Total synthesis of (±)-maistemonine, (±)-stemonamide, and (±)-isomaistemonine

Article abstract of DOI:10.1021/jo202042x

A full account of the total synthesis of (±)-maistemonine, (±)-stemonamide, and (±)-isomaistemo-nine is presented. Two approaches have been developed to construct the basic pyrrolo[1,2-a]azepine core of the Stemona alkaloids, featuring a tandem semipinaco

Full text of DOI:10.1021/jo202042x

Article
pubs.acs.org/joc
Total Synthesis of (±)-Maistemonine, (±)-Stemonamide, and
(±)-Isomaistemonine
Zhi-Hua Chen, Zhi-Min Chen, Yong-Qiang Zhang, Yong-Qiang Tu,* and Fu-Min Zhang*
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R.
China
S
* Supporting Information
ABSTRACT: A full account of the total synthesis of
(±)-maistemonine, (±)-stemonamide, and (±)-isomaistemo-
nine is presented. Two approaches have been developed to
construct the basic pyrrolo[1,2-a]azepine core of the Stemona
alkaloids, featuring a tandem semipinacol/Schmidt rearrange-
ment of a secondary azide and a highly stereoselectively
desymmetrizing intramolecular Schmidt reaction, respectively.
To build the common spiro-γ-butyrolactone, a new protocol was carried out by utilizing an intramolecular ketone-ester
condensation as the key transformation. The vicinal butyrolactone moiety of (±)-maistemonine was stereoselectively introduced
via a one-pot procedure involving the epimerization at C-3 and carbonyl allylation/lactonization. Moreover, (±)-stemonamide
was divergently synthesized from a common intermediate, and (±)-isomaistemonine was obtained via the epimerization of
(±)-maistemonine at C-12.
treat respiratory diseases and as anthelmintics,9−11 it is not
surprising that the pure natural products possess interesting
INTRODUCTION
■
The Stemona alkaloids represent a class of polycyclic alkaloids
with relatively complex structures. More than 130 Stemona
alkaloids have been isolated to date from the monocotyledo-
nous family Stemonaceae.1−4 Recently, Pilli and co-workers
classified Stemona alkaloids into eight groups according to their
structural features.4 The stemonamine group (Figure 1), which
bioactivities. For example, maistemonine (1e) has been shown
to display significant antitussive activity.12
Maistemonine (1e) is a pentacyclic Stemona alkaloid that was
originally isolated by Xu et al. in 1991 from the roots of
Stemona mairei.6 The striking molecular architecture of 1e
includes an azatetracyclic 7,5,5,5-ring system and an α-methyl-
γ-butyrolactone moiety annexed to C-3 as a side chain. The
azatetracyclic system, which is common to stemonamide (1c)
and isomaistemonine (1g), possesses two contiguous hetero-
quaternary stereocenters.
Since the report of the first total synthesis of (+)-croomine
by Williams’ group in 1989,13 the challenging structural
complexity and various biological activities of the Stemona
alkaloids have attracted considerable interest from the synthetic
community.1,4,14−19 Among them, a number of elegant total
syntheses of the stemonamine group alkaloids 1a−1d have
been reported in the literature.20−27 However, maistemonine
(1e) and isomaistemonine (1g), which have more intricate
skeletons, had not been synthesized until we disclosed our first
total synthesis of 1e in 2010.28 Herein, we provide a full
account of the development and execution of our strategy,
which culminated in the total synthesis of maistemonine (1e)
and isomaistemonine (1g) and divergent synthesis of
stemonamide (1c).
Figure 1. Structures of 10 alkaloids of the stemonamine group.
is characterized by the presence of a cyclopenta[1,2-b]pyrrolo-
[1,2-a]azepine nucleus, includes stemonamine (1a),5 isoste-
monamine (1b),5 stemonamide (1c),5 isostemonamide (1d),5
maistemonine (1e),5,6 oxymaistemonine (1f),5,6 isomaistemo-
nine (1g),7 and sessilistemonamines A−C (1h−1j).8 Since the
plants from which the Stemona alkaloids are obtained have been
used in folk medicine in East Asia for thousands of years to
Received: October 5, 2011
Published: November 15, 2011
© 2011 American Chemical Society
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Scheme 1. First-Generation Retrosynthetic Analysis of (±)-Maistemonine
DIBAL-H reduction of the ester group to afford aldehyde 14.
Then, Grignard addition to 14 with ethynylmagnesium
bromide gave alcohol 15, which is followed by the mesylation
to form the mesylate 16. Substitution of mesylate 16 with NaN3
was conducted at 40 °C, affording secondary azide 17. It should
be noted that the introduction of the alkynyl group was
elaborated to be an aldehyde precursor for the convenient
establishment of ring E and also made it possible to obtain
stemonamide (1c) in the later stage. We initially chose a vinyl
group as the aldehyde precursor and found that the SN2′
reaction was a prominent side reaction, giving a double bond
migration product in the subsequent NaN3 displacement
process.36 The dioxolane group of 17 was rapidly removed
under standard conditions (PTS, acetone) to give enone 18.
Next, 1,2-addition of the (2-methylenebutyl)magnesium
reagent, derived from 2-(bromomethyl)but-1-ene,37 with 18
proceeded in good yield, affording diastereoisomers 19, which
are not separable on silica gel. Regioselective epoxidation of 19
was conducted to furnish 20 in 86% yield via optimization of
RESULTS AND DISCUSSION
■
Our initial retrosynthetic analysis of maistemonine (1e) is
depicted in Scheme 1. We anticipated that the lactone ring E of
the natural product 1e could be conveniently formed via a
stereoselective carbonyl allylation/lactonization29,30 of aldehyde
2, which could be derived via oxidative cleavage of alkene 3.
Ring D could be formed by means of Dieckmann condensation
and subsequent O-methylation of diester 4. Simplification of 4
according to our previously developed strategy23 reveals tricycle
5. Key reaction in this section of the synthesis would be the
stereoselective establishment of the oxa-quaternary center (C-
12). Construction of the enone and terminal vinyl moieties of 5
by a sequence of ozonolysis, Lindlar reduction, and aldol
condensation leads back to ketone 6, which has the common
pyrrolo[1,2-a]azepine core of most Stemona alkaloids. We
hoped to rapidly fashion the bicyclic core of 6 via a tandem
semipinacol rearrangement/Schmidt reaction31 developed by
our group. Precursor 7 could be derived from the known ester
832 by a route featuring DIBAL-H reduction, Grignard addition,
SN2 displacement, and regioselective epoxidation.
t
the reaction conditions. Increasing the amount of BuOOH or
prolonging the reaction time gave a prominent diepoxidation
byproduct. TMS protection of the labile tertiary alcohol 20
resulted in the formation of the key intermediate 21. We
elected not to optimize the 1,2-addition (18 → 19) to get the
single diastereoisomer 7 mentioned in our retrosynthetic
analysis (Scheme 1), as diastereoisomers 21 were competent
to permit the examination of the subsequent tandem reaction.
When we exposed 21 to TiCl4 in CH2Cl2 at −78 °C to room
temperature, the expected rearrangement proceeded smoothly
to afford the separable diastereoisomers 22 and 23 in the ratio
of 5:1. The relative configurations of the newly formed
stereocenters of 22 and 23 were assigned by X-ray analysis.38
Unfortunately, by comparing the relative configurations of
the major diastereoisomer 22 and maistemonine (1e), we
found that their stereochemistries at C-3 and C-9a were
inconsistent. Apparently, the ratio of the diastereoisomers 19
formed in the 1,2-addition step (18→19) ultimately enabled
the undesired rearrangement product 22 to be primarily
generated. Then, 22 and 23 were oxidized to yield ketones 24
and 6, respectively. Although the designed bicyclic intermediate
6 was obtained via the anticipated tandem semipinacol/
Schmidt rearrangement of the secondary azide substrate
(Scheme 3), its lengthy preparation course (12 steps) and
low stereoselectivity in the tandem reaction impelled us to seek
a more concise approach toward the synthesis of 6.
In 2006, our laboratory developed a general method for the
efficient construction of aza-quaternary carbon units via a Lewis
́
acid promoted tandem semipinacol/Aube’s type intramolecular
Schmidt reaction of α-siloxy-epoxy-azide (Scheme 2).31 Shortly
Scheme 2. Tandem Semipinacol/Schmidt Rearrangement
thereafter, we applied this methodology as part of an efficient
total synthesis of stemonamine (1a).23 Despite the fact that the
tandem process is effective for a wide scope of substrates, the
secondary azide, such as 7 (Scheme 1), was not investigated
until recently. Although some precedent existed for the
intramolecular Schmidt reaction of secondary azide,33−35 we
were unsure if the secondary azide 7 would undergo the
tandem reaction to give the desired bicyclic product.
Our attempt at constructing 6 according to the plan
described above commenced with the preparation of the
known ester 8,32 as depicted in Scheme 3. Treatment of enone
12 and ethyl acrylate with a catalytic amount of DBU in DMF
at 185 °C (sealed tube) afforded 8. Protection of the keto
carbonyl group provided 1,3-dioxolane 13, which underwent
A modified retrosynthesis of 1e, based on the concept
mentioned above, is portrayed in Scheme 4. We did not
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Scheme 3. Preparation and Tandem Semipinacol/Schmidt Rearrangement of Secondary Azide 21
subjected to Michael addition with acrolein to yield the keto-
aldehyde 28. Selective Grignard addition of ethynylmagnesium
chloride to 28 was performed at low temperature to give
hemiketal 29. Mesylation of 29 with MsCl and Et3N or pyridine
in CH2Cl2 proceeded in low yield (10−20%, 2 steps). After
optimization of the reaction conditions, it was found that
changing the solvent to pyridine with a catalytic amount of
DMAP could afford the desired keto-mesylate 30 in 50% yield
over two steps. Mesylate substitution of 30 with NaN3 gave the
secondary azide 25. Then, the key desymmetrizing intra-
molecular Schmidt reaction of the secondary azide was
investigated. The rearrangement was enabled by treatment of
25 with 1.2 equiv of TiCl4 in CH2Cl2 at −15 °C to afford the
bicyclic product 24 as a single product in 72% yield.
Scheme 4. Second-Generation Retrosynthetic Analysis of
(±)-Maistemonine
envision our new strategy requiring changes to the 6→1e stages
of the synthesis. However, 6 would now be derived from a
desymmetrizing intramolecular Schmidt reaction33,39−43 of
azido-ketone 25, which could be easily obtained in five steps
from inexpensive material 26.
To verify the high stereoselectivity of the desymmetrizing
intramolecular Schmidt reaction, an analogue of 25 with a
terminal ethyl moiety instead of the alkynyl group was
As shown in Scheme 5, treatment of cyclohexane-1,3-dione
with 2-(bromomethyl)but-1-ene in the presence of copper
powder afforded the C-alkylation product 27, which was
Scheme 5. Preparation and Desymmetrizing Intramolecular Schmidt Reaction of Azide 25
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Scheme 6. Preparation and Desymmetrizing Intramolecular Schmidt Reaction of Azide 33
Figure 2. Proposed process for the diastereotopic group selective Schmidt reaction.
Scheme 7. Third-Generation Retrosynthetic Analysis of (±)-Maistemonine
Scheme 8. Synthesis of Tricyclic Skeleton 40
prepared. The synthesis of 33, which parallels the above route
used to prepare 25, is shown in Scheme 6. Similarly, treatment
of 33 with TiCl4 in CH2Cl2 at −15 °C afforded another
rearrangement product 34 in the form of a single
diastereoisomer.
