Stereochemical assignments of the chlorinated residues in victorin C

Article abstract of DOI:10.1055/s-0029-1216910

Victorins are cyclic pentapeptide natural products isolated from the fungus Cochliobus victoriae. Using a combination of synthesis and spectroscopic methods we have assigned the geometry of the vinyl chloride residue and determined the stereochemistry of the 5,5-dichloroleucine moiety. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216910

2954
PAPER
Stereochemical Assignments of the Chlorinated Residues in Victorin C
Stereochemical
A
s
m
signments of the
C
h
a
lorinated
R
n
esidue
s
in
V
d
ictorin
C
a C. Durow, Craig Butts, Christine L. Willis*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax +44(117)0298611; E-mail: chris.willis@bristol.ac.uk
Received 30 May 2009
R2
Abstract: Victorins are cyclic pentapeptide natural products isolat-
ed from the fungus Cochliobus victoriae. Using a combination of
synthesis and spectroscopic methods we have assigned the geome-
try of the vinyl chloride residue and determined the stereochemistry
of the 5,5-dichloroleucine moiety.
O
CO2H
NH
R3
O
O
HN
H
N
Key words: amino acids, halogenation, natural products, spectros-
copy, stereoselective synthesis
O
R1
O
HN
HN
CHCl
O
H2N
OH
Victoria blight is a disease of oats caused by the fungus
Cochliobolus victoriae (also known as Helminthosporium
victoriae) which only affects oat crops that have been de-
rived from the oat variety Victoria. Five fractions display-
ing host-selective activity were isolated from the culture
filtrate of C. victoriae and collectively these are known as
‘victorin’, ‘the victorins’ or HV-toxins.1 Approximately
1–2 mg of the major metabolite, victorin C 2, was isolated
from 1 L of culture broth and the NMR spectrum was
complicated by the presence of different conformers.1a,b
R3 = COCH(OH)2
R3 = COCH(OH)2
R3 = COCH(OH)2
R3 = COCH(OH)2
R3 = COCH2NH2
R1 = CH2Cl
R1 = CHCl2
R2 = OH
R2 = OH
R2 = H
victorin B
1
2
victorin C
victorin D
victorin E
victorin M
R1 = CHCl2
R1 = CCl3
3
4
R2 = OH
R2 = OH
R1 = CHCl2
5
Figure 1 Structures of the victorins1,2
ers isolated a further metabolite, victorin M (or HV-toxin
M) (5), which differs from the other victorins in that the
glyoxylic acid portion (R3, Figure 1) is replaced by gly-
cine.2 Following acetylation of victorin M (5) and methyl-
ation with diazomethane, they isolated methyl ester 6 as
the major product as well as traces of methyl enol ethers 7
and 8, formed by displacement of the vinyl chloride
(Scheme 1).
Kinoshita, Daly, and co-workers2 suggested that the geo-
metry of the vinyl chloride in victorin M (5) was Z by
comparison of the chemical shift (d = 7.68) of the olefinic
proton in derivative 6 to that of (E) and (Z)-chloroacrylic
acids 9 and 10 (Figure 2). In the E-isomer 9, the b-proton
is cis to the carboxylic acid and resonates at d = 7.32, sim-
ilar to that observed for the signal assigned to the vinyl
chloride in 6, whereas in the Z-isomer 10 the signal is up-
field at d = 6.85. However, this assignment does not take
into account the effect of the nitrogen of the peptide bond
on the chemical shift of the vinylic proton.
The cyclic pentapeptide structures of the victorins 1–5
(Figure 1) were elucidated by extensive spectroscopic
studies combined with degradation of the natural prod-
ucts.1,2 The L-configuration of each amino acid residue
was determined from the ORD shifts of their 2,4-DNP de-
rivatives.2 In addition the stereochemistry of erythro-b-
hydroxyleucine and threo-b-hydroxylysine residues were
assigned by correlation with synthetic materials.1,2 How-
ever, the unequivocal assignment of the stereochemistry
of the two chlorinated moieties, 5,5-dichloroleucine and
the a-amino-b-chloroacrylic acid requires further investi-
gation. Herein we describe our synthetic and spectroscop-
ic studies leading to elucidation of the geometry of the
vinyl chloride moiety and stereochemistry of 5,5-dichlo-
roleucine.
Assignment of the Geometry of the a-Amino-b-chlo-
roacrylic Acid Residue
Kinoshita, Daly, and co-workers2a,b also compared the
NMR spectra of the (E)- and (Z)-methoxy derivatives 7
and 8. The signal at d = 6.78 was attributed to the vinylic
proton in E-isomer 7 whereas for the second product, with
the vinylic proton at d =7.55, was assigned as Z-isomer 8;
no explanation for the assignment of these geometries was
given. More recently, Leibold et al.3 synthesised E- and Z-
isomers of b-methoxyacrylates 11 and 12 and found that
the vinylic proton of the E-isomer 11 resonated further
downfield (d = 8.08) than that of the Z-isomer 12, contrary
to that proposed for the victorin derivatives 7 and 8. The
The 1H NMR spectrum of the major metabolite from cul-
tures of C. victoriae, victorin C (2) displayed a signal at
d = 7.52, which was attributed to the vinylic proton, but
the geometry of the vinyl chloride (highlighted in
Figure 1) was not assigned by Macko, Arigoni and co-
workers.1a–c Subsequently Kinoshita, Daly, and co-work-
SYNTHESIS 2009, No. 17, pp 2954–2962
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.07.2009
DOI: 10.1055/s-0029-1216910; Art ID: C02209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereochemical Assignments of the Chlorinated Residues in Victorin C
2955
HO
HO
HO
O
O
O
CO2Me
NH
CO2Me
NH
CO2Me
NH
O
O
O
O
i) Ac2O
O
O
5
Me
N
Me
N
ii) MeOH⋅HCl
CH2N2
Me
N
O
O
HN
HN
O
HN
(E)
(Z)
(Z)
H
OMe
MeO
H
Cl
H
δ 7.68
δ 6.78
δ 7.55
6
7
8
Scheme 1 Derivatisation of victorin M and proposed geometry of the vinyl groups in 6, 7, and 82
The data were compared with the nonchlorinated ana-
logue 13 and the 3JC–H was found to be in accord with the
more upfield proton (cis to the ester carbonyl group).
