Total synthesis of (?)-4-desacetoxy-1-oxovindoline: Single atom exchange of an embedded core heteroatom in vindoline

Article abstract of DOI:10.1016/j.tet.2021.132117

A concise total synthesis of (?)-4-desacetoxy-1-oxovindoline is disclosed, bearing a single heteroatom exchange in the core structure of the natural product 4-desacetoxyvindoline. Central to the synthesis is powerful oxadiazole intramolecular [4 + 2]/[3 +

Full text of DOI:10.1016/j.tet.2021.132117

Tetrahedron 87 (2021) 132117
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Tetrahedron
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Total synthesis of (ꢀ)-4-desacetoxy-1-oxovindoline: Single atom
exchange of an embedded core heteroatom in vindoline
Byron A. Boon, Yi-Yun Yu, Dale L. Boger*
Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of (ꢀ)-4-desacetoxy-1-oxovindoline is disclosed, bearing a single heteroatom
exchange in the core structure of the natural product 4-desacetoxyvindoline. Central to the synthesis is
powerful oxadiazole intramolecular [4 þ 2]/[3 þ 2] cycloaddition cascade that formed four CeC bonds,
created three new rings, and established five contiguous stereocenters about the new formed central 6-
membered ring.
Received 26 February 2021
Received in revised form
21 March 2021
Accepted 23 March 2021
Available online 29 March 2021
© 2021 Elsevier Ltd. All rights reserved.
Dedication. This article is dedicated to
Professor Steve Martin, a good friend and
long-time member of the Tetrahedron
Board of Editors alongside which I had the
pleasure of serving for many years.
Keywords:
Oxadiazole cycloaddition cascade
Vindoline analogue
Vinca alkaloids
1. Introduction
where peripheral neuropathy is the dose-limiting side effect of
vincristine chemotherapy, whereas reversible myelosuppression is
Vindoline (1) and its naturally occurring immediate biosyn-
thetic precursor 4-desacetoxyvindoline (2) are found as compo-
nents of the more complex Vinca alkaloids, constituting the lower
half of the structures of vinblastine (3) and 4-desacetoxyvinblastine
(Fig. 1) [1,2]. Although both 3 and 4-desacetoxyvinblastine exhibit
efficacious antitumor activity [3], the former is found in natural
sources in amounts at least 10-fold higher. Consequently, vinblas-
tine and the related naturally occurring Vinca alkaloid vincristine
(4) were explored and introduced into the clinic by Eli Lilly [1].
Today, they are widely used in a variety of curative combination
therapies for the treatment of cancer and vinblastine is the second
most prescribed small molecule oncology drug. Despite their sim-
ilarities, differing only in the N1 methyl versus formyl substituent,
vinblastine and vincristine display near identical on target tubulin
binding affinities [4], but exhibit distinguishable characteristic
cellular uptake and efflux rates [5], and different tumor sensitivities
[1]. In addition, they display different dose limiting toxicities,
common to vinblastine treatments [6,7]. These observations sug-
gest that the embedded N1-heteroatom and its substituent affect
the in vivo disposition of drugs, but do not appear to impact
intracellular target engagement and the ensuing functional activity.
As a result of this and in an extension of our studies on vinblastine
[8], we targeted single heteroatom replacements [9] (O and S) of
the N1 center embedded in the core structure of the natural
product drugs with the intention of further probing this unique
impact. Of the initial candidate replacements to explore, the O1 (5)
versus N1 substitution was most attractive, providing a cLogP and
calculated polar surface area (PSA) that lies precisely halfway be-
tween those of vinblastine (N1Me, 3) and vincristine (N1CHO, 4).
As a result, we first targeted the total synthesis 4-desacetoxy-1-
oxovindoline (6) with use of methodology inspired by and first
explored with vindoline [10] that in turn was utilized in the total
synthesis of vinblastine [11], vincristine and related natural prod-
ucts [12], and subsequently for a series of analogs [13e26]. Key to
the approach to vindoline that maps seamlessly onto the analogue
6 was a powerful oxadiazole intramolecular [4 þ 2]/[3 þ 2] cyclo-
addition cascade with tethered dienophile-dipolarophile pairs
[27,28] (Fig. 1).
* Corresponding author.
E-mail addresses: boger@scripps.edu, bogeradm@scripps.edu (D.L. Boger).
https://doi.org/10.1016/j.tet.2021.132117
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

B.A. Boon, Y.-Y. Yu and D.L. Boger
Tetrahedron 87 (2021) 132117
2. Results and discussion
Synthesis of 6 began with the commercial phenol 7 and its use in
the preparation of the known, but not commercially available,
starting ketone 11 [29] (Scheme 1). Phenol alkylation with methyl
2-bromoacetate in the presence of K2CO3 gave diester 8 in excellent
yield (87%). In a two-step procedure, hydrolysis of 8 (aq NaOH,
MeOH) afforded crude diacid 9, which underwent an intra-
molecular cyclization/decarboxylation reaction sequence mediated
by Ac2O/NaOAc in AcOH to provide benzofuran 10. Completion of
the preparation of the benzofuran starting material 11 [29] was
accomplished by hydrolysis of 10 under acidic conditions (1 N HCl,
MeOH/H2O, reflux, 99%), which was subsequently converted to the
known nitrile 12 [30] in excellent yield (91%, 2 steps from 10) with
use of a HornereWadswortheEmmons reaction (NaH, diethyl
cyanomethylphosphonoacetate).
