Synthetic studies toward paraherquamides E and F and related 13C-labeled putative biosynthetic intermediates: stereocontrolled synthesis of the α-alkyl-β-methylproline ring system

Article abstract of DOI:10.1016/j.tet.2008.05.068

A substituted 2R-allyl-3S-methylproline ethyl ester suitable for elaboration to paraherquamides E, F and related ¹³C-labeled putative biosynthesis intermediates have been prepared efficiently in six steps and?24% overall yield. The key steps are a 5-exo-trig cyclization of a zinc enolate on an unactivated alkene and a stereocontrolled alkylation of the enolate formed from 3S-methyl-pyrrolidine-1,2R-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester.

Full text of DOI:10.1016/j.tet.2008.05.068

Tetrahedron 64 (2008) 7106–7111
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
13
Synthetic studies toward paraherquamides E and F and related C-labeled
putative biosynthetic intermediates: stereocontrolled synthesis
of the a-alkyl-b-methylproline ring system
,b,
Konrad Sommer a, Robert M. Williams a
*
a Department of Chemistry, Colorado State University, Fort Collins, CO 80523, United States
b University of Colorado Cancer Center, Aurora, CO 80045, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A substituted 2R-allyl-3S-methylproline ethyl ester suitable for elaboration to paraherquamides E, F and
related 13C-labeled putative biosynthesis intermediates have been prepared efficiently in six steps
and 24% overall yield. The key steps are a 5-exo-trig cyclization of a zinc enolate on an unactivated alkene
and a stereocontrolled alkylation of the enolate formed from 3S-methyl-pyrrolidine-1,2R-dicarboxylic
acid 1-tert-butyl ester 2-ethyl ester.
Received 19 February 2008
Received in revised form 14 May 2008
Accepted 15 May 2008
Available online 18 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Methylproline
Asymmetric synthesis
Paraherquamide
Asperparaline
1. Introduction
This family of prenylated alkaloids has attracted considerable
attention due to their molecular complexity, intriguing biogenesis,
The paraherquamides constitute part of an unusual family of
prenylated indolic natural products derived from various genera of
fungi, which contain a common bicyclo[2.2.2]diazaoctane core
structure, a spiro-oxindole, and a substituted proline moiety. The
parent member, paraherquamide A 1, was first isolated from cul-
tures of Penicillium paraherquei by Yamazaki and co-workers in
1981.1 Since then, paraherquamides B-I,2 VM55595, VM55596, and
VM55597,3 SB203105, and SB200437,4 and sclerotamide5 have been
isolated from various Penicillium and Aspergillus species. Marcfor-
tines A–C are structurally similar, containing a pipecolic acid unit in
place of proline.6 In addition, VM55599,3 aspergamides A and B,7
avrainvillamide (CJ-17,665),8 and the most recently isolated mem-
bers of this family, stephacidin A (10) and stephacidin B (11),9 and
malbrancheamide10 are closely related members of this rapidly
expanding family of prenylated indole alkaloids. This last group of
compounds contains a 2,3-disubstituted indole in place of the
spiro-oxindole, spiro-indoxyl or spiro-succinimide. Brevianamides
A and B (9),11 which contain a spiro-indoxyl rather than a spiro-
oxindole, and the asperparalines, which contain a spiro-succin-
imide,12 are also structurally comparable (Fig. 1).
and biological activities.13 Some members, most notably para-
herquamide A, display potent anthelmintic activity and anti-
nematodal properties.14 Since, the paraherquamides are unique
both structurally and in their mode of action,15 they represent
a potentially promising new class of anthelmintics.16
From a biogenetic perspective, the paraherquamides along with
thebrevianamides, asperparalines,marcfortines, malbrancheamides,
notoamides,17 and sclerotamide comprise an interesting class of
structurally related secondary metabolites containing
a bicy-
clo[2.2.2]diazaoctane core. An emerging body of evidence supports
the notion that this structural motif is formed by a biosynthetic
intramolecular [4þ2] cycloaddition of the isoprene-derived olefin
across a preformed azadiene moiety derived from an oxidized
piperazinedione.13,18,19
Everett and co-workers described in 1993 the isolation of
VM55599 (15, Scheme 1), a minor metabolite from culture extracts
of a Penicillium sp. (IMI332995) that also produces paraherquamide
A (1).3 These authors proposed that VM55599 might indeed be
a biosynthetic precursor of paraherquamide A.3
Recent experimental observations from this laboratory brought
into question the capacity of VM55599 to serve as a biosynthetic
precursor to the paraherquamides and we proposed a distinct
biosynthesis of the paraherquamides and VM55599.20 This hy-
pothesis was recently experimentally tested through feeding ex-
periments of racemic, doubly 13C-labeled compounds 15–18.21
* Corresponding author. Tel.: þ1 970 491 6747; fax: þ1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.068

K. Sommer, R.M. Williams / Tetrahedron 64 (2008) 7106–7111
7107
23 O
Me
derived isoprenylation and the S-adenosylmethionine-mediated
N-methylation reactions probably occur late in the pathway.
It has been demonstrated that in paraherquamide A bio-
22
1
O
Me
NH
2
Me
19H
24
25
Me
H
21
8
NMe
O
O
3
R
20
29Me
17
Me
9
7
6
13
O
H
10
11
14
synthesis, L-tryptophan, L-b-methylproline, and an isoprene moiety
27
O 26
Me
18N
4
O
Me
Me
28
are coupled together to provide the hexacyclic indole 17.22 Based on
the experimental observation that the same three primary
biosynthetic building blocks ((S)-tryptophan, (S)-isoleucine (the
N
12
5
15
N
Me
N
16
8, asperparaline A
1, paraherquamide A, R = OH
2, paraherquamide E, R = H
H
Me
b
-methylproline22), and dimethylallyl
N
Me
H
biosynthetic precursor to
O
Me
pyrophosphate) constitute asperparaline A, we proposed a unified
biogenesis of the paraherquamides and the asperparalines as
shown in Scheme 2.23
Me
H
Me
NH
H
N
O
O
9, (-)-brevianamide B
R
N
O
Me
Me
Me
O
N
O
N
Me
X
H
Me
H
3, paraherquamide F (VM55594), R = H
Me
N
Me
O
N
Y
4, paraherquamide G, R = OH
24
Me
H
Me
H
O
1
23
Me
2
Me
H
NH
3
H
N
25
O
N
18H
17
8
22
19
O
2, 3
Me
H
9
7
6
26
10
N
H
21
16
15
O
, (+)-stephacidin A
10
28
11
Me
N
O27
12HO4
O
N
O
Cl
21
N20
Me
Me
O
5
Me29
TBSO
Me
Me
O
13
Y
14
OH
Me
O
Me
Me
Me
H
N
5, (-)-sclerotiamide
X
NH
O
OEt
NBoc
23
Me
O
N
Me
NBoc
O
H
Me
NH
Me
H
N
O
O
N
O
22
R
O
O
N
H
N
Scheme 2. Retro-synthetic approach to paraherquamides E and F.
