Functionality propagation by alkylative oxidation of cross-conjugated cycloheptadienyl sulfones

Article abstract of DOI:10.1002/anie.200350955

Getting the most out of sulfur. Enantiopure epoxyvinyl sulfone 1 is transformed to syn- and anti-dienyl sulfones 2 and 3, respectively, by means of a nucleophilic methylation/sulfenylation/directed elimination reaction sequence. Compound 2 has been converted into termini-differentiated seven-carbon polypropionate segments found in five biologically significant natural products.

Full text of DOI:10.1002/anie.200350955

Communications
Polypropionate Synthesis
Functionality Propagation by Alkylative
Oxidation of Cross-Conjugated Cycloheptadienyl
Sulfones**
Eduardo Torres, Yuzhong Chen, In Chul Kim, and
P. L. Fuchs*
Chemists routinely adopt multiply convergent syntheses that
combine stereochemically defined, functionality-rich seg-
ments. Yet this strategy alone does not guarantee an efficient
synthesis. Rather, the selection of easily scaled segments
primarily determines the success of a synthetic project.
Catalytic processes for the preparation of enantiopure seg-
ments have intrinsic advantages over the stoichiometric use of
enantiopure auxiliaries or reagents, as these “high-overhead”
strategies generate added time and expense. Even successful
syntheses that adopt the latter approach may be limited with
respect to potential scale-up.
All syntheses that target a single enantiomer must be
related ultimately to one or more substances in the chiral
pool.[1] Syntheses that generate their asymmetry by means of
a chiral catalyst are highly desirable because one molecule of
catalyst is responsible for the creation of a multitude of new
chiral progeny.
Over the past five years we have been developing cross-
conjugated six- and seven-membered dienyl sulfones to
[*] Prof. P. L. Fuchs, E. Torres, Y. Chen, I. C. Kim
Department of Chemistry
Purdue University
West Lafayette, IN 47907 (USA)
Fax: (+1)765-494-7679
E-mail: pfuchs@purdue.edu
[**] We thank Karl Wood and Arlene Rothwell for MS data and Daniel Lee
for elemental analyses. E.T. wishes to thank Pfizer, Inc. for a
fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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generate a collection of termini-differentiated acyclic arrays
bearing two to five stereocenters.[2] Jacobsen asymmetric
epoxidation of dienyl sulfone 2 with ca. 1% catalyst loading
gives either epoxide (R,R)-3 or (S,S)-3 in > 80% yield and
> 97% ee (Scheme 1).[3,4] When the same protocol was
applied to 5, double stereoselection (> 12:1) resulted and
the individual isomers of 6 and 7 were isolated as crystalline
products in > 75% yield and > 97% de.[5,6]
The complementary reactions of trimethylaluminum and
dimethylcuprate with silyl ether syn-7 gave alcohols 8 and
10b, respectively (Scheme 1). Alternatively, when alcohol
Scheme 2. Initial sulfenylation attempts. a) MeLi, THF, ꢀ788C, b) Me2S.
TMS=trimethylsilyl.
anions. Attempted hydrolysis of these mixtures to enones
16 or 17 was unrewarding.
A subsequent experiment showed that reaction of the
allylic anions 4-Li2 and 5-Li with the sterically more
demanding diphenyl disulfide suffered regiospecific
quenching at the g-position, initially affording syn-18
and anti-19 as a mixture of sulfide diastereomers
(Scheme 3). We monitored the reaction to find that the
intermediate vinyl sulfones syn-18 and anti-19 isomerize
to allyl sulfones syn-21 and anti-22 under the basic
reaction conditions. While ionization of the g-phenyl-
sulfonyl moiety of acyclic vinyl ethers and vinyl sulfides is
known to generate enones and enals, the corresponding
reaction for cyclic substrates is far less common.[7,8] After
considerable experimentation we found that reaction of
allyl sulfones syn-21 and anti-22 with TMS triflate and
triethylamine in methylene chloride at reflux effected
regiospecific elimination to dienylsulfides syn-29 and
anti-27. This transformation relies upon the unique
amphoteric nature of the sulfone moiety.[9] While sulfones
are commonly used as electron-withdrawing groups to
polarize olefins and inductively stabilize anions, it is the
Scheme 1. Preparation of acyclic arrays. For reaction conditions, see
refs. [3–6]. TBS=tert-butyldimethylsilyl.
syn-6 was treated with methyllithium, methylation occurred
on the a-face of the vinyl sulfone, providing product 9a.
