Explorations on the asymmetric total synthesis of isoschizogamine

Article abstract of DOI:10.1021/jo070144x

(Chemical Equation Presented) Two approaches to the synthesis of isoschizogamine were reported. Both routes utilized an efficient aza-Claisen rearrangement to establish the absolute stereochemistry of the all-carbon quaternary center in the natural produc

Full text of DOI:10.1021/jo070144x

Explorations on the Asymmetric Total Synthesis of Isoschizogamine
Jianguang Zhou*,† and Nabi A. Magomedov‡
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
jzhou@mail.chem.tamu.edu
ReceiVed January 24, 2007
Two approaches to the synthesis of isoschizogamine were reported. Both routes utilized an efficient
aza-Claisen rearrangement to establish the absolute stereochemistry of the all-carbon quaternary center
in the natural product. In the first approach, a highly diastereoselective (10:1) hetero-Diels-Alder reaction
was utilized to reach a densely functionalized tetrahydroquinoline derivative as an advanced intermediate
to the targeted alkaloid. An acylamidine intermediate was prepared and studied in the intramolecular
cyclization reaction under acidic conditions in our second approach.
Introduction
Isoschizozygane alkaloids were isolated from the monotypic
shrub Schizozygia caffaeoides (Boj.) Baill growing in East
Africa.1 Isoschizogamine (1a) and isoschizogaline (1b) are the
two members of the isoschizozygane family (Figure 1). Both
were isolated in the 1960s; however, the correct structures of
1a and 1b containing the aminal functionality were reported in
19982 and 2002,3 respectively, as a result of extensive NMR
experiments. Although there were no reports regarding the
biological activities of isoschizogamine (1a), bioassay-guided
isolation of isoschizogaline (1b) showed that it had weak
antibacterial activities, with an MIC of 62.5 µg/mL for Bacillus
subtilis and 125 µg/mL for Staphylococcus aureas.3
The unusual structures of the isoschizozyganes as compared
to those of the more abundant schizozygane alkaloids (i.e.,
schizozygine 2 in Figure 1)4,5 made them challenging targets
for total synthesis. Heathcock and Hubbs6 reported a concise
total synthesis of (()-isoschizogamine (1a) based on a partial
biosynthesis proposed by Hajicek.2 In their synthesis, the key
step to forming the aminal functionality was realized through
the attack of an aniline nitrogen onto a transient iminium ion
embedded in a 6-6-5 fused ring system. The same kind of
FIGURE 1. The isoschizozygane alkaloids and schizozygine.
transformation was also employed by Padwa and co-workers7
in their model studies toward a total synthesis, but their approach
to the 6-6-5 fused ring system, a precursor to the iminium
ion, was based on a 1,4-dipolar cycloaddition reaction. During
the context of our own interest in this area, we developed an
alternative strategy to construct the cyclopenta[b]quinoline core
of these alkaloids via a highly diastereoselective intramolecular
formal hetero-Diels-Alder reaction.8 In this Article, we describe
our continuing endeavors toward this total synthesis.
We considered the ambitious goal of making our synthesis
asymmetric. Thus, we proposed a plan shown in Scheme 1 for
the synthesis of the specific enantiomer of isoschizogamine 1a,
the absolute stereochemistry of which is still unknown. We
envisioned that the synthesis of isoschizogaline 1b would
probably follow a similar route if this were successful for 1a.
In this plan, we imagined the formation of the N-acyl aminal
in 3 by the attack of the allylic amine on the imine (dihydro-
quinoline) in 4 followed by lactam formation. The imine group
was originally envisioned to be generated by the oxidation of a
suitable tetrahydroquinoline intermediate derived from 5. On
† Current address: Department of Chemistry, Texas A&M University, College
Station, TX 77840.
‡ Passed away on Feb 7, 2006.
(1) Renner, U. Lloydia 1964, 27, 406.
(2) Hajicek, J.; Taimr, J.; Budesinsky, M. Tetrahedron Lett. 1998, 39,
505.
(3) Kariba, R. M.; Houghton, P. J.; Yenesew, A. J. Nat. Prod. 2002, 65,
566.
(4) Renner, U.; Kernweisz, P. Experientia 1963, 19, 244.
(5) Renner, U.; Fritz, H. HelV. Chim. Acta 1965, 48, 308.
(6) Hubbs, J. L.; Heathcock, C. H. Org. Lett. 1999, 1, 1315.
(7) Padwa, A.; Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925.
(8) Magomedov, N. A. Org. Lett. 2003, 5, 2509.
10.1021/jo070144x CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/12/2007
3808
J. Org. Chem. 2007, 72, 3808-3815

Total Synthesis of the Isoschizozygane Alkaloid
SCHEME 1. Retrosynthetic Analysis of Isoschizogamine 1a
SCHEME 3. Synthesis of N-Actetyl Aziridine 12 Beginning
with Enantiopure Aldehyde 9
In the event, efforts to synthesize both the N-acetyl aziridine
intermediates leading to 16a and 16b were undertaken. Toward
this goal, R,â-unsaturated ester 10 was readily synthesized
through Horner-Wadsworth-Emmons olefination10 between
phosphonate 811 and enantiomerically pure aldehyde 912,13 to
provide an inseparable mixture of E/Z isomers (11:1). A number
of acidic conditions were attempted for the deprotection of the
trityl group in 10, and finally the conditions of TFA, Et3SiH, 0
°C were observed to give the best results.14 After detritylation,
the Z-isomer was readily removed during separation, and
geometrically pure aziridine 11 was obtained. N-Acetylation of
11 (Ac2O, Et3N, CH2Cl2) gave compound 12, the precursor of
enolate 16a (Scheme 3). At the same time, the synthesis of a
silyl ether analogue of 12 was attempted to generate the more
attractive enolate 16b. Thus, compound 13, derived from ester
10 via reduction (LAH, THF, 0 °C) and protection (TBDPSCl,
Et3N, CH2Cl2), was chosen as a starting material. The depro-
tection of the trityl group on this substrate, however, proved to
be problematic. Under all of the conditions we tried, no aziridine
product 14 could be isolated. The failure may result from the
sensitivity of 14 toward acidic conditions, in which protonated
aziridine would easily open to form a stable carbocation, which
could then be trapped by nucleophiles in the solution. For
example, the formation of compound 15 was observed under
the conditions of TFA, Et3SiH. The success of the detritylation
of 10 demonstrates that the electron-withdrawing methyl ester
played an important role in the prevention of aziridine ring from
opening by destabilizing a carbocation analogue (Scheme 4).
We therefore decided to study the aza-Claisen rearrangement
of N-acetyl aziridine 12. Under the Somfai conditions (LHMDS,
THF, -78 to 0 °C),9 the rearrangement did not occur at all.
The failure was presumably due to a much higher activation
energy for this reaction as compared to those reported by
Somfai. We speculated that heating of enolate 16a would
overcome this higher energy barrier for the rearrangement to
SCHEME 2. Synthetic Plan To Prepare Aldehyde 7
through an Aza-Claisen Rearrangement
the basis of our previous studies,8 we decided to synthesize the
densely functionalized tetrahydroquinoline 5 by a reaction
between aniline 6 and aldehyde 7. However, at this point, we
could not predict the diastereoselectivity of this transformation.
