Aminoalkyl-substituted α-methylene-γ-butyrolactones from α-amino acids using an indium-mediated Barbier allyl addition

Article abstract of DOI:10.1002/(sici)1099-0690(199907)1999:7<1551::aid-ejoc1551>3.0.co;2-8

The indium-mediated reaction of Z-protected α-amino aldehydes 1-6 with 2-(bromomethyl)acrylates 8/9 in aqueous solvents has been investigated. The preference for the formation of syn-configured homoallyl alcohols 10-16 (diastereoselectivities ranging from

Full text of DOI:10.1002/(sici)1099-0690(199907)1999:7<1551::aid-ejoc1551>3.0.co;2-8

FULL PAPER
Aminoalkyl-Substituted ␣-Methylene-γ-butyrolactones from ␣-Amino Acids
Using an Indium-Mediated Barbier Allyl Addition
Steffen Steurer[a] and Joachim Podlech*[a]
Keywords: α-Methylene-γ-butyrolactones / Indium / Amino aldehydes / Allyl addition / Barbier reaction
The indium-mediated reaction of Z-protected α-amino
transformation of the amino aldehydes. Acid-catalyzed
aldehydes 1–6 with 2-(bromomethyl)acrylates 8/9 in aqueous esterification (H2SO4 in Et2O) led to α-methylene-γ-
solvents has been investigated. The preference for the
formation of syn-configured homoallyl alcohols 10–16
(diastereoselectivities ranging from 2:1 to 32:1, yields 68–
butyrolactones 17–22 with yields ranging from 89 to 97%.
The configurations of all diastereoisomers were established
by five X-ray crystallographic analyses and by comparision
93%) may be explained by a chelate-controlled reaction. No of the NMR spectra.
racemization occurred during the preparation and
als employed in the Barbier reaction (Zn,[13,14,16,17,19,20]
Introduction
Sn,[16,17,19,20] Pb,[21] Cr,[22][23] Bi,[24] Sb,[25][26] Mn,[27] and
In[19,23,28Ϫ43]), indium is especially important.[44][45] Since
no activation by sonication or acid catalysis is necessary
with indium, even acid-sensitive substrates like acetals can
be allylated under these conditions. Indium has been re-
ported to lead to better yields and diastereoselectivi-
ties,[19,23,28Ϫ35] especially in the allyl addition to hydroxy al-
dehydes, where drastic improvements were observed.[36Ϫ43]
In addition, indium-mediated Barbier reactions can be
favourably performed in water or in mixtures of water with
organic solvents.[16,17,19,20] Though one might assume that
water-sensitive species should be intermediates in these re-
actions, no hydrolysis of the organometallic compound oc-
curs. The intermediacy of radical species might be respon-
sible for this observation.[16][46] As both a hydroxy group
and a CϭC double bond are simultaneously introduced
into a molecule, the allyl addition to carbonyl compounds
is very interesting with respect to the possibility of further
transformations of the resulting intermediates.
The α-methylene-γ-butyrolactone ring is a central struc-
tural element in a plethora of natural products, most of
them sesquiterpenoids.[1Ϫ4] Most of the 6000 known com-
pounds exhibit various biological activities including anti-
biotical,[5][6] fungicidal,[7] anthelmintical,[8] and antitumo-
ral properties.[6][8] Additionally, some of them are potent
antiplatelet agents,[8] antifeedants[5] or antagonists against
opioid receptors.[9] Furthermore, it is not only complex, po-
lycyclic structures that show biological activity, as even the
parent α-methylene-γ-butyrolactone (tulipaline A) and its
hydroxylated derivative tulipaline B are effective fungi-
cides.[10][11]
Figure 1. Tulipaline A and B Ϫ fungicidal α-methylene-γ-butyro-
lactones
Only a few examples of indium-mediated allyl additions
to amino aldehyde derivatives have been reported up to
Nevertheless, most α-methylene-γ-butyrolactones are too now.[47][48] In this paper we describe the utilization of α-
toxic for therapeutic utilization; consequently, there is a amino acids for the preparation of γ-aminoalkyl-substituted
need for new, nontoxic compounds with this structural mo- α-methylene-γ-butyrolactones.
iety. In addition to their biological activities, α-methylene-
γ-butyrolactones are useful intermediates in organic syn-
Results and Discussion
thesis; starting with such compounds peptide analogues or
HIV-1 protease inhibitors have, for example, been pre-
pared.[12Ϫ14]
α-Methylene-γ-butyrolactones can be prepared by cycli-
zation of γ-hydroxy-α-methylene esters, which are accessible
from aldehydes through allyl addition of 2-(bromometh-
yl)acrylates in a Barbier-type reaction.[15Ϫ18] Of all the met-
The intended reaction sequence for the preparation of the
homoallyl alcohols is depicted in Scheme 1.
We started with different amino acids: alanine, phenylala-
nine, leucine, valine, isoleucine, and tert-leucine. We chose
a Z protection of the amino functions to allow for an easier
detection of the products during HPLC or MPLC separ-
ation. To establish the best method for the preparation of
the respective amino aldehydes,[49] we tried several reaction
sequences (Scheme 2): Swern[50][51] or DessϪMartin per-
iodinane (DMP)[52][53] oxidation of the corresponding am-
ino alcohols, reduction of N-methoxy-N-methyl carboxam-
[a]
Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax: (internat.) ϩ 49(0)711/685-4269
E-mail: joachim.podlech@po.uni-stuttgart.de
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/eurjoc or from the author.
Eur. J. Org. Chem. 1999, 1551Ϫ1560
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0707Ϫ1551 $ 17.50ϩ.50/0
1551

S. Steurer, J. Podlech
FULL PAPER
v/v). The presence of water seems to be essential for a clean
and fast reaction. With anhydrous THF or CH2Cl2, the re-
action times increased drastically; the reaction was not
complete even after 3 d. With DMF the reaction proceeded,
but the diastereoselectivity dropped significantly. No salt
effect[63] was observed when anhydrous lithium bromide
was added to DMF. With allyl iodide, no diastereoselec-
tivity was observed. We therefore used ethanol/water as the
solvent for the following reactions. In the allyl addition to
amino aldehydes 1Ϫ6 with 2-(bromomethyl)acrylates 8 or
9, the homoallyl alcohols 10Ϫ16 were formed in yields
ranging from 68 to 93%. Diastereoisomer ratios were deter-
mined by HPLC analysis of the crude isomer mixtures. The
diastereoselectivities (67:33 up to 97:3) are essentially de-
pendent on the bulkyness of the amino acid side chain;
while with less demanding side chains (starting with alani-
nal or phenylalaninal, Table 1, entries 1Ϫ3) the diastereosel-
ectivities are about 2:1, leucinal and valinal gave 3:1 and
5:1 ratios, respectively (entries 4, 5). Best diastereoselectivit-
ies could be obtained with isoleucinal (8:1, entry 6) and
tert-leucinal (32:1, entry 7). No changes in yield or dia-
stereoselectivity were observed, when the sterically more de-
manding tert-butyl 2-(bromomethyl)acrylate (9)[48][64] was
used instead of the methyl ester 8 (entry 2). All isomers
could be easily separated by MPLC.
Scheme 1. Allyl addition of amino aldehydes 1Ϫ6 with 2-(bromo-
methyl)acrylates 8 or 9 (for specification of substituents see Table 1)
ides[54][55] (Weinreb amides[56]) with LiAlH4 or reduction
of methyl esters with DIBAl-H.[57] Since amino aldehydes
should not be purified (vide infra) it is essential to have a
clean and complete preparation method. DIBAl-H re-
duction led to considerable amounts of amino alcohols as
side products. Contrary to published data,[58] we found it
necessary to purify Weinreb amides before transformation
to obtain a clean reduction. Amino aldehyde derivatives are
not very stable[59] and racemization to a considerable extent
has been observed during chromatography;[60] purification
at this stage is, therefore, not profitable. It has been noticed
before that reduction of Weinreb amides leads to a partial
racemization during the reaction.[54] We checked this by
NMR-spectroscopic analysis of amino aldehyde 4 by ad-
dition of a chiral shift reagent. Using 21 mol-% of tris{3-
[(heptafluoropropyl)(hydroxy)methylene]-d-camphorato}-
praseodym(III) [Pr(hfc)3],[61] we found that reduction of
Weinreb amides led to products with about 96% ee. Never-
theless, no racemization occurred when amino alcohols
were oxidized with DMP. Since this method is, in addition,
very easy to perform, we chose it for the preparation of all
aldehydes used in this work. Minor amounts of side prod-
ucts were not removed, since the products of the allyl ad-
ditions could be easily purified by chromatography.
Table 1. Allyl addition to amino aldehydes 1؊6 with 2-(bromome-
thyl)acrylates 8 or 9 (see Scheme 1)
Entry Aldehyde R1
R2
Yield (%) d.r.
Product
1
2
3
4
5
6
7
1
1
2
3
4
5
6
Me
Me
Bn
Me
tBu
Me
Me
Me
Me
Me
68
72
73
81
84
85
93
68:32
10a/b
11a/b
12a/b
13a/b
14a/b
15a/b
16a/b
67:33
68:32
75:25
82:18
89:11
97:3
iBu
iPr
sBu
tBu
Chemical determination of the relative configuration of
the newly formed stereogenic centres failed; a transform-
ation to the corresponding oxazolidin-2-ones and sub-
sequent measurement of the coupling constants could not
be achieved.[47,65,66] Fortunately, the homoallyl alcohols 12a
and 16b yielded crystals suitable for an X-ray crystallo-
graphic analysis (homoallyl alcohol 12a is depicted in Fig-
ure 2).[67] The hydroxy and amino functions in this isomer
turned out to be syn-arranged (2ЈS,3ЈS). By comparision of
the NMR spectra, this configuration could be established
for all the first eluted, major isomers 10aϪ16a. The lower
polarity of the syn isomers has already been mentioned for
similar compounds.[47]
Scheme 2. Preparation of amino aldehydes
The amino aldehydes generated in situ were immediately
The results presented herein for the preparation of homo-
(within 1 h) allylated with methyl 2-(bromomethyl)acrylate allyl alcohols are significantly better than those achieved in
(8). We used reaction conditions which we optimized for similar Barbier reactions. The allyl addition to Boc-valinal
the allyl addition to Z-protected valinal 4 with the parent with ethyl 2-(bromomethyl)acrylate and CrCl2 as reducing
allyl bromide 7.[62] We found that 1.7 equivalents allyl bro- salt led to the corresponding homoallyl alcohol with a poor
mide and 1.1 equivalents of indium in ethanol/water (4:1, 55:45 diastereoselectivity and with 75% yield.[22]
v/v) gave best results. No differences in diastereoselectivity
2-(2-Hydroxyalkyl)propenoates usually cyclize easily to
and yield have been observed with THF/NH4Cl(aq.) (5:1, the corresponding α-methylene-γ-butyrolactones. The
1552
Eur. J. Org. Chem. 1999, 1551Ϫ1560

Aminoalkyl-Substituted α-Methylene-γ-butyrolactones
FULL PAPER
Scheme 3. Cyclization of homoallyl alcohols 10Ϫ16 to α-methy-
lene-γ-butyrolactones 17Ϫ22 (for specification of substituents see
Table 2)
Table 2. Cyclization of homoallyl alcohols 10Ϫ16 to α-methylene
γ-butyrolactones 17Ϫ22 (see Scheme 3)
Figure 2. Molecular structure of the homoallyl alcohol 12a as de-
termined by X-ray crystallographic analysis
Entry
Homoallyl alcohol R
Method[a] Yield (%) Lactone
1
10a
10b
10a
12a
12b
13a
13b
14a
14a
14a
14b
15a
16a
Me
A
B
61[b]
61[b]
95
17a
17b
17a
18a
18b
19a
19b
20a
20a
20a
20b
21a
22a
homoallyl alcohols presented herein turned out to be quite
stable; we think that intramolecular hydrogen bonds (which
are present in the crystal structure, too) might be respon-
sible for this unusual stability. Whilst several methods for
the lactonization of similar homoallyl alcohols are reported
in the literature,[35] the first γ-hydroxy ester 14a tested was
neither cyclized by a catalytic amount of toluenesulfonic
acid,[68] nor by addition of trifluoroacetic acid.[69] Addition
of sodium hydride[22] led to decomposition of the starting
material and thermal cyclization[70] gave very slow conver-
sion. When we used 6  hydrogen chloride in methanol as
the solvent, lactonization proceeded quickly, but in addition
formation of the chlorinated lactone 23 was observed
(Scheme 3 and Table 2, entry 9). Obviously, a Michael ad-
dition of hydrogen chloride to the unsaturated lactone 20a
2
Me
Me
Bn
3
C
B
4
61[b]
58[b]
90
5
Bn
A
C
C
A
A[c]
C
B
6
iBu
iBu
iPr
iPr
iPr
iPr
sBu
tBu
7
89
8
63[b]
17[d]
97
9
10
11
12
13
63[b]
94
C
C
96
[a]
[b]
See Experimental Section. Ϫ 15Ϫ25% starting material could
be recovered. Ϫ [c] 6  HCl/MeOH. Ϫ [d] 20% starting material and
40% HCl adduct 23 were isolated.