This result might rule out the possibility that the metal−π
interaction of the titanium alkoxide with the alkynyl moiety was
responsible for the stereochemical outcome of the Schmidt
reaction (25→24). Presumably, the unfavored steric hindrance
between the 2-methylenebutyl and alkynyl moieties (or ethyl
moieties) in the transition state (36) might result in the
observed high stereoselectivity of the diastereotopic group
selective intramolecular Schmidt reaction (Figure 2).
Apparently, the relative configuration of the rearrangement
product 24 was still inconsistent with that of the designed
bicyclic intermediate 6. However, by comparing the two
different approaches to the bicyclic core 24 (Schemes 3 and 5),
we found that the first route to the bicyclic intermediates 24
and 6 (ca. 5:1) would need 12 steps in 16% overall yield, but
the second process to the single diastereoisomer 24 would only
need 6 steps in 26% overall yield. Furthermore, all of the
procedures in Scheme 5 could be conveniently and rapidly
performed and 24 could be easily obtained on a gram scale.
Given that more manipulations and a large mass of bicyclic
precursor would be required in the subsequent exploration of
the synthesis, the second approach was chosen as the material
supplying route to complete the total synthesis of 1e. As
depicted in Scheme 7, we therefore planned to slightly modify
our strategy and take advantage of the aldehyde intermediate
37, which would be formed in the final stages, to adjust the C-3
stereochemistry. Comparison of the two strategies, listed in
Schemes 1 and 7, shows that the transformations of the bicyclic
intermediates 6 or 24 into 1e involve the same process, except
for epimerization of 37 at C-3 in Scheme 7.
After drafting the new synthetic route to 1e from the readily
available 24, we turned our attention to forge ring C in 1e
(Scheme 8). Ozonolysis of 24, by bubbling ozone through the
reaction mixture very slowly at −78 °C (approximately 11 h),
proceeded in good yield to furnish diketone 41. Slightly
accelerating the rate of ozone bubbling resulted in reduction of
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Scheme 9. Preparation and Examination of Dieckmann Condensation
Scheme 10. Fourth-Generation Retrosynthetic Analysis of (±)-Maistemonine
Scheme 11. Preparation and Construction of Ring D via Ketone-Ester Condensation
reaction time but a significantly decreased yield of 41. At this
point, we envisioned that some of the subsequent procedures to
the tetracyclic intermediate 38 would be performed under basic
conditions, and therefore, the terminal alkynyl moiety
containing an active hydrogen atom might interfere with the
procedures. As a consequence, reduction of 41 was carried out,
using Lindlar Pd as catalyst,44 to give alkene 42. Then, the key
aldol condensation for formation of ring C was examined.
Surprisingly, exposure of 42 to tBuOK in tBuOH afforded a 5:1
mixture of enone 40 and its diastereoisomer, which could not
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Scheme 12. Preparation and Examination of Epimerization of Aldehyde 37
be separated by column chromatography. In fact, the
diastereoisomer of 40 was a desired intermediate, mentioned
in Scheme 1 as compound 5, whose relative configuration was
consistent with that of 1e. In order to form 5 as the sole
product, a series of bases (tBuOK, NaOEt, NaH, and LHMDS)
in combination with various solvents (tBuOH, benzene, EtOH,
and THF) were carefully examined for the aldol condensation
of 42; however, similar results to the generation of 40 and 5 in
an approximate ratio of 5:1 were obtained. It was assumed that
the epimerization at C-2 of 40 via a retro-aza-Michael process45
might account for the formation of 5 in the aldol condensation.
During this study, we found that treatment of 42 with K2CO3
in MeOH produced 40 without formation of its diaster-
eoisomer 5, and the structure of 40 was confirmed by X-ray
analysis.38
configuration of the newly formed stereocenter. Then,
oxidation of 48 to β-diketone 49 was achieved using the
Dess−Martin periodinane.49 To install the oxa-quaternary
center (C-12), the potassium enolate of 49 was initially treated
with Davis’ reagent, which was used to prepare 45, providing an
unexpected rearrangement product 50.50 The successful
introduction of hydroxyl group was conducted by bubbling
i
O2 to 49 with a catalytic amount of CeCl3·7H2O in PrOH at
room temperature,51,52 furnishing an 8:1 mixture of separable
diastereoisomeric alcohols 51 and 52. Reaction of the major
isomer 51 with di-tert-butyl dicarbonate and DMAP in CH2Cl2
afforded carbonate 53 in 95% yield.
Then, the key intramolecular ketone-ester condensation was
attempted. To our disappointment, the ring-closure product 46
was not obtained once again by treatment of 53 with a series of
basic systems such as LDA/THF, LHMDS/THF, NaHMDS/
THF, KHMDS/THF, tBuOK/18-crown-6/benzene, and
tBuOK/tBuOH. On the basis of molecular model studies, we
reasoned that the bulky tert-butoxy group might retard the
nucleophilic attack of the enolate anion on the carbonyl carbon.
Thus, replacement of the bulky tert-butoxy group in 53 by a less
sterically hindered group such as an ethoxy group might enable
the ketone-ester condensation to proceed. Exposure of 51 to
Et3N, DMAP, and ethyl chloroformate in CH2Cl2 at room
temperature generated carbonate 54 in nearly quantitative yield
(Scheme 11). Fortunately, the designed ketone-ester con-
densation for accessing spirolactone D was achieved by
treatment of 54 with KHMDS in THF at −78 to 10 °C,
giving tetracycle 46, which was labile on column chromatog-
raphy. It should be noted that treatment of 54 with other bases
With tricycle 40 in hand, we commenced our investigation of
the construction of ring D (Scheme 9). Reaction of the lithium
enolate of 40 with Mander’s reagent46 in THF at −78 °C
provided β-ketoester 43. The introduction of oxa-quaternary
center C-12 was accomplished by direct addition of Davis’
reagent 4447 to the potassium enolate of 43 in THF at −15 °C,
affording tertiary alcohol 45 as a single compound in 87% yield
over two steps. The supposed Dieckmann condensation
precursor 39 was obtained by treatment of 45 with propionic
anhydride/DMAP/Et3N in nearly quantitative yield, and its
stereochemistry was verified by X-ray crystallography.38 Then,
the key Dieckmann condensation for formation of ring D was
examined. Unfortunately, all attempts (tBuOK/18-crown-6/
t
t
t
benzene, BuOK/DMF, BuOK/tBuOH, BuOK/THF, LDA/
THF, LHMDS/THF, and NaH/THF, etc.) failed to furnish the
desired tetracycle 46 and resulted in no reaction or substrate
decomposition. After extensive examinations without any
success, we had to give up the Dieckmann condensation and
explore an alternative method for building ring D.
t
(LDA, LHMDS, NaHMDS, and BuOK) resulted in substrate
decomposition and no observation of the ring-closure product
46. O-Methylation of the crude product 46 with Me2SO4 in
CH2Cl2 afforded 38 in low yield (20%, 2 steps). An acceptable
result was obtained when the methylation reagent was changed
to CH2N2: 76% yield over two steps. Furthermore, the
structure of 38 was confirmed by X-ray analysis.38
The α-methyl-β-methoxy unsaturated spiro-γ-butyrolactone
(ring D) is a common structural feature of Stemona alkaloids
1a−1g. As depicted in Scheme 10, previous studies showed that
ring D could be constructed by ultimate formation of the C15−
O bond (path a)22 or the C13−C14 bond (path b).23 However,
to our knowledge, the ultimate formation of the C14−C15
bond (path c) to build the spiro-γ-butyrolactone has not been
reported. Therefore, we would like to design a new protocol to
access the spirolactone D (path c) via an intramolecular ketone-
ester condensation.48 Accordingly, tricycle 40 was still
projected as a key precursor to tetracycle 38, and the final
stages of the synthesis would not need to be changed (Scheme
10).
According to the aforementioned idea, we started to explore
the establishment of spirolactone D over again, as described in
Scheme 11. Aldol reaction of 40 was carried out by treatment
of propanal with the lithium enolate of 40 in THF at −78 °C,
affording β-hydroxy ketone 48 as a single diastereoisomer in
98% yield. Considering that the hydroxyl in 48 would be
oxidized to form a ketone, we did not identify the relative
After the tetracyclic skeleton had been set up, adjustment of
the C-3 stereochemistry was envisaged to generate the correct
relative configurations in line with 1e. As shown in Scheme 12,
oxidation of 38 with K2OsO4/NMO followed by treatment of
the resulting crude diol 55 with NaIO4, affording aldehyde 37
in 96% yield. Then, the epimerization of aldehyde 37 at C-3
was investigated. At the outset, we did not anticipate that this
task would be problematic, and two approaches for this purpose
were explored. Initially, we hoped to carry out the
epimerization by subjecting 37 to a catalytic amount of
DBU;53,54 however, no C-3 epimer was observed. Subse-
quently, a strategy involving enolization and protonation from
the α-face was attempted.55 Examinations of a variety of bases
t
(LDA, LHMDS, NaHMDS, KHMDS, and BuOK, etc.) and
proton sources (H2O, phenol, and 2,6-di-tert-butyl-4-methyl-
phenol) only resulted in substrate recovery. At this point, we
noticed that a report by Boger and co-workers describing a
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Scheme 13. Completion of Total Synthesis of (±)-Maistemonine (1e)
Scheme 14. Synthesis of (±)-Stemonamide (1c)
Scheme 15. Conversion of (±)-Maistemonine (1e) into (±)-Isomaistemonine (1g) via a Proposed Retro-Mannich and
Mannich Processes
rapid epimerization of an unstable α-aminoaldehyde.56 This
report gave us an enlightenment that the neighboring lactam
carbonyl in 37 might retard the epimerization at C-3 as a result
of unfavored steric hindrance effect or electronic effect.
Therefore, we decided to modify our synthetic plan once
more and to perform reduction of the lactam carbonyl in
advance.
which was converted to aldehyde 58 using 1.4 equiv of NaIO4
at 0 °C in 64% yield.
