Synthesis of optically active constrained 2-substituted norstatines: A straightforward application of Seebach's "SRS" synthetic principle

Article abstract of DOI:10.1021/jo0486793

A straightforward two-step methodology of synthesis of optically active (2R)-substituted norstatines via addition of N-teri-butoxycarbonyl-substituted aldimines to (2S)-chiral enolates of 1,3-dioxolan-4-ones has been developed. In particular, the use of t

Full text of DOI:10.1021/jo0486793

Synthesis of Optically Active Constrained 2-Substituted
Norstatines: A Straightforward Application of Seebach’s “SRS”
Synthetic Principle
Arturo Battaglia,*,† Andrea Guerrini,*,† and Carlo Bertucci‡
Istituto CNR per la Sintesi Organica e Fotoreattivita` “I.S.O.F.”, Area della Ricerca di Bologna,
via P. Gobetti 101, 40129 Bologna, Italy, and Dipartimento di Scienze Farmaceutiche,
Universita` di Bologna, via Belmeloro 6, Bologna, Italy
battaglia@isof.cnr.it; carlo.bertucci@unibo.it
Received July 30, 2004
A straightforward two-step methodology of synthesis of optically active (2R)-substituted norstatines
via addition of N-tert-butoxycarbonyl-substituted aldimines to (2S)-chiral enolates of 1,3-dioxolan-
4-ones has been developed. In particular, the use of the natural (2S)-malic acid is examined for the
synthesis of potential GABAergic spirocyclic γ-lactams.
Introduction
Statine- and norstatine-based compounds7 are also
very active against malaria proteases expressed by the
parasite Plasmodium falcifarum, plasmepsins I-II,8
which are responsible of the hemoglobin degradation
pathway, as well as the human protease cathepsin D.
This protease is overexpressed in several cases of breast
cancer9 and is associated with an increased risk for
Alzheimer’s disease.10
Specific peptide-based inhibitors of peptidases, which
incorporate â-amino acid residues into substrates, have
shown an extraordinary biological stability compared to
the normally incorporated R-amino acids and exhibit
remarkable biological activity.1 In recent years, the
discovery of R,R-disubstituted â-amino acids in natural
bioactive compounds have been attracting biochemical
interest in connection with the design and synthesis of
constrained analogues.2 Moreover, when incorporated
into peptides their conformational restraints induce a
large variety of stable secondary structures.3 In fact, an
important aspect of this family is their ability to fold into
well defined and stable helices, turns, pleated sheets, etc.
Among the â-amino acid family, statine and norstatine,4
and their structurally modified analogues, are probably
the most important members because they are found in
a variety of natural products and pharmaceutical sub-
stances, such as Taxol, and have been widely used in the
design of peptidomimetics as inhibitors of proteases.5 For
instance, a set of isosters containing the statines and
norstatine scaffolds, including bestatine, JE-2147, and
KNI-272, are potent HIV-1-PR inhibitors.6
Minor attention has been paid to the synthesis, con-
formational, and biological activity studies of chiral
R-substituted norstatines. It is worth noting that the
(5) (a) Sakurai, M.; Sugano, M.; Handa, H.; Komai, T.; Yiagi, R.;
Nishigaki, T., Yabe, Y. Chem Pharm. Bull. 1993, 41, 1369-1377. (b)
Mimoto, T.; Imai, J.; Tanaka, S.; Hattori, N.; Takahashi, O.; Kisanuki,
S.; Nagano, Y.; Shintani, M.; Hayashi, H.; Sakikawa, H.; Akaji, K.;
Kiso, Y. Chem Pharm. Bull. 1991, 39, 2465-2467. (c) Tam, T. F.;
Carriere, J.; Macdonald, I. D.; Castelhano, A. L.; Pliura, D. H.;
Dewdney, N. J.; Thomas, E. M.; Bach, C.; Barnett, J.; Chan, H.; Kranz,
A. J. Med. Chem. 1992, 35, 1318-1320. (d) Mimoto, T.; Kato, R.;
Takaku, H.; Nojima, S.; Terashima, K.; Misawa, S.; Fukazawa, T.;
Ueno, T.; Sato, H.; Shintani, M.; Kiso, Y.; Hayashi, H. J. Med. Chem.
1999, 42, 1789-1802. (e) Wlodawer, A.; Erickson, J. W. Annu. Rev.
Biochem. 1993, 62, 543-585. (f) Murcko, M. A.; Govinda Rao, B.;
Gomperts, R. J. Comput. Chem. 1997, 18, 1151-1166. (g) Senese, C.
L.; Hopfinger A. J. ChemInform 2003, 34, Issue 42. (h) Brik, A.; Wong,
C.-H. Org. Biomol. Chem. 2003, 1, 5-14. (i) Yoshimura, K.; Kato, R.;
Yusa, K.; Kavlick, M. F.; Maroun, V.; Nguyen, A.; Mimoto, T.; Ueno,
T.; Shintani, M.; Falloon, J.; Masur, H.; Masur, H.; Erickson, J.;
Mitsuya, H. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8675-8680.
(6) (a) Blundell, T. L.; Cooper, J.; Foundling, S. I.; Jones, D. M.;
Atrash, B.; Szelke, M. Biochemistry 1987, 26, 5585. (b) Abdel-Meguid,
S. S. Med. Res. Rev. 1993, 13, 731. (c) Shewale, J. G.; Takahashi, R.;
Tang, J. In Aspartic Proteinases and Their Inhibitors; Kokstka, V., Ed.;
Walter de Gruyter: Hawthorne, NY,, 1986; pp 101-116. (d) Rich, D.
H. In Proteinase Inhibitors; Barrett, A. J., Salvensen, G., Eds.; Elsevier
Science Publishers B. V.: Amsterdam, 1986; Chapter 5 and references
therein.
† Istituto CNR per la Sintesi Organica e Fotoreattivita` “I.S.O.F.”.
‡ Universita` di Bologna.
(1) (a) Hintermann, T.; Seebach, D. Chimia 1997, 51, 244-247. (b)
Seebach, D.; Abele, S.; Schreiber, J. V.; Martinoni, B.; Nussbaum, A.
K.; Schild, H., Schulz, H., Hennecke, H.; Woessner, R.; Bitsch, F.
