Use of aziridines for the stereocontrolled synthesis of (-)-LL-C10037α, (+)-MT35214, and (+)-4-epi-MT35214

Article abstract of DOI:10.1021/jo402535j

Strategies for the synthesis of the title compounds have been developed using a diastereoselective aziridination reaction of 4-O-substituted cyclohexenones. Aziridination using a chiral amine permitted resolution of a 4-hydroxycyclohexane derivative, and this resulted in the synthesis of both enantiomers of the title compound. Alternatively, the chiral 4-hydroxycyclohexenone starting material was derived from quinic acid. In both cases stereoselective epoxidation and opening of the aziridine ring with hydrazoic acid afforded the 2-azidocyclohexenone, which was transformed to the 2-acetamido group present in the natural product.

Full text of DOI:10.1021/jo402535j

Article
pubs.acs.org/joc
Use of Aziridines for the Stereocontrolled Synthesis of (−)-LL-
C10037α, (+)-MT35214, and (+)-4-epi-MT35214
Christopher D. Maycock,*,†,‡ Paula Rodrigues,† and M. Rita Ventura†
†
́
́
́
Instituto de Tecnologia Quımica e Biologica, Universidade Nova de Lisboa, Av. da Republica, 2780-157 Oeiras, Portugal
‡
́
́
̂
Departamento de Quımica e Bioquımica, Faculdade de Ciencias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
S
* Supporting Information
ABSTRACT: Strategies for the synthesis of the title
compounds have been developed using a diastereoselective
aziridination reaction of 4-O-substituted cyclohexenones.
Aziridination using a chiral amine permitted resolution of a
4-hydroxycyclohexane derivative, and this resulted in the
synthesis of both enantiomers of the title compound.
Alternatively, the chiral 4-hydroxycyclohexenone starting
material was derived from quinic acid. In both cases
stereoselective epoxidation and opening of the aziridine ring
with hydrazoic acid afforded the 2-azidocyclohexenone, which was transformed to the 2-acetamido group present in the natural
product.
linked to many human cancers.4 Ansamycin antibiotics, such as
INTRODUCTION
Antibiotics LL-C10037α (1) and MM 14201 (2) (Figure 1) are
representative examples of small metabolites with structural
■
Rifamycin B, Mitomycin C, and Ansamitocin, also present a
mC7N unit5 even though it is not in the form of an amido
epoxycyclohexenone core, indicating that both classes of
compounds are derived from the shikimate pathway.5−7
Due to these important biological activities and the scarcity
of the natural compounds in nature, several syntheses have
been developed. The syntheses in the racemic form of
enantiomers 1 and 3 as well as its 4-epimer 4 have been
reported by Wipf’s6,7 and Taylor’s8 groups. By a similar
procedure using a chiral acetal protecting group, Wipf et al.7
synthesized the optically active LL-C10037α (1), whereas
Johnson9 and Altenbach10 reported the enantioselective
synthesis of 1 from benzoquinone by enzymatic resolution of
a racemic intermediate. An asymmetric synthesis of MT 35214
(3) from 2,5-dimethoxyaniline was achieved by Taylor and co-
workers11 employing a chiral phase-transfer catalyst to effect an
enantioselective epoxidation. All published stereoselective
syntheses started from the achiral compounds 2,5-dimethox-
yaniline (Wipf7 and Taylor11) and benzoquinone (Johnson9
and Altenbach10); thus, a resolution step was necessary during
these syntheses.
Figure 1. Antibiotics LL-C10037α and MM14201 and their
stereoisomers.
similarities to the mC7N unit of the manumycin group of
compounds.1 LL-C10037α (1) is an antitumor antibiotic
isolated from the fermentation filtrate of Streptomyces LL-
C10037 by Lee and co-workers,2 for which the correct
structural assignment3 and absolute stereochemistry4 were
established by Gould and collaborators. MM 14201 (2) is an
antibiotic with a broad antibacterial spectrum produced by
Streptomyces sp. NCIB 11813, which due to its unstable nature
was isolated as the acetamide MT 35214 (3).5 The
manumycins show a variety of biological activities, including
antibiotic, cytotoxic, and insecticidal properties, as well as a
number of enzyme inhibition activities, the most important of
which is the inhibition of the Ras farnesyltransferase, an enzyme
As part of our studies on 4-hydroxy-α-halocycloenones, we
report herein our approach to the synthesis of (−)-LL-
C10037α (1) and (+)-MT 35214 (3) in optically active form
starting from racemic 4-TBSO-2-iodocyclohexenone, via
resolution by an aziridination protocol. We also report the
asymmetric synthesis of the (+)-4-epimer MT 35214 (4) from
(−)-quinic acid.
Received: November 15, 2013
Published: February 5, 2014
© 2014 American Chemical Society
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a
Scheme 1.
a
Legend: (a) toluene, 1,10-phenanthroline, Cs2CO3, (R)-(+)-4-OMe-α-MeBnNH2, room temperature, 88%, cis:trans 5:1.
a
Scheme 2.
a
Legend: (a) THF, LDA, PhSClNtBu, −78 °C, 73%; (b) THF, H2O2, Triton B, 0 °C, 87%, syn:anti 4:1; (c) toluene, HN3, room temperature, 89%;
(d) THF, Ph3P, H2O, Ac2O, room temperature, 89%; (e) THF, H2O, TBAF, room temperature, 93%.
a
Scheme 3.
a
Legend: (a) THF, LDA, PhSClNtBu, −78 °C, 76%; (b) THF, H2O2, Triton B, 0 °C, 84%, syn:anti 5:1; (c) toluene, HN3, room temperature, 74%;
(d) THF, Ph3P, H2O, Ac2O, room temperature, 73%; (e) THF, H2O, TBAF, room temperature, 84%.
trans isomers in 88% yield. Chromatographic separation
RESULTS AND DISCUSSION
■
20
afforded cis-aziridine cis-(+)-6 ([α]D = +107.3 (c 2.44,
Synthesis of (−)-LL-C10037α and (+)-MT 35214 from
20
CH2Cl2)), cis-aziridine cis-(−)-7 ([α]D = −64.1 (c 3.05,
Racemic 4-TBSO-2-iodocyclohexenone. Starting from rac-
4-TBSO-2-iodocyclohexenone12 (( )-5), the strategy used
comprised the following steps: (i) resolution via an
aziridination reaction with a chiral amine,13 (ii) formation of
a new α,β-unsaturated system, (iii) incorporation of the
epoxide ring, (iv) formation of an α-azidoenone, (v) formation
of the enamide, and (vi) deprotection.
CH2Cl2)), and an inseparable mixture of trans-aziridines 8 and
9 (Scheme 1). We believe that the cis stereoselectivity of this
reaction is due to hydrogen bonding between the amine proton
and the adjacent ether or hydroxyl group during the Michael
addition. This is the first reaction to occur and determines the
relative stereochemistry of the aziridine formed. Under these
conditions the amine is not deprotonated. However, tosylamide
under these conditions adds to form the trans-aziridine, and
here we assume the formation of an anion that does not
hydrogen bond to the adjacent ether or alcohol and hence the
sterically controlled product is formed. A study of this reaction
The resolution of ( )-5 was achieved via a Gabriel−
Cromwell aziridination reaction14 with optically pure (R)-
(+)-4-methoxy-α-methylbenzylamine. Carrying out the reaction
at room temperature for 17 h afforded a 5:1 mixture of cis and
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a
Scheme 4.
a
Legend: (a) AlCl3, toluene, −78 °C, 88%; (b) THF, NaOH 0.5 M, 0 °C, 75%; (c) CH2Cl2, DIPEA, TBSCl, DMAP, room temperature, 98%; (d)
Py:CCl4 1:1, I2, DMAP, room temperature, 94%; (e) toluene, 1,10-phen, Cs2CO3, 4-OMeBnNH2, room temperature, 92%; (f) Ph2O, reflux, 91%.
under different conditions has been carried out and will be
published separately.
With the optically pure cis diastereomers separated, the
subsequent steps of our strategy were carried out using cis-
aziridine cis-(+)-6 (Scheme 2) and cis-aziridine cis-(−)-7
(Scheme 3).
A key step in the strategy was the formation of the enone cis-
(+)-10 (Scheme 2). Although several oxidative elimination
protocols were attempted, most were unsuccessful and a little-
used method discovered by Mukaiyama et al.15 gave excellent
results. Thus reaction of the enolate of ketone cis-(+)-6 with N-
before the addition of the TBAF solution afforded (−)-LL-
C10037α (1), in 93% yield, after 15 min at room temperature.
The specific rotations obtained for (−)-LL-C10037α (1),
[α]D20 = −199.1 (c 0.11, CH2Cl2) and [α]D20 = −238.8 (c 0.08,
MeOH), were in accord with those reported, [α]D20 = −202 (c
9
0.334, MeOH),4 [α]D20 = −201 (c 0.34, MeOH), and [α]D
=
20
−194 (c 1.1, MeOH),10 and the spectroscopic data were
identical with those previously described.5
The synthesis of MT 35214 (3), the enantiomer of LL-
C10037α (1), was accomplished from the cis-aziridine cis-(−)-7
(Scheme 3). The same strategy described in Scheme 2 was
followed, but in this case the aziridine ring of cis-(−)-7, being
on the opposite plane of the molecule in comparison to cis-
(+)-6, directed the epoxide formation to afford the correct
configuration present in the final product 3.
tert-butyl phenylsulfinimidoyl chloride followed by a basic
workup15 afforded directly the enone cis-(+)-10 ([α]D
+103.8 (c 1.05, CH2Cl2)), in 73% yield.
