Enantioselective synthesis of structurally intricate and complementary polyoxygenated building blocks of spongistatin 1 (altohyrtin a)

Article abstract of DOI:10.1135/cccc2008181

Enantioselective approaches to the construction of four complex building blocks of the structurally intricate marine macrolide known as spongistatin 1 are presented. The first phase of the synthetic effort relies on a practical approach to a desymmetrized, enantiomerically pure spiroketal ring system incorporating rings A and B. Concurrently, the C17-C28 subunit, which houses one-fifth of the stereogenic centers of the target in the form of rings C and D, was assembled via a composite of stereocontrolled aldol condensations. Once arrival at the entire C1-C28 sector had been realized, routes were devised to provide two additional highly functionalized sectors consisting of C29-C44 and C38-C51. A series of subsequent transformations including cyclization of the E ring and hydroboration to afford the B-alkyl intermediate for the key Suzuki coupling to append the side chain took advantage of efficient stereocontrol. Ultimately, complete assembly and functionalization of the western EF sector of spongistatin was thwarted by an inoperative Suzuki coupling step intended to join the side chain to the C29-C44 sector, and later because of complications due to protecting groups, which precluded the complete elaboration of the late stage C29-C51 intermediate.

Full text of DOI:10.1135/cccc2008181

Spongistatin 1
651
ENANTIOSELECTIVE SYNTHESIS OF STRUCTURALLY INTRICATE AND
COMPLEMENTARY POLYOXYGENATED BUILDING BLOCKS OF
SPONGISTATIN 1 (ALTOHYRTIN A)
1
2
3
4
Alain BRAUN , Il Hwan CHO , Stephane CIBLAT , Dean CLYNE ,
5
6
7
8
Pat FORGIONE , Amy C. HART , Guoxiang HUANG , Jungchul KIM ,
Isabelle MODOLO , Leo A. PAQUETTE *, Xiaowen PENG , Stefan PICHLMAIR ,
Catherine A. STEWART , Jizhou WANG and Dmitry ZUEV
9
10,
11
12
1
3
14
15
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, U.S.A.;
1
2
3
e-mail: alain.braun@sanofi-aventis.com, ilhwancho@cj.net, stephane_ciblat@hotmail.com,
4
7
1
1
1
5
6
dean.clyne@abbott.com, pforgione@lav.boehringer-ingelheim.com, amy.hart@bms.com,
ghuang@ttpharma.com, jungchul.kim@spcorp.com, isabellemdl@hotmail.com,
paquette@chemistry.ohio-state.edu, pengxiaowen@hotmail.com,
stefan.pichlmair@basf.com, castewart@kalexsyn.com, jizhou.2@gsk.com,
dmitry.zuev@bms.com
8
9
0
11
2
5
13
14
Received August 28, 2008
Accepted February 5, 2009
Publish ed on lin e Jun e 1, 2009
Dedicated to Dr. Alfred Bader on the occasion of his 85th birthday in recognition of his outstanding
contributions to the science of chemistry.
En an tioselective approach es to th e con struction of four com plex buildin g blocks of th e
structurally in tricate m arin e m acrolide kn own as spon gistatin 1 are presen ted. Th e first
ph ase of th e syn th etic effort relies on a practical approach to a desym m etrized, en an tio-
m erically pure spiroketal rin g system in corporatin g rin gs A an d B. Con curren tly, th e
C17–C28 subun it, wh ich h ouses on e-fifth of th e stereogen ic cen ters of th e target in th e
form of rin gs C an d D, was assem bled via a com posite of stereocon trolled aldol con den sa-
tion s. On ce arrival at th e en tire C1–C28 sector h ad been realized, routes were devised to
provide two addition al h igh ly fun ction alized sectors con sistin g of C29–C44 an d C38–C51.
A series of subsequen t tran sform ation s in cludin g cyclization of th e E rin g an d h ydro-
boration to afford th e B-alkyl in term ediate for th e key Suzuki couplin g to appen d th e side
ch ain took advan tage of efficien t stereocon trol. Ultim ately, com plete assem bly an d fun c-
tion alization of th e western EF sector of spon gistatin was th warted by an in operative Suzuki
couplin g step in ten ded to join th e side ch ain to th e C29–C44 sector, an d later because of
com plication s due to protectin g groups, wh ich precluded th e com plete elaboration of th e
late stage C29–C51 in term ediate.
Keyw ord s: Total syn th esis; Cytotoxic agen ts; Marin e m acrolides; Spiroketals; Couplin g reac-
tion s.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769
©
2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2008181

6
52
Braun et al.:
Th e an ticipation th at m arin e organ ism s would con stitute im portan t
sources of prom isin g an tican cer agen ts of un usual structural type h as been
justified on m an y occasion s. In recen t years, powerful cell growth in h ibi-
tory m acrolides such as bryostatin 11 an d h alich on drin B h ave been dis-
covered. Th ese com plex large-rin g lacton es, wh ich con tain in terlocked
tetrah ydropyran subun its, bear som e resem blan ce to th e equally cytotoxic
,2
3,4
an titum or agen ts swin h olide A5 an d m isakin olide A . Th e latter two fas-
,6
7,8
cin atin g com poun ds, alth ough obtain ed from m arin e spon ges, m ay ulti-
7
c
m ately be derived from sym biotic blue-green algae .
In 1993, Pettit succeeded in isolatin g from an Eastern In dian spon ge of
th e gen us Spongia th e extrem ely poten t an tin eoplastic m acrocyclic lacton e
9
spon gistatin 1 (1a) an d con gen ers th ereof . In th e sam e year, bioassay-guided
isolation led Fusetan i an d co-workers to th e discovery of cin ach yrolide A,
1
0
subsequen tly recogn ized to be iden tical to spon gistatin 4 (1b) . Kitagawa
also iden tified addition al exam ples of th is im portan t n ew com poun d class,
1
1
wh ich h e term ed th e altoh yrtin s (1a, 1d –1e) . Alth ough several m acrolide
an tibiotics featurin g on e spiro ketal as a vital structural com pon en t (e.g.,
1
2,13
14,15
16,17
th e averm ectin s
A an d B
, oligom ycin s A–C
, cytovaricin
, an d rutam ycin s
1
8,19
), h ave previously been discovered as ferm en tation products of
actin om ycetes, n on e of th ese sh are th e distin ctive bisspiro ketal pattern
presen t in 1a–1e.
Spon gistatin 1 in h ibits th e glutam ate-in duced polym erization of tubulin
with an in credibly low IC50 (3.6 n m ol dm – ) . Th is in h ibition of m itosis is
accom plish ed n ot by occupation of th e dom ain utilized by colch icin e in its
bin din g to tubulin , but by altern ative position in g n ear th e Vin ca alkaloid
3 9c
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
653
dom ain . Spon gistatin 4 in h ibits L12120 m urin e leukem ia cells with an IC
5
0
1
0
of <0.6 n g/m l . As a con sequen ce, 1a an d 1b h ave given eviden ce of bein g
am on g th e m ost poten t can cer cell growth in h ibitory an tim itotic sub-
stan ces un covered to th e presen t tim e!
