Aziridines from intramolecular alkene aziridination of sulfamates: Reactivity toward carbon nucleophiles. application to the synthesis of spisulosine and its fluoro analogue

Article abstract of DOI:10.1021/jo201209x

Catalytic intramolecular alkene aziridination of sulfamate is an emerging methodology for the asymmetric synthesis of chiral functionalized amines involving the formation of bicyclic aziridines. This study demonstrates the ability of the latter to undergo

Full text of DOI:10.1021/jo201209x

ARTICLE
pubs.acs.org/joc
Aziridines from Intramolecular Alkene Aziridination of Sulfamates:
Reactivity toward Carbon Nucleophiles. Application to the Synthesis
of Spisulosine and Its Fluoro Analogue
Guillaume Malik, Audrey Estꢀeoule, Pascal Retailleau, and Philippe Dauban*
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette, France
S Supporting Information
b
ABSTRACT: Catalytic intramolecular alkene aziridination of sulfamate is
an emerging methodology for the asymmetric synthesis of chiral function-
alized amines involving the formation of bicyclic aziridines. This study
demonstrates the ability of the latter to undergo ring-opening with various
carbon nucleophiles: Grignard reagents, lithium salts of terminal alkynes,
dithiane, malonate. These SN2-type reactions occur with high levels of
regio- and chemoselectivity to generally afford seven-membered cyclic
sulfamidates in good yields. Carbon nucleophiles have also been found to
react with these sulfamidates provided that the sulfamate ester has been previously activated by introduction of a tosyl substituent on
the NH group. The versatility of this strategy has been illustrated with the syntheses of spisulosine and its fluoro analogue.
’ INTRODUCTION
aziridination of sulfonamides.12 However, in comparison, the
application of the reaction conditions to sulfamates affords much
more versatile heterocycles. These are ambident synthetic inter-
mediates that could undergo successive regioselective nucleo-
philic displacements leading, after acidic hydrolysis, to substituted
deprotected amines (Scheme 1).13,14
Surprisingly, whereas the reactivity of bicyclic aziridines of
type 1 and their corresponding sulfamidates 2 with heteroatom
nucleophiles has been documented, the use of carbon reagents
has been investigated very rarely.15 Particularly, in the case of
compounds 2, the limited number of examples involving a
C-nucleophile reported until now generally occur under rather
harsh conditions and with low to moderate yields. In this context,
Kumada coupling starting from a phenol-derived sulfamate
appears to be the sole reaction of broad application described
so far.16 These observations prompted us to study the nucleo-
philic ring-opening of either sulfamate-derived aziridines or
seven-membered cyclic sulfamidates, with various C-reagents
in order to broaden the scope of the methodology. The results of
our investigations as well as their application to the synthesis of
spisulosine and its fluoro analogue are described therein.
The ability of aziridines to undergo ring-opening with a wide
range of nucleophiles offers unique opportunities for the pre-
paration of substituted nitrogen-containing products that are
ubiquitous in nature or medicinal chemistry.1 As a result, these
heterocycles are receiving increasing attention, and among the
various reactions available for their preparation, catalytic olefin
aziridination stands as one of the most attractive methods. The
simple insertion of a metallanitrene into a π-bond provides an
efficient straightforward access to aziridines,2 and the variety of
alkenes which have been found to react makes this transforma-
tion a versatile tool to generate molecular diversity. Several
nitrogen reagents such as azides, haloamines, and N-sulfonyl-
oxycarbamates have proved to be efficient nitrene precursors,3 but
the most significant results have been reported with species
produced with iodine(III) oxidants. Initially based on the use of
preformed iminoiodanes (PhIdNSO2R),2a,4 the synthetic value
of catalytic nitrene transfer has then been improved with the
discovery of one-pot procedures allowing in situ formation of
these reagents from sulfonamides, carbamates, and sulfamates.5
In parallel, a growing number of metals6 has been found suitable
to catalyze alkene aziridination, with copper7 and rhodium8
complexes remaining the catalysts of choice in terms of enantio-
selective catalysis9 and synthetic applications.10
’ RESULTS AND DISCUSSION
Intramolecular alkene aziridination of sulfamates, easily pre-
pared by simple sulfamoylation of the corresponding alcohols
using a combination of chlorosulfonyl isocyanate and formic
acid,17 is catalyzed by either copper(I) salts and iodosylben-
zene13 or rhodium(II) complexes in the presence of PhI(OAc)2
and MgO.14 Both metals efficiently mediate the intramolecular
The search for strategies involving intramolecular metallani-
trene delivery has culminated in processes that occur with high
levels of chemo- and stereocontrol. They give access to new
heterocyclic scaffolds that offer unique opportunities as high-
lighted in several successful total syntheses of complex natural
alkaloids achieved by the group of Du Bois.11 We have been
extensively involved in these methodological developments
with initial studies devoted to the intramolecular catalytic
Received: June 10, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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Scheme 1. Catalytic Aziridination of Sulfamates and Nucleophilic Ring-Opening
Scheme 2. Ring-Opening of Aziridines 1a and 1b with
C-Nucleophiles
the carbon atom bearing the incoming nucleophile hence C5.18
However, contrary to what was initially reported, we have
noticed that the substitution pattern on the sulfamate has an
influence on the sense of the addition. A reversal of selectivity has
thus been observed in the case of aziridine 1b. Whereas addition
of malonate provides the expected seven-membered cyclic
sulfamidate 7, methylmagnesium bromide attacks at the benzylic
site, leading to oxathiazinane 8 in good yield. Evidence for this
difference in reactivity was provided by NMR experiments:
COSY spectra allowed us to unambiguously identify the hydro-
gen R to the NH for both compounds. But correlation between
the latter and the ortho-carbons of the phenyl group was detected
by HMBC only in the case of the seven-membered derivative 7.19
Formation of compounds 3ꢀ7 has been rationalized by Du Bois
who has invoked a higher coefficient of the LUMO orbital at
C5.14b Nucleophilic attack at C4 would also be disfavored by
torsional strain in the transition state while X-ray studies and
modeling calculations suggest a slightly shorter hence weaker
C5ꢀN bond in aziridines 1. In the case of 1b, introduction of a
phenyl group did not reverse the regioselectivity with azide or
thiophenol which can be considered as soft nucleophiles.14b
Therefore, the result obtained with methylmagnesium bromide,
a rather hard nucleophile, might be attributed to a ring-opening
at the benzylic site which would be under charge control.20
The chemoselectivity of the aziridine ring-opening offers
the opportunity to introduce a second nucleophile because the
other electrophilic sites have been left intact. Nucleophilic ring-
opening of five- and six-membered cyclic sulfamates is well
documented,15,21 but less attention has been paid to seven-
membered analogues. As initially demonstrated by Du Bois
and our group, such a process is facilitated by introduction of
an electron-withdrawing substituent on the sulfamidate nitrogen
prior to ring-opening. Cbz or Boc groups have thus been found
appropriate to activate the sulfamate.13a,14b However, these
protecting groups proved not to be robust enough in the
presence of a carbon nucleophile because addition preferentially
takes place at the carbamoyl center, affording the starting NH-
free cyclic sulfamidates. This observation led us to consider
N-(sulfonyl)sulfamates as a viable alternative. Nosyl derivatives
were first investigated though unsuccessfully regardless of the
reagents used (Grignard reagents, lithium alkynides, etc.). The
reactions generally provide complex mixtures as a consequence
of the preferred nucleophilic attack at the sulfur center. Intro-
duction of the less electrophilic tosyl group thus allowed us to
find suitable conditions to perform ring-opening of a cyclic
sulfamate of type 2. Within the aim of synthesizing spisulosine
(vide infra), it was decided to carry out these studies with the
N-(tosyl)sulfamate 9 (Scheme 3).
nitrene addition affording bicycle-[4.1.0] and -[5.1.0] systems in
good yields (generally greater than 70%). The hallmark of this
reaction, which tolerates the presence of various functional
groups, is its stereospecificity with respect to olefin geometry,
i.e., trans- and cis-alkenes give rise to trans- and cis-aziridines,
respectively. Enantioselective processes have also been reported
though only with chiral copper salts so far, allowing the formation
of aziridines with ees of up to 84%.13b For the purpose of our
study, application of the previously published procedure13a
allowed us to isolate cyclic sulfamates 1a and 1b in 72% and
78% yield, respectively.
Reactivity with Carbon Nucleophiles. Heterocycles of type
1 display several electrophilic sites likely to react with a nucleo-
phile: both carbon atoms of the aziridine, the carbon atom
substituted by the sulfamoyl group, and the sulfur center.
Fundamentally, Du Bois14b and our group13a have shown that
nucleophilic displacement occurs chemo- and regioselectively at
C5 position to afford seven-membered cyclic sulfamidates of
type 2 with nitrogen-, oxygen-, and sulfur-derived reagents. On
the basis of these results, we decided to document the reaction of
1 with carbon nucleophiles, particularly with nonstabilized
reagents, for the formation of CꢀC bonds. We were thus very
pleased to observe that heterocycles 1 react smoothly in the
presence of various C-nucleophiles to afford the ring-opened
products with yields in the 52ꢀ78% range (Scheme 2).
In the case of aziridine 1a, addition of anions generated from
dimethyl malonate, 1,3-dithiane, or pentyne proceeds with
complete regio- and stereocontrol at C-5, and so does the
reaction with methylmagnesium bromide. The regioselectivity,
identical to that observed in previous work, was demonstrated by
HMBC experiments, which show a correlation between H7 and
Nucleophilic substitution proceeds with the soft nucleophiles
diethyl malonate or dithiane to afford the expected products 10
and 11 in 34% and 48% yield, respectively. Comparable yields of
28% and 32% are observed with reactions involving 3 equiv of
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Scheme 3. Ring-Opening of Sulfamate 9 with C-Nucleophiles
lithiated pent-1-yne and tridecyne. Attempts to increase the
reactivity of these reagents by addition of HMPA did not really
improve the conversion though compound 13 was obtained with
a similar yield of 34% using only 1.2 equiv of lithium tridecynide.