Further, we were faced with a question of finding an efficient
way to prepare the seven-membered lactam 7.
Results and Discussion
Synthesis of Aldehyde 7. After inspection of the structure
features of aldehyde 7, we decided to devise an aza-Claisen
rearrangement strategy.9 As shown in Scheme 2, amide enolate
16a or 16b would adopt a boat-like transition state during the
rearrangement so that the chirality of the aziridine would be
transferred to the quaternary center. The release of the aziridine
ring-strain would then facilitate the formation of a seven-
membered lactam. We expected at this point that the rearrange-
ment of 16a would be less facile than 16b due to disruption of
conjugation of the R,â-unsaturated ester in the transition state,
so the synthesis of 16b seems more attractive at first sight.
(10) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(11) Synthesized by the alkylation of methyl diethylphosphonoacetate
with trans-1-iodo-3,5-hexadiene.
(12) Kato, S.; Harada, H.; Morie, T. J. J. Chem. Soc., Perkin Trans.
1997, 1, 3219.
(13) Nakajima, K.; Tanaka, T.; Meya, M.; Okawa, K. Bull. Chem. Soc.
Jpn. 1982, 55, 3237.
(14) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org. Chem.
2001, 66, 7542.
(9) Lindstrom, U. M.; Somfai, P. Chem.-Eur. J. 2001, 7, 94.
J. Org. Chem, Vol. 72, No. 10, 2007 3809

Zhou and Magomedov
SCHEME 4. Unsuccessful Detritylation of 13
SCHEME 5. Synthesis of Aldehyde 7
SCHEME 6. Diastereoselective Synthesis of
Tetrahydroquinoline 20b
occur. Indeed, after 12 was deprotonated (LHMDS, PhMe, -78
°C, 30 min) and then heated to 80 °C, the starting material
disappeared, and the rearranged product 17 was produced
cleanly within 10 min. This reaction was also tried in refluxing
THF after enolate generation in the same solvent, but the product
was obtained in lower yield. Analysis of 17 via chiral HPLC
showed an optical purity of 97% ee. This confirmed that the
stereochemistry of the aziridine was transferred to the quaternary
center with high fidelity. The subsequent transformation of the
methyl ester in 17 to an aldehyde group required some
optimization to avoid interference with other functional groups
in the same molecule. Although superhydride (LiBHEt3)15
reduced the methyl ester to an alcohol, the diene was also
reduced. Lithium aluminum hydride reduction followed by
Swern oxidation gave the desired aldehyde 7, but in a low yield
(31%). Using the conditions of DIBALH reduction, a higher
and acceptable yield (59%) of aldehyde 7 was obtained, albeit
with some over-reduction to the alcohol. It should be noted that
aldehyde 7 was not stable and had to be used in the next step
immediately after isolation.
Toward the Synthesis of Imine 24. To continue the
synthesis, aldehyde 7 and 3,4-dimethoxyaniline 6 were refluxed
in toluene (0.03 M) under the catalysis of p-toluenesulfonic acid
(10 mol %). To our delight, the highly functionalized tetrahy-
droquinoline product 20 was produced with a 10:1 diastereo-
selectivity. The major diastereomer was unequivocally shown
to be the desired one through NOE experiments, followed by
X-ray crystallographic analysis. Consistent with our previous
studies,8 nucleophilic attack of the diene on the protonated imine
(18) gave exclusively the trans-cyclopentane in 19. The facial
selectivity of this attack then determines the ratio of diastereo-
mers 20a and 20b after the electrophilic aromatic substitution
(Scheme 6).
selectively transformed to the primary alcohol 21 (9-BBN, THF;
H2O2, NaOH) and then protected (TBDPSCl, Et3N) as silyl ether
5 (Scheme 7). The lactam nitrogen in 5 can be selectively Boc
protected in the presence of the tetrahydroquinoline nitrogen
(Boc2O, Et3N, DMAP) to give 22. This selectivity is probably
due to the steric hindrance around the latter nitrogen. Lactam
22 underwent nucleophilic ring-opening conditions (NaOMe,
MeOH)16 to afford methyl ester 23. This intermediate combined
all of the necessary functionalities except an imine group for
the aminal formation. Thus, we were in a position to establish
such an imine functionality starting with compound 23. Unfor-
tunately, all of our efforts to generate imine 24 by oxidation of
23 were not successful (Scheme 8). The oxidation conditions
With the requisite tetracyclic compound 20b in hand, we
began to investigate further functional group transformations
to generate the imine intermediate 4 in our retrosynthetic plan
(Scheme 1). Toward this goal, the vinyl group in 20b was first
(15) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980,
45, 1.
(16) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424.
3810 J. Org. Chem., Vol. 72, No. 10, 2007

Total Synthesis of the Isoschizozygane Alkaloid
SCHEME 7. Functional Group Transformations from 20b
to 22
SCHEME 9. An Alternative Plan To Avoid Imine
Formation
SCHEME 8. Attempted Oxidations To Generate Imine 24
by the appended alkene chain. The carbocation thus formed was
to be trapped by the aromatic ring to afford pentacyclic
compound 3, an immediate precursor to the natural product 1.
This plan obviously avoided the tricky oxidation state manipula-
tion of our previous route. The N-acylamidine compound 26
was envisioned to be derived from diamide 27 via dehydration.
A homoallylic silyl ether in the R group of 27 was installed at
an early stage to make this synthetic sequence more convergent
(Scheme 9).
En route to the synthesis of diamide 27, synthetic sequences
similar to those shown in Schemes 3 and 5 were applied to the
preparation of the seven-membered lactam 29 (98% ee) begin-
ning with the new phosphonate 28.24 Lactam 29 was then
converted to open chain intermediate 30 after N-nosyl protection
(p-NsCl, NaHMDS)25 and lactam ring opening (NaOMe,
MeOH). It was necessary to use elevated temperatures (DBU,
CH3CN, reflux) on 30 to promote the formation of a six-
membered lactam, which was then converted to lactam 31 after
nosyl deprotection (PhSH, K2CO3, DMF). Reaction of secondary
lactam 31 with 3,4-dimethoxyaniline 6 (AlMe3, CH2Cl2)26 gave
diamide 27 in 96% yield (Scheme 10).
Next, we turned our attention to the formation of amidine 26
from diamide 27. Dehydration conditions (I2, PPh3, i-Pr2NEt)27
were first attempted, and a new compound was cleanly generated
whose in situ NMR and MS data were consistent with structure
32. Not surprisingly, this imidate-like intermediate was very
unstable and could not be isolated. The attempted in situ
isomerization of 32 (LiAlMe3SPh27 or piperidine28) only led to
decomposition (sequence 1 in Scheme 11). After much experi-
mentation, it was discovered that the lactam in 27 could be
selectively O-methylated (Meerwein reagent, Cs2CO3, CH2Cl2)
to afford stable compound 33 in 82% yield. The observed
selectivity should result from the stronger Lewis basicity of the
lactam oxygen as compared to the phenyl amide oxygen. Bases
other than Cs2CO3 gave considerable amounts of lactam
N-methylated product for this transformation, although the
used include TPAP, NMO;17 Swern oxidation;18 MnO2;19 Hg-
(OAc)2;20 (NH4)2Ce(NO3)6;21 trichloroisocyanuric acid;22 and
H2O2, Na2WO4.23 Among these, TPAP, NMO were the only
conditions reported that partially oxidize the simple tetrahyd-
roquinoline to dihydroquinoline. These conditions did not
produce any imine product from the more sophisticated tet-
rahydroquinoline 23. The main problem of this transformation
resulted from the very sensitive nature of the dihydroquinoline
(imine) intermediate toward aromatization to quinoline deriva-
tives by both over-oxidation and disproportionation. The lesson
we learned from this prompted us to revise our original synthetic
plan to avoid this nontrivial oxidation step.
