Total synthesis of (-)-exiguolide via an organosilane-based strategy

Article abstract of DOI:10.1039/c5cc02448j

An organosilane-based strategy has been used to accomplish the convergent total synthesis of (-)-exiguolide. The key steps involve: (1) geminal bis(silyl) Prins cyclization to construct the A ring; (2) silicon-protected RCM reaction to construct the 20-me

Full text of DOI:10.1039/c5cc02448j

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Total Synthesis of (−)-Exiguolide via An Organosilane-Based
Strategy†
Hongze Li,a Hengmu Xie,a Zhigao Zhang,a Yongjin Xu,a Ji Lu,a Lu Gao,a and Zhenlei Song*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An organosilane-based strategy has been used to accomplish a steric or electronic bias to control enoate geometry. Roulland6c-d
convergent total synthesis of (-)-exiguolide. The key steps involve: constructed the A ring in a single step via a ruthenium-catalyzed
1) geminal bis(silyl) Prins cyclization to construct the A ring; 2) ene–yne cross-coupling/Michael addition process developed by
silicon-protected RCM reaction to construct the 20-membered Trost,9 but the key step showed only moderate yield of 47% and a
macrocycle; and 3) Hiyama-Denmark cross-coupling of vinylsilane cis:trans ratio of 8:1 (Scheme 1, eq. 2). In addition, both Lee6a and
with vinyliodide to install the triene side chain.
Fuwa3b found that the C20-C21 vinyl iodide moiety, which is
required to install the side chain, interfered severely with the RCM
reaction to form the E-C16-C17 double bond. As a result, the
macrocycle was constructed in only low to moderate yield with
poor reproducibility (Scheme 1, eq. 3).
(−)-Exiguolide (1) was isolated from the marine sponge Geodia
exigua Thiele by Ohta and co-workers in 2006 (Scheme 1).1 This
unique, 20-membered macrolide inhibits fertilization of the
gametes of sea urchin (H. pulcherrimus) but not embryogenesis of
the fertilized egg, implying it may possess anticancer activity,2
We envisioned solving all these synthetic challenges using an
organosilane-based strategy involving the following steps (Scheme
1): (1) geminal bis(silyl) Prins cyclization10 to construct the A ring
and establish cis-Z stereochemistry in one step; (2) After Prins
which was recently confirmed when
1 was found to inhibit
proliferation of various cancer cell lines.3 Cossy4 proposed that 1
may even be a structurally simpler analogue of naturally occurring
bryostatins,5 which exhibit excellent activity against a wide range of
cancers and other non-cancer diseases. Given that detailed
investigations of 1 are hampered by its low natural abundance, the
synthetic community has expended substantial effort to prepare
the compound in the laboratory. 3, 6
cyclization/bromination11 to construct the B-ring,
a silicon-
protected RCM reaction12 to give a 20-membered macrocycle via E-
Stepwise: E. Lee.; K. A. Scheidt.; H. Fuwa.
Me
CO2Me
MeO2C
22
O
Z:E = 5:1
to 7:1
HWE
One of the most distinctive structural features of 1 is a methylene
bis-cis-tetrahydropyran motif, in which the A ring contains an
unusual exocyclic Z-methyl enoate.7 Both Scheidt3a and Fuwa3b-c
have shown that while the Z-isomer inhibits the growth of cancer
cell lines, the E-isomer shows only minimal biological activity.
H iyama-Denmark Cross
Coupling
21
A
62-94%
(eq. 1)
Me
R2
O
R1
R2
O
R1
Silicon-Protected
Si
17
RCM
16
Me
O
O
One-step: E. Roulland
R1
SiMe3
O
Geminal Bis(silyl) Prins
Cyclization
Ru(II)
OH
O
Therefore efficient synthesis of
1 requires stereocontrolled
(eq. 2)
R1
+
A
B
A
47%
MeO2C
assembly of the structurally unique A ring. In the previous total
syntheses of 1, three groups3a, 6a-b constructed the A ring using a
stepwise strategy in which the cis-pyranone was generated first,
followed by Fuji’s asymmetric Horner–Wadsworth–Emmons
reaction.8 Z/E selectivity ranged from only 5:1 to 7:1 (Scheme 1, eq.
1). This moderate Z-selectivity probably reflects the fact that
substitutions at C4 and C5 are methylene groups, which exert no
R2
O
O
R1
SiMe3
[dr = 8:1]
(–)-exiguolide (1)
I
I
side chain required, but it
interf eres with RCM
Me
16
Me
16
Me
RCM : E. Lee.; H. Fuwa.