occurred. HPLC analysis showed that at the beginning of for the configurations of the parent homoallyl alcohols.[67]
the reaction the lactone 20a was formed, whose concen- The α-methylene-γ-butyrolactone ring turned out to be al-
tration decreased with longer reaction times at the benefit most planar due to three sp2-configured atoms O-1, C-2,
of the chlorinated lactone 23 (only one isomer was ob- and C-3, which is very advantageous for further dia-
served!). The amount and the rate of the chlorination was stereoselective reactions at the double bonds. One side of
lower with 3  HCl/MeOH and could be essentially sup- the molecule is effectively blocked by the aminoalkyl side
pressed with 1  HCl/MeOH (careful HPLC monitoring is chain.
necessary). Nevertheless, under these conditions 15Ϫ25% of
To exclude racemization during the Barbier reaction, we
the starting materials were recovered (method A in Table checked the NMR spectra of the isoleucine-derived prod-
2). To avoid a conjugate addition of chloride, we used ucts 15a/b. Since in these compounds an additional stereo-
Dowex-Hϩ as a strong, non-nucleophilic acid. No side genic centre is present, one should be able to observe signals
product was observed, but complete reaction could not be of a second pair of diastereoisomers when epimerization
obtained under these reaction conditions. About 20% start- occurred. Actually, no signals of a second pair of dia-
ing material was isolated (method B). Best results were ob- stereoisomers could be detected. (Additional peaks in the
served with 2 vol-% concd. sulfuric acid in ether (method spectra of 15a and 15b turned out to be due to rotamers;
C). After aqueous work up, the α-methylene-γ-butyrolac- the peaks disappear completely at 60°C.)
tones 17Ϫ22 were isolated as pure compounds (elemental
analysis within 0.3% boundaries without further purifi- lyl alcohol 14a by treatment with (S)-α-methoxy-α-(trifluo-
cation!) with yields ranging from 89 to 97%.
romethyl)phenylacetyl chloride (MTPA-Cl).[71][72] Inspec-
In addition, we prepared the Mosher ester of the homoal-
The configuration of lactones 17a, 19b, and 20a could tion of the (Z)-methylene proton signal (which is not super-
1
be unambiguously determined by crystallographic analyses imposed by other signals) in the H-NMR spectra showed
(lactone 17a is depicted in Figure 3) giving again evidence no trace of the “false” diastereoisomer. Therefore, we esti-
Eur. J. Org. Chem. 1999, 1551Ϫ1560
1553

S. Steurer, J. Podlech
FULL PAPER
Conclusion
We have shown that α-amino aldehydes can be cleanly
transformed into δ-amino-γ-hydroxy-α-methylenecar-
boxylic esters with high yields and without racemization by
an indium-mediated Barbier reaction. The preference for
the syn-configured products can be explained by a chelate
model. The α-methylene lactones, which are effectively ac-
cessible by acid-catalyzed cyclization should be ideal start-
ing materials for further transformations at the conjugate
double bond. Work in this direction is ongoing in our
laboratories.
Experimental Section
General: Solvents for chromatography and for work up, e.g. ethyl
acetate (EA) and light petroleum ether (PE) were distilled prior to
use; diethyl ether (ether) was distilled from KOH/FeSO4. Ether and
THF used for reactions were distilled from Na/benzophenone.
Et3N was distilled from CaH2 and stored over molecular sieves (4
˚
A); ClCO2Et was distilled. Dowex 50 W X 8 (Fluka) was purified
Figure 3. Molecular structure of lactone 17a as determined by X-
ray crystallographic analysis
and acidified as published.[77] 2-(Bromomethyl)acrylates 8[78Ϫ82]
and 9[64] were synthesized in accordance with published procedures,
whilst amino acid derivatives were prepared by standard meth-
ods.[83][84] Amino aldehydes have been prepared as published
[Swern oxidation,[50] periodinane oxidation (GP1),[53] reduction of
mate the enantiopurity of the homoallyl alcohols to be
greater than 98:2.
methyl esters with DIBAl-H[57], reduction of Weinreb amides.[54]
]
The observed stereochemistry might be explained by a
ZimmermanϪTraxler-like transition state[73] with ad-
ditional complexation of the indium ion by the carbamate
nitrogen atom (Scheme 4) or by the double-bonded carba-
mate oxygen atom (via a seven-membered ring[74]). As-
suming that the bulky side chain in the amino aldehyde is
opposite to the approaching allyl compound would explain
the preference for the syn-configured product. This ap-
proach is equivalent to a model proposed by Felkin and
Anh (Scheme 4, left hand).[75][76] Similar explanations have
been given for allyl additions to α-hydroxy aldehydes.[47]
Nevertheless, a boat-like conformation of the transition
state could be assumed as well; again, this would explain,
by similar arguments, the observed diastereoselectivity.
Indium was purchased from Aldrich (powder, 100 mesh, 99.99%).
Common amino acid abbreviations are used.[85] Moisture-sensitive
reactions were performed in dried vessels (150°C, 24 h) under nitro-
gen using syringe techniques. Ϫ Flash column chromatography:
Merck silica gel 60 (230Ϫ400 mesh). Ϫ TLC: Precoated sheets,
Alugram SIL G/UV254 MachereyϪNagel; detection by UV extinc-
tion or by cerium molybdate solution [phosphomolybdic acid
(25 g), Ce(SO4)2 · H2O (10 g), concd. H2SO4 (60 mL), H2O (940
mL)]. Ϫ MPLC: Detection with a UV detector. HPLC: Analyses
of diastereoisomer distribution were carried out with a Pharmacia
LKB, RSD 2140 apparatus with a Pharmacia LKB, RSD 2249
mixer and diode-array detection (Pharmacia RSD 2140) on a
LiChrosorb Si 60, Merck (hexane/EA, flow: 2.0 mL/min) chroma-
tographic column. Ϫ 1H- and 13C-NMR spectra were recorded
with a Bruker ARX 500 spectrometer at room temp. in CDCl3
unless otherwise indicated. Chemical shifts, δ, in ppm relative to
internal TMS (δ ϭ 0 or to resonances of the solvent (1H: CHCl3,
δ ϭ 7.24; 13C: CDCl3, δ ϭ 77.0), J in Hz. Ϫ Mass spectra were
recorded using a Finnigan MAT 95 [FAB or CI (CH4 or NH3)
technique] or a Varian MAT 711 instrument (EI). Ϫ IR spectra
were recorded with a Bruker IFS 28 or a PerkinϪElmer 283 instru-
ment. Ϫ Elemental analyses were performed by the service of the
Institut für Organische Chemie, Stuttgart. Ϫ Melting points are
not corrected.
General Procedure for the Oxidation of Amino Alcohols with Dess
؊Martin Periodinane (GP1):[53] The Z-protected amino alcohol
(1.00 mmol) in dry CH2Cl2 (2 mL) was added to a stirred solution
of periodinane (530 mg, 1.25 mmol) in CH2Cl2 (5 mL) at 0°C and
warmed to room temp. When the reaction was finished (as moni-
tored by TLC; occasionally, addition of further DMP is necessary),
excess of the oxidant was destroyed by addition of 1  NaOH solu-
tion After 5 min of vigorous stirring, the mixture was diluted with
Et2O (10 mL), the organic layer was separated, and the aqueous
layer was extracted twice with Et2O. The organic layers were
washed with brine, dried (MgSO4), and the solvent was removed.
Scheme 4. A chelating model as a possible explanation for the ob-
served diastereoselectivity in the formation of homoallyl alcohols
1554
Eur. J. Org. Chem. 1999, 1551Ϫ1560

Aminoalkyl-Substituted α-Methylene-γ-butyrolactones
General Procedure for the Synthesis of Homoallyl Alcohols 10؊16a/b 1, CHCl3). Ϫ IR (film): ν˜ ϭ 3430, 3300 cmϪ1 (NϪH, OϪH), 3020,
FULL PAPER
(GP2): The Z-protected α-amino aldehyde (1.00 mmol) was dis-
2980, 2930 (CϪH), 1710 (CϭO, ester), 1690 (CϭO, carbamate),
solved in EtOH (8 mL) at room temp. After addition of water (2 1530 (CϭC). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 1.23 (d, 3J ϭ
2
mL), methyl 2-(bromomethyl)acrylate (1.70 mmol, 304 mg), and in-
dium (1.10 mmol, 121 mg), the reaction mixture was stirred for 4 h
at room temp. (monitored by TLC). 1  HCl solution (5 mL) was
6.8 Hz, 3 H, 4Ј-H), 1.47 [s, 9 H, C(CH3)3], 2.42 (dd, J ϭ 14.1 Hz,
2
3
3J ϭ 8.9 Hz, 1 H, 1Ј-HA), 2.47 (dd, J ϭ 14.1 Hz, J ϭ 2.8 Hz, 1
H, 1Ј-HB), 3.26 (d, 3J ϭ 2.9 Hz, 1 H, OH), 3.65 (dddd, 3J ϭ 8.8 Hz,
added and the solution was extracted with EA (3 ϫ 10 mL). The 3J ϭ 3J ϭ 3J ϭ 3.0 Hz, 1 H, 2Ј-H), 3.76 (mc, 1 H, 3Ј-H), 5.09Ϫ5.13
organic layers were combined, subsequently extracted with satd.
(m, 3 H, NH, CH2Ph), 5.61 (s, 1 H, 3-HE), 6.13 (s, 1 H, 3-HZ),
NaHCO3 solution (10 mL) and satd. NaCl solution (2 ϫ 10 mL), 7.31Ϫ7.36 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ
dried (MgSO4), and the solvents were removed in a rotatory evap-
orator yielding a crude product, which was dissolved in EA and
filtered through a pad of silica gel (5 g). The diastereomeric ratio
was determined by HPLC, separation of the isomers was achieved
by MPLC.
