A strategy for the asymmetric aminohomologation of α,β-dihydroxy aldehydes: Application to the synthesis of the southwest tripeptide segment of echinocandin B

Article abstract of DOI:10.1021/jo990964c

The synthesis of the (2S,3S,4S)-3,4-dihydroxyhomotyrosine amino acid segment, present in echinocandin B, in its activated form ready for peptide coupling is described. The key steps of the approach are the enantioselective AD reaction of 4-methoxycinnamic

Full text of DOI:10.1021/jo990964c

J . Org. Chem. 2000, 65, 41-46
41
A Str a tegy for th e Asym m etr ic Am in oh om ologa tion of
r,â-Dih yd r oxy Ald eh yd es: Ap p lica tion to th e Syn th esis of th e
Sou th w est Tr ip ep tid e Segm en t of Ech in oca n d in B
Claudio Palomo,* Mikel Oiarbide, and Aitor Landa
Departamento de Quı´mica Orga´nica. Facultad de Qu´ımica. Universidad del Paı´s Vasco, Apdo 1072,
20080 San Sebastia´n, Spain
Received J une 15, 1999
The synthesis of the (2S,3S,4S)-3,4-dihydroxyhomotyrosine amino acid segment, present in
echinocandin B, in its activated form ready for peptide coupling is described. The key steps of the
approach are the enantioselective AD reaction of 4-methoxycinnamic acid methyl ester, a completely
diastereoselective [2 + 2] hydroxyketene-imine cycloaddition, and the TEMPO-assisted cycloex-
pansion of the resulting 3-hydroxy â-lactam to the corresponding R-amino acid N-carboxy anhydride
(NCA). The smooth opening of the latter upon treatment with L-Thr(OSitBuPh2)OMe and further
acylation with the N-Cbz protected L-4-tert-butyldiphenylsilyloxy proline rendered the southwest
portion of echinocandin B.
The echinocandins, Figure 1, are cyclic hexapeptides,
isolated from Aspergillus ruglosus, that are characterized
by their high antifungal and antiyeast activities.1,2 The
related lypopeptide L-688,786 (1) exhibits potent activity
in animal models of Pneumocystis carinii pneumonia
(PCP), in addition to the activity against several species
of Candida.2 Both PCP and Candida infections are
problematic in immunocomprised patients, particularly
those infected with HIV.1 The structures of echinocandin
B and 1 contain the unusual amino acid (2S,3S,4S)-3,4-
dihydroxyhomotyrosine 2 linked, on one side, to a threo-
nine derivative and, on the other side, to a 4-hydrox-
yproline moiety.3 While the synthesis of the amino acid
(2S,3R)-3-hydroxyhomotyrosine present in echinocandins
C and D as well as the synthesis of these cyclic hexapep-
tides have been described,3,4 to our knowledge there
appears to be no reports concerning the synthesis of
echinocandin B. On the other hand, structure-activity
F igu r e 1.
studies have revealed the amino acid 2 to be a crucial
element for echinocandin B to exhibit biological proper-
ties.5 Furthermore, echinocandin B can also be converted
into echinocandin C.6 Consequently, a concise approach
to the amino acid dihydroxyhomotyrosine 2 becomes a
key point for the synthesis of echinocandins and synthetic
analogues thereof.5,7
One of the most direct approaches to R-amino acids
involves the aminohomologation of aldehydes or, in other
terms, the asymmetric carboxylation of imines.8 The most
commonly applied carboxylating and/or formylating agents
are cyanide ion (the Strecker synthesis),9 isocyanides (the
Ugi reaction),10 and heteroatom-stabilized carbanions.11,12
In most of these cases, the acyl anion is typically
employed in a masked form, and thus, masked R-amino
aldehydes, carboxylic acids, or esters are formed, which
subsequently have to be unmasked. On the other hand,
(1) For pertinent information on this topic, see: Heck, J . V.;
Balkovec, J . M.; Black, R.; Hammond, M. L.; Zambias, R. In Antibiotics
and Antiviral Compounds; Krohn, K., Kirst, H. A., Maag, H., Eds.;
VCH: New York, 1993; p. 153.
(2) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz,
R. E.; Fromtling, R. A.; Nollstadt, K. H.; Van Middlesworth, F. L.;
Wilson, K. E.; Tirner, M. J . Proc. Natl. Acad. Sci. U.S.A. 1990, 87,
5950.
(3) For related cyclic hexapeptides containing the amino acid 3,4-
dihydroxyhomotyrosine, see: (a) Kurukowa, N.; Ohfune, Y. Tetrahe-
dron 1993, 49, 6195. (b) Bouffard, F. A.; Hamilton, M. L.; Arison, B.
H. Tetrahedron Lett. 1995, 36, 1405. (c) J ournet, M.; Cai, D.; DiMichele,
L. M.; Hughes, D. L.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J . J .
Org. Chem. 1999, 64, 2411.
(7) For semisynthetic analogues of echinocandin B, see: Taft, C. S.;
Selitrennikoff, C. P. J . Antibiot. 1990, 43, 433.
(4) (a) Kurokawa, N.; Ohfune, Y. J . Am. Chem. Soc. 1986, 108, 6041.
(b) Idem Ibid. 1986, 108, 6043. (c) Evans, D. A.; Weber, A. E. J . Am.
Chem. Soc. 1987, 109, 7151. For an extensive list of references on
â-hydroxy R-amino acids, see: (d) Kimura, T.; Vassilev, V. P.; Shen,
G.-J .; Wong, C.-H. J . Am. Chem. Soc. 1997, 119, 11734.