=
20
Epoxidation of the cis-aziridine cis-(+)-10 with hydrogen
peroxide, in the presence of Triton B, afforded syn-epoxy-cis-
aziridine 11 ([α]D20 = +47.9 (c 1.49, CH2Cl2)) and anti-epoxy-
cis-aziridine 12 ([α]D20 = +109.7 (c 2.38, CH2Cl2)) in 87% total
yield and in a 4:1 ratio. Under the same conditions but in the
absence of the aziridine ring, the peroxide approached the
enone from the face opposite to the OTBS group, affording
exclusively the trans diastereomer.16 Therefore, formation of
the syn-epoxy-cis-aziridine 11 in a 4:1 ratio provided good
evidence for the stereodirecting effect of the aziridine ring on
the diastereofacial selectivity of the epoxidation. The directing
ability of an aziridine group during the epoxidation of adjacent
double bonds has been demonstrated previously in the
synthesis of (+)-Bromoxone.17 In this work it was shown that
the stereodirecting effect of the aziridine ring was much
stronger than the effect of a free hydroxyl group for the
stereochemical outcome of the epoxidation reaction and that
the influence of the bulky silyl group was steric.
Dehydrogenation (LDA, PhSClNtBu, −78 °C, 76%) of cis-
20
aziridine cis-(−)-7 afforded the α,β-enone cis-(−)-15 ([α]D
=
−49.1 (c 0.66, CH2Cl2)) in 76% yield. Epoxidation (H2O2,
20
Triton B, 84%) afforeded syn-epoxy-cis-aziridine 16 ([α]D
+13.4 (c 1.51, CH2Cl2)) and anti-epoxy-cis-aziridine 17 ([α]D
= −62.6 (c 1.0, CH2Cl2)) in a 5:1 ratio.
=
20
Aziridine ring cleavage of syn-epoxy-cis-aziridine 16, with
HN3 at room temperature for 20 min, gave syn-epoxy-azide 18
20
([α]D = +111.2 (c 1.03, CH2Cl2)) in 74% yield, that after
Staudinger reduction and in situ N-acetylation (Ph3P, H2O,
20
Ac2O) afforded syn-epoxy-acetamide 19 ([α]D = +119.6 (c
1.21, CH2Cl2)) in 74% yield.
The spectroscopic data for compounds 18 ([α]D = +111.2
(c 1.03, CH2Cl2)) and 19 ([α]D = +119.6 (c 1.21, CH2Cl2))
20
20
20
were identical with those for syn-epoxy-azide 13 ([α]D
−107.9 (c 0.82, CH2Cl2)) and syn-epoxy-acetamide 14 ([α]D
=
20
= −110.5 (c 1.69, CH2Cl2)), and their specific rotations
For the formation of the α-azidoenone, an acid-catalyzed
confirmed the enantiomeric relationship.
aziridine ring cleavage−elimination reaction was used.17
Desilylation (H2O, TBAF) of syn-epoxy-acetamide 19
afforded (+)-MT 35214 (3) in 83% yield, which had
spectroscopic data identical with those published.5 The
Treatment of syn-epoxy-cis-aziridine 11 with HN3 at room
20
temperature for 20 min gave syn-epoxy-azide 13 ([α]D
−107.9 (c 0.82, CH2Cl2)) in 89% yield.
=
20
obtained specific rotation, [α]D = +225.0 (c 0.02, MeOH),
The conversion of syn-epoxy-azide 13 into syn-epoxy-
acetamide 14 ([α]D20 = −110.5 (c 1.69, CH2Cl2)) was achieved
by N-acetylation, with acetic anhydride, during the Staudinger
reduction of the azido group, with triphenylphosphine in the
presence of water,18 at room temperature in 89% yield.
Finally, a controlled cleavage of the TBS group of syn-epoxy-
acetamide 14 by the addition of a small amount of water19
indicated that it forms an enantiomeric pair with (−)-LL-
C10037α (1) and was comparable with the reported value,
11
20
[α]D = +186.7 (c 0.35, MeOH).
Synthesis of (+)-MT 35214 Precursor and 4-epi-MT
35214 from (−)-Quinic Acid Derivatives. (+)-MT 35214
Precursor. Starting from the (−)-quinic acid derived 4,5-
isopropylidene-cyclohexenone19,20 20, we were able to obtain
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a
the (+)-MT 35214 precursor cis-(−)-26 by a different approach
(Scheme 4). Quinic acid is a chiral, abundant, and relatively
inexpensive starting material, isolated from the plant species
Cinchona. It has the advantage of being readily available and
suitably functionalized for conversion to a wide range of
interesting structures, particularly polysubsituted cyclohexanes.
To protect the double bond of enone 20, a Diels−Alder
reaction with cyclopentadiene was used. The stereochemistry of
the cycloadduct obtained was expected to influence the
stereochemical outcome of the aziridination. A retro-Diels−
Alder reaction would re-form the double bond.
Scheme 5.
The Diels−Alder reaction of enone 20 with cyclopentadiene,
in the presence of AlCl3 in toluene at −78 °C, proceeded
smoothly and cleanly in a completely diastereofacial and endo-
selective manner to provide the correspondent cycloadduct 21
([α]D20 = +36.9 (c 3.24, CH2Cl2)) in 88% yield. In accordance
with the results reported by Danishefsky and co-workers,21
cycloadduct 21 corresponds to the product resulting from
addition to the less hindered face of the bicyclic system 20.
Treatment of trans,endo-norbornene-acetonide 21 with a
catalytic amount of aqueous NaOH solution in THF19 afforded
trans,endo-norbornene-hydroxy enone 22 as a white solid
([α]D20 = +36.5 (c 2.31, CH2Cl2)) in 75% yield. The measured
physical properties of trans,endo-22 were different from those
reported for the cis,endo isomer,22,23 providing further evidence
for the proposed stereochemistry.
a
Legend: (a) Et2O:Py (1:1), I2, DMAP, room temperature, 85%; (b)
toluene, 1,10-phenanthroline, Cs2CO3, 4-MeOBnNH2, 95 °C, 84%,
cis:trans 1:4; (c) (i) THF, NaOH 0.5 M, 0 °C, (ii) CH2Cl2, DIPEA,
TBSCl, DMAP, room temperature, 80%; (d) THF, H2O2, Triton B, 0
°C, 90%; (e) HN3, benzene, 60 °C, 78%; (f) THF, PPh3, Ac2O,
DMAP, room temperature, 82%; (g) CH3CN, HF, room temperature,
80%; (h) (i) THF, NaOH 0.5 M, 0 °C, (ii) CH2Cl2, DIPEA, TBSCl,
DMAP, room temperature, 69%.
The following reactions were straightforward. Protection of
the free hydroxyl group of enone 22 with TBSCl, in the
presence of DIPEA and catalytic DMAP in CH2Cl2, gave
20
silyloxy 23 ([α]D = −49.5 (c 2.13, CH2Cl2)) in 98% yield.
Treatment with iodine, in a 1:1 mixture of pyridine and CCl4,17
afforded α-iodoenone 24 ([α]D20 = −79.2 (c 3.04, CH2Cl2)) in
94% yield. Aziridination of α-iodoenone 24 in toluene with 4-
methoxybenzylamine, in the presence of 1,10-phenanthroline
and Cs2CO3 at room temperature, occurred at the convex face
to provide only cis-aziridine cis-(−)-25 ([α]D20 = −62.3 (c 0.87,
CH2Cl2)) in 92% yield.
Treatment of the minor diastereomer cis-aziridine 2817 in
THF with aqueous NaOH, followed by protection of the allylic
alcohol in CH2Cl2 with TBSCl, in the presence of DIPEA and
20
DMAP, afforded cis-aziridine-enone cis-(+)-34 ([α]D = +
The retro-Diels−Alder reaction of cis-aziridine-trans-norbor-
149.2 (c 0.63; CH2Cl2)) in 69% yield. NMR data and specific
rotation of cis-(+)-34 showed that it forms an enantiomeric pair
with cis-aziridine-enone cis-(−)-26 and therefore should
provide (−)-LL-C10037α.
nene 25 proceeded effectively, by thermolysis in diphenyl ether
20
under reflux, to afford cis-aziridine-enone cis-(−)-26 ([α]D
=
−139.2 (c 0.97, CH2Cl2)) in 91% yield, demonstrating the
stability of the aziridine ring under these conditions. Following
the same synthetic strategy described in Scheme 3 from
aziridine cis-(-) 15, (+)-MT 35214 (3) should be obtained.
(−)-LL-C10037α Precursor and (+)-4-epi-MT 35214.
Derivatisation of 4,5-isopropylidene-cyclohexenone 20 also
enabled us to obtain the (−)-LL-C10037α precursor cis-(+)
34 and (+)-4-epi-MT 35214 (4) (Scheme 5).