18.8 (C-4Ј), 28.0 [C(CH3)3], 38.3 (C-1Ј), 50.9 (C-3Ј), 66.7 (CH2Ph),
73.9 (C-2Ј), 81.6 [C(CH3)3], 127.5, 128.0, 128.1, 128.5 (C6H5, C-3),
136.6, 138.9 (C6H5 ipso, C-2), 156.3 (NϪCϭO), 167.7 (C-1). Ϫ MS
(CI, NH3); m/z (%): 367 (17) [Mϩ ϩ NH4], 350 (33) [Mϩ ϩ H],
178 (10), [Mϩ Ϫ (CH3)3COH Ϫ C5H5O2], 91 (100), [C7H7ϩ]. Ϫ
C19H27NO5 (349.4): calcd. C 65.31, H 7.79, N 4.01; found C 65.40,
H 7.78, N 3.92. Ϫ 11b: Colourless oil. Ϫ tR (HPLC; hexane/EA,
77:23) ϭ 7.75 min. Ϫ [α]D20 ϭ Ϫ5.7 (c ϭ 0.8, CHCl3). Ϫ IR (film):
ν˜ ϭ 3435, 3350 cmϪ1 (NϪH, OϪH), 3020, 2980, 2940 (CϪH), 1715
(2ЈS,3ЈS)- and (2ЈR,3ЈS)-Methyl 2-[3-(Benzyloxycarbonylamino)-2-
hydroxybutyl]propenoate (10a,b): Z-Ala-H (1, 820 mg, 3.96 mmol)
was treated in accordance with GP2 yielding a crude mixture of
isomers, whose isomeric ratio was determined to be 10a/b ϭ 68:32.
Separation by MPLC (PE/EA ϭ 4:1) led to the pure isomers 10a
(560 mg, 46%) and 10b (270 mg, 22%). Ϫ 10a: Colourless solid,
m.p. 58Ϫ60°C. Ϫ tR (HPLC; hexane/EA, 7:3) ϭ 11.3 min. Ϫ
[α]D20 ϭ Ϫ8.9 (c ϭ 1, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3480 cmϪ1 (OϪH),
3320 (NϪH), 2970, 2920 (CϪH), 1680 (CϭO), 1520 (CϭC). Ϫ
1
(CϭO, ester), 1695 (CϭO, carbamate), 1535 (CϭC). Ϫ H NMR
3
(500 MHz, CDCl3): δ ϭ 1.16 (d, J ϭ 6.6 Hz, 3 H, 4Ј-H), 1.49 [s,
2
3
9 H, C(CH3)3], 2.32 (dd, J ϭ 14.0 Hz, J ϭ 9.2 Hz, 1 H, 1Ј-HA),
2.44 (dd, 2J ϭ 14.1 Hz, 3J ϭ 2.9 Hz, 1 H, 1Ј-HB), 3.17 (d, 3J ϭ
3.1 Hz, 1 H, OH), 3.75 (mc, 1 H, 2Ј-H), 3.78 (mc, 1 H, 3Ј-H),
5.07Ϫ5.12 (m, 1 H, NH), 5.09 (s, 2 H, CH2Ph), 5.62 (s, 1 H, 3-
HE), 6.16 (s, 1 H, 3-HZ), 7.30Ϫ7.36 (m, 5 H, C6H5). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 14.6 (C-4Ј), 28.0 [C(CH3)3], 37.0 (C-1Ј),
51.2 (C-3Ј), 66.7 (CH2Ph), 73.7 (C-2Ј), 81.6 [C(CH3)3], 127.1, 128.1,
128.5 (C6H5, C-3, one signal covered), 136.5, 138.9 (C6H5 ipso, C-
2), 156.1 (NϪCϭO), 167.4 (C-1). Ϫ MS (CI, NH3); m/z (%): 372
(4) [Mϩ ϩ Na], 350 (40) [Mϩ ϩ H], 294 (64) [Mϩ Ϫ C4H7], 276
(17) [Mϩ Ϫ (CH3)3CO], 91 (100) [C7H7ϩ]. Ϫ C19H27NO5 (349.4):
calcd. C 65.31, H 7.79, N 4.01; found C 64.96, H 7.81, N 3.99.
3
1H NMR (500 MHz; CDCl3): δ ϭ 1.22 (d, J ϭ 6.7 Hz, 3 H, 4Ј-
H), 2.43 (dd, 2J ϭ 14.1 Hz, 3J ϭ 8.8 Hz, 1 H, 1Ј-HA), 2.54 (dd,
3
2J ϭ 14.1 Hz, J ϭ 3.3 Hz, 1 H, 1Ј-HB), 3.03 (d, 3J ϭ 3.9 Hz, 1 H,
OH), 3.68 (mc, 1 H, 2Ј-H), 3.75Ϫ3.80 (m, 1 H, 3Ј-H), 3.76 (s, 3 H,
OCH3), 5.10 (s, 2 H, CH2Ph), 5.16 (d, 3J ϭ 8.9 Hz, 1 H, NH), 5.69
(s, 1 H, 3-HE), 6.24 (s, 1 H, 3-HZ), 7.29Ϫ7.39 (m, 5 H, C6H5). Ϫ
13C NMR (125 MHz; CDCl3): δ ϭ 18.7 (C-4Ј), 38.1 (C-1Ј), 50.6
(C-3Ј), 52.2 (OCH3), 66.7 (CH2Ph), 73.4 (C-2Ј), 128.1, 128.5, 128.6
(C6H5, C-3, one signal covered), 136.5, 137.0 (C6H5 ipso, C-2), 156.4
(NϪCϭO), 168.4 (C-1). Ϫ MS (FAB); m/z (%): 330 (6) [Mϩ
Na], 308 (41) [Mϩ ϩ H], 276 (14) [Mϩ Ϫ CH3O], 178 (4) [Mϩ
ϩ
(2ЈS,3ЈS)- and (2ЈR,3ЈS)-Methyl 2-[3-(Benzyloxycarbonylamino)-2-
hydroxy-4-phenylbutyl]propenoate (12a,b): Z-Phe-H (2, 1.08 mg,
3.81 mmol) was treated in accordance with GP2 yielding a crude
mixture of isomers, whose isomeric ratio was determined to be 12a/
b ϭ 68:32. Separation by MPLC (PE/EA, 85:15) led to the pure
isomers 12a (716 mg, 49%) and 12b (354 mg, 24%). Ϫ 12a: Colour-
less solid, m.p. 62Ϫ64°C. Ϫ tR (HPLC; hexane/EA, 7:3) ϭ 7.3 min.
Ϫ
CH3OH Ϫ C5H5O2], 91 (100) [C7H7ϩ]. Ϫ C16H21NO5 (307.3):
calcd. C 62.53, H 6.89, N 4.56; found C 62.52, H 6.90, N 4.50. Ϫ
10b: Colourless solid, m.p. 85Ϫ87°C. Ϫ tR (HPLC; hexane/EA,
20
7:3) ϭ 14.4 min. Ϫ [α]D ϭ Ϫ7.4 (c ϭ 1, CHCl3). Ϫ IR (KBr):
ν˜ ϭ 3300 cmϪ1 (br., OϪH, NϪH), 3040, 2920 (CϪH), 1710 (Cϭ
O, ester), 1690 (CϭO, carbamate), 1540 (CϭC). Ϫ 1H NMR
(500 MHz; CDCl3): δ ϭ 1.16 (d, 3J ϭ 6.5 Hz, 3 H, 4Ј-H), 2.36 (dd,
2J ϭ 14.1 Hz, 3J ϭ 9.0 Hz, 1 H, 1Ј-HA), 2.50 (dd, 2J ϭ 14.2 Hz,
3J ϭ 3.0 Hz, 1 H, 1Ј-HB), 2.97 (d, 3J ϭ 3.7 Hz, 1 H, OH),
3.72Ϫ3.78 (m, 2 H, 2Ј-H, 3Ј-H), 3.76 (s, 3 H, OCH3), 5.07 (d, 2J ϭ
12.2 Hz, 1 H, CHAHBPh), 5.10 (d, 2J ϭ 12.2 Hz, 1 H, CHAHBPh),
20
Ϫ [α]D ϭ Ϫ27.9 (c ϭ 1, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3500 cmϪ1
(OϪH), 3300 (NϪH), 3010, 2930 (CϪH), 1695 (CϭO, ester), 1680
1
(CϭO, carbamate), 1530 (CϭC). Ϫ H NMR (500 MHz; CDCl3):
δ ϭ 2.47Ϫ2.48 (m, 2 H, 1Ј-H), 2.89 (dd, 2J ϭ 13.6 Hz, 3J ϭ 7.8 Hz,
1 H, 4Ј-HA), 2.91 (dd, 2J ϭ 13.6 Hz, 3J ϭ 7.3 Hz, 1 H, 4Ј-HB), 3.14
3
(d, J ϭ 3.5 Hz, 1 H, OH), 3.70 (s, 3 H, OCH3), 3.72 (mc, 1 H, 2Ј-
3
5.17 (d, J ϭ 8.9 Hz, 1 H, NH), 5.71 (s, 1 H, 3-HE), 6.26 (d, J ϭ
3
3
3
H), 3.88 (dtd, J ϭ 9.6 Hz, J ϭ 7.7 Hz, J ϭ 1.8 Hz, 1 H, 3Ј-H),
1.2 Hz, 1 H, 3-HZ), 7.29Ϫ7.39 (m, 5 H, C6H5). Ϫ 13C NMR
(125 MHz; CDCl3): δ ϭ 14.7 (C-4Ј), 36.8 (C-1Ј), 51.1 (C-3Ј), 52.2
(OCH3), 66.7 (CH2Ph), 73.4 (C-2Ј), 128.1, 128.2, 128.5 (C6H5, C-
3, one signal covered), 136.5, 137.0 (C6H5 ipso, C-2), 156.1 (NϪCϭ
O), 168.3 (C-1). Ϫ MS (FAB); m/z (%): 330 (10) [Mϩ ϩ Na], 308
(100) [Mϩ ϩ H], 276 (7), [Mϩ Ϫ CH3O], 178 (8), [Mϩ Ϫ CH3OH
Ϫ C5H5O2], 97 (9) [C5H5O2ϩ], 91 (81) [C7H7ϩ]. Ϫ C16H21NO5
(307.3): calcd. C 62.53, H 6.89, N 4.56; found C 62.55, H 6.98,
N 4.34.
