 4199.

3938 J . Org. Chem., Vol. 65, No. 13, 2000
Moglioni et al.
practical purposes: crystals; mp 65-68 °C (ether) (lit.15a mp
68-70 °C); [R]D -77.8 (c 2.03, MeOH) (lit.24 [R]D -77.1 (c 5.0,
CHCl3)); IR and 1H NMR data were in good accordance with
those in ref 24; previously undescribed 13C NMR (acetone-d6)
17.36, 23.71, 30.09, 30.33, 35.15, 38.68, 43.39, 54.42, 174.38,
207.05.
139.97, 173.35. Anal. calcd for C17H24O3: C, 73.88; H, 8.75.
Found: C, 73.81; H, 8.66.
Meth yl (1S,3R)-3-a cetyl-2,2-d im eth ylcyclobu ta n eca r -
boxyla te (22): yield 0.5 g (98%); oil; [R]D -7.14 (c 0.3, MeOH);
IR (film) 1736, 1708 cm-1; 1H NMR (CDCl3) 0.81 (s, 3H), 1.42
(s, 3H), 1.88 (ddd, J ) 11.3 Hz, J ′ ) 7.7 Hz, J ′′ ) 7.7 Hz, 1H),
2.67 (ddd, J ) 11.3, J ′ ) 10.8 Hz, J ′′ ) 10.3 Hz, 1H), 2.78 (dd,
J ) 10.8 Hz, J ′ ) 7.7 Hz, 1H), 2.88 (dd, J ) 10.3 Hz, J ′ ) 7.7
Hz, 1H); 13C NMR (acetone-d6) 18.27, 19.29, 30.09, 30.21, 44.83,
45.36, 51.27, 53.06, 172.85, 206.08. Anal. calcd for C10H16O3:
C, 65.19; H, 8.75. Found: C, 64.97; H, 9.02.
Gen er a l P r oced u r e for th e Syn th esis of Keta ls 13 a n d
23. A typical experiment is described. A mixture of ketone (7.6
mmol), ethyleneglycol (3 mL, 57.4 mmol), and PPTS (0.3 g,
1.2 mmol) in anhydrous benzene (170 mL) was heated to reflux
for 4 h, using a Dean-Stark trap to remove water from the
reaction mixture. Solvent was evaporated at reduced pressure,
and the residue was poured into ether (240 mL). The resultant
solution was subsequently washed with saturated aqueous
NaHCO3 and brine and dried (MgSO4). Solvent was removed,
and the residue was chromatographed (1:5 ethyl acetate-
hexane) to afford pure ketals 13 and 23.
Met h yl (1′R,3′R)-2-[2′,2′-d im et h yl-3′-(2-m et h yl-1,3-d i-
oxola n -2-yl)cyclobu tyl]a ceta te (13): yield 1.5 g (81%); oil;
ot 130-134 °C (0.05 Torr) (lit.12 peb 100-105 °C (0.3 Torr));
[R]D -6.50 (c 2.1, MeOH). Previously undescribed NMR spectra
follow. 1H NMR (CDCl3) 1.00 (s, 3H), 1.09 (s, 3H), 1.21 (s, 3H),
1.57 (m, 1H), 1.87-1.97 (m, 1H) 2.07-2.36 (complex absorp-
tion, 4H), 3.60 (3H, s), 3.80-3.93 (complex absorption, 2H);
13C NMR (acetone-d6) 17.49, 23.95, 25.53, 31.35, 35.40, 39.42,
41.47, 50.87, 51.09, 64.18, 65.95, 110.17, 173.52.
(1S,3R)-3-Acet yl-2,2-d im et h ylcyclob u t a n eca r b oxylic
a cid [(-)-(cis)-p in on on ic Acid , 21]. This compound was
prepared starting from (-)-verbenone following the procedure
described above. Crude 21 was used without further purifica-
tion in the next step: yield 2.7 g (100%); [R]D -34.1 (c 1.53,
MeOH). Spectroscopic data agree with those in ref 16.
Gen er a l P r oced u r e for Lieben Degr a d a tion . Syn th esis
of Acid s 9 a n d 17. A typical experiment is described. To a
stirred solution of methyl ketone (7.7 mmol) in dioxane (25
mL), cooled at -15 °C was added an aqueous solution of
NaOBr prepared from bromine (1.2 mL, 24 mmol), NaOH (4.1
g, 102 mmol), and water (98 mL), and previously cooled to 0
°C. After being stirred at 0 °C for 2 h and at room temperature
for 6 h, the solution was extracted with dichloromethane.
