Total Syntheses of Disorazoles A1 and B1 and Full Structural Elucidation of Disorazole B1

Article abstract of DOI:10.1021/jacs.7b09843

Described herein are the first total syntheses of naturally occurring antitumor agents disorazoles A₁ and B₁ and the full structural assignment of the latter. The syntheses were achieved through convergent strategies employing enantioselective constructions of the required building blocks, including a novel Sharpless epoxidation/enzymatic kinetic resolution of stannane-containing substrates that led selectively to both enantiomeric forms of an epoxy vinyl stannane, and a series of coupling reactions, including a Wittig reaction, a Suzuki coupling, a Stille coupling, a Yamaguchi esterification and a Yamaguchi macrolactonization.

Full text of DOI:10.1021/jacs.7b09843

Communication
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX-XXX
pubs.acs.org/JACS
Total Syntheses of Disorazoles A and B and Full Structural
1
1
Elucidation of Disorazole B1
K. C. Nicolaou,* Gabriel Bellavance, Marek Buchman, and Kiran Kumar Pulukuri
Department of Chemistry, BioScience Research Collaborative, Rice University, 6100 Main Street, Houston, Texas 77005, United
States
*
S Supporting Information
disorazole A has not been reported, despite several studies
1
5c,7
1
ABSTRACT: Described herein are the first total
syntheses of naturally occurring antitumor agents dis-
directed toward this goal. Disorazole B , whose structure has
1
only been partially assigned as 2 (C symmetric) or 3 (6,8,23,25-
2
orazoles A and B and the full structural assignment of the
1
1
tetra-epi-disorazole B , Figure 1) presents another challenging
1
latter. The syntheses were achieved through convergent
strategies employing enantioselective constructions of the
required building blocks, including a novel Sharpless
epoxidation/enzymatic kinetic resolution of stannane-
containing substrates that led selectively to both
enantiomeric forms of an epoxy vinyl stannane, and a
series of coupling reactions, including a Wittig reaction, a
Suzuki coupling, a Stille coupling, a Yamaguchi ester-
ification and a Yamaguchi macrolactonization.
calling to both structural elucidation and total synthesis. In this
Communication, we report: (a) total synthesis of disorazole A1
(
1); (b) total synthesis of disorazole B (2) and 6,8,23,25-tetra-
1
epi-disorazole B (3); and (c) full assignment of disorazole B as
1
1
structure 2.
Figure 2 summarizes the retrosynthetic analysis of disorazoles
A (1) and B (2). Thus, disorazole A was traced to key building
1
1
1
1
he disorazoles are a distinguished class of tubulin binding
T
antitumor agents due to their unique mode of action and2
high potencies against a broad range of cancer cell lines.
Although too cytotoxic to be used as anticancer drugs, these
natural products may become powerful payloads for antibody−
3
drug conjugates (ADCs), a hotly pursued paradigm for targeted
4
personalized cancer therapies. Elegant total syntheses of
1
1
5
disorazole C and related synthetic studies have been reported.
From the members of this family of compounds, disorazole A (1,
1
Figure 1) stands as the flagship, not only because it is the most
studied, but also due to its single digit picomolar potencies and
1
,6
synthetically challenging structure. Indeed, a total synthesis of
Figure 2. Retrosynthetic analyses of disorazoles A (1) and B (2).
1
1
blocks 4−7 and (−)-8 through the strategic bond disconnections
indicated on structure 1 (Wittig reaction, Stille coupling, Suzuki
coupling, Yamaguchi esterification and Yamaguchi macro-
lactonization). By virtue of its symmetrical nature, disorazole
8
B (2) required only building blocks 5, 7 and (−)-8, revealed
1
through a simpler disconnection pattern requiring two identical
Wittig and Stille couplings, a Yamaguchi esterification, and a
Yamaguchi macrolactonization as shown in structure 2 (Figure
2
).
Figure 1. Structures of disorazole A (1) and B (2) and 6,8,23,25-tetra-
1
1
Received: September 14, 2017
epi-disorazole B (3).
