Synthesis of Cyclic β-Amino Acid Esters from Methionine, Allylglycine, and Serine

Article abstract of DOI:10.1021/jo049794g

Here we report a versatile ring-closing metathesis-based approach to 5-, 6-, and 7-membered cyclic β-amino esters starting with simple and readily available building blocks-methionine, allylglycine, and serine-where the nature of the amino acid determines

Full text of DOI:10.1021/jo049794g

Syn th esis of Cyclic â-Am in o Acid Ester s fr om Meth ion in e,
Allylglycin e, a n d Ser in e
J ames Gardiner, Kelly H. Anderson, Alison Downard, and Andrew D. Abell*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
a.abell@chem.canterbury.ac.nz
Received February 4, 2004
Here we report a versatile ring-closing metathesis-based approach to 5-, 6-, and 7-membered cyclic
â-amino esters starting with simple and readily available building blockssmethionine, allylglycine,
and serineswhere the nature of the amino acid determines the size of the carbocyclic ring.
In tr od u ction
â-Peptides are biologically and structurally important
oligomers of â-amino acids that possess a high resistance
to peptidase hydrolysis1,2 and an ability to adopt stable
secondary structures such as helices, sheets, and turns.3,4
For example, oligomers of trans-2-aminocyclopentanecar-
boxylic acid 1 and trans-aminocyclohexanecarboxylic acid
2 have recently been shown by Gellman and co-workers
to form 14- and 12-helices that are generally more rigid
and stable than those comprised of linear R- and â-amino
acids (Figure 1).5-7 Furthermore, modification of the
carbocyclic ring of these monomeric units to include
additional functional groups has led to foldamers with
enhanced solubility in aqueous media.8 As such, â-pep-
tides have promise as a new class of medicinal agents
with application to the generation of inhibitors of a range
of biological processes.2,9-11
F IGURE 1. Cyclic â-amino acids and RCM catalysts.
resolution as a key step. Recently, several enantioselec-
tive syntheses have also been reported.20-25 Here, we
report a versatile method for the preparation of a range
of functionalized cyclic â-amino esters from simple and
readily available building blockssmethionine, allylgly-
cine, and serineswhere the nature of the amino acid
starting material determines the size of the carbocyclic
ring. The key to our strategy is the diastereoselective
preparation of dienes of type 6 (Figure 2), which cyclize
in the presence of catalysts 3 or 4 to give cyclopentenyl,
cyclohexenyl,26 and cycloheptenyl-based â-amino esters
A number of methods have been reported for the
preparation of cyclic â-amino acids,7,12-19 the majority of
which employ an enzymatic resolution or chemoselective
(1) Frackenpohl, J .; Arvidsson, P. I.; Schreiber, J . V.; Seebach, D.
ChemBioChem 2001, 2, 445-455.
(2) Weigand, H.; Wirz, B.; Schweitzer, A.; Camenisch, G. P.; Rod-
riguez-Perez, M. I.; Gross, R.; Woessner, R.; Voges, R.; Arvidsson, P.
I.; Franckenpohl, J .; Seebach, D. Biopharm. Drug Dispos. 2002, 23,
251-262.
(14) Bolm, C.; Schiffers, I.; Dinter, C. L.; Defrere, L.; Gerlach, A.;
Raabe, G. Synthesis 2001, 1719-1730.
(15) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S.
H. Nature 2000, 405, 298.
(3) J uaristi E., E. Enantioselective Synthesis of â-Amino Acids;
Wiley-VCH: New York, 1997.
(4) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
101, 3219-3232.
(16) Schinnerl, M.; Murray, J . K.; Langenhan, J . M.; Gellman, S.
H. Eur. J . Org. Chem. 2003, 721-726.
(5) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J . Am. Chem. Soc. 1996, 118, 13071-13072.
(6) Appella, D. H.; Christianson, L. A.; Karle, I. A.; Powell, D. R.;
Gellman, S. H. J . Am. Chem. Soc. 1999, 121, 6206-6212.
(7) LePlae, P. R.; Umezawa, N.; Lee, H.-S.; Gellman, S. H. J . Org.
Chem. 2001, 66, 5629-5632.
(17) Woll, M. G.; Fisk, J . D.; LePlae, P. R.; Gellman, S. H. J . Am.
Chem. Soc. 2002, 124, 12447-12452.
(18) Nohira, H.; Ehara, K.; Miyashita, A. Bull. Chem. Soc. J pn. 1970,
43, 2230-2233.
(19) Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron
Lett. 1984, 25, 2557.
(20) Wipf, P.; Wang, X. Tetrahedron Lett. 2000, 41, 8747-8751.
(21) Enders, D.; Bettray, W.; Schankat, J .; Wiedemann, J . In
Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-
VCH: New York, 1997; pp 187-210.
(22) Enders, D.; Wiedemann, J . Liebigs Ann./ Recueil 1997, 699-
706.
(8) Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J .
Org. Chem. 2000, 65, 4766-4769.
(9) Hamuro, Y.; Schneider, J . P.; DeGrado, W. F. J . Am. Chem. Soc.
1999, 121, 12200-12201.
(10) Arvidsson, P. I.; Frackenpohl, J .; Ryder, N. S.; Liechty, B.;
Petersen, F.; Zimmermann, H.; Camenisch, G. P.; Woessner, R.;
Seebach, D. ChemBioChem 2001, 2, 771-773.
(23) Enders, D.; Wiedemann, J .; Bettray, W. Synlett 1995, 369-
371.
(11) Seebach, D.; Rueping, M.; Arvidsson, P. I.; Kimmerlin, T.;
Micuch, P.; Langenegger, D.; Hoyer, D. Helv. Chim. Acta 2001, 84,
3503-3510.
(24) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.;
Smethurst, C. A. P.; Smith, A. D.; Rodrigues-Solla, H. Tetrahedron
2003, 59, 3253-3265.
(25) Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J . Org. Chem. 2003,
4, 756-760.
(12) Fulop, F. Chem. Rev. 2001, 101, 2181-2204.
(13) Berkessel, A.; Glaubitz, K.; Lex, J . Eur. J . Org. Chem. 2002,
2948-2952.
10.1021/jo049794g CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/07/2004
J . Org. Chem. 2004, 69, 3375-3382
3375

Gardiner et al.
SCHEME 1a
F IGURE 2. Retrosynthetic analysis.
of type 7. There are few reports on 7-membered cyclic
â-amino esters, and their related acids, of the type
reported here.12,27
Resu lts a n d Discu ssion
Preparations of the key unsubstituted dienes of type
6, specifically (-)-11, (+)-13, and (-)-16, from the amino
acids (S)-methionine, (R)-allyl glycine, and (S)-serine are
shown in Scheme 1, pathways A, B, and C, respectively.
The syntheses begin with an Arndt-Eistert homologation
of the appropriate R-amino acid28 to give the correspond-
ing â-amino acid, which is stereoselectively allylated to
introduce one of the olefinic groups of the diene, the
second being derived from the amino acid R group. The
R groups of the serine- and methionine-based examples
provide a masked alkene that is liberated at the ap-
propriate time in the synthesis to give the required diene.
Natural (S)-methionine and (S)-serine were used in the
preparation of (-)-11 and (-)-16, while (R)-allylglycine
was used to prepare (+)-13. A second series of R-substi-
tuted dienes (-)-19, (()-21, and (()-22 were also pre-
pared in an analogous fashion by carrying out a second
alkylation step as shown in Schemes 2 and 3.
a
Reagents and conditions: (a) (i) Et3N, ClCO2Et, THF, -15 °C,
15 min; (ii) CH2N2, 0 °C; (iii) AgBz, Et3N, MeOH, -25 °C; (b) (i)
H2O2, AcOH, rt 4 h, (ii) xylene 200 °C, sealed tube; (c) LiCl, 2 equiv
of LDA, allyl bromide, THF, -78 °C; (d) NaOH, MeOH, reflux.