Aqueous NaHSO3 (40%, 30 mL) and concentrated HCl were
subsequently added to the aqueous phase. The resultant acid
solution was extracted with ether, the extracts were dried
(MgSO4), and solvent was removed to afford the carboxylic acid
pure enough to be used in the next step without further
purification. Acids 9 and 17 were prepared by this protocol.
(1′R,3′R)-2-[3′-Ca r b oxy-2′,2′-d im et h ylcyclob u t yl]a ce-
tic a cid (cis-p in ic a cid , 9): yield 1.0 g (70%); IR (film) 3093,
1
3079 (broad), 1705 cm-1; H NMR (CDCl3) 0.98 (s, 3H), 1.23
(s, 3H), 1.89 (complex absorption, 2H), 2.32 (complex absorp-
tion, 3H), 2.76 (dd, J ) 10.2 Hz, J ′ ) 7.3 Hz, 1H); 13C NMR
(CDCl3) 17.88, 25.30, 30.24, 35.42, 39.03, 42.80, 46.53, 173.82,
173.91.
(1R,3R)-3-(2′-Ben zyloxyeth yl)-2,2-d im eth ylcyclobu ta n -
eca r boxylic a cid (17): yield 0.8 g (41%); 1H NMR (CDCl3)
0.96 (s, 3H), 1.18 (s, 3H), 1.53 (m, 1H), 1.67 (m, 1H) y 1.94
(complex absorption, 3H), 2.70 (dd, J ) 10.2 Hz, J ′ ) 8.0 Hz,
1H), 3.42 (t, J ) 6.6 Hz, 2H), 4.47 (s, 2H), 7.32 (complex
absorption, 5H); 13C NMR (CDCl3) 17.80, 25.39, 30.42, 31.30,
40.21, 42.80, 46.56, 69.39, 73.24, 128.06, 128.24, 129.00,
140.00, 174.05.
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth yl
Ester s 10, 12, 18, a n d 22. A typical experiment was run as
follows. To an ice-cooled solution of carboxylic acid (3 mmol)
in ether (40 mL) was added a freshly distilled ethereal solution
of diazomethane (from N-methyl-N-nitroso-p-toluenesulfona-
mide (3.4 g, 16 mmol) in ether (38 mL) and KOH (0.8 g, 15
mmol) in EtOH (12 mL). The resultant solution was stirred
at room temperature for 1 h, and excess diazomethane was
destroyed by addition of benzoic acid. The reaction mixture
was filtered, solvent was evaporated at reduced pressure, and
the residue was chromatographed through Baker-silica (mix-
tures of EtOAc-pentane) to furnish the corresponding pure
ester 10, 12, 18, or 22. The new compounds 10, 18, and 22
are described below.
Meth yl (1S,3R)-2,2-d im eth yl-3-(2-m eth yl-1,3-d ioxola n -
2-yl)cyclobu ta n eca r boxyla te (23): yield 1.6 g (90%); oil; [R]D
1
+10.42 (c 1.0, MeOH); IR (film) 1739 cm-1; H NMR (CDCl3)
1.03 (s, 3H), 1.21 (s, 3H), 1.24 (s, 3H), 1.84-1.91 (m, 1H), 2.15-
2.31 (m, 2H), 2.57-2.64 (m, 1H), 3.64 (s, 3H), 3.79, 3.96
(complex absorption, 4H); 13C NMR (acetone-d6) 20.47, 22.91,
26.02, 33.59, 45.98, 48.39, 52.05, 53.30, 66.41, 68.13, 112.07,
175.31. Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found:
C, 62.72; H, 8.76.
Gen er a l P r oced u r e for th e Red u ction of Ester s to
Alcoh ols 11, 14, 19, a n d 24. A 2 M solution of LiBH4 in THF
(7 mL, 13 mmol) was added to a solution of ester (5.8 mmol)
in dry THF (20 mL). The mixture was heated to reflux under
nitrogen atmosphere for 6-8 h. Excess hydride was destroyed
by slow addition of methanol, and then water (30 mL) was
added. The resultant solution was extracted with ethyl acetate,
and the combined extracts were dried (MgSO4). Solvents were
removed at reduced pressure, and the residue was chromato-
graphed (ethyl acetate) to provide alcohols 11, 14, 19, and 24.