(5) Zambias, R. A.; Hammond, M. L.; Heck, J . V.; Bartizal, K.;
Trainor, C.; Abruzzo, G.; Schmatz, D. M.; Nollstadt, K. M. J . Med.
Chem. 1992, 35, 2843.
(8) For reviews on amino acid synthesis, see: (a) Williams, R. M.
Synthesis of Optically Active Amino Acids; Baldwin, J . E.; Magnus, P.
D., Eds.; Pergamon: Oxford; 1989. (b) Duthaler, R. Tetrahedron 1994,
50, 1539. (c) Bailey, P. D.; Clayson, J .; Boa, A. N. Contemp. Org. Synth.
1995, 2, 173. (d) Smith, M. B. Methods of Non R-Amino Acid Synthesis;
Marcel Dekker: New York, 1995. (e) For an annual review on amino
acids, see: Barret, G. C. In Amino Acids, Peptides and Proteins:
Specialists Periodical Report; Davies, J . S., senior reporter; The Royal
Society of Chemistry: London.
(6) Balkovec, J . M.; Black, R. M. Tetrahedron Lett. 1992, 33, 4529.
10.1021/jo990964c CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/10/1999

42 J . Org. Chem., Vol. 65, No. 1, 2000
Palomo et al.
metric carboxylation of imines, our strategy leads to
simultaneously amino-protected and carboxy-activated
forms of R-amino acids ready for subsequent peptide
couplings.15 The success and generality of the strategy
is predicated, on one hand, on the highly predictable
stereoselectivity of the ketene-imine cycloaddition reac-
tion13,16 and, on the other hand, on the enantioselective
Sharpless AD reaction17 as the means by which a number
of enantiomerically enriched R,â-dihydroxy aldehyde-
derived imines are readily and economically available.
For example, the dihydroxylated derivative 4a , Scheme
1, was formed from 3a according to the Sharpless
procedure in 85% isolated yield and g99% ee.18 Acetal
protection in 4a led to 5a , which upon DIBAL reduction
produced the aldehyde 6a in 82% yield over the two steps.
Subsequent imine formation and further reaction with
acetoxyacetyl chloride and triethylamine gave 7a , which
was then converted into the R-hydroxy â-lactam 11 in
84% yield. Of interest, from the careful examination of
1H and 13C NMR spectra of the crude reaction products
no peaks assignable to compound 8a were observed. On
the contrary, when the imine derived from 6a was treated
with benzyloxyketene, generated from benzyloxyacetyl
chloride and triethylamine, a 75:25 mixture of â-lactams
9a and 10a was obtained.19 This different behavior of
both ketenes toward other closely related imines could
be corroborated later. Thus, while the reaction of benzyl-
oxyketene, generated as above, with the imines derived
from 6b and 6c gave â-lactams 9b/10b and 9c/10c in
75:25 and 80:20 diastereomeric ratios, respectively, the
reaction of acetoxyketene with the same imines afforded
â-lactams 7b and 7c with no traces of the corresponding
F igu r e 2. General strategy for aminohomologation of car-
boxylic acids with concomitant amino group protection and
carboxyl group activation: (a) Sharpless AD-imine formation;
(b) ester enolate-imine condensation or ketene-imine [2 +
2] cycloaddition; (c) TEMPO-assisted one-pot oxidation and
Baeyer-Villiger rearrangement.
control of the newly created stereogenic center can be
achieved either by a stereogenic center positioned R to
the imine nitrogen or by chiral auxiliaries in the carban-
ion, albeit the degree of asymmetric induction is, in some
instances, disappointing.
Our strategy, Figure 2, to â,γ-dihydroxy-R-amino acids
uses glycolic acid that derivatizes imines in such a way
that a four-membered ring is formed, an R-hydroxy
â-lactam.13 Then the oxidation of the carbinol and
subsequent Baeyer-Villiger rearrangement of the result-
ing intermediate R-keto â-lactam provides, in a one-pot
procedure, an R-amino acid N-carboxy anhydride (NCA).14
Thus, in contrast to the existing methods for the asym-
1
isomers 8, as judged by H and 13C NMR of the corre-
(9) For a recent review, see: (a) Kunz, H. In Stereoselective Synthesis
(Houben-Weyl); Helmchen, G., Hoffmann, W., Mulzer, J ., Shaumann,
E., Eds.; Thieme: Stuttgart, 1996; Vol. E21/3, p 1931. For some recent
examples, see: (b) Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M.
Liebigs Ann. Chem. 1991, 649. (c) Andres, C.; Maestro, A.; Pedrosa,
R.; Pe´rez-Encabo, A.; Vicente, M. Synlett 1992, 45. (d) Moon, S.-H.;
Ohfune, Y. J . Am. Chem. Soc. 1994, 116, 7405. (e) Cativiela, C.; Diaz-
de-Villegas, M. D.; Ga´lvez, J . A. Tetrahedron Lett. 1995, 36, 2859. (f)
Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995,
51, 9179. (g) Iyer, M. S.; Gigstad, K. M.; Nawdev, N. D.; Lipton, M. J .
Am. Chem. Soc. 1996, 118, 4910. (h) Davis, F. A.; Portonovo, P. S.;
Reddy, R. E.; Chiv, Y. J . Org. Chem. 1996, 61, 440. (i) Kobayashi, S.;
Ishikani, H.; Ueno, M. Synlett 1997, 115. (j) Davies, F. A.; Zhou, P.;
Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.
