Applications of ring closing metathesis. Total synthesis of (±)-pseudotabersonine

Article abstract of DOI:10.1016/j.tet.2015.04.082

Abstract A novel approach to the Aspidosperma family of alkaloids was developed and applied to a concise total synthesis of (±)-pseudotabersonine that was accomplished in 11 steps. Key transformations include a stepwise variant of a Mannich-like multicomp

Full text of DOI:10.1016/j.tet.2015.04.082

Tetrahedron 71 (2015) 7323e7331
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Applications of ring closing metathesis. Total synthesis
of (ꢀ)-pseudotabersonine
Bo Cheng, James D. Sunderhaus, Stephen F. Martin
*
Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the Aspidosperma family of alkaloids was developed and applied to a concise total
synthesis of (ꢀ)-pseudotabersonine that was accomplished in 11 steps. Key transformations include
a stepwise variant of a Mannich-like multicomponent assembly process, a double ring-closing metath-
esis sequence, and a one-pot deprotection/cyclization reaction.
Received 20 February 2015
Received in revised form 16 April 2015
Accepted 23 April 2015
Available online 29 April 2015
Ó 2015 Elsevier Ltd. All rights reserved.
This paper is dedicated to the memory of
Professor Alan R. Katritzky, a long-time
colleague and friend
Keywords:
Double ring-closing metathesis
Multicomponent assembly process
Alkaloid
Total synthesis
1. Introduction
been isolated from numerous plant sources.5 Compounds of this
family have long captured the attention of the synthetic commu-
The design and development of new strategies and tactics that
may be generally applied to the efficient synthesis of biologically
important natural products has long been a cornerstone of research
in our laboratories and is vital to advancing the science of organic
chemistry. Reactions that form new carbonecarbon bonds assume
particular importance. It is in that context that we were drawn in
the early 1990s to the potential power of ring-closing metathesis
(RCM),1,2 which has since emerged as one of the most powerful
tools in organic synthesis. Beginning with developing methods in
which RCM was used to construct nitrogen heterocycles,3 we have
since applied RCM as a key step in the syntheses of a number of
alkaloids of varying complexity, including FR900482, manzamine
A, (þ)-anatoxin-a, dihydrocorynantheol, isolysergol, and a number
of other natural products.4 In connection with our continued in-
terest in expanding the scope and utility of RCM as a strategic
construct for the synthesis of complex molecules, we queried
whether we might be able to apply a double RCM sequence as a key
step in forming the pentacyclic core of the Aspidosperma alkaloids.
The Aspidosperma family of alkaloids is one of the largest fam-
ilies of indole alkaloids known, and over 250 unique alkaloids have
nity because of the biological activities of many of its members.
Most Aspidosperma alkaloids feature a pentacyclic core with an
ethyl group or a functionalized ethyl group at C20, as illustrated by
the structure of aspidospermidine (1) (Fig. 1). However, there is
a small family of Aspidosperma alkaloids that are related to pan-
doline (2), which bears a proton at the C14 bridge-head position
(Fig. 1). Pseudotabersonine (4), which was isolated from Pandaca
caducifolia in 1975,6 is a representative member of this family of
alkaloids. Prior to our work, only two total syntheses of pseudota-
bersonine (4) had been reported, and one other synthesis has been
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180; e-mail
address: sfmartin@mail.utexas.edu (S.F. Martin).
Fig. 1. Representative Aspidosperma alkaloids.
http://dx.doi.org/10.1016/j.tet.2015.04.082
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
published subsequently.7 Herein we report the details of our total
Table 1
synthesis of (ꢀ)-pseudotabersonine.8
Regioselectivity in additions of pentadienyl anions to 11
2. Results and discussion
The endgame in our approach to pseudotabersonine (4), which
is outlined in retrosynthetic format in Scheme 1, involves trans-
forming the tetracyclic alcohol 5 into 4 using a one-pot depro-
tection and cyclization sequence that was inspired by Bosch.9
Access to 5 would then feature the key double ring-closing me-
tathesis reaction of the tetraene 6. The preparation of 6 would then
be achieved by a stepwise variant of a Mannich-type multicom-
ponent assembly process (MCAP), which has been extensively de-
veloped in our laboratory for the rapid construction of
functionalized heterocyclic scaffolds,10 from the readily available 1-
(phenylsulfonyl)-3-indolecarboxaldehyde (7).
Entry
MXn
Branched (12): linear (13)a
% Conv.a
1
2
3
4
Li
1:3
1:10
1:4
30
100
50
ZnBr
InCl2
AlCl2
7.5:1
100
a
Determined by 1H NMR spectrum of crude reaction mixture.
reagent 10b to 11 proceeded with similar selectivities to afford the
linear adduct 13 as the major product (12:13¼1:3 and 1:4, re-
spectively). Although previous work in our lab4h and the labs of
others12 suggested that the pentadienyl zinc reagent 10a should
add with a high preference for forming the branched product, the
addition of 10a to imine 11 led mainly to the linear product 13
(12:13z1:10). Miginiac had observed increased selectivities for
branched products when pentadienyl aluminum reagent 10c was
allowed to react with aldehydes and ketones.13 Gratifyingly, 10c
added to 11 to afford the branched product 12 as the major adduct
(12:13z7.5:1). It was essential to allow this reaction to warm to
room temperature, because increased amounts of the linear adduct
13 were isolated if the reaction was quenched at ꢁ78 ꢂC.
Having thus established the necessary conditions to effect the
preferential formation of branched adducts in the additions of
pentadienyl anions to imines, we could initiate our synthesis of
members of the Aspidosperma alkaloids. Although our primary in-
terest was in pseudotabersonine (4), we also wanted to explore the
option of using a double RCM strategy to prepare Aspidosperma al-
kaloids such as rosicine (3), which lack the ethyl group at C20. Ac-
cordingly, the commercially-available aldehyde 7 was condensed
with the allylamines 14 and 15 to give the corresponding in-
termediate imines 16 and 17 with nearly 100% conversion
(Scheme 3). When the crude imines 16 and 17 were treated with 10c
under conditions previously developed for the pentadienylation of
11, the branched adducts 18 and 19 were formed with high (>10:1)
regioselectivity. These adducts were not purified, but rather they
were treated directly with ethylene oxide at 60 ꢂC in MeOH in
Scheme 1. Retrosynthetic analysis of (ꢀ) pseudotabersonine (4).
Formation of the adduct 6 entailed the regioselective addition of
a pentadienyl organometallic reagent to an imine to generate the
branched pentadienyl adduct. Although there was a body of prior
art relevant to the regiochemistry of additions of pentadienyl an-
ions to carbonyl compounds,11 there were only a few reports of
such additions to imines.4h,12 These reports suggest that the
branched adduct likely arises from a Zimmerman-Traxler transition
state, whereas the linear product is formed via either an eight-
membered or open transition state. The challenge was to identify
conditions that favored a six-membered transition state, and from
what was known in the literature coupled with our contempora-
neous work directed toward the synthesis of lysergol,4h it was ap-
parent that some experimentation would be required.
Toward identifying optimal conditions for inducing the addition
of pentadienyl anions to imines to furnish the branched adducts,
a brief exploratory study was undertaken. In the event, 1,4-
pentadiene (8) was deprotonated by treatment with n-BuLi at
ꢁ78 ꢂC, and transmetalation of the lithio anion 9 thus produced
with other metal halide salts gave the anions 10aec (Scheme 2).
Scheme 2. Synthesis of pentadienyl metal reagents.
With a selection of metalated pentadienyl anions in hand, we
examined the regioselectivities in their additions to the model
imine 11. Reactions of 11 with 9 and 10aec at ꢁ78 ꢂC gave a mixture
of branched and linear products 12 and 13, respectively (Table 1).
The additions of the pentadienyl lithium reagent 9 and the indium
Scheme 3. Synthesis of branched trienes 22 and 23.

B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
7325
a sealed tube to deliver the corresponding alcohols 20 and 21. After
a single recrystallization, 20 and 21 were isolated in 71% overall
yields from 16 and 17, respectively. Protection of the primary alcohol
groups in 20 and 21 as their TBS ethers then afforded 22 and 23.