(eq. 3)
17
O
RCM
17
O
O
O
Me
30-44%
O
O
O
O
A
B
B
A
PO
PO
Scheme 1 Organosilane-based strategy for the synthesis of (-)-exiguolide
(upper left). Stepwise construction of the ring (eq. 1). One-step
A
construction of the A ring (eq. 2). Vinyliodide interferes with the RCM
reaction that forms the macrocycle (eq. 3).
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Table 1 Screening of Prins Cyclization/Bromination Conditions. a
C16-C17 double bond formation; and (3) Hiyama-Denmark cross-
coupling13 of the silyl group (reacting as vinylsilane) and vinyliodide
to install the triene side chain. Here we report detailed studies of
this organosilane-based total synthesis of (−)-exiguolide (1).
We began our synthetic efforts from the known chiral epoxide
2.14 Epoxide ring opening by 1-trimethylsilylvinyl magnesium
bromide and subsequent bromination gave vinyl bromide 3 in 81%
yield.15 Pd(0)-catalyzed Kumada coupling of 3 with bis(trimethylsilyl)
magnesium chloride gave the key precursor 4 in 88% yield.16
TMSOTf-promoted Prins cyclization of 4 with TIPSOCH2CH2CHO
constructed the A ring, generating the desired tetrahydropyran 5 in
88% yield with exclusive cis-Z selectivity.10a From 5, four aldehydes
containing different R groups were synthesized with retention of
the Z configuration: 6a (R = SiMe3), 6b (R = CO2Me), 6c (R = Br) and
6d (R = I).17 These aldehydes were used directly in Prins
cyclization/bromination with homoallylic alcohol 9 to form the B
ring. To prepare 9, we subjected the known aldehyde 718 to Kishi’s
Fe/Cr-mediated asymmetric allylation.19 Sulfonamide (R)-8 proved
the most effective chiral ligand, giving 9 in 81% yield with 91:9 dr.
First, Prins cyclization/bromination to form the B ring was tested
Entry
6
Br source/L.A. T (°C)
(equiv)
Product (yield% b)
1
2
6a
6b
TMSBr/InBr3
(1.2/0.2)
TMSBr/InBr3
(1.2/0.2)
-78
-78
10a (0); 11 (44)
10b (30); 12b (28); 13 (23)
3
4
5
6b
6c
6d
SnBr4 (2.2)
SnBr4 (2.2)
SnBr4 (2.2)
-78 to -20
-78 to -20
-78 to -20
10b (45); 12b (22); 13 (55)
10c (59); 12c (14); 13 (9)
10d (86); 12d (0); 13 (0)
o
using 6a at −78 C with Me3SiBr/InBr3, which was developed by
a Reaction conditions: 0.15 mmol of 6, 0.18 mmol of 9 in 2.0 mL of CH2Cl2.
b
Loh20 as the combined bromine source and Lewis acid to promote a
non-racemic Prins cyclization.21 Unfortunately, the cyclized product
11 was obtained in 44% yield rather than 10a, with concurrent
elimination of the silyl group (Table 1, entry 1). Replacing 6a
with the CO2Me-substituted aldehyde 6b gave the desired
product 10b as a 3:2 mixture of two bromo-isomers, but in a
low yield of 30% (entry 2). No racemization was essentially
Isolated yields after purification by silica gel column chromatography. c 10b-
10d were obtained as mixtures of two bromo-isomers in ratios ranging from
1:1 to 2:1; these mixtures collapsed into a single product after bromide
d
removal. The cis/cis stereochemistry on the B ring was assigned based on
the results from ref. 20a. The 1,3-syn stereochemistry was assigned based
on the results from ref. 23. 13 was obtained as a mixture of two bromo-
e
f
isomers in ratios ranging from 6:4 to 7:3; the major isomer was
characterized.
Scheme 3 Rationalization of the formation of 10, 12 and 13 in the Prins
cyclization/bromination reaction of 6b-6d with 9.
observed, since the mixture of 10b collapsed into a single product
after bromide removal. Two major by-products were 12b (28%) and
13 (23%). Promoting cyclization by Rychnovsky’s protocol22 using
2.2 equiv of SnBr4 afforded a higher yield of 45% at temperatures
o
from −78 to −20 C with no loss of optical purity, but the reaction
still generated substantial proportions of 12b and 13 (entry 3).
Similar results were observed in the reaction of Br-substituted
aldehyde 6c, although the yield of 10c was higher at 59% (entry 4).
