Exploring the chemistry of epoxy amides for the synthesis of the 2′′-epi -diazepanone core of liposidomycins and caprazamycins

Article abstract of DOI:10.1021/jo202061t

New synthetic strategies have been explored for the synthesis of the structural core of liposidomycins and caprazamycins, an intriguing class of complex nucleoside-type antibiotics. This structural core is comprised of a cyclic diazepanone system linked to an uridyl fragment. The various synthetic approaches have in common that they originate from an epoxy amide derived from uridine, obtained via reaction of uridyl aldehyde 19 with an amide-stabilized sulfur ylide. Two different strategies were shown to be efficient in constructing the diazepanone ring system: (a) a reductive amination of an epoxy aldehyde with N-methylamine with subsequent intramolecular oxirane ring opening and (b) a carbene insertion reaction of an acyclic diazoamine precursor.

Full text of DOI:10.1021/jo202061t

Article
pubs.acs.org/joc
Exploring the Chemistry of Epoxy Amides for the Synthesis of the
2′′-epi-Diazepanone Core of Liposidomycins and Caprazamycins
Francisco Sarabia,* Carlos Vivar-García, Cristina García-Ruiz, Laura Martín-Ortiz,
and Antonio Romero-Carrasco
Department of Organic Chemistry, Faculty of Sciences, University of Malaga, 29071 Malaga, Spain
S
* Supporting Information
ABSTRACT: New synthetic strategies have been explored for the synthesis of the structural core of liposidomycins and
caprazamycins, an intriguing class of complex nucleoside-type antibiotics. This structural core is comprised of a cyclic
diazepanone system linked to an uridyl fragment. The various synthetic approaches have in common that they originate from an
epoxy amide derived from uridine, obtained via reaction of uridyl aldehyde 19 with an amide-stabilized sulfur ylide. Two different
strategies were shown to be efficient in constructing the diazepanone ring system: (a) a reductive amination of an epoxy aldehyde
with N-methylamine with subsequent intramolecular oxirane ring opening and (b) a carbene insertion reaction of an acyclic
diazoamine precursor.
in the natural nucleosides would arise from two key
disconnections at the amide and amine sites respectively,
requiring a two-step process consisting of an amide bond
formation (step 1) and an epoxide opening reaction (step 2).
To this end, the advanced precursors cis-N-indole epoxy amide
10 and diamine 11 were identified as key compounds to
achieve this goal (Scheme 1).
For the assignment of configuration of the new chiral centers
formed during the construction of the oxirane ring, we assumed
the stereochemistry of epoxy amide 15, demonstrated via
Sharpless asymmetric epoxidations.17 Thus, sequential reactions
of aldehyde 12 to epoxy alcohols 13 and 1418 and comparison
of the physical and spectroscopic properties of both epoxy
alcohols with that obtained by reduction of epoxy amide 15 let
us to establish the configurations at 5′ and 6′ positions as 5′-(R)
and 6′-(S), which was supported by molecular modeling studies
of the starting aldehyde 12.19 As a consequence of these
studies, we extended this stereochemical result to the epoxy
amides derived from uridine, compounds 16−18,20 assuming a
similar stereochemical outcome for the reactions of their
corresponding aldehydes with the sulfur ylide, supported again
by theoretical calculations of the starting aldehydes. However,
recent studies conducted by Ducho and co-workers21 have
1. INTRODUCTION
The liposidomycins1 and caprazamycins2 are unique nucleo-
side-type antibiotics isolated from Streptomyces belonging to the
family of the complex nucleoside-type antibiotics.3 Other
notable members include muraymycins,4 mureidomycins,5
pacidamycins,6 napsamycins,7 and FR-900493.8 These natural
products (1−6, Figure 1) have elicited intense interest in the
scientific community because of their antibiotic properties,
which are characterized by an intriguing mechanism of action
based on the inhibition of phospho-N-acetylmuramoylpenta-
peptide transferase (MraY),9 also known as translocase I, an
enzyme involved in the biosynthesis of the cell wall of
bacteria.10 In addition to their striking antibiotic profiles,11 their
complex and unprecedented molecular architectures have
appealed to synthetic chemists to investigate these molecules
as synthetic targets12 of great biological interest.13 As a result,
diverse synthetic approaches have been published, and one total
synthesis of the diazepanone system from the caprazamycins,
termed caprazol, has recently been reported by Matsuda et al.14
Our initial synthetic efforts toward the liposidomycins15 were
based on reactions of the N-indole epoxy amide16 derived from
uridine 7 with 1,3-diamines as bidentade nucleophiles as a
means of constructing the diazepanone core in a straightfor-
ward and efficient manner to afford compounds of type 8. In an
attempt to extend this strategy to the fully functionalized
system found in caprazol (9), the diazepanone core contained
Received: October 10, 2011
Published: January 9, 2012
© 2012 American Chemical Society
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demonstrated by X-ray analysis that the oxirane ring
constructed via sulfur ylides (for example, compound 20)
resulted in the opposite stereochemistry with respect to that
proposed by us (Scheme 2).
Scheme 2. Established Configurations for Epoxyamides 16−
18 and Corrected Configuration by Ducho et al.
Figure 1. Molecular structures of representative members of
liposidomycins and caprazamycins.
Scheme 1. Synthetic Strategy toward the Liposidomycin and
Caprazamycin Antibiotics
In the present paper, we report our synthetic efforts directed
to the construction of the key diazepanone ring found in this
class of antibiotics, including the establishment of the absolute
configurations of the synthesized epoxy amides, precursors of
the diazepanonic derivatives. The successful generation of a
fully functionalized diazepanone core occurred in this family of
complex nucleosides should serve as the basis for an eventual
total synthesis of the natural antibiotics.
2. RESULTS AND DISCUSSION
2.1. Establishment of the Absolute Configuration of
Epoxyamides. For this first objective, we prepared allylic
alcohol 21 from aldehyde 19 via a Wittig reaction followed by
DIBAL reduction of the resulting α,β-unsaturated ester. Then,
21 was subjected to Sharpless asymmetric epoxidations by
treatment with (+)-diethyl L-tartrate [(+)-DET] and (−)-di-
ethyl D-tartrate [(−)-DET], respectively, in the presence of
Ti(O-i-Pr)4 and TBHP to provide epoxy alcohols 22 and 23 in
59 and 65% yields. With both epoxy alcohols in hand, we
initially attempted the transformation of epoxy amide 18 to its
corresponding epoxy alcohol by the action of Super-H,22 but
this reaction proved to be unsuccessful and provided a complex
mixture of decomposition products. This result compelled us to
transform epoxy alcohols 22 and 23 to the corresponding N-
indoline epoxy amides. This conversion was undertaken by
oxidation of 22 and 23 to the epoxy acids 24 and 25 by the
action of TEMPO/BAIB23 in the presence of water, followed
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by coupling with indoline assisted by PyBOP [benzotriazol-1-
yloxytri(pyrrolidino)phosphonium hexafluorophosphate]24 to
give epoxy amides 18 and 18′. Inspection of their
1
corresponding H NMR spectra and comparison with that
obtained from the resulting epoxy amide via the sulfur ylide
1
revealed that the H NMR spectra of 18′, obtained from 25,
matched completely with the spectra obtained through the
sulfur ylide chemistry. This finding corroborates the stereo-
chemical assignment accomplished by Ducho et al., and
consequently, the initial stereochemical assignment, proposed
by us in previous articles is not correct (Scheme 3).
Scheme 3. Synthetic Studies for the Establishment of
Configuration of Epoxyamide 18
Figure 2. Preferred conformation of aldehyde 19.
methodologies capable of installing the complete functionality
found in the diazepanonic system of the liposidomycins and
caprazamycins. Toward this goal, we investigated N-allylamides
as potentially useful acyclic precursors of the cyclic diazepanone
derivatives, supported by our previous studies15 based on
epoxidation of the double bond. An extension of this reaction
to the more functionalized N-allylamide could lead us to the
desired diazepanone system via cyclization with N-methyl-
amine. Thus, allylamine 2727 was chosen as a suitable starting
point. Direct displacement of this amine to the N-indole amide
26, prepared from 18′ by treatment with DDQ,20 was
unsuccessful resulting in starting amide. This result forced us
to introduce an additional step consisting of the hydrolysis of
N-indole amide 26 to the corresponding acid, which was
accomplished by treatment with LiOH to give the epoxy acid
25 in 89% yield, followed by coupling with amine 27 by the
action of EDCI/HOBt to give amide 29 in 52% yield. However,
when epoxidation of the double bond was attempted by use of
m-CPBA, the expected diepoxide was not obtained, only
recovered starting material. Other oxidative agents such as
DMDO28 or methyl(trifluoromethyl)dioxirane29 were similarly
unsuccessful. Since more simple N-allylamides were oxidized by
the action of peracids, the lack of reactivity of the double bond
to oxidative agents found in this case was ascribed to steric
factors, which led us to consider allylamine 28. In this case,
direct displacement of the indole moiety was possible,
providing amide 30 in a reasonably good yield (62%). On
the other hand, coupling of acid 25 with 28 also afforded 30
but in a surprisingly poor yield (35%). Then, we proceeded
with the epoxidation reaction by treatment of 30 with peracids
or dioxiranes. Disappointingly, the result was no formation of
the desired diepoxide (Scheme 4, part A). Additional attempts
of epoxidation assisted by the hydroxyl group, such as Sharpless
epoxidation or methods mediated by VO(acac)2,30 were
similarly unsuccessful.
Interestingly, molecular modeling studies performed for
aldehyde 1925 revealed a preference for a conformational
arrangement, depicted in Figure 2, in which the carbonyl group
is perpendicular with respect to the C−O bond of the
furanoside ring. According to this, the preferential attack of a
nucleophile should take place at the re face to form the epoxide
with the stereochemistry initially proposed and should be in
agreement with the prediction of the Felkin−Ahn model.26
However, this theoretical observation does not correspond with
the experimental result obtained. We propose that the uracil
heterocycle is playing an essential role in directing the
nucleophilic attack from the opposite face of the aldehyde
with respect to the model's prediction.