(10) (a) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds; Perga-
mon: Oxford, 1991, Vol. 2, p 1083. (b) Ugi, I.; Bembarter, A.; Ho¨rl,
W.; Schmid, T. Tetrahedron 1996, 52, 11657. (c) Tempest, P. A.; Brown,
S. D.; Armstrong, R. W. Angew. Chem., Int. Ed. Engl. 1996, 35, 640.
(d) Keating, T. A.; Armstrong, R. W. J . Am. Chem. Soc. 1996, 118,
2574. For a highlight on this subject, see: Dyker, G. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1700.
(11) For some recent examples, see: (a) J ackson, R. F. W.; Palmer,
N. J .; Wythes, M. J .; Clegg, W.; Elsegood, M. R. J . J . Org. Chem. 1995,
60, 6431. (b) Dondoni, A.; Perrone, D. Aldrichchim. Acta 1997, 30, 35.
(c) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Schermann,
M.-C.; Tejero, T. J . Org. Chem. 1997, 62, 5484. (d) Dondoni, A.; Franco,
S.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. J . Org. Chem.
1997, 62, 5497. (e) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1997, 8, 3489. (f) Casiraghi, G.; Zanardi, F.;
Rassu, G.; Spanu, P. Chem. Rev. 1995, 95, 1677. (g) Rassu, G.; Zanardi,
F.; Cornia, M.; Casiraghi, G. J . Chem. Soc., Perkin Trans. 1 1994, 2431.
(h) Enders, D.; Reinhold, V. Tetrahedron Asymmetry 1997, 8, 1895.
(15) For reviews on NCAs, see: (a) Kricheldorf, H. R. R-Amino Acid
N-Carboxy Anhydrides and Related Heterocycles; Springer-Verlag:
Berlin 1987. (b) Blacklock, T. J .; Hirschmann, R. Veber, D. F. The
Peptides; Academic Press: New York, 1987, 9, 39.
(16) For further experimental evidence on the stereochemical
outcome of cycloaddition reactions involving R-oxyaldehyde-derived
imines, see: (a) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983,
66, 2206. (b) Wagle, A. R.; Garai, G.; Chiang, J .; Monteleone, M. G.;
Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose,
A. K. J . Org. Chem. 1988, 53, 4277. (c) Palomo, C.; Coss´ıo, F. P.;
Ontoria, J . M.; Odriozola, J . M. Tetrahedron Lett. 1991, 32, 3105. (d)
Brown, A. D.; Colvin, E. W. Tetrahedron Lett. 1991, 32, 5187. (e)
Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito, Y.; Tera-
shima, S. Tetrahedron 1992, 48, 1853. (f) Palomo, C.; Aizpurua, J . M.;
Urchegui, R.; Garc´ıa, J . M. J . Org. Chem. 1993, 58, 1646. (g) Alcaide,
B.; Miranda, M.; Pe´rez-Castells, J .; Polanco, C. Sierra, M. A. J . Org.
Chem. 1994, 59, 8003. (h) Kramer, B.; Franz, T.; Picasso, S.; Pruschek,
P.; J ager, V. Synlett 1997, 295. For reviews on asymmetric ketene-
imine cycloadditions, see: (i) Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York;
1992; p 295. (j) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M.
Eur. J . Org. Chem. 1999, 3223.
(17) For reviews on Sharpless AD, see: (a) Lohray, B. B. Tetrahedron
Asymm. 1992, 3, 1317. (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(18) The enantiomeric excess of products 4 was determined by
HPLC, using a Chiralpak AS chiral column and an 2-propanol/hexane
10:90 mixture as the eluant. The racemic samples of diols 4 were
prepared and their chromatograms showed the peaks for each enan-
tiomer with a clear baseline resolution. The chromatogram correspond-
ing to the nonracemic sample showed the peak for one enantiomer and
no peak for the other was detected. On this basis, an enantiomeric
exccess of >99% was established. For the preparation of 4 from 3 using
dihydroquinidine p-chlorobenzoate (DHQD-pClBz) as the chiral aux-
iliary, see: Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56,
2869.
(19) Alternatively, 9a could also be obtained in 50% isolated yield
by reaction of the titanium enolate of S-2-pyridylbenzyloxythioacetate
and the imine derive from 6a . For this approach to â-lactams, see: (a)
Annunziata, R. Benaglia, M.; Cinquini, M.; Cozzi, F.; Ponzini, F. J .
Org. Chem. 1993, 58, 4746. (b) Gennari, C.; Vulpetti, A. In Enanti-
oselective Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH:
New York, 1997; p 151.
(12) For
a review on acyl anion equivalents, see: Hase, T. A.
Umpoled Synthons; J ohn Wiley: New York, 1987.
(13) For general reviews on this subject, see: (a) Backes, J . In
Houben-Weyl, Methoden der Orgaschen Chemie; Muller, E., Bayer, O.,
Eds.; Band E16B.; Thieme: Stuttgart, 1991; p 31. (b) De Kimpe, N. In
Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon:
Oxford; 1996; Vol. 1B., p 507.
(14) (a) Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Urchegui, R.;
Linden, A, J . Org. Chem. 1996, 61, 4400. For a review on Baeyer-
Villiger oxidations of ketones and aldehydes, see: (b) Krow, G. R. Org.
React. 1993, 43, 251.

Aminohomologation of R,â-Dihydroxy Aldehydes
J . Org. Chem., Vol. 65, No. 1, 2000 43
Sch em e 1
Sch em e 2
Sch em e 3
sponding crude reaction products. The uniform stereo-
chemical course of these reactions was established by
conversion of 7a and 9a into the same R-hydroxy â-lactam
11a . On the other hand, the relative cis configuration of
each â-lactam product was determined on the basis of
the 1H NMR coupling constants corresponding to both
hydrogens at C3 and C4 positions (J 3,4 ≈ 5 Hz), whereas
the absolute configuration of the major isomers was
determined by chemical correlation with 13, Scheme 2.