Subsequent reduction of nitrile 12 with LiAlH4, followed by N-
acylation of the crude free amine with CDI (N,N-carbon-
yldiimidazole) gave urea 13 (Scheme 1). Addition of methyl oxa-
lylhydrazide (14) [27] in the presence of AcOH in THF furnished the
oxadiazole precursor 15 (77%). Upon treatment with tosyl chloride
(TsCl) and Et3N, 15 underwent a dehydrative cyclization to provide
oxadiazole 16 in good yield (84%). The key cycloaddition precursor
was prepared by N-acylation of 16 with carboxylic acid 17 [27]
promoted by EDCI, providing 18 in excellent yield (88%).
We turned to [4 þ 2]/[3 þ 2] cascade cycloaddition reaction of
oxadiazole 18 initiated by the inverse electron demand DielseAlder
of the tethered alkene with the activated electron-deficient oxa-
diazole [31]. Precedent for the anticipated [3 þ 2] cycloaddition
participation of a tethered benzofuran was disclosed in our original
work disclosing the cycloaddition cascade [27] (Fig. 2). Notably, a
Fig. 1. Structure of natural products, target analogue 6, and key cycloaddition cascade.
Fig. 2. Precedent for cycloaddition cascade [27].
single diastereomer is formed that results from exclusive endo
[3 þ 2] cycloaddition of the benzofuran with the uniquely stabilized
intermediate 1,3-dipole directed to the face opposite the newly
formed lactam, a stereochemical outcome dictated by the benzo-
furan linking tether.
Initial attempts to promote the cascade cycloaddition reaction of
18 under standard reaction conditions in 1,2-dichlorobenzene
(DCB) at 180 ꢁC or in 1,3,5-triisopropylbenzene (TIPB) at
180e230 ꢁC did not provide 19 in significant quantities although
trace amounts of product were observed at the higher tempera-
tures (Fig. 3). Other high boiling solvents (xylenes, dimethyl sulf-
oxide (DMSO), N-methylpyrrolidine (NMP) and decalin), added
Scheme 1. Synthesis of oxadiazole 18.
2

B.A. Boon, Y.-Y. Yu and D.L. Boger
Tetrahedron 87 (2021) 132117
Scheme 2. Completion of the synthesis of (ꢀ)-4-desacetoxy-1-oxovindoline (6).
Fig. 3. Cascade cycloaddition optimization.
NaBH4, removing the C8 functionality, releasing the C3-hydroxyl
group and introducing the C19 stereochemistry, to provide (ꢀ)-6
(50%, 2 steps) and its enantiomer.
Lewis acids, and microwave conditions were unsuccessful in facil-
itating the cycloaddition cascade reaction (not shown). Although
the initiating [4 þ 2] cycloaddition was observed to proceed un-
eventfully, providing the product derived from hydrolysis of the
intermediate 1,3-dipole upon workup, the ensuing [3 þ 2] cyclo-
addition with the electron-rich benzofuran proved surprisingly
slow. To explore higher temperature reaction conditions, the ther-
mal heat transfer fluid Dowtherm A was examined as solvent
where promising yields of 19 were observed upon warming at
230 ꢁC (18%). The yield of 19 increased with further elevated tem-
peratures of 250 ꢁC (27%) and reflux (30%, bp Dowtherm
A ¼ 257 ꢁC). Solvents such as Therminol 62 and Therminol 66 with
even higher boiling points gave similar yields of 19 at higher
temperatures and shorter reaction times (330 ꢁC, 2 h), but removal
of these solvents proved challenging, precluding their general use.
Cycloadduct yields were similar for reactions run for 24 h or 72 h in
Dowtherm A and further examination of the reaction gave reliable
yields on the scales of 0.01e0.18 mmol (31e40%, 24 h, 250 ꢁC). As
highlighted previously, this reaction displays a remarkable dia-
steroselectivity, generating a single cascade cycloadduct 19 whose
structure was unambiguously established with a single-crystal X-
ray structure determination [32]. Although the conversion was
more modest than we would like, the powerful reaction assembles
the full target skeleton, forming four CeC bonds, creating three new
rings, and establishing five contiguous and four quaternary ster-
eocenters about the new formed central 6-membered ring.
