Beyond the chiral pool: A general approach to β-amino-α-keto amides

Article abstract of DOI:10.1016/j.tet.2010.11.018

A simple route was developed for the synthesis of optically enriched β-amino-α-keto amides. The highly diastereoselective addition of alkyl dithiolanecarboxylates to optically enriched sulfinimines affords the corresponding β-amino-α-keto esters in which

Full text of DOI:10.1016/j.tet.2010.11.018

Tetrahedron 67 (2011) 41e47
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Beyond the chiral pool: a general approach to
b-amino-
a
-keto amides
y
*
Cristian L. Harrison, Mariusz Krawiec, Raymond E. Forslund , William A. Nugent
Chemical Development Department, Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2010
Received in revised form 28 October 2010
Accepted 2 November 2010
Available online 6 November 2010
A simple route was developed for the synthesis of optically enriched b-amino-a-keto amides. The highly
diastereoselective addition of alkyl dithiolanecarboxylates to optically enriched sulfinimines affords the
corresponding -amino- -keto esters in which the ketone carbonyl group is protected as a dithiolane.
b
a
Amidation of the ester functionality with a primary amine proceeds readily at room temperature.
Treatment with HCl cleaves the NeS bond of the sulfinyl group to provide a free amine functionality,
which can then be incorporated into a peptide. Removal of the dithiolane protecting group under oxi-
dative conditions proceeds without epimerization as exemplified by a model dipeptide.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Sulfinylimine
Dithiolanecarboxylate
a
a
-Ketoamide
-Ketoester
Stereoselective synthesis
1. Introduction
Nevertheless, manufacture of drugs containing this functional-
ity pattern as a single diastereomer is potentially advantageous.
Peptidyl
a
-keto amides are broadly useful in medicinal chem-
Peptidyl b-amino-a-keto amides do not epimerize under the acidic
istry because they can serve as potent inhibitors of proteolytic
enzymes such as serine and cysteine proteases. One example of
a cellular target is thrombin, a serine protease that converts fi-
brinogen to fibrin.1 Others include calpain, a calcium-activated
cysteine protease that has been implicated in stroke, Alzheimer’s
disease and muscular dystrophy2 and caspase, a cysteine protease
that plays a role in apoptosis.3 An area of considerable current in-
conditions of the gut2 so that administering a single compound
rather than a mixture of substances should simplify the pharma-
cokinetics of drug uptake. Moreover, synthesis of a single di-
astereomer allows crystallization of the drug substance, expanding
options for purification and formulation.
In general, conventional routes to
b
-amino-a-keto amides rely
on the one-carbon homologation of an N-protected
a-amino acid
terest is the use of
b
-amino-
a
-keto amide peptide isosteres as viral
derivative. In older versions of this approach, the carbon nucleo-
phile is cyanide6 or an isonitrile;7 however, using such nucleophiles
the reaction is not stereoretentive. Wasserman and co-workers
disclosed an improved route utilizing a (cyanomethylene)phos-
phorane as a nucleophile followed by ozonolysis of the resulting
Wittig type intermediate.8 This procedure affords the ketoamides
in a stereoretentive fashion and has been widely embraced. In an
important recent advance, Bode and co-workers9 have demon-
strated the use of a stabilized sulfur ylide to convert a protected
amino acid or peptide to a homologated intermediate of type 1. This
procedure is especially attractive because such ylides are rapidly
protease inhibitors for the treatment of hepatitis C, which has led to
the drug candidates telaprevir4 and boceprevir.5
Peptidyl b-amino-a-keto amides are expected to undergo epi-
merization under mildly basic physiological conditions.2 Indeed,
the HCV drug candidate boceprevir is manufactured as a mixture of
diastereomers5 as shown below:
O
N
N
H
N
H
O
O
NH
O
oxidized to
a-keto acids with mild and easy to handle Oxone
O
NH2
(potassium peroxymonosulfate) as shown in Eq. 1.
boceprevir
O
O
Oxone
PgHN
CN
PgHN
OH
ð1Þ
R
S
DMF/H2O
R
O
1
* Corresponding author. E-mail address: william_nugent@vrtx.com (W.A. Nugent).
y
Present address: Ironwood Pharmaceuticals, Inc., Cambridge, MA, United States.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.018

42
C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
These one-carbon homologation routes are most useful when
the required -amino acid is a readily available natural amino acid.
2. Results and discussion
a
We initially screened three commercially available thioacetal
carboxylates, namely ethyl bis(ethylthio)acetate 2, ethyl 1,3-
dithiane-2-carboxylate 3, and ethyl 1,3-dithiolane-2-carboxylate 4.
However, a potential limitation occurs when the requisite starting
material is an ‘unnatural’ (non-proteinaceous) amino acid. Such
amino acids are themselves prepared by multi-step synthetic se-
quences; some are commercially available, but in general are ex-
pensive. Consequently, we sought an alternative route to optically
S
SEt
S
OEt
OEt
OEt
S
EtS
S
enriched a-keto-b-amino amides that does not require an amino
acid starting material.
O
O
O
2
3
4
Over the last two decades, the diastereoselective addition of
carbon nucleophiles to optically enriched sulfinimines has
emerged as a premiere method for synthesizing chiral amines.
Major contributions have come from the research groups of
Davis10 and of Ellman.11 We wondered whether addition of the
anion of a suitably protected glyoxylic acid ester to a chiral sul-
Screening reactions were carried using sulfinimine 5 prepared
from (S)-tert-butylsulfininylamine and butyraldehyde16 and
LiHMDS as base (HMDS¼hexamethyldisilazide, THF, ꢁ78 ꢀC, 1 h). It
became evident that pre-generation of the thioacetal anions (es-
pecially in the case of 4) led to significant aldol type self-conden-
sation of the thioacetal starting material. Consequently, a simplified
protocol was adapted in which LiHMDS was added dropwise to
a 1:1 mixture sulfinimine and thioacetal at ꢁ78 ꢀC (Eq. 6).
finimine would provide a more general approach to b-amino-a-
keto esters (Eq. 2). The literature contains a number of examples
where addition of a sterically encumbered nucleophile to a sul-
finimine proceeds with particularly high (often >99%)
diastereoselectivity.12
O
O
O
S
O
LiHMDS
THF
S
1) base
2) H2O
O
X
O HN
S
O
S
RS
+
O HN
H
N
OEt
+
R'
ð6Þ
ð2Þ
OEt
EtO
RS SR
R'
R
N
SR
EtO
R
X
X
X
5
We elected to explore the use of glyoxylic acid esters protected
as thioacetals as the nucleophiles in Eq. 2. This choice was influ-
enced by three seminal papers from different research groups.