SCHEME 2a
Thus, (3R)-3-benzyloxycarbonylamino-5-methylsulfan-
ylpentanoic acid methyl ester (-)-8 was prepared from
Cbz-protected methionine in 93% yield over two steps
(Scheme 1). Conversion to diene (-)-11 then required
oxidative elimination of the methylsulfanyl side chain
and an allylation R to the ester group. In the first
instance, we found that oxidation of the methylsulfanyl
group of (-)-8, using hydrogen peroxide in acetic acid,
followed by thermal elimination, at 200 °C in xylene in
a sealed tube,29,30 gave the vinyl â-amino acid methyl
ester 9 in 63% yield (Scheme 1, pathway D). Subsequent
alkylation of 9, in the presence of LDA and allyl bromide,
gave the optically active diene (-)-11 as a single diaste-
(26) Abell, A. D.; Gardiner, J . Org. Lett. 2002, 4, 3663-3666.
(27) Fustero, S.; Bartolome, A.; Sanz-Cervera, J . F.; Sanchez-Rosello,
M.; Soler, J . G.; de Arellano, C. R.; Fuentes, A. S. Org. Lett. 2003, 5,
2523-2526.
a
Reagents and conditions: (a) (i) LiCl, 2 equiv of LDA, THF,
-78 °C, MeI; (b) LiCl, 2 equiv of LDA, THF, -78 °C, allyl bromide,
(c) (i) H2O2, AcOH, rt 15 min, (ii) xylene, 200 °C, sealed tube.
(28) Podlech, J .; Seebach, D. Liebigs Ann. 1995, 1217; Seebach, D.;
Esterman, H. Tetrahedron Lett. 1987, 28, 3103-3106.
(29) Afzali-Ardakani, A., Rapoport, H. J . Org. Chem. 1980, 45,
4817-4820.
(30) Weber, T., Aeschimann, R., Waetzke, T. Seebach, D. Helv. Chim.
Acta 1986, 69, 1365-1377.
reoisomer31 by 1H NMR spectroscopy, in 27% yield.
However, a reversal in the order of the steps, i.e.,
allylation followed by oxidative elimination (pathway E),
gave an improved yield of the required diene. In particu-
3376 J . Org. Chem., Vol. 69, No. 10, 2004

Synthesis of Cyclic â-Amino Acid Esters
SCHEME 3a
The diene (-)-16 was prepared from (S)-serine using
the general method described for the preparation of (-)-
11 and (+)-13sallylation of 3-tert-butoxycarbonylamino-
hept-6-enoic acid methyl ester (-)-15 gave diene (-)-16,
1
as a single diastereoisomer by H NMR spectroscopy,31
in 42% yield after chromatography. The key starting
R-amino ester, N-Boc-but-3-enylglycine methyl ester (-)-
14, was obtained in 82% yield from N-Boc-(S)-serine
methyl ester, via reaction of the corresponding iodide
with zinc dust and allyl chloride in the presence of CuBr‚
SMe2.36 Hydrolysis of the methyl ester of (-)-14, followed
by C-terminus extension using Ardnt-Eistert methodol-
ogy, gave (-)-15 in 92% yield over two steps. It is worth
noting that the enantiomer (+)-15 can be similarly
prepared from (S)-aspartic acid.37
With the R-substituted â-amino ester dienes in hand,
we next demonstrated an ability to prepare R,R-disub-
stituted dienes in which a second substituent is intro-
duced stereoselectively at the R-position; see Schemes 2
and 3 for the preparation of R,R-disubstituted dienes (-)-
19, (()-21a , (()-21b, and (()-22. Here, alkylation of (-)-8
(prepared as shown in Scheme 1) with methyl iodide gave
the R-methyl substituted ester (-)-17 as a single dia-
a
Reagents and conditions: (a) (i) LiCl, 2 equiv of LDA, THF,
-78 °C, MeI or EtI; (b) LiCl, 2 equiv of LDA, THF, -78 °C, allyl
bromide.
1
stereoisomer31 by H NMR spectroscopy in 92% yield. A
second alkylation with allyl bromide gave R,R-disubsti-
tuted (-)-18, again as a single diastereoisomer and in
43% yield.31 Oxidative elimination of the methyl sulfanyl
group of (-)-18 then gave the desired R-methyl-R-allyl-
substituted diene (-)-19 in 88% yield over two stepss
we chose to carry out the oxidative elimination as the
final step in keeping with our earlier observation that
this sequence gave the best yields of (-)-11.
lar, alkylation of (-)-8 in the presence of LDA and allyl
1
bromide gave (-)-10 as a single diastereoisomer by H
NMR spectroscopy,31 in 53% yield. Oxidation and thermal
elimination of the methylsulfanyl group of (-)-10 pro-
ceeded cleanly to give diene (-)-11 in 76% yield after
chromatography (41% yield from (-)-8). An optical rota-
tion of -37° was obtained for samples of (-)-11 prepared
by pathways D and E.
Hexenoate-based dienes (()-21a and (()-21b were
prepared in a manner similar to that described for (-)-
19. Here, alkylation of (()-12 (prepared from racemic
allyl glycine)38 with either methyl or ethyl iodide gave
the R-methyl- and R-ethyl-substituted esters (()-20a and
(()-20b, respectively. These were then allylated to give
dienes (()-21a and (()-21b, with the stereochemistry
shown,31 and in 47% and 42% yield, respectively. The
allylation/methylation sequence was reversed to provide
(()-22 in 68% yield via the intermediacy of (()-13, thus
further demonstrating the versatility of the methodology.
The thus-prepared dienes 11, 13, 16, 19, 21a ,b, and
22 were subjected to ring-closing metathesis (RCM)
conditions in order to prepare the desired cyclic â-amino
esters, and the results of these studies are summarized
in Table 1. Initially, RCM reactions were carried out on
the unsubstituted dienes 11, 13, and 16 using Grubbs’
ruthenium catalysts 3 or 4, in benzene at rt, and in all
cases ring-closure proceeded in high yield, 92%, 91%, and
93%, respectively. It is worth noting that the diene 13
cyclized equally well in the presence of 3 at rt and at
reflux to give the six-membered cyclic â-amino ester 24
in high yield. However, in the case of (-)-11, refluxing
conditions gave rise to some isomerization of the double
bond of the five-membered cyclic â-amino ester (+)-23
to give 29 (see Figure 3)s1.5:1 by 1H NMR spectroscopy.
In a preliminary communication, we reported the
synthesis of diene (+)-13 in >95% ee from optically active
(+)-12, itself obtained by Evan’s chiral auxiliary chem-
istry.26 We now report full details for the conversion of
(+)-12 to (+)-13 and an alternative method for the
preparation of (+)-12 from optically active allylglycine
via an Arndt-Eistert homologationsa method analogous
to that described for (-)-10 above. We also report full
details for the RCM cyclization of (+)-13 to the six-
membered cyclic amino acid (-)-24. (R)-Allyglycine was
obtained commercially and by asymmetric allylation of
a chiral Ni(II)-glycine complex using the method of
Belokon et al.32-35 Stereoselective alkylation of (+)-12
with allyl bromide gave (+)-13 as a single diastereoisomer
by 1H NMR spectroscopy,31 in 59% yield after purification,
the data for which was consistent with that obtained
previously.26
(31) It is well documented that these conditions proceed via a doubly
lithiated intermediate where alkylation of the enolate takes place with
relative topicity lk-1, 2.28 In all cases, we found little or no evidence of
a minor isomer in the NMR spectra of crude mixtures before chroma-
tography.
(32) Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov, Y. T.;
Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin, V. A.; Ryzhov, M. G.;
Lysova, L. A.; Bakhmutov, V. I.; Belikov, V. M. J . Am. Chem. Soc. 1985,
107, 4252-4259.
(33) Belokon, Y. N.; Tararov, V. I.; Maleev, V. I.; Savel’eva, T. F.;
Ryzhov, M. G. Tetrahedron: Asymmetry 1998, 9, 4249-4252.
(34) Collet, S.; Bauchat, P.; Danion-Bougot, R.; Danion, D. Tetra-
hedron Asym. 1998, 9, 2121-2131.
(35) Collet, S.; F.Carreaux; Boucher, J .-L.; Pethe, S.; Lepoivre, M.;
Danion-Bougot, R.; Danion, D. J . Chem. Soc., Perkin Trans. 1 2000,
177-182.