3. Conclusions
A concise total synthesis of (ꢀ)-4-desacetoxy-1-oxovindoline
(6) is disclosed, bearing a single heteroatom exchange in the core
structure of the natural product 4-desacetoxyvindoline (2). Central
to the synthesis is a powerful oxadiazole intramolecular [4 þ 2]/
[3 þ 2] cycloaddition cascade that formed four CeC bonds, created
three new rings, and established five contiguous and four quater-
nary stereocenters about the new formed central 6-membered ring.
Extensions of the studies to the synthesis of 1-oxovindoline and
their incorporation into vinblastine analogs are in progress and will
be reported in due course.
4. Experimental section
4.1. General information
All reactions were carried out in flame-dried glassware under an
argon atmosphere unless otherwise noted. All commercial com-
pounds were used as received unless otherwise noted. Lawesson’s
reagent was purchased from Acros Organics (lot #A0352925) and
was recrystallized from toluene prior to use. Dowtherm A was
purchased from Fisher Scientific (lot #10200385) and was dried for
2 d over activated 4 Å mol sieves and passed through a column of
oven-dried basic alumina prior to use. Basic alumina was purchased
from Acros Organics (lot# A0390637) and was oven dried at 150 ꢁC
for 2 d prior to use. 4 Å mol sieves (8e12 mesh) were purchased
from Acros Organics (lot #A0356556) and were oven dried at 150 ꢁC
for 2 d prior to use. Reactions were monitored using MilliporeSigma
TLC plates (0.25 mm, 60-F254) and were visualized using short-
wave UV light as well as cerium ammonium molybdate stain.
Preparative thin-layer chromatography (PTLC) was performed with
MilliporeSigma plates (0.5 mm, 60-F254). Column chromatography
Completion of the synthesis of 6 required C6eC7 double bond
installation and removal of the C8 amide carbonyl (Scheme 2).
Phenylselenation of amide 19 was successfully mediated by LiTMP
to provide 20 (65%, 10.9:1 dr). A H2O2-mediated selenide oxidation
and subsequent selenoxide elimination in THF gave
rated amide 21 in good yield (75%). Resolution of 21 was accom-
plished (
¼ 1.25) on a semipreparative Daicel CHIRALPAK AD
a,b-unsatu-
a
column (2 ꢂ 25 cm, 30% iPrOH/hexanes, 7 mL/min) to provide
(þ)-21 (tr ¼ 24.1 min), bearing the natural absolute configuration of
vindoline, and ent-(ꢀ)-21 (tr ¼ 19.3 min). Both the structure and
absolute stereochemistry of natural (þ)-21 and ent-(ꢀ)-21 were
unambiguously established by single crystal X-ray diffraction [32].
Amide 21 was converted to thioamide 22 with Lawesson reagent
(66%). In a two-step one pot sequence, each enantiomer of 22 was
S-alkylated with Meerwein salt (Me3OBF4), and subjected to
reductive N,O-ketal cleavage and desulfurization by treatment with
was performed using SiliCycle silica gel (SiO2, 40e63 mm) and re-
agent grade solvents. NMR spectra were recorded on Bruker AVIII
400 (5 mm BBFO probe), Bruker AV NEO 500 (5 mm BBFO Smart
Probe), or Bruker AVIII HD 600 spectrometers (either a 5 mm
CPDCH CryoProbe or a 5 mm CPQCl CryoProbe). Spectra recordings
were calibrated to the solvent signal (CDCl3 d ¼ 7.26 for 1H NMR and
d
¼ 77.0 for 13C NMR, DMSO‑d6 d ¼ 2.50 for 1H NMR and
d
¼ 39.52
3

B.A. Boon, Y.-Y. Yu and D.L. Boger
Tetrahedron 87 (2021) 132117
for 13C NMR). Multiplicities are indicated by s (singlet), d (doublet),
t (triplet), q (quartet), p (pentet), m (multiplet), or b (broadened).
Coupling constants (J) (H,H) are given in Hz. The single crystal X-ray
diffraction studies were carried out on a Bruker SMART APEX II CCD
4.4. Compound 15
Compound 13 (3.02 g, 10.6 mmol) was dissolved in THF (67 mL)
and AcOH (0.67 mL, 11.7 mmol) was added at 25 ꢁC. Compound 14
[27] (1.38 g, 11.7 mmol) was added in one portion, and the solution
was warmed at 40 ꢁC for 22 h. The solvent was removed in vacuo.