O
O
H
H
OH
OH
H
Cl
Cl
H
δ 7.32
3JCH 2.5 Hz
δ 6.85
3JCH 2.5 Hz
δ 5.75
10 (Z)
9 (E)
H
O
δ 6.78
H
O
H
OCH3
NHBoc
δ 6.18
Cl
OCH3
O
O
Z
H
N
H
N
3JCH 12.2 Hz
NHBoc
Ph
Ph
OMe
OMe
OMe
13
14
O
MeO
Cl
E
O
O
H
H
δ 7.31
δ 8.08
H
OCH3
12 (Z)
11 (E)
= NOE
NHBoc
15
Figure 2 Chemical shifts of vinylic protons in unsaturated esters 9,
10, 11, and 12
Figure 3 Comparison of 1H–13C couplings in 13 and 14
assignments by Leibold were supported by the NOE inter-
actions indicated between the b-protons and methoxy and
methyl ester groups for 11 and 12 (Figure 2). These re-
sults are in accord with the proposal that the amide carbo-
nyl has a deshielding effect and there are several examples
of where alkene geometry has been assigned in this way.4
Hence if chemical shifts are to be used as a basis to assign
the geometry of the vinyl chloride of the victorins a more
closely related model than the simple acrylic acids 9 and
10 is needed.
There was no observable NOE interaction between the
olefinic and nitrogen protons in the vinyl chloride and,
hence, the product was tentatively assigned as the Z-iso-
mer 14. To gain further evidence for this assignment, the
1
13C–1H coupling constants from a H-coupled 13C NMR
experiment were examined. Typically a proton cis to a
carbonyl group in an a,b-unsaturated ester will have a
much smaller coupling (4–10 Hz) to the carbonyl carbon
than a proton trans (10–18 Hz).7 Despite this being a well-
documented coupling, measurements of this type have
rarely been used to assign the geometry in acrylate deriv-
atives. The spectrum of 14 showed a ddq (2JC–CH3 = 3.5
Hz, 3JC–NH = 4.0 Hz and 3JC–CH = 4.0 Hz) assigned to C1.
The coupling (4 Hz) from the carbonyl carbon to the vinyl
proton is rather low even for a cis relationship, but this is
not unreasonable given the electron-withdrawing geminal
chlorine atom. To support this hypothesis, spin-spin cou-
pling constants were calculated for both Z- and E-isomers
14 and 15 using Density Functional Theory (DFT) meth-
Our goal was to gain substantial evidence for assignment
of the geometries of protected a-amino-b-chloroacrylic
acids and to compare the data with that reported for the vi-
nyl chloride residue in the victorins. First the known5 alk-
ene 13 was converted into the novel vinyl chloride 14 by
a modification of the procedure of Kolar and Olsen.6 Ap-
proximately one equivalent of chlorine gas (measured by
volume) was bubbled through a solution of 13 in carbon
tetrachloride and the mixture put under vacuum to ensure
that all the chlorine had been removed prior to being con-
centrated in vacuo. Treatment of the crude product with
1,4-diazabicyclo[2.2.2]octane gave, after flash chroma-
tography, a single isomer of a vinyl chloride (at this stage,
3
ods. The JC–H coupling constants were calculated as 3.4
Hz for the cis coupling and 8.1 Hz for the trans. Thus
there is an excellent correlation between the authentic
couplings measured experimentally for 14 and those cal-
culated (Table 1). This evidence strongly supports our
original assignment, i.e., that the product is indeed the Z-
isomer 14.
1
either 14 or 15) in 78% isolated yield. In the H NMR
spectrum of the vinyl chloride the olefinic proton reso-
nates at d = 6.78 with a three-bond 13C–1H coupling, (3JC–H
of 2.5 Hz between H3 and the ester carbonyl (Figure 3).
)
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

2956
A. C. Durow et al.
PAPER
Table 1 Comparison of Calculated Couplings and Measured Cou-
plings in 14
geometry of the vinyl chloride in the victorins is E rather
than Z as originally suggested.2
Coupling
3JC1–H
Calculated value (Hz) Measured value (Hz)
3.4
201.5
2.4
4.0
201
3.0
Stereochemical Assignment of 5,5-Dichloroleucine in
Victorin C
JC3–H
3JC3–NH
5,5-Dichloroleucine and 4,4-dichloro-3-methylbutanoic
acid are components of a number of marine natural prod-
ucts including the dysamides, dechlorobarbamide, and a
series of polychlorinated pyrrolidinones.8 In all cases
where the structures have been fully assigned the config-
uration at C4 of 19 and C3 of 20 as S (Figure 4). To the
best of our knowledge the victorins are the only known
metabolites from a terrestrial organism with structures en-
compassing a 5,5-dichloroleucine moiety and therefore it
is of interest to establish its stereochemistry for compari-
son with dichloroleucine from marine origins. Following
degradation of victorin C, the dichloroleucine fragment
was characterised as the trifluoroacetate salt and shown to
have the 2S stereochemistry, but the configuration at C4
was not assigned.1,2 Hence synthetic samples of both
(2S,4R)- and (2S,4S)-dichloroleucine 19 and 21 as their
trifluoroacetate salts were required. (2S,4S)-Dichloroleu-
cine 19 has been prepared previously and used for exam-
ple by Jiménez, Rodríguez, and co-workers in the total
synthesis of (–)-dysithiazolamide9 and by our group in the
preparation of dysamide B.10 The NMR spectroscopic
data of the synthetic material reported by both groups did
not match exactly with that given for 5,5-dichloroleucine
isolated following degradation of victorin C. It is well
known that the chemical shifts of amino acids are affected
by pH;11 in order for us to reliably compare the data for
both diastereomers of L-dichloroleucine with the sample
obtained from victorin C, it was necessary to acquire the
NMR spectra under similar conditions. Hence protected
(2S,4S)-dichloroleucine 22 was prepared as reported
previously10 and converted into the trifluoroacetate salt 23
in quantitative yield (Scheme 3).
In order to allow a reliable comparison of our data with
that from the victorins, synthesis of the E-isomer 15 was
investigated, but under a variety of conditions only the Z-
isomer 14 was isolated. Hence we turned our attention to
the known E- and Z-vinyl chlorides 17 and 18 bearing the
acetamides rather that the Boc-protected amine.6 These
were readily prepared in 70% overall yield by chlorination
of commercially available unsaturated ester 16
(Scheme 2). In the major isomer, 18, the vinyl proton res-
onated at d = 6.92 whereas in the minor isomer, 17, the
signal was downfield at d = 7.69.
δ = 6.92
O
Cl
O
H
O
i) Cl2, CCl4
ii) DABCO
OMe
H
OMe
Cl
OMe
56%
δ = 7.69
NHAc
NHAc
NHAc
14%
17 (E)
18 (Z)
16
Scheme 2 Synthesis of E- and Z-vinyl chlorides 17 and 18
The data from the 1H-coupled 13C spectrum of both 17 and
18 are given in Table 2. The spin-spin calculations pre-
dicted the 3JC1–CH coupling to be 3.2 Hz in the cis-isomer
and 8.1 Hz in the trans-isomer. Hence again there is good
agreement between our experimental and calculated data.
These assignments are in accord with the results of Kolar
and Olsen6 with the Z geometry for the major isomer 18
(d = 6.92) and the minor product 17 (d = 7.69) being E.