While cleavage of the vinyl sulfones 8 and 10b gave the
pseudoenantiomers (enantiomers with protecting group
reversal) 11 and 12b, respectively, it is apparent that further
evolution of these compounds in order to access polypropi-
onates with functional groups at C4 and C5 (marked with
arrows in compound 12b, Scheme 1) would not be easily
accomplished.
Our newprotocol for functionalizing the remaining two
centers began by treating compounds 4 and 5 with methyl-
lithium to generate allyl sulfonyl anions 4-Li2 and 5-Li,
respectively (Scheme 2). Quenching of these anions at low
temperature delivered 14a and 15b (as mixtures of sulfone
diastereomers) in > 85% yield. HPLC analysis revealed that
methylation of both intermediates occurred with comple-
mentary > 10:1 diastereoselectivity. Unfortunately, sulfenyl-
ation with dimethyl disulfide or methyl thiolsulfonate gave a
complicated mixture of products, which appeared to result
from both a- and g-sulfenylation of the intermediate allylic
Scheme 3. g-Sulfenylation and diene transposition. a) 1. MeLi, THF,
ꢀ788C, 2. Ph2S2; b) warm to RT, c) TMSOTf, Et3N, CH2Cl2, d) reflux.
RT=room temperature, Tf=trifluoromethanesulfonyl.
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leaving group ability of phenyl sulfinic acid (pKa = 7.1), which
enables the lone pair of phenylvinyl sulfide group to expel
sulfinate.[10] Presumably the silyl triflate serves to activate the
sulfone moiety by forming silyl ethers 24 and 25 reversibly,
thereby also preventing readdition of silyl sulfinate 26 once
the vinyl thionium ion loses the proximal proton Ha.[11]
Compounds 27 and 29 can be oxidized to the key dienyl
sulfones 27ox and 29ox simply by addition of mCPBA to the
crude reaction mixture. This two-operation sequence enables
stereoselective methylation with simultaneous establishment
of a new, transposed diene (Scheme 3). The enantiopure
stereodiads 27 and 29 are obtained in five operations from
cycloheptanone 1 (overall yields are > 40% on a 40-g scale).
These key substrates can serve as progenitors to compounds
bearing up to five stereocenters, thereby potentially enabling
synthesis of an entire collection of enantiopure diastereomers
from catalytically generated epoxide 3 (or ent-3). Elimination
of the sulfone moiety from the TMS ether 13 afforded the
unexpected syn-28 (Scheme 3). syn-Addition directed by OLi
groups has been demonstrated on many occasions, but since
the oxygen atom in silyloxy groups is generally not thought to
be accessible for coordination, it appeared possible that more
subtle conformational effects were involved.[12] Conforma-
tional modeling shows that in the preferred conformation of
the TMS derivative of 19 the silyl ether function is equatorial,
which places the TMS group away from the a-face of the vinyl
sulfone, providing unencumbered access for conjugate addi-
tion.
