Total synthesis of sporolide B

Full text of DOI:10.1002/anie.200900264

Angewandte
Chemie
DOI: 10.1002/anie.200900264
Natural Product Synthesis
Total Synthesis of Sporolide B**
K. C. Nicolaou,* Yefeng Tang, and Jianhua Wang
Sporolides A (1a) and B (1b) are two highly unusual natural
products reported by the research group of Fenical in 2005.[1]
Isolated from the marine actinomycete Salinospora tropica,
these molecules possess no obvious biological activity, yet
their intriguing molecular architectures imply the existence of
an as yet unidentified, secondary metabolite of the enediyne
class,[2] whose fleeting nature may explain the incorporation
of the chloro-substituted aryl rings within their structures[2,3]
through a Bergman cycloaromatization reaction.[4] In view of
the importance of the enediyne family of natural products[5]
and to better understand the biosynthetic origins of the
sporolides A and B, as well as their postulated enediyne
precursor, we embarked on the total synthesis of these
molecules. Herein, we report the first total synthesis of
sporolide B (1b) in its naturally occurring enantiomeric form
through a highly stereoselective and convergent strategy that
involves two important cycloaddition reactions.
These special structural elements and unique connectiv-
ities amounted to a formidable synthetic challenge that was
eventually met by adopting the devised synthetic strategy
outlined retrosynthetically in Scheme 1. This strategy was
The unprecedented 24-carbon polycyclic structure of
sporolide B (1b) includes 12 oxygen atoms, 10 stereogenic
centers, a 13-membered macrolide ring, a chlorobenzene
nucleus embedded within an indane structural motif, and two
oxygen bridges that, together with the ester bond, connect the
two domains of the molecule into its cagelike structure.
Scheme 1. Retrosynthetic analysis of sporolide B (1b). Ac=acetyl,
Bn=benzyl, TBS=tert-butyldimethylsilyl.
based on two key retrosynthetic disconnections: 1) a ther-
mally induced, intramolecular [4+2] cycloaddition reaction
involving an o-quinone and a tetrasubstituted olefin to form
the macrocyclic structure of the molecule (2!1b),[6] and 2) a
ruthenium-catalyzed, intermolecular [2+2+2] cycloaddition
reaction between two acetylenic units,[7] building blocks 3 and
4, to forge its chlorobenzenoid indane structural motif. The
complexity of the substrates involved in these planned
reactions and the lack of any precedent for their application
in complex natural product synthesis made them risky
propositions with regards to both feasibility and topology
(regio- and stereoselectivity). Nevertheless, model studies[6]
and inspection of molecular models were encouraging.
Scheme 2 summarizes the construction of chloroacetylene
building block 3. Thus, enantiomerically pure iodoenone 5
(ee > 99%)[8] was reduced under Luche conditions[9] (NaBH4,
CeCl3·7H2O, ꢀ788C), affording, upon benzylation (NaH,
BnBr, THF), vinyl iodide 6 (ca. 10:1 diastereomeric ratio,
95% combined yield).[10] Carboxymethylation of the latter
[*] Prof. Dr. K. C. Nicolaou, Dr. Y. Tang, J. Wang
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic
and mass spectroscopic assistance, respectively. We thank Dr. R.
Hungate and R. Jensen of Amgen, Thousand Oaks, California, for
the 13C NMR spectrum of synthetic sporolide B and Prof. W. Fenical
for a sample of natural sporolide B. Financial support for this work
was provided by the National Institutes of Health (USA), the Skaggs
Institute for Research, and an Andrea Elizabeth Vogt Memorial
Fellowship (to J.W.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900264.
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compound under palladium-catalyzed conditions ([PdCl2-
(PPh3)2] cat., CO, MeOH) led to methyl ester 7 (95%
yield), whose reduction (DIBAL-H, 95% yield), protection as
a THP ether (DHP, TsOH·H2O), and desilylation (TBAF)
furnished allylic alcohol 8. Oxidation of 8 with Dess–Martin
periodinane[11] (DMP) gave the corresponding enone (83%
overall yield over the last three steps), which was iodinated
(I2, CH2Cl2/pyridine (1:1)), affording iodoenone 9 in 80%
yield. Luche reduction of the latter (NaBH4, CeCl3·7H2O,
ꢀ788C) proceeded stereoselectively (ca. 5:1 diastereomeric
ratio)[10] and afforded, upon silylation (TBSCl, imidazole,
DMAP), vinyl iodide 10 in 94% yield over the two steps.