2
2
5.05 (d, J ϭ 12.3 Hz, 1 H, OCHAHBPh), 5.08 (d, J ϭ 12.3 Hz, 1
H, OCHAHBPh), 5.20 (d, 3J ϭ 9.6 Hz, 1 H, NH), 5.63 (d, J ϭ
1.2 Hz, 1 H, 3-HE), 6.19 (d, J ϭ 1.4 Hz, 1 H, 3-HZ), 7.16Ϫ7.37 (m,
10 H, 2 C6H5). Ϫ 13C NMR (125 MHz; CDCl3): δ ϭ 38.8 (C-1Ј),
39.4 (C-4Ј), 52.6 (OCH3), 56.7 (C-3Ј), 67.1 (OCH2Ph), 71.0 (C-2Ј),
126.8, 128.3, 128.5, 128.9, 129.1, 129.7 (2 C6H5, C-3, one signal
covered), 137.0, 137.4, 138.5 (2 C6H5 ipso, C-2), 156.8 (NϪCϭO),
169.0 (C-1). Ϫ MS (FAB); m/z (%): 384 (18) [Mϩ ϩ H], 352 (15)
[Mϩ Ϫ CH3O], 292 (23) [Mϩ Ϫ C7H7], 254 (20) [Mϩ Ϫ CH3OH
Ϫ C5H5O2], 91 (100) [C7H7ϩ]. Ϫ C22H25NO5 (383.4): calcd. C
(2ЈS,3ЈS)- and (2ЈR,3ЈSS)-tert-Butyl 2-[3-(Benzyloxycarbonyl-
amino)-2-hydroxybutyl]propenoate (11a,b): In slight variation of 68.91, H 6.57, N 3.65; found C 69.00, H 6.65, N 3.68. Ϫ 12b:
GP2 Z-Ala-H (1, 438 mg, 2.11 mmol) was treated with tert-butyl 2-
(bromomethyl)propenoate (9) yielding a crude mixture of isomers,
Colourless solid, m.p. 110Ϫ112°C. Ϫ tR (HPLC; hexane/EA,
24
4:1) ϭ 10.8 min. Ϫ [α]D ϭ Ϫ26.5 (c ϭ 1, CHCl3). Ϫ IR (KBr):
whose isomeric ratio was determined to be 11a/b ϭ 67:33. Separ- ν˜ ϭ 3300 cmϪ1 (br., OϪH, NϪH), 3010, 2910, 2900 (CϪH), 1725
1
ation by MPLC (PE/EA, 85:15) led to the pure isomers 11a
(CϭO, ester), 1690 (CϭO, carbamate), 1540 (CϭC). Ϫ H NMR
2
3
(359 mg, 49%) and 11b (168 mg, 23%). Ϫ 11a: M.p. 64Ϫ66°C. Ϫ (500 MHz; CDCl3): δ ϭ 2.43 (dd, J ϭ 14.2 Hz, J ϭ 8.8 Hz, 1 H,
20
tR (HPLC; hexane/EA, 77:23) ϭ 6.38 min. Ϫ [α]D ϭ Ϫ1.8 (c ϭ
1Ј-HA), 2.64 (ddd, 2J ϭ 14.2 Hz, 3J ϭ 3.1 Hz, 4J ϭ 1.2 Hz, 1 H,
Eur. J. Org. Chem. 1999, 1551Ϫ1560
1555

S. Steurer, J. Podlech
FULL PAPER
1Ј-HB), 2.84 (dd, 2J ϭ 14.1 Hz, 3J ϭ 9.1 Hz, 1 H, 4Ј-HA), 3.00 (dd,
isomers 14a (686 mg, 68%) and 14b (164 mg, 16%). Ϫ 14a: Colour-
3
3
2J ϭ 14.1 Hz, J ϭ 4.7 Hz, 1 H, 4Ј-HB), 3.28 (d, J ϭ 4.6 Hz, 1 H, less solid, m.p. 100Ϫ102°C. Ϫ tR (HPLC; hexane/EA, 4:1) ϭ
OH), 3.77 (s, 3 H, OCH3), 3.78 (mc, 1 H, 2Ј-H), 3.93 (ddt, 3J ϭ
10.8 min. Ϫ [α]D21 ϭ Ϫ29.0 (c ϭ 1, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3500
3
3
3J ϭ 9.2 Hz, J ϭ 4.7 Hz, 1 H, 3Ј-H), 4.87 (d, J ϭ 9.2 Hz, 1 H, cmϪ1 (OϪH), 3300 (NϪH), 2940, 2860 (CϪH), 1705 (CϭO, ester),
NH), 5.02 (s, 2 H, OCH2Ph), 5.71 (s, 1 H, 3-HE), 6.27 (d, J ϭ 1680 (CϭO, carbamate), 1530 (CϭC). Ϫ 1H NMR (500 MHz;
1.2 Hz, 1 H, 3-HZ), 7.19Ϫ7.35 (m, 10 H, 2 C6H5). Ϫ 13C NMR CDCl3): δ ϭ 0.95, 0.97 [2 d, 3J ϭ 6.9 Hz, 3J ϭ 6.7 Hz, 6 H,
(125 MHz; CDCl3): δ ϭ 35.6 (C-1Ј), 36.8 (C-4Ј), 52.3 (OCH3), CH(CH3)2], 1.90 (dsept, 3J ϭ 8.5 Hz, 3J ϭ 6.7 Hz, 1 H, 4Ј-H), 2.44
56.7 (C-3Ј), 66.7 (OCH2Ph), 72.8 (C-2Ј), 126.5, 127.9, 128.1,
128.5, 129.4 (2 C6H5, C-3, 2 signals covered), 136.4, 137.0, 137.7
(2 C6H5 ipso, C-2), 156.4 (NϪCϭO), 168.5 (C-1). Ϫ MS (FAB);
(dd, 2J ϭ 14.0 Hz, 3J ϭ 8.5 Hz, 1 H, 1Ј-HA), 2.50 (dd, 2J ϭ
14.0 Hz, 3J ϭ 3.7 Hz, 1 H, 1Ј-HB), 2.92 (d, 3J ϭ 3.6 Hz, 1 H, OH),
3.30 (ddd, 3J ϭ 10.2 Hz, 3J ϭ 8.3 Hz, 3J ϭ 1.9 Hz, 1 H, 3Ј-H), 3.76
m/z (%): 406 (16) [Mϩ ϩ Na], 384 (83) [Mϩ ϩ H], 352 (5), [Mϩ
Ϫ
(s, 3 H, OCH3), 3.94 (dtd, J ϭ 8.7 Hz, J ϭ 3.7 Hz, J ϭ 1.9 Hz,
3
3
3
CH3O], 254 (7) [Mϩ Ϫ HOCH3 Ϫ C5H5O2], 97 (17) [C5H5O2ϩ], 91 1 H, 2Ј-H), 5.10 (d, J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.12 (d, J ϭ
2
2
(100) [C7H7ϩ]. Ϫ C22H25NO5 (383.4): calcd. C 68.91, H 6.57, N 12.3 Hz, 1 H, CHAHBPh), 5.13 (d, J ϭ 10.2 Hz, 1 H, NH), 5.70
3
3.65; found C 68.64, H 6.66, N 3.53.
(s, 1 H, 3-HE), 6.23 (s, 1 H, 3-HZ), 7.29Ϫ7.37 (m, 5 H, C6H5). Ϫ
13C NMR (125 MHz; CDCl3): δ ϭ 19.3, 19.7 [CH(CH3)2], 30.6 (C-
4Ј), 38.9 (C-1Ј), 52.3 (OCH3), 60.6 (C-3Ј), 66.7 (CH2Ph), 70.2 (C-
(2ЈS,3ЈS)- and (2ЈR,3ЈS)-Methyl 2-[3-(Benzyloxycarbonylamino)-2-
hydroxy-5-methylhexyl]propenoate (13a,b): Z-Leu-H (3, 616 mg,
2.47 mmol) was treated in accordance with GP2 yielding a crude
mixture of isomers, whose isomeric ratio was determined to be 13a/
b ϭ 75:25. Separation by MPLC (PE/EA, 85:15) led to the pure
2Ј), 128.0, 128.1, 128.5, 128.7 (C6H5, C-3), 136.7, 137.2 (C6H5 ipso
,
C-2), 157.0 (NϪCϭO), 169.7 (C-1). Ϫ MS (EI, 70 eV); m/z (%):
335 (1) [Mϩ], 206 (9) [Mϩ Ϫ CH3OH Ϫ C5H5O2], 162 (19) [Mϩ
Ϫ
CH3OH Ϫ C5H5O2 Ϫ C3H8], 97 (7) [C5H5O2ϩ], 91 (100) [C7H7ϩ].
Ϫ C18H25NO5 (335.4): calcd. C 64.46, H 7.51, N 4.18; found C
64.76, H 7.52, N 4.26. Ϫ 14b: Colourless oil. Ϫ tR (HPLC; hexane/
isomers 13a (520 mg, 60%) and 13b (181 mg, 21%). Ϫ 13a: Colour-
less oil. Ϫ tR (HPLC; hexane/EA, 77:23) ϭ 6.53 min. Ϫ [α]D
20
ϭ
Ϫ21.6 (c ϭ 0.5, CHCl3). Ϫ IR (film): ν˜ ϭ 3380 cmϪ1 (br., OϪH,
NϪH), 3033, 2955, 2870 (CϪH), 1710 (CϭO, ester), 1680 (CϭO,
carbamate), 1527 (CϭC). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 0.91
[d, 3J ϭ 6.7 Hz, 3 H, CH(CH3)2], 0.93 [d, 3J ϭ 6.5 Hz, 3 H,
20
EA, 4:1) ϭ 17.9 min. Ϫ [α]D ϭ Ϫ8.2 (c ϭ 0.83, CHCl3). Ϫ IR
(film): ν˜ ϭ 3441 cmϪ1 (OϪH), 3350 (NϪH), 2959 (CϪH), 1695
1
(CϭO, ester), 1690 (CϭO, carbamate), 1537 (CϭC). Ϫ H NMR
(500 MHz; CDCl3): δ ϭ 0.90, 0.98 [2 d, 3J ϭ 3J ϭ 6.8 Hz, 6 H,
CH(CH3)2], 1.90 (septd, 3J ϭ 6.8 Hz, 3J ϭ 5.2 Hz, 1 H, 4Ј-H), 2.29
(dd, 2J ϭ 14.0 Hz, 3J ϭ 9.5 Hz, 1 H, 1Ј-HA), 2.65 (dd, 2J ϭ
14.1 Hz, 3J ϭ 2.6 Hz, 1 H, 1Ј-HB), 2.80 (d, 3J ϭ 4.9 Hz, 1 H, OH),
2
3
3
CH(CH3)2], 1.32 (ddd, J ϭ 13.6 Hz, J ϭ 8.6 Hz, J ϭ 4.8 Hz, 1
H, 4Ј-HA), 1.53 (ddd, 2J ϭ 13.9 Hz, 3J ϭ 9.6 Hz, 3J ϭ 5.5 Hz, 1 H,
4Ј-HB), 1.65 (mc, 1 H, 5Ј-H), 2.43 (dd, 2J ϭ 14.1 Hz, 3J ϭ 8.7 Hz, 1
2
3
H, 1Ј-HA), 2.54 (dd, J ϭ 14.1 Hz, J ϭ 3.5 Hz, 1 H, 1Ј-HB), 2.91
3
3
3
3.60 (dd, J ϭ 9.9 Hz, J ϭ 5.2 Hz, 1 H, 3Ј-H), 3.73 (dddd, J ϭ
9.3 Hz, 3J ϭ 3J ϭ 4.9 Hz, 3J ϭ 2.6 Hz, 1 H, 2Ј-H), 3.76 (s, 3 H,
OCH3), 4.79 (d, 3J ϭ 9.8 Hz, 1 H, NH), 5.11 (s, 2 H, CH2Ph), 5.70
(s, 1 H, 3-HE), 6.26 (s, 1 H, 3-HZ), 7.30Ϫ7.37 (m, 5 H, C6H5). Ϫ
13C NMR (125 MHz; CDCl3): δ ϭ 17.5, 20.6 [CH(CH3)2], 28.6 (C-
4Ј), 36.9 (C-1Ј), 52.6 (OCH3), 60.9 (C-3Ј), 67.4 (CH2Ph), 71.8 (C-
(d, 3J ϭ 3.7 Hz, 1 H, OH), 3.71 (mc, 1 H, 2Ј-H), 3.76 (s, 3 H,
3
OCH3), 3.78 (mc, 1 H, 3Ј-H), 5.00 (d, J ϭ 9.7 Hz, 1 H, NH), 5.10
(s, 2 H, CH2Ph), 5.70 (s, 1 H, 3-HE), 6.23 (s, 1 H, 3-HZ), 7.29Ϫ7.36
(m, 5 H, C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 22.2, 23.1
[CH(CH3)2], 24.7 (C-5Ј), 38.3 (C-1Ј), 42.1 (C-4Ј), 52.2, 53.1 (C-3Ј,
OCH3), 66.7 (CH2Ph), 72.8 (C-2Ј), 128.0, 128.1, 128.5, 128.6 (C-3,
C6H5), 136.7, 137.2 (C6H5 ipso, C-2), 156.7 (NϪCϭO), 168.6 (C-1).
Ϫ MS (FAB); m/z (%): 372 (3) [Mϩ ϩ Na], 350 (23) [Mϩ ϩ H],
306 (8) [Mϩ Ϫ C3H8], 91 (100) [C7H7ϩ]. Ϫ C19H27NO5 (349.4):
calcd. C 65.31, H 7.79, N 4.01; found C 65.23, H 7.89, N 4.04. Ϫ
13b: Colourless solid, m.p. 47Ϫ49°C. Ϫ tR (HPLC; hexane/EA,
2Ј), 128.5, 128.6, 128.9, 128.9 (C6H5, C-3), 136.8, 137.3 (C6H5 ipso
,
C-2), 157.5 (NϪCϭO), 168.7 (C-1). Ϫ MS (FAB); m/z (%): 358
(12) [Mϩ ϩ Na], 336 (61), [Mϩ ϩ H], 206 (8), [Mϩ Ϫ CH3OH
Ϫ C5H5O2], 162 (7), [Mϩ Ϫ CH3OH Ϫ C5H5O2 Ϫ C3H8], 97 (8)
[C5H5O2ϩ], 91 (100) [C7H7ϩ]. Ϫ C18H25NO5 (335.4): calcd. C
64.46, H 7.51, N 4.18; found C 64.53, H 7.64, N 3.96.