Table 2 Comparison of the Couplings in 17 and 18
Coupling
Measured coupling (Hz) Measured coupling (Hz)
for 17
NH2
for 18
Cl
Cl
CO2H
CO2H
3JC1–CH
3JC1–NH
2JC1–CH3
10.5 (calcd 8.1)
3.0 (calcd 3.2)
19
20
Cl
Cl
NH2
CO2H
4.0
4.0
4.0
4.0
Cl
21
Cl
Figure 4
Having unequivocally assigned the geometries of protect-
ed a-amino-b-chloroacrylic esters 14, 17, and 18, the
chemical shift data were revisited and compared with that
of the vinyl chloride fragment isolated from degradation
of the victorins as well as for the natural products them-
selves. There was a good correlation in the chemical shift
of the vinylic proton in the victorins (e.g., victorin C, dH =
7.52) and derivative 6 (dH = 7.68) with the synthetic E-iso-
mer 17 (dH = 7.69) whereas in both our synthetic Z-iso-
mers 14 and 18 the analogous proton resonated upfield
(dH = 6.78 and dH = 6.92). Hence we concluded that the
+
NH3
–
CF3CO2
NBoc2
CO2t-Bu
TFA
100%
Cl
Cl
CO2H
23
22
Cl
Cl
Scheme 3 Preparation of the trifluoroacetate salt 2312
(2S,4R)-5,5-Dichloroleucine (21) has been prepared pre-
viously in 13 steps from methyl (S)-2-(hydroxymeth-
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

PAPER
Stereochemical Assignments of the Chlorinated Residues in Victorin C
2957
NBoc2
CO2t-Bu
NBoc2
NBoc2
i) NH2NH2
Cl
ii) CuCl2
O
CO2t-Bu
CO2t-Bu
+
24
25
Et3N
26
Cl
35%
7%
Scheme 4 Preparation of dichloride 2512
yl)propanoate and used in an elegant study of J- sis of (2S,4R)-dichloroleucine, aldehyde 24 was treated
configurational assignments in 1,3-nitrogen-containing with hydrazine monohydrate in anhydrous methanol fol-
acyclic moieties.12 A key step was conversion of aldehyde lowed by reaction with copper(II) chloride as previously
24 to dichloride 25 in 35% yield using a modification of described12 to give the expected dichloride 35 in 27%
the Takeda conditions.13 Alkene 26 was formed as a yield. A second product, the novel vinyl chloride 34, was
byproduct in this reaction (Scheme 4).
also formed in the chlorination reaction and was separated
from dichloride 35 by HPLC (Scheme 6). This reaction
proved capricious in our hands and yields of dichloride 35
varied from 15–27%. Interestingly we detected none of
alkene 26 which had been reported previously
(Scheme 4).12 Finally protected dichloroleucine 35 was
stirred in neat trifluoroacetic acid for one hour to give the
trifluoroacetate salt of (2S,4R)-5,5-dichloroleucine 36 in
quantitative yield.
We have developed a more efficient approach to aldehyde
24 using N-Boc-pyroglutamate 27 as the starting material
(Scheme 5). The stereocentre at C4 was established via
alkylation of protected pyroglutamate 27 using lithium
hexamethyldisilazanide and methyl triflate to give 28 and
29 in 4:1 ratio in favour of the unwanted cis-isomer 28.14
Hence 28 was epimerised under the conditions reported
by Joullié et al.15 with 1,8-diazabicyclo[5.4.0]undec-7-
ene in tetrahydrofuran over three days giving a 1:3 ratio of With trifluoroacetate salts 36 and 23 of both (2S,4R)-5,5-
28 and 29 in favour of the required trans-product 29. Hy- dichloroleucine (21) and (2S,4S)-5,5-dichloroleucine (19)
drolytic ring opening of lactam 29 using lithium hydrox- in hand their NMR spectra in deuterium oxide were com-
ide gave a carboxylic acid15,16 that was temporarily pared with that of 5,5-dichloroleucine from victorin C
protected as an allyl ester 30. It was necessary to introduce simulated using the chemical shifts and coupling con-
a second Boc group to prevent competing cyclisations lat- stants reported by Macko, Arigoni and co-workers
er in the synthesis and allyl ester 30 was converted into di- (Figure 5, spectrum C).1a The most striking difference in
Boc-protected ester 31 in 69% yield over three steps from the spectra of 23 and 36 lies in the chemical shifts of the
pyroglutamate derivative 29.
diastereotopic protons at C3, which are more separated
(d = 1.81 and 2.27) in the (2S,4R)-diastereomer 36 than in
the (2S,4S)-diastereomer 23 (d = 1.19 and 2.14) (Figure 5,
spectrums A and B).
The allyl ester was removed via a p-allyl complex [using
Pd(PPh3)4/NaBH417] and reduction of acid 32 with bo-
rane–dimethyl sulfide (BMS) complex gave alcohol 33 in
92% yield. Finally oxidation of 33 using Dess–Martin There were no significant differences in the 13C NMR data
periodinane (DMP)18 gave the required aldehyde 24 in of the two salts 23 and 36 and dichloroleucine isolated fol-
eight steps and 34% overall yield. To complete the synthe- lowing degradation of victorin C. Hence from comparison
i) LiOH, THF
0 °C, 85%
NHBoc
CO2t-Bu
i) LiHMDS
THF, –78 °C
AllO2C
77%
CO2t-Bu
CO2t-Bu
ii) MeOTf
83%
CO2t-Bu
4 : 1
O
O
O
N
Boc
N
Boc
N
Boc
30
ii) allyl bromide
Cs2CO3, DMF
27
28
29
(Boc)2O
CH2Cl2, DMAP
88%
DBU, CHCl2, 78% (brsm)
NBoc2
NBoc2
CO2t-Bu
NBoc2
CO2t-Bu
BMS, Et2O
DMP, CH2Cl2
99%
O
HO
RO2C
CO2t-Bu
92%
33
24
Pd(PPh3)4
31 R = Allyl
32 R = H
NaBH4
94%
Scheme 5 Preparation of aldehyde 24
–
+
CF3CO2
NH3
NBoc2
CO2t-Bu +
NBoc2
CO2t-Bu
NBoc2
TFA
i) NH2NH2
Cl
Cl
O
CO2H
CO2t-Bu
100%
ii) CuCl2
Et3N
34
35
36
Cl
Cl
24
Cl
28%
27%
Scheme 6 Completing the synthesis of 36
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

2958
A. C. Durow et al.
PAPER
Figure 5 NMR spectra of various dichloroleucine residues (D2O)
of the 1H NMR data obtained from dichloroleucine isolat-
ed from degradation of victorin C with our synthetic sam-
ples leads us to conclude that the (2S,4S)-diastereomer 19
is a component of the natural product.19
out using Merck Kieselgel 60 silica gel. Dry solvents acetonitrile,
dichloromethane, diethyl ether, toluene and tetrahydrofuran were
obtained using the ‘Anhydrous Engineering Solvent Purification
System’. All other reagents and solvents were used as supplied from
Aldrich, Acros, Fischer or Lancaster Synthesis. PE refers to petro-
leum ether (boiling range 40–60 °C).