N
O
N
H
O
O
Me
Me
Me
As previously reported, coupling of L-tryptophan, L-b-methyl-
Me
, marcfortineA, R = Me
6
N
proline, and dimethylallyl pyrophosphate (DMAPP) gives, via
intramolecular Diels–Alder cycloaddition, compound 17, which can
be oxidized to hypothetical intermediate 19. Compound 19 is
considered to be a key branch-point species for the two respective
pathways to paraherquamide A and asperparaline A. In para-
herquamide biosynthesis, 19 would suffer prenylation and
conversion to the dioxepin.
In asperparaline biosynthesis, 19 would undergo further oxi-
dation ultimately removing four carbon atoms from the benzenoid
ring of the tryptophan moiety. In order to test this hypothesis
experimentally and to evaluate the late-stage steps in the
biosynthesis of paraherquamide A and asperparaline A, we have
initiated studies on the synthesis of 13C-labeled functionalized
proline derivatives that will be useful to interrogate the structural
constitution of putative biosynthetic intermediates in these
pathways.
, (-)-stephacidin B
11
7, marcfortineB, R = H
Figure 1. Structures of selected paraherquamides and various related prenylated
indole alkaloids.
These experiments revealed that only intermediate 17 was in-
corporated into paraherquamide A, while racemic, doubly 13C-la-
beled VM55599 (15), 16, and 18 were not incorporated. The lack of
incorporation of the diketopiperazine 18 raises interesting ques-
tions concerning the timing of the reduction of the tryptophan-
derived carbonyl group.
The incorporation of 17 indicates that formation of the bicy-
clo[2.2.2]diazaoctane occurs at the stage of the non-oxidized
tryptophyl moiety. This requires oxidations to the indole ring to
form both the catechol-derived dioxepin and spiro-oxindole to
occur after the formation of this intermediate. The dioxepin-
Me
H
N
H Me
N
Me
O
O
Me
HO
H
Me
H
OH
Me
OH
-2H2O
[4e- ox]
OH
N
Me
NH2
13, L-Trp
H
NH2
N
H
OPP
N
Me
12, L-Ile
N
N
+
Me
Me
X
X
A
B
[4+2]
14, DMAPP
Y
H
N
H
H
N
Me
Me
Me
H
Me
Me
Me
H
N
OH
[ox]
H
Me
H
H
H
N
O
N
H
N
H
O
N
Me
O
H
N
Me
19a, Y = H
MAJOR
MINOR
19b, X = OH
X
N
X
[ox]
17, X = H2
18, X = O
15, X = H2, VM55599
16, X = O
OPP
Me
Me
SAM; [ox]
O
R
O
Me
Me
Me
Me
H
OH
Z
Me
N
NH
O
Me
Me
N
H
H
OH
H
O
H
O
Me
N
O
N
Me
Me
N
Me
O
R
Me
Me
Me
N
O
N
N
20a, Z = H
20b, Z = OH
8, asperparaline A
1, paraherquamide A & congeners
Scheme 1. Proposed unified biogenesis of paraherquamides and asperparalines.

7108
K. Sommer, R.M. Williams / Tetrahedron 64 (2008) 7106–7111
Our synthetic strategy to these
b
-methylproline-containing
cyclization substrate 28 (67% yield). Deprotonation of 28 with LDA
natural products, envisions an oxidative spiro-ring contraction of
the generic hexacycle 21 that can be constructed via a face-selective
intramolecular SN20 cyclization reaction (Scheme 2).24 The 3-hy-
droxy-3-methyl-analogue of compound 23 has recently been pre-
pared for the asymmetric total synthesis of paraherquamide A and
has been found to lead to the analogous hexacycle 21 selectively.24
Our plan thus requires the synthesis of the critical 2-substituted,3-
methylproline derivative (23), with the desired absolute and rela-
tive stereochemistry.
We report here, a preparative synthesis of compound 23 that
should prove to be a useful substrate from which 2 and 3 as well as
asperparaline can be constructed. Significantly, this synthetic
strategy offers a rapid and inexpensive means to incorporate 13C-
labels into 23 that will prove useful for the evaluation of the
biosynthesis of these agents.
in diethyl ether/THF followed by transmetalation at ꢀ90 ꢁC with
zinc bromide, warming to room temperature, and quenching with
aqueous NH4Cl, provided selectively the N-protected cis-b-methyl-
proline derivative 29 in 80% yield from 28. Finally, hydrogenolysis
of 29 with 5% Pd/C (10 wt %) followed by Boc-protection of the
crude material afforded the protected b-methylproline derivative
30 in 84% yield over the two steps. Enolate formation of 30 with
KHMDS at ꢀ78 ꢁC followed by the addition of allylic iodide 26 gave
23 in 82% yield and was the identical compound to that obtained in
Scheme 3 as confirmed by NMR and optical rotation. This route
provides for an economical and practical route for the synthesis of
the key species 23 in 13C-labeled form starting from 1-13C-ethyl
bromoacetate (US$170/g).
Me
NH2
a, b
c, d, e
CO2Et
N
N
CO2Et
Ph
28
Me
Ph
2. Results and discussion
Ph
Me
27
Me
Me
CO2Et
29
In our initial study, the synthesis of
by Lavergne and co-workers was applied to access the core of the
methylproline derivative 23.25,26 Treatment of
-isoleucine (12)
with thionyl chloride in refluxing ethanol afforded the corre-
sponding ethyl ester, which was then treated with tert-butyl hy-
pochlorite to yield the N-chloride 24 (Scheme 3). Exposure of 24 to
a mercury lamp in 80% sulfuric acid according to the Hofman–
b-methylproline developed
TBSO
Me
Me
O
L
h, i
f, g
N
OE
t
Boc
NBoc
30
23
Scheme 4. (a) H2C]CH(CH)2Br, K2CO3, NaI, DMF, 100 ꢁC, 22 h, 66%; (b) BrCH2CO2Et,
NEt3, DMSO, 50 ꢁC, 46 h, 67%; (c) LDA, Et2O, THF, ꢀ78 ꢁC/ꢀ20 ꢁC; (d) ZnBr2, Et2O,
ꢀ90 ꢁC/room temperature; (e) NH4Cl, H2O, 80%; (f) 5% Pd/C (10 wt %), H2, 80 psi,
room temperature, 24 h; (g) Boc2O, K2CO3, dioxane/H2O, 0 ꢁC/room temperature,
19 h, 84%; (h) KHMDS, THF, ꢀ78 ꢁC, 35 min; (i) 26, ꢀ78 ꢁC/room temperature,
12 h, 82%.