First, Davis and co-workers13 have shown that certain dithianes
can be added to p-tolylsulfinimines in 92e97% de (Eq. 3). We have
subsequently found that replacing the methyl group of the dithiane
in Eq. 3 with an electron-withdrawing carboxylate group greatly
retards this transformation; nevertheless, the high diaster-
eoselectivity observed by the Davis group was encouraging.
Under these conditions, thioacetal 2 gave none of the desired
adduct. In contrast, thioacetal 3 upon hydrolysis afforded the de-
sired adduct in up to 50% yield. Prolonged reaction time or higher
temperatures did not improve the conversion. We tentatively
suggest that the reaction reaches equilibrium due to reversible
addition of the relatively stable dithiane anion to the sulfinimine.
By far the best results were achieved using dithiolane 4. After
hydrolytic workup, the desired adduct could be isolated in >90%
yield and the diastereomer ratio (dr) was 99:1. The stereochemistry
of the predominant diastereomer was initially assigned as S,SS by
analogy to the dithiane additions of Davis13 and this was sub-
sequently confirmed by an X-ray crystal structure (see below). This
stereochemical result is consistent with the closed transition state
model proposed by Ellman.17
O
1) -78 oC
Li Me
S
O
S
HN
Tol
+
ð3Þ
S
S
S
Tol
R
N
R
2) H2O
S
Based on these results, we explored the scope of the addition
of dithiolane 4 to sulfinimines. We examined the effect of a va-
riety of solvents and bases as well as the effect of the groups R, R0,
and R00 for the general reaction shown in Eq. 7. Results are
summarized in Table 1. In all cases, diastereoselectivity was ex-
cellent; for reactions utilizing tert-butylsulfinimines the dr was
consistently at least 99:1.
The solvent THF used in the screening studies could be
replaced by other ethereal solvents such as methyl tert-butyl ether
(MTBE) or 2-methyltetrahydrofuran (entries 2 and 8). However,
the use of a less polar solvent toluene (entry 3) led to a signifi-
cantly reduced conversion. A variety of alternative alkali metal
bases provided the desired sulfinamide in good yield and dia-
stereoselectivity. Effective bases included hexynyllithium, LDA
(lithium diisopropylamide), and NaHMDS (entries 4e6) while
KHMDS (entry 7) gave a lower conversion. (This may reflect the
use of KHMDS as a commercial solution in toluene.) A particularly
attractive alternative in terms of ease of handling is potassium
tert-butoxide (entries 11e13) and this base should prove useful in
larger scale applications.
Secondly, Powers and co-workers14 have demonstrated that
a-
keto esters, after protection as dithiolanes, undergo remarkably
facile amidation reactions (Eq. 4). When the R0 group of the
amine is sterically small, these reactions were found to proceed
even at 0 ꢀC.
PG
R
PG
R
R'NH2
0 oC
NH O
NH O
ð4Þ
OEt
NHR'
S
S
S
S
Finally, Papanikos and Meldal15 reported that optically enriched
-amino- -keto amides could be protected as dithiolane de-
rivatives and subsequently deprotected without epimerization at
the nitrogen-bearing -carbon. Deprotection was accomplished in
an oxidative fashion using NBS in 10% aqueous acetone (Eq. 5).
b
a
b
PG
R
PG
R
NBS
NH O
NH O
O
As expected, substitution on the aliphatic side-chain of the
sulfinimine was well tolerated. In the case of entry 10, it was noted
that when the reaction was re-run at 0 ꢀC using LiHMDS as base,
a 3:2 mixture of diastereomers 9a and 9b was formed. These
ð5Þ
NHR'
NHR'
S
S
H2O/acetone

C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
43
Not surprisingly, changing the ester substituent R00 from ethyl
to methyl (entry 15) had minimal impact and afforded 11 as
expected. However, when the ester moiety of dithiolane 4 was
replaced by a secondary amide, as exemplified by the N-methyl-
N-benzyl derivative, no addition was observed. Therefore it was
of interest to explore the conversion of the product esters to the
corresponding amides.
Table 1
Effect of reaction parameters on yield for Eq. 7a
,
Entry
R
Product
Solvent
Base
% Yieldb
1
n-Propyl
6
THF
LiHMDS
92
100
42c
97
2
3
4
n-Propyl
n-Propyl
n-Propyl
6
6
6
MTBE
Toluene
THF
HexynylLi
LDA
5
n-Propyl
6
THF
95c
96
Consistent with the literature report,14 this amidation could be
carried out at room temperature in an alcoholic solvent. Commer-
cial 33% methylamine in ethanol was conveniently employed for
the examples in Eq. 8. In all cases, the reaction was complete in 16 h
at room temperature.
6
n-Propyl
6
THF
NaHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
KOt-Bu
KOt-Bu
KOt-Bu
LiHMDS
LiHMDS
7
8
9
10
11
12
13
14
15
n-Propyl
6
7
8
9a
6
THF/toluene
2-MeTHF
THF
THF
THF
THF
THF
THF
THF
71c
83
Cyclopropylmethyl
2-Naphthyl
Isobutyl
78d,e
95
n-Propyl
96d
95d
93d
91d
95d
Cyclopropylmethyl
Isobutyl
7
9a
10
11
O
S
O
S
Isobutylf
MeNH2
EtOH
Isobutylg
O HN
O HN
R'
R'
a
EtO
R
MeHN
R
Unless otherwise indicated, R0¼tert-butyl; R00¼ethyl; see text for reaction
S
S
S
S
conditions.
ð8Þ
b
c
d
e
f
Isolated yield after vacuum drying.
Product not isolated; reported value is percent conversion of sulfinimine.
Yield after flash chromatography.
Sulfinimine of 15% was recovered.
R0¼p-tolyl.
