Electrophilic amination of ketone enolates mediated by the DiTOX asymmetric building block: Enantioselective formal synthesis of α-aminoacids

Article abstract of DOI:10.1016/S0040-4020(00)00923-6

Diastereoselective electrophilic amination of enolates derived from 2-acyl-1,3-dithiane 1-oxides is used as the key step for an enantioselective synthesis of two α-hydrazido carboxylic acids, well-known precursors of α-amino acids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00923-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9683±9695
Electrophilic Amination of Ketone Enolates Mediated by the
DiTOX Asymmetric Building Block: Enantioselective Formal
Synthesis of a-Aminoacids
a
a
b
Philip C. Bulman Page,a, Michael J. McKenzie, Steven M. Allin and Derek R. Buckle
*
aThe Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bSmithKline Beecham Pharmaceuticals, Yew Tree Bottom Road, Epsom, Surrey KT18 5XQ, UK
Received 24 July 2000; revised 13 September 2000; accepted 28 September 2000
AbstractÐDiastereoselective electrophilic amination of enolates derived from 2-acyl-1,3-dithiane 1-oxides is used as the key step for an
enantioselective synthesis of two a-hydrazido carboxylic acids, well-known precursors of a-amino acids. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
Sharpless,11 ceric ammonium nitrate/sodium azide,12 and
azodicarboxylate esters; indeed, the electrophilic amination
of diethylmalonate with azodicarboxylates was reported as
far back as 1924.13Oppolzer14 and Gennari15 independently
reported the asymmetric amination of chiral silyl ketene
acetals with di-tert-butylazodicarboxylate (DBAD). In the
same year, Evans16,17 and Vederas18 both published enantio-
selective approaches to a-amino acids using chiral
N-acyloxazolidinone enolates and DBAD. DBAD has a
number of advantages over other electrophilic aminating
reagents: Vederas has established that, of a series of azo-
dicarboxylate esters, the tert-butyl derivative gives some of
the highest levels of diastereofacial selectivity on reaction
with various chiral enolates: methods for the removal of the
tert-butyloxycarbonyl protecting groups under mild, non-
racemizing conditions are well established and are comple-
mentary to known methods for N±N bond cleavage; DBAD
is a stable, crystalline solid; it is available commercially.
Since then, DBAD has been used extensively as an aminat-
ing reagent for chiral enolates,19 and recently Evans has
developed a chiral magnesium bis(sulfonamide) complex
as a catalyst for the concomitant enolization and enantio-
selective amination of N-acyloxazolidinones.20 Vederas has
also synthesised chiral diazenedicarboxylate esters21 and a
chiral azodicarboxamide22 for the electophilic amination of
achiral ester and amide enolates.
1,3-Dithiane 1-oxide (DiTOX) derivatives can act as
combined chiral auxiliaries and asymmetric building
blocks. Asymmetric sulfur oxidation allows access to both
enantiomers of the acyl dithiane unit with excellent enantio-
selectivities.1 Previously we have shown that 2-acyl substi-
tuted DiTOX derivatives undergo
a
variety of
transformations with excellent diastereoselectivities,
including reactions of the derived enolates with electro-
philes.2 A chelation control model of these systems allows
us to predict the stereochemical outcome of these reactions.
We describe here the stereoselective electrophilic amination
of enolates using the DiTOX unit as the stereocontrolling
element, and application to an enantioselective formal
synthesis of a-amino acids via a-hydrazido carboxylic
acids.
Discussion
The synthesis of non-racemic amino acids, natural and
unnatural, has received considerable attention in the litera-
ture.3 Among the many methods developed, electrophilic
amination of enolates is one of the most important. Many
electrophilic aminating reagents have been employed,
including sulfonyl azides,4 diazonium salts,5 O-substituted
hydroxylamines,6 nitrosyl chloride,7 (N-tosylimino)-phenyl-
iodinane,8 N-alkoxycarbonyl oxaziridines,9 lithium tert-
butyl-N-tosyloxycarbamate,10 the aminating reagent of
a-Hydrazinocarboxylic acids are useful intermediates for
use in the synthesis of enzyme inhibitors and peptidomi-
metics.23 We report here in full the diastereoselective
amination of enolates derived from syn and anti 2-acyl-2-
alkyl-1,3-dithiane 1-oxides with DBAD,24 and we describe
the application of this process to an enantioselective synthe-
sis of a-hydrazido carboxylic acids and an enantioselective
formal synthesis of a-amino acids.
Keywords: asymmetric synthesis; aminoacid; chiral auxiliary; enolate.
* Corresponding author. Tel. 11509-222581; fax: 11509-223926; e-mail:
p.c.b.page@lboro.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00923-6

9684
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
Scheme 1.
Table 1. Acylation of 2-alkyl-1,3-dithianes
Asymmetric electrophilic amination was next examined.
The lithium enolate of (^)-anti 2-ethyl-2-propanoyl-1,3-
dithiane 1-oxide (^)-anti-4c was generated using LHMDS
(1.1 equiv.) in dry THF at 2788C and transferred via
cannula to a pre-cooled solution of DBAD (1.1 equiv.) in
THF solution at 2788C. The solution was allowed to reach
room temperature over 12 h before quenching with aqueous
ammonium chloride and normal work-up. The desired
aminated product (^)-anti-5c was isolated as a 2: 1 mixture
of inseparable diastereoisomers in 52% yield (Scheme 4).27
R
R0
Alcohol
Yield/%
Ketone
Yield/%
H
Et
2a
2b
2c
2d
2e
2f
80
92
65
65
74
52
76
97
3a
3b
3c
3d
3e
3f
77
48
67
68
98
81
82
88
Me
Me
Me
Bn
Ph
Me
Et
Ph
Et
Et
Et
Et
i-Pr
t-Bu
2g
2h
3g
3h
1
The H NMR spectra observed at 208C were to a large
degree uninterpretable due to signal broadening. This effect
is presumably a result of hindered rotation about the BOC
groups, and, as observed by Evans,16 spectra obtained at
higher temperatures (47±528C) were much improved.
Eight substrates were chosen for study and were prepared
using standard transformations from 2-alkyl-1,3-dithianes
1: Deprotonation of 1 and treatment with the corresponding
aldehydes gave the secondary alcohols 2a±h. Swern oxida-
tion produced the ketones 3a±h in excellent yields
(Scheme 1, Table 1). 2-Acetyl derivative 3a was also
prepared in comparable yield by acylation of the 2-ethyl-
1,3-dithiane anion with excess ethyl acetate.1
The reaction was repeated under identical conditions but,
after allowing ca 5±15 min for reaction with DBAD at
2788C, by which time the persistent yellow colour of the
DBAD had disappeared, acetic acid was added at 2788C,
and the reaction was allowed to reach room temperature. A
similar yield of (^)-anti-5c was observed, but with a much
improved diastereoselectivity of $99:1, only one product
isomer being detectable by 400 MHz 1H NMR spectroscopy
(Scheme 4, RˆMe, R0ˆEt). As expected, the major isomer
proved to have the same stereochemistry for both 2788C
quench and for room temperature quench. The low tempera-
ture acetic acid quench presumably prevents loss of stereo-
chemical integrity at the new asymmetric centre which
otherwise occurs at a higher temperature.
Mono-sulfoxidation of four of these acyl dithianes 3a±d
was carried out by treatment with sodium periodate in
methanol to give the corresponding racemic anti and syn
dithiane oxides 4a±d in excellent yields and with varying
diastereoselectivities in favour of the anti isomers
(Scheme 2, Table 2).
Four of the acyl dithianes having R0ˆEt were selected for
asymmetric sulfur oxidation using the Kagan procedure,25
which took place smoothly to give the (1)-anti (R)-1-oxides
4e±h, again in excellent yields and with very high enantio-
meric excesses (Scheme 3, Table 3).
The sense of induced stereochemistry was ultimately proven
Scheme 2.
Scheme 3.
Table 2. Achiral sulfoxidation of 2-acyl-2-alkyl-1,3-dithianes
Table 3. Asymmetric sulfoxidation of 2-acyl-2-ethyl-1,3-dithianes
R
R0
Substrate
Product:
Yield of
(^)-anti-4/%
Yield of
(^)-syn-4/%
R
R0
Substrate
Product
Yield/%
ee/%26
Bn
Ph
i-Pr
t-Bu
Et
Et
Et
Et
3e
3f
3g
3h
(1)-anti-4e
(1)-anti-4f
(1)-anti-4g
(1)-anti-4h
81
64
65
66
.98
94
89
90
H
Et
Me
Et
3a
3b
3c
3d
4a
4b
4c
4d
39
28
39
36
28
17
27
20
Me
Me
Me
Ph

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9685
Scheme 5.
Table 5. Amination of (1)-2-acyl-2-ethyl-1,3-dithiane 1-oxides
R
Substrate
Product
Yield/%
Bn
Ph
i-Pr
t-Bu
(1)-anti-4e
(1)-anti-4f
(1)-anti-4g
(1)-anti-4h
(1)-anti-5e
(1)-anti-5f
(1)-anti-5g
(1)-anti-5h
93
85
89
91
Scheme 4.
Electrophilic amination of the lithium enolates derived from
syn and anti 2-acetyl-2-ethyl-1,3-dithiane 1-oxides 4a with
DBAD under our standard conditions also proceeded
smoothly and in good yields. The (achiral) products are of
interest as potential synthons for chiral a-aminoacid
synthesis.
Table 4. Diastereoselectivity of electrophilic amination of (^)-2-acyl-2-
alkyl-1,3-dithiane 1-oxide enolates using DBAD
R
R0
Substrate
Product
Isomer ratioa
Yield/%
H
H
Et
Et
anti-4a
syn-4a
anti-4b
syn-4b
anti-4c
syn-4c
anti-4d
anti-5a
syn-5a
anti-5b
syn-5b
anti-5c
syn-5c
anti-5d
±
±
2:1
72
89
69
76
48
42
37
Me
Me
Me
Me
Me
Me
Me
Et
Et
Ph
The four non-racemic acyl dithiane oxides anti-4e±h were
next investigated, and underwent deprotonation and
amination with DBAD smoothly under similar conditions
to give the a-hydrazido ketones anti-5e±h in excellent
yields (Scheme 5, Table 5).
3:1
$99:1b
12:1
2:1
a Determined by 400 MHz 1H NMR spectroscopy.27
b Minor isomer not detected.
Although the reactions proceeded smoothly and in high
yields, in these cases we were unable to determine the dia-
stereoselectivities of the reactions. Acceptable H NMR
1
to be that shown by conversion of two other examples into
known a-hydrazido acids in the non-racemic series (vide
infra).
spectra could not be recorded at any temperature; in
CDCl3 the spectra were still broad at 558C and in higher
boiling point solvents decomposition of the compounds
occurred before the spectra became acceptable. We believe
the systems are too sterically congested to allow free
rotation even at these high temperatures. Efforts to separate
the diastereoisomers by chromatographic methods includ-
ing chiral HPLC, normal and reverse phase HPLC and GC
were all in vain.