An Acylamidine Cyclization Strategy. We therefore de-
signed an alternative synthetic plan shown in Scheme 9. In this
approach, the protonated amidine group in 25 would be a
precursor to an aminal after intramolecular nucleophic attack
(17) Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567.
(18) Jinbo, Y.; Kondo, H.; Taguchi, H.; Sakamoto, F.; Tsukamoto, G.
J. Org. Chem. 1994, 59, 6057.
(19) Kashdan, D. S.; Schwartz, J. A.; Rapoport, H. J. Org. Chem. 1982,
2638.
(20) Leonarda, N.; Hay, L.; Fulmer, R. W.; Gash, V. W. J. Am. Chem.
Soc. 1955, 77, 439.
(21) White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc. 1994,
1831.
(22) Tilstam, U.; Harre, M.; Heckrodt, T.; Weinmann, H. Tetrahedron
Lett. 2001, 42, 5385.
(23) Murahashi, S.; Oda, T.; Sugahara, T.; Masui, Y. J. Org. Chem. 1990,
55, 1744.
(24) Details of the syntheses were included in the Supporting Information.
(25) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 1338.
(26) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171.
(27) Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001, 123, 5892.
(28) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
J. Org. Chem, Vol. 72, No. 10, 2007 3811

Zhou and Magomedov
SCHEME 12. Reactions of Amidine 26 under Acidic
SCHEME 10. Synthesis of Diamide 27
Conditions
of the aminal carbon to be 79 ppm as compared to 166 ppm for
the amindine carbon in 26. However, we were disappointed that
the desired cyclization product 35 was not obtained, as
1
evidenced in the H NMR spectrum that the three hydrogens
on the phenyl ring remained.
Summary
SCHEME 11. Efforts Leading to the Synthesis of Amidine 26
Although our synthetic investigations did not result in a
completed total synthesis of isoschizogamine, an efficient aza-
Claisen rearrangement for the installation of the quaternary
center, and a highly diastereoselective hetero-Diels-Alder
reaction for the preparation of an advanced intermediate, the
densely functionalized tetrahydroquinoline 23 was developed.
Our synthesis of lactam 31 with high optical purity may be
useful for the enantioselective synthesis of this alkaloid via the
route previously described by Padwa and co-workers.7 With an
alternate R group installed, this could also be a useful intermedi-
ate for the synthesis of other alkaloids such as Eburnamonine
and Rhazinilam.29,30
Experimental Section
(2E)-2-(1-Tritylaziridin(2R)-2-ylmethylene)octa(5E)-5,7-di-
enoic Acid Methyl Ester (10). To a suspension of Ba(OH)2 (8.8
g, 27.9 mmol, activated by heating at 140 °C for 2 h) in wet THF
(50 mL, THF:H2O/40:1) at rt was added dropwise a solution of
phosphonate 8 (8.12 g, 27.9 mmol) in THF (50 mL) via cannula.
After 30 min at rt, aldehyde 9 (8.7 g, 27.9 mmol) was added in
one portion, and stirring was continued for 5 h. The reaction mixture
was diluted with CH2Cl2 (150 mL) and washed with saturated
aqueous solution of NaHCO3 (40 mL) followed by brine (50 mL).
The organic layer was separated, dried (Na2SO4), and concentrated
in vacuo. Purification by flash column chromatography on silica
gel, eluting with EtOAc/hexanes (gradient from 5% to 20%), gave
phenyl amide was still unreactive. Further efforts to activate
the phenyl amide of 33 (NaH, DBU, LHMDS, or KHMDS in
different solvents at rt or elevated temperatures) toward the
formation of amidine 26 were not successful. Finally, this
transformation could be effected using the conditions of AlMe2-
Cl, CH2Cl2 at room temperature. In contrast, the use of AlMe3
gave no trace of product 26 (sequence 2 in Scheme 11).
After establishing a viable way for the preparation of
N-acylamidine 26, we were encouraged to investigate its
intramolecular cyclization behavior (Scheme 12). It was then
discovered that, under acidic conditions of triflic acid in CH2-
Cl2 at room temperature, no cyclization reactions occurred even
when up to 5 equiv of triflic acid was added. Instead, desilylation
product 34 was identified after basic workup (NaHCO3). The
crude material was then subjected to the forcing conditions of
triflic acid in refluxing toluene, which led to complete consump-
tion of the starting material within 1 h. After isolation, a
compound was identified as a single diastereomer. Aminal
formation was clearly shown in 13C NMR, with chemical shift
R,â-unsaturated methyl ester 10 (11.1 g, 88%) as a colorless oil:
1
[R]23 -109.6 (c 3.05, CHCl3); IR (neat) 1713 cm-1; H NMR
D
(400 MHz, CDCl3) δ 7.51-7.45 (m, 6H), 7.32-7.22 (m, 9H), 6.73
(d, J ) 9.5 Hz, 1H), 6.06 (td, J ) 10.5, 17.0 Hz, 1H), 5.85 (dd, J
) 10.5, 15.0 Hz, 1H), 5.48 (td, J ) 7.0, 15.0 Hz, 1H), 5.06 (d, J
) 17.0 Hz, 1H), 4.93 (d, J ) 10.5 Hz, 1H), 3.80 (s, 3H), 2.29-
(29) Herrmann, J. L.; Cregge, R. J.; Richman, J. E.; Kieczykowski, G.
R.; Normandin, S. N.; Quesada, M. L.; Semmelhack, C. L.; Poss, A. J.;
Schlessinger, R. H. J. Am. Chem. Soc. 1979, 101, 1540.
(30) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647.
3812 J. Org. Chem., Vol. 72, No. 10, 2007

Total Synthesis of the Isoschizozygane Alkaloid
2.24 (m, 2H), 2.08-1.99 (m, 2H), 1.97 (d, J ) 3.5 Hz, 1H), 1.90
(ddd, J ) 3.5, 6.0, 9.5 Hz, 1H), 1.52 (d, J ) 6.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.6, 144.0, 143.6, 137.0, 133.7, 133.2,
131.4, 129.3, 127.4, 126.8, 115.0, 74.3, 51.7, 32.1, 31.0. HRMS
(ESI): exact mass calcd for C31H31NNaO2 [M + Na]+, 472.2252.
Found: 472.2256.