Th e ch allen ge presen ted by th e total syn th esis of th e arch itecturally com -
plex spon gipyran m acrolides h as attracted wide in terest, an d routes aim ed
2
0
21
at th e stereocon trolled assem bly of th e AB an d CD spiroketal sectors ,
as well as th e E an d F rin gs22 h ave been defin ed23. However, th e m asterful
2
4
total syn th eses of (+)-spon gistatin 2 by th e Evan s group
spon gistatin 1 by Kish i an d co-workers25 establish ed con vin cin gly th at th e
spon gistatin s an d altoh yrtin s were in deed con figuration ally iden tical. Five
an d of (+)-
2
6a–26d
, Heath cock26e,26f,
an d by Ley27b, an d of both
con stitute key ben ch m arks of strategy level design .
addition al m ore recen t syn th eses, of 1d by Sm ith
2
2v,26g
27a
an d (form ally) Nakata
targets by Crim m in s
, of 1a by Paterson
2
7c
Our own approach to spon gistatin 1 en vision ed m acrocyclization subse-
quen t to th e con join in g of th e two bisspiroketal subun its an d lin kup of
suitably fun ction alized E an d F pyran rin gs. Th e tactics are expressed
retrosyn th etically in Sch em e 1 wh ere th e eastern A–D sector was projected
to arise from en an tiocon trolled aldol couplin g of th e proper en olate of
keton e 5 with aldeh yde 6. Th is m ode of assem bly was selected so as to capi-
SCHEME 1
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
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Braun et al.:
talize on th e th erm odyn am ically advan taged double an om eric arran gem en t
residen t in 5, wh ich was expected to guaran tee th e equatorial disposition of
th e side ch ain s position ed at C3 an d C11. Beyon d th is, th e logistical de-
m an ds of appropriately settin g th e stereocen ters in buildin g block 6 were
an ticipated to be solved by th e proper com bin ation of aldol con den sation s
in acyclic precursors. Elaboration of th e western sector was en vision ed to
in volve eith er possible Suzuki–Miyaura cross-couplin g to afford 3 or car-
bon yl addition ch em istry to even tually yield en ol eth er 4.
Herein we detail th e im plem en tation of a plan for th e syn th esis of sub-
un its 4 to 6 based on th e above strategy elem en ts an d varian ts th ereof as
dictated by th e experim en tal results.
RESULTS AND DISCUSSION
Assembly of the AB Spiroketal. Th is fragm en t of th e cytotoxic target in cor-
porates C1–C14 an d features a [5.5] spirocyclic fram ework wh ose stereo-
ch em istry at C7 is presum ably govern ed by a th erm odyn am ically favored
double an om eric arran gem en t. If so, th ose substituen ts residin g at C3 an d
C11 are equatorially disposed. Beyon d th is, we en vision ed th e assem bly of
5
to be m ost gain fully realized by m ean s of an approach th at skirts C2-
sym m etrical in term ediates an d passes th rough properly desym m etrized,
en an tiom erically pure precursors. Am algam ation of th e two acyclic precur-
sors 18 an d 27 was con sidered to be con sisten t with th is syn th etic plan .
Th e first gen eration route to 14, detailed in Sch em e 2, began with th e
two-step con version of com m ercial 2-brom oben zyl alcoh ol (7) to aldeh yde
9
via th e carbin ol 8. Altern ate attem pts to gen erate 9 by th e Mich ael addi-
tion of 7 to acrolein proved un successful. Th e con den sation of 9 with th e
levorotatory (S)-th iazolidin eth ion e 1028 un der Nagao con dition s with
tin (II) triflate in th e presen ce of N-eth ylpiperidin e furn ish ed exclusively th e
aldol product 11 in 83% yield. After sign ifican t experim en tation , it was
m ade clear th at th e optim al way to secure aldeh yde 14 from th is direction
2
9
was th rough gen eration of th e Wein reb am ide , protection of th e h ydroxyl
substituen t as its tetrah ydropyran yl (THP) eth er, an d reduction with
Dibal-H at –78 °C.
From th is poin t, en an tiocon trolled ch ain exten sion was realized by
repeat application of th e Nagao protocol, wh ich gen erated 15 as an 87:13
ratio of diastereom ers. Successful tran sform ation in to th e correspon din g
Wein reb am ide 16 was followed by protection of th e h ydroxyl group in th e
form of its tert-butyldim eth ylsilyl (TBS) eth er as in 17. Th e n eed to in tro-
duce a m eth yl group in order to secure 18 was m et with m eth ylm agn esium
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
655
brom ide. Th e two ch rom atograph ic purification s th at followed th e gen era-
tion of 15 as an 87:13 diastereom eric m ixture proved sufficien t to deliver
pure 18, th e structural features of wh ich were assign ed th rough spectrosco-
3
0
pic m ean s an d on th e basis of well preceden ted tran sition state an alysis .
SCHEME 2
Alth ough th e path way to 14 defin ed above is ch aracterized by very rea-
son able efficien cy at each step, th e sequen ce is rath er lon g. Con sideration
was th erefore given to th e possibility th at in creased brevity could be
ach ieved. Two altern ate, som ewh at sh orter routes to th is aldeh yde are out-
lin ed in Sch em e 3. Both rely on th e ready availability of en an tiopure
3
1
oxiran e 19 from (R)-aspartic acid by th e Rapoport protocol . Con trolled
3
2
n ucleoph ilic attack of th e dith ian yl an ion on epoxide 19 , followed by
exposure to 3,4-dih ydropyran in th e presen ce of pyridin ium p-toluen e-
sulfon ate, an d treatm en t with m ercuric perch lorate in 9:1 aceton itrile–
water buffered with calcium carbon ate2 furn ish ed 14 in m odest yield. An
0a
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
56
Braun et al.:
im proved sequen ce in volved in itial exposure of epoxide 19 to th e vin yl
3
3
cuprate reagen t an d arrival at 14 by periodate cleavage of th e 1,2-glycol .
SCHEME 3
Th e C9–C12 segm en t was n ext elaborated by con version of th e p-
m eth oxyben zyl (PMB) eth er of (S)-glycidol (24, 96% ee) to carboxaldeh yde
2
7 in a m an n er parallelin g th e 19 → 14 sequen ce. With two n ecessary
buildin g blocks in h an d, th eir aldol couplin g was n ext en tertain ed
Sch em e 4). Alth ough th e stereogen icity of th e ch iral cen ter would appear
to carry little im port because of pen din g oxidation to th e keton e level, re-
(
3
4
course was n everth eless m ade to a h igh ly (S)-diastereoselective reaction
for th e purpose of sim plifyin g an alysis an d facilitatin g spirocyclization
SCHEME 4
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
657
th rough h ydrogen bon din g. Wh en a n um ber of accepted m eth ods for th e
deprotection of THP groups in 2835 were un expectedly foun d n ot to result
in rin g closure, we m ade recourse to th e reagen t com bin ation con sistin g of
3
6
boron trifluoride eth erate an d eth an eth iol in CH Cl . Un der th ese con di-
2
2
tion s, th e desired tran sform ation did occur, but with con com itan t cleavage
of th e TBS protectin g group37. Furth er studies in volvin g th e resultin g diol
(
viz. deacetoxy 30) were n ot pursued because of an an ticipated in ability to
distin guish ch em ically between th e two secon dary h ydroxyl groups. An ex-
perim en tally valid altern ative m aterialized in th e form of acetylation prior
to cyclization . Th is tactic resulted in th e con version of 29 to 30 in 66%
yield an d provided an advan ced in term ediate am en able to X-ray crystallo-
2
0g
graph ic an alysis . Th e absolute con figuration of 30 was th ereby con -
firm ed to be fully as expected.