Lo¨ffler–Freytag protocol, afforded b-methylproline ethyl ester 25
upon neutralization, however, in a disappointingly poor yield of
25% on gram-scale. Nevertheless, with 25 in our hands, we focused
our attention on the alkylation of 25 to afford 23. Thus, enolization
with KHMDS at ꢀ78 ꢁC followed by addition of allylic iodide 26
gave the desired proline 23. This highly stereoselective reaction
gave a single diastereomer as evidenced by analysis of the 1H NMR
spectrum. The relative and absolute stereochemistry of the alkyl-
ation product was secured through 1H NMR NOE experiments in-
dicating a strong NOE-effect between the allylic and vinyl protons
3. Conclusion
In summary, we have demonstrated an efficient route to the
b-methylproline derivative 23 from (R)-a-methyl benzyl amine 27.
We are currently deploying this route for use in asymmetric total
syntheses of paraherquamides E (2) and F (3) as well as asper-
paraline A (8). Significantly, this route will prove useful for the
preparation of 13C-labeled putative biosynthetic intermediates.
Efforts along these lines are currently in progress in our laboratory
and will be reported on in due course.
of the introduced side chain and the
conversely, we did not observe an NOE-effect on the protons of the
b-proton of proline ring;
b-methyl group.
Cl
O
NH2
HN
a, b
c
OH
OEt
Me
Me
Me
O
4. Experimental
Me
12
24
4.1. General methods
TBSO
OTBS
O
Me
O
Me
26
Unless otherwise noted, materials were obtained from com-
mercial sources and utilized without purification. All reactions re-
quiring anhydrous conditions were performed under argon using
flame-dried glassware. Tetrahydrofuran, dimethylformamide, and
toluene were degassed with argon and passed through a solvent
purification system (J.C. Meyer of Glass Contour) containing alu-
mina or molecular sieves. Dichloromethane was distilled from CaH2
prior to use. Column chromatography was performed on Merck
silica gel Kieselgel 60 (230–400 mesh). Mass spectra were obtained
on Fisons VG Autospec. HPLC data were obtained on a Waters 600
HPLC. 1H NMR, 13C NMR, and NOE experiments were recorded on
a Varian 300 or 400 MHz spectrometer. Chemical shifts were given
in parts per million and were recorded relative to the residual
solvent peak unless otherwise noted. 1H NMR signals were tabu-
lated in the following order: multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; and m, multiplet), coupling constant in hertz,
and number of protons. When a signal was deemed ‘broad’ it was
noted as such. IR spectra were recorded on a Nicolet Avatar 320 FT-
IR spectrometer. Optical rotations were determined with a Rudolph
Me
d
I
Me
OEt
NBoc
25
OEt
NBoc
23
Scheme 3. (a) SOCl2, EtOH, 38 h, reflux, 97–100%; (b) t-BuOCl, benzene, 0–5 ꢁC, 4 h,
88–98%; (c) (i) hn
, 80% H2SO4, 3–9 ꢁC, 3 h; (ii) KOH, H2O; (iii) Boc2O, THF, H2O, 0 ꢁC/
room temperature, 17 h, 25%; (d) (i) KHMDS, THF, ꢀ78 ꢁC, 35 min; (ii) 26, ꢀ78 ꢁC/
room temperature, 12 h, 88%.
However, due to high cost of the 1-13C-(S)-isoleucine (US$1025/
g),27 the amounts of labeled substrate required for biosynthetic
feeding studies, and the low overall yield of this approach, we
turned to other more economical alternatives.
For that reason, we decided to examine methodology developed
by Chassaing and co-workers as a potentially more practical route
to 13C-labeled
(R)-
b
-methylproline derivative 23 (Scheme 4).28 Thus,
a
-methyl benzyl amine 27 was alkylated with 3-butenyl bro-
mide to give the corresponding secondary amine (66% yield).
Subsequent alkylation with ethyl bromoacetate afforded the

K. Sommer, R.M. Williams / Tetrahedron 64 (2008) 7106–7111
7109
Research Autopol III automatic polarimeter referenced to the D-line
of sodium.
up in water (1800 mL), lowered to pH 2 with 10% aqueous KHSO4
solution, and extracted with ethyl acetate (6ꢂ150 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and the
solvent was removed under vacuum. The crude residue was puri-
fied via silica gel flash column chromatography as a 1:1 oil mixture
with hexanes/diethyl ether and was subjected to gradient elution
9:1, 7:3, 6:4, 0:10 to afford (2S,3S)-1-tert-butyl 2-ethyl 3-methyl-
4.2. 2-Amino-3-methyl-pentanoic acid ethyl ester ((S)-
isoleucine ethyl ester) (12a)
To a cooled (0 ꢁC) and stirred suspension of (S)-isoleucine (12)
(50.0 g, 381 mmol) in dry ethanol (1500 mL) was added thionyl
chloride (317 g, 2.67 mol) dropwise. The mixture was allowed to
come to room temperature and refluxed for 38 h until the gas
evolution stopped. The solvent was removed under reduced pres-
sure and the crude (S)-isoleucine ethyl ester hydrochloride (88 g)
was redissolved in cold water (1500 mL). The solution was extrac-
ted with diethyl ether (400 mL) and the aqueous phase was made
basic (pH¼10–12) by the addition of 30% ammonium hydroxide
(40 mL). The mixture was extracted with methylene dichloride
(5ꢂ200 mL) and the combined organic layers were dried over an-
hydrous Na2SO4. The solvent was removed under reduced pressure
pyrrolidine-1,2-dicarboxylate (25) (32.2 g, 25%) as a pale yellow oil.
25
[a
]
ꢀ49.2 (c 1.2, MeOH). IR (thin film): 2975, 2933, 2877, 1748,
D
1701, 1398, 1249, 1174, 1032 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
(rotamers)
d
1.17 (d, J¼7.0 Hz, 3H), 1.29 (t, J¼7.3 Hz, 3H), 1.42, 1.46
(2s, 9H), 1.50–1.60 (m, 1H), 1.96–2.10 (m, 1H), 2.24–2.40 (m, 1H),
3.40–3.66 (2m, 2H), 3.74, 3.84 (2d, J¼6.6 Hz, 1H), 4.10–4.30 (m, 2H).
13C NMR (100 MHz, CDCl3): (rotamers)
d 173.1, 172.8, 154.5, 154.0,
79.9, 79.8, 66.3, 65.9, 60.9, 46.0, 45.8, 39.7, 38.6, 32.7, 32.2, 28.5, 28.4
(2C), 18.7, 18.5, 14.4, 14.3. HRMS (FABþ) calcd for C13H23NO4 (m/z)
258.1705 [Mþþ1]; found (m/z) 258.1696.