MHz, CDCl3) δ 6.28 (td, J ) 10.5, 17.0 Hz, 1H), 6.07 (dd, J )
10.5, 15.0 Hz, 1H), 5.92 (s, br, 1H), 5.86-5.76 (m, 2H), 5.63 (td,
J ) 7.0, 15.0 Hz, 1H), 5.10 (d, J ) 17.0 Hz, 1H), 4.98 (d, J )
10.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.72 (s, 3H), 3.60 (td, J ) 6.5,
18.0 Hz, 1H), 3.10 (d, J ) 13.0 Hz, 1H), 2.81 (d, J ) 13.0 Hz,
1H), 2.32-2.22 (m, 1H), 2.06-1.96 (m, 1H), 1.89 (dt, J ) 5.0,
14.0 Hz, 1H), 1.79 (dt, J ) 5.0, 11.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 174.0, 173.9, 136.9, 133.6, 133.4, 131.6, 125.5, 115.3,
52.5, 48.0, 39.3, 19.0, 37.9, 27.4. HRMS (ESI): exact mass calcd
for C14H20NO3 [M + H]+, 250.1437. Found: 250.1443. Optical
purity determination: HPLC analysis of the purified product 17
(Chiralpak AD-H, hexane/2-propanol ) 80:20, flow rate: 0.4 mL/
min, λ ) 240 nm) showed a 98.5:1.5 mixture of enantiomers (tR(R)
) 12.52 min, tR(S) ) 13.74 min). For comparison purpose, rac-17
was prepared starting with rac-9.
(4R)-4-Hexa(3E)-3,5-dienyl-2-oxo-2,3,4,7-tetrahydro-1H-aze-
pine-4-carbaldehyde (7). To a solution of compound 17 (662 mg,
2.66 mmol) in toluene (12 mL) cooled to -78 °C was added DIBAL
(4 mL, 1 M in hexanes, 4 mmol) dropwise along the flask side
over a 10-min period of time. After an additional 20 min, EtOAc
(1 mL) was added, and the reaction mixture was immediately poured
into a rapidly stirred mixture of saturated aqueous solution of
Rochelle’s salt (20 mL) and EtOAc (20 mL). After 1 h, the clear
biphasic mixture was transferred to a separation funnel, the organic
layer was separated, and the aqueous layer was extracted with
EtOAc (3 × 5 mL). The combined organic extracts were dried (Na2-
SO4) and concentrated in vacuo. Purification by flash column
chromatography on silica gel, eluting with EtOAc/hexanes (50%),
gave aldehyde 7 (342 mg, 59%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 9.48 (s, 1H), 6.54 (s, br, 1H), 6.28 (td, J ) 10.5,
17.0 Hz, 1H), 6.08 (dd, J ) 10.5, 15.0 Hz, 1H), 5.96 (ddd, J )
4.5, 6.5, 11.0 Hz, 1H), 5.68 (d, J ) 11.0 Hz, 1H), 5.62 (td, J )
6.5, 15.0 Hz, 1H), 5.12 (d, J ) 17.0 Hz, 1H), 5.00 (d, J ) 10.5
Hz, 1H), 3.95-3.88 (m, 1H), 3.65 (td, J ) 6.5, 17.4 Hz, 1H), 2.91
(d, J ) 13.5 Hz, 1H), 2.71 (d, J ) 13.5 Hz, 1H), 2.29-2.20 (m,
1H), 2.08-1.99 (m, 1H), 1.87-1.74 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 200.0, 173.8, 136.7, 133.0, 131.9, 130.2, 127.8, 115.6,
51.6, 39.5, 36.9, 26.7. HRMS (ESI): exact mass calcd for C29H37-
NNaO3Si [M + Na]+, 498.2443. Found: 498.2435.
6,7-Dimethoxy-(3,3,4′,4′)spiro[2-oxo-2,3,4,7-tetrahydro-1H-
azepine](9S)-9-vinyl(3R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinoline (20b). Aldehyde 7 (470 mg, 2.14 mmol)
was dissolved in toluene (70 mL) at rt. Next, 3,4-dimethoxyaniline
6 (393 mg, 2.57 mmol) and TsOH‚H2O (40 mg, 0.21 mmol) were
added, and the reaction flask was placed into a preheated (120 °C)
oil bath for 30 min. The resulting mixture was then allowed to
cool to rt and partitioned between a saturated aqueous solution of
NaHCO3 (30 mL) and EtOAc (30 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc (3 ×
10 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Purification by flash column chromatography
on silica gel, eluting with EtOAc, gave compound 20b (532 mg,
70%) as a white solid. Recrystallization from CH2Cl2 gave a suitable
single crystal for X-ray analysis (data in the Supporting Informa-
tion): [R]23D +103.4 (c 1.70, CHCl3); mp 182-183 °C; IR (neat)
3336, 3306, 1666 cm-1; 1H NMR (400 MHz, C6D6) δ 7.42 (s, br,
1H), 6.88 (s, 1H), 6.30 (s, 1H), 5.64 (td, J ) 9.6, 17.0 Hz, 1H),
5.50 (d, J ) 11.8 Hz, 1H), 5.35 (ddd, J ) 4.2, 6.4, 11.8 Hz, 1H),
5.18 (dd, J ) 2.0, 17.0 Hz, 1H), 5.15 (dd, J ) 2.0, 9.6 Hz, 1H),
4.14 (s, br, 1H), 3.60 (s, 3H), 3.44 (s, 3H), 3.30-3.23 (m, 1H),
3.14 (t, J ) 9.6 Hz, 1H), 3.07 (d, J ) 11.1 Hz, 1H), 2.99 (dt, J )
6.4, 17.4 Hz, 1H), 2.70 (d, J ) 12.3 Hz, 1H), 2.41 (d, J ) 12.3
Hz, 1H), 1.96 (m, 1H), 1.79-1.71 (m, 1H), 1.64-1.58 (m, 1H),
1.17-1.06 (m, 1H), 1.87-1.74 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 175.0, 150.1, 143.0, 141.6, 140.2, 136.3, 127.5, 116.1,
115.4, 115.3, 101.8, 67.2, 56.9, 55.2, 50.2, 45.2, 44.9, 44.5, 38.9,
38.6, 25.7. Anal. Calcd for C21H26N2O3: C, 71.16; H, 7.39; N, 7.90.
Found: C, 71.13; H, 7.63; N, 7.82.
(2E)-2-Aziridin(2R)-2-ylmethyleneocta(5E)-5,7-dienoic Acid
Methyl Ester (11). To a solution of compound 10 (5.0 g, 11.1
mmol) in CH2Cl2 (37 mL) cooled to 0 °C were added triethylsilane
(7.1 mL, 44.5 mmol) followed by dropwise addition of trifluroacetic
acid (3.4 mL, 44.5 mmol). The reaction mixture became slightly
yellow and turned colorless upon the addition of each drop of TFA.