Next, th e structural m odification of 30 so as to gen erate 37 in an un am -
biguous fash ion was un dertaken . Th e rem ain in g OH fun ction ality was
3
8
m asked as its SEM eth er prior to reduction with Dibal-H to furn ish 31
Sch em e 5). En suin g perruth en ate oxidation 39 provided th e correspon din g
(
keton e, wh ich respon ded to th e action of m eth ylm agn esium brom ide in a
very diastereoselective fash ion (94:6) by way of equatorial attack to m ake
3
2 available in 93% yield. Th e diastereoselectivity of th e 1,2-addition pro-
cess was readily con firm ed by COSY an d n Oe an alysis. Th e tertiary n ature
an d axial disposition of th e n ewly gen erated h ydroxyl substituen t required
recourse to a silyl triflate40 for protection purposes. Followin g in troduction
of a TBS group in th is m an n er, th e prim ary carbin ol 33 was acquired by
DDQ oxidation . Both steps proceeded in a h igh ly efficien t m an n er. At th is
poin t, it proved possible to prepare th e prim ary iodide 34 an d to brin g
about h om ologation of th e side ch ain by SN2 displacem en t with cyan ide
ion . Our con cern for poten tial com plication s arisin g from β-elim in ation
with in 35 prom pted its direct tran sform ation in to th e eth yl keton e 37 by
a th ree-step sequen ce com prised of Dibal-H reduction to th e aldeh yde,
1
,2-addition of eth ylm agn esium brom ide with out delay, an d perruth en ate
3
9
oxidation
.
Our in ten t was to carry th e TBS group presen t in 37 th rough to th e en d
of th e syn th esis. We subsequen tly becam e aware of th e fact th at th is de-
protection could n ot be successfully im plem en ted in th e late stages wh en
4
1
m ost of th e spon gistatin structure h ad been establish ed . Th erefore, th e
substitution of a trieth ylsilyl (TES) group at th is site was un dertaken . Atten -
tion was turn ed in itially to th e acidic h ydrolysis of 37 with 3 M HCl in
m eth an ol. As expected, n o selectivity was observed an d diol 38 was isolated
in 90% yield (Sch em e 6). Treatm en t of 38 with a sligh t excess of SEM ch lo-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
58
Braun et al.:
SCHEME 5
SCHEME 6
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
659
ride in th e presen ce of tetra-n-butylam m on ium iodide gave predom in an tly
9 alon g with sign ifican tly lesser quan tities of th e two-fold O-alkylated
3
product 40. Reaction of 39 with TES triflate in th e presen ce of Hün ig’s base
afforded 41 in 56% yield alon g with 5% of silyl en ol eth er 42. Th e latter
could readily be con verted in to 41 by selective h ydrolysis in dilute aqueous
acetic acid.
Alth ough th e studies defin ed in Sch em e 6 dem on strate th at th e critical
exch an ge of protectin g groups is clearly feasible, th e tactics im plem en ted
for th is purpose are h ardly econ om ical of steps. A m ore efficien t route to
4
1, defin ed in Sch em e 7, begin s with th e efficien t low-tem perature con -
version of 32 to th e TES derivative 43 in advan ce of con version to prim ary
iodide 44 (90% over two steps). Couplin g of 44 to lith iated 2-eth yl-
4
2
1
,3-dith ian e at –78 °C in THF con tain in g HMPA proved well suited to th e
2
2v,26
gen eration of 45 with out con curren t E elim in ation
. Hydrolysis of 45
2
with h ydrated m ercury(II) perch lorate accordin g to a predescribed proto-
4
3
col m ade 41 readily available.
SCHEME 7
Enantioselective Synthesis of the CD Spiroketal Component
From th e outset, th e successful elaboration of th e AB sector was to be com -
plem en ted by a con cise, con vergen t an d h igh ly stereocon trolled route to
th e CD subun it con sistin g of C17–C28. Th e retrosyn th etic an alysis pre-
sen ted in Sch em e 8 in dicates th at relian ce was to be placed on a diastereo-
selective syn-aldol con den sation to set th e two side ch ain stereocen ters in
target com poun d 46. Aldeh yde 47 was to be obtain ed in turn by oxidative
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
60
Braun et al.:
cleavage of th e double bon d in spiroacetal 48. Th e key step was con sidered
to be th e two-fold PMB-group deprotection with in h ydroxy keton e 49 th at
would h opefully trigger a spon tan eous, th erm odyn am ically con trolled
spirocyclization . Th is open -ch ain in term ediate was to be prepared stereo-
selectively by a Mukaiyam a reaction 44 between silyl en ol eth er 50 an d alde-
h yde 51.
SCHEME 8
Th e acquisition of 50 began with com m ercially available (S)-(–)-glycidol
5
2, wh ich was tran sform ed in to its ben zyl eth er 53 un der con ven tion al
4
5
46
con dition s . Regioselective open in g of th e oxiran e rin g with vin yl-
m agn esium brom ide in th e presen ce of CuI was followed directly by con -
version
to catalytic levels of OsO in th e presen ce of NMO as co-oxidan t , th e re-
sultin g diastereom eric diols were cleaved with sodium periodate to afford
th e desired aldeh yde 55.
4
7,48
to th e PMB eth er 54 (Sch em e 9). Followin g th e exposure of 54
4
9
4
5
0
In troduction of a secon d ch iral cen ter was un dertaken with th e tin
5
1
en olate of th e Nagao auxiliary 10 derived from L-valin e . Un der th ese con -
dition s, 56 was form ed sm ooth ly with h igh diastereoselectivity (92:8). Th e
success of th is tran sform ation was m atch ed by th at in volvin g con version to
5
2
th e correspon din g Wein reb am ide 57 (97% yield) . Protection of th e sec-
5
3
on dary h ydroxyl group in th is product as its TBDPS eth er proceeded very
slowly at room tem perature even in th e presen ce of DMAP. Appreciable ac-
celeration was n oted in a dich lorom eth an e/DMF solven t m ixture at reflux
(
98% yield of 58). Followin g th e addition of m eth ylm agn esium bro-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
661
SCHEME 9
m ide29,52 to 58 in order to gen erate m eth yl keton e 59, regioselective
en olization an d in situ O-silylation was accom plish ed with th e bulky
lith ium h exam eth yldisilazide base in th e presen ce of ch lorotrim eth yl-
5
4
silan e . Th e very h igh purity of 50 so form ed en abled it to be used with out
an y recourse to ch rom atograph y. Th e ten -step con version of 52 to 50 is
n otable in th at it proceeds with an average yield of 93% for each step.