Preparation of tert-butyl hypochlorite: in a 2-L Erlenmeyer flask
was placed a commercial bleach solution (1000 mL, CloroxÒ, 6%
NaOCl) and the solution cooled in an ice bath until the temperature
dropped below 10 ꢁC. At this point, lights in the vicinity of the
apparatus were turned off and a solution of tert-butyl alcohol
(74 mL) in glacial acetic acid (49 mL) was added in a single portion
to the rapidly stirred bleach solution, and stirring was continued for
3 min. The entire reaction mixture was poured into a 2-L separatory
funnel. The lower aqueous layer was discarded, and the oily yellow
organic layer was washed first with 10% Na2CO3 (100 mL) and then
with water (100 mL). The oil was dried over anhydrous CaCl2 (2 g)
and filtered to yield tert-butyl hypochlorite (80 mL, 85%). The
product was stored over anhydrous CaCl2.
to yield 2-amino-3-methyl-pentanoic acid ethyl ester ((S)-iso-
25
leucine ethyl ester) (60.6 g, 100%) as a colorless oil. [
a]
þ37.2 (c
D
1.0, MeOH). IR (thin film): 3387, 3319, 2964, 2935, 1732, 1464, 1180,
1028, 859 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
0.91 (t, J¼7.3 Hz, 3H),
0.93 (t, J¼7.0 Hz, 3H), 1.10–1.32 (m, 1H), 1.27 (t, J¼7.0 Hz, 3H), 1.36–
1.57 (m, 1H), 1.52 (br s, 2H), 1.67–1.82 (m, 1H), 3.33 (d, J¼5.1 Hz, 1H),
4.08–4.26 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 175.8, 60.8, 59.2,
39.3, 24.8, 15.9, 14.5, 11.9. HRMS (FABþ) calcd for C8H17NO2 (m/z)
160.1338 [Mþþ1]; found (m/z) 160.1337.
4.3. (2S,3S)-1-tert-butyl 2-ethyl 3-methyl-pyrrolidine-1,2-
dicarboxylate (25)
To a stirred and cooled (0 ꢁC) solution of 2-amino-3-methyl-
pentanoic acid ethyl ester ((S)-isoleucine ethyl ester) (60.5 g,
380 mmol) in benzene (450 mL) was added freshly prepared tert-
butyl hypochlorite (38.3 mL, 380 mmol) and the reaction mixture
was stirred at 0 ꢁC in the dark for 4 h. The mixture was washed with
0.1 N HCl (150 mL), and water (3ꢂ150 mL) before drying over an-
hydrous Na2SO4. The solvent was removed under reduced pressure
to yield N-chloro-2-amino-3-methyl-pentanoic acid ethyl ester (N-
chloro-(S)-isoleucine ethyl ester) (72.2 g, 98%) as a pale yellow oil.
The product was carried on to the next step without further puri-
4.4. Butyl-(4-iodo-2-methyl-but-2E-enyloxy)-dimethyl-
silane (26)
To
a stirred solution of 2-methyl-2-vinyl-oxirane (4.70 g,
55.9 mmol) in CH2Cl2 (90 mL) were added MgSO4 (3 g), TBSCl
(7.58 g, 50.3 mmol), and TBAI (22.3 g, 60.2) at 0 ꢁC. The reaction
mixture was allowed to warm to room temperature and stirred for
48 h. The solvent was removed under vacuum, hexane was added,
and the resulting suspension filtered. The filtrate was concentrated
under vacuum and the residue purified by column filtration (silica,
hexane/methylene dichloride: 10:0, then 9:1, then 8:2) to give the
tert-butyl-(4-iodo-2-methyl-but-2E-enyloxy)-dimethyl-silane (26)
(7.43 g, 41%) and the cis-isomer (1.51 g, 8.3%). TLC (SiO2, hexanes/
CH2Cl2: 4:1): Rf¼0.42. IR (thin film): 2956, 2930, 2886, 2857, 1472,
fication. 1H NMR (300 MHz, CDCl3):
d
0.92 (t, J¼7.3 Hz, 6H), 1.16–
1.38 (m, 1H), 1.33 (t, J¼7.3 Hz, 3H), 1.50–1.66 (m, 1H), 1.67–1.82 (m,
1H), 3.48 (dd, J¼6.6, 11.4 Hz, 1H), 4.28 (q, J¼7.0 Hz, 2H), 4.64 (d,
J¼11.4 Hz, 1H), 7.37 (s, 1H). A solution of N-chloro-(S)-isoleucine
ethyl ester (95.8 g, 495 mmol) in 85% H2SO4 (475 mL) was prepared
in a photochemical reaction vessel fitted with a quartz immersion
well and Hg lamp. After purging the system with argon for 15 min,
the reaction mixture was then irradiated with a mercury lamp for
3 h under an atmosphere of argon while maintaining the temper-
ature between 3 and 9 ꢁC. The reaction was tested for completion
by taking an aliquot (five drops) of the reaction mixture and
treating with 5 mL of a 5% KI solution in water and acetone (1:1).
When a clear pale yellow color was obtained, the reaction was
complete. After an addition of 6 L of an ice/water mixture the re-
action was carefully neutralized with aqueous 10 M NaOH solution
at 0 ꢁC. The reaction mixture was concentrated under reduced
pressure, the residue was taken up in absolute ethanol, and the
solids filtered off. Evaporation of the ethanolic solution under re-
1463, 1389, 1362, 1254, 1147, 1115, 1078, 837 cmꢀ1 1H NMR
.
(300 MHz, CDCl3): (trans-isomer) d 0.09 (s, 6H), 0.93 (s, 9H), 1.69 (s,
3H), 4.06 (s, 2H), 4.14 (d, J¼8.1 Hz, 2H), 5.73 (t, J¼8.1 Hz, 1H). 13C
NMR (75 MHz, CDCl3):
d 141.2, 119.3, 67.4, 40.5, 26.0, 18.5, 13.4,
ꢀ5.2.