(36) Rodriguez, A.; Miller, D. D.; J ackson, R. F. W. Org. Biomol.
Chem. 2003, 1, 973-977.
(37) Dexter, C. S.; J ackson, R. F. W. J . Org. Chem. 1999, 64, 7579-
7585.
(38) Racemic material was used in this case since the reactions were
done on a large scale.
J . Org. Chem, Vol. 69, No. 10, 2004 3377

Gardiner et al.
SCHEME 4a
TABLE 1. RCM Cycliza tion s
a
Reagents and conditions: (a) 10% Pd-carbon, H2, MeOH, rt;
(b) Boc2O, NaHCO3, MeOH, rt; (c) DIEA, CbzCl, DMAP, CH2Cl2,
rt.
isomeric mixture of 23 and 29, obtained previously
through the cyclization of diene (-)-11 at reflux, was
reduced under the same conditions to give (+)-30 as the
sole product by 1H NMR spectroscopy, further confirming
our assignment of (+)-23 and 29. The optical rotation of
this sample of (+)-30 was also in accordance with the
39
literature value.
In conclusion, we have reported methods for the
construction of methionine, allylglycine, and serine-
derived dienes and their RCM conversion to 5-, 6-, and
7-membered cyclic â-amino esters, respectively. The R
groups of methionine and serine provide a masked alkene
that is liberated at the appropriate time in the synthesis.
The amino acid-derived dienes cyclize equally well in
refluxing benzene with either Grubbs’ first- or second-
generation catalysts, the exception being the 5-membered
series where some doubl-bond isomerization was evident
at elevated temperatures. We have also presented meth-
ods for the stereoselective introduction of a further
substituent into the diene and hence the product cyclic
â-amino esters. The double bond in the cyclic â-amino
esters provides suitable functionality for further deriva-
tization.40 Finally, the double bonds of cyclic â-amino
esters were hydrogenated to give the saturated analogues
which were, in the case of 30 and 31, identical in all
respects with literature compounds.8,39
a
All reactions were carried out in benzene except for c, where
b
CH2Cl2 was used. Isolated yield after chromatography.
F IGURE 3.
Given this, we chose to treat the related, but further
substituted, diene (-)-19 with 4 at rt in order to minimize
the likelihood of double-bond isomerization. This resulted
in a high yield of (+)-26 without evidence of double-bond
isomerization. The substituted six-membered cyclic â-ami-
no esters 27a , 27b, and 28 were all prepared on treat-
ment of the respective diene with 4 at reflux, and as for
diene 13, double-bond isomerization was not observed.
Exp er im en ta l Section
Gen er a l Meth od A: R-Alk yla tion of â-Am in o Ester s.
To a suspension of anhydrous LiCl (3 equiv) in THF at -78
°C under argon was added LDA (2.2 equiv), and the solution
was stirred at -78 °C for 10 min. The N-protected â-amino
acid methyl ester (1 equiv) was then added, and the mixture
was stirred at -78 °C for 1 h. The electrophile (4 equiv) was
added slowly, and the mixture was stirred at -78 °C for 2 h
and then allowed to warm to rt over 16 h. The reaction was
quenched with aqueous saturated NH4Cl, and the organic
Finally, the alkenes (+)-23, (-)-24, and (+)-25 were
reduced to the corresponding cycloalkanes (+)-30, (-)-
31, and (+)-32 as outlined in Scheme 4. Optical rotations
obtained for aminocyclopentane carboxylic acid methyl
ester (+)-30 and aminocyclohexane carboxylic acid meth-
yl ester (-)-31 were in close agreement with those
reported in the literature.8,39 In addition, the 1.5:1
(39) Noteberg, D.; Branalt, J .; Kvarnstrom, I.; Classon, B.; Sam-
uelsson, B.; Nillroth, U.; Danielson, H.; Karlen, A.; Hallberg, A.
Tetrahedron 1997, 53, 7975-7984.
(40) Kobayashi, S.; Kamiyama, K.; Ohno, M. J . Org. Chem. 1990,
55, 1169-1177.
3378 J . Org. Chem., Vol. 69, No. 10, 2004

Synthesis of Cyclic â-Amino Acid Esters
phase was washed with satd NaHCO3 (10 mL), NH4Cl (10 mL),
and NaCl (10 mL) solutions, dried (MgSO4), and evaporated
under reduced pressure. The resulting residue was purified
by chromatography on silica gel eluting with an ethyl acetate
(EA)/petroleum ether (PE) mix.
(2S,3S)-2-Allyl-3-b en zyloxyca r b on yla m in o-2-m et h yl-
p en t-4-en oic Acid Meth yl Ester ((-)-11). (a) Hydrogen
peroxide (0.086 mL of a 50% w/w solution, 1.26 mmol, 1.4
equiv) was reacted with (-)-10 (295 mg, 0.84 mmol) and
subjected to oxidative elimination according to general method
B. Purification of the residue by radial chromatography (EA/
PE 1:3) gave diene (-)-11 (211 mg, 76%) as a yellow oil. (b)
Anhydrous LiCl (94 mg, 2.3 mmol, 3 equiv), LDA (0.837 mL
of a 2 M solution in THF, 1.67 mmol, 2.2 equiv), and allyl
bromide (0.263 mL, 3.0 mmol, 4 equiv) were reacted with 9
(200 mg, 0.76 mmol, 1 equiv) dissolved in THF (4 mL)
according to general method A. Purification by radial chro-
matography (EA/PE 15:85) gave (-)-11 (62 mg, 27%) as a
yellow oil: [R]20D ) -37.1 (c1.0 CHCl3);. νmax cm-1 3342, 2953,
1724, 1643, 1504; 1H NMR (500 MHz, CDCl3) δ 2.35 (1H, m),
2.43 (1H, m), 2.72 (1H, m), 3.63 (3H, s), 4.45 (1H, m), 5.05-
5.23 (6H, m), 5.76 (2H, m), 7.32-7.37 (5H, m); 13C NMR (75
MHz, CDCl3) δ 33.8, 48.6, 51.5, 53.4, 66.7, 115.8, 117.6, 127.9,
128.0, 128.4, 134.2, 136.3, 136.4, 155.9, 174.1; HRMS calcd
for C17H21NO4 (M) 303.1471, found 303.1465.
Gen er a l Meth od B: Oxid a tive Elim in a tion of Me-
th ion in e Sid e Ch a in . Hydrogen peroxide (1.4 equiv of 50%
w/w solution) was added to a solution of the methionine
derivative dissolved in acetic acid (5 mL), and the mixture was
stirred at rt for 4 h. Dichloromethane (20 mL) was added, and
the solution was carefully neutralized with satd aq Na2CO3.
The organic phase was washed with water (10 mL) and dried
(MgSO4) and the solvent removed under reduced pressure. The
resulting sulfoxide was then dissolved in degassed m-xylene
(10 mL), sealed in a glass tube under vacuum, and heated at
200 °C for 16 h. The solvent was evaporated under reduced
pressure, and the residue was chromatographed on silica gel
eluting with an ethyl acetate/petroleum ether mixture.
Gen er a l Meth od C: Syn th esis of Cyclic â-Am in o Acid s
by Rin g-Closin g Meta th esis. A solution of catalyst 3 (or 4)
(5 mol %) in dry degassed benzene (or CH2Cl2) was added to a
solution of the diene (1 equiv) in dry degassed benzene (or CH2-
Cl2) (∼0.1 mmol) under argon. The solution was then either
stirred at rt or at reflux. The solvent was evaporated under
reduced pressure, and the residue was purified by silica
chromatography, eluting with an ethyl acetate/petroleum ether
mix, to give the desired cyclic â-amino acid.
(3R*)- a n d (3R)-3-Ben zyloxyca r bon yla m in oh ex-5-en o-
ic Acid Meth yl Ester (12). (a) (()-N-Cbz-allylglycine (5 g,
20.1 mmol, 1 equiv) in THF (90 mL), Et3N (2.548 mL, 17.67
mmol, 1 equiv), ClCO2Et (1.663 mL, 17.67 mmol, 1 equiv),
ethereal diazomethane, and silver benzoate (506 mg, 2.21
mmol, 0.11 equiv) dissolved in Et3N (8.103 mL, 58.23 mmol,
2.9 equiv) was reacted according to general literature proce-
dure.28 Purification by column chromatography (EA/PE 1:3)
gave (()-12 (5.254 g, 94%) as a colorless oil. (b) An equivalent
reaction using (R)-N-Cbz-allylglycine (225 mg, 0.87 mmol) gave
(3R)-3-Ben zyloxyca r bon yla m in o-5-m eth ylsu lfa n ylp en -
ta n oic Acid Meth yl Ester ((-)-8). (S)-N-Cbz-methionine (5
g, 17.67 mmol) in THF (90 mL), Et3N (2.548 mL, 17.67 mmol,
1 equiv), ClCO2Et (1.663 mL, 17.67 mmol, 1 equiv), ethereal
diazomethane, and a solution of silver benzoate (445 mg, 1.94
mmol, 0.11 equiv) dissolved in Et3N (7.128 mL, 51.24 mmol,
2.9 equiv) was reacted according to general literature proce-
dure.28 Purification by column chromatography (EA/PE 1:3)
(+)-12 (234 mg, 94%): [R]20 ) +4.2 (c 2.0 CHCl3, lit.41
D
[R]20D ) +4.7); νmax cm-1 3339, 1724, 1643, 1529; 1H NMR (500
MHz, CDCl3) δ 2.34 (2H, m), 2.56 (2H, brd, J ) 5.4 Hz), 3.67
(3H, s), 4.06 (1H, m), 5.08 (4H, m), 5.22 (1H, m), 5.74 (1H, m),
7.35 (5H, m); 13C NMR (75 MHz, CDCl3) δ 37.9, 38.6, 47.5,
51.6, 66.5, 118.4, 127.9, 128.0, 128.4, 133.7, 136.4, 155.6, 171.8;
HRMS calcd for C15H19NO4 (MH+) 278.1392, found 278.1391.
Anal. Calcd for C15H19NO4. C, 64.96; H, 6.91; N, 5.05. Found:
C, 64.67; H, 6.79; N, 5.33.
gave (-)-8 (5.12 g, 93%) as a colorless oil: [R]20 ) -18.8 (c
D
1
1.0 CHCl3); νmax cm-1 3321, 1736, 1690, 1541; H NMR (500
MHz, CDCl3) δ 1.80 (1H, m), 1.88 (1H, m), 2.09 (3H, s), 2.52
(2H, m), 2.58 (2H, m), 3.66 (3H, s), 4.09 (1H, m), 5.08 (2H, s),
5.35 (1H, d, J ) 8.8 Hz), 7.32 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 15.4, 30.6, 33.6, 38.5, 47.3, 51.7, 66.6, 128.0, 128.0,
128.4, 136.4, 155.7, 171.7; HRMS calcd for C15H22NO4S (MH+)
312.1270, found 312.1272. Anal. Calcd for C15H21NO4S: C,
57.81; H, 6.80; N, 4.50; S, 10.50. Found: C, 57.61; H, 7.04; N,
4.52; S, 10.54.
(2R*,3R*)- a n d (2R,3R)-2-Allyl-3-ben zyloxyca r bon yl-
a m in oh ex-5-en oic Acid Meth yl Ester (13). (a) Anhydrous
LiCl (294 mg, 7.17 mmol, 3 equiv), LDA (2.629 mL of a 2 M
solution in THF, 5.25 mmol, 2.2 equiv), and allyl bromide
(0.833 mL, 9.56 mmol, 4 equiv) were reacted with (+)-12 (662
mg, 2.39 mmol, 1 equiv), dissolved in THF (12 mL) according
to general method A. Purification by radial chromatography
(EA/PE 1:4) gave (+)-13 (370 mg, 49%) as a colorless oil:
(3S)-3-Ben zyloxyca r bon yla m in op en ten oic Acid Meth -
yl Ester (9). Hydrogen peroxide (0.230 mL of a 50% w/w
solution, 3.25 mmol, 1.4 equiv) was reacted with (-)-8 (720
mg, 2.32 mmol) and subjected to oxidative elimination accord-
ing to general method B. Purification by radial chromatogra-
phy (EA/PE 15:85) gave 9 (430 mg, 63%) as a yellow oil: νmax
[R]20 ) +8.3 (c1.0 CH2Cl2). (b) An equivalent reaction using
D
(()-12 (1 g) gave (()-13 (672 mg, 59%): νmax cm-1 3344, 2953,
1717, 1643, 1506; 1H NMR (500 MHz, CDCl3) δ 2.18-2.44 (4H,
m), 2.69 (1H, m), 3.67 (3H, s), 3.93 (1H, m), 5.02-5.13 (6H,
m), 5.63 (1H, d, J ) 9.8 Hz), 5.73 (2H, m), 7.35 (5H, s); 13C
NMR (75 MHz, CDCl3) δ 34.2, 39.0, 47.5, 51.2, 51.6, 66.6,
117.5, 118.1, 127.9, 128.0, 128.4, 133.8, 134.4, 136.6, 156.1,
174.7; HRMS calcd for C18H23NO4Na (MNa+) 340.1525, found
340.1536. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.3; N, 4.41.
Found: C, 68.37; H, 7.47; N, 4.53.
1
cm-1 3339, 2953, 1720.4, 1514; H NMR (500 MHz, CDCl3) δ
2.65 (2H, m), 3.67 (3H, s), 4.58 (1H, m), 5.11 (2H, s), 5.18 (2H,
m), 5.45 (1H, brs), 5.85 (1H, m), 7.31-7.45 (5H, m); 13C NMR
(75 MHz, CDCl3) δ 38.5, 49.5, 51.3, 66.2, 67.4, 115.15, 127.6,
127.9, 128.0, 136.4, 136.5, 155.4, 171.0.
(1S,2S)-2-(1-Ben zyloxyca r bon yla m in o-3-m eth ylsu lfa n -
ylp r op yl)p en ta n oic Acid Meth yl Ester ((-)-10). Anhy-
drous LiCl (198 mg, 4.8 mmol, 3 equiv), LDA (1.768 mL of a 2
M solution in THF, 3.54 mmol, 2.2 equiv), and allyl bromide
(0.557 mL, 6.43 mmol, 4 equiv) were reacted with (-)-8 (500
mg, 1.61 mmol, 1 equiv) dissolved in THF (10 mL) according
to general method A. Purification by radial chromatography
(EA/PE 1:4) gave (-)-10 (301 mg, 53%) as a colorless oil:
[R]20D ) -20.9 (c 1.0 CHCl3); νmax cm-1 3342, 2953, 1717, 1701,
(3S)-3-ter t-Bu t oxyca r b on yla m in oh ep t -6-en oic Acid
Meth yl Ester ((-)-15). To a solution of (-)-1436 (1.37 g, 5.63
mmol, 1 equiv) dissolved in MeOH (∼0.05 M) was added 1 M
aq NaOH (11.3 mL of 2 M solution, 11.3 mmol, 2 equiv) and
the solution stirred at reflux for 4 h. The MeOH was removed
under reduced pressure, and water was added to make a
workable volume. The solution was acidified to pH 2 with 10%
HCl and extracted with ethyl acetate (3 × 20 mL). The
combined ethyl acetate extracts were dried over MgSO4, and
the solvent was removed under reduced pressure to give the
free acid (1.29 g, quant). The free acid (1.29 g, 5.63 mmol, 1
equiv) in THF (20 mL) was treated with Et3N (0.784 mL, 5.63
1
1653, 1506; H NMR (500 MHz, CDCl3) δ 1.72 (2H, m), 2.08
(3H, s), 2.31 (1H, m), 2.41 (1H, m), 2.52 (2H, m), 2.66 (1H, m),
3.67 (3H, s), 3.99 (1H, m), 5.03-5.14 (4H, m), 5.57 (1H, d, J )
9.8 Hz), 5.74 (1H, m), 7.32-7.37 (5H, m); 13C NMR (CDCl3) δ
15.3, 30.4, 33.8, 33.8, 48.2, 50.7, 51.4, 66.4, 117.3, 127.8, 127.8,
128.2, 134.2, 136.3, 156.1, 174.3; HRMS calcd for C18H25NO4S
(M) 351.1504, found 351.1516.
(41) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Tsubata, K. Tetrahedron
Lett. 1988, 29, 231-234.
J . Org. Chem, Vol. 69, No. 10, 2004 3379

Gardiner et al.
mmol, 1 equiv), ClCO2Et (0.536 mL, 5.63 mmol, 1 equiv),
ethereal diazomethane, and silver benzoate (159 mg, 0.11
equiv) dissolved in Et3N (2.535 mL, 16.3 mmol, 2.9 equiv)
according to the general literature procedure.28 Purification
by column chromatography (EA/PE 1:9-1:3) gave (-)-15 (1.382
7.26-7.36 (5H, m); 13C NMR (75 MHz, CDCl3) δ 19.1, 41.0,
49.3, 51.8, 59.2, 66.7, 117.83, 119.0, 128.1, 128.4, 132.7, 134.3,
136.4, 155.7, 175.6; HRMS calcd for C18H23NO4Na (MNa+)
340.1525, found 340.1526.
(2R*,3R*)-2-Meth yl-3-ben zyloxyca r bon yla m in oh ex-5-
en oic Acid Meth yl Ester ((()-20a ). Anhydrous LiCl (266
mg, 6.5 mmol, 3 equiv), LDA (2.383 mL of a 2 M solution in
THF, 4.76 mmol, 2.2 equiv), and MeI (0.543 mL, 8.66 mmol, 4
equiv) were reacted with (()-12 (600 mg, 2.17 mmol) dissolved
in THF (10 mL), according to general method A. Purification
by radial chromatography (EA/PE 1:4) gave (()-20a (543 mg,
86%) as a colorless oil: νmax cm-1 3317, 2952, 1717, 1642, 1506,
1206; 1H NMR (500 MHz, CDCl3) δ 1.22 (3H, d, J ) 6.Hz),
2.26 (2H, m), 2.73 (1H, m), 3.67 (3H, s), 3.86 (1H, m), 5.08
(4H, m), 5.50 (1H, d, J ) 9.3 Hz), 5.75 (1H, m), 7.35 (5H, m);
13C NMR (75 MHz, CDCl3) δ 14.7, 38.2, 41.7, 51.5, 52.8, 66.4,
117.8, 127.8, 127.9, 128.3, 133.9, 136.5, 156.2, 175.4. Anal.
Calcd for C16H21NO4: C, 65.96; H, 7.26; N, 4.81. Found: C,
66.05; H, 7.33; N, 4.99.
(2R*,3R*)-3-Ben zyloxycar bon ylam in o-2-eth ylh ex-5-en o-
ic Acid Meth yl Ester ((()-20b). Anhydrous LiCl (193 mg,
4.7 mmol, 3 equiv), LDA (1.727 mL of a 2 M solution in THF,
3.45 mmol, 2.2 equiv), and EtI (0.503 mL, 6.28 mmol, 4 equiv)
were reacted with (()-12 (435 mg, 1.57 mmol) dissolved in THF
(10 mL), according to general method A. Purification by radial
chromatography (EA/PE 15/85) gave (()-20b (302 mg, 63%)
as a colorless oil: νmax cm-1 3342, 2930, 1720, 1643, 1502, 1227;
1H NMR (500 MHz, CDCl3) δ 0.93 (3H, t, J ) 7.2 Hz), 1.58
(1H, m), 1.71 (1H, m), 2.17-2.27 (2H, m), 2.51 (1H, m), 3.68
(3H, s), 3.93 (1H, m), 5.05-5.13 (4H, m), 5.62 (1H, d, J ) 9.8
Hz), 5.75 (1H, m), 7.35 (5H, m); 13C NMR (75 MHz, CDCl3) δ
11.7, 23.0, 38.7, 49.2, 51.0, 51.3, 66.3, 117.8, 127.7, 127.8, 128.2,
133.8, 136.5, 156.1, 175.2; HRMS calcd for C17H24NO4 (MH+)
306.1705, found 306.1711. Anal. Calcd for C17H23NO4: C,
66.86; H, 7.59; N, 4.59. Found: C, 66.14; H, 7.31; N, 4.59.
(2R*,3R*)-2-Allyl-3-b en zyloxyca r b on yla m in o-2-m et h -
ylh ex-5-en oic Acid Meth yl Ester ((()-21a ). Anhydrous LiCl
(25 mg, 0.62 mmol, 3 equiv), LDA (0.226 mL of a 2 M solution
in THF, 0.45 mmol, 2.2 equiv), and allyl bromide (0.072 mL,
0.84 mmol, 4 equiv) were reacted with (()-20a (60 mg, 0.21
mmol) dissolved in THF (1 mL), according to general method
A. Purification by radial chromatography (EA/PE 1:9) gave (()-
21a (32 mg, 47%) as a colorless oil: νmax cm-1 3348, 3076, 2980,
1724, 1641; 1H NMR (500 MHz, CDCl3) δ 1.19 (3H, s), 1.93
(1H, m), 2.24 (1H, dd, J ) 7.3 and 13.7 Hz), 2.43 (1H, m), 2.51
(1H, dd, J ) 7.3 and 13.7 Hz), 3.65 (3H, s), 3.80 (1H, td, J )
3.4 and 10.8 Hz), 5.07 (6H, m), 5.44 (1H, d, J ) 10.7 Hz), 5.79
(2H, m), 7.30 (5H, m); 13C NMR (75 MHz, CDCl3) δ 19.4, 36.0,
41.3, 49.6, 51.7, 56.3, 66.5, 117.5, 118.8, 127.9, 127.9, 128.4,
133.0, 134.4, 136.6, 156.2, 175.9; HRMS calcd for C19H25NO4
(MH+) 332.1862, found 332.1863. Anal. Calcd for C19H25NO4:
C, 68.86; H, 7.60; N, 4.23. Found: C, 68.80; H, 7.60; N, 4.23.
g, 96%) as a colorless oil: [R]20 ) -10 (c1.06 CH2Cl2) [lit.
D
(ent)37 [R]20D ) +20.8)]; νmax cm-1 3361, 2978, 1734, 1710, 1517,
1367, 1170; 1H NMR (500 MHz, CDCl3) δ 1.43 (9H, s), 1.60
(2H, m), 2.10 (2H, m), 2.52 (2H, m), 3.68 (3H, s), 3.92 (1H, m),
4.93 (1H, d, J ) 8.3 Hz), 4.96-5.05 (2H, m), 5.79 (1H, m); 13
C
(75 MHz, CDCl3) δ 28.3, 30.3, 33.7, 39.0, 47.1, 51.6, 79.2, 115.2,
137.6, 155.3, 172.1; HRMS calcd for
280.1525, found 280.1529.
C
15H19NO4 (MNa+)
(3S)-2-Allyl-3-ter t-b u t oxyca r b on yla m in oh ep t -6-en oic
Acid Meth yl Ester [(-)-16]. Anhydrous LiCl (73 mg, 1.75
mmol, 3 equiv), LDA (0.642 mL of a 2 M solution in THF, 1.28
mmol, 2.2 equiv), and allyl bromide (0.202 mL, 9.56 mmol, 4
equiv) were reacted with (-)-15 (150 mg, 0.58 mmol, 1 equiv)
dissolved in THF (3 mL) according to general method A.
Purification by radial chromatography (EA/PE 1:20) gave (-)-
16 (71 mg, 42%) as a colorless oil: [R]20 ) -23 (c1.0 CHCl3);
D
1
νmax cm-1 2930, 1717, 1507, 1367, 1169; H NMR δ 1.43 (9H,
s), 1.47 (2H, m), 2.10 (2H, dd, J ) 15.1 and 6.8 Hz), 2.31 (1H,
m), 2.40 (1H, m), 2.62 (1H, m), 3.68 (3H, s), 3.81 (1H, m), 4.54-
5.09 (4H, m), 5.22 (1H, d, J ) 10.3 Hz), 5.72-5.81 (2H, m);
13C NMR δ 28.3, 30.4, 33.9, 34.1, 48.6, 50.4, 51.5, 79.0. 115.1,
117.3, 134.7, 137.7, 155.7, 174.9; HRMS calcd for C16H27NO4-
Na (MNa+) 320.1838, found 320.1835.
(2S,3S)-3-Ben zyloxyca r bon yla m in o-2-m eth yl-5-m eth -
ylsu lfa n ylp en ta n oic Acid Meth yl Ester ((-)-17). Anhy-
drous LiCl (396 mg, 9.65 mmol, 3 equiv), LDA (3.537 mL of a
2 M solution in THF, 7.07 mmol, 2.2 equiv), and MeI (0.801
mL, 12.86 mmol, 4 equiv) were reacted with (-)-8 (1 g, 3.22
mmol), dissolved in THF (15 mL), according to general method
A. Purification by radial chromatography (EA/PE 1:4) gave (-)-
17 (0.962 g (92%) as a colorless oil: [R]20D ) -14.3 (c1.0 CHCl3);
1
νmax cm-1 3337, 2953, 1717, 1699, 1510, 1454; H NMR (500
MHz, CDCl3) δ 1.22 (3H, d, J ) 6.8 Hz), 1.73 (2H, m), 2.08
(3H, s), 2.52 (2H, m), 2.70 (1H, m), 3.67 (3H, s), 3.91 (1H, m),
5.10 (2H, dd, J ) 12.4 and 14.4 Hz), 5.49 (1H, d, J ) 9.8 Hz),
7.29-7.37 (5H, m); 13C NMR (CDCl3) δ 14.8, 15.5, 30.7, 33.6,
42.6, 51.7, 52.6, 66.6, 127.9, 128.0, 128.4, 136.5, 156.5, 175.4;
HRMS calcd for C16H24NO4S (MH+) 326.1426, found 326.1429.
Anal. Calcd: C, 59.05; H, 7.12; N, 4.30; S, 9.85. Found: C,
59.15; H, 7.30; N, 4.40; S, 9.95.
(1S,2S)-2-(1-Ben zyloxyca r bon yl-3-m eth ylsu lfa n ylp r o-
p yl)-2-m eth ylp en t-3-en oic Acid Meth yl Ester ((-)-18).
Anhydrous LiCl (326 mg, 7.95 mmol, 3 equiv), LDA (2.918 mL
of a 2 M solution in THF, 5.83 mmol, 2.2 equiv), and allyl
bromide (0.918 mL, 10.6 mmol, 4 equiv) were reacted with (-)-
17 (862 mg, 2.65 mmol), dissolved in THF (15 mL), according
to general method A. Purification by radial chromatography
(EA/PE 1:9) gave (-)-18 (411 mg, 43%) as a colorless oil:
[R]D ) -30.6 (c1.0 CHCl3); νmax cm-1 3343, 2951, 1720, 1641,
1510; 1H NMR (500 MHz, CDCl3) δ 1.19 (3H, s), 1.42 (1H, m),
1.91 (1H, m), 2.07 (3H, s), 2.23 (1H, dd, J ) 7.4 and 13.7 Hz)
2.43-2.58 (3H, m), 3.66 (3H, s), 3.79 (1H, dt, J ) 10.7 and 2.4
Hz), 5.02-5.16 (4H, m), 5.42 (1H, d, J ) 10.7 Hz), 5.67 (1H,
m), 7.31-7.37 (5H, m); 13C NMR (75 MHz, CDCl3) δ 15.7, 19.5,
31.2, 31.4, 41.2, 49.8, 51.8, 56.3, 66.7, 118.9, 128.0, 128.1, 128.4,
132.9, 136.5, 156.4, 175.8.
(2R*,3R*)-2-Allyl-3-b en zyloxyca r b on yla m in o-2-et h yl-
h ex-5-en oic Acid Meth yl Ester ((()-21b). Anhydrous LiCl
(36 mg, 0.89 mmol, 3 equiv), LDA (0.324 mL of a 2 M solution
in THF, 0.65 mmol, 2.2 equiv), and allyl bromide (0.103 mL,
1.2 mmol, 4 equiv) were reacted with (()-20b (90 mg, 0.3
mmol) dissolved in THF (1.5 mL), according to general method
A. Purification by radial chromatography (EA/PE 1:9) gave (()-
21b (41 mg, 42%) as a colorless oil: νmax cm-1 3350, 2930, 1720,
1
1643, 1502, 1223; H NMR (500 MHz, CDCl3) δ 0.89 (3H, t,
J ) 7.5 Hz), 1.64 (1H, m), 1.78-1.96 (2H, m), 2.35 (2H, m),
2.52 (1H, ddd, J ) 6.8, 16.1, and 30.7 Hz), 3.68 (3H, s), 3.97
(1H, ddd, J ) 3.2, 11.3, and 21.2 Hz), 4.97-5.14 (6H, m), 5.32
(1H, d, J ) 10.3 Hz), 5.55-5.77 (2H, m), 7.35 (5H, m); 13C NMR
(CDCl3) δ 7.7, 24.3, 36.2, 36.3, 51.8, 52.9, 54.1, 66.6, 117.4,
118.3, 127.9, 128.0, 128.4, 133.7, 134.5, 136.7, 156.5, 175.8.
(2S*,3R*)-2-Allyl-3-ben zyloxyca r bon yla m in o-2-m eth yl-
h ex-5-en oic Acid Meth yl Ester ((()-22). Anhydrous LiCl
(43 mg, 1.0 mmol, 3 equiv), LDA (0.381 mL of a 2 M solution
in THF, 0.76 mmol, 2.2 equiv), and MeI (0.086 mL, 1.4 mmol,
4 equiv) were reacted with (()-13 (110 mg, 0.35 mmol)
(2S,3S)-2-Allyl-3-b en zyloxyca r b on yla m in o-2-m et h yl-
p en t-4-en oic Acid Meth yl Ester ((-)-19). Hydrogen perox-
ide (0.092 mL of a 50% w/w solution, 1.35 mmol, 1.4 equiv)
was reacted with (-)-18 (352 mg, 0.97 mmol) and subjected
to oxidative elimination according to general method B.
Purification of the residue by radial chromatography (EA/PE
1:3) gave diene (-)-19 (267 mg, 88%) as a colorless oil: [R]20
)
D
-30.2 (c1.0 CHCl3); νmax cm-1 3342, 2951, 1707, 1641, 1501;
1H NMR (500 MHz, CDCl3) δ 1.17 (3H, s), 2.26 (1H, dd, J )
7.3 and 13.7 Hz), 2.51 (1H, dd, J ) 7.3 and 13.7 Hz), 3.65 (3H,
s), 4.22 (1H, t, J ) 8.3 Hz), 5.04-5.26 (6H, m), 5.71 (2H, m),
3380 J . Org. Chem., Vol. 69, No. 10, 2004

Synthesis of Cyclic â-Amino Acid Esters
dissolved in THF (1.8 mL), according to general method A.
Purification by radial chromatography (EA/PE 15:85) gave (()-
22 (71 mg, 68%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 1.14 (3H, s), 1.99 (1H, m), 2.19-2.33 (2H, m), 2.56 (1H, dd,
J ) 6.6 and 23.9 Hz), 3.67 (3H, s), 4.00 (1H, td, J ) 3.4 and
10.7 Hz), 4.93 (1H, d, J ) 10.3 Hz), 4.97-5.13 (6H, m), 5.73
(2H, m), 7.29-7.37 (5H, m).
catalyst 4 (24 mg, 5mol %), in benzene (0.5 mL), was added to
a solution of diene (-)-19 (180 mg, 0.57 mmol), in benzene (5
mL), and stirred at rt for 2 h according to general method C.
Purification by radial chromatography (EA/PE 1:3) gave (+)-
26 (151 mg, 92%) as a white solid: [R]20D ) +50.5 (c1.0 CHCl3);
1
νmax cm-1 3350, 2951, 1697, 1634, 1502; H NMR (500 MHz,
CDCl3) δ 1.19 (3H, s), 2.24 (1H, d, J ) 17.1 Hz), 2.95 (1H, d,
J ) 17.1 Hz), 3.73 (3H, s), 4.74 (1H, brd, J ) 7.3 Hz), 5.10
(2H, ddAB, J ) 12.5 Hz), 5.21 (1H, brd, J ) 9.3 Hz), 5.53 (1H,
brs), 5.83 (1H, brs), 7.25-7.36 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 18.8, 44.2, 51.4, 52.1, 62.8, 66.5, 127.9, 128.3, 129.5,
131.6, 131.8, 136.4, 155.7, 177.2; HRMS calcd for C16H19NO4
(MH+) 290.1392), found 290.1396.
(2S,3S)-3-Ben zyloxyca r b on yla m in ocyclop en t -3-en e-
ca r boxylic Acid Meth yl Ester (+)-23 a n d (1S,5S)-5-Ben -
zyloxyca r bon yla m in ocyclop en ten -2-en eca r boxylic Acid
Meth yl Ester 29. (a) A solution of 4 (18 mg, 5 mol %), in
benzene (0.5 mL), was added to a solution of diene (-)-11 (126
mg, 0.42 mmol, 1 equiv), in benzene (4 mL), and the solution
stirred at rt for 2 h according to general method C. Purification
by radial chromatography (EA/PE 1:3) gave (+)-23 (105 mg,
92%) as a white solid. (b) In a second reaction, a solution of 4
(4.2 mg, 5mol %), in benzene (0.5 mL), was added to a solution
of diene (-)-11 (30 mg, 0.1 mmol, 1 equiv), in benzene (1 mL),
and stirred at reflux for 4 h according to general method C.
Purification by radial chromatography (EA/PE 1:3) gave a
fraction containing 23 and 29 (24 mg, 89%), in a ratio of 1.5:1
by 1H NMR, that could not be separated further. Data for (+)-
(1R*,2R*)-2-Ben zyloxyca r bon yla m in o-1-m eth ylcyclo-
h ex-4-en eca r boxylic Acid Meth yl Ester ((()-27a ). A solu-
tion of catalyst 4 (3 mg, 5mol %), in benzene (0.5 mL), was
added to a solution of diene (()-21a (25 mg, 0.08 mmol), in
benzene (1 mL), and stirred at reflux for 4 h according to
general method C. Purification by radial chromatography (EA/
PE 1:3) gave (()-27a (24 mg, 96%) as a colorless oil: νmax cm-1
3346, 3032, 2932, 2851, 1728, 1526; 1H NMR (500 MHz, CDCl3)
δ 1.17 (3H, s), 1.89 (1H, dd, J ) 17.1 and 2 Hz), 1.95 (1H, dd,
J ) 17.6 and 2 Hz), 2.42 (1H, d, J ) 17.6 Hz), 2.72 (1H, d,
J ) 17.1), 3.65 (3H, s), 4.31 (1H, m), 4.79 (1H, d, J ) 9.3 Hz),
5.09 (2H, s), 5.56 (1H, m), 5.65 (1H, m), 7.35 (5H, m).
23: [R]20 ) +102.3 (c1.0 CHCl3); mp 92-93 °C; νmax cm-1
D
2953, 1734, 1684, 1537; 1H NMR (500 MHz, CDCl3) δ 2.62 (1H,
m), 2.75 (1H, m), 2.87 (1H, m), 3.72 (3H, s), 4.86 (1H, brs),
5.06 (1H, m), 5.12 (2H, m), 5.63 (1H, brs), 5.86 (1H, m), 7.30-
7.38 (5H, m); 13C NMR (CDCl3) δ 35.5, 50.7, 52.1, 61.1, 66.7,
128.1, 128.5, 130.0, 132.4, 133.5, 136.3, 155.5, 174.8; HRMS
Calcd for C15H17NO4 (M+) 275.1158, found 275.1158. Anal.
Calcd for C15H17NO4: C, 65.44; H, 6.23; N, 5.09. Found: C,
65.13; H, 6.31; N, 5.25. Selected data for 29 (from mixture):
1H NMR (500 MHz, CDCl3) δ 2.28 (1H, brd, J ) 17.6 Hz), 2.93
(1H, dd, J ) 7.3 and 17.1 Hz), 3.28 (1H, brs), 4.58 (1H, m),
4.83 (1H, brs), 5.69 (1H, s), 5.86 (1H, s).
(1R*,2R*)-2-Ben zyloxycar bon ylam in o-1-eth ylcycloh ex-
4-en oic Acid Meth yl Ester ((()-27b). A solution of catalyst
4 (2.5 mg, 5mol %), in benzene (0.5 mL), was added to a
solution of diene (()-21b (21 mg, 0.06 mmol), in benzene (1
mL), and stirred at reflux for 4 h according to general method
C. Purification by radial chromatography (EA/PE 1:9) gave (()-
27b (18 mg, 94%) as a colorless oil: νmax cm-1 3343, 3032, 2951,
1
1732, 1717, 1504, 1454, 1234; H NMR (500 MHz, CDCl3) δ
0.81 (1H, t, J ) 7.8 Hz), 1.51 (1H, ddd, J ) 28.8, 14.2, and 7.3
Hz), 1.77 (2H, m), 2.02 (1H, d, J ) 18.6 Hz), 2.38 (1H, d, J )
18.6 Hz, 1H), 2.75 (1H, d, J ) 18.6 Hz), 3.68 (3H, s), 4.37 (1H,
d, J ) 10.2 Hz), 4.86 (1H, d, J ) 10.2 Hz), 5.10 (2H, dd, J )
(1R*,2R*)- a n d (1R,2R)-2-Ben zyloxyca r bon yla m in ocy-
cloh ex-4-en eca r boxylic Acid Meth yl Ester (24). (a) A
solution of 3 (7 mg, 5mol %) in CH2Cl2 (0.5 mL) was added to
a solution of (()-13 (54 mg, 0.17 mmol), in CH2Cl2 (1 mL), and
stirred at rt for 2 h according to general method C. Purification
by radial chromatography (EA/PE 1:3) gave (()-24 (49 mg,
91%) as a colorless oil. (b) A solution of 3 (8 mg, 0.01 mmol,
5mol %), in benzene (0.5 mL), was added to a solution of diene
(+)-13 (59 mg, 0.19 mmol), in benzene (10 mL), and stirred at
reflux for 4 h according to general method C to give (-)-24
(51 mg, 96%): [R]20 ) -31.2 (c 1 CHCl3) (lit.19 [R]20 ) 33.5);
21.5 and 2.2 Hz), 5.55 (1H, m), 5.70 (1H, m), 7.34 (5H, m); 13
C
NMR (75 MHz, CDCl3) δ 8.4, 28.6, 29.3, 30.5, 49.0, 49.8, 51.9,
66.9, 123.4, 125.9, 128.2, 128.5, 136.3, 156.3, 175.0; HRMS
calcd for C18H24NO4 (MH+) 318.1705, found 318.1691.
(1S*,2R*)-2-Ben zyloxyca r b on yla m in o-1-m et h ylcyclo-
h ex-4-en eca r boxylic Acid Meth yl Ester ((()-28). A solu-
tion of catalyst 4 (1.7 mg, 5mol %), in benzene (0.5 mL), was
added to a solution of diene (()-20 (14 mg, 0.04 mmol, 1 equiv),
in benzene (1 mL), and stirred at reflux for 4 h according to
general method C. Purification by radial chromatography (EA/
PE 1:3) gave (()-28 (12 mg, 91%) as a colorless oil: νmax cm-1
3437, 2951, 1724, 1504; 1H NMR (500 MHz, CDCl3) δ 1.27 (3H,
s), 2.06 (1H, dd, J ) 2.4 and 21.0 Hz), 2.12 (1H, m), 2.37 (1H,
m), 2.69 (1H, dd, J ) 4.4 and 17.1 Hz), 3.66 (3H, s), 3.94 (1H,
m), 5.10 (2H, dd, J ) 1.0 and 12.7 Hz), 5.56-5.65 (3H, m),
7.30.7.37 (5H, m); 13C NMR (75 MHz, CDCl3) δ 23.3, 30.8, 35.1,
45.2, 51.9, 52.6, 66.6, 125.1, 125.3, 128.0, 128.5, 136.6, 156.2,
176.6; HRMS calcd for C17H21NO4 (MH+) 303.1475, found
303.1471.
D
D
1
νmax cm-1 3339, 3032, 2930, 2853, 1732, 1520; H NMR (500
MHz, CDCl3) δ 1.99 (1H, brd, J ) 9.8 Hz), 2.30 (1H, dd, J )
12.2 and 5.9 Hz), 2.49 (2H, m), 2.72 (1H, m), 3.64 (3H, s), 4.11
(1H, m), 4.90 (1H, brs), 5.08 (2H, s), 5.59 (1H, m), 5.66 (1H,
m), 7.33 (5H, m); 13C NMR (75 MHz, CDCl3) δ 26.6, 31.0, 44.3,
47.8, 51.8, 66.6, 124.1, 124.9, 128.0, 128.1, 128.4, 136.4, 155.5,
173.9; HRMS calcd for C16H20NO4 (MH+) 290.1392, found
290.1402. Anal. Calcd for C16H19NO4: C, 66.48; H, 6.62; N,
4.84. Found: C, 66.38; H, 6.83; N, 4.94.
(1S,2S)-2-ter t-Bu t oxyca r b on yla m in ocycloh ep t -4-en e-
ca r boxylic Acid Meth yl Ester ((+)-25). A solution of
catalyst 4 (6 mg, 5 mol %), in benzene (0.5 mL), was added to
a solution of diene (-)-16 (40 mg, 0.13 mmol), in benzene (3
mL), and stirred at rt for 2 h according to general method C.
Purification by radial chromatography (EA/PE 1:3) gave (+)-
(1S,2S)-2-ter t-Bu t yloxyca r b on yla m in ocyclop en t a n e-
ca r boxylic Acid Meth yl Ester ((+)-30). To a solution of (+)-
23 (30 mg, 0.11 mmol), dissolved in dry MeOH (3 mL) under
a hydrogen atmosphere, was added 10% palladium-on-carbon
(6 mg, 20% w/w). The solution was then deoxygenated and
stirred vigorously under hydrogen for 12 h. The mixture was
filtered through a small bed of Celite and washed with MeOH,
and the solvent volume was reduced to approximately 2 mL.
NaHCO3 (14 mg, 0.17 mmol, 1.5 equiv) and di-tert-butyl
dicarbonate (37 mg, 0.17 mmol, 1.5 equiv) was then added and
the solution stirred at rt for 3 h. Removal of the solvent under
reduced pressure and purification of the residue by radial
chromatography (EA/PE 1:7) gave (+)-30 (20 mg, 75%) as a
white solid: [R]20D ) +41.6 (c 0.65 CHCl3) [lit.39 [R]20D ) +44.6
18 (33 mg, 93%) as a white solid: [R]20 ) +2 (c1.0, CHCl3);
D
mp 72-74 °C; νmax cm-1 3371, 2936, 1736, 1686, 1524; 1H NMR
(500 MHz, CDCl3) δ 1.42 (9H, s), 1.45 (1H, m), 2.02 (1H, m),
2.08-2.21 (2H, m), 2.28 (1H, dd, J ) 7.1 and 13.7 Hz), 2.40
(1H, m), 2.43 (1H, m), 3.67 (3H, s), 4.05 (1H, m), 4.63 (1H,
brs), 5.73 (1H, m), 5.83 (1H, m); 13C NMR (75 MHz, CDCl3) δ
23.9, 27.3, 28.3, 32.3, 49.7, 51.8, 54.1, 79.3, 128.8, 133.0, 154.6,
174.3; HRMS calcd for C14H23NO4Na (MNa+) 292.1525, found
292.1526.
(1S,2S)-2-Ben zyloxyca r bon yla m in o-1-m eth ylcyclop en -
3-en eca r boxylic Acid Meth yl Ester ((+)-26). A solution of
1
(c 1.3)]; H NMR (500 MHz, CDCl3) δ 1.43 (9H, s), 1.47 (1H,
J . Org. Chem, Vol. 69, No. 10, 2004 3381

Gardiner et al.
m) 1.72 (2H, m), 1.89 (1H, m), 1.97 (1H, m), 2.11 (1H, m), 2.57
(1H, dd, J ) 16.1 and 8.3 Hz), 3.68 (3H, s), 4.11 (1H, m), 4.57
(1H, brs).
(1S,2S)-2-ter t-Bu toxyca r bon yla m in ocycloh ep ta n eca r -
boxylic Acid Meth yl Ester ((+)-32). To a solution of (+)-25
(15 mg, mmol, 1 equiv) dissolved in dry MeOH (∼0.05 M) was
added 10% palladium-on-carbon (5 mg). The solution was then
deoxygenated and stirred vigorously under hydrogen for 12
h. The mixture was then filtered through a small bed of Celite
and washed with MeOH and the solvent removed under
reduced pressure to give (+)-32 (15 mg, 96%) as a white solid:
(1R,2R)-2-Ben zyloxyca r b on yla m in ocycloh exa n eca r -
boxylic Acid Meth yl Ester ((-)-31). To a solution of (-)-17
(50 mg, 0.17 mmol, 1 equiv) dissolved in MeOH (3 mL) was
added 10% palladium-on-carbon (10 mg, 20% w/w). The
solution was then deoxygenated and stirred vigorously under
hydrogen for 12 h. The mixture was filtered through Celite,
washing with MeOH, and the solvent removed under reduced
pressure. The residue was then taken up in CH2Cl2 (3 mL)
and diisopropylethylamine (0.072 mL, 0.42 mmol, 2.4 equiv),
benzylchloroformate (0.04 mL, 0.27 mmol, 1.6 equiv) and
(dimethylamino)pyridine (6.2 mg, 0.05 mmol, 0.3 equiv) were
added, and the solution was stirred at rt overnight. The solvent
was removed under reduced pressure and the residue taken
up in ethyl acetate, successively washed with satd aq NaHCO3
(10 mL), NaCl (10 mL), and water (10 mL), and dried (MgSO4)
and the solvent removed to give (-)-31 (43 mg, 86%) as a
colorless oil: [R]20 ) -18.4 (c 0.9 CHCl3 (lit.8 [R]20 ) -18);
[R]20 ) +2 (c 0.5 CHCl3); νmax cm-1 3364, 2936, 1730, 1686,
D
1524; 1H NMR (500 MHz, CDCl3) δ 1.41 (9H, s), 1.40-1.92
(10H, m), 2.43 (1H, m), 3.66 (3H, s), 3.91 (1H, m), 4.57 (1H,
brs); 13C NMR (75 MHz, CDCl3) δ 23.7, 26.0, 28.0, 28.3, 34.4,
51.8, 52.2, 53.5, 154.8, 175.5; HRMS calcd for C14H25NO4Na
(MNa+) 294.1681, found 294.1678.
Ack n ow led gm en t. The work was supported by a
Royal Society of New Zealand Marsden grant.
D
D
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds (-)-8, 9, (-)-10, (-)-11, (+)-12, (+)-13, (-)-15, (-)-
16, (-)-17, (-)-18, (-)-19, 20a ,b, 21a ,b, 22, (+)-23, 24, (+)-
25, (+)-26, 27a ,b, 28, (+)-30, (-)-31, and (+)-32. This material
is available free of charge via the Internet at http://pubs.acs.org.
ν
max cm-1 3331, 1733; 1H NMR (500 MHz, CDCl3) δ 1.13-1.44
(3H, m), 1.56-1.81 (3H, m), 1.90 (1H, m), 2.06 (1H, m), 2.27
(1H, m), 3.61 (3H, s), 3.73 (1H, ddd, J ) 20.5,11.3, and 4.2
Hz), 4.08 (1H, brs), 5.06 (2H, s), 7.27-7.37 (5H, m); 13C NMR
(75 MHz, CDCl3) δ 24.3, 24.6, 28.6, 32.8, 49.7, 51.7, 66.5, 128.0,
128.4, 136.6, 155.4, 174.3; HRMS calcd for C16H21NO4 (M+)
291.1471, found 291.1474.
J O049794G
3382 J . Org. Chem., Vol. 69, No. 10, 2004