Given the challenges, we considered N-allylamide 31, readily
prepared from N-indole amide 26 in 87% yield by smooth
treatment with allylamine, to investigate new cyclizations
procedures. Thus, after epoxide opening with methylamine,
to provide amino alcohol 32, we attempted various procedures
to accomplish the cyclization process. These new strategies
required activation of the olefinic group, for which procedures
based on Sharpless asymmetric dihydroxylation,31 or cycliza-
2. Synthetic Studies toward the Diazepanone Ring
System. The following step in this study was to establish new
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Scheme 4. Synthetic Studies toward the Complex Diazepanone System
tions assisted by palladium(II) or mercury(II) were considered.
In the first case, treatment of 32 with ADmixβ resulted in no
reaction, only recovered starting material. More interesting and
promising seemed to be the procedures based on the use of
palladium(II)32 or mercury(II)33 followed by oxidative work-
ups. However, treatment of 32 with Pd(OAc)2 and Hg(OTf)2
respectively followed by oxidative workup with BAIB for the
first case and O2/NaBH4 for the second, resulted again in no
formation of the desired products, obtaining only complex
mixtures of decomposition products instead (Scheme 4, part
B).
Due to the synthetic hurdles encountered in the function-
alization of the amine fragment linked to the uridyl derivative, it
seemed clear that such functionalization must be done prior to
the assembly to the uridine moiety. On the other hand, we
deemed it of interest to introduce the amine fragment by
opening of the oxirane ring instead of an earlier formation of
the amide. This new strategy therefore commenced with the
installation of the acyclic amine, already possessing the required
functionalization and stereochemistry, via oxirane ring opening.
For this installation, the amino alcohol 33 was reacted with
epoxide 18′ by heating in DMF to obtain compound 34 in 44%
yield. Oxidation of the N-indoline amide to its corresponding
N-indole should provide a suitable compound that could be
cyclized via intramolecular attack by the amine group present in
the molecule. However, oxidation of 34 with DDQ did not
furnish the coveted indole derivative (Scheme 4, part C).
After all the discouranging results encountered in pursuit of
the diazepanonic system, we decided to revisit the strategy
based on the early formation of the amide with the requisite of
introducing an amine with the required functionalization. For
this purpose, amine 3535 was selected as a preferred candidate
to address this synthetic challenge. Direct introduction of the
amine from epoxy amide 26 was not possible, which compelled
us to introduce it via coupling with epoxy acid 25 by the action
of BOP [benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate]24 to obtain complex epoxy amide 36 in
65% yield. Selective deprotection of the primary silyl ether was
successfully performed by treatment of 36 with CSA to afford
alcohol 37 in a good 88% yield. This compound offered diverse
possibilities for chemical transformations and was amenable to
a cyclization reaction, taking advantage of the presence of the
oxirane ring.
Thus, we initiated a series of chemical screenings with the
introduction of a good leaving group at this position. However,
an initial attempt at introducing a sulfonate group did not work.
As an alternative, introduction of the amine group was
performed by treatment of 37 with methylamine. The oxirane
ring opened product, amino alcohol 38, was then subjected to
an intramolecular Mitsunobu-type reaction that should have
formed compound 40. Again, the result was unsuccessfull,
resulting in recovered starting material. Considering that steric
hindrance present in these molecules one could rationalize
these discouraging results, thus we decided to remove the
benzyl protecting group, which was undertaken by catalytic
hydrogenation to give the dihydroxy amide 39. From this point,
the introduction of a leaving group at the terminal hydroxyl
group or a Mitsunobu reaction was feasible. With this advanced
acyclic product in hand, the cyclization was attempted again by
the action of methylamine, disappointingly the reaction did not
work as desired, resulting in the formation of a complex mixture
of products, not detecting the formation of 41 (Scheme 5).
In our continuing quest to establish a strategy to prepare the
fully functionalized diazepanone, we determined that a few
other approaches were left to be attempted. To this end, we
considered a cyclization via reductive amination of an aldehyde
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rhodium(II) acetate.37 For this new route, we considered the
ester 45 as a potential precursor for the introduction of the
diazo functionality. Thus, we prepared the compound 45 by
coupling epoxy acid 25 with allyl ester 4638 by the assistance of
EDCI/HOBt to provide amide 45 in 72% yield. After allyl ester
deprotection by the action of palladium(0), the corresponding
epoxy acid 47 was subjected to conventional methods39 for the
introduction of the diazo group. Oddly, treatment of 47 with
oxalyl chloride to give the acid chloride followed by reaction
with freshly prepared diazomethane did not produce diazo
derivative 48. In addition, utilization of mesylchloride for
activation of the acid, a method recently reported that proved
to be efficient for hindered acids,40 did not give the desired
product (Scheme 6).
Scheme 5. Synthesis of the Complex Diazepanone System. I.
Reductive Amination/Cyclization Strategy
These results forced us to introduce the diazo group prior to
the coupling with the uridyl derivative. Toward this aim, diazo
compound 51 was prepared from commercially available serine
Fmoc-D-Ser(t-Bu)-OH (49) in two steps that included diazo
coupling, through the acid chloride intermediate, to give diazo
ketone 50, followed by Fmoc deprotection. The acid 25 was
coupled with diazo ketone 51 by treatment with EDCI/HOBt
to provide epoxy diazo amide 52 in 49% yield. Subsequent
reaction of 52 with N-methylamine afforded the corresponding
epoxide-opened product, amino diazo derivative 53, in 76%
yield. This product represents a key compound for investigation
of the utility of this new synthetic approach for the
liposidomycins and related complex nucleosides. Gratifyingly,
when 53 was subjected to the action of a catalytic amount of
Rh2(OAc)4 in CH2Cl2 at 25 °C, formation of a new product
was detected. After purification and NMR analysis, the new
product was determined to be the cyclic ketone 54, obtained in
57% yield. Catalytic hydrogenation using Pd−C provided a
single alcohol which was tentatively assigned as compound 55.
Inspection of its NMR spectra indicated the loss of the tert-
butyl ether group, most likely occurring during the hydro-
genation reaction due to the acidic character of the employed
catalyst. Finally, compound 55 was peracetylated by treatment
with acetic anhydride in pyridine to provide tri-O-acetyl
derivative 56 (Scheme 7).
with concomitant intramolecular epoxide opening by the
resulting amine. In the event, the aldehyde 42 was obtained
by oxidation of alcohol 37 with Dess−Martin periodinane,36
which was not isolated and allowed to react with methylamine
in the presence of NaBH(OAc)3. The result was the
preparation of the cyclic diazepanone system 40 in a modest,
albeit reasonable, 40% yield over two steps. Acetylation of 40
was carried out to support the structure of the diazepanonic
ring system, providing the acetyl derivative 43 (Scheme 5).
Finally, another approach was explored based on a carbene
insertion process for the construction of the cyclic diazepanone
core. This carbene insertion reaction would consist of an
intramolecular NH trapping by the carbenoid species, depicted
in Scheme 6, produced from an amino diazo derivative,
represented by compound 44, and mediated by the action of
In order to gain insight into the stereochemical outcome of
the reduction step and to assign the correct stereochemistry for
the reduction product 55, we undertook theoretical calculations
of compound 54. The study revealed a conformation (Figure
3), in which the β-face of the ketone displayed steric hindrance
due to the presence of the hydroxyl group, while on the α-face
an equatorial attack of a hydrogen appeared to be favored, thus
allowing us to predict and justify the configuration indicated.
Scheme 6. Toward the Synthesis of Diazo Ketone 48
3. CONCLUSIONS
In conclusion, the synthetic results described herein show
promise for the construction of the diazepanone ring system
contained in the liposidomycins and caprazamycins antibiotics.
Thus, an extensive synthetic study based on the use of epoxy
amides, obtained via sulfur ylides, has been carried out,
demonstrating the synthetic potential of this methodology for
the construction of the diazepanonic system contained in these
natural products. The application of these synthetic method-
ologies to the corresponding cis epoxide should allow for the
synthesis of the diazepanone system with the proper functional
groups and correct stereochemistry. Synthetic efforts in this
direction are currently being explored in our laboratories.
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The following abbreviations were used to explain the multiplicities: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; band, several
overlapping signals; b, broad. Optical rotations were recorded on a
polarimeter. High resolution mass spectra (HRMS) were recorded on
a mass spectrometer under fast atom bombardment (FAB) conditions
in a m-nitrobenzyl alcohol (NBA) matrix.
Scheme 7. Synthesis of the Complex Diazepanone System.
