A General, Catalytic, and Enantioselective Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones

Article abstract of DOI:10.1021/jo9720851

A catalytic asymmetric synthesis of N-phthaloyl (S)-γ-[(S)-1-aminoalkyl]-γ-lactones, widely used intermediates in the preparation of hydroxyethylene dipeptide isosteres, is described. The highly enantiopure epoxy alcohols arising from the Sharpless epoxid

Full text of DOI:10.1021/jo9720851

3560
J . Org. Chem. 1998, 63, 3560-3567
A Gen er a l, Ca ta lytic, a n d En a n tioselective Syn th esis of
(S)-γ-[(S)-1-Am in oa lk yl]-γ-la cton es†
Nu´ria Aguilar, Albert Moyano,* Miquel A. Perica`s,* and Antoni Riera
Unitat de Recerca en S´ıntesi Asime`trica, Departament de Quı´mica Orga`nica, Facultat de Qu´ımica,
Universitat de Barcelona, Martı´ i Franque`s 1-11, 08028 Barcelona, Spain
Received November 13, 1997
A catalytic asymmetric synthesis of N-phthaloyl (S)-γ-[(S)-1-aminoalkyl]-γ-lactones, widely used
intermediates in the preparation of hydroxyethylene dipeptide isosteres, is described. The highly
enantiopure epoxy alcohols arising from the Sharpless epoxidation of (E)-allyl alcohols are first
converted to (S)-N-phthaloyl-[(S)-1-aminoalkyl]oxiranes by means of an efficient four-step sequence
involving the regio- and stereoselective ring opening of the starting epoxide by azide, reduction,
phthaloylation, and intramolecular Mitsunobu cyclization of the intermediate phthalimido diol.
Treatment of the resulting oxirane with lithium (1R)-menthyloxyacetylide in the presence of boron
trifluoride etherate, followed by in situ hydrolysis of the ynol ether, leads to a (4R,5S)-5-phthalimido-
4-hydroxy ester. A Mitsunobu reaction with p-nitrobenzoic acid (which establishes the correct (S)-
configuration at C-4) and subsequent selective saponification of the benzoate and cyclization of the
inverted hydroxy ester afford the target N-protected (S)-γ-[(S)-1-aminoalkyl]-γ-lactones. Using this
methodology, lactones 19 and 26 were obtained in seven steps from the readily available epoxy
alcohols 5 and 20, respectively, in high enantiomeric purity.
In tr od u ction
2,5-Disubstituted (2R,4S,5S)-5-amino-4-hydroxypen-
tanoic acids (1) provide the structural motif of the
hydroxyethylene dipeptide isostere unit and are therefore
present in some of the most efficient and selective
inhibitors of the key aspartic proteases, renin1 and the
virally encoded HIV-1 protease (see Figure 1).2
Due to the pharmacological significance, of δ-amino-
γ-hydroxy acids 1, several synthetic strategies directed
toward the stereocontrolled preparation of these com-
pounds have been explored in the past few years.3-6 An
important number of these routes rely on the alkylation
of N-protected (S)-γ-[(S)-1-aminoalkyl]-γ-lactones 2, which
takes place almost exclusively from the C2-re face of the
corresponding enolate (Scheme 1). The requisite γ-lac-
tones are, in turn, usually obtained from N-protected
R-amino aldehydes or other R-amino acid derivatives by
means of more or less stereospecific reaction sequences
which depend on the chirality of the starting amino acid
to direct the formation of the stereogenic center of the
lactone ring.3 A catalytic asymmetric synthesis of lac-
tones 2 from readily available achiral starting materials
that could provide access to both enantiomers and that
F igu r e 1. Representative examples of aspartic protease
inhibitors.
Sch em e 1
† We dedicate this paper to our colleague Francesc Trull, in
memoriam.
(1) (a) Selzke, M.; J ones, D. M.; Hallett, A. Eur. Pat. 45,665, 1982;
Chem. Abstr. 1982, 97, 39405. (b) Selzke, M. In Aspartic Proteinases
and Their Inhibitors; Kostka, V., Ed.; De Gruyter: Berlin, 1985; pp
421-441.
(2) (a) Meek, T. D.; Lambert, D. M.; Dreyer, G. B.; Carr, T. J .;
Tomaszek, J r., T. A.; Moore, M. L.; Strickler, J . E.; Debouck, C.;
Hyland, L. J .; Matthews, T. J .; Metcalf, B. W.; Petteway, S. R. Nature
1990, 343, 90-92. (b) McQuade, T. J .; Tomasselli, A. G.; Liu, L.;
Karacostas, V.; Moss, B.; Sawyer, T. K.; Heinrikson, R. L.; Tarpley,
W. G. Science 1990, 247, 454-456. (c) Lyle, T. A.; Wiscount, C. M.;
Guare, J . P.; Thompson, W. J .; Anderson, P. S.; Darke, P. L.; Zugay,
J . A.; Emini, E. A.; Schleif, W. A.; Quintero, J . C.; Dixon, R. A.; Sigal,
I. S.; Huff, J . R. J . Med. Chem. 1991, 34, 1228-1230. (d) Vacca, J .;
Dorsey, B.; Levin, R.; McDaniel, S.; Darke, P.; Zugay, J .; Schleif, W.
A.; Quintero, J .; Sardana, V.; Lin, J .; Chen, I.-W.; Ostovic, D.; Anderson,
P. S.; Emini, E. A.; Huff, J . R. Proc. Natl. Acad. Sci. 1994, 91, 4096-
4100. (e) De Clercq, E. J . Med. Chem. 1995, 38, 2491-2512.
could accommodate a large variety of R1 substituents
would obviously be of interest but is conspicuously absent
from the literature. We report in this paper the full
S0022-3263(97)02085-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/02/1998

Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones
J . Org. Chem., Vol. 63, No. 11, 1998 3561
Sch em e 2
details of a novel synthetic procedure which fulfills these
requirements and which allows the efficient and enan-
tioselective preparation of lactones 2 from (E)-allyl alco-
hols through the use of the catalytic Sharpless epoxida-
tion7 as the only external source of chirality.
Resu lts a n d Discu ssion
In an ongoing line of research of our laboratory, we
have been exploring the synthetic utility of anti N-
protected 3-amino-1,2-alkanediols of general structure 3,
which can be obtained in high enantiomeric purity by
asymmetric epoxidation of (E)-allyl alcohols, followed by
the regio- and stereoselective ring opening (by primary
amines or by other nitrogen nucleophiles) of the resulting
epoxy alcohols.8 In particular, aminodiols 3 with NPP′
) NHBoc have been efficiently transformed into R-amino
acids,9 â-amino acids,10a,d â-amino-R-hydroxy acids,10b-d
and γ-amino-â-hydroxy acids.11 A simple retrosynthetic
analysis of lactones 2 shows that these compounds can
also be derived from aminodiols 3 by activation of the
primary hydroxyl, substitution by an acetate enolate
synthon, and inversion of configuration at C-2 (Scheme
2).
Sch em e 3
Attempting to implement this synthetic strategy for
the first time and taking into account that anti amino-
diols 3 can be converted into the corresponding syn (1-
aminoalkyl)epoxides 4,12 we explored the feasibility of
effecting the regioselective opening of the oxirane ring
in 4 with a 1-alkoxyacetylide, followed by in situ acid-
promoted cyclization of the resulting â-hydroxyalkyne to
the γ-lactone (Scheme 3). It is worth noting that epoxides
4 do not react directly with simple acetate enolates,3a so
that the use of an 1-alkoxyacetylene as an acetic acid
enolate synthetic equivalent appeared to be an attractive
way to overcome this difficulty.