12a, R = Pr; R' = t-Bu, 98%
12b, R = i-Bu; R' = t-Bu, 96%
12c, R = cycPrCH2; R' = t-Bu, 97%
12d, R = i-Bu; R' = p-tolyl, 59%
g
R00¼methyl.
In the case of sterically encumbered cyclopropylamine, the
analogous reaction proved sluggish and an alternative approach
was developed. Ester 6 was first hydrolyzed to the corresponding
acid 13 using lithium hydroxide (25 ꢀC, 4.5 h). Acid 13 was then
coupled to the amine using n-propylphosphonic anhydride (T3P) as
shown in Eq. 9. Extractive workup provided amide 14 in 84% overall
yield for the two steps.
O
S
O
O
S
O HN
base
R'
ð7Þ
+
S
OR"
R"O
R
R'
R
N
S
S
S
diastereomers could be separated by flash chromatography, pro-
viding a reference standard of the (R,SS) diastereomer 9b (In con-
trast, use of potassium tert-butoxide at 0 ꢀC gave a complex mixture
of products.).
O
S
O
S
T3P
O HN
O HN
NH2
+
ð9Þ
HO
N
DCM
88%
S
S
S
S
H
O
S
O
S
14
13
O HN
O HN
EtO
EtO
S
S
S
S
The amidation product 12d proved to be a crystalline solid,
which provided an opportunity to confirm the stereochemistry of
the initial sulfinimine addition. As a result of the presence of three
strongly diffracting sulfur atoms the structure refined remarkably
well (R1¼2.25% and wR2¼6.22%). The resulting high resolution
9a
9b
Addition to an aromatic sulfinimine, namely R¼2-naphthyl
(entry 9), also proceeded in 99:1 dr. The conversion was
somewhat lower than that for the aliphatic sulfinimines; how-
ever, the product was readily isolated as a single diastereomer
by flash chromatography. Entry 14 examines the effect of
replacing the tert-butyl group of the sulfinimine with a p-tolyl
substituent. In this case the dr was lower (98:2); however, we
anticipate that such p-tolylsulfinyl derivatives may have
a higher tendency to exist as crystalline solids when compared
to their tert-butyl counterparts, which could prove advanta-
geous when working at larger scale. In this case the ethyl ester
10 was an oil but the corresponding N-methylamide 12d was
crystalline (see below).
ꢀ
(0.83 A) taken together with anomalous scattering data, confirmed
that both stereocenters possess the S configuration. The molecular
structure is shown in Fig. 1.
O
S
O
S
O HN
O HN
Tol
EtO
MeO
S
S
S
S
10
11
Fig. 1. Molecular structure of dithiolane amide 12d showing S,SS stereochemistry.

44
C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
Cleavage of the SeN bond to remove the sulfinyl group in the
25 ꢀC). These were shown15 by variable temperature NMR to arise
from the presence of two amide conformers.
product sulfinamides was readily accomplished by treatment with
4 N HCl in dioxane (Eq. 10). Upon addition of the resulting solution
to diethyl ether, the amine hydrochloride salt precipitated and
could be collected by filtration. In general, these hydrochlorides
proved mildly hygroscopic. However, in the case of 15a the product
was deliquescent and changed from a white powder to a yellow
gum during attempted isolation by filtration. Consequently it was
not possible to obtain suitable elemental analysis for this com-
pound. The remaining products were obtained in useful yields and
purity.
Finally, we note that our protocol is particularly well-suited for
the preparation of deuterium-labeled
b-amino-a-keto amides
bearing deuterium at the position. For example, deuterium-la-
b
beled 2-naphthylcarboxaldehyde was conveniently prepared from
the Weinreb amide using chemistry developed by Georg and co-
workers19 (Eq. 12).
O
Cp2ZrDCl
98%
O
Me
ð12Þ
N
D
OMe
O
O
S
NH3Cl
S
4N HCl
O HN
The aldehyde was converted to the tert-butylsulfinimine in the
usual manner.16 Addition of ethyl dithiolanecarboxylate proceeded
as in the case of the protio analogue 8 and afforded 18 in >98%
isotopic purity (Eq. 13).
R'HN
R
S
R'HN
R
dioxane
S
S
ð10Þ
15a, R = Pr; R' = Me
15b
, R = i-Bu; R' = Me, 93%
15c, R = cycPrCH2; R' = Me, 88%
D
O
S
O
15d
, R = Pr; R' = cycPr, 69%
S
N
OEt
+
S
It has been shown that dithiolane-protected peptidyl
-keto amides can be deprotected with NBS without epimeriza-
b
-amino-
LiHMDS
a
O
S
ð13Þ
tion.15 Since the earlier work involved polymer-supported pep-
tides, we felt it was worthwhile to confirm this result in the
solution phase. Dozens of reagents and protocols have been
reported for removal of the dithiolane protecting group.18 How-
ever, neighboring electron-withdrawing functionality in the
dithiolanes of the present study makes them less susceptible to-
ward oxidative cleavage. Nevertheless, NBS and DBDMH13b (1,3-
dibromo-5,5-dimethylhydantoin) both proved to be suitable re-
agents for this deprotection. Although these two reagents per-
formed comparably, an advantage of the latter is that less
hydantoin side-product is formed, thereby simplifying extractive
workup.
HN
74%
D
EtO2C
S
S
18
3. Conclusion
Taken together, the two-step dithiolane addition/amidation
sequence provides a straightforward approach to the synthesis of
protected
high yield and purity. A particular advantage of this approach is that
it does not derive its chirality from an -amino acid, providing
b-amino-a-keto amides and affords these compounds in
The protected dipeptide 16 was conveniently prepared by
treating dithiolane amide 15c with Cbz-proline using HOBT/EDCl as
coupling reagent (HOBT¼1-hydroxybenzotriazole, EDCl¼N-(3-
dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride). Hy-
drolytic workup provided 16 as a white foam, which retained some
solvent. The protected dipeptide was then treated with 4 equiv of
1,3-dibromo-5,5-dimethylhydantoin in 10% aqueous acetonitrile
(Eq. 11). Aqueous workup and vacuum drying provided the
deprotected dipeptide 17 as a white waxy solid in 64% overall yield
for two steps.
a
a broad scope and equally ready access to the (R)- and (S)-enan-
tiomers. The products can be elaborated into peptide structures and
deprotected under oxidative conditions without epimerization.
4. Experimental
4.1. General
Commercial anhydrous tetrahydrofuranwasused asreceived. The
starting tert-butylsulfinimines used in this study are known com-
pounds, which were prepared following Ellman’s protocol16 (copper
sulfate-promoted condensation) and purified by flash chromatog-
raphy in 5:1 hexanes/ethyl acetate. The tolyl sulfinimine starting
material used in the preparation of 10 was prepared according to the
literature procedure.20 All other materials were reagent grade
chemicals used asreceived. Flashchromatography was carried outon
H
N
H
N
S
S
N
O
Bn
DBDMH
MeCN/H2O
O
O
O
64%
Bn
17
ð11Þ
16
O
H
N
H
N
21
ꢀ
N
O
60 A silica gel following the procedure of Still and co-workers.
Glassware used in the sulfinimine additions was not flame dried
but was flushed with dry nitrogen for 30 min prior to use. 1H and 13
O
O
O
C
NMR were obtained on a Bruker Avance 400 or Avance 500 NMR
spectrometer. Coupling constants J are given in hertz.
Consistent with the report of Papanikos and Meldal,15 dipeptide
17 was homogeneous on several HPLC columns. Given the presence
of two stereogenic centers in 17, this indicates that deprotection
4.2. Synthesis
proceeds without epimerization at the nitrogen-bearing
b
-carbon
4.2.1. Addition of alkyl dithiolanecarboxylates to sulfinimines
atom. Also in accord with the earlier studies, the 1H and 13C NMR
spectra of both the protected dipeptide 16 and deprotected 17
showed two sets of resonances (approximately 60:40 ratio at
4.2.1.1. Ethyl (S,SS)-2-[1-tert-butylsulfinylamino]butyl-1,3-dithio-
lanecarboxylate, 6. A flask was charged with a solution of ethyl 1,3-

C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
45
dithiolanecarboxylate (713 mg, 4.00 mmol) and [N(E),S(S)]-2-
methyl-N-(butylidene)-2-propanesulfinamide (701 mg, 4.00 mmol)
in tetrahydrofuran (10 mL) under a nitrogen atmosphere. The solu-
tion was cooled to ꢁ78 ꢀC whereupon a 1.0 M solution of potassium
tert-butoxide in THF (5.00 mL, 5.00 mmol) was added dropwise. The
mixture was stirred an additional 1 h at ꢁ78 ꢀC and was then added
to half-saturated aqueous ammonium chloride (100 mL) and the
product was extracted into ethyl acetate (50 mL then 25 mL). The
organic phase was dried over magnesium sulfate, the solvent was
distilled at reduced pressure, and the residue was dried in high
vacuum to afford 6 as a colorless liquid. HPLC analysis and NMR
indicate the product is >99% a single diastereomer. The crude
product is >97% AUC by HPLC and should be suitable for most
synthetic applications. Nevertheless the product was purified by
flash chromatography in 4:1 ethyl acetate/hexanes (Rf¼0.31) to af-
ford analytically pure 6 (1.36 g, 96%). 1H NMR (400 MHz, CDCl3):
4.2.1.6. Methyl (S,SS)-2-[1-tert-butylsulfinylylamino]-3-methyl-
butyl-1,3-dithiolanecarboxylate, 11. Colorless oil (95%). Rf¼0.34 in
4:1 ethyl acetate/hexanes. 1H NMR (C6D6):
d
0.73 (d, J¼6.5, 3H), 0.77
(d, J¼6.5, 3H), 0.98 (s, 9H), 1.26 (m, 1H), 1.51 (m, 1H), 1.80 (m, 1H),
2.82e3.92 (m, 3H), 3.10e3.16 (m, 1H), 3.36 (s, 3H), 3.77 (d, J¼9.6,
1H), 4.03 (td, J¼10.0, 1.8, 1H). 13C NMR (C6D6):
d 21.0, 22.8, 24.0,
25.2, 40.4, 40.2, 45.0, 52.9, 56.6, 61.0, 77.1, 171.7. Anal. Calcd for
C14H27NO3S3: C, 47.56; H, 7.70; N, 3.96. Found: C, 47.77; H, 7.56; N,
3.94.
4.2.1.7. Ethyl
(R,SS)-2-[1-tert-butylsulfinylylamino]-3-methyl-
butyl-1,3-dithiolanecarboxylate, 9b. A solution of ethyl 1,3-dithio-
lanecarboxylate (360 mg, 2.02 mmol) and [N(E),S(S)]-2-methyl-N-
(3-methylbutylidene)-2-propanesulfinamide (380 mg, 2.01 mmol)
in THF (8.0 mL) was cooled to 0 ꢀC. A 1.0 M solution of lithium bis
(trimethylsilyl)amide in THF (2.5 mL, 2.5 mmol) was added drop-
wise and stirring was continued for 15 min at 0 ꢀC. The solution was
added to 50 mL of half-saturated aqueous ammonium chloride and
the product was extracted into ethyl acetate (2ꢂ25 mL). The or-
ganic extracts were dried over sodium sulfate and the solvent was
distilled at reduced pressure to afford 0.89 g of a pale yellow liquid,
which contained two principal components by NMR. Flash chro-
matography in 4:1 ethyl acetate/hexanes allowed the separation of
9b (150 mg, Rf¼0.55) from its lower Rf diastereomer 9a (190 mg,
Rf¼0.37). Compound 9b was a pale yellow solid. 1H NMR (400 MHz,
d
0.82 (t, J¼7, 3H), 1.19 (s, 9H), 1.23 (t, J¼7, 3H), 1.23e1.58 (m, 4H),
3.22e3.42 (m, 4H), 3.70 (m, 1H), 3.81 (m, 1H), 4.19 (q, J¼7, 2H). 13C
NMR (100 MHz, CDCl3):
d 13.5, 13.9, 20.0, 22.1, 37.8, 39.95, 39.98,
56.9, 61.7, 62.3, 76.24, 171.00. Anal. Calcd for C14H27NO3S3: C, 47.56;
H, 7.70; N, 3.96. Found: C, 47.71; H, 7.58; N, 7.64.
4.2.1.2. Ethyl
(S,SS)-2-[(1-tert-butylsulfinylamino)-2-cyclo-
propylethyl]-1,3-dithiolane-2-carboxylate, 7. Colorless oil (95%).
Rf¼0.33 in 4:1 ethyl acetate/hexanes. 1H NMR (500 MHz, DMSO-d6):
d
5.05 (d, J¼12.7, 1H), 4.14e4.07 (m, 2H), 3.82 (t, J¼7.2, 1H), 3.44e3.36
C6D6):
d
0.89 (d, J¼6.7, 3H), 0.94 (t, J¼7.1, 3H), 1.05 (J¼6.3, 3H), 1.11
(m, 3H), 3.30e3.19 (m, 2H), 1.21e1.16 (m, 3H), 1.11 (s, 9H), 0.98e0.94
(m, 2H), 0.48e0.36 (m, 1H), 0.35e0.30 (m, 1H), 0.11e0.08 (m, 1H),
ꢁ0.036 to ꢁ0.09 (m, 1H). 13C NMR (125 MHz, DMSO-d6): 168.6, 74.5,
60.8, 60.0, 54.3, 48.6, 36.5, 36.3, 20.8, 12.0, 7.2, 3.9, 2.5. Anal. Calcd for
C15H27NO3S3: C, 49.28; H, 7.44; N, 3.83. Found: C, 49.41; H, 7.35; N,
3.72.
(s, 9H), 1.61e1.70 (m, 1H), 1.79e1.88 (m, 1H), 2.45 (m, 1H),
2.72e2.83 (m, 2H), 2.91e3.01 (m, 2H), 3.84e4.00 (m, 3H), 4.13 (t,
J¼9.2, 1H). 13C NMR (100 MHz, C6D6):
d 13.8, 21.4, 22.9, 24.10, 24.12,
39.8, 40.1, 45.0, 56.6, 62.0, 63.0, 76.9, 171.5. Anal. Calcd for
C15H29NO3S3: C, 49.01; H, 7.95; N, 3.81. Found: C, 49.27; H, 8.01; N,
3.91.
4.2.1.3. Ethyl
methyl]-1,3-dithiolane-2-carboyxlate, 8. Colorless oil (78%). Rf¼0.35
in 2:1 ethyl acetate/hexanes. 1H NMR (500 MHz, CDCl3):
1.10 (s,
2-(S,SS)-[(tert-butylsulfinylamino)-(2-naphthyl)
4.2.2. Amidation reactions
d
4.2.2.1. (S,SS)-2-[1-(tert-Butylsulfinylamino)butyl]-N-methyl-1,3-
dithiolane-2-carboxamide, 12a. A heavy-walled glass tube was
charged with ethyl (S,SS)-2-[1-(tert-butylsulfinylamino)butyl]-1,3-
dithiolane-2-carboxylate (0.50 g, 1.4 mmol) and a chilled 8.0 M
solution of methylamine in ethanol (5 mL, 40 mmol). The mixture
was allowed to warm to room temperature and was allowed to
stand for 16 h. Distillation of the solvent at reduced pressure
afforded 12a (0.47 g, 98%) as a viscous amber-colored oil. 1H NMR
9H), 1.12 (t, J¼7.3, 3H), 3.14e3.27 (m, 4H), 4.04 (m, 2H), 4.52 (d,
J¼5.4, 1H), 5.19 (d, J¼5.4, 1H), 7.36e7.41 (m, 2H), 7.49 (m, 1H),
7.68e7.74 (m, 3H), 7.79 (s, 1H). 13C NMR (125 MHz, CDCl3):
d 13.9,
22.5, 40.1, 40.4, 56.3, 62.8, 63.7, 77.0, 126.17, 126.24, 126.4, 127.6,
127.8, 128.2, 128.9, 132.8, 133.5, 135.0, 170.2. Anal. Calcd for
C21H27NO3S3: C, 57.63; H, 6.22; N, 3.20. Found: C, 57.71; H, 6.18; N,
3.35.
(500 MHz, CD3OD):
(m, 1H), 1.59 (m, 1H), 2.75 (s, 3H), 3.19 (m, 2H), 3.40 (m, 2H), 3.91
(m, 1H). 13C NMR (125 MHz, CD3OD):
14.2, 21.3, 24.7, 27.4, 37.8,
41.0, 41.2, 58.4, 64.7, 78.7, 174.2. Anal. Calcd for C13H26N2O2S3: C,
46.12; H, 7.74; N, 8.27. Found: C, 45.99; H, 7.83; N, 8.39.
d
0.89 (t, J¼7, 3H), 1.22 (s, 9H), 1.34 (m, 1H), 1.50
4.2.1.4. Ethyl
butyl-1,3-dithiolanecarboxylate, 9a. Pale yellow oil (93%). Rf¼0.37 in
4:1 ethyl acetate/hexanes. 1H NMR (C6D6):
(S,SS)-2-[1-tert-butylsulfinylylamino]-3-methyl-
d
d
0.72 (d, J¼7, 3H), 0.79
(d, J¼7, 3H), 0.89 (t, J¼7, 3H), 0.98 (s, 9H), 1.28 (m, 1H), 1.50 (m, 1H),
1.81 (m, 1H), 3.80e3.94 (m, 3H), 3.15 (m, 1H), 3.75 (m, 1H), 3.92 (q,
J¼7, 2H), 4.07 (m, 1H). 13C NMR (C6D6):
d
12.0, 19.1, 20.7, 22.0, 23.2,
4.2.2.2. (S,SS)-2-[1-(tert-Butylsulfinylamino)-3-methylbutyl]-N-
methyl-1,3-dithiolane-2-carboxamide, 12b. Straw-colored liquid
38.3, 38.4, 43.3, 54.7, 58.9, 60.3, 75.3, 169.2. Anal. Calcd for
C15H29NO3S3: C, 49.01; H, 7.95; N, 3.81. Found: C, 49.15; H, 7.97; N,
3.69.