II. Diazo Strategy
Allylic Alcohol 21. A solution of aldehyde 19 (500 mg, 1.06 mmol,
1.0 equiv) in CH2Cl2 (10 mL) was treated with the phosphorus ylide
Ph3PCHCO2Et (738 mg, 2.12 mmol, 2.0 equiv) at 25 °C. After
being stirred at this temperature for 8 h, the reaction mixture was
concentrated under reduced pressure and the resulting crude purified
by flash column chromatography (silica gel, 30% EtOAc in hexanes) to
obtain the corresponding α,β-unsaturated ester (458 mg, 80%) as a
white solid: Rf = 0.43 (silica gel, 30% EtOAc in hexanes); mp = 62−64
°C; 1H NMR (400 MHz, CDCl3) δ = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09
(s, 3 H), 0.13 (s, 3 H), 0.90 (s, 9 H), 0.91 (s, 9 H), 1.31 (t, J = 7.1 Hz,
3 H), 3.38 (dd, J = 6.8, 4.1 Hz, 1 H), 4.19 (dd, J = 4.0, 2.7 Hz, 1 H),
4.25 (dc, J = 7.1, 3.8 Hz, 2 H), 4.63 (dt, J = 6.2, 1.6 Hz, 1 H), 5.71 (d, J
= 2.7 Hz, 1 H), 5.79 (dd, J = 8.1, 2.2 Hz, 1 H), 6.15 (dd, J = 15.7, 1.7
Hz, 1 H), 6.97 (dd, J = 15.7, 5.7 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H),
9.42 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.8, −4.7, −4.5,
−4.2, 14.2, 18.0, 18.1, 25.7, 25.8, 60.8, 75.0, 75.2, 81.9, 91.8, 102.5,
123.3, 139.6, 143.1, 150.0, 163.3, 165.6. Then, a solution of DIBAL in
CH2Cl2 (1.0 M, 2.1 mL, 2.1 mmol, 2.5 equiv) was dropwise added to a
solution of the α,β-unsaturated ester (458 mg, 0.84 mmol) in CH2Cl2
(8 mL) at −78 °C. After 0.5 h at this temperature, the reaction mixture
was treated with MeOH (1 mL) followed by EtOAc (5 mL). After 10
min, a saturated aqueous NaK tartrate solution was added, and the
resulting mixture was diluted with EtOAc and allowed to reach room
temperature. After vigorous stirring for 1 h, the biphasic system was
separated, the aqueous phase was extracted with EtOAc, and the
combined organic solution was dried (MgSO4), filtered, and
concentrated. Purification by flash column chromatography (silica
gel, 50% AcOEt in hexanes) afforded allylic alcohol 21 (272 mg, 65%)
1
as a colorless oil: Rf = 0.63 (silica gel, 50% EtOAc in hexanes); H
NMR (400 MHz, CDCl3) δ = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09 (s, 3
H), 0.11 (s, 3 H), 0.90 (s, 9 H), 0.91 (s, 9 H), 1.75 (bs,1 H), 3.81 (dd,
J = 5.7, 4.2 Hz, 1 H), 4.22−4.27 (m, 2 H), 4.27−4.31 (m, 1 H), 4.50
(dd, J = 7.3, 6.1 Hz, 1 H), 5.62 (d, J = 3.4 Hz, 1 H), 5.76 (dd, J = 8.1,
2.0 Hz, 1 H), 5.83 (ddt, J = 15.4, 7.8, 1.7 Hz, 1 H), 6.03 (ddt, J = 15.4,
4.6, 0.9 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 8.86 (bs, 1 H); 13C NMR
(100 MHz, CDCl3) δ = −4.8, −4.7, −4.5, −4.2, 18.0, 18.1, 25.7, 25.8,
62.4, 74.9, 75.5, 84.2, 92.1, 102.2, 126.8, 134.9, 140.4, 150.0, 162.9;
FAB HRMS (NBA) m/e 499.2656, M + H+ calcd for C23H42N2O6Si2
499.2660.
Epoxy Alcohol 22. A solution of titanium tetraisopropoxide (11
μL, 0.037 mmol, 0.25 equiv) and 4 Å molecular sieves (35 mg) in
CH2Cl2 (3 mL) was added L-(+)-DET (7.0 μL, 0.037 mmol, 0.25
equiv) at −23 °C. After 15 min at this temperature, a solution of allylic
alcohol 21 (75 mg, 0.150 mmol, 1.0 equiv) in CH2Cl2 (2.5 mL) was
added dropwise, followed by the addition, after additional 30 min, of
TBHP (5.5 M solution in decane, 40 μL, 0.225 mmol, 1.5 equiv) at
−23 °C. After 24 h at this temperature, the reaction mixture was
filtered, and the filtrate was diluted with EtOAc and washed with a
saturated aqueous solution of sodium sulfate. After decantation, the
aqueous phase was extracted with EtOAc, and the combined organic
layer was dried (MgSO4), filtered, and concentrated. The resulting
crude product was purified by flash column chromatography (silica gel,
2.5% MeOH in CH2Cl2) to obtain epoxy alcohol 22 (38 mg, 49%
yield) as a colorless oil: Rf = 0.30 (silica gel, 2.5% MeOH in CH2Cl2);
Figure 3. Preferred conformation of ketone 54.
4. EXPERIMENTAL SECTION
General Techniques. All reactions were carried out under an
argon atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF) and ethyl
ether (ether) were distilled from sodium benzophenone, and
methylene chloride (CH2Cl2), benzene (PhH), and toluene from
calcium hydride. Yields refer to chromatographically and spectroscopi-
cally (1H NMR) homogeneous materials, unless otherwise stated. All
solutions used in workup procedures were saturated unless otherwise
noted. All reagents were purchased at highest commercial quality and
used without further purification unless otherwise stated.
All reactions were monitored by thin-layer chromatography carried
out on 0.25 mm silica gel plates (60F-254) using UV light as
visualizing agent and 7% ethanolic phosphomolybdic acid or p-
anisaldehyde solution and heat as developing agents. Silica gel (60,
particle size 0.040−0.063 mm) was used for flash column
chromatography. Preparative thin-layer chromatography (PTLC)
separations were carried out on 0.25, 0.50, or 1 mm silica gel plates
(60F-254).
[α]D22 −21.5 (c 0.2, CH2Cl2); H NMR (400 MHz, CDCl3) δ = 0.03
1
(s, 3 H), 0.06 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H), 0.87 (s, 9 H), 0.91
(s, 9 H), 3.17 (dt, J = 3.9, 2.6 Hz, 1 H), 3.34 (dd, J = 4.2, 2.4 Hz, 1 H),
3.75 (dd, J = 12.9, 4.0 Hz, 1 H), 3.94 (ddd, J = 9.8, 4.7, 2.1 Hz, 1 H),
4.09 (dd, J = 4.2, 2.9 Hz, 1 H), 4.45 (dd, J = 5.8, 4.2 Hz, 1 H), 5.69 (d,
J = 5.8 Hz, 1 H), 5.78 (dd, J = 8.1, 2.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 1
H), 9.11 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.9, −4.7,
−4.6, −4.3, 17.9, 18.1, 25.8, 54.4, 57.1, 60.9, 72.1, 74.1, 83.4, 84.2, 91.2,
102.7, 141.4, 150.3, 163.0; FAB HRMS (NBA) m/e 515.2612, M + H+
calcd for C23H42N2O7Si2 515.2609.
NMR spectra were recorded on a 400 MHz instrument and
calibrated using residual undeuterated solvent as an internal reference.
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Epoxy Alcohol 23. Epoxy alcohol 23 (48 mg, 58%) was obtained
from allylic alcohol 21 (80 mg, 0.160 mmol) according to the same
procedure described above for 22 but using D-(−)-DET. 23: colorless
oil; Rf = 0.30 (silica gel, 2.5% MeOH in CH2Cl2); [α]D22 +32.9 (c 0.3,
88.3, 102.7, 139.8, 163.7, 172.0, 176.4; FAB HRMS (NBA) m/e
551.2225, M + Na+ calcd for C23H40N2O8Si2 551.2221.
Epoxyamide 29 from Epoxy Acid 25. Epoxy acid 25 (194 mg,
0.37 mmol, 1.0 equiv) was dissolved in dry CH2Cl2 (10 mL) and
treated with HOBt (61 mg, 0.44 mmol, 1.2 equiv) at room
temperature. After the mixture was stirred for 5 min, EDCI (87 mg,
0.44 mmol, 1.2 equiv) was added and the resulting mixture was stirred
for 45 min prior to the addition to a solution of 27 (103 mg, 0.48
mmol, 1.3 equiv) in CH2Cl2 (5 mL). The mixed system was stirred for
12 h, after which aqueous 15% NH3 solution (0.3 mL) was added and
the resulting mixture was diluted with Et2O and washed with a
saturated aqueous NH4Cl solution. The layers were separated, and the
aqueous phase was extracted with Et2O. The combined organic
solution was dried (MgSO4), filtered, and concentrated. Purification by
flash column chromatography (silica gel, 20% EtOAc, 10% MeOH in
hexanes) afforded epoxy amide 29 (138 mg, 52%) as a colorless oil: Rf
= 0.39 (silica gel, 20% EtOAc, 10% MeOH in hexanes); 1H NMR (400
MHz, CDCl3) (mixture of rotamers in a 1:1 ratio) δ = −0.01 (s, 1.5
H), 0.01 (s, 1.5 H), 0.02 (s, 3 H), 0.03 (s, 3 H), 0.04 (s, 3 H), 0.09 (s,
3 H), 0.10 (s, 3 H), 0.82 (s, 4.5 H), 0.83 (s, 4.5 H), 0.84 (s, 4.5 H),
0.85 (s, 4.5 H), 0.89 (s, 4.5 H), 0.90 (s, 4.5 H), 2.84 (s, 1.5 H), 3.0 (s,
1.5 H), 3.32 (s, 0.5 H), 3.34 (s, 0.5 H), 3.69−3.78 (m, 2 H), 3.79 (d, J
= 2.1 Hz, 0.5 H), 3.93 (d, J = 2.1 Hz, 0.5 H), 4.05−4.30 (m, 3 H),
4.48−4.53 (m, 1 H), 5.14−5.32 (m, 2 H), 5.70−5.80 (m, 1 H), 5.97
(d, J = 5.9 Hz, 0.5 H), 6.02 (d, J = 5.9 Hz, 0.5 H), 7.73 (d, J = 8.1 Hz,
1 H), 8.42 (bs, 1 H); 13C NMR (100 MHz, CDCl3) (mixture of
rotamers in a 1:1 ratio) δ = −5.6, −5.55, −5.5, −5.4, −4.8, −4.7, −4.6,
−4.4, −4.3, 14.0, 18.0, 18.1, 18.2, 23.0, 23.8, 25.7, 25.8, 25.9, 28.5, 28.9,
30.4, 31.4, 32.0, 36.5, 38.8, 51.3, 51.9, 58.3, 60.3, 61.8, 62.6, 68.2, 71.0,
71.1, 71.9, 72.5, 75.1, 75.9, 81.2, 82.8, 89.2, 89.6, 101.8, 102.3, 118.5,
119.3, 128.8, 130.9, 131.7, 132.4, 140.8, 141.0, 150.0, 150.2, 162.6,
162.8, 168.8, 170.0; FAB HRMS (NBA) m/e 726.3996, M + H+ calcd
for C34H63N3O8Si3 726.4001.
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ = 0.08 (s, 6 H), 0.12 (s, 3
H), 0.13 (s, 3 H), 0.89 (s, 9 H), 0.93 (s, 9 H), 1.72 (bs, 1 H), 3.31 (dd,
J = 2.3, 1.1 Hz, 1 H), 3.36 (dt, J = 3.3, 2.3 Hz, 1 H), 3.76 (dd, J = 13.0,
3.4 Hz, 1 H), 4.04 (dd, J = 13.0, 2.2 Hz, 1 H), 4.07−4.12 (m, 2 H),
4.31 (dd, J = 4.0, 1.2 Hz, 1 H), 5.76 (dd, J = 8.2, 2.3 Hz, 1 H), 5.87 (d,
J = 3.7 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 8.55 (bs, 1 H); 13C NMR
(100 MHz, CDCl3) δ = −4.9, −4.7, −4.6, −4.4, 18.0, 18.1, 25.7, 25.8,
54.3, 55.6, 60.2, 73.4, 75.3, 79.5, 88.6, 102.5, 139.8, 150.2, 162.8; FAB
HRMS (NBA) m/e 515.2615, M + H+ calcd for C23H42N2O7Si2
515.2609.