It was now necessary to introduce an acrylate ester moiety at
C2 of 22 and 23 in order to set the stage for the anticipated double
RCM. This objective was readily achieved in a straightforward two-
step sequence starting with 22 (Scheme 4). Deprotonation of 22
with LDA followed by trapping the anion thus formed with methyl
pyruvate provided the alcohol 24 as an inconsequential mixture of
diastereoisomers (drz1.4:1) in 60% yield (74% conversion based
upon 26% recovery of starting 22). Dehydration of 24 with MsCl
deficient olefins are known to react more slowly in such cycliza-
tions.15 Moreover, the acrylate is also a 2,2-disubstituted olefin, and
such alkenes are also known to be less reactive toward RCM.
At this juncture, it was clear that our initial plan to generate
a fully substituted E ring by RCM was going to be problematic. We
also decided to focus our attention on the synthesis of pseudota-
bersonine (4) because there are more Aspidosperma alkaloids that
contain an ethyl group at C20 than those lacking such an ethyl
group. Accordingly, we turned our attention toward introducing
a vinyl group at the C2 position of 23. This was easily achieved by
treating 23 with LDA followed by the addition of acetaldehyde to
give the alcohol 28, which was smoothly converted to tetraene 29
€
€
and Hunig’s base furnished the desired tetraene 25 in 70% crude
upon reaction with Tf2O and Hunig’s base in about 70% overall yield
yield. Unfortunately, tetraene 25 proved to be somewhat unstable
and could not be purified to homogeneity by column
chromatography.
(Scheme 5).
Scheme 5. Synthesis of tetraene 29.
The opportunity for a double RCM was again at hand. However,
considerable experimentation was required in order to optimize
this transformation because the course of the reaction was highly
dependent upon the conditions, especially the reaction tempera-
ture. For example, when a solution of 29 containing 5% of Hoveyda-
Grubbs catalyst was heated at 100 ꢂC (oil bath), the double RCM
proceeded smoothly to afford a mixture (7:10) of the D/E cis-fused
and D/E trans-fused tetracycles 30 and 31, respectively, in >90%
combined overall crude yield (Scheme 6).16 It should be noted that
pseudotabersonine has a cis-fused D/E ring junction, and 30 was
unfortunately the minor diastereoisomer produced by the RCM.
Interestingly, if the RCM reaction was performed at lower tem-
peratures, the ratio of 30 to 31 improved to approximately 1:1, but
the overall conversions were low. On the other hand, when the
RCM was conducted in refluxing toluene, none of the desired D/E
cis-fused product 30 was observed. Instead, the D/E trans-fused
tetracycle 31 was isolated in 50% yield together with about 15% of
the ring-opening product 32. Collectively, these findings suggest
that the desired D/E cis-fused product 30 was unstable at higher
Scheme 4. Double RCM approach to 27.
Notwithstanding the instability of the tetraene 25, we attemp-
ted to induce the planned double RCM. However, to our dismay,
when impure 25 was subjected to a number of RCM conditions
using a variety of standard precatalysts (Fig. 2), none of the desired
product 27, which would arise from the anticipated double RCM
process, was observed. Under all of the conditions tried, the major
isolable product was the mono-cyclized product 26, which was
formed in at best 50% yield. Attempts to drive the reaction to 27 at
higher temperatures and using microwave heating were uniformly
unsuccessful. Even the Grubbs-Stewart catalyst, which is known to
show increased reactivity towards sterically hindered olefins,14
failed to provide 27. In retrospect the inability to close the E ring
in 27 via RCM is not completely surprising because electron
Scheme 6. Double RCM of tetraene 29.
Fig. 2. Selected precatalysts for RCM reactions.

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B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
temperatures, undergoing sequential 1,4-elimination and aroma-
tization reactions that led to the formation of 32.17 Owing to the
apparent thermal instability of 30, it was necessary to carefully
monitor the temperature and time for the double RCM of 29 to give
optimal quantities of 30.
The tetracycles 30 and 31 were inseparable by column chro-
matography, so they were simply subjected as a crude mixture to
the regioselective catalytic hydrogenation of the less substituted
carbonecarbon double bond, followed by acid-induced depro-
tection of the TBS ether to afford a readily separable mixture (3:5)
of 33 and 34 in 70% overall yield from 29 (Scheme 7).18
Scheme 9. Synthesis of (ꢀ)-14-epi-pseudotabersonine (37) and attempt to prepare 39.
We also explored the possibility of inverting the two stereo-
centers at C3 and C7 of 36 via a reversible retro-Mannich/Mannich
sequence involving the intermediacy of 38 to furnish the penta-
cycle 39 in which the D/E fusion is cis. This process is well pre-
cedented for related compounds having a cis-fused D/E ring
system.21 However, to our chagrin, all of our efforts to epimerize 36
under a variety of acidic conditions (TsOH, TFA, AcOH, BF3$Et2O,
Cu(OTf)2 and HCl) led only to recovery of starting material or de-
composition. In retrospect, this finding was not entirely unexpected
because Kuehne had also failed to isomerize a trans-fused D/E ring
in a similar system.22
Undaunted we examined another strategy to transform 36 into
39 (Scheme 10). Imine 36 underwent an acid promoted cyanide
addition to afford 40 in an unoptimized 51% yield. We had envi-
sioned that treating 40 with AgOTf might result in a Grob-like
fragmentation to generate the tetracyclic iminium ion in-
termediate 38 that would cyclize via a Mannich-like reaction to
give 39. However, heating of 40 with AgOTf in CH3CN at 120 ꢂC led
only to the regeneration of 36 in 77% yield. Presumably, loss of
cyanide ion from 40 occurred without scission of the C3 and C7
carbonecarbon bond, so none of the isomerized product 39 was
formed.
Scheme 7. Synthesis of tetracycles 33 and 34.
Conversion of 33 to pentacycle 35 was achieved via a one-pot
N-deprotection/O-sulfonylation sequence followed by a cycliza-
tion that was inspired by a report by Bosch and co-workers who
performed a similar transformation.9 Namely, addition of a solution
of KOt-Bu in THF to a solution of 33 in DME delivered 35 in 66%
yield (Scheme 8). The choice of solvent was critical for the success
of this process. Solvents other than DME (e.g., THF, hexane,
dichloromethane, toluene and Et2O) gave only trace amounts of 35.
Finally, following a procedure developed by Rawal,19 pentacycle 35
was deprotonated with LDA, and the intermediate imine anion was
allowed to react with Mander’s reagent to furnish (ꢀ)-pseudota-
bersonine (4) in 61% yield; only a trace of the corresponding N-
acylated product was observed. The synthetic pseudotabersonine
thus obtained gave 1H and 13C NMR spectra that are consistent with
the assigned structure of 4 and with those reported and provided
by Kuehne.7a,20
Scheme 8. Completion of the synthesis of (ꢀ)-pseudotabersonine (4).
Scheme 10. Other attempts to isomerize 36 to give 39.
3. Summary
This sequence of reactions was then readily applied to the
synthesis of (ꢀ)-14-epi-pseudotabersonine (37). Although the
conversion of 34 into 36 proceeded without event, the C-carbo-
methoxylation of 36 to give 37 following the Rawal protocol was
accompanied by extensive N-acylation, and the carbamate analog
of 37 was formed in about 26% yield (Scheme 9). The significant
difference in the regioselectivity in the acylations of the anions
derived from 34 and 36 using Mander’s reagent is noteworthy and
unexpected, but we tentatively speculate that differences in ring
strain in the two systems might be at play.
In conclusion, we developed a concise route to access the
pentacyclic core of Aspidosperma alkaloids via a double RCM
strategy. The total synthesis of (ꢀ)-pseudotabersonine was ac-
complished in 11 steps from commercially available 1-(phenyl-
sulfonyl)-3-indolecarboxaldehyde (7). Key transformations include
a stepwise variant of a Mannich-like, multicomponent assembly
process, a double RCM, and a one-pot deprotection/cyclization
reaction.

B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
7327
4. Experimental procedures
4.1. General
1453, 1111, 994, 917, 700 cmꢁ1; Mass spectrum (CI) m/z 214.1601
[C15H20N (Mþ1) requires 214.1596].