4.5. 2R-[4-(tert-Butyl-dimethyl-silanyloxy)-3S-methyl-but-
2E-enyl]-3-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester 2-ethyl ester (23)
To a stirred solution of compound 25 (500 mg, 1.94 mmol) in dry
THF (10 mL) was added 0.5 M solution of KHMDS (5.06 mL,
2.52 mmol) in toluene at ꢀ78 ꢁC and the reaction mixture was
stirred at ꢀ78 ꢁC for 30 min. A solution of tert-butyl-(4-iodo-2-
methyl-but-2E-enyloxy)-dimethyl-silane (26) (824 mg, 2.52 mmol)
in dry THF (2 mL) was added at ꢀ78 ꢁC and the reaction mixture
was allowed to warm slowly to room temperature overnight. The
solvent was removed under vacuum, a saturated aqueous solution
of potassium sodium tartrate (30 mL) was added and the mixture
extracted with ethyl acetate (3ꢂ50 mL). The combined organic
phases were dried over anhydrous Na2SO4, the solvent was
duced pressure left a mixture of L-(2S,3S)-methylproline ethyl ester
and (S)-isoleucine ethyl ester (78.9 g total). The mixture was dis-
solved in 1050 mL of a 1:1 mixture of dioxane and water and cooled
to 0 ꢁC. Di-tert-butyl dicarbonate (119 g, 545 mmol) and solid
K2CO3 (68.4 g, 495 mmol) were added. The reaction mixture was
slowly brought to room temperature and stirred for 17 h. The sol-
vent was removed under reduced pressure; the reaction was taken

7110
K. Sommer, R.M. Williams / Tetrahedron 64 (2008) 7106–7111
removed under vacuum, and the residue was purified by flash
column chromatography (silica, hexane/diethyl ether: 100:0, then
99:1, then 98:2, then 95:5, then 90:10, then 80:20) to yield 2R-[4-
(tert-butyl-dimethyl-silanyloxy)-3S-methyl-but-2E-enyl]-3-methyl-
pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (23)
1029, 912 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
1.27 (t, J¼7.0 Hz, 3H),
1.36 (d, J¼6.6 Hz, 3H), 2.12–2.30 (m, 2H), 2.60–2.78 (m, 2H), 3.30
(1/2 ABq, J¼17.2 Hz, 1H), 3.45 (1/2 ABq, J¼17.2 Hz, 1H), 4.06 (q,
J¼7.0 Hz, 1H), 4.15 (q, J¼7.3 Hz, 2H), 4.97 (dq, J¼1.2, 10.5 Hz, 1H),
5.01 (dq, J¼1.8, 17.6 Hz, 1H), 5.76 (ddt, J¼6.6, 10.3, 17.2 Hz, 1H), 7.23
(t, J¼7.3 Hz, 1H), 7.31 (t, J¼7.7 Hz, 2H), 7.37 (t, J¼7.0 Hz, 2H). 13C
(780 mg, 88%) as a clear oil. TLC (SiO2, hexanes/Et2O: 7:3): Rf¼0.43.
25
[a]
ꢀ63.2 (c 1.0, CH2Cl2). IR (thin film): 2960, 2927, 2877, 2857,1738,
NMR (100 MHz, CDCl3): d 172.3, 144.7, 136.9, 128.4 (2C), 127.7, 127.1
D
1700, 1461, 1392, 1251, 1228, 1065, 837 cmꢀ1
.
1H NMR (300 MHz,
(2C), 115.7, 60.6, 60.4, 51.6, 51.0, 32.6, 19.5, 14.4. HRMS (FABþ) calcd
CDCl3): (rotamers) 0.06 (s, 6H), 0.86–0.96 (m, 12H), 1.20–1.32 (m,
d
for C16H23NO2 (m/z) 262.1807 [Mþþ1]; found (m/z) 262.1796.
3H),1.41,1.44 (2s, 9H),1.61,1.64 (2s, 3H),1.64–1.80 (m, 2H), 2.16–2.32
(m, 1H), 2.56–2.70 (m, 1H), 2.87, 3.18 (2dd, J¼5.1, 15.4 Hz, 1H), 3.10–
3.24 (m, 1H), 3.70, 3.83 (2t, J¼8.8 Hz, 1H), 4.03 (s, 2H), 4.06–4.28 (m,
4.8. 3S-Methyl-1-(1R-phenyl-ethyl)-pyrrolidine-2R-carboxylic
acid ethyl ester (29)
2H), 5.29 (m,1H).13C NMR (75 MHz, CDCl3): (rotamers)
d 173.2,153.9,
153.7, 138.1, 137.6, 118.8, 118.3, 80.1, 79.4, 71.3, 71.0, 68.8, 68.4, 60.9,
60.8, 47.8, 47.5, 41.8, 40.5, 31.0, 30.9, 30.5, 29.6, 28.7, 28.6, 26.2, 26.2,
18.7, 14.8, 14.7, 14.7, 14.5, 14.3, 14.2, ꢀ4.90, ꢀ4.93. HRMS (FABþ) calcd
for C24H45NO5Si (m/z) 456.3145 [Mþþ1]; found (m/z) 456.3150.
To a solution of [but-3-enyl-(1R-phenyl-ethyl)-amino]-acetic
acid ethyl ester (28) (172 mg, 0.659 mmol) in dry diethyl ether
(2.5 mL) was added 1.8 M solution of LDA (0.476 mL, 0.857 mmol)
in heptane/THF/ethylbenzene at ꢀ78 ꢁC. The temperature was
raised to ꢀ20 ꢁC and then cooled down to ꢀ90 ꢁC. Freshly prepared
1 M solution of anhydrous ZnBr2 (2.0 mL, 1.98 mmol) in dry diethyl
ether was added dropwise at ꢀ90 ꢁC, and the mixture was allowed
to warm to room temperature over 3 h, and then stirred for 30 min.