Noteworthy, a slow epimerization of α-aminoaldehyde 58 at
room temperature was observed. This phenomenon was similar
to Boger’s observation mentioned above. At this juncture, we
conceived that epimerization of 58 at C-3 and construction of
ring E via carbonyl allylation/lactonization might be carried out
through a one-pot process. With this idea, direct addition of
ethyl 2-(bromomethyl)acrylate65 in THF to Zn and 58 in
refluxing THF afforded 59, which was unstable on column
chromatography. Subsequently, hydrogenation of the exo-
double bond in the nonpurified adduct 59, using palladium
on carbon as catalyst, generated maistemonine (1e) stereo-
selectively. Its NMR spectra were in all aspects identical to the
spectra of the natural product. The relative configuration of 1e
was unambiguously established, for the first time, by X-ray
analysis.38
During the preparation of 58, a byproduct was obtained in
15% yield, and its spectroscopic data (1H NMR and 13C NMR)
exactly matched with the authentic data of stemonamide (1c).5
Although appropriate experiments were not performed to verify
the mechanism, it is likely that stemonamide (1c) was an
oxidation product of 58. Indeed, stemonamide (1c) was
obtained in 83% yield (2 steps) by increasing the amount of
NaIO4 (10 equiv), elevating the reaction temperature (40 °C)
and prolonging the reaction time (Scheme 14). Thus, the
divergent total synthesis of stemonamide (1c) was accom-
plished from a same synthetic intermediate 56 by varying the
In fact, selective reduction of the lactam carbonyl without
touching the double bond and other carbonyls in 38 was
proved to be a troublesome task. Initial attempt to reduce the
amide group in 38 with BH3·Me2S57 gave a complex mixture of
products. Then, a series of featured reduction reagents
including 9-BBN,58 Tf2O/Hantzsch ester,59 RhH(CO)-
(PPh3)3/Ph2SiH2,60 and Et3OBF4/NaBH4/2,6-di-tert-butylpyr-
idine61 were examined but resulted in no reaction. Treatment
of 38 with Lawesson’s reagent or P4S10 in refluxing toluene62
afforded a thioamide in 11% yield, which was subjected to
Raney Ni63 in EtOH at room temperature to generate an
undesired terminal double bond saturated amine. During this
study, we noticed that treatment of the tertiary amide with
methyl trifluoromethanesulfonate could afford an alkoxy
imminium salt,64 which might be reduced by NaBH3CN to
furnish the corresponding tertiary amine. Then, a one-pot
protocol (MeOTf/CH2Cl2, then NaBH3CN/EtOH) to selec-
tively reduce the lactam was attempted, and fortunately, the
desired amine 56 was obtained in 50% yield (47% of recovered
starting material, Scheme 13). Oxidation of 56 with K2OsO4/
NMO in a mixed solvent provided diol 57 as a crude product,
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isopropyl alcohol were distilled from activated magnesium under
argon. All other solvents and reagents were used as received. Analytical
TLC was carried out on precoated plates (silica gel 60, F254). Column
reaction conditions. Additionally, stemonamide (1c) could be
converted into stemonamine (1a) by reduction of the lactam
carbonyl group in 1c.24
1
chromatography was performed with silica gel (200−300 mesh). H
In particular, we observed that an NMR sample of
(±)-maistemonine (1e) in CDCl3 was smoothly converted
into (±)-isomaistemonine (1g) at room temperature. This
process could not be accelerated by heat, and the ratio of 1e
and 1g approximately remained 1:1. It was assumed that the
epimerization of (±)-maistemonine (1e) at the stereogenic
center C-12 via a retro-Mannich and Mannich processes might
account for the generation of (±)-isomaistemonine (1g)
(Scheme 15).24 The 1H NMR and 13C NMR spectra of
(±)-isomaistemonine (1g) were in agreement with that of the
natural product provided by Ye’s group.7,66−69 However, there
have been some reports of the isolation of (−)-isomaistemo-
nine, which gave different relative configurations at C-4 and C-
12.70,71 Finally, the synthetic (±)-isomaistemonine (1g) was
crystallized, and for the first time, an X-ray crystal structure was
obtained which fully confirmed the structural assignment.38
NMR spectra were recorded at 400 or 600 MHz. 13C NMR spectra
were recorded at 100 or 150 MHz. Chemical shifts are recorded in
parts per million, and coupling constants J are recorded in hertz. IR
spectra were recorded on a Fourier transform infrared spectrometer.
The MS data were obtained with EI (70 eV). HRMS data were
determined on an APEXII 47e FT-ICR spectrometer. Melting point
was measured on a melting point apparatus and was uncorrected.
Ester (8). To a solution of cyclohex-2-enone (1.70 mL, 17.500
mmol) in DMF (32 mL) was added DBU (523 μL, 3.500 mmol) and
ethyl acrylate (2.48 mL, 22.739 mmol). The reaction tube was sealed
and heated at 185 °C for 24 h. After cooling to room temperature, the
reaction mixture was poured into ice water (30 mL), and the mixture
was extracted with Et2O (3 × 30 mL). The combined organic layers
were washed with water (2 × 10 mL) and brine (10 mL), then dried
(MgSO4). The solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography on silica gel (5%
EtOAc/petroleum ether to 10% EtOAc/petroleum ether) to give ester
8 (2.57 g, 75%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 6.72−
6.70 (t, J = 4.0 Hz, 1H), 4.06−4.01 (dd, J = 14.4, 7.2 Hz, 2H), 2.44−
2.41 (m, 2H), 2.37−2.32 (m, 4H), 2.30−2.26 (dd, J = 10.4, 5.6 Hz,
2H), 1.93−1.87 (ddd, J = 12.8, 6.4, 6.4 Hz, 2H), 1.18−1.14 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 198.8, 172.9, 146.1, 138.0,
60.0, 38.3, 33.1, 25.9, 25.3, 22.9, 14.1.
CONCLUSION
■
We have achieved the total synthesis of (±)-maistemonine
(1e), (±)-stemonamide (1c), and (±)-isomaistemonine (1g).
Two approaches were developed to construct the basic
pyrrolo[1,2-a]azepine core of the Stemona alkaloids. Initially,
we investigated the feasibility of the tandem semipinacol/
Schmidt rearrangement of a secondary azide 21 and utilized the
cascade protocol to build the bicyclic subunit. However, the
lengthy preparation course of substrate 21 (12 steps) prompted
us to explore a more efficient route to the bicycle 24, featuring a
highly stereoselectively desymmetrizing intramolecular Schmidt
reaction. A subsequent strategy based on Dieckmann
condensation for construction of the spiro-γ-butyrolactone D
was unsuccessful. Therefore, we designed and developed a new
method to establish the spiro-lactone via an intramolecular
ketone-ester condensation. To selectively reduce the lactam
carbonyl without touching double bond and other carbonyls in
38, a variety of reduction procedures were attempted, and
MeOTf/NaBH3CN was proved to be a very effective approach.
In the final stage of the synthesis of (±)-maistemonine (1e), a
one-pot protocol involving the epimerization at C-3 and
carbonyl allylation/lactonization was successfully performed to
stereoselectively install the vicinal butyrolactone moiety.
Moreover, (±)-stemonamide (1c) was synthesized from
intermediate 56 using a divergent approach and (±)-iso-
maistemonine (1g) was obtained via the epimerization of 1e at
C-12. The structures of the synthetic (±)-maistemonine (1e)
and (±)-isomaistemonine (1g) were unambiguously confirmed,
for the first time, by X-ray crystallographic analysis. Finally, it is
noteworthy that the synthetic strategies of the total synthesis of
1e, 1c, and 1g from cyclohexane-1,3-dione 26 are step-
economic processes, and no extra protecting-group manipu-
lations were required.
1,3-Dioxolane (13). A solution of ester 8 (3.94 g, 20.102 mmol),
ethylene glycol (4.40 mL, 80.194 mmol), and p-TsOH·H2O (173.0
mg, 1.005 mmol) in benzene (80 mL) was refluxed for 24 h in a
Dean−Stark apparatus. The reaction mixture was cooled, poured into
saturated aqueous NaHCO3 solution (10 mL), the aqueous layer
extracted with Et2O (3 × 20 mL). The combined organic layers were
washed with water (2 × 10 mL) and brine (10 mL), then dried
(MgSO4). The solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography on silica gel (2%
EtOAc/petroleum ether to 5% EtOAc/petroleum ether) to give 1,3-
1
dioxolane 13 (4.44 g, 92%) as a yellow oil: H NMR (400 MHz,
CDCl3) δ 5.71−5.69 (t, J = 4.0 Hz, 1H), 4.14−4.08 (dd, J = 14.4, 7.2
Hz, 2H), 4.00−3.97 (m, 4H), 2.48−2.44 (m, 2H), 2.36−2.32 (m, 2H),
2.01−2.00 (t, J = 2.0 Hz, 2H), 1.74−1.67 (m, 4H), 1.25−1.22 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7, 136.6, 129.4,
107.6, 64.9, 60.1, 33.9, 33.7, 25.2, 25.0, 20.6, 14.2; HRMS (ESI) calcd
for C13H21O4 (M + H)+: 241.1434, found 241.1428.
Aldehyde (14). To a solution of 1,3-dioxolane 13 (809.5 mg,
3.373 mmol) in hexane (16 mL) was added DIBAL-H (1.0 M in
cyclohexane, 3.71 mL, 3.710 mmol) dropwise under argon at −78 °C.
The resultant mixture was stirred at −78 °C for 10 min, then treated
with water (1 mL), and warmed to room temperature. The mixture
was filtered through a plug of Celite and washed with CH2Cl2 (3 × 10
mL). The filtrate was washed with water (3 × 10 mL) and brine (10
mL), then dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue was purified by flash column chromatography
on silica gel (5% EtOAc/petroleum ether to 15% EtOAc/petroleum
1
ether) to give aldehyde 14 (595.0 mg, 90%) as a yellow oil: H NMR
(400 MHz, CDCl3) δ 9.74−9.73 (t, J = 2.0 Hz, 1H), 5.70−5.69 (m,
1H), 3.98 (s, 4H), 2.60−2.56 (m, 2H), 2.38−2.34 (m, 2H), 2.02−1.99
(m, 2H), 1.74−1.66 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 202.8,
136.3, 129.8, 107.5, 64.8, 43.1, 33.6, 25.2, 22.1, 20.5; HRMS (ESI)
calcd for C11H17O3 (M + H)+: 197.1172, found 197.1165.
Alcohol (15). To a solution of aldehyde 14 (662.1 mg, 3.378
mmol) in anhydrous THF (10 mL) was added ethynylmagnesium
bromide (0.5 M in THF, 8.11 mL, 4.055 mmol) dropwise under argon
at −78 °C. The resultant mixture was stirred at 0 °C for 1 h, then
treated with water (1 mL), and warmed to room temperature. The
mixture was diluted with Et2O (10 mL) and saturated aqueous NH4Cl
(5 mL). The aqueous phase was extracted with Et2O (3 × 10 mL),
then the combined organic extracts were dried over Na2SO4. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (10% EtOAc/
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions requiring anhy-
drous conditions were carried out under an argon atmosphere using
oven-dried glassware (120 °C), which was cooled under argon.
Anhydrous tetrahydrofuran and benzene were distilled from sodium
metal under argon. Anhydrous dichloromethane was dried by
distillation from CaH2 immediately prior to use under argon.
Anhydrous N,N-dimethylformamide was dried by distillation from
MgSO4 under reduced pressure. Anhydrous methanol, ethanol, and
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petroleum ether to 20% EtOAc/petroleum ether) to give alcohol 15
(622.4 mg, 83%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 5.80−
5.78 (t, J = 4.0 Hz, 1H), 4.41−4.39 (t, J = 5.6 Hz, 1H), 4.05−3.97 (m,
4H), 2.57 (s, 1H), 2.45−2.44 (d, J = 2.4 Hz, 1H), 2.24−2.16 (m, 2H),
2.04−2.03 (t, J = 2.0 Hz, 2H), 1.92−1.87 (dd, J = 14.4, 7.2 Hz, 2H),
1.75−1.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 136.6, 130.3,
107.9, 85.1, 72.6, 64.9, 64.8, 61.9, 37.2, 33.7, 25,3, 24.7, 20.6; HRMS
(ESI) calcd for C13H18O3Na (M + Na)+: 245.1148, found 245.1157.
Enone (18). A solution of alcohol 15 (486.6 mg, 2.192 mmol) in
anhydrous CH2Cl2 (5 mL) under argon was treated with Et3N (762
μL, 5.482 mmol) and methanesulfonyl chloride (339 μL, 4.380 mmol)
at 0 °C. The reaction mixture was stirred for 30 min and then
quenched with water (1 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL), then the combined organic extracts were dried
over MgSO4, filtered, and concentrated to give the crude mesylate 16
as a yellow oil.