1
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b09843
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 1 depicts the asymmetric synthesis of intermediates 4
and 5 starting with building blocks 9 and 10. Thus, reaction of 9
Scheme 2. Synthesis of Vinyl Bromide 6
9
a
Scheme 1. Synthesis of Vinyl Boronic Acid 4 and Iodide 5
a
Reagents and conditions: (a) AgNO (0.1 equiv), NIS (1.2 equiv),
3
acetone, 23 °C, 10 min, 98%; (b) 19 (0.9 equiv), 5:2 THF:i-PrOH, 23
°
(
C, 16 h, 53%; (c) Pd(PhCN) Cl (0.05 equiv), PPh (0.1 equiv), CuI
2 2 3
0.07 equiv), 21 (1.5 equiv), i-Pr NH, 23 °C, 1 h, 90%; (d) 50% aq.
2
TFA (10 equiv), 23 °C, 30 min; (e) Red-Al (2.05 equiv), 0 to 23 °C,
a
Reagents and conditions: (a) 10 (1.0 equiv), TiCl (1.5 equiv),
4
0.5 h, Et O, quant. from 22; (f) DMP (2.0 equiv), CH Cl , 0 to 23 °C,
2
2
2
CH Cl , 0 °C, 5 min; then −78 °C, i-Pr NEt (1.1 equiv), 30 min; then
2
2
2
2 h; (g) CH(OMe) (1.0 equiv), p-TsOH (0.01 equiv), CH Cl , 23
9
3
2
2
−
50 °C, 2 h; then −78 °C, 9 (1.0 equiv), 1 h, 89%, 12:1 dr; (b) 2,6-
°
C, 1 h, 99% from 23; (h) 10 (1.0 equiv), TiCl (1.1 equiv), CH Cl , 0
4 2 2
lutidine (3.0 equiv), TMSOTf (2.0 equiv), CH Cl , 0 °C, 25 min; (c)
2
2
°C, 5 min; then −78 °C, i-Pr NEt (1.1 equiv), 30 min; then −50 °C, 2
2
DIBAL-H (2.5 equiv), Et O, −78 °C, 2 h, 80% from 11; (d) 14 (1.5
equiv), NaHMDS (1.5 equiv), THF, 0 to 23 °C, 5 min; then −78 °C,
DMPU (7.5 equiv), 13 (1.0 equiv), 1 h; then 23 °C, 30 min, 73%; (e)
2
h; then −78 °C, BF ·Et O (1.0 equiv), 24 (1.0 equiv), 1 h, 67%, ca. 3:1
3
2
dr; (i) 26 (1.5 equiv), i-Pr NEt (2.0 equiv), THF, 23 °C, 10 min; then
2
2
5 (1.0 equiv), imidazole (3.0 equiv), 23 °C, 16 h, 92%; (j) Deoxo-
1
5 (1.0 equiv), B(Oi-Pr) (1.1 equiv), n-BuLi (1.15 equiv), −78 °C, 30
3
Fluor (1.2 equiv), CH Cl , −20 °C, 30 min; (k) BrCCl (4.0 equiv),
2
2
3
min; then TBAF (1.4 equiv), 23 °C, 48 h, 77%; (f) DIBAL-H (5.0
equiv), Et O, −78 to 23 °C, 2 h, 71% from 11; (g) imidazole (1.5
equiv), I (1.35 equiv), PPh (1.2 equiv), 23 °C, 1 h, 77%. TMSOTf =
trimethylsilyl trifluoromethanesulfonate, DIBAL-H = diisobutylalumi-
num hydride, NaHMDS = sodium bis(trimethylsilyl)amide, DMPU =
1
DBU (4.0 equiv), CH Cl , 0 to 23 °C, 16 h, 91% from 27; (l) Ag CO
2
2
2
3
2
(1.0 equiv), NBS (1.25 equiv), HFIP, 0 °C, 2 h, 91%. NBSH = 2-
nitrobenzenesulfonylhydrazide, Red-Al = sodium bis(2-methoxyeth-
oxy)aluminum, p-TsOH = p-toluenesulfonic acid, HFIP = hexafluoro-
2
3
2
-propanol.
,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, TBAF = tetra-n-
butylammonium fluoride.