Chimia 1998, 52, 734-739. (c) Frackenpohl, J.; Arvidsson, P. I.;
Schreiber, J. V.; Seebach, D. ChemBioChem 2001, 2, 445-455.
(2) (a) Avenoza, A.; Cativiela, C.; Francisco Corzana, F.; Peregrina,
J. M.; Zurbano M. M. Tetrahedron: Asymmetry 2000, 11, 2195-2204.
(b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517-3599. (c) Cativiela, C.; Diaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2000, 11, 645-732.
(7) Nezami, A.; Luque, I.; Rimura, T. Kiso, Y. Freire, E. Biochemistry
2002, 41, 2273-2280
(8) (a). Francis, S. E.; Gluzman, I. Y.; Oksman, A.; Knikerbocker,
A.; Mueller, R.; Bryant, M. L.; Shermana, D. R.; Russel, D. G. Goldberg,
D. E. EMBO J. 1994, 13, 306-307. (b). Wyatt, D. M.; Berry, C. FEBS
Lett. 2002, 513, 159-162
(9) Rochefort, H.; Liauddet,-Coopman, E. Apmis 1999, 107, 86-95.
(10) Papassotiropulous, A.; Bagli, M.; Feder, O.; Jesse, F., Maier,
W.; Rao, M.; Ludwig, M.; Shwab, S. G.; Heun, R. Neurosci. Lett 1999,
262, 171-174.
(3) (a) Seebach, D.; Abele, S.; Sifferlen, T.; Ha¨nggi, Martin. Gruner,
S.; Seiler, P. Helv. Chim. Acta 1998, 81, 2218-2243. (b) Seebach, D.;
Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel,
U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913-941. (c) Seebach, D.;
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10.1021/jo0486793 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/10/2004
J. Org. Chem. 2004, 69, 9055-9062
9055

Battaglia et al.
CHART 1
synthesis of constrained analogues of active compounds
is a common procedure adopted in medicinal chemistry
to restrict the possible low energy conformations.11
Provided that the activity is still retained, this less
flexible analogue can reach the binding site more easily.
Synthetic procedures of the syn-(2R) members of norsta-
tines were especially developed to target constrained
analogues bearing aliphatic substituents at the C-2
position of the isoserine chain of taxanes and endowed
of higher cytotoxic activity of the parent paclitaxel and
docetaxel,12 as well as racemic syn-norstatines bearing
an aromatic substituent at C-2.13 Instead, only one
methodology is reported regarding the synthesis of asym-
metric anti-R-substituted norstatines with moderate
selectivity.14 This protocol finds a serious limit due to a
poor availability of the starting reagents, i.e., the (R)-3-
amino-3-phenylpropanoic acid and the (S)-3-aminobu-
tanoic acid, which were obtained in racemic form and
resolved by enzymatic hydrolysis. These reagents gave
anti-(2S,3S)-epimers of 3-phenyl and 3-methyl deriva-
tives of 3-benzoylamino-2-alkylnorstatines (alkyl ) Me,
Et, n-Pr, allyl, benzyl), respectively. Another limit of this
protocol was the type of substituent at the nitrogen,
which was restricted only to the benzoylamino group.
While â-amino acid oligomers form well-defined stable
secondary structures in solution, such as helices,15 pleated
sheets,16 and turns,17 geminally dialkyl-substituted de-
rivatives do not fit into any of these major structures.18
Thus, the stereochemical effects of the simultaneous
presence of an alkyl and a hydroxyl group on the
quaternary C-2 stereogenic center on secondary struc-
tures is not easily predictable.19 As a consequence,
additional methodologies are required to selectively
target all four epimers of the trisubstituted 2-alkyl-
CHART 2
CHART 3
norstatines. Our interest in the development of novel
procedures for the synthesis of 2-substituted norstatines
was stimulated by our previous studies on the chemistry
of (3R)-3-hydroxy-3-substituted â-lactams20 and (2S,5R,
1′S)-1′-amino-1,3-dioxolanones,21 which were shown to be
chemically interconnected using suitable methodologies
(Chart 1).
To date, C(1′)-amino dioxolanones are only prepared
by conversion of the C(1′)-hydroxy group of dioxolanone
alcohols to the corresponding C(1′)-azido followed by
reduction (Chart 2). A major problem with this protocol
is that the synthesis of dioxolanone alcohols lacked
stereochemical control at both C-(5) and C-(1′).22
In this paper, we will explore a variant of our â-lactam
protocol, which directly targets 1′-aminodioxolanones as
equivalents of conformationally restricted and fully pro-
tected 2-substituted norstatines. In particular, we will
examine the use of (2S)-malic acid as a natural precursor
of either a particular type of 1′-aminodioxolanones bear-
ing an additional workable carboxyethyl appendant or
cyclic conformationally restrained norstatines (Chart 3).
(11) (a) Rizo, J.; Gierasch, L. M. Annu. Rev. Biochem. 1992, 61, 387-
418. (b) Hruby, V. J.; Bonner, G. C. Methods. Mol. Biol. 1994, 35, 201-
240.
(12) (a) Ojima, I.; Slater, J. C.; Kuduk, S. D.; Takeuchi, C. S.; Gimi,
R. I.; Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J. M.; Bernacki, R. J. J.
Med. Chem. 1997, 40, 267. (b) Battaglia, A.; Bernacki, R. J.; Bertucci,
C.; Bombardelli, E.; Cimitan, S.; Ferlini, C.; Fontana, G.; Guerrini,
A.; Riva, A. J. Med. Chem. 2003, 46, 4822-4825. (c) Kant, J.; Schwartz,
W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long, B. H.; Kadow, J. F.;
Langley, D. R.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996, 37, 6495-
6498. (d) Denis, J.-N.; Fkyerat, A.; Gimbert, Y.; Coutterez, C.; Man-
tellier, P.; Jost, S.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1 1995,
1811-1816. (e) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.;
Rinaldi, S. Org. Lett. 2004, 6, 2571-2574.
(13) Clerici, A.; Clerici, L.; Porta, O. Tetrahedron Lett. 1995, 36,
5955-5958
(14) Cardillo; G.; Tolomelli, A.; Tomasini, C. Eur. J. Org. Chem.
1999, 155, 5-161
(15) (a) Seebach, D.; Abele, S.; K. Gademann, K.; Guichard, G.;
Hintermann, T.; Jaun, B.; Matthews, J. L.; J. V. Schreiber, J. V.;
Oberer, L.; U. Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81,
932-982. (b) See ref 3a.