ethyl]oxirane (4, R1 ) CH2Ph), chosen as a model, by
means of the methodology previously developed in our
laboratory.12 Nevertheless, the reaction of this epoxide
with the lithium derivatives of several 1-alkoxyethynes
(n-decyloxyethyne, t-butoxyethyne, and (1R)-menthyloxy-
ethyne) under the conditions reported by Schreiber for a
related transformation (2.5 molar equiv of the acetylide,
2.5 molar equiv of boron trifluoride etherate, THF, -78
To investigate the feasibility of this approach, we
prepared (R)-2-[(S)-1-(t-butoxycarbonylamino)-2-phenyl-
(3) Through the intermediacy of (S)-γ-[(S)-1-aminoalkyl]-γ-lactones:
(a) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J . P.;
Hirshfield, J .; Weber, D. F. J . Org. Chem. 1985, 50, 4615-4625. (b)
Kempf, D. J . J . Org. Chem. 1986, 51, 3921-3926. (c) Fray, A. H.; Kaye,
R. L.; Kleinman, E. F. J . Org. Chem. 1986, 51, 4828-4833. (d) Wuts,
P. G. M.; Putt, S. R.; Ritter, A. R. J . Org. Chem. 1988, 53, 4503-4508.
(e) Vara Prasad, J . V. N.; Rich, D. H. Tetrahedron Lett. 1990, 31, 1803-
1806. (f) Kano, S.; Yokomatsu, T.; Shibuya, S. Tetrahedron Lett. 1991,
32, 233-236. (g) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.;
Shinkai, I. Tetrahedron Lett. 1991, 32, 1867-1870. (h) Radunz, H.-E.;
Eiermann, V.; Schneider, G.; Riethmu¨ller, A. Tetrahedron 1991, 47,
1887-1894. (i) Thompson, W. J .; Fitzgerald, P. M. D.; Holloway, M.
K.; Emini, E. A.; Darke, P. L.; McKeever, B. M.; Schlief, W. A.;
Quintero, J . C.; Zugay, J . A.; Tucker, T. J .; Schwering, J . E.; Homnick,
C. F.; Nunberg, J .; Springer, J . P.; Huff, J . R. J . Med. Chem. 1992, 35,
1685-1701. (j) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1992, 33,
7259-7262. (k) Sakurai, M.; Saito, F.; Ohata, Y.; Yabe, Y.; Nishi, T.
J . Chem. Soc., Chem. Commun. 1992, 1562-1563. (l) Dreyer, G. B.;
Lambert, D. M.; Meek, T. D.; Carr, T. J .; Tomaszek, T. A., J r.;
Fernandez, A. V.; Bartus, H.; Cacciavillani, E.; Hassell, A. M.; Minnich,
M.; Petteway, S. R., J r.; Metcalf, B. W. Biochemistry 1992, 31, 6646-
6659. (m) Sakurai, M.; Hata, T.; Yabe, Y. Tetrahedron Lett. 1993, 34,
5939-5942. (n) Diederich, A. M.; Ryckman, D. M. Tetrahedron Lett.
1993, 34, 6169-6172. (o) Hormuth, S.; Reissig, H.-U.; Dorsch, D.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1449-1450. (p) Liotta, D. C.;
Lagu, B. K. Tetrahedron Lett. 1994, 35, 547-550. (q) Peyrat, J .-F.;
Chaboche, C.; Figade`re, B.; Cave´, A. Tetrahedron Lett. 1995, 36, 2757-
2760. (r) Dondoni, A.; Perrone, D.; Semola, M. T. J . Org. Chem. 1995,
60, 7927-7933. (s) Hanessian, S.; Park, H.; Yang, R.-Y. Synlett 1997,
351-352. (t) Dragovich, P. S.; Prins, T. J .; Zhou, R. J . Org. Chem. 1997,
62, 7872-7876.
(5) Miscellaneous: (a) Holladay, N. W.; Rich, D. H. Tetrahedron Lett.
1983, 24, 4401-4404. (b) Chakravarty, P. K.; de Laszlo, S. E.; Sarnella,
C. S.; Springer, J . P.; Schuda, P. F. Tetrahedron Lett. 1989, 30, 415-
418. (c) Bradbury, R. H.; Revill, J . M.; Rivett, J . E.; Waterson, D.
Tetrahedron Lett. 1989, 30, 3845-3848. (d) Herold, P.; Duthaler, R.;
Rihs, G.; Angst, C. J . Org. Chem. 1989, 54, 1178-1185. (e) Plata, D.
J .; Leanna, M. R.; Morton, H. E. Tetrahedron Lett. 1991, 32, 3623-
3626. (f) Boyd, S. A.; Mantei, R. A.; Hsiao, C.-N.; Baker, W. R. J . Org.
Chem. 1991, 56, 438-442. (g) Poss, M. A.; Reid, J . A. Tetrahedron Lett.
1992, 33, 1411-1414. (h) D’Aniello, F.; Taddei, M. J . Org. Chem. 1992,
57, 5247-5250. (i) D’Aniello, F.; Ge´hanne, S.; Taddei, M. Tetrahedron
Lett. 1992, 33, 5621-5624. (j) Askin, D.; Wallace, M. A.; Vacca, J . P.;
Reamer, R. A.; Volante, R. P.; Shinkai, I. J . Org. Chem. 1992, 57, 2771-
2773. (k) Armstrong, J . D., III.; Hartner, F. W., J r.; DeCamp, A. E.;
Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33, 6599-6002. (l)
Wuts, P. G. M.; Ritter, A. R.; Pruitt, L. E. J . Org. Chem. 1992, 57,
6696-6700. (m) J ones, D. M.; Nilsson, B.; Szelke, M. J . Org. Chem.
1993, 58, 2286-2290. (n) D’Aniello, F.; Mann, A.; Mattii, D.; Taddei,
M. J . Org. Chem. 1994, 59, 3762-3768. (o) Ciapetti, P.; Taddei, M.;
Ulivi, P. Tetrahedron Lett. 1994, 35, 3183-3186. (p) Pe´gorier, L.;
Larcheveˆque, M. Tetrahedron Lett. 1995, 36, 2753-2756. (q) McWil-
liams, J . C.; Armstrong, J . D., III.; Zheng, N.; Bhupathy, M.; Volante,
R. P.; Reider, P. J . J . Am. Chem. Soc. 1996, 118, 11970-11971. (r)
Captain, L. F.; Xia, X.; Liotta, D. C. Tetrahedron Lett. 1996, 37, 4293-
4296. (s) Tao, J .; Hoffman, R. V. J . Org. Chem. 1997, 62, 6240-6244.
(6) For a review, see: Henning, R. In Organic Synthesis Highlights
II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 251-259.
(7) (a) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780. (b)
J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 101-158. (c)
Katsuki, T.; Mart´ın, V. S. Org. React. 1996, 48, 1-299.
(8) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.;
Riera, A. Tetrahedron Lett. 1991, 32, 6931-6934.
(4) Carbohydrates as chiral starting materials: (a) Shiozaki, M.;
Hata, T.; Furukawa, Y. Tetrahedron Lett. 1989, 30, 3669-3670. (b)
Chakraborty, T. K.; Gangakhedkar, K. K. Tetrahedron Lett. 1991, 32,
1897-1898. (c) Ghosh, A. K.; McKee, S. P.; Thompson, W. J . J . Org.
Chem. 1991, 56, 6500-6503. (d) Kotsuki, H.; Miyazaki, A.; Ochi, M.
Tetrahedron Lett. 1991, 32, 4503-4504.

3562 J . Org. Chem., Vol. 63, No. 11, 1998
Aguilar et al.
Sch em e 4
Sch em e 5
To increase its optical purity, this compound was recrys-
tallized from ethyl acetate. In this way, enantiomerically
pure 7 could be readily secured from epoxy alcohol 5 in
a 63% global yield. Finally, 7 was converted into the
desired phthalimido diol 8 by means of the PyBOP
mediated procedure recently developed in our laborato-
ries.18 According to the 19F NMR spectrum of the Mosher
diester,19 the enantiomeric purity of the so-prepared 8 is
higher than 98.5%.
°C)13 did not lead to the desired lactone, complex mixtures
of products being obtained in all instances.14 Given that
the origin of these problems could be traced both to the
instability of the t-butoxycarbonylamino function in the
presence of boron trifluoride and to the acidic nature of
the carbamate NH, a change in the nature of the nitrogen
protecting group was next investigated. We reasoned
that the phthaloyl function should be more suitable for
our purposes due to its greater resistance to acidic media
(relative to that of the benzyloxycarbonyl or t-butoxycar-
bonyl groups)15.
We set out, therefore, to prepare the previously un-
known (2S,3S)-4-phenyl-3-phthalimido-1,2-butanediol 8
in order to assay its conversion into the corresponding
syn-epoxide. The preparation of the phthalimido diol 8,
which took place according to our expectations, is sum-
marized in Scheme 4.