In conclusion, based on the synthetic and spectroscopic
studies described herein, the structure of victorin C may
be more fully assigned with the 4S configuration for the
5,5-dichloroleucine moiety and the E geometry for the vi-
nyl chloride residue.
Chlorination of Acrylic Acid Derivatives; General Procedure
Cl2 gas (~1 equiv by volume) was bubbled through a soln of alkene
in CCl4 (10 mL per mmol). The mixture was stirred for 5 min and
the flask was evacuated under reduced pressure to remove any ex-
cess Cl2. The mixture was concentrated in vacuo and taken up in
CH2Cl2 or MeCN (5 mL per mmol). DABCO (1.1 equiv) was added
portionwise and the mixture stirred for 20 min. The mixture was
concentrated in vacuo, the residue dissolved in H2O and acidified
using 1.0 M HCl. The aqueous soln was extracted with EtOAc and
the combined extracts were dried (MgSO4), filtered, and concentrat-
ed in vacuo.
1H and 13C NMR spectra were recorded using either a Jeol GX 400
MHz or Jeol Eclipse 400 MHz, using tetramethylsilane (TMS) as an
internal reference. The chemical shifts are reported in parts per mil-
lion (ppm) and the coupling constants are in hertz (Hz). DEPT 135,
COSY, HBQC and HMBC NMR spectra were routinely used to de-
finitively assign the signals of the 1H and 13C NMR spectra. Electro-
spray (ESI) mass spectra were recorded on a Micromass lCT mass
spectrometer or a VG Quattro mass spectrometer. Where chlorine
atoms are present in a molecule, the high-resolution molecular ion
mass quoted is for that of the 35Cl isotope. Infrared spectra were re-
corded on a Perkin-Elmer FTIR spectrometer as neat solutions or
solids. Melting points were measured in open capillary tubes using
a Gallenkamp melting point apparatus and are uncorrected. Optical
rotation measurements were carried out as solutions on a Perkin-
Elmer 241 MC polarimeter irradiating with the sodium D line (l =
589) and [a]D is given in units of 10–1 deg·cm2·g–1.
Methyl (Z)-2-(tert-Butoxycarbonylamino)-3-chloroprop-2-
enoate (14)
Following the general procedure using 13 (5.0 g, 24.9 mmol) gave
14 as an oil in 78% yield.
1H NMR (400 MHz, CDCl3): d = 1.50 [s, 9 H, C(CH3)3], 3.81 (s, 3
H, OCH3), 6.54 (br s, 1 H, NH), 6.78 (s, 1 H, H3).
13C NMR (100 MHz, CDCl3): d = 27.9 [C(CH3)3], 52.5 (OCH3),
81.3 [C(CH3)3], 120.4 (C3), 129.9 (C2), 151.9 (NCO), 162.9 (CO).
MS (ESI): m/z (%) = 260 (33), 258 ([M + Na]+, 100), 203 (22), 201
(66), 180 (5).
Thin layer chromatography (TLC) was carried out on Merck Kiesel-
gel 60 F254 aluminium-backed plates. The plates were developed
with the appropriate solvent system and visualised either by UV
lamp or by dipping in saturated potassium permanganate solution
and heating with a hot air gun. Flash chromatography was carried
HRMS (ESI): m/z [M + Na]+ calcd for C9H14ClNO4Na: 258.0506;
found: 258.0509.
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

PAPER
Stereochemical Assignments of the Chlorinated Residues in Victorin C
2959
Methyl (E)-2-(Acetylamino)-3-chloroacrylate (17) and Methyl
(Z)-2-(Acetylamino)-3-chloroacrylate (18)
Following the general procedure using commercially available 16
(2.0 g, 14.0 mmol) gave 17 (0.35 g, 14%) as a clear oil and 18 (1.4
g, 56%) as a white solid. Purification was carried out by column
chromatography (10% EtOAc–PE).
orange oil. Purification by column chromatography (5–20%
EtOAc–PE) gave 28 (6.3 g, 67%) as a white solid and 29 (1.50 g,
16%) as a white solid.
(2S,4S)-Isomer 28
Mp 68–69 °C (Lit.15 69–71 °C).
[a]D23 –38.2 (c 2.2, CHCl3) [Lit.14 –44.8 (c 1.1, CHCl3)].
(E)-Isomer 17
1H NMR (400 MHz, CDCl3): d = 2.15 (s, 3 H, COCH3), 3.90 (s, 3
H, OCH3), 7.85 (s, 1 H, NH) 7.69 (s, 1 H, H3).
1H NMR (400 MHz, CDCl3): d = 1.27 (d, J = 7.0 Hz, 3 H, CH3),
1.49, 1.51 [2 s, each 9 H, 2 C(CH3)3], 1.60 (m, 1 H, H3), 2.58 (m, 2
H, H3, H4), 4.40 (dd, J = 9.0, 6.0 Hz, 1 H, H2).
13C NMR (100 MHz, CDCl3): d = 24.3 (CH3), 52.9 (OCH3), 118.9
(C3), 131.2 (C2), 163.3, 168.9 (2 CO).
13C NMR (100 MHz, CDCl3): d = 16.2 (CH3), 27.7, 29.4
[2 C(CH3)3], 37.2 (C4), 57.8 (C2), 81.8, 82.0 [2 C(CH3)3], 149.3
(NCO), 170.4, 175.8 (2 CO).
(Z)-Isomer 18
Mp 99 °C (Lit.20 96–97 °C).
(2S,4R)-Isomer 29
Mp 61–63 °C [Lit.14 62–64 °C].
1H NMR (400 MHz, CDCl3): d = 2.14 (s, 3 H, COCH3), 3.81 (s, 3
H, OCH3), 6.92 (s, 1 H, H3), 7.44 (s, 1 H, NH).
[a]D21 –16.0 (c 2.0, CHCl3) [Lit.14 –16.9 (c 1.0, CHCl3)].
13C NMR (100 MHz, CDCl3): d = 22.9 (CH3), 52.9 (OCH3), 124.14
(C3), 129.7 (C2), 163.0, 168.8 (2 CO).
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 7.0 Hz, 3 H, CH3), 1.47
[s, 9 H, C(CH3)3], 1.51 [s, 9 H, C(CH3)3], 1.89 (ddd, J = 13.0, 12.0,
9.5 Hz, 1 H, H3), 2.24 (ddd, J = 13.0, 8.5, 1.5 Hz, 1 H, H3), 2.65
(ddq, J = 12.0, 8.5, 7.0 Hz, 1 H, H4), 4.42 (dd, J = 9.5, 1.5 Hz, 1 H,
H2).
(2S,4S)-5,5-Dichloroleucine Trifluoroacetic Acid Salt (23) and
(2S,4S)-5,5-Dichloroleucine (19)
Dichloro ester 22 (22 mg, 5 mmol) was dissolved in TFA and stirred
for 1 h. The mixture was concentrated in vacuo to give 23 (10 mg,
100%) as a white solid.