This somewhat disappointing result can be explained by the
formation of a side product, the unsaturated amino alcohol 14,
which is isolated in 30% yield. The latter would be generated by
elimination of the sulfamate induced by the alkynide, the basicity
of which would be exacerbated by HMPA. Finally, the best results
were found with Grignard reagents in the presence of a sub-
stoichiometric amount of copper iodide. Good conversions are
therefore achieved using commercially available ethyl- and decyl-
magnesium bromide, leading to the isolation of the expected
products 15 and 16 in 70% and 58% yield, respectively.
Synthesis. Having demonstrated the capacity to transform
aziridines 1 by sequential addition of various carbon and
heteroatom nucleophiles into substituted amines, our studies
were then aimed at applying the intramolecular aziridination of
sulfamates to the total synthesis of natural bioactive compounds.
Spisulosine [(2S,3R)-2-amino-3-octanedecanol 17] was thus
regarded as a relevant target in this context. This marine natural
product was first isolated from the clam Spisulosa polynyma and
displays potent antitumoral activities against several cancer cell
lines and has entered clinical trials for the treatment of solid
tumors.22 Also worthy of note is the mechanism of action
because spisulosine is a potent apoptotic inducer as a conse-
quence of intracellular ceramide accumulation and PKCS
activation.23 Not surprisingly, its biological activity as well as its
rather simple structure have triggered the interest of several
synthetic chemists.24 Various efficient strategies, generally rely-
ing on the use of the chiral pool, have therefore been reported
and only recently has the first catalytic asymmetric synthesis of
spisulosine, based on the application of Sharpless dihydroxyla-
tion, been described by Panda et al.24g By comparison, one of the
features of our approach involving catalytic asymmetric aziridi-
nation of sulfamates is its versatility. In addition to the total
synthesis, it provides the opportunity to carry out SAR studies by
simple choice of the nucleophiles added sequentially to the
aziridine 1a (Scheme 4). Therefore, while we obviously planned
to successively introduce an alcohol and then a C-nucleophile as
part of the preparation of 17, we also decided to target the fluoro
analogue 18.
Scheme 4. Synthetic Strategy for the Preparation of
Spisulosine and Its Fluoro Analogue
Copper-catalyzed asymmetric alkene aziridination mediated
by PhIO and applied to sulfamate 19 leads to aziridine 1a in 78%
yield and 80% ee (Scheme 5).13b The latter can then be trans-
formed efficiently by reaction with benzyl alcohol in the presence
of boron trifluoride etherate to afford the seven-membered
sulfamidate 20 as a white solid, which can be recrystallized to
give enantiomerically pure material. X-ray analysis thus allowed
us to confirm the absolute configuration, namely 4S,5R, that
matches the stereochemistry of the natural product. Installation
of an N-tosyl group is finally carried out by simple protection in
the presence of sodium tert-butylate in DME.
Similar results were obtained when aziridine 1a was subjected
to nucleophilic ring-opening with TBAF in THF: reaction takes
place at C5 to give the fluoro derivative 21 isolated with a good
yield of 75%. A subsequent tosylation step then leads to a solid,
the recrystallization of which affords optically pure 22. X-ray
crystallography analysis, once again, allowed us to secure the
regio- and stereochemistry of the aziridine ring-opening.
We next capitalized on the ability of cyclic sulfamates to
undergo reactions with carbon nucleophiles to introduce the
lipophilic alkyl chain. As previously demonstrated, the lithiated
anion of tridecyne reacts with 9 to give the expected product 13
though with a modest yield of 34% (Scheme 6).25 Removal of the
N-tosyl group from nitrogen then proceeds via a two-step
procedure involving carbamoylation with a Boc group prior to
reductive cleavage using magnesium in methanol under sonica-
tion.26 Hydrogenolysis of the resulting compound 23 with palla-
dium on charcoal efficiently induces reduction of the triple bond
and concomitant removal of the benzyl group. Finally, acidic
hydrolysis of the Boc group affords the hydrochloride salt of
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Scheme 5. Preparation of N-(Tosyl)sulfamidates 9 and 22
Scheme 6. Final Steps for the Synthesis of Spisulosine 17
in favor of the (E)-isomer. Finally, an identical sequence of
deprotection reactions applied to 26 led us to isolate the fluoro
analogue of spisulosine 18. Cytotoxic properties were then
evaluated on various cancer cell lines at the ICSN. While the
potent biological activity of spisulosine has been confirmed on
KB, HCT116, and HL60 cells (IC50 in the 100 nM range), the
fluoro derivative 18 has been found completely inactive even at
micromolar concentrations.
In conclusion, copper-catalyzed intramolecular asymmetric
aziridination of sulfamates is a versatile method for the syn-
thesis of optically pure substituted amines as highlighted by its
application to spisulosine and its fluoro analogue. The metho-
dology involves the formation of bicyclic aziridines displaying
several electrophilic sites, the relative reactivity of which can be
nicely controlled. Importantly, this work has demonstrated that
chemoselective sequential addition of different carbon nucleo-
philes can be achieved. Application of this strategy to the asym-
metric total synthesis of natural nitrogen-containing products is in
progress in our group.
Scheme 7. Final Steps for the Synthesis of the Fluoro Deri-
vative 18
’ EXPERIMENTAL SECTION
General Procedure for the Preparation of Bicyclic Azir-
idines 1a and 1b. A solution of [Cu(MeCN)4]PF6 (5 mol %) in
MeCN was stirred under argon at room temperature for 30 min in the
presence of 4 Å molecular sieves. The appropriate sulfamate (1 equiv)
dissolved in MeCN and PhIO (1.5 equiv) were then sequentially added.
The mixture was stirred for 48 h. After completion of the reaction
(monitored by TLC), the mixture was filtered through a pad of Celite
and concentrated. The products were purified by flash chromatography
to afford the desired aziridine in racemic form.
spisulosine 17. Isolation of the latter was confirmed by physical
and spectroscopic data that were comparable to those previously
reported.24
In contrast, starting from the fluoro intermediate 22, applica-
tion of the same strategy proved unsuccessful. Thus, contrary to
the previous case, reaction with lithium alkynides only affords the
vinylic fluoro derivative 25 in 60% yield (Scheme 7). This result
can be explained by the presence of the fluorine that increases the
lability of the sulfamate, thereby favoring its elimination under
basic conditions. This was confirmed by the reaction performed
with nBuLi and HMPA that gives the same product with the same
yield. Nevertheless, alkene 25 was considered as a useful inter-
mediate. Inspired by the previous studies of the Chemla group,24c
Grubbs-II-catalyzed cross-metathesis was found to proceed
nicely to give the alkene 26 as a mixture of isomers in a 2:1 ratio
trans-7-Methyl-3-oxa-2-thia-1-azabicyclo[4.1.0]heptane 2,2-Diox-
ide (1a). Prepared following the general procedure using Cu(MeCN)4-
PF6 (52 mg, 0.091 mmol), PhIO (600 mg, 2.7 mmol), the sulfamate
(300 mg, 1.8 mmol), and MeCN (10 mL). Purification by flash chro-
matography with heptane/EtOAc (60/40) affords compound 1a as an
1
oil (72%). Rf = 0.15 (heptane/EtOAc 50/50); H NMR (300 MHz,
CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 4.63 (ddd, 1H, J = 12.7, 6.4 and
6.1), 4.37 (ddd, 1H, J = 12.2, 6.4 and 6.3), 2.93 (m, 2H), 2.38 (m, 1H),
2.25 (m, 1H), 1.35 (d, 3H, J = 5); 13C NMR (75 MHz, CDCl3, 25 °C, δ
CDCl3 = 77.16 for the central peak): δ = 68.6 (CH2), 48.8 (CH), 42.9
(CH), 19.0 (CH2), 17.1 (CH3); IR (Neat): ν = 2977, 2358, 1445, 1359,
1182, 780 cmꢀ1; HRMS (TOF MS ES+; MeOH/CH2Cl2): m/z
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calculated for C5H9NO3S: (M + Na) calcd = 186.0201, found =
186.0206.
(4R*,5S*)-4,5-Dimethyl-1,2,3-oxathiazepane 2,2-Dioxide (5). MeMgBr
in ether (410 μL, 1.2 mmol, 2 equiv) was added to a suspension of CuI
(18 mg, 0.09 mmol, 0.15 equiv) in THF (2 mL) under an atmosphere of
argon at ꢀ78 °C. After 20 min of stirring, aziridine 1a (100 mg, 0.6 mmol,
1 equiv) was added and the solution was stirred for 15 min at ꢀ78 °C and
45 min at 0 °C. The mixture was quenched with a saturated solution
of NH4Cl. The aqueous layer was extracted three times with EtOAc.
The organic layers were combined, dried over MgSO4, and concentrated.
The product was purified by flash chromatography with heptane/EtOAc
(60/40) to yield a white solid (56%). Rf = 0.54 (heptane/EtOAc 60/40);
mp 75ꢀ76 °C; 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26):
δ =4.78(d, 1H, J = 9.5), 4.33ꢀ4.24 (m, 1H), 4.21 (tt, 1H, J = 11.6 and 3.2),
3.10 (ddt, 1H, J = 15.8, 9.5 and 6.6), 1.92ꢀ1.74 (m, 2H), 1.73ꢀ1.59
(m, 1H), 1.21 (d, 3H, J = 6.8), 0.89 (d, 3H, J = 6.6); 13C NMR (75 MHz,
CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak): δ = 69.6 (CH2), 54.5
(CH), 41.3 (CH), 37.1 (CH2), 20.2 (CH3), 19.4 (CH3); IR (Nujol): ν =
3266, 2958, 1334, 1168, 1121, 971, 746 cmꢀ1; HRMS: (TOF MS ESꢀ;
MeOH/CH2Cl2): m/z calculated for C6H13NO3S: (M ꢀ H) calcd =
178.0538, found = 178.0538.