Thus, removal of the acetonide protective group in 9a was
followed by oxidative cleavage of the resulting glycol 12
to give the known 4-formyl azetidin-2-one 13 (Scheme
2).20a
Once we had established the best conditions for high
diastereoselective â-lactam formation, the synthesis of
the homotyrosine framework of echinocandin B was
undertaken. To this end, the 3-hydroxy â-lactam 11a
obtained from 7a as above, was converted into the NCA
14, eq 1, by using a solution of commercial bleach and a
yield. Thus, the access to this NCA, which traditionally
would require the previous synthesis of the corresponding
R-amino acid,15 can now be obtained from a non R-amino
acid precursor in a very concise and practical fashion.
From this approach two additional key elements are
especially noteworthy. First, the creation of the R-amino
stereogenic center of the dihydroxyhomotyrosine segment
with essentially complete diastereoselectivity and, sec-
ond, the generation of the amino acid as an active species
thus overcoming the need of additional protection and
activation steps for peptide couplings.21 Accordingly, the
coupling of 14 with L-threonine should provide the
dipeptide segment found in the west part of echinocandin
B. To this end, the L-threonine derivative 18 was pre-
pared as shown in Scheme 3. Namely, L-threonine was
first transformed into the O-tert-butyldiphenylsilyl de-
(20) (a) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.;
Roma´n, P.; Luque, A.; Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992,
114, 9360. (b) J ayaraman, M.; Deshmukh, A. R.; Bhawal, B. M. J . Org.
Chem. 1994, 59, 932.
(21) For a recent review on coupling methods for the incorporation
of noncoded amino acids into peptides, see: (a) Humphrey, J . M.;
Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. (b) For an annual review
on peptide synthesis, see: (b) Elmore, D. T. In ref 8e.
catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl
(TEMPO). The transformation occurred almost instan-
taneously (3-5 min) to produce 14 in nearly quantitative

44 J . Org. Chem., Vol. 65, No. 1, 2000
Palomo et al.
(column: fused silica gel, 15 m, 0.25 mm, 0.25 mm phase SPB-
5). Optical rotations were measured at 25 (0.2 °C in methylene
chloride unless otherwise stated. HPLC analyses were per-
formed on analitycal columns (25 cm, phase Lichrosorb-Si60)
and (25 cm, phase Chiralpak AS) with flow rates using 1 mL/
min and 0.5 mL/min respectively, using a DAD system. Flash
chromatography was executed with Merck Kiesegel 60 (230-
400 Mesh) using mixtures of ethyl acetate and hexane as
eluants. Et2O and THF were distilled over sodium. Methylene
chloride was shaken with concentrated sulfuric acid, dried over
potassium carbonate and distilled. DMF was purified by
distillation on barium oxide. CH3CN was dried by refluxing
over calcium hydride and distilled. MeOH was dried over
magnessium metal and iodine. HRMS analyses29 were ob-
tained by the LSIMS ionization system using a 3-nitrobenzyl
alcohol matrix and poly(ethylene glycol) as the internal
standard.
Sch em e 4
Gen er a l P r oced u r e for Keta liza tion of 4. To a solution
of the corresponding diol 4 (20 mmol) in benzene (200 mL) was
added 2,2-dimethoxypropane (4.88 mL, 40 mmol) and p-
toluenesulfonic acid monohydrate (0.043 g, 0.2 mmol). The
mixture was stirred at reflux for 30 min and then it was
distilled until 160 mL of liquid was collected. Additional 2,2-
dimetoxypropane (1.22 mL, 10 mmol) and benzene (100 mL)
were added, and the mixture was kept at reflux for 30 min
again, and a further 80 mL of distillate was collected. To the
resulting residue were added Et2O (160 mL) and a saturated
aqueous solution of NaHCO3 (40 mL). The organic phase was
separated and washed with a saturated solution of NaHCO3
(80 mL) and brine (60 mL). The organic solution was dried
over MgSO4 and the solvent removed under reduced pressure.
The crude product was purified by column chromatography
(eluent hexane/ethyl acetate 3:1).
rivative 1622 according to the procedure of Orsini et al.23
Subsequent amino protection and “in situ” esterification
with methyl iodide and DBU24 in benzene as solvent gave
17 in 70% yield over the two steps. Final hydrogenolysis
of 17 afforded pure 18 in high yield. Likewise, the
L-proline derivative 20 was also prepared by standard
silylation of the commercially available 19. As Scheme 4
illustrates, the coupling of 14 with a slight excess of 18
in methylene chloride at room-temperature overnight
provided, after purification by column chromatography,
the dipeptide product 21 in 73% yield. The one-pot25
N-debenzylation of 21 and subsequent Boc-protection
gave 22 in 92% yield as the alternatively protected
adduct. With 21 in hand, the southwest portion of this
cyclic hexapeptide appeared to be more readily built-up.
Thus, the coupling of 23, obtained from standard hydro-
genolysis of 21, with 20 under usual DCC-HOBt condi-
tions26 furnished the tripeptide 24 in 80% yield, after
column chromatography.
