Ring-closing metathesis of sulfoximine-substituted N-tethered trienes: Modular asymmetric synthesis of medium-ring nitrogen heterocycles

Article abstract of DOI:10.1002/chem.201003172

A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyz

Full text of DOI:10.1002/chem.201003172

FULL PAPER
DOI: 10.1002/chem.201003172
Ring-Closing Metathesis of Sulfoximine-Substituted N-Tethered Trienes:
Modular Asymmetric Synthesis of Medium-Ring Nitrogen Heterocycles
Vishal Mahajan[a, b] and Hans-Joachim Gais*[a]
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
Abstract: A synthesis of sulfoximine-
substituted medium-ring nitrogen het-
N-sulfonyl amines, 3) allylation, hy-
droxylalkylation, and formylation of a-
lithioalkenylsulfoximines, and 4) allyla-
tion of a-formylalkenylsulfoximines.
The Ru-catalyzed RCM reaction of the
sulfoximine-substituted 1,7,10- and
1,7,12-trienes stereoselectively afforded
the corresponding nine-, ten-, and
eleven-membered MRNHs in good
yields. An interesting difference in re-
activity was noted in the case of a sul-
foximine-substituted 1,7,10-triene and
its corresponding 1,10-diene. While the
triene readily underwent a RCM reac-
tion, the diene reacted only in the pres-
erocycles (MRNHs) having
a high
degree of substitution has been devel-
oped. Its key steps are the modular
asymmetric synthesis of sulfoximine-
substituted N-tethered trienes and their
Ru-catalyzed ring-closing metathesis
(RCM) reaction. The highly substituted
N-tethered trienes were obtained enan-
tio- and diastereopure through 1) the
diastereoselective aminoalkylation of
ence of TiACHTNUGTRENUNG(OiPr)4 under formation of
the corresponding MRNH. The feasi-
bility of a removal of the sulfoximine
auxiliary and the N-sulfonyl protecting
group from the MRNHs were demon-
strated through reduction and cleavage,
respectively, of a nine-membered het-
erocycle, both of which proceeded
readily and gave the corresponding
cyclic alkene and amine, respectively.
Keywords: heterocycles · ring-clos-
ing metathesis · ruthenium · sulfox-
imine
sulfoximine-substituted
allyltitanium
complexes with N-tert-butylsulfonylimi-
noester, 2) N-allylation of homoallylic
Introduction
Medium-ring nitrogen heterocycles (MRNHs) are frequent-
ly found as structural elements in biologically active natural
products and drug candidates.[1] In recent years ring-closing
metathesis (RCM)[2] has received much attention as a per-
haps general method for the synthesis of MRNHs.[3–5] While
the RCM of N-tethered dienes is well documented, that of
N-tethered trienes, which would give access to synthetically
attractive double unsaturated MRNHs, has been much less
studied.[3,4] Furthermore, the RCM studies of N-tethered
dienes and trienes were generally confined to those having a
low degree of substitution and functionalization.[6] We decid-
ed to investigate the synthesis and Ru-catalyzed RCM of
the sulfoximine-substituted N-tethered trienes I (Scheme 1).
Scheme 1. Sulfoximine-substituted N-tethered trienes and MRNHs
(PG=protecting group) and substituted MRNHs.
[a] Dr. V. Mahajan, Prof. Dr. H.-J. Gais
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-8092665
The study of the sterically hindered trienes I was meant to
open an access to sulfoximine-substituted MRNHs of type
II and further explore the potential of the RCM for the syn-
thesis of highly substituted MRNHs.
E-mail: gais@rwth-aachen.de
The sulfoximine-substituted MRNHs II would be interest-
ing building blocks for the synthesis of MRNHs of type III–
V and the corresponding cyclic a-amino acids (CO2H in-
stead of CH2OPG2). The alkenylsulfoximine moiety of II for
example should allow for a number of synthetically useful
transformations including Michael reactions[7–9] followed by
the replacement of the sulfoximine group by reduc-
tion[10,11,12b] to give III, cross-coupling reactions[12a,13] and re-
[b] Dr. V. Mahajan
Present address: SAI Advantium Pharma Ltd, Chrysalis Enclave
International Biotech Park, Phase II
Hinjewadi, Pune 411057 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003172: General informa-
tion; general experimental procedures; experimental procedures and
characterization data for 2–7, 9–15, 17, 20–25, 27–29, 32, and 34;
copies of the NMR spectra of all new compounds.
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duction to yield IV (R3 =alkyl, aryl, H) and migratory sub-
stitution by halide ions to furnish V.[12c,d,14] Finally, a conver-
sion of the protected hydroxymethyl group to the carboxy
group should yield the corresponding cyclic a-amino acids,
which are of general interest as conformationally restricted
peptide analogs.[15] Previously, we had studied the Ru-cata-
lyzed RCM of the C- and O-tethered trienes VI and VIII,
respectively (Scheme 2), which gave the corresponding
medium-sized carbocycles VII and lactones IX.[10] These in-
vestigations had shown that 1) hindered trienes of this type
are amendable to a RCM reaction, and 2) a likely coordina-
tion of the Lewis basic sulfoximine group to the Ru-atom of
intermediates derived from VI and VIII does not impair the
catalytic cycle.
Alternatively, an introduction of the chain B at the C-atom
can be envisioned by a two-step route, which includes a for-
mylation of the C-based anion and reaction of the corre-
sponding aldehyde with a suitable unsaturated organometal-
lic reagent.
In this paper we describe a modular asymmetric synthesis
of N-tethered trienes of type I starting from the homoallylic
amines X and a study of their RCM which led to the synthe-
sis of nine-, ten- and eleven-membered MRNHs of type II.
Finally, the feasibility of the replacement of both the sulfox-
imine and sulfonyl group of II (PG1 =tBuSO2) by an H-
atom is demonstrated.
Results and Discussion
Synthesis of the sulfoximine-substituted N-tethered diene:
The allylation of the sulfoximine-substituted homoallylic
amine 1, which was obtained from the corresponding allylti-
tanium complex[16] and N-tert-butylsulfonyl imino ester[17] as
described previously,[12] with allyl bromide afforded the N-
tethered 1,7-diene 2 in 91% (Scheme 4).[12b,18] The N-tert-bu-
tylsulfonyl group was selected as protecting group for the N-
atom of 2 in the anticipation of a selective deprotection of
the MRNHs II–V (PG1 =tBuSO2).[12,19]
Scheme 2. Sulfoximine-substituted C- and O-tethered trienes and
medium-sized carbocycles and lactones.