MS (ESI): m/z (%) = 322 ([M + Na]+, 100), 221 (15), 207 (45), 200
(55).
Subsequent purification by ion exchange chromatography gave
(2S,4S)-5,5-dichloroleucine (19) as a white solid (0.6 mg); mp 222–
223 °C.
(2S,4R)-N-(tert-Butoxycarbonyl)-4-methylpyroglutamate (29)
by Epimerisation of (2S,4S)-Isomer 2815
(2S,4R)-Isomer 28 (6.3 g, 21.1 mmol) was taken up in CH2Cl2 (150
mL) and cooled to 0 °C. DBU (18.8 mL, 125.7 mmol) was added
dropwise and the mixture stirred at this temperature for 15 min, al-
lowed to warm to r.t. and stirred for a further 48 h. The mixture was
diluted with CH2Cl2 (100 mL) and washed with 1.0 M HCl (2 ꢀ 100
mL), H2O (50 mL), and brine (50 mL). The organic layer was sep-
arated, dried (MgSO4), filtered, and concentrated to give a dark
brown oil. Purification by column chromatography (5–20%
EtOAc–PE) gave 29 (3.9 g, 62%) as a white solid and 28 (1.3 g,
21%) as a white solid.
TFA Salt 23
1H NMR (400 MHz, D2O): d = 1.11 (d, J = 6.5 Hz, 3 H, CH3), 1.99
(ddd, J = 14.5, 9.5, 5.0 Hz, 1 H, H3), 2.14 (ddd, J = 14.5, 9.5, 4.0
Hz, 1 H, H3), 2.35 (m, 1 H, H4), 4.08 (dd, J = 9.5, 5.0 Hz, 1 H, H2),
6.03 (d, J = 3.0 Hz, 1 H, H5).
13C NMR (100 MHz, D2O): d = 15.9 (CH3), 34.1 (C3), 41.4 (C4),
52.2 (C2), 79.6 (C5), 173.0 (C1).
Acid 19
Mp 222–223 °C.
(2S,4R)-2-(tert-Butoxycarbonylamino)-4-methylpentan-1,5-di-
oic Acid 1-tert-Butyl Ester
[a]D –38 (c 1.0, H2O) [Lit.9a –23 (c 0.16, 1 M HCl)].
An aq soln of 1.0 M LiOH (11.0 mL, 11.0 mmol) was added drop-
wise to 29 (3.0 g, 10.0 mmol) in THF (60 mL) at 0 °C. After 0.5 h
a further portion of aq 1.0 M LiOH (11.0 mL, 11.0 mmol) was add-
ed, the mixture allowed to warm to r.t. and stirred for 2 h. The mix-
ture was poured into EtOAc (100 mL) and washed with sat. aq
NaHCO3 (3 ꢀ 50 mL). The aqueous layers were combined and acid-
ified to pH 5 with 10% citric acid soln and extracted with EtOAc
(3 ꢀ 100 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo to give the title compound (2.7
g, 85%) as a white solid; mp 73–74 °C [Lit.16 100–101 °C, Lit.15 72–
74 °C].
1H NMR (400 MHz, D2O): d = 1.20 (d, J = 7 Hz, 3 H, CH3), 2.01
(ddd, J = 15, 10, 5 Hz, 1 H, H3), 2.16 (ddd, J = 15, 9, 4 Hz, 1 H, H3),
2.40 (m, 1 H, H4), 3.92 (dd, J = 9, 5 Hz, 1 H, H2), 6.12 (d, J = 3 Hz,
1 H, H5).
13C NMR (100 MHz, D2O): d = 17.0 (CH3), 36.0 (C3), 42.6 (C4),
57.1 (C2), 81.5 (C5), 177.4 (C1).
MS (ESI): m/z (%) = 204 (12), 202 (67), 200 ([M + H]+, 100).
HRMS (ESI): m/z [M + H]+ calcd for C6H12Cl2NO2: 200.0240;
found: 200.0245.
[a]D23 –24.0 (c 2.0, MeOH) [Lit.15 –23.4 (c 1.4, MeOH)].
tert-Butyl (2S,4S)-N-(tert-Butoxycarbonyl)-4-methylpyro-
glutamate (28) and tert-Butyl (2S,4R)-N-(tert-Butoxycarbonyl)-
4-methylpyroglutamate (29)
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 7.0 Hz, 3 H, CH3),
1.40, 1.43 [2 s, each 9 H, 2 C(CH3)3], 1.63 (m, 1 H, H3), 2.17 (m, 1
H, H3), 2.61 (m, 1 H, H4), 4.22 (m, 1 H, H2), 5.29 (d, J = 8.5 Hz, 1
H, NH).
A 1.0 M soln of LiHMDS in THF (37.9 mL, 37.9 mmol) was added
to a soln of 27 (9.0 g, 31.5 mmol) in anhyd deoxygenated THF (60
mL) at –78 °C. The mixture was stirred for 1 h before addition of
MeOTf (5.4 mL, 47.4 mmol). After 1 h the reaction was quenched
with sat. aq NH4Cl and allowed to warm to r.t. The layers were sep-
arated and the aqueous portion extracted with EtOAc (3 ꢀ 100 mL).
The combined organic extracts were washed with H2O (50 mL) and
brine (50 mL), dried (MgSO4), filtered, and concentrated to give an
13C NMR (100 MHz, CDCl3): d = 17.6 (CH3), 27.9, 28.2
[2 C(CH3)3], 36.3 (C4), 37.1 (C3), 52.5 (C2), 80.2, 82.3
[2 C(CH3)3], 155.6 (NCO), 171.2, 180.1 (2 CO).
MS (ESI): m/z (%) = 340 ([M + Na]+, 100), 324 (90), 289 (52).
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

2960
A. C. Durow et al.
PAPER
5-Allyl 1-tert-Butyl (2S,4R)-2-(tert-Butoxycarbonylamino)-4-
methylpentanedioate (30)
mL). The combined organic extracts were washed with H2O (30
mL) and brine (30 mL), dried (MgSO4), filtered, and concentrated
in vacuo. Purification by column chromatography (10–20%
EtOAc–PE) gave 32 (1.0 g, 94%) as a white solid; mp 79–80 °C.
1-tert-Butyl 5-hydrogen (2S,4R)-2-(tert-butoxycarbonylamino)-4-
methylpentanedioate (2.7 g, 8.51 mmol) and Cs2CO3 (2.8 g, 8.5
mmol) were suspended in DMF (30 mL) and stirred vigorously for
15 min. Allyl bromide (1.5 mL, 17.0 mmol) was added dropwise
and the mixture stirred at r.t. for 1 h. It was then filtered, poured into
sat. aq NaHCO3 (100 mL), and extracted with EtOAc (3 ꢀ 50 mL).
The combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. Purification by column chromatography
(20% EtOAc–PE) gave 30 (2.3 g, 77%) as a clear oil.
IR: 2978 (CH), 1737, 1729 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.24 (d, J = 7.0 Hz, 3 H, CH3), 1.45
[s, 9 H, C(CH3)3], 1.49 [s, 18 H, 2 C(CH3)3], 1.97 (ddd, J = 14.0,
10.0, 4.0 Hz, 1 H, H3), 2.47 (ddd, J = 14.0, 10.0, 5.0 Hz, 1 H, H3),
2.55 (m, 1 H, H4), 4.86 (dd, J = 10.0, 4.0 Hz, 1 H, H2).
13C NMR (100 MHz, CDCl3): d = 17.8 (CH3), 27.9 [3 C(CH3)3],
32.8 (C3), 36.0 (C4), 57.1 (C2), 81.4, 83.0 [3 C(CH3)3], 152.3,
169.4 (2 NCO), 180.1 (C5).
[a]D23 +6.0 (c 2.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.19 (d, J = 8.0 Hz, 3 H, CH3),
1.40, 1.43 [2 s, each 9 H, 2 C(CH3)3], 1.70 (ddd, J = 14.0, 9.0, 5.5
Hz, 1 H, H3), 2.19 (ddd, J = 14.0, 8.5, 5.5 Hz, 1 H, H3), 2.57 (m, 1
H, H4), 4.22 (m, 1 H, H2), 4.56 (app dt, J = 5.5, 1.5 Hz, 2 H, 2 H1¢),
5.01 (br d, J = 8.5 Hz, 1 H, NH), 5.2 (app dq, J = 10.5, 1.5 Hz, 1 H,
H3¢), 5.29 (app dq, J = 17.0, 1.5 Hz, 1 H, H3¢), 5.90 (ddt, J = 17.0,
10.5, 5.5 Hz, 1 H, H2¢).
MS (ESI): m/z (%) = 440 ([M + Na]+, 100), 377 (40), 359 (87), 341
(76), 295 (45), 267 (20).
HRMS (ESI): m/z [M + Na]+ calcd for C20H25NNaO8: 440.2255;
found: 440.2257.
Anal. Calcd for C20H25NO8: C, 57.54; H, 8.45; N, 3.35. Found: C,
57.30; H, 8.26; N, 3.48.
13C NMR (100 MHz, CDCl3): d = 17.5 (CH3), 27.9 [C(CH3)3], 28.2
[C(CH3)3], 36.0 (C4), 36.2 (C3), 52.4 (C2), 65.1 (C1¢), 77.3, 81.9
[2 C(CH3)3], 118.0 (C3¢), 132.2 (C2¢), 155.1, (NCO), 171.7, 175.4
(2 CO).
tert-Butyl (2S,4S)-2-[Bis(tert-butoxycarbonyl)amino]-5-hy-
droxy-4-methylpentanoate (33)
A 2.0 M soln of BMS in THF (1.5 mL, 3.0 mmol) was added drop-
wise to 32 (1.25 g, 3.0 mmol) in Et2O (10 mL). The mixture was
stirred at r.t. for 0.5 h and then concentrated in vacuo. Purification
by column chromatography (10–20% EtOAc–PE) gave 33 (1.1 g,
92%) as a white solid; mp 63–65 °C (previously reported as an
oil12).
MS (ESI): m/z (%) = 380 ([M + Na]+, 26), 313 (34), 291 (33), 289
(92), 226 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C18H31NNaO6: 380.2043;
found: 380.2034.
Anal. Calcd for C18H31NO6: C, 60.37; H, 8.59; N, 3.06. Found: C,
60.53; H, 8.66; N, 3.12.
[a]D23 –47.0 (c 2.0, CHCl3).
IR: 3554 (CH), 2527 (OH), 2159, 1737, 1700 (C=O), 1367 (CO),
1152, 1126 cm–1.
5-Allyl 1-tert-Butyl (2S,4R)-2-[Bis(tert-butoxycarbonyl)amino]-
4-methylpentanedioate (31)
1H NMR (400 MHz, CDCl3): d = 0.97 (d, J = 7.0 Hz, 3 H, CH3), 1.35
[s, 9 H, C(CH3)3], 1.38 [s, 18 H, 2 C(CH3)3], 1.61 (ddd, J = 14.5, 8.0,
5.5 Hz, 1 H, H3), 1.73 (m, 1 H, H4), 2.0 (br s, 1 H, OH), 2.22 (ddd,
J = 14.5, 8.0, 5.5 Hz, 1 H, H3), 3.51 (d, J = 5.5 Hz, 2 H, H5), 4.8
(dd, J = 8.0, 5.5 Hz, 1 H, H2).
Diester 30 (1.2 g, 3.4 mmol) was dissolved in CH2Cl2 (100 mL) and
cooled to 0 °C. (Boc)2O (2.2 g, 10.1 mmol) in CH2Cl2 (10 mL) was
added dropwise followed by DMAP (0.08 g, 0.67 mmol) and the
mixture stirred at r.t. for 16 h. A second portion of (Boc)2O (2.2 g,
10.1 mmol) followed by DMAP (0.08 g, 0.67 mmol) was added to
the mixture which was stirred for 48 h. The mixture was concentrat-
ed in vacuo; purification by column chromatography (20% EtOAc–
PE) gave diester 31 (1.3 g, 88%) as a pale yellow oil.
13C NMR (100 MHz, CDCl3): d = 17.6 (CH3), 27.9 [C(CH3)3], 28.0
[2 C(CH3)3], 33.5 (C3), 33.6 (C4), 57.4 (C2), 67.2 (C5), 81.3
[C(CH3)3], 82.8 [2 C(CH3)3], 152.5 (2 NCO), 170.3 (CO).
MS (ESI): m/z (%) = 426 ([M + Na]+, 30), 289 (15), 207 (35), 172
(25), 142 (10).