Th e com plem en tary righ t h alf of 49 was crafted from th e previously de-
5
5
scribed 3-buten al 61 . For our purposes, th e isolation of th is low-boilin g
β,γ-un saturated aldeh yde was skirted by sim ple extraction of th e acid h y-
drolysis m ixture an d dryin g of th e com bin ed organ ic ph ases prior to use.
Sin ce n o solven t evaporation was in volved, m ech an ical losses of th is start-
in g m aterial were m in im ized (Sch em e 10). In ligh t of th e con ven ien ce an d
reliability of th e Nagao aldol reaction 30, th is protocol was selected for gen -
eration of th e th ird residen t ch iral cen ter. Con son an t with earlier exam ples,
th e con den sation of ent-10 with 61 led to th iazolidin eth ion e 62 as th e m a-
jor product with excellen t diastereoselection (95:5). It is n oteworth y th at
th e very m ild con dition s of th is aldol reaction do n ot in duce double bon d
m igration with in th e sen sitive aldeh yde 61. As before, th e tran sam idation
leadin g to 63 on ce again proceeded sm ooth ly. In con trast, subsequen t in -
troduction of th e PMB protectin g group proved to be un ch aracteristically
difficult. Not un expectedly, th e sodium h ydride/DMF con dition s proved
too basic. However, th e trich loroacetim idate altern ative, as catalyzed by
5
6
cam ph orsulfon ic acid in dich lorom eth an e , gave a 78% yield of th e pro-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
62
Braun et al.:
tected alcoh ol alon gside un reacted 63 (22%). Fin ally, low-tem perature re-
5
7
duction with Dibal-H in tetrah ydrofuran gave aldeh yde 51 of h igh purity
1H NMR an alysis). Th us, th e sequen ce from allylm agn esium brom ide to 51
(
traverses six tran sform ation s at an average yield per step of 92%.
SCHEME 10
With th e cross-couplin g partn ers 50 an d 51 in h an d, th eir proper am al-
5
8
gam ation was effected by way of catalysis with boron trifluoride eth erate .
Advan tage was taken of th e ability of th e β-OPMB substituen t presen t in
th e aldeh yde to guide 1,3-stereoin duction h eavily in th e anti direction
5
9–63
64
(
Sch em e 11)
. In agreem en t with preceden t , th is effect proved to be
operative, an d 49 was produced with a facial bias in excess of 92:8. As
SCHEME 11
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
663
a con sequen ce of th e in terplay of th ose dipole m om en ts depicted in A,
on ly on e side of th e carbon yl group is available for attack by th e in com in g
n ucleoph ile.
Th e tim e h ad n ow arrived to effect th e spirocyclization . Rath er un expect-
edly, th e treatm en t of 49 with DDQ in a dich lorom eth an e–water solven t
6
5
system did n ot afford th e desired product. TLC an alysis of th e reaction
m ixture in dicated form ation of very polar m aterial, presum ably th e triol.
We con sidered a possible reason for kin etic retardation of th e rin g closure
to be th e presen ce of a free h ydroxyl at C21, wh ich by way of in tra-
m olecular h ydrogen bon din g, could h am per proper fun ction al group in ter-
6
6
action . In deed on ce th e OH group was m asked as its TES derivative , th e
con version to 64 proceeded very efficien tly (92%). Ch em oselective cleavage
of th e TES eth er was readily accom plish ed with aqueous acetic acid in
6
7
68
THF , th ereby m akin g possible con ven tion al O-m eth ylation on ly at C21
to yield 65 (98%). Altern atively, aldol 49 can be directly O-m eth ylated at
C21 (Me OBF , proton spon ge, CH Cl ) an d treated with DDQ to give rise
3
4
2
2
to spiroacetal 65 efficien tly. In con trast to th e com plication s experien ced
by several research groups in volved in th e syn th esis of spon gistatin
2
0j,k;21a,b,d,e;22s;24b,d
1
, th e presen t route avoided th e problem of n on -selective
spiroketal form ation . In our view, th is success stem s from th e presen ce of a
sterically dem an din g TBDPS protectin g group at C25, wh ich apparen tly
serves as an effective con trol elem en t durin g ketal form ation .
At th is stage, proof of th e absolute con figuration of 65 was secured with
1
th e h elp of n Oe experim en ts as sh own . Th e diagn ostic 300 MHz H NMR
spectrum in C D solution n icely corroborates each of th e stereoch em ical
6
6
expectation s. Th us H19 (δ 3.85) exh ibits a sign ifican t (6%) n Oe in teraction
with H21 (δ 3.60), an d n eith er of th ese proton s resides in close proxim ity
to H25 (δ 4.18). Th ese data require th at H19 an d H21 be axially disposed.
Furth erm ore, H27 (δ 4.24) in teracts with H21 (6%), th ereby m an datin g
axial residen cy for H27 as well. Fin ally, selective irradiation of H27 gave rise
to a n Oe in teraction (2%) with th e ph en yl proton s of th e TBDPS group.
Th ese features an d th e equatorial n ature of H25 appear to m im ic th e con -
form ation of th e CD sector presen t in 11
1a
.
Cleavage of th e double bon d in 65 to arrive at aldeh yde 66 was best real-
ized by OsO -prom oted dih ydroxylation followed by periodate cleavage of
4
th e diastereom eric diol m ixture.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
64
Side Chain Elaboration on the CD Spiroketal Ring System
Braun et al.:
With th e ready availability of aldeh yde 66 in quan tity, th e n ext order of
busin ess was to properly establish th e stereogen ic cen ters position ed at C16
an d C17. To th is en d, th e Sn (OTf) -prom oted aldol reaction of 67 with 66
2
was carried out (Sch em e 12). Th e on ly isolated product, expected to be 68,
was isolated in 97% yield. Elucidation of th e syn arran gem en t of th e m eth yl
an d h ydroxyl substituen ts was approach ed by way of detailed NMR an aly-
ses (300 MHz, C D ). Th e sm all couplin g con stan t of 2.7 Hz between H16
6
6
6
9
an d H17 suggested th e presen ce of a syn relation sh ip . However, th e ques-
tion of absolute con figuration persisted. To address th is question , th e
SCHEME 12
m odel reaction between 67 an d propion aldeh yde was im plem en ted in th e
expectation th at th e Z-en olate of th e th iazolidin eth ion e would again be
form ed an d en ter in to th e aldol reaction via a ch elated ch air-like tran sition
7
0
state . Excellen t kin etic con trol was operative an d on ly 71 was produced in
6% yield (Sch em e 13). Particularly useful to us was th e h igh crystallin ity
9
of th is yellow solid, wh ich perm itted un equivocal defin ition of th e absolute
stereoch em ical relation sh ips by X-ray m eth ods2
.
0h
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Spongistatin 1
665
To set th e stage for covalen t bon din g to th e AB subun it, 68 was subjected
to clean tran sam idation for th e purpose of arrivin g at Wein reb am ide 69.