20
77:23) ϭ 10.03 min. Ϫ [α]D ϭ Ϫ19.2 (c ϭ 1.1, CHCl3). Ϫ IR
(KBr): ν˜ ϭ 3310 cmϪ1 (br., OϪH, NϪH), 3050, 3020, 2940, 2870
(CϪH), 1725 (CϭO, ester), 1690 (CϭO, carbamate), 1540 (CϭC).
1H NMR (500 MHz, CDCl3): δ ϭ 0.93 [d, 3J ϭ 6.3 Hz, 3 H,
CH(CH3)2], 0.94 [d, 3J ϭ 6.6 Hz, 3 H, CH(CH3)2], 1.37 (2 mc, 2
H, 4Ј-HA, 4Ј-HB), 1.68 (mc, 1 H, 5Ј-H), 2.35 (dd, 2J ϭ 14.3 Hz,
(R) Mosher Derivative of 14a: 1H NMR (500 MHz; [D6]DMSO;
333 K): δ ϭ 5.99 (s, 1 H, ϭCHEHZ).
(R) Mosher Derivative of ent-14a: 1H-NMR (500 MHz;
[D6]DMSO; 333 K): δ ϭ 5.84 (s, 1 H, ϭCHEHZ).
2
3
3J ϭ 9.4 Hz, 1 H, 1Ј-HA), 2.51 (dd, J ϭ 14.1 Hz, J ϭ 2.9 Hz, 1
(2ЈS,3ЈS,4ЈS)- and (2ЈR,3ЈS,4ЈS)-Methyl 2-[3-(Benzyloxycarbonyla-
mino)-2-hydroxy-4-methylhexyl]propenoate (15a,b): Z-Ile-H (5,
463 mg, 1.86 mmol) was treated in accordance with GP2 yielding
a crude mixture of isomers, whose isomeric ratio was determined
to be 15a/b ϭ 89:11. Separation by MPLC (PE/EA, 85:15) led to
the pure isomers 15a (491 mg, 76%) and 15b (58 mg, 9%). Ϫ 15a:
Colourless solid, m.p. 77Ϫ79°C. Ϫ tR (HPLC; hexane/EA, 4:1) ϭ
3
H, 1Ј-HB), 3.01 (d, J ϭ 4.9 Hz, 1 H, OH), 3.72Ϫ3.80 (2 m, 2 H,
3
2Ј-H, 3Ј-H), 3.76 (s, 3 H, OCH3), 4.89 (d, J ϭ 9.2 Hz, 1 H, NH),
5.09 (s, 2 H, CH2Ph), 5.72 (s, 1 H, 3-HE), 6.26 (s, 1 H, 3-HZ),
7.29Ϫ7.37 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ
21.7, 23.7 [CH(CH3)2], 24.7 (C-5Ј), 36.4 (C-1Ј), 38.6 (C-4Ј), 52.2,
54.1 (C-3Ј, OCH3), 66.9 (CH2Ph), 73.8 (C-2Ј), 128.1 (C-3), 128.0,
128.2, 128.5 (C6H5), 136.4, 137.1 (C6H5 ipso, C-2), 156.7 (NϪCϭ
O), 168.3 (C-1). Ϫ MS (FAB); m/z (%): 699 (3) [2 Mϩ ϩ H], 372
(10), [Mϩ ϩ Na], 350 (100), [Mϩ ϩ H], 306 (16) [Mϩ Ϫ C3H8], 91
(100) [C7H7ϩ]. Ϫ C19H27NO5 (349.4): calcd. C 65.31, H 7.79, N
4.01; found C 65.30, H 7.79, N 3.98.
20
8.3 min. Ϫ [α]D ϭ Ϫ25.0 (c ϭ 1.1, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3500, 3300 cmϪ1 (OϪH, NϪH), 3020, 2950, 2910 (CϪH), 1695
1
(CϭO, ester), 1680 (CϭO, carbamate), 1530 (CϭC). Ϫ H NMR
3
(500 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 7.4 Hz, 3 H, 6Ј-H), 0.94 (d,
2
3
3J ϭ 6.7 Hz, 3 H, CHCH3), 1.14 (ddq, J ϭ 13.5 Hz, J ϭ 8.9 Hz,
2
(2ЈS,3ЈS)- and (2ЈR,3ЈS)-Methyl 2-[3-(Benzyloxycarbonylamino)-2-
hydroxy-4-methylpentyl]propenoate (14a,b): Z-Val-H (4, 710 mg,
3J ϭ 7.4 Hz, 1 H, 5Ј-HA), 1.56 (dqd, J ϭ 13.7 Hz, 3J ϭ 7.6 Hz,
3J ϭ 3.5 Hz, 1 H, 5Ј-HB), 1.63 (mc, 1 H, 4Ј-H), 2.45 (dd, 2J ϭ
3.02 mmol) was treated in accordance with GP2 yielding a crude 14.0 Hz, 3J ϭ 8.4 Hz, 1 H, 1Ј-HA), 2.50 (dd, 2J ϭ 14.0 Hz, 3J ϭ
mixture of isomers, whose isomeric ratio was determined to be 14a/
3.7 Hz, 1 H, 1Ј-HB), 2.91 (br. s, 1 H, OH), 3.37 (mc, 1 H, 3Ј-H),
3
3
b ϭ 82:18. Separation by MPLC (PE/EA, 85:15) led to the pure 3.76 (s, 3 H, OCH3), 3.96 (dddd, 3J ϭ 8.4 Hz, J ϭ J ϭ 3.6 Hz,
1556
Eur. J. Org. Chem. 1999, 1551Ϫ1560

Aminoalkyl-Substituted α-Methylene-γ-butyrolactones
FULL PAPER
3
3
3
3
3J ϭ 1.6 Hz, 1 H, 2Ј-H), 5.11 (s, 2 H, CH2Ph), 5.13 (d, 3J ϭ
(dddd, J ϭ 10.1 Hz, J ϭ 7.3 Hz, J ϭ 3.8 Hz, J ϭ 2.2 Hz, 1 H,
3
2
10.4 Hz, 1 H, NH), 5.70 (s, 1 H, 3-HE), 6.23 (s, 1 H, 3-HZ), 2Ј-H), 4.81 (d, J ϭ 9.0 Hz, 1 H, NH), 5.12 (d, J ϭ 12.2 Hz, 1 H,
7.29Ϫ7.36 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ CHAHBPh), 5.14 (d, J ϭ 12.1 Hz, 1 H, CHAHBPh), 5.68 (s, 1 H,
2
11.2 (C-6Ј), 15.7 (CHCH3), 25.6 (C-5Ј), 36.9 (C-4Ј), 39.0 (C-1Ј),
52.3 (OCH3), 59.1 (C-3Ј), 66.7 (CH2Ph), 70.0 (C-2Ј), 128.0, 128.1
3-HE), 6.26 (d, J ϭ 1.5 Hz, 1 H, 3-HZ), 7.32Ϫ7.38 (m, 5 H, C6H5).
Ϫ
13C NMR (125 MHz; CDCl3): δ ϭ 27.3 [C(CH3)3], 34.0 (C-4Ј),
128.5 (C6H5), 128.7 (C-3), 136.7, 137.2 (C6H5 ipso, C-2), 156.9 37.4 (C-1Ј), 52.0 (OCH3), 65.2 (C-3Ј), 67.2 (CH2Ph), 70.8 (C-2Ј),
(NϪCϭO), 168.7 (C-1). Ϫ MS (FAB); m/z (%): 372 (6) [Mϩ
ϩ
128.4 (C-3), 128.2, 128.3, 128.6 (C6H5), 136.3, 136.9 (C6H5 ipso, C-
Na], 350 (53) [Mϩ ϩ H], 306 (15) [Mϩ Ϫ C3H7], 91 (100) [C7H7ϩ]. 2), 157.6 (NϪCϭO), 167.9 (C-1). Ϫ MS (FAB); m/z (%): 372 (6)
Ϫ C19H27NO5 (349.4): calcd. C 65.31, H 7.79, N 4.01; found C [Mϩ ϩ Na], 350 (28) [Mϩ ϩ H], 318 (9) [Mϩ Ϫ CH3O], 220 (6),
65.17, H 7.79, N 4.00. Ϫ 15b: Colourless oil. Ϫ tR (HPLC; hexane/
[Mϩ ϪCH3OH Ϫ C5H5O2], 91 (100) [C7H7ϩ]. Ϫ C19H27NO5
(349.4): calcd. C 65.31, H 7.79, N 4.01; found C C 65.18, H 7.70,
20
EA, 4:1) ϭ 15.4 min. Ϫ [α]D ϭ Ϫ12.7 (c ϭ 2.4, CHCl3). Ϫ IR
(film): ν˜ ϭ 3370, 3300 cmϪ1 (OϪH, NϪH), 3030, 2955, 2870 N 3.89.
(CϪH), 1710 (CϭO, ester), 1690 (CϭO, carbamate), 1530 (CϭC).
General Procedures for the Synthesis of ␣-Methylene-γ-butyrolac-
3
Ϫ 1H-NMR (500 MHz, CDCl3): δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H, 6Ј-
tones 17؊22 (See Table 2 for the Respective Method Used). ؊
Method A: The homoallyl alcohol (0.5 mmol) was stirred in satd.
methanolic HCl (16 mL) for 2 h at room temp. with careful moni-
toring by HPLC. The reaction mixture was poured in satd.
NaHCO3 solution (40 mL) and extracted with EA (3 ϫ 50 mL).
The combined organic layers were extracted with satd. NaHCO3
solution (40 mL) and satd. NaCl solution (2 ϫ 40 mL), dried
(MgSO4), and concentrated in a rotary evaporator. Purification by
MPLC yielded the α-methylene-γ-butyrolactones. Ϫ Method B:
The homoallyl alcohol (0.6 mmol) and ion-exchange resin Dowex-
Hϩ (400 mg) were stirred in EtOH (30 mL) for 3 d at 70°C. The
cooled reaction mixture was filtered and concentrated in a rotary
evaporator. Purification by MPLC yielded the α-methylene-γ-bu-
tyrolactones and about 15Ϫ25% of starting material. Ϫ Method C:
The homoallyl alcohol (1.1 mmol) was stirred in Et2O (16 mL) with
concd. H2SO4 (0.3 mL) for 2 d at room temp. The reaction mixture
was poured in satd. NaHCO3 solution (25 mL) and extracted with
Et2O (3 ϫ 45 mL). The combined organic layers were extracted
with satd. NaHCO3 solution (30 mL) and satd. NaCl solution (2
ϫ 30 mL), dried (MgSO4), and concentrated in a rotary evaporator.