The yellow color persisted at the end of the addition. Stirring was
then continued for 20 min, and the reaction was quenched with
N,N-diisopropylethylamine (9.7 mL, 55.5 mmol) followed by
diethyl ether (100 mL). The resulting mixture was washed with
brine (30 mL), and the organic layer was separated, dried (Na2-
SO4), and concentrated in vacuo. Purification by flash column
chromatography on silica gel (deactivated with Et3N), using EtOAc/
hexanes as an eluent (gradient from 30% to 50%), gave the
deprotected aziridine 11 (1.63 g, 71%) as a colorless oil: [R]23
D
+30.0 (c 1.19, CHCl3); IR (neat) 3292, 1711 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.32 (td, J ) 10.5, 17.0 Hz, 1H), 6.14 (d, J ) 9.6
Hz, 1H), 6.09 (dd, J ) 10.5, 15.0 Hz, 1H), 5.74 (td, J ) 7.0, 15.0
Hz, 1H), 5.12 (d, J ) 17.0 Hz, 1H), 5.00 (d, J ) 10.5 Hz, 1H),
3.73 (s, 3H), 2.68-2.66 (m, 1H), 2.57-2.54 (m, 2H), 2.34-2.24
(m, 2H), 2.11 (d, J ) 5.2 Hz, 1H), 1.80 (d, J ) 3.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.4, 143.3, 136.9, 133.6, 133.4, 131.7,
115.3, 51.7, 32.2, 28.9, 28.0, 26.8. HRMS (ESI): exact mass calcd
for C12H18NO2 [M + H]+, 208.1332. Found: 208.1334.
(2E)-2-(1-Acetylaziridin(2R)-2-ylmethylene)octa(5E)-5,7-di-
enoic Acid Methyl Ester (12). To a solution of aziridine 11 (3.69
g, 17.8 mmol) in CH2Cl2 (30 mL) cooled to 0 °C were added
triethylamine (5.0 mL, 35.6 mmol) and DMAP (108 mg, 0.89
mmol) followed by dropwise addition of acetic anhydride (1.85
mL, 19.6 mmol). After 5 min, the reaction mixture was diluted
with Et2O (150 mL) and washed successively with water (20 mL),
a saturated aqueous solution of NaHCO3 (25 mL), and brine (20
mL). The organic extract was dried (Na2SO4) and concentrated in
vacuo. Purification by flash column chromatography on silica gel,
eluting with EtOAc/hexanes (30%), gave compound 12 (4.0 g, 90%)
as a colorless oil: [R]23 -2.30 (c 1.14, CHCl3); IR (neat) 1707,
D
1651 cm-1; H NMR (400 MHz, CDCl3) δ 6.30 (td, J ) 10.5,
1
17.0 Hz, 1H), 6.26 (d, J ) 9.0 Hz, 1H), 6.09 (dd, J ) 10.5, 15.0
Hz, 1H), 5.71 (td, J ) 7.0, 15.0 Hz, 1H), 5.13 (d, J ) 17.0 Hz,
1H), 5.01 (d, J ) 10.5 Hz, 1H), 3.77 (s, 3H), 3.22 (ddd, J ) 3.0,
6.0, 9.0 Hz, 1H), 2.63 (d on top of m, J ) 6.0 Hz, 1H), 2.67-2.56
(m, 2H), 2.39-2.23 (m, 2H), 2.30 (d on top of m, J ) 3.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 181.8, 166.9, 138.4, 136.7,
135.6, 133.1, 132.1, 115.7, 51.9, 34.4, 32.0, 26.9, 23.7. HRMS
(ESI): exact mass calcd for C14H20NO3 [M + H]+, 250.1432.
Found: 250.1438.
(4R)-4-Hexa(3E)-3,5-dienyl-2-oxo-2,3,4,7-tetrahydro-1H-aze-
pine-4-carboxylic Acid Methyl Ester (17). To a solution of
compound 12 (1.0 g, 4.01 mmol) in toluene (20 mL) cooled to
-78 °C was added LHMDS (8 mL, 1 M in hexanes, 8 mmol)
dropwise within a 5-min period of time. The reaction mixture turned
slightly yellow. After 20 min, the reaction mixture was placed in
a preheated (100 °C) oil bath. After 10 min at this temperature, the
reaction turned orange, and disappearance of starting material was
indicated by TLC analysis. Next, the reaction mixture was allowed
to cool to rt. Diethyl ether (50 mL) was added followed by saturated
aqueous solution of NH4Cl (20 mL). The organic layer was
separated, and the aqueous layer was extracted with Et2O (3 × 5
mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Purification by flash column chromatography
on silica gel, eluting with EtOAc/hexanes (50%), gave the seven-
membered lactam 17 (770 mg, 77%) as a colorless oil: [R]23D +3.70
(c 2.71, CHCl3); IR (neat) 3238, 1730, 1670 cm-1; 1H NMR (400
J. Org. Chem, Vol. 72, No. 10, 2007 3813

Zhou and Magomedov
6,7-Dimethoxy(3,3,4′,4′)spiro[2-oxo-2,3,4,7-tetrahydro-1H-
aze-pine](9S)-9-(2-hydroxyethyl)(3R,3aS,9aS)-2,3,3a,4,9,9a-hexahy-
dro-1H-cyclopenta[b]quinoline (21). To a solution of 20b (532
mg, 1.05mmol) in THF (11 mL) cooled to 0 °C was added dropwise
a solution of 9-BBN (10.5 mL, 0.5 M in THF, 5.26 mmol). The
resulting mixture was allowed to warm to rt and stirred for 24 h.
It was then quenched with water (10 mL) at 0 °C, and H2O2 (5.4
mL of a 30% aqueous solution) and NaOH (12 mL of a 2 N aqueous
solution) were added. The resulting mixture was stirred for 2 h,
and then a saturated aqueous solution of Na2S2O3 (2 mL) was added.
The mixture was extracted with EtOAc (3 × 10 mL), and the
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. Purification by flash column chromatography on silica
gel, eluting with MeOH/EtOAc (10%), gave alcohol 21 (215 mg,
22 and recycled to afford a second batch of 23 (7.2 mg), making
the combined yield of 23 to be 55%: [R]23D -6.7 (c 1.51, CHCl3);
1
IR (neat) 3368, 1728, 1700 cm-1; H NMR (400 MHz, C6D6) δ
7.75-7.34 (m, 4H), 7.23-7.21 (m, 6H), 6.86 (s, 1H), 6.26 (d, J )
12.0 Hz, 1H), 6.24 (s, 1H), 5.48 (s, br, 1H), 5.37 (td, J ) 7.5, 12.0
Hz, 1H), 4.39 (s, br, 1H), 4.04-3.88 (m, 4H), 3.58 (s, 3H), 3.32
(s, 3H), 3.27 (s, 3H), 2.90 (d on top of m, J ) 15.0 Hz, 1H), 2.92-
2.87 (m, 1H), 2.75 (d, J ) 11.0 Hz, 1H), 2.22 (d on top of m, J )
15.0 Hz, 1H), 2.33-2.11 (m, 3H), 2.06-1.99 (m, 1H), 1.88-1.80
(m, 1H), 1.46 (s, 9H), 1.45-1.38 (m, 1H), 1.17 (s, 9H), 1.13-
1.05 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.1, 155.6, 148.3,
141.5, 140.7, 135.5, 134.7, 134.3, 133.8, 129.5, 127.6, 115.9, 112.3,
100.4, 79.3, 68.5, 61.5, 56.9, 55.7, 51.7, 46.8, 45.5, 45.0, 40.2, 39.2,
38.7, 35.9, 28.4, 27.7, 26.8, 26.7, 19.1. HRMS (ESI): exact mass
calcd for C43H59N2O7Si [M + H]+, 743.4086. Found: 743.4074.