To our delight, cyclization of I-substituted aldehyde 6d with 9
proceeded smoothly to give 10d in 86% yield with no detectable
production of 12d or 13 (entry 5).
Scheme 2 Synthesis of the A ring. (a) (1) CH2=CH(SiMe3)MgBr, CuCN, THF, -
30 °C to rt, 1 h. (2) Br2, MeONa/MeOH, CH2Cl2, -78 °C to rt, 2 h, 81%, 2 steps;
(b) (Me3Si)2CHMgCl, MeMgCl, 5 mo% Pd(PPh3)4, THF, 40 °C, 10 h, 88%; (c)
TIPSOCH2CH2CHO, TMSOTf, Et2O, -78 °C, 15 min, 88%; (d) (1) DDQ,
CH2Cl2/H2O, 0 °C, 3 h. (2) IBX, THF/DMSO, rt, 30 min, 83%, 2 steps; (e) (1)
NIS, CH3CN/DMF, 0 °C, 1.5 h, 86%. (2) 15 mol% PdCl2(CH3CN)2, dppf, CO,
Et3N, MeOH, DMF, 80 °C, 5 h, 93%. (3) DDQ, CH2Cl2/H2O, 0 °C, 3 h. (4) IBX,
THF/DMSO, rt, 30 min, 78%, 2 steps; (f) (1) NBS, DMF, 0 °C, 3 h, 91%. (2)
DDQ, CH2Cl2/H2O, 0 °C, 3 h. (3) IBX, THF/DMSO, rt, 30 min, 81%, 2 steps; (g)
(1) NIS/ CH3CN/DMF, 0 °C, 1.5 h, 86%. (2) DDQ, CH2Cl2/H2O, 0 °C, 3 h. (3) IBX,
THF/DMSO, rt, 30 min, 83%, 2 steps.
The results in Table 1 indicate that the exocyclic R group on the A
ring, although it lies far from the reactive site on the nascent B ring,
nevertheless strongly influences the reaction course. We propose
the following mechanism to rationalize this interesting effect
(Scheme 3). Condensation of aldehyde 6 with 9 occurs first to
generate the oxacarbenium 14. Normally, the Prins
2 | J. Name., 2012, 00, 1-3
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cyclization/bromination of 14 should form the B ring to give the three steps. Esterification of acid 16 with the 22 provided 17 in 90%
desired cyclized product 10. However, if the oxonia-Cope yield. As expected, the bulky, inert silyl group at C21 effectively
rearrangement of 14 is more favorable than Prins/bromination, prevented the C20-C21 double bond from interfering with the RCM
then enantioselective allyl transfer23 should occur, generating reaction in which the C16-C17 alkene formed. Macrocyclization
oxacarbenium 15. While 15 can still undergo cyclization to give 10, catalyzed by 10 mol% Hoveyda-Grubbs second-generation catalyst30
it can also undergo H2O-promoted dissociation to generate by- proceeded cleanly, affording macrocycle 18 in 85% yield as a single
product 12 and aldehyde 7. Further Prins cyclization/bromination of E-isomer.
7 with 9 would afford another by-product 13. We speculate that the
Following the silicon-protected RCM reaction, the dimethylbenzyl
electronic effect of the R group plays a key role in determining the silyl group31 in 18 was ready (as vinylsilane) to undergo Hiyama-
actual reaction pathways. Because bromine is more electronegative Denmark cross-coupling with vinyliodide 23-2532 to install the triene
than iodine, its stronger electron-withdrawing inductive effect side chain (Scheme 5). Considerable attempts using various Pd(0)
should make the A ring more electron-deficient, driving oxonia- catalysts and fluorine sources failed to work for the ester-
Cope rearrangement of 14 to generate the more stable substituted vinyliodide 23. This fragment was unstable in the
oxacarbenium 15. The ester group also destabilizes 14 but probably presence of F- and it decomposed quickly before any coupling could
by an electron-withdrawing conjugation effect, which renders the occur. Based on the hypothesis that 23 may be prone to double
corresponding A ring more electron-deficient.
bond isomerization via F--promoted enolization, we selected the
Continuing the synthesis from 10d, we subjected this compound acid-substituted 24 as an alternative coupling partner. The target
to Pd(0)-catalyzed carbonylation9 to deliver methyl enoate 10b in compound was indeed obtained after methylation, but only in 10%
93% yield (Scheme 4). Then 10b was converted to the acid 16 in yield because of the low coupling efficiency to form acid 26.