Meth yl (2R,3S)-2,3-d ih yd r oxy-2,3-d i-O-isop r op ylid en e-
3-(4-m eth oxyp h en yl)p r op ion a te 5a : yield 4.52 g (85%); oil;
[R]25 ) -20.9 (c ) 1.0, CH2Cl2); IR (film) 1755 cm-1 (CO); 1H
D
NMR (CDCl3, δ) 7.25 (d, 2H, J ) 7.1 Hz), 6.80 (d, 2H, J )
8.84 Hz), 5.00 (d, 1H, J ) 2.57 Hz), 4.24 (d, 1H, J ) 3.02 Hz),
3.67, 3.65, 1.51 and 1.46 (s, 3H); 13C NMR (CDCl3, δ) 171.2,
160.3, 131.9, 129.8, 128.4, 114.5, 114.4, 111.8, 81.7, 81.0, 55.7,
52.8, 27.4, 26.2; MS (FAB) 266.1140 (C14H18O5 requires
266.1154).
Meth yl (2R,3S)-2,3-d ih yd r oxy-2,3-d i-O-isop r op ylid en e-
3-(4-m eth ylp h en yl)p r op ion a te 5b: yield 4.50 g (90%); oil;
In summary, the use of the Sharpless AD in combina-
tion with our â-lactam-derived NCA method27 represents,
from a conceptual standpoint, a new aminohomologation
strategy of R,â-unsaturated carboxylic acid esters that,
in its turn, enables direct peptide couplings.
[R]25 ) -33.8 (c ) 1.0, CH2Cl2); IR (film) 1756 cm-1 (CO); 1H
D
NMR (CDCl3, δ) 7.29 (d, 2H, J ) 8.05 Hz), 7.15 (d, 2H, J )
7.98 Hz), 5.10 (d, 1H, J ) 7.82 Hz), 4.31 (d, 1H, J ) 7.78 Hz),
3.74, 2.32, 1.58, and 1.53 (s, 3H); 13C NMR (CDCl3, δ) 171.2,
138.8, 134.9, 129.7, 126.9, 111.9, 81.7, 81.2, 52.8, 27.4, 26.3,
21.6.
Exp er im en ta l Section
Meth yl (2R,3S)-2,3-d ih yd r oxy-2,3-d i-O-isop r op ylid en e-
3-p h en ylp r op ion a te 5c: yield 4.39 g (93%); oil; [R]25
)
D
Melting points were determined with capillary apparatus
and are uncorrected. Proton nuclear magnetic resonance (300
MHz) spectra and 13C spectra (75 MHz) were recorded at room
temperature for CDCl3 solutions, unless otherwise stated. All
chemical shifts are reported as δ values (ppm) relative to
residual CHCl3 δH (7.26 ppm) and CDCl3 δC (77.7 ppm) as
internal standards, respectively. Mass spectra were obtained
on a mass spectrometer (70 eV) using GC-MS coupling
-28.5 (c ) 1.0, CH2Cl2); IR (film) 1755 cm-1 (CO); H NMR
(CDCl3, δ) 7.42-7.32 (m, 5H), 5.13 (d, 1H, J ) 7.69 Hz), 4.33
(d, 1H, J ) 7.65 Hz), 3.74, 1.58, and 1.53 (s, 3H); 13C NMR
(CDCl3, δ) 171.1, 138.1, 128.9, 128.9, 126.9, 111.9, 81.6, 81.1,
52.7, 27.3, 26.2.
1
Gen er a l P r oced u r e for th e Syn th esis of â-La cta m s. To
a solution of the corresponding methyl ester 5 (13.5 mmol) in
toluene (50 mL) cooled to -78 °C was added dropwise a 1 M
solution of diisobutylaluminum hydride in hexane (20 mL, 20
mmol), ensuring that the temperature was below -70 °C
during addition. The solution was stirred at the same tem-
perature for 2 h, MeOH (6 mL) was added, and the resulting
solution was poured into a cold (0 °C) solution of 1 N HCl (60
mL). The resulting solution was stirred for 1 h at 0 °C and
then extracted with EtOAc (3 × 60 mL). The combined organic
phase was washed with brine (60 mL) and dried over MgSO4
and the solvent evaporated under reduced pressure to give the
respective aldehyde 6 as an oil, which was used as such in
the next step. A mixture of thus prepared aldehyde 6, 4A MS,
(22) For the use of the tert-butyldiphenylsilyl moiety as protective
group of the hydroxyl function in peptide synthesis, see: Davies, J .
S.; Higginbotham, C. L.; Tremeer, E. J .; Brown, C.; Treadgold, R. C.
J . Chem. Soc., Perkin Trans. 1 1992, 3043.
(23) Orsini, F.; Pelizzoni, F.; Sisti, M.; Verotta, L. Org. Prep. Proc.
Int. 1989, 21, 505.
(24) Ono, N.; Yamada, T.; Saito, T.; Tanaka, K.; Kaji, A. Bull. Chem.
Soc. J pn. 1978, 51, 2401.
(25) Bajwa, J . S. Tetrahedron Lett. 1992, 33, 2955.
(26) (a) Ko¨ning, W.; Geiger, R. Chem. Ber. 1970, 103, 788. (b) Lloyd-
Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches to the
Synthesis of Peptides and Proteins; CRC Press: New York, 1997.
(27) For the application of this aminohomologation strategy to
peptidyl nucleoside antibiotics, see: (a) Palomo, C.; Oiarbide, M.; Esnal,
A.; Landa, A.; Miranda, J . I.; Linden, A. J . Org. Chem. 1998, 63, 5838.
For a brief account on this subject, see: (b) Palomo, C.; Aizpurua, J .
M.; Ganboa, I. Oiarbide, M. Amino Acids 1999, 16, 321.
(28) Zhong, Y.-L., Shing, T. K. M. J . Org. Chem. 1997, 62, 2622.
(29) We thank Dr. J esu´s Orduna of the Universidad de Zaragoza,
Zaragoza, Spain for performing the HRMS analyses here included.