(
chromatographically separated), whose reaction with ammo-
1
0
with Nagao auxiliary 10 (TiCl ; then i-Pr NEt) led stereo-
nium salt 26 in the presence of i-Pr NEt and imidazole afforded
hydroxy amide 27 in 92% yield. Conversion of 27 to oxazole
intermediate 28 was achieved through sequential exposure of the
4
2
2
13
selectively to alcohol 11 (89% yield, ca. 12:1 dr). Protection of
the latter (TMSOTf, 2,6-lut.) gave TMS ether 12, whose
reduction with 2.5 equiv of DIBAL-H afforded aldehyde 13 in
14
latter to Deoxo-Fluor and BrCCl /DBU (91% overall yield).
3
8
0% yield from 11. Reaction of 13 with the ylide generated from
Finally, the targeted intermediate 6 was generated from 28
iodophosphonium iodide 14 (NaHMDS; then DMPU) gave
selectively (Z)-vinyl iodide 15 in 73% yield. Conversion of 15 to
the desired boronic acid (4) required sequential treatment with
through the action of NBS in the presence of Ag CO (91%
2
3
yield).
The asymmetric synthesis of advanced intermediate 37 started
from propargyl alcohol (29) and proceeded as shown in Scheme
n-BuLi, B(Oi-Pr) , and TBAF (77% yield). Iodide 5 was obtained
3
from common intermediate 12 (Scheme 1) through a two-step
sequence involving reduction of the latter to the corresponding
primary alcohol (5.0 equiv of DIBAL-H, 71% yield from 11)
3. Thus, AIBN facilitated addition of n-Bu SnH to 29, followed
3
by buffered DMP oxidation of the resulting alcohol, led to the
formation of vinyl tin aldehyde 30 in 42% overall yield. Still−
Gennari reaction of the latter with the anion generated from
phosphonate ester 31 (KHMDS, 18-crown-6) followed by
DIBAL-H reduction of the resulting methyl ester furnished
alcohol 32 in 85% overall yield. Sharpless asymmetric
11
followed by an Appel reaction [I , PPh , imidazole (77%
2
3
yield)].
Intermediate 6 was synthesized asymmetrically from TIPS-
acetylene (17) (Scheme 2). Thus, 17 was converted to iodide 18
(
NIS, AgNO , 98% yield) and then to (Z)-vinyl iodide 20
epoxidation of 32 [t-BuOOH, Ti(Oi-Pr) , (−)-DET] gave
3
4
through the action of hydrazine 19 (53% yield). Coupling of 20
with acetylene 21 [Pd(PhCN) Cl , PPh , CuI, i-Pr NH, 90%
yield] furnished enyne diethoxy ketal 22, whose sequential
treatment with TFA and Red-Al led to hydroxy TIPS diene 23 in
quantitative yield. Oxidation (DMP) of the latter, followed by
epoxide 33 (61% yield), albeit in low enantiomeric excess (43%
ee). This result was remedied through kinetic resolution of 33.
Thus, acetylation of hydroxy epoxide 33 with vinyl acetate in the
2
2
3
2
15
presence of Amano lipase PS furnished enantiomerically
enriched hydroxy epoxide (+)-33 (71% yield, >95% ee) and
enantiomerically enriched acetoxy epoxide (−)-34 (25% yield,
>95% ee). The absolute configuration assignments of (+)-33 and
(−)-34 were made tentatively based on the use of (−)-DET that
was expected to afford (+)-33 as the major enantiomer. These
exposure of the resulting aldehyde to CH(OMe) and p-TsOH
3
(
cat.) furnished dimethyl acetal 24 in 99% overall yield.