The crude mesylate 16 was dissolved in anhydrous DMF (4 mL)
under argon, and then NaN3 (427.5 mg, 6.577 mmol) was added. After
being stirred at 40 °C for 4 h, the solution was allowed to cool on an
ice−water bath. Then, the reaction mixture was diluted with Et2O (10
mL) and quenched with water (5 mL). The aqueous phase was
extracted with Et2O (3 × 5 mL), and the combined organic phase was
washed with water (2 × 5 mL) and brine (5 mL). The organic phase
was dried over MgSO4, filtered, and concentrated to give the crude
azide 16 as a yellow oil.
for 30 min and then treated with water (1 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 5 mL), then the combined organic
extracts were dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by flash column
chromatography on silica gel (2% EtOAc/petroleum ether to 5%
EtOAc/petroleum ether) to give diastereomers 20 (402.5 mg, 86%) as
a yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.90−4.89 (d, J = 1.2 Hz,
1H), 4.77 (s, 1H), 4.15−4.11 (ddd, J = 6.4, 6.4, 2.0 Hz, 1H), 3.20−
3.19 (t, J = 1.6 Hz, 1H), 2.58−2.49 (m, 2H), 2.30−2.11 (m, 4H),
1.92−1.73 (m, 4H), 1.72−1.66 (m, 2H), 1.56−1.51 (m, 1H), 1.47−
1.25 (m, 3H), 1.07−1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.9, 112.2, 79.2, 79.1, 75.2, 75.1, 73.9, 64.6, 61.5, 61.4,
52.8, 42.1, 42.0, 32.4, 30.1, 29.9, 26.0, 25.9, 23.1, 17.7, 12.4; HRMS
(ESI) calcd for C16H24N3O2 (M + H)+: 290.1863, found 290.1858.
Trimethylsiloxy (21). A solution of epoxide 20 (174.0 mg, 0.602
mmol) in anhydrous DMF (2 mL) under argon was treated with
imidazole (246.0 mg, 3.613 mmol) and chlorotrimethylsilane (228 μL,
1.805 mmol) at room temperature. The reaction mixture was stirred
for 24 h and then was diluted with Et2O (5 mL) and water (1 mL).
The aqueous phase was extracted with Et2O (3 × 5 mL), and the
combined organic phase was washed with water (2 × 5 mL). The
organic phase was dried over MgSO4, filtered, and concentrated. The
residue was purified via silica gel chromatography (petroleum ether to
1% EtOAc/petroleum ether) to give diastereomers 21 (212.8 mg,
1
98%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.87−4.86
To a solution of azide 16 in acetone (5 mL) was added p-
TsOH·H2O (75.5 mg, 0.438 mmol) at room temperature. The
resultant mixture was stirred at room temperature for 30 min and then
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (2% EtOAc/petroleum
ether to 5% EtOAc/petroleum ether) to give enone 18 (347.0 mg,
(d, J = 1.6 Hz, 1H), 4.73 (s, 1H), 4.13−4.07 (m, 1H), 3.05−3.04 (d, J
= 2.0 Hz, 1H), 2.58−2.57 (t, J = 2.0 Hz, 1H), 2.48−2.43 (d, J = 13.6
Hz, 1H), 2.27−2.12 (m, 4H), 1.85−1.74 (m, 4H), 1.70−1.59 (m, 1H),
1.58−1.52 (m, 2H), 1.46−1.35 (m, 2H), 1.06−1.02 (t, J = 7.2 Hz,
3H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 148.3, 112.1, 79.2,
78.8, 75.1, 75.0, 64.2, 58.9, 58.8, 52.9, 52.8, 42.3, 29.9, 29.7, 29.5, 24.4,
24.2, 21.9, 19.0, 12.6, 2.6,; HRMS (ESI) calcd for C19H31N3O2SiNa
(M + Na)+: 384.2078, found 384.2074.
1
78%, 3 steps) as a yellow oil: H NMR (400 MHz, CDCl3) δ 6.78−
6.76 (t, J = 4.0 Hz, 1H), 4.06−4.02 (ddd, J = 6.8, 6.8, 2.0 Hz, 1H),
2.58−2.57 (d, J = 2.4 Hz, 1H), 2.44−2.40 (t, J = 6.8 Hz, 2H), 2.38−
2.32 (m, 4H), 2.01−1.95 (m, 2H), 1.85−1.79 (dd, J = 14.4, 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 199.0, 146.2, 138.2, 79.2, 75.2,
52.3, 38.5, 33.9, 26,2, 26.1, 23.0; HRMS (ESI) calcd for C11H14N3O
(M + H)+: 204.1131, found 204.1138.
Amides (22) and (23). To a solution of trimethylsiloxy 21 (116.0
mg, 0.321 mmol) in anhydrous CH2Cl2 (3 mL) at −78 °C under
argon was added TiCl4 (1.0 M in CH2Cl2, 707 μL, 0.707 mmol). The
resultant mixture was stirred at −78 °C for 15 min. After being
warmed slowly to 10 °C for additional times (about 3 h), it was
quenched with water (1 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL), then the combined organic extracts were dried
over MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by flash column chromatography on silica gel
(50% EtOAc/petroleum ether to 75% EtOAc/petroleum ether) to
give amide 22 (49.6 mg, 59%) and amide 23 (9.9 mg, 12%) as white
Alcohol (19). To dry magnesium powder (403.7 mg, 16.821
mmol) covered with anhydrous THF (5 mL) under argon was added
HgCl2 (1 mg), and a few drops of freshly distilled 2-(bromomethyl)-
but-1-ene (501.3 mg, 3.364 mmol) in THF (5 mL) were added while
heating the mixture to reflux. When the formation of the Grignard
reagent had started, the rest of 2-(bromomethyl)but-1-ene in THF was
added at room temperature and the stirring was continued for 1 h.
Then, the resultant mixture was used for the following Grignard
addition.
To a solution of enone 18 (455.3 mg, 2.243 mmol) in anhydrous
THF (5 mL) was added the above prepared (2-methylenebutyl)-
magnesium bromide dropwise under argon at −78 °C. The resultant
mixture was stirred at −78 °C for 30 min, then treated with water (1
mL), and warmed to room temperature. The mixture was diluted with
Et2O (10 mL) and water (5 mL). The aqueous phase was extracted
with Et2O (3 × 10 mL), then the combined organic extracts were
dried over Na2SO4. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography on silica
gel (2% EtOAc/petroleum ether to 5% EtOAc/petroleum ether) to
give diastereomers 19 (489.7 mg, 80%) as a yellow oil: 1H NMR (400
MHz, CDCl3) δ 5.51−5.50 (t, J = 4.0 Hz, 1H), 4.92−4.91 (d, J = 1.6
Hz, 1H), 4.80 (s, 1H), 4.14−4.10 (t, J = 6.4 Hz, 1H), 2.58−2.57 (t, J =
2.0 Hz, 1H), 2.47−2.44 (m, 3H), 2.21−1.83 (m, 7H), 1.82−1.71 (m,
2H), 1.68−1.57 (m, 3H), 1.06−1.02 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 148.1, 140.5, 125.1, 125.0, 112.2, 79.5, 75.0,
74.9, 72.2, 52.6, 44.9, 36.1, 36.0, 34.7, 34.6, 30.6, 26.6, 25.5, 19.3, 12.5;
HRMS (ESI) calcd for C16H24N3O (M + H)+: 274.1914, found
274.1916.
1
crystalline solid, respectively. Amide 22: mp 115−117 °C; H NMR
(400 MHz, CDCl3) δ 4.94−4.93 (d, J = 1.2 Hz, 1H), 4.89−4.87 (d, J =
8.0 Hz, 1H), 4.84 (s, 1H), 3.74 (s, 1H), 2.87−2.79 (m, 2H), 2.75−2.62
(m, 2H), 2.37−2.36 (d, J = 2.0 Hz, 1H), 2.21−2.17 (d, J = 14.0 Hz,
1H), 2.05−1.79 (m, 8H), 1.72−1.64 (m, 1H), 1.05−1.01 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.1, 146,9, 113.9, 84.4,
71.0, 70.7, 69.3, 51.2, 42.2, 37.4, 34.0, 30.2, 29.7, 28.5, 16.3, 12.6;
HRMS (ESI) calcd for C16H24NO2 (M + H)+: 262.1801, found
1
262.1805. Amide 23: mp 127−128 °C; H NMR (400 MHz, CDCl3)
δ 4.99−4.98 (d, J = 1.2 Hz, 1H), 4.91−4.89 (m, 2H), 3.92 (s, 1H),
2.77−2.62 (m, 4H), 2.58−2.51 (m, 1H), 2.25−2.03 (m, 6H), 1.89−
1.78 (m, 3H), 1.71−1.66 (m, 1H), 1.07−1.04 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 173.3, 146.5, 114.0, 84.1, 73.2, 70.2, 69.0,
51.2, 44.0, 37.5, 37.4, 31.5, 30.4, 30.2, 17.0, 12.5; HRMS (ESI) calcd
for C16H24NO2 (M + H)+: 262.1801, found 262.1807.
Ketone (24). To a solution of pyridinium chlorochromate (PCC)
(40.0 mg, 0.185 mmol) in anhydrous CH2Cl2 (3 mL) at room
temperature under argon were added silica (40.0 mg) and NaOAc
(15.1 mg, 0.184 mmol). After 10 min of stirring at room temperature,
a solution of amide 22 (16.0 mg, 0.061 mmol) in anhydrous CH2Cl2
(3 mL) was added dropwise. The resultant mixture was stirred for 12 h
at room temperature under argon, then filtered through a plug of
Celite and washed with CH2Cl2 (3 × 10 mL). The filtrate was
concentrated in vacuo, and the residue was purified by flash column
chromatography on silica gel (10% EtOAc/petroleum ether to 30%
EtOAc/petroleum ether) to give ketone 24 (13.8 mg, 87%) as a white
Epoxide (20). A solution of alcohol 19 (441.9 mg, 1.619 mmol) in
t
anhydrous benzene (5 mL) under argon was treated with BuOOH
(5.5 M in decane, 353 μL, 1.942 mmol) and VO(acac)2 (23.2 mg,
0.087 mmol) at room temperature. The reaction mixture was stirred
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1
amorphous solid: H NMR (400 MHz, CDCl3) δ 4.92−4.91 (d, J =
for 30 min, the solution allowed to cool on an ice−water bath. The
reaction was diluted with Et2O (30 mL) and quenched with water (10
mL). The biphasic mixture was vigorously stirred for 30 min prior to
separation of the layers. The organic phase was washed with water (2
× 20 mL) followed by back-extraction of the combined aqueous
extracts with Et2O (3 × 50 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated to yield a yellow oil
which was then purified via column chromatography (15% EtOAc/
petroleum ether to 25% EtOAc/petroleum ether) to afford keto-
mesylate 30 (3.62 g, 50%, 2 steps) as a light yellow oil: 1H NMR (400
MHz, CDCl3) δ 5.08−5.05 (dt, J = 6.4, 2.0 Hz, 1H), 4.82−4.81 (d, J =
1.2 Hz, 1H), 4.54 (s, 1H), 3.09 (s, 3H), 2.72−2.71 (d, J = 2.4 Hz, 1H),
2.62−2.59 (m, 4H), 2.51 (s, 2H), 2.04−1.89 (m, 3H), 1.88−1.84 (m,
3H), 1.69−1.63 (m, 2H), 0.97−0.93 (t, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 210.3, 210.2, 146.2, 113.0, 78.6, 77.3, 70.5, 67.7,
43.6, 39.6, 39.1, 31.0, 30.9, 30.0, 16.7, 12.2; IR (neat) 3269, 1691,
1360, 903 cm−1; MS (EI) m/z 340, 311, 261, 245, 201, 173, 131;
HRMS (ESI) calcd for C17H28NO5S (M + NH4)+: 358.1683, found
358.1676.