(96%).1HNMR (400 MHz,CD3OD):
d
0.89(t, J¼6.5, 6H),1.23 (sþm,10H
total), 1.55 (m, 1H), 1.84 (m, 1H), 3.29 (m, 2H), 3.40 (m, 2H), 4.02 (d,
J¼10.6, 1H). 13C NMR (100 MHz, CD3OD):
d 21.4, 23.4, 24.4, 25.9, 27.4,
4.2.1.5. Ethyl (S,SS)-2-[4-methylphenylsulfinylamino]-3-methyl-
butyl-1,3-dithiolanecarboxylate, 10. Pale yellow oil (91%). HPLC
analysis indicated that the product consisted of two diastereomers
in a 98:2 ratio. For the major diastereomer, Rf¼0.31 in 1:1 ethyl
40.9, 41.2, 44.8, 58.4, 68.1, 78.8,174.2. Anal. Calcd for C14H28N2O2S3: C,
47.71; H, 8.01; N, 7.95. Found: C, 47.68; H, 7.90; N, 7.86.
4.2.2.3. (S,SS)-2-[1-(tert-Butylsulfinylamino)-2-cyclopropylethyl]-
N-methyl-1,3-dithiolane-2-carboxamide, 12c. Amber glass (97%). 1H
NMR (500 MHz, DMSO-d6): d 7.38 (s, 1H), 4.06e4.00 (m, 2H),
acetate/hexanes. 1H NMR (500 MHz, CDCl3):
d
0.80 (d, J¼6.5, 3H),
0.85 (d, J¼6.5, 3H), 1.17 (td, J¼7.1, 1.9, 3H), 1.41 (m, 1H), 1.79 (m, 1H),
2.14e2.25 (m, 1H), 2.27 (s, 3H), 3.15e3.34 (m, 4H), 3.93e4.04 (m,
1H), 4.11 (q, J¼7.1, 2H), 4.36 (d, J¼9.7, 1H), 7.16 (d, J¼8.1, 2H), 7.49 (d,
3.97e3.88 (m, 1H), 3.45e3.40 (m, 1H), 3.34e2.95 (m, 2H), 2.77 (s,
3H), 1.60e1.54 (m, 1H), 1.15 (s, 9H), 1.05e0.99 (m, 1H), 0.83e0.74
(m, 1H), 0.46e0.40 (m, 1H), 0.35e0.30 (m, 1H), 0.06 to ꢁ0.03 (m,
J¼8.1, 2H). 13C NMR (125 MHz, CDCl3):
d 13.9, 20.9, 21.3, 23.8, 24.9,
39.99, 40.02, 44.7, 60.9, 62.5, 76.1, 125.3, 129.3, 141.2, 144.0, 171.0.
Anal. Calcd for C18H27NO3S3: C, 53.83; H, 6.78; N, 3.49. Found: C,
53.93; H, 6.71; N, 3.57.
2H). 13C NMR (125 MHz, DMSO-d6):
d 171.0, 77.2, 63.2, 56.0, 40.1,
39.9, 26.8, 22.5, 9.1, 5.9, 4.1. Anal. Calcd for C14H26N2O2S3: C, 47.97;
H, 7.48; N, 7.99. Found: C, 47.73; H, 7.62; N, 7.99.

46
C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
4.2.2.4. (S,SS)-2-[1-(4-Methylphenylsulfinylamino)-3-methyl-
butyl]-N-methyl-1,3-dithiolane-2-carboxamide, 12d. White crystals
(59%), mp 147e154 ꢀC. 1H NMR (500 MHz, DMSO-d6):
0.83 (d,
4.2.3.3. (S)-2-[1-Aminobutyl]-N-cyclopropyl-1,3-dithiolane-2-
carboxamide hydrochloride, 15d. Pale yellow solid (69%). 1H NMR
d
(500 MHz, CD3OD):
1.34e1.73 (m, 4H), 2.68 (m,1H), 3.36e3.63 (m, 4H), 3.91 (m,1H). 13C
NMR (125 MHz, CD3OD): 6.7, 6.9, 14.2, 20.7, 24.6, 35.3, 41.2, 42.0,
d
0.61 (m, 2H), 0.76 (m, 2H), 0.93 (t, 3H, J¼7),
J¼6.5, 3H), 0.84 (d, J¼6.5, 3H), 1.12 (m, 1H), 1.50 (m, 1H), 1.82 (m,
1H), 2.36 (s, 3H), 2.61 (s, 3H), 3.16e3.39 (m, 4H), 4.01 (dd, J¼10.6,
1.9, 1H), 7.33 (d, J¼8.1, 2H), 7.52 (d, J¼8.1, 2H). 13C NMR (125 MHz,
d
58.2, 74.8, 173.2. Anal. Calcd for C11H21ClN2OS2: C, 44.50; H, 7.13; N,
9.44. Found: C, 44.58; H, 6.92; N, 9.64.
DMSO-d6):
d 20.76, 20.87, 23.64, 23.71, 26.6, 42.5, 60.4, 77.5, 125.2,
129.1, 140.1, 144.0, 170.8. Anal. Calcd for C17H26N2O2S3: C, 52.82; H,
6.78; N, 7.25. Found: C, 52.70; H, 6.80; N, 7.47.
4.3. Applications
4.2.2.5. (S,SS)-2-[1-(tert-Butylsulfinylamino)butyl]-N-cyclo-
propyl-1,3-dithiolanecarboxamide, 14. A flask was charged with
dithiolane ester 6 (1.41 g, 4.00 mmol), methanol (9.6 mL), and water
(1.6 mL). Lithium hydroxide (0.19 g, 7.93 mmol) was added and the
mixturewas stirred for 4.5 h at room temperature, after which it was
added to water (25 mL) and was acidified with 1 N HCl (9.0 mL,
9.0 mmol). The product was extracted into dichloromethane
(2ꢂ20 mL) and was dried over sodium sulfate. Removal of the sol-
vent at reduced pressure afforded (S,SS)-2-[1-tert-butylsulfinyla-
mino]butyl-1,3-dithiolanecarboxylic acid 13 (1.14 g, 88%) as a crisp
4.3.1. Preparation of dipeptide 17
1-Hydroxybenzotriazole (2.25 g, 14.7 mmol), N-methyl-
morpholine (2.97 g, 29.4 mmol), N-(3-dimethylaminopropyl)-N0-
ethylcarbodiimide hydrochloride (3.94 g, 20.6 mmol), and dithio-
lane amide 15c (5.08 g, 90% purity, 16.2 mmol) were added in that
order to
a
cooled (0e5 ꢀC) solution of CBz-proline (3.70 g,
14.7 mmol) in dichloromethane (37 mL). The mixture was stirred
overnight (18 h) and then quenched with water (37 mL). After
phase separation, the organic phase was washed with NaHCO3 (5%
w/w solution, 36 mL) and HCl (1 M solution, 36 mL) and then
concentrated by rotary evaporation. The mixture was dried under
high vacuum, furnishing dithiolane-protected dipeptide 16 as
a white foam, which retained 15% of ethyl acetate by NMR. This
material was used in the subsequent step without further purifi-
off-white solid. 1H NMR (500 MHz, CDCl3):
d
0.82 (t, J¼7.0, 3H),
1.12e1.35 (m, 2H), 1.19 (s, 9H), 1.51 (m, 2H), 3.32e3.63 (m, 4H), 3.74
(m, 1H), 4.59 (d, J¼9.8, 1H). 13C NMR (125 MHz, CDCl3):
d 13.6, 20.5,
22.9, 38.1, 40.12, 40.14, 57.7, 63.5, 75.5, 173.7. A flask was charged
with a portion of this material (0.94 g, 2.9 mmol), triethylamine
(2.4 mL, 17 mmol), and dichloromethane (9.4 mL). The mixture was
cooled to 0 ꢀC and a 50% w/w solution of propylphosphonic anhy-
dride in ethyl acetate (2.76 g, 4.3 mmol) was added. After 1 h at 0 ꢀC,
cation. 1H NMR (500 MHz, DMSO-d6):
d 8.00e8.05 (m, 1H),
7.50e765 (m, 1H), 7.24e7.39 (m, 5H), 5.04e5.10 (m, 1.5H, part of
a mixture of two rotamers), 4.89 (d, 0.5H, J¼20, part of a mixture of
two rotamers), 4.65e4.74 (m,1H), 4.35e4.45 (m,1H), 3.35e3.50 (m,
2H), 3.15e3.32 (m, 4H), 2.60e2.64 (m, 3H), 2.02e2.18 (m, 1H),
1.76e1.96 (m, 3H), 1.34e1.43 (m, 1H), 1.00e1.07 (m, 0.5H, part of
a mixture of two rotamers), 0.86e0.93 (m, 0.5H, part of a mixture of
two rotamers), 0.61e0.68 (m, 0.5H, part of a mixture of two
rotamers), 0.40e0.47 (m, 0.5H, part of a mixture of two rotamers),
0.33e0.40 (m, 0.5H, part of a mixture of two rotamers), 0.22e0.28
(m, 0.5H, part of a mixture of two rotamers), 0.02e0.11 (m, 1.5H,
part of a mixture of two rotamers), ꢁ0.12eꢁ0.02 (m, 1.5H, part of
cyclopropylamine (300 mL, 4.3 mmol) was added and the mixture
was allowed to warm to room temperature overnight. The mixture
was added to 50 mL of water and the product was extracted into
dichloromethane (25 mL) and dried over sodium sulfate. Distillation
of solvent at reduced pressure afforded 14 (1.00 g, 95%) as a yellow
oil.1H NMR (500 MHz, CDCl3):
d
0.48 (m, 2H), 0.74 (d, J¼7.0, 2H), 0.81
(t, J¼6.5, 3H), 1.05e1.55 (m, 4H), 1.16 (s, 9H), 2.67 (m, 1H), 3.12e3.46
(m, 4H), 3.87 (td, J¼9.6, 2.3,1H), 4.05 (d, J¼9.5,1H), 7.43 (d, J¼2.7,1H).
13C NMR (125 MHz, CDCl3):
d 6.4, 6.6, 13.6, 20.0, 22.7, 22.9, 37.4,
39.85, 39.91, 56.9, 63.5, 77.0, 172.4. Anal. Calcd for C15H28N2O2S3: C,
49.41; H, 7.74; N, 7.68. Found: C, 49.25; H, 7.99; N, 7.79.
a mixture of two rotamers). 13C NMR (125 MHz, DMSO-d6):
d 171.7,
171.4, 170.7, 154.2, 153.9, 137.1, 128.3, 128.1, 127.7, 127.4, 126.8, 76.1,
65.8, 65.6, 59.9, 59.2, 54.7, 54.5, 47.1, 46.5, 38.3, 38.2, 31.3, 29.8, 26.9,
23.9, 22.9, 8.4, 4.8, 4.7, 4.1, 4.0. HRMS: 478.1825, calcd for
C23H32O4N3S2þHþ: 477.1829. Water (2.00 mL) and 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH, 2.34 g, 8.20 mmol) were added in
that order to a solution of 16 (1.00 g, 2.05 mmol) in acetonitrile
(20 mL), generating an orange solution. The mixture is stirred for
1 h, at which point the reaction was determined to be complete by
HPLC. Isopropyl acetate (35 mL) was added to the solution. The
mixture was washed with a solution of Na2S2O3 (4.32 g, 17.4 mmol)
in water (20 mL), after which the organic phase was colorless. The
organic phase was washed with NaHCO3 (5% w/w solution,
2ꢂ50 mL), and was analyzed by HPLC to ensure complete removal
of hydantoin by-products. The mixture was concentrated by rotary
evaporation and the resulting oil was dried under high vacuum to
yield dipeptide 17 (533 mg, 64% for two steps) as a white waxy
4.2.3. Removal of sulfinyl group
4.2.3.1. (S)-2-[1-Amino-3-methylbutyl]-N-methyl-1,3-dithiolane-
2-carboxamide hydrochloride, 15b. A 4.0 M solution of hydrogen
chloride in dioxane (21 mL, 84 mmol) was added to a flask con-
taining
(S,SS)-2-[(1-tert-butylsulfinylamino)-3-methylbutyl]-N-
methyl-1,3-dithiolane-2-carboxamide (2.43 g, 6.89 mmol). The
mixture was stirred for 1 h, was filtered to remove a trace of
cloudiness, and was added dropwise to diethyl ether (100 mL) with
stirring. The precipitate was collected by filtration and dried in high
vacuum to afford 15b (1.59 g, 93%) as a yellowish solid. 1H NMR
(500 MHz, CD3OD):
d
0.94 (d, J¼5.1, 3H), 0.96 (d, J¼5.1, 3H), 1.26 (m,
1H), 1.60 (m, 1H), 1.79 (m, 1H), 2.79 (s, 3H), 3.40e3.58 (m, 4H), 3.97
(dd, J¼9.9, 2.0, 1H). 13C NMR (125 MHz, CD3OD):
d 21.4, 24.0, 26.0,
27.6, 41.1, 41.7, 42.1, 56.6, 75.3, 172.1. Anal. Calcd for C10H21ClN2OS2:
C, 42.16; H, 7.43; N, 9.83. Found: C, 42.34; H, 7.37; N, 9.67.
solid. 1H NMR (500 MHz, DMSO-d6):
d 8.59e8.61 (m, 1H),
8.35e8.39 (m, 1H), 7.28e7.37 (m, 5H), 5.00e5.06 (m, 3H), 4.33 (dd,
0.6H, J¼8.0, 2.5, part of a mixture of two rotamers), 4.28 (dd, 0.4H,
J¼8.0, 2.5, part of a mixture of two rotamers), 3.33e3.45 (m, 2H),
2.64 (d, J¼5.0, 3H), 2.09e2.19 (m, 1H), 1.75e1.86 (m, 3H), 1.68 (ddd,
0.4H, J¼14.0, 8.0, 6.0, part of a mixture of two rotamers), 1.60 (ddd,
0.6H, J¼14.0, 8.0, 6.0, part of a mixture of two rotamers), 1.37e1.49
(m, 1H), 0.77e0.85 (m, 0.4H, part of a mixture of two rotamers),
0.65e0.73 (m, 0.5H, part of a mixture of two rotamers), 0.21e0.44
(m, 2H), ꢁ0.05 to 0.09 (m, 2H). 13C NMR (125 MHz, DMSO-d6):
4.2.3.2. (S)-2-[1-Amino-2-cyclopropylethyl]-N-methyl-1,3-dithio-
lane-2-carboxamide hydrochloride, 15c. Light yellow solid (88%),
24
mp: 75e76 ꢀC. [
a
]
ꢁ6.85 (c 2.22, H2O). 1H NMR (500 MHz,
D
CD3OD): d 3.82e3.77 (m, 1H), 3.35e3.21 (m, 4H), 3.31e3.10 (m, 1H),
2.57 (s, 3H), 1.51e1.44 (m, 1H), 1.17e1.11 (m, 1H), 0.67e0.60 (m, 1H),
0.43e0.31 (m, 2H), 0.03 to ꢁ0.11 (m, 2H). 13C NMR (125 MHz,
CD3OD):
d 171.2, 74.4, 59.4, 41.8, 41.1, 37.8, 27.5, 8.7, 6.4, 4.8. Anal.
Calcd for C10H19ClN2OS2: C, 42.46; H, 6.77; N, 9.90. Found: C, 42.57;
H, 6.70; N, 9.75.
d
196.9, 172.2, 171.9, 161.2, 161.1, 153.9, 153.7, 137.0, 136.9, 128.4,
128.1, 127.7, 127.5, 127.4, 126.9, 65.8, 59.2, 58.7, 54.5, 54.5, 47.1, 46.4,

C.L. Harrison et al. / Tetrahedron 67 (2011) 41e47
47
34.8, 31.1, 29.9, 25.4, 24.6, 23.7, 22.9, 7.9, 4.9, 4.2, 4.1. HRMS:
application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: þ44 (0)1223 336033 or email: deposit@ccdc.cam.ac.uk).
402.2021, calcd for C21H27N3O5þHþ: 402.2024.
4.3.2. Ethyl 2-(S,SS)-[(tert-butylsulfinylamino)-2-deuterio-(2-naph-
thyl)methyl]-1,3-dithiolane-2-carboxylate, 18. A flask was charged
with ethyl 1,3-dithiolane-2-carboxylate (0.23 g, 1.3 mmol) and [N
(E),S(S)]-N-[deuterio-(2-naphthyl)methylene]-2-methylpropane-
2-sulfinamide (0.33 g, 1.3 mmol) in tetrahydrofuran (5.0 mL) under
a nitrogen atmosphere. The solution was cooled to ꢁ78 ꢀC where-
upon a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF
(1.5 mL,1.5 mmol) was added dropwise. The mixture was stirred for
2 h at ꢁ78 ꢀC and was then added to half-saturated aqueous am-
monium chloride (30 mL) and the product was extracted into ethyl
acetate (2ꢂ15 mL). After drying over sodium sulfate, the solvent was
removed at reduced pressure. The crude product was purified by
flash chromatography, eluting with 4:1 ethyl acetate/hexanes. Dis-
tillation of solvent afforded 18 (0.41 g, 74%) as a colorless oil.1H NMR
References and notes
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1278.
(500 MHz, CDCl3):
d
1.10 (s, 9H),1.12 (t, J¼7.3, 3H), 3.14e3.27 (m, 4H),
4.04 (m, 2H), 4.52 (s, 1H), 7.36e7.41 (m, 2H), 7.49 (m, 1H), 7.68e7.74
(m, 3H), 7.79 (s, 1H). 13C NMR (125 MHz, CDCl3):
d 13.9, 22.5, 40.1,
40.4, 56.3, 62.8, 63.3 (1:1:1 triplet, J [2He13C]¼20.7), 77.0, 126.17,
126.24, 126.4, 127.6, 127.8, 128.2, 128.9, 132.8, 133.5, 135.0, 170.2.
4.4. X-ray crystal structure of dithiolane amide 12d
17. Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913.
18. For reviews, see: (a) Burghardt, T. E. J. Sulfur Chem. 2005, 26, 411; (b) Banerjee,
A. K.; Laya, M. S. Russ. Chem. Rev. 2000, 69, 947.
19. Spletstoser, J. T.; White, J. M.; Georg, G. I. Tetrahedron Lett. 2004, 45, 2787.
20. Kamimura, A.; Okawa, H.; Morisaki, Y.; Ishikawa, S.; Uno, H. J. Org. Chem. 2007,
72, 3569.
A suitable crystal was grown by slow evaporation of an ether/
heptane solution. Crystallographic data (excluding structure fac-
tors) for structure 12d have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC 790869. Copies of the data can be obtained, free of charge, on
21. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.