The enantioenriched aziridine 1a (78%, 80% ee) was prepared by
using 5.5 mol % of (S,S)-2,20-isopropylidene-bis(4-tert-butyl-2-oxazoline)
according to the procedure previously described in the literature.13b
Enantiomeric excess was determined by chiral HPLC (chiral column
AD, hexane/i-PrOH/Et3N 95/5/0.1) after ring-opening of aziridine
with BnNH2.
trans-7-Phenyl-3-oxa-2-thia-1-azabicyclo[4.1.0]heptane 2,2-Dioxide
(1b). Prepared following the general procedure using Cu(MeCN)4PF6
(52 mg, 0.091 mmol), PhIO (600 mg, 2.7 mmol), the sulfamate (405 mg,
1.8 mmol), and MeCN (10 mL). Purification by flash chromatography
with heptane/EtOAc (60/40) affords compound 1b as an oil (78%).
Rf = 0.28 (heptane/EtOAc 60/40); mp 94ꢀ95 °C; 1H NMR (300 MHz,
CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.32ꢀ7.19 (m, 5H), 4.70 (dt, 1H, J =
11.6, and 6.8), 4.46 (dt, 1H, J = 11.5 and 6.4), 3.80 (d, 1H, J = 4.4), 3.18
(dq, 1H, J = 4.6 and 3.2), 2.39 (m, 2H); 13C NMR (75 MHz, CDCl3,
25 °C, δ CDCl3 = 77.16 for the central peak): δ = 134.2 (C quat), 128.8
(4 CHar), 126.3 (CHar), 68.8 (CH2), 50.4 (CH), 47.8 (CH), 18.8
(CH2); IR (Neat): ν = 2985, 1497, 1373, 1357, 1243, 1180, 1054, 955,
905, 693 cmꢀ1; HRMS (TOF MS ES+; MeOH/CH2Cl2): m/z calculated
for C10H11NO3S: (M + Na) calcd = 248.0357, found = 248.0337.
(4R*,5R*)-Dimethyl 2-(4-Methyl-2,2-dioxo-1,2,3-oxathiazepan-5-
yl)malonate (3). Dimethyl malonate (145 μL, 1.2 mmol, 2 equiv) was
added to a suspension of NaH (50 mg, 1.2 mmol, 60% in oil, 2 equiv) in
THF (2 mL) at 0 °C under argon. After 15 min of stirring, aziridine 1a
(100 mg, 0.6 mmol, 1 equiv) was added and the mixture was stirred 12 h
at room temperature before being quenched with a saturated solution of
NH4Cl. The aqueous layer was extracted three times with EtOAc. The
organic layers were combined, dried over MgSO4, and concentrated.
The product was purified by flash chromatography with heptane/EtOAc
(60/40) to yield a colorless oil (65%). Rf = 0.5 (heptane/EtOAc 60/40);
1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 5.30 (d,1H,
J = 8.8), 4.28 (ddd, 2H, J = 5.6, 3.8 and 1.3), 3.72 (s, 6H), 3.59 (d, 1H, J =
4.3), 3.50ꢀ3.35 (m, 1H), 2.42 (ddd, 1H, J = 13.8, 8.8 and 3.7),
2.14ꢀ2.07 (m, 2H), 1.31 (d, 3H, J = 6.9); 13C NMR (75 MHz, CDCl3,
25 °C, δ CDCl3 = 77.16 for the central peak): δ = 168.8 (C quat), 168.1
(C quat), 69.3 (CH2), 52.9 (CH), 52.8 (CH3), 52.7 (CH3), 51.3 (CH),
45.3 (CH), 30.3 (CH2), 20.0 (CH3); IR (Neat): ν = 3283, 2936, 1730,
1434, 1345, 1173, 1122, 1086, 974, 913, 746 cmꢀ1; HRMS: (TOF MS
ES+; MeOH/CH2Cl2): m/z calculated for C10H17NO7S: (M + H) calcd
= 296.0804, found = 296.0811.
(4R*,5S*)-5-(1,3-Dithian-2-yl)-4-methyl-1,2,3-oxathiazepane 2,
2-Dioxide (4). n-BuLi in hexane (770 μL, 1.2 mmol, 2 equiv) was
added to a solution of dithiane (147 mg, 1.2 mmol, 2 equiv) in THF
(2 mL) under argon at ꢀ78 °C. After 15 min, aziridine 1a (100 mg,
0.6 mmol, 1 equiv) was added. The solution was stirred for 15 min
at ꢀ78 °C, 15 min at 0 °C, and 45 min at room temperature.
The mixture was quenched with a saturated solution of NH4Cl.
The aqueous layer was extracted three times with EtOAc. The organic
layers were combined, dried over MgSO4, and concentrated. The
product was purified by flash chromatography with heptane/EtOAc
(60/40) to yield an amorphous yellow solid (52%). Rf = 0.63
(heptane/EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C,
δ CDCl3 = 7.26): δ = 5.06 (d, 1H, J = 8.3), 4.38ꢀ4.24 (m, 2H),
4.21 (d, 1H, J = 3.8), 3.58 (qdd, 1H, J = 8.7, 6.7 and 4.1), 2.97 (ddd,
1H, J = 14.5, 12.3 and 2.6), 2.89ꢀ2.80 (m, 3H), 2.25ꢀ2.20 (m, 5H),
1.38 (d, 3H, J = 6.7); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 =
77.16 for the central peak): δ = 69.4 (CH2), 51.6 (CH), 50.9 (CH),
50.7 (CH), 31.4 (CH2), 30.7 (CH2), 30.3 (CH2), 25.9 (CH2), 19.8
(CH3); IR (Neat): ν = 3305, 3017, 2894, 1454, 1423, 1344, 1214,
1178, 907, 666 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2):
m/z calculated for C9H17NO3S3: (M + Na) calcd = 306.0279,
found = 306.0283.
(4R*,5R*)-4-Methyl-5-(pent-1-yn-1-yl)-1,2,3-oxathiazepane 2,2-Di-
oxide (6). n-BuLi in hexane (770 μL, 1.2 mmol, 2 equiv) was added
to a solution of 1-pentyne (121 μL, 1.2 mmol, 2 equiv) in THF (2 mL)
under an atmosphere of argon at ꢀ78 °C. After 20 min of stirring,
azridine 1a (100 mg, 0.6 mmol, 2 equiv) was added and the solution was
stirred for 15 min at ꢀ78 °C, 45 min at 0 °C, and 12 h at room
temperature. The mixture was quenched with a saturated solution of
NH4Cl. The aqueous layer was extracted three times with EtOAc. The
organic layers were combined, dried over MgSO4, and concentrated.
The product was purified by flash chromatography with heptane/EtOAc
(60/40) to yield a yellow solid (71%). Rf = 0.79 (heptane/EtOAc 60/
1
40); mp 76ꢀ77 °C; H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 =
7.26): δ = 4.91 (d,1H, J = 8), 4.24ꢀ4.11 (m, 2H), 3.29 (ddt, 1H, J = 13.9,
6.9 and 8.2), 2.47ꢀ2.38 (m, 1H), 2.15ꢀ1.90 (m, 2H), 1.99 (dt, 2H, J =
6.9 and 2.1), 1.35 (q, 2H, J = 7.2), 1.29 (d, 3H, J = 6.8), 0.81 (t, 3H, J =
7.3); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the
central peak): δ = 84.5 (C quat), 79.4 (C quat), 68.4 (CH2), 53.0 (CH),
39.1 (CH), 34.5 (CH2), 22.2 (CH2), 20.6 (CH2), 19.6 (CH3), 13.4
(CH3); IR (Neat): ν = 3263, 2964, 1437, 1341, 1170, 964, 912,
752 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated
for C10H17NO3S: (M + Na) calcd = 254.0827, found = 254.0839.
(4R*,5S*)-Dimethyl 2-(2,2-Dioxo-4-phenyl-1,2,3-oxathiazepan-5-
yl)malonate (7). Dimethyl malonate (47 μL, 0.4 mmol, 2 equiv) was
added to a suspension of NaH (20 mg, 0.5 mmol, 60% in oil, 2.5 equiv)
in THF (1 mL) at 0 °C under an atmosphere of argon. After 15 min of
stirring, aziridine 1b (45 mg, 0.2 mmol, 1 equiv) was added and the
mixture was stirred for 12 h at room temperature before being quenched
with a saturated solution of NH4Cl. The aqueous layer was extracted
three times with EtOAc. The organic layers were combined, dried over
MgSO4, and concentrated. The product was purified by flash chroma-
tography with heptane/EtOAc (60/40) to yield an amorphous white
foam (78%). Rf = 0.24 (heptane/EtOAc 60/40); 1H NMR (300 MHz,
CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.41ꢀ7.25 (m, 5H), 5.41 (d, 1H, J
= 8.1), 4.52ꢀ4.41 (m, 2H), 4.36 (dt, 1H, J = 12.9 and 3.4), 3.69 (s, 3H),
3.63 (s, 3H), 3.08 (d, 1H, J = 3.1), 2.90 (tt, 1H, J = 10.6 and 3.2),
2.45ꢀ2.30 (m, 1H), 2.27ꢀ2.18 (m, 1H); 13C NMR (75 MHz, CDCl3,
25 °C, δ CDCl3 = 77.16 for the central peak): δ = 168.8
(C quat), 167.9 (C quat), 138.3 (C quat), 129.5 (CH ar), 129.0 (CH
ar), 127.2 (CH ar), 70.0 (CH2), 59.9 (CH), 52.8 (CH), 52.5 (CH3),
52.4 (CH3), 44.5 (CH), 30.7 (CH2); IR (Neat): ν = 3281, 2954, 2922,
1727, 1434, 1346, 1169, 1050, 701 cmꢀ1; HRMS: (TOF MS ES+;
MeOH/CH2Cl2): m/z calculated for C15H19NO7S: (M + Na) calcd =
380.0780, found = 380.0747.