1.6 Hz, 1H), 4.86 (s, 1H), 4.81−4.80 (d, J = 6.4 Hz, 1H), 3.33−3.25
(m, 1H), 2.72−2.53 (m, 3H), 2.56−2.41 (m, 1H), 2.34−2.16 (m, 5H),
2.08−1.92 (m, 5H), 1.01−0.98 (t, J = 3.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 211.9, 171.1, 146.2, 114.6, 82.7, 74.5, 71.0, 50.0, 40.5,
35.9, 34.8, 33.0, 29.6, 29.1, 22.6, 12.2; IR (neat) 3254, 1713, 1661, 907
cm−1; MS (EI) m/z 259, 230, 217, 202, 190, 162, 136; HRMS (ESI)
calcd for C16H22NO2 (M + H)+: 260.1645, found 260.1649.
Ketone (6). To a solution of pyridinium chlorochromate (PCC)
(17.4 mg, 0.081 mmol) in anhydrous CH2Cl2 (2 mL) at room
temperature under argon were added silica (17.4 mg) and NaOAc (6.6
mg, 0.080 mmol). After 10 min of stirring at room temperature, a
solution of amide 23 (7.0 mg, 0.027 mmol) in anhydrous CH2Cl2 (2
mL) was added dropwise. The resultant mixture was stirred for 12 h at
room temperature under argon, then filtered through a plug of Celite
and washed with CH2Cl2 (3 × 10 mL). The filtrate was concentrated
in vacuo, and the residue was purified by flash column chromatography
on silica gel (20% EtOAc/petroleum ether to 50% EtOAc/petroleum
ether) to give ketone 6 (5.6 mg, 80%) as a white amorphous solid: 1H
NMR (400 MHz, CDCl3) δ 5.06 (s, 1H), 4.95−4.94 (d, J = 1.6 Hz,
1H), 4.93−4.88 (ddd, J = 4.4, 4.4, 2.0 Hz, 1H), 2.97−2.93 (d, J = 14.0
Hz, 1H), 2.85−2.77 (ddd, J = 11.2, 11.2, 8.4 Hz, 1H), 2.65−2.57 (ddd,
J = 13.6, 13.6, 7.6 Hz, 1H), 2.53−2.49 (d, J = 13.6 Hz, 1H), 2.41−2.35
(m, 4H), 2.27−2.06 (m, 4H), 2.04−1.93 (m, 3H), 1.04−1.00 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.6, 171.2, 146.3,
115.7, 83.3, 75.6, 71.5, 49.7, 40.1, 37.8, 35.6, 33.3, 30.1, 29.9, 22.8,
12.5; IR (neat) 2964, 1722, 1392, 960 cm−1; MS (EI) m/z 259, 234,
216, 208, 190, 174, 146, 91; HRMS (ESI) calcd for C16H22NO2 (M +
H)+: 260.1645, found 260.1641.
Keto-aldehyde (28). A solution of KOH (3.47 g, 61.964 mmol)
in water (26 mL) was treated with cyclohexane-1,3-dione (5.78 g,
51.607 mmol), copper powder (0.33 g, 5.156 mmol), and 2-
(bromomethyl)but-1-ene (9.23 g, 61.946 mmol) at room temperature.
The reaction mixture was stirred for 24 h and then cooled to 0 °C.
NaOH (2.48 g, 62.000 mmol) was added portionwise to the mixture,
and it was stirred at 0 °C for 2 h. The resultant mixture was filtered,
and the filtrate was extracted with Et2O (2 × 10 mL). The water phase
was neutralized to pH = 1 using concentrated hydrochloric acid at 0
°C, then filtered under reduced pressure to give the crude C-alkylation
product 27 as a light yellow amorphous solid.
Azide (25). A solution of keto-mesylate 30 (406.6 mg, 1.196
mmol) in anhydrous DMF (4 mL) was treated with NaN3 (233.2 mg,
3.588 mmol) at 40 °C under argon. After 1.5 h, the mixture was cooled
to 0 °C and then diluted with Et2O (10 mL). The resultant mixture
was washed with water (2 × 10 mL). The organic phase was dried over
MgSO4, filtered, and concentrated to yield a yellow oil which was
purified via column chromatography (15% EtOAc/petroleum ether)
1
to give the azide 25 (288.3 mg, 84%) as a light yellow oil: H NMR
(400 MHz, CDCl3) δ 4.82−4.81 (d, J = 1.6 Hz, 1H), 4.54−4.53 (d, J =
0.8 Hz, 1H), 4.02−3.98 (dt, J = 6.8, 2.4 Hz, 1H), 2.61−2.57 (m, 5H),
2.50 (s, 2H), 2.03−1.95 (m, 1H), 1.93−1.82 (m, 5H), 1.49−1.42 (m,
2H), 0.97−0.93 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
210.4, 146.3, 112.9, 78.5, 75.4, 67.8, 52.5, 43.7, 39.7, 39.6, 32.3, 30.5,
30.0, 16.7, 12.2; IR (neat) 3268, 2104, 1693, 906 cm−1; MS (EI) m/z
287, 258, 244, 216, 188, 136; HRMS (ESI) calcd for C16H25N4O2 (M
+ NH4)+: 305.1972, found 305.1969.
Amide (24). To a solution of the azide 25 (2.58 g, 8.974 mmol) in
anhydrous CH2Cl2 (90 mL) at −15 °C under argon was added TiCl4
(1.0 M in CH2Cl2, 10.83 mL, 10.830 mmol). The resultant mixture
was stirred at −15 °C for 20 min, then it was quenched with water (15
mL). The aqueous phase was extracted with CH2Cl2 (3 × 20 mL),
then the combined organic extracts were dried over MgSO4. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (20% EtOAc/
petroleum ether to 35% EtOAc/petroleum ether) to give amide 24
(1.67 g, 72%) as a yellow amorphous solid.
Keto-mesylate (32). To a solution of keto-aldehyde 28 (500.0
mg, 2.119 mmol) in anhydrous THF (5 mL) at −78 °C under argon
was added ethylmagnesium bromide (1.0 M in THF, 2.12 mL, 2.120
mmol). The mixture was stirred for 10 min at −78 °C and then
quenched with water (1 mL). After warming up to room temperature,
the reaction mixture was diluted with Et2O (10 mL) and saturated
aqueous NH4Cl (5 mL). The aqueous phase was extracted with Et2O
(3 × 10 mL), then the combined organic extracts were dried over
MgSO4, filtered, and concentrated. Chromatography (10% EtOAc/
petroleum ether to 20% EtOAc/petroleum ether) afforded the crude
hemiketal 31 as a light yellow oil.
To a solution of the crude 27 in THF (25 mL) and H2O (25 mL)
was added acrolein (8.62 mL, 129.008 mmol) at room temperature.
After stirring for 24 h at room temperature, the mixture was diluted
with Et2O (50 mL). The aqueous phase was extracted with Et2O (3 ×
10 mL), then the combined organic extracts were dried over Na2SO4.
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (10% EtOAc/
petroleum ether to 30% EtOAc/petroleum ether) to give keto-
1
aldehyde 28 (10.34 g, 85%, 2 steps) as a yellow oil: H NMR (400
MHz, CDCl3) δ 9.62 (s, 1H), 4.83−4.82 (d, J = 0.8 Hz, 1H), 4.55 (s,
1H), 2.64−2.60 (m, 4H), 2.51 (s, 1H), 2.29−2.26 (t, J = 7.2 Hz, 2H),
2.10−1.98 (m, 3H), 1.92−1.85 (m, 3H), 0.97−0.94 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 210.2, 200.8, 146.1, 113.1, 67.6,
43.6, 39.4, 39.3, 30.0, 27.4, 16.8, 12.2; MS (EI) m/z 236, 218, 207,
192, 55, 41; HRMS (ESI) calcd for C14H24NO3 (M+NH4)+: 254.1751,
found 254.1755.
Keto-mesylate (30). To a solution of keto-aldehyde 28 (5.03 g,
21.297 mmol) in anhydrous THF (140 mL) at −78 °C under argon
was added ethynylmagnesium chloride (0.6 M in THF, 35.50 mL,
21.300 mmol). The mixture was stirred for 7.5 h at −78 °C and then
quenched with water (5 mL). After warming up to room temperature,
the reaction mixture was diluted with Et2O (100 mL) and saturated
aqueous NH4Cl (50 mL). The aqueous phase was extracted with Et2O
(3 × 50 mL), then the combined organic extracts were dried over
MgSO4, filtered, and concentrated. Chromatography (15% EtOAc/
petroleum ether) afforded the crude hemiketal 29 as a white
amorphous solid.
The crude hemiketal 31 was dissolved in pyridine (5 mL) at 40 °C
under argon, and DMAP (30.0 mg, 0.246 mmol) and methanesulfonyl
chloride (600 μL, 7.752 mmol) were added. After stirring for 30 min,
the solution allowed to cool on an ice−water bath. The reaction was
diluted with Et2O (10 mL) and quenched with water (5 mL). The
biphasic mixture was vigorously stirred for 30 min prior to separation
of the layers. The organic phase was washed with water (2 × 5 mL)
followed by back-extraction of the combined aqueous extracts with
Et2O (3 × 10 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated to yield a yellow oil which was then
purified via column chromatography (20% EtOAc/petroleum ether to
30% EtOAc/petroleum ether) to afford keto-mesylate 32 (378.9 mg,
52%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.83−4.82 (d, J =
1.2 Hz, 1H), 4.59−4.53 (m, 2H), 3.01 (s, 3H), 2.62−2.59 (m, 4H),
The crude hemiketal 29 was dissolved in pyridine (35 mL) at 40 °C
under argon, and DMAP (350.0 mg, 2.869 mmol) and methane-
sulfonyl chloride (7.00 mL, 90.441 mmol) were added. After stirring
10182
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2.50 (s, 2H), 2.05−1.93 (m, 1H), 1.91−1.81 (m, 5H), 1.72−1.65 (m,
2H), 1.47−1.40 (m, 2H), 0.98−0.92 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 210.8, 210.6, 146.3, 113.1, 84.1, 68.0, 44.1, 39.8, 38.7, 31.2,
30.0, 29.1, 27.0, 16.7, 12.2, 9.2; HRMS (ESI) calcd for C17H32NO5S
(M + NH4)+: 362.1996, found 362.1990.
1H), 5.23−5.15 (m, 2H), 4.63−4.59 (t, J = 6.8 Hz, 1H), 2.86−2.81
(dd, J = 8.0, 4.8 Hz, 1H), 2.67−2.58 (m, 2H), 2.48−2.41 (m, 1H),
2.32−2.10 (m, 5H), 1.93−1.83 (m, 2H), 1.76 (s, 3H), 1.50−1.42 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.3, 170.7, 137.4,
135.9, 115.4, 70.7, 60.0, 50.7, 38.6, 33.1, 29.1, 23.9, 22.3, 8.1; IR (neat)
1700, 1654, 1000 cm−1; MS (EI) m/z 245, 230, 202, 178, 135, 91;
HRMS (ESI) calcd for C15H20NO2 (M + H)+: 246.1489, found
246.1482.