10
Sequential treatment of 24 with Nagao auxiliary 10 and
12
TiCl , i-Pr NEt and BF ·Et O afforded intermediate 25
4
2
3
2
B
DOI: 10.1021/jacs.7b09843
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 3. Enantioselective Synthesis of Epoxide Fragment
Scheme 4. Total Synthesis of Disorazole A (1)
1
a
3
7
a
Reagents and conditions: (a) 4 (1.4 equiv), Tl CO (5.0 equiv),
a
2
3
Reagents and conditions: (a) n-Bu SnH (1.3 equiv), AIBN (0.08
3
Pd(dppf)Cl (10 mol %), THF:H O 3:1, 23 °C, 16 h, 84%; (b)
Me SnOH (10 equiv), DCE, 80 °C, 3 h; (c) 39 (2.0 equiv), 38 (1.0
equiv), Et N (6.0 equiv), DMAP (8.0 equiv), TCBC (3.0 equiv),
toluene, 23 °C, 1.5 h, 99%; (d) Et N·3HF (3.0 equiv), THF, 23 °C, 1
h, 99%; (e) Me SnOH (10 equiv), DCE, 80 °C, 1.5 h; (f) TCBC (10
equiv), Et N (11 equiv), toluene, 23 °C, 1 h; then DMAP (4.0 equiv),
2
2
2
equiv), 80 °C, 2.5 h, 49%; (b) DMP (1.2 equiv), NaHCO (1.2 equiv),
CH Cl , 23 °C, 1 h, 86%; (c) 18-crown-6 (4.0 equiv), 31 (1.3 equiv),
KHMDS (1.2 equiv), THF, −78 °C, 0.5 h, 92%; (d) DIBAL-H (2.5
equiv), Et O, −78 °C, 1 h, 92%; (e) Ti(Oi-Pr) (1.0 equiv), (−)-DET
3
3
2
2
3
3
2
4
3
(
1.4 equiv), t-BuOOH (3.0 equiv), CH Cl , −20 °C, 16 h, 61%, 43%
2
2
3
ee; (f) Amano lipase PS from Burkholderia cepacia (100%, w/w), vinyl
acetate (2.0 equiv), CH Cl , 23 °C, 48 h, 71%, >95% ee for (+)-33,
2
3 to 40 °C, 29 h, 48% from 41; (g) TASF (12 equiv), H O, DMF, 41
2
2
2
°
C, 72 h, 17%. DCE = dichloroethane, TCBC = 2,4,6-trichlorobenzoyl
chloride.
5%, >95% ee for (−)-34; (g) DMP (1.3 equiv), NaHCO (1.3 equiv),
3
CH Cl , 23 °C, 1 h, 81%; (h) 5 (1.05 equiv), PPh (1.75 equiv), i-
2
2
3
Pr NEt (7.0 equiv), 90 °C, 16 h; then −78 °C, LiHMDS (1.05 equiv),
2
DMPU (0.6 equiv), (−)-8 (1.0 equiv), THF, 15 min; then 23 °C, 1 h,
7
6%; (i) 7 (1.0 equiv), CuTC (1.5 equiv), NMP, 23 °C, 1 h, 74%; (j)
3
1
8
Me SnOH, Scheme 4) under Yamaguchi conditions to afford
Et N·3HF (3.0 equiv), THF, 23 °C, 1 h, 76%. AIBN = 2,2′-azobis(2-
3
diester 40 in 99% overall yield from 38. The more labile TMS
silyl ether was cleaved from 40 (Et N·3HF) leading to hydroxy
methyl ester 41 (99% yield). The methyl ester of the latter was
methylpropionitrile), DMP = Dess−Martin periodinane, KHMDS =
potassium bis(trimethylsilyl)amide, LiHMDS = lithium bis-
3
(
trimethylsilyl)amide, CuTC = copper(I) thiophene-2-carboxylate.
18
selectively hydrolyzed using Me SnOH, and the resulting
3
hydroxy acid was cyclized under Yamaguchi conditions to afford
macrolactone 42 in 48% overall yield. Finally, the TBS groups
were cleaved from 42 by treatment with TASF (17% yield),
assignments were confirmed by successful synthesis of disorazole
1
6
19
A1 (1), whose absolute configuration was known. This
resolution presented us with the opportunity to synthesize
enantioselectively disorazole A1 (1) and the two diaster-
furnishing disorazole A (1). Synthetic disorazole A exhibited
1
1
1
13
identical H- and C NMR spectroscopic data and comparable
2
5
1
22
D
eoisomers (2 and 3, Figure 1) of disorazole B (whose relative
specific rotation {[α] = −85 (c = 0.08, MeOH); Lit. [α] =
1
D
1
,16
configuration and absolute structure were not known). Based
on biosynthetic considerations, we reasoned the likelihood of
both disorazoles featuring the same configuration at their
epoxide sites was higher than being antipodal. We, therefore,
−77 (c = 0.75, MeOH)} with the natural product. Further
improvements in this challenging and rather puzzling step are in
progress.