In common with our earlier work, variation of 2-alkyl
substituent was expected to exert a dramatic effect upon
diastereoselectivity. A selection of the results obtained by
variation of the 2-substituent is given in Table 4 and closely
parallels those observed during our investigations of enolate
alkylation and other reactions of acyl dithiane oxides,28
optimum diastereoselection being obtained with a 2-ethyl
substituent. The sense of induced stereochemistry and the
pattern of diastereoselectivity may be rationalized on the
basis of a chelation-control model of acyl dithiane oxide
reactivity successful for other reactions;29 additional inter-
action of the metal counter-ion with the reagent is also a
possibility. It is also conceivable that some loss of stereo-
chemical integrity by equilibration may still be occurring
under the reaction conditions in some cases. Readers are
referred to our investigation of Mannich reactions for a
full discussion.30
In a further effort to determine diastereoselectivity we
synthesised one of the compounds by an alternative route.
The enolate derived from acyl dithiane 3e was aminated
with DBAD to give a-hydrazido ketone (^)-6, which was
then oxidised with sodium periodate to give (^)-anti-5e, as
shown in Scheme 6. We believed that the oxidation step
would prove unselective, and so produce a mixture of
observable diastereoisomers. Attempts to separate or
distinguish the isomers of this mixture were, however,
again unsuccessful.
Scheme 6.

9686
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
cleaved with sodium periodate to give the corresponding
carboxylic acids with negligible loss of stereochemical
integrity.31 To convert the a-hydrazido diketones 7 into
the carboxylic acids, they were therefore treated with
sodium periodate in aqueous methanol (Scheme 8). Unfor-
tunately, the reactions did not take place as smoothly as in
the a-arylpropanoic acid series.31 The diketone (2)-7e was
oxidised cleanly overnight to the acid (2)-8e in 85% yield.
Diketone (2)-7g was also oxidised to the acid (2)-8g, but
the reaction required two days to reach completion and was
lower yielding. The remaining two diketones (1)-7f and
(1)-7h proved resistant to cleavage, even at elevated
temperatures. Treatment of (1)-7h with lead tetraacetate,
a more powerful oxidant, was also unsuccessful.
Scheme 7.
Table 6. Hydrolysis of a-hydrazido acyl dithiane 1-oxides
R
Substrate
Diketone
Yield/%
[a]2D0
Bn
Ph
i-Pr
t-Bu
(1)-anti-5e
(1)-anti-5f
(1)-anti-5g
(1)-anti-5h
(2)-7e
(1)-7f
(2)-7g
(1)-7h
85
72
72
54
242
180
264
154
In order to determine the ees of our a-hydrazido acids, we
®rst synthesised acid 8e in racemic form for comparison.
Dihydrocinnamic acid was esteri®ed with benzyl alcohol
under standard coupling conditions to give 9 in 84% yield.32
Deprotonation of 9 with LDA and amination with DBAD
gave (^)-10e in an extremely capricious reaction. Removal
of the benzyl ester with palladium on charcoal under a
hydrogen atmosphere gave racemic a-hydrazido acid (^)-
8e in 94% yield (Scheme 9).
Attempts to separate acid (^)-8e by chiral HPLC using a
variety of conditions were unsuccessful. Also unsuccessful
were many attempts to differentiate the enantiomers by a
Scheme 8.
Scheme 9.
Despite the lack of stereochemical analysis, we decided to
take our non-racemic material further through the synthesis,
and to check the ee at a later stage, following removal of the
sulfoxide moiety. During the DiTOX-mediated enantio-
selective synthesis of a-aryl propanoic acis,31 we found
aqueous N-bromosuccinimide (NBS) to be an effective
reagent for hydrolysis of the dithiane oxide grouping in
acylated derivatives containing an asymmetric centre at
the a-position, allowing isolation of the corresponding
1,2-diketones with negligible loss of stereochemical
integrity. Accordingly, we treated the hydrazido acyl
dithiane oxides (1)-anti-5e±h with the same reagent system
to access the diketones 7 in good yields as bright yellow oils
or glasses (Scheme 7, Table 6).
variety of chiral 1H NMR shift reagents. We next turned our
attention to benzyl ester (^)-10e and the methyl ester (^)-
11 derived from (^)-8e. Unfortunately the enantiomers of
these esters were also inseparable and indistinguishable.
Evans has reported the optical rotations for the benzyl esters
of acids 8e and 8g with .99% ee.16 Acids (2)-8e and (2)-
8g were therefore converted into their corresponding
benzyl esters (2)-10e and (2)-10g, again under standard
dehydrating conditions (Scheme 10).
Analysis of their optical rotations indicates formation of the
(S) esters with ees of 69% and 72% for compounds (2)-10e
and (2)-10g, respectively. The (S) con®guration is indeed
1
Fortunately the H NMR spectra of the diketones could be
resolved at elevated temperatures, and furthermore the
compounds all possessed signi®cant optical rotations,
supporting our contention that the initial enolate aminations
were diastereoselective.
We have previously shown that 1,2-diketones containing an
asymmetric centre at the a-position may be oxidatively
Scheme 10.

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9687
that predicted to be the major isomer according to our usual
rules of thumb for reactions of dithiane oxide enolates.2 The
conversion of these compounds into the corresponding
amino acids has been demonstrated.14±16
186.40 mmol) added. The reaction mixture was stirred and
allowed to reach room temperature overnight. Normal
work-up followed by ¯ash column chromatography (5±
15% ethyl acetate/petroleum ether) gave 2a as a viscous,
yellow oil (14.30 g, 80%); found: C, 50.38; H, 8.57;
C8H16OS2 requires C, 49.96; H, 8.38%; nmax (®lm)
3465 cm21; dH (250 MHz, CDCl3) 1.15 (3H, t, Jˆ7.6 Hz),
1.37 (3H, d, Jˆ6.9 Hz), 1.60±2.13 (4H, series m), 2.56±
2.65 (1H, m), 2.65±2.71 (1H, m), 2.81 (1H, s), 2.92±3.08
(2H, m), and 4.28 (1H, dq, Jˆ6.5, 1.8 Hz); m/z (EI)
192.0644 (M1), C8H16OS2 requires 192.0643.
An enantioselective synthesis of two a-hydrazido acids has
thus been successfully achieved, albeit with limited ee, in
contrast to the results observed in our parallel synthesis of
a-arylpropanoic acids. We cannot however determine
whether this limitation in the ees is a result of poor dia-
stereoselectivity in the key amination step, or of a degree
of racemization subsequently.
2-(1-Hydroxypropyl)-2-methyl-1,3,-dithiane 2b. 1,3-
Dithiane (5 g, 41.58 mmol) was dissolved in dry THF
(200 mL) and cooled to 2208C. A solution of n-butyl-
lithium (28.58 mL, 45.73 mmol) was added slowly via
syringe and stirring continued at 2208C for 40 min before
cooling to 2788C. Iodomethane (2.59 mL, 41.60 mmol)
was added and the reaction mixture allowed to reach room
temperature over 2 h before recooling to 2208C prior to
further addition of a solution of n-butyllithium (28.58 mL,
45.73 mmol). The reaction mixture was stirred at this
temperature for 1 h, cooled to 2788C and propanal
(6.00 mL, 83.16 mmol) added. The reaction mixture was
stirred and allowed to reach room temperature overnight.
Normal work-up followed by ¯ash column chromatography
(15% ethyl acetate/petroleum ether) gave 2b as a pale
yellow oil (7.38 g, 92%); found: C, 50.95; H, 8.68;
C8H16OS2 requires C, 49.96; H, 8.38%; nmax (®lm)
3460 cm21; dH (250 MHz, CDCl3) 1.12 (3H, t, Jˆ7.4 Hz),
1.40 (3H, s), 1.75±2.20 (4H, m), 2.55±2.70 (2H, m), 2.81
(1H, s), 2.90±3.10 (2H, m), and 3.85 (1H, br d, Jˆ10.9 Hz);
m/z (EI) 192.0643 (M1), C8H16OS2 requires 192.0643.
Experimental
General experimental details
Puri®cation of reagents. Commercially available reagents
were used as supplied unless otherwise stated. Butyllithium
was purchased from the Aldrich chemical company in
100 mL bottles as a 2.5 M solution in hexane; the molarity
was determined by titration against a solution of diphenyl-
acetic acid. Lithium hexamethyldisilazide was purchased
from the Aldrich chemical company in 100 mL bottles as
a 1 M solution in THF. N-Bromosuccinimide was recrystal-
lized from water. Diethyl tartrate was distilled under
Ê
reduced pressure and stored over 4 A molecular sieve.
Puri®cation of solvents. Petroleum ether refers to
petroleum ether, bp 40±608C, unless otherwise stated.
Ethyl acetate and petroleum ether were distilled prior to
use. Tetrahydrofuran was freshly distilled under argon
from the sodium/benzophenone ketyl radical before use.
Dichloromethane was distilled from calcium hydride.
2-(1-Hydroxypropyl)-2-ethyl-l,3-dithiane 2c. 1,3-Dithiane
(10 g, 83.17 mmol) was dissolved in dry THF (300 mL) and
cooled to 2208C. A solution of n-butyllithium (57.17 mL,
91.47 mmol) was added slowly via syringe and stirring
continued at 2208C for 40 min before cooling to 2788C.
Iodoethane (6.66 mL, 83.27 mmol) was added and the reac-
tion mixture allowed to reach room temperature over 2 h
before recooling to 2208C prior to further addition of a
solution of n-butyllithium (57.17 mL, 91.47 mmol). The
reaction mixture was stirred at this temperature for 1 h,
cooled to 2788C and propanal (9.02 mL, 125.08 mmol)
added. The reaction mixture was stirred and allowed to
reach room temperature overnight. Normal work-up
followed by ¯ash column chromatography (5±15% ethyl
acetate/petroleum ether) gave 2c as a viscous, clear oil
which solidi®ed to colourless crystals on application of a
high vacuum (11.16 g, 65%); mp 41±438C; found: C, 52.19;
H, 8.77; C9Hl8OS2 requires C, 52.38; H, 8.79%; nmax (®lm)
3440 cm21; dH (200 MHz, CDCl3) 1.06 (3H, t, Jˆ7.4 Hz),
1.08 (3H, t, Jˆ7.2 Hz), 1.30±1.55 (1H, m), 1.55±2.10 (5H,
series m), 2.55±2.70 (2H, m), 2.73 (1H, t, Jˆ2.2 Hz), 2.88±
3.08 (2H, m), and 3.90 (1H, dt, Jˆ10.8, 1.8 Hz); m/z (EI)
206.0800 (M1), C9H18OS2 requires 206.0799.
Normal work-up procedures. After reaching room
temperature, the reaction mixture was poured onto saturated
aqueous ammonium chloride and extracted into dichloro-
methane. The combined organic extracts were dried over
anhydrous magnesium sulfate and the solvents removed in
vacuo to yield the crude products.