Alcohol (45). To a solution of enone 40 (123.6 mg, 0.504 mmol)
in anhydrous THF (5 mL) at −78 °C under argon was added LHMDS
(1.0 M in THF, 757 μL, 0.757 mmol). After 30 min of stirring at −78
°C, NCCO2Me (68 μL, 0.857 mmol) was added and followed HMPA
(132 μL, 0.759 mmol). The resultant mixture was stirred for 30 min
and then quenched with water (1 mL). After warming up to room
temperature, the reaction mixture was diluted with CH2Cl2 (10 mL)
and water (5 mL). The aqueous phase was extracted with CH2Cl2 (3 ×
5 mL), then the combined organic extracts were dried over MgSO4,
filtered, and concentrated to give the crude β-ketoester 43 as a yellow
oil.
Azide (33). A solution of keto-mesylate 32 (105.0 mg, 0.305
mmol) in anhydrous DMF (1 mL) was treated with NaN3 (59.5 mg,
0.915 mmol) at 40 °C under argon. After 1.5 h, the mixture was cooled
to 0 °C and then diluted with Et2O (5 mL). The resultant mixture was
washed with water (2 × 5 mL). The organic phase was dried over
MgSO4, filtered, and concentrated to yield a yellow oil which was
purified via column chromatography (5% EtOAc/petroleum ether to
10% EtOAc/petroleum ether) to give the azide 33 (81.8 mg, 92%) as a
light yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.80−4.79 (d, J = 1.2
Hz, 1H), 4.52 (s, 1H), 3.11−3.05 (ddd, J = 16.8, 11.6, 5.2 Hz, 1H),
2.59−2.56 (t, J = 6.8 Hz, 4H), 2.49 (s, 2H), 2.01−1.83 (m, 5H), 1.79−
1.72 (m, 1H), 1.53−1.45 (m, 2H), 1.28−1.17 (m, 2H), 0.96−0.90 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 210.8, 210.7, 146.5, 112.6, 68.0,
64.2, 43.7, 39.8, 39.7, 33.4, 30.0, 29.2, 27.0, 16.6, 12.2, 10.2; HRMS
(ESI) calcd for C16H29N4O2 (M + NH4)+: 309.2285, found 309.2280.
Amide (34). To a solution of the azide 33 (23.4 mg, 0.080 mmol)
in anhydrous CH2Cl2 (1 mL) at −15 °C under argon was added TiCl4
(1.0 M in CH2Cl2, 96 μL, 0.096 mmol). The resultant mixture was
stirred at −15 °C for 20 min, then it was quenched with water (1 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 5 mL), then the
combined organic extracts were dried over MgSO4. The solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (10% EtOAc/petroleum ether to
25% EtOAc/petroleum ether) to give amide 34 (16.7 mg, 79%) as a
The crude β-ketoester 43 was dissolved in anhydrous THF (7 mL)
at −15 °C under argon followed by addition of KHMDS (0.91 M in
THF, 666 μL, 0.606 mmol). After 30 min of stirring, Davis’ reagent 44
(167.0 mg, 0.607 mmol) was added. The resulting mixture was stirred
for 1.5 h and then quenched with water (1 mL). After warming up to
room temperature, the reaction mixture was diluted with CH2Cl2 (10
mL) and water (5 mL). The aqueous phase was extracted with CH2Cl2
(3 × 5 mL), then the combined organic extracts were dried over
MgSO4, filtered, and concentrated. The residue was purified via silica
gel chromatography (20% EtOAc/petroleum ether to 50% EtOAc/
petroleum ether) to give alcohol 45 (140.0 mg, 87%, 2 steps) as a
1
yellow amorphous solid: H NMR (400 MHz, CDCl3) δ 4.92−4.91
1
(d, J = 1.2 Hz, 1H), 4.86 (s, 1H), 4.05−4.01 (t, J = 8.0 Hz, 1H), 3.09−
3.01 (dd, J = 20.4, 10.8 Hz, 1H), 2.74−2.70 (d, J = 14.0 Hz, 1H),
2.64−2.55 (m, 2H), 2.42−2.31 (m, 2H), 2.24−2.06 (m, 2H), 2.03−
1.88 (m, 6H), 1.70−1.60 (m, 1H), 1.22−1.15 (m, 1H), 1.04−1.00 (t, J
= 7.6 Hz, 3H), 0.94−0.90 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 212.8, 171.2, 146.9, 114.5, 75.3, 61.9, 41.0, 35.5, 35.1, 34.3,
29.8, 25.5, 25.2, 22.4, 12.5, 11.2; HRMS (ESI) calcd for C16H26NO2
(M + H)+: 264.1958, found 264.1950.
white amorphous solid: H NMR (400 MHz, CDCl3) δ 5.83−5.74
(ddd, J = 17.2, 10.0, 7.2 Hz, 1H), 5.21−5.12 (m, 2H), 4.50−4.46 (t, J
= 8.0 Hz, 1H), 3.84 (brs, 1H), 3.72 (s, 3H), 2.93−2.88 (dd, J = 12.4,
10.4 Hz, 1H), 2.81−2.73 (ddd, J = 14.0, 14.0, 6.4 Hz, 1H), 2.58−2.44
(m, 2H), 2.22−2.09 (m, 3H), 2.00−1.94 (m, 2H), 1.89 (s, 3H), 1.77−
1.72 (dd, J = 6.4, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 199.6,
172.4, 170.8, 170.3, 138.7, 136.9, 115.1, 84.4, 77.4, 60.8, 53.4, 34.1,
33.1, 29.3, 22.9, 22.5, 8.7; MS (EI) m/z 319, 301, 260, 231, 203, 175,
91; HRMS (ESI) calcd for C17H22NO5 (M + H)+: 320.1492, found
320.1486.
Diketone (41). Amide 24 (201.0 mg, 0.776 mmol) was dissolved
in CH2Cl2 (12 mL) at room temperature. The reaction mixture was
cooled to −78 °C, after a brief oxygen purge (ca. 5 min), ozone was
bubbled through the reaction mixture very slowly until the reaction
was completed by tlc (approximately 11 h). After dimethylsulfide (5
mL) addition, the reaction was stirred at room temperature for 3 days.
Concentration of the reaction mixture to give a yellow oil.
Chromatography afforded diketone 41 (165.4 mg, 82%) as a sticky
Ester (39). A solution of alcohol 45 (140.0 mg, 0.439 mmol) in
anhydrous CH2Cl2 (8 mL) under argon was treated with Et3N (366
μL, 2.638 mmol), DMAP (33.1 mg, 0.271 mmol), and propionic
anhydride (281 μL, 2.192 mmol) at room temperature. The reaction
mixture was stirred for 48 h and then concentrated. The residue was
purified via silica gel chromatography (15% EtOAc/petroleum ether to
35% EtOAc/petroleum ether) to give ester 39 (164.0 mg, 99%) as a
white crystalline solid: mp 138−140 °C; 1H NMR (400 MHz, CDCl3)
δ 5.84−5.75 (ddd, J = 17.6, 10.4, 7.2 Hz, 1H), 5.20−5.10 (m, 2H),
4.56−4.52 (t, J = 8.0 Hz, 1H), 3.63 (s, 3H), 2.85−2.79 (dd, J = 12.4,
9.2 Hz, 1H), 2.65−2.50 (m, 2H), 2.48−2.35 (m, 3H), 2.15−2.03 (m,
3H), 2.01−1.94 (m, 2H), 1.86 (s, 3H), 1.77−1.72 (dd, J = 6.4, 6.4 Hz,
1H), 1.19−1.15 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
194.7, 172.1, 171.9, 167.3, 166.2, 138.6, 136.7, 115.0, 88.1, 75.9, 60.8,
52.9, 35.2, 32.6, 28.9, 27.5, 23.3, 22.1, 8.8, 8.5; MS (EI) m/z 375, 319,
301, 260, 231, 203, 175; HRMS (ESI) calcd for C20H26NO6 (M + H)+:
376.1755, found 376.1750.
β-Hydroxy Ketone (48). To a solution of enone 40 (172.0 mg,
0.702 mmol) in anhydrous THF (10 mL) at −78 °C under argon was
added LHMDS (1.0 M in THF, 1.06 mL, 1.060 mmol). After 1 h of
stirring at −78 °C, propanal (103 μL, 1.420 mmol) was added. The
resultant mixture was stirred for 1 h and then quenched with water (1
mL). After warming to room temperature, the reaction mixture was
diluted with CH2Cl2 (10 mL) and water (5 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 5 mL), then the combined organic
extracts were dried over MgSO4, filtered, and concentrated.
Chromatography (40% EtOAc/petroleum ether to 75% EtOAc/
petroleum ether) afforded β-hydroxy ketone 48 (208.2 mg, 98%) as a
white crystalline solid: mp 161−163 °C; 1H NMR (400 MHz, CDCl3)
δ 5.88−5.79 (ddd, J = 17.2, 10.4, 6.8 Hz, 1H), 5.21−5.13 (m, 2H),
1
oil: H NMR (400 MHz, CDCl3) δ 4.81−4.79 (d, J = 5.6 Hz, 1H),
3.27−3.19 (m, 1H), 2.92−2.77 (m, 2H), 2.72−2.62 (m, 1H), 2.54−
2.38 (m, 4H), 2.36−2.17 (m, 5H), 2.14−2.00 (m, 2H), 1.08−1.05 (t, J
= 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 211.4, 207.4, 170.3,
82.5, 74.6, 71.2, 49.7, 44.4, 38.8, 34.4, 33.5, 33.4, 29.4, 22.9, 7.6; IR
(neat) 3302, 1712, 1661 cm−1; MS (EI) m/z 261, 232, 204, 190, 176,
148, 108; HRMS (ESI) calcd for C15H20NO3 (M + H)+: 262.1438,
found 262.1431.
Enone (40). To a solution of diketone 41 (421.0 mg, 1.613 mmol)
in CH2Cl2 (10 mL) were added Lindlar catalyst (299.1 mg) and
quinoline (38 μL, 0.322 mmol). The mixture was exposed to an
atmosphere of H2 at room temperature. After 1.5 h, the resulting
mixture was filtered and concentrated to give the crude ene 42 as a
yellow oil.