(4R*,5R*)-5-Methyl-4-phenyl-1,2,3-oxathiazepane 2,2-Dioxide (8).
MeMgBr in ether (300 μL, 0.9 mmol, 2 equiv) was added to a suspension of
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CuI (13 mg, 0.07 mmol, 0.15 equiv) in THF (2 mL) under an
atmosphere of argon at ꢀ78 °C. After 20 min of stirring, aziridine 1b
(100 mg, 0.45 mmol, 1 equiv) was added and the solution was stirred for
15 min at ꢀ78 °C and 45 min at 0 °C. The mixture was quenched with a
saturated solution of NH4Cl. The aqueous layer was extracted three
times with EtOAc. The organic layers were combined, dried over
MgSO4, and concentrated. The product was purified by flash chroma-
tography with heptane/AcOEt (60/40) to yield compound 8 (69%).
Rf = 0.50 (heptane/EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C,
δ CDCl3 = 7.26): δ = 7.40ꢀ7.16 (m, 5H), 4.70 (dt, 1H, J = 11 and 4.5),
4.50 (dt, 1H, J = 10.9 and 3.0), 3.99 (d, 1H, J = 9), 3.93ꢀ3.82 (m, 1H),
2.91 (qd, 1H, J = 7.3 and 6.4), 1.83ꢀ1.69 (m, 2H), 1.38 (d, 3H, J = 7.3);
13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central
peak): δ = 140.3 (C quat), 129.1 (CH ar), 128.0 (CH ar), 127.6 (5 CH
ar), 71.9 (CH2), 60.3 (CH), 43.7 (CH), 27.9 (CH2), 17.6 (CH3); IR
(Neat): ν = 3230, 2958, 1463, 1318, 1197, 1160, 1045, 932, 777,
684 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated for
C11H15NO3S: (M + Na) calcd = 264.0670, found = 264.0668.
(CH2), 27.2 (CH2), 26.0 (CH2), 21.7 (CH3), 15.8 (CH3); IR (Neat): ν =
3276, 2929, 1725, 1598, 1496, 1454, 1423, 1325, 1161, 1090, 908, 815, 738,
699, 667 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated
for C23H31NO3S 3: (M + Na) calcd = 488.1364; found = 488.1382.
(2R*,3S*)-3-Benzyloxy-2-N-(tosyl)aminodec-6-yne (12). n-BuLi in
hexane (530 μL, 0.51 mmol, 3 equiv) was added to a solution of n-
pentyne (52 μL, 0.51 mmol, 3 equiv) in THF (0.75 mL) at ꢀ78 °C
under an atmosphere of argon. The mixture was stirred 1 h, and the
oxathiazepane 9 (75 mg, 0.17 mmol, 1 equiv) in THF (0.75 mL) was
added at ꢀ78 °C. The mixture was allowed to warm to room
temperature. After 16 h of stirring, the mixture was hydrolyzed and
concentrated. The residue was taken up in EtOAc and treated with 1 M
HCl. After 30 min, the aqueous layer was basified with 3 M NaOH
(pH = 11). The aqueous layer was extracted three times with EtOAc, and
the organic layers were combined, dried over MgSO4, and concentrated.
The product was purified by flash chromatography (heptane/EtOAc
80/20) to yield a colorless oil (28%). Rf = 0.43 (heptane/EtOAc 70/30);
1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.69 (d, 2H,
Jo = 8.5), 7.38ꢀ7.20 (m, 7H), 4.62 (d, 1H, J = 7), 4.46 (d, 1H, J = 11.8),
4.31 (d, 1H, J = 11.8), 3.49 (m, 2H), 2.41 (s, 3H), 2.19 (m, 2H), 2.09
(m, 2H), 1.77ꢀ1.43 (m, 4H), 1.07 (d, 3H, J = 6.5), 0.96 (t, 3H, J = 7.2);
13C NMR (75 MHz, CDCl3 , 25 °C, δ CDCl3 = 77.16 for the central
peak): δ = 143.3 (C quat), 138.2 (C quat), 138.0 (C quat), 129.8
(CH ar), 128.6 (CH ar), 128.0 (CH ar), 127.8 (CH ar), 127.2 (CH ar),
81.2 (C quat), 80.4 (CH), 79.1 (C quat), 72.4 (CH2), 51.3 (CH), 29.8
(CH2), 22.6 (CH2), 21.7 (CH3), 20.9 (CH2), 16.1 (CH3), 15.4 (CH2),
13.7 (CH3); IR (Neat): ν = 3279, 2961, 2932, 2872, 1599, 1497, 1455,
1379, 1328, 1163, 1092, 815, 737, 699, 669 cmꢀ1; HRMS: (TOF MS
ES+; MeOH/CH2Cl2): m/z calculated for C24H31NO3S: (M + Na)
calcd = 436.1922, found = 436.1942.
(4R*,5S*)-Ethyl 5-Benzyloxy-2-ethoxycarbonyl-6-N-(tosyl)aminohep-
tanoate (10). Diethyl malonate (53 μL, 0.35 mmol, 2 equiv) was dissolved
in THF (1.5 mL) under an atmosphere of argon at 0 °C. NaH (17 mg, 60%
in oil, 0.42 mmol, 2.5 equiv) was added, and the mixture was stirred for
15 min. Oxathiazepane 9 (75 mg, 0.17 mmol, 1 equiv) in THF (1 mL) was
then added. After overnight stirring at room temperature, the reaction was
quenched with water and concentrated. The residue was taken up
in EtOAc and 1 M HCl. The solution was stirred for 1 h and then treated
with 5 M NaOH (pH = 11). The aqueous layer was extracted three times
with EtOAc. The organic layers were combined, dried over MgSO4, and
concentrated. The product was purified by flash chromatography
(heptane/EtOAc, 85/15 then 70/30) to yield a colorless oil (34%). Rf =
1
0.29 (heptane/EtOAc 70/30); H NMR (300 MHz, CDCl3, 25 °C, δ
(2R*,3S*)-3-Benzyloxy-2-N-(tosyl)aminooctadec-6-yne (13). n-BuLi
in hexane (411 μL, 0.66 mmol, 1.4 equiv) was added to a solution of
tridecyne (153 μL, 0.66 mmol, 1.4 equiv) in a mixture THF/HMPA (5/1,
6 mL) at ꢀ78 °C under an atmosphere of argon. The mixture was stirred
for 1 h, and the oxathiazepane 9 (200 mg, 0.47 mmol, 1 equiv) in THF
(4 mL) was added at ꢀ78 °C. The mixture was allowed to warm to room
temperature. After 16 h of stirring, the mixture was hydrolyzed and
concentrated. The residue was taken up in EtOAc and treated with 1 M
HCl. After 30 min of stirring, the aqueous layer was basified with 3 M
NaOH (pH = 11). The aqueous layer was extracted three times with
EtOAc, and the organic layers were combined, dried over MgSO4, and
concentrated. The product was purified by flash chromatography
(heptane/EtOAc 90/10) to yield compound 13 as a colorless oil
(34%) and the side product 14 (30%). Analysis for compound 13.
Rf = 0.50 (heptane/EtOAc 70/30); 1H NMR (300 MHz, CDCl3, 25 °C,
δ CDCl3 = 7.26): δ = 7.69 (d, 2H, J = 8.2), 7.34ꢀ7.21 (m, 7H), 4.64 (d,
1H, J = 7), 4.45 (d, 1H, J = 11.6), 4.3 (d, 1H, J = 11.6), 3.47 (m, 2H), 2.41
(s, 3H), 2.18 (m, 2H), 2.10 (m, 2H), 1.76ꢀ1.52 (m, 2H), 1.50ꢀ1.2 (m,
18H), 1.07 (d, 3H, J = 6.2), 0.88 (t, 3H, J = 6.6); 13C NMR (75 MHz,
CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak): δ = 143.3 (C quat),
138.2 (C quat), 138.0 (C quat), 129.8 (CH ar), 128.6 (CH ar), 127.9
(CH ar), 127.8 (CH ar), 127.2 (CH ar), 81.4 (C quat), 80.4 (CH), 78.9
(C quat), 72.4 (CH2), 51.3 (CH), 32.1 (CH2), 29.8 (CH2), 29.75
(CH2), 29.7 (CH2), 29.5 (CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2),
22.8 (CH2), 21.7 (CH3), 18.9 (CH2), 16.2 (CH3), 15.4 (CH2), 14.3
(CH3 ); IR (Neat): ν = 3280, 2923, 2852, 1599, 1454, 1326, 1163, 1090,
1027, 813, 735, 697, 668 cmꢀ1; HRMS: (TOF MS ES+; MeOH/
CH2Cl2): m/z calculated for C32H47NO3S: (M + Na) calcd = 548.3174,
found = 548.3183. Analysis for compound 14. Rf = 0.41 (heptane/
EtOAc 70/30); 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26):
δ = 7.67 (d, 2H, Jo = 8.6 Hz,), 7.39ꢀ7.20 (m, 7H), 5.71ꢀ5.56 (m, 1H),
5.34ꢀ5.15 (m, 2H), 4.88 (d, 1H, J = 8.4), 4.5 (d, 1H, J = 12.5 Hz), 4.17
(d, 1H, J = 12.5 Hz), 3, 70ꢀ3.63 (m, 1H), 3.43ꢀ3.34 (m, 1H), 2.40
(s, 3H), 1.07 (d, 3H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3, 25 °C,
CDCl3 = 7.26): δ=7.67(d, 2H,Jo = 8.3), 7.40ꢀ7.20 (m, 7H), 4.68 (d, 1H,
J = 7.4), 4.45 (d, 1H, J = 11.3), 4.29 (d, 1H, J = 11.3), 4.19 (q, 4H, J = 6.7),
3.44 (m, 1H), 3.29 (m, 1H), 3.22 (t, 1H, J = 7.4), 2.41 (s, 3H), 1.85 (m,
2H), 1.60ꢀ1.37 (m, 2H), 1.26 (t, 6H, J = 7.3), 1.03 (d, 3H, J = 6.7); 13
C
NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak): δ =
169.2 (C quat), 143.4 (C quat), 138.1 (C quat), 138.0 (C quat), 129.8
(CH ar), 128.6 (CH ar), 128.0 (CH ar), 127.8 (CH ar), 127.2 (CH ar),
80.8 (CH), 72.1 (CH2), 61.6 (CH2), 51.8 (CH), 51.2 (CH), 27.9 (CH2),
24.9 (CH2), 21.6 (CH3), 15.7 (CH3), 14.2 (CH3); IR (Neat): ν = 3291,
2982, 1730, 1454, 1370, 1331, 1163, 1093, 671 cmꢀ1; HRMS: (TOF MS
ES+; MeOH/CH2Cl2): m/z calculated for C26H35NO7S: (M + Na) calcd
= 528.2032, found = 528.2038.