Column chromatography (SiO2, 80:18:2 CH2Cl2/acetone/MeOH)
gave 2.73 g (77%) of 15 as a white solid: 1H NMR (500 MHz, CDCl3)
diffractometer equipped with Cu Ka radiation (
l
¼ 1.54178). IR
spectra were recorded with a Nicolet 380 FTIR with an ATR
attachment and selected absorptions are reported in cmꢀ1. High
resolution mass spectral data was recorded on a Waters LC with a
Waters G2-XS detector. Chiral HPLC separations were performed on
Shimadzu LC-6AD with a Shimadzu SPD-10A VP UVeVis detector
with a CHIRALPAK AD column (2 ꢂ 25 cm). Optical rotations were
recorded on a Rudolph Research Analytical Autopol III Automatic
Polarimeter. Compound 11 [29], 12 [30] and 17 [27] were prepared
by previously established literature procedures and were identical
in all respects with reported material.
d
9.57 (s, 1H), 8.13 (s, 1H), 7.42e7.31 (m, 2H), 6.95 (d, J ¼ 2.0 Hz, 1H),
6.84 (dd, J ¼ 8.5, 2.3 Hz,1H), 5.97 (t, J ¼ 5.7 Hz, 1H), 3.82 (s, 3H), 3.81
(s, 3H), 3.45 (q, J ¼ 6.6 Hz, 2H), 2.79 (t, J ¼ 6.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 159.2,158.1,157.2,156.3,154.9,141.1,121.2,119.6,
117.0, 111.5, 96.1, 55.7, 53.7, 39.6, 24.1; IR (neat) 3320, 3120, 1722,
1634, 1579, 1492, 1254, 1147, 1126 cmꢀ1; HRMS (ESI-TOF): calcd
[MþH]þ (C15H18N3O6) 336.1196, found 336.1198.
4.2. Compound 12
4.5. Compound 16
Sodium hydride (2.63 g, 73.3 mmol) was suspended in THF
(100 mL). Diethyl (cyanomethyl)phosphonate (11.9 mL, 73.3 mmol)
was added dropwise over 10 min at 25 ꢁC and the reaction mixture
was stirred for 30 min. The solution was cooled to 0 ꢁC, stirred for
30 min, and a solution of 11 [29] (5.95 g, 36.7 mmol) in THF (20 mL)
was added dropwise over 10 min at that temperature. The solution
was warmed to 25 ꢁC over 1 h and stirred for 15 h. The reaction was
quenched with the addition of water and the mixture was extracted
with EtOAc (3x). The organic layers were combined, washed with
saturated aq NaCl, dried with MgSO4, filtered, and concentrated in
vacuo. Column chromatography (SiO2, 20% EtOAc/hexanes) gave
6.22 g (91%) of 12 as a yellow solid identical in all respects with
Compound 15 (2.71 g, 8.09 mmol) was dissolved in CH2Cl2
(81 mL) followed by Et3N (3.38 mL, 24.3 mmol) and TsCl (2.01 g,
10.5 mmol). The reaction mixture was stirred for 17 h at 25 ꢁC
before the solvent was removed in vacuo. Column chromatography
(SiO2, 50:47:3 EtOAc/hexanes/Et3N) gave 2.17 g (84%) of 16 as a tan
solid: 1H NMR (500 MHz, CDCl3)
d 7.45e7.42 (m, 2H), 7.02 (d,
J ¼ 2.2 Hz,1H), 6.90 (dd, J ¼ 8.6, 2.2 Hz,1H), 5.35 (s, 1H), 3.99 (s, 3H),
3.85 (s, 3H), 3.79 (q, J ¼ 6.5 Hz, 2H), 3.03 (t, J ¼ 6.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d 163.7, 158.5, 156.6, 154.9, 151.8, 141.4, 120.9,
119.6, 116.3, 111.9, 96.3, 55.9, 53.4, 42.9, 23.8; IR (neat) 3235, 3120,
2958,1731,1628,1439,1187,1142, 1055,1021, 807 cmꢀ1; HRMS (ESI-
TOF): calcd [MþH]þ (C15H16N3O5) 318.1090, found 318.1093.
authentic material [30]: 1H NMR (400 MHz, CDCl3)
d 7.60 (t,
J ¼ 1.3 Hz, 1H), 7.46 (d, J ¼ 8.6 Hz, 1H), 7.06 (d, J ¼ 2.3 Hz, 1H), 6.96
4.6. Compound 18
(dd, J ¼ 8.6, 2.2 Hz,1H), 3.89 (s, 3H), 3.76 (d, J ¼ 1.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d
158.9,156.7,141.8, 119.6,119.2,116.9,112.5, 110.1,
Compound 16 (3.09 g, 9.75 mmol) was dissolved in CH2Cl2
(16 mL) and a solution of 17 [27] (3.12 g, 24.4 mmol) in CH2Cl2
(16 mL) was added dropwise over 10 min at 0 ꢁC. EDCI∙HCl (5.61 g,
29.2 mmol) and DMAP (2.38 g,19.5 mmol) were added sequentially,
each in a single portion, at 0 ꢁC and the mixture was stirred for
30 min. The solution was allowed to warm to 25 ꢁC and stirred for
24 h. The solvent was removed in vacuo. Column chromatography
(SiO2, 33% EtOAc/hexanes) gave 3.68 g (88%) of 18 as a light yellow
96.4, 55.9, 13.3; IR (neat) 3108, 2916, 2834, 2202, 1623, 1585, 1442,
1265, 1193, 1224, 1144, 1121, 1018, 932, 807 cmꢀ1; HRMS (ESI-TOF):
calcd [MþH]þ (C11H9NO2) 188.0712, found 188.0711.