We planned a modular synthesis of trienes of type I start-
ing from the homoallylic amines X (Scheme 3). Previously,
we had described an asymmetric synthesis of derivatives of
X carrying an ester instead of the protected hydroxymethyl
group through aminoalkylation of sulfoximine-substituted
allyltitanium complexes with a N-tert-butylsulfonylimino
ester (see below).[12] Further key steps of the envisioned syn-
thesis of I are the attachment of different unsaturated moi-
eties to the N-atom and C-atom in a-position to the sulfox-
imine group of X (chains A and B) via the successive reac-
tion of the corresponding stabilized N- and C-based anions
with allyl halides and unsaturated aldehydes, respectively.
Scheme 4. Synthesis of the N-tethered 1,7-diene 2.
Next a selective reduction of the ester group of 2 to the
hydroxymethyl group was required. Treatment of the ester 2
with two equivalents of iBu2AlH at À788C resulted, howev-
er, in a highly selective reduction of the sulfoximine-substi-
tuted double bond[20] and finally gave the alkylsulfoximine 3
in 91% yield (Scheme 5). The use of one equivalent of
Scheme 5. Reduction of alkenylsulfoximine 2.
LiAlH4 at 08C led to the reduction of both the ester group
and the double bond of 2 and furnished the alcohol 4 in
88% yield. In addition, the tetrahydrofuran 5 was isolated
as a single diastereomer in 11% yield. The isolation of 5
Scheme 3. Sulfoximine-substituted N-tethered trienes and MRNHs.
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Medium Ring-Nitrogen Heterocycles
FULL PAPER
points to a reduction of the ester group of 2 with formation
of the corresponding alcohol which underwent a stereoselec-
tive intramolecular Michael reaction.[9]
Because of these results, a protection of the double bond
of the alkenylsulfoximine 2 was required in order to achieve
a selective reduction of the ester group. A sulfide protection
was selected based on the results of our previous study of
the Michael reaction of alkenylsulfoximines with PhSH.[21]
Therefore, the neat alkenylsulfoximine 2 was treated with
six equivalents of neat PhSH, which furnished a mixture of
the diastereomeric sulfides 6a/b in a ratio of 6:4 in 95%
yield (Scheme 6). Chromatography gave the pure diastereo-
Scheme 7. Synthesis of the N-tethered (E)-configured 1,7,10-triene 9.
Scheme 6. Synthesis of the reduced N-tethered 1,7-diene 8.
mers, the configuration of which at the newly generated ste-
reogenic C-atom was not assigned. The reduction of the
mixture of esters 6a/b with LiAlH4 gave a mixture of the al-
cohols 7a/b in 71% yield. Protection of the hydroxy group
and deprotection of the double bond of 7a/b were accom-
plished in a one-pot operation. Thus, the treatment of the
mixture of the alcohols 7a/b with tBuMe2SiCl and imidazole
(ImH) in DMF at 08C afforded the corresponding silyl
ethers, which were, however, not isolated but converted
upon heating to 1008C alkenylsulfoximine 8 in 78% yield.
Scheme 8. Synthesis of the C-9-substituted N-tethered (E)-configured
1,7,10-trienes 11a/b and 12.
(E)-but-2-enal furnished a mixture of the alcohols 10a and
10b in a ratio of 3:1 in 79% yield. Chromatography afford-
ed the pure alcohols 10a (55%) and 10b (17%), which
were protected as the corresponding silyl ether 11a (91%)
and 11b (86%) upon treatment with tBuMe2SiOTf. The oxi-
dation of the mixture of the alcohols 10a and 10b with
DMP[23] gave the 1,7,10-ketotriene 12 in 90% yield. Al-
though the low selectivity of the formation of 10a and 10b
was somewhat disappointing, it provided a welcomed tool
for the study of the potential influence of the configuration
at C-9 upon the RCM reaction of the trienes 11a and 11b.
The synthesis of the 1,7,11-trienes 14a/b, the RCM of
which should afford ten-membered MRNHs, was accom-
plished by the two-step route depicted in Scheme 9. The
treatment of the a-lithioalkenylsulfoximine Li-8 with N-for-
mylmorpholine[24] at À788C in THF afforded the aldehyde
13 in 76% yield. The aldehyde was reacted with allylmagne-
sium bromide in THF at À788C, which furnished a mixture
of the alcohols 14a and 14b in a ratio of 6:4 in 78% yield.
The pure alcohols 14a (36%) and 14b (29%) were obtained
by HPLC. The silylation of the alcohols with tBuMe2SiOTf
afforded the 1,7,11-trienes 15a (96%) and 15b (94%). The
route depicted in Scheme 9 is synthetically interesting since
it should allow a general access to 1,7,n-trienes of type I
Synthesis of sulfoximine-substituted N-tethered trienes:
Having obtained the N-tethered 1,7-diene 8, the introduc-
tion of the chain B was required in order to obtain a triene.
Generally, alkenylsulfoximines are readily lithiated with
nBuLi at the a-position to give exclusively the correspond-
ing (E)-configured a-lithioalkenylsulfoximines, irrespective
of the configuration of the alkenylsulfoximine.[8a,22] Thus,
treatment of 8 with nBuLi at À788C in THF generated the
(E)-configured a-lithioalkenylsulfoximine Li-8, which upon
reaction with allyl bromide afforded the 1,7,10-triene 9,
having the C-based substituents of the sulfoximine-substitut-
ed double bond in the required syn-position, in 62% yield
(Scheme 7).
Next the synthesis of the 1,7,10-trienes 11 and 12 was in-
vestigated, which carry
a
functional group at C-9
(Scheme 8). The treatment of the alkenylsulfoximine 8 with
nBuLi at À788C in THF gave Li-8 which upon reaction with
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H.-J. Gais and V. Mahajan
RCM of sulfoximine-substituted N-tethered trienes: Having
at hand the 1,7,10-, 1,7,11- and 1,7,12-N-tethered trienes,
which are at the C-9 position either unsubstituted or carry a
silyloxy and carbonyl group, their RCM reaction with the
Ru-catalyst 19 (Scheme 11)[2a,e,25] was studied. Initially, the
RCM of the trienes was probed in CH2Cl2 (0.005m) at room
to reflux temperature. However, no RCM was observed and
the trienes were recovered in quantitative yield. Treatment
of the trienes with the Ru-catalyst 19 in toluene at room
temperature also saw no conversion. However, a RCM reac-
tion of the trienes took place in toluene at higher tempera-
tures.
Scheme 9. Synthesis of the C9-substituted N-tethered (E)-configured
1,7,11-trienes 15a/b.
through reaction of 13 with vinyl- and unsaturated alkylme-
tal reagents.
A route similar to the one followed for the synthesis of
the 1,7,10-trienes 10a/b was used for the synthesis of the
1,7,12-trienes 17a/b, the RCM of which should lead to
eleven-membered MRNHs (Scheme 10). The treatment of
Scheme 11. RCM reaction of the N-tethered 1,7,10-triene 9.