(1′R,3′R)-2-(3′-Hydr oxym eth yl-2′,2′-dim eth ylcyclobu tyl)-
1-eth a n ol (11): yield 0.8 g (85%); oil; [R]D +26.13 (c 1.1,
MeOH); IR (film) 3333 (broad) cm-1; 1H NMR (CDCl3) 0.94 (s,
3H), 1.09 (s, 3H), 1.10-2.15 (complex absorption, 6H), 3.40-
3.67 (complex absorption, 6H); 13C NMR (CDCl3) 16.53, 26.36,
30.89, 33.47, 38.97, 39.53, 44.56, 61.53, 63.77. Anal. Calcd. for
C9H18O2: C, 68.31; H, 11.47. Found: C, 68.31; H, 11.65.
(1′R,3′R)-2-[2′,2′-Dim eth yl-3′-(2-m eth yl-1,3-d ioxola n -2-
yl)cyclobu tyl]-1-eth a n ol (14): yield 1.1 g (85%); oil, ot 125
°C (0.01 Torr); [R]D -1.9 (c 2.06, MeOH); IR (film) 3431 (broad)
cm-1; 1H NMR (CDCl3) 0.91 (s, 3H), 0.99 (s, 3H), 1.12 (s, 3H),
1.26-1.89 (complex absorption, 5H), 2.00 (dd, J ) 10.9 Hz, J ′
) 7.3 Hz, 1H), 2.45 (broad s), 3.42 (t, J ) 6.9 Hz, 2H), 3.83,
3.72 (complex absorption, 4H); 13C NMR (CDCl3) 16.98, 23.55,
24.63, 31.12, 33.09, 38.99, 40.65, 49.94, 61.06, 63.47, 65.27,
109.82. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found:
C, 67.02; H, 10.15.
Meth yl (1′R,3′R)-2-[2′,2′-d im eth yl-3′-m eth yloxyca r bo-
n ylcyclobu tyl]a ceta te (10): yield 0.6 g (96%); oil; [R]D +16.17
1
(c 2.4, CHCl3); IR (film) 1737 cm-1; H NMR (CDCl3) 0.88 (s,
3H), 1.18 (s, 3H), 2.02 (complex absorption, 2H), 2.30 (complex
absorption, 3H), 2.70 (dd, J ) 10.2 Hz, J ′ ) 8.0 Hz, 1H), 3.61
(s, 3H), 3.62 (s, 3H); 13C NMR (CDCl3) 17.56, 24.44, 29.86,
35.06, 38.21, 42.56, 46.09, 51.15, 51.41, 173.17. Anal. calcd for
C
11H18O4: C, 61.66; H, 8.47. Found: C, 61.61; H, 8.49.
Meth yl (1R,3R)-3-(2′-ben zyloxyeth yl)-2,2-d im eth ylcy-
clobu ta n eca r boxyla te (18): yield 0.8 g (92%); oil; [R]D -2.15
1
(c 0.9, MeOH); IR (film) 1730 cm-1; H NMR (CDCl3) 0.89 (s,
3H), 1.16 (s, 3H), 1.54 (m, 1H), 1.65 (m, 1H), 1.97 (complex
absorption, 3H), 2.70 (dd, J ) 10.2 Hz, J ′ ) 7.3 Hz, 1H), 3.40
(t, J ) 6.6 Hz, 2H), 3.59 (s, 3H), 4.47 (s, 2H), 7.32 (complex
absorption, 5H); 13C NMR (CDCl3) 17.80, 25.30, 29.48, 31.24,
40.24, 43.03, 46.56, 51.06, 69.33, 73.21, 128.03, 128.20, 128.97,
(1R,3R)-3-(2′-Ben zyloxyeth yl)-2,2-d im eth ylcyclobu tyl-
m eth a n ol (19): yield 1.0 g (68%); oil; ot 115-120 °C (0.01-
0.05 Torr); [R]D +17.8 (c 0.4, MeOH); IR (film) 3510-3259
(broad) cm-1; 1H NMR (CDCl3) 0.93 (s, 3H), 1.07 (s, 3H), 1.50
(complex absorption, 2H), 1.66 (complex absorption, 2H), 1.97
(complex absorption, 3H), 3.37 (t, J ) 6.6 Hz, 2H), 3.54
(complex absorption, 2H), 4.46 (s, 2H), 7.31 (complex absorp-
tion, 5H); 13C NMR (CDCl3) 16.54, 26.39, 30.51, 30.95, 39.30,
(24) Ferna´ndez, F.; Lo´pez, C.; Hergueta, A. R. Tetrahedron 1995,
51, 10317.