4.3. Compound 13
LiAlH4 (3.78 g, 99.6 mmol) was suspended in Et2O (81 mL) at
0 ꢁC and a solution of compound 12 [30] (6.21 g, 33.2 mmol) in Et2O
(186 mL) was added dropwise over 30 min. The solution was
warmed at reflux for 3 h before being cooled to 0 ꢁC and quenched
with the slow sequential dropwise addition of water (3.8 mL), aq
15% NaOH (3.8 mL) and water (11.3 mL). The solution was warmed
to 25 ꢁC and stirred for 1 h. MgSO4 was added until the mixture was
free flowing, and stirred for an additional 30 min. The mixture was
filtered, the solids were rinsed with Et2O, and the mixture was
concentrated in vacuo to give 4.44 g of crude amine as a red oil that
was used without further purification. For the synthesis of 13, 1,10-
carbonyldiimidazole (5.65 g, 34.8 mmol) was dissolved in THF
(23 mL) at 0 ꢁC and a solution of the crude amine (4.44 g,
23.2 mmol) in CH2Cl2 (116 mL) was added dropwise over 30 min.
The solution was warmed to 25 ꢁC and stirred for 19 h. The reaction
mixture was concentrated in vacuo. Column chromatography (SiO2,
85:11:4 CH2Cl2/acetone/MeOH) gave 3.02 g (32% over 2 steps) of 13
solid: 1H NMR (500 MHz, CDCl3)
d
7.54 (d, J ¼ 8.5 Hz, 1H), 7.36 (s,
1H), 6.96 (d, J ¼ 2.3 Hz,1H), 6.88 (dd, J ¼ 8.6, 2.2 Hz,1H), 4.76 (s,1H),
4.70 (s, 1H), 4.29e4.22 (m, 2H), 4.02 (s, 3H), 3.83 (s, 3H), 3.07e2.97
(m, 4H), 2.40 (t, J ¼ 7.7 Hz, 2H), 2.04 (q, J ¼ 7.4 Hz, 2H), 1.03 (t,
J ¼ 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 172.0, 162.0, 158.3,
156.5, 154.2, 153.6, 149.5, 141.5, 120.9, 119.8, 115.9, 111.9, 108.6, 96.2,
55.8, 53.8, 46.8, 35.0, 30.9, 29.1, 22.8, 12.4; IR (neat) 2965, 1754,
1707, 1623, 1563, 1493, 1439, 1319, 1284, 1181, 1023, 932, 896 cmꢀ1
;
HRMS (ESI-TOF): calcd [MþH]þ (C22H26N3O6) 428.1822, found
428.1822.
4.7. Compound 19
Compound 18 (50.0 mg, 0.117 mmol) was dissolved in Dow-
therm A (234 mL) and the solution was sparged for 30 min with N2
with a gas dispersion tube in a 350 mL pressure vessel (Dowtherm
A was dried for 2 d over activated 4 Å mol sieves and passed
through a small column of oven-dried basic alumina prior to use).
The reaction vessel was sealed, and the solution was warmed at
250 ꢁC for 24 h. The reaction mixture was cooled to 25 ꢁC and
passed through a small column (SiO2), and the column was flushed
with hexanes (500 mL) to dryness. The cycloadduct was flushed
through the column with EtOAc (100 mL) and concentrated in
vacuo. PTLC (SiO2 50% EtOAc/hexanes) gave 17.7 mg (38%, typically
as an orange solid: 1H NMR (500 MHz, CDCl3)
d 8.06 (s, 1H),
7.44e7.35 (m, 2H), 7.24 (t, J ¼ 1.3 Hz, 1H), 7.03 (s, 1H), 7.01 (d,
J ¼ 2.2 Hz, 1H), 6.88 (dd, J ¼ 8.5, 2.2 Hz, 1H), 6.16 (br s, 1H), 3.85 (s,
3H), 3.74 (q, J ¼ 6.5 Hz, 2H), 3.01 (t, J ¼ 6.8 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d 158.3, 156.4, 149.1, 141.0, 135.8, 129.6, 121.1,
119.5, 116.9, 116.5, 111.8, 96.3, 55.8, 40.6, 23.8; IR (neat) 3030, 3014,
2998, 2971, 1739, 1420, 1366, 1240, 1217, 1150 cmꢀ1; HRMS (ESI-
TOF): calcd [MþH]þ (C15H16N3O3) 286.1192, found 286.1195.