The treatment of the 1,7,10-triene 9 with 10 mol% of 19
in toluene at reflux temperature gave the (Z)-configured
nine-membered MRHN 20 with ꢀ98% de in 85% yield.
Next the RCM reaction of the diastereomeric 1,7,10-tri-
enes 11a and 11b, which carry a silyloxy group at C-9, was
investigated (Scheme 12). The treatment of the (9R)-config-
ured triene 11a with 10 mol% of 19 (at 0.005m) in toluene
at reflux temperature for 18 h gave the (Z)-configured nine-
membered MRNH 21a in 53% yield with ꢀ98% de.
Scheme 10. Synthesis of the N-tethered (E)-configured 1,7,12-trienes 17a/
b and 18.
Scheme 12. RCM reaction of the C-9-substituted N-tethered 1,7,10-triene
11a.
the a-lithioalkenylsulfoximine Li-8 in THF at À788C with
pent-4-enal yielded a mixture of the alcohols 16a and 16b in
a ratio of 7:3. HPLC afforded the pure alcohols 16a (53%)
and 16b (28%). The mixture of the alcohols 16a and 16b
was subjected to a silylation with tBuMe2SiOTf, which gave
the corresponding 1,7,12-trienes 17a (58%) and 17b (31%)
after separation by chromatography. The treatment of the
mixture of the alcohols 16a and 16b with DMP afforded the
1,7,12-ketotriene 18 in 96% yield.
In stark contrast, the treatment of the (9S)-configured
triene 11b with 19 under the same conditions did not result
in a RCM reaction and formation of 21b. Triene 11b was re-
covered in high yield along with traces of compounds de-
rived from a cross-metathesis of the triene. We have no in-
formation at which stage of the catalytic cycle of the RCM
of 11b the tert-butyldimethylsilyloxy group at the (S)-config-
ured C-9 exerts an impeding effect. The relative configura-
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Medium Ring-Nitrogen Heterocycles
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tion of 21a was determined by NOE experiments. On the
basis of this assignment the configuration of the trienes 11a
and 11b was assigned.
The RCM reaction of the 1,7,10-ketotriene 12 with 19
(10 mol%) in toluene at reflux for 6 h gave the (Z)-config-
ured nine-membered MRNH 22 in only 21% yield (62%
based on conversion) together with the starting triene in
66% yield (Scheme 13).
Scheme 15. RCM reaction of the N-tethered 1,7,12-trienes 17a/b.
Scheme 13. RCM reaction of the N-tethered 1,7,10-ketotriene 12.
Having recorded an interesting difference in the RCM of
the 1,7,10-trienes 11a and 11b with 19 depending on the
configuration at C-9, the reactivity of the diastereomeric
1,7,11-trienes 13a/b towards 19 was studied (Scheme 14).
ment of the (9S)-configured triene 17b with 19 under the
same reaction conditions gave a mixture of the (E)- and
(Z)-configured eleven-membered MRNHs 25a and 25b in a
ratio of 1:1 in 92% yield. HPLC furnished the pure
MRNHs 25a (38%) and 24b (34%).
Finally, the 1,7,12-ketotriene 18 was subjected to a RCM
reaction with 19 under the same conditions, which afforded
the eleven-membered (E)-configured MRNH 26 carrying a
carbonyl group at C-9 with ꢀ98% de in 95% yield
(Scheme 16).
Scheme 14. RCM reaction of the N-tethered 1,7,11-trienes 13a/b.
The (9R)-configured triene 13a gave upon treatment with
10 mol% of 19 in toluene at 808C for 2 h the (E)-configured
ten-membered MRNH 23a with ꢀ98% de in 71% yield.
Surprisingly, the (9S)-configured triene 13b also underwent
a RCM reaction with 19 under the same conditions and af-
forded the (E)-configured ten-membered MRNH 23b in
71% yield. The relative configuration of 23a and 23b was
determined by NOE experiments. Based on this assignment
the configuration of 13a and 13b was assigned. These results
show that in contrast to the diastereomeric 1,7,10-trienes
11a and 11b the RCM reaction of the 1,7,11-trienes 13a
and 13b is not influenced by the configuration at C-9. How-
ever, while the RCM of the 1,7,10-triene 11a gave the (Z)-
configured MRNH that of the 1,7,11-trienes 13a/b afforded
the (E)-configured MRNHs.
It was now of interest to study the RCM of the 1,7,12-tri-
enes 17a and 17b. Treatment of the (9R)-configured triene
17a with 10 mol% of 19 in toluene at 1008C for 3 h gave a
mixture of the (E)- and (Z)-configured eleven-membered
MRNHs 24a and 24b, respectively, in a ratio of 7:3 in 94%
yield (Scheme 15). HPLC afforded the pure MRNHs 24a
(56%) and 24b (30%). The configuration of 24a and 24b at
C-9 was secured by NOE experiments. This allowed the as-
signment of the configuration of 17a and 17b. The treat-
Scheme 16. RCM reaction of the N-tethered 1,7,12-ketotriene 18.
The RCM reactions of the N-tethered trienes were run
with the exemption of 12 (cf. Scheme 13) at high conversion.
Thus, the E/Z selectivities are most likely governed by ther-
modynamic factors.
RCM of sulfoximine-substituted N-tethered dienes: The
availability of the alkene 4 prompted the synthesis and
study of the RCM reaction of the N-tethered 1,10-diene 28
(Scheme 17). Diene 28 is an analogue of the N-tethered
1,7,10-triene 9 (cf. Scheme 7), which carries, however, the
sulfoximine group at a stereogenic center and thus lacks the
internal double bond. The protection of the alcohol 4 afford-
ed the silyl ether 27 in 95% yield. The lithiation of the sul-
foximine 27 with nBuLi and the treatment of the lithioalkyl-
sulfoximine Li-27 with allyl bromide gave a mixture of the
diastereomeric sulfoximines 28a and 28b in a ratio of 62:18
in 80% yield. The configuration of the diastereomers at C-8
was not assigned. Because of the low selectivity of the ally-
lation of Li-27, the mixture of the diastereomeric allylated
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H.-J. Gais and V. Mahajan
deactivating coordination of the amino group to the Ru-
atom. Thus, one or several intermediates of the catalytic
cycle of the RCM reaction of 28a and 28b with 19 are per-
haps deactivated by an intramolecular coordination[2d,28] of
the sulfoximine group to the Ru atom as exemplary depict-
ed for complex 30. A complexation of the sulfoximine group
of 30 by TiACTHNURGTNEUNG(OiPr)4 should generate a complex of type 31,
which lacks the coordination to the Ru atom and could,
thus, participate in the catalytic cycle. A deactivating coordi-
nation of a transition metal by the sulfoximine group had
been found for example in sulfoximine-substituted allyltita-
nium complexes,[29] which do not react with aldehydes at low
Scheme 17. Synthesis of the N-tethered 1,10-dienes 28a/b.