Aminohomologation of R,â-Dihydroxy Aldehydes
J . Org. Chem., Vol. 65, No. 1, 2000 45
and benzylamine (13.5 mL, 13 mmol) in methylene chloride
(50 mL) was stirred at 0 °C under a nitrogen atmosphere for
1 h. The solution was filtered, the solvent evaporated, and the
residue analyzed by 1H NMR to ensure complete consumption
of the aldehyde. The crude imine thus obtained was dissolved
in dry methylene chloride (40 mL) and cooled to -78 °C under
a nitrogen atmosphere, and to the resulting solution were
successively added triethylamine (3.22 mL, 23 mmol) and
dropwise a solution of (acetoxy)acetyl chloride (1.6 mL, 15
mmol) or benzyloxyacetyl chloride (2.38 mL, 15 mmol) in dry
methylene chloride (20 mL). The resulting mixture was stirred
overnight at room temperature and then was washed with
water (20 mL), 0.1 N HCl (20 mL), and a saturated aqueous
solution of NaHCO3 (20 mL). The organic layer was dried over
MgSO4 and filtered, and the solvent was evaporated under
reduced pressure to give the crude â-lactam product, which
was further purified by column chromatography.
solution of 2.57 g of NaIO4 in 5 mL of water)28 (2.0 g) was
suspended on 5 mL of methylene chloride. To this slurry, was
added a solution of diol 12 (0.433 g, 1 mmol) in methylene
chloride (5 mL), and the resulting mixture was stirred at room
temperature for 1 h. Then the solution was filtered and the
solvent evaporated to give essentialy pure compound 13 as a
white solid: yield 0.266 g (90%); mp 114-116 °C; [R]25
)
D
+87.66 (lit.20a mp 114-116 °C; [R]25 ) +86.7).
D
P r ep a r a tion of r-Am in o Acid N-Ca r boxya n h yd r id e 14.
To a magnetically stirred solution of 3-hydroxyazetidine-2-one
11a (0.57 g, 1.5 mmol) in 25 mL of methylene chloride were
added 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) (0.003 g,
0.015 mmol) and a solution of potassium bromide (0.018 g, 0.15
mmol) in water (0.25 mL) at room temperature. The solution
was cooled to -5 to 0 °C (ice-salt bath), and aqueous sodium
hypochlorite (Aldrich, 23,930-5) (15 mL) buffered at pH 7 (0.9
g of sodium hydrogen carbonate for 45 mL of a concentrate
buffer solution phosphate, Aldrich 22,358-1) was added. The
resulting reaction mixture was stirred at 0 °C for 3 min. The
organic layer was separated and washed with 30 mL of 10%
HCl containing 0.75 g of KI, a 10% solution of Na2S2O3 (15
mL), and water (15 mL). The resulting solution was dried over
MgSO4, and the solvent was evaporated under reduced pres-
sure to afford the corresponding NCA: yield 0.6 g (98%); oil;
1H NMR (CDCl3, δ) 7.39-7.22 (m, 5H), 7.13 (d, 2H, J ) 8.61
Hz), 6.85 (d, 2H, J ) 8.75 Hz), 5.02 (d, 1H, J ) 15.37 Hz),
4.94 (m, 1H0, 4.15 (m, 2H), 4.08 (d, 1H, J ) 15.38 Hz), 3.78
(s, 3H), 1.54 and 1.44 (s, 3H); 13C NMR (CDCl3, δ) 166.1, 160.8,
136.2, 135.5, 134.4, 129.9-128.4, 114.9, 111.2, 81.9, 79.9, 59.4,
56.0, 47.3, 27.9, 27.5; EIMS (m/z) 255, 177 (BP).
Da ta for 7a : yield 5.11 g (89%); mp 101-103 °C; [R]25
)
D
+12.3 (c ) 1.0, CH2Cl2); IR (KBr) 1763 cm-1 (CO), 1751 cm-1
1
(CO); H NMR (CDCl3, δ) 7.38 (m, 5H), 7.12 (d, 2H, J ) 8.61
Hz), 6.85 (d, 2H, J ) 8.74 Hz), 5.81 (d, 1H, J ) 4.93 Hz), 4.95
(d, 1H, J ) 14.83 Hz), 4.55 (d, 1H, J ) 7.91 Hz), 4.22 (d, 1H,
J ) 14.97 Hz), 4.20 (t, 1H, J ) 7.71 Hz), 3.81 (q, 1H, J ) 4.95
Hz, J ′ ) 7.73 Hz), 3.77, (s, 3H), 1.53 (s, 3H), 1.45 and 1.39 (s,
3H); 13C NMR (CDCl3, δ) 169.7, 165.3, 160.5, 135.7, 129.3,
129.1, 128.5, 114.7, 110.3, 82.0, 81.9, 73.9, 58.5, 55.9, 46.2, 27.8,
27.7, 20.2; EIMS m/z 426 (M+). Anal. Calcd for C24H27NO6
(425.48): C, 67.82; H, 6.40; N, 3.29. Found: C, 67.45; H, 6.52;
N, 3.40.
Da ta for 7b: yield 4.86 g (88%); mp 93-95 °C; [R]25
)
D
+16.1 (c ) 1.0, CH2Cl2); IR (KBr) 1780 cm-1 (CO), 1750 cm-1
(CO); 1H NMR (CDCl3, δ) 7.35-7.03 (m, 9H), 5.78 (d, 1H, J )
4.94 Hz), 4.90 (d, 1H, J ) 14.8 Hz), 4.50 (d, 1H, J ) 7.9 Hz),
4.22 (d, 1H, J ) 14.9 Hz), 4.19 (m, 1H), 3.78 (q, 1H, J ) 4.8
Hz), 2.27, 1.51, 1.37 and 1.35 (s, 3H); 13C NMR (CDCl3, δ)
169.4, 165.1, 138.8, 135.7, 134.1, 129.8, 129.4, 129.2, 129.0,
128.3, 128.0, 127.8, 110.2, 81.9, 73.8, 58.3, 58.1, 46.0, 27.6, 21.4,
19.8. Anal. Calcd for C29H27NO5 (409.48): C, 70.40; H, 6.65;
N, 3.42. Found: C, 70.47; H, 6.61; N, 3.50.