55%) as a white foam: [R]23 +104.3 (c 1.56, CHCl3); IR (neat)
D
1
3349, 1713 cm-1; H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H),
(2R)-2-[6-(tert-Butyldiphenylsilanyloxy)hex(3E)-3-enyl]-2-[3-
(4-nitrobenzenesulfonylamino)propenyl]succinic Acid Dimethyl
Ester (30). To a solution of lactam 29 (1.81 g, 3.57 mmol) in THF
(20 mL) cooled to -78 °C was added dropwise NaHMDS (4.2
mL, 1 M in THF, 4.2 mmol) over a 10-min period of time. The
reaction mixture turned orange at the end of addition. After 20 min,
a solution of 4-nitrobenzenesulfonyl chloride (1.06 g, 4.78 mmol)
in THF (3 mL and 2 × 1 mL for rinsing) was cannulated into the
reaction mixture, which first turned purple and then clear yellow
at the end of the addition. After being stirred for 3 h, the reaction
mixture was partitioned between Et2O (35 mL) and water (15 mL),
and was allowed to warm to rt. The organic layer was separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. Purification by flash column chromatography on silica
gel, eluting with EtOAc/hexanes (gradient from 10% to 50%), gave
the N-nosyl lactam (1.98 g, 80%) as a light yellow viscous oil:
6.44 (t, J ) 4.9 Hz, 1H), 6.20 (s, 1H), 5.80-5.70 (m, 2H), 3.89-
3.85 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74-3.69 (m, 1H), 3.70
(t, J ) 7.0 Hz, 1H), 3.06 (d, J ) 10.7 Hz, 1H), 2.88-2.86 (m,
1H), 2.86 (d, J ) 12.5 Hz, 1H), 2.64 (d, J ) 12.5 Hz, 1H), 2.15-
2.07 (m, 4H), 1.93-1.86 (m, 2H), 1.46-1.43 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 175.5, 148.2, 142.2, 140.1, 136.1, 123.5,
116.4, 111.8, 101.1, 68.1, 60.1, 56.8, 55.6, 44.9, 44.8, 44.2, 40.5,
39.5, 38.7, 35.5, 26.4. HRMS (ESI): exact mass calcd for
C21H29N2O4 [M + H]+, 373.2122. Found: 373.2125.
6,7-Dimethoxy(3,3,4′,4′)spiro[1-(carboxylic acid tert-butyl ester)-
2-oxo-2,3,4,7-tetrahydro-1H-azepine](9S)-9-[2-(tert-butyl-
diphenylsilanyloxy)ethyl](3R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinoline (22). To a solution of alcohol 21 (413
mg, 1.11 mmol) in CH2Cl2 (5 mL) at rt were added Et3N (0.46
mL, 3.3 mmol) and DMAP (149 mg, 1.22 mmol) followed by
TBDPSCl (367 mg, 1.34 mmol, rinsed with 0.5 mL of CH2Cl2).
The reaction mixture was stirred for 3 h, and then diluted with
Et2O (30 mL). The resulting mixture was washed successively with
water (5 mL), a saturated aqueous solution of NaHCO3 (5 mL),
and NH4Cl (5 mL). The organic layer was separated, dried (Na2-
SO4), and concentrated in vacuo. The resulting residue was
dissolved in CH2Cl2 (5 mL) at rt, and to this solution were added
Et3N (0.3 mL, 2.15 mmol) and DMAP (117 mg, 0.95 mmol)
followed by di-tert-butyldicarbonate (242 mg, 1.1 mmol, rinsed with
0.5 mL of CH2Cl2). The reaction mixture was stirred for 30 min,
and then was concentrated in vacuo. The resulting yellow residue
was purified by flash column chromatography on silica gel, eluting
with EtOAc/hexanes (50%), to give 22 (517 mg, 66%) as a white
[R]23 +3.4 (c 3.49, CHCl3); IR (neat) 1737, 1709, 1532, 1351,
D
1310 cm-1; H NMR (400 MHz, CDCl3) δ 8.42-8.39 (m, 2H),
1
8.25-8.22 (m, 2H), 7.75-7.73 (m, 4H), 7.53-7.44 (m, 6H), 6.09
(td, J ) 5.6, 11.1 Hz, 1H), 5.94 (d, J ) 11.1 Hz, 1H), 5.41 (td, J
) 7.1, 15.5 Hz, 1H), 5.33 (td, J ) 6.1, 15.5 Hz, 1H), 4.72 (dd, J
) 5.6, 17.0 Hz, 1H), 4.61 (dd, J ) 5.6, 17.0 Hz, 1H), 3.71 (t, J )
6.6 Hz, 2H), 3.67 (s, 3H), 3.20 (d, J ) 13.8 Hz, 1H), 3.00 (d, J )
13.8 Hz, 1H), 2.30-2.24 (m, 2H), 2.07-1.97 (m, 1H), 1.86-1.70
(m, 2H), 1.44 (ddd, J ) 5.2, 11.6, 13.8 Hz, 1H), 1.13 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 172.6, 170.6, 150.4, 144.4, 135.6, 135.5,
133.9, 130.1, 130.0, 129.5, 128.0, 127.5, 123.8, 123.7, 63.6, 52.5,
49.1, 41.7, 40.8, 37.9, 35.8, 27.0, 26.8, 19.1. HRMS (ESI): exact
mass calcd for C36H42N2NaO8SSi [M + Na]+ 713.2323. Found:
713.2303.
foam: [R]23 +35.7 (c 1.15, CHCl3); IR (neat) 3360, 1766, 1716
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.67-7.64 (m, 4H), 7.43-
7.36 (m, 6H), 6.64 (s, 1H), 6.16 (s, 1H), 5.85 (td, J ) 5.5, 11.5
Hz, 1H), 5.67 (d, J ) 11.5 Hz, 1H), 4.39 (dd, J ) 5.5, 11.0 Hz,
1H), 4.29 (dd, J ) 5.5, 11.0 Hz, 1H), 3.81 (s, 3H), 3.74-3.69 (m,
2H), 3.71 (s, 3H), 3.05 (d, J ) 13.0 Hz, 1H), 2.95 (d, J ) 10.5 Hz,
1H), 2.81 (td, J ) 4.0, 9.5 Hz, 1H), 2.77 (d, J ) 13.0 Hz, 1H),
2.12-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.87-1.74 (m, 2H), 1.57
(s, 9H), 1.43-1.30 (m, 1H), 1.06 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 172.9, 151.9, 147.9, 142.1, 139.9, 137.4, 135.5, 133.7,
129.5, 127.5, 122.8, 116.6, 111.7, 101.0, 83.3, 67.9, 61.3, 56.6,
55.5, 48.1, 46.5, 44.3, 42.2, 40.2, 38.6, 35.6, 28.0, 26.8, 26.5, 19.1.