sulfoximines was submitted to a deprotonation-protonation
sequence hoping that this would afford one of the diastereo-
mers in large excess. The treatment of the mixture of the
diastereomers 28a/b with nBuLi afforded the substituted
lithioalkylsulfoximine Li-28, the protonation of which with
AcOH was, however, unselective and gave a mixture of the
two diastereomers 28a and 28b in a ratio of 50:50 in practi-
cally quantitative yield.[26] Although this result was not the
one hoped for, it provided more of the originally minor
isomer 28b for the study of the RCM reaction of both iso-
mers.
temperatures. The addition of TiACHTNUGTRENUNG(OiPr)4, however, causes its
coordination to the sulfoximine group and formation of a
coordinative unsaturated allyltitanium complex that readily
reacts with aldehydes at low temperatures. The difference in
reactivity between the 1,7,10-triene 9 and the corresponding
1,10-dienes 28a and 28b towards 19 is remarkable. It is not
clear, however, at which stage of the catalytic cycles the dif-
ferent reactivity has its origin.
The 1,10-dienes 28a and 28b did, in stark contrast to the
corresponding 1,7,10-triene 9, not undergo a RCM with 19
(10 mol%) in toluene at reflux temperature (Scheme 18).
Reduction and deprotection of MRNHs: The synthesis of
MRNHs of type IV (R3 =H) from II requires the replace-
ment of the sulfoximine group through reduction, which
generally proceeds under preservation of the chirality of the
auxiliary.[10,11,13,30] The reduction was exemplary probed with
the nine-membered MRNH 20. Thus, treatment of sulfox-
imine 20 with freshly prepared Al/Hg in aqueous THF af-
forded the alkene 32 in 82% yield along with the sulfina-
mide 33 of ꢀ98% ee in 80% yield (Scheme 19). The conver-
sion of 33 into enantiopure (S)-N,S-dimethyl-S-phenylsulfox-
imine, the starting material for the synthesis of 1, has al-
ready been described.[30]
Scheme 18. RCM reaction of the N-tethered 1,10-dienes 28a and 28b.
However, the treatment of the minor diastereomer 28b with
19 (10 mol%) in the presence of 20 mol% of TiACTHNURGTNEUNG(OiPr)4 in
refluxing toluene gave the nine-membered MRNH 29 in
63% yield. Surprisingly, no RCM of the major diastereomer
28a was observed under the same conditions. Only a partial
decomposition of the diene occurred under elimination of
N-methylphenylsulfinamide and formation of the corre-
sponding 1,8,10-triene. A similar effect of TiACTHNUGTRENUNG(OiPr)4 had
been previously found in the Ru-catalyzed RCM of N-alkyl-
substituted N-tethered dienes.[27] It was proposed that the
Lewis acid suppresses at some stage of the catalytic cycle a
Scheme 19. Reduction and deprotection of the MRNH 20.
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Medium Ring-Nitrogen Heterocycles
FULL PAPER
J=16.2, 8.7 Hz, 1H, NCHH), 3.94–4.12 (m, 2H, NCHH, NCH), 5.02–
5.12 (m, 2H, CH=CH2), 6.04 (m, 1H, CH=CH2), 6.32 (d, J=14.8 Hz, 1H,
CH=CHS), 6.70 (dd, J=14.8, 10.9 Hz, 1H, CH=CHS), 7.60–7.75 (m, 3H,
Ph), 7.98–8.01 ppm (m, 2H, Ph);13C NMR (100 MHz, CDCl3): d=À5.5
(d), À5.4 (d), 17.3 (d), 18.4 (u), 21.3 (d), 25.1 (d), 26.0 (d), 27.5 (d), 29.6
(d), 49.6 (d), 60.9 (u), 62.6 (u), 63.9 (u), 116.6 (u), 128.4 (u), 129.3 (d),
132.1 (d), 132.6 (d), 137.7 (d), 139.2 (u), 144.4 ppm (d); IR (KBr): n=
2958 (s), 1628 (w), 1467 (m), 1317 (s), 1249 (s), 1118 (s), 836 cmÀ1 (m);
MS (EI, 70 eV): m/z (%): 571 [M ++1] (1.95), 513 (5), 449 (12), 238 (36),
237 (38), 214 (100), 155 (35), 57 (26); MS (CI, CH4): m/z (%): 571 [M+
+1] (100), 449 (11), 214 (15); HRMS (EI, 70 eV): m/z: calcd for
C24H41N2O4S2Si: 513.22770; found: 513.22773 [M +ÀC4H9].
Having demonstrated the feasibility of a reductive remov-
al of the sulfoximine group of a MRNH of type II, the de-
protection of the N-atom of II (PG1 =tBuSO2) was probed
with the MRNH 20. Treatment of sulfonamide 20 with
[12a,19]
CF3SO3H in CH2Cl2
led to a cleavage of both then N-
and O-protecting group and gave the amino alcohol 34 in
86% yield.[31]
Conclusion
N-Allyl-N-((2S,3R,6R,E)-1-(tert-butyldimethylsilyloxy)-6-hydroxy-3-iso-
propyl-5-((S)-N-methyl-S-phenylsulfonimidoyl)deca-4,9-dien-2-yl)-2-
methylpropane-2-sulfonamide (16a) and N-allyl-N-((2S,3R,6S,E)-1-(tert-
butyldimethylsilyloxy)-6-hydroxy-3-isopropyl-5-((S)-N-methyl-S-phenyl-
sulfonimidoyl)deca-4,9-dien-2-yl)-2-methylpropane-2-sulfonamide (16b):
To a solution of alkenylsulfoximine 8 (100 mg, 0.175 mmol) in THF
(3 mL) at À788C was added nBuLi (109 mL, 1.6m solution in n-hexane,
0.175 mmol). After the mixture was stirred for 15 min, a solution of pent-
4-enal (17 mg, 0.202 mmol) in THF (1 mL) was added dropwise. Then
the mixture was stirred for 20 min, after which time the conversion of Li-
8 was complete. Then the mixture was quenched through addition of sa-
turated aqueous NH4Cl and extracted with EtOAc. The combined organ-
ic phases were dried (MgSO4) and concentrated in vacuo. Purification by
The Ru-catalyzed RCM reaction of the sulfoximine-substi-
tuted sterically hindered N-tethered 1,7,10-, 1,7,11- and
1,7,12-trienes, for which a modular asymmetric synthesis was
developed, gave the corresponding nine-, ten- and eleven-
membered MRNHs. The MRNHs of type II contain func-
tional groups that should make them useful synthetic build-
ing blocks. Also bicyclic MRNHs of type II could be accessi-
ble in which R1 and R2 and the adjacent C-atoms are em-
bedded in a five–seven-membered ring since the corre-
sponding homoallylic amines X in are readily available.[12] It
seems noteworthy that the Lewis basic sulfoximine group of
the N-tethered trienes generally does not require a protec-
tion like most amines in RCM reactions.[3f,4d,27] The feasibili-
ty of an efficient removal of both the chiral auxiliary and
the N-protecting group was demonstrated for a MRNH. The
synthesis of MRHNHs II, carbocycles VII and lactones IX
demonstrates the applicability of the modular sulfoximine-
RCM-route to sulfoximine-substituted medium-sized rings.