Puri®cation of products. Flash column chromatography
was carried out using Merck art. 9385 Kieselgel 60 (230±
Ê
400 mesh) or ICN Silica 32±63 60 A, using hand-bellows or
an air line to apply pressure to the column. Mixtures of ethyl
acetate and petroleum ether (bp 40±608C) were used as
eluent, unless otherwise stated.
Procedures
2-(1-Hydroxyethyl)-2-ethyl-1,3-dithiane 2a. 1,3-Dithiane
(11.18 g, 92.98 mmol) was dissolved in dry THF (400 mL)
and cooled to 2208C. A solution of n-butyllithium
(64.05 mL, 102.48 mmol) was added slowly via syringe
and stirring continued at 2208C for 40 min before cooling
to 2788C. Iodoethane (7.45 mL, 93.14 mmol) was added
and the reaction mixture allowed to reach room temperature
over 2 h before recooling to 2208C prior to further addition
of a solution of n-butyllithium (64.05 mL, 102.48 mmol).
The reaction mixture was stirred at this temperature for
1 h, cooled to ±78 8C and acetaldehyde (10.42 mL,
2-(1-Hydroxypropyl)-2-phenyl-1,3-dithiane 2d. 2-Phenyl-
1,3-dithiane (5 g, 25.47 mmol) was dissolved in dry THF
(200 mL) and cooled to ±208C. A solution of n-butyllithium
(17.50 mL, 28 mmol) was added slowly via syringe and
stirring continued at 2208C for 40 min before cooling to

9688
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
2788C. Propanal (3.67 mL, 50.89 mmol) was added and the
reaction mixture allowed to reach room temperature over-
night. Normal work-up followed by ¯ash column chromato-
graphy (15% ethyl acetate/petroleum ether) gave 2d as a
viscous, clear oil which solidi®ed to colourless crystals on
trituration with petroleum ether (4.20 g, 65%); mp 68±
708C; found: C, 60.63; H, 7.13; C13Hl8OS2 requires C,
61.38; H, 7.13%; nmax (®lm) 3465 cm21; dH (200 MHz,
CDCl3) 0.90 (3H, t, Jˆ7.2 Hz), 1.09±1.33 (1H, m), 1.51±
1.72 (1H, m), 1.87±2.00 (2H, m), 2.13 (1H, d, Jˆ5.4 Hz),
2.65±2.81 (4H, m), 3.68±3.79 (1H, m), 7.26±7.46 (3H, m),
and 7.92±8.00 (2H, m); m/z (EI) 254.0796 (M1), Cl3Hl8OS2
requires 254.0799.
(2H, m), and 4.08 (1H, dd, Jˆ10.1 and 1.7 Hz); m/z
(CI) 234.1112 (M1); C11H22OS2 requires 234.1112.
Found: C, 56.78; H, 9.72%. Calcd for C11H22OS2: C,
56.36; H, 9.46%.
2-(1-Hydroxy-3,3-dimethylbutyl)-2-ethyl-1,3-dithiane
2h. A solution of n-butyllithium in hexanes (17.5 mL,
37.1 mmol) was added to a stirred solution of 2-ethyl-1,3-
dithiane (5.4 g, 36.5 mmol) in THF (100 mL) at 2208C.
After 1 h, 3,3-dimethylbutyraldehyde (5.00 mL, 40.2
mmol) was added, and the mixture allowed to reach room
temperature over 0.5 h. Normal work-up and column chro-
matography using 10% ethyl acetate/ isohexane as eluent
gave 2h as a colourless oil (8.73 g, 97%); nmax 3480 cm21
;
2-(1-Hydroxy-3-phenylpropyl)-2-ethyl-1,3-dithiane 2e. A
solution of n-butyllithium in hexanes (21.7 mL,
52.0 mmol) was added to a stirred solution of 2-ethyl-1,3-
dithiane (7.0 g, 47.3 mmol) in THF (150 mL) at 2208C.
After 1 h, dihydrocinnamaldehyde (7.61 mL, 52.0 mmol)
was added, and the mixture allowed to reach room tempera-
ture over 1 h. Normal work-up, extraction with dichloro-
methane, drying over magnesium sulfate, and column
chromatography using 5% ethyl acetate/hexane as eluent
gave 2e as a colourless oil (9.91 g, 74%); nmax 3200±
3600 cm21; dH (270 MHz, CDCl3) 1.06 (3H, t, Jˆ7.4 Hz),
1.60±1.98 (4H, m), 2.25±2.38 (1H, m), 2.47±3.01 (8H, m),
3.96 (1H, d, Jˆ10.2 Hz), and 7.18±7.30 (5H, m); m/z (EI)
282.1112 (M1); C15H22OS2 requires 282.1111.
dH (270 MHz, CDCl3) 1.01 (9H, s), 1.09 (3H, t, Jˆ7.4 Hz),
1.31 (1H, dd, Jˆ14.1 and 8.5 Hz), 1.57±1.71 (1H, m), 1.76±
1.96 (3H, m), 2.01±2.11 (1H, m), 2.57±2.66 (2H, m), 2.76±
2.78 (1H, m), 2.92±3.04 (2H, m), and 4.11 (1H, d,
Jˆ8.8 Hz); m/z (FAB) 248.1268 (M1); C12H24OS2 requires
248.1269. Found: C, 58.29; H, 10.08%. Calcd for
C12H24OS2: C, 58.01; H, 9.74%.
2-Acetyl-2-ethyl-1,3-dithiane 3a. A 2 M solution of oxalyl
chloride (28.65 mL, 57.30 mmol) in dry CH2Cl2 was added
to a solution of DMSO (8.13 mL, 114.57 mmol) in dry
CH2Cl2 (100 mL) via cannula at 2788C. After stirring at
2788C for 30 min, 2a (10 g, 51.99 mmol) was added as a
solution in dry CH2Cl2 (100 mL) via cannula and stirring
continued for a further 2 h. Triethylamine (36.30 mL,
260.44 mmol) was added and the reaction mixture allowed
to reach 08C overnight. The mixture was poured onto 5%
aqueous HCl (100 mL) and shaken thoroughly. The organic
phase was washed with saturated aqueous sodium hydrogen
carbonate, dried over magnesium sulfate, and the solvents
removed under reduced pressure. Flash column chromato-
graphy (15% ethyl acetate/petroleum ether) gave 3a as a
yellow oil (7.65 g, 77%); found: C, 50.78; H, 7.50;
C8H14OS2 requires C, 50.49; H, 7.41%; nmax (®lm)
1737 cm21; dH (200 MHz, CDCl3) 1.00 (3H, t, Jˆ7.5 Hz),
1.70±1.90 (1H, m), 1.95±2.10 (3H, m), 2.33 (3H, s), 2.55±
2.75 (2H, m), and 2.90±3.05 (2H, m); m/z (EI) 190.0489
(M1), C8H14OS2 requires 190.0486.
2-(1-Hydroxy-2-phenylethyl)-2-ethyl-1,3-dithiane 2f. A
solution of n-butyllithium in hexanes (39.9 mL,
91.6 mmol) was added to a stirred solution of 1,3-dithiane
(10 g, 83.3 mmol) in THF (350 mL) at 2208C. After 1 h, the
reaction mixture was cooled to 2788C and ethyl iodide
(7.33 mL, 91.6 mmol) added. The mixture was allowed to
reach room temperature over 1.5 h, then recooled to 2208C,
and a solution of n-butyllithium in hexanes (39.9 mL,
91.6 mmol) added. After 1 h, the mixture was cooled to
2788C, phenylacetaldehyde (10.25 mL, 91.6 mmol)
added, and the mixture allowed to reach room temperature
over 17 h. Normal work-up procedure followed by ¯ash
column chromatography using 5% ethyl acetate/petroleum
ether as eluent furnished 2f as a colourless oil (11.71 g,
52%); nmax 3469 cm21; dH (400 MHz, CDCl3) 1.14 (3H, t,
Jˆ7.4 Hz), 1.66±2.07 (4H, m), 2.51±3.10 (6H, m), 3.30±
3.36 (1H, m), 4.13±4.18 (1H, m), and 7.17±7.36 (5H, m);
m/z 268.0955 (M1); C14H20OS2 requires 268.0956. Found:
C, 62.73; H 7.53%. Calcd for C14H20OS2: C, 62.64; H
7.51%.
2-Propanoyl-2-methyl-1,3-dithiane 3b. A 2 M solution of
oxalyl chloride (10.31 mL, 20.62 mmol) in dry CH2Cl2 was
added to a solution of DMSO (2.93 mL, 41.29 mmol) in dry
CH2Cl2 (10 mL) via cannula at 2788C. After stirring at
2788C for 30 min, 2b (3.56 g, 18.72 mmol) was added as
a solution in dry CH2Cl2 (50 mL) via cannula and stirring
continued for a further 2 h. Triethylamine (7.84 mL,
56.25 mmol) was added and the reaction mixture allowed
to reach 08C overnight. The mixture was poured onto 5%
aqueous HCl (50 mL) and shaken thoroughly. The organic
phase was washed with saturated aqueous sodium hydrogen
carbonate, dried over magnesium sulfate, and the solvents
removed under reduced pressure. Flash column chromato-
graphy (15% ethyl acetate/petroleum ether) gave 3b as a
yellow oil (1.70 g, 48%); found: C, 51.39; H, 7.64;
C8Hl4OS2 requires C, 50.49; H, 7.41%; nmax (®lm)
1710 cm21; dH (250 MHz, CDCl3) 1.04 (3H, t, Jˆ7.2 Hz),
1.60 (3H, s), 1.63±1.84 (1H, m), 1.98±2.10 (1H, m), 2.50±
2.61 (2H, m), 2.64 (2H, q, Jˆ7.14 Hz), and 2.97±3.12 (2H,
m); m/z (EI) 190.0484 (M1), C8Hl4OS2 requires 190.0486.
2-(1-Hydroxy-3-methylbutyl)-2-ethyl-1,3-dithiane 2g. A
solution of n-butyllithium in hexanes (15.5 mL,
37.1 mmol) was added to a stirred solution of 2-ethyl-1,3-
dithiane (5.0 g, 33.8 mmol) in THF (100 mL) at 2208C.