93% yield over the following four steps: reduction of the bromide Successful coupling was finally achieved using primary hydroxyl-
on the B ring with NaBH4/InBr3,24 removal of the silyl group to substituted vinyliodide 25, which was assembled with 18 to give
generate
a
primary alcohol, oxidation with Dess–Martin triene 27 in 82% yield. Although Pd(0) catalyst is generally effective
periodinane25 to the aldehyde, and finally Pinnick oxidation.26 The enough to promote Hiyama-Denmark cross-coupling, we found Cu(I)
requisite vinylsilyl fragment 22 was prepared from aldehyde 1927 to be essential for high reaction efficiency; no coupling occurred in
and chiral oxazolidinone 20, which underwent Evans’ asymmetric the absence of 1.0 equiv of CuI.33 Subsequent Dess-Martin
aldol28 reaction to give 21 in 81% yield with ≥ 95:5 dr. This product oxidation of 27 to aldehyde, Pinnick oxidation to acid, and
was then subjected to Weinreb amide formation,29 reduction to an methylation with Me3SiCHN2 in MeOH/benzene produced (-)-
aldehyde and Wittig olefination to generate 22 in 68% yield over
exiguolide in 81% yield over three steps. Spectroscopic data for
synthetic 1 were identical to those reported for the naturally
occurring compound and for compound produced by other
synthetic methods ([α]D = – 84.6 [c 0.09 in CHCl3], ref.1 [α]D = –
20
20
92.5 [c 0.069 in CHCl3]).
Scheme 4 Synthesis of the macrocycle. (a) 15 mol% PdCl2(CH3CN)2, dppf, CO,
Et3N, MeOH, DMF, 80 °C, 5 h, 93%; (b) (1) NaBH4, InBr3, THF, rt, 2 h. (2)
HF•Pyridine, THF, rt, 1 h, 95%, 2 steps. (3) Dess-Martin periodinane, CH2Cl2,
0 °C to rt. (4) NaClO2, NaH2PO4, 2-Me-2-butene, THF/t-BuOH/H2O, rt, 1 h,
98%, 2 steps; (c) 22, DIC, DMAP, CH2Cl2, rt, 4 h, 90%; (d) 10 mol% HG-II,
benzene, reflux, 22 h, 85%; (e) Bu2BOTf, Et3N, CH2Cl2, -78 to 0 °C, 15 min,
then 19, -78 to -20 °C, 2 h, 81%, dr ≥ 95:5; (f) (1) NH(OMe)Me•HCl, AlMe3,
CH2Cl2, -15 to 0 °C, 1 h. (2) LiAlH4, THF, 0 oC, 20 min. (3) Ph3PCH3I, t-BuOK,
THF, 0 °C, 1 h, 68%, 3 steps.
Scheme 5 Hiyama-Denmark cross-coupling to install the triene side chain.
(a) 24 (1.5 equiv), 10 mol% [allyPdCl]2, 20 mol% Ruphos, TBAF, THF, rt to 50
°C, 3 h; (b) TMSCHN2, MeOH/benzene, rt, 10 min, 10%, 2 steps; (c) 25 (1.5
equiv), 10 mol% Pd(PPh3)4, 100 mol% CuI, TBAF, Et3N, THF, 30 °C, 3 h, 82%;
(d) (1) Dess-Martin periodinane, NaHCO3, CH2Cl2, rt, 1 h. (2) NaClO2,
NaH2PO4, 2-Me-2-butene, THF/t-BuOH/H2O, rt,
1 h. (3) TMSCHN2,
MeOH/benzene, rt, 10 min, 81%, 3 steps.
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VCH: Weinheim, Germany, 1998; Chapter 10; (b) T. Hiyama, E.
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In summary, we have completed a convergent total synthesis of
(-)-exiguolide from the known chiral epoxide 2 in 16.8% yield over
19 steps as the longest linear path. The synthesis relies on an
organosilane-based strategy to overcome most synthetic
challenges. Employing the geminal bis(silyl) Prins cyclization allowed
one-step construction of the
A ring with exclusive cis-Z
stereochemical control. silicon-protected RCM reaction
A
substantially improved on the low efficiency of previous efforts to
form the macrocycle. The silyl group persisted as vinylsilane, which
underwent Hiyama-Denmark cross-coupling with vinyliodide to
furnish the triene side chain. Further studies including synthesis and
biological evaluations of (-)-exiguolide analogues are underway.
We are grateful for financial support from the NSFC (21172150,
21321061, 21290180), the NCET (12SCU-NCET-12-03), and the
Sichuan University 985 project.
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4 | J. Name., 2012, 00, 1-3
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