The key steps of this route are 1) the diastereoselective hy-
droxy- and aminoalkylation of sulfoximine-substituted allyl-
titanium complexes with unsaturated aldehydes and N-sulfo-
nylimino esters, respectively, 2) the synthesis of trienes via
alkylation of a-lithioalkenylsulfoximines, and 3) the Ru-cat-
alyzed RCM reaction of the trienes. The facile Ru-catalyzed
RCM of the highly substituted trienes I, VI and VIII with
formation of the corresponding heterocycles and carbocycles
once more demonstrates the power of this method for the
synthesis of medium-sized rings.
flash chromatography (n-hexane/EtOAc 8:2) gave
a 7:3 mixture
(1H NMR: NMe) of the diastereomeric alcohols 16a/b (100 mg, 87%).
HPLC (n-hexane/EtOAc 85:15) afforded alcohol 16a (65 mg, 53%) and
alcohol 16b (32 mg, 28%) as viscous liquids. 16a: [a]D =À13.6 (c=0.55
in CHCl3); Rf =0.75 (n-hexane/EtOAc 8:2); 1H NMR (400 MHz, CDCl3,
558C): d=0.00 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3), 0.86 (s including a
doublet, J=6.6 Hz, 12H, SiC
CH3CH), 1.44 (s, including a merged m, 10H, SiC
1.80–2.00 (m, 2H, CHHCHOH, CHHCH2CHOH), 2.10–2.22 (m, 1H,
CHHCH2CHOH), 2.33 (app septd, J=6.3, 2.4 Hz, 1H, CH(CH3)3), 2.81
(s, including a merged bt, 4H, NCH3, CH(CH3)3), 3.41 (dd, J=11.2,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
4.6 Hz, 1H, CHHO), 3.52 (t, J=10.7 Hz, 1H, CHHO), 3.71 (dd, J=16.4,
9.07 Hz, 1H, NCHH), 3.89 (bs, 1H, CHN), 4.12 (dd, J=16.2, 2.4 Hz, 1H,
NCHH), 4.50 (dd, J=8.8, 3.02 Hz, 1H, CHOH), 4.95 (ddd, J=17.0, 9.6,
1.3 Hz, 2H, CH2CH2CH=CH2), 5.12 (dd, J=16.3, 10.4 Hz, 2H,
NCH2CH=CH2), 5.50 (brs, 1H, OH), 5.62–5.76 (m, 1H, CH2CH2CH=
CH2), 5.87–6.10 (m, 1H, NCH2CH=CH2), 6.51 (d, J=11.5 Hz, 1H, CH=
CS), 7.50–7.60 (m, 3H, Ph), 7.90 ppm (dd, J=6.8, 1.65 Hz, 2H, Ph);
13C NMR (100 MHz, CDCl3): d=À5.2 (d), À4.9 (d), 16.7 (d),18.7 (u),
21.1 (u), 25.1 (d), 26.2 (d), 28.4 (d), 29.4 (d), 30.7 (u), 36.6 (u), 45.1 (d),
48.9 (u), 61.0 (d), 63.0 (u), 63.3 (u), 69.1 (d), 115.1 (u), 116.2 (u), 128.6
(d), 129.4 (d), 132.6 (d), 137.2 (d), 138.5 (d), 140.5 (u), 142.1 (d),
143.7 ppm (u); IR (KBr): n=3453 (w), 3290 (w), 2956 (s), 1639 (w), 1464
(m), 1318 (s), 1245 (s), 1118 (s), 846 cmÀ1 (s); MS (EI, 70 eV): m/z (%):
655 [M + +1] (3), 597 (3), 214 (39.8), 156 (34), 125 (20), 57 (100); MS
(CI, CH4): m/z (%): 655 [M + +1] (100), 597 (10), 378 (11), 214 (26), 156
(14); HRMS (EI, 70 eV): m/z: calcd for C33H59N2O5S2Si: 655.36347;
found: 655.36025 [M + +H]. 16b: [a]D =+36.6 (c=1.0 in CHCl3); Rf =
Experimental Section
N-Allyl-N-((2S,3R,E)-1-(tert-butyldimethylsilyloxy)-3-isopropyl-5-((S)-N-
methyl-S-phenylsulfonimidoyl)pent-4-en-2-yl)-2-methylpropane-2-sulfo-
1
0.75 (n-hexane/EtOAc 8:2); H NMR (400 MHz, CDCl3): d=0.00 (s, 6H,
Si
CH3CH), 0.85 (s, 9H, SiC
1H, CHHCHOH), 1.99 (oct, J=7.6 Hz, 1H, CHHCH2CHOH), 2.12–2.23
(m, 3H, CHHCH2CHOH, CHHCHOH, CH(CH3)2), 2.64 (s, 3H, NCH3),
2.71 (t, J=4.6 Hz, 1H, CHCH(CH3)2), 3.42–3.53 (m, 2H, CH2OSi), 3.69–
3.75 (m, 2H, NCH, NCHH), 4.00 (dd, J=16.4, 1.92 Hz, 1H, NCHH),
4.40 (d, J=7.9 Hz, 1H, CHOH), 4.85 (brs, 1H, OH), 4.95 (ddd, J=17.3,
10.7, 1.37 Hz, 2H, CH2CH2CH=CH2), 5.10 (dd, J=17.3, 10.1 Hz, 2H,
NCH2CH=CH2), 5.62–5.70 (m, 1H, CH2CH2CH=CH2), 5.85–5.96 (m, 1H,
NCH2CH=CH2), 6.04 (d, J=11.8 Hz, 1H, CH=CS), 7.46–7.56 (m, 3H,
Ph), 7.80 ppm (d, J=7.4 Hz, 2H, Ph); 13C NMR (100 MHz, CDCl3): d=
À5.0 (d), 17.5 (d),18.7 (u), 21.8 (d), 25.1 (d), 26.2 (d), 28.2 (d), 29.4 (d),
30.5 (u), 36.0 (u), 45.6 (d), 48.9 (u), 60.9 (d), 62.9 (u), 63.0 (u), 69.1 (d),
115.2 (u), 116.7 (u), 128.7 (d), 129.3 (d), 132.9 (d), 137.6 (d), 138.0 (d);
139.0 (u), 140.3 (d), 145.5 ppm (u); IR (KBr): n = 3492 (m), 2956 (s),
ACHTUNGTRENNUNG
namide (8): To
a solution of a mixture of alcohols 7a/b (420 mg,
G
ACHTUNGTRENNUNG
0.742 mmol) and imidazole (252 mg, 3.70 mmol) in DMF (4 mL) at 08C
was added tBuMe2SiCl (222 mg, 1.48 mmol). The mixture was stirred first
at 08C for 30 min and then at room temperature for 4 h. After the com-
plete consumption of alcohols 7a/b (TLC), the mixture was heated at
1008C for 4 h. Then the mixture was diluted with EtOAc and washed