H), 0.98 (d, 3J ϭ 6.8 Hz, 3 H, CHCH3), 1.05 (mc, 1 H, 5Ј-HA),
1.58 (mc, 1 H, 5Ј-HB), 1.73 (mc, 1 H, 4Ј-H), 2.26 (dd, 2J ϭ 14.0 Hz,
2
3
3J ϭ 9.5 Hz, 1 H, 1Ј-HA), 2.63 (dd, J ϭ 14.1 Hz, J ϭ 2.5 Hz, 1
H, 1Ј-HB), 2.80 (d, 3J ϭ 5.1 Hz, 1 H, OH), 3.65 (ddd, 3J ϭ 9.7 Hz,
3J ϭ J ϭ 6.1 Hz, 1 H, 3Ј-H), 3.76 (s, 3 H, OCH3), 3.96 (mc, 1 H,
3
3
2Ј-H), 4.72 (d, J ϭ 9.7 Hz, 1 H, NH), 5.12 (s, 2 H, CH2Ph), 5.71
(s, 1 H, 3-HE), 6.26 (s, 1 H, 3-HZ), 7.31Ϫ7.37 (m, 5 H, C6H5). Ϫ
13C-NMR (125 MHz, CDCl3): δ ϭ 11.5 (C-6Ј), 16.1 (CHCH3), 24.1
(C-5Ј), 35.3, 36.2 (C-1Ј, C-4Ј), 52.1 (OCH3), 60.4 (C-3Ј), 67.0
(CH2Ph), 71.1 (C-2Ј), 128.1, 128.2 128.6 (C6H5), 128.5 (C-3), 136.4,
137.0 (C6H5 ipso, C-2), 157.3 (NϪCϭO), 168.3 (C-1). Ϫ MS (CI,
CH4); m/z (%): 350 (10) [Mϩ ϩ H], 318 (21) [Mϩ Ϫ CH3O], 306
(28) [Mϩ Ϫ C3H7], 220 (28), [Mϩ Ϫ CH3OH Ϫ C5H5O2], 176 (35)
[Mϩ Ϫ CH3OH Ϫ C5H5O2 Ϫ C3H8], 97 (7) [C5H5O2ϩ], 91 (100)
[C7H7ϩ]. Ϫ C19H27NO5 (349.4): calcd. C 65.31, H 7.79, N 4.01;
found C 65.08, H 7.79, N 4.00.
(2ЈS,3ЈS)- and (2ЈR,3ЈS)-Methyl 2-[3-(Benzyloxycarbonylamino)-2-
hydroxy-4,4-dimethylpentyl]propenoate (16a,b): Z-Tle-H (6, 997 mg,
4.00 mmol) was treated in accordance with GP2 yielding a crude
mixture of isomers, whose isomeric ratio was determined to be 16a/
b ϭ 97:3. Separation by MPLC (PE/EA, 85:15) led to the pure
isomers 16a (1.23 g, 88%) and 16b (64 mg, 5%). Ϫ 16a: Colourless
(5S,1ЈS)-5-[1-(Benzyloxycarbonylamino)ethyl]-3-methylene-
dihydro-2(3H)-furanone (17a): Colourless solid, m.p. 117Ϫ119°C.
20
Ϫ [α]D ϭ ϩ4.8 (c ϭ 0.83, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3280 cmϪ1
20
oil. Ϫ tR (HPLC; hexane/EA, 77:23) ϭ 4.4 min. Ϫ [α]D ϭ Ϫ25.0
(NϪH), 3040, 2960, 2910 (CϪH), 1760 (CϭO, lactone), 1680 (Cϭ
(c ϭ 1.1, CHCl3). Ϫ IR (film): ν˜ ϭ 3440 cmϪ1 (br., OϪH, NϪH),
3034, 2956, 2870 (CϪH), 1714 (CϭO, ester), 1695 (CϭO, carba-
1
O, carbamate), 1540 (CϭC). Ϫ H NMR (500 MHz, CDCl3): δ ϭ
1.31 (d, 3J ϭ 7.0 Hz, 3 H, 2Ј-H), 2.85 (ddt, 2J ϭ 17.5 Hz, 3J ϭ
8.1 Hz, 4J ϭ 2.6 Hz, 1 H, 4-HA), 2.94 (ddt, 2J ϭ 17.5 Hz, 3J ϭ
1
mate), 1514 (CϭC). Ϫ H NMR (500 MHz; CDCl3): δ ϭ 0.95 [s,
2
3
9 H, C(CH3)3], 2.43 (dd, J ϭ 13.9 Hz, J ϭ 7.9 Hz, 1 H, 1Ј-HA),
2.47 (dd, 2J ϭ 13.8 Hz, 3J ϭ 4.5 Hz, 1 H, 1Ј-HB), 2.71 (d, 3J ϭ
3.8 Hz, 1 H, OH), 3.35 (dd, 3J ϭ 10.3 Hz, 3J ϭ 0.9 Hz, 1 H, 3Ј-
H), 3.75 (s, 3 H, OCH3), 4.10 (dddd, 3J ϭ 7.9 Hz, 3J ϭ 4.5 Hz,
4
5.7 Hz, J ϭ 2.9 Hz, 1 H, 4-HB), 4.00 (mc, 1 H, 1Ј-H), 4.51 (ddd,
3
3J ϭ 8.0 Hz, 3J ϭ 5.8 Hz, J ϭ 2.1 Hz, 1 H, 5-H), 4.83 (d, 3J ϭ
8.6 Hz, 1 H, NH), 5.07 (d, 2J ϭ 12.2 Hz, 1 H, CHAHBPh), 5.09 (d,
2J ϭ 12.2, 1 H, CHAHBPh), 5.54 (t, 4J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE),
3
2
3J ϭ 3.8 Hz, J ϭ 0.8 Hz 1 H, 2Ј-H), 5.11 (d, J ϭ 12.3 Hz, 1 H,
4
6.16 (t, J ϭ 3.0 Hz, 1 H, 1ЈЈ-HZ), 7.29Ϫ7.36 (m, 5 H, C6H5). Ϫ
2
3
CHAHBPh), 5.13 (d, J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.26 (d, J ϭ
10.2 Hz, 1 H, NH), 5.70 (s, 1 H, 3-HE), 6.23 (s, 1 H, 3-HZ),
7.29Ϫ7.39 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz; CDCl3): δ ϭ
27.0 [C(CH3)3], 35.2 (C-4Ј), 40.1 (C-1Ј), 52.3 (OCH3), 61.5 (C-3Ј),
66.7 (CH2Ph), 69.0 (C-2Ј), 128.0, 128.1, 128.5 (C6H5), 129.1 (C-3),
136.7, 136.8 (C6H5 ipso, C-2), 157.0 (NϪCϭO), 168.6 (C-1). Ϫ MS
(FAB); m/z (%): 372 (6) [Mϩ ϩ Na], 350 (69) [Mϩ ϩ H], 318 (6)
13C NMR (125 MHz, CDCl3): δ ϭ 18.4 (C-2Ј), 30.2 (C-4), 49.6 (C-
1Ј), 67.0 (CH2Ph), 79.4 (C-5), 122.2 (ϭCH2), 128.0, 128.2, 128.5
(C6H5), 133.9, 136.2 (C6H5 ipso, C-3), 156.4 (NϪCϭO), 170.2 (C-
2). Ϫ MS (FAB); m/z (%): 298 (3) [Mϩ ϩ Na], 276 (18) [Mϩ ϩ H],
91 (100) [C7H7ϩ]. Ϫ C15H17NO4 (275.3): calcd. C 65.44, H 6.22, N
5.09; found C 65.63, H 6.30, N 5.06.
[Mϩ Ϫ CH3O], 306 (13) [Mϩ Ϫ C3H7], 220 (6) [Mϩ Ϫ CH3OH Ϫ (5R,1ЈS)-5-[1-(Benzyloxycarbonylamino)ethyl]-3-methylenedihy-
C5H5O2], 91 (100) [C7H7ϩ]. Ϫ C19H27NO5 (349.4): calcd. C 65.31, dro-2(3H)-furanone (17b): Colourless solid, m.p. 83Ϫ86°C. Ϫ
H 7.79, N 4.01; found C 65.18, H 7.82, N 3.97. Ϫ 16b: Colourless
20
[α]D ϭ Ϫ76.7 (c ϭ 0.3, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3300 cmϪ1
solid, m.p. 88Ϫ90°C. Ϫ tR (HPLC; hexane/EA, ϭ 77:23) ϭ
10.4 min. Ϫ [α]D ϭ Ϫ0.6 (c ϭ 0.55, CHCl3). Ϫ IR (KBr): ν˜ ϭ O, carbamate), 1520 (CϭC). Ϫ H NMR (500 MHz, CDCl3): δ ϭ
(NϪH), 3020, 2960, 2940 (CϪH), 1750 (CϭO, lactone), 1680 (Cϭ
20
1
3400 cmϪ1 (br., OϪH), 3260 (NϪH), 3060, 3010, 2940 (CϪH),
1710 (CϭO, ester), 1680 (CϭO, carbamate), 1545 (CϭC). Ϫ 5.6 Hz, 4J ϭ 2.8 Hz, 1 H, 4-HA), 3.02 (ddt, 2J ϭ 17.7 Hz, 3J ϭ
1H NMR (500 MHz; CDCl3): δ ϭ 1.03 [s, 9 H, C(CH3)3], 2.16 (dd, 8.4 Hz, 4J ϭ 2.5 Hz, 1 H, 4-HB), 3.89 (mc, 1 H, 1Ј-H), 4.57 (dt,
2J ϭ 13.8 Hz, J ϭ 10.0 Hz, 1 H, 1Ј-HA), 2.62 (dd, J ϭ 13.8 Hz, 3J ϭ 8.6 Hz, 3J ϭ 4.7 Hz, 1 H, 5-H), 5.03 (d, 3J ϭ 7.1 Hz, 1 H,
3J ϭ 2.2 Hz, 1 H, 1Ј-HB), 2.90 (d, 3J ϭ 7.2 Hz, 1 H, OH), 3.63 (dd, NH), 5.10 (s, 2 H, CH2Ph), 5.66 (t, 4J ϭ 2.3 Hz, 1 H, 1ЈЈ-HE), 6.25
3J ϭ 9.0 Hz, 3J ϭ 3.6 Hz, 1 H, 3Ј-H), 3.75 (s, 3 H, OCH3), 3.91 (t, 4J ϭ 3.0 Hz, 1 H, 1ЈЈ-HZ), 7.29Ϫ7.37 (m, 5 H, C6H5). Ϫ
1.15 (d, 3J ϭ 6.9 Hz, 3 H, 2Ј-H), 2.73 (ddt, 2J ϭ 17.6 Hz, 3J ϭ
3
2
Eur. J. Org. Chem. 1999, 1551Ϫ1560
1557

S. Steurer, J. Podlech
FULL PAPER
13C NMR (125 MHz, CDCl3): δ ϭ 14.3 (C-2Ј), 30.0 (C-4), 50.3 (C- (5R,1ЈS)-5-[1-(Benzyloxycarbonylamino)-3-methylbutyl]-3-meth-
1Ј), 66.9 (CH2Ph), 79.0 (C-5), 122.9 (ϭCH2), 128.1, 128.2, 128.6 ylenedihydro-2(3H)-furanone (19b): Colourless solid, m.p.
20
(C6H5), 133.5, 136.2 (C6H5 ipso, C-3), 155.7 (NϪCϭO), 170.0 (C-
89Ϫ91°C. Ϫ [α]D ϭ Ϫ86.3 (c ϭ 0.9, CHCl3). Ϫ IR (KBr): ν˜ ϭ
2). Ϫ MS (FAB); m/z (%): 298 (7) [Mϩ ϩ Na], 276 (17) [Mϩ ϩ H], 3310 cmϪ1 (NϪH), 3050, 2940, 2860 (CϪH), 1760 (CϭO, lactone),
91 (100) [C7H7ϩ]. Ϫ C15H17NO4 (275.3): calcd. C 65.44, H 6.22, N 1680 (CϭO, carbamate), 1540 (CϭC). Ϫ 1H NMR (500 MHz,
3
5.09; found C 65.40, H 6.27, N 5.03.
CDCl3): δ ϭ 0.92 [d, J ϭ 6.6 Hz, 6 H, CH(CH3)2], 1.26, 1.33 (2
3
mc, 2 H, 2Ј-HA, 2Ј-HB), 1.70 (sept, J ϭ 6.7 Hz, 1 H, 3Ј-H), 2.75
(5S,1ЈS)-5-[1-(Benzyloxycarbonylamino)-2-phenylethyl]-3-meth-
ylenedihydro-2(3H)-furanone (18a): Colourless solid, m.p.