Divergent Routes to Chiral Cyclobutane Synthons
J . Org. Chem., Vol. 65, No. 13, 2000 3939
39.51, 44.56, 63.86, 68.97, 72.94, 127.49, 127.61, 128.34,
138.61. Anal. Calcd for C16H24O2: C, 77.38; H, 9.74. Found:
C, 77.58; H, 9.71.
identified by their IR and 1H NMR data, as described below,
and used immediately in the respective Wittig-Horner con-
densations without further purification.
(1S,3R)-3-(2-Meth yl-1,3-d ioxola n -2-yl)-2,2-d im eth ylcy-
clobu tylm eth a n ol (24): yield 1.1 g (95%); oil; [R]D -10.87 (c
1.8, MeOH); IR (film) 3436 (broad) cm-1; 1H NMR (CDCl3) 0.99
(s, 3H), 1.06 (s, 3H), 1.08 (s, 3H), 1.3-1.49 (m, 1H), 1.62-1.72
(m, 1H), 1.80-2.03 (m, 2H), 3.17 (broad s), 3.31-3.49 (complex
absorption, 2H), 3.70, 3.80 (complex absorption, 4H); 13C NMR
(acetone-d6) 17.06, 22.19, 23.88, 32.33, 40.82, 44.86, 50.21,
63.16, 64.05, 65.79, 110.23. Anal. Calcd for C11H20O3: C, 65.97;
H, 10.07. Found: C, 65.70; H, 10.19.
(1′R,3′R)-2-(3′-F or m yl-2′,2′-d im eth ylcyclobu tyl)a ceta l-
d eh yd e (1): yield 65 mg (70%) (method A); IR (film) 2726, 1718
1
cm-1; H NMR (CDCl3) 0.97 (s, 3H), 1.31 (s, 3H), 1.90-2.60
(complex absorption, 5H), 2.85 (m, 1H), 9.70 (d, J ) 2.2 Hz,
1H), 9.72 (t, J ) 1.47 Hz, 1H).
(1R,3R)-3-(2′-Ben zyloxyeth yl)-2,2-dim eth ylcyclobu tan o-
ca r ba ld eh yd e (2): yield 270 mg (91%) (method B); IR (film)
1
1714 cm-1; H NMR (CDCl3) 0.99 (s, 3H), 1.23 (s. 3H), 1.31-
2.49 (complex absorption, 5H), 2.73 (dt, J ) 8.78 Hz, J ′ ) 2.2
Hz, 1H), 3.38 (t, J ) 7.3 Hz, 2H), 4.46 (s, 2H), 7.31 (complex
absorption, 5H), 9.66 (d, J ) 2.2).
Syn th esis of (1′R,3′R)-2-[2′,2′-Dim eth yl-3′-(2-m eth yl-1,3-
d ioxola n -2-yl)cyclobu tyl]-1-eth a n ol (15). To a solution of
alcohol 6 (2.0 g, 9.4 mmol) in dry and freshly distilled DMF
(21 mL) was added NaH (1.6 g of 60% oil suspension, 65 mmol),
and the mixture was stirred under nitrogen atmosphere for
1.5 h. Then benzyl bromide (6 mL, 53 mmol) was added
dropwise, and the resultant mixture was stirred at room
temperature for 72 h. After removal of excess benzyl bromide,
the residue was subsequently poured into dichloromethane
(110 mL) and washed with water. The organic solution was
dried (MgSO4), and solvent was evaporated at reduced pres-
sure. The residue was chromatographed eluting successively
with 1:1 dichloromethane-hexane, dichloromethane, and 1.1
ethyl acetate-hexane: yield 2.6 g (90%); oil; ot 145-150 °C
(1′R,3′R)-2-[2′,2′-Dim eth yl-3′-(2-m eth yl-1,3-d ioxola n -2-
yl)cyclobu tyl]a ceta ld eh yd e (3): yield 220 mg (92%) (method
1
A); 240 mg (95%) (method B); IR (film) 2720, 1722 cm-1; H
NMR (CDCl 3) 0.99 (s, 3H), 1.11 (s, 3H), 1.20 (s, 3H), 1.30-
2.59 (complex absorption, 6H), 3.87 (complex absorption, 4H),
9.70 (t, J ) 2.2 Hz, 1H).