(2R*,3S*)-3-Benzyloxy-5-(1,3-dithian-2-yl)-2-N-(tosyl)aminopentane
(11). Dithiane (43 mg, 0.35 mmol, 2 equiv) was dissolved in THF (1 mL)
at ꢀ78 °C under an atmosphere of argon then n-BuLi in hexane (350 μL,
0.35 mmol, 2 equiv), was added. After 20 min of stirring, the oxathiaze-
pane 9 (75 mg, 0.17 mmol, 1 equiv) in THF (1 mL) was added. After 1 h
of stirring at 0 °C and 2 h at room temperature, the mixture was quenched
with water and concentrated. The residue was taken up in EtOAc and 1 M
HCl. After 30 min of stirring, the mixture was basified with 5 M NaOH
(pH = 11). The aqueous layer was extracted with EtOAc three times. The
organic layers were combined, washed with brine, dried over MgSO4, and
concentrated. The product was purified by flash chromatography with
heptane/EtOAc (80/20) to yield a yellow oil (48%). R f = 0.59 (heptane/
EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26):
δ = 7.67 (d, 2H, Jo = 8.5), 7.38ꢀ7.28 (m, 5H), 7.25 (d, 2H, Jo = 8.5), 4.68
(d, 1H, J = 7.5), 4.45 (d, 1H, J = 11.6), 4.31 (d, 1H, J = 11.6), 3.89 (t, 1H,
J = 6.6), 3.44ꢀ3.36 (m, 1H), 3.30ꢀ3.25 (m, 1H), 2.85ꢀ2.63 (m, 4H),
2.41 (s, 3H), 2.16ꢀ1.98 (m, 2H), 1.80ꢀ1.55 (m, 4H), 1.05 (d, 3H, J =
7.0); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central
peak): δ = 143.4 (C quat), 138.1(C quat), 137.9 (C quat), 129.8 (CHar),
128.6 (CH ar), 128.0 (CH ar), 127.9 (CH ar), 127.2 (CH ar), 80.5 (CH),
72.0 (CH2), 51.2 (CH), 47.2 (CH), 31.5 (CH2), 30.4 (CH2), 30.3
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δ CDCl3 = 77.16 for the central peak): δ = 143.3 (C quat), 138.2
(C quat), 138.1 (C quat), 134.8 (CH), 129.7 (CH ar), 128.6 (CH ar),
127.9 (CH ar), 127.8 (CH ar), 127.2 (CH ar), 119.7 (CH2), 82.2 (CH),
70.6 (CH2), 53.0 (CH), 21.6 (CH3), 15.9 (CH3); IR (Neat): ν = 3283,
2981, 2925, 2857, 1599, 1497, 1454, 1421, 1329, 1161, 1090, 995, 934,
815, 665 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z
calculated for C19H23NO3S: (M + Na) calcd = 368.1296, found =
368.1298.
and quenched with a saturated solution of NaHCO3. The aqueous layer
was extracted three times with DCM, and all the organic layers were
combined, dried over MgSO4, and concentrated. The product was
purified by flash chromatography (heptane/EtOAc 70/30) to yield a
white solid (77%). This solid can be crystallized from cold toluene to
furnish enantioenriched compound (ee = 97%). Rf = 0.51 (heptane/
EtOAc 50:50); mp 88ꢀ89 °C; [R]24 = ꢀ20.0 (c = 1.14 in CHCl3);
D
1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.42ꢀ7.27
(5H, m), 5.05 (1H, br), 4.62 (1H, d, J = 11.9), 4.5 (1H, ddd, J = 12,8, 9.1
and 2,1), 4.5 (1H, d, J = 11.9), 4.19 (1H, ddd, J = 13.1, 6.7 and 2.1), 3.48
(2H, m), 2.27 (1H, ddt, J = 16.1, 9.2, 2.3), 2.06 (1 H, m), 1.43 (3H, d,
J = 6.6); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the
central peak): δ = 137.5 (C quat), 128.8 (CH ar), 128.3 (CH ar), 127.9
(CH ar), 79.5 (CH), 71.6(CH2), 65.7 (CH), 52.9 (CH), 30.9 (CH), 15.9
(CH3); IR (Neat): ν = 3289, 2873, 1454, 1428, 1347, 1176, 1176, 1072,
976, 916, 746 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z
calculated for C12H17NO4S: (M + Na) calcd = 294.0776, found =
294.0768; Chiral HPLC: IC column 5 μm, Hept/i-prOH 80/20, tR1:
19.07 min, tR2: 20.515 min.
(2R*,3S*)-3-Benzyloxy-2-N-(tosyl)aminoheptane (15). EtMgBr in
ether (235 μL, 0.35 mmol, 2 equiv) was added to a suspension of CuI
(10 mg, 0.053 mmol, 0.3 equiv) in THF (0.75 mL) at ꢀ78 °C under an
atmosphere of argon. After 20 min of stirring, the oxathiazepane 9
(75 mg, 0.17 mmol, 1 equiv) in THF (0.75 mL) was added and the
mixture was allowed to warm to room temperature overnight. The
mixture was quenched with a saturated solution of NH4Cl and con-
centrated. The residue was taken up in EtOAc and 1 M HCl and stirred
for 1 h. The solution was then basified with a solution of 5 M NaOH
(pH = 11). The aqueous layer was extracted with EtOAc three times.
The organic layers were combined, washed with brine, dried over
MgSO4, and concentrated. The product was purified by flash chroma-
tography with heptane/EtOAc (80/20) to yield a colorless oil (78%).
Rf = 0.63 (heptane/EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C,
δ CDCl3 = 7.26): δ = 7.66 (d, 2H, Jo = 7.9), 7.40ꢀ7.28 (m, 5H), 7.24
(d, 2H, Jo = 7.9), 4.75 (d, 1H, J = 7.9), 4.47 (d, 1H, J = 12.0), 4.26 (d, 1H,
J = 12.0), 3.41 (td, 1H, J = 7.4 and 3.6), 3.23 (td, 1H, J = 6.7 and 3.6), 2.41
(s, 3H), 1.60ꢀ1.14 (m, 6H), 1.05 (d, 3H, J = 6.7), 0.86 (t, 3H, J = 6.7);
13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central
peak): δ = 143.1 (C quat), 138.3 (C quat), 138.0 (C quat), 129.6 (CH
ar), 128.4 (CH ar), 127.7 (CH ar), 127.6 (CH ar), 127.0 (CH ar), 81.2
(CH), 71.8 (CH2), 51.2 (CH), 29.8 (CH2), 27.7 (CH2), 22.6 (CH2),
21.5 (CH3), 15.4 (CH3), 13.9 (CH3); IR (Neat): ν = 3281, 2955, 2870,
1599, 1496, 1454, 1324, 1159, 1092, 1066, 1028, 814, 735, 697,
666 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated
for C21H29NO3S: (M + Na) calcd = 398.1766; found = 398.1784.
(2R*,3S*)-3-Benzyloxy-2-N-(tosyl)aminopentadecane (16).C10H21MgBr
in ether (700 μL, 0.35 mmol, 2 equiv) was added to a suspension of CuI
(10 mg, 0.053 mmol, 0.3 equiv) in THF (0.75 mL) at ꢀ78 °C under an
atmosphere of argon. After 20 min of stirring, the oxathiazepane 9 (75 mg,
0.17 mmol, 1 equiv) in THF (0.75 mL) was added and the mixture
was allowed to warm to room temperature overnight. The mixture
was quenched with a saturated solution of NH4Cl and concentrated.
The residue was taken up in EtOAc and 1 M HCl and stirred for 1 h.
The solution was then basified with a solution of 5 M NaOH (pH = 11).
The aqueous layer was extracted with EtOAc three times. The organic
layers were combined, washed with brine, dried over MgSO4, and
concentrated. The product was purified by flash chromatography with
heptane/AcOEt (80/20) to yield anorange oil (57%). Rf =0.73(heptane/
EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26):
δ = 7.59 (d, 2H, Jo = 8.3), 7.32ꢀ7.11 (m, 7H), 4.62 (d, 1H, J = 7.6),
4.39 (d, 1H, J = 11.9), 4.19 (d, 1H, J = 11.9), 3.34 (td, 1H, J = 7.3 and
3.7), 3.16 (td, 1H, J = 6.6 and 3.0), 2.34 (s, 3H), 1.30ꢀ1.05 (m, 22H),
0.98 (d, 3H, J = 6.6), 0.81 (t, 3H, J = 6.6); 13C NMR (75 MHz, CDCl3,
25 °C, δ CDCl3 = 77.16 for the central peak): δ = 143.3 (C quat),
138.4 (C quat), 138.2 (C quat), 129.7 (CH ar), 128.6 (CH ar), 127.9
(CH ar), 127.8 (CH ar), 127.2 (CH ar), 81.3 (CH), 71.9 (CH2), 51.3
(CH), 32.1, 30.3, 29.9, 29.8, 29.7, 29.6, 29.5, 25.7, 22.8 (11 CH2), 21.7
(CH3), 15.6 (CH3), 14.3 (CH3); IR (Neat): ν = 3279, 2923, 2853,
1599, 1497, 1455, 1327, 1161, 1092, 814, 734, 697, 668 cmꢀ1; HRMS:
(TOF MS ES+; MeOH/CH2Cl2): m/z calculated for C29H45NO3S:
(M + Na) calcd = 510.3018; found = 510.3030.