Subsequen t m askin g of th e h ydroxyl as a TBS eth er allowed for reductive
con version to th e targeted aldeh yde 70. We n ote h ere th at 70 was gen er-
ated from (S)-glycidol in 23% yield over 21 steps (93% average yield).
SCHEME 13
Construction of the Complete C1–C28 Sector
Alth ough several syn th etic strategies for am algam ation of th e AB an d CD
buildin g blocks were in itially pursued37, recourse was ultim ately m ade to
th e con join in g of keton es 37 an d 41 to aldeh yde 70 via a Mukaiyam a aldol
4
4
reaction . Sch em e 14 depicts th e route developed to arrive at 75. In itially,
SCHEME 14
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6
66
Braun et al.:
th e a (R = TBS) an d b (R = TES) series were advan ced sim ultan eously. How-
ever, wh en it was m ade kn own th at in surm oun table difficulties h ad been
2
2v,26
en coun tered elsewh ere
in th e attem pted rem oval of a sim ilarly posi-
tion ed TBS protectin g group, our focus was restricted exclusively to th e TES
derivatives.
Th e two-step procedure for arrival at 73 in volved in itial con version of 37
7
1
an d 41 to th eir Z-en olsilan es accordin g to th e Masam un e protocol . Very
h igh levels of regio- an d stereocon trol (>99:1) were realized th rough th e
agen cy of th e bulky bis(ph en yldim eth ylsilyl)am ide base. Wh en 72a an d 72b
were purified ch rom atograph ically, severe m aterial losses were in curred.
Wh en exposure to an adsorben t was skirted an d th e un purified en ol eth ers
were treated directly with 70 in th e presen ce of boron trifluoride eth erate,
th e yields of 73 (67–72%) proved to be quite satisfactory. Wh en th is aldol
reaction was perform ed at –78 °C, syn selectivity was observed as expected,
leadin g to proper in stallation of absolute con figuration at C15 an d C16.
Th e assign m en t of stereoch em istry was addressed by 1H NMR an alysis of
th e acetate of 73a in C D solution at 500 MHz. Th e syn relation sh ip be-
6
6
tween H14 (δ 2.88) an d H15 (δ 4.22) was readily deduced on th e basis of th e
low m agn itude (2.8 Hz) of th e correspon din g couplin g con stan t. Sim ilarly,
th e sign ifican t spin –spin in teraction between H15 an d H16 (9.2 Hz) un -
equivocally defin ed th eir anti relation sh ip. No added con firm ation was se-
cured an d th e assign m en t sh ould th erefore be regarded as ten tative.
Followin g selection of th e SEM protectin g group38, it becam e n ecessary to
effect m eth ylen ation of th e keton e carbon yl at C13. Alth ough th is tran s-
form ation proved to be problem atic wh en a variety of direct m eth ods
7
2,73
74
75
76
77
(
Tebbe
th e Peterson olefin ation
un der th e proper circum stan ces. However, in itial recourse to Me SiCH Li
, Lom bardo , Wittig , Nysted , Cp ZrCl , etc.) were applied,
2 2
7
8
proved itself to be reliable an d reproducible
3
2
in THF gave rise to n o reaction as a con sequen ce of wh olesale en olization ,
as recogn ized by th e form ation of a deep red color. Altern ate use of th e
n on polar solven t system 1:1 toluen e/h exan es at –78 °C resulted in stead in
efficien t form ation of th e adduct. Treatm en t of th e resultin g α-h ydroxy-
silan e with KH in 10:1 THF/DMF led to clean elim in ation , but with som e
con curren t rem oval of th e TBS protectin g group. Con sequen tly, reprotect-
ion was routin ely practiced in advan ce of th e isolation of 75 (70% overall).
Retrosynthetic Analysis of the Western Region
Two im peratives directed our earliest th in kin g in th is ph ase of th e in vesti-
gation . Certain ly, our plan n ed routes sh ould be as distin ctive as possible
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
667
an d differ in trin sically from earlier preceden t. As well, we looked forward
to th e im plem en tation of two com plem en tary path ways (Sch em e 15).
Cleavage across C37–C38 would m an date th e evaluation of rin g F as th e
electroph ilic reaction partn er 77. Hopefully in th is way we could assess
th e feasibility of en gagin g sulfon e 78 in 1,2-addition to th is aldeh yde. Also
to be focused on was altern ative dissection of th e C38–C39 bon d in 76,
such th at sulfon e 79 m igh t be coupled to th e h igh ly fun ction alized
tetrah ydropyran yl aldeh yde 80. In both cases, we rem ain ed m in dful of th e
fact th at th e ch lorodien e side ch ain h ad to be assim ilated at a m ore ad-
van ced poin t in th e total syn th esis. At th is jun cture, vin yl iodide 81 was
regarded to be a poten tially useful prospect.
SCHEME 15
Synthesis and Chemistry of 2-(Phenylsulfonyl) Pyrans
Pursuit of th e secon d retrosyn th etic option outlin ed in Sch em e 15 required
th at atten tion be paid to th e preparation of oxidized derivatives of th io-
glycoside 89 (Sch em e 16). To th is en d, we m ade recourse to th e readily
available lacton e 84. Sequen tial acid-catalyzed two-fold ketalization an d
7
9
Swern oxidation of D-m an n ose gave 82 . As a con sequen ce of th e α-oxy-
8
0
gen ated n ature of th e lacton e carbon yl in 82 an d th e possibility th at th e
derived en olate an ion could un dergo β-elim in ation , serious reservation s
existed with regard to th e base-prom oted α-m eth ylation of 82. We were
th erefore deligh ted to un cover th at th e desired con version to 83 was partic-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
68
Braun et al.:
ularly facile81. Reduction of 83 with sam arium iodide as th e electron -
8
2
tran sfer reagen t accom plish ed con curren t α-deoxygen ation an d loss of
aceton e to liberate th e C3 h ydroxyl as in 84. Its h ydroxyl fun ction n eed
n ot be m asked durin g Dibal-H reduction to th e lactol level, th ereby provid-
in g th e opportun ity for dual acetylation . Diacetate 85 was obtain ed as an
1
in separable 2:3 m ixture of α- an d β-an om ers ( H NMR an alysis). Treatm en t
of 85 with boron trifluoride eth erate in th e presen ce of th ioph en ol resulted
in th e form ation of 86 with en h an cem en t of th e diastereotopic m odality to
>
9:1 in favor of th e α-sulfide. Sin ce cleavage of th e ketal in 85 is com peti-
tive with th iol capture, routin e use was m ade of an excess of boron trifluor-
ide eth erate in order to un m ask th e pair of h ydroxyl groups to th e
m axim ally elevated level. Th is reactivity pattern allowed for direct form a-
tion of p-m eth oxyben zylidin e acetal 87, wh ose tran sform ation in to th e
bis-PMB alcoh ol 89 was accom plish ed in a two-step sequen ce capped by a
regiodirected Dibal-H reduction of th e m-dioxan e rin g. In con trast to oth er
altern atives, th is sequen ce of steps proved un even tful an d allowed for th e
SCHEME 16
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
669
subsequen t im plem en tation of peracid oxidation to gen erate th e h ydroxy-
m eth yl sulfon e 90. Th e axial n ature of th e Ph SO2 group rests securely on
th e sm all m agn itude of th e couplin g con stan t registered for th e in teraction
of H2 an d H3 (Jax-eq = 5.3 Hz).