Sonogashira coupling of 10 with TMS-acetylene ([PdCl2-
(PPh3)2] cat., CuI cat., Et2NH, 98% yield) and subsequent
removal of the THP protecting group (Et2AlCl, ꢀ25!258C,
99% yield) and oxidation of the resulting primary alcohol
(DMP, 79% yield) furnished aldehyde 11. The required
chloroacetylene structural motif was then installed within the
Scheme 2. Construction of building block 3. Reagents and conditions:
a) NaBH4 (1.2 equiv), CeCl3·7H2O (1.2 equiv), MeOH, ꢀ788C, 1 h;
b) NaH (60% in mineral oil, 1.5 equiv), THF, 08C, 30 min; then BnBr
(1.5 equiv), TBAI (0.2 equiv), THF, 0!258C, 16 h, 95% over two
steps; c) [PdCl2(PPh3)2] (0.05 equiv), Et3N (5.0 equiv), CO (balloon
pressure), MeOH, 708C, 3 h, 95%; d) DIBAL-H (1.0m in toluene,
2.5 equiv), toluene, ꢀ78!ꢀ108C, 1 h, 95%; e) DHP (1.5 equiv),
TsOH·H2O (0.1 equiv), CH2Cl2, 08C, 30 min; f) TBAF (1.0m in THF,
1.5 equiv), THF, 258C, 3 h; g) DMP (1.2 equiv), NaHCO3 (5.0 equiv),
CH2Cl2, 258C, 30 min, 83% over three steps; h) I2 (3.0 equiv), CH2Cl2/
pyridine (1:1), 258C, 15 h, 80%; i) NaBH4 (1.2 equiv), CeCl3·7H2O
(1.2 equiv), MeOH, ꢀ788C, 1 h; j) TBSCl (2.0 equiv), imidazole
(2.0 equiv), DMAP (0.1 equiv), CH2Cl2, 258C, 3 h, 94% over two steps;
k) TMS-acetylene (1.2 equiv), [PdCl2(PPh3)2] (0.02 equiv), CuI
(0.04 equiv), Et2NH, 258C, 16 h, 98%; l) Et2AlCl (1.8m in toluene,
2.0 equiv), CH2Cl2, ꢀ25!258C, 2 h, 99%; m) DMP (1.2 equiv),
NaHCO3 (5.0 equiv), CH2Cl2, 258C, 1 h, 79%; n) cis-1,2-dichloroethy-
lene (4.5 equiv), MeLi (1.6m in Et2O, 3.0 equiv), Et2O, 08C, 30 min;
then 11, Et2O, 08C, 10 min; o) DMP (1.5 equiv), NaHCO3 (5.0 equiv),
CH2Cl2, 258C, 1 h, 93% over two steps; p) DIBAL-H (1.0m in toluene,
1.5 equiv), toluene, ꢀ788C, 30 min, 81%; q) K2CO3 (1.5 equiv), MeOH,
258C, 1 h, 99%; r) Ac2O (1.5 equiv), Et3N (1.5 equiv), DMAP
(0.1 equiv), CH2Cl2, 08C, 30 min, 98%. DHP=3,4-dihydro-2H-pyran,
DIBAL-H=diisobutylaluminum hydride, DMAP=4-dimethylaminopyri-
dine, DMP=Dess–Martin periodinane, TBAF=tetra-n-butylammonium
fluoride, TBAI=tetra-n-butylammonium iodide, THF=tetrahydrofuran,
THP=tetrahydropyranyl, TMS=trimethylsilyl, Ts=4-toluenesulfonyl.
Scheme 3. Construction of building block 4. Reagents and conditions:
a) MePPh3Br (1.5 equiv), KHMDS (1.0m in toluene, 1.2 equiv), THF,
08C, 30 min; then 15, THF, ꢀ78!08C, 30 min, 98%; b) AD-mix-b
(1.4 g per mmol 16), tBuOH/H2O (1:1), 258C, 8 h, 96%; c) TBSCl
(1.5 equiv), Et3N (1.5 equiv), DMAP (0.1 equiv), CH2Cl2, 258C, 8 h,
99%; d) tBuOK (3.0 equiv), MeI (4.0 equiv), MeCN, 0!258C, 16 h,
95%; e) TBAF (1.0m in THF, 1.5 equiv), THF, 258C, 16 h, 99%;
f) DMP (1.5 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 258C, 1 h, 78%;
g) NaClO2 (4.5 equiv), NaH2PO4·2H2O (3.0 equiv), 2-methyl-2-butene
(2.5 equiv), tBuOH/H2O (1:1), 258C, 30 min, 96%; h) 20 (1.3 equiv),
EDCI (1.2 equiv), DMAP (0.2 equiv), CH2Cl2, 258C, 3 h, 73%;
i) Pb(OAc)4 (1.5 equiv), benzene, 758C, 1 h, 89%. EDCI=1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
HMDS=bis(trimethylsilyl)amide.