(2R,3R)-2,3-Epoxy-4-phenylbutan-1-ol 5 (obtained in
94% ee by catalytic Sharpless epoxidation of (E)-4-phenyl-
2-buten-1-ol with D-(-)-DIPT)16 was first treated with
titanium (diazido)diisopropoxide in refluxing benzene,17
affording the expected (2S,3S)-4-phenyl-3-azidobutan-1,2-
diol (6) in essentially quantitative yield. Without further
purification, 6 was submitted to catalytic hydrogenation
to provide the corresponding amino diol 7 in 90% yield.
With 8 in our hands, all that remained for the
synthesis of the syn-epoxide 12 was the silylation of the
primary hydroxyl, the mesylation of the secondary one,
and the fluoride-induced desilylation-cyclization of the
resulting silyloxy mesylate, as we had previously estab-
lished for the preparation of the N-Boc analogue 4 (R1 )
CH2Ph). Although the first two steps of the sequence
took place uneventfully (Scheme 5), all our attempts to
obtain 12 from the mesylate 10 were unsuccessful. In
effect, while the treatment of 10 with anhydrous tet-
rabutylammonium fluoride (TBAF) in THF allowed the
isolation of the unstable hydroxy mesylate 11 in moderate
yields, the subsequent assays of base-induced cyclization
of 11 (obtained either in situ or after isolation) under a
variety of conditions (KOtBu, NaOMe, or nBuLi in THF,
KOtBu/DMF) led either to the recovery of the starting
material or to the production of complex mixtures of
products in which the desired epoxide 12 could not be
identified. Eventually, the activation of the hydroxyl
group of 9 as a triflate (triflic anhydride, EtiPr2N, CH2-
Cl2) and the subsequent reaction with TBAF/NaOMe
produced the epoxide 12 in low yields together with
substantial amounts of the starting phthalimido diol 8.20
It is worth noting here that although 12 could also in
principle be obtained from a syn-N-phthaloyl-3-amino-
1,2-diol (ultimately arising from a cis-epoxy alcohol
through nucleophilic ring opening), this approach is very
likely to meet with serious practical difficulties. In effect,
it is well-known that, in general, the Sharpless epoxida-
tion of (Z)-allyl alcohols takes place with rates and
enantioselectivities lower than that of the corresponding
(E)-allyl alcohols;7c moreover, the nucleophilic ring open-
ing of cis-epoxy alcohols proceeds with low yields and/or
regioselectivities.9d,10c
(9) (a) Poch, M.; Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781-7784. (b) Castejo´n, P.; Moyano, A.;
Perica`s, M. A.; Riera, A. Synth. Commun. 1994, 24, 1231-1238. (c)
Medina, E.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron: Asymmetry 1997, 8, 1581-1586. (d) Pasto´, M.; Moyano,
A.; Perica`s, M. A.; Riera, A. J . Org. Chem. 1997, 62, 8425-8431.
(10) (a) Alco´n, M.; Canas, M.; Poch, M.; Moyano, A.; Perica`s, M. A.;
Riera, A. Tetrahedron Lett. 1994, 35, 1589-1592. (b) Pasto´, M.;
Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1995,
6, 2329-2342. (c) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron: Asymmetry 1996, 7, 243-262. (d) Perica`s, M. A.; Riera,
A.; Moyano, A. In Enantioselective Synthesis of â-Amino Acids; J uaristi,
E., Ed.; Wiley-VCH: New York, 1997; pp. 373-389.
(11) (a) Castejo´n, P.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahe-
dron 1996, 52, 7063-7086. (b) Castejo´n, P.; Moyano, A.; Perica`s, M.
A.; Riera, A. Chem. Eur. J . 1996, 2, 1001-1006.
(12) Castejo´n, P.; Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1995, 36, 3019-3022.
(13) (a) Schreiber, S. L.; Sammakia, T.; Uehling, D. E. J . Org. Chem.
1989, 54, 15-16. (b) Nakatsuka, M.; Ragan, J . A.; Sammakia, T.;
Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J . Am. Chem. Soc. 1990,
112, 5583-5601.
In view of the difficulties encountered in the prepara-
tion of the syn-(1-phthalimidoalkyl)epoxides, we decided
to invert the order of synthetic operations in Scheme 2
(14) Extensive product decomposition and complex reaction mixtures
were also observed in the reaction of (R)-2-[(S)-1-(t-butoxycarbonyl-
amino)ethyl]oxirane12 with several lithium alkoxyacetylides.
(15) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991; p 246.
(16) (a) Lentz, N. L.; Peet, N. P. Tetrahedron Lett. 1990, 31, 811-
814. (b) Bennett, F.; Girijavallabhan, V. M.; Patel, N. J . Chem. Soc.,
Chem. Commun. 1993, 737-738.
(18) Aguilar, N.; Moyano, A.; Perica`s, M. A.; Riera, A. Synthesis
1998, 313-316.
(19) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(17) (a) Caron, M.; Carlier, P. R.; Sharpless, K. B. J . Org. Chem.
1988, 53, 5185-5187. (b) Choukroun, R.; Gervais, D. J . Chem. Soc.,
Dalton Trans. 1980, 1800-1802.
(20) Similar negative results were obtained in the attempted conver-
sion of (2S,3S)-N-phthaloyl-3-aminobutan-1,2-diol18 into the corre-
sponding (R)-2-[(S)-1-phthalimidoethyl]oxirane.

Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones
J . Org. Chem., Vol. 63, No. 11, 1998 3563
Sch em e 6
Sch em e 7
and postpone the configuration inversion at C-2 to a more
advanced stage after the two-carbon extension of the
starting amino diol. According to this new strategy, the
starting anti-3-phthalimido-1,2-alkanediol 3 would be
first converted to an anti epoxide (13), which by opening
with alkoxyacetylide (as a synthetic equivalent of an
acetic ester enolate) and by careful hydrolysis should
furnish an intermediate hydroxyester 14. Due both to
its ready availability21 and to the possibility of controlled
hydrolysis, (1R)-menthyloxyethyne was selected as the
alkoxyacetylene of choice for this application. Inversion
of configuration of the secondary alcohol of 14 followed
by cyclization would then provide the phthaloyl-protected
lactone 2 (Scheme 6).
The implementation of this approach in the case of the
phthalimido diol 8 is outlined in Scheme 7. In the first
place, the intramolecular Mitsunobu reaction12,22 of 8
(1.07 equiv of DEAD, 1.07 equiv of Ph3P in refluxing
dichloroethane) cleanly accomplished the desired conver-
sion into oxirane 15 with complete retention of configu-
ration at C-2, as demonstrated by the fact that the global
chemical purity of 15, measured by DSC techniques,23
was higher than 98.9%, in accordance with the enantio-
meric purity of 8. Exposure of a THF solution of 15 to
lithium (1R)-menthyloxyacetylide21 in the presence of
boron trifluoride etherate at low temperature followed
by carefully controlled hydrolysis of the ynol ether (8
equiv of water and slow warming to rt) gave, after
chromatographic purification, the stereoisomerically pure
(4R)-hydroxyester 16 in good yield (66%).24 The requisite
inversion of configuration at C-4 could then be easily
performed by Mitsunobu methodology, with p-nitroben-
zoic acid as the nucleophile,10c,25 and the (4S)-diester 18
was obtained in high yield. The selective hydrolysis of
the p-nitrobenzoate moiety in 18 was best accomplished
with 2 equiv of NaOMe in MeOH at rt. The intermediate
(4S)-hydroxy ester, which was not isolated, was directly
submitted to acid-promoted cyclization to afford the
N-phthaloyl lactone 19, a new potential precursor of
selective HIV-1 protease inhibitors such as L-685,4342c
and SB203386.26
An additional assessment of the versatility of our
approach was provided by the stereoselective synthesis
of the N-phthaloyl-(S)-γ-[(S)-1-amino-3-methylbutyl]-γ-
lactone 26, a valuable potential intermediate in the
synthesis of the aspartic protease inhibitor H-26127
(Scheme 8). The key phthalimidodiol intermediate 21
was obtained in 46% overall yield from the known28 epoxy
alcohol 20 (89% ee) by means of the azide opening-
hydrogenation-phthaloylation sequence that we have
just described and converted to the oxirane 22 in 69%
yield. As in the previous case, the boron trifluoride-
mediated reaction of 22 with lithium (1R)-menthyloxy-
acetylide, followed by hydrolysis, gave access to the
hydroxy ester 23 (61% yield), as well as to minor amounts
of the (5R)-lactone 24.29 The inverted p-nitrobenzoate
25, arising from 23 by Mitsunobu reaction, could be
selectively saponified by exposure to NaOMe/MeOH, and
the resulting hydroxy ester led to the target lactone 26
by being heated in a weakly acidic toluene solution. The
ee of 26, measured by HPLC, was not less than 97.6%,
(21) Moyano, A.; Charbonnier; F.; Greene, A. E. J . Org. Chem. 1987,
52, 2919-2922.