We were n ow position ed to in troduce an exocyclic double bon d at C6 in
order to allow for possible Suzuki–Miyaura couplin g between th e F-rin g
fragm en t an d a trien yl side ch ain . Alth ough iodide 91 was secured by expo-
sure of 90 to th e action of triph en ylph osph in e an d elem en tal iodin e in th e
presen ce of im idazole, attem pts to accom plish E elim in ation with in 91
2
proved m ore problem atic th an an ticipated. For exam ple, th e addition of 90
to a solution of potassium tert-butoxide in THF gave rise to oxetan e 92 in
3
0% yield alon gside a m yriad of oth er products th at were left un iden tified.
On th e positive side, th e desired con version to 93 could be accom plish ed
with m oderate efficien cy by h eatin g with DBU in toluen e.
Subm ission of 93 to con ven tion al h ydroboration with 9-BBN afforded
un iquely 94 rath er th an th e desired diastereom er 90. Experim en ts con -
ducted at 100 °C for prolon ged reaction periods did n ot alter th e stereo-
ch em ical outcom e. Operatin g on th e belief th at th is even tuality m ay arise
as a result of th e axial orien tation of th e Ph SO substituen t, we un dertook
2
efforts to equilibrate th e an om eric carbon in 93 to n o avail, in lin e with
8
3
preceden t . Th e m an n er in wh ich th is com plication was bypassed is dis-
cussed later.
Route Selection for Ring E Construction
To con tin ue th e projected route to 1a, we h ad n eed for a h eavily fun ction -
alized E-rin g subtarget akin to 80. Gen eration of aldeh yde 95 from
pen tan e-1,5-diol in itiated th e effort. Th e stereocon trolled four-carbon
ch ain exten sion to deliver alcoh ol 96 (Sch em e 17) took advan tage of th e
reliability provided by (–)-B-m eth oxydiisopin ocam ph eylboran e, boron tri-
fluoride eth erate an d cis-2-buten e un der stron gly basic con dition s to pro-
8
4
vide th e syn h om oallylic alcoh ol 96 . Followin g gen eration of th e m ixed
8
5
86
BOC carbon ate 97 , iodocyclization by way of IBr set th e stage for arrival
8
7
at epoxy ester 98 upon treatm en t with K CO3 in aqueous MeOH . Th e
2
un ion of 98 with th e lith iated an ion of dith ian e 99 proved to be a som e-
wh at erratic process, advan cin g to 100 with m odest efficien cy (31%) un der
th e con dition s specified in th e sch em e. Th is assem bly step was followed by
con version to th e fun ction alized tetrah ydropyran 101, a m an euver best ac-
com plish ed th rough th e use of m ercuric perch lorate in aqueous pyridin e
4
3b
con tain in g a catalytic quan tity of cam ph orsulfon ic acid . Th e stereo-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
70
Braun et al.:
ch em istry of 101, readily deduced to be as in B on th e basis of n Oe experi-
m en ts, con form s to expectation s based on th e an om eric effect.
SCHEME 17
Heatin g 101 with cesium fluoride in 9:1 aceton itrile–water for 4 days
m ade available diol 102, th e prim ary h ydroxyl fun ction ality in wh ich could
be selectively tran sform ed in to iodide 103 in advan ce of E elim in ation
2
prom oted by DBU in ben zen e at reflux. Th e con version to 104 proceeded
quan titatively. Quite un expected, h owever, was our in ability to protect th e
h ydroxyl at C4 in 104. Wh en 101 proved to be equally recalcitran t to vari-
ous m askin g protocols, we recogn ized th at th e axial orien tation of th is OH
group (see B) was brin gin g in to play sufficien t steric con gestion so as to
m ake th is step kin etically un rewardin g. Con sequen tly, th e altern ative
th rust depicted in Sch em e 18 was pursued. We first im plem en ted th e
m on osilylation of pen tan e-1,5-diol (105) with tert-butyldiph en ylch loro-
8
8
89
silan e (TBDPSCl) an d followed with a Swern oxidation . Pen tan al 95 was
9
0,91
th en brough t in to reaction with th e dibutylboron en olate of 106
,
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
671
th ereby givin g rise to th e en an tiopure syn aldol 107 as a sin gle diastereom er
in 94% yield (Sch em e 18). Th e n ewly form ed h ydroxyl group in 107 was
also tran sform ed in to a TES eth er to con form with our projected stratagem
for th e sim ultan eous un m askin g of h ydroxyl fun ction alities at a later stage.
Th e subsequen t lith ium boroh ydride reduction an d o-iodoxyben zoic acid
9
2
(
IBX) oxidation of 108 resulted in con version to th e h om ologated alde-
h yde 109, th us settin g th e stage for a secon d iteration of th e aldol process
2
8
usin g th e Nagao protocol . In th e even t, th e tin (II) en olate of ent-10 fun c-
tion ed very efficien tly to furn ish 110 as th e sin gle diastereom er sh own
(
96%). On ce 110 was in h an d, its two-step con version to 112 was brough t
about by tran sam idation to Wein reb am ide 111 an d gen eration of th e TBS
eth er.
SCHEME 18
Treatm en t of 112 with th e lith ium reagen t produced by tran sm etalation
of 11393,94 with n-BuLi gave rise to 114. Th is reaction is very tem perature
depen den t an d con siderable atten tion to detail is n ecessary to ach ieve a
9
1
6% yield of th e keton e product. Rem oval of th e PMB group in 114 to give
15 was expected to allow for subsequen t acid-catalyzed cyclization . In -
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
72
Braun et al.:
deed, con version to th e an om erically h om ogen eous m eth yl acetal 116 was
sm ooth ly accom plish ed in 82% overall yield. Oxidation to aldeh yde 80 was
9
5
subsequen tly brough t about with th e Parikh –Doerin g reagen t .
At th is poin t, it was our in ten tion to couple 80 with a protected form of
sulfon e 90 via th e correspon din g carban ion . Th e feasibility studies in volved
both 117 an d 118 (Sch em e 19). Followin g th e deproton ation of both in ter-
m ediates with a variety of bases (LDA, n-BuLi, t-BuLi, MeMgBr, Ph Li,
m esityllith ium ) an d adm ixture with 80 un der a variety of con dition s, n o
eviden ce was obtain ed th at th e targeted C–C bon d form ation h ad taken
place. Th e failure of th ese reaction s proved con trary to results defin ed in
sim ilar sterically con gested substrates2
2m
an d led us to screen sim pler alde-
h ydes such as CH O, Ph CHO, an d t-BuCHO. Th e possibility th at th ese fail-
2
ures stem from th e low reactivity of th e sulfon e prom pted com pan ion
in vestigation of th e 2-pyridyl con gen er 123. Th is m odification would allow
th e fusion of rin gs E an d F to be effected in stead via a sam arium iodide-
in duced Barbier reaction 96
.