Epoxy Amide 18. To a solution of epoxy alcohol 22 (132 mg,
0.256 mmol) in acetonitrile/H2O (4 mL, 1:1) was added BAIB (495
mg, 1.536 mmol, 6.0 equiv) and the crude mixture treated with
TEMPO (32 mg, 0.205 mmol, 0.8 equiv) at 25 °C. After being stirred
for 40 min at this temperature, the reaction mixture was diluted with
EtOAc and washed with a saturated aqueous Na2S2O3 solution. The
aqueous layer was extracted with EtOAc and the combined organic
layer washed with brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. The resulting epoxy acid 24 was used for the
next step without further purification. A solution of crude epoxy acid
24 (∼0.256 mmol) in DMF (10 mL) was treated with DIPEA (92 μL,
0.524 mmol, 2.0 equiv) at 25 °C. After the mixture was stirred for 10
min, indoline (44 μL, 0.393 mmol, 1.5 equiv) and PyBOP (163 mg,
0.315 mmol, 1.2 equiv) were added, and the resulting mixture was
stirred at 25 °C for 12 h. After this time, the reaction mixture was
diluted with Et2O, and the resulting organic solution washed with a
saturated aqueous NH4Cl solution. After separation of both phases,
the organic layer was washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography (silica gel, 10% → 50% AcOEt in
hexanes) to obtain epoxy amide 18 (68 mg, 43% yield over two steps)
as a colorless oil: Rf = 0.50 (silica gel, 50% EtOAc in hexanes); [α]D22
Epoxyamide 30 from Epoxy Amide 26. A solution of epoxy
amide 26 (66 mg, 0.106 mmol, 1.0 equiv) in acetonitrile (3 mL) was
treated with allylamine 28 (16.1 mg, 0.159 mmol, 1.5 equiv) at 25 °C.
Then, the reaction mixture was heated at 80 °C for 36 h. After this
time, the crude mixture was concentrated under reduced pressure and
purified by flash column chromatography (silica gel, 40% EtOAc, 5%
MeOH in hexanes) to obtain epoxy amide 30 (40 mg, 62%) as a white
1
−11.3 (c 0.2, CH2Cl2); H NMR (400 MHz, CDCl3) δ = 0.03 (s, 3
H), 0.07 (s, 3 H), 0.13 (s, 6 H), 0.88 (s, 9 H), 0.93 (s, 9 H), 3.25 (t, J
= 8.3 Hz, 2 H), 3.56 (dd, J = 5.2, 0.8 Hz, 1 H), 3.68 (d, J = 1.0 Hz, 1
H), 4.00 (dd, J = 5.3, 2.8 Hz, 1 H), 4.12−4.15 (m, 1 H), 4.15−4.22
(m, 1 H), 4.22−4.28 (m, 1 H), 4.44−4.48 (m, 1 H), 5.75−5.79 (m, 2
H), 7.06 (t, J = 7.1 Hz, 1 H), 7.21 (t, J = 6.4 Hz, 2 H), 7.37 (d, J = 8.1
Hz, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.64 (bs, 1 H); 13C NMR (100
MHz, CDCl3) δ = −4.8, −4.7, −4.6, −4.4, 17.9, 18.1, 25.7, 25.8, 28.2,
47.2, 52.9, 56.8, 72.9, 74.0, 84.1, 90.8, 102.8, 117.4, 124.7, 127.7, 131.0,
141.0, 142.3, 150.0, 162.7, 163.8; FAB HRMS (NBA) m/e 630.3025,
M + H+ calcd for C31H47N3O7Si2 630.3031.
1
foam: Rf = 0.21 (silica gel, 40% EtOAc, 5% MeOH in hexanes); H
NMR (400 MHz, CDCl3) (mixture of rotamers in a 1:1 ratio) δ =
−0.08 (s, 1.5 H), −0.04 (s, 1.5 H), −0.02 (s, 3 H), 0.04 (s, 3 H), 0.05
(s, 1.5 H), 0.06 (s, 1.5 H), 0.78 (s, 4.5 H), 0.79 (s, 4.5 H), 0.84 (s, 4.5
H), 0.85 (s, 4.5 H), 2.82 (s, 1.5 H), 2.97 (s, 1.5 H), 3.28 (s, 0.5 H),
3.36 (s, 0.5 H), 3.63−3.79 (m, 3 H), 3.99−4.27 (m, 3 H), 4.72 (bs, 0.5
H), 5.07 (bs, 0.5 H), 5.11−5.26 (m, 2 H), 5.61−5.73 (m, 1 H), 5.87
(d, J = 4.8 Hz, 0.5 H), 5.90 (d, J = 4.8 Hz, 0.5 H), 7.61 (d, J = 8.1 Hz,
0.5 H), 7.66 (d, J = 8.1 Hz, 0.5 H), 9.08 (bs, 1 H); 13C NMR (100
MHz, DMSO-d6) (mixture of rotamers in a 1:1 ratio) δ = −4.8, −4.7,
−4.3, −4.2, −4.1, 18.1, 18.2, 18.3, 26.0, 26.2, 29.0, 31.0, 51.4, 52.0,
55.4, 58.0, 60.9, 61.1, 70.8, 71.3, 73.7, 74.1, 74.9, 75.2, 85.0, 85.2, 86.4,
86.6, 103.3, 117.7, 118.9, 134.0, 134.1, 140.2, 140.4, 151.3, 151.4,
163.3, 163.4, 167.9, 168.2; FAB HRMS (NBA) m/e 612.3138, M + H+
calcd for C28H49N3O8Si2 612.3136.
Epoxyamide 30 from Epoxy Acid 25. Epoxy acid 25 (142 mg,
0.268 mmol, 1.0 equiv) and amine 28 (41 mg, 0.403 mmol, 1.5 equiv)
were subjected to the action of HOBt (44 mg, 0.322 mmol, 1.2 equiv)
and EDCI (63 mg, 0.322 mmol, 1.2 equiv) under the same conditions
as described above for 29 to obtain epoxy amide 30 (57 mg, 35%)
which showed physical and spectroscopic properties identical to
described above for this compound.
Epoxy Amide 18′. Synthesis of epoxy amide 18′ (44 mg, 76%
yield over two steps) was achieved from epoxy alcohol 23 (48 mg,
0.092 mmol) in exactly the same manner as described above for epoxy
amide 18′ through epoxy acid 25. Physical and spectroscopic
properties of 18′ were exactly the same as epoxy amide obtained via
sulfur ylides as reported by us elsewhere.20
Epoxy Acid 25. To a solution of epoxy amide 26 (300 mg, 0.48
mmol, 1.0 equiv) in THF (10 mL) was added a 0.1 M aqueous LiOH
solution (11.9 mL, 1.19 mmol, 2.5 equiv) dropwise during 15 min at 0
°C. After 5 min, the reaction mixture was diluted with EtOAc (15 mL)
and both phases were separated. The aqueous layer was washed with
EtOAc and acidified with Amberlyst-15 until pH 5. Then, the solution
was extracted with EtOAc, and the combined organic extracts were
concentrated in vacuo to obtain crude epoxy acid 25 (225 mg, 89%)
which did not require further purification and was used in the next
Epoxy Amide 31. A solution of epoxy amide 26 (150 mg, 0.239
mmol, 1.0 equiv) in acetonitrile (5 mL) was treated with allylamine
(59 μL, 0.764 mmol, 3.2 equiv) at 25 °C for 7 h. After this time, the
reaction mixture was diluted with toluene and concentrated under
reduced pressure. Purification by flash column chromatography (silica
gel, 45% EtOAc, 5% MeOH in hexanes) furnished epoxy amide 31
(118 mg, 87%) as a colorless oil: Rf = 0.50 (silica gel, 50% EtOAc, 5%
MeOH in hexanes); [α]D22 +11.3 (c 0.4, CH2Cl2); 1H NMR (400 MHz,
1
step: Rf = 0.10 (silica gel, 50% EtOAc in hexanes); H NMR (400
MHz, CDCl3) δ = 0.03 (s, 3 H), 0.04 (s, 3 H), 0.10 (s, 3 H), 0.11 (s, 3
H), 0.86 (s, 9 H), 0.91 (s, 9 H), 3.46 (bs, 1 H), 3.64 (d, J = 1.6 Hz, 1
H), 4.05 (dd, J = 4.3, 4.3 Hz, 1 H), 4.09−4.13 (m, 1 H), 4.33 (d, J =
4.3 Hz, 1 H), 5.78 (d, J = 8.1 Hz, 1 H), 5.88 (d, J = 4.8 Hz, 1 H), 7.68
(d, J = 8.1 Hz, 1 H), 9.33 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ =
−4.9, −4.7, −4.4, 17.9, 18.1, 25.7, 25.8, 50.0, 57.2, 73.3, 75.0, 78.8,
1334
dx.doi.org/10.1021/jo202061t | J. Org. Chem. 2012, 77, 1328−1339

The Journal of Organic Chemistry
Article
CDCl3) δ = 0.05 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 6 H), 0.86 (s, 9 H),
0.90 (s, 9 H), 3.26 (d, J = 2.1 Hz, 1H), 3.63 (d, J = 2.1 Hz, 1H), 3.86−
3.91 (m, 2 H), 4.05 (d, 2 H), 4.30 (d, J = 2.7 Hz, 1 H), 5.14−5.20 (m,
2 H), 5.71−5.85 (m, 3 H), 6.22 (d, J = 5.9 Hz, 1 H), 7.59 (d, J = 8.1
Hz, 1 H), 8.80 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.9,
−4.8, −4.7, −4.4, 17.9, 18.1, 25.6, 25.7, 41.3, 52.4, 58.0, 73.2, 75.0,
78.8, 88.8, 102.6, 117.1, 133.2, 139.4, 150.1, 162.9, 166.8; FAB HRMS
(NBA) m/e 590.2690, M + Na+ calcd for C26H45N3O7Si2 590.2694.