(1S,3R)-2,2-Dim eth yl-3-(2-m eth yl-1,3-d ioxola n -2-yl)cy-
clobu ta n oca r ba ld eh yd e (4): yield 175 mg (74%) (method B);
1
IR (film) 2713, 1715 cm-1; H NMR (acetone-d6) 1.11 (s, 3H),
1.16 (s, 3H), 1.32 (s, 3H), 1.71-2.36 (m, 3H), 2.65-2.75 (m,
1H), 3.81 y 3.92 (complex absorption, 4H), 9.70 (d, J ) 1.45
Hz).
Gen er a l P r oced u r e for Wit t ig-H or n er Con d en sa -
tion s: Syn th esis of Deh yd r o Am in o Acid s 5a ,b-8a ,b. A
typical experiment for the condensation of aldehydes 1-4 with
phosphonate 25a , to afford Cbz derivatives, is described. In a
similar manner, condensations with phosphonate 25b led to
acetyl derivatives.
Phosphonate 25a (0.4 g, 1.1 mmol) in dry dichloromethane
(2 mL) was added to a solution of KO-t-Bu (0.1 g, 1.1 mmol)
in dichloromethane (2.5 mL) at -78 °C, under nitrogen
atmosphere. After the mixture was stirred for 30 min at this
temperature, aldehyde (0.6 mmol) in dichloromethane (2 mL)
was slowly added. The mixture was allowed to reach room
temperature, and stirring was continued for 54 h. Then water
(8 mL) was added, layers were separated, and the aqueous
layer was extracted with dichloromethane. The combined
organic phases were dried (MgSO4), solvent was removed at
reduced pressure, and the residue was chromatographed on
Baker-silica using mixtures of ethyl acetate-hexane as eluents
(solvent ratio is given for each compound).
1
(0.01-0.05 Torr); [R]D + 4.1 (c 3.4, MeOH); H NMR (CDCl3)
0.97 (s, 3H), 1.03 (s, 3H), 1.17 (s, 3H), 1.38-1.80 (complex
absorption, 5H) y 1.82-2.13 (m, 1H), 3.34 (t, J ) 6.9 Hz, 2H),
3.76-3.88 (complex absorption, 4H), 4.43 (s, 2H), 7.27 (complex
absorption, 5H); 13C NMR (CDCl3) 17.07, 23.69, 24.80, 30.21,
31.21, 39.42, 40.77, 50.03, 63.62, 65.38, 69.00, 72.85, 109.01,
127.37, 127.52, 128.26, 138.58. Anal. Calcd for C19H28O3: C,-
74.96; H, 9.27. Found: C, 75.20; H, 9.37.
Syn th esis of (1R,3R)-3-(2′-Ben zyloxyeth yl)-2,2-d im eth -
ylcyclobu tyl Meth yl Keton e (16). A mixture of ketal 15 (2.5
g, 8.3 mmol) and PPTS (1.1 g, 4.3 mmol) in acetone (21 mL)
was heated to reflux for 8 h. Then solvent was removed, and
the residue was poured into ether (100 mL). The resultant
solution was washed with saturated aqueous NaHCO3 and
dried (MgSO4). Solvent was evaporated to afford crude ketone
16 pure enough to be used in the next step without further
purification: yield 2.1 g (98%); oil; 95-100 °C (0.01-0.05 Torr);
[R]D -30.6 (c 3.1, MeOH); IR (film) 1715 cm-1; 1H NMR (CDCl3)
0.82 (s, 3H), 1.24 (s, 3H), 1.99 (s, 3H), 1.39-2.19 (complex
absorption, 5H), 2.78 (dd, J ) 9.9 Hz, J ′ ) 7.7 Hz, 1H), 3.36
(t, J ) 6.6 Hz, 2H), 4.45 (s, 2H), 7.29 (complex absorption, 5H);
13C NMR (CDCl3) 17.71, 23.00, 30.06, 30.36, 30.83, 38.91,
43.21, 54.27, 68.53, 72.88, 127.44, 127.56, 128.29, 138.47,
207.93. Anal. Calcd for C17H24O2: C, 78.42; H, 9,21. Found:
C, 77.93; H, 9.31.