with water (3ꢁ10 mL). The organic layer was washed with brine and
dried (MgSO4). Concentration in vacuo and purification by column chro-
matography (n-hexane/EtOAc 8:2) gave the silyl ethers 8a/b (331 mg,
78%) as a colorless oil. [a]D =À2.6 (c=1.05 in CH2Cl2); Rf =0.47 (n-
hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3): d=0.01 (s, 3H,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
SiCH3), 0.08 (s, 3H, SiCH3), 0.93 (s, 9H, SiC
3H, CH3CH), 1.00 (d, J=6.9 Hz, 3H, CH3CH), 1.51 (s, 9H, SC
2.34 (app septd, J=6.5, 2.1 Hz, 1H, CH(CH3)2), 2.63 (t, J=9.9 Hz, 1H,
CHCH(CH3)2), 2.87 (s, 3H, NCH3), 3.58–3.73 (m, 2H, CH2O), 3.90 (dd,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Chem. Eur. J. 2011, 17, 6187 – 6195
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6193

H.-J. Gais and V. Mahajan
1639 (m), 1462 (m), 1317 (s), 1241 (s), 1118 (s), 846 cmÀ1 (s); MS (EI,
70 eV): m/z (%): 655 [M ++1] (4), 597 (57), 317 (11), 214 (63), 156 (44),
125 (26), 73.2 (14), 57 (100); MS (CI, CH4): m/z (%): 655 [M ++1] (100),
599 (14), 214 (21.8), 156 (12), 67 (12); HRMS (EI, 70 eV): m/z: calcd for
C33H59N2O5S2Si: 655.36347; found: 655.36204 [M ++H].
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (GK
440). We thank C. Vermeeren for the HPLC separations and Dr. J. Run-
sink for the NOE experiments.
N-Allyl-N-ACHTUNGTRENNUNG((2S,3R,E)-1-(tert-butyldimethylsilyloxy)-3-isopropyl-6-oxo-5-
((S)-N-methyl-S-phenylsulfonimidoyl)deca-4,9-dien-2-yl)-2-methylpro-
pane-2-sulfonamide (18): To a solution of the mixture of alcohols 16a/b
(100 mg, 0.15 mmol) in CH2Cl2 (4 mL) DMP (611 mL, 0.183 mmol) was
added. The mixture was stirred at ambient temperature for 0.5 h, after
which time all of the starting material was consumed as indicated by
TLC. Then the mixture was quenched through the successive addition of
aqueous Na2S2O3 (10 mL, 10 wt.%) and saturated aqueous NaHCO3. The
mixture was stirred for 10 min and then extracted with EtOAc. The com-
bined organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification by flash chromatography (n-hexane/EtOAc 9:1) afforded
ketone 18 (95 mg, 96%) as a colorless oil. [a]D =À41.2 (c=0.50 in
CH2Cl2); Rf =0.72 (n-hexane/EtOAc 8:2); 1H NMR (300 MHz, CDCl3):
d=0.00 (s, 3H, CH3Si), 0.009 (s, 3H, CH3Si), 0.73 (d, J=6.9 Hz, 3H,
[1] a) D. J. Faulkner, Nat. Prod. Rep. 1984, 1, 251–280; b) D. J. Faulk-
ner, Nat. Prod. Rep. 1986, 3, 1–33; c) P. A. Evans, A. B Holmes, Tet-
rahedron 1991, 47, 9131–9166; d) M. Tsuda, J. Kobayashi, Heterocy-
cles 1997, 46, 765–794; e) N. Matzanke, R. Gregg, S. Weinreb, Org.
Prep. Proced. Int. 1998, 30, 1–52; f) E. Magnier, Y. Langlois, Tetra-
hedron 1998, 54, 6201–6258.
[2] a) R. H. Grubbs, T. M. Trnka in Ruthenium in Organic Synthesis
(Ed.: S.-I. Murahashi), Wiley-VCH, Weinheim, 2004, pp. 153–177;
b) B. Schmidt, J. Hermanns, Curr. Org. Chem. 2006, 10, 1363–1396;
c) R. C. D. Brown, V. Satcharoen, Heterocycles 2006, 70, 705–736;
d) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010, 110, 1746–
1787; e) Metathesis in Natural Product Synthesis (Eds.: J. Cossy, S.
Arseniyadis, C. Meyer), Wiley-VCH, Weinheim, 2010.
CH3CH), 0.86 (s, 9H, SiC
(s, 9H, SC(CH3)3), 2.20–2.38 (m, 3H, CH2CO, CH
2H, CHCH(CH3)2, CHHCH2CO), 2.80 (s, 3H, NCH3), 3.04 (dd, J=16.8,
ACHTUNGTRENNUNG
[3] a) L. Yet, Chem. Rev. 2000, 100, 2963–3008; b) I. Nakamura, Y. Ya-
mamoto, Chem. Rev. 2004, 104, 2127–2198; c) A. Deiters, S. F.
Martin, Chem. Rev. 2004, 104, 2199–2238; d) P. Compain, Adv.
Synth. Catal. 2007, 349, 1829–1846; e) S. K. Chattopadhyay, S. Kar-
makar, T. Biswas, K. C. Mujumdar, H. Rahaman, B. Roy, Tetrahe-
dron 2007, 63, 3919–3952.
[4] For recent examples, see: a) P. Jakubec, D. M. Cockfield, D. J.
Dixon, J. Am. Chem. Soc. 2009, 131, 16632–16633; b) K. C. Majum-
dar, S. Mondal, D. Ghosh, Synthesis 2010, 1176–1180; c) K. C. Ma-
jumdar, S. Samanta, B. Chattopadhyay, R. K. Nandi, Synthesis 2010,
863–869; d) K. M. Kuhn, T. M. Champagne, S. H. Hong, W.-H. Wei,
A. Nickel, C. W. Lee, S. C. Virgil, R. H. Grubbs, R. L. Pederson,
Org. Lett. 2010, 12, 984–987.