Amino Alcohol 32. To a solution of epoxy amide 31 (61 mg,
0.107 mmol, 1.0 equiv) in MeOH (3 mL) was added an aqueous
MeNH2 solution (40% w/v solution, 0.17 mL, 2.15 mmol, 20.0 equiv).
Then, the reaction mixture was heated at 60 °C for 36 h. After this
time, the crude mixture was allowed to reach room temperature and
concentrated under reduced pressure. The resulting crude product was
subjected to purification by flash column chromatography (silica gel,
45% EtOAc, 5% MeOH in hexanes) to obtain amino alcohol 32 (58
mg, 90%) as a colorless oil: Rf = 0.31 (silica gel, 60% EtOAc, 5%
MeOH in hexanes); [α]D22 +3.3 (c 0.12, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ = 0.02 (s, 3 H), 0.03 (s, 3 H), 0.05 (s, 3 H), 0.06 (s, 3 H),
0.85 (s, 9 H), 0.87 (s, 9 H), 2.43 (s, 3 H), 3.25 (bs, 1 H), 3.88−3.93
(m, 3 H), 4.12 (d, J = 3.8 Hz, 1H), 4.17 (dd, J = 4.3, 3.8 Hz, 1H), 4.29
(d, J = 4.8, 4.3 Hz, 1 H), 5.12−5.21 (m, 2 H), 5.72 (d, J = 8.1 Hz, 1
H), 5.76 (d, J = 4.8 Hz, 1 H), 5.77−5.87 (m, 1 H), 7.69 (bs, 1 H), 8.03
(d, J = 8.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.8, −4.7,
−4.6, −4.5, 17.9, 18.0, 25.8, 34.5, 41.5, 63.1, 70.5, 72.2, 74.7, 84.1, 90.2,
102.3, 116.6, 133.6, 141.6, 150.5, 163.3, 174.0; FAB HRMS (NBA) m/
e 599.3293, M + H+ calcd for C27H50N4O7Si2 599.3296.
−5.4, 4.9, −4.8, −4.7, −4.5, 17.8, 18.0, 18.2, 18.3, 25.6, 25.7, 25.8, 29.6,
50.0, 50.4, 55.6, 56.8, 56.9, 63.2, 65.5, 65.9, 72.9, 73.5, 74.7, 75.0, 78.2,
78.4, 78.8, 79.1, 87.7, 87.9, 102.7, 102.9, 114.6, 114.7, 115.3, 115.4,
127.7, 127.9, 128.0, 128.1, 128.3, 128.6, 137.1, 137.9, 139.4, 139.5,
150.3, 150.4, 152.1, 152.4, 153.9, 154.2, 163.1, 166.7, 167.5; FAB
HRMS (NBA) m/e 956.4951, M + H+ calcd for C48H77N3O11Si3
956.4944.
Hydroxy Epoxy Amide 37. Epoxy amide 36 (355 mg, 0.371
mmol, 1.0 equiv) was dissolved in CH2Cl2:MeOH (1:1, 10 mL), the
solution was cooled to 0 °C, and CSA (0.15 mg, 0.63 mmol, 1.7 equiv)
was added. The mixture was stirred for 4 h and allowed to reach room
temperature. Then, TEA (87 μL, 0.63 mmol, 1.7 equiv) was added
and, after 5 min, the solvents were removed under reduced pressure.
Flash column chromatography (silica gel, 60% EtOAc in hexanes)
furnished alcohol 37 (275 mg, 88%) as a colorless oil: Rf = 0.51 (silica
gel, 80% EtOAc in hexanes); [α]D22 +9.2 (c 0.2, CH2Cl2); H NMR
1
(400 MHz, CDCl3) (mixture of rotamers in a 1:1 ratio) δ = 0.02 (s, 3
H), 0.07 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H), 0.81 (s, 4.5 H), 0.83 (s,
4.5 H), 0.88 (s, 4.5 H), 0.89 (s, 4.5 H), 2.86 (s, 1.5 H), 3.15 (s, 1.5 H),
3.28 (d, J = 2.1 Hz, 1 H), 3.36 (d, J = 2.1 Hz, 1 H), 3.32−3.38 (m, 1
H), 3.86−3.89 (m, 1 H), 3.71−3.73 (m, 1 H), 3.71 (s, 1.5 H), 3.74 (s,
1.5 H), 3.84 (d, J = 2.1 Hz, 1 H), 4.03−4.25 (m, 5 H), 4.29 (s, 1 H),
4.47−4.70 (m, 2 H), 5.68−5.73 (m, 1 H), 5.94−5.96 (m, 1 H), 6.70−
6.81 (m, 4 H), 7.27−7.33 (m, 5 H), 7.60 (d, J = 8.6 Hz, 0.5 H), 7.67
(d, J = 8.6 Hz, 0.5 H), 9.10 (bs, 0.5 H), 9.33 (bs, 0.5 H); 13C NMR
(100 MHz, CDCl3) δ = −5.0, −4.8, −4.6, −4.5, 17.8, 18.0, 25.6, 25.7,
28.7, 29.6, 50.3, 50.7, 54.4, 55.6, 56.9, 57.7, 58.4, 59.9, 65.9, 66.3, 72.2,
73.5, 73.9, 74.4, 74.7, 76.2, 79.1, 79.8, 86.9, 87.6, 102.9, 103.0, 114.6,
114.7, 115.2, 115.4, 128.0, 128.1, 128.5, 128.7, 136.7, 137.4, 139.4,
139.6, 150.5, 152.0, 152.2, 153.9, 154.1, 163.0, 168.0; FAB HRMS
(NBA) m/e 865.4045, M + Na+ calcd for C42H63N3O11Si2 865.4052.
Amino Diol 38. To a solution of epoxide 37 (153 mg, 0.182 mmol,
1.0 equiv) in MeOH (3 mL) was added a 40% aqueous MeNH2
solution (0.21 mL, 2.73 mmol, 15.0 equiv), and the resulting reaction
mixture was heated at 60 °C for 7 h. After this time, the solvents were
removed under reduced pressure, and the crude product was purified
by flash column chromatography (silica gel, 80% EtOAc, 5% MeOH in
hexanes) to obtain amino diol 38 (131 mg, 83%) as a colorless oil: Rf =
0.58 (silica gel, 80% EtOAc, 5% MeOH in hexanes); [α]D22 +4.3 (c 0.1,
CH2Cl2); 1H NMR (400 MHz, CDCl3) (mixture of rotamers in a 1:1
ratio) δ = −0.01 (s, 1.5 H), 0.01 (s, 1.5 H), 0.02 (s, 3 H), 0.05 (s, 3
H), 0.07 (s, 3 H), 0.82 (s, 4.5 H), 0.84 (s, 4.5 H), 0.88 (s, 9 H), 2.28
(s, 1.5 H), 2.39 (s, 1.5 H), 2.77 (s, 1.5 H), 2.99 (s, 1.5 H), 3.49−3.62
(m, 2 H), 3.66 (s, 1.5 H), 3.64−3.71 (m, 1 H), 3.73 (s, 1.5 H), 3.84−
3.90 (m, 2 H), 4.05−4.25 (m, 5 H), 4.41 (s, 1 H), 4.42−4.76 (m, 2 H),
5.26 (d, J = 8.1 Hz, 0.5 H), 5.48 (d, J = 4.3 Hz, 0.5 H), 5.68 (d, J = 8.1
Hz, 0.5 H), 5.84 (d, J = 4.3 Hz, 0.5 H), 6.70−6.79 (m, 4 H), 7.26−7.33
(m, 5 H), 7.54 (d, J = 8.1 Hz, 0.5 H), 7.75 (d, J = 8.1 Hz, 0.5 H); 13C
NMR (100 MHz, CDCl3) δ = −5.1, −4.8, −4.7, −4.6, −4.5, 17.8, 17.9,
18.0, 25.7, 25.8, 28.8, 29.6, 34.4, 55.6, 55.7, 57.7, 59.8, 61.0, 66.0, 67.5,
71.4, 71.7, 72.1, 72.9, 73.2, 75.0, 76.4, 83.9, 88.4, 102.1, 102.3, 114.6,
114.7, 115.1, 115.2, 127.9, 128.1, 128.2, 128.4, 128.6, 137.2, 137.6,
140.4, 150.3, 150.5, 152.3, 154.0, 154.2, 163.1, 163.2; FAB HRMS
(NBA) m/e 896.4427, M + Na+ calcd for C43H68N4O11Si2 896.4422.
Epoxy Diol 39. To a solution of epoxy alcohol 37 (103 mg, 0.122
mmol, 1.0 equiv) in MeOH (5 mL) was added 10% Pd/C (103 mg).
The reaction was allowed to proceed under an atmosphere of H2 at 25
°C for 30 min, after which no starting benzyl ether was detected by
TLC. The mixture was filtered through Celite, and the clear solution
was concentrated under reduced pressure. The resulting crude product
was purified by flash column chromatography (silica gel, 80% EtOAc
in hexanes) to give epoxy diol 39 (74 mg, 81%) as a colorless oil: Rf =
0.24 (silica gel, 80% EtOAc in hexanes); [α]D22 +23.3 (c 0.3, CH2Cl2);
1H NMR (400 MHz, CDCl3) (mixture of rotamers in a 1:1 ratio) δ =
−0.08 (s, 1.5 H), −0.01 (s, 1.5 H), 0.02 (s, 1.5 H), 0.04 (s, 1.5 H),
0.07 (s, 3 H), 0.09 (s, 1.5 H), 0.11 (s, 1.5 H), 0.80 (s, 4.5 H), 0.84 (s,
4.5 H), 0.87 (s, 4.5 H), 0.89 (s, 4.5 H), 2.98 (s, 1.5 H), 3.16 (s, 1.5 H),
3.35 (d, J = 1.6 Hz, 0.5 H), 3.42 (d, J = 1.6 Hz, 0.5 H), 3.54−3.66 (m,
2 H), 3.69 (s, 1.5 H), 3.72 (s, 1.5 H), 3.85−3.92 (m, 2 H), 4.06−4.57
(m, 6 H), 4.41 (s, 1 H), 5.66−5.75 (m, 1 H), 5.91 (d, J = 4.8 Hz, 0.5
Amide 34. To a solution of epoxy amide 18′ (160 mg, 0.253 mmol,
1.0 equiv) in DMF (5 mL) was added a solution of amino alcohol 33
(73 mg, 0.265 mmol, 1.05 equiv) in DMF (2 mL) at 25 °C. Then, the
reaction mixture was heated at 110 °C for 48 h. After this time, the
crude mixture was concentrated under reduced pressure and purified
by flash column chromatography (silica gel, 40% EtOAc in hexanes) to
obtain amide 34 (100 mg, 44%) as a colorless oil: Rf = 0.25 (silica gel,
1
40% EtOAc, 5% MeOH in hexanes); H NMR (400 MHz, CDCl3) δ
= −0.03 (s, 3 H), 0.02 (s, 3 H), 0.08 (s, 3 H), 0.10 (s, 3 H), 0.82 (s, 9
H), 0.89 (s, 9 H), 1.43 (s, 15 H), 2.46−2.72 (m, 4 H), 3.15−3.24 (m,
3 H), 3.61−4.54 (m, 11 H), 5.66 (d, J = 6.5 Hz, 1 H), 5.75 (dd, J = 8.1,
1.6 Hz, 1 H), 7.01−7.22 (m, 3 H), 7.77 (d, J = 8.1 Hz, 1 H), 8.17−
8.21 (m, 1 H), 8.84 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.9,
−4.8, −4.6, −4.5, −4.4 17.9, 18.1, 25.7, 25.8, 25.9, 28.1, 28.3, 29.7,
47.9, 58.5, 71.8, 73.3, 85.2, 91.2, 102.7, 117.6, 124.5, 124.6, 124.7,
124.8, 127.4, 127.7, 131.7, 141.9, 142.2, 150.5, 163.1, 164.8; FAB
HRMS (NBA) m/e 904.4918, M + H+ calcd for C44H73N5O11Si2
904.4923.
Epoxyamide 36 from Epoxy Acid 25. Epoxy acid 25 (453 mg,
0.856 mmol, 1.0 equiv) was dissolved in dry DMF (10 mL) and
treated with DIPEA (0.29 mL, 1.71 mmol, 2.0 equiv) at room
temperature. After the mixture was stirred for 5 min, a solution of
amine 35 (458 mg, 1.03 mmol, 1.2 equiv) in DMF (4 mL) was added.
After additional stirring for 5 min, the mixed system was treated with
BOP (464 mg, 1.03 mmol, 1.2 equiv) and stirred for 12 h. After this
time, a saturated aqueous NH4Cl solution was added followed by
dilution with EtOAc. The layers were separated, and the aqueous
phase was extracted with EtOAc. The combined organic solution was
dried (MgSO4), filtered and concentrated. Purification by flash column
chromatography (silica gel, 35% EtOAc in hexanes) afforded epoxy
amide 36 (529 mg, 65%) as a colorless oil: Rf = 0.70 (silica gel, 50%
EtOAc in hexanes); [α]D22 +27.8 (c 0.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3) (mixture of rotamers in a 1:1 ratio) δ = 0.02 (s, 3 H), 0.03 (s,
3 H), 0.04 (s, 3 H), 0.09 (s, 3 H), 0.10 (s, 3 H), 0.11 (s, 3 H), 0.85 (s,
4.5 H), 0.86 (s, 4.5 H), 0.88 (s, 9 H), 0.89 (s, 4.5 H), 0.90 (s, 4.5 H),
2.93 (s, 1.5 H), 3.14 (s, 1.5 H), 3.32 (d, J = 2.1 Hz, 1 H), 3.41 (d, J =
2.1 Hz, 1 H), 3.65−3.80 (m, 3 H), 3.72 (s, 1.5 H), 3.74 (s, 1.5 H), 3.96
(d, J = 2.1 Hz, 1 H), 4.01−4.15 (m, 3 H), 4.19−4.44 (m, 2 H), 4.49
(d, J = 11.3 Hz, 1 H), 4.73 (d, J = 11.3 Hz, 1 H), 5.59 (dd, J = 8.1, 1.6
Hz, 0.5 H), 5.76 (dd, J = 8.1, 1.6 Hz, 0.5 H), 5.88 (d, J = 4.8 Hz, 0.5
H), 5.95 (d, J = 4.8 Hz, 0.5 H), 6.74−6.80 (m, 4 H), 7.27−7.34 (m, 5
H), 7.68 (d, J = 8.1 Hz, 0.5 H), 7.73 (d, J = 8.1 Hz, 0.5 H), 9.14 (bs,
0.5 H), 9.25 (bs, 0.5 H); 13C NMR (100 MHz, CDCl3) δ = −5.5,
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H), 5.95 (d, J = 4.8 Hz, 0.5 H), 6.74−6.79 (m, 4 H), 7.62 (d, J = 8.1
Hz, 0.5 H), 7.68 (d, J = 8.1 Hz, 0.5 H), 9.49 (bs, 0.5 H), 9.52 (bs, 0.5
H); 13C NMR (100 MHz, CDCl3) δ = −4.7, −4.5, −4.4, 17.8, 17.9,
18.0, 25.6, 25.8, 29.6, 50.3, 50.7, 55.6, 57.0, 63.2, 66.0, 66.4, 69.5, 70.0,
71.4, 73.4, 74.0, 74.3, 74.8, 75.3, 79.0, 79.9, 86.2, 86.9, 88.0, 89.8,
101.9, 102.8, 103.1, 114.6, 115.3, 115.5, 139.5, 139.8, 150.4, 150.7,
152.1, 152.2, 154.2, 163.3, 163.9, 168.0; FAB HRMS (NBA) m/e
775.3530, M + Na+ calcd for C35H57N3O11Si2 775.3533.
after which time aqueous 15% NH3 solution (0.2 mL) was added and
the resulting mixture was diluted with Et2O and washed with a
saturated aqueous NH4Cl solution. The layers were separated, and the
aqueous phase was extracted with Et2O. The combined organic
solution was dried (MgSO4), filtered, and concentrated. Purification by
flash column chromatography (silica gel, 20% EtOAc, 10% MeOH in
hexanes) afforded epoxy amide 45 (340 mg, 72%) as a yellow oil: Rf =
1
0.50 (silica gel, 30% EtOAc, 10% MeOH in hexanes); H NMR (400
Diazepanone 40. To a solution of alcohol 37 (104 mg, 0.123
mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added solid NaHCO3 (83
mg, 0.988 mmol, 8.0 equiv). The mixture was cooled to 0 °C, and then
Dess−Martin periodinane (DMP) (122 mg, 0.28 mmol, 2.25 equiv)
was added in one portion. After the mixture was stirred for 1 h at 0 °C,
TLC revealed depletion of starting material and formation of aldehyde
42. The reaction mixture was then diluted with EtOAc and treated
with a saturated aqueous NaHCO3. After the mixture was stirred for an
additional 20 min, both phases were separated, and the organic layer
was washed with brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. The resulting crude aldehyde was then used
for the next step without further purification. A solution of crude
aldehyde 42 in EtOAc (9 mL) in the presence of 4 Å MS was treated
with a solution of methylamine (2.0 M in THF, 93 μL, 0.185 mmol,
1.5 equiv), glacial AcOH (92 μL), and NaBH(OAc)3 (110 mg, 0.494
mmol, 4.0 equiv) at 25 °C. After being stirred for 48 h at this
temperature, the crude mixture was filtered through a Celite pad,
diluted with EtOAc, and washed with a saturated aqueous NaHCO3.
The organic solution was then washed with brine, dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, 40% EtOAc
in hexanes) to obtain diazepanone 40 (42 mg, 40% over two steps
from 37) as a white foam: Rf = 0.56 (silica gel, 60% EtOAc in
hexanes); [α]D22 +66.7 (c 0.6, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
= −0.02 (s, 3 H), 0.01 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.83 (s, 9
H), 0.88 (s, 9 H), 2.54 (s, 3 H), 3.14 (s, 3 H), 3.41−3.46 (m, 1 H),
3.73 (s, 3 H), 3.67−3.81 (m, 4 H), 4.03−4.23 (m, 5 H), 4.42 (bs, 1
H), 4.57 (d, J = 11.3 Hz, 1 H), 4.60 (d, J = 11.3 Hz, 1 H), 5.61 (d, J =
8.1 Hz, 1 H), 5.73 (d, J = 2.7 Hz, 1 H), 6.64−6.75 (m, 4 H), 7.23−
7.35 (m, 5 H), 8.00 (d, J = 8.1 Hz, 1 H), 8.35 (bs, 1 H); 13C NMR
(100 MHz, CDCl3) δ = −4.9, −4.7, −4.4, 17.9, 18.0, 25.7, 25.8, 29.6,
37.0, 38.9, 50.3, 55.6, 63.7, 69.9, 71.0, 72.1, 74.5, 75.7, 82.9, 88.3,
102.0, 114.5, 114.8, 127.2, 127.8, 128.5, 140.9, 150.2, 152.1, 153.9,
163.4; FAB HRMS (NBA) m/e 877.4222, M + Na+ calcd for
C43H66N4O10Si2 877.4215.
MHz, CDCl3) δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.10 (s, 6 H), 0.86 (s, 9
H), 0.99 (s, 9 H), 3.35 (s, 1 H), 3.63 (d, J = 2.1 Hz, 1 H), 3.69 (dd, J =
9.7, 2.7 Hz, 1 H), 3.95 (dd, J = 9.7, 2.7 Hz, 1 H), 4.03 (dd, J = 4.8, 4.3
Hz, 1 H), 4.10 (dd, J = 4.3 Hz, 1 H), 4.31 (d, J = 4.3 Hz, 1 H), 4.47 (d,
J = 11.8 Hz, 1 H), 4.55 (d, J = 11.8 Hz, 1 H), 4.61 (d, J = 5.4 Hz, 2 H),
4.73−4.76 (m, 1 H), 5.21−5.31 (m, 2 H), 5.75 (dd, J = 8.1, 2.1 Hz, 1
H), 5.79−5.87 (m, 1 H), 5.89 (d, J = 4.8 Hz, 1 H), 6.98 (d, J = 8.6 Hz,
1 H), 7.26−7.34 (m, 5 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.74 (bs, 1 H);
13C NMR (100 MHz, CDCl3) δ = −4.9, −4.7, −4.5, 17.9, 18.1, 25.6,
25.7, 52.0, 57.8, 66.3, 69.2, 73.3, 75.0, 78.8, 88.1, 102.8, 119.0, 127.7,
128.0, 128.5, 131.3, 137.2, 139.3, 150.2, 162.8, 163.3, 167.1; FAB
HRMS (NBA) m/e 768.3319, M + Na+ calcd for C36H55N3O10Si2
768.3324.
