Stereoselective total synthesis of (+)-giganin and its C10 epimer by using late-stage lithiation-borylation methodology

Article abstract of DOI:10.1002/anie.201208403

The first total synthesis of (+)-giganin and its unnatural diastereoisomer (+)-C10-epi-giganin has been completed in a total of 13 linear steps, and 7 % and 8 % overall yield, respectively (see scheme; (-)-sp= (-)-sparteine, (+)-sps=(+)-sparteine surrogate). Lithiation-borylation methodology has been successfully applied in the key step, to couple together advanced intermediates with very high diastereoselectivity, thus demonstrating its power as a tool for total synthesis. Copyright

Full text of DOI:10.1002/anie.201208403

Angewandte
Chemie
DOI: 10.1002/anie.201208403
Natural Products
Stereoselective Total Synthesis of (+)-Giganin and Its C10 Epimer by
Using Late-Stage Lithiation–Borylation Methodology**
Catherine J. Fletcher, Katherine M. P. Wheelhouse, and Varinder K. Aggarwal*
Giganin (1a; Scheme 1)[1] is a member of the annonaceous
acetogenins, a class of compounds characterized by a long
aliphatic chain punctuated by oxygen-containing functional
groups and bearing a terminal methyl-substituted a,b-unsat-
urated g-lactone. They exhibit a broad range of important
to human lung carcinoma, human breast carcinoma, and
human colon adenocarcinoma in preliminary tests,[5] thus
making it an especially important target for total synthesis.
Several members of the annonaceous acetogenins have
previously been synthesized (of particular relevance are the
syntheses of annonacin,[6] pyranicin,[7] and pyragonicin)[7c,8]
but giganin itself has not. A common strategy towards this
family of molecules has been to first add a functional group
(an alkene) somewhere between the remote hydroxy groups
and then to use it to aid disconnection.[6–9] However, this is
wasteful as the functional group has to be introduced and then
removed at the end. An alternative approach would be to
disconnect the molecule directly at a secondary alcohol as this
À
would not only enable C C bond formation but also
potentially control stereochemistry in the process. Herein,
we report the application of our lithiation–borylation meth-
odology to a highly convergent and stereoselective synthesis
of giganin and demonstrate facile access to other stereoiso-
mers.
Recently, we reported the synthesis of enantioenriched
secondary alcohols through a lithiation–borylation reac-
tion.[10] The method involved the reaction of an a-lithiated
carbamate, generated by stereoselective deprotonation in the
presence of (À)-sparteine,[11] with a borane or boronic ester
thus forming a boron ate complex with retention of stereo-
chemistry. The boron ate complex then underwent a 1,2-
metallate rearrangement with migration of the R group and
expulsion of the carbamate leaving group, resulting in
a secondary boronic ester.[12,13] Oxidation led to secondary
alcohols in very high enantiomeric ratios (Scheme 2).
Exchanging the diamine ligand for (+)-sparteine surrogate[14]
enables access to the opposite enantiomer of secondary
alcohol from the same starting materials. The methodology is
particularly good for generating secondary alcohols flanked
by similar side chains, as present in giganin, which are difficult
to synthesize by other methods (e.g. stereoselective reduc-
tion).
Scheme 1. Annonaceous acetogenins.
biological activities[2] but in particular are highly active
anticancer agents. These compounds are potent inhibitors of
adenosine triphosphate (ATP) production and consequently
deprive the cell of energy leading to cell death.[3] As cancer
cells have a high energy demand owing to rapid multi-
plication, this action renders the annonaceous acetogenins
selective inhibitors of cancer cell growth. Of particular
interest is that the annonaceous acetogenins show potential
for the treatment of multidrug resistant cancer cells as these
have an even higher requirement for ATP than the parental
wild-type.[4] Giganin, in particular, exhibits good cytotoxicity
[*] C. J. Fletcher, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Dr. K. M. P. Wheelhouse
GlaxoSmithKline UK LtD
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
[**] We thank the EPSRC and