After 1 h, isovaleraldehyde (3.99 mL, 37.1 mmol) was
added, and the mixture allowed to reach room temperature
over 2 h. Normal work-up and column chromatography
using 10% ethyl acetate/hexane as eluent gave 2g as a
colourless oil (6.02 g, 76%); nmax 3479 cm21
; dH
(270 MHz, CDCl3) 0.96 (3H, d, Jˆ5.5 Hz), 0.99 (3H, d,
Jˆ5.8 Hz), 1.08 (3H, t, Jˆ7.4 Hz), 1.38±1.48 (1H, m),
1.63±1.74 (2H, m), 1.76±1.96 (3H, m), 1.99±2.12 (1H,
m), 2.44±2.53 (1H, m), 2.60±2.69 (2H, m), 2.91±3.04

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9689
2-Propanoyl-2-ethyl-1,3-dithiane 3c. A 2 M solution of
oxalyl chloride (6.41 mL, 12.82 mmol) in dry CH2Cl2 was
added to a solution of DMSO (1.82 mL, 25.65 mmol) in dry
CH2Cl2 (10 mL) via cannula at 2788C. After stirring at
2788C for 30 min, 2b (2.4 g, 11.63 mmol) was added as a
solution in dry CH2Cl2 (50 mL) via cannula and stirring
continued for a further 2 h. Triethylamine (8.12 mL,
58.26 mmol) was added and the reaction mixture allowed
to reach 08C overnight. The mixture was poured onto 5%
aqueous HCl (50 mL) and shaken thoroughly. The organic
phase was washed with saturated aqueous sodium hydrogen
carbonate, dried over magnesium sulfate, and the solvents
removed under reduced pressure. Flash column chromato-
graphy (15% ethyl acetate/petroleum ether) gave 3b as a
yellow oil (1.60 g, 67%); found: C, 51.93; H, 7.84;
C9H16OS2 requires C, 52.90; H, 7.89%; nmax (®lm)
1700 cm21; dH (250 MHz, CDCl3) 1.02 (3H, t, Jˆ7.5 Hz),
1.15 (3H, t, Jˆ7.3 Hz), 1.70±1.90 (2H, m), 2.10 (2H, q,
Jˆ7.4 Hz), 2.58±2.70 (2H, m), 2.70 (2H, q, Jˆ7.2 Hz),
2.85±3.10 (2H, m); m/z (EI) 204 (M1).
2-(20-Phenylacetyl)-2-ethyl-1,3-dithiane 3f. A solution of
TFAA (8.93 mL, 63.2 mmol) in CH2Cl2 (40 mL) was added
to a stirred solution of DMSO (6.58 mL, 92.6 mmol) in
CH2Cl2 (70 mL) at 2788C. After stirring at 2788C for
30 min, a solution of 2f (11.29 g, 42.1 mmol) in CH2Cl2
(40 mL) was added dropwise, and stirring continued at
2788C for 1.5 h. Triethylamine (17.61 mL, 126.3 mmol)
was added, and the mixture allowed to reach room tempera-
ture over 1.5 h. The mixture was poured into 5% aqueous
hydrochloric acid (300 mL), and the organic phase
collected, washed with aqueous sodium hydrogen carbonate
(2£50 mL), dried over magnesium sulfate and concentrated
in vacuo to yield an orange solid. Trituration with petroleum
ether gave 3f as a colourless crystalline solid (9.12 g, 81%),
mp 85±868C; nmax 1702 cm21; dH (400 MHz, CDCl3) 1.03
(3H, t, Jˆ7.1 Hz), 1.70±2.18 (4H, m), 2.53±2.60 (2H, m),
2.80±2.93 (2H, m), 3.96 (2H, s), and 7.26±7.33 (5H, m);
m/z 266.0798 (M1); C14H18OS2 requires 266.0799. Found:
C, 62.83; H, 6.78%. Calcd for C14H18OS2: C, 63.12; H,
6.81%.
2-Propanoyl-2-phenyl-1,3-dithiane 3d. A 2 M solution of
oxalyl chloride (9.09 mL, 18.18 mmol) in dry CH2Cl2 was
added to a solution of DMSO (2.60 mL, 36.64 mmol) in dry
CH2Cl2 (10 mL) via cannula at 2788C. After stirring at
2788C for 30 min, 2d (4.20 g, 16.51 mmol) was added as
a solution in dry CH2Cl2 (50 mL) via cannula and stirring
continued for a further 2 h. Triethylamine (6.92 mL,
49.65 mmol) was added and the reaction mixture allowed
to reach 08C overnight. The mixture was poured onto 5%
aqueous HCl (50 mL) and shaken thoroughly. The organic
phase was washed with saturated aqueous sodium hydrogen
carbonate, dried over magnesium sulfate, and the solvents
removed under reduced pressure. Flash column chromato-
graphy (15% ethyl acetate/petroleum ether) gave 3d as
colourless crystals on trituration with petroleum ether
(2.83 g, 68%); mp 78±808C; found: C, 61.87; H, 6.39;
Cl3Hl6OS2 requires C, 61.82; H, 6.38%; nmax (®lm)
1710 cm2l; dH (200 MHz, CDCl3) 0.98 (3H, t, Jˆ7.3 Hz),
1.73±1.96 (1H, m), 1.98±2.15 (1H, m), 2.36 (2H, q,
Jˆ7.4 Hz), 2.63±2.78 (2H, m), 3.03±3.20 (2H, m), 7.25±
7.42 (3H, m), 7.45±7.55 (2H, m); m/z (EI) 252.0638 (M1),
Cl3Hl6OS2 requires 252.0643.
2-(3-Methylbutan-1-oyl)-2-ethyl-1,3-dithiane 3g. TFAA
(5.34 mL, 38.1 mmol) was added to a stirred solution of
DMSO (3.94 mL, 55.9 mmol) in CH2Cl2 (50 mL) at
2788C. After stirring at 2788C for 30 min, a solution of
2g (5.90 g, 25.4 mmol) in CH2Cl2 (50 mL) was added drop-
wise, and stirring continued at 2788C for 1.5 h. Triethyl-
amine (10.54 mL, 76.3 mmol) was added, and the mixture
allowed to reach room temperature over 1 h. The mixture
was poured into 5% aqueous hydrochloric acid (150 mL),
extracted into CH2Cl2, and the organic phase collected,
washed with aqueous sodium hydrogen carbonate, dried
over magnesium sulfate and concentrated in vacuo. Column
chromatography using 10% ethyl acetate/hexane as eluent
gave 3g as a colourless oil (4.80 g, 82%); nmax 1702 cm21
;
d
H (270 MHz, CDCl3) 0.95 (6H, d, Jˆ6.9 Hz), 1.01 (3H, t,
Jˆ7.4 Hz), 1.74±1.91 (1H, m), 2.03 (2H, q, Jˆ7.4 Hz),
2.03±2.13 (1H, m), 2.16±2.32 (1H, m), 2.59 (2H, d,
Jˆ6.9 Hz), 2.60±2.68 (2H, m), and 2.95±3.06 (2H, m);
m/z (CI) 233.1035 (M11H); C11H21OS2 requires
233.1034. Found: C, 56.73; H, 8.58%. Calcd for
C11H20OS2: C, 56.85; H, 8.67%.
2-(3,3-Dimethylbutan-1-oyl)-2-ethyl-1,3-dithiane
3h.
2-(3-Phenylpropan-1-oyl)-2-ethyl-1,3-dithiane 3e. TFAA
(6.00 mL, 42.4 mmol) was added to a stirred solution of
DMSO (4.42 mL, 62.2 mmol) in CH2Cl2 (75 mL) at
2788C. After 30 min, a solution of 2e (8.0 g, 28.3 mmol)
in CH2Cl2 (30 mL) was added dropwise, and stirring con-
tinued at 2788C for 1.5 h. Triethylamine (11.93 mL,
84.8 mmol) was added, and the mixture allowed to reach
room temperature over 1 h. The mixture was poured into 5%
aqueous hydrochloric acid (200 mL), extracted into CH2Cl2,
and the organic phase collected, washed with aqueous
sodium hydrogen carbonate, dried over magnesium sulfate,
and concentrated in vacuo. Column chromatography using
10% ethyl acetate/hexane as eluent gave 3e as a colourless
solid (7.78 g, 98%); nmax 1704 cm21; dH (270 MHz, CDCl3)
0.91 (3H, t, Jˆ7.6 Hz), 1.61±1.86 (1H, m), 1.99 (2H, q,
Jˆ7.6 Hz), 1.95±2.16 (1H, m), 2.53±2.61 (2H, m), 2.81±
3.06 (6H, m), and 7.15±7.31 (5H, m); m/z (EI) 280.0956
(M1); C15H20OS2 requires 280.0957. Found: C, 64.36; H,
7.22%. Calcd for C15H20OS2: C, 64.24; H, 7.19%.
TFAA (7.26 mL, 51.4 mmol) was added to a stirred solution
of DMSO (5.35 mL, 75.4 mmol) in CH2Cl2 (75 mL) at
2788C. After stirring at 2788C for 30 min, a solution of
2h (8.50 g, 34.3 mmol) in CH2Cl2 (75 mL) was added drop-
wise, and stirring continued at 2788C for 1.5 h. Triethyl-
amine (14.33 mL, 102.8 mmol) was added, and the mixture
allowed to reach room temperature over 1 h. The mixture
was poured into 5% aqueous hydrochloric acid (200 mL),
extracted into CH2Cl2, and the organic phase collected,
washed with aqueous sodium hydrogen carbonate, dried
over magnesium sulfate and concentrated in vacuo. Column
chromatography using 10% ethyl acetate/hexane as eluent
gave 3h as a colourless oil (7.38 g, 88%); nmax 1706 cm21
;
dH (270 MHz, CDCl3) 1.02 (3H, t, Jˆ7.4 Hz), 1.07 (9H, s),
1.74±1.89 (1H, m), 2.02 (2H, q, Jˆ7.4 Hz), 2.03±2.12 (1H,
m), 2.61±2.68 (2H, m), 2.63 (2H, s), and 2.95±3.06 (2H, m);
m/z (FAB) 246.1111 (M1); C12H22OS2 requires 246.1112.
Found: C, 58.17; H, 9.20%. Calcd for C12H22OS2: C, 58.49;
H, 9.00%.

9690
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
General procedure for the achiral sulfoxidation of 2-
acyl-2-alkyl-1,3 dithianes to the corresponding
sulfoxides
1705 and 1040 cm21; dH (250 MHz, CDCl3) 1.08 (3H, t,
Jˆ7.3 Hz), 1.84 (3H, s), 2.20±2.50 (3H, m), 2.50±2.90
(2H, m), and 3.0±3.30 (3H, m); m/z (EI) 206.0436 (M1),
C8H14O2S2 requires 206.0435.
Using sodium metaperiodate. A solution of sodium meta-
periodate (1 equiv.) in water (ca. 10 mL/g) was added drop-
wise to a solution of the substrate in methanol (ca. 50 mL/g
of substrate) at 08C over 0.5 h. The mixture was stirred at
this temperature overnight and then allowed to reach room
temperature. The precipitate was removed by ®ltration and
washed thoroughly with CH2Cl2. The ®ltrate was evapo-
rated to half its original volume and partitioned between
water and CH2Cl2. The aqueous layer was twice washed
with CH2Cl2, the combined organic extracts were dried
over magnesium sulfate and the solvents removed under
reduced pressure to yield a crude mixture of diastereo-
isomeric sulphoxides. These were separated by ¯ash column
chromatography using 50±100% ethyl acetate/petroleum
ether solvent systems as eluent.
For anti-4b: (0.52 g, 28%), mp 56±578C; found: C, 46.62;
H, 6.85; C8H14O2S2 requires C, 46.57; H, 6.84%; nmax (soln)
1695 and 1040 cm21; dH (250 MHz, CDCl3) 1.13 (3H, t,
Jˆ7.4 Hz), 1.68 (3H, s), 1.79±1.89 (1H, m), 2.36±2.74
(4H, m), 2.9±3.06 (2H, m), 3.18±3.26 (1H, m); m/z (EI)
206.0439 (M1); C8H14O2S2 requires 206.0435.