(26) Abdel-Meguid, S. S.; Metcalf, B. W.; Carr, T. J .; Demarsh, P.;
Desjarlays, R. L.; Fisher, S.; Green, D. W.; Ivanoff, L.; Lambert, D.
M.; Murthy, K. H. M.; Petteway, S. R.; Pitts, W. J .; Tomaszek, T. A.;
Winborne, E.; Zhao, B.; Dreyer, G.; Meek, T. D. Biochemistry 1994,
33, 11671-11677.
(22) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Robinson, P. L.;
Barry, C. N.; Bass, S. W.; J arvis, S. E.; Evans, S. A., J r. J . Org. Chem.
1983, 48, 5396-5398.
(23) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates,
and Resolutions; J ohn Wiley & Sons: New York, 1981; pp 151-159.
(24) Small amounts (ca. 20%) of the (R)-γ-[(S)-1-phthalimidoalkyl]-
γ-lactone 17 could also be isolated, although not in totally pure form,
from the reaction mixture. This compound showed both 1H and 13C
NMR spectra clearly different from that of its diastereomer 19.
(25) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020.
(27) Blundell, T. L.; Cooper, J .; Foundling, S. I.; J ones, D. M.; Atrash,
B.; Selzke, M. Biochemistry 1987, 26, 5585-5590.
(28) (a) Wood, J . L.; J ones, D. R.; Hirschmann, R.; Smith, A. B., III.
Tetrahedron Lett. 1990, 31, 6329-6330. (b) Bertelli, L.; Fiaschi, R.;
Napolitano, E. Gazz. Chim. Ital. 1993, 123, 521-524.
(29) Minor amounts (17% yield estimated by NMR) of the (5R)-
lactone 24 were also obtained after chromatographic purification.

3564 J . Org. Chem., Vol. 63, No. 11, 1998
Aguilar et al.
Sch em e 8
drich) was used when indicated. All reactions were performed
in flame- or oven-dried glassware under a N2 atmosphere.
Reaction progress was followed by TLC. Silica gel (70-230
mesh) was used for column chromatography; hexanes-ethyl
acetate mixtures of increasing polarity were used as eluents,
unless specified otherwise.
indicating that a significant enantiomeric enrichment
had taken place along the reaction sequence, probably
at the level of the ester 23. Finally, it is worth mention-
ing that lactone 26 of very high enantiomeric purity (ee
higher than 99.97%, according to HPLC) can be obtained
if the intermediate p-nitrobenzoate 25 is submitted to a
single recrystallization from hexane.
In summary, we report in this article a new approach
for the highly enantioselective preparation of N-protected
(S)-γ-[(S)-1-aminoalkyl]-γ-lactones 2, which takes place
in only seven steps from the chiral epoxy alcohols
generated by the catalytic asymmetric epoxidation of (E)-
allyl alcohols. Contrary to most of the previous routes
to these important precursors of the δ-amino-γ-hydroxy
acid unit of hydroxyethylene dipeptide isosteres, the
present one does not rely on the availability of specific
enantiopure R-amino acids or R-amino aldehydes as
starting materials, and all steps take place with complete
stereochemical control. Moreover, both enantiomers of
lactones 2 are equally available through this approach,
given that the precursor epoxy alcohols can be obtained
in both enantiomeric forms.
(2S,3S)-3-Am in o-4-p h en ylbu ta n e-1,2-d iol, 7. To a pre-
heated (70-80 °C) suspension of Ti(OiPr)2(N3)217b (5.47 g, 21.9
mmol, 1.3 equiv) in dry benzene (80 mL) under argon was
added a solution of (2R,3R)-2,3-epoxy-4-phenylbutan-1-ol (5)16
(2.99 g, 18.2 mmol) of 94% ee (HPLC, CHIRALCEL OD
column) in dry benzene (100 mL), and the mixture was heated
at 70-80 °C for 10-15 min. Benzene was eliminated in vacuo,
and the resulting crude was vigorously stirred with a mixture
of diethyl ether (335 mL) and 5% aqueous H2SO4 (130 mL)
until both layers were completely transparent. The mixture
was transferred to a separation funnel, and the aqueous layer
was then extracted twice with dichloromethane. The combined
organic layers were dried over Na2SO4, and the solvent was
eliminated in vacuo. The crude (2S,3S)-3-azido-4-phenylbu-
tane-1,2-diol 6 thus obtained was dissolved in methanol (40
mL), and the solution was added on a suspension of 10% Pd/C
(0.377 g) in methanol (40 mL) under hydrogen (1 atm). The
suspension was stirred at rt for 24 h and then filtered over
Celite. Methanol was evaporated in vacuo, and 2.96 g of
(2S,3S)-3-amino-4-phenylbutane-1,2-diol 7 (90% yield) was
obtained as a yellow solid. Recrystallization from ethyl acetate
gave 2.07 g (63% yield) of enantiomerically enriched 7: mp
105-107 °C; [R]D ) -34.2 (c ) 1.37, MeOH); IR (KBr) νmax
3300, 3080, 2920, 2860, 1610, 1080, 1050 cm-1; 1H NMR (200
MHz, CD3OD) δ 2.42-2.59 (m, 1H), 2.95-3.05 (m, 2H), 3.55-
3.77 (m, 3H), 7.20-7.38 (m, 5H) ppm; 13C NMR (50 MHz, CD3-
OD) δ 40.0 (CH2), 56.2 (CH), 64.8 (CH2), 75.4 (CH), 127.4 (CH),
129.6 (CH), 130.4 (CH), 140.4 (Cq) ppm; MS (CI) m/z (relative
intensity) 182 (MH+, 100), 199 (MNH4+, 6). Anal. Calcd for
Exp er im en ta l Section
Gen er a l. Melting points were determined in an open
capillary tube and are uncorrected. Optical rotations were
measured at rt (23 °C). Infrared spectra were recorded using
NaCl film or KBr pellet techniques. 1H NMR spectra were
recorded at 200 or 300 MHz in CDCl3, unless specified
otherwise, with tetramethylsilane as internal standard. 13C
NMR spectra were recorded at 50.3 or 75.4 MHz in CDCl3,
unless specified otherwise, with CHCl3 as internal standard.
Signal multiplicities were established by DEPT experiments.
Mass spectra were recorded at 70 eV ionizing voltage; am-
monia was used for chemical ionization (CI) and glycerol for
fast atom bombardment (FAB). High-resolution mass spectra
(CI) were performed by the “Servicio de Espectrometr´ıa de
Masas, Universidad de Co´rdoba”. Elemental analyses were
performed by the “Servei d’Ana`lisis Elementals del CSIC de
Barcelona”. THF was distilled from sodium benzophenone
ketyl, and benzene and toluene were dried over sodium.
Dichloromethane, 1,2-dichloroethane, and DMF were distilled
from CaH2. Commercially available pure dry methanol (Al-
C
10H15NO2: C, 66.27; H, 8.35; N, 7.72. Found: C, 66.27; H,
8.33; N, 7.80.
(2S,3S)-4-P h en yl-3-p h th a lim id obu ta n e-1,2-d iol, 8. To
a suspension of PyBOP (2.84 g, 5.46 mmol, 1.1 equiv) in dry
THF (10 mL) was added a solution of 2-ethoxycarbonylbenzoic
acid30 (1.08 g, 5.46 mmol, 1.1 equiv) in THF (10 mL) and Eti-
Pr2N (1.27 mL, 7.44 mmol, 1.5 equiv), and the resulting
mixture was stirred for 30-40 min at rt. Afterwards, this
(30) 2-(Ethoxycarbonyl)benzoic acid was obtained in essentially
quantitative yield by refluxing phthalic anhydride in absolute etha-
nol: Beilstein, H9, 797b.

Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones
J . Org. Chem., Vol. 63, No. 11, 1998 3565
solution was added to a suspension of 7 (0.898 g) in THF (10
mL) at 0 °C, and the mixture was stirred at rt for 3 h. The
solvent was eliminated in vacuo, and the residue was heated
at 85 °C overnight. The reaction mixture was then dissolved
in 250 mL of dichloromethane and washed with saturated
NaHCO3 solution (2 × 100 mL) and with brine (100 mL). The
organic layer was dried (Na2SO4) and evaporated to give a
crude product which was purified by column chromatography
to yield 1.28 g of (2S,3S)-4-phenyl-3-phthalimidobutane-1,2-
diol (8) (83%) as a white solid: mp 91-93 °C; [R]D ) -177.7 (c
) 1.05, CH2Cl2) [ee > 98.5%]; IR (KBr) νmax 3480, 3020, 2950,
1785, 1710 cm-1; 1H NMR (200 MHz, CDCl3) δ 3.22-3.43 (m,
2H), 3.58-3.75 (m, 2H), 4.20-4.32 (m, 1H), 4.55-4.62 (m, 1H),
7.08-7.20 (m, 5H), 7.62-7.81 (m, 4H) ppm; 13C NMR (50 MHz,
CDCl3) δ 35.3 (CH2), 56.5 (CH), 65.1 (CH2), 72.8 (CH), 123.9
(CH), 127.3 (CH), 129.2 (CH), 129.9 (CH), 132.6 (Cq), 135.4
(CH), 139.5 (Cq), 169.6 (Cq) ppm; MS (CI) m/z (relative
intensity) 312 (MH+, 15), 329 (MNH4+, 100). Anal. Calcd for
solvent was evaporated in vacuo to give a crude product which
was purified by column chromatography to give 0.401 g of the
oxirane 15 (71%): white solid; mp 131-132 °C (lit.31 mp 180-
182 °C; we have no explanation for this discrepancy); [R]D
)
-156.1 (c ) 1.14, CH2Cl2) [lit.31 [R]20 ) -155.2 (c ) 0.5% in
D
CH2Cl2)]; [ee > 98.9%, according to DSC]; IR (KBr) νmax 3080,
2960, 2930, 1780, 1710 cm-1; 1H NMR (300 MHz, d6-DMSO) δ
2.58 (dd, J ) 4.8 Hz, J ′ ) 2.7 Hz, 1H), 2.77 (dd, J ) 4.8 Hz, J ′
) 3.9 Hz, 1H), 3.19 (dd, J ) 13.8 Hz, J ′ ) 5.1 Hz, 1H), 3.44
(dd, J ) 13.8 Hz, J ′ ) 11.1 Hz, 1H), 3.52 (ddd, J ) 6.6 Hz, J ′
) 4.1 Hz, J ′′ ) 2.7 Hz, 1H), 4.12 (ddd, J ) 11.1 Hz, J ′ ) 5.1
Hz, J ′′ ) 6.1 Hz), 7.09-7.19 (m, 5H), 7.80 (s, 4H); 13C NMR
(50 MHz, CDCl3) δ 35.6 (CH2), 46.5 (CH2), 51.8 (CH), 55.7 (CH),
123.3 (CH), 126.6 (CH), 128.4 (CH), 128.8 (CH), 131.4 (Cq),
134.0 (CH), 136.9 (Cq), 168.0 (Cq) ppm.
(1R)-Men th yl (4R,5S)-4-Hyd r oxy-6-p h en yl-5-p h th a lim -
id oh exa n oa te, 16. To a solution of the oxirane 15 (0.173 g,
0.59 mmol) in dry THF (2 mL) at -78 °C was added dropwise
freshly distilled BF3‚Et2O (180 µL, 1.46 mmol, 2.5 equiv), and
the mixture was stirred at the same temperature for 40 min.
Meanwhile, to a solution of (1R)-menthyloxyethine21 (0.317 g,
1.76 mmol, 3 equiv) in dry THF (1 mL) at -78 °C was added
a 1.4 M solution of nBuLi in hexanes (1.06 mL, 1.46 mmol,
2.5 equiv), and the mixture was also stirred at -78 °C for 40
min. This solution was added over the first one, and the
mixture was stirred at -78 °C for 1.5 h. Finally, H2O (85 µL,
4.70 mmol, 8 equiv) was added, and the mixture was allowed
to slowly reach rt. Subsequently, diethyl ether (10 mL) was
added, and the reaction mixture was washed with saturated
NaHCO3 (2 × 10 mL) and with brine (10 mL). The organic
layer was dried (Na2SO4), and the solvents were evaporated
in vacuo to give a crude product which was purified by column
chromatography to yield (1R)-menthyl-(4R,5S)-4-hydroxy-6-
phenyl-5-phthalimidohexanoate (16) (0.192 g, 66% yield) as a
colorless oil. A fraction containing 46 mg (22% estimated by
NMR) of impure (5R)-5-[(1S)-2-phenyl-1-phthalimidoethyl]-
dihydrofuran-2(3H)-one (17) was also isolated.
C
18H17NO4‚H2O: C, 65.64; H, 5.81; N, 4.25. Found: C, 65.59;
H, 5.59; N, 4.26. According to 19F NMR (282.2 MHz, CDCl3,
TFA as external reference), a single set of signals (-72.03,
-72.61 ppm for the (S)-diester; -72.30, -72.57 ppm for the
(R)-diester) was observed for each one of the corresponding
Mosher diesters of 8.
(2S,3S)-1-(ter t-Bu tyld im eth ylsilyloxy)-3-(p h th a lim ido)-
4-p h en ylbu ta n -2-ol, 9. A solution of the diol 8 (0.500 g, 1.61
mmol), tert-butyldimethylsilyl chloride (0.275 g, 1.76 mmol,
1.1 equiv), and imidazole (0.240 g, 3.54 mmol, 2.2 equiv) in
anhydrous DMF (2 mL) was stirred at rt for 24 h. The mixture
was then poured over water (10 mL) and extracted with
dichloromethane (3 × 10 mL). The combined organic layers
were washed with saturated NH4Cl solution (25 mL) and dried
over Na2SO4. After the organic layers were concentrated in
vacuo, purification of the residue by column chromatography
gave 0.496 g (72%) of 9: white solid; mp 63-65 °C; [R]D
)
-125.0 (c ) 1.08, CHCl3) IR (KBr) νmax 3480, 3030, 2930, 2860,
1
1780, 1715 cm-1; H NMR (200 MHz, CDCl3) δ 0.02 (s, 3H),
0.03 (s, 3H), 0.92 (s, 9H), 3.33 (d, J ) 8 Hz, 2H), 3.48 (broad
d, 1H), 3.58-3.68 (m, 2H), 4.20-4.38 (m, 1H), 4.62-4.78 (m,
1H), 7.10 (s, 5H), 7.60-7.78 (m, 4H) ppm; 13C NMR (50 MHz,
CDCl3) δ -5.8 (CH3), 18.0 (Cq), 25.6 (CH3), 33.1(CH2), 54.2
(CH), 63.7 (CH2), 72.3 (CH), 123.2 (CH), 126.0 (CH), 128.2
(CH), 128.7 (CH), 130.9 (Cq), 133.8 (CH), 137.8 (Cq), 168.4
(Cq); MS (CI) m/z (relative intensity) 426 (MH+, 43), 443
(MNH4+, 100). Anal. Calcd for C24H31NO4Si: C, 67.73; H,
7.34; N, 3.29. Found: C, 67.52; H, 7.34; N, 3.32.
(1R)-Men th yl (4R,5S)-h yd r oxy-6-p h en yl-5-p h th a lim i-
d oh exa n oa te (16): colorless oil; [R]D ) -125.1 (c ) 1.58,
CHCl3); IR (film) νmax 3460, 3020, 2950, 2920, 2860, 1775, 1715
cm-1; 1H NMR (200 MHz, CDCl3) δ 0.71-0.91 (m, 12H), 1.10-
2.00 (m, 8H), 2.39-2.61 (m, 2H), 3.21-3.42 (m, 2H), 3.79-
3.81 (m, 1H), 4.17-4.22 (m, 1H), 4.47 (dt, J ) 10.5 Hz, J ′ )
5.8 Hz, 1H), 4.68 (td, J ) 4.4 Hz, J ′ ) 11.0 Hz, 1H), 7.11 (s,
5H), 7.62-7.81 (m, 4H) ppm; 13C NMR (50 MHz, CDCl3) δ 16.2
(CH3), 20.7 (CH3), 22.0 (CH3), 23.3 (CH2), 26.2(CH), 29.5(CH2),
31.0 (CH2), 31.3 (CH), 33.0 (CH2), 34.2 (CH2), 40.8 (CH2), 46.9
(CH), 58.2 (CH), 72.3 (CH), 74.4 (CH), 123.3 (CH), 126.3 (CH),
128.3 (CH), 129.0 (CH), 131.3 (Cq), 134.1 (CH), 137.7 (Cq),
168.2 (Cq), 173.5 (Cq) ppm; MS (CI) m/z (relative intensity)
353 (M - C10H18+, 15), 492 (MH+, 28), 509 (MNH4+, 100).
(1S,2S)-1-(ter t-Bu tyld im eth ylsilyloxy)m eth yl-2-p h th a l-
im id o-3-p h en ylp r op yl Meth a n esu lfon a te, 10. To a solu-
tion of 9 (0.256 g, 0.60 mmol) in dry dichloromethane (0.5 mL)
were added Et3N (93 µL, 0.66 mmol, 1.1 equiv) and 4-DMAP
(12 mg). The mixture was cooled at -15 °C, and methane-
sulfonyl chloride (50 µL, 0.66 mmol, 1.1 equiv) in dichlo-
romethane (1 mL) was added. The mixture was stirred at
rtovernight. Dichloromethane (20 mL) was then added to the
reaction mixture, and it was washed with 5% aqueous HCl (2
× 20 mL), saturated NaHCO3 (25 mL), and brine (25 mL).
After the mixture was dried (Na2SO4) and the solvent was
evaporated, 0.271 g of 10 (89%) were obtained: colorless oil;
[R]D ) - 94.0 (c ) 1.4, CHCl3); IR (film) νmax 3040, 2940, 2860,
HRMS (CI) calcd for
492.2765.
C
30H38NO5 [MH+] 492.2750, found
(5R)-5-[(1S)-2-P h en yl-1-ph th alim idoeth yl]dih ydr ofu r an -
2(3H)-on e (17): colorless oil; IR (film) νmax 3020, 2930, 2860,
1775, 1715 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.85-1.98 (m,
1H), 2.01-2.15 (m, 1H), 2.55-2.61 (m, 2H), 3.39-3.45 (m, 2H),
4.50 (td, J ) 9.6 Hz, J ′ ) 6 Hz, 1H), 5.19-5.30 (m, 1H), 7.12
(s, 5H), 7.69-7.73 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ
25.5 (CH2), 28.2 (CH2), 35.4 (CH2), 55.8 (CH), 79.0 (CH), 123.4
(CH), 126.7 (CH), 128.5 (CH), 128.8 (CH), 131.0 (Cq), 134.3
(CH), 136.7 (Cq), 168.0 (Cq), 176.5 (Cq) ppm.
(1R)-Men th yl (4S,5S)-4-(p-Nitr op h en ylca r bon yloxy)-6-
p h en yl-5-p h th a lim id oh exa n oa te, 18. To a solution of 16
(0.186 g, 0.38 mmol) in dry benzene (9 mL) were added
sequentially PPh3 (0.487 g, 1.86 mmol, 4.9 equiv) and p-
nitrobenzoic acid (0.273 g, 1.63 mmol, 4.4 equiv). The resulting
suspension was cooled at 0 °C, and DEAD (0.29 mL, 1.85
mmol, 4.9 equiv) was added via syringe. The mixture was
stirred at rt for 24 h. The solvent was evaporated in vacuo to
1780, 1720, 1320, 1185 cm-1 1H NMR (200 MHz, CDCl3) δ
;
-0.02 (s, 3H), -0.05 (s, 3H), 0.81 (s, 9H), 3.14 (s, 3H), 3.22-
3.58 (m, 2H), 3.77-3.98 (m, 2H), 4.78-4.92 (m, 1H), 5.25-
5.36 (m, 1H), 7.12 (s, 5H), 7.63-7.75 (m, 4H) ppm; 13C NMR
(50 MHz, CDCl3) δ -5.67 (CH3), 18.2 (Cq), 25.7 (CH3), 33.9
(CH2), 38.7 (CH3), 52.4 (CH), 63.2 (CH2), 81.5 (CH), 123.2 (CH),
126.7 (CH), 128.4 (CH), 128.8 (CH), 131.0 (Cq), 134.0 (CH),
136.7 (Cq), 168.5 (Cq); MS (CI) m/z (relative intensity) 521
(MNH4+, 100). HRMS (CI) calcd for C25H34NO6SSi [MH+]
504.1878, found 504.1855.
(S)-[(S)-2-P h en yl-1-p h th a lim id oeth yl]oxir a n e, 15.31 To
a solution of (2S,3S)-4-phenyl-3-phthalimidobutane-1,2-diol (8)
(0.600 g, 1.93 mmol) and Ph3P (0.540 g, 2.06 mmol, 1.07 equiv)
in dry 1,2-dichloroethane (8 mL) was added dropwise a solution
of DEAD (0.372 g, 2.06 mmol, 1.07 equiv) in dry 1,2-dichloro-
ethane (7 mL), and the mixture was refluxed for 38 h. The
(31) Parkes, K. E. B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon, S.
J .; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.;
Martin, J . A.; Merrett, J . H.; Redshaw, S.; Spurden, W. C.; Thomas,
G. J . J . Org. Chem. 1994, 59, 3656-3664.

3566 J . Org. Chem., Vol. 63, No. 11, 1998
Aguilar et al.
give a crude product which was purified by column chroma-
tography to yield 0.198 g of hexanoate 18 (82%): colorless oil;
IR (film) νmax 2960, 2920, 2860, 1780, 1730, 1720 cm-1; 1H NMR
(200 MHz, CDCl3) δ 0.72-0.95 (m, 12H), 1.10-1.98 (m, 6H),
2.01-2.45 (m, 4H), 3.21 (dd, J ) 5.1 Hz, J ′ ) 13.9 Hz, 1H),
3.58 (dd, J ) 11.8 Hz, J ′ ) 13.9 Hz, 1H), 4.66 (td, J ) 4.4 Hz,
J ′ ) 10.6 Hz, 1H), 4.83 (ddd, J ) 5.5 Hz, J ′ ) 7.0 Hz, J ′′ )
11.8 Hz, 1H), 5.80-5.90 (m, 1H), 7.15 (s, 5H), 7.58-7.75 (m,
4H), 8.05-8.25 (m 4H) ppm; 13C NMR (50 MHz, CDCl3) δ 16.8
(CH3), 21.3 (CH3), 22.5 (CH3), 23.8 (CH2), 26.7 (CH), 27.7 (CH2),
30.7 (CH2), 31.8 (CH), 34.6 (CH2 × 2), 41.3 (CH2), 47.4 (CH),
56.0 (CH), 75.0 (CH), 75.1 (CH), 123.7 (CH), 124.0 (CH), 127.3
(CH), 129.1 (CH), 129.2 (CH), 131.5 (CH), 134.6 (CH), 135.3
(Cq), 137.1 (Cq), 152.3 (Cq), 165.2 (Cq), 168.3 (Cq), 172.3 (Cq)
ppm; MS (FAB) 641 (MH+), 663 (MNa+).
(5S)-5-[(1S)-2-P h en yl-1-ph th alim idoeth yl]dih ydr ofu r an -
2(3H)-on e, 19. To a suspension of hexanoate 18 (50 mg, 0.078
mmol) in dry methanol (1 mL) was added a solution of sodium
methoxide (8.4 mg, 0.156 mmol, 2 equiv) in dry methanol (1
mL), and the mixture was stirred for 6 h at rt. Acetic acid
was then added dropwise until the pH was slightly acidic, and
the solvent was eliminated in vacuo. Finally, dry toluene (3
mL) was added, and the solution was refluxed overnight.
Toluene was evaporated in vacuo to give a crude product which
was purified by column chromatography to yield 19 mg of the
lactone 19 (70%): white solid; mp 152-153 °C; [R]D ) -73.1
(c 0.78, CHCl3); IR (KBr) νmax 3030, 2945, 1785, 1725 cm-1; 1H
NMR (300 MHz, CDCl3) δ 2.01-2.19 (m, 1H), 2.41-2.71 (m,
3H), 3.07 (dd, J ) 5.1 Hz, J ′ ) 13.8 Hz, 1H), 3.40 (dd, J )
11.1 Hz, J ′ ) 13.8 Hz, 1H), 4.58 (ddd, J ) 4.9 Hz, J ′ ) 9.7 Hz,
J ′′ ) 11.1 Hz, 1H), 5.18-5.30 (m, 1H), 7.17 (s, 5H), 7.62-7.78
(m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 26.5 (CH2), 28.8
(CH2), 33.5 (CH2), 56.4 (CH), 76.6 (CH), 123.3 (CH), 126.9 (CH),
128.6 (CH), 128.8 (CH), 131.4 (Cq), 134.0 (CH), 136.1 (Cq),
168.0 (Cq), 175.8 (Cq) ppm; MS (CI) m/z (relative intensity)
353 (MNH4+, 100). Anal. Calcd for C20H17NO4: C, 71.63; H,
5.11; N, 4.18. Found: C, 71.54; H, 5.23; N, 4.19.
1.54-1.68 (m, 1H), 2.17-2.31 (m, 1H), 2.80 (broad s, 2H),
3.58-3.63 (m, 2H), 4.02-4.18 (m, 1H), 4.30-4.41 (m, 1H),
7.72-7.87 (m, 4H) ppm; 13C NMR (50 MHz, CDCl3) δ 21.3
(CH3), 23.6 (CH3), 24.9 (CH), 36.2 (CH2), 51.5 (CH), 63.9 (CH2),
72.9 (CH), 123.5 (CH), 131.5 (Cq), 134.3 (CH), 169.0 (Cq) ppm;
MS (CI) m/z (relative intensity) 278 (MH+, 41), 295 (MNH4
,
+
100). HRMS (CI) calcd for C15H20NO4 [MH+] 278.1392, found
278.1379. Conditions for GC determination of the enantio-
meric purity of 20: R-DEX 120 (30 m) column, 80 °C; tR(2R,3R)
53.0 min, tR(2S,3S) 54.8 min.
(S)-[(S)-3-Meth yl-1-p h th a lim id obu tyl]oxir a n e, 22. The
procedure described above for the synthesis of 15 was followed
using these reactives and amounts: (2S,3S)-5-methyl-3-ph-
thalimidohexane-1,2-diol (21) (0.527 g, 1.90 mmol), PPh3 (0.563
g, 2.15 mmol, 1.1 equiv), DEAD (0.375 g, 2.15 mmol, 1.1 equiv),
and 1,2-dichloroethane (16 mL). After purification, 0.343 g
(69% yield) of the oxirane 22 was obtained: colorless oil; [R]D
) -1.38 (c ) 1.98, CHCl3); IR (film) νmax 2970, 2880, 1780,
1720, 1380 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.88-0.92 (m,
6H), 1.44-1.58 (m, 1H), 1.73 (ddd, J ) 5.1 Hz, J ′ ) 9 Hz, J ′′
) 13.9 Hz, 1H), 2.18 (dd, J ) 3.9 Hz, J ′ ) 4.8 Hz, 1H), 2.58
(dd, J ) 2.4 Hz, J ′ )4.8 Hz, 1H), 2.94 (ddd, J ) 4.8 Hz, J ′ )
10.7 Hz, J ′′ ) 14.7 Hz, 1H), 3.50 (ddd, J ) 2.4 Hz, J ′ ) 3.9 Hz,
J ′′ ) 7.7 Hz, 1H), 3.95 (ddd, J ) 4.8 Hz, J ′ ) 7.7 Hz, J ′′ ) 10.7
Hz, 1H), 7.72-7.87 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3)
δ 21.6 (CH3), 23.0 (CH3), 24.9 (CH), 38.6 (CH2), 46.1 (CH2),
52.3 (CH), 52.6 (CH), 123.3 (CH), 131.7 (Cq), 134.1 (CH), 168.1
(Cq) ppm; MS (CI) m/z (relative intensity) 260 (MH+, 42), 277
(MNH4+, 100). HRMS (CI) calcd for C15H18NO3 [MH+] 260.1287,
found 260.1278.
(1R)-Men th yl (4R,5S)-4-Hyd r oxy-7-m eth yl-6-p h th a lim -
id oocta n oa te, 23. The procedure described above for the
synthesis of 16 was followed using these reactives and
amounts: (S)-[(S)-3-methyl-1-phthalimidobutyl]oxirane (22)
(0.309 g, 1.19 mmol), freshly distilled BF3‚OEt2 (370 µL, 2.95
mmol, 2.5 equiv), (1R)-menthyloxyethine (0.640 g, 3.55 mmol,
3 equiv), 1.85 M solution of nBuLi in hexanes (1.16 mL), H2O
(170 µL, 9.52 mmol, 8 equiv), and THF (6 mL). After
chromatographic purification, 0.333 g of 23 (61% yield) was
obtained. A fraction containing 62 mg of impure (5R)-5-[(1S)-
3-methyl-1-phthalimidobuthyl]dihydrofuran-2(3H)-one 24 was
also isolated (17% yield estimated by NMR).
(2S,3S)-5-Meth yl-3-p h th a lim id oh exa n e-1,2-d iol, 21. (a)
To a preheated (70-80 °C) suspension of Ti(OiPr)2(N3)217b (3.92
g, 15.7 mmol, 1.3 equiv) in dry benzene (60 mL) under argon
was added a solution of (2R,3R)-2,3-epoxy-5-methylhexane-1-
ol28 (20) (1.60 g, 12.3 mmol) of 89% ee in dry benzene (65 mL),
and the resulting mixture was heated at 70-80 °C for 10-15
min. Benzene was eliminated in vacuo, and the residue was
vigorously stirred with a mixture of diethyl ether (250 mL)
and 5% aqueous H2SO4 (98 mL) until both layers were
completely transparent. The mixture was transferred to a
separation funnel, and the aqueous layer was extracted with
dichloromethane (2 × 100 mL). The combined organic layers
were dried over Na2SO4, and the solvents were eliminated in
vacuo. The crude (2S,3S)-3-azido-5-methylhexan-1,2-diol thus
obtained was dissolved in dry methanol (30 mL), and the
solution was added to a suspension of 10% Pd/C (0.213 g) in
methanol (30 mL) under hydrogen atmosphere (1 atm). The
suspension was stirred at rt for 30 h and then filtered over
Celite. Methanol was eliminated in vacuo to yield the expected
(2S,3S)-3-amino-5-methylhexan-1,2-diol which was used in the
next step without purification. (b) To a suspension of PyBOP
(4.24 g, 8.15 mmol, 1.1 equiv) in dry THF (10 mL) were
sequentially added a solution of 2-ethoxycarbonylbenzoic acid30
(1.61 g, 8.15 mmol, 1.1 equiv) in THF (10 mL) and EtiPr2N
(2.6 mL, 11.1 mmol, 1.5 equiv), and the resulting mixture was
stirred for 30-40 min at rt. This solution was then added to
a suspension of the unpurified amino diol obtained in (a) in
THF (10 mL) at 0 °C, and the mixture was stirred at rt for 3
h. The solvent was eliminated in vacuo, and the mixture
heated at 85 °C overnight. The reaction mixture was then
solved in dichloromethane (20 mL) and washed with saturated
NaHCO3 solution (10 mL) and with brine (10 mL). The organic
layer was dried (Na2SO4) and evaporated to give a crude
product which was purified by column chromatography to
afford 1.57 g of the diol 21 (46% overall yield): colorless oil;
[R]D ) -12.7 (c ) 1.26, CHCl3); IR (film) νmax 3460, 2980, 2900,
(1R)-Men th yl (4R,5S)-4-h yd r oxy-7-m eth yl-6-p h th a lim i-
d oocta n oa te 23: colorless oil; [R]D ) -30.7 (c ) 1.21, CHCl3);
IR (film) νmax 3460, 2960, 2930, 2870, 1775, 1710 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.71-0.94 (m, 18H), 1.25-1.98 (m, 10H),
2.15-2.22 (m, 1H), 2.38-2.57 (m, 2H), 3.55 (s, 1H), 4.05-4.10
(m, 1H), 4.21-4.30 (m, 1H), 4.65 (td, J ) 4.5 Hz, J ′ ) 10.9 Hz,
1H), 7.72-7.87 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.3
(CH3), 20.7 (CH3), 21.4 (CH3), 22.0 (CH3), 23.4 (CH2), 23.7
(CH3), 25.0 (CH), 26.2 (CH), 29.5 (CH2), 31.0 (CH2), 31.4 (CH),
34.2 (CH2), 35.5 (CH2), 40.9 (CH2), 47.0 (CH), 54.9 (CH), 72.9
(CH), 74.3 (CH), 123.4 (CH), 131.8 (Cq), 134.2 (CH), 168.4 (Cq),
173.7 (Cq) ppm. MS (CI) m/z (relative intensity) 319 ([M -
C
10H18]+, 89), 458 (MH+, 100), 475 (MNH4+, 29).
(5R)-5-[(1S)-3-Met h yl-1-p h t h a lim id ob u t yl]d ih yd r ofu -
r a n -2(3H)-on e, 24: colorless oil; IR (film) νmax 2960, 2930,
1
2880, 1790, 1710 cm-1; H NMR (300 MHz, CDCl3) δ 0.89 (d,
J ) 6.6 Hz, 3H), 0.92 (d, J ) 6.6 Hz, 3H), 1.37-150 (m, 1H),
1.69-1.78 (m, 1H), 1.82-1.95 (m, 1H), 2.10-2.33 (m, 2H),
2.51-2.57 (m, 2H), 4.34 (ddd, J ) 3.3 Hz, J ′ ) 9.6 Hz, J ′′ )
11.7 Hz, 1H), 5.04 (ddd, J ) 6.7 Hz, J ′ ) 8.1 Hz, J ′′ ) 9.5 Hz,
1H), 7.76-7.88 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 21.2
(CH3), 23.4 (CH3), 24.9 (CH), 25.4 (CH2), 28.1 (CH2), 38.1 (CH2),
53.2 (CH), 79.5 (CH), 123.5 (CH), 131.3 (Cq), 134.3 (CH), 168.2
(Cq), 176.2 (Cq) ppm.
(1R)-Men th yl (4S,5S)-7-Meth yl-4-(p-n itr op h en ylca r bo-
n yloxy)-5-p h th a lim id oocta n oa te, 25. The procedure de-
scribed above for the synthesis of 18 was followed using these
reactives and amounts: (1R)-menthyl (4R,5S)-4-hydroxy-7-
methyl-6-phthalimidooctanoate (23) (0.28 g, 0.612 mmol), PPh3
(0.79 g, 3.02 mmol, 4.9 equiv), p-nitrobenzoic acid (0.453 g,
2.70 mmol, 4.4 equiv), DEAD (0.47 mL, 3.00 mmol, 4.9 equiv),
and dry benzene (12 mL). After purification, 0.281 g of 25
(74% yield) was obtained: white solid; mp 66.5-67.5 °C; [R]D
1
1780, 1710, 1150 cm-1; H NMR (200 MHz, CDCl3) δ 0.89 (d,
J ) 6.2 Hz, 3H), 0.92 (d, J ) 6.2 Hz, 3H), 1.38-1.42 (m, 1H),

Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones
J . Org. Chem., Vol. 63, No. 11, 1998 3567
) -7.48 (c ) 0.98, CHCl3); IR (KBr) νmax 2960, 2940, 2880,
2.64 (m 2H), 4.34 (ddd, J ) 3.3 Hz, J ′ ) 9.9 Hz, J ′′ ) 12.0 Hz,
1H), 5.11 (ddd, J ) 6.6 Hz, J ′ ) 8.7 Hz, J ′′ ) 9.9 Hz, 1H),
7.71-7.85 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 21.3
(CH3), 23.5 (CH3), 24.7 (CH), 26.4 (CH2), 28.8 (CH2), 35.7 (CH2),
53.7 (CH), 78.8 (CH), 123.3 (CH), 131.7 (Cq), 134.0 (CH), 168.3
(Cq), 175.8 (Cq) ppm; MS (CI) m/z (relative intensity) 319
(MNH4+, 100), 336 (MN2H7+, 1). Anal. Calcd for C17H19NO4:
C, 67.76; H, 6.35; N, 4.65. Found: C, 67.74; H, 6.35; N, 4.63.
Conditions for the determination of the enantiomeric purity
of 26 by HPLC analysis: CHIRALCEL ODR (25 cm) column,
10% NaClO4 0.1 M/ 90% MeOH, 0.5 mL/min, 27 °C, λ ) 254
nm; tR(1S,5′S) 11.3 min, tR(1R,5′R) 12.7 min.
1
1780, 1735, 1715 cm-1; H NMR (200 MHz, CDCl3) δ 0.73-
0.94 (m, 18H), 1.22-2.50 (m, 13H), 4.54-4.68 (m, 2H), 5.63-
5.79 (m, 1H), 7.68-7.79 (m, 4H), 8.08-8.22 (m 4H) ppm; 13C
NMR (50 MHz, CDCl3) δ 16.3 (CH3), 20.7 (CH3), 21.2 (CH3),
21.9 (CH3), 23.3 (CH2), 23.3 (CH3) 25.0 (CH), 26.2 (CH), 27.1
(CH2), 30.1 (CH2), 31.3 (CH), 34.1 (CH2), 36.4 (CH2), 40.7 (CH2),
46.9 (CH), 52.5 (CH), 74.5 (CH), 75.0 (CH), 123.2 (CH), 123.4
(CH), 130.9 (CH), 131.5 (Cq), 134.0 (CH), 134.8 (Cq), 150.5
(Cq), 164.1 (Cq), 168.3 (Cq), 171.8 (Cq) ppm; MS (CI) m/z
+
(relative intensity) 624 (MNH4
, 8). Anal. Calcd for
C34H42N2O8: C, 67.31; H, 6.98; N, 4.61. Found: C, 67.70; H,
7.28; N, 4.42.
(5S)-5-[(1S)-3-Meth yl-1-ph th alim idobu tyl]dih ydr ofu r an -
2(3H)-on e, 26. The same procedure described above for the
synthesis of 19 was followed using these reactives and
amounts: (1R)-menthyl (4S,5S)-7-methyl-4-(p-nitrophenylcar-
bonyloxy)-5-phthalimidooctanoate (25) (0.112 g, 0.185 mmol),
sodium methoxide (20 mg, 0.37 mmol, 2 equiv), dry methanol
(4.7 mL), and toluene (6 mL). After flash chromatography
purification, 46 mg of 26 was obtained (83% yield): white solid;
mp 130-131 °C; [R]D ) +38.1 (c ) 1.40, CHCl3); [ee 97.8%];
IR (KBr) νmax 2960, 2915, 2870, 1780, 1715 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.92 (d, J ) 6.6 Hz, 3H), 0.95 (d, J ) 6.6 Hz,
3H), 1.24 (ddd, J ) 3.3 Hz, J ′ ) 10.5 Hz, J ′′ ) 13.8 Hz, 1H),
1.44-1.54 (m, 1H), 1.90-2.00 (m, 1H), 2.27 (ddd, J ) 3.4 Hz,
J ′ ) 12.1 Hz, J ′′ ) 13.7 Hz, 1H), 2.39-2.52 (m, 1H), 2.58-
Ack n ow led gm en t. We thank the DGICYT (Grant
PB93-0806) and the CIRIT (Grant 1996SGR-00013) for
financial support. N.A. is grateful to CIRIT (Generalitat
de Catalunya) for a predoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 10, 16, 18, 21, 22, and 23 (7 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 O9720851