The reaction mixture was quenched with saturated aqueous solu-
tion of NH4Cl, stirred overnight, diluted with diethyl ether (20 mL),
and 10% aqueous NaHCO3 solution (20 mL) was added. The organic
phase was separated and the aqueous phase extracted with diethyl
ether (2ꢂ30 mL). The combined organic phases were dried over
anhydrous Na2SO4, the solvent was removed under vacuum, and
the residue was purified by flash column chromatography (silica,
hexane/diethyl ether: 100:0, then 95:5, then 90:10, then 80:20) to
4.6. But-3-enyl-(1R-phenyl-ethyl)-amine
To a stirred solution of R-(þ)-
a-methyl-benzyl amine (27)
(9.30 g, 76.7 mmol) in dry DMF (90 mL) were added K2CO3 (35.0 g,
253 mmol) and NaI (38.0 g, 253 mmol) at room temperature under
argon. Finally, 4-bromobut-1-ene (9.42 g, 69.8 mmol) was added
and the reaction mixture stirred at 100 ꢁC for 22 h. The reaction
mixture was cooled to room temperature, diluted with diethyl
ether (200 mL), water (200 mL) was added, the organic phase
separated, and the aqueous phase extracted with diethyl ether
(2ꢂ100 mL) and methylene chloride (1ꢂ100 mL). The combined
organic phases were dried over anhydrous Na2SO4, the solvent was
removed under vacuum, the residue (40 g) taken in water (400 mL),
and extracted with diethyl ether (4ꢂ100 mL). The combined or-
ganic phases were dried over anhydrous Na2SO4, the solvent was
removed under vacuum, and the residue was purified by flash
column chromatography (silica, hexane/diethyl ether: 95:5, then
80:20, then 60:40, then 40:60) to yield but-3-enyl-(1R-phenyl-
yield
3S-methyl-1-(1R-phenyl-ethyl)-pyrrolidine-2R-carboxylic
acid ethyl ester (29) (138 mg, 80%) as a clear oil and recovered
[but-3-enyl-(1R-phenyl-ethyl)-amino]-acetic acid ethyl ester (28)
25
(26 mg, 15%). TLC (SiO2, hexanes/Et2O: 4:1): Rf¼0.25. [
a]
þ68.0 (c
D
1.0, CH2Cl2). IR (thin film): 3062, 3027, 2970, 2933, 2874, 1727, 1454,
1372, 1156, 1026 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d
0.93 (d,
J¼7.0 Hz, 3H), 1.22 (t, J¼7.3 Hz, 3H), 1.35 (d, J¼6.9 Hz, 3H), 1.52–1.70
(m, 1H), 1.88–2.02 (m, 1H), 2.32–2.50 (m, 1H), 2.78–2.90 (m, 1H),
2.96–3.08 (m, 1H), 3.31 (d, J¼8.4 Hz, 1H), 3.71 (q, J¼8.0 Hz, 1H), 4.09
(q, J¼7.0 Hz, 2H), 7.18–7.32 (m, 5H). 13C NMR (100 MHz, CDCl3):
ethyl)-amine (8.02 g, 66%) as a clear oil. TLC (SiO2, hexanes/Et2O:
25
3:2): Rf¼0.26. [
a
]
D
þ49.0 (c 1.05, MeOH). IR (thin film): 3352, 3077,
3025, 2974, 2932, 2812, 1450, 1130, 913 cmꢀ1
.
1H NMR (300 MHz,
CDCl3):
d
1.37 (d, J¼6.6 Hz, 3H), 1.45 (br s, 1H), 2.24 (cm, 2H), 2.55
d 173.5, 144.6, 128.3 (2C), 127.6 (2C), 127.2, 67.6, 62.0, 59.8, 50.7,
(cm, 2H), 3.78 (q, J¼6.6 Hz, 1H), 5.03 (d, J¼10.3 Hz, 1H), 5.08 (d,
J¼17.9 Hz, 1H), 5.76 (ddt, J¼6.6, 10.3, 17.2 Hz, 1H), 7.20–7.38 (m, 5H).
36.6, 32.1, 22.8, 15.8, 14.5. HRMS (FABþ) calcd for C16H23NO2 (m/z)
262.1807 [Mþþ1]; found (m/z) 262.1803.
13C NMR (100 MHz, CDCl3):
d 145.8, 136.6, 128.5 (2C), 127.0, 126.7
(2C),116.4, 58.4, 46.8, 34.5, 24.5. HRMS (FABþ) calcd for C12H17N (m/
z) 176.1439 [Mþþ1]; found (m/z) 176.1435.
4.9. (2R,3S)-1-tert-butyl 2-ethyl 3-methyl-pyrrolidine-1,2-
dicarboxylate (30)
4.7. [But-3-enyl-(1R-phenyl-ethyl)-amino]-acetic acid ethyl
A solution of 3S-methyl-1-(1R-phenyl-ethyl)-pyrrolidine-2R-
ester (28)
carboxylic acid ethyl ester (29) (100 mg, 383
(2 mL) was stirred under H2 (80 psi) for 24 h at room temperature
in the presence of Pd/C (10 wt %) (20.4 mg, 19.1 mol). The catalyst
was removed by filtration through a pad of Celite, which was
washed with ethanol (30 mL), and the majority of solvent was re-
moved under vacuum to yield 3S-methyl-pyrrolidine-2R-carboxylic
acid ethyl ester, which was redissolved in dioxane/H2O (2 mL, 1:1).
The solution was cooled to 0 ꢁC and solid di-tert-butyl dicarbonate
mmol) in dry ethanol
To a stirred solution of but-3-enyl-(1R-phenyl-ethyl)-amine
(1.00 g, 5.70 mmol) in dry DMSO (5 mL) was slowly added ethyl
bromacetate (524 mg, 3.14 mmol); after 30 min of stirring, dry NEt3
(317 mg, 3.14 mmol) was slowly added followed by a new addition
of ethyl bromacetate (524 mg, 3.14 mmol) and NEt3 (317 mg,
3.14 mmol). The reaction mixture was heated to 50–60 ꢁC for 46 h,
cooled to room temperature, and then diluted with diethyl ether
(20 mL). Water (20 mL) was added and the separated organic phase
was washed with water (2ꢂ10). The combined aqueous phases
were extracted with methylene dichloride (1ꢂ10 mL). The com-
bined organic phases were dried over anhydrous Na2SO4, the sol-
vent was removed under vacuum, and the residue was purified by
flash column chromatography (silica, hexane/diethyl ether: 100:0,
then 90:10, then 80:20) to yield [but-3-enyl-(1R-phenyl-ethyl)-
m
(91.9 mg, 421 mmol) followed by K2CO3 (52.9 mg, 383 mmol) was
added. The reaction mixture was allowed to warm to room tem-
perature and stirred for 19 h. The solvent was removed under re-
duced pressure, the residue taken up in water (30 mL), and the
mixture was extracted with ethyl acetate (3ꢂ30 mL). The combined
organic phases were dried over anhydrous Na2SO4 and the solvent
removed under reduced pressure and the residue was purified by
flash column chromatography (silica, hexane/diethyl ether: 10:0,
then 9:1, then 8:2, then 7:3) to yield 3-methyl-pyrrolidine-1,2-di-
amino]-acetic acid ethyl ester (28) (1.00 g, 67%) as a clear oil. TLC
25
(SiO2, hexanes/Et2O: 9:1): Rf¼0.20. [
a
]
þ34.7 (c 0.9, MeOH). IR
carboxylic acid 1-tert-butyl ester 2-ethyl ester (30) (82.5 mg, 84%)
D
25
(thin film): 3063, 3027, 2977, 2935, 2847, 1735, 1453, 1370, 1179,
as a clear oil. TLC (SiO2, hexanes/Et2O: 7:3): Rf¼0.20. [
a
]
ꢀ9.38
D

K. Sommer, R.M. Williams / Tetrahedron 64 (2008) 7106–7111
7111
Sakemi, S.; Sugiura, A.; Suzuki, Y.; Brennan, L.; Duignan, J.; Huang, L. H.; Sut-
cliffe, J.; Kojima, N. J. Antibiot. 2001, 54, 911.