CONCLUSION
■
A stereoselective synthesis of the enantiopure target com-
pounds (−)-LL-C10037α (1) and (+)-MT 35214 (3) from
( )-4-TBSO-2-iodocyclohexenone (( )-5) has been achieved,
as have the syntheses of (+)-4-epi-MT 35214 (4) from
(−)-quinic acid derivatives.
The first part of the synthesis (steps a−d) followed previous
work by our group, in which the major diastereomer 29 (28:29
= 1:4) led to anti-epoxy-trans-aziridine 31, an intermediate in
the stereoselective synthesis of natural product (+)-bromox-
one.17
The acid-catalyzed regioselective aziridine ring cleavage of
31, with a 2 M HN3 solution for 12 h at 60 °C, afforded α-
azidoenone 32 ([α]D20 = +171.5 (c 0.2, CH2Cl2)) in 78% yield.
N-acetylation during the Staudinger azide reduction (THF,
Ph3P, DMAP, Ac2O, room temperature) of α-azidoenone 32
Separation of ( )-5 via the aziridination protocol allowed us
to obtain both enantiomers (−)-LL-C10037α (1) and (+)-MT
35214 (3) along with all intermediates in optically pure form.
The presence of the aziridine nitrogen atom was also shown to
be important in the sequence of reactions, due to its
stereodirecting effect on the epoxidation reaction. It allowed
the formation of an α-azidoenone via acid-catalyzed regiose-
lective ring cleavage followed by spontaneous elimination of the
amine moiety.
gave α-enamide 33 in 82% yield. Desilylation (CH3CN, HF,
The (+)-MT 35214 precursor 26 was obtained from the
quinic acid derivative 20 by combining a stereoselective Diels−
Alder/aziridination/retro-Diels−Alder sequence. Applying our
strategy to the major diastereomer of the aziridination of the
quinic acid derivative 27 afforded (+)-4-epi-MT 35214 (4),
20
room temperature) afforded trans-epoxy alcohol 4 ([α]D
=
+72 (c 0.05; MeOH)) in 80% yield. The spectroscopic data of 4
were in accord with those reported6 for racemic 4-epi-MT
35214.
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H-3), 1.61−1.55 (1H, m, H-4), 1.40 (3H, d, J = 6.4 Hz, CH3), 0.71
[9H, s, (CH3)3C-Si], −0.03 (3H, s, CH3-Si), −0.15 (3H, s, CH3-Si)
ppm. 13C NMR (100 MHz, CDCl3): δ 206.0 (CO), 158.6 (Ar-C),
135.9 (Ar-C), 127.8 (Ar-C), 113.6 (Ar-C), 68.0 (C-8), 67.6 (C-5),
55.2 (OMe), 47.2 (C-1), 46.8 (C-6), 35.6 (C-3), 25.8 (C-4), 25.6
[(CH3)3C-Si], 23.7 (CH3), 17.8 [(CH3)3-C-Si], −4.8 (CH3-Si), −5.0
(CH3-Si) ppm. FTIR (neat): νmax 1711 (CO) cm−1. Anal. Calcd for
C21H33NO3Si: C, 67.16; H, 8.86; N, 3.73. Found: C, 67.35; H, 8.72; N,
3.71.
whereas the minor diastereomer led to the (−)-LL-C10037α
precursor 34.
EXPERIMENTAL SECTION
■
General Considerations. When required, solvents and reagents
were purified or dried according to standard procedures24 prior to use.
All commercial reagents were purchased from Sigma-Aldrich.
Reactions requiring anhydrous conditions were performed under an
argon atmosphere. After workup the organic layers were dried over
anhydrous MgSO4. Purification was performed on silica gel 60 for flash
chromatography (230−400 mesh) or on silica gel 60 GF254 for
preparative TLC. NMR chemical shifts are reported in ppm downfield
from TMS or using the residual solvent peak as reference. Peak
assignments were based on COSY and HMQC experiments. The
NMR spectra were measured on a Bruker Avance II+ 400 MHz
instrument, specific rotations were obtained with a Perkin-Elmer 241
automatic polarimeter, infrared spectra were recorded using a Mattson
Research Series FTIR, and melting points were determined on a Buchi
B-540 apparatus.
20
cis-Aziridine 7. Rf = 0.55 (hexane:EtOAc 8:2). [α]D = −64.1 (c
1
3.05, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.22 (2H, d, J = 8.8
Hz, Ar-H), 6.83 (2H, d, J = 8.4 Hz, Ar-H), 4.12 (1H, ddd, J = 10.6 Hz,
J = 5.2 Hz, J = 1.8 Hz, H-5), 3.78 (3H, s, OMe), 2.67 (1H, q, J = 6.4
Hz, H-8), 2.40 (1H, ddd, J = 18.4 Hz, J = 5.6 Hz, J = 2.0 Hz, H-3),
2.31−2.20 (2H, m, H-4, H-6), 2.07−1.98 (2H, m, H-1, H-3), 1.65−
1.59 (1H, m, H-4), 1.42 (3H, d, J = 6.4 Hz, CH3), 0.95 [9H, s,
(CH3)3C-Si], 0.15 (3H, s, CH3-Si), 0.18 (3H, s, CH3-Si) ppm. 13C
NMR (100 MHz, CDCl3): δ 205.5 (CO), 158.6 (Ar-C), 135.8 (Ar-
C-1), 127.5 (Ar-C), 113.7 (Ar-C), 67.7 (C-8), 67.6 (C-5), 55.2
(OMe), 47.8 (C-6), 46.7 (C-1), 35.4 (C-3), 25.9 (C-5), 25.8
[(CH3)3C-Si], 23.8 (CH3), 18.1 [(CH3)3C-Si], −4.6 (CH3-Si), −4.7
(CH3-Si) ppm. FTIR (neat): νmax 1711 (CO) cm−1. HRMS (ESI-
FIA-TOF): m/z calcd for C21H34NO3Si, 376.2308; found, 376.2287
(M + H).
Abbreviations: 1,10-phen, 1,10-phenanthroline; Cs2CO3, cesium
carbonate; (R)-(+)-4-OMe-α-MeBnNH2, (R)-(+)-4-methoxy-α-meth-
ylbenzylamine; THF, tetrahydrofuran; LDA, lithium diisopropylamide;
PhSClNtBu, N-tert-butyl phenylsulfinimidoyl chloride; H2O2, hydro-
gen peroxide; Triton B, benzyltrimethylammonium hydroxide; HN3,
hydrazoic acid; Ph3P, triphenylphosphine; Ac2O, acetic anhydride;
TBAF, tetrabutylammonium fluoride; AlCl3, aluminum chloride;
NaOH, sodium hydroxide; CH2Cl2, dichloromethane; DIPEA,
diisopropylethylamine; TBDMSCl, tert-butyldimethylsilyl chloride;
DMAP, 4-(dimethylamino)pyridine; Py, pyridine; CCl4, carbon
tetrachloride; I2, iodine; Ph2O, diphenyl ether; Et2O, diethyl ether;
CH3CN, acetonitrile; HF, hydrofluoric acid.
(1R,5R,6S)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]heptan-2-one (6),
(1S,5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
Methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]heptan-2-one (7),
(1S,5R,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]heptan-2-one (8),
and (1R,5S,6S)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]heptan-2-one (9). At
96 °C. To a solution of rac-4-TBSO-2-iodocyclohexenone12 (( )-5;
0.123 g, 0.35 mmol) in toluene (1 mL) were added 1,10-
phenanthroline (0.063 g, 0.35 mmol), Cs2CO3 (0.126 g, 0.39
mmol), and (R)-(+)-4-methoxy-α-methylbenzylamine (0.078 mL,
0.53 mmol). The reaction mixture was stirred for 1 h at 96 °C and
after rapid cooling was quenched with water and extracted with
CH2Cl2. The combined organic layers were dried, filtered, and
concentrated. The residue was purified by preparative TLC (hexane/
EtOAc 9/1), affording, in ascending order of polarity, an inseparable
mixture of trans-aziridines 8 and 9 as a colorless oil (0.051 g, 39%), cis-
aziridine 6 as a colorless oil (0.030 g, 23%), and cis-aziridine 7 as a
colorless oil (0.026 g, 20%).
Inseparable Mixture of trans-Aziridines 8 and 9. Rf = 0.67
(hexane:EtOAc 8:2). FTIR (neat): νmax 1709 (CO) cm−1. Anal.