(d, J ϭ 17.2 Hz, 1 H, 4-HA), 3.01 (dd, J ϭ 17.5 Hz, 3J ϭ 8.7 Hz,
1 H, 4-HB), 3.84 (mc, 1 H, 1Ј-H), 4.54 (mc, 1 H, 5-H), 4.78 (d, 3J ϭ
8.7 Hz, 1 H, NH), 5.10 (d, 2J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.12 (d,
2
2
20
88Ϫ90°C. Ϫ [α]D ϭ ϩ3.8 (c ϭ 1.6, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3300 cmϪ1 (NϪH), 3000, 2900 (CϪH), 1765 (CϭO, lactone), 1690
4
1
2J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.66 (s, 1 H, 1ЈЈ-HE), 6.25 (t, J ϭ
(CϭO, carbamate), 1530 (CϭC). Ϫ H NMR (500 MHz, CDCl3):
2.8 Hz, 1 H, 1ЈЈ-HZ), 7.30Ϫ7.38 (m, 5 H, C6H5). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 21.4, 23.7 [CH(CH3)2], 24.5 (C-3Ј), 30.0
(C-4), 37.8 (C-2Ј), 52.9 (C-1Ј), 67.0 (CH2Ph), 79.2 (C-5), 122.9 (ϭ
CH2), 128.0, 128.2, 128.6 (C6H5), 133.6, 136.2 (C6H5 ipso, C-3),
156.1 (NϪCϭO), 169.9 (C-2). Ϫ MS (EI, 70 eV); m/z (%): 317 (2)
[Mϩ], 220 (26) [Mϩ Ϫ C5H5O2], 176 (32) [Mϩ Ϫ C5H5O2 Ϫ C3H8],
97 (35) [C5H5O2ϩ], 91 (100) [C7H7ϩ]. Ϫ C18H23NO4 (317.4): calcd.
C 68.12, H 7.30, N 4.41; found C 68.11, H 7.27, N 4.45.
δ ϭ 2.84 (ddt, 2J ϭ 17.6 Hz, 3J ϭ 7.8 Hz, 4J ϭ 2.7 Hz, 1 H, 4-HA),
2.87 (ddt, 2J ϭ 17.6 Hz, 3J ϭ 6.4 Hz, 4J ϭ 3.0 Hz, 1 H, 4-HB), 2.95
(dd, 2J ϭ 13.7 Hz, 3J ϭ 8.4 Hz, 1 H, 2Ј-HA), 2.97 (dd, 2J ϭ
3
3
3
13.7 Hz, J ϭ 7.5 Hz, 1 H, 2Ј-HB), 4.11 (dddd, J ϭ 8.5 Hz, J ϭ
3J ϭ 7.4 Hz, 3J ϭ 1.6 Hz, 1 H, 1Ј-H), 4.51 (ddd, 3J ϭ 7.8 Hz, 3J ϭ
6.3 Hz, J ϭ 1.6 Hz, 1 H, 5-H), 4.98 (d, 3J ϭ 7.9 Hz, 1 H, NH),
3
4
5.04 (s, 2 H, OCH2Ph), 5.51 (t, J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE), 6.15 (t,
4J ϭ 3.0 Hz, 1 H, 1ЈЈ-HZ), 7.24Ϫ7.34 (m, 10 H, 2 C6H5). Ϫ
13C NMR (125 MHz, CDCl3): δ ϭ 30.4 (C-4), 39.3 (C-2Ј), 55.6 (C-
1Ј), 67.4 (OCH2Ph), 76.9 (C-5), 122.6 (ϭCH2), 127.3, 128.3, 128.6,
128.9, 129.1, 129.7 (2 C6H5), 134.3, 136.6, 137.3 (2 C6H5 ipso, C-3),
157.0 (NϪCϭO), 170.7 (C-2). Ϫ MS (CI, CH4); m/z (%): 352 (3)
[Mϩ ϩ H], 260 (6) [Mϩ Ϫ C7H7], 91 (100) [C7H7ϩ]. Ϫ C21H21NO4
(351.4): calcd. C 71.78, H 6.02, N 3.99; found C 72.03, H 6.08,
N 3.96.
(5S,1ЈS)-5-[1-(Benzyloxycarbonylamino)-2-methylpropyl]-3-meth-
ylenedihydro-2(3H)-furanone (20a): Colourless solid, m.p.
20
58Ϫ60°C. Ϫ [α]D ϭ Ϫ19.0 (c ϭ 0.83, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3300 cmϪ1 (NϪH), 2960, 2940 (CϪH), 1755 (CϭO, lactone), 1685
1
(CϭO, carbamate), 1530 (CϭC). Ϫ H NMR (500 MHz; CDCl3):
δ ϭ 0.98, 1.04 [2 d, 3J ϭ 6.8 Hz, 3J ϭ 6.7 Hz, 6 H, CH(CH3)2],
3
3
2
1.90 (dsept, J ϭ 8.7 Hz, J ϭ 6.7 Hz, 1 H, 2Ј-H), 2.81 (ddt, J ϭ
17.5 Hz, 3J ϭ 5.8 Hz, 4J ϭ 2.9 Hz, 1 H, 4-HA), 2.94 (ddt, 2J ϭ
17.5 Hz, 3J ϭ 8.1 Hz, 4J ϭ 2.7 Hz, 1 H, 4-HB), 3.53 (dd, 3J ϭ
10.2 Hz, 3J ϭ 8.6 Hz, 1 H, 1Ј-H), 4.78 (dd, 3J ϭ 7.5 Hz, 3J ϭ
(5R,1ЈS)-5-[1-(Benzyloxycarbonylamino)-2-phenylethyl]-3-meth-
ylenedihydro-2(3H)-furanone (18b): Colourless solid, m.p.
20
146Ϫ148°C. Ϫ [α]D ϭ Ϫ40.3 (c ϭ 0.93, CHCl3). Ϫ IR (KBr):
ν˜ ϭ 3320 cmϪ1 (NϪH), 3040, 2940, 2890 (CϪH), 1760 (CϭO, lac-
3
2
5.9 Hz, 1 H, 5-H), 4.84 (d, J ϭ 10.2 Hz, 1 H, NH), 5.08 (d, J ϭ
tone), 1680 (CϭO, carbamate), 1530 (CϭC).
Ϫ
1H NMR
12.3 Hz, 1 H, CHAHBPh), 5.10 (d, 2J ϭ 12.3 Hz, 1 H, CHAHBPh),
(500 MHz, CDCl3): δ ϭ 2.77Ϫ2.82, 2.90Ϫ2.94 (2 m, 4 H, 4-H, 2Ј-
4
4
5.52 (t, J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE), 6.15 (t, J ϭ 3.0 Hz, 1 H, 1ЈЈ-
HZ), 7.28Ϫ7.36 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz; CDCl3):
δ ϭ 18.4, 18.7 [CH(CH3)2], 29.6 (C-4), 29.8 (C-2Ј), 58.7 (C-1Ј), 66.0
(CH2Ph), 75.2 (C-5), 121.0 (ϭCH2), 126.9, 127.1, 127.5 (C6H5),
133.0, 135.3 (C6H5 ipso, C-3), 156.0 (NϪCϭO), 169.4 (C-2). Ϫ
MS (EI, 70 eV); m/z (%): 303 (1) [Mϩ], 206 (30) [Mϩ Ϫ C5H5O2],
162 (30) [Mϩ Ϫ C5H5O2 Ϫ C3H8], 97 (20) [C5H5O2ϩ], 91 (100)
[C7H7ϩ]. Ϫ C17H21NO4 (303.4): calcd. C 67.31, H 6.98, N 4.62;
found C 67.28, H 7.05, N 4.62.
3
H), 4.00 (mc, 1 H, 1Ј-H), 4.40 (d, J ϭ 6.9 Hz, 1 H, 5-H), 4.69 (d,
3J ϭ 8.6 Hz, 1 H, NH), 4.97 (s, 2 H, OCH2Ph), 5.59 (br. s, 1 H,
4
1ЈЈ-HE), 6.20 (t, J ϭ 2.9 Hz, 1 H, 1ЈЈ-HZ), 7.10Ϫ7.29 (m, 10 H, 2
C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 29.3, 34.7 (C-4, C-
2Ј), 54.2 (C-1Ј), 66.0 (OCH2Ph), 76.2 (C-5), 122.1 (ϭCH2), 125.9,
126.9, 127.2, 127.5, 127.7, 128.4 (2 C6H5), 132.5, 135.0, 135.1 (2
C6H5 ipso, C-3), 154.9 (NϪCϭO), 168.8 (C-2). Ϫ MS (CI, CH4);
m/z (%): 352 (26) [Mϩ ϩ H], 254 (9) [Mϩ Ϫ C5H5O2], 91 (100)
[C7H7ϩ]. Ϫ C21H21NO4 (351.4): calcd. C 71.78, H 6.02, N 3.99;
found C 71.60, H 6.15, N 4.01.
(5R,1ЈS)-5-[1-(Benzyloxycarbonylamino)-2-methylpropyl]-3-meth-
ylenedihydro-2(3H)-furanone (20b): Colourless solid, m.p.
(5S,1ЈS)-5-[1-(Benzyloxycarbonylamino)-3-methylbutyl]-3-meth-
ylenedihydro-2(3H)-furanone (19a): Colourless solid, m.p.
107Ϫ108°C. Ϫ [α]D20 ϭ Ϫ12.2 (c ϭ 0.9, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3280 cmϪ1 (NϪH), 3050, 2940, 2880 (CϪH), 1760 (CϭO, lactone),
1690 (CϭO, carbamate), 1540 (CϭC). Ϫ 1H NMR (500 MHz,
20
63Ϫ65°C. Ϫ [α]D ϭ Ϫ16.7 (c ϭ 1.1, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3340 cmϪ1 (NϪH), 3020, 2940 (CϪH), 1770 (CϭO, lactone), 1690
1
(CϭO, carbamate), 1530 (CϭC). Ϫ H NMR (500 MHz, CDCl3):
δ ϭ 0.90 [2 d, 3J ϭ 3J ϭ 6.9 Hz, 6 H, CH(CH3)2], 2.18 (dsept, 3J ϭ
9.4 Hz, 3J ϭ 6.7 Hz, 1 H, 2Ј-H), 2.86 (ddt, 2J ϭ 17.4 Hz, 3J ϭ
5.6 Hz, 4J ϭ 2.8 Hz, 1 H, 4-HA), 2.99 (ddt, 2J ϭ 17.4 Hz, 3J ϭ
8.0 Hz, 4J ϭ 2.6 Hz, 1 H, 4-HB), 3.70Ϫ3.76 (m, 1 H, 1Ј-H), 4.39
3
CDCl3): δ ϭ 0.93 [d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 1.39 (mc, 1 H,
2
2Ј-HA), 1.59Ϫ1.71 (m, 2 H, 2Ј-HB, 3Ј-H), 2.86 (ddt, J ϭ 17.4 Hz,
3J ϭ 5.8 Hz, 4J ϭ 2.8 Hz, 1 H, 4-HA), 2.94 (ddt, 2J ϭ 17.5 Hz,
3J ϭ 7.9 Hz, 4J ϭ 2.7 Hz, 1 H, 4-HB), 3.95 (dddd, 3J ϭ 3J ϭ 9.7 Hz,
3J ϭ 5.1 Hz, 3J ϭ 1.7 Hz, 1 H, 1Ј-H), 4.54 (ddd, 3J ϭ 7.8 Hz, 3J ϭ
3
3
3
(td, J ϭ 8.4 Hz, J ϭ 5.7 Hz, 1 H, 5-H), 4.70 (d, J ϭ 10.2 Hz, 1
H, NH), 5.11 (mc, 2 H, CH2Ph), 5.65 (t, 4J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE),
6.23 (mc, 1 H, 1ЈЈ-HZ), 7.31Ϫ7.39 (m, 5 H, C6H5). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 15.7, 19.8 [CH(CH3)2], 27.8 (C-2Ј), 30.9
(C-4), 59.1 (C-1Ј), 67.2 (CH2Ph), 76.3 (C-5), 122.9 (ϭCH2), 128.1,
128.4, 128.6 (C6H5), 133.6, 136.1 (C6H5 ipso, C-3), 156.7 (NϪCϭ
O), 169.9 (C-2). Ϫ MS (CI, CH4); m/z (%): 304 (31) [Mϩ ϩ H],
206 (43) [Mϩ Ϫ C5H5O2], 162 (26) [Mϩ Ϫ C5H5O2 Ϫ C3H8], 97
(6) [C5H5O2ϩ], 91 (100) [C7H7ϩ]. Ϫ C17H21NO4 (303.4): calcd. C
67.31, H 6.98, N 4.62; found C 67.06, H 7.02, N 4.54.