Met h yl (1′R,3′S)-2-Ben zyloxyca r b on yla m in o-4-(2′,2′-
d im et h yl-3′(2-b en zyloxyca r b on yla m in o-2-m et h oxyca r -
bon yl-(Z)-eth en yl)cyclobu tyl-(Z)-2-bu ten oa te (5a ). Chro-
matographed with 2:1 ethyl acetate-pentane: yield 135 mg
(40%); oil; [R]D +16.42 (c 0.7, MeOH); IR (film) 3325 (broad),
1712, 1654 cm-1 1H NMR (acetone-d6) 0.95 (s, 3H), 1.04 (s,
;
Gen er a l P r oced u r es for th e Oxid a tion of Alcoh ols 11,
14, 19, a n d 24: Syn t h esis of Ald eh yd es 1, 2, 3, a n d 4.
Meth od A: Sw er n Oxid a tion . A typical experiment was run
as follows. To a solution of oxalyl chloride (0.15 mL, 1.7 mmol)
in dry dichloromethane (3 mL), cooled at -60 °C, was slowly
added dry DMSO (0.2 mL, 2.8 mmol) in dichloromethane (1
mL), keeping the internal temperature below -50 °C. The
resultant mixture was stirred for 2 min, and then a solution
of alcohol (0.6 mmol) in dichloromethane (2 mL) was very
slowly added. The mixture was stirred at -50 °C for 15 min,
and freshly distilled triethylamine (1.8 mL, 3.2 mmol) was
added. The mixture was allowed to reach room temperature,
and water (15 mL) was added. The resultant solution was
extracted with dichloromethane, and the combined organic
phases were washed with water and dried (MgSO4). Solvent
was evaporated to afford the corresponding crude aldehyde.
Meth od B: Oxid a tion w ith P DC. To a solution of aldehyde
(1.2 mmol) in dry dichloromethane (8 mL) was added PDC (0.5
g, 1.3 mmol). After the mixture was stirred at room temper-
ature for 4 h, a small portion of Florisil was added, and stirring
was continued for 30 min. The mixture was filtered through
Celite, and solvent was removed to afford a crude aldehyde.
Aldehydes 1-4 were unstable products unusable for mi-
croanalysis and for specific rotation measures. They were
3H), 1.59 (m, 1H), 2.05-2.40 (complex absorption, 4H), 2.90
(complex absorption, 1H), 3.67 (s, 6H), 5.15 (complex absorp-
tion, 4H), 6.43 (t, J ) 7.3 Hz, 1H), 6.52 (d, J ) 9.5 Hz, 1H),
7.36 (complex absorption, 10H), 7.57 (broad s, 1H), 7.70 (broad
s, 1H); 13C NMR (acetone-d6) 20.26, 31.7, 32.1, 32.9, 43.6, 44.8,
46.3, 54.5, 69.1, 69.3, 130.0, 130.4, 130.9, 131.1, 138.3, 140.2,
141.1, 157.4, 167.8. Anal. Calcd for C31H36N2O8: C, 65.94; H,
6.43; N, 4.96. Found: C, 65.91; H, 6.55; N, 4.95.
Met h yl (1′S,3′R)-2-Ben zyloxyca r bon yla m in o-3-[3′-(2-
ben zyloxy-et h yl)-2′,2′-d im et h ylcyclob u t yl]-(Z)-2-p r op e-
n oa te, 6a . Chromatographed with 1:3 ethyl acetate-hexane:
yield 140 mg (52%); oil; [R]D +9.90 (c 0.9, CHCl3); IR (film)
3395 (broad), 1729, 1644 cm-1; 1H NMR (CDCl3) 0.94 (s, 3H),
1.02 (s, 3H), 1.50 (complex absorption, 2H), 1.69 (m, 1H), 1.98
(m, 1H), 2.10 (m, 1H), 2.80 (complex absorption, 1H), 3.39 (t,
J ) 6.58 Hz, 2H), 3.73 (s, 3H), 4.46 (s, 2H), 5.13 (s, 2H), 5.98
(complex absorption, 1H), 6.60 (d, J ) 8.0 Hz), 7.32 (complex
absorption, 10H); 13C NMR (CDCl3) 17.95, 29.51, 30.34, 30.45,
39.96, 41.40, 43,15, 52.53, 67.32, 68.82, 72.98, 125.10, 127.51,
127.59, 128.18, 128.23, 128.35, 128.51, 136,08, 138,52, 138,-
74, 154.24, 165.11. Anal. Calcd for C27H33NO5: C, 71.82; H,
7.37; N, 3.10. Found: C, 71.79; H, 7.40; N, 3.10.