Calcd for C21H33NO3Si: C, 67.16; H, 8.86; N, 3.73. Found: C, 67.24;
H, 8.86; N, 3.71.
trans-Aziridine 8. 1H NMR (400 MHz, CDCl3): δ 7.17 (2H, d, J =
8.8 Hz, Ar-H), 6.82 (2H, d, J = 8.8 Hz, Ar-H), 4.41−4.39 (1H, m, H-
5), 3.76 (3H, s, OMe), 2.69 (1H, q, J = 6.6 Hz, H-8), 2.31−2.25 (6H,
m, 2xH-3, H-4, H-6 of 8, and 2xH-3 of 9), 2.05 (1H, d, J = 6.0 Hz, H-
1), 1.65−1.56 (2H, m, H-4′ of 8, and H-4′ of 9), 1.38 (3H, d, J = 6.8
Hz, CH3), 0.90 [9H, s, (CH3)3C-Si], 0.13 (3H, s, CH3-Si), 0.10 (3H, s,
CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 206.6 (CO), 158.7
(Ar-C), 136.6 (Ar-C-1), 127.4 (Ar-C), 113.80 (Ar-C), 67.7 (C-8), 66.1
(C-5), 55.19 (OMe), 48.7 (C-6), 45.9 (C-1), 32.2 (C-3 of 8, and C-3
of 9), 27.4 (C-4), 25.8 [(CH3)3C-Si], 23.8 (CH3), 18.1 [(CH3)3C-Si],
−4.6 (CH3-Si), −4.7 (CH3-Si) ppm.
trans-Aziridine 9. 1H NMR (400 MHz, CDCl3): δ 7.23 (2H, d, J =
8.8 Hz, Ar-H), 6.87 (2H, d, J = 8.8 Hz, Ar-H), 4.10 (1H, dt, J = 4.0 Hz,
J = J = 2.8 Hz, H-5), 3.80 (3H, s, OMe), 2.64 (1H, q, J = 6.6 Hz, H-8),
2.31−2.25 (6H, m, 2 × H-3 of 9, and 2 × H-3, H-4, H-6 of 8), 2.18−
2.13 (3H, m, H-1, H-4, H-6), 1.65−1.56 (2H, m, H-4′ of 9, and H-4′
of 8), 1.35 (3H, d, J = 6.4 Hz, CH3), 0.82 [9H, s, (CH3)3C-Si], −0.03
(3H, s, CH3-Si), −0.04 (3H, s, CH3−Si) ppm. 13C NMR (100 MHz,
CDCl3): δ 206.9 (CO), 158.8 (Ar-C), 136.3 (Ar-C-1), 127.5 (Ar-
C), 113.84 (Ar-C), 68.1 (C-8), 65.5 (C-5), 55.24 (OMe), 48.0 (C-6),
46.5 (C-1), 32.2 (C-3 of 9, and C-3 of 8), 27.1 (C-4), 25.7 [(CH3)3C-
Si], 23.4 (CH3), 18.0 [(CH3)3C-Si], −4.8 (CH3-Si), −4.9 (CH3-Si)
ppm.
At Room Temperature. To a solution of rac-4-TBSO-2-
iodocyclohexenone12 (( )-5; 1.320 g, 3.75 mmol) in toluene (10
mL) were added 1,10-phenanthroline (0.676 g, 3.75 mmol), Cs2CO3
(1.344 g, 4.13 mmol), and (R)-(+)-4-methoxy-α-methylbenzylamine
(0.831 mL, 5.63 mmol). After it was stirred for 17 h at room
temperature, the reaction mixture was quenched with water and
extracted with CH2Cl2. The combined organic layers were dried,
filtered, and concentrated. The residue was purified by flash
chromatography (hexane/EtOAc 9/1), a mixture of trans-aziridines
8 and 9 eluting first as a colorless oil (0.215 g, 15%), followed by cis-
aziridine 6 as a colorless oil (0.554 g, 39%), and finally cis-aziridine 7 as
a colorless oil (0.482 g, 34%).
(1R,5R,6S)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]hept-3-en-2-one
(10). To a solution of LDA (prepared at 0 °C from n-BuLi (0.806 mL,
1.6 M in hexane, 1.29 mmol) and DIPA (0.217 mL, 1.55 mmol) in
THF (2 mL)) cooled to −78 °C was added a solution of ketone 6
(0.385 g, 1.03 mmol) in THF (3 mL). After 10 min, a solution of
PhSClNtBu25 (0.334 g, 1.55 mmol) in THF (3 mL) was added and
stirring continued for 3 h at this temperature. The reaction mixture
was quenched with NaHCO3 saturated solution and extracted with
CH2Cl2. The combined organic layers were dried, filtered, and
concentrated. Purification by flash chromatography (hexane:EtOAc
9:1) yielded enone 10 as a viscous oil (0.280 g, 73%). [α]D20 = +103.8
(c 1.05, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.29 (2H, d, J = 8.4
Hz, Ar-H), 6.83 (2H, d, J = 8.8 Hz, Ar-H), 6.33 (1H, dt, J = 10.4 Hz, J
= 2.4 Hz, H-4), 5.81 (1H, dt, J = 10.8 Hz, J = 2.0 Hz, H-3), 4.59 (1H,
dt, J = 4.4 Hz, J = 2.0 Hz, H-5), 3.77 (3H, s, OMe), 2.70 (1H, q, J =
6.4 Hz, H-8), 2.37 (1H, ddd, J = 6.4 Hz, J = 4.2 Hz, J = 2.2 Hz, H-6),
2.24 (1H, dd, J = 6.2 Hz, J = 1.8 Hz, H-1), 1.43 (3H, d, J = 6.4 Hz,
CH3), 0.74 [9H, s, (CH3)3C-Si], −0.01 (3H, s, CH3-Si), −0.18 (3H, s,
20
cis-Aziridine 6. Rf = 0.61 (hexane:EtOAc 8:2). [α]D = +107.3 (c
1
2.44, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.31 (2H, d, J = 8.4
Hz, Ar-H), 6.83 (2H, d, J = 8.4 Hz, Ar-H), 4.00 (1H, ddd, J = 10.8 Hz,
J = 4.8 Hz, J = 1.6 Hz, H-5), 3.78 (3H, s, OMe), 2.67 (1H, q, J = 6.4
Hz, H-8), 2.45 (1H, ddd, J = 18.4 Hz, J = 5.4 Hz, J = 1.8 Hz, H-3),
2.28−2.19 (1H, m, H-4), 2.17 (1H, br d, J = 6.0 Hz, H-6), 2.13 (1H, d,
J = 6.4 Hz, H-1), 2.07 (1H, ddd, J = 18.6 Hz, J = 12.6 Hz, J = 6.4 Hz,
1933
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The Journal of Organic Chemistry
Article
CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 195.1 (CO), 158.8
(Ar-C), 148.3 (C-4), 135.3 (Ar-C-1), 128.2 (Ar-C), 125.5 (C-3), 113.8
(Ar-C), 68.6 (C-8), 65.7 (C-5), 55.2 (OMe), 44.3 (C-1), 42.5 (C-6),
25.7 [(CH3)3C-Si], 23.5 (CH3), 18.1 [(CH3)3C-Si], −5.0 (CH3-Si),
−5.1 (CH3-Si) ppm. FTIR (neat): νmax 1685 (CO) cm−1. HRMS
(ESI-FIA-TOF): m/z calcd for C21H31NO3SiNa, 396.1971; found,
396.1960 (M + Na).
added and stirring continued for 3 h more. Ac2O (0.0557 mL, 0.585
mmol) was added at 0 °C, and the mixture was again warmed to room
temperature. After 5 h, the reaction mixture was neutralized with
NaHCO3 saturated solution and extracted with EtOAc. The combined
organic layers were dried, filtered, and concentrated. Purification by
preparative TLC (hexane:EtOAc 8:2) yielded acetamide 14 as a
viscous oil (0.031 mg, 89%). [α]D = −110.5 (c 1.69, CH2Cl2). H
NMR (400 MHz, CDCl3): δ 7.51 (1H, br s, NH), 7.38 (1H, t, J = 2.8
Hz, H-4), 4.97 (1H, t, J = 3.0 Hz, H-5), 3.72 (1H, dt, J = 4.0 Hz, J =
2.8 Hz, H-6), 3.52 (1H, d, J = 4.0 Hz, H-1), 2.11 (3H, s, CH3CO),
0.96 [9H, s, (CH3)3C-Si], 0.202 (3H, s, CH3-Si), 0.198 (3H, s, CH3-
Si) ppm. 13C NMR (100 MHz, CDCl3): δ 188.8 (CO enone), 169.1
(CO acetamide), 127.9 (C-3), 126.2 (C-4), 65.6 (C-5), 53.7 (C-6),
52.0 (C-1), 25.7 [(CH3)3C-Si], 24.5 (CH3−CO), 18.2 [(CH3)3C-
Si], −4.52 (CH3-Si), −4.54 (CH3-Si) ppm. FTIR (neat): νmax 3280
(NH), 1674 (CO) cm−1. HRMS (ESI-FIA-TOF): m/z calcd for
C14H23NO4SiNa, 320.1294; found, 320.1277 (M + Na).
20
1
(1R,3S,5R,6S,7S)-6-[(tert-Butyldimethylsilyl)oxy]-8-[(1R)-1-(4-
methoxyphenyl)ethyl]-4-oxa-8-azatricyclo[5.1.0.03,5]octan-2-
one (11) and (1R,3R,5S,6S,7S)-6-[(tert-Butyldimethylsilyl)oxy]-
8-[(1R)-1-(4-methoxyphenyl)ethyl]-4-oxa-8-azatricyclo-
[5.1.0.03,5]octan-2-one (12). To a an ice-cooled solution of enone
10 (0.230 g, 0.62 mmol) in THF (2 mL) were added H2O2 (0.6 mL,
30 wt.% in water, 5.88 mmol) and Triton B (1 mL, 40 wt.% in
methanol, 2.2 mmol). After it was stirred for 30 min at this
temperature, the reaction mixture was quenched with NH4Cl saturated
solution and extracted with CH2Cl2. The combined organic layers
were dried, filtered, and concentrated. The residue was purified by
preparative TLC (hexane:EtOAc 9:1) to yield the less polar anti-
epoxide 12 as a colorless oil (0.042 g, 17%) and the more polar syn-
epoxide 11 as a colorless oil (0.170 g, 70%).