To demonstrate the value of enantiopure anti and syn
stereodiads 27 and 29, we have explored the preparation of a
group of termini-differentiated seven-carbon segments pro-
jected to be of use in the synthesis of bioactive polypropio-
nate-derived natural products. Initially, the syntheses of the
highest priority targets relied on syn intermediates 21, 23, and
29 as starting materials; however, recent (unpublished) results
indicate that the anti intermediates 19, 22, and 27 are equally
useful (Scheme 4). Further functionalization of these sub-
strates gives cycloheptenyl sulfones, which afford termini-
differentiated aldehyde segments after oxidative cleavage.[13]
For example, direct methylation of the dianion of alcohol 29
produces dienylsulfide 31 (Scheme 4, structure confirmed by
X-ray diffraction analysis).[14] Oxidation of 31 provides dienyl
sulfone 32 in 70% overall yield from 29. The necessity of
“protecting” the hydroxy group as an oxido anion is apparent
from attempted alkylation of 27, which suffers b-elimination
to give trienylsulfide 30, as expected. Treatment of the
Scheme 4. Preparation of stereopentad progenitors. a) 2.2 equiv nBuLi,
THF ꢀ788C to ꢀ78C; b) 5 equiv MeI, ꢀ908 to ꢀ508C; c) 2.2 equiv
¼
nBuLi, THF, ꢀ788C to ꢀ58C, 90 min; d) 2.5 equiv H2C N(CH3)2I,
THF, ꢀ708C to 08C, 1.5 h; e) 4 equiv mCPBA, CH2Cl2, 258C, 1 h;
f) 2.2 equiv mCPBA, CH2Cl2, 258C, 30 min; g) TBHP, 5%[Mo(CO)6],
88%, >15:1 a/b; h) 10% [(R,R)-Mn(salen)Cl], H2O2, 1 equiv
NH4OAc, 83%, <1:20 a/b; i) cat. OsO4, >80%, single diastereomer.
j) 1.2 equiv TBSOTf, 2 equiv lutidine, CH2Cl2, 258C, 2 h. mCPBA=
meta-chloroperbenzoic acid, TBHP=tert-butyl hydroperoxide.
¼
dianion of 29 with Eschenmoser's salt (H2C N(CH3)2I) gives
amine 34, which undergoes smooth trisoxidation to afford
trienylsulfone 35 upon exposure to excess mCPBA.[15] Oxi-
dation of dienyl sulfones 32 and 33 with mCPBA was
unselective, but 36–39 could be obtained with high diastereo-
selectivity when molybdenum, manganese, and osmium
complexes were used to catalyze the oxidizations (Scheme 4).
Rhizoxin, the bisepoxide of rhizoxin D (40, Scheme 5),
was isolated by Okuda et al. from rice seedlings infected with
Rhizopus chinensis.[16–18] Eight total and/or formal syntheses
of rhizoxin (four via rhizoxin D) have been reported.[19]
Our strategy for the synthesis of rhizoxin D (40) was to
develop a one- or two-pot method for sequentially linking a
pair of carbonyl compounds through a two-carbon unit that
would be the the C–C single bond in a butadienyl unit in the
final compound (Scheme 5). In the event, acylation of ent-21
followed by hydrolysis gave b-sulfonyl ketone 41, which was
then transformed into silyl dienyl ether 42.[20] Addition of
singlet oxygen to 42 effected stereospecific formation of
stable bicyclic peroxide 43 (the OTIPS group was necessary
for selective addition (> 95%) to the b-face).[21] Epoxidation
of silyl enol ether 43 with dimethyl dioxirane (DMDO)
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Scheme 5. Synthesis of C12–C18 of rhizoxin D (40). a) 1. Ac2O, Et3N,
DMAP, CH2Cl2, RT, 0.5 h, 2. HgCl2, TMSCl, NaI, H2O, CH3CN, RT, 16 h,
85% from ent-21; b) 1. DBU, toluene, RT, 2 h, 2. TBDMSOTf, iPr2EtN,
CH2Cl2, RT, 1 h, 3. KOH, MeOH, RT, 10 min, 4. TIPSOTf, Et3N, CH2Cl2,
RT, 1 h, 68% overall from 41; c) 1O2, TPP, CH2Cl2, ꢀ788C, 30 min;
d) DMDO, CH2Cl2, 08C, 2 h; e) H2, Pd/C, NaHCO3, MeOH, RT,
20 min, 53% from 42; f) cat. Me2SnCl2, MeOTf, K2CO3, CH2Cl2, 17–
208C, 8 h, 88%; g) Pb(OAc)4, pyridine, MeOH/C6H6, 08C, 1.5 h, 85%.
DMAP=dimethylaminopyridine, DMDO=dimethyldioxirane,
TBDMS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl,
TPP=5,10,15,20-tetraphenyl-21H,23H-porphine.
provided the isolable a-epoxysilyl ether 44.[22] Hydrogenation
of 44 proceeded, as desired, with silicon migration to give diol
46 in 83% yield. Methylation of the keto-diol 46 absolutely
required the dimethyltin chloride catalyst to effect regiospe-
cific O-methylation at the more electron-rich distal hydroxy
group, rapidly providing ketone 47 in high yield. (This is the
first example for a 1-keto-2,3-diol).[23] Methylation or silyla-
tion without the tin catalyst was very slow and strongly
favored functionalization of the opposite hydroxy group.
Cleavage of 47 in methanol with lead tetraacetate completed
the synthesis of enantiopure aldehyde ester 48 (Scheme 5).[24]
Concanamycin F (49), also called concanolide A, is the
most intricate parent aglycone of a series of related macro-
cyclic lactones bearing considerable structural homology
(Scheme 6). This family also includes biafilomycin A and
hygrolidin.[25–27] Concanamycin F (49) has been synthesized
by the groups of Paterson in 2000 and Toshima in 2001 in 44
and 53 steps, respectively.[28,29]
Our analysis of concanamycin F (49) envisages the con-
struction of a pair of stereopentads derived from vinyl
sulfones 50 and 53 (Scheme 6). While synthesis of compound
50 is not yet complete, we have been able to make good use of
the diol 39 for generation of stereopentad 51. Silylation of 39
Scheme 6. Synthesis of the ent-C15–C21 fragment of concanomycin F (49). a) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 2 h, 99%; b) KOH/MeI/
DMSO, 258C, 5 min, 94%; c) O3, CH2Cl2/MeOH (1:2), NaHCO3, ꢀ788C, 15 min, then PPh3, 92%.
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provided vinyl sulfone 52 in near-quantitative yield, which
the only viable source. Five total syntheses and related
synthetic approaches all based on aldol-based stereoselection
strategies with acyclic substrates have been reported which
begin with enantiopure 3-hydroxy 2-methylpropionate.[34] The
second-generation synthesis by Smith et al. utilized a total of
34 steps with a linear supply line of only 24 operations and
provided the first gram of (þ)-discodermolide (55). The
overall yield was 6%.[35]
Our approach to apoptolidin (54) and discodermolide (55)
makes use of the central stereotriads 32 and 33 as precursors
to the key epoxides 36a and 36b, respectively. Preparation of
the C21–C27 segment of apoptolidin (54) is accomplished
from epoxide 36b beginning with selective 1,2-reduction with
DIBAL-H to provide alcohol 56. The complementary 1,4-
reduction to produce alcohol 59 can be achieved selectively
with borane–THF. Completing the synthesis of the apopto-
lidin segment simply requires ozonol-
was directly methylated in DMSO to give vinyl sulfone 53 in
94% yield. Ozonolysis of 53 afforded ester aldehyde 51 in
92% yield. Compound 51 is the enantiomer of the C15–C21
stereopentad of concanamycin F (49, Scheme 6).