4

B.A. Boon, Y.-Y. Yu and D.L. Boger
Tetrahedron 87 (2021) 132117
32e40%) of 19 as a white solid: 1H NMR (500 MHz, CDCl3)
d
6.88e6.82 (m, 1H), 6.47e6.43 (m, 2H), 5.11 (d, J ¼ 1.1 Hz, 1H), 3.96
(d, J ¼ 10.4 Hz, 1H), 3.96 (dd, J ¼ 10.4, 2.4 Hz, 1H), 3.88 (s, 3H), 3.79
(s, 3H), 2.52 (dt, J ¼ 12.9, 10.4 Hz, 1H), 2.45e2.37 (m, 1H), 2.34e2.21
(m, 3H), 2.20 (d, J ¼ 13.0 Hz, 1H), 1.84 (dd, J ¼ 13.0, 1.3 Hz, 1H),
1.79e1.74 (m, 1H), 0.92 (dq, J ¼ 14.8, 7.3 Hz, 1H), 0.63 (t, J ¼ 7.4 Hz,
3H), 0.29 (dq, J ¼ 14.7, 7.4 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
170.4, 170.3, 162.4, 161.9, 124.3, 120.1, 107.9, 107.1, 97.1, 94.2, 84.4,
64.5, 55.7, 53.1, 47.1, 43.7, 37.9, 35.1, 29.4, 28.0, 22.4, 9.9; IR (neat)
2958,1738,1592,1394,1355,1322,1217,1122,1083,1056, 864 cmꢀ1
;
HRMS (ESI-TOF): calcd [MþH]þ (C22H26NO6) 400.1760, found
400.1765. The structure and relative stereochemistry of 19 were
unambiguously established with a single crystal X-ray crystal
structure (CCDC 2064479), see Supporting Information S23eS24.
4.8. Compound 20
Fig. 4. Chiral HPLC trace of racemic 21.
Compound 19 (52.6 mg, 0.132 mmol) and PhSeCl (50.4 mg,
0.263 mmol) were dissolved in THF at ꢀ78 ꢁC. In a separate flask,
2,2,6,6-tetramethylpiperidine (0.3 mL, 1.78 mmol) was dissolved in
THF (3.7 mL) at 0 ꢁC then n-BuLi (0.71 mL, 1.78 mmol, 2.5 M in
hexanes) was added dropwise and the solution was stirred for 1 h,
before being cooled to ꢀ78 ꢁC. The LiTMP solution (0.66 mL,
0.263 mmol) was added dropwise at ꢀ78 ꢁC and the mixture was
stirred for an additional 30 min before additional LiTMP solution
was added (0.33 mL, 0.132 mmol). After 1 h, a third portion of
LiTMP was added (0.16 mL, 0.066 mmol) and the solution was
stirred for an additional 30 min prior to quench with saturated aq
NH4Cl (3.2 mL). The solution was warmed to 25 ꢁC, diluted with
water (4 mL), and the mixture was extracted with EtOAc (3x). The
organic layers were combined, dried with MgSO4, filtered, and
concentrated in vacuo. Column chromatography (SiO2, 33% EtOAc/
hexanes) gave 47.8 mg (65%, 10.9:1 dr) of 20 as a clear colorless oil:
(CHIRALPAK AD, 2 ꢂ 25 cm, 30% iPrOH/Hexanes, 7 mL/min) allowed
21 to be separated into individual enantiomers (tR
[unnatural] ¼ 19.3 min, tR [natural] ¼ 24.1 min) Fig. 4. For natural
(þ)-21: [
a]
24 þ153 (c 1.0, CHCl3). For unnatural (ꢀ)-21: [
a]
24 ꢀ 154
D
D
(c 1.0, CHCl3). The structure and absolute stereochemistry of each
enantiomer of 21 were unambiguously established by X-ray crys-
tallography conducted with colorless crystals obtained from slow
vapor diffusion with CH2Cl2/pentanes (CCDC 2064480 for natural
(þ)-21 and CCDC 2064481 for ent-(ꢀ)-21). For further X-ray crys-
tallography details, see supplementary data pages S25eS28.
4.10. Compound (þ)-22
Compound 21 (30.0 mg, 0.0755 mmol) was dissolved in toluene
(15 mL) and Lawesson’s reagent (33.6 mg, 0.0803 mmol) was added
in a single portion. The solution was warmed at 100 ꢁC for 45 min.