(−)-LL-C10037α2 (1). To a solution of silyl ether 14 (0.0186 g,
0.0625 mmol) in THF (1 mL) at room temperature was added H2O
(2 drops, ca. 0.024 mL, 1.33 mmol) followed by TBAF (0.0625 mL, 1
M in THF, 0.0625 mmol). After 15 min, the reaction mixture was
diluted with water (1 mL) and extracted with EtOAc. The combined
organic layers were dried, filtered, and concentrated. Purification by
preparative TLC (hexane:EtOAc 2:8) yielded the title compound
(0.0107 g, 93%), which had spectroscopic data identical with those
published.5 [α]D20 = −199.1 (c 0.11, CH2Cl2) and [α]D20 = −238.8 (c
0.08, MeOH). Lit.: [α]D20 = −202 (c 0.334, MeOH),4 [α]D20 = −201
20
syn-epoxide 11. Rf = 0.20 (hexane:EtOAc 9:1). [α]D = +47.9 (c
1
1.49, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.35 (2H, d, J = 8.8
Hz, Ar-H), 6.85 (2H, d, J = 8.4 Hz, Ar-H), 4.33 (1H, dd, J = 4.2 Hz, J
= 2.2 Hz, H-6), 3.79 (3H, s, OMe), 3.43 (1H, dt, J = 4.0 Hz, J = 2.4
Hz, H-5), 3.31 (1H, dd, J = 4.0 Hz, J = 2.0 Hz, H-3), 2.37 (1H, q, J =
6.6 Hz, H-9), 2.26−2.20 (2H, m, H-1, H-7), 1.39 (3H, d, J = 6.4 Hz,
CH3), 0.77 [9H, s, (CH3)3C-Si], 0.02 (3H, s, CH3-Si), −0.16 (3H, s,
CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 200.9 (CO), 158.7
(Ar-C), 135.3 (Ar-C-1), 128.2 (Ar-C), 113.7 (Ar-C), 70.1 (C-9), 65.6
(C-6), 61.1 (C-5), 55.5 (C-3), 55.2 (OMe), 49.3 (C-7), 46.3 (C-1),
25.7 [(CH3)3C-Si], 23.6 (CH3), 18.1 [(CH3)3C-Si], −4.91 (CH3-Si),
−4.95 (CH3-Si) ppm. FTIR (neat): νmax 1699 (CO) cm−1. HRMS
(ESI-FIA-TOF): m/z calcd for C21H31NO4SiNa, 412.1920; found,
412.1917 (M + Na).
(c 0.34, MeOH),9 [α]D = −194 (c 1.1, MeOH).10 1H NMR (400
20
MHz, CDCl3): δ 7.56 (1H, br s, NH), 7.44 (1H, t, J = 2.8 Hz, H-4),
4.85 (1H, dt, J = 10.0 Hz, J = 3.0 Hz, H-5), 3.88 (1H, dd, J = 3.4 Hz, J
= 2.8 Hz, H-6), 3.60 (1H, d, J = 4.0 Hz, H-1), 2.40 (1H, d, J = 10.4 Hz,
OH), 2.13 (3H, s, CH3−CO) ppm. 13C NMR (100 MHz, CDCl3):
δ 188.5 (CO enone), 169.2 (CO acetamide), 128.4 (C-3), 124.7
(C-4), 64.5 (C-5), 54.1 (C-6), 52.6 (C-1), 24.6 (CH3−CO) ppm.
FTIR (neat): νmax 3345 (NH and OH), 1655 (CO) cm−1. MS
(calcd for C8H9NO4 183.1): m/z 184.0 (M + 1, 100%).
anti-Epoxide 12. Rf = 0.34 (hexane:EtOAc 9:1). [α]D20 = +109.7 (c
1
2.38, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.26 (2H, d, J = 8.4
(1S,5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(1R)-1-(4-
methoxyphenyl)ethyl]-7-azabicyclo[4.1.0]hept-3-en-2-one
(15). To a solution of LDA (prepared at 0 °C from n-BuLi (0.508 mL,
1.6 M in hexane, 0.81 mmol) and DIPA (0.137 mL, 0.98 mmol) in
THF (2 mL)) cooled to −78 °C was added a solution of ketone 7
(0.244 g, 0.66 mmol) in THF (2 mL). After 10 min, a solution of
PhSClNtBu24 (0.210 g, 0.98 mmol) in THF (2 mL) was added and
stirring continued for 3 h at this temperature. The reaction mixture
was quenched with NaHCO3 saturated solution and extracted with
CH2Cl2. The combined organic layers were dried, filtered, and
concentrated. Purification by flash chromatography (hexane:EtOAc
9:1) yielded enone 15 as a viscous oil (0.185 g, 76%). [α]D20 = −49.1
(c 0.66, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.20 (2H, d, J = 8.8
Hz, Ar-H), 6.81 (2H, d, J = 8.8 Hz, Ar-H), 6.37 (1H, dt, J = 10.4 Hz, J
= 2.2 Hz, H-4), 5.77 (1H, dt, J = 10.8 Hz, J = 1.8 Hz, H-3), 4.73 (1H,
dt, J = 4.4 Hz, J = 2.0 Hz, H-5), 3.76 (3H, s, OMe), 2.75 (1H, q, J =
6.6 Hz, H-8), 2.45 (1H, ddd, J = 6.4 Hz, J = 4.6 Hz, J = 2.4 Hz, H-6),
2.17 (1H, dd, J = 6.0 Hz, J = 1.6 Hz, H-1), 1.47 (3H, d, J = 6.4 Hz,
CH3), 0.98 [9H, s, (CH3)3C-Si], 0.21 (3H, s, CH3-Si), 0.20 (3H, s,
CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 194.5 (CO), 158.6
(Ar-C), 147.3 (C-4), 135.2 (Ar-C-1), 127.6 (Ar-C), 125.7 (C-3), 113.7
(Ar-C), 68.1 (C-8), 65.6 (C-5), 55.1 (OMe), 44.1 (C-6), 43.3 (C-1),
25.8 [(CH3)3C-Si], 23.7 (CH3), 18.2 [(CH3)3C-Si], −4.6 (CH3-Si),
−4.9 (CH3-Si) ppm. FTIR (neat): νmax 1687 (CO) cm−1. Anal.
Calcd for C21H31NO3Si: C, 67.52; H, 8.36; N, 3.75. Found: C, 67.53;
H, 8.44; N, 3.70.
Hz, Ar-H), 6.84 (2H, d, J = 8.4 Hz, Ar-H), 4.25 (1H, d, J = 4.0 Hz, H-
6), 3.79 (3H, s, OMe), 3.20 (1H, d, J = 3.2 Hz, H-3), 3.17 (1H, dd, J =
3.2 Hz, J = 1.2 Hz, H-5), 2.76 (1H, q, J = 6.6 Hz, H-9), 2.19 (1H, ddd,
J = 5.4 Hz, J = 4.4 Hz, J = 1.0 Hz, H-7), 2.11 (1H, dd, J = 5.6 Hz, J =
0.8 Hz, H-1), 1.42 (3H, d, J = 6.4 Hz, CH3), 0.75 [9H, s, (CH3)3C-Si],
0.00 (3H, s, CH3-Si), −0.17 (3H, s, CH3-Si) ppm. 13C NMR (100
MHz, CDCl3): δ 197.2 (CO), 159.0 (Ar-C), 134.9 (Ar-C-1), 128.3
(Ar-C), 113.9 (Ar-C), 68.9 (C-9), 64.5 (C-6), 56.5 (C-5), 55.3
(OMe), 51.2 (C-3), 43.0 (C-7), 42.3 (C-1), 25.8 [(CH3)3C-Si], 23.2
(CH3), 18.2 [(CH3)3C-Si], −5.0 (CH3-Si), −5.1 (CH3-Si) ppm.
(1S,5S,6R)-3-Azido-5-[(tert-butyldimethylsilyl)oxy]-7-
oxabicyclo[4.1.0]hept-3-en-2-one (13). A solution of aziridine 11
(0.059 g, 0.152 mmol) in HN3 (1 mL, 2 M in toluene; HN3 is volatile
and highly toxic) was stirred at room temperature for 20 min. The
reaction mixture was cooled to 0 °C, quenched with NaHCO3
saturated solution, and extracted with CH2Cl2. The combined organic
layers were dried, filtered, and concentrated. Purification by
preparative TLC (hexane:EtOAc 9:1) afforded vinyl azide 13 as a
colorless oil (0.038 g, 89%). [α]D = −107.9 (c 0.82, CH2Cl2). H
NMR (400 MHz, CDCl3): δ 5.85 (1H, t, J = 2.6 Hz, H-4), 4.88 (1H, t,
J = 2.8 Hz, H-5), 3.69 (1H, dt, J = 3.6 Hz, J = 2.8 Hz, H-6), 3.52 (1H,
d, J = 4.0 Hz, H-1), 0.95 [9H, s, (CH3)3C-Si], 0.19 (3H, s, CH3-Si),
0.18 (3H, s, CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 188.5
(CO), 131.3 (C-3), 128.1 (C-4), 65.8 (C-5), 54.1 (C-6), 52.8 (C-
1), 25.7 [(CH3)3C-Si], 18.2 [(CH3)3C-Si], −4.6 (CH3-Si), −4.7 (CH3-
Si) ppm. FTIR (neat): νmax 2114 (N3), 1697 (CO) cm−1. HRMS
(ESI-FIA-TOF): m/z calcd for C12H19N3O3SiNa, 304.1093; found,
304.1078 (M + Na).