(^)-syn and anti 2-Propanoyl-2-ethyl-1,3-dithiane 1-
oxides 4c. Treatment of ketone 3c (2.50 g, 12.23 mmol) as
above with sodium metaperiodate (2.62 g, 12.25 mmol) in
water (20 mL) and methanol (125 mL) furnished the
diastereoisomeric sulfoxides, separated to yield the syn
and anti diastereoisomers as colourless crystalline solids,
after application of a high vacuum.
For syn-4c: (0.72 g, 27%), mp 69±718C; found: C, 48.96; H,
7.29; C9Hl6O2S2 requires C, 49.06; H, 7.32%; nmax (®lm)
1710 and 1050 cm21; dH (250 MHz, CDCl3) 1.09 (3H, t,
Jˆ7.4 Hz), 1.15 (3H, t, Jˆ7.1 Hz), 2.01±2.20 (1H, m),
2.20±2.50 (3H, m), and 2.50±3.35 (6H, series m); m/z
(EI) 220.0593 (M1), C9H16O2S2 requires 220.0592.
Tartaric acid work-up. The reaction mixture was allowed
to reach room temperature, and concentrated in vacuo. The
crude material was dissolved in diethyl ether (100 mL) and
cooled to 2108C before addition of saturated aqueous
tartaric acid (100 mL). After stirring for 1.5 h at 2108C,
the mixture was allowed to reach room temperature and
the ether layer separated. The aqueous layer was extracted
with diethyl ether (3£75 mL) and CH2Cl2 (3£75 mL), and
the organic fractions combined, dried over magnesium
sulfate, and concentrated in vacuo.
For anti-4c: (1.05 g, 39%), mp 61±638C; found: C, 49.01;
H, 7.25; C9Hl6O2S2 requires C, 49.06; H, 7.32%; nmax (soln)
1700 and 1060 cm21; dH (250 MHz, CDCl3) 1.03 (3H, t,
Jˆ7.4 Hz), 1.14 (3H, t, Jˆ7.5 Hz), 1.71±1.91 (2H, m),
2.10±2.30 (1H, m), 2.40±2.74 (4H, m), and 2.95±3.13
(3H, m); m/z (EI) 220.0593 (M1), C9Hl6O2S2 requires
220.0592.
(^)-syn and anti 2-Acetyl-2-ethyl-1,3-dithiane 1-oxides
4a. Treatment of ketone 3a (2.50 g, 13.14 mmol) as
described above with sodium metaperiodate (2.81 g,
13.14 mmol) in water (20 mL) and methanol (125 mL)
furnished the diastereoisomeric sulfoxides, separated to
yield the syn and anti diastereoisomers, both as colourless
crystalline solids after application of a high vacuum.
(^)-syn and anti 2-Propanoyl-2-phenyl-1,3-dithiane 1-
oxides 4d. Treatment of ketone 3c (2.30 g, 9.11 mmol) as
above with sodium metaperiodate (1.95 g, 9.12 mmol) in
water (20 mL) and methanol (100 mL) furnished the
diastereoisomeric sulfoxides, separated to yield the syn
and the anti diastereoisomers as colourless crystalline solids
after application of a high vacuum.
For syn-4a: (0.76 g, 28%), mp 57±588C; found: C, 46.76; H,
6.87; C8H14O2S2 requires C, 46.57; H, 6.84%; nmax (soln)
1701 and 1041 cm21; dH (200 MHz, CDCl3), 1.10 (3H, t,
Jˆ7.9 Hz), 2.00±2.20 (1H, m), 2.30±2.45 (3H, m), 2.45
(3H, s), 2.50±2.70 (1H, m), and 2.85±3.30 (3H, m); m/z
(EI) 206.0437 (M1), C8Hl4O2S2 requires 206.0435.
For syn-4d: (0.50 g, 20%), mp 72±748C; found: C, 58.08; H,
6.01; C13Hl6O2S2 requires C, 58.18; H, 6.01%; nmax (®lm)
1710 and 1060 cm21; dH (200 MHz, CDCl3) 0.92 (3H, t,
Jˆ7.2 Hz), 1.80±2.05 (1H, s), 2.25±2.40 (6H, series m),
3.05±3.20 (1H, m), 7.30±7.49 (3H, m), and 7.58±7.68
(2H, m); m/z (EI) 268.0593 (M1), C13Hl6O2S2 requires
268.0592.
For anti-4a: (1.07 g, 39%), mp 40±418C; found: C, 46.53;
H, 6.87; C8H14O2S2 requires C, 46.57; H, 6.84%; nmax (soln)
1694 and 1055 cm21; dH (200 MHz, CDCl3), 1.05 (3H, t,
Jˆ7.7 Hz), 1.70±1.90 (2H, m), 2.10±2.30 (1H, m), 2.45
(3H, s), 2.45±2.70 (3H, m), and 3.05±3.15 (2H, m); m/z
(EI) 206.0439 (M1), C8H14O2S2 requires 206.0435.
For anti-4d: (0.88 g, 36%), mp 125±1268C; found: C,
57.95; H, 5.99; C13Hl6O2S2 requires C, 58.18; H, 6.01%;
nmax (®lm) 1690 and 1050 cm21; dH (200 MHz, CDCl3)
1.06 (3H, t, Jˆ3 Hz), 1.70±1.90 (1H, m), 2.35±2.60 (2H,
m), 2.61±2.90 (3H, m), 3.04±3.15 (1H, m), 3.27±3.45 (1H,
m), and 7.45±7.55 (5H, m); m/z (EI) 268.0590 (M1),
C13Hl6O2S2 requires 268.0592.
(^)-syn and anti 2-Propanoyl-2-methyl-1,3,dithiane 1-
oxides 4b. Treatment of ketone 3b (1.70 g, 8.93 mmol) as
described above with sodium metaperiodate (1.92 g,
8.98 mmol) in water (20 mL) and methanol (100 mL) furn-
ished the diastereoisomeric sulfoxides, separated to yield
the syn and anti diastereoisomers as colourless crystalline
solids.
(1)-anti-2-(R)-(3-Phenylpropanoyl)-2-ethyl-1,3-dithiane
1-(R)-oxide (1)-anti-4e. Titanium isopropoxide (7.54 mL,
25.3 mmol) was added to a stirred solution of (1)-diethyl
tartrate (8.68 mL, 50.7 mmol) in dichloromethane (60 mL)
For syn-4b: (0.31 g, 17%), mp 40±428C; found: C, 46.55; H,
6.87; C8H14O2S2 requires C, 46.57; H, 6.84%; nmax (soln)

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9691
at room temperature. After 5 min, water (0.41 mL,
23.0 mmol) was added, and the mixture stirred for 30 min.
The mixture was cooled to 2308C, and a solution of 3e
(6.45 g, 23.0 mmol) in dichloromethane (50 mL) added.
After 5 min, a cooled solution of cumene hydroperoxide
(5.13 mL, 27.6 mmol) in dichloromethane (10 mL) was
added dropwise over 20 min. After stirring for 3 days at
2308C, tartaric acid work-up and ¯ash column chromato-
graphy using 50% EtOAc/hexane as eluent gave (1)-anti-4e
as a colourless solid (5.54 g, 81%), mp 59±608C; nmax 1696
and 1053 cm21; dH (270 MHz, CDCl3) 0.92 (3H, t,
Jˆ7.6 Hz), 1.62±1.83 (2H, m), 2.05±2.49 (4H, m), 2.81±
3.07 (5H, m), 3.36±3.58 (1H, m), and 7.17±7.32 (5H, m);
m/z (CI) 296.0903 (M1); C15H20O2S2 requires 296.0905.
Found: C, 60.80; H, 6.79%. Calcd for C15H20O2S2: C,
60.77; H, 6.80%. [a]2D5ˆ1177.0 (cˆ1.02, CHCl3).
(1)-anti-2-(R)-(3,3-Dimethylbutanoyl)-2-ethyl-1,3-di-
thiane 1-(R)-oxide (1)-anti-4h. Titanium isopropoxide
(8.64 mL, 29.1 mmol) was added to a stirred solution of
(1)-diethyl tartrate 9.95 mL, 58.1 mmol) in dichloro-
methane (75 mL) at room temperature. After 5 min, water
(0.48 mL, 26.4 mmol) was added and the mixture stirred for
30 min. The mixture was cooled to 2308C, and a solution of
3h (6.50 g, 26.4 mmol) in dichloromethane (50 mL) was
added. After 5 min, a cooled solution of cumene hydro-
peroxide (5.88 mL, 31.7 mmol) in dichloromethane
(10 mL) was added dropwise over 20 min. After stirring
for 3 days at 2308C, tartaric acid work-up and ¯ash column
chromatography using 50% EtOAc/hexane as eluent gave
(1)-anti-4h as an off-white solid (4.58 g, 66%); nmax 1692,
1056 cm21; dH (270 MHz, CDCl3) 1.07 (3H, t, Jˆ7.4 Hz),
1.08 (9H, s), 1.71±1.85 (2H, m), 2.07±2.21 (1H, m), 2.39±
2.66 (3H, m), 2.46 (1H, d, Jˆ18.7 Hz), 3.04 (1H, d,
Jˆ18.7 Hz), and 3.05±3.10 (2H, m); m/z (FAB) 262.1070
(M1); C12H22O2S2 requires 262.1062. Found: C, 55.09; H
8.45%. Calcd for C12H22O2S2: C, 54.92; H 8.45%.
[a]2D5ˆ1179.0 (cˆ1.03, CHCl3).
(1)-anti-2-(R)-(2-Phenylacetyl)-2-ethyl-1,3-dithiane 1-(R)-
oxide (1)-anti-4f. Titanium isopropoxide (9.84 mL,
33.1 mmol) was added to a stirred solution of (1)-diethyl
tartrate (11.3 mL, 66.2 mmol) in dichloromethane (75 mL)
at room temperature. After 5 min, water (0.54 mL,
30.1 mmol) was added, and the mixture stirred for 30 min.
The mixture was cooled to 2308C, and a solution of 3f
(8.00 g, 30.1 mmol) in dichloromethane (50 mL) added.
After 5 min, a cooled solution of cumene hydroperoxide
(8.33 mL, 45.2 mmol) in dichloromethane (10 mL) was
added dropwise over 20 min. After stirring for 3 days at
2268C, tartaric acid work-up and ¯ash column chromato-
graphy using 50% EtOAc/Petroleum ether as eluent gave
(1)-anti-4f as a colourless crystalline solid (5.44 g, 64%),
mp 112±1138C; nmax 1697, 1040 cm21; dH (400 MHz,
CDCl3) 1.07 (3H, t, Jˆ7.5 Hz), 1.66±1.70 (1H, m), 1.87±
1.97 (1H, m), 2.20±2.30 (1H, m), 2.34±2.50 (3H, m), 2.96±
3.38 (2H, m), 3.82 (1H, d, Jˆ15.5 Hz), 4.31 (1H, d,
Jˆ15.5 Hz), and 7.27±7.38 (5H, m); dC (100 MHz,
CDCl3) 8.3, 14.8, 26.3, 26.8, 43.7, 44.5, 75.5, 127.5,
128.9, 130.0, 133.4, and 206.1; m/z 282.0752 (M1);
C14H18O2S2 requires 282.0748. Found: C, 59.30; H,
6.41%. Calcd for C14H18O2S2: C, 59.54; H, 6.42%.