The crude ene 42 was dissolved in anhydrous MeOH (10 mL),
followed by addition of K2CO3 (262.4 mg, 1.901 mmol). After stirring
at room temperature for 1 h, the solution was diluted with CHCl3 (20
mL) and water (10 mL). The aqueous phase was extracted with
CHCl3 (3 × 10 mL), then the combined organic extracts were dried
over MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified by column chromatography (50% EtOAc/
petroleum ether to 75% EtOAc/petroleum ether) to give enone 40
(367.5 mg, 93%, 2 steps) as a white crystalline solid: mp 152−154 °C;
1H NMR (400 MHz, CDCl3) δ 5.89−5.80 (ddd, J = 16.8, 10.4, 6.4 Hz,
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4.58−4.54 (t, J = 7.2 Hz, 1H), 3.59−3.55 (ddd, J = 8.0, 5.6, 2.4 Hz,
1H), 3.09−3.00 (m, 1H), 2.88−2.82 (dd, J = 12.4, 9.6 Hz, 1H), 2.49−
2.41 (m, 1H), 2.30−2.15 (m, 3H), 2.13−1.99 (m, 3H), 1.91−1.79 (m,
4H), 1.75 (s, 3H), 1.42−1.38 (dd, J = 11.6, 4.8 Hz, 1H), 0.97−0.94 (t,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.3, 173.3, 170.6,
138.2, 137.3, 115.0, 73.4, 73.0, 61.2, 60.6, 40.0, 33.5, 29.4, 29.2, 22.6,
22.4, 10.5, 7.9; IR (neat) 3333, 1702, 1629, 1000 cm−1; MS (EI) m/z
303, 274, 246, 204, 175, 148, 91; HRMS (ESI) calcd for C18H26NO3
(M + H)+: 304.1907, found 304.1904.
reaction mixture was stirred for 24 h and then concentrated. The
residue was purified via silica gel chromatography (15% EtOAc/
petroleum ether to 35% EtOAc/petroleum ether) to give carbonate 54
1
(350.0 mg, 99%) as a white amorphous solid: H NMR (400 MHz,
CDCl3) δ 5.84−5.76 (ddd, J = 17.6, 10.4, 7.2 Hz, 1H), 5.26−5.16 (m,
2H), 4.60−4.56 (t, J = 8.0 Hz, 1H), 4.33−4.22 (m, 2H), 2.86−2.80
(dd, J = 12.4, 8.8 Hz, 1H), 2.67−2.51 (m, 3H), 2.40−2.31 (m, 2H),
2.13−2.02 (m, 4H), 2.01−1.92 (m, 1H), 1.88 (s. 3H), 1.86−1.82 (m,
1H), 1.37−1.33 (t, J = 6.8 Hz, 3H), 1.05−1.01 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 206.5, 196.7, 172.7, 166.1, 153.5, 138.1,
137.0, 115.8, 93.4, 75.8, 65.3, 61.4, 35.1, 33.0, 32.2, 29.2, 23.3, 22.1,
14.0, 8.4, 7.5; IR (neat) 1760, 1729, 1710, 1655, 954 cm−1; MS (EI)
m/z 389, 332, 299, 260, 214, 175, 120; HRMS (ESI) calcd for
C21H28NO6 (M + H)+: 390.1911, found 390.1918.
Alcohols (51) and (52). To a solution of β-hydroxy ketone 48
(278.5 mg, 0.919 mmol) in anhydrous CH2Cl2 (10 mL) under argon
at 0 °C was added Dess−Martin periodinane (549.4 mg, 1.296 mmol)
followed by slow warming of the reaction mixture to room
temperature. After stirring for 1.5 h, the reaction was quenched via
addition of saturated aqueous NaHCO3 (10 mL) and Na2S2O3 (10
mL) and diluted with CH2Cl2 (20 mL). The biphasic mixture was
vigorously stirred at room temperature for 30 min, and then the
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated to yield the crude β-diketone 49 as a yellow oil.
Lactone (38). To a solution of the carbonate 54 (77.0 mg, 0.198
mmol) in anhydrous THF (14 mL) at −78 °C under argon was added
KHMDS (0.91 M in THF, 436 μL, 0.397 mmol). The reaction
mixture was warmed slowly to 10 °C over 5 h, and then it was
quenched with water (3 mL) at 0 °C. The resultant mixture was
diluted with CH2Cl2 (10 mL) and treated with 2N HCl to PH = 2.
The aqueous phase was extracted with CH2Cl2 (3 × 10 mL), then the
combined organic extracts were dried over MgSO4, filtered, and
concentrated to give the crude 46 as a yellow amorphous solid.
The crude 46 was dissolved in anhydrous CH2Cl2 (16 mL) under
argon, followed by addition of CH2N2 (1.0 M in CH2Cl2, 1.00 mL,
1.000 mmol). After stirring at 0 °C for 1 h, the solution was quenched
with acetic acid (1 mL). Removal of solvent in vacuo resulted in a
yellow solid which was purified by chromatography (50% EtOAc/
petroleum ether to 70% EtOAc/petroleum ether) to give lactone 38
(53.9 mg, 76%, 2 steps) as a white crystalline solid: mp 178−180 °C;
1H NMR (400 MHz, CDCl3) δ 5.80−5.71 (ddd, J = 17.2, 10.0, 7.2 Hz,
1H), 5.20−5.12 (m, 2H), 4.44−4.40 (t, J = 7.6 Hz, 1H), 3.98 (s, 3H),
2.98−2.92 (m, 1H), 2.86−2.77 (dt, J = 14.4, 6.4 Hz, 1H), 2.57−2.49
(m, 1H), 2.30−2.25 (ddd, J = 14.4, 4.4, 2.8 Hz, 1H), 2.16−2.07 (m,
4H), 2.03 (s, 3H), 1.97−1.90 (m, 1H), 1.87 (s, 3H), 1.77−1.74 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 195.7, 173.6, 173.1, 170.7,
169.7, 138.6, 137.4, 115.3, 98.6, 88.1, 75.9, 60.9, 59.1, 35.6, 33.8, 29.2,
22.5, 21.8, 8.9, 8.8; IR(neat) 1761, 1719, 1647, 1000 cm−1; MS (EI)
m/z 357, 302, 242, 202, 175, 149, 83; HRMS (ESI) calcd for
C20H24NO5 (M + H)+: 358.1649, found 358.1646.
Aldehyde (37). Potassium osmate dehydrate (1.0 mg) was added
to a stirred solution of lactone 38 (22.0 mg, 0.062 mmol) and N-
methylmorpholine N-oxide (41.7 mg, 0.309 mmol) in acetone (1 mL),
tBuOH (500 μL), and water (500 μL). After stirring for 5.5 h at room
temperature, the reaction mixture was diluted with CH2Cl2 (10 mL).
The resultant mixture was dried over MgSO4, filtered and evaporated
under reduced pressure to give the crude diol 55 as a sticky oil.
The crude diol 55 was dissolved in THF (4 mL) and water (2 mL)
under argon, followed by addition of NaIO4 (26.2 mg, 0.122 mmol).
After stirring at room temperature for 2 h, the solution was diluted
with CH2Cl2 (10 mL). The aqueous phase was extracted with CH2Cl2
(3 × 5 mL), and then the combined organic extracts were dried over
MgSO4, filtered, and concentrated. Chromatography (50% EtOAc/
petroleum ether to 75% EtOAc/petroleum ether) afforded the
aldehyde 37 (21.2 mg, 96%, 2 steps) as a white amorphous solid:
1H NMR (400 MHz, CDCl3) δ 9.65−9.64 (d, J = 0.8 Hz, 1H), 4.56−
4.53 (d, J = 9.2 Hz, 1H), 3.99 (s, 3H), 2.94−2.84 (m, 3H), 2.34−2.29
(m, 1H), 2.23−2.07 (m, 4H), 2.04 (s, 3H), 2.01−1.94 (m, 1H), 1.89
(s, 3H), 1.87−1.86 (d, J = 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 197.5, 195.4, 173.4, 170.0, 169.6, 137.8, 98.8, 88.2, 75.3, 65.0, 59.2,
35.6, 32.2, 23.0, 22.4, 22.2, 8.9, 8.7; MS (EI) m/z 359, 330, 290, 256,
202, 149, 83; HRMS (ESI) calcd for C19H22NO6 (M + H)+: 360.1442,
found 360.1440.
i
The β-diketone 49 was dissolved in anhydrous PrOH (10 mL) at
room temperature, followed by addition of CeCl3·7H2O (34.2 mg,
0.092 mmol). The flask was then evacuated to 300 mbar and flushed
with O2, and the reaction mixture was stirred at room temperature for
20 h, while a slow stream of oxygen (ca. 50 cm3 h−1) was passed
through. After removal of the solvent, the residue was purified by
column chromatography (25% EtOAc/petroleum ether to 50%
EtOAc/petroleum ether) to give alcohol 51 (214.7 mg, 74%, 2
steps) and alcohol 52 (27.1 mg, 9%, 2 steps) as white amorphous
solids. Alcohol 51: 1H NMR (400 MHz, CDCl3) δ 5.82−5.73 (ddd, J
= 17.6, 10.4, 7.2 Hz, 1H), 5.20−5.09 (m, 2H), 4.57−4.53 (t, J = 8.0
Hz, 1H), 4.42 (brs, 1H), 2.84−2.64 (m, 3H), 2.63−2.52 (m, 1H),
2.51−2.32 (m, 2H), 2.06−1.99 (m, 2H), 1.98−1.89 (m, 3H), 1.82 (s,
3H), 1.77−1.72 (dd, J = 12.4, 5.6 Hz, 1H), 0.92−0.89 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 212.4, 203.4, 172.7, 170.6,
138.3, 135.7, 115.5, 89.8, 76.6, 61.3, 34.9, 32.9, 31.5, 29.1, 23.5, 22.5,
8.2, 7.3; IR (neat) 3284, 1723, 1700, 1625, 984 cm−1; MS (EI) m/z
317, 260, 232, 204, 178, 132, 105; HRMS (ESI) calcd for C18H24NO4
1
(M + H)+: 318.1700, found 318.1708. Alcohol 52: H NMR (400
MHz, CDCl3) δ 5.84−5.76 (ddd, J = 17.2, 10.0, 7.2 Hz, 1H), 5.19−
5.13 (m, 2H), 4.57−4.53 (t, J = 4.0 Hz, 1H), 3.04−2.95 (m, 1H),
2.90−2.80 (m, 2H), 2.76−2.66 (m, 1H), 2.48−2.40 (m, 1H), 2.15−
2.04 (m, 4H), 1.93−1.86 (m, 1H), 1.82 (s, 3H), 1.72−1.69 (m, 1H),
1.62−1.54 (m, 1H), 1.14−1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 211.9, 201.2, 174.4, 173.0, 138.1, 134.7, 115.4, 86.0,
77.4, 60.5, 34.9, 34.1, 32.8, 28.8, 23.5, 22.4, 8.3, 7.5; IR (neat) 2922,
1728, 1689, 1383, 1026 cm−1; MS (EI) m/z 317, 260, 236, 218, 188,
123, 91; HRMS (ESI) calcd for C18H24NO4 (M + H)+: 318.1700,
found 318.1706.
Carbonate (53). A solution of alcohol 51 (13.0 mg, 0.041 mmol)
in anhydrous CH2Cl2 (2 mL) under argon was treated with di-tert-
butyl dicarbonate (21.0 mg, 0.096 mmol) and DMAP (1.1 mg, 0.009
mmol) at room temperature. The reaction mixture was stirred for 5 h
and then concentrated. The residue was purified via silica gel
chromatography (15% EtOAc/petroleum ether to 35% EtOAc/
petroleum ether) to give carbonate 53 (16.2 mg, 95%) as a white
1
crystalline solid: mp 138−140 °C; H NMR (400 MHz, CDCl3) δ
5.85−5.76 (ddd, J = 17.6, 10.4, 7.2 Hz, 1H), 5.30−5.16 (m, 2H),
4.61−4.57 (t, J = 8.0 Hz, 1H), 2.85−2.79 (dd, J = 12.8, 9.2 Hz, 1H),
2.69−2.52 (m, 3H), 2.38−2.26 (m, 2H), 2.12−1.95 (m, 5H), 1.88−
1.81 (m, 4H), 1.52 (s, 9H), 1.06−1.02 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.0, 197.1, 172.9, 165.7, 151.8, 138.3, 137.0,
115.8, 93.3, 84.3, 75.7, 61.5, 35.3, 33.0, 32.0, 29.2, 27.6, 23.4, 22.2, 8.4,
7.6; IR (neat) 2921, 1721, 1650, 1259, 932 cm−1; MS (EI) m/z 417,
360, 344, 316, 270, 216, 188, 133; HRMS (ESI) calcd for C23H32NO6
(M + H)+: 418.2224, found 418.2231.