9. Qian-Cutrone, J.; Huang, S.; Shu, Y.-Z.; Vyas, D.; Fairchild, C.; Menendez, A.;
Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao, Q. J. Am. Chem. Soc. 2002, 124, 14556.
10. Martinez-Luis, S.; Rodriguez, R.; Acevedo, L.; Gonzalez, M. C.; Lira-Rocha, A.;
Mata, R. Tetrahedron 2006, 62, 1817.
11. (a) Birch, A. J.; Wright, J. J. J. Chem. Soc. D 1969, 644; (b) Birch, A. J.; Wright, J. J.
Tetrahedron 1970, 26, 2329; (c) Birch, A. J.; Russell, R. A. Tetrahedron 1972, 28,
2999; (d) Bird, B. A.; Remaley, A. T.; Campbell, I. M. Appl. Environ. Microbiol. 1981,
42, 521; (e) Bird, B. A.; Campbell, I. M. Appl. Environ. Microbiol. 1982, 43, 345; (f)
Robbers, J. E.; Straus, J. W. Lloydia 1975, 38, 355; (g) Paterson, R. R. M.;
Hawksworth, D. L. T. Brit. Mycol. Soc. 1985, 85, 95; (h) Wilson, B. J.; Yang, D. T. C.;
Harris, T. M. Appl. Microbiol. 1973, 26, 633; (i) Coetzer, J. Acta Crystallogr. 1974,
B30, 2254.
(c 1.3, CH2Cl2). IR (thin film): 2974, 2933, 2879, 1743, 1702, 1457,
1396, 1193, 1149, 1116, 1028 cmꢀ1 1H NMR (400 MHz, CDCl3):
(rotamers)
.
d
1.00 (t, J¼7.0 Hz, 3H), 1.26 (q, J¼7.3 Hz, 3H), 1.39, 1.44
(2s, 9H), 1.60–1.83 (m, 1H), 1.88–2.00 (m, 1H), 2.35–2.58 (m, 1H),
3.23–3.40 (1H, m), 3.56–3.74 (m, 1H), 4.08–4.30 (m, 3H). 13C NMR
(100 MHz, CDCl3): (rotamers) d 172.1, 172.0, 154.6, 154.0, 79.9, 79.8,
63.6, 63.1, 60.8, 60.7, 46.4, 46.0, 37.3, 36.4, 32.2, 31.4, 28.6, 28.5, 28.5,
15.0, 15.0, 14.6, 14.5. HRMS (FABþ) calcd for C13H23NO4 (m/z)
258.1705 [Mþþ1]; found (m/z) 258.1693.
4.10. 2-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-but-2-
enyl]-3-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester (23)
12. (a) Hayashi, H.; Nishimoto, Y.; Nozaki, H. Tetrahedron Lett. 1997, 38, 5655; (b)
Hayashi, H.; Nishimoto, Y.; Akiyama, K.; Nozaki, H. Biosci. Biotechnol. Biochem.
2000, 64, 111; (c) Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger, B. R.;
Reading, C. J. Antibiot. 1998, 50, 840.
13. (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127; (b) Williams, R. M.
Chem. Pharm. Bull. 2002, 50, 711; (c) Williams, R. M.; Stocking, E. M.; Sanz-
Cevera, J. F. Top. Curr. Chem. 2000, 209, 98.
To a stirred solution of 3-methyl-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-ethyl ester (30) (50 mg, 195
mmol) in dry
14. (a) Ostlind, D. A.; Mickle, W. G.; Ewanciw, D. V.; Andriuli, F. J.; Campbell, W. C.;
Hernandez, S.; Mochales, S.; Munguira, E. Res. Vet. Sci. 1990, 48, 260; (b) Shoop,
W. L.; Egerton, J. R.; Eary, C. H.; Suhayda, D. J. Parasitol. 1990, 76, 349; (c) Shoop,
W. L.; Eary, C. H.; Michael, H. W.; Haines, H. W.; Seward, R. L. Vet. Parasitol. 1991,
40, 339; (d) Shoop, W. L.; Michael, B. F.; Haines, H. W.; Eary, C. H. Vet. Parasitol.
1992, 43, 259; (e) Shoop, W. L.; Haines, H. W.; Eary, C. H.; Michael, B. F. Am. J.
Vet. Res. 1992, 53, 2032; (f) Schaeffer, J. M.; Blizzard, T. A.; Ondeyka, J.; Goe-
gelman, R.; Sinclair, P. J.; Mrozik, H. Biochem. Pharmacol. 1992, 43, 679; For
a review, see: (g) Geary, T. G.; Sangster, N. C.; Thompson, D. P. Vet. Parasitol.
1999, 84, 275.
15. Lee, B. H.; Clothier, M. F.; Dutton, F. E.; Nelson, S. J.; Johnson, S. S.; Thompson,
D. P.; Geary, T. G.; Whaley, H. D.; Haber, C. L.; Marshall, V. P.; Kornis, G. I.;
McNally, P. L.; Ciadella, J. I.; Martin, D. G.; Bowman, J. W.; Baker, C. A.;
Coscarelli, E. M.; Alexander-Bowman, S. J.; Davis, J. P.; Zinser, E. W.; Wiley, V.;
Lipton, M. F.; Mauragis, M. A. Curr. Top. Med. Chem. 2002, 2, 779.
16. Lee, B. H. J. Labelled Compd. Radiopharm. 2002, 45, 1209.
THF (1 mL) was added 0.5 M solution of KHMDS (506
m
L, 253 mol)
m
in toluene at ꢀ78 ꢁC and the reaction mixture was stirred at ꢀ78 ꢁC
for 30 min. A solution of tert-butyl-(4-iodo-2-methyl-but-2E-enyl-
oxy)-dimethyl-silane (26) (82.5 mg, 253 mmol) in dry THF (0.2 mL)
was added at ꢀ78 ꢁC and the reaction mixture was allowed to
warm slowly to room temperature overnight. The solvent was re-
moved under vacuum, a saturated aqueous solution of potassium
sodium tartrate (5 mL) was added, and the mixture extracted with
ethyl acetate (3ꢂ10 mL). The combined organic phases were dried
over anhydrous Na2SO4, the solvent was removed under vacuum,
and the residue was purified by flash column chromatography
(silica, hexane/diethyl ether: 100:0, then 99:1, then 98:2, then 95:5,
then 90:10, then 80:20, then 70:30, then 60:40) to yield 2-[4-(tert-
butyl-dimethyl-silanyloxy)-3-methyl-but-2-enyl]-3-methyl-pyrrol-
idine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (23)
17. (a) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.; Ohta, T.; Williams, R. M.;
Tsukamoto, S. Angew. Chem., Int. Ed. 2007, 46, 2254; (b) Grubbs, A. W.; Artman,
G. D., III; Tsukamoto, S.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 2257; (c)
Greshock, T. J.; Grubbs, A. W.; Tsukamoto, S.; Williams, R. M. Angew. Chem., Int.