[a]2D5ˆ1251.4 (cˆ0.7, CHCl3).
General procedure for the generation of lithium enolates
of syn or anti 2-acyl-2-alkyl-1,3-dithiane 1-oxides and
their amination with di-tert-butylazodicarboxylate
A stirred solution of the 2-acyl-2-alkyl-1,3-dithiane 1-oxide
substrate in THF (ca. 25 mL/g substrate) was cooled to
2788C and a 1 M solution of LHMDS (1.1 equiv.) added
via syringe. After 10220 min, the solution was transferred
by cannula into a pre-cooled solution of DBAD (1.1 equiv.)
in dichloromethane at 2788C, with ¯ushing of the cannula
using THF (2 mL). After 5 min, acetic acid (3.0 equiv.) was
added, and the reaction allowed to reach room temperature.
Normal work-up and column chromatography using 50%
ethyl acetate/hexane gave the a-hydrazido ketone products.
Ammonium chloride variant work-up procedure. After
reaching room temperature, the reaction mixture was poured
onto a solution of saturated aqueous ammonium chloride
(ca. 50 mL/mmol substrate) and extracted into dichloro-
methane (3£25 mL). The combined organic extracts were
dried over magnesium sulfate and the solvents removed
under reduced pressure to yield the crude diastereoisomeric
products which were analysed by 250 or 400 MHz 1H NMR
spectroscopy either directly or after ¯ash column chromato-
graphy through a short column of silica gel (Merck 9385)
using ethyl acetate/petroleum ether solvent systems as
eluent.
(1)-anti-2-(R)-(3-Methylbutanoyl)-2-ethyl-1,3-dithiane
1-(R)-oxide (1)-anti-4g. Titanium isopropoxide (6.32 mL,
21.2 mmol) was added to a stirred solution of (1)-diethyl
tartrate (7.28 mL, 42.5 mmol) in dichloromethane (50 mL)
at room temperature. After 5 min, water (0.35 mL,
19.3 mmol) was added and the mixture stirred for 30 min.
The mixture was cooled to 2308C, and a solution of 3g
(4.48 g, 19.3 mmol) in dichloromethane (30 mL) added.
After 5 min, a cooled solution of cumene hydroperoxide
(4.44 mL, 23.1 mmol) in dichloromethane (10 mL) was
added dropwise over 20 min. After stirring for 3 days at
2308C, tartaric acid work-up and ¯ash column chromato-
graphy using 50% EtOAc/hexane as eluent gave (1)-anti-
4g as an off-white solid (3.12 g, 65%); nmax 1693,
(^)-syn-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-
acetyl)-2-(S)-ethyl-1,3-dithiane 1-(R)-oxide (^)-syn-5a.
The lithium enolate of syn-2-acetyl-2-ethyl-1,3-dithiane
1-oxide (^)-syn-4a (0.40 g, 1.94 mmol) was generated as
described above and added via cannula to a stirred solution
of DBAD (0.49 g, 2.13 mmol) in THF (8 mL) at 2788C.
The reaction mixture was allowed to reach room tempera-
ture overnight. Normal work-up procedure gave (^)-syn-5a
as a colourless crystalline solid (0.75 g, 89%), mp 57±588C;
found: C, 49.15; H, 7.38; N, 6.43; C18H32O6N2S2 requires C,
49.52; H, 7.39; N, 6.42%; nmax (soln) 3244, 1719, 1479, and
1054 cm21; dH (400 MHz, CDCl3, 325 K) 1.11 (3H, t,
Jˆ7.2 Hz), 1.45 (18H, s), 2.05±2.15 (1H, m), 2.24±2.45
1059 cm21
;
dH (270 MHz, CDCl3) 0.98 (6H, d,
Jˆ6.9 Hz), 1.04 (3H, t, Jˆ7.4 Hz), 1.71±1.88 (2H, m),
2.12±2.28 (2H, m), 2.42±2.65 (4H, m), 2.96 (1H, dd.
Jˆ18.0, 6.9 Hz), and 3.05±3.10 (2H, m); m/z (CI)
249.0964 (M11H); C11H21O2S2 requires 249.0983. Found:
C, 53.08; H, 8.12%. Calcd for C11H20O2S2: C, 53.19; H,
8.12%. [a]2D5ˆ1220.0 (cˆ1.03, CHCl3).

9692
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
(2H, m), 2.47±2.61 (1H, m), 2.80±3.30 (4H, series m),
4.50±4.80 (2H, m), and 6.60 (1H, br s); m/z (CI, NH3)
437 (M111).
isomer signals: 1.47 (d, Jˆ6.6 Hz), 1.62 (s), and 5.55 (br
s); m/z (CI, NH3) 437 (M111).
(^)-syn-2-(2-(S)-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
propanoyl)-2-(S)-ethyl-1,3-dithiane 1-(R)-oxide (^)-syn-
5c. The lithium enolate of syn 2-propanoyl-2-ethyl-1,3-
dithiane 1-oxide (^)-syn-4c (0.20 g, 0.908 mmol) was
generated as described above and added via cannula to a
stirred solution of DBAD (0.23 g, 0.999 mmol) in THF
(5 mL) at 2788C. The reaction mixture was stirred for
10 min at 2788C before addition of glacial acetic acid
(0.26 mL, 4.54 mmol). The reaction mixture was allowed
to reach room temperature overnight. Normal work-up
procedure gave (^)-syn-5c, a 12:1 mixture of inseparable
product diastereoisomers, as a colourless crystalline solid
(0.17 g, 42%), mp 139±1418C; found: C, 49.15; H, 7.45;
N, 6.58; C19H34O6N2S2 requires C, 50.64; H, 7.60; N,
6.22%; nmax (soln) 3568, 1745, 1701, 1478, and
1053 cm21; dH (400 MHz, CDCl3, 325 K) major isomer:
1.08 (3H, t, Jˆ7.5 Hz), 1.40±1.55 (21H, m), 2.10±2.30
(2H, m), 2.35±2.54 (3H, bm), 2.74 (1H, br t, Jˆ10.8 Hz),
3.00 (1H, br t, Jˆ14.5 Hz), 3.60 (1H, br s), 5.40 (1H, br s),
and 6.75 (1H, br s); characteristic minor isomer signal 1.39
(d, Jˆ6.9 Hz); m/z (CI, NH3) 451 (M11 1).
(^)-anti-2-(2-(S)-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
propanoyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-oxide (^)-
anti-5c. The lithium enolate of anti 2-propanoyl-2-ethyl-
1,3-dithiane 1-oxide (^)-anti-4c (0.20 g, 0.908 mmol) was
generated as described above and added via cannula to a
stirred solution of DBAD (0.23 g, 0.999 mmol) in THF
(5 mL) at 2788C. The reaction mixture was stirred for
15 min at 2788C before addition of glacial acetic acid
(0.26 mL, 4.54 mmol). The reaction mixture was allowed
to reach room temperature overnight. Normal work-up
procedure gave (^)-anti-5c, a single diastereoisomer by
1H NMR spectroscopy ($99:1), as a colourless crystalline
solid which was recrystallized from diethyl ether (0.20 g,
48%), mp 154±156 8C; found: C, 50.57; H, 7.63; N, 6.23;
C19H34O6N2S2 requires C, 50.64; H, 7.60; N, 6.22%; nmax
(soln) 3401, 1747, 1712, 1455, and 1058 cm21; dH
(400 MHz, CDCl3, 325 K) 0.98 (3H, t, Jˆ7.5 Hz), 1.46
(9H, s), 1.48 (9H, s), 1.53 (3H, d, Jˆ7.3 Hz), 1.65±85
(2H, m), 2.10±2.20 (1H, m), 2.40±2.60 (2H, m), 2.70
(1H, br t, Jˆ12.6 Hz), 2.95 (1H, br d, Jˆ14.0 Hz), 3.30
(1H, br s), 5.65 (1H, br s), and 6.40 (1H, br s); m/z (CI,
NH3) 450.1848 (M1), C19H34O6N2S2 requires 450.1858.
(^)-anti-2-(2-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
acetyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-oxide (^)-anti-5a.
The lithium enolate of anti 2-acetyl-2-ethyl-1,3-dithiane
1-oxide (^)-anti-4a (0.10 g, 0.485 mmol) was generated
as described above and added via cannula to a stirred solu-
tion of DBAD (0.123 g, 0.534 mmol) in THF (3 mL) at
2788C. The reaction mixture was allowed to reach room
temperature overnight. Normal work-up procedure gave
(^)-anti-5a as a colourless crystalline solid (0.153 g,
72%), mp 51±538C; found: C, 48.97; H, 7.39; N, 6.40;
C18H32O6N2S2 requires C, 49.52; H, 7.39; N, 6.42%; nmax
(soln) 3244, 1719, 1479, and 1054 cm21; dH (400 MHz,
CDCl3, 325 K) 1.07 (3H, t, Jˆ7.5 Hz), 1.46 (18H, s),
1.69±1.82 (2H, m), 2.13±2.30 (1H, m), 2.40±2.60 (2H,
m), 2.70±2.80 (1H, m), 2.90±3.12 (2H, m), 4.50 (1H, m),
5.10 (1H, m), and 6.55 (1H, br s); m/z (CI, NH3) 437
(M111).
(^)-syn-2-(2-(S)-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
propanoyl)-2-(S)-methyl-1,3-dithiane 1-(R)-oxide (^)-
syn-5b. The lithium enolate of syn 2-propanoyl-2-methyl-
1,3-dithiane 1-oxide (^)-syn-4b (0.20 g, 0.969 mmol) was
generated as described above and added via cannula to a
stirred solution of DBAD (0.25 g, 1.09 mmol) in THF
(5 mL) at 2788C. The reaction mixture was stirred for
10 min at 2788C before addition of glacial acetic acid
(0.28 mL, 4.66 mmol). The reaction mixture was allowed
to reach room temperature overnight. Normal work-up
procedure gave (^)-syn-5b, a 3:1 mixture of inseparable
product diastereoisomers, as a colourless oil (0.32 g,
76%); found: C, 49.15; H, 7.45; N, 6.58; C18H32O6N2S2
requires C, 49.52; H, 7.39; N, 6.42%; nmax (soln) 3301,
1750, 1705, 1454, and 1059 cm21; dH (400 MHz, CDCl3,
325 K) major isomer: 1.35 (3H, d, Jˆ6.6 Hz), 1.43 (9H, s),
1.44 (9H, s), 1.90 (3H, s), 2.20±2.39 (2H, m), 2.40±2.50
(1H, m), 2.84±2.95 (1H, m), 3.00±3.09 (1H, m), 3.72 (1H,
br t, Jˆ12.4 Hz), 5.35 (1H, br s), and 6.85 (1H, br s); char-
acteristic minor isomer signals: 1.87 (s) and 6.70 (br s); m/z
(CI, NH3) 437.1771 (M111), C18H32O6N2S2 requires
437.1780.