Dip ep tid e P r od u ct 21. To a solution of the NCA 14 (0.397
g, 1 mmol) in CH2Cl2 (5 mL) was added (S)-Thr(OSitBuPh2)-
OMe 18 (0.56 g, 1.5 mmol) and the resulting mixture stirred
at room temperature for 24 h. Then diethyl ether (10 mL) was
added, the organic layer was washed with 0.1 N HCl (2 × 5
mL) and with a saturated aqueous solution of NaHCO3 (2 × 5
mL) and dried over MgSO4, and the solvent was evaporated
under reduced pressure to afford compound 21, which was
purified by column chromatography (eluent hexane/ethyl
Da ta for 7c: yield 4.48 g (84%); mp 77-80 °C; [R]25D ) +18.6
(c ) 1.0, CH2Cl2); IR (KBr) 1763 cm-1 (CO), 1751 cm-1 (CO);
1H NMR (CDCl3, δ) 7.44-7.21 (m, 10H), 5.85 (d, 1H, J ) 4.94
Hz), 4.94 (d, 1H, J ) 14.6 Hz), 4.60 (d, 1H, J ) 7.87 Hz), 4.27
(d, 1H, J ) 14.65 Hz), 4.24 (t, 1H, J ) 7.86 Hz), 3.85 (dd, 1H,
J ) 7.73 Hz), 1.58, 1.44 and 1.40 (s, 3H); 13C NMR (CDCl3, δ)
169.1, 164.8, 137.1, 135.1, 128.9, 128.8, 128.0, 127.6, 110.1,
81.8, 73.6, 58.1, 45.8, 27.3, 19.7. Anal. Calcd for C23H25NO5
(395.45): C, 69.86; H, 6.37; N, 3.54. Found: C, 69.70; H, 6.30;
N, 3.50.
acetate 3:1): yield 0.53 g (73%); oil; [R]25 ) -6.7 (c ) 1.0,
D
CH2Cl2); IR (film) 1743 cm-1 (CO), 1677 cm-1 (CO); H NMR
1
(CDCl3, δ) 8.20 (d, 1H, J ) 9.75 Hz), 7.69-7.33 (m, 15H), 7.25
(d, 2H, J ) 8.74 Hz), 6.81 (d, 2H, J ) 8.75 Hz), 5.04 (d, 1H, J
) 8.01 Hz), 4.48 (1H), 4.40 (d, 1H, J ) oo Hz), 4.15 (m, 2H),
3.87 (d, 1H, J ) 13.01 Hz), 3.75 (s, 3H), 3.63 (s, 3H), 3.41 (d,
1H, J ) 5.35 Hz), 1.60 and 1.53 (s, 3H), 1.06 (s, 9H), 0.66 (d,
3H, J ) 6.40 Hz); 13C NMR (CDCl3, δ) 172.0, 171.6, 160.2,
140.0, 136.4, 134.4, 133.5, 130.5-127.8, 109.8, 84.2, 80.3, 70.6,
64.1, 57.9, 55.8, 52.9, 52.7, 27.9, 27.4, 20.7, 19.8; MS (FAB)
725.3601 (C42H53N2O7Si requires 725.3622).
3-Hyd r oxya zetid in -2-on e 11a . To a solution of 3-acetoxy
â-lactam 7a (4.25 g, 10 mmol) in a mixture of THF (50 mL)
and water (34 mL) at 0 °C were added LiOH (0.48 g, 20 mmol)
and a 30% solution of H2O2 (6.1 mL, 60 mmol). The resulting
solution was stirred at the same temperature for 1 h, and then
a solution of Na2SO3 (1.5 M, 33.3 mL, 50 mmol) was added.
Most of the THF was removed from the mixture under
vacuum. The resulting residue was dissolved in methylene
chloride (50 mL), the solution was washed with a saturated
solution of NaHCO3 (2 × 100 mL) and dried over MgSO4, and
the solvent was finally removed under reduced pressure. The
crude product thus obtained was purified by crystallization
Dip ep tid e P r od u ct 22. To a solution of 21 (0.52 g, 0.72
mmol) and (Boc)2O (0.33 g, 1.5 mmol) in EtOAc (5 mL) was
added 10% Pd(OH)2 on charcoal (0.052 g), and the mixture was
kept under hydrogen (1 atm) at room temperature for 16 h.