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growing molecule by treatment of aldehyde 11 with a
preformed solution of lithiochloroacetylene (cis-1,2-dichloro-
ethylene, MeLi, Et2O, 0 8C) and furnished the expected
secondary alcohol, which, however, possessed the undesired
configuration at C11.[12] This configuration was inverted
through an oxidation/reduction protocol. Thus, oxidation of
this alcohol with DMP led to ketone 12 (93% overall yield
over the last two steps), which was reduced stereoselectively
(chelation controlled, ca. 7:1 diastereomeric ratio) with
DIBAL-H (toluene, ꢀ788C)[12] and afforded the desired
alcohol 13 with 81% yield after silica gel chromatographic
separation from its undesired diastereomer. Finally, removal
of the TMS group from its acetylene host in 13 (K2CO3,
MeOH, 99% yield), and subsequent acetylation (Ac2O, Et3N,
DMAP, 98% yield), led to the targeted acetoxy chloroace-
tylene 3 through hydroxy precursor 14.
tion of diynes with alkyl substrates to form benzenoid
systems[7] was complicated in this instance by the presence
of the chlorine atom and the complexity of the substrates
involved. However, we were counting on the steric bulk of the
chlorine residue on 3 (as compared to a hydrogen atom) and
the coordinating ability of the free hydroxy group in 4 to
provide favorable conditions for the desired outcome of the
reaction, which included its regiochemistry with regards to the
position of the chlorine atom on the aryl ring. In the event,
combining 3 and 4 in 1,2-dichloroethane in the presence of
[Cp*RuCl(cod)] catalyst[16] resulted, within 30 min, in the
formation of compound 22 in 87% yield and as a single
regioisomer (Scheme 4). The highly productive process that
led rapidly and exclusively to the desired meta-chloro isomer
may be explained by inspection of transition states 3-TSa, 3-
TSb, and 3-TSc, via which this reaction is presumed to
proceed.
Scheme 3 depicts the construction of propargyl alcohol
building block 4 starting from aldehyde 15.[13] Thus, 15 was
In preparation for the next challenging task, namely the
forging of the cyclic framework of the sporolide molecule
through the proposed [4+2] cycloaddition reaction,[6] com-
pound 22 was converted into o-quinone 2 via catechol
=
subjected to Wittig olefination (Ph3P CH2, ꢀ78!08C, 98%
yield) and afforded styrene derivative 16, which entered a
highly enantioselective Sharpless asymmetric dihydroxylation
reaction[14] (AD-mix-b, 96%
yield, 98% ee) and furnished,
after sequential silylation
(TBSCl, Et3N, DMAP, 99%
yield)
and
methylation
(tBuOK, MeI, 95% yield),
fully protected pentasubsti-
tuted aryl system 18. The
latter compound was con-
verted into carboxylic acid 19
through a three-step sequence
involving desilylation (TBAF,
99% yield) and oxidation of
the resulting primary alcohol,
first with DMP (78% yield),
and then with NaClO2 (96%
yield). Coupling of 19 with
acetylenic alcohol 20,[15] as
facilitated by EDCI and
DMAP, led to the selective
formation of hydroxy ester 21
(73% yield). Treatment of the
latter intermediate with Pb-
(OAc)4 in benzene at 758C led
smoothly to the required hy-
droxy acetylenic building
block 4 in 89% yield (ca. 6:1
diastereoisomeric mixture).
With the two fragments 3
and 4 in hand, we set out to
investigate their fusion into
the desired polycyclic precur-
sor for the final casting of the
sporolide B macrocyclic struc-
ture. Although known to pro-
ceed well, the intermolecular,
ruthenium-catalyzed
Scheme 4. Synthesis of o-quinone 2. Reagents and conditions: a) 3 (1.0 equiv), 4 (1.1 equiv), [Cp*RuCl-
(cod)] (0.07 equiv), DCE, 258C, 30 min, 87%; b) Ac2O (2.0 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv),
CH2Cl2, 08C, 30 min, 92%; c) HF (48% aqueous solution, excess), MeCN, 258C, 30 min; then MeOH
(excess), 258C, 3 h, 74%; d) Ag2O (2.5 equiv), CH2Cl2, 258C, 30 min, 94%. cod=cycloocta-l,5-diene,
Cp*=pentamethylcyclopentadienyl, DCE=1,2-dichloroethane.