[5] For alternative methods, see: a) T. J. Donohoe, A. Raoof, I. D.
Linney, M. Helliwell, Org. Lett. 2001, 3, 861–864; b) F. Iradier,
R. G. Arrayꢂs, J. C. Carretero, Org. Lett. 2001, 3, 2957–2960;
c) U. M. Lindstrçm, P. Somfai, Chem. Eur. J. 2001, 7, 94–98; d) H.-
U. Reissig, G. Bçttcher, R. Zimmer, Can. J. Chem. 2004, 82, 166–
176; e) A. Klapars, K. W. Anderson, S. L. Buchwald, J. Am. Chem.
Soc. 2005, 127, 3529–3533; f) M. Mizukami, H. Saito, T. Higuchi, M.
Imai, H. Bando, N. Kawahara, S. Nagumo, Tetrahedron Lett. 2007,
48, 7228–7231; g) M. H. Weston, K. Nakajima, T. G. Back, J. Org.
Chem. 2008, 73, 4630–4637; h) R. K. Boeckmann, Jr., N. E. Genung,
K. Chen, T. R. Ryder, Org. Lett. 2010, 12, 1628–1631.
[6] For exemptions in the case of dienes, see: a) G. R. Cook, P. S.
Skanker, S. L. Peterson, Org. Lett. 1999, 1, 615–617; b) I. Fellows,
D. E. Kaelin, S. F. Martin, J. Am. Chem. Soc. 2000, 122, 10781–
10787; c) A. Fꢃrstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738–
1742; d) J. D. White, P. Hrnciar, J. Org. Chem. 2000, 65, 9129–9142;
e) P. Wipf, S. R. Rector, H. Takahashi, J. Am. Chem. Soc. 2002, 124,
14848–14849; f) J. Barluenga, C. Mateos, F. Aznar, C. Valdes, J.
Org. Chem. 2004, 69, 7114–7122.
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6.6 Hz, 1H, CHHCH2CO), 3.44 (dd, J=11.6, 4.9 Hz, 1H, CHHO), 3.55–
3.75 (m, 2H, CHHO, NCHH), 3.95 (brs, 1H, NCH), 4.06 (dd, J=16.3,
1.9 Hz, 1H, NCHH), 4.94–5.14 (m, 4H, NCH2CH=CH2, CH=CH2), 5.60–
5.81 (m, 1H, CH2CH2CH=CH2), 5.85–6.01 (m, 1H, NCH2CH=CH2), 6.52
(d, J=12.1 Hz, 1H, CH=CS), 7.39–7.62 (m, 3H, Ph), 7.80–7.86 ppm (m,
2H, Ph); 13C NMR (75 MHz, CDCl3): d=À5.3 (d), À5.1 (d), 17.0 (d),
18.6 (u), 21.7 (d), 25.02 (d), 26.1 (d), 27.1 (u), 27.7 (d), 29.5 (d), 43.8 (u),
46.7 (d), 48.8 (u), 60.6 (d), 63.0 (u), 115.3 (d), 116.9 (u), 128.6 (d), 129.2
(d), 133.0 (d), 136.6 (d), 138.0 (d); 138.7 (u), 142.4 (d), 145.6 (u),
199.7 ppm (u); IR (KBr): n=2932 (s), 1700 (m), 1593 (m), 1380 (m),
1255 (m), 1118 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 653 [M ++1] (2), 318
(10), 214 (63), 156 (27); MS (CI, CH4): m/z (%): 681 [M ++C2H5] (100),
378 (13), 214 (19), 156 (11); HRMS (EI, 70 eV): m/z: calcd for
C33H57N2O5S2Si: 653.34782; found: 653.34959 [M++H].
(2S,3R,4E,9E)-2-((tert-Butyldimethylsilyloxy)methyl)-1-(tert-butylsulfon-
yl)-3-isopropyl-5-((S)-N-methyl-S-phenylsulfonimidoyl)azacycloundeca-
4,9-dien-6-one (26): To a solution of catalyst 19 (8 mg, 0.008 mmol) in tol-
uene (20 mL) a solution of the ketotriene 18 (63 mg, 0.096 mmol) in tolu-
ene (1 mL) was added and the mixture was heated at reflux for 24 h,
after which time all of the starting material was consumed as indicated
by TLC. The mixture was filtered through a short pad of silica gel, and
the solvent was removed in vacuo. Purification by flash chromatography
(n-hexane/EtOAc 8:2) afforded the MRNH 26 (57 mg, 95%) as a color-
less viscous liquid. [a]D =+119.4 (c=0.85 in CH2Cl2); Rf =0.42 (n-
hexane/EtOAc 8:2); 1H NMR (300 MHz, CDCl3): d=0.00 (s, 3H,
SiCH3), 0.82 (s, 3H, SiCH3), 0.39 (d, J=6.8 Hz, 3H, CH3CH), 0.63 (d, J=
6.8 Hz, 3H, CH3CH), 0.81 (s, 9H, SiC
2.34–2.40 (m, 3H, CH(CH3)3, CH2CH2CO), 2.46 (dt, J=15.9, 6.3 Hz, 1H,
CH2CHHCO), 2.55 (dt, J=12.9, 3.02 Hz, 1H, CHCH(CH3)2, 2.79 (s, 3H,
ACHTUNTGRENNGU(CH3)3), 1.25 (s, 9H, SCACHTUGNTREN(NUGN CH3)3),
[7] a) S. G. Pyne, Sulfur Rep. 1999, 21, 281–334; b) M. Reggelin, C.
Zur, Synthesis 2000, 1–64.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[8] a) H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe, Eur. J. Org.
Chem. 2003, 1500–1526; b) H.-J. Gais, Heteroat. Chem. 2007, 18,
472–481; c) A. Adrien, H.-J. Gais, F. Kçhler, J. Runsink, G. Raabe,
Org. Lett. 2007, 9, 2155–2158; d) H.-J. Gais in Asymmetric Synthesis
with Chemical and Biological Methods (Eds.: D. Enders, K.-E.
Jaeger), Wiley-VCH, Weinheim, 2007, pp. 75–115.
[9] M. Reggelin, B. Junker, T. Heinrich, S. Slavik, P. Buehle, J. Am.
Chem. Soc. 2006, 128, 4023–4034.
[10] M. Lejkowski, H.-J. Gais, P. Banerjee, C. Vermeeren, J. Am. Chem.
Soc. 2006, 128, 15378–15379.
[11] M. Lejkowski, P. Banerjee, J. Runsink, H.-J. Gais, Org. Lett. 2008,
10, 2713–2716.
[12] a) M. Schleusner, H.-J. Gais, S. Koep, G. Raabe, J. Am. Chem. Soc.