(16) (a) Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew.
Chem., Int. Ed. 1999, 111, 1595-1597. (b) Seebach, D.; Abele, S.;
Gademann, K.; Jaun, B. Angew. Chem., Int. Ed. 1999, 111, 1700-1703.
(c) See refs 1a and 15a.
(17) (a) Seebach, D.; Abele, S.; Seiler, P. Helv. Chim. Acta 1999, 82,
1559-1571. (b) See ref 3a.
Results and Discussion
(18) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 20, 1-15.
(19) By contrast, it is worth noting that the incorporation into
peptides of geminally R,R-disubstituted or R-branched R-amino acids
leads to a restricted conformational flexibility and to stabilization of
defined helix-inducing secondary structures. See, for example: (a)
Karle, I. L.; R. Kaul, R.; Rao, R. B.; S. Raghothama, S.; Balaram, P. J.
Am. Chem. Soc. 1997, 119, 12048-12054. (b) Karle, I. L.; P. Balaram,
P. Biochemistry 1990, 29, 6747-6756. (c) Toniolo, C.; Benedetti, E.
Macromolecules 1991, 24, 400424009. (d) Toniolo, C.; Crisma, M.,
Formaggio, F.; Valle, G.; Gavicchioni, G.; Precigoux, G.; Aubry, A.;
Kamphuis, J. Biopolymers 1993, 33, 1061-1072.
Our protocol follows Seebach’s “self-regeneration of
stereocenters” synthetic principle (SRS),23 and it has been
(20) Battaglia, A.; Barbaro, G.; Guerrini, A.; Bertucci, C. J. Org.
Chem. 1999, 64, 4643-4651. In this paper, we have erroneously
assigned an S descriptor at position 4 to the Z-â-lactam (3R,4R)- 22.
(21) Battaglia, A.; Barbaro, G.; Giorgianni P.; Guerrini, A.; Pepe,
A. Tetrahedron: Asymmetry 2001, 12, 1015-1023.
(22) Battaglia, A.; Barbaro, G.; Giorgianni, P.; Guerrini, A.; Bertucci,
C.; Geremia, S. Chem Eur. J. 2000, 6, 3551-3557.
9056 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of Optically Active Constrained 2-Substituted Norstatines
SCHEME 1
SCHEME 2. Stereochemical Outcome of the
Addition Reactions of the (2S)-Enolate of a
Dioxolanone with an Aldehyde (X ) O) or an
Aldimine (X ) NR3)
applied to addition reactions of (2S)-chiral enolates of 1,3-
dioxolan-4-ones to a number of imines in a versatile and
predictable manner (Scheme 1). Major vantage of this
method is that dioxolanon-4-ones are readily available
from the acetalization of inexpensive natural (S)-R-
hydroxycarboxylic acids, and aldeydes or ketones such
as pivalaldehyde or pinacolone. Usually, these lactones
are obtained as major (2S,5S)-isomers of (2S,5S)/(2R,5S)
diasteromeric mixtures but can be isolated as pure
homochiral material via fractional crystallization at low
temperatures.
When N-trimethlylsilylimines were the partners, the
addition to the enolate, the cyclization, and the removal
of the auxiliary center directly afforded the corresponding
(3R)-3-hydroxy-3-alkyl-â-lactams in good yields, full (3R)-
stereocontrol, and moderate to good selectivity at position
4.
the tert-butyl substituent, this allowing the formation of
consistent amounts of the corresponding products of
condensation. When an imine is the partner of the enolate
in TS IV, the presence of the hydrogen and the bulky R3
substituent at the carbon and nitrogen atoms, both
oriented toward the tert-butyl substituent, inhibit the
formation of products of the corresponding stereoisomers.
As a consequence, random mixtures of three stereoiso-
mers, derived from TS I, TS II, and TS IV, are obtained
with aldehydes. Instead, imines only afford â-lactams
derived from transition states TS I and TS II whose
common feature is the presence of the (3R)-stereogenic
center which bears the HO and the R substituents.
Remarkably, this methodology affords the corresponding
enantiomeric (3S)-â-lactams, provided that (2R)-R-hy-
droxy carboxylic acids, easily available from the corre-
sponding naturally occurring (2S)-R-amino acids, are the
starting reagents. Sequential protection of the 3-hydroxy
group of the (3R)-Z- and (3S)-Z-â-lactams, acylation of
the nitrogen atom and base induced ring opening25
affords the corresponding (2R)-syn- or (2S)-syn-R-hy-
droxy-â-amino acids (norstatines), respectively.
The full (3R)-stereocontrol of these reactions was
rather gratifying since the “SRS” synthetic principle fails
to provides good diastereoselectivity in aldol condensa-
tions of enolates of dioxolanones with aldehydes or
ketones due to a lack of face stereochemical control at
the (2S)-stereocenter of the enolate.22,24 The different
behavior of imines and aldehydes is not unexpected when
comparing the stereochemical outcome of the reaction of
an aldehyde, or an imine, to (2S)-enolate of a dioxolanone
(Scheme 2). Four possible stereoisomers can be in prin-
ciple obtained from a reaction of an aldehyde or an imine
with the (2S)-enolate of a dioxolanone. Two stereoisomers
are formed via transition states TS I and TS II. The other
two stereoisomers are formed via the transition states
TS III and TS IV. Transition states TS I and TS II are
kinetically favored over TS III and TS IV because the
aldehyde, or the imine, approaches the enolate from the
less hindered enantiotopic face which bear the small R1
substituent. No products of addition are formed via
transition state TS III due to the severe interaction
between the R2 substituents of the aldheyde, or the imine,
with the tert-butyl substituent.
In this paper, a variant of this protocol, which uses
N-tert-butoxycarbonyl (N-BOC)-protected aldimines26 bear-
ing a phenyl (4) or a 2-thienyl substituent (5), will be
examined. These partners were selected for their high
electrophilicity, which favors the attack to the sterically
demanding enolates of dioxolanones 1-3. At the same
By contrast, the hydrogen atom of the aldehyde in
transition state TS IV does not interact significantly with
(25) (a) Ojima, I.; Lin, S. J. Org. Chem. 1998, 63, 224-225. (b) Ojima,
I.; Wang H.; Wang, T.; Ng, E. W. Tetrahedron Lett. 1998, 39, 923-
926.