Met h yl (1′R,3′R)-2-Ben zyloxyca r b on yla m in o-4-[2′,2′-
d im eth yl-3′-(2-m eth yl-1,3-d ioxola n -2-yl)cyclobu tyl]-(Z)-

3940 J . Org. Chem., Vol. 65, No. 13, 2000
Moglioni et al.
2-bu ten oa te (7a ). Chromatographed with 1:1 ethyl acetate-
pentane: yield 155 mg (62%); oil; [R]D -1.82 (c 2.2, CHCl3);
IR (film) 3325 (broad), 1722, 1659 cm-1; 1H NMR (acetone-d6)
1.01 (s, 3H), 1.08 (s, 3H), 1.15 (s, 3H), 1.57 (m, 1H), 1.84
(complex absorption, 2H), 2.18 (complex absorption, 3H), 3.67
(s, 3H), 3.77-3.90 (complex absorption, 4H), 5.11 (s, 2H), 6.44
(t, J ) 7.3 Hz, 1H), 7.36 (complex absorption, 5H), 8.70 (broad
s, 1H); 13C NMR (acetone-d6) 17.35, 23.88, 25.01, 29.92, 31.12,
41.03, 41.51, 50.71, 52.23, 63.63, 65.50, 67.50, 109.9, 125.20,
127.98, 128.01, 128.12, 135.95, 136.8, 153.90, l65.02. Anal.
Calcd for C23H31NO6: C, 66.17; H, 7.48; N, 3.35. Found: C,
66.03; H, 7.52; N, 3.46.
1.09-2.19 (complex absorption, 5H), 1.96 (s, 3H), 2.78 (complex
absorption, 1H), 3.40 (t, J ) 6.6 Hz, 2H), 3.66 (s, 3H), 4.46 (s,
2H), 6.48 (d, J ) 8.8 Hz), 7.22-7.39 (complex absorption, 5H),
8.21 (broad s, 1H); 13C NMR (CDCl3) 16.92, 22.74, 24.39, 25.98,
31.24, 41.06, 41.68, 43,77, 52.06, 69.50, 73.24, 128.06, 128.23,
129.00, 138.32, 139.29, 140.06, 165.73, 169.11. Anal. Calcd for
C21H29NO4: C, 70.17; H, 8.13, N, 3.90. Found: C, 69.93; H,
8.17; N, 3.94.
Meth yl (1′R,3′R)-2-Acetyla m in o-4-[2′,2′-d im eth yl-3′-(2-
m eth yl-1,3-dioxolan -2-yl)cyclobu tyl]-(Z)-2-bu ten oate (7b).
Chromatographed with ethyl acetate: yield 210 mg (54%); oil;
[R]D -6.50 (c 2.0, MeOH); IR (film) 3283 (broad), 1729, 1666
1
cm-1; H NMR (acetone-d6) 1.00 (s, 3H), 1.08 (s, 3H), 1.15 (s,
Met h yl (1′R,3′R)-2-Ben zyloxyca r b on yla m in o-3-(2′,2′-
d im eth yl-3′-(2-m eth yl-1,3-d ioxola n -2-yl)cyclobu tyl)-(Z)-
2-p r op en oa te, 8a . Chromatographed with 1:2 ethyl acetate-
pentane: yield 120 mg (50%); oil; [R]D +17.80 (c 0.2, MeOH);
3H), 1.54 (m, 1H), 1.87 (complex absorption, 2H), 2.00 (s, 3H),
2.10 (complex absorption, 3H), 3.66 (s, 3H), 3.77-3.89 (complex
absorption, 4H), 6.39 (t, J ) 7.3 Hz), 8.36 (broad s, 1H); 13C
NMR (acetone-d6) 17.51, 22.74, 23.98, 25.45, 29.59, 31.71,
41.55, 42.18, 50.71, 52.09, 64.18, 65.94, 110.24, 128.06, 135.85,
l65.64, 168.82. Anal. Calcd for C17H27NO5: C, 62.75; H, 8.36;
N, 4.3. Found: C, 62.73; H, 8.27; N, 3.94.