(4S,5R)-5-(Benzyloxy)-4-methyl-3-N-tosyl-1,2,3-oxathiazepane 2,
2-Dioxide (9). The oxathiazepane 20 (215 mg, 0.80 mmol, 1 equiv) in
DME (3 mL) was added to a suspension of tBuONa (115 mg, 1.2 mmol,
1.5 equiv) in DME (5 mL). After 1 h 30 min of stirring, TsCl (380 mg,
2 mmol, 2.5 equiv) was added and the mixture was stirred for 3 h. The
reaction was quenched with water. The aqueous layer was extracted
three times with EtOAc. The organic layers were combined, dried over
MgSO4, and concentrated. The product was purified by flash chroma-
tography with heptane/EtOAc (90/10 and then 70/30) to yield a white
solid (70%). Rf = 0.44 (heptane/EtOAc 60/40); mp 121ꢀ123 °C;
1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.88 (d, 2H,
Jo = 8.5), 7.40ꢀ7.27(m, 7H,), 4.70ꢀ4.20 (m, 5H), 3.80 (t, 1H, J = 7.1),
2.43 (s, 3H), 2.32ꢀ2.12 (m, 2H), 1.41 (d, 3H, J = 6.6 Hz); 13C NMR
(75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak):
δ = 145.3 (C quat), 137.5 (C quat), 129.7 (CH ar), 128.7 (CH ar), 128.6
(CH ar), 128.2 (CH ar), 128.0 (CH ar), 116.9 (C quat), 82.4 (CH), 72.2
(CH2), 70.2 (CH2), 59.4 (CH), 32.0 (CH2), 21.8 (CH3), 18.0 (CH3);
IR (Neat): ν = 2924, 1596, 1487, 1454, 1404, 1357, 1194, 1186, 1172,
1069, 1039, 990, 964, 890, 866, 815, 781, 736, 705, 653 cmꢀ1; HRMS:
(TOF MS ES+; MeOH/CH2Cl2): m/z calculated for C19H23NO6S2:
(M + Na) calcd = 448.0865, found = 448.0848.
(4S,5R)-5-Fluoro-4-methyl-1,2,3-oxathiazepane 2,2-Dioxide (21).
Aziridine 1a (600 mg, 3.7 mmol, 1 equiv) was dissolved in THF (50 mL),
and TBAF (5.5 mL, 1 M in THF, 5.5 mmol, 1.5 equiv) was added under
an atmosphere of argon. The mixture was stirred for 1 h 30 min, and the
solvent was evaporated. The product was purified by flash chromatog-
raphy (DCM/MeOH 100/0 and 90/10) to yield a brownish oil (75%).
1
Rf = 0.30 (heptane/EtOAc 50/50); H NMR (300 MHz, acetone-d6,
25 °C, δ acetone-d6 = 2.05): δ = 4.52 (dtd, 1H, J = 45.8, 8.9 and 4.7),
4.4ꢀ4.12 (m, 2H), 3.45 (m, 1H), 2.92 (br, 1H), 2.44 (ttd, 1H, J = 14.9,
4.7 and 1.7), 2.25ꢀ2.10 (m, 1H), 1.32 (dd, 3H, J = 6.6 and 2.3); 13C
NMR (75 MHz, acetone-d6, 25 °C, δ acetone-d6 = 29.84 for the central
peak): δ = 94.1 (d, J = 175.6, CH), 66.1 (d, J = 11.6, CH), 52.5 (d, J =
27.2, CH2), 34.9 (d, J = 24.5, CH2), 17.8 (d, J = 2.2, CH3); 19F NMR
decoupling (300 MHz, acetone-d6, δ TFA = 100.5): δ = 2.75; IR (Neat):
ν = 3425, 3064, 1561, 1493, 1483, 1430, 1407, 1331, 1190, 1136, 1066,
920, 877, 817, 781, 722 cmꢀ1; HRMS: (TOF MS ESꢀ; MeOH/
CH2Cl2): m/z calculated for C5H10FNO3S: (M ꢀ H) calcd = 182.0287;
found = 182.0283.
(4S,5R)-5-Fluoro-4-methyl-3-N-tosyl-1,2,3-oxathiazepane 2,2-Dioxide
(22). Oxathiazepane21 (500 mg, 2.7 mmol, 1 equiv) in DME(10mL) was
added to a suspension of tBuONa (415 mg, 4.1 mmol, 1.5 equiv) in DME
(20 mL). After 1 h 30 min of stirring, TsCl (1.3 g, 6.8 mmol, 2.5 equiv) was
added and the mixture was stirred for 5 h. The reaction was quenched with
water and poured into a H2O/EtOAc mixture (1/2.5). The aqueous layer
(4S,5R)-5-Benzyloxy-4-methyl-1,2,3-oxathiazepane 2,2-Dioxide (20).
Benzyl alcohol (640 μL, 6.0 mmol) and BF3 Et2O (40 μL, 0.30 mmol)
3
were added to a solution of aziridine 1a (500 mg, 3.0 mmol) in DCM
(7 mL) at 0 °C. The reaction was stirred overnight at room temperature
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The Journal of Organic Chemistry
ARTICLE
was extracted twice with EtOAc. The organic layers were combined, dried
over MgSO4, and concentrated. The product was purified by flash
chromatography with heptane/AcOEt (90/10 and then 70/30) to yield
a white solid (44%) that can be crystallized from toluene to yield enan-
tioenriched compound (97% ee). Rf = 0.62 (heptane/EtOAc 50/50); mp
127ꢀ132 °C; [R]24D = 68.2 (c = 0.29 in CHCl3); 1H NMR (300 MHz,
CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.89 (d, 2H, Jo = 8.4), 7.35 (d, 2H,
Jo = 8.4), 4.83 (d, 1H, J = 50.7), 4.72 (m, 1H), 4.48ꢀ4.40 (m, 1H),
4.38ꢀ4.30 (m, 1H), 2.46 (s, 3H), 2.31ꢀ2.34 (m, 2H), 1.49 (m, 3H); 13C
NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak): δ =
145.6 (C quat), 129.8 (C quat and CH ar), 128.7 (CH ar), 93.8 (d, J =
175.0, CH), 68.5 (d, J = 9.1, CH), 58.5 (d, J = 35.8, CH2), 33.5 (d, J = 23.6,
CH2), 21.9 (CH3), 17.3 (CH3); 19F NMR decoupling (300 MHz, CDCl3,
δ TFA = ꢀ75.69): δ = ꢀ169.55; IR (Neat): ν = 2983, 1718, 1597, 1409,
1395, 1366, 1198, 1174, 1031, 997, 868 cmꢀ1; HRMS: (TOF MS ES+;
MeOH/CH2Cl2): m/z calculated for C12H16FNO5S2: (M + Na) calcd =
360.0302, found = 360.0351, Chiral HPLC: IC column 5 μm, Hept/
i-prOH 80/20, tR1: 15.98 min, tR2: 27.55 min.
(2S,3R)-3-Hydroxy-2-N-(tert-butylcarbamate)aminooctadecane (24).
N-Boc protected alkyne 23 (34 mg, 0.072 mmol, 1 equiv) was dissolved in
EtOH (0.5 mL), and Pd/C (3 mg) was added. The flask was purged with
argon and placed under an atmosphere of H2 (P = 1 bar). The mixture was
stirred for 24 h, filtered through a pad of Celite, and concentrated to afford a
clean crude product (90% yield). Rf = 0.52 (heptane/EtOAc 70/30); 1H
NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 4.43 (m, 1H),
3.77ꢀ3.55 (m, 2H), 1.44 (s, 9H), 1.41ꢀ1.21 (br, 29H), 1.08 (d, 3H,
J = 6.8), 0.88 (t, 3H, J = 6.8); 13C NMR (75 MHz, CDCl3, 25 °C, δ
CDCl3 = 77.16 for the central peak): δ = 156.0 (C quat), 79.6 (C quat),
74.6 (CH), 50.7 (CH), 33.6, 32.1, 29.8, 29.7, 29.5, 28.6, 26.2, 22.8 (14
CH2 and 1 CH3), 14.5 (CH3), 14.3 (CH3); IR (Neat): ν = 2927, 2855,
1717, 1498, 1366, 1170, 1061 cmꢀ1; HRMS: (TOF MS ES+; MeOH/
CH2Cl2): m/z calculated for C23H47NO3: (M + Na) calcd = 408.3454;
found = 408.3468.
Spisulosine HCl (17). N-Boc protected spisulosine 24 (20 mg,
0.052 mmol, 1 equiv) was dissolved in a solution of HCl in ether
(2M, 1 mL) and stirred for 1 h. The mixture was concentrated, taken up
in ether, and filtered to yield a white solid (60%). Rf = 0.60 (heptane/
(2S,3R)-3-Benzyloxy-2-N-(tert-butylcarbamate)aminooctadec-6-yne
(23). Tosylamine 13 (85 mg, 0.16 mmol, 1 equiv) was dissolved in DCM
under an atmosphere of argon at room temperature, and then di-tert-butyl
dicarbonate (70 mg, 0.32 mmol, 2 equiv), DMAP (4 mg, 0.032 mmol,
0.2 equiv), and triethylamine (68 μL, 0.48 mmol, 3 equiv) were added.