(26) (a) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem.
1994, 59, 1238-1240. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 12964-12965.
(23) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708-2748.
(24) (a) Hale, K. J.; Jiaqiang, C.; Manaviazar, S.; Peak, S. A.
Tetrahedron Lett. 1995, 36, 6965-6968. (b) Ogawa, T.; Niwa, H.;
Yamada, K. Tetrahedron 1993, 49, 1571.
J. Org. Chem, Vol. 69, No. 26, 2004 9057

Battaglia et al.
SCHEME 3
TABLE 1. Yields and Product Distribution of 1′-Aminodioxolanones 6, 7, 10, 11, 14, 15, 18, and 19
products
product yield
(%, % eea)
diastereomeric ratio
(overall yields (%))
entry
reagents
(yield (%), % eea)
1
2
3
4
1 + 4
1 + 5
2 + 5
3 + 5
(2S,5R,1′S)-6 (25, 86)
(2S,5R,1′R)-10 (15, 86)
(2S,5R,1′R)-14 (63, 100)
(2S,5R,1′R)-18 (31, 96)
(2S,5R,1′R)-7 (63, 86)
(2S,5R,1′S)-11 (68, 86)
(2S,5R,1′S)-15 (18, 100)
(2S,5R,1′S)-19 (31, 96)
6/7 ) 0.4/1.0 (88)
10/11 ) 0.2/1.0 (83)
14/15 ) 3.6/1.0 (81)
18/19 ) 1.0/1.0 (62)b
a Determined by enantioselective HPLC analysis. b 82% conversion.
time, the electron-withdrawing acyl substituent is ex-
pected to prevent the cyclization step to â-lactam. Even
so, the sterical requirements of the transition states
derived from N-BOC-imines are similar to those derived
from imines leading to the formation of â-lactams. This
allowed the isolation of C(1′)-N-BOC-amino-1,3-dioxolan-
4-ones 6, 7, 10, 11, 14, 15, 18, and 19 only derived from
TS I and TS II (Scheme 3) in which the absolute
stereochemistry at C(5) is conserved.27
These heterocycles can be considered as suitable
protected norstatines bearing two orthogonal protecting
groups: the BOC substituent at the nitrogen atom which
can be removed under mild acidic conditions and the
acetal protecting group of the carboxy and the adjacent
alcoholic substituents which can be opened under basic
conditions. Finally, the heteroaromatic aldimine 5 was
selected to explore the possibility of insertion of the
thiophene group into the framework of the constrained
norstatine, since it well mimics the phenyl group of
phenyl alanine, an amino acid commonly found in HIV-
protease inhibitors.28 Partners of the imines 4 and 5 were
the dioxolan-4-ones 1-3. The lactone 1 was obtained, and
directly used, as a (2S,5S)/(2R,5S) ) 93:7 mixture by
acetalization of (S)-lactic with pinacolone.29 The acetal-
ization of (S)-mandelic and (S)-malic acids with pival-
aldeide, respectively, gave the lactone 2, as pure homo-
chiral material, and compound 3 which was isolated, and
directly used, as a (2S,5S)/(2R,5S) ) 98:2 mixture.30 The
treatment of dioxolanones 1-3 with lithium (bis)trimeth-
ylsilyl amide gave their nonracemic (2S)-lithium enolates
which were reacted with imines 4 and 5 in the mixed
solvent THF/HMPA ) 85:15 at low temperatures (-80/
-50 °C).
Yields, product distribution, and enantiomeric excesses
(% ee) of the 1′-aminodioxolanones 6, 10, 14, and 18 and
their diastereomers 7, 11, 15, and 19 are reported in
Table 1.
The mixtures of pair of epimers31 (2S,5R,1′S)-6/
(2S,5R,1′R)-7 and (2S,5R,1′R)-10/(2S,5R,1′S)-11 were
separated by chromatography, while compounds (2S,5R,
1′R)-14/(2S,5R,1′S)-15 and (2S,5R,1′R)-18/(2S,5R,1′S)-19
were isolated as mixtures. MeO--induced methanolysis
of the acetal auxiliary of the pair 6/7, 10/11, and 14/15
yielded the methyl isoserinates (2R,3S)-8/(2R,3R)-9,
(2R,3R)-12/(2R,3S)-13, and (2R,3R)-16/(2R,3S)-17. This
allowed the stereochemical assessment of the 1′ -amino-
dioxolanones 6-7 and 10-11 by chemical correlation
methods. In fact, (2S,5R,1′S)-6 was chemical correlated
with the ester (2R,3S)-syn-8, synthesized via an inde-
pendent route.21 Similarly, (2R,3R)-syn-12 was chemi-
cally correlated to the (3R,4R)-Z-â-lactam 2220 (Scheme
4) according to the following procedure. The hydroxy
group and the nitrogen atoms of 22 were sequentially
(27) It is worth noting that the use of N-acylated imines as the
partenters of dioxolanones, prevents the formation of unwanted
byproducts derived from an addition to the enolate of pivalaldehyde
formed during the cyclizzation step to the â-lactam.
(28) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720.
(29) Ortholand, Y. J.; Greiner, A. Bull. Soc. Chim. Fr. 1993, 130,
133-142.
(30) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313-1324.
(31) Even if compounds 6, 10, 14, and 18 possess an identical
stereochemistry, the inversion in the descriptor of the 1′ position of
compound 6 (1′S) with respect to 10, 14, and 18 (1′R) is due to the
priority rule at this stereocenter.
9058 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of Optically Active Constrained 2-Substituted Norstatines
SCHEME 4a
93:7 mixture of the enolate of 1 and the homochiral (2S)-
enolate of 2 was confirmed by enantioselective HPLC
analysis the final diastereomeric pairs of isoserines 8 and
9, 12 and 13, and 16 and 17. In fact, compounds 8, 9, 12,
and 13 were obtained as enantiomeric couples in a 93:7
ratio (86% ee) while 16 and 17 were obtained as pure
homochiral material. This result indicated that the
addition of the imines 4 and 5 to the enolates of 1 and 2
occurred under total facial-diastereocontrol since the
obtained ee correspond to that expected on the basis of
the diastereomeric excesses (de) of 1 and 2.