The reaction was concentrated in vacuo. PTLC (SiO2, 50% EtOAc/
hexanes) gave 20.7 mg (66%) of 22 as a yellow oil: 1H NMR
1H NMR (600 MHz, CDCl3)
d
(major diastereomer) 7.67 (dd, J ¼ 7.5,
1.7 Hz, 2H), 7.31e7.26 (m, 3H), 6.86e6.81 (m, 1H), 6.46e6.41 (m,
2H), 5.10 (s, 1H), 4.05e3.92 (m, 2H), 3.90e3.84 (m, 1H), 3.86 (s, 3H),
3.77 (s, 3H), 2.55 (dt, J ¼ 12.9, 10.4 Hz, 1H), 2.45 (t, J ¼ 13.3 Hz, 1H),
2.25 (dd, J ¼ 12.8, 7.8 Hz, 1H), 2.11 (d, J ¼ 13.1 Hz, 1H), 1.99 (dd,
J ¼ 13.8, 6.2 Hz, 1H), 1.79 (d, J ¼ 13.1 Hz, 1H), 0.88 (dq, J ¼ 14.7,
(600 MHz, CDCl3)
d 7.09e6.98 (m, 1H), 6.51e6.44 (m, 2H), 6.43 (d,
J ¼ 9.5 Hz, 1H), 5.91 (d, J ¼ 9.5 Hz, 1H), 5.18 (d, J ¼ 1.1 Hz, 1H), 4.48
(ddd, J ¼ 13.4, 9.7, 1.2 Hz, 1H), 4.16 (ddd, J ¼ 13.4, 11.4, 7.6 Hz, 1H),
3.86 (s, 3H), 3.78 (s, 3H), 2.61 (ddd, J ¼ 12.8, 11.3, 9.6 Hz, 1H),
2.42e2.29 (m, 3H), 0.80 (dq, J ¼ 15.1, 7.7 Hz, 1H), 0.71 (dq, J ¼ 14.1,
7.1 Hz, 1H), 0.53 (t, J ¼ 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3)
7.3 Hz, 1H), 0.50 (t, J ¼ 7.4 Hz, 3H), 0.23 (dq, J ¼ 14.7, 7.4 Hz, 1H); 13
C
NMR (150 MHz, CDCl3)
d (major diastereomer) 169.9, 162.4, 162.0,
135.3, 129.2, 128.9, 128.3, 124.3, 119.8, 107.9, 106.9, 97.1, 94.1, 84.3,
64.4, 60.5, 55.7, 53.0, 47.8, 44.9, 39.6, 37.7, 36.7, 35.2, 22.8, 21.2, 14.3,
9.8; HRMS (ESI-TOF): calcd [MþH]þ (C28H30NO6Se) 556.1233, found
556.1231.
d
191.2, 169.4, 162.6, 162.2, 140.8, 129.9, 124.3, 118.7, 107.7, 104.8,
96.9, 94.2, 83.5, 65.3, 55.7, 53.2, 53.1, 48.2, 45.9, 34.9, 27.5, 9.1; IR
(neat) 2955, 2923, 1738, 1673, 1622, 1594, 1499, 1261, 1123, 1033,
907, 801 cmꢀ1; HRMS (ESI-TOF): calcd [MþH]þ (C22H24NO5S)
26
414.1375, found 414.1384; For natural (þ)-22: [
a
]
þ383 (c 0.5,
D
4.9. Compound (þ)-21
CHCl3). For unnatural (ꢀ)-22: [
a
]
D
24 ꢀ 390 (c 0.5, CHCl3).
Compound 20 (112 mg, 0.202 mmol) was dissolved in THF
(20 mL) followed by the addition of aq 30% H2O2 (70
m
L,
4.11. (ꢀ)-4-Desacetoxy-1-oxovindoline [(ꢀ)-6]
0.809 mmol) and the solution was stirred at 25 ꢁC. After 2 h the
reaction was quenched with the addition of saturated aq Na2S2O3
(3 mL). The mixture was diluted with water, extracted with CH2Cl2
(3x), dried with MgSO4, filtered, and concentrated in vacuo. Column
chromatography (SiO2, 33% hexanes/EtOAc) gave 59.9 mg (75%) of
Compound 22 (19.1 mg, 0.0462 mmol) and Me3OBF4 (20.5 mg,
0.139 mmol) were dissolved in CH2Cl2 (9.4 mL) and the solution was
stirred at 25 ꢁC for 1 h. CH2Cl2 was removed by passing a stream of
N2 over the reaction mixture, MeOH (9.4 mL) was added, and the
solution was cooled to 0 ꢁC. NaBH4 (17.5 mg, 0.462 mmol) was
added and the solution was stirred for 30 min. The reaction was
quenched with the addition of saturated aq NaHCO3, the mixture
was extracted with CH2Cl2 (3x), dried with MgSO4, filtered and
concentrated in vacuo. PTLC (SiO2, 50% EtOAc/hexanes) gave 8.9 mg
21 as a white solid: 1H NMR (600 MHz, CDCl3)
d 7.04e7.00 (m, 1H),
6.50e6.45 (m, 2H), 6.24 (d, J ¼ 9.8 Hz, 1H), 5.97 (d, J ¼ 9.8 Hz, 1H),
5.17 (s, 1H), 4.18 (ddd, J ¼ 11.5, 9.9, 1.3 Hz, 1H), 3.96 (td, J ¼ 11.4,
7.6 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 2.56 (dt, J ¼ 12.8, 10.3 Hz, 1H),
2.42e2.27 (m, 3H), 0.84e0.71 (m, 2H), 0.59 (t, J ¼ 7.4 Hz, 3H); 13C
NMR (150 MHz, CDCl3)
d
169.3, 163.1, 162.0, 161.5, 148.8, 123.7,
(50%) of 6 as a white solid: 1H NMR (600 MHz, CDCl3)
d 8.85 (s, 1H),
122.3, 118.5, 107.1, 106.7, 96.3, 93.5, 82.8, 64.2, 55.1, 52.6, 47.2, 46.3,
38.9, 34.7, 27.0, 8.6; IR (neat) 3055, 2952, 1743, 1658, 1620, 1498,
1438, 1379, 1268, 1120, 905, 727 cmꢀ1; HRMS (ESI-TOF): calcd
[MþH]þ (C22H24NO6) 398.1604, found 398.1608. Chiral HPLC
6.97 (d, J ¼ 8.3 Hz, 1H), 6.45 (dd, J ¼ 8.3, 2.3 Hz, 1H), 6.36 (d,
J ¼ 2.3 Hz, 1H), 5.70 (ddd, J ¼ 9.9, 5.4, 1.7 Hz, 1H), 5.48 (ddd, J ¼ 9.9,
2.7, 1.4 Hz, 1H), 4.86 (d, J ¼ 1.7 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H),
3.40e3.33 (m, 2H), 2.78 (dt, J ¼ 15.7, 2.2 Hz, 1H), 2.55e2.46 (m, 2H),
5

B.A. Boon, Y.-Y. Yu and D.L. Boger
Tetrahedron 87 (2021) 132117
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Fig. 5. Diagnostic nOes.