20
1
(1S,3R,5S,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-8-[(1R)-1-(4-
methoxyphenyl)ethyl]-4-oxa-8-azatricyclo[5.1.0.03,5]octan-2-
one (16) and (1S,3S,5R,6R,7R)-6-[(tert-Butyldimethylsilyl)oxy]-
8-[(1R)-1-(4-methoxyphenyl)ethyl]-4-oxa-8-azatricyclo-
[5.1.0.03,5]octan-2-one (17). To a 0 °C cooled solution of enone 15
(0.112 g, 0.30 mmol) in THF (2 mL) were added H2O2 (0.3 mL, 30
wt % in water, 2.94 mmol) and Triton B (0.5 mL, 40 wt % in
methanol, 0.22 mmol). After it was stirred for 1 h at this temperature,
N-[(1S,5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-2-oxo-7-
oxabicyclo[4.1.0]hept-3-en-3-yl]acetamide (14). Ph3P (0.0307 g,
0.117 mmol) was added to a solution of azide 13 (0.0328 g, 0.117
mmol) in THF (1 mL) at 0 °C. After the mixture was stirred for 2 h at
room temperature, H2O (10 drops, ca. 0.120 mL, 6.7 mmol) was
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The Journal of Organic Chemistry
Article
the reaction mixture was quenched with NH4Cl saturated solution and
extracted with CH2Cl2. The combined organic layers were dried,
filtered, and concentrated. The residue was purified by preparative
TLC (hexane:EtOAc 9:1) to yield the less polar anti-epoxide 17 as a
colorless oil (0.016 g, 14%) and the more polar syn-epoxide 16 as a
134.6 (C-13), 108.0 (C-5), 75.9 (C-3), 75.1 (C-7), 52.4 (C-10), 49.0
(C-14), 47.2 (C-1), 46.4 (C-11), 44.6 (C-2), 44.4 (C-8), 28.2 (CH3a),
25.9 (CH3b) ppm. FTIR (neat): νmax 1709 (CO) cm−1. HRMS
(ESI-FIA-TOF): m/z calcd for C14H18O3Na, 257.1154; found,
257.1149 (M + Na).
(1R,2S,6S,7R,8S)-6-[(tert-Butyldimethylsilyl)oxy]-4-
iodotricyclo[6.2.1.02,7]undeca-4,9-dien-3-one (24). To a solution
of acetonide 21 (0.200 g, 0.854 mmol) in THF (2 mL) at 0 °C was
added dropwise a 0.5 M NaOH solution, until no starting material was
detected by TLC. The reaction mixture was quenched with NH4Cl
saturated solution and extracted with EtOAc. The combined organic
layers were dried, filtered, and concentrated. Allyl alcohol 22 was
colorless oil (0.086 g, 74%).
syn-Epoxide 16. Rf = 0.26 (hexane:EtOAc 9:1, twice). [α]D
20
=
+13.4 (c 1.51, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.25 (2H, d, J
= 8.8 Hz, Ar-H), 6.83 (2H, d, J = 8.8 Hz, Ar-H), 4.47 (1H, dd, J = 4.0
Hz, J = 2.4 Hz, H-6), 3.78 (3H, s, OMe), 3.48 (1H, dt, J = 4.0 Hz, J =
2.4 Hz, H-5), 3.28 (1H, dd, J = 4.0 Hz, J = 2.4 Hz, H-3), 2.39−2.35
(2H, m, H-7, H-9), 2.10 (1H, dd, J = 6.4 Hz, J = 2.4 Hz, H-1), 1.45
(3H, d, J = 6.4 Hz, CH3), 1.00 [9H, s, (CH3)3C-Si], 0.23 (3H, s, CH3-
Si), 0.22 (3H, s, CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 200.4
(CO), 158.7 (Ar-C), 135.2 (Ar-C-1), 127.7 (Ar-C), 113.8 (Ar-C),
70.0 (C-9), 65.6 (C-6), 60.8 (C-5), 55.6 (C-3), 55.2 (OMe), 50.5 (C-
7), 46.1 (C-1), 25.9 [(CH3)3C-Si], 23.7 (CH3), 18.3 [(CH3)3C-Si],
−4.5 (CH3-Si), −4.6 (CH3-Si) ppm. FTIR (neat): νmax 1705 (CO)
cm−1. HRMS (ESI-FIA-TOF): m/z calcd for C21H31NO4SiNa,
20
obtained as a white solid (0.113 g, 75%). Mp: 167.4−168.6 °C. [α]D
1
= +36.5 (c 2.31, CH2Cl2). H NMR (400 MHz, CDCl3): δ 6.68 (1H,
dd, J = 10.4 Hz, J = 3.2 Hz, H-5), 6.16 (1H, dd, J = 5.6 Hz, J = 2.8 Hz,
H-10), 6.09 (1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-9), 5.87 (1H, dd, J =
10.0 Hz, J = 2.0 Hz, H-4), 4.06−4.03 (1H, m, H-6), 3.36 (1H, br s, H-
1), 3.27 (1H, br s, H-8), 2.99 (1H, dd, J = 10.2 Hz, J = 3.8 Hz, H-2),
2.79 (1H, dt, J = 10.0 Hz, J = 4.2 Hz, H-7), 2.52 (1H, br s, OH), 1.52
(1H, dt, J1 = 8.4 Hz, J = 1.6 Hz, H-11a), 1.40 (1H, d, J = 8.4 Hz, H-
11b) ppm. 13C NMR (100 MHz, CDCl3): δ 200.2 (CO), 150.4 (C-
5), 137.9 (C-10), 135.3 (C-9), 129.4 (C-4), 67.3 (C-6), 49.3 (C-2),
48.2 (C-11), 46.47 (C-7), 46.44 (C-1), 46.40 (C-8) ppm. FTIR
(neat): νmax 3407 (OH), 1661 (CO) cm−1.
412.1920; found, 412.1924 (M + Na).
anti-Epoxide 17. Rf = 0.44 (hexane:EtOAc 9:1, twice). [α]D
20
=
−62.6 (c 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.18 (2H, d, J
= 8.8 Hz, Ar-H), 6.84 (2H, d, J = 8.8 Hz, Ar-H), 4.38 (1H, d, J = 4.0
Hz, H-6), 3.79 (3H, s, OMe), 3.24 (1H, dd, J = 3.2 Hz, J = 1.6 Hz, H-
5), 3.16 (1H, d, J = 3.2 Hz, H-3), 2.81 (1H, q, J = 6.6 Hz, H-9), 2.23
(1H, ddd, J = 5.6 Hz, J = 4.2 Hz, J = 1.4 Hz, H-7), 2.06 (1H, dd, J =
5.6 Hz, J = 1.2 Hz, H-1), 1.47 (3H, d, J = 6.4 Hz, CH3), 1.00 [9H, s,
(CH3)3C-Si], 0.24 (3H, s, CH3-Si), 0.23 (3H, s, CH3-Si) ppm. 13C
NMR (100 MHz, CDCl3): δ 196.6 (CO), 158.9 (Ar-C), 134.7 (Ar-
C-1), 127.7 (Ar-C), 113.8 (Ar-C), 68.3 (C-9), 64.6 (C-6), 56.3 (C-5),
55.2 (OMe), 51.0 (C-3), 44.4 (C-7), 41.7 (C-1), 25.9 [(CH3)3-C-Si],
23.6 (CH3), 18.4 [(CH3)3C-Si], −4.5 (CH3-Si), −4.8 (CH3-Si) ppm.
FTIR (neat): νmax 1720 (CO) cm−1. Anal. Calcd for C21H31NO4Si:
C, 64.75; H, 8.02; N, 3.60. Found: C, 64.54; H, 7.92; N, 3.60.