As opposed to other 1′-aminodioxolanones, the 1:1
product distribution of the (2S)-malic acid derivatives
(2S,5R,1′R)-18 and (2S,5R,1′S)-19 was confirmed by
HPLC analysis. These compounds served for the synthe-
sis of â-amino acids 29 and 30 whose conformational
restriction is due to the presence of the quaternary
stereogenic center in a rigid cyclic spirolactone structure.
In fact, the treatment of 18 and 19 with TFA in
anhydrous conditions favored a sequential deprotection
of the N-BOC group with the formation of γ-aminobutyric
acid derivatives and their spontaneous cyclization to the
corresponding γ-lactams (2-pyrrolidones) (2S,5R,1′S)-29
and (2S,5R,1′R)-30, respectively (Scheme 6).33 Confor-
mationally constrained 2-pyrrolidinones, bearing a qua-
ternary stereogenic center, are found in biologically active
molecules, such as inhibitors of proteases34 and choles-
terol absorption,35 antibiotics,36 and GABAergic ago-
nists.37 In our case, these heterocycles are substituted
in various positions with precise configurations and are
conformationally constrained in a spirocyclic γ-lactam
structure as in the agonist GBP-L.38
a Reagents: (i) TesCl/imidazole; (ii) BOC2O/DMAP; (iii) MeOH,
Et3N, DMAP; (iv) TBAF in THF; (v) MeO-/MeOH.
SCHEME 5a
The structures of 29 and 30 were assessed by ASIS
effect of the aromatic 2-thienyl substituent and qualita-
tive homonuclear NOE experiments. In fact, the acetal
H-2 proton of (2S,5R,1′S)-29 absorbed at 4.0 ppm, upfield
to that of (2S,5R,1′R)-30 (5.3 ppm), since it is strongly
shielded by the 2-thienyl substituent (Figure 1). In line
with these findings, the irradiation of the tert-butyl
substituent of (2S,5R,1′S)-29 at 0.81 ppm caused an
enhancement of one of the two protons, Ha of the CH2
group of the oxazolidone ring which located on the same
face centered at 2.66 ppm (Scheme 6). Consequently, the
irradiation of the geminal Hb proton caused an enhance-
ment of 1′-H at 5.35 ppm (4%).
a Reagents: (i) TFA/HCO3-; (ii) LHMDS/THF/HMPA, 15:1/
-50 °C.
silylated and carbonylated, according to usual protocols,12b
to give the (3R, 4R)-Z-â-lactam 23. Methanolysis of 23,32
followed by desilylation, gave the target (2R,3R)-syn-12,
thus allowing the stereochemical assessment of the 1′-
aminodioxolanone (2S,5R,1′R)-10. An identical chemical
correlation between the (3R,4S)-E-â-lactam 24 and
(2R,3S)-anti-13, via the fully protected â-lactam 25, was
also performed. Finally, N-BOC deprotection of (2S,5R,
1′R)-14 and (2S,5R,1′S)-15 with trifluoro acetic acid
yielded the 1′-aminodioxolanones (2S,5R,1′R)-26 and
(2S,5R,1′S)-27 (Scheme 5). The two epimers were sepa-
rated by chromatography. The major isomer (2S,5R,1′R)-
26 was converted into the corresponding â-lactam (3R,
4R)-28 by LHMDS-induced cyclization. The stereochem-
istry of 28 was assessed by NOE and HSQC difference
spectra. In fact, the relevant connection of the HSQC was
that of the two ortho-ortho′ carbon atoms of the aromatic
ring at 125.6 ppm and the directly linked ortho-ortho′
protons which absorbed in the region between 7.54 and
7.58 ppm. The irradiation of these two aromatic protons
showed a consistent NOE of 3% with CHN proton at 5.06
ppm and vice versa, while the irradiation of OH group
at 3.3 ppm showed an NOE of 2.5% with one of the
hydrogen atoms of the thiophene ring at 7.10 ppm. Full
stereocontrol in the reactions involving the (2S)/(2R) )
(33) For similar deprotection and cyclization reactions, see: Jones,
J. In Amino Acid and Peptide Synthesis; Davies, S. G., Ed.; Oxford
University Press: New York, 1992; p 49.
(34) See, for example: (a) Aube, J. Adv. Amino Acid Mimetics
Peptidomimetics 1997, 1, 193. (b) Scheidt, K. A.; Roush, W. R.;
McKerrow, J. H.; Selzer, P. M.; Hansell, E.; Rosenthal, P. J. Bioorg.
Med. Chem. 1998, 6, 2477-2494. (c) Hulme, C.; Moriarty, K.; Huang,
F.-C.; Mason, J.; McGarry, D.; Labaudiniere, R.; Souness J.; Djuric, S.
Bioorg. Med. Chem. 1998, 6, 399-404.
(35) Dugar, S.; Kirkup, M. P.; Clader, J. W.; Lin, S.-I.; Rizvi, R.;
Snow, M. E.; Davis, H. R.; McCombie, S. W. Bioorg. Med. Chem. 1995,
5, 2947-2952.
(36) Ge´rardin, P.; Ahrach, M.; Schneider, R.; Houillon, F.; Lou-
binoux, B.; Spreng, M.; Colin, J. L. Bioorg. Med. Chem. 1995, 5, 1467-
1470.
(37) (a) Roberts, E.; Chase, T. N.; Tower, D. B. GABA in Nervous
System Function, Raven Press: New York, 1976. (b) Silverman, R. B.;
Nanavati, S. M. J. Med. Chem. 1990, 33, 931. (c) McAlonan, H.;
Stevenson, P. J. Tetrahedron: Asymmetry 1995, 6, 239-244. (d)
Carlier, P. R.; Chow, E. S.-H.; Barlowb R. L.; Bloomquist J. R. Bioorg.
Med. Chem. 2002, 12, 1985-1988.
(32) Ojima, I.; Wang, H.; Wang, T.; Ng, E. W. Tetrahedron Lett.
1998, 40, 923-926.
(38) Moglioni, A. G.; Brousse, B. N.; Alvarez-Larena, A.; Moltrasio
G. Y.; Ortun˜o R. M. Tetrahedron: Asymmetry 2002, 13, 451-454.
J. Org. Chem, Vol. 69, No. 26, 2004 9059

Battaglia et al.