(^)-anti-2-(2-(S)-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
propanoyl)-2-(R)-methyl-1,3-dithiane 1-(R)-oxide (^)-
anti-5b. The lithium enolate of anti 2-propanoyl-2-methyl-
1,3-dithiane 1-oxide (^)-anti-4b (0.20 g, 0.969 mmol) was
generated as described above and added via cannula to a
stirred solution of DBAD (0.25 g, 1.09 mmol) in THF
(5 mL) at 2788C. The reaction mixture was stirred for
10 min at 2788C before addition of glacial acetic acid
(0.28 mL, 4.66 mmol). The reaction mixture was allowed
to reach room temperature overnight. Normal work-up
procedure gave (^)-anti-5b, a 2:1 mixture of inseparable
product diastereoisomers, as a pale yellow oil (0.292 g,
69%); found: C, 47.80; H, 7.24; N, 6.80; C18H32O6N2S2
requires C, 49.52; H, 7.39%; N, 6.42; nmax (soln) 3300,
1740, 1700, 1460, and 1060 cm21; dH (400 MHz, CDCl3,
325 K) major isomer: 1.34±1.45 (21H, m), 1.78 (3H, s),
2.30±2.55 (3H, m), 2.81±2.95 (2H, m), 3.25 (1H, br s),
5.35 (1H, br s), and 6.40 (1H, br s); characteristic minor
(^)-anti-2-(2-(S)-(N,N0-Bis-(t-butoxycarbonyl)hydrazino)-
propanoyl)-2-(R)-phenyl-1,3-dithiane 1-(R)-oxide (^)-
anti-5d. The lithium enolate of anti 2-propanoyl-2-phenyl-
1,3-dithiane 1-oxide (^)-anti-4d (0.20 g, 0.792 mmol) was
generated as described above and added via cannula to a
stirred solution of DBAD (0.188 g, 0.816 mmol) in THF
(5 mL) at ±78 8C. The reaction mixture was stirred for
15 min at 2788C before addition of glacial acetic acid
(0.22 mL, 3.84 mmol). The reaction mixture was allowed
to reach room temperature overnight. Normal work-up
procedure gave (^)-anti-5d as a 2:1 mixture of product
1
diastereoisomers by 400 MHz H NMR spectroscopy. The
product isomers were separated by ¯ash column chromato-
graphy using ethyl acetate as eluent to yield the major
isomer (0.099 g, 27%) and the minor isomer (0.038 g,

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9693
10%) both as pale yellow oils; found: C, 55.71; H, 6.96; N,
5.13; C23H34O6N2S2 requires C, 55.40; H, 6.87; N, 5.62%;
(^)-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-
phenylpropanoyl)-2-ethyl-1,3-dithiane (^)-6. 1 M
A
nmax (soln) 3590, 1748, 1708, 1534, 1446, and 1051 cm21
;
solution of LHMDS (1.83 mL, 1.83 mmol) in THF was
added to a stirred solution of 3e (0.47 g, 1.7 mmol) in
THF (10 mL) at 2788C. After 30 min, the solution was
transferred by cannula into a solution of DBAD (0.42 g,
1.83 mmol) in dichloromethane (10 mL) at ±78 8C, and
the solution allowed to reach room temperature. Normal
work-up and column chromatography using 10% ethyl ace-
tate/hexane as eluent gave (^)-6 as a colourless solid
(0.79 g, 93%), mp 55±578C; nmax 1747, 1713 and
1703 cm21; dH (400 MHz, DMSO-d6, 370 K) 0.99 (3H, t,
Jˆ7.3 Hz), 1.34 (9H, s), 1.42 (9H, s), 1.47±1.53 (1H, m),
1.88±1.92 (2H, m), 2.13±2.21 (2H, m), 2.40±2.48 (1H, m),
2.53±2.59 (1H, m), 2.86±2.89 (1H, m), 3.01±3.06 (1H, m),
3.15±3.21 (1H, m), 5.64 (1H, br s), 7.14±7.19 (1H, m),
7.21±7.29 (4H, m), and 8.35 (1H, br s); m/z (CI) 510.2223
(M1); C25H38N2O5S2 requires 510.2223. Found: C, 58.83;
H, 7.70; N, 5.32%. Calcd for C25H38N2O5S2: C, 58.80 H,
7.50; N, 5.49%.
dH (400 MHz, CDCl3, 325 K) major isomer: 1.34 (3H, d,
Jˆ7.6 Hz), 1.36 (9H, s), 1.44 (9H, s), 1.78±1.87 (1H, m),
2.42±2.55 (1H, m), 2.60±2.80 (2H, m), 3.00±3.10 (1H, m),
3.35 (1H, br t, Jˆ12.9 Hz), 5.24 (1H, br s), 5.78 (1H, br s),
7.36±7.50 (3H, m), and 7.55±7.60 (2H, m); minor isomer:
1.40±1.54 (21H, m), 1.70±1.80 (1H, m), 2.50±2.62 (1H,
m), 2.67±2.75 (1H, m), 2.92±3.07 (2H, m), 3.40 (1H, br
s), 5.74 (1H, br s), 6.32 (1H, br s), and 7.35±7.50 (5H,
m); m/z (CI, NH3) 499 (M111).
(1)-anti-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-
3-phenylpropanoyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-oxide
(1)-anti-5e. Treatment of (1)-anti-4e (3.0 g, 10.1 mmol)
with a 1 M solution of LHMDS in THF (11.2 mL,
11.2 mmol), DBAD (2.57 g, 11.2 mmol) and acetic acid
(1.80 mL, 30.5 mmol) as described above gave (1)-anti-
5e as a colourless powder (4.99 g, 93%), mp 82±838C;
nmax 1735, 1718, 1701 and 1050 cm21; m/z (CI) 526.2179
(M1); C25H38N2O2S2 requires 526.2172. Found: C, 56.91;
H, 7.26; N, 5.26%. Calcd for C25H38N2O6S2: C, 57.06; H,
7.28; N, 5.32%. [a]2D5ˆ1138 (cˆ1.0, CHCl3).
(1)-anti-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-
2-phenylethanoyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-oxide
(1)-anti-5f. Treatment of (1)-anti-4f (0.60 g, 2.13 mmol)
with a 1 M solution of LHMDS in THF (2.34 mL,
2.34 mmol), DBAD (0.54 g, 2.34 mmol) and acetic acid
(0.38 mL, 6.38 mmol) as described above gave (1)-anti-
5f as a colourless foam (0.92 g, 85%), mp 52±548C; nmax
3241, 1745, 1731, 1690 and 1041 cm21; m/z (FAB)
513.2092 (M11H); C24H37N2O6S2 requires 513.2093.
(^)-anti-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-
3-phenylpropanoyl)-2-ethyl-1,3-dithiane 1-oxide (^)-
anti-5e. A solution of sodium metaperiodate (0.14 g,
0.65 mmol) in water (5 mL) was added to a stirred solution
of (^)-6 (0.31 g, 0.61 mmol) in methanol (15 mL) at 08C.
After 2 days, the reaction was ®ltered, the ®ltrate extracted
with dichloromethane, the organic fractions were combined
and dried over magnesium sulfate, and the solvents removed
in vacuo. Column chromatography using 50% ethyl acetate/
hexane gave (^)-5e (0.22 g, 70%). Data as above.
General procedure for hydrolysis of 1,3-dithiane
1-oxides to give diketones
Found: C, 56.09; H, 7.19;
N 5.06%. Calcd for
C24H36N2O6S2: C, 56.22; H, 7.08; N, 5.47%. [a]2D5ˆ
A solution of the substrate in acetone was added to a stirred
solution of N-bromosuccinimide (8.0 equiv.) in acetone/
water (97:3) at 08C. The resulting mixture was stirred at
08C until completion of the reaction (15±30 min) and then
quenched with saturated aqueous sodium sul®te. The reac-
tion mixture was extracted with dichloromethane (£3), the
organic fractions combined, dried over magnesium sulfate,
and concentrated in vacuo. The crude product was puri®ed
by ¯ash column chromatography using dichloromethane as
eluent.
1210.0 (cˆ0.23, CHCl3).
(1)-anti-2-(2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-
3-methylpropanoyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-oxide
(1)-anti-5g.
Treatment
of
(1)-anti-4g
(2.28 g,
9.19 mmol) with a 1 M solution of LHMDS in THF
(10.1 mL, 10.1 mmol), DBAD (2.32 g, 10.1 mmol) and
acetic acid (1.65 mL, 30.3 mmol) as described above gave
(1)-anti-5g as a colourless powder (3.92 g, 89%), mp 144±
1458C; nmax 3207, 1729, 1709, 1693 and 1056 cm21; m/z
(FAB) 479.2242 (M11H); C21H39N2O6S2 requires
479.2250. Found: C, 52.28; H, 8.04; N, 5.67%. Calcd for
C21H38N2O6S2: C, 52.69; H, 8.00; N, 5.85%. [a]2D5ˆ185
(cˆ0.53, CHCl3).
(2)-2-(S)-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-1-
phenylhexan-3,4-one (2)-7e. Treatment of (1)-anti-5e
(4.00 g, 7.6 mmol) in acetone (100 mL) with NBS (10.9 g,
60.8 mmol) in aqueous acetone (150 mL) as described
above gave (2)-7e as a bright yellow glass (2.70 g, 85%);
max 1718 cm21; dH (400 MHz, CDCl3, 323 K) 1.05 (3H, t,
(1)-anti-2-(2-(N,N'-Bis-(tert-butoxycarbonyl)hydrazino)-
3,3-dimethylpropanoyl)-2-(R)-ethyl-1,3-dithiane 1-(R)-
oxide (1)-anti-5h. Treatment of (1)-anti-4h (3.00 g,
11.5 mmol) with a 1 M solution of LHMDS in THF
(11.6 mL, 11.6 mmol), DBAD (2.90 g, 11.6 mmol) and
acetic acid (1.96 mL, 34.7 mmol) as described above gave
(1)-anti-5h as a colourless powder (5.11 g, 91%), mp 126±
1288C; nmax 3173, 1707, 1692 and 1056 cm21; m/z (FAB)
493.2407 (M11H); C22H41N2O6S2 requires 493.2413.