The mixture was stirred for 24 h and quenched with water. The aqueous
layer was extracted with DCM three times. The organic layers were
combined, dried over MgSO4, and concentrated. The product was
purified by flash chromatography with heptane/EtOAc (95/5) to yield
EtOAc 60/40); [R]24 = +7.15 (c = 0.42 in MeOH); 1H NMR
D
(300 MHz, CD3OD, 25 °C, δ CD3OD = 3.31): δ = 4.84 (br, 4H),
3.69 (td, 1H, J = 6.5 and 3.0), 3.27 (qd, 1H, J = 7.0 and 3.4), 1.56ꢀ1.25
(br, 28H), 1.21 (d, 3H, J = 6.8), 0.90 (t, 3H, J = 6.8); 13C NMR (75 MHz,
CD3OD, 25 °C, δ CD3OD = 49.0 for the central peak): δ = 71.7 (CH),
52.6 (CH), 34.0, 33.1, 30.8, 30.7, 30.65, 30.6, 30.5, 27.0, 23.7 (11 CH2),
14.4 (CH3), 12.1 (CH3); IR (Neat): ν = 3392, 2920, 2851, 1501,
1051 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated
for C18H39NO: (M + H) calcd = 286.3110; found = 286.3121.
1
a colorless oil (55%). Rf = 0.71 (heptane/EtOAc 70/30); H NMR
(300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 7.82 (d, 2H, J = 8.2),
7.36ꢀ7.27 (m, 7H), 4.73 (d, 1H, J = 11), 4.62 (d, 1H, J = 11), 4.53ꢀ4.43
(m, 1H), 4.14 (td, 1H, J = 8.9 and 3.7), 2.43 (s, 3H), 2.40ꢀ2.32 (m, 2H),
2.20ꢀ2.10 (m, 2H), 1.52 (d, 3H, J = 6.7), 1.55ꢀ1.20 (large, m, 20 H),
1.40 (s, 9H), 0.88 (t, 3H, J = 6.8); 13C NMR (75 MHz, CDCl3, 25 °C, δ
CDCl3 = 77.16 for the central peak): δ = 150.8 (C quat), 144.1 (C quat),
138.6 (C quat), 137.7 (C quat), 129.3 (CH ar), 128.5 (CH ar), 128.3
(CH ar), 128.0 (CH ar), 127.8 (CH ar), 84.5 (C quat), 81.0 (C quat),
79.9 (CH), 79.7 (C quat), 74.0 (CH2), 57.7 (CH), 32.1 (CH2), 31.9
(CH2), 29.8 (CH2), 29.75 (CH2), 29.7 (CH2), 29.5 (CH2), 29.4 (CH2),
29.3 (CH2), 29.2 (CH2), 28.1 (CH3), 22.8 (CH2), 21.8 (CH3), 19.0
(CH2), 17.3 (CH3), 14.8 (CH2), 14.3 (CH3); IR (Neat): ν = 2924, 2853,
1732, 1455, 1371, 1352, 1263, 1170, 1089, 1067, 989, 672 cmꢀ1; HRMS:
(TOF MSES+; MeOH/CH2Cl2): m/z calculatedfor C37H55NO5S:(M +
Na) calcd = 648.3699, found = 648.3692. The protected amine (55 mg,
0.088 mmol, 1 equiv) was dissolved in MeOH (0.75 mL), and magnesium
powder (21 mg, 0.88 mmol, 10 equiv) was added. The mixture was stirred
at room temperature under sonication for 30 min. The solution was then
hydrolyzed with a saturated solution of NH4Cl and extracted three times
with ether. The organic layers were combined, dried over MgSO4, and
concentrated. The product was purified by flash chromatography
(heptane/EtOAc 90/10) to yield a colorless oil (82%). Rf = 0.72
(heptane/EtOAc 60/40); 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 =
7.26): δ = 7.35 (m, 4H,), 7.28 (m, 1H,), 4.62 (d, 1H, J = 11.8), 4.57 (d,
1H, J = 11.8), 3.85 (br, 1H), 3.58 (q, 1H, J = 3.9 Hz), 2.27 (m, 2H), 2.14
(m, 2H), 1.72 (m, 1H), 1.64 (m, 1H), 1.47 (m, 1H), 1.43 (s, 9H), 1.36
(m, 2H), 1.26 (br, 16H), 1.11 (d, 3H, J = 7.3), 0.88 (t, 3H, J = 7.1); 13C
NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for the central peak): δ
= 155.5 (C quat), 138.8, (C quat), 128.6 (CH ar), 128.0 (CH ar), 127.8
(CH ar), 81.2 (C quat), 80.5 (CH and C quat), 79.3 (C quat), 72.8
(CH2), 48.2 (CH), 32.1 (CH2), 30.6 (CH2), 29.8 (CH2), 29.75 (CH2),
29.7 (CH2), 29.5 (CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2), 28.6
(CH3), 22.8 (CH2), 18.9 (CH2), 15.6 (CH3), 15.5 (CH2), 14.2 (CH3);
IR (Neat): ν = 2927, 2855, 1717, 1498, 1366, 1170, 1061 cmꢀ1; HRMS:
(TOF MS ES+; MeOH/CH2Cl2): m/z calculated for C30H49NO3:
(M + Na) calcd = 494.3610; found = 494.3623.
(2S,3R)-3-Fluoro-2-N-(tosyl)aminopent-4-ene (25). A solution of
fluorooxathiazepane 22 (58 mg, 0.17 mmol, 1 equiv) in THF (0.5 mL)
was added to a solution of n-BuLi in hexane (215 μL, 0.26 mmol,
1.5 equiv) in a THF/HMPA mixture (0.5 mL/0.2 mL) under argon
at ꢀ78 °C. After being stirred overnight at room temperature, the
reaction was quenched with water and concentrated. The residue was
taken up in EtOAc and 1 M HCl, stirred for 30 min, and then basified
with 3 M NaOH (pH = 11). The aqueous layer was extracted three times
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated. The product was purified by flash
chromatography with heptane/EtOAc (90/10) to yield a colorless oil
(60%). Rf = 0.33 (heptane/EtOAc 70/30); 1H NMR (300 MHz, CDCl3,
25 °C, δ CDCl3 = 7.26): δ = 7.76 (d, 2H, Jo = 8.4), 7.30 (d, 2H, Jo = 8.4),
5.73 (tq, 1H, J = 17.4 and 5.3), 5.36ꢀ5.26 (m, 2H), 4.92ꢀ4.88 and
4.77ꢀ4.72 (2 m, 1H), 4.80 (d, 1H, J = 9.1), 3.64ꢀ3.40 (m, 1H), 2.42 (s,
3H), 1.03 (d, 3H, J = 6.9); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 =
77.16 for the central peak): δ = 143.6 (C quat), 138.1 (C quat), 132.4 (d,
J = 19.9, CH), 128.6 (CH ar), 127.1 (CH ar), 119.0 (d, J = 11.1, CH2),
94.7 (d, J = 177.4, CH), 52.6 (d, J = 20.6, CH), 21.6 (CH3), 15.0 (d,
J = 5.2, CH3); 19F NMR decoupling (300 MHz, CDCl3, 25 °C,
δ TFA = ꢀ75.69): δ = ꢀ195.5; IR (Neat): ν = 3279, 2986, 1599,
1431, 1331, 1160, 1092, 942, 815, 666 cmꢀ1; HRMS: (TOF MS ES+;
MeOH/CH2Cl2): m/z calculated for C12H16FNO2S: (M + Na) calcd =
280.0883, found = 280.0773.
(2S,3R)-3-Fluoro-2-N-(tosyl)aminooctadec-4-ene (26). Grubbs II
catalyst (24 mg, 0.028 mmol, 0.08 equiv) was placed in a flame-dried
50 mL flask, and degassed DCM (4 mL) was added. The tosyl amine 25
(90 mg, 0.35 mmol, 1 equiv) in degassed DCM (4 mL) and pentadecene
(285 μL, 1.1 mmol, 3 equiv) in degassed DCM (4 mL) were then added,
and the mixture was refluxed overnight. The mixture was concentrated
and purified by flash chromatography (heptane/EtOAc 90/10) to yield a
brownish oil (75%, mixture of E and Z olefin). Rf = 0.50 (heptane/
EtOAc 70/30); 1H NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26):
δ = 7.76 (d, 2H, Jo = 8.4 Hz), 7.30 (d, 2H, Jo = 8.4), 5.81ꢀ5.20
(m, ethylenic H of Z and E configuration), 4.84ꢀ4.60 (m, 2H, NH and
CHFE), 4.33 (2 m, J = 47.9, CHFZ) 3.58ꢀ3.37 (m, 1H), 2.43 (s, 3H),
7445
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The Journal of Organic Chemistry
ARTICLE
2.06ꢀ1.89 (m, 2H), 1.40ꢀ1.17 (br, 22H), 1.06 (d, 3H, J = 6.9), 0.88
(t, 3H, J = 6.6); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 = 77.16 for
the central peak): δ = 143.6 (C quat), 138.3 (C quat), 133.7 (d, J = 10.8,
CH), 128.9 (CH ar), 127.1 (CH ar), 123.9 (d, J = 19.9, CH), 95.2 (d, J =
174.6, CH), 53.0 (d, J = 23.4, CH), 32.7 (CH2), 32.4 (CH2), 32.1
(CH2), 29.8 (CH2), 29.7 (CH2), 29.65 (CH2), 29.6(CH2), 29.5 (CH2),
29.4 (CH2), 29.35 (CH2), 29.3 (CH2), 28.8 (CH2), 22.8 (CH2), 21.7
(CH3), 15.4 (d, J = 6.1, CH3), 14.3 (CH3); 19F NMR decoupling
(300 MHz, CDCl3, δ TFA = ꢀ75.69): δ = ꢀ188.3 and ꢀ196.1; IR
(Neat): ν = 3281, 2924, 2854, 1463, 1332, 1163, 1093, 942, 970, 814,
668 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z calculated for
C25H42FNO2S: (M + Na) calcd = 462.2818, found = 462.2820.
ether (2 mL) and stirred at room temperature for 2 h. The mixture was
concentrated, taken up in DCM, and treated with a 3 M solution of
NaOH for 30 min. The aqueous layer was then extracted with DCM
three times, and all organic layers were combined, washed with water,
dried over MgSO4, and concentrated. The product was purified by flash
chromatography to yield a colorless oil (60%). Rf = 0.31 (heptane/
EtOAc 95:5); [R]24 = ꢀ10 (c = 1.15 in chloroform); 1H NMR
D
(300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 4.28 (d, 1H, J =
50.3), 3.07ꢀ2.95 (m, 1H), 1.67ꢀ1.41 (m, 4H), 1.38ꢀ1.18 (br, 26H,)
1.09 (d, 3H, J = 6.5), 0.88 (t, 3H, J = 6.6); 13C NMR (75 MHz, CDCl3,
25 °C, δ CDCl3 = 77.16 for the central peak): δ = 98.3 (d, J = 171.3,
CH), 49.9 (d, J = 20.7, CH), 32.1 (CH2), 30.9 (CH2), 30.6 (CH2), 29.8
(CH2), 29.7 (CH2), 29.65 (CH2), 29.6 (CH2), 29.5 (CH2), 25.5 (d, J =
3.2), 22.8, 18.1 (CH3), 14.2 (CH3); 19F NMR decoupling (300 MHz,
CDCl3, δ TFA = ꢀ75.69): δ = ꢀ191.9; IR (Neat): ν = 3335, 2917,
2850, 1583, 1485, 1469, 1356, 1328 cmꢀ1; HRMS: (TOF MS ES+;
MeOH/CH2Cl2): m/z calculated for C18H38FN: (M + H) calcd =
288.3067, found = 288.3061.