Epoxy Acid 47. A solution of epoxy amide 45 (337 mg, 0.45
mmol, 1.0 equiv) in THF (15 mL) was treated with morpholine (0.39
mL, 4.51 mmol, 10.0 equiv) and Pd[PPh3]4 (78 mg, 0.067 mmol, 0.15
equiv) at 25 °C. After being stirred for 1 h, the reaction mixture was
diluted Et2O and the resulting solution washed with a 0.5 M aqueous
citric acid solution twice and brine. The layers were separated, and the
organic solution was dried (MgSO4), filtered, and concentrated.
Purification by flash column chromatography (silica gel, 10% MeOH
in CH2Cl2) afforded epoxy acid 47 (277 mg, 87%) as a yellow oil: Rf =
0.25 (silica gel, 10% MeOH in CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ = 0.05 (s, 6 H), 0.10 (s, 6 H), 0.86 (s, 9 H), 0.89 (s, 9 H), 3.36 (s, 1
H), 3.61 (d, J = 2.1 Hz, 1 H), 3.73 (dd, J = 9.7, 3.2 Hz, 1 H), 3.97 (dd,
J = 9.7, 3.2 Hz, 1 H), 4.04 (dd, J = 4.8, 4.3 Hz, 1 H), 4.12 (dd, J = 4.3,
3.8 Hz, 1 H), 4.30 (d, J = 3.8 Hz, 1 H), 4.53 (s, 2 H), 4.73−4.75 (m, 1
H), 5.78 (d, J = 8.1 Hz, 1 H), 5.90 (d, J = 4.8 Hz, 1 H), 7.27−7.71 (m,
6 H); 13C NMR (100 MHz, CDCl3) δ = −4.8, −4.6, −4.4, 19.2, 26.0,
30.1, 52.9, 58.3, 71.3, 74.0, 75.1, 79.8, 88.2, 103.9, 128.5, 128.6, 129.6,
129.7, 134.1, 139.8, 151.1, 163.9, 167.4, 172.3; FAB HRMS (NBA) m/
e 728.3015, M + Na+ calcd for C33H51N3O10Si2 728.3011.
Diazo Ketone 50. A solution of Fmoc-D-Ser(t-Bu)-OH (49) (1.2
g, 3.13 mmol, 1.0 equiv) in CH2Cl2 (60 mL) was treated with 2,6-
lutidine (0.44 mL, 3.76 mmol, 1.2 equiv) and (COCl)2 (0.29 mL, 3.44
mmol, 1.1 equiv) at −15 °C. After being stirred for 4 h at this
temperature, the solvent was removed under reduced pressure, and the
crude mixture was dissolved in THF (40 mL) and cooled at −20 °C.
Then, an ethereal solution of freshly prepared CH2N2 (31.3 mmol,
10.0 equiv) was dropwise added at −20 °C, and the reaction mixture
was stirred for 45 min. After this time, depletion of the starting amino
acid derivative was checked by TLC and the reaction was quenched by
addition of several drops of acetic acid. The resulting organic solution
was washed twice with a saturated aqueous NaHCO3 solution and
brine, the layers were separated, and the organic solution was dried
(MgSO4), filtered, and concentrated. Purification by flash column
chromatography (silica gel, 50% EtOAc in hexanes) afforded diazo
ketone 50 (820 mg, 64%) as a white solid, together with the methyl
ester (Fmoc-D-Ser(t-Bu)-OMe) (359 mg, 29%). 50: Rf = 0.65 (silica
gel, 50% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ = 1.14 (s,
9 H), 3.42−3.45 (m, 1 H), 3.72−3.76 (m, 1 H), 4.19−4.26 (m, 2 H),
4.39−4.43 (m, 1 H), 4.51−4.55 (m, 1 H), 5.37 (bs, 1 H), 5.60 (d, J =
7.5 Hz, 1 H), 7.29−7.33 (m, 2 H), 7.36−7.41 (m, 2 H), 7.55−7.61 (m,
2 H), 7.74−7.76 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ = 27.3,
47.3, 54.1, 58.4, 61.6, 66.7, 73.7, 120.0, 124.9, 125.1, 127.0, 127.1,
127.7, 141.3, 143.6, 155.9, 192.8.
Acetyl Diazepanone 43. A solution of diazepanone 40 (20 mg,
0.023 mmol, 1.0 equiv) in pyridine (3 mL) was treated with Ac2O (44
μL, 0.47 mmol, 20.0 equiv) and 4-DMAP (2.9 mg) at 25 °C. After
being stirred for 24 h, the crude mixture was concentrated under
reduced pressure and the crude product purified by flash column
chromatography (silica gel, 50% EtOAc in hexanes) to obtain acetyl
diazepanone 40 (18 mg, 86%) as a colorless oil: Rf = 0.22 (silica gel,
60% EtOAc in hexanes); [α]D22 +25.8 (c 0.2, CH2Cl2); H NMR (400
1
MHz, CDCl3) δ = −0.16 (s, 3 H), −0.08 (s, 3 H), 0.06 (s, 3 H), 0.08
(s, 3 H), 0.78 (s, 9 H), 0.90 (s, 9 H), 2.04 (s, 3 H), 2.52 (s, 3 H), 3.10
(s, 3 H), 3.42−3.48 (m, 1 H), 3.61−3.64 (m, 2 H), 3.73 (s, 3 H),
3.72−3.76 (m, 1 H), 3.97−4.01 (m, 1 H), 4.09−4.15 (m, 2 H), 4.25−
4.33 (m, 2 H), 4.54−4.63 (m, 3 H), 5.60 (d, J = 8.1 Hz, 1 H), 5.62 (d,
J = 2.1 Hz, 1 H), 5.89 (d, J = 7.5 Hz, 1 H), 6.63 (d, J = 9.1 Hz, 1 H),
6.72 (d, J = 9.1 Hz, 1 H), 7.27−7.34 (m, 5 H), 7.40 (d, J = 8.1 Hz, 1
H), 8.07 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = −5.3, −4.9,
−4.7, −4.5, 17.9, 18.0, 20.9, 23.6, 25.5, 25.6, 28.8, 29.6, 38.6, 54.0, 60.7,
65.7, 68.2, 71.3, 102.2, 128.7, 130.7, 147.2, 148.0, 162.4, 167.5, 169.4;
FAB HRMS (NBA) m/e 919.4325, M + Na+ calcd for C45H68N4O11Si2
919.4321.
Epoxyamide 45 from Epoxy Acid 25. Epoxy acid 25 (336 mg,
0.635 mmol, 1.0 equiv) was dissolved in dry CH2Cl2 (12 mL) and
treated with HOBt (105 mg, 0.76 mmol, 1.2 equiv) at room
temperature. After the mixture was stirred for 5 min, EDCI (149 mg,
0.76 mmol, 1.2 equiv) was added and the resulting mixture stirred for
45 min prior to the addition of a solution of 46 (224 mg, 0.953 mmol,
1.5 equiv) in CH2Cl2 (5 mL). The mixed system was stirred for 2 h,
Amino Diazo Ketone 51. Diazo Ketone 50 (373 mg, 0.915 mmol,
1.0 equiv) was dissolved in pyridine (9 mL) and treated with TEA (3.2
mL, 22.9 mmol, 25.0 equiv) at 25 °C. The reaction mixture was stirred
for 12 h, after which time the solvents were removed under reduced
pressure. The crude product was then subjected to purification by flash
column chromatography (silica gel, 10% MeOH in CH2Cl2) to obtain
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amino diazo ketone 51 (101.5 mg, 60%) as a yellow oil: Rf = 0.39
(silica gel, 10% MeOH in CH2Cl2); 1H NMR (400 MHz, CDCl3) δ =
1.13 (s, 9 H), 2.12 (bs, 2 H), 3.39−3.41 (m, 1 H), 3.47−3.51 (m, 2
H), 5.76 (bs, 1 H); 13C NMR (100 MHz, CDCl3) δ = 27.1, 54.0, 56.1,
58.9, 63.8, 73.4, 196.1.
FAB HRMS (NBA) m/e 721.3636, M + Na+ calcd for C32H58N4O9Si2
721.3640.
Triol 55. To a solution of diazepanodione 54 (21 mg, 0.033 mmol,
1.0 equiv) in MeOH (2 mL) was added 10% Pd/C (21 mg). The
reaction was allowed to proceed under an atmosphere of H2 at 25 °C
for 12 h. After this time, the mixture was filtered through Celite, the
solid washed with MeOH (3 × 3 mL), and the clear solution
concentrated under reduced pressure. The resulting crude product was
purified by flash column chromatography (silica gel, 85% EtOAc, 5%
MeOH in hexanes) to give triol 55 (14.5 mg, 75%) as a white foam: Rf
= 0.47 (silica gel, 85% EtOAc, 5% MeOH in hexanes); [α]D22 +8.6 (c
Diazo Epoxy Amide 52. Epoxy acid 25 (178 mg, 0.34 mmol, 1.0
equiv) was dissolved in dry CH2Cl2 (6 mL) and treated with HOBt
(56 mg, 0.404 mmol, 1.2 equiv) at room temperature. After the
mixture was stirred for 5 min, EDCI (79 mg, 0.404 mmol, 1.2 equiv)
was added and the resulting mixture stirred for 45 min prior to the
addition of a solution of 51 (72 mg, 0.39 mmol, 1.15 equiv) in CH2Cl2
(3 mL). The mixed system was stirred for 1 h, after which time
aqueous 15% NH3 solution (0.2 mL) was added, and the resulting
mixture was diluted with Et2O and washed with a saturated aqueous
NH4Cl solution. The layers were separated, and the aqueous phase
was extracted with Et2O. The combined organic solution was dried
(MgSO4), filtered, and concentrated. Purification by flash column
chromatography (silica gel, 70% EtOAc in hexanes) afforded diazo
epoxy amide 52 (114 mg, 49%) as a yellow oil: Rf = 0.39 (silica gel,
1
0.5, CH2Cl2); H NMR (400 MHz, CDCl3) δ = −0.01 (s, 3 H), 0.02
(s, 3 H), 0.05 (s, 3 H), 0.06 (s, 3 H), 0.85 (s, 9 H), 0.88 (s, 9 H), 2.57
(s, 3 H), 3.16 (d, J = 10.2 Hz, 1 H), 3.62−3.65 (m, 2 H), 3.78−3.92
(m, 4 H), 4.10−4.13 (m, 3 H), 4.22 (dd, J = 5.9, 4.8 Hz, 1 H), 4.31 (s,
1 H), 5.56 (bs, 1 H), 5.75 (d, J = 8.1 Hz, 1 H), 6.00 (d, J = 5.9 Hz, 1
H), 7.00 (bs, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 8.95 (bs, 1 H); 13C NMR
(100 MHz, CDCl3) δ = −4.9, −4.8, −4.6, 17.8, 17.9, 18.0, 25.7, 25.8,
43.9, 51.4, 60.8, 61.5, 68.5, 71.9, 72.7, 74.2, 75.5, 83.3, 88.0, 102.4,
141.1, 150.5, 163.5, 174.5; FAB HRMS (NBA) m/e 667.3185, M +
Na+ calcd for C28H52N4O9Si2 667.3171.