Found: C, 53.37; H, 8.23; N, 5.65%. Calcd for
C22H40N2O6S2: C, 53.63; H, 8.18; N, 5.69%. [a]2D5ˆ122
(cˆ1.0, CHCl3).
n
Jˆ7.0 Hz), 1.38 (9H, s), 1.43 (9H, s), 2.68±2.78 (3H, m),
3.11 (2H, br s), 6.25 (1H, br s, NH), and 7.16±7.30 (5H, m);
m/z (FAB) 443.2177 (M11Na); C22H32NaN2O6 requires
443.2158. Found: C, 62.71; H, 7.64; N, 6.63%. Calcd for
C22H32N2O6: C, 62.83; H, 7.67; N, 6.66%. [a]2D5ˆ242
(cˆ1.0, CHCl3).
(1)-1-(S)-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-1-
phenylpentan-2,3-one (1)-7f. Treatment of (1)-anti-5f
(0.60 g, 1.17 mmol) in acetone (25 mL) with NBS (1.67 g,
9.37 mmol) in aqueous acetone (35 mL) gave (1)-7f as a

9694
P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
bright yellow oil (0.320 g, 72%); nmax 1710, 1682 and
1651 cm21; dH NMR (400 MHz, CDCl3, 323 K) 1.02 (3H,
t, Jˆ7.1 Hz), 1.46 (9H, s), 1.50 (9H, s), 2.83 (2H, q,
Jˆ7.0 Hz), 6.40 (1H, br s, NH), and 7.28±7.54 (5H, m).
[a]2D5ˆ180 (cˆ1.0, CHCl3).
(2)-3-(S)-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-2-
methylheptan-4,5-one (2)-7g. Treatment of (1)-anti-5g
(2.30 g, 4.8 mmol) in acetone (75 mL) with NBS (6.85 g,
38.4 mmol) in aqueous acetone (100 mL) gave (2)-7g as a
bright yellow oil (1.28 g, 72%); nmax 1737, 1721, 1713 and
1699 cm21; dH (400 MHz, CDCl3, 323 K) 0.91 (3H, br d,
Jˆ6.4 Hz), 0.98 (3H, d, Jˆ6.4 Hz), 1.10 (3H, t, Jˆ7.2 Hz),
1.44 (9H, s), 1.48±1.52 (9H, m), 2.27±2.37 (1H, m), 2.72±
2.81 (2H, m), 5.02 (1H, br s), and 6.21 (1H, br s, NH); m/z
(FAB) 372.2256 (M1); C18H32N2O6 requires 372.2261.
[a]2D5ˆ264 (cˆ1.0, CHCl3).
diimide (3.03 g, 14.7 mmol), 4-dimethylaminopyridine
(0.16 g, 1.3 mmol) and benzyl alcohol (1.52 mL,
14.7 mmol) were added to a stirred solution of dihydro-
cinnamic acid (2.0 g, 13.3 mmol) in diethyl ether (50 mL).
After 4 h, the solution was ®ltered, the ®ltrate washed with
water (4£50 mL), dried over magnesium sulfate, and
concentrated in vacuo. Column chromatography using
10% ethyl acetate/ petroleum ether as eluent gave 9 as a
colourless oil (2.70 g, 84%); nmax 1735 cm21; dH (200 MHz,
CDCl3) 2.68 (2H, t, Jˆ7.4 Hz), 2.97 (2H, t, Jˆ7.4 Hz), 5.10
(2H, s), and 7.16±7.31 (10H, m); m/z (EI) 240.1151 (M1);
C16H16O2 requires 240.1150.
(^)-2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-phenyl-
propanoic acid, benzyl ester (^)-10e.16 A solution of
n-butyllithium in hexanes (1.04 mL, 2.50 mmol) was
added To a stirred solution of diisopropylamine (0.30 mL,
2.29 mmol) in THF (5 mL) at 08C. After 30 min, the reac-
tion was cooled to 2788C, and a solution of 9 (0.50 g,
2.08 mmol) in THF (3 mL) added. After a further 30 min,
a cooled solution of DBAD (0.53 g, 2.30 mmol) in dichloro-
methane was transferred by cannula into the reaction vessel.
The reaction was allowed to reach room temperature before
normal work-up. Column chromatography using dichloro-
methane as eluent gave (^)-10e as a colourless viscous oil
(0.550 g, 56%); nmax 3325 and 1735 cm21; dH (400 MHz,
CDCl3, 323 K) 1.40 (9H, s), 1.42 (9H, s), 3.18 (2H, d,
Jˆ7.2 Hz), 5.03 (1H, br s), 5.09 (2H, s), 6.23 (1H, br s,
NH), and 7.15±7.32 (10H, m); m/z (FAB) 493.2304
(M11Na); C26H34NaN2O6 requires 493.2315.
(1)-3-(S)-(N,N'-Bis-(tert-butoxycarbonyl)hydrazino)-2,2-
dimethylheptan-4,5-one (1)-7h. Treatment of (1)-anti-5h
(2.50 g, 5.1 mmol) in acetone (100 mL) with NBS (7.23 g,
40.7 mmol) in aqueous acetone (100 mL) gave (1)-7h as a
bright yellow oil (1.06 g, 54%); nmax 1721, 1710 and
1684 cm21; dH (400 MHz, CDCl3, 323 K) 1.01 (3H, t,
Jˆ7.0 Hz), 1.06 (9H, s), 1.49 (9H, s), 1.53 (9H, s), 1.46±
1.53 (2H, m), and 3.92 (1H, s); m/z (FAB) 387.2489
(M11H); C19H35N2O6 requires 387.2495. Found: C,
58.65; H, 8.92; N, 6.95%. Calcd for C19H34N2O6: C,
59.04; H, 8.87; N, 7.25%. [a]2D5ˆ154 (cˆ1.0, CHCl3).
(2)-2-(S)-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-
phenylpropanoic acid (2)-8e. A solution of sodium meta-
periodate (1.02 g, 4.76 mmol) in water (50 mL) was added
to a stirred solution of (2)-7e (1.0 g, 2.38 mmol) in metha-
nol (50 mL). After 24 h, the reaction was ®ltered, the ®ltrate
extracted with dichloromethane, and the organic fractions
combined, dried over magnesium sulfate, and concentrated
in vacuo. Flash column chromatography using 50% ethyl
acetate/dichloromethane as eluent gave (2)-8e as a colour-
less oil (0.770 g, 85%); nmax 3400±2600, 1745 and
1711 cm21; dH (400 MHz, CDCl3, 323 K) 1.47 (18H, s),
3.15 (1H, br s), 3.41 (1H, br d, Jˆ7.4 Hz), 3.46 (1H, br s),
6.19 (1H, br s, NH), and 7.18±7.33 (5H, m); m/z (FAB)
403.1850 (M11Na); C19H28NaN2O6 requires 403.1845.
Found: C, 59.98; H, 7.64%. Calcd for C19H28N2O6: C,
59.98; H, 7.42%. [a]2D0ˆ256 (cˆ1.0, CHCl3).
(^)-2-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-phenyl-
propanoic acid (^)-8e. Palladium on carbon catalyst
(0.060 g) was added to a solution of (^)-10e (0.500 g,
1.06 mmol) in ethyl acetate (20 mL), and the mixture placed
under a slight static positive pressure of hydrogen and
rapidly stirred. After 4 h, the reaction was ®ltered through
a pad of celite and the ®ltrate concentrated to give (^)-8e as
a colourless foam (0.381 g, 94%). Data as given above.
(2)-2-(S) (N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-
phenylpropanoic acid, benzyl ester (2)-10e.16 Dicyclo-
hexylcarbodiimide (0.45 g, 2.17 mmol), 4-dimethylamino-
pyridine (0.024 g, 0.20 mmol) and benzyl alcohol (0.22 mL,
2.17 mmol) were added to a stirred solution of (2)-8e
(0.75 g, 1.97 mmol) in diethyl ether (20 mL). After 8 h,
the solution was ®ltered, the ®ltrate washed with water
(4£50 mL), dried over magnesium sulfate, and concentrated
in vacuo. Column chromatography using 10% ethyl acetate/
dichloromethane as eluent gave (2)-10e as a clear colour-
less glass (0.814 g, 88%). [a]2D0ˆ24.16 (cˆ2.0, CHCl3),
other data as above for racemate.
(2)-2-(S)-(N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-
methylbutanoic acid (2)-8g. A solution of sodium meta-
periodate (1.53 g, 4.86 mmol) in water (25 mL) was added
to a stirred solution of (2)-7g (0.90 g, 2.42 mmol) in metha-
nol (40 mL). After 48 h, the reaction was ®ltered, the ®ltrate
extracted with dichloromethane, and the organic fractions
combined, dried over magnesium sulfate, and concentrated
in vacuo. Flash column chromatography using 50% ethyl
acetate/dichloromethane as eluent gave (2)-8g as a colour-
(2)-2-(S) (N,N0-Bis-(tert-butoxycarbonyl)hydrazino)-3-
methylbutanoic acid, benzyl ester (2)-10g.16 Dicyclo-
hexylcarbodiimide (0.068 g, 0.33 mmol), 4-(dimethyl-
amino)pyridine (0.004 g, 0.03 mmol) and benzyl alcohol
(0.034 mL, 0.33 mmol) were added to a stirred solution of
(2)-8g (0.100 g, 0.30 mmol) in diethyl ether (3 mL). After
4 h, the solution was ®ltered, the ®ltrate washed with water
(4£5 mL), dried over magnesium sulfate, and concentrated
in vacuo. Column chromatography using 10% ethyl acetate/
dichloromethane as eluent gave (2)-10g as a viscous oil
less oil (0.328 g, 41%); nmax 3600±2600, and 1718 cm21
;
dH (400 MHz, CDCl3, 323 K) 1.01 (3H, d, Jˆ6.8 Hz), 1.08
(3H, d, Jˆ6.8 Hz), 1.47 (9H, s), 1.51 (9H, s), 2.31±2.38
(1H, m), and 6.65 (1H, br s, NH); m/z (FAB) 355
(M11Na). [a]2D0ˆ224 (cˆ1.0, CHCl3).
Hydrocinnamic acid, benzyl ester 9. Dicyclohexylcarbo-

P. C. B. Page et al. / Tetrahedron 56 (2000) 9683±9695
9695
(0.106 g, 83%). [a]2D0ˆ25.09 (cˆ1.9, CHCl3), other data as
Appl. Chem. 1988, 60, 39; Oppolzer, W.; Tamura, O. Tetrahedron
Lett. 1990, 31, 991; Oppolzer, W.; Moretti, R. Helv. Chim. Acta
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above for racemate.
15. Gennari, C.; Bertolini, G.; Colombo, L. J. Am. Chem. Soc.
1986, 108, 6394.
Acknowledgements
16. Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria Jr., J. F.
J. Am. Chem. Soc. 1986, 108, 6395.
This investigation has enjoyed the support of the EPSRC
and SmithKline Beecham Pharmaceuticals.
17. Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria Jr, J. F.
Tetrahedron 1988, 44, 5525; Evans, D. A.; Evrard, D. A.;
Rychnovsky, S. D.; FruÈch, T.; Whittingham, W. G.; DeVries,
K. M. Tetrahedron Lett. 1992, 33, 1189; Evans, D. A.; Britton,
T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,
4011.
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