Then, the suspension was filtered through a pad of Celite and
evaporated to yield 22, which was purified by column chro-
matography (eluent hexane/ethyl acetate 3:1 to 1:1): yield 0.50
g (92%); oil; [R]25 ) -7.9 (c ) 1.0, CH2Cl2); IR (film) 3505
D
cm-1 (NH), 1748 cm-1 (CO), 1720 cm-1 (CO), 1683 cm-1 (CO);
1H NMR (CDCl3, δ) 7.66-7.35 (m, 12H), 6.90 (d, 2H, J ) 8.68
Hz), 5.38 (d, 1H, J ) 8.86 Hz), 4.67 (d, 1H, J ) 8.79 Hz), 4.45
(m, 3H), 4.40 (d, 1H, J ) 8.79 Hz), 3.80, 3.61, 1.56 and 1.55 (s,
3H), 1.49 and 1.02 (s, 9H), 0.99 (d, 3H, J ) 6.23 Hz); 13C NMR
(CDCl3, δ) 171.2, 170.5, 160.5, 136.4-128.3, 114.8, 110.0, 82.6,
79.9, 70.8, 58.6, 55.9, 53.1, 52.9, 30.4, 28.9, 27.8, 27.6, 27.5,
21.4, 19.9; MS (FAB) 867.2643 (C40H54N2O9CsSi requires
867.2653).
from diethyl ether: yield 3.22 g (84%); mp 227-229 °C; [R]25
D
) -15.1 (c ) 1.0, CH2Cl2); IR (KBr) 1725 cm-1 (CO); 1H NMR
(CDCl3, δ) 7.6-7.24 (m, 5H), 6.87-6.82 (d, 2H, J ) 8.93 Hz),
6.76-6.72 (d, 2H, J ) 8.89 Hz), 5.02 (d, 1H, J ) 15.36 Hz),
4.81 (q, 1H, J ) 11.53 Hz, J ′ ) 4.94 Hz), 4.65 (d, 1H, J ) 9.15
Hz), 4.19 (d, 1H, J ) 15.38 Hz), 3.91 (dd, 1H, J ) 9.11 Hz, J ′
) 2.15 Hz), 3.74 (s, 3H), 3.64 (q, 1H, J ) 4.94 Hz, J ′ ) 2.20
Hz), 3.04 (d, 1H, J ) 4.94 Hz, J ′ ) 11.57 Hz), 1.54 and 1.45 (s,
3H). 13C NMR (CDCl3, δ) 170.1, 160.6, 135.5, 129.7-128.2,
114.8, 110.7, 81.5, 80.5, 78.0, 56.8, 55.9, 46.3, 28.1, 27.9. Anal.
Calcd for C22H25NO5 (383.44): C, 68.91; H, 6.57; N, 3.65.
Found: C, 68.59; H, 6.13; N, 3.86.
Tr ip ep tid e P r od u ct 24. A mixture of the dipeptide 21
(0.725 g, 1 mmol), MeOH (5 mL), and 10% Pd on charcoal
(0.072 g) was kept under hydrogen (1 atm) at room tempera-
ture overnight. Then, the solution was filtered through a pad
of Celite and the solvent evaporated under reduced pressure
to afford compound 23 (0.58 g, 92%). A solution of thus
obtained crude 23, the amino acid 20 (0.87 g, 1.8 mmol), DCC
(0.37 g, 1.8 mmol), and HOBt (0.2 g, 1.5 mmol) in THF (5 mL)
Oxid a tion of Diol 12. Silica gel precoated with NaIO4
(prepared by adding 10 g of silica gel to a vigorously stirred

46 J . Org. Chem., Vol. 65, No. 1, 2000
Palomo et al.
was stirred at 0 °C for 1 h and at room temperature for an
additional 1 h. The solution was filtered and the solvent
removed under vacuum. The resulting residue was dissolved
in EtOAc (40 mL) and washed with a saturated aqueous
solution of NaHCO3 (20 mL), 1 N citric acid (20 mL), saturated
NaHCO3 (20 mL), and water. The organic phase was dried over
MgSO4 and the solvent evaporated under reduced pressure to
give the title compound, which was purified by column
chromatography (eluent hexane:ethyl acetate 1:1): yield 0.89
128.7, 128.6, 128.4, 128.4, 128.3, 128.2, 128.0, 114.6, 109.8,
81.9, 79.7, 72.2, 70.6, 68.2, 60.5, 58.7, 55.7, 52.9, 52.8, 51.6,
38.6, 27.8, 27.5, 27.4, 27.3, 21.3, 19.7, 19.6; MS (FAB)
1142.5041 (C64H77N3O11NaSi requires 1142.4994).
Ack n ow led gm en t. This work was financially sup-
ported by Universidad del Pa´ıs Vasco (Project 170.215-G
47/98) and by Ministerio de Educacio´n y Cultura,
Spanish Government (Project SAF-98-0159-CO2-01).
g (80%); oil; [R]25 ) -8.9 (c ) 1.0, CH2Cl2); IR (film) 1751,
D
1655-1700 (broad) cm-1 (CO); 1H NMR (CDCl3, δ) 7.63-7.22
(m, 25H), 7.20 (d, 2H, J ) 8.11 Hz), 7.05 (d, 1H, J ) 8.89 Hz),
6.75 (d, 2H, J ) 8.17 Hz), 5.15 (d, 1H, J ) 12.21 Hz), 5.05 (d,
1H, J ) 12.26 Hz), 4.73 (d, 1H, J ) 7.76 Hz), 4.59, 4.45 and
4.28 (m, 2H), 4.07 (m, 1H), 3.62 and 3.58 (s, 3H), 3.51, 3.08,
2.14 and 1.91 (m, 1H), 1.53 (s, 6H), 0.99 and 0.97 (s, 9H), 0.97
(s, 3H); 13C NMR (CDCl3, δ) 172.5, 171.1, 169.9, 160.3, 157.1,
136.7, 136.4, 136.2, 136.1, 134.2, 133.9, 133.7, 133.3, 130.7,
130.6, 130.5, 130.5, 129.5, 129.4, 129.4, 129.3, 129.1, 18.9,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 4a -c,
9a -c, 11a , 12, 16-18, and 20, including copies of some
representative 1H and 13C NMR spectra, HPLC chromato-
grams, and HRMS spectra.29 This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990964C