SCHEME 19
Th e route to 123 th at was developed (Sch em e 20) capitalized on th e abil-
ity of un stable trich loroacetim idates97 to give 2-pyridyl sulfides wh en
treated with 2-m ercaptopyridin e an d a catalytic am oun t of trim eth ylsilyl
9
8
triflate . Readily available 84 can be protected as its PMB eth er 119. Due to
th e poten tial β-elim in ation , acidic or n eutral con dition s were exploited.
Wh ile use of PMB-trich loroacetim idate was effective, rem oval of th e am ide
byproducts was far from trivial an d led to com plication s in subsequen t
ch em istry. Exploitation of th e lepidin e derivative allowed for facile access
9
9
of 119 . Hydrolysis of th e aceton ide an d subsequen t silyl protection of th e
prim ary alcoh ol yielded 120, wh ich could un dergo an oth er PMB protec-
tion , followed by h em iacetal form ation . Followin g th e oxidation of 122, we
were in a position to exploit th e in terestin g couplin g in volvin g sam arium
iodide. Wh en th is reaction was applied to cycloh exan e carboxaldeh yde,
carbin ol 124 was obtain ed in 75% yield as a 3:1:1 m ixture of diastereom ers.
However, th e adaptation of th is ch em istry to aldeh yde 80 proved sin gularly
un con structive. Th e m agn itude of th is effort was exten sive an d in cluded
dem on stration of th e fact th at n ickel(II) iodide was also in effective as a pro-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
673
m oter96d. Th ese experim en ts h ave seem in gly dem on strated th e h eigh ten ed
steric screen in g in 80 to be a serious deterren t to attack at its carbon yl
group. Th e developm en t of a differen t route was th erefore m an dated.
SCHEME 20
Synthesis of Aldehyde 77
On e of th e m ore in terestin g altern ative possibilities for con structin g th e
western sector of spon gistatin 1 in volves application of th e Suzuki–Miyaura
1
00
cross-couplin g of an alkylboran e to a vin yl iodide . More specifically,
th e palladium -catalyzed con join in g of a boran e derived from a suitable
2
-m eth ylen epyran (see 4) an d 81 h eld th e prospect of a con ven ien t ap-
proach to in stallation of th e C44–C45 bon d th at lin ks th e ch loro-dien e side
1
01
ch ain to th e E/F segm en t. In th e n early twen ty years sin ce its discovery
,
th is reaction h as seen ever-in creasin g application in total syn th esis102,
alth ough it h ad n ot previously been utilized in pursuit of spon gipyran
m arin e m acrolides.
It was furth er con jectured th at th is approach could develop alon g two
aven ues. Th e Suzuki–Miyaura step could be perform ed after proper am al-
gam ation of h ydropyran s E an d F (see 4). Th e secon d option would en tail
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
74
Braun et al.:
in corporation of th e side ch ain in to an exten sively fun ction alized F-rin g
buildin g block with subsequen t un ion to rin g E (see 3). A description of
both approach es follows in th is section .
Operation ally, th e route to 77 began with th e readily available PMB-
protected lacton e 119. Th e carbon yl was con verted to th e olefin with th e
7
2,73
Tebbe reagen t
to effect con version to 125 (Sch em e 21), wh ich was
h ydroborated im m ediately so as to avoid adven titious rearran gem en t with
in tern alization of th e double bon d. With arrival at 126, all five stereogen ic
cen ters about th e h ydropyran rin g h ad been set in th eir proper absolute
con figuration .
SCHEME 21
Th e rem ain in g issues to be addressed in cluded a ch an ge in th e n ature of
th e acetal protectin g group. Wh ile th e aceton ide m oiety was quite am en a-
ble to acidic h ydrolysis, con cern over oth er possible side reaction s durin g
subsequen t exposure to p-m eth oxyben zaldeh yde dim eth ylacetal prom pted
in itial advan cem en t by way of acetate 127. Th e con servative th ree-step
sequen ce in tercon n ectin g 127 with 129 was subsequen tly im proved upon
9
2
by a m ore direct routin g from 126 as sh own . IBX was exploited for th e
oxidative con version of 129 to 77.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
675
Formation of the Sulfone Fragment 78
To gen erate th e desired sulfon e, we first im plem en ted th e m on osilylation
8
8
of pen tan e-1,5-diol (105) with TBSCl an d followed with a Swern oxida-
tion 89. Th e con version of 105 to 136 closely parallels th e path way from 105
to 110 developed earlier, with proper proviso for a differen t array of pro-
tectin g groups. Th e subsequen t lith ium boroh ydride reduction an d Swern
8
9
oxidation
of 132 resulted in con version to th e h om ologated aldeh yde
1
33, th us settin g th e stage for a secon d aldol process in th e sequen ce. Adap-
tation of th e Evan s protocol in volvin g th e (S)-con figured N-acetyloxazol-
idin on e proceeded sluggish ly an d was m axim ized at 50% of 135. As a direct
2
8
con sequen ce of th is lim itation , we turn ed to th e Nagao altern ative . Sin ce
th e first of th ese aldols proceeds th rough a n on -ch elated tran sition state
such as E an d th e secon d is h igh ly ch elated (see F), th e th iazolidin eth ion e
m ust be con stituted of th e opposite con figuration to th e oxazolidin on e
(
Fig. 1). Th e tin (II) en olate of ent-10 th us fun ction ed very efficien tly to fur-
n ish 136 as th e sin gle diastereom er sh own (91%).
FIG. 1
Th e availability of 136 tran slated in to a relatively direct route to th e tar-
geted sulfon e. Protection of th e free h ydroxyl as th e triisopropylsilyl (TIPS)
eth er as plan n ed was followed by efficien t reductive cleavage of th e
th iazolidin eth ion e. Th e subsequen t gen eration of iodide 138 provided th e
opportun ity to com pare a two-step sequen ce to gen erate 78 relative to a
on e-step altern ative (Sch em e 22).
The Status of E/F Assembly Involving Sulfone 78 and Aldehyde 77
As a specific version of an operation al route to 76 (Sch em e 15), we n ext
studied th e usefuln ess of com bin in g th e readily available sulfon e 78 to th e
h eavily fun ction alized pyran yl aldeh yde 77. After con siderable experim en -
tation , it was recogn ized th at th e presen ce of HMPA as an additive was es-
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6
76
Braun et al.:
SCHEME 22
sen tial to th e production of carbin ol 140 (Sch em e 23). Un der optim ized
con dition s, th is couplin g step was best im plem en ted by h eatin g 78 in itially
with eth ylm agn esium brom ide in ben zen e at 95 °C for 3 h . Th is step was
followed by coolin g to room tem perature, addition of 15% HMPA in ad-
van ce of th e carboxaldeh yde, an d con tin ued stirrin g for 1 h . In th e even t,
1
40 was isolated in 71% yield as a m ixture of diastereom ers.