HRMS (ESI): exact mass calcd for C42H55N2O6Si [M + H]+,
711.3824. Found: 711.3839.
To a solution of the above N-Ns protected lactam (812 mg, 1.17
mmol) in THF/MeOH (2 mL/2 mL) at rt was added NaOMe (126
mg, 2.34 mmol) in one portion. The reaction mixture immediately
turned purple. After 30 min, Et2O (20 mL) and a saturated aqueous
solution of NH4Cl (10 mL) were added. The organic layer was
separated, and the aqueous layer was extracted with Et2O (3 × 5
mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Purification by flash column chromatography
on silica gel, eluting with EtOAc/hexanes (gradient from 20% to
50%), gave compound 30 (753 mg, 89%) as a colorless oil: [R]23
D
+7.64 (c 0.68, CHCl3); IR (neat) 3287, 1734, 1531, 1428, 1349
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.38 (d, J ) 6.9 Hz, 2H),
{(3R)-3-(3-tert-Butoxycarbonylaminopropenyl)(9S)-9-[2-(tert-
butyldiphenyl-silanyloxy)ethyl]-6,7-dimethoxy(3aS,9aS))-
2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-3-yl}acetic Acid
Methyl Ester (23). To a solution of compound 22 (47.1 mg, 0.0662
mmol) in MeOH (0.5 mL) at 0 °C was added NaOMe (7 mg, 0.132
mmol) in one portion. After 30 min, the reaction mixture was
quenched with brine (2 mL) and extracted with CH2Cl2 (3 × 5
mL). The organic layers were combined, dried (Na2SO4), and
concentrated in vacuo. Purification by flash column chromatography
on silica gel, eluting with EtOAc/hexanes (50%), gave 23 (19.4
mg) and 5 (20 mg). Compound 5 was reprotected as the Boc imide
8.08 (d, J ) 6.9 Hz, 2H), 7.68-7.66 (m, 4H), 7.44-7.37 (m, 6H),
5.51 (d, J ) 12.0 Hz, 1H), 5.47-5.31 (m, 3H), 5.20 (t, J ) 6.0
Hz, 1H), 3.67 (t, J ) 7.0 Hz, 2H), 3.65 (s, 3H), 3.64 (s, 3H), 3.61-
3.55 (m, 2H), 2.84 (d, J ) 15.5 Hz, 1H), 2.60 (d, J ) 15.5 Hz,
1H), 2.24 (q, J ) 6.5 Hz, 2H), 1.93-1.74 (m, 4H), 1.06 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 174.4, 171.1, 149.9, 146.1, 135.5,
134.1, 133.9, 130.4, 129.5, 128.2, 127.8, 127.5, 127.0, 124.2, 63.6,
52.4, 51.8, 48.7, 41.2, 40.9, 38.9, 35.8, 27.5, 26.7, 19.1. HRMS
(ESI): exact mass calcd for C37H46N2NaO9SSi [M + Na]+,
745.2610. Found: 745.2611.
3814 J. Org. Chem., Vol. 72, No. 10, 2007

Total Synthesis of the Isoschizozygane Alkaloid
{(3R)-3-[6-(tert-Butyldiphenylsilanyloxy)hex(3E)-3-enyl]-2-
oxo-1,2,3,6-tetrahydropyridin-3-yl}acetic Acid Methyl Ester
(31). Compound 30 (703 mg, 0.97 mmol) was dissolved in CH3-
CN (10 mL) at rt, and to this solution was added dropwise DBU
(0.15 mL, 1.45 mmol). The reaction mixture, which turned purple,
was refluxed in an oil bath for 1 h and was allowed to cool to rt
after that. A saturated aqueous solution of NH4Cl (10 mL) followed
by Et2O (15 mL) were added. The organic layer was separated,
and the aqueous layer was extracted with Et2O (3 × 5 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. Purification by flash column chromatography on silica
gel, eluting with EtOAc/hexanes (30%), gave six-membered N-Ns
135.5, 133.9, 131.9, 130.9, 129.5, 129.4, 127.5, 127.3, 121.3, 111.4,
111.3, 104.6, 63.7, 56.0, 55.8, 47.2, 45.5, 43.6, 39.9, 35.9, 27.7,
26.8, 19.2. HRMS (ESI): exact mass calcd for C37H46N2NaO5Si
[M + Na]+, 649.3068. Found: 649.3061.
2-{(3R)-3-[6-(tert-Butyldiphenylsilanyloxy)hex(3E)-3-enyl]-2-
methoxy-3,6-dihydropyridin-3-yl}-N-(3,4-dimethoxyphenyl)ac-
etamide (33). To a vigorously stirred solution of diamide 27 (327
mg, 0.522 mmol) in CH2Cl2 (5.2 mL) at rt were added Cs2CO3
(510 mg, 1.56 mmol) followed by trimethyloxonium tetrafluorobo-
rate (116 mg, 0.782 mmol) in one portion. After 1 h, the reaction
mixture was quenched with saturated aqueous solution of NaHCO3
(12 mL) and then taken up in CH2Cl2 (15 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3 × 8 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. Purification by flash column chroma-
tography on silica gel, eluting with EtOAc/hexanes (50%), gave
lactam (550 mg, 82%) as a colorless oil: [R]23 +10.8 (c 0.98,
D
1
CHCl3); IR (neat) 1736 1695, 1533, 1350, 1245 cm-1; H NMR
(400 MHz, CDCl3) δ 8.34 (d, J ) 9.1 Hz, 2H), 8.24 (d, J ) 9.1
Hz, 2H), 7.68-7.64 (m, 4H), 7.45-7.36 (m, 6H), 5.97 (td, J )
3.2, 10.1 Hz, 1H), 5.39-5.27 (m, 3H), 4.63 (ddd, J ) 1.7, 3.2,
17.0 Hz, 1H), 4.50 (td, J ) 3.2, 17.0 Hz, 1H), 3.64 (t, J ) 6.9 Hz,
2H), 3.47 (s, 3H), 2.89 (d, J ) 17.0 Hz, 1H), 2.29 (d, J ) 17.0 Hz,
1H), 2.24-2.19 (m, 2H), 1.98-1.72 (m, 3H), 1.37-1.31 (m, 1H),
1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.8, 170.6, 150.3,
144.3, 143.0, 135.4, 133.8, 130.1, 129.8, 129.4, 127.7, 127.4, 123.4,
121.7, 63.6, 51.4, 48.1, 46.7, 43.5, 39.9, 35.7, 27.4, 26.7, 19.1.
HRMS (ESI): exact mass calcd for C36H42N2NaO8SSi [M + Na]+,
713.2323. Found: 713.2323.
Potassium carbonate (811 mg, 5.88 mmol) was added to a
solution of the above N-nosyl lactam (1.36 g, 1.96 mmol) in DMF
(5 mL). Thiophenol (0.24 mL, 2.35 mmol) was added dropwise,
and the reaction mixture was stirred at rt for 1 h. Next, a saturated
aqueous solution of NaHCO3 (5 mL) and Et2O (15 mL) were added.
The organic layer was separated, and the aqueous layer was
extracted with Et2O (3 × 5 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. Purification by
flash column chromatography on silica gel, eluting with EtOAc/
hexanes (gradient from 50% to 100%), gave lactam 31 (912 mg,
92%) as a colorless viscous oil: [R]23D +29.1 (c 2.85, CHCl3); IR
(neat) 3213, 1740, 1682 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.76-
7.74 (m, 4H), 7.52-7.43 (m, 6H), 6.90 (s, br, 1H), 5.83 (d, J )
10.1 Hz, 1H), 5.46 (td, J ) 2.0, 10.1 Hz, 1H), 5.49-5.46 (m, 2H),
4.00 (d, J ) 17.7 Hz, 1H), 3.89 (d, J ) 17.7 Hz, 1H), 3.65 (t, J )
6.6 Hz, 1H), 3.61 (s, 3H), 3.11 (d, J ) 15.8 Hz, 1H), 2.36 (d, J )
15.8 Hz, 1H), 2.23-2.221 (m, 2H), 2.00-1.95 (m, 3H), 1.39-
1.36 (m, 1H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.2,
171.1, 135.4, 133.8, 131.2, 129.4, 128.6, 127.4, 126.9, 122.1, 63.7,
51.3, 44.0, 43.6, 43.3, 39.6, 35.8, 27.6, 26.7, 19.1. HRMS (ESI):
exact mass calcd for C30H39NNaO4Si [M + Na]+, 528.2541.