FIGURE 1. ChemBats3D picture of 29 and 30.
SCHEME 6
Removal of the acetal auxiliary of 29 and 30 by MeO--
induced methanolysis yielded the corresponding methyl
isoserinates (2R,3S)-31 and (2R,3R)-32, respectively.
NOE experiments allowed the assessment of their ster-
eochemistry, which were fully consistent with those of
their parent 29 and 30. The irradiation of the HO group
at 3.96 ppm of (2R,3R)-32 showed NOE of 3% with C3-H
and 1% with the Ha proton of the CH2 group of the
oxazolidone ring located on the same face. The irradiation
of this proton showed an NOE of 2% with the C3-H
proton. Consistently, the irradiation of the 2-OH group
of the isomer (2R,3S)-31 (in CD3COCD3) gave an NOE
of 2% with the Ha proton of the CH2 group centered at
2.46 ppm, while the irradiation of the Hb proton at 2.97
ppm gave an NOE of 2% with the C3-H proton at 5.44
ppm. Moreover, ASIS effect of the aromatic 2-thienyl
substituent shifted upfield the 2-OH proton (2.92 ppm)
of (2R,3S)-31, with respect to that of (2R,3R)-32 (3.96
ppm).
reagents are converted into optically active (2S,5S)-
dioxolan-4-ones by acetalization with pivalaldehyde or
pinacolone. In the second step, the corresponding (2S)-
enolates are reacted with N-BOC imines to afford R-hy-
droxy-R-substituted â-amino acids orthogonally protected
at the nitrogen atom and the acetal R-OH group in a form
of N-BOC-1′-aminodioxolanones. In fact, the BOC pro-
tecting group is removed under acidic conditions, such
as TFA or formic acid, while the acetal group of the
dioxolanone ring is removed under base-induced alco-
holysis. A proper choice of substituents in the reagents
allowed a preliminary investigation on the diastereose-
lectivity of these reactions. Products are obtained with
total (2R)-stereocontrol at the 2-position of the amino acid
(5 of the 1′-aminodioxolanone) due to a preferential
approach of the sterically demanding imine to the less
hindered face of the dioxolanone ring. The variable 3R
or 3S selectivity (1′R or 1′S of the 1′-aminodioxolanone)
depends on the steric demand of the substituent at C-5
of dioxolanone and the substituent at the carbon atom
of the imine (Scheme 2). When a small methyl substitu-
ent is present at C-5, a syn relationship between the two
substituents is preferred in the transition state. As a
consequence, the 1′-aminodioxolanone epimers which
afforded the anti-isoserines as the major products were
Conclusions
We have developed an efficient two-step protocol for
synthesis of trisubstituted R-hydroxy-R-substituted-â-
amino acids starting from naturally and economically
available (2S)-hydroxy acids. In the first step, these
9060 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of Optically Active Constrained 2-Substituted Norstatines
(2S,5R,1′R)-7 (0.30 g, 0.79 mmol) gave (2R,3R)-9 (0.177 g, 0.75
obtained (entries 1 and 2 of Table 1). A similar selectivity
was also found in the formation of â-lactams when the
diphenyl imine was the partner of the enolate of 1.20 An
anti approach is favored with the dioxolanones 2 and 3
which bear more sterically hindered C-5 substituents
(C6H5 and CH2COOH, entries 3 and 4).
A quite interesting application of this methodology is
the synthesis of R-hydroxy-â-amino acids from malic acid
whose conformational constrain is due to the presence
of a γ-lactam cyclic structure typical of GABAergic
products which opens new perspectives in the synthesis
of pharmacologically active peptidomimetics. Evaluation
of biological activity data for spirolactones 29 and 30 and
their derivatives 31 and 32 is currently underway.
mmol, 95%): 1H NMR (CDCl3, 400 MHz) δ 7.20-7.35 (m, 5
H), 5.64 (d, 1 H, J ) 9.0 Hz), 4.94 (d, 1 H), 3.62 (s, 3 H, OMe),
3.15-3.25 (b, 1 H), 1.57 (s, 3 H, Me), 1.42 (s, 9 H, 3 Me); 13C
NMR (CDCl3) δ 175.5, 155.8, 138.5, 128.5, 128.2, 127.7, 79.9,
77.7, 59.8, 53.0, 28.6, 23.6; [R]20 -30.0 (c 1.0, CHCl3); IR
D
(Nujol, cm-1) 2109, 1739; MS m/z 235 (M+), 208, 193, 158, 148,
133, 106. Anal. Calcd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53.
Found: C, 61.95; H, 7.60; N, 4.48
Synthesis of â-Lactams (3R,4R)-23 and (3R,4S)-25.
These â-lactams were prepared from (3R,4R)-22 and (3R,4S)-
24, respectively, according to a two-step protocol described in
ref 12b. Compound 23 was prepared in 84% overall yields with
respect to the starting 22 while 25 was prepared in 80% with
respect to 24. (3R,4R)-23: 1H NMR (CDCl3, 400 MHz) δ 7.25-
7.30 (m, 1H), 6.90-7.0 (m, 2H), 4.99 (s, 1 H), 1.64 (s, 3 H),
1.43 (s, 9 H, 3 Me), 0.82 (t, 9 H, 3 Me), 0.50-0.60 (m, 6 H); 13
C
Experimental Section
NMR (CDCl3, 100 MHz) δ 168.0, 148.3, 138.0, 127.1, 126.6,
125.9, 85.5, 83.8, 65.3, 28.1, 27.6, 6.6, 6.0; [R]20D + 54.3 (c 0.9,
CHCl3); IR (Nujol, cm-1) 2960, 1815, 1722; MS m/z 397, 342,
297, 268, 225. Anal. Calcd for C19H31NO4SSi: C, 57.39; H, 7.86;
N, 3.52. Found: C, 57.58; H, 7.80; N, 3.44. (3R,4S)-25: 1H
NMR (CDCl3, 400 MHz) δ 7.28-7.30 (m, 1H, 7.0-7.5 (m, 1H,
6.94-6.98 (m, 1H, 5.03 (s, 1 H), 1.44 (s, 9 H, 3 Me), 1.21 (s, 3
H, Me), 0.98 (t, 9 H, 3 Me), 0.68-0.78 (m, 6 H); 13C NMR
(CDCl3, 100 MHz) δ 168.0, 148.0, 138.3, 127.1, 125.5, 125.0,
87.7, 83.7, 66.3, 27.9, 19.1, 6.7, 5.9; [R]20D - 63.1 (c 0.5, CHCl3);
IR (Nujol, cm-1) 2955, 1811, 1717; MS m/z 397, 342, 297, 268,
225. Anal. Calcd for C19H31NO4SSi: C. 57.39; H, 7.86; N, 3.52.
Found: C. 57.18; H, 7.94; N, 3.60.