Disorazole B (2) was synthesized as summarized in Scheme 5.
1
opted to pursue first the synthesis of disorazole B (2), rather
than its diastereoisomer (3). To this end, hydroxy epoxide
Thus, esterification of hydroxy compound 37 (see Scheme 3)
with carboxylic acid 39 (see Scheme 4) under Yamaguchi
conditions led to ester 43 in 98% yield (based on 36). Selective
1
(
+)-33 was oxidized to aldehyde (−)-8 (DMP, 81% yield), and
then reacted with the ylide generated from iodide 5 (PPh , i-
desilylation of the latter with Et N·3HF (−TMS group)
3
3
Pr NEt; LiHMDS, DMPU) to afford selectively (Z)-olefin vinyl
furnished hydroxy methyl ester 44, whose exposure to
2
18
tin triene epoxide 35 in 76% yield. Coupling of vinyl stannane 35
Me SnOH afforded the corresponding hydroxy acid. Yama-
3
8
with bromide 7 under palladium-free conditions (thus evading
guchi macrolactonization of the so-obtained crude seco acid led
potential side reactions caused by the multiple olefinic bonds
present in the two substrates) then led to key intermediate 36
to precursor 45 (48% overall yield), from which disorazole B (2)
1
17
was liberated through TASF-mediated desilylation (64% yield).
1
13
(
74% yield), whose desilylation (Et N·3HF) furnished key
Synthetic disorazole B exhibited identical H- and C NMR
3
1
2
5
fragment 37 (76% yield).
spectral data and comparable specific rotation value {[α] = −59
D
1 20
22
Scheme 4 summarizes the completion of the total synthesis of
(c = 0.61, MeOH:CH Cl 1:1, v/v); Lit. [α] = −65 (c = 0.5,
2
2
D
disorazole A . Thus, Suzuki coupling of boronic acid 4 with vinyl
MeOH:CH Cl 1:1, v/v)} to those of the natural product.
1
2 2
bromide 6 [Pd(dppf)Cl cat., Tl CO ] furnished conjugated
hydroxy triene 38 (84% yield), which was reacted with carboxylic
acid 39 (obtained from methyl ester 36 through the action of
Starting with acetoxy epoxide (−)-34 (Scheme 3) and
2
2
3
following a similar sequence, we synthesized disorazole B
1
diastereoisomer 3, whose spectral data were in agreement with
C
DOI: 10.1021/jacs.7b09843
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 5. Total Synthesis of Disorazole B (2)
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b09843.
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Corresponding Author
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̈
K. C. Nicolaou: 0000-0001-5332-2511
Gabriel Bellavance: 0000-0002-4229-1155
Notes
̈
1
(
2
3
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
We thank Drs. Lawrence B. Alemany and Quinn Kleerekoper
(
Rice University) for NMR-spectroscopic assistance, Drs.
(
Christopher L. Pennington (Rice University) and Ian
Riddington (University of Texas at Austin) for mass-
spectrometric assistance, and Dr. Rolf Jansen for H- and
NMR spectra of disorazoles A and B . This work was supported
inadvertently reported erroneously as positive in the original isolation
paper (ref 1). We are grateful to Dr. Rolf Jansen for this clarification and
for providing us with a scan of the lab book entry of the initial isolation
indicating the true sign for the specific rotation as negative.
1
13
C
1
1
by the Cancer Prevention Research Institute of Texas (CPRIT)
and The Welch Foundation (grant C-1819). G. B. gratefully
acknowledges the Natural Sciences and Engineering Research
Council of Canada (NSERC) for a postdoctoral fellowship.
D
DOI: 10.1021/jacs.7b09843
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX