Asymmetric total synthesis of soraphen a: A flexible alkyne strategy

Full text of DOI:10.1002/anie.200901907

Communications
DOI: 10.1002/anie.200901907
Natural Product Synthesis
Asymmetric Total Synthesis of Soraphen A: A Flexible Alkyne
Strategy**
Barry M. Trost,* Joshua D. Sieber, Wei Qian, Rajiv Dhawan, and Zachary T. Ball
Soraphen A (1, Scheme 1) is a complex polyketide natural
product whose structre was first disclosed in 1988 after
isolation from the soil bacterium Sorangium cellulosum by
Hꢀfle and co-workers.[1] Importantly, 1 is a potent antifungal
agent possessing activity against a broad spectrum of fungi.[2]
Furthermore, the antifungal activity of 1 results from a unique
mode of action, whereby selective inhibition of the acetyl-
CoA carboxylase (ACC) enzyme of the fungus results in cell
death by disruption of lipid synthesis in the cell.[3] As a result,
1 has the potential for application in the treatment of obesity,
diabetes,[4] and cancer.[5] Structurally, 1 is comprised of an 18-
membered macrolactone, which includes ten stereocenters
and a highly substituted pyranose ring system. These features
make 1 a challenging target for total synthesis. To date, only
one completed total synthesis of 1 has been reported by Giese
and co-workers.[6] In addition, several groups have reported
their efforts towards the synthesis of 1.[7] Herein we report our
asymmetric total synthesis of 1 that relies on the versatility of
the alkyne functional group to provide a concise route to 1.
Alkynes are flexible functional groups because they can
be used both as nucleophiles by deprotonation of a terminal
alkyne and as electrophiles[8] by activation of the alkyne with
a transition metal. Our retrosynthetic plan (Scheme 1) was
devised around the concept of using this dual nature of the
alkyne moiety to provide a concise synthesis of the target.
À
Accordingly, the C10 C11 bond could arise from a Felkin-
selective acetylide addition of alkyne 3 to aldehyde 2.
Scheme 1. Retrosynthetic analysis. BDMS=benzyldimethylsilyl,
Bn=benzyl, PMB=para-methoxybenzyl, TBS=tert-butyldimethylsilyl.
Subsequent treatment of the resultant internal alkyne with a
hydrosilylation/protodesilylation[9] sequence should conven-
iently allow for reduction of the alkyne group to the requisite
À
C9 C10 trans olefin present in 1. The completion of 1 was
then envisioned to arise from a late-stage macrolactoniza-
tion.[10]
3 was then proposed to arise from oxidation of epoxysilane 4.
We have previously demonstrated the utility of epoxysilanes
as masked a-hydroxyketones, wherein Tamao–Fleming oxi-
dation of the epoxysilane conveniently unmasks this group.[11]
Furthermore, these epoxysilane groups are readily prepared
from an alkyne functional group by hydrosilylation and
subsequent epoxidation. Thus, an alkyne group serves as a
convenient synthon for an a-hydroxyketone to facilitate the
The hemiketal portion of 1 was envisioned to arise from
treatment of ketone 3 (R2 = H) with acid. The a-alkoxyketone
[*] Prof. B. M. Trost, Dr. J. D. Sieber, W. Qian, Dr. R. Dhawan,
Dr. Z. T. Ball
Department of Chemistry, Stanford University
Stanford, CA 94305 (USA)
À
Fax: (+1)650-725-0002
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost/
formation of a C C bond and minimizing the use of
protecting groups. Installation of the requisite stereochemis-
try at C6 and C7 in 4 could arise from a substrate-controlled
diastereoselective aldol condensation between ketone 6 and
[**] We thank the National Institute of Health (GM13598) for their
generous support of our program, and S. Lynch for assistance with
NMR spectroscopy. J.D.S. thanks the American Cancer Society for a
postdoctoral fellowship. We gratefully thank the Johnson Matthey
Chemical Co. for donation of precious metal salts, and the Aldrich
Chemical Co. for donation of (S,S)-8.
À
aldehyde 7 while forming the C6 C7 bond. Finally, aldehyde 2
was envisioned to arise from alkyne 5 by a catalyst-controlled
acetylide addition of the alkyne to benzaldehyde using the
dinuclear zinc catalyst system[12] developed in our laboratory.
Furthermore, alkyne 5 in turn derives from ring opening of an
epoxide with a terminal alkyne. Both terminal alkynes have
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901907.
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their origin in 1-propyne where it serves as a lynchpin for our
synthesis. After utilizing the terminal alkyne of 1-propyne as a
nucleophile, zipping[13] it recreates a new terminal alkyne that
can repeat its function as a new nucleophile. This reactivity
profile provides two strategies for controlling absolute
stereochemistry: 1) use of the chiral pool and 2) catalyst-
controlled asymmetric induction.
Synthesis of the aldehyde fragment began with the
preparation of alkyne 5 in three steps from (S)-glycidol
(Scheme 2). Opening of the epoxide ring with the lithium
acetylide of propyne, subsequent isomerization of the internal
alkyne to the terminal position using potassium 3-amino-
propylamide,[13] and protection of the diol with TBS gave 5.
Coupling of 5 with benzaldehyde using 10 mol% of (S,S)-8 as
Scheme 3. Synthesis of the alkyne fragment. Reagents and conditions:
a) NaHCO3, 10 mol% KBr, 1 mol% TEMPO, NaOCl, RT, 1 h, 75%;
b) 0.5 mol% [Cp*Ru(MeCN)3]PF6, benzyldimethylsilane, 08C to RT,
30 min, 86%; c) LDA, TMSCl, THF, À788C to RT, >99%, ca. 1:1 E/Z;
d) aldehyde 7, TiCl4, CH2Cl2, À788C, 73% (major diastereomer,
9:1 d.r.); e) Et2BOMe, NaBH4, THF/MeOH (1:1), À788C, 4 h; 30%
H2O2, 84% (>50:1 d.r.); f) mCPBA, CH2Cl2, À258C, 36 h, , 75%
(desired epimer, 8:1 d.r.); g) 2-methoxypropene, PPTS, CH2Cl2, RT, 1 h,
82%; h) H2 (1 atm) 10 wt% Pd/C, EtOAc, RT, 24 h, 91%; i) (COCl)2,
DMSO, CH2Cl2, Et3N; dimethyl-1-diazo-2-oxopropylphosphonate,
NaOMe, THF, À788C to À408C, 81% over two steps. Cp*=pentame-
thylcyclopentadienyl, LDA=lithium diisopropylamide, mCPBA=
m-chloroperbenzoic acid, PPTS=pyridinium toluene-p-sulfonate,
TEMPO=2,2,6,6-tetramethylpiperidin-1-yloxyl.
approximate 1:1 mixture of E and Z isomers. As the
diastereoselectivity of some Mukaiyama aldol reactions
have been shown to be independent of silyl enol ether
geometry, presumably owing to the involvement of open
transition states,[17] the mixture of enols (12) was subjected to
these types of reaction conditions. Gratifyingly, the use of
TiCl4 as the Lewis acid furnished the syn-aldol adduct 13.
Subsequent 1,3-syn reduction of enone 13,[18] followed by
alcohol directed epoxidation of the vinyl silane, and protec-
tion of the 1,3-diol allowed for stereoselective synthesis of
epoxysilane 14. The terminal alkyne was installed by hydro-
genolysis of the primary benzyl ether, Moffatt–Swern oxida-
tion of the primary alcohol, and final conversion into the
alkyne was achieved using the Ohira–Bestmann reagent.[19]
With aldehyde 10 and alkyne 15 in hand, conditions for
coupling the two fragments through a Felkin-controlled metal
acetylide addition were explored (Scheme 4). Interestingly,
use of the alkynyl titanate of 15 (not shown) gave the product
of formal chelation-controlled addition in good diastereose-
lectivity (9:1 d.r.) despite the tendency of these reagents to
give good Felkin-controlled addition.[20] Only the lithium
acetylide of 15 was found to slightly favor the Felkin addition
product 16. Various additives which are potential lithium
atom chelators were examined with the hypothesis that this
chelation may increase the steric bulk of the lithium acetylide
and thereby increase selectivity for the Felkin product.
Ultimately, use of TMEDA as an additive led to the formation
of 16 in 4.8:1 d.r. and excellent yield. However, the diaste-
reomers could not be separated at this point and the mixture
was carried forward.
Scheme 2. Synthesis of the aldehyde fragment 10. Reagents and
conditions: a) propyne, nBuLi, THF/DMPU (10:1), À788C to RT, 20 h,
68%; b) 1,3-diaminopropane, Li, KOtBu, 66%; c) TBSCl, imidazole,
DMF, 08C to RT, 2 h, 78%; d) 10 mol% (S,S)-8, benzaldehyde, 5,
ZnMe2, toluene, 48C, 48 h, 88% (18:1 dr); e) H2 (1 atm), 5 mol%
PtO2·H2O, EtOAc, RT, 1 h, 92%; f) TBAI, KHMDS, PMBCl, THF, RT,
90%; g) HF·py, py, THF, 50% and 20% diol; h) COCl2, DMSO, Et3N,
CH2Cl2, 98%. DMF=N,N-dimethylformamide, DMPU=1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone, DMSO=dimethyl sulfoxide,
HMDS=1,1,1,3,3,3-hexamethyldisilazane, py=pyridine, TBAI=tetra-n-
butylammonium iodide, THF=tetrahydrofuran.
the ligand furnished the desired propargylic alcohol 9 in
excellent yield and diastereoselectivity. Exhaustive reduction
of the alkyne to the alkane using Adamsꢁ catalyst[14] pro-
ceeded in excellent yield with minimal reduction of the
benzylic alcohol (as is often observed when using Pd/C as the
catalyst).[15] The benzylic secondary alcohol was then pro-
tected as a PMB ether followed by selective deprotection of
the primary TBS ether using HF·py. Finally, Moffatt–Swern
oxidation provided aldehyde 10 in excellent yield.
The alkyne fragment was prepared starting from 4-
heptyn-3-ol (11, Scheme 3). Oxidation and subsequent hydro-
silylation afforded ketone 6. At this point, attempts at a
chelation-controlled diastereoselective aldol condensation
between ketone 6 and aldehyde[16] 7 was examined. Classical
metal–enolate aldols that use the enolate generated from
LDA or by soft enolization techniques (TiCl4/NR3) were futile
and led to the decomposition of 6 along with recovery of 7.
Next we turned to a Mukaiyama aldol process, where
deprotonation of 6 with LDA and subsequent trapping with
TMSCl allowed for the synthesis of silyl enol ether 12 as an
With access to 16, we turned our attention to Tamao–
Fleming oxidation[21] of the epoxysilane moiety of 16 to
unmask the a-hydroxyketone. First, the secondary alcohol
was methylated with Meerweinꢁs salt before Tamao–Fleming
oxidation was explored. The use of aqueous H2O2, under
reaction conditions first reported by Hosomi and co-work-
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was subjected to protodesilylation without purifica-
tion. A variety of protodesilylation conditions were
examined, however, only AgF was successful in this
system[23] thus allowing access to 20 in good overall
yield from 17. It was at this point that the epimeric
mixture at C11 could be separated by chromatog-
raphy.
To complete the total synthesis, formation of the
hemiketal portion of 1 and macrolactonization was
required. Global methylation of the free alcohol
groups in 20, and subsequent Mander carboxylation
of the enolate (formed from kinetic deprotonation of
the ketone) provided 21 as an inseparable epimeric
mixture at C2. Heating this mixture in aqueous acetic
acid removed the acetonide protecting group and
facilitated cyclization to furnish hemiketals 22a and
22b, which were separable by chromatography.
Subjection of the incorrect epimer (22a) to basic
conditions allowed access to the open form of 22a,
and subsequent treatment with acid reformed the
cyclic hemiketal and allowed for epimerization of
22a to give an approximate 1.4:1 mixture of 22a/22b
in 75% yield for this equilibration step. Separation
and recycling of 22a allowed for the conversion of
22a into 22b in 53% overall yield after three cycles.
At this point all that remained to complete the
synthesis of 1 was formation of the macrocycle. The
desired seco-acid 23 was prepared by initial con-
version of hemiketal 22b into the corresponding
methyl ketal, subsequent removal of the PMB
protecting group, and lastly saponification of the
methyl ester. Previous studies by Hꢀfle and co-
workers[1c] had shown that a related analogue to 23
bearing a protecting group on the hydroxy group at
C5 was inert to typical macrolactonization proce-
dures that rely on activation of the carboxylic acid
functionality. However, Hꢀfle was able to effect
macrolactonization of this system through a four-step
sequence utilizing activation of the alcohol moiety.
While our synthesis is amenable to this approach by
protection of the hydroxy group at C5 of 22b prior to
removal of the PMB group and saponification, this
route is somewhat cumbersome. Furthermore, it was
envisioned that the absence of a protecting group at
C5 might allow for more efficient macrolactoniza-
tion. Therefore, we chose to examine the viability of
Scheme 4. Completion of the synthesis. Reagents and conditions: a) TMEDA,
nBuLi, THF, À788C to À208C, 92% (4.8:1 d.r.); b) Me3OBF4, proton sponge,
CH2Cl2, RT, 1.5 h, 89%; c) UHP, TBAF (syringe-pump addition), THF, 08C to RT,
2 h, 75%; d) HF·py, py, THF, RT, 48 h, 92%; e) NH(SiMe2H)2 (neat), 858C, 3 h;
f) 5 mol% [CpRu(MeCN)3]PF6, CH2Cl2, RT, 2 h; g) AgF, DMSO, MeOH, H2O,
THF, RT, 1.5 h, 60% over three steps; h) Me3OBF4, proton sponge, CH2Cl2, RT,
2 h, 88%; i) LDA (4.0 equiv), THF, À788C; then Et2O, HMPA, methyl cyanofor-
mate, 57–75% (1:1 d.r.); j) 60% AcOH, 558C, 3 h, 68%; k) Mg(OMe)2, MeOH,
RT, 12 h; 60% AcOH, 558C, 2 h, 53% after three cycles; l) amberlyst-15, MeOH,
RT, 9 h, 70%; m) DDQ, pH 7 buffer, CH2Cl2, MeOH, 48C, 5 h, 80%;
n) Ba(OH)2·8H2O, MeOH, 558C, 12 h, 75%; o) MNBA, DMAP, toluene, M.S.
(4 ꢀ), syringe-pump addition of 23, 17 h, 25%; p) 1m HCl, THF, RT, 25 min,
>99%. Cp=cyclopentadienyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
DMAP=4-dimethylaminopyridine, HMPA=hexamethylphosphoramide,
MNBA=2-methyl-6-nitrobenzoic acid anhydride, M.S.=molecular sieves,
TBAF=tetra-n-butylammonium fluoride, TMEDA=N,N,N’,N’-tetramethylethylene-
diamine, UHP=urea hydrogen peroxide.
ers[22] and which we have previously exploited for this
transformation,[11] led to substantial amounts of protodesily-
lation product. However, when using anhydrous conditions
developed in our laboratory,[11] which employ the urea
hydrogen peroxide (UHP) complex as the oxidant, clean
oxidation was observed in good yield with only small amounts
of the protodesilylation product (ca. 10-15%). The secondary
TBS ether was not removed during the oxidation, and
subsequent removal was achieved using HF·py to afford 17.
directly converting 23 into the desired macrolactone using this
approach. Gratifyingly, macrolactonization of 23 using the
method of Shiina et al.[24] furnished the desired macrolactone.
Subsequent removal of the methyl ketal[1c] afforded synthetic
1 whose spectroscopic data was consistent with those of the
natural product.
In conclusion, we have prepared soraphen A (1) in 25
linear and 34 total steps beginning from commercially
available materials 11, glycidol, and methyl (S)-3-hydroxy-2-
methylpropiolate.[16] This synthesis further illustrates the
versatility of the alkyne functional group in the synthesis of
complex molecules.
À
Synthesis of the C9 C10 trans olefin by hydrosilylation/
protodesilylation of the internal alkyne of 17 was next
examined. Silylation of the secondary alcohols of 17, and
subsequent hydrosilylation[9] afforded vinylsilane 19, which
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Published online: June 24, 2009
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[11] B. M. Trost, Z. T. Ball, K. M. Laemmerhold, J. Am. Chem. Soc.
2005, 127, 10028.
Keywords: alkynes · asymmetric synthesis · macrolactones ·
.
natural products · total synthesis
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