Apoptolidin (54) is a 20-membered macrocyclic lactone
isolated from Norcardiopsis sp. (Scheme 7).[30] “Apoptolidin
induced apoptotic cell death in rat gila cells transformed with
the E1A oncogene at 11 ngmLꢀ1 but did not cause cell death
in normal gila cells or fibroblasts at > 100 gmLꢀ1.”[30f–g,31] The
group of K. C. Nicolaou provided the first total synthesis of
apoptolidin (54) in ca. 90 steps.[30f–g,31]
Discodermolide (55), like paclitaxel (taxol), has been
shown to stabilize microtubules but is more potent and
inhibits the growth of paclitaxel-resistant cells.[32,33] The
material is in high demand for clinical trials, and synthesis is
ysis of 56 to give a d-hydroxy aldehyde
intermediate, which cyclizes to hemi-
acetal 57. Protection of 57 as acetal 58
gave a 4:1 mixture of anomers, which
can be separated easily by chromatog-
raphy (Scheme 7). Acetal 58 is also the
C20–26 segment of phorboxazole (not
shown).[36]
In parallel fashion to the synthesis
of 58, we prepared the C1–C7 segment
of discodermolide (55) by employing
epoxide 36a for 1,2-reduction with
DIBAL-H. This afforded alcohol 60
in 65% yield. Subsequent ozonolysis
afforded
hemiacetal
61,
which
smoothly underwent PDC oxidation
to give lactone ester 62 in 75% yield
(Scheme 7).
The lessons that Trost is teaching
about atom economy prompt questions
of the strategic validity of the dienyl
sulfone methodology since sulfur is not
found in the product.[37] We can
address this point by briefly examining
our synthesis of segment 51, which
begins with cycloheptanone (1) The
sulfur atoms used in this strategy are
essential for the synthesis (Scheme 8).
The initial vinyl sulfide activates the
olefin for bromination in operation 1b.
The sulfone formed by oxidization
(operation 1c) activates the allylic
position for base-promoted 1,4-elimi-
nation in operation 1d to yield dienyl
sulfone 2. The electrophilic double
bond in the cross-conjugated dienyl
sulfone 2 is flanked by a sterically
demanding sp3-hybridized sulfone
moiety, which has been shown to be
crucial for the high enantiomeric
excess obtained in the Jacobsen epox-
idation (operation 2).[5] Once again, in
Scheme 7. Preparation of C21–C27 of apoptolidin (54) and C1–C7 of discodermolide (55).
a) 1.6 equiv BH3·THF, THF, 08C warming to 258C, 12 h; b) 1.5 equiv DIBAL-H, ꢀ788C; c) O3,
CH2Cl2/MeOH (1:2), NaHCO3, ꢀ788C, 15 min; d) Ag2O, MeI, CH3CN, reflux, 3 h; e) 5 equiv PDC,
CH2Cl2, 258C, 10 h. DIBAL-H=diisobutylaluminum hydride.
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Scheme 8. Evaluation of the contribution of sulfur functional groups in the synthesis of ester aldehyde 51 (for a discussion of the operations refer
to the text).
a 1,4-elimination (operation 3a) epoxy vinyl sulfone 3 is
transformed into intermediate 4, which undergoes conjugate
addition with methyllithium (operation 3b) to provide the
allyl sulfonyl anion 64, which is directly sulfenylated to 65
(operation 3c). Vinyl sulfone 65 equilibrates to 66 in oper-
ation 3d and is finally protonated to 21 in operation 3e.
Vinylogous dioxythioacetal 21 undergoes vinyl-sulfide-pro-
moted loss of sulfinic acid in operation 4 to afford cross-
conjugated dienyl sulfide 29 after workup. Methylation of the
dianion of 29 (operation 5), followed by oxidation of sulfide,
and alcohol protection gives 33. Catalytic substrate-based
dihydroxylation followed by regiospecific silylation of the
more available hydroxy group generates alcohol 52, which
undergoes O-methylation to 53, and finally, cleavage of the
vinyl sulfone (operation 10) to deliver the target stereopentad
51.
stereospecific functionalization of all seven carbons of a
cycloheptyl system, ultimately providing seven-carbon ter-
mini-differentiated polypropionate stereotetrads and stereo-
pentads appropriate for natural product synthesis.
Received: January 16, 2003 [Z50955]
Keywords: epoxidation · polypropionates · stereoselectivity ·
.
sulfones · synthetic methods
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dienyl sulfone exploits a chiral catalyst, and all further
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