(1R,5R,6S)-3-Azido-5-[(tert-butyldimethylsilyl)oxy]-7-
oxabicyclo[4.1.0]hept-3-en-2-one (18). Following the procedure
for 13, aziridine 16 (0.067 g, 0.17 mmol) and HN3 (1 mL, 1.5 M in
toluene, HN3 is volatile and highly toxic) afforded vinyl azide 18 as a
colorless oil (0.036 g, 74%), which had spectroscopic data identical
To a 0 °C cooled solution of alcohol 22 (0.081 g, 0.46 mmol) in
CH2Cl2 (2 mL) were added DIPEA (0.200 mL, 1.15 mmol), TBSCl
(0.139 g, 0.92 mmol), and a catalytic amount of DMAP. The solution
was stirred for 12 h at room temperature and then diluted with EtOAc
and washed with water. The organic layer was dried, filtered, and
concentrated. Silyloxy 23 was obtained as a colorless viscous oil (0.131
20
g, 98%). [α]D = −49.5 (c 2.13, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ 6.52 (1H, dd, J = 10.0 Hz, J = 2.8 Hz, H-5), 6.20 (1H, dd, J
= 5.6 Hz, J = 2.8 Hz, H-10), 6.08 (1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-9),
5.81 (1H, dd, J = 10.2 Hz, J = 2.2 Hz, H-4), 3.99 (1H, dt, J = 4.8 Hz, J
= 2.4 Hz, H-6), 3.34 (1H, br s, H-1), 3.18 (1H, br s, H-8), 2.98 (1H,
dd, J = 10.6 Hz, J = 3.8 Hz, H-2), 2.80−2.74 (1H, dt, J = 10.8 Hz, J =
4.4 Hz, H-7), 1.50 (1H, dt, J = 8.4 Hz, J = 1.6 Hz, H-11a), 1.39 (1H, d,
J = 8.8 Hz, H-11b), 0.93 [9H, s, (CH3)3C-Si], 0.15 (3H, s, CH3-Si),
0.11 (3H, s, CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 200.0
(CO), 151.6 (C-5), 138.3 (C-10), 135.3 (C-9), 128.6 (C-4), 68.3
(C-6), 49.6 (C-2), 48.2 (C-11), 46.9 (C-7), 46.0 (C-8), 45.9 (C-1),
25.7 [(CH3)3C-Si], 18.0 [(CH3)3C-Si], −4.5 (CH3-Si), −4.6 (CH3-Si)
ppm. FTIR (neat): νmax 1679 (CO) cm−1.
20
with those of vinyl azide 13. [α]D = +111.2 (c 1.03, CH2Cl2).
N-[(1R,5R,6S)-5-[(tert-butyldimethylsilyl)oxy]-2-oxo-7-
oxabicyclo[4.1.0]hept-3-en-3-yl]acetamide (19). Following the
procedure for 14, azide 18 (0.0207 g, 0.074 mmol), Ph3P (0.0193 mg,
0.074 mmol), H2O (6 drops, ca. 0.072 mL, 4 mmol), and Ac2O (0.035
mL, 0.367 mmol) in THF (1 mL) yielded acetamide 19 as a viscous oil
(0.016 mg, 73%), which had spectroscopic data identical with those of
To a 0 °C cooled solution of enone 23 (0.104 g, 0.36 mmol) in
Py:CCl4 1:1 (2 mL) were added a solution of I2 (0.183 g, 0.72 mmol)
in Py:CCl4 1:1 (2 mL) and a catalytic amount of DMAP. After it was
stirred for 25 min at room temperature, the reaction mixture was
diluted with EtOAc and washed with 20% Na2S2O3 solution and water.
The organic layer was dried, filtered, and concentrated. Purification by
flash chromatography (hexane:EtOAc 9:1) yielded α-iodoenone 24 as
a yellow viscous oil (0.140 g, 94%). [α]D20 = −79.2 (c 3.04, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ 7.22 (1H, d, J = 3.2 Hz, H-5), 6.21
(1H, dd, J = 5.8 Hz, J = 3.0 Hz, H-10), 6.09 (1H, dd, J = 5.6 Hz, J = 2.8
Hz, H-9), 3.98 (1H, dd, J = 5.2 Hz, J = 3.2 Hz, H-6), 3.37 (1H, br s, H-
1), 3.16 (1H, br s, H-8), 3.11 (1H, dd, J = 10.4 Hz, J = 4.0 Hz, H-2),
2.84 (1H, ddd, J = 10.4 Hz, J = 5.2 Hz, J = 4.0 Hz, H-7), 1.50 (1H, dt, J
= 8.8 Hz, J = 1.8 Hz, H-11a), 1.41 (1H, d, J = 8.8 Hz, H-11b), 0.93
[9H, s, (CH3)3C-Si], 0.14 (3H, s, CH3-Si), 0.12 (3H, s, CH3-Si) ppm.
13C NMR (100 MHz, CDCl3): δ 193.3 (CO), 160.0 (C-5), 138.5
20
acetamide 14. [α]D = +119.6 (c 1.21, CH2Cl2).
(+)-MT 352145 (3). Following the procedure for 1, silyl ether 19
(0.0123 g, 0.0414 mmol), THF (1 mL), H2O (1 drop, ca. 0.012 mL,
0.67 mmol), and TBAF (0.0414 mL, 1 M in THF, 0.0414 mmol)
yielded the title compound (0.0064 g, 84%), which had spectroscopic
data identical with those for 1 and with those published.5 [α]D
+225.0 (c 0.02, MeOH); lit. [α]D = +186.7 (c 0.35, MeOH).
=
20
11
20
(1S,2R,3S,7R,10S,11R)-5,5-Dimethyl-4,6-dioxatetracyclo-
[9.2.1.0.2,1003,7]tetradec-12-en-9-one (21). A solution of cyclo-
hexenone19,20 20 (0.900 g, 5.35 mmol) in toluene (14 mL) was added
dropwise to a solution of AlCl3 (0.656 g, 4.92 mmol) in toluene (20
mL) at −78 °C. After 10 min, a solution of cyclopentadiene (2.2 mL,
27.29 mmol) in toluene (7 mL) was added dropwise. The resulting
mixture was stirred for 15 min and then poured onto an ice-NaHCO3
saturated solution and extracted with Et2O. The combined organic
layers were dried, filtered, and concentrated. Purification by flash
chromatography (hexane:EtOAc 8:2) yielded adduct 21 as a colorless
viscous oil (1.107 g, 88%). [α]D20 = +36.9 (c 3.24, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ 6.22 (1H, dd, J1 = 5.6 Hz, J = 2.8 Hz, H-12),
6.16 (1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-13), 4.10−4.03 (2H, m, H-3
and H-7), 3.26 (1H, br s, H-11), 3.16 (1H, br s, H-1), 3.04−2.97 (2H,
m, H-2 and H-10), 2.50−2.40 (2H, m, 2xH-8), 1.48−1.47 (4H, m, H-
14a and CH3a), 1.37 (1H, d, J = 8.4 Hz, H-14b), 1.34 (3H, s, CH3b)
ppm. 13C NMR (100 MHz, CDCl3): δ 211.1 (CO), 138.4 (C-12),
(C-10), 135.5 (C-9), 102.2 (C-4), 70.9 (C-6), 49.4 (C-2), 48.3 (C-
11), 47.3 (C-7), 46.7 (C-1), 45.9 (C-8), 25.7 [(CH3)3C-Si], 17.9
[(CH3)3C-Si], −4.5 (CH3-Si), −4.6 (CH3-Si) ppm. FTIR (neat): νmax
1687 (CO) cm−1. HRMS (ESI-FIA-TOF): m/z calcd for
C17H25IO2SiNa, 439.0566; found, 439.0553 (M + Na).
(1R,2S,4S,6R,7S,8R,9S)-7-[(tert-Butyldimethylsilyl)oxy]-5-[(4-
methoxyphenyl)methyl]-5-azatetracyclo[7.2.1.0.2,804,6]dodec-
10-en-3-one (25). To a solution of α-iodoenone 24 (0.089 g, 0.21
mmol) in toluene (1 mL) were added 1,10-phenanthroline (0.038 g,
0.21 mmol), Cs2CO3 (0.075 g, 0.23 mmol), and 4-methoxybenzyl-
amine (0.042 mL, 0.32 mmol). After it was stirred for 4 h at room
1935
dx.doi.org/10.1021/jo402535j | J. Org. Chem. 2014, 79, 1929−1937

The Journal of Organic Chemistry
Article
temperature, the reaction mixture was quenched with water and
extracted with CH2Cl2. The combined organic layers were dried,
ppm. HRMS (ESI-FIA-TOF): m/z calcd for C14H23NNaO4Si,
320.12940; found, 320.12921 (M + Na).
N-[(1R,5S,6R)-5-Hydroxy-2-oxo-7-oxabicyclo[4.1.0]hept-3-
en-3-yl]acetamide (4). To a solution of silyl ether 33 (0.0040 g,
0.0135 mmol) in CH3CN (0.6 mL) was added HF (0.0845 mL, 0.4%
in water, 0.0169 mmol), and the mixture was stirred at room
temperature for 2 h. The reaction was quenched with NaHCO3
saturated solution and extracted with EtOAc. The combined organic
layers were dried, filtered, and concentrated. The residue was purified
by preparative TLC (hexane:EtOAc 3:7) to yield epoxy alcohol 4 as a
colorless oil (0.002 g, 80%), which had spectroscopic data consistent
filtered, and concentrated. Purification by flash chromatography
20
(hexane:EtOAc 9:1) afforded aziridine 25 (0.082 g, 92%). [α]D
=
−62.3 (c 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.31 (2H, d,
J = 8.4 Hz, Ar-H), 6.85 (2H, d, J = 8.8 Hz, Ar-H), 6.25 (1H, dd, J = 5.6
Hz, J = 2.4 Hz, H-11), 5.96 (1H, dd, J = 5.8 Hz, J = 3.0 Hz, H-10),
3.79 (3H, s, OMe), 3.73 (1H, d, J = 13.6 Hz, H-13a), 3.49 (1H, dd, J =
8.8 Hz, J = 0.8 Hz, H-7), 3.31 (1H, d, J = 13.6 Hz, H-13b), 3.09−3.06
(2H, m, H-2 and H-1), 2.94 (1H, br s, H-9), 2.77 (1H, ddd, J = 11.0
Hz, J = 8.6 Hz, J = 2.8 Hz, H-8), 2.17 (1H, dd, J = 6.6 Hz, J = 1.0 Hz,
H-6), 2.12 (1H, d, J = 6.8 Hz, H-4), 1.45 (1H, d, J = 8.4 Hz, H-12a),
1.26 (1H, d, J = 8.4 Hz, H-12b), 0.89 [9H, s, (CH3)3C-Si], 0.09 (3H, s,
CH3-Si), 0.02 (3H, s, CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ
210.2 (CO), 158.8 (Ar-C), 138.7 (C-11), 134.5 (C-10), 130.3 (Ar-
C-1), 128.7 (Ar-C), 113.8 (Ar-C), 72.1 (C-7), 61.4 (C-13), 55.3
(OMe), 52.6 (C-6), 50.8 (C-2), 47.8 (C-12), 47.0 (C-4), 46.7 (C-8),
44.2 (C-9), 43.1 (C-1), 25.7 [(CH3)3C-Si], 17.9 [(CH3)3C-Si], −4.1
(CH3-Si), −4.7 (CH3-Si) ppm. FTIR (neat): νmax 1705 (CO) cm−1.