(2S,3R)-3-Fluoro-2-N-(tert-butylcarbamate)aminooctadec-4-ene
(27). The N-tosyl protected amine 26 (110 mg, 0.25 mmol, 1 equiv) was
dissolved in DCM (5 mL) under argon at room temperature. Boc2O
(163 mg, 0.75 mmol, 3 equiv) and DMAP (15 mg, 0.13 mmol, 0.5 equiv)
were then added. The mixture was stirred overnight, concentrated, and
purified by flash chromatography (heptane/EtOAc 90/10). Isolated
product (125 mg, 0.23 mmol, 1 equiv) was dissolved in MeOH (2 mL),
and then Mg (56 mg, 2.3 mmol, 10 equiv) was added. The mixture was
submitted to sonic bath for 20 min and concentrated under vacuum. The
residue was taken up in ether and quenched with saturated ammonium
chloride solution. The aqueous layer was extracted three times with
ether. The organic layers were combined, dried over MgSO4, and
concentrated. The product was purified by flash chromatography
(heptane/EtOAc 95/5) to yield a colorless oil (46% overall yield,
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra of all compounds. HMBC, HSQC, and COSY experiments
for compounds 3, 4, 7, and 8. Crystallographic data for 20 and 22.
This material is available free of charge via the Internet at http://
pubs.acs.org.
1
mixture of E and Z olefins). Rf = 0.30 (heptane/EtOAc 95/5); H
NMR (300 MHz, CDCl3, 25 °C, δ CDCl3 = 7.26): δ = 5.89ꢀ5.30
(m, ethylenic H of Z and E configuration), 5.01ꢀ4.65 (m, 2H, NH and
CHFE), 4.60ꢀ4.35 (2 m, CHFZ), 3.89ꢀ3.64 (m, 1H), 2.12ꢀ1.93
(m, 2H), 1.44 (s, 9H), 1.40ꢀ1.19 (br, 22H), 1.13 (d, 3H, J = 6.8),
0.87 (t, 3H, J = 6.8); 13C NMR (75 MHz, CDCl3, 25 °C, δ CDCl3 =
77.16 for the central peak): δ = 155.3 (C quat), 136.8 (d, J = 11.2, CH),
123.0 (d, J = 20.1, CH), 95.5 (d, J = 170.5, CH), 79.6 (C quat), 49.8
(d, J = 25.8, CH), 32.7 (CH2), 32.5 (CH2), 32.1 (CH2), 29.8 (CH2),
29.7 (CH2), 29.65 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 29.3
(CH2), 29.0 (CH2), 28.5 (CH3), 22.8 (CH2), 14.2 (2 CH3); 19F NMR
decoupling (300 MHz, CDCl3, 25 °C, δ TFA = ꢀ75.69): δ = ꢀ190.3
and ꢀ197.3; IR (Neat): ν = 3351, 2921, 2851, 1686, 1535, 1468, 1367,
1252, 1181 cmꢀ1; HRMS: (TOF MS ES+; MeOH/CH2Cl2): m/z
calculated for C23H44FNO2: (M + Na) calcd = 408.3264, found =
408.3243.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: philippe.dauban@icsn.cnrs-gif.fr.
’ ACKNOWLEDGMENT
G.M. and A.E. contributed equally to this work. We thank the
Institut de Chimie des Substances Naturelles for financial sup-
port and fellowships (G.M. and A.E.). Support and sponsorship
concerted by COST Action D40 “Innovative Catalysis: New
Processes and Selectivities” are kindly acknowledged. We thank Dr.
T. Cresteil (ICSN, CNRS, Gif-sur-Yvette) for cytotoxicity assays.
’ REFERENCES
(2S,3R)-3-Fluoro-2-N-(tert-butylcarbamate)aminooctadecane (28).
Olefin 27 (38 mg, 0.1 mmol, 1 equiv) was dissolved under an atmosphere
of argon in degassed DCM (2 mL). PtO2 (4.5 mg, 0.02 mmol, 0.2 equiv)
was then added. The flask was flushed with argon before being placed
under an atmosphere of H2 (1 bar) for 1 h 30 min (monitored by NMR).
The mixture was filtered through a pad of Celite and concentrated to
afford a white solid (quantitative yield). Rf = 0.43 (heptane/EtOAc
90/10); mp: 41ꢀ42 °C; 1H NMR (300 MHz, CDCl3, 25 °C, δ
CDCl3 = 7.26): δ = 4.76 (d, 1H, J = 8.1), 4.47 (d, 1H, J = 49.3),
3.88ꢀ3.58 (m, 1H), 1.44 (s, 9H), 1.37ꢀ1.17 (br, 28 H), 1.12 (d, 3H,
J = 7.0), 0.87 (t, 3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3, 25 °C,
δ CDCl3 = 77.16 for the central peak): δ = 155.3 (C quat), 96.4 (d, J =
170.9 Hz, CH), 79.6 (C quat), 49.1 (d, J = 19.8 Hz, CH), 32.1 (CH2),
32.05 (CH2), 31.9 (CH2), 29.85 (CH2), 29.8 (CH2), 29.75 (CH2), 29.7
(CH2), 29.6 (CH2), 29.5 (CH2), 28.6 (CH2), 28.5 (CH3), 25.5 (CH2),
22.8 (CH2), 14.3 (CH3), 14.03 (d, J = 5.6, CH3); 19F NMR decoupling
(300 MHz, CDCl3, δ TFA = ꢀ75.69): δ = ꢀ198.0; IR (Neat): ν = 3341,
(1) For reviews of the aziridine chemistry, see: (a) Yudin, A. K., Ed.
Aziridines and Epoxides in Organic Synthesis, Wiley-VCH: Weinheim,
2006. (b) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599. (c) Sweeney,
J. B. Chem. Soc. Rev. 2002, 31, 247. (d) Hu, X. E. Tetrahedron 2004,
60, 2701. (e) Dauban, P.; Malik, G. Angew. Chem., Int. Ed. 2009,
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(3) For relevant examples involving azides, see: (a) Bach, T.;
Schlummer, B.; Harms, K. Chem.—Eur. J. 2001, 7, 2581. (b) Omura,
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(c) Jones, J. E.; Ruppel, J. V.; Gao, G.-Y.; Moore, T. M.; Zhang, X. P.
J. Org. Chem. 2008, 73, 7260. For relevant examples involving
haloamines, see: (d) Albone, D. P.; Aujla, P. S.; Taylor, P. C.; Challenger,
S.; Derrick, A. M. J. Org. Chem. 1998, 63, 9569. (e) Chanda, B. M.; Vyas,
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involving N-(sulfonyloxycarbamates), see: (g) Lebel, H.; Huard, K.;
2924, 2854, 1704, 1501, 1456, 1391, 1366, 1246, 1172, 1055, 967 cmꢀ1
;
HRMS: (TOF MS ES+; MeOH/CH2Cl2):m/zcalculated for C23H46FNO2:
(M + Na) calcd = 410.3410, found = 410.3424.
(2S,3R)-3-Fluorooctadecan-2-amine (18). N-Boc protected fluoro
spisulosine 28 (38 mg, 0.1 mmol, 1 equiv) was dissolved in 2 M HCl in
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(18) Similar correlations were observed in HMBC spectra of products
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then unambiguously determined by X-ray crystallography.
(19) An identical result was obtained when aziridine 1b was reacted
with methanol in the presence of BF3 OEt2. Ring-opening exclusively
3
occurs at C4 position, allowing isolation of the same regioisomer in 86%
yield. HMBC spectrum points out the absence of correlation between
H4 and the ortho-carbon atoms of the phenyl moiety. The reversed
regioselectivity was then confirmed by X-ray crystallography.
(8) Relevant examples of rhodium-catalyzed olefin aziridination:
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Lett. 2010, 51, 4140. (g) Dinda, S. K.; Das, S. K.; Panda, G. Tetrahedron
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(25) On the basis of the observation made with Grignard reagents in
the presence of CuI (see results in Scheme 3), ring-opening of cyclic
sulfamidate 9 has also been performed with C13H27MgBr which,
contrary to its lower and higher homologues, is not commercially
available. Whereas reactions with ethyl- or decylmagnesium bromide
have proved to be efficient, use of freshly prepared tridecylmagnesium
bromide affords the expected product albeit with a lower yield of
35ꢀ40%, a result attributed to the nonoptimized preparation of the
Grignard reagent. We have therefore decided to use alkynides as
C-nucleophiles because the triple bond could afford additional oppor-
tunities in the context of SAR studies.
(26) Xu, Y.-M.; Shi, M. J. Org. Chem. 2004, 69, 417.
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