1
70% EtOAc in hexanes); [α]D22 +11.1 (c 0.3, CH2Cl2); H NMR (400
MHz, CDCl3) (mixture of rotamers in a 1:1 ratio) δ = 0.02 (s, 1.5 H),
0.04 (s, 1.5 H), 0.05 (s, 1.5 H), 0.09 (s, 1.5 H), 0.10 (s, 3 H), 0.11 (s, 3
H), 0.85 (s, 9 H), 0.89 (s, 9 H), 1.13 (s, 4.5 H), 1.15 (s, 4.5 H), 3.26
(s, 0.5 H), 3.33 (s, 0.5 H), 3.40−3.47 (m, 1 H), 3.66−3.71 (m, 1 H),
3.63 (d, J = 2.1 Hz, 0.5 H), 3.64 (d, J = 2.1 Hz, 0.5 H), 4.02−4.11 (m,
2 H), 4.30 (d, J = 4.8 Hz, 0.5 H), 4.32 (d, J = 4.8 Hz, 0.5 H), 4.53 (bs,
1 H), 5.47 (bs, 0.5 H), 5.54 (bs, 0.5 H), 5.73 (d, J = 8.1 Hz, 0.5 H),
5.74 (d, J = 8.1 Hz, 0.5 H), 5.83 (d, J = 4.8 Hz, 0.5 H), 5.87 (d, J = 4.8
Hz, 0.5 H), 7.11 (d, J = 7.0 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 0.5 H), 7.62
(d, J = 8.1 Hz, 0.5 H), 8.93 (d, J = 4.8 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ = −4.9, −4.8, −4.5, −4.4, 17.9, 18.0, 25.6, 25.7, 27.3, 51.9,
52.1, 54.8, 56.1, 57.8, 61.6, 73.1, 73.3, 73.8, 73.9, 74.9, 75.1, 78.4, 78.8,
88.1, 88.6, 102.7, 139.3, 150.2, 163.0, 167.0, 191.1; FAB HRMS
(NBA) m/e 718.3272, M + Na+ calcd for C31H53N5O9Si2 718.3280.
Diazo Amino Alcohol 53. To a solution of diazo epoxy amide 52
(72 mg, 0.103 mmol, 1.0 equiv) in MeOH (3 mL) was added a 40%
aqueous MeNH2 solution (80 μL, 1.03 mmol, 10.0 equiv), and the
resulting reaction mixture was heated at 60 °C for 12 h. After this time,
the solvents were removed under reduced pressure, and the crude
product was purified by flash column chromatography (silica gel, 10%
MeOH in CH2Cl2) to obtain diazo amino alcohol 53 (57 mg, 76%) as
a yellow oil: Rf = 0.44 (silica gel, 10% MeOH in CH2Cl2); [α]D22 +4.9
(c 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) (mixture of rotamers in
a 1:1 ratio) δ = −0.02 (s, 3 H), 0.00 (s, 3 H), 0.03 (s, 6 H), 0.82 (s, 9
H), 0.85 (s, 9 H), 1.13 (s, 9 H), 2.37 (s, 1.5 H), 2.42 (s, 1.5 H), 3.19
(d, J = 8.6 Hz, 0.5 H), 3.24 (d, J = 8.6 Hz, 0.5 H), 3.45−3.51 (m, 1 H),
3.66−3.73 (m, 1 H), 3.77 (d, J = 8.6 Hz, 0.5 H), 3.87 (d, J = 8.6 Hz,
0.5 H), 4.13 (s, 1 H), 4.24−4.32 (m, 2 H), 4.54 (bs, 1 H), 5.67−5.75
(m, 3 H), 7.91 (d, J = 8.1 Hz, 0.5 H), 7.97 (d, J = 8.1 Hz, 0.5 H), 8.12
(d, J = 8.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ = −4.9, −4.8,
−4.7, −4.6, 17.9, 25.7, 25.8, 27.2, 34.4, 34.5, 54.5, 57.0, 61.3, 61.5, 63.7,
64.2, 70.5, 70.9, 72.2, 72.5, 73.8, 74.4, 74.6, 84.0, 84.3, 90.2, 90.4,
102.2, 141.6, 141.8, 150.6, 163.6, 174.1, 191.8, 192.3; FAB HRMS
(NBA) m/e 727.3876, M + H+ calcd for C32H58N6O9Si2 727.3882.
Diazepanodione 54. Amino Diazo Ketone 53 (42 mg, 0.058
mmol, 1.0 equiv) was dissolved in CH2Cl2 (5 mL) and treated with
Rh2(OAc)4 (2.6 mg, 0.0058 mmol, 0.1 equiv) at 25 °C. After the
mixture was stirred for 2 h, TLC revealed depletion of starting diazo.
Then, the solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography (silica gel, 70%
EtOAc, 5% MeOH in hexanes) to obtain compound 54 (23 mg, 57%)
as a colorless oil: Rf = 0.46 (silica gel, 70% EtOAc, 5% MeOH in
hexanes); [α]D22 +5.7 (c 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
= 0.07 (s, 3 H), 0.09 (s, 3 H), 0.14 (s, 6 H), 0.88 (s, 9 H), 0.89 (s, 9
H), 1.23 (s, 9 H), 2.51 (s, 3 H), 3.64 (s, 1 H), 3.78 (d, J = 5.4 Hz, 0.5
H), 4.04−4.24 (m, 7 H), 4.45 (d, J = 5.4 Hz, 1 H), 5.78 (s, 1 H), 5.94
(d, J = 8.1 Hz, 1 H), 6.12 (bs, 1 H), 7.98 (d, J = 8.1 Hz, 1 H), 9.63 (bs,
1 H); 13C NMR (100 MHz, CDCl3) δ = −5.1, −4.9, −4.7, −4.4, −4.1,
18.0, 18.2, 25.8, 25.9, 35.3, 59.1, 59.9, 66.8, 69.0, 69.3, 71.6, 72.6, 73.9,
75.1, 75.7, 77.7, 102.2, 103.5, 140.8, 149.5, 168.0, 171.4, 173.9, 191.5;
Triacetyl Diazepanone 56. A solution of diazepanone 55 (12.5
mg, 0.019 mmol, 1.0 equiv) in pyridine (1.5 mL) was treated with
Ac2O (73 μL, 0.775 mmol, 40.0 equiv) at 25 °C. After being stirred for
48 h, the crude mixture was concentrated under reduced pressure and
the crude product purified by flash column chromatography (silica gel,
65% EtOAc, 5% MeOH in hexanes) to obtain tri-O-acetyl diazepanone
56 (6.5 mg, 44%) as a colorless oil: Rf = 0.47 (silica gel, 30% EtOAc,
5% MeOH in hexanes); [α]D22 +12.5 (c 0.1, CH2Cl2); H NMR (400
1
MHz, CDCl3) δ = 0.00 (s, 3 H), 0.05 (s, 3 H), 0.08 (s, 6 H), 0.87 (s, 9
H), 0.88 (s, 9 H), 2.08 (s, 3 H), 2.48 (s, 3 H), 2.53 (s, 3 H), 2.58 (s, 3
H), 3.50 (d, J = 9.7 Hz, 1 H), 3.65−4.32 (m, 7 H), 4.60 (bs, 1 H),
4.91−4.96 (m, 1 H), 5.40 (d, J = 9.7 Hz, 1 H), 5.77 (d, J = 8.1 Hz, 1
H), 5.89 (d, J = 3.8 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 8.34 (bs, 1 H);
13C NMR (100 MHz, CDCl3) δ = −4.7, −4.6, −4.3, 14.9, 18.4, 22.8,
26.7, 26.8, 29.8, 30.1, 39.3, 55.8, 62.3, 66.1, 68.5, 68.8, 72.1, 72.9, 82.5,
98.5, 103.2, 128.7, 131.7, 150.5, 164.1, 168.3, 171.2, 173.5; FAB
HRMS (NBA) m/e 793.3492, M + Na+ calcd for C34H58N4O12Si2
793.3487.
ASSOCIATED CONTENT
■
S
* Supporting Information
Theoretical calculations data and H and 13C NMR spectra for
1
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: 34 952 134258. Fax: 34-952 131941. E-mail: frsarabia@
uma.es.
■
ACKNOWLEDGMENTS
This work was financially supported by the Direccion
■
́
General
́
de Investigacion
́
y Cientifica Tec
́
nica (ref CTQ2010-16933)
́
́
and Consejeria de Educacion
(FQM-03329). C.G.-R. thanks the Ministerio de Educacion
́
y Ciencia of Junta de Andalucia
́
y
Ciencia for a fellowship. We thank Dr. J. I. Trujillo for
assistance in the preparation of this manuscript. We thank
́
Unidad de Espectroscopia de Masas de la Universidad de
Granada for exact mass spectroscopic assistance.
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