Ed. 2007, 46, 2262.
(88.9 mg, 82%) as a clear oil. TLC (SiO2, hexanes/Et2O: 7:3): Rf¼0.43.
18. Porter, A. E. A. J. Chem. Soc., Chem. Commun. 1970, 1103.
25
[
a]
ꢀ62.8 (c 1.0, CH2Cl2). The NMR and IR spectral properties of
D
19. (a) Williams, R. M.; Kwast, E.; Coffman, H.; Glinka, T. J. Am. Chem. Soc. 1989, 111,
3064; (b) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am. Chem.
Soc. 1990, 112, 808; (c) Domingo, L. R.; Sanz-Cervera, J. F.; Williams, R. M.; Picher,
M. T.; Marco, J. A. J. Org. Chem. 1997, 62, 1662; (d) Sanz-Cervera, J. F.; Glinka, T.;
Williams, R. M. J. Am. Chem. Soc. 1993, 115, 347; (e) Sanz-Cervera, J. F.; Glinka, T.;
Williams, R. M. Tetrahedron 1993, 49, 8471; (f) Williams, R. M.; Sanz-Cervera, J. F.;
Sancenon, F.; Marco, J. A.; Halligan, K. Bioorg. Med. Chem. 1998, 6, 1233.
20. (a) Williams, R. M.; Sanz-Cervera, J. F.; Sancenon, F.; Marco, J. A.; Halligan, K.
J. Am. Chem. Soc. 1997, 119, 1090; (b) Stocking, E. M.; Sanz-Cervera, J. F.; Wil-
liams, R. M. J. Am. Chem. Soc. 2000, 122, 1675; (c) Greshock, T. J.; Williams, R. M.
Org. Lett. 2007, 9, 4255; (d) Greshock, T. J.; Grubbs, A. W.; Williams, R. M. Tet-
rahedron 2007, 63, 6124; (e) Adams, L. A.; Valente, M. W. N.; Williams, R. M.
Tetrahedron 2006, 62, 5195.
this substance matched those for 23 provided above.
Acknowledgements
Financial support from the National Institutes of Health (Grant
CA 70375) is gratefully acknowledged. K.M.S. acknowledges the
Deutsche Forschungsgemeinschaft Postdoctoral Fellowship (SO
507/1-2).
21. Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. Angew. Chem., Int. Ed. 2001,
40, 1296.
References and notes
22. (a) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1996, 118,
7008; (b) Stocking, E. M.; Martinez, R. A.; Silks, L. A.; Sanz-Cervera, J. F.; Wil-
liams, R. M. J. Am. Chem. Soc. 2001, 123, 3391; (c) Stocking, M.; Sanz-Cervera,
J. F.; Unkefer, C. J.; Williams, R. M. Tetrahedron 2001, 51, 5303.
23. Gray, C. R.; Sanz-Cervera, J. F.; Silks, L. A.; Williams, R. M. J. Am. Chem. Soc. 2003,
125, 14692.
24. (a) Artman, G. D.; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129,
6336; (b) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc.
1993, 115, 9323; (c) Williams, R. M.; Cao, J.; Tsujishima, H. Angew. Chem., Int. Ed.
2000, 39, 2540.
1. Yamazaki, M.; Okuyama, E.;Kobayashi, M.; Inoue, H. Tetrahedron Lett.1981, 22,135.
2. (a) Ondeyka, J. G.; Goegelman, R. T.; Schaeffer, J. M.; Kelemen, L.; Zitano, L.
J. Antibiot. 1990, 43, 1375; (b) Liesch, J. M.; Wichmann, C. F. J. Antibiot. 1990, 43,
1380; (c) Blanchflower, S. E.; Banks, R. M.; Everett, J. R.; Manger, B. R.; Reading,
C. J. Antibiot. 1991, 44, 492; (d) Pilar Lopez-Gresa, M.; Carmen Gonzalez, M.;
Ciavatta, L.; Ayala, I.; Moya, P.; Primo, J. J. Agric. Food Chem. 2006, 54, 2921.
3. Blanchflower, S. E.; Banks, R. M.; Everett, J. R.; Reading, C. J. Antibiot. 1993, 46,
1355.
4. Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger, B. R.; Reading, C.
J. Antibiot. 1997, 50, 840.
25. Williams, R. M.; Cao, J. Tetrahedron Lett. 1996, 37, 5441.
26. (a) Titouani, S. L.; Lavergne, J.-P.; Vaillefont, P.; Jaqueier. Tetrahedron 1980, 36,
2961; (b) Stocking, E. M.; Sanz-Cervera, J. F.; Unkefer, C. J.; Williams, R. M.
Tetrahedron 2001, 57, 5303.
27. Stable Isotopes Catalog; Cambridge Isotope Laboratories: Andover, MA, 2005;
p 60.
28. (a) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38, 85; (b) Karoyan, P.;
Chassaing, G. Tetrahedron: Asymmetry 1997, 8, 2025; (c) Lorthiois, E.; Marek, I.;
Normant, J.-F. Tetrahedron Lett. 1997, 38, 89; (d) Karoyan, P.; Chassaing, G. Tet-
rahedron Lett. 2002, 43, 253; (e) Karoyan, P.; Chassaing, G. Tetrahedron Lett.
2002, 43, 1221.
5. Whyte, A. C.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 1996, 59, 1093.
´
6. (a) Polonsky, J.; Merrien, M.-A.; Prange, T.; Pascard, C.; Moreau, S. J. Chem. Soc.,
Chem. Commun. 1980, 601; (b) Prange´, T.; Billion, M.-A.; Vuilhorgne, M.; Pas-
card, C.; Polonsky, J.; Moreau, S. Tetrahedron Lett. 1981, 22, 1977.
7. Fuchser, J. Beeinflussung der Sekundarstoffbildung bei Aspergillusochraceus
durch Variation der Kulturbedingungen sowie Isolierung, Strukturaufklarung
und Biosynthese der neuen Naturstoffe. Ph.D. Thesis, University of Go¨ttingen,
Germany, 1995.
8. (a) Fenical, W.; Jensen, P. R.; Cheng, X.C. U.S. Patent 6,066,635, 2000; (b) Sugie,
Y.; Hirai, H.; Inagaki, T.; Ishiguro, M.; Kim, Y.-J.; Kojima, Y.; Sakakibara, T.;