Anal. Calcd for C25H35NO3Si: C, 70.55; H, 8.29; N, 3.29. Found: C,
70.40; H, 8.45; N, 3.24.
with those reported for rac-4-epi-MT35214.6 [α]D = +72 (c 0.05,
20
1
MeOH). H NMR (300 MHz, CDCl3): δ 7.69 (1H, br s, NH), 7.61
(1H, dd, J = 5.3 Hz, J = 2.3 Hz, H-4), 4.92−4.88 (1H, m, H-5), 3.86−
3.83 (1H, m, H-6), 3.62 (1H, d, J = 3.4 Hz, H-1), 2.14 (3H, s,
CH3CO) ppm.
(1R,5R,6S)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(4-
methoxyphenyl)methyl]-7-azabicyclo[4.1.0]hept-3-en-2-one
(34). To a solution of acetonide17 28 (0.061 g, 0.20 mmol) in THF (1
mL) at 0 °C was added dropwise a 0.5 M NaOH solution, until no
starting material was detected by TLC. The reaction mixture was
quenched with NH4Cl saturated solution and extracted with CH2Cl2.
The combined organic layers were dried, filtered, and evaporated. The
crude residue was dissolved in CH2Cl2 (2 mL), and at 0 °C were
added DIPEA (0.087 mL, 0.50 mmol), TBSCl (0.060 g, 0.40 mmol),
and a catalytic amount of DMAP. The mixture was stirred overnight at
room temperature and then diluted with EtOAc and washed with
water. The organic layer was dried, filtered, and concentrated.
Purification by preparative TLC (hexane:EtOAc 8:2) afforded enone
34 as a viscous oil (0.050 g, 69%), which had spectroscopic data
(1S,5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-7-[(4-
methoxyphenyl)methyl]-7-azabicyclo[4.1.0]hept-3-en-2-one
(26). To diphenyl ether (1.5 mL) under reflux was added a solution of
adduct 25 (0.013 g, 0.03 mmol) in diphenyl ether (0.5 mL). After 45
min, the mixture was cooled and loaded onto a pad of silica gel
(hexane:EtOAc 9:1), affording enone 26 as a viscous oil (0.010 g,
20
91%). [α]D = −139.2 (c 0.97, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ 7.27 (2H, d, J = 8.4 Hz, Ar-H), 6.84 (2H, d, J = 8.4 Hz, Ar-
H), 6.36 (1H, dt, J = 10.4 Hz, J = 2.4 Hz, H-4), 5.80 (1H, dt, J = 10.8
Hz, J = 2.0 Hz, H-3), 4.70 (1H, dt, J = 4.4 Hz, J = 2.0 Hz, H-5), 3.78
(3H, s, OMe), 3.75 (1H, d, J = 13.6 Hz, H-8), 3.51 (1H, d, J = 13.6
Hz, H-8′), 2.46 (1H, ddd, J = 6.4 Hz, J = 4.4 Hz, J = 2.4 Hz, H-6), 2.29
(1H, dd, J = 6.0 Hz, J = 1.6 Hz, H-1), 0.90 [9H, s, (CH3)3C-Si], 0.13
(3H, s, CH3-Si), 0.08 (3H, s, CH3-Si) ppm. 13C NMR (100 MHz,
CDCl3): δ 194.8 (CO), 158.9 (Ar-C), 147.8 (C-4), 129.5 (Ar-C-1),
129.3 (Ar-C), 125.5 (C-3), 113.8 (Ar-C), 65.9 (C-5), 62.5 (C-8), 55.2
(OMe), 43.6 (C-1), 43.2 (C-6), 25.7 [(CH3)3C-Si], 18.2 [(CH3)3C-
Si], −4.7 (CH3-Si), −4.9 (CH3-Si) ppm. FTIR (neat): νmax 1687 (C
O) cm−1. HRMS (ESI-FIA-TOF): m/z calcd for C20H30NO3Si,
360.1995; found, 360.1989 (M + H).
20
identical with those of 26. [α]D = +149.2 (c 0.63, CH2Cl2).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for C.D.M.: maycock@itqb.unl.pt.
■
(1R,5S,6S)-3-Azido-5-[(tert-butyldimethylsilyl)oxy]-7-
oxabicyclo[4.1.0]hept-3-en-2-one (32). In a screw-capped vial, a
solution of aziridine17 31 (0.019 g, 0.051 mmol) in HN3 (2 mL, 1.3 M
in benzene; HN3 is volatile and highly toxic) was stirred at 60 °C for
12 h. After rapid cooling, the reaction mixture was loaded onto a
preparative TLC (hexane:EtOAc 8:2), affording vinyl azide 32 as a
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
P.R. acknowledges a grant (SFRH/BD/27423/2006) from the
■
20
1
colorless oil (0.011 g, 78%). [α]D = +171.5 (c 0.2, CH2Cl2). H
NMR (400 MHz, CDCl3): δ 5.96 (1H, dd, J = 5.2 Hz, J = 2.4 Hz, H-
4), 4.79 (1H, dt, J = 5.2 Hz, J = 1.2 Hz, H-5), 3.66 (1H, ddd, J = 3.6
Hz, J = 2.4 Hz, J = 1.2 Hz, H-6), 3.59 (1H, dd, J = 3.6 Hz, J = 1.2 Hz,
H-1), 0.92 [9H, s, (CH3)3C-Si], 0.18 (3H, s, CH3-Si), 0.15 (3H, s,
CH3-Si) ppm. 13C NMR (100 MHz, CDCl3): δ 188.6 (CO), 133.5
(C-3), 126.0 (C-4), 64.0 (C-5), 58.2 (C-6), 53.6 (C-1), 25.6
[(CH3)3C-Si], 18.1 [(CH3)3C-Si], −4.4 (CH3-Si), −4.7 (CH3-Si)
ppm. FTIR (neat): νmax 2107 (N3), 1694 (CO) cm−1.
Fundaca
̧
o para a Cien
̂
cia e Tecnologia (FCT). This work has
̃
been supported by the FCT through grant no. PEst-OE/EQB/
LA0004/2011 and projects PTDC/QUI-QUI/104056/2008
and POCI/QUI/62794/2004. The NMR spectrometers are
part of The National NMR Facility, supported by Fundaca̧ o
̃
̂
para a Ciencia e a Tecnologia (RECI/BBB-BQB/0230/2012).
We wish to acknowledge the Analytical Services Unit (ASU)
for providing CHNS elemental analysis data from the Mass
Spectrometry Laboratory at the ITQB-UNL.
N-[(1R,5S,6S)-5-[(tert-butyldimethylsilyl)oxy]-2-oxo-7-
oxabicyclo[4.1.0]hept-3-en-3-yl]acetamide (33). Ph3P (0.0068 g,
0.026 mmol) was added to a solution of azide 32 (0.0089 g, 0.032
mmol) in THF (1 mL) at 0 °C. After the mixture was stirred for 20
min, Ac2O (0.007 mL, 0.074 mmol) and DMAP (0.0039 g, 0.032
mmol) were added and the mixture was warmed to room temperature.
After 5 h, the mixture was concentrated and loaded onto a preparative
TLC (hexane:EtOAc 8:2), affording acetamide 33 as a colorless oil
(0.0077 g, 82%). 1H NMR (400 MHz, CDCl3): δ 7.66 (1H, br s, NH),
7.50 (1H, dd, J = 5.2 Hz, J = 2.4 Hz, H-4), 4.87 (1H, dt, J = 5.2 Hz, J =
1.2 Hz, H-5), 3.70 (1H, ddd, J = 3.6 Hz, J = 2.4 Hz, J = 1.2 Hz, H-6),
3.59 (1H, dd, J = 3.6 Hz, J = 1.2 Hz, H-1), 2.13 (3H, s, CH3−CO),
0.92 [9H, s, (CH3)3C-Si], 0.19 (3H, s, CH3-Si), 0.17 (3H, s, CH3-Si)
REFERENCES
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