1
IR (film) 3320 (broad) 1722, 1649 cm-1; H NMR (acetone-d6)
1.03 (s, 3H), 1.10 (s, 3H), 1.16 (s, 3H), 1.76-2.10 (m, 2H), 2.2
(complex absorption, 1H), 2.61-2.80 (m, 1H), 3.67 (s, 3H),
3.70-4.00 (complex absorption, 4H), 5.10 (complex absorption,
2H), 6.54 (d, J ) 9.5 Hz), 7.35 (complex absorption, 5H), 7.53
(broad s, 1H); 13C NMR (acetone-d6) 21.08, 26.10, 27.91, 34.11,
43.32, 46.70, 53.02, 54.43, 66.44, 68.21, 69.18, 112.32, 130.21,
130.87, 131.40, 140.24, 141.43, 157.68, 167.91. Anal. Calcd for
C22H29NO6: C, 65.49; H, 7.24; N, 3.47. Found: C, 64.99; H, 7.15;
N, 3.48.
Meth yl (1′R,3′R)-2-Acetyla m in o-3-(2′,2′-d im eth yl-3′-(2-
m et h yl-1,3-d ioxola n -2-yl)cyclob u t yl)-(Z)-2-p r op en oa t e
(8b). Chromatographed with ethyl acetate: yield 224 mg
(60%); oil; [R]D +38.04 (c 0.2, MeOH); IR (film) 3292 (broad),
1726, 1668 cm-1 1H NMR (acetone-d6) 1.07 (s, 3H), 1.11 (s,
;
3H), 1.16 (s, 3H), 1.76-2.33 (m, 3H), 1.96 (s, 3H), 2.63-2.90
(m, 1H), 3.67 (s, 3H), 3.73-3.97 (m, 4H), 6.49 (d, J ) 8.77 Hz,
1H), 8.22 (broad s, 1H); 13C NMR (CDCl3) 18.50, 23.39, 23.62,
24.50, 31.56, 41.33, 43.74, 49.83, 52.33, 63.92, 65.41, 109.67,
124.88, 139.29, 165.11, 168.52. Anal. Calcd for C16H25O5N: C,
61.72; H, 8.09; N, 4.5. Found: C, 61.24; H, 7.90; N, 4.33.
Meth yl (1′R,3′S)-2-Acetyla m in o-4-(2′,2′-d im eth yl-3′(2-
acetylam in o-2-m eth oxycar bon yl-(Z)-eth en yl))cyclobu tyl-
(Z)-2-bu ten oa te (5b). Chromatographed with ethyl acetate:
yield 155 mg (34%); oil; [R]D +5.80 (c 1.03, CHCl3); IR (film)
1
3275 (broad), 1728, 1665 cm-1; H NMR (acetone-d6) 0.96 (s,
3H), 1.06 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 1.60 (m, 1H), 2.00-
2.35 (m, 4H), 2.80 (m, 1H), 3.66 (s, 6H), 6.37 (t, J ) 7.31 Hz,
1H), 6.46 (d, J ) 8.8 Hz, 1H), 8.23 (broad s, 1H), 8.32 (broad
s, 1H); 13C NMR (CDCl3) 14.1, 17.9, 23.4, 29.3, 30.3, 30.4, 40.8,
41.6, 43.1, 52.3, 52.4, 124.7, 124.9, 136.7, 138.8, 165.1, 168.3,
168.5, 171.1. Anal. Calcd for C19H28N2O6: C, 59.99; H, 7.42; N,
7.36. Found: C, 59.49; H, 7.34; N, 7.01.
Ack n ow led gm en t. A.G.M. thanks the CONICET
(Argentina) for a grant. E.G.-E. thanks the CIRIT
(Generalitat de Catalunya) and G.P.A. thanks the
Ministerio de Educacio´n (Spain) for respective predoc-
toral fellowships. Financial support from DGESIC (Spain)
and from Fundacio´n Antorchas (Argentina) through the
projects PB97-0214 and A-1362211-70, respectively, is
gratefully acknowledged.
Meth yl (1′S,3′R)-2-Acetylam in o-3-[3′-(2-ben zyloxyeth yl)-
2′,2′-d im et h ylcyclob u t yl]-(Z)-2-p r op en oa t e (6b ). Chro-
matographed with 1:1 ethyl acetate-hexane: yield 130 mg
(30%); oil; [R]D -2.40 (c 2.1, MeOH); IR (film) 3353 (broad),
1
1729, 1673 cm-1; H NMR (CDCl3) 0.96 (s, 3H), 1.04 (s, 3H),
J O991773C