4.2.2. 2-Methylenebutan-1-amine hydrochloride (15). NaBH4 (7.1 g,
0.19 mol) was added portionwise to a solution of 2-ethylacrolein
(18.5 mL, 15.89 g, 0.19 mol) in Et2O (125 mL) and MeOH (35 mL) at
0 ꢂC. The reaction was stirred for 1 h at 0 ꢂC and then for 1 h at room
temperature. The reaction was partitioned between H2O (200 mL)
and Et2O (100 mL). The aqueous layer was backwashed with Et2O
(3ꢃ100 mL), and the combined organics were dried (MgSO4), fil-
tered, and concentrated by simple distillation to give 15.6 g of 2-
methylidenebutan-1-ol as a w78% solution in Et2O (by NMR). An
additional volume of Et2O (200 mL) was added, and the solutionwas
cooled to 0 ꢂC. PBr3 (13.5 mL, 38.88 g, 0.14 mol) was added dropwise,
and the reaction was warmed to room temperature and stirred for
15 h. The reaction was then cooled to 0 ꢂC, and ice water (100 mL)
was slowly added. Additional H2O (100 mL) and Et2O (100 mL) were
then added, and the phases were separated. The organic phase was
washed sequentially with H2O (50 mL), saturated aqueous NaHCO3
(50 mL) and brine (2ꢃ50 mL). The organic layer was dried (MgSO4),
filtered, and concentrated by simple distillation to give 23.1 g of 2-
(bromomethyl)but-1-ene as a w70% solution in Et2O (by NMR). This
solution of crude 2-(bromomethyl)but-1-ene was added to LiHMDS
(1.44 M in hexane, 90 mL) at ꢁ40 ꢂC. The reaction was warmed to
room temperature and then heated under reflux for 24 h. The re-
actionwas cooled to room temperature and filtered through a pad of
Celite that was washed with pentane (3ꢃ20 mL). The filtrates and
washings were concentrated under reduced pressure, and the res-
idue was diluted with pentane (100 mL). The suspension was fil-
tered through a pad of Celite that was washed with pentane
(3ꢃ20 mL). The filtrates and washings were concentrated under
reduced pressure, and the crude bis(silyl)amine was added drop-
wise to a solution of HCl in MeOH/Et2O [prepared from AcCl (35 mL)
and MeOH (100 mL) in Et2O (100 mL) at 0 ꢂC]. The reaction was
warmed to room temperature and stirred for 15 h, whereupon the
reaction was concentrated under reduced pressure. The residue was
crystallized from EtOH (w15 mL) to give 5.27 g (22%) of 15 as a white
Unless otherwise noted, all other reagents and solvents were
obtained from commercial suppliers and used without further
purification. Tetrahydrofuran (THF) and ether (Et2O) were dried by
passage through two columns of activated neutral alumina. Meth-
anol (MeOH) and N,N-dimethylformamide (DMF) were dried by
passage through two columns of activated molecular sieves.
Dichloromethane (CH2Cl2), triethylamine (Et3N), and N,N-diiso-
propylamine (i-Pr2NH) were distilled from calcium hydride. N,N-
Diisopropylethylamine (i-Pr2NEt) was distilled from KOH. Dime-
ꢀ
thoxyethane (DME) was dried by 4 A molecular sieves. AlCl3 and
KOt-Bu were sublimed under reduced pressure. Reactions involving
air- or moisture-sensitive reagents were performed using oven-
dried glassware under an atmosphere of dry nitrogen or argon.
Removal of solvent or concentration under reduced pressure was
performed using a rotary evaporator. Unless otherwise indicated,
all 1H and 13C NMR spectra were recorded at room temperature in
CDCl3, C6D6 or DMSO-d6. Chemical shifts were reported in parts per
million (ppm,
d
) downfield from TMS (
d
¼0.00 ppm) and referenced
relative to CDCl3 (7.26 ppm for 1H and 77.0 ppm for 13C), C6D6
(7.15 ppm for 1H and 128.0 ppm for 13C) and DMSO-d6 (2.50 ppm for
1H and 39.4 ppm for 13C). Coupling constants were reported in
hertz (Hz). Splitting patterns were designated as: s¼singlet;
d¼doublet; dd¼doublet of doublet; ddd¼doublet of doublet of
doublets; t¼triplet; q¼quartet; p¼pentuplet; hep¼heptet;
m¼multiplet; comp¼overlapping multiplets of non-magnetically
equivalent protons; br¼broad; app¼apparent. Melting points
were determined on a melting point apparatus and are un-
corrected. Infrared (IR) spectra were obtained as thin films on so-
dium chloride plates and reported in wave numbers (cmꢁ1).
Analytical thin-layer chromatography (TLC) was performed on
Merck-60 TLC plates with the indicated solvents. Visualization was
accomplished by UV light or stained with KMnO4 solution. Flash
chromatography was performed with Merck 250e400 mesh silica
gel with the indicated solvents according to the procedure of Still.23
waxy solid, mp¼158e159 ꢂC. 1H NMR (400 MHz, CDCl3)
d 8.40 (s,
3H), 5.22 (s, 1H), 5.11 (s, 1H), 3.58 (s, 2H), 2.17 (q, J¼7.4 Hz, 2H), 1.08
(t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 142.2,113.6, 43.8, 27.0,
4.2. Preparation and characterization of selected new
compounds
11.7; IR (film) 3409, 2971, 1603, 1515, 1458, 1378, 909, 736 cmꢁ1
;
Mass spectrum (CI) m/z 86.0973 [C5H12N (MþH)þ requires 86.0970].
4.2.1. Amine 12. n-BuLi (0.4 mL, 2.3 M in hexane, 0.94 mmol) was
added to a solution of 1,4-pentadiene (0.1 mL, 66 mg, 0.97 mmol) in
THF (0.5 mL) at ꢁ78 ꢂC. The reaction was stirred at ꢁ78 ꢂC for
15 min, whereupon the bath was replaced with a 0 ꢂC bath. The
reaction was stirred for an additional 30 min at 0 ꢂC. A solution of
AlCl3 (140 mg, 1.05 mmol) in Et2O (1 mL) was added, and the re-
action was stirred for 1 h at 0 ꢂC. The pentadienyl Al reagent 10c
thus prepared was added to a solution of imine 11 (112 mg,
0.77 mmol) in CH2Cl2 (2 mL), and the reaction was stirred for 18 h at
room temperature. H2O (3 mL) and 6 M NaOH (4 mL) were added,
and the mixture was filtered through a pad of Celite, washing with
CH2Cl2 (3ꢃ5 mL). The layers were separated, and the aqueous phase
was extracted with CH2Cl2 (2ꢃ5 mL). The combined organics were
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with
EtOAc/hexane (1:9 to 1:3) to give 116 mg (70%) of amine 12 and
4 mg (2%) of amine 13 as colorless oils. Amine 12: 1H NMR
4.2.3. Imine 17. A mixture of indole-3-carboxaldehyde (7) (4.28 g,
15.0 mmol), 2-ethylallylamine hydrochloride (15) (3.65 g,
30.0 mmol), Et3N (4.32 mL, 3.13 g, 31.0 mmol) and activated 4 A
molecular sieves (w2 g) in CH2Cl2 (50 mL) was stirred for 20 h at
room temperature, and then Et2O (250 mL) was added. The mixture
was stirred for 10 min at room temperature and filtered through
a pad of Celite that was washed with Et2O (3ꢃ50 mL). The com-
bined filtrates and washings were concentrated under reduced
pressure to give w5.4 g (100%) crude imine 17 as an orangish brown
oil that was used without further purification. 1H NMR (400 MHz,
ꢀ
CDCl3)
d
8.43 (s, 1H), 8.37 (d, J¼7.6 Hz, 1H), 7.98 (d, J¼8.2 Hz, 1H),
7.92 (d, J¼8.0 Hz, 2H), 7.85 (s, 1H), 7.55 (t, J¼7.6 Hz, 1H), 7.45 (t,
J¼8.0 Hz, 2H), 7.38 (td, J¼8.2, 1.0 Hz, 1H), 7.31 (t, J¼7.6 Hz, 1H), 4.96
(s, 1H), 4.87 (s, 1H), 4.19 (s, 2H), 2.19 (q, J¼7.4 Hz, 2H), 1.21 (t,
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 154.6,149.5,137.8,135.5,
134.1, 129.5, 129.4, 128.0, 126.8, 125.6, 124.2, 123.2, 120.8, 113.2,
109.0, 66.8, 27.5, 12.1; IR (film) 1642, 1446, 1378, 1177, 1126, 1100,
979 cmꢁ1; Mass spectrum (CI) m/z 353.1316 [C20H21N2O2S (MþH)þ
requires 353.1310].
(400 MHz, CDCl3)
d 7.33e7.21 (comp, 5H), 5.87e5.72 (comp, 2H),
5.59 (ddd, J¼17.8, 10.8, 7.2 Hz,1H), 5.19e5.03 (comp, 4H), 4.95e4.89
(comp, 2H), 3.58 (d, J¼7.9 Hz, 1H), 3.08 (ddt, J¼14.3, 5.2, 1.7 Hz, 1H),
3.02 (dt, J¼7.8, 7.8 Hz, 1H), 2.94 (ddt, J¼14.3, 6.8, 1.0 Hz, 1H); 13C
4.2.4. Amine 19. n-BuLi (7.97 mL, 2.5 M in hexane, 20.0 mmol) was
added to a solution of 1,4-pentadiene (2.1 mL, 1.36 g, 20.0 mmol) in
THF (10 mL) at ꢁ78 ꢂC. The reaction was stirred at ꢁ78 ꢂC for
NMR (100 MHz, CDCl3) d 141.4, 138.1, 137.7, 136.8, 128.3, 127.9, 127.0,
117.4, 116.0, 115.6, 65.1, 55.1, 49.7; IR (neat) 3078, 2977, 2817, 1642,

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B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
15 min, whereupon the bath was replaced with a 0 ꢂC bath, and the
reaction was stirred for 30 min at 0 ꢂC. A solution of AlCl3 (2.86 g,
21.4 mmol) in Et2O (10 mL) was added, and the reaction was stirred
for 1 h at 0 ꢂC. The pentadienyl Al reagent 10c thus prepared was
added to a solution of imine 17 (w5.4 g, 15.0 mmol) in CH2Cl2
(50 mL), and the reaction was stirred for 24 h at room temperature,
whereupon the reaction was opened to air, and 1 N NaOH (200 mL)
was added. The mixture was stirred vigorously for 5 min and then
filtered through a pad of Celite, and the pad was washed with
CH2Cl2 (3ꢃ50 mL). The filtrates were combined, and the aqueous
layer was separated and extracted with CH2Cl2 (2ꢃ100 mL). The
combined organic layers were concentrated under reduced pres-
sure to give w6.5 g crude 19 as an orangish brown oil that was used
5.12e5.07 (comp, 2H), 4.84e4.82 (comp, 3H), 4.70 (d, J¼10.3 Hz,
1H), 4.07 (d, J¼10.9 Hz, 1H), 3.71e3.62 (comp, 2H), 3.40 (dt, J¼10.3,
7.4 Hz, 1H), 3.12 (d, J¼13.9 Hz, 1H), 2.76 (dt, J¼13.2, 6.7 Hz, 1H), 2.62
(d, J¼13.9 Hz, 1H), 2.30 (dt, J¼13.2, 6.5 Hz, 1H), 2.03 (dq, J¼23.2,
7.4 Hz, 1H), 2.00 (dq, J¼23.2, 7.4 Hz, 1H), 0.98 (t, J¼7.4 Hz, 3H), 0.90
(s, 9H), 0.059 (s, 3H), 0.056 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
149.6, 139.9, 138.4, 138.1, 134.9, 133.7, 132.5, 129.1, 126.7, 124.7,
124.6, 123.2, 120.7, 120.1, 116.0, 115.1, 113.7, 110.8, 62.9, 59.6, 57.3,
52.3, 50.9, 26.5, 26.0, 18.4, 12.2, ꢁ5.30, ꢁ5.31; IR (film) 2928, 1446,
1370, 1255, 1176, 1095, 835 cmꢁ1; Mass spectrum (CI) m/z 579.3087
[C33H47N2O3SSi (MþH)þ requires 579.3077].
4.2.7. TBS ether 22. The TBS ether 22 was prepared as an off-white
solid in 68% overall yield from 7 without purifying any in-
termediates using the same procedures outlined for the synthesis
without further purification. 1H NMR (600 MHz, CDCl3)
d 7.99 (d,
J¼8.3 Hz, 1H), 7.82e7.80 (m, 2H), 7.70 (d, J¼7.8 Hz, 1H), 7.49 (t,
J¼7.5 Hz, 1H), 7.42 (s, 1H), 7.38 (t, J¼7.5 Hz, 2H), 7.29 (t, J¼7.8 Hz,
1H), 7.20 (t, J¼7.8 Hz, 1H), 5.75 (ddd, J¼17.1, 10.2, 8.7 Hz, 1H),
5.65e5.59 (m, 1H), 5.14 (dd, J¼10.2, 1.7 Hz, 1H), 5.09 (d, J¼17.1 Hz,
1H), 4.83 (d, J¼1.1 Hz, 1H), 4.82e4.80 (m, 1H), 4.77 (s, 1H), 4.74 (s,
1H), 3.82 (d, J¼7.7 Hz, 1H), 3.14 (app q, J¼7.7 Hz, 1H), 3.02 (d,
J¼14.3 Hz, 1H), 2.91 (d, J¼14.3 Hz, 1H), 1.97 (dq, J¼23.1, 7.4 Hz, 1H),
1.92 (dq, J¼23.1, 7.4 Hz, 1H), 1.61 (s, 1H), 0.93 (t, J¼7.4 Hz, 3H); 13C
of 23 from 7, mp¼85.5e87.5 ꢂC. 1H NMR (600 MHz, CDCl3)
d 7.96 (d,
J¼8.2 Hz, 1H), 7.78 (d, J¼8.5 Hz, 1H), 7.59 (d, J¼8.2 Hz, 1H), 7.49 (t,
J¼7.6 Hz, 1H), 7.40 (s, 1H), 7.38 (t, J¼7.6 Hz, 1H), 7.27 (t, J¼8.2 Hz,
1H), 7.20 (t, J¼8.2 Hz, 1H), 5.97 (ddd, J¼17.5, 10.3, 7.5 Hz, 1H), 5.74
(dddd, J¼17.7, 10.2, 7.7, 4.5 Hz, 1H), 5.47 (ddd, J¼17.3, 10.3, 7.5 Hz,
1H), 5.08e5.03 (comp, 4H), 4.84 (dt, J¼17.3, 1.3 Hz, 1H), 4.73 (d,
J¼10.3 Hz, 1H), 4.03 (d, J¼10.4 Hz, 1H), 3.67e3.60 (comp, 2H), 3.38
(app q, J¼7.4 Hz, 1H), 3.27e3.23 (m, 1H), 2.73 (dd, J¼14.5, 7.7 Hz,
1H), 2.70 (ddd, J¼13.2, 7.2, 6.1 Hz, 1H), 2.35 (dt, J¼6.6, 13.2 Hz, 1H),
NMR (150 MHz, CDCl3)
d 149.4, 138.2, 137.8, 137.7, 135.8, 133.6,
130.3, 129.0, 126.6, 124.8, 124.6, 123.8, 123.1, 120.9, 117.7, 116.1, 113.9,
108.9, 57.7, 53.7, 52.0, 27.0, 12.2. IR (film) 3073, 2964, 1446, 1368,
1176, 1120, 918, 747 cmꢁ1; Mass spectrum (CI) m/z 421.1949
[C25H29N2O2S (MþH)þ requires 421.1950].
0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (150 MHz, CDCl3)
d 139.8, 138.3,
138.1,137.4,134.9,133.7,132.3,129.1,126.7,124.7,124.6,123.2,120.6,
120.4, 116.6, 116.1, 115.0, 113.6, 63.0, 59.9, 54.7, 52.3, 50.9, 26.0, 18.3,
ꢁ5.3; IR (neat) 2928, 1447, 1370, 1176, 1119, 1094, 914, 834 cmꢁ1
;
4.2.5. Triene 21. A solution of 19 (w6.5 g, w15 mmol) and ethylene
oxide (7.7 mL, 6.8 g, 154 mmol) in MeOH (15 mL) was heated at
65 ꢂC in a sealed tube for 64 h. After cooling to room temperature,
the reaction was concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with EtOAc/hexane
(1:3) to give 6.39 g (89%) of a mixture (>10:1) of branched and
linear adducts as a slightly brown gum that was crystallized from
MeOH (w2 mL) to give 5.1 g (71% overall yield from 7) 21 as a pale
Mass spectrum (CI) m/z 551.2765 [C31H42N2O3SSi (Mþ1) requires
551.2764].
4.2.8. Alcohols 24. TBS ether 22 (318 mg, 0.58 mmol) was dried by
azeotroping with benzene (3ꢃw10 mL) and dissolved in THF
(4 mL). The solution was cooled to ꢁ78 ꢂC. LDA (1 M in THF/hexane,
1.1 mL, 1.1 mmol) was added, and the reaction was stirred for
10 min at ꢁ78 ꢂC. The ꢁ78 ꢂC bath was exchanged for a 0 ꢂC bath,
and the reaction was stirred for 2 h at 0 ꢂC. The reaction was
recooled to ꢁ78 ꢂC, and methyl pyruvate (226 mg, 2.21 mmol) was
added. The reaction was stirred for 2 h over, which time the mixture
warmed to 5 ꢂC. The mixture was partitioned between Et2O (5 mL)
and saturated aqueous NH4Cl (5 mL). The organic phase was re-
moved, and the aqueous layer was extracted with CH2Cl2 (2ꢃ5 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with EtOAc/hexane (gradient elution,
1:19 to 1:9) to give 84 mg (26%) of 22 together with two di-
astereomers of 24: 135 mg (35%) (major diastereomer) and 95 mg
(25%) (minor diastereomer). Major diastereomer: 1H NMR
yellow solid, mp¼90e92 ꢂC. 1H NMR (600 MHz, CDCl3)
d 8.00 (d,
J¼7.8 Hz, 1H), 7.83e7.81 (m, 2H), 7.54e7.51 (m, 1H), 7.43e7.40
(comp, 3H), 7.32 (ddd, J¼8.4, 7.2, 0.9 Hz, 1H), 7.24 (ddd, J¼8.4, 7.2,
0.9 Hz,1H), 5.91e5.85 (m,1H), 5.40e5.35 (m,1H), 5.24e5.20 (comp,
2H), 4.95 (m, 1H), 4.91 (m, 1H), 4.84 (dt, J¼16.8, 1.2 Hz, 1H), 4.66
(ddd, J¼16.2, 1.5, 0.9 Hz, 1H), 4.00 (d, J¼12.0 Hz, 1H), 3.67 (td,
J¼10.8, 3.0 Hz, 1H), 3.53 (app d, J¼10.8 Hz, 1H), 3.47e3.43 (m, 1H),
3.12 (d, J¼13.8 Hz, 1H), 2.97 (ddd, J¼13.2, 10.8, 4.8 Hz, 1H), 2.64 (app
d, J¼13.8 Hz, 2H), 2.18 (dt, J¼13.2, 2.4 Hz, 1H), 2.16e2.10 (m, 1H),
2.06e2.00 (m, 1H), 1.05 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d
148.5, 139.7, 138.0, 137.9, 134.9, 133.8, 132.1, 129.1, 126.6, 125.1,
124.8, 123.3, 120.2, 118.7, 116.6, 116.1, 113.8, 112.2, 58.8, 58.2, 56.2,
51.5, 51.2, 26.6, 12.1; IR (film) 3468, 3077, 2965, 2921, 2833, 1447,
1369, 1177, 1121, 914 cmꢁ1; Mass spectrum (CI) m/z 465.2215
[C27H33N2O3S (MþH)þ requires 465.2212].
(500 MHz, C6D6)
d 10.14 (s, 1H), 7.99e7.96 (comp, 3H), 7.30e7.28
(m, 1H), 6.94e6.91 (comp, 2H), 6.71 (t, J¼7.4 Hz, 1H), 6.63 (t, J¼7.4,
1H), 6.06e5.98 (m, 1H), 5.89 (ddd, J¼17.7, 10.4, 7.6 Hz, 1H), 5.30
(ddd, J¼16.9, 10.0, 8.7 Hz, 1H), 5.07 (d, J¼17.7 Hz, 1H), 5.03e5.00
(comp, 2H), 4.91 (d, J¼16.9 Hz, 1H), 4.80 (d, J¼17.1 Hz, 1H), 4.51 (d,
J¼7.6 Hz, 1H), 4.40 (dd, J¼10.0, 1.8 Hz, 1H), 3.96e3.87 (comp, 2H),
3.81e3.77 (comp, 3H), 3.62 (s, 1H), 3.37 (dt, J¼6.5, 13.0 Hz, 1H),
2.92e2.87 (m, 1H), 2.40 (s, 3H), 0.97 (s, 9H), 0.69 (s, 3H), 0.65 (s,
4.2.6. TBS ether 23. A solution of amino alcohol 21 (5.1 g,
11.0 mmol), TBSCl (1.99 g, 13.2 mmol) and imidazole (1.12 g,
16.5 mmol) in DMF (12 mL) was stirred for 6 h at room temperature.
The reaction was partitioned between H2O (100 mL) and Et2O
(100 mL). The organic phase was separated, and the aqueous phase
was extracted with Et2O (2ꢃ100 mL). The combined organic phases
were washed with brine (100 mL), dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with EtOAc/hexane (1:4) to give
6.23 g (98%) 23 as a white solid, mp¼58e59.5 ꢂC. 1H NMR
3H); 13C NMR (125 MHz, C6C6)
d 174.6, 142.8, 142.6, 139.0, 138.1,
136.9, 133.1, 131.6, 128.6, 127.7, 125.1, 124.4, 123.7, 119.6, 115.9, 115.3,
115.2, 77.7, 61.6, 61.3, 54.5, 51.8, 51.6, 27.4, 26.2, 18.5, ꢁ5.3, ꢁ5.4; IR
(neat) 3070, 2950, 1755, 1728, 1448, 1376, 1176, 1116, 916, 836 cmꢁ1
;
Mass spectrum (CI) m/z 653.3081 [C35H48N2O6SSi (Mþ1) requires
653.3081]. Minor Diastereomer: 1H NMR (600 MHz, CDCl3)
d
10.77
(600 MHz, CDCl3)
d
7.98 (d, J¼8.3 Hz, 1H), 7.82e7.80 (m, 2H), 7.59
(br, 1H), 7.72 (d, J¼7.6 Hz, 2H), 7.68e7.66 (m, 1H), 7.46e7.42 (comp,
2H), 7.33e7.30 (m, 2H), 7.17e7.11 (comp, 2H), 6.05 (app dt, J¼10.0,
17.6 Hz, 1H), 5.93 (ddt, J¼17.2, 10.3, 7.0 Hz, 1H), 5.83 (ddd, J¼17.4,
10.3, 7.9 Hz, 1H), 5.22 (d, J¼10.3 Hz, 1H), 5.18 (d, J¼17.4 Hz, 1H), 5.07
(app d, J¼7.7 Hz, 1H), 7.50 (t, J¼7.5 Hz, 1H), 7.40 (s, 1H), 7.38 (t,
J¼7.5 Hz, 2H), 7.29 (t, J¼7.7 Hz, 1H), 7.21 (t, J¼7.7 Hz, 1H), 6.06 (ddd,
J¼17.5, 10.4, 7.4 Hz, 1H), 5.43 (ddd, J¼17.5, 10.3, 7.4, Hz, 1H),

B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
7329
(d, J¼17.2 Hz, 1H), 5.05 (d, J¼17.6 Hz, 1H), 5.01 (d, J¼10.3 Hz, 1H),
4.84 (dd, J¼10.0 Hz, 1H), 4.07 (d, J¼7.4 Hz, 1H), 3.87 (ap q, J¼7.9 Hz,
1H), 3.79e3.73 (comp, 2H), 3.47 (dd, J¼14.9, 5.6 Hz, 1H), 3.67 (s,
3H), 3.35e3.28 (m, 1H), 2.98e2.86 (comp, 2H), 2.01 (s, 3H), 0.88 (s,
CH2Cl2 (15 mL) at ꢁ78 ꢂC. The reaction was stirred for 30 min at
ꢁ78 ꢂC and then partitioned between 1 M NaOH (6 mL) and CH2Cl2
(10 mL). The organic phase was separated, and the aqueous layer
was extracted with CH2Cl2 (2ꢃ10 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with EtOAc/hexane (1:10) to give 2.5 g (92%) of 29 as a colorless oil.
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 172.2,
142.1, 140.9, 139.2, 138.4, 136.2, 133.3, 132.3, 130.8, 128.7, 127.0,
125.0, 123.3, 122.3, 119.9, 115.5, 115.3, 115.0, 77.4, 60.9, 60.1, 52.9,
51.9, 51.1, 50.2, 30.3, 26.0, 18.3, ꢁ5.38, ꢁ5.41; IR (neat) 3072, 2950,
1738, 1637, 1448, 1361, 1255, 1117, 1098, 914, 836 cmꢁ1; Mass
spectrum (CI) m/z 653.3083 [C35H48N2O6SSi (Mþ1) requires
653.3081].
1H NMR (600 MHz, CDCl3)
d
8.24 (d, J¼7.7 Hz, 1H), 7.77 (d, J¼7.7 Hz,
1H), 7.60e7.58 (m, 2H), 7.45 (t, J¼7.5 Hz, 1H), 7.32e7.25 (comp, 3H),
7.21 (t, J¼7.7 Hz,1H), 6.96 (dd, J¼17.7,11.4 Hz,1H), 5.92 (ddd, J¼16.8,
10.8, 7.4 Hz, 1H), 5.59 (dd, J¼11.4, 1.8 Hz, 1H), 5.35 (ddd, J¼17.3, 10.3,
7.4 Hz, 1H), 5.31 (dd, J¼17.7, 1.8 Hz, 1H), 5.10e5.06 (comp, 2H), 4.84
(s, 1H), 4.73 (s, 1H), 4.71 (d, J¼17.3 Hz, 1H), 4.54 (d, J¼10.3 Hz, 1H),
4.14 (d, J¼10.7 Hz, 1H), 3.70 (dt, J¼10.7, 7.4 Hz, 1H), 3.56e3.51 (m,
1H), 3.48e3.44 (m, 1H), 3.15 (d, J¼14.0 Hz, 1H), 2.74 (ddd, J¼13.1,
8.4, 6.5 Hz,1H), 2.65 (d, J¼14.0 Hz,1H), 2.23 (ddd, J¼13.1, 7.8, 5.0 Hz,
1H), 2.00 (dq, J¼15.1, 7.5 Hz, 1H), 1.91 (dq, J¼15.1, 7.5 Hz, 1H), 0.94 (t,
J¼7.4 Hz, 3H), 0.86 (s, 9H), ꢁ0.011 (s, 3H), ꢁ0.014 (s, 3H); 13C NMR
4.2.9. Alcohols 28. TBS ether 23 (1.16 g, 2.0 mmol) was azeotroped
from benzene (3ꢃw10 mL), dissolved in THF (8 mL) and cooled to
ꢁ78 ꢂC. LDA (1.0 M in THF/hexane, 4.0 mL, 4.0 mmol) was added,
and the reaction was stirred for 10 min at ꢁ78 ꢂC. The ꢁ78 ꢂC bath
was exchanged for a 0 ꢂC bath, and the reaction was stirred for 2 h
at 0 ꢂC. The reaction was then cooled to ꢁ78 ꢂC, and freshly distilled
acetaldehyde (0.45 mL, 353 mg, 8.0 mmol) was added. The reaction
was allowed to slowly warm to ꢁ30 ꢂC over 2 h. The reaction was
cooled to ꢁ78 ꢂC, and saturated NH4Cl (3 mL) was added. The re-
action was partitioned between Et2O (20 mL) and brine (15 mL).
The organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (2ꢃ10 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with EtOAc/hexane (gradient elution, 1:49 to 1:19 to 1:9) to give
0.71 g (56%) of 28a (major diastereomer, less polar) as a colorless
oil, and 0.27 g (22%) of 28b (minor diastereomer, more polar) as
a colorless oil. For 28a (major diastereomer). 1H NMR (600 MHz,
(150 MHz, CDCl3)
d 149.7, 139.8, 138.2, 138.1, 137.8, 136.9, 133.5,
128.7, 128.1, 126.6, 124.7, 123.5, 122.9, 122.1, 120.7, 115.5, 115.34,
115.33, 110.0, 61.6, 60.7, 57.3, 52.2, 48.7, 26.5, 26.0, 18.3, 12.1, ꢁ5.30,
ꢁ5.31; IR (film) 2928, 1448, 1374, 1253, 1175, 1091, 987, 916, 836,
751 cmꢁ1; Mass spectrum (CI) m/z 605.3246 [C35H49N2O3SSi
(MþH)þ requires 605.3233].
4.2.11. D/E cis Tetracycle 33 and D/E trans tetracycle 34. A solution
of tetraene 29 (326 mg, 0.57 mmol) and Hoveyda-Grubbs II catalyst
(18 mg, 0.029 mmol) in toluene (56 mL) was placed in a pre-heated
oil bath (100 ꢂC) and heated for 3.5 h. The mixture was cooled to
room temperature, and the toluene was removed under reduced
pressure. The residue was dissolved in degassed EtOH (3 mL)
containing PtO2 (13 mg, 0.057 mmol), and the mixture was stirred
under H2 (1 atm) for 21 h at room temperature. The reaction was
filtered through a pad of Celite, and the pad was washed with
MeOH (10 mL). The combined filtrates and washings were con-
centrated under reduced pressure. The residue was dissolved in
MeOH (5 mL), and 1.25 M HCl in MeOH (5 mL) was added. The
reaction was stirred for 1 h at room temperature and then parti-
tioned between 1 N NaOH (10 mL) and CH2Cl2 (20 mL). The organic
phase was separated, and the aqueous phase was extracted with
CH2Cl2 (3ꢃ15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel eluting
with EtOAc/hexane (1:6) and EtOAc/hexane (1:4) to give 45 mg
(26%) 33 as a white foam and 76 mg (44%) 34 as a white foam. D/E
DMSO-d6)
d
7.99 (d, J¼8.2 Hz, 1H), 7.90e7.88 (m, 1H), 7.69 (d,
J¼7.5 Hz, 2H), 7.59 (t, J¼7.5 Hz, 1H), 7.45 (d, J¼7.5 Hz, 1H), 7.22 (t,
J¼7.7 Hz, 1H), 7.16 (t, J¼7.7 Hz, 1H), 6.04e6.00 (m, 1H), 5.56e5.53
(m, 1H), 5.46e5.40 (m, 1H), 5.27 (d, J¼4.7 Hz,1H), 5.05 (d, J¼17.5 Hz,
1H), 5.00 (d, J¼10.3 Hz, 1H), 4.84 (s, 1H), 4.71 (s, 1H), 4.65 (d,
J¼9.3 Hz, 1H), 4.56 (d, J¼16.7 Hz, 1H), 4.43 (d, J¼9.4 Hz, 1H), 3.70
(app q, J¼8.3 Hz, 1H), 3.52 (t, J¼6.8 Hz, 1H), 3.14 (d, J¼13.8 Hz, 1H),
2.75 (d, J¼13.8 Hz, 1H), 2.61 (dt, J¼13.4, 6.8 Hz, 1H), 2.44 (dt, J¼13.4,
6.8 Hz,1H), 2.01 (dq, J¼14.9, 7.4 Hz,1H), 1.91 (dq, J¼14.9, 7.4 Hz,1H),
1.57 (d, J¼6.6 Hz, 3H), 0.86 (t, J¼7.4 Hz, 3H), 0.81 (s, 9H), ꢁ0.06 (s,
6H); 13C NMR (150 MHz, DMSO-d6)
d 150.0, 142.4, 140.9, 138.4,
137.0,136.5,134.1,130.2,129.1, 126.1,124.3,123.4,123.3,122.2,114.8,
114.6, 114.3, 109.9, 62.5, 61.2, 60.9, 57.6, 52.2, 49.1, 25.72, 25.71, 24.7,
17.8, 11.9, ꢁ5.5; IR (film) 3551, 2930, 1447, 1362, 1254, 1174, 1092,
835 cmꢁ1; Mass spectrum (CI) m/z 623.3331 [C35H51N2O4SSi
(MþH)þ requires 623.3339]. For 28b (minor diastereomer). 1H NMR
cis tetracycle 33. 1H NMR (600 MHz, CDCl3)
d
8.14 (d, J¼7.8 Hz, 1H),
(600 MHz, DMSO-d6)
d
8.02 (d, J¼8.3 Hz, 1H), 7.86e7.84 (m, 1H),
7.68 (dd, J¼8.7, 0.9 Hz, 2H), 7.63 (d, J¼7.2 Hz, 1H), 7.49 (tt, J¼7.5,
1.2 Hz, 1H), 7.37 (app t, J¼8.1 Hz, 2H), 7.26 (app td, J¼7.8, 1.2 Hz, 1H),
7.21 (td, J¼7.4, 1.2 Hz, 1H), 5.36 (s, 1H), 4.03 (d, J¼4.8 Hz, 1H),
3.63e3.50 (m, 2H), 3.00e2.97 (m, 2H), 2.90e2.83 (comp, 2H),
2.76e2.69 (comp, 2H), 2.60 (app br s, 1H), 2.02 (m, 1H), 1.86e1.77
(comp, 3H), 0.92 (t, J¼7.5 Hz, 3H); 13C NMR (150 MHz, CDCl3)
7.63 (d, J¼7.5 Hz, 2H), 7.58 (t, J¼7.5 Hz, 1H), 7.43 (t, J¼7.5 Hz, 1H),
7.24 (t, J¼7.3 Hz, 1H), 7.17 (t, J¼7.3 Hz, 1H), 6.01 (ddd, J¼17.2, 10.3,
6.9 Hz, 1H), 5.69 (br, 1H), 5.45e5.39 (comp, 2H), 5.08 (d, J¼17.2 Hz,
1H), 5.03 (d, J¼10.3 Hz, 1H), 4.75 (m, 1H), 4.71 (s, 1H), 4.68 (d,
J¼17.4 Hz, 1H), 4.65 (s, 1H), 4.57 (d, J¼10.3 Hz, 1H), 3.74e3.72 (m,
1H), 3.50e3.42 (comp, 2H), 3.08 (d, J¼13.8 Hz, 1H), 2.61 (d,
J¼13.8 Hz, 1H), 2.52e2.47 (m, 1H), 2.35 (dt, J¼12.6, 5.8 Hz, 1H), 1.99
(dq, J¼15.1, 7.2 Hz,1H),1.88 (dq, J¼15.1, 7.2 Hz,1H),1.48 (d, J¼5.4 Hz,
1H), 0.83 (t, J¼7.2 Hz, 3H), 0.82 (s, 9H), ꢁ0.05 (s, 3H), ꢁ0.06 (s, 3H);
d
138.9, 138.1, 137.9, 136.7, 133.5, 130.2, 129.1, 126.1, 124.1, 123.6,
120.3, 119.6, 118.4, 114.6, 58.9, 55.8, 53.7, 49.0 (br), 30.3 (br), 27.6,
26.7, 22.3, 12.0; IR (film) 3419, 2960, 2923, 2875, 1449, 1369, 1187,
1170, 1146, 1092, 1051 cmꢁ1; Mass spectrum (ESI) m/z 437.1895
[C25H29N2O3S (MþH)þ requires 437.1893]. D/E trans tetracycle 34.
13C NMR (150 MHz, DMSO-d6)
d 150.4, 142.8, 140.7, 138.1, 136.9,
136.5, 134.0, 131.0, 129.1, 126.1, 124.2, 123.5, 122.2, 115.4, 115.1, 114.7,
109.4, 63.1, 61.3, 60.0, 57.5, 51.9, 48.4, 26.1, 25.8, 25.6, 17.9, 11.8,
ꢁ5.41, ꢁ5.42; IR (film) 3555, 2929, 1448, 1362, 1173, 1091, 914,
836 cmꢁ1; Mass spectrum (CI) m/z 623.3333 [C35H51N2O4SSi
(MþH)þ requires 623.3339].
1H NMR (600 MHz, CDCl3)
d
8.14 (dt, J¼7.8, 0.90 Hz, 1H), 7.90 (d,
J¼7.8 Hz, 1H), 7.77e7.75 (comp, 2H), 7.52 (tt, J¼7.5, 1.2 Hz, 1H),
7.43e7.40 (comp, 2H), 7.26 (app td, J¼7.8, 1.2 Hz, 1H), 7.21 (td, J¼7.5,
1.2 Hz,1H), 5.49 (s, 1H), 3.93 (d, J¼9.6 Hz,1H), 3.69 (ddd, J¼10.8, 9.6,
4.8 Hz, 1H), 3.60 (d, J¼18.0 Hz, 1H), 3.48 (ddd, J¼10.8, 9.6, 3.0 Hz,
1H), 3.22 (d, J¼17.4 Hz, 1H), 3.16 (ddt, J¼18.0, 5.4, 1.8 Hz, 1H),
3.02e2.96 (m, 1H), 2.45 (dt, J¼12.6, 3.9 Hz, 1H), 2.42e2.37 (m, 1H),
2.29 (ddd, J¼15.0, 9.0, 6.0 Hz, 1H), 2.07 (app ddt, J¼13.2, 6.0, 2.1 Hz,
1H), 2.01e1.90 (comp, 2H), 1.53 (qd, J¼13.2, 5.4 Hz, 2H), 1.04 (t,
4.2.10. Tetraene 29. Freshly distilled Tf2O (0.92 mL, 1.53 g,
€
5.4 mmol) and Hunig’s base (2.3 mL, 1.74 g, 13.4 mmol) were added
in rapid succession to a solution of alcohol 28 (2.8 g, 4.5 mmol) in

7330
B. Cheng et al. / Tetrahedron 71 (2015) 7323e7331
J¼7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d
139.0,138.2,137.4, 136.8,
J¼7.5 Hz, 1H), 7.30 (td, J¼7.5, 1.0 Hz, 1H), 7.19 (td, J¼7.5, 1.0 Hz, 1H),
5.49 (app dd, J¼3.0, 1.5 Hz, 1H), 3.65e3.59 (comp, 2H), 3.24 (dt,
J¼18.5, 2.5 Hz, 1H), 3.08 (ddd, J¼11.0, 9.0, 5.0 Hz, 1H), 2.98 (ddd,
J¼13.5, 3.7, 2.5 Hz, 1H), 2.67 (td, J¼13.0, 5.5 Hz, 1H), 2.46 (ddd,
J¼13.3, 10.8, 5.0 Hz, 1H), 2.40e2.33 (m, 1H), 2.32 (d, J¼9.5 Hz, 1H),
2.11 (dp, J¼13.0, 2.5 Hz, 1H), 1.96e1.89 (comp, 3H), 1.25 (qd, J¼12.5,
133.6,129.2,128.8,126.3,124.2, 123.4,122.2,120.5,119.5, 114.4, 61.6,
59.9, 53.1, 48.2, 31.4, 28.5, 27.4, 25.6, 12.2; IR (film) 3416 (br), 2960,
2926, 2855, 1449, 1370, 1173, cmꢁ1; Mass spectrum (CI) m/z
437.1906 [C25H29N2O3S (MþH)þ requires 437.1889].
4.2.12. D/E cis Pentacycle 35. A solution of KOt-Bu (40 mg,
0.36 mmol) in THF (2 mL) was added to a solution of 33 (62 mg,
0.14 mmol) in DME (4 mL) at ꢁ20 ꢂC, and the reaction was slowly
warmed to ꢁ5 ꢂC over 10 min. After being stirred for 15 min at
ꢁ5 ꢂC, the reaction was quenched with brine (1.5 mL). The reaction
was partitioned between brine (5 mL) and Et2O (10 mL). The or-
ganic phase was separated, and the aqueous phase was extracted
with Et2O (3ꢃ10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel eluting
with EtOAc/hexane (2:1), DCM/MeOH (50:1) and DCM/MeOH
(25:1) to give 26 mg (66%) of 35 as a yellow oil. 1H NMR (600 MHz,
3.5 Hz,1H),1.00 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 186.4,
153.8, 146.2, 104.1, 127.4, 125.3, 123.2, 121.0, 119.6, 72.0, 63.1, 51.4,
51.3, 31.5, 31.0, 30.9, 30.7, 27.3, 12.4; IR (film) 3248, 3047, 2963,
2928, 2877, 1574, 1454, 1338, 1145; Mass spectrum (ESI) m/z
279.1858 [C19H23N2 (MþH)þ requires 279.1856].
4.2.15. 14-epi Pseudotabersonine (37). Pentacycle 36 (70 mg,
0.25 mmol) was azeotroped from benzene (3ꢃw10 mL), dissolved
in THF (3 mL) and cooled to ꢁ78 ꢂC. LDA (1.0 M in THF/hexane,
0.75 mL, 0.75 mmol) was added, and the reaction was stirred for 1 h
while warming to ꢁ20 ꢂC. Stirring was continued at ꢁ20 ꢂC for 1 h,
whereupon the reaction was cooled to ꢁ78 ꢂC, and methyl cyano-
formate (0.09 mL, 96 mg, 1.13 mmol) was added. The reaction was
stirred for 1 h at ꢁ78 ꢂC. The reaction was then partitioned between
CH2Cl2 (5 mL) and saturated aqueous NH4Cl (5 mL). The organic
phase was separated, and the aqueous layer was extracted with
CH2Cl2 (3ꢃ5 mL). The combined organics were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with EtOAc/hexane (3:97)
to give 39 mg (46%) of 37 as a viscous oil and 22 mg (26%) of the N-
acylated analog of 37. 14-epi pseudotabersonine (37). 1H NMR
C6D6)
d
7.76 (d, J¼7.8 Hz, 1H), 7.21 (app dq, J¼7.2, 0.6 Hz, 1H), 7.17
(td, J¼7.8, 1.2 Hz, 1H), 7.05 (td, J¼7.2, 1.2 Hz, 1H), 5.19e5.17 (m, 1H),
3.13 (d, J¼15.0 Hz, 1H), 2.93 (t, J¼7.2 Hz, 1H), 2.89e2.82 (comp, 2H),
2.74e2.70 (comp, 2H), 2.57 (ddd, J¼10.8, 8.4, 4.8 Hz, 1H), 2.28e2.20
(m, 1H), 2.03 (ddd, J¼12.6, 10.8, 6.6 Hz, 1H), 1.78 (q, J¼7.6 Hz, 2H),
1.60e1.54 (comp, 2H), 1.52e1.46 (m, 1H), 0.88 (t, J¼7.6 Hz, 3H); 13
C
NMR (150 MHz, C6D6) d 188.5, 156.2, 147.9, 138.7, 128.0, 125.2, 123.1,
121.7, 120.6, 70.7, 61.5, 54.5, 53.6, 35.1, 34.2, 27.9, 26.9, 25.9, 12.8. IR
(film) 2962, 2931, 2872, 2783, 1576, 1455, 1535, 1239, 1148; Mass
spectrum (CI) m/z 279.1861 [C19H23N2 (MþH)þ requires 279.1861].
(600 MHz, CDCl3)
d
9.07 (s,1H), 7.52 (d, J¼7.5 Hz,1H), 7.08 (td, J¼7.5,
1.3 Hz, 1H), 6.83 (td, J¼7.5, 1.0 Hz, 1H), 6.75 (d, J¼7.5 Hz, 1H), 5.51 (d,
J¼1.5 Hz, 1H), 3.75 (s, 3H), 3.70 (d, J¼18.5 Hz, 1H), 3.39 (ddd, J¼9.0,
9.0, 5.5 Hz, 1H), 3.20 (d, J¼18.5 Hz, 1H), 2.92 (ddd, J¼10.8, 9.0,
4.7 Hz, 1H), 2.81 (d, J¼9.8 Hz, 1H), 2.71 (dd, J¼15.6, 5.5 Hz, 1H),
2.56e2.50 (comp, 2H), 2.06 (dd, J¼15.6, 12.8 Hz, 1H), 1.99e1.96
(comp, 2H), 1.91 (ddd, J¼13.3, 9.0, 4.7 Hz, 1H), 1.05 (t, J¼7.5 Hz, 3H);
4.2.13. Pseudotabersonine (4). Pentacycle 35 (26 mg, 0.09 mmol)
was azeotroped from benzene (3ꢃw10 mL), dissolved in THF (2 mL)
and cooled to ꢁ78 ꢂC. LDA (1.0 M in THF/hexane, 0.28 mL,
0.28 mmol) was added. The reaction was allowed to warm slowly to
ꢁ20 ꢂC over 1 h and then stirred at ꢁ20 ꢂC for 30 min. The solution
was cooled to ꢁ78 ꢂC, freshly distilled methyl cyanoformate (37
mL,
13C NMR (150 MHz, CDCl3)
d 169.1, 165.3, 144.2, 138.9, 138.2, 127.3,
40 mg, 0.46 mmol) was added, and the reaction was stirred for
30 min at ꢁ78 ꢂC. Brine (2 mL) was added, and the reaction was
partitioned between Et2O (10 mL) and brine (5 mL). The organic
phase was separated, and the aqueous phase was extracted with
Et2O (3ꢃ5 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with EtOAc/hexane (1:5)
to give 19 mg (61%) of 4 as a colorless oil. 1H NMR (600 MHz, CDCl3)
123.1, 121.2, 120.8, 109.2, 95.0, 63.4, 55.0, 51.5, 51.0, 49.8, 40.7, 29.3,
28.1, 27.3, 12.3; IR (film) 3354, 2963, 1677, 1606, 1463, 1283, 1233,
1215, 1163 cmꢁ1; Mass spectrum (CI) m/z 337.1910 [C21H25N2O2
(MþH)þ requires 337.1916].
Acknowledgements
We thank the National Institutes of Health (GM 25439), the
Robert A. Welch Foundation (F-652) for their generous support of
this research. We are also grateful to Dr. Richard Pederson (Materia,
Inc.) for catalyst support. Finally, we would like to thank Prof.
Martin E. Kuehne (The University of Vermont) for providing copies
of 1H and 13C NMR spectra of pseudotabersonine.
d
8.98 (s, 1H), 7.30 (d, J¼7.2 Hz, 1H), 7.15 (td, J¼7.8, 1.2 Hz, 1H), 6.88
(td, J¼7.2, 0.6 Hz, 1H), 6.81 (d, J¼7.8 Hz, 1H), 5.51 (app d, J¼6.0 Hz,
1H), 3.77 (s, 3H), 3.36 (d, J¼15.6 Hz, 1H), 3.27 (d, J¼15.6 Hz, 1H),
3.05e3.01 (comp, 2H), 2.83e2.77 (m, 1H), 2.68 (dd, J¼15.0, 3.0 Hz,
1H), 2.15 (dd, J¼15.0, 11.4 Hz, 1H), 2.09e2.03 (comp, 3H), 1.90 (ddd,
J¼11.6, 4.8, 2.0 Hz, 1H), 1.77 (app br s, 1H), 1.06 (t, J¼7.8 Hz, 3H); 13
C
NMR (150 MHz, CDCl3)
d 168.7, 165.9, 143.6, 139.3, 138.0, 127.7,
References and notes
121.9, 121.4,120.6,109.1, 95.4, 65.2, 55.5, 53.2, 51.0, 50.95, 44.4, 36.8,
27.8, 26.4, 12.5; IR (film) 3367, 2965, 2916, 1675, 1609, 1465, 1436,
1. For a general review of olefin metathesis and its applications, see: Handbook of
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1240, 1203, 1118 cmꢁ1
; Mass spectrum (CI) m/z 336.1833
[C21H24N2O2 (M)þ requires 336.1838].
4.2.14. D/E trans Pentacycle 36. A solution of KOt-Bu (191 mg,
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d
7.59 (d, J¼7.0 Hz,1H), 7.54 (d,

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6. Zeches, M.; Debray, M. M.; Ledouble, G.; Le Men-Olivier, L.; Le Men, J. Phyto-
chemistry 1975, 14, 1122e1124.
d, J¼7.2 Hz); for 31, H3
(
d
4.10, d, J¼16.4 Hz).
17. For similar aromatizations, see: (a) Magnus, P.; Gallagher, T.; Brown, P.; Huff-
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for 34, H3
(d
4.03, d, J¼4.4 Hz);
(d
3.93, d, J¼9.6 Hz).
19. Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120, 13523e13524 See also:
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20. Kuehne reported a multiplet for three protons in the range
and a peak for one proton at
1.61 in the 1H NMR spectrum of 4. In our spectra
there are four protons in the range of 2.03e2.20, and although there is
sometimes a proton at 1.60, this signal has been shown to be water. 2D
d 2.01e2.20 ppm
d
d
d
spectra support our assignments. Given the difference in field strength at,
which our spectra and those of Kuehne were measured, the spectra appear
consistent, although there are no integrations on the spectrum of the authentic
sample. There are no significant differences in the 13C NMR spectra.
ꢁ
21. For examples, see: (a) Smith, G. F.; Wrobel, J. T. J. Chem. Soc. 1960, 792e795; (b)
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ꢂ
Lewin, G.; Poisson, J. Tetrahedron Lett. 1984, 23, 3813e3814; (d) Pilarcík, T.;
ꢂ
ꢁ
ꢂ
ꢁ
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Havlícek, J.; Hajícek, J. Tetrahedron Lett. 2005, 46, 7909e7911; (e) Toth, F.; Olah,
ꢁ
ꢁ
}
}
€
€
ꢁ
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