2002, 124, 7789–7800; b) M. Gꢃnter, H.-J. Gais, J. Org. Chem. 2003,
68, 8037–8041; c) S. Koep, H.-J. Gais, G. Raabe, J. Am. Chem. Soc.
NCH3), 2.88 (dd, J=15.6, 6.0 Hz, 1H, CH2CHHCO), 3.30 (dd, J=15.1,
9.8 Hz, 1H, NCHH), 3.48–3.61 (m, 2H, CH2O), 3.90 (brs, 1H, NCH),
4.10 (d, J=12.9 Hz, 1H, NCHH), 5.34 (ddd, J=16.1, 5.4, 3.5 Hz, 1H,
NCH2CH=CH), 5.46 (ddt, J=15.9, 5.4, 1.3 Hz, 1H, NCH2CH), 6.26 (d,
J=12.9 Hz, 1H, CH=CS), 7.30–7.45 (m, 3H, Ph), 7.68–7.78 ppm (m, 2H,
Ph); 13C NMR (75 MHz, CDCl3): d=À5.1 (d), À5.08 (d), 16.4 (d), 18.6
(u), 21.3 (d), 24.9 (d), 25.2 (d), 28.1 (u), 29.6 (d), 32.2 (d), 40.7 (u), 48.4
(u), 51.0 (d), 62.3 (d), 62.7 (u), 127.6 (d), 128.1 (d), 129.1 (d), 130.4 (d),
132.1 (d), 132.8 (d), 141.0 (u), 144.9 (d), 146.6 (u), 202.0 ppm (u); IR
(KBr): n=2932 (s), 1700 (m), 1691 (w), 1466 (m), 1317 (m), 1119 (s)
cmÀ1; MS (EI, 70 eV): m/z (%): 625 [M++1] (2.5), 348 (10), 57 (100); MS
(CI, CH4): m/z (%): 625 [M ++1] (100), 551 (10), 350 (11), 156 (23), 125
(26); HRMS (EI, 70 eV): m/z: calcd for C31H53N2O5S2Si: 625.31652;
found: 625.31535 [M ++H].
6194
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6187 – 6195

Medium Ring-Nitrogen Heterocycles
FULL PAPER
2003, 125, 13243–13251; d) S. K. Tiwari, H.-J. Gais, A. Lindenmaier,
G. S. Babu, G. Raabe, L. R. Reddy, F. Kçhler, M. Guenter, S. Koep,
V. B. R. Iska, J. Am. Chem. Soc. 2006, 128, 7360–7373.
[24] G. A. Olah, L. Ohannesian, M. Arvanaghi, J. Org. Chem. 1984, 49,
3856–3857.
[25] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–
956.
[26] Salt Li-28 is expected to have a pyramidalized anionic C atom and
exist as a rapidly equilibrating mixture of two diastereomeric car-
banions, see: a) H.-J. Gais, D. Lenz, G. Raabe, Tetrahedron Lett.
1995, 36, 7437–7440; b) J. F. K. Mꢃller, R. Batra, Spingler, M.
Zehnder, Helv. Chim. Acta 1996, 79, 820–826; c) R. Scholz, G. Hell-
mann, S. Rohs, G. Raabe, J. Runsink, D. ꢄzdemir, O. Luche, T.
Hess, A. W. Giesen, J. Atodiresei, H. J. Lindner, H.-J. Gais, Eur. J.
Org. Chem. 2010, 4559–4587.
[27] Q. Yang, W.-J. Xiao, Z. Yu, Org. Lett. 2005, 7, 871–874, and referen-
ces therein.
[28] A. Fꢃrstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130–
9136.
[29] H.-J. Gais, P. R. Bruns, G. Raabe, R. Hainz, M. Schleusner, J. Run-
sink, G. S. Babu, J. Am. Chem. Soc. 2005, 127, 6617–6631.
[30] C. R. Johnson, E. U. Jonsson, A. Wambsgans, J. Org. Chem. 1979,
44, 2061–2065.
[13] a) I. Erdelmeier, H.-J. Gais, J. Am. Chem. Soc. 1989, 111, 1125–
1126; b) H.-J. Gais, G. Bꢃlow, Tetrahedron Lett. 1992, 33, 461–464;
c) H.-J. Gais, G. Bꢃlow, Tetrahedron Lett. 1992, 33, 465–468; d) H.-J.
Gais, C. V. Rao, R. Loo, Chem. Eur. J. 2008, 14, 6510–6528.
[14] H.-J. Gais, R. L. Reddy, G. S. Babu, G. Raabe, J. Am. Chem. Soc.
2004, 126, 4859–4864.
[15] a) C. Cativiela, M. Ordonez, Tetrahedron: Asymmetry 2009, 20, 1–
63; b) S. Reissmann, D. Imhof, Curr. Med. Chem. 2004, 11, 2823–
2844; c) S. Hanessian, L. Auzzas, Acc. Chem. Res. 2008, 41, 1241–
1251.
[16] H.-J. Gais, R. Hainz, H. Mꢃller, P. R. Bruns, N. Giesen, G. Raabe, J.
Runsink, ; S. Nienstedt, J. Decker, M. Schleusner, J. Hachtel, R.
Loo, C.-W. Woo, P. Das, Eur. J. Org. Chem. 2000, 3973–4009; S.
Nienstedt, J. Decker, M. Schleusner, J. Hachtel, R. Loo, C.-W. Woo,
P. Das, Eur. J. Org. Chem. 2000, 3973–4009.
[17] M. Schleusner, S. Koep, M. Guenter; S. K. Tiwari, H.-J. Gais, Syn-
thesis 2004, 967–969.
[18] M. Gꢃnter, PhD Thesis, RWTH Aachen (Germany), 2003.
[19] P. Sun, S. M. Weinreb, M. Shang, J. Org. Chem. 1997, 62, 8604–8608.
[20] S. Acikalin, PhD Thesis, RWTH Aachen (Germany), 2009.
[21] V. B. R. Iska, PhD Thesis, RWTH Aachen (Germany), 2008.
[22] a) H.-J. Gais, H. Mꢃller, J. Decker, R. Hainz, Tetrahedron Lett.
1995, 36, 7433–7436; b) R. L. Reddy, H.-J. Gais, C.-W. Woo, G.
Raabe, J. Am. Chem. Soc. 2002, 124, 10427–10434.
[31] The configuration of the newly created double bond of MRNHs 20,
21a, 22, 23a, 23b, 24a, 24b, 25a, 25b, 26, and 29 was determined by
1
1H NMR spectroscopy. The H NMR spectra of MRNHs 20, 22, 23a,
23b, 25b, and 27 in CDCl3 at room temperature indicated the exis-
tence of conformational equilibria.
Received: November 4, 2010
[23] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
Published online: April 18, 2011
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