Wh en subsequen t attem pts to effect direct oxidation of th e an ion of 140
with reagen ts such as MoOPh 1 , O , or th e Davis oxaziridin e
03
104
failed,
2
subsequen t effort was focused on th e dih ydroxylation of un saturated in ter-
m ediates 141 an d 142 as a m ean s of in troducin g an oxygen atom at C37.
Un fortun ately, th ese easily accessible in term ediates proved totally un -
reactive to OsO an d NMO, even at stoich iom etric levels of OsO . Th erefore
4
4
9
2
1
40 was oxidized with IBX to provide th e α-sulfon yl keton e 143. Al-
th ough a com parable recalcitran ce to oxidation was exh ibited by 143,
recourse to th e m ore reactive William s oxaziridin e 144
1
05
proved to be an
effective ploy. In th is way, α-diketon e 145 was reach ed in 65% yield.
With 145 in h an d, we en tered on e of th e m ost frustratin g ph ases of th is
un dertakin g. From th e begin n in g, we expected th at th e projected rem oval
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Spongistatin 1
677
SCHEME 23
of th e two TBS groups would be readily ach ieved, th is deprotection m an eu-
ver len din g itself in turn to con ven tion al in tram olecular cyclization with
gen eration of th e E-rin g. However, th e prospect of dual deblockin g un der
con dition s in volvin g acidic reagen ts such as th e HF·pyridin e com plex was
th warted by com petin g cleavage of th e acetal. Un der basic con dition s, th e
prim ary OTBS group could be selectively rem oved, but regiocon trol durin g
cleavage of a secon d Si–O bon d was n ot realized.
Advance Toward Assembly of the Western EF Sector
Th e elaboration of an altern ate rin g F can didate was n ext addressed. Th us
carbin ol 126 was oxidized to carboxylic acid 147 via sequen tial application
8
9
106
of th e Swern protocol an d th e Lin dgren –Kraus oxidation
(Sch em e 24).
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
78
Braun et al.:
Con version to th e couplin g partn ers 148 an d 149 was accom plish ed via
eith er in situ form ation of acid ch loride 148 or carbodiim ide-m ediated
couplin g to arrive at pen tafluoroph en yl ester 149.
SCHEME 24
Con com itan t with developm en t of th e n ew F-rin g in term ediates 148 an d
1
1
1
49, in vestigation of th e likelih ood th at th iazolidin eth ion e in term ediate
10 could be used to our advan tage for th e syn th esis of th e E-rin g sulfon e
53 began . Silylation of th e rem ain in g free h ydroxyl group was m ade dis-
tin ctive th rough form ation of th e TBS derivative (Sch em e 25). Reduction
with lith ium boroh ydride in THF served to con vert 150 to 151 an d en able
subsequen t form ation of prim ary iodide 152. Treatm en t of th is substan ce
with sodium ben zen esulfin ate in warm DMF afforded th e targeted sulfon e
1
53 in good yield. With reason able am oun ts of 153 in h an d, we proceeded
to exam in e th e acylation of its lith ium salt with 148, wh ich was in depen d-
en tly gen erated by exposin g th e carboxylic acid to th e action of 1-ch loro-
N,N-trim eth ylpropen ylam in e1 . Alth ough effective, use of th e acid ch lo-
ride was un derm in ed by in stability issues. In th e in terest of workin g with
a m ore stable in term ediate, altern ative use of th e pen tafluoroph en yl ester
07
1
08
was also developed . Followin g discovery of th e sluggish n ess exh ibited by
1
03
th e an ion of keto sulfon e 154 toward, for exam ple, MoOPH
an d trans-2-
ph en ylsulfon yl)-3-ph en yloxaziridin e1 , recourse was again m ade to th e
04
(
1
05
purportedly m ore reactive reagen t 144 . Form ation of th e α-diketon e was
reproducibly ach ieved in th is m an n er. Direct ch em oselective rem oval of
th e TES group an d h ydrolysis of th e aceton ide were sim ultan eously accom -
plish ed with p-toluen esulfon ic acid in a solven t system con sistin g of THF
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

Spongistatin 1
679
SCHEME 25
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769

6
80
Braun et al.:
an d eth ylen e glycol. Un der th ese con dition s, th e TBS substituen t is n ot af-
fected, an d cyclization to give lactol 155 occurs in a fully stereocon trolled
m an n er.
Th e n ext step was origin ally program m ed to in volve form ation of th e
O-m eth yl glycoside. However, our efforts to reach th is goal directly from
1
54 were seem in gly th warted by th e presen ce of th e n eigh borin g carbon yl
in 155. Th is step was th erefore deferred. Con version to iodide 156 was
followed by reduction un der Luch e con dition s1 . Th e latter step led to th e
form ation of two products (157 an d 158). Wh en th e tim e in terval between
th e in troduction of CeCl an d NaBH was on th e order of 5 m in , th e de-
09
3
4
sired triol 157 was foun d to be th e m ore dom in an t isom er, but on ly by a
factor of 6:1. Matters are im proved sign ifican tly by sh orten in g of th e tim e
gap to on ly 5 s. Th is sim ple operation al m odification led to an in crease in
th e product distribution to 20:1.
At th is poin t, th e m eth an olysis of 157 to gen erate 159 proceeded n or-
m ally; con version of th e diol to th e bis-silyl eth er 160 was realized with out
even t. In lin e with expectation s, both m eth yl eth ers featured exclusively an
axial m eth oxy group. Both 159 an d 160 un derwen t facile elim in ation in
th e presen ce of DBU to deliver th e pair of exocyclic olefin s 161 an d 162.
A m ajor effort was n ext in vested in probin g th e workability of th e Suzuki–
Miyaura couplin g of th ese advan ced in term ediates to a suitable trien yl side
ch ain . No palladium catalyst, solven t system , tem perature, or ch oice of base
gave eviden ce of C–C bon d form ation with in reason able tim e lim its. En -
h an cem en ts in th e stoich iom etric levels of reagen ts were likewise un able to
override th is serious lim itation . Th e very appreciable kin etic retardation ob-
served h ere appears to exceed th at n oted by Kish i1 durin g h is application
of th e related Pd(0)-m ediated Suzuki dien e process to th e assem bly of
palytoxin . Th e extrem e rate deceleration th at accom pan ies an appreciable
in crease in th e m olecular weigh t of th e reactan ts m ay be a gen eral ph en om -
en on . In our case, it proved to be an in surm oun table roadblock requirin g
relian ce on an altern ative m ean s of structural assem bly.
10
Investigation of Initial Suzuki–Miyaura Cross-Coupling
Th is ph ase of th e un dertakin g started with gen eration of th e ch lorin ated
C45–C51 side ch ain derivative 81. (R)-(+)-Glycidol (ent-52) was first con -
verted in to alkyn ol 163 accordin g to preceden t1 (Sch em e 26). Rem oval of
11
1
12
th e TMS group an d treatm en t of th e term in al alkyn e with B-iodo-9-BBN
led un even tfully to th e 2-iodo-1-alken e, wh ich was subsequen tly protected
as th e TBS derivative 164. From th is poin t, th e pivalate ester was reduct-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 5, pp. 651–769