[2+2+2] cycloaddition reac-
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derivative 23 through sequential acetylation (Ac2O, Et3N, and
via transition state 2-TS. Although the remarkable diastereo-
selectivity (facial orientation of o-quinone) of this reaction
can be rationalized by the steric bias of the dienophile (top
face blocked by the substituents on the five-membered rings),
an explanation for its regioselectivity (o-quinone rotation
DMAP, 92% yield), desilylation (aq.HF and MeOH, 74%
yield), and oxidation (Ag2O, 94% yield) as shown in
Scheme 4.
Scheme 5 presents the final stages and the completion of
the total synthesis of sporolide B (1b). Thus, upon heating in
toluene at 1108C, o-quinone 2 underwent the much antici-
pated Diels–Alder reaction and afforded the desired product
24 (40% yield based on ca. 50% conversion),[17] apparently
ꢀ
around the C2’ C3’ bond) remains elusive. Notably, the
oxygen substituent at C9 within 24 and all its precursors have
(by design) the opposite configuration from that required for
sporolide B (1b), and therefore requires inversion. This task
was to be achieved at some point downstream through an
oxidation/reduction sequence, with the hydroxy group at C7
playing a directing role in the reduction step. Therefore,
subsequent steps had to accommodate, in addition to the
obligatory dearomatization of the trioxygenated benzenoid
ring, the two steps required for this inversion. To this end, a
TES group was placed on the well positioned oxygen atom at
C7 (TESOTf, Et3N, 95% yield) before the two benzyl groups
were removed (H2, Pd(OH)2 cat., 92% yield), affording
hydroxy phenol 26 via intermediate 25. Exposure of 26 to
PhI(OCOCF3)2 in the presence of PMBOH in acetonitrile
furnished para-ketal quinone 27 in 75% yield, thus providing
the opening for the oxidation/reduction protocol to invert the
configuration at C9. Indeed, oxidation of 27 (DMP, 90%
yield) and subsequent removal of the TES protecting group
(aq. HF, MeCN, 85% yield) gave, through the corresponding
carbonyl compound, b-hydroxy ketone 28, whose reduction
with Me4NBH(OAc)3 (MeCN/AcOH 10:1) led to 1,3-diol 29
as a single stereoisomer in 85% yield. This compound was
treated sequentially with DDQ (CH2Cl2/H2O (10:1), 70%
yield) and DBU (CH2Cl2/MeOH (3:1), 78% yield) to remove
the PMB and acetate protecting groups, thus furnishing
deoxysporolide B 30. The final step of the total synthesis of
sporolide B (1b) involved regio- and stereoselective intro-
duction of the missing oxygen atom from precursor 30 in the
required epoxide form by reaction with tBuOOH in the
presence of DBU in CH2Cl2 at 408C (3 h, 63% yield).
Synthetic sporolide B (1b) exhibited identical chromato-
graphic data, spectroscopic data, and optical rotation sign to
those of the authentic sample (see the Supporting Informa-
tion).
The regio- and stereocontrolled total synthesis of spor-
olide B (1b) described here demonstrates the power of the
ruthenium-catalyzed intermolecular [2+2+2] cycloaddition
reaction of acetylenic substrates and provides further insight
into possible biosynthetic pathways to this novel secondary
metabolite and its regioisomeric sibling sporolide A (1a).
Scheme 5. Completion of the total synthesis of sporolide B (1b).
Reagents and conditions: a) toluene, 1108C, 1.5 h, 40% (based on
50% recovered starting material); b) TESOTf (1.5 equiv), Et3N
(2.0 equiv), CH2Cl2, 08C, 30 min, 95%; c) H2 (balloon pressure),
Pd(OH)2 (10% on carbon, 2.0 equiv), EtOAc, 258C, 4 h, 92%; d) PIFA
(1.5 equiv), PMBOH (10 equiv), K2CO3 (5.0 equiv), MeCN, 08C,
30 min, 75%; e) DMP (2.0 equiv), CH2Cl2, 258C, 1 h, 90%; f) HF (48%
aqueous solution, excess), MeCN, 258C, 2 h, 85%; g) Me4NBH(OAc)3
(10 equiv), MeCN/AcOH (10:1), 258C, 2 h, 85%; h) DDQ (5.0 equiv),
CH2Cl2/H2O (10:1), 258C, 5 h, 70%; i) DBU (10 equiv), CH2Cl2/MeOH
(3:1), 408C, 4 h, 78%; j) tBuOOH (10 equiv), DBU (5.0 equiv), CH2Cl2,
408C, 3 h, 63%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone, PIFA=phenyliodine(III) bis(tri-
fluoroacetate), PMB=4-methoxybenzyl, TES=triethylsilyl,
Received: January 15, 2009
Published online: February 24, 2009
Keywords: cycloaddition · Diels–Alder reactions ·
.
natural products · o-quinones · total synthesis
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