3
5.7 Hz, J ϭ 1.8 Hz, 1 H, 5-H), 4.61 (d, 3J ϭ 9.6 Hz, 1 H, NH),
2
2
5.06 (d, J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.11 (d, J ϭ 12.5 Hz, 1
H, CHAHBPh), 5.52 (t, 4J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE), 6.15 (t, 4J ϭ
2.6 Hz, 1 H, 1ЈЈ-HZ), 7.30Ϫ7.36 (m, 5 H, C6H5). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 21.9, 23.0 [CH(CH3)2], 24.7 (C-3Ј), 30.2
(C-4), 41.7 (C-2Ј), 52.2 (C-1Ј), 67.0 (CH2Ph), 78.8 (C-5), 122.0 (ϭ
CH2), 127.9, 128.2, 128.5 (C6H5), 134.0, 136.3 (C6H5 ipso, C-3),
156.7 (NϪCϭO), 170.3 (C-2). Ϫ MS (EI, 70 eV); m/z (%): 317 (6)
[Mϩ], 220 (38) [Mϩ Ϫ C5H5O2], 176 (41) [Mϩ Ϫ C5H5O2 Ϫ C3H8],
97 (6) [C5H5O2ϩ], 91 (100) [C7H7ϩ]. Ϫ C18H23NO4 (317.4): calcd. (5S,1ЈS,2ЈS)-5-[1-(Benzyloxycarbonylamino)-2-methylbutyl]-3-meth-
20
C 68.12, H 7.30, N 4.41; found C 67.95, H 7.28, N 4.42.
1558
ylenedihydro-2(3H)-furanone (21a): Colourless oil. Ϫ [α]D
ϭ
Eur. J. Org. Chem. 1999, 1551Ϫ1560

Aminoalkyl-Substituted α-Methylene-γ-butyrolactones
FULL PAPER
Ϫ13.1 (c ϭ 1, CHCl3). Ϫ IR (film): ν˜ ϭ 3310 cmϪ1 (OϪH, NϪH),
3020, 2970, 2930 (CϪH), 1760 (CϭO, lactone), 1695 (CϭO, carba-
Acknowledgments
1
mate), 1540 (CϭC). Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.89 (t,
The generous support of Prof. Dr. V. Jäger and Prof. Dr. Dr. h. c.
F. Effenberger (Universität Stuttgart) is gratefully acknowledged.
We are greatly indepted to Dr. W. U. Frey who performed the nu-
merous X-ray crystallographic analyses. This work was supported
by the Fonds der Chemischen Industrie, the Deutsche Forschungs-
gemeinschaft, the Stiftungsfonds Mitsubishi Electric Europe, the
Landesgraduiertenförderung Baden-Württemberg and the Degussa
AG (gift of amino acids).
3
3J ϭ 7.4 Hz, 3 H, 4Ј-H), 1.02 (d, J ϭ 6.7 Hz, 3 H, CHCH3), 1.18
2
3
(dqd, J ϭ 13.9 Hz, 3J ϭ 8.7 Hz, J ϭ 7.3 Hz, 1 H, 3Ј-HA), 1.57
(dqd, 2J ϭ 13.7 Hz, 3J ϭ 7.6 Hz, J ϭ 3.5 Hz, 1 H, 3Ј-HB), 1.67
3
(mc, 1 H, 2Ј-H), 2.82 (ddt, 2J ϭ 17.8 Hz, 3J ϭ 5.6 Hz, 4J ϭ 3.0 Hz,
2
3
4
1 H, 4-HA), 2.94 (ddt, J ϭ 17.6 Hz, J ϭ 8.2 Hz, J ϭ 2.6 Hz, 1
H, 4-HB), 3.60 (dd, 3J ϭ 3J ϭ 9.4 Hz, 1 H, 1Ј-H), 4.75 (d, 3J ϭ
9.8 Hz, 1 H, NH), 4.80 (mc, 1 H, 5-H), 5.07 (d, 2J ϭ 12.3 Hz, 1 H,
CHAHBPh), 5.11 (d, J ϭ 12.3 Hz, 1 H, CHAHBPh), 5.51 (t, J ϭ
2.5 Hz, 1 H, 1ЈЈ-HE), 6.15 (t, J ϭ 2.9 Hz, 1 H, 1ЈЈ-HZ), 7.30Ϫ7.35
2
4
4
[1]
N. Petragnani, H. M. C. Ferraz, G. V. J. Silva, Synthesis 1986,
(m, 5 H, C6H5). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 10.8 (C-4Ј),
15.8 (CHCH3), 25.6 (C-3Ј), 30.6 (C-4), 37.0 (C-2Ј), 58.2 (C-1Ј), 67.0
(CH2Ph), 122.0 (ϭCH2), 127.9, 128.2 128.5 (C6H5), 134.0, 136.3
(C6H5 ipso, C-3), 157.0 (NϪCϭO), 170.4 (C-2). Ϫ MS (FAB); m/z
(%): 340 (3) [Mϩ ϩ Na], 318 (19) [Mϩ ϩ H], 91 (100) [C7H7ϩ]. Ϫ
C18H23NO4 (317.4): calcd. C 68.12, H 7.30, N 4.41; found C 67.89,
H 7.34, N 4.37.
157Ϫ183.
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H. M. R. Hoffmann, J. Rabe, Angew. Chem. 1985, 97, 96Ϫ112;
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(5S,1ЈS)-5-[1-(Benzyloxycarbonylamino)-2,2-dimethylpropyl]-3-
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´
´
´
T. Martın, C. M. Rodrıguez, V. S. Martın, J. Org. Chem. 1996,
20
methylenedihydro-2(3H)-furanone (22a): Colourless oil. Ϫ [α]D
ϭ
61, 6450Ϫ6453.
Ϫ20.3 (c ϭ 0.8, CHCl3). Ϫ IR (film): ν˜ ϭ 3333 cmϪ1 (NϪH), 3034,
2964, 2874 (CϪH), 1767 (CϭO, lactone), 1696 (CϭO, carbamate),
1531 (CϭC). Ϫ 1H NMR (500 MHz; CDCl3): δ ϭ 1.01 [s, 9 H,
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D. Brookes, B. K. Tidd, W. B. Turner, J. Chem. Soc. 1963,
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2
3
4
C(CH3)3], 2.75 (ddt, J ϭ 17.4 Hz, J ϭ 6.4 Hz, J ϭ 3.0 Hz, 1 H,
[9]
2
3
4
4-HA), 2.97 (ddt, J ϭ 17.4 Hz, J ϭ 8.0 Hz, J ϭ 2.6 Hz, 1 H, 4-
[10]
[11]
[12]
HB), 3.57 (d, 3J ϭ 10.7 Hz, 1 H, 1Ј-H), 4.87 (dd, 3J ϭ 8.0 Hz, 3J ϭ
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3
2
6.4 Hz, 1 H, 5-H), 4.94 (d, J ϭ 10.4 Hz, 1 H, NH), 5.09 (d, J ϭ
12.4 Hz, 1 H, CHAHBPh), 5.10 (d, 2J ϭ 12.2 Hz, 1 H, CHAHBPh),
4
4
5.54 (t, J ϭ 2.6 Hz, 1 H, 1ЈЈ-HE), 6.16 (t, J ϭ 2.9 Hz, 1 H, 1ЈЈ-
HZ), 7.31Ϫ7.37 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz; CDCl3):
δ ϭ 27.1 [C(CH3)3], 31.7 (C-4), 35.0 (C-2Ј), 61.8 (C-1Ј), 67.1
(CH2Ph), 75.0 (C-5), 122.0 (ϭCH2), 128.0, 128.2, 128.5 (C6H5),
133.7, 136.2 (C6H5 ipso, C-3), 157.1 (NϪCϭO), 170.4 (C-2). Ϫ MS
(FAB); m/z (%): 340 (3) [Mϩ ϩ Na], 318 (38) [Mϩ ϩ H], 220 (3)
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A. Lubineau, J. Auge, Y. Queneau, Synthesis 1994, 741Ϫ760.
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[Mϩ
Ϫ Ϫ
C5H5O2], 97 (8) [C5H5O2ϩ], 91 (100) [C7H7ϩ].
C18H23NO4 (317.4): calcd. C 68.12, H 7.30, N 4.41; found C 67.96,
H 7.35, N 4.45.
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nated lactone 23 was formed as a side product (40%), which was
isolated by MPLC (PE/EA, 85:15) and recrystallized from ether:
colourless solid, m.p. 92Ϫ94°C. Ϫ tR (HPLC; hexane/EA, 7:3) ϭ
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20
8.5 min. Ϫ [α]D ϭ Ϫ20.1 (c ϭ 1, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3360
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C. Chen, Y. Shen, Y.-Z. Huang, Tetrahedron Lett. 1988, 29,
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3
1.02 [2 d, J ϭ 6.8 Hz, J ϭ 6.7 Hz, 6 H, CH(CH3)2], 1.89 (dsept,
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3J ϭ 8.0 Hz, 3J ϭ 6.8 Hz, 1 H, 2Ј-H), 2.19 (ddd, 2J ϭ 12.9 Hz,
3J ϭ 11.6 Hz, J ϭ 10.2 Hz, 1 H, 4-HA), 2.39 (ddd, J ϭ 13.0 Hz,
3J ϭ 9.2 Hz, 3J ϭ 6.2 Hz, 1 H, 4-HB), 3.06 (mc, 1 H, 3-H), 3.59
(ddd, 3J ϭ 10.2 Hz, 3J ϭ 8.0 Hz, 3J ϭ 1.5 Hz, 1 H, 1Ј-H), 3.74 (mc,
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2
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3
3
3
2 H, 1ЈЈ-H), 4.68 (ddd, J ϭ 10.2 Hz, J ϭ 6.2 Hz, J ϭ 1.5 Hz, 1
3
2
[31]
[32]
[33]
H, 5-H), 4.90 (d, J ϭ 10.2 Hz, 1 H, NH), 5.09 (d, J ϭ 11.6 Hz,
1 H, CHAHBPh), 5.15 (d, 2J ϭ 11.6 Hz, 1 H, CHAHBPh),
7.30Ϫ7.37 (m, 5 H, C6H5). Ϫ 13C NMR (125 MHz; CDCl3): δ ϭ
19.3, 19.7 [CH(CH3)2], 28.6 (C-4), 31.4 (C-2Ј), 42.7 (C-1ЈЈ), 58.1
(C-1Ј), 67.1 (CH2Ph), 77.6 (C-5), 127.1, 128.2, 128.6 (C6H5), 136.3
(C6H5 ipso), 157.0 (NϪCϭO), 175.0 (C-2). Ϫ MS (FAB); m/z (%):
362 (4) [Mϩ ϩ Na], 340 (39) [Mϩ ϩ H], 91 (100) [C7H7ϩ].
C17H22ClNO4 (339.8): calcd. C 60.09, H 6.53, Cl 10.43, N 4.12;
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1559

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Received November 24, 1998
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Eur. J. Org. Chem. 1999, 1551Ϫ1560