Amine (56). Methyl trifluoromethanesulfonate (748 μL, 6.819
mmol) was added in one portion to a solution of 38 (64.0 mg, 0.179
mmol) in anhydrous CH2Cl2 (10 mL) under argon. The reaction
mixture was stirred at room temperature for 12 h and concentrated.
The residue was dissolved in anhydrous EtOH (3 mL), and treated
with NaCNBH3 (53.5 mg, 0.849 mmol). The reaction mixture was
stirred at room temperature for 10 min, treated with a mixture of acetic
Carbonate (54). A solution of alcohol 51 (285.2 mg, 0.900 mmol)
in anhydrous CH2Cl2 (10 mL) under argon was treated with Et3N
(1.50 mL, 10.792 mmol), DMAP (439.1 mg, 3.599 mmol), and ethyl
chloroformate (860 μL, 9.037 mmol) at room temperature. The
10184
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The Journal of Organic Chemistry
Article
t
acid and water (3 mL, ca. 1:1), and sequentially stirred at room
temperature for 30 min. The resultant mixture was diluted with
CH2Cl2 (10 mL) and treated with saturated aqueous NaHCO3 (5
mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL), and
then the combined organic extracts were dried over MgSO4, filtered,
and concentrated. Chromatography (15% EtOAc/petroleum ether to
65% EtOAc/petroleum ether) afforded the tertiary amine 56 (30.9 mg,
50%) as a white amorphous solid and recovered starting material 38
μL), BuOH (240 μL), and water (240 μL). After stirring for 3.5 h at
room temperature, the reaction mixture was diluted with CH2Cl2 (10
mL). The resulting mixture was dried over MgSO4, filtered, and
evaporated under reduced pressure to give the crude diol 57 as a sticky
oil.
The crude diol 57 was dissolved in THF (2 mL) and water (1 mL)
under argon, followed by addition of NaIO4 (54.3 mg, 0.254 mmol).
After stirring at 40 °C for 10 h, the solution was diluted with CH2Cl2
(10 mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL),
and then the combined organic extracts were dried over MgSO4,
filtered, and concentrated. Chromatography (70% EtOAc/petroleum
ether) afforded stemonamide 1c (7.0 mg, 83%, 2 steps) as a white
1
(30.0 mg, 47% of recovered starting material). Amine 56: H NMR
(400 MHz, CDCl3) δ 5.37−5.28 (ddd, J = 18.0, 10.0, 8.0 Hz, 1H),
5.11−5.01 (m, 2H), 3.96 (s, 3H), 3.66−3.61 (dd, J = 15.2, 8.8 Hz,
1H), 3.09−3.05 (d, J = 15.6 Hz, 1H), 2.92−2.81 (m, 2H), 2.18−2.09
(m, 2H), 2.03 (s, 3H), 2.01−1.90 (m, 2H), 1.82−1.74 (m, 4H), 1.68−
1.53 (m, 2H), 1.39−1.34 (dd, J = 14.0, 3.6 Hz, 1H), 1.29−1.20 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 198.7, 175.0, 174.2, 172.4,
141.5, 135.7, 115.9, 97.0, 91.3, 77.7, 63.9, 58.5, 45.7, 36.3, 31.8, 28.3,
26.6, 24.8, 8.8, 8.3; IR(neat) 1758, 1710, 1663, 992 cm−1; MS (EI) m/
z 343, 300, 284, 256, 216, 174, 132; HRMS (ESI) calcd for
C20H26NO4 (M + H)+: 344.1856, found 344.1859.
1
amorphous solid: H NMR (400 MHz, CDCl3) δ 4.21−4.17 (d, J =
14.8 Hz, 1H), 4.00 (s, 3H), 3.02−2.97 (dd, J = 10.0, 5.6 Hz, 1H),
2.88−2.82 (t, J = 12.8 Hz, 1H), 2.66−2.56 (m, 1H), 2.41−2.27 (m,
2H), 2.18−2.11 (m, 2H), 2.02 (s, 3H), 2.00−1.91 (m, 1H), 1.87 (s,
3H), 1.84−1.81 (d, J = 11.2 Hz, 1H), 1.47−1.30 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 196.6, 175.8, 172.9, 170.9, 168.7, 137.0, 99.7,
90.0, 74.5, 59.2, 41.3, 31.9, 30.2, 29.9, 27.5, 27.4, 9.1, 8.4; IR (neat)
2925, 1766, 1699, 1662 cm−1; MS (EI) m/z 331, 286, 221, 181, 164,
131, 83; HRMS (ESI) calcd for C18H21NO5 (M + H)+: 332.1492,
found 332.1495.
Aldehyde (58). Potassium osmate dehydrate (1.0 mg) was added
to a stirred solution of 56 (15.7 mg, 0.046 mmol) and N-
methylmorpholine N-oxide (31.0 mg, 0.229 mmol) in acetone (800
t
Isomaistemonine (1g). A white crystalline solid: mp 219−221
°C; 1H NMR (600 MHz, CDCl3) δ 4.34−4.31 (ddd, J = 10.8, 5.4, 5.4
Hz, 1H), 4.13 (s, 3H), 3.72−3.68 (ddd, J = 10.8, 5.4, 5.4 Hz, 1H),
3.33−3.29 (dd, J = 15.6, 3.6 Hz, 1H), 2.95−2.88 (m, 2H), 2.64−2.57
(m, 1H), 2.42−2.39 (dd, J = 13.2, 6.6 Hz, 1H), 2.27−2.23 (ddd, J =
13.8, 8.4, 5.4 Hz, 1H), 2.11−2.08 (m, 4H), 2.03−2.01 (d, J = 11.4 Hz,
1H), 1.90−1.86 (m, 1H), 1.77−1.69 (m, 5H), 1.51−1.45 (m, 3H),
1.30−1.19 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 198.5, 179.1,
175.2, 173.2, 169.6, 135.4, 102.3, 88.4, 81.0, 60.8, 59.5, 47.2, 34.9, 32.5,
32.2, 27.9, 26.9, 25.5, 24.1, 15.0, 9.2, 8.1; IR (neat) 2925, 1826, 1659,
1073 cm−1; MS (EI) m/z 415, 386, 356, 316, 288, 162, 134, 91;
HRMS (ESI) calcd for C23H30NO6 (M + H)+: 416.2068, found
416.2062.
μL), BuOH (400 μL), and water (400 μL). After stirring for 3.5 h at
room temperature, the reaction mixture was diluted with CH2Cl2 (10
mL). The resulting mixture was dried over MgSO4, filtered, and
evaporated under reduced pressure to give the crude diol 57 as a sticky
oil.
The crude diol 57 was dissolved in THF (3 mL) and water (1.5
mL) under argon, followed by addition of NaIO4 (13.8 mg, 0.065
mmol). After stirring at 0 °C for 3 h, the solution was diluted with
CH2Cl2 (10 mL). The aqueous phase was extracted with CH2Cl2 (3 ×
5 mL), and then the combined organic extracts were dried over
MgSO4, filtered, and concentrated. Chromatography (20% EtOAc/
petroleum ether) afforded the aldehyde 58 (10.0 mg, 64%, 2 steps) as
1
a white amorphous solid: H NMR (600 MHz, CDCl3) δ 8.99−8.98
(d, J = 4.2 Hz, 1H), 4.02 (s, 3H), 3.68−3.65 (m, 1H), 3.08−3.04 (m,
1H), 2.95−2.93 (d, J = 13.2 Hz, 2H), 2.27−2.25 (dd, J = 12.0, 5.4 Hz,
1H), 2.18−2.14 (m, 1H), 2.03−2.01 (m, 5H), 1.93−1.84 (m, 2H),
1.81 (s, 3H), 1.71−1.64 (m, 1H), 1.49−1.46 (m, 1H), 1.33−1.24 (m,
1H); 13C NMR (150 MHz, CDCl3) δ 201.9, 198.0, 174.5, 172.2,
172.0, 137.0, 97.4, 90.8, 78.1, 68.3, 58.8, 47.9, 36.6, 28.2, 26.5, 25.5,
25.4, 8.8, 8.5; IR (neat) 2779, 1759, 1713, 1662 cm−1; MS (EI) m/z
345, 316, 283, 266, 188, 162, 83; HRMS (ESI) calcd for C19H24NO5
(M + H)+: 346.1649, found 346.1643.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full spectroscopic data for all new compounds and X-ray
crystallographic data in CIR format of 22, 23, 40, 39, 38, 1e,
and 1g. This material is available free of charge via the Internet
at http://pubs.acs.org.
Maistemonine (1e). Zinc powder (16.5 mg, 0.254 mmol) was
added to a solution of aldehyde 58 (17.9 mg, 0.052 mmol) in
anhydrous THF (6 mL) under argon. The solution was heated, and
when reflux started, a solution of ethyl 2-(bromomethyl)acrylate (16.9
mg, 0.088 mmol) in anhydrous THF (5 mL) was added dropwise for 5
min. After stirring for additional 5 min, the resultant mixture was
cooled to room temperature, quenched with water (10 μL), and
concentrated. The residue was dissolved in anhydrous EtOH (7 mL),
and treated with 10% Pd/C (8.0 mg). The reaction mixture was stirred
in an atmosphere of H2 for 15 h, filtered, and concentrated.
Chromatography (75% chloroform/petroleum ether) afforded mais-
temonine 1e (14.2 mg, 66%, 2 steps) as a white crystalline solid: mp
189−190 °C; 1H NMR (600 MHz, CDCl3) δ 4.00 (s, 3H), 3.87−3.83
(ddd, J = 11.4, 7.8, 6.0 Hz, 1H), 3.60−3.58 (d, J = 15.6 Hz, 1H), 3.40−
3.36 (m, 1H), 2.95−2.88 (m, 2H), 2.60−2.55 (m, 1H), 2.36−2.32
(ddd, J = 13.8, 8.4, 5.4 Hz, 1H), 2.28−2.24 (m, 1H), 2.13−2.10 (m,
1H), 2.02 (s, 3H), 1.98−1.97 (m, 1H), 1.89−1.85 (m, 2H), 1.82−1.75
(m, 4H), 1.54−1.46 (m, 3H), 1.39−1.33 (m, 1H), 1.26−1.25 (d, J =
7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 197.9, 179.7, 175.0,
173.2, 172.5, 136.4, 96.9, 91.6, 85.1, 79.3, 63.6, 58.8, 47.2, 35.8, 34.8,
34.5, 28.4, 26.6, 25.5, 24.9, 14.9, 8.9, 8.4; IR (neat) 1760, 1709, 1662
cm−1; MS (EI) m/z 415, 372, 316, 272, 188, 162, 83; HRMS (ESI)
calcd for C23H30NO6 (M + H)+: 416.2068, found 416.2058.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tuyq@lzu.edu.cn; zhangfm@lzu.edu.cn.
ACKNOWLEDGMENTS
■
The authors thank Prof. W. Lin (Peking University) and Prof.
Y. Ye (Shanghai Institute of Materia Medica) for providing the
NMR spectra and the sample of (−)-maistemonine and
(−)-isomaistemonine. This work was supported by the NSFC
(Nos. 20621091, 20672048, 20732002, and 20972059), “973”
program of 2010CB833200, “111” program of MOE and the
fundamental research funds for the central universities (lzujbky-
2010-k09, lzujbky-2009-76, lzujbky-2009-158).
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