2.43e2.30 (m, 2H), 2.07 (dd, J ¼ 14.9, 1.8 Hz, 1H), 1.82 (d, J ¼ 15.0 Hz,
1H), 1.02 (dq, J ¼ 14.7, 7.4 Hz, 1H), 0.78 (dq, J ¼ 14.3, 7.3 Hz, 1H), 0.61
(t, J ¼ 7.4 Hz, 3H) (see Fig. 5); 13C NMR (150 MHz, CDCl3)
d 172.3,
161.3, 160.0, 136.4, 123.3, 123.2, 121.5, 107.7, 96.1, 93.5, 76.5, 68.1,
55.6, 53..0, 52.6, 51.6, 51.0, 41.1, 37.4, 37.3, 34.3, 8.0; IR (neat) 2923,
2852, 1716, 1541, 1499, 1379, 1268, 1151, 913, 826 cmꢀ1; HRMS (ESI-
TOF): calcd [MþH]þ (C22H28NO5) 386.1967, found 386.1962; For
natural (ꢀ)-6 [
a
]
25 ꢀ 32 (c 0.07, CHCl3).
D
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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Acknowledgements
[26] (a) H. Gotoh, J.E. Sears, A. Eschenmoser, D.L. Boger, J. Am. Chem. Soc. 134
(2012) 13240;
(b) B.A. Boon, D.L. Boger, J. Am. Chem. Soc. 141 (2019) 14349.
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J. Am. Chem. Soc. 128 (2006) 10589;
(b) G.D. Wilkie, G.I. Elliott, B.S.J. Blagg, S.E. Wolkenberg, D.R. Soenen,
M.M. Miller, S. Pollack, D.L. Boger, J. Am. Chem. Soc. 124 (2002) 11292.
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[29] (a) A.M. Venkatesan, O. Dos Santos, J. Ellingboe, D.A. Evrard, B.L. Harrison,
D.L. Smith, R. Scerni, G.A. Hornby, L.E. Schechter, T.H. Andree, Bioorg. Med.
Chem. Lett 20 (2010) 824;
We are especially grateful to the National Institutes of Health for
financial support of the studies (CA042056, DLB). We thank Porina
Va, Justin Sears and Youqian Deng for preliminary studies and Dr.
Milan Gembicky of the UCSD Crystallography Lab for the X-ray
structure determinations disclosed herein.
Appendix A. Supplementary data
(b) D.T. Connor, W.A. Cetenko, M.D. Mullican, R.J. Sorenson, P.C. Unangst,
R.J. Weikert, R.L. Adolphson, J.A. Kennedy, D.O. Thueson, J. Med. Chem. 35
(1992) 958;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132117.
(c) J. Brewer, W. Davidson, J. Elix, R. Leppik, Aust. J. Chem. 24 (1971) 1883.
[30] J. Chan, J. Elix, B. Ferguson, Aust. J. Chem. 28 (1975) 1097.
[31] J. Zhang, V. Shukla, D.L. Boger, J. Org. Chem. 84 (2019) 9397.
[32] The structure and relative stereochemistry of 19 were unambiguosly estab-
lished with a single crystal X-ray structure determination (CCDC 2064479).
The structure and relative and absolute stereochemistry of (þ)-21 (CCDC
2064480) and ent-(ꢀ)-21 (CCDC 2064481) were unambiguosly established
with single crystal X-ray structure determinations. Crystallographic data for
the structures are provided in the supplementary data and have been
deposited with the Cambridge Crystallographic Data Centre. Copies can be
obtained from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)
1223e336033 or e-mail: deposit@ccdc.cam.ac.uk).
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6