General Procedure for Synthesis of 1-Aminodioxol-
anones. A THF solution of dioxolanone (2.0 mL × 0.25 g of
dioxolanone) was added dropwise at -78 °C to a THF solution
(10.0 mL × 0.25 g of dioxolanone) of LHMDS (1.4 equiv, 1.0
M in THF). The solution was left at this temperature for 25
min, and then HMPA (2.5 mL in 2.0 mL of THF × 0.25 g of
dioxolanone) was added. The temperature was lowered at -90
°C, and after 5 min a THF solution (2.0 mL) of freshly prepared
N-BOC-imine (1.5 equiv) was added dropwise. The tempera-
ture was kept at -80 °C for 1 h, then raised to -50 °C over 2
h, and left at this temperature for 1 h. The reaction was
quenched at this temperature with HCl 1.0 N and warmed,
under stirring, at room temperature. The reaction solution was
washed three times with 0.2 N HCl and then with saturated
NH4Cl to completely remove the cosolvent HMPA and ex-
tracted with ethyl acetate. The organic phase was dried and
evaporated in vacuo. The diasteromers were purified or
separated, when possible, by chromatography.
Synthesis of (2S,5R,1′R)- and (2S,5R,1′S)-2-tert-Butyl-
5-(1′-amino-1′-(2-thienyl)methyl-5-phenyl-1,3-dioxolan-4-
ones [(2S,5R,1′R)-26 and (2S,5R,1′S)-27]. To a mixture of
dioxolanones 14/15 ) 3.6:1 (0.120 g, 0.278 mmol) was added
a solution of 0.36 mL of TFA in CH2Cl2 (6.0 mL) for 30 min at
0 °C and 5.0 h at 20 °C. The solvent was evaporated, and the
residue was dissolved in 5.0 mL of MeOH/H2O 1:1, and then
3.0 mL of a 0.5 M aqueous solution of NaHCO3 was added.
The mixture was extracted with EtOAc, dried, and evaporated
under vacuo. The residue was chromatographed (SiO2, EtOAc/
n-hexane, 1:3) to afford (2S,5R,1′R)-26 (0.066 g, 0.198 mmol,
71%) and (2S,5R,1′S)-27 (0.018 g, 0.055 mmol, 20%). (2S,5R,
Synthesis of (2S,5R,1′S)- and (2S,5R,1′R)-2-tert-Butyl-
5-(1′-tert-butoxycarbonylamino-1′-phenylmethyl)-2,5-di-
methyl-1,3-dioxolan-4-ones [(2S,5R,1′S)-6 and (2S,5R,1′R)-
7]. A 0.30 g (1.74 mmol) sample of 1 (93:7 mixture) and imine
4 gave a 1:2.5 mixture of 6/7. Chromatography (SiO2, n-hexane/
Et2O/CH2Cl2, 16:1:2) gave 0.017 g (0.44 mmol, 25%) of
(2S,5R,1′S)-6 and 0.415 g (1.10 mmol, 63%) of (2S,5R,1′R)-7.
(2S,5R,1′S)-6: 1H NMR (CDCl3, 400 MHz) δ 7.25-7.35 (m, 5
H), 5.70-5.84 (d, 1 H), 4.80-4.94 (d, 1 H), 1.54-1.58 (b, 3 H),
1.38 (s, 9 H, 3 Me), 0.95 (s, 9 H, 3 Me), 0.64-0.68 (b, 3 H, Me);
13C NMR (CDCl3) δ 175.0, 155.0, 139.0, 129.0, 128.5, 116.8,
1′R)-26: [R]20 -42.0 (c 1.1, CHCl3); IR (Nujol, cm-1) 3387,
D
3323, 2961,1789, 1602, 1483, 1198; MS m/z 331, 316, 173, 156,
1
112; H NMR (CDCl3, 400 MHz) δ 7.58 (d, 2 H, arom), 7.22-
7.30 (m, 3 H, arom), 7.15 (d, 1 H, arom), 6.78 (m, 1 H), 6.60
(m, 1 H), 5.62 (s, 1 H), 4.73 (s, 1 H), 1.90 (b, 2H), 0.95 (s, 9 H);
13C NMR (CDCl3) δ 173.5, 142.8, 136.8, 128.2, 128.1, 126.3,
125.9, 125.5, 125.3, 111.8, 86.2, 61.3, 35.6, 23.8. Anal. Calcd
for C18H21NO3S: C, 65.23; H, 6.39; N, 4.23. Found: C, 65.01;
82.6, 80.2, 60.5, 39.3, 28.5, 25.5, 24.0, 21.7; [R]20 + 21.0 (c
D
0.7, CHCl3); IR (Nujol, cm-1) 3420,1790, 1715, 1708, 1490,
1367, 1151; MS m/z 378, 347, 321, 291, 229, 206, 173, 150.
Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N, 3.71. Found:
C, 67.03; H, 8.17; N, 3.65. (2S,5R,1′R)-7: 1H NMR (CDCl3, 400
MHz) δ 7.20-7.45 (m, 5 H), 5.40 (d, 1 H, J ) 9.0 Hz), 5.16 (d,
1 H), 1.47 (s, 3 H), 1.30-1.43 (b, 9 H, 3 Me), 1.00 (s, 3 H),
0.90-1.00 (b, 9 H, 3 Me); 13C NMR (CDCl3) δ 173.5, 155.0,
137.6, 128.3, 128.0, 127.9, 115.6, 82.6, 80.0, 59.9, 38.9, 28.3,
H, 6.45; N, 4.16. (2S,5R,1′S)-27: [R]20 +81.9 (c 0.6, CHCl3);
D
IR (Nujol, cm-1) 3385, 3321, 2964,1789, 1607, 1485, 1200; MS
m/z 331, 316, 173, 156,112; 1H NMR (CDCl3, 400 MHz) δ 7.82
(d, 2 H), 7.35-7.45 (m, 3 H), 7.33 (d, 1 H) 7.15 (m, 1 H), 7.00
(m, 1 H), 4.83 (s, 1 H), 4.55 (s, 1 H), 1.58 (b, 2H, NH2), 0.84 (s,
9 H); 13C NMR (CDCl3) δ 172.5, 142.5, 136.3, 128.7, 127.2,
126.3, 125.9, 125.6, 110.9, 86.1, 59.7, 35.5, 23.7. Anal. Calcd
for C18H21NO3S: C. 65.23; H, 6.39; N, 4.23. Found: C. 65.28;
H, 6.48; N, 4.14.