Found: 528.2547.
imidate 33 (172 mg, 87%) as a colorless oil: [R]23 -1.6 (c 3.5,
D
1
CHCl3); IR (neat) 3315, 1689, 1659 cm-1; H NMR (400 MHz,
CDCl3) δ 7.69-7.67 (m, 4H), 7.46-7.37 (m, 6H), 7.27 (d, J )
2.5 Hz, 1H), 7.15 (s, br, 1H), 6.77 (d, J ) 8.5 Hz, 1H), 6.70 (dd,
J ) 2.5, 8.5 Hz, 1H), 5.96 (td, J ) 3.0, 10.0 Hz, 1H), 5.55 (d, J )
10.0 Hz, 1H), 5.40-5.37 (m, 2H), 4.10-4.08 (m, 2H), 3.85 (s,
3H), 3.84 (s, 3H), 3.73 (s, 3H), 3.66 (t, J ) 6.5 Hz, 2H), 2.85 (d,
J ) 13.6 Hz, 1H), 2.30 (d, J ) 13.6 Hz, 1H), 2.26-2.22 (m, 2H),
1.93-1.87 (m, 2H), 1.78-1.72 (m, 1H), 1.40-1.38 (m, 1H), 1.05
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.9, 162.3, 149.0, 145.8,
135.5, 133.9, 131.4, 131.2, 129.4, 128.1, 127.5, 127.1, 126.8, 111.7,
111.3, 105.0, 63.8, 56.1, 55.8, 52.3, 48.7, 47.5, 41.2, 39.5, 35.9,
27.9, 26.8, 19.1. HRMS (ESI): exact mass calcd for C38H49N2O5-
Si [M + H]+, 641.3405. Found: 641.3424.
(3aR)-3a-[6-(tert-Butyldiphenylsilanyloxy)hex(3E)-3-enyl]-1-
(3,4-dimethoxyphenyl)-1,3,3a,6-tetrahydropyrrolo[2,3-b]pyridin-
2-one (26). To a solution of compound 33 (32 mg, 0.05 mmol) in
CH2Cl2 (1 mL) at rt was added dropwise Me2AlCl solution (0.25
mL, 1 M in hexanes, 0.25 mmol). Stirring was continued for 48 h,
and the resulting reaction mixture was quenched with a saturated
aqueous solution of Rochelle’s salt (2 mL), and then diluted with
CH2Cl2 (2 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 1 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. Purification
by flash column chromatography on silica gel, eluting with EtOAc/
hexanes (25%), gave amidine 26 (20.7 mg, 68%) as a colorless
1
oil: [R]23 +0.6 (c 0.9, CHCl3); IR (neat) 1744, 1678 cm-1; H
D
NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.44-7.35 (m,
6H), 6.92 (d, J ) 8.4 Hz, 1H), 6.86 (dd, J ) 2.0, 8.4 Hz, 1H), 6.79
(d, J ) 2.0 Hz, 1H), 6.09 (ddd, J ) 1.4, 4.6, 9.6 Hz, 1H), 5.98 (dd,
J ) 2.8, 9.6 Hz, 1H), 5.45-5.40 (m, 2H), 4.24 (dd, J ) 4.6, 21.0
Hz, 1H), 4.01 (ddd, J ) 1.4, 2.8, 21.0 Hz, 1H), 3.88 (s, 3H), 3.85
(s, 3H), 3.66 (t, J ) 6.4 Hz, 1H), 2.77 (d, J ) 16.8 Hz, 1H), 2.70
(d, J ) 16.8 Hz, 1H), 2.23 (q, J ) 6.4 Hz, 1H), 2.12-2.07 (m,
2H), 1.72-1.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.7,
166.1, 149.3, 148.8, 135.6, 134.0, 133.9, 130.4, 129.6, 129.0, 128.1,
127.6, 126.4, 119.4, 111.3, 110.4, 63.7, 56.0, 55.9, 49.3, 41.6, 41.0,
39.2, 35.9, 27.7, 26.8, 19.2. HRMS (ESI): exact mass calcd for
C37H45N2O4Si [M + H]+, 609.3143. Found: 609.3149.
2-{(3R)-3-[6-(tert-Butyldiphenylsilanyloxy)hex(3E)-3-enyl]-2-
oxo-1,2,3,6-tetrahydropyridin-3-yl}-N-(3,4-dimethoxyphenyl)ac-
etamide (27). To a solution of compound 31 (279 mg, 0.55 mmol)
in CH2Cl2 (5 mL) at rt were added 3,4-dimethoxyaniline 6 (169
mg, 1.10 mmol) in one portion followed by dropwise addition of
AlMe3 (0.55 mL, 2 M in hexanes, 1.10 mmol). Stirring was
continued for 48 h, and the resulting reaction mixture was quenched
with a saturated aqueous solution of Rochelle’s salt (5 mL) and
then diluted with CH2Cl2 (5 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. Purification by flash column chromatography on silica
gel, eluting with EtOAc, gave diamide 27 (332 mg, 96%) as a white
Acknowledgment. This paper is dedicated to the memory
of Prof. Nabi Magomedov, his wife Natalya Scherbinina, and
their son Amir Magomedov. Support was provided by the
University of Rochester. We thank Prof. Robert Boeckman, Jr.,
for helpful discussions and Drs. Christine Flaschenriem and
Sandip Sur for X-ray analysis and NMR assistance, respectively.
foam: [R]23 -2.1 (c 0.90, CHCl3); IR (neat) 3306, 1681, 1654
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.23 (s, br, 1H), 7.66-7.64
(m, 4H), 7.43-7.34 (m, 6H), 7.29 (d, J ) 2.1 Hz, 1H), 6.85 (J )
8.6 Hz, 1H), 6.72 (dd, J ) 2.1, 8.6 Hz, 1H), 6.52 (s, br, 1H), 5.84
(d, J ) 10.5 Hz, 1H), 5.67 (d, J ) 10.5 Hz, 1H), 5.44-5.32 (m,
2H), 3.98-3.86 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.64 (t, J )
6.5 Hz, 2H), 3.00 (d, J ) 13.5 Hz, 1H), 2.35 (d, J ) 13.5 Hz, 1H),
2.23-2.19 (m, 2H), 2.04-1.88 (m, 3H), 1.50-1.41 (m, 1H), 1.04
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1, 168.1, 148.9, 145.5,
Supporting Information Available: X-ray data for compound
20b, and experimental details and copies of NMR spectra of new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO070144X
J. Org. Chem, Vol. 72, No. 10, 2007 3815