[a]D23 –45.0 (c 2.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.18 (d, J = 7.0 Hz, 3 H, CH3), 1.40
[s, 9 H, C(CH3)3], 1.41 [s, 18 H, 2 C(CH3)3], 1.91 (m, 1 H, H3),
2.41–2.55 (m, 2 H, H3, H4), 4.50 (app ddt, J = 13.0, 5.5, 1.5 Hz, 1
H, H1¢), 4.59 (app ddt, J = 13.0, 5.5, 1.5 Hz, 1 H, H1¢), 4.82 (dd,
J = 10.0, 5.5 Hz, 1 H, H2), 5.17 (app dq, J = 10.5, 1.5 Hz, 1 H, H3¢),
5.27 (app dq, J = 17.0, 1.5 Hz, 1 H, H3¢), 5.88 (ddt, J = 17.0, 10.5,
5.5 Hz, 1 H, H2¢).
HRMS (ESI): m/z [M + Na]+ calcd for C20H37NNaO7: 426.2462;
found: 426.2463.
tert-Butyl (2S,4R)-2-[Bis(tert-butoxycarbonyl)amino]-4-methyl-
5-oxopentanoate (24)
Alcohol 33 (0.75 g, 1.9 mmol) in anhyd CH2Cl2 (4 mL) was added
dropwise to Dess–Martin periodinane (15% wt, 4.7 mL, 2.3 mmol)
at r.t. under N2. After 1 h, 1 M NaOH (2 mL) was added. The organ-
ic layer was washed with H2O (1 mL), dried (MgSO4), filtered, and
concentrated. Purification by column chromatography (15%
EtOAc–PE) gave 24 (0.75 g, 99%) as a white solid; mp 59–61 °C;
mp and optical rotation not reported previously.12
13C NMR (100 MHz, CDCl3): d = 18.0 (CH3), 27.9, 28.0
[3 C(CH3)3], 32.8 (C3), 26.2 (C4), 57.0 (C2), 65.0 (C1¢), 81.2, 82.8
[2 C(CH3)3], 117.9 (C3¢), 132.3 (C2¢), 152.3 (CO), 169.4 (CO),
175.4 (CO).
MS (ESI): m/z (%) = 480 ([M + Na]+, 32), 324 (25), 289 (70), 189
(8), 176 (100).
[a]D23 –10.0 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C23H39NNaO8: 480.2568;
found: 480.2583.
IR: 2978 (CH), 1732, 1700 (C=O), 1366 (CO), 1149, 1127 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.13 (d, J = 7.0 Hz, 3 H, CH3), 1.44
[s, 9 H, C(CH3)3], 1.50 [s, 18 H, 2 C(CH3)3], 1.82 (m, 1 H, H3),
2.45–2.51 (m, 2 H, H3, H4), 4.82 (dd, J = 9.0, 5.0 Hz, 1 H, H2), 9.66
(app s, 1 H, H5).
1-tert-Butyl (2S,4R)-2-[Bis(tert-butoxycarbonyl)amino]-4-
methylpentanedioate (32)
Pd(PPh3)4 (60 mg, 53.0 mmol) was added to 31 (1.2 g, 2.65 mmol)
in THF (15 mL). After 5 min NaBH4 (0.15 g, 4.0 mmol) was added
and the mixture was stirred overnight. The reaction was quenched
with 1.0 M HCl and the aqueous layer extracted with Et2O (3 ꢀ 50
13C NMR (100 MHz, CDCl3): d = 13.9 (CH3), 27.9 [C(CH3)3], 28.0
[2 C(CH3)3], 30.2 (C3), 43.4 (C4), 56.9 (C2), 81.5 [C(CH3)3], 83.0
[2 C(CH3)3], 153.2 (2 NCO), 169.3, 203.7 (2 CO).
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

PAPER
Stereochemical Assignments of the Chlorinated Residues in Victorin C
2961
Anal. Calcd for C20H35NO7: C, 59.83; H, 8.79; N, 3.49. Found; C,
60.01; H, 8.67; N, 3.61.
TFA salt 36
1H NMR (400 MHz, D2O): d = 1.13 (d, J = 6.5 Hz, 3 H, CH3), 1.81
(ddd, J = 14.0, 9.5, 5.0 Hz, 1 H, H3), 2.27 (ddd, J = 14.0, 9.5, 4.0
Hz, 1 H, H3), 2.47 (m, 1 H, H4), 4.09 (dd, J = 9.5, 5.0 Hz, 1 H, H2),
6.02 (d, J = 3.0 Hz, 1 H, H4).
tert-Butyl (2S)-2-[Bis(tert-butoxycarbonyl)amino]-5-chloro-4-
methylpent-4-enoate (34) and tert-Butyl (2S,4R)-2-[Bis(tert-bu-
toxycarbonyl)amino]-5,5-dichloro-4-methylpentanoate (35)
Aldehyde 24 (0.3 g, 0.75 mmol) in MeOH (2 mL) was added drop-
wise to hydrazine hydrate (0.47 mL, 15 mmol) in MeOH (2 mL).
The mixture was stirred at r.t. for 2 h, a further portion of hydrazine
hydrate (0.47 mL, 15 mmol) was added and it was stirred for 1 h.
The mixture was concentrated in vacuo. Meanwhile Et3N (0.31 mL,
2.25 mmol) was added to CuCl2 (0.6 g, 4.5 mmol) in MeOH (3 mL)
and stirred for 10 min. The crude hydrazone was dissolved in
MeOH (1 mL) and added dropwise to the slurry of CuCl2 and Et3N
and stirred for 3 h, 3.5% aq NH3 soln (3 mL). EtOAc (10 mL) was
added, and the mixture washed with H2O (2 mL) and brine (2 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
column chromatography (0–10% EtOAc–PE) gave a 1:1 mixture of
34 and 35 (0.23 g). Further purification of 20 mg of the mixture by
preparative HPLC yielded dichloride 35 as a white solid (8 mg, 27%
overall) and vinyl chloride 34 as a clear oil (7 mg, 28%).
13C NMR (100 MHz, D2O + 1% TFA): d = 15.9 (CH3), 34.1 (C3),
41.4 (C4), 52.2 (C2), 79.6 (C5), 172.8 (C1).
Acid 21
[a]D23 +3.0 (c 1.0, H2O).
IR: 2940 (CH), 1591, 1510, 1402, 1071, 758 cm–1 (CCl).
1H NMR (400 MHz, D2O): d = 1.20 (d, J = 6.5 Hz, 3 H, CH3), 1.83
(ddd, J = 14.0, 9.5, 5.5 Hz, 1 H, H3), 2.25 (ddd, J = 14.0, 8.5, 4.0
Hz, 1 H, H3), 2.48 (m, 1 H, H4), 3.85 (dd, J = 9.5, 5.5 Hz, 1 H, H2),
6.10 (d, J = 3.0 Hz, 1 H, H4).
13C NMR (100 MHz, D2O): d = 17.7 (CH3), 35.9 (C3), 42.7 (C4),
55.4 (C2), 81.0 (C5), 176.5 (C1).
MS (ESI): m/z (%) = 204 (12), 202 (67), 200 ([M + H]+, 100).
HRMS (ESI): m/z [M + H]+ calcd for C6H12Cl2NO2: 200.0240;
found: 200.0245.
Dichloride 35
Mp 68–69 °C (Lit.12 mp 60 °C).
[a]D23 –22.0 (c 1.0, CHCl3) [Lit.12 –14.3 (c 0.465, CH2Cl2)].
Acknowledgment
IR: 2979 (CH), 1750, 1725, 1700 (C=O), 1367 (CO), 1131, 738
cm–1 (CCl).
We are grateful to the BBSRC for funding to A.C.D.