25.3, 25.0, 22.3; [R]20 + 26.0 (c 0.5, CHCl3); IR (Nujol, cm-1
)
D
3423,1794, 1719, 1702, 1493, 1367, 1151; MS m/z 378, 347,
321, 291, 229, 206, 173, 150. Anal. Calcd for C21H31NO5: C,
66.82; H, 8.28; N, 3.71. Found: C, 66.68; H, 8.35; N, 3.74.
General Procedure for the Synthesis of â-Aminoesters.
To a solution of 1′-aminodioxolanones (3.0 mL × 0.100 g) in
dry ethanol were added 1.5 equiv of a freshly prepared solution
of 1. 5 M of MeO- in MeOH. The solution was stirred under
nitrogen at 65 °C and monitored by TLC until disappearance
of the starting material. After cooling, the reaction was
quenched with 0.1 M HCl and extracted with ethyl acetate.
The solution was dried and evaporated under vacuo. The
residue was chromatographed (SiO2, EtOAc/n-hexane, 1:2) to
give the aminoesters.
Synthesis of 3-Hydroxy-3-phenyl-4-(2-thienyl)azetidin-
2-one (3R,4R)-28. The reaction of (2S,5R,1′R)-26 (0.066 g,
0.198 mmol) with 2.5 equiv of LHMDS in a mixed solvent THF/
HMPA (95:5) at -50 °C gave after 1 h the â-lactam (3R, 4R)-
28 (0.042 g, 0.172 mmol, 87%): 1H NMR (CDCl3, 400 MHz) δ
7.54-7.58 (m, 2 H),7.38-7.46 (m, 4 H), 7.09-7.0 (m, 2 H), 6.77
(s, 1 H), 5.06 (s, 1 H), 3.35 (b, 1 H); 13C NMR (CDCl3, 100 MHz)
δ 170.4, 139.3, 137.9, 129.1, 129.0, 128.0, 126.9, 126.8, 125.6,
89.4, 63.4; [R]20 -71 (c 0.3, CHCl3); IR (Nujol, cm-1) 3275,
D
1756; MS m/z 228 (M+ - 17), 202, 112. Anal. Calcd for C13H11-
NO2S: C, 63.65; H, 4.52; N, 5.71. Found: C, 63.45; H, 4.43;
N, 5.80.
(2R,3R)-3-(tert-Butoxycarbonylamino)-2-hydroxy-2-
methyl-3-phenylpropionic Acid Methyl Ester (2R,3R)-9.
J. Org. Chem, Vol. 69, No. 26, 2004 9061

Battaglia et al.
2-tert-Butyl-6-thiophen-2-yl-1,3-dioxa-7-azaspiro[4.4]-
nonane-4,8-diones (2S,5R,1′S)-29 and (2S,5R,1′R)-30. To
the 1:1 mixture of acids (2S,5R,1′S)-18/(2S,5R,1′R)-19 (0160
g, 0.387 mmol) in anhydrous CH2Cl2 (4.0 mL) at 0 °C was
added 0.5 mL of TFA. The reaction mixture was left at this
temperature for 2 h and 15 h at 25 °C. The solution was
concentrated at 20 °C, quenched with 10% NaHCO3, extracted
twice with EtOAc, and dried, and the solvent was evaporated.
Chromatography (SiO2, cyclohexane/acetone 17:3) gave (2S,5R,
1′S)-29 (0.047 g, 0.159 mmol, 41%) and (2S,5R,1′R)-30 (0.049
4.74. Found: C, 56.75; H, 5.88; N, 4.70. (2S,5R,1′R)-30: [R]20
D
-39.0 (c 0.4, CHCl3); IR (Nujol, cm-1) 1794, 1713, 1675, 1230;
MS m/z 295, 153, 110; 1H NMR (CDCl3, 400 MHz) δ 7.32 (d, 1
H), 7.08 (d, 1 H), 7.03 (d, 1 H) 6.90 (s, 1 H), 5.30 (s, 1 H), 5.23
(s, 1 H), 3.05 (d, 1 H, J ) 17.6 Hz), 2.70 (d, 1 H, J ) 17.6 Hz),
0.94 (s, 9 H); 13C NMR (CDCl3) δ 172.8, 170.0, 138.3, 128.1,
126.6, 126.4, 109.1, 85.1, 62.0, 39.3, 35.0, 23.2. Anal. Calcd
for C14H17NO4S: C, 56.93; H, 5.80; N, 4.74. Found: C, 56.80;
H, 5.73; N, 4.81.
g, 0.166 mmol, 43%). (2S,5R,1′S)-29: [R]20 + 91.0 (c 0.5,
D
Supporting Information Available: Experimental de-
tails and spectroscopy data for compounds 10-19, 31, and 32.
This material is available free of charge via the Internet at
http://pubs.acs.org.
CHCl3); IR (Nujol, cm-1) 1792, 1714, 1674, 1231; MS m/z 295,
1
153, 110; H NMR (CDCl3, 400 MHz) δ 7.43 (d, 1 H), 7.13 (d,
1 H), 7.02 (d, 1 H), 6.70 (s, 1 H), 5.35 (s, 1 H), 4.05 (s, 1 H), 3.1
(d, 1 H), 2.65 (d, 1 H), 0.81 (s, 9 H, 3 Me); 13C NMR (CDCl3) δ
173.2, 171.9, 136.2, 128.2, 127.9, 127.2, 110.5, 84.0, 60.8, 41.7,
34.6, 23.2. Anal. Calcd for C14H17NO4S: C, 56.93; H, 5.80; N,
JO0486793
9062 J. Org. Chem., Vol. 69, No. 26, 2004