1H NMR (400 MHz, CDCl3): d = 1.20 (d, J = 6.5 Hz, 3 H, CH3), 1.47
[s, 9 H, C(CH3)3], 1.54 [s, 18 H, 2 C(CH3)3], 1.83 (ddd, J = 14.5, 8.5,
6.5 Hz, 1 H, H3), 2.29 (app sextet d, J = 6.5, 3.5 Hz, 1 H, H4), 2.39
(ddd, J = 14.5, 6.5, 6.0 Hz, 1 H, H3), 4.76 (dd, J = 8.5, 6.0 Hz, 1 H,
H2), 6.03 (d, J = 3.5 Hz, 1 H, H5).
References
(1) (a) Macko, V.; Wolpert, T. J.; Acklin, W.; Jaun, B.; Seibl, J.;
Meili, J.; Arigoni, D. Experientia 1985, 41, 1366.
(b) Wolpert, T. J.; Macko, V.; Acklin, W.; Jaun, B.; Seibl, J.;
Meili, J.; Arigoni, D. Experientia 1985, 41, 1524.
(c) Wolpert, T. J.; Macko, V.; Acklin, W.; Jaun, B.; Arigoni,
D. Experientia 1986, 42, 1296. (d) Gloer, J. B.; Meinwald,
J.; Walton, J. D.; Earle, E. D. Experientia 1985, 41, 1370.
(2) (a) Kono, Y.; Kinoshita, T.; Takeuchi, S.; Daly, J. M. Agric.
Biol. Chem. 1986, 50, 2689. (b) Kono, Y.; Kinoshita, T.;
Takeuchi, S.; Daly, J. M. Agric. Biol. Chem. 1989, 53, 505.
(c) Kinoshita, T.; Kono, Y.; Takeuchi, S.; Daly, J. M. Agric.
Biol. Chem. 1989, 53, 1283.
(3) Leibold, T.; Sasse, F.; Reichenbach, H.; Höfle, G. Eur. J.
Org. Chem. 2004, 431.
(4) See for example: (a) Brown, A. G.; Smale, T. C. Chem.
Commun. 1969, 1489. (b) Srinivasan, A.; Richards, K. D.;
Olsen, R. K. Tetrahedron Lett. 1976, 17, 891.
13C NMR (100 MHz, CDCl3): d = 14.5 (CH3), 28.0, 28.1
[3 C(CH3)3], 33.5 (C3), 41.1 (C4), 56.6 (C2), 78.0 (C5), 81.7, 83.4
[C(CH3)3], 152.5 (2 NCO), 169.3 (CO).
MS (ESI): m/z (%) = 482 (10), 480 (60), 478 ([M + Na]+, 90).
HRMS (ESI): m/z [M + Na]+ calcd for C20H35Cl2NNaO: 478.1734;
found: 478.1744.
Vinyl Chloride 34
[a]D23 +42.0 (c 1.0 CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.44 [s, 9 H, C(CH3)3], 1.50 [s, 18
H, C(CH3)3], 1.79 (d, J = 1.5 Hz, 3 H, CH3), 2.72 (dd, J = 14.5, 5.0
Hz, 1 H, H3), 2.79 (dd, J = 14.5, 10.5 Hz, 1 H, H3), 4.92 (dd, J =
10.5, 5.0 Hz, 1 H, H2), 5.79 (s, 1 H, H5).
(c) Morgenstern, P.; Schutij, C.; Nauta, W. T. Chem.
Commun. 1969, 321. (d) Graham, D. W.; Ashton, W. T.;
Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.;
Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem. 1987,
30, 1074.
13C NMR (100 MHz, CDCl3): d = 16.1 (CH3), 27.9, 28.0
[3 C(CH3)3], 36.7 (C3), 56.6 (C2), 81.6, 82.9 [3 C(CH3)3], 114.8
(C5), 137.0 (C4), 153.9 (NCO), 168.7 (C1).
MS (ESI): m/z (%) = 444 (33), 442 ([M + Na]+, 100), 398 (7), 96
(20), 315 (30), 284 (28), 214 (20), 147 (14).
(5) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249.
(6) Kolar, A. J.; Olsen, R. K. J. Org. Chem. 1980, 45, 3246.
(7) (a) Marshall, J. L. Methods in Stereochemical Analysis, Vol.
2; VCH: Weinheim, 1983. (b) Fischer, P.; Schweizer, E.;
Langer, J.; Schmidt, U. Magn. Reson. Chem. 1994, 32, 567.
(8) See for example: (a) Sitachitta, N.; Marquez, B. L.;
Williamson, R. T.; Rossi, J.; Roberts, M. A.; Nguyen, V.-A.;
Willis, C. L. Tetrahedron 2000, 56, 9103. (b) Su, J.-Y.;
Zhong, Y.-L.; Zheng, L.-M.; Wei, S.; Wong, Q.-W.; Mak, T.
C. W.; Zhou, Z.-Y. J. Nat. Prod. 1993, 56, 637. (c) Unson,
M. D.; Rose, C. B.; Fulkner, D. J.; Brinen, L. S.; Steiner, J.
R.; Clardy, J. J. Org. Chem. 1993, 58, 6336.
HRMS (ESI): m/z [M + Na]+ calcd for C20H34ClNO6Na: 442.1967;
found: 442.1981.
(2S,4R)-5,5-Dichloroleucine Trifluoroacetic Acid Salt (36)12 and
(2S,4R)-5,5-Dichloroleucine (21)
Dichloro ester 35 (5 mg, 10 mmol) was dissolved in TFA and stirred
for 1 h. The mixture was concentrated in vacuo to give 36 (3 mg,
100%) as a white solid.
Subsequent purification by ion exchange chromatography gave
(2S,4R)-5,5-dichloroleucine (21) (2 mg, 100%) as a white solid; mp
195–196.
(9) (a) Ardá, A.; Jiménez, C.; Rodríguez, J. Tetrahedron Lett.
2004, 45, 3241. (b) Ardá, A.; Soengas, R. G.; Nieto, M. I.;
Jiménez, C.; Rodríguez, J. Org. Lett. 2008, 10, 2175.
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York

2962
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(10) Durow, A. C.; Long, G. C.; O’Connell, S. J.; Willis, C. L.
Org. Lett. 2006, 8, 5401.
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(12) Ardá, A.; Jiménez, C.; Rodríguez, J. Eur. J. Org. Chem.
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(13) Takeda, T.; Sasaki, R.; Yamaguchi, S.; Fujiwara, T.
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(14) Charrier, J.-D.; Duffy, J. E. S.; Hitchcock, P. B.; Young, D.
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(18) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(19) The optical rotation has not been reported for 5,5-
dichloroleucine isolated following degradation of the
victorins,1,2 hence the absolute stereochemistry is assumed
from the earlier reported ORD shifts of the 2,4-DNP
derivatives.2
(20) Richards, K. D.; Kolar, A.; Srinivasan, A.; Stephenson, R.
W.; Olsen, R. K. J. Org. Chem. 1976, 41, 3674.
Synthesis 2009, No. 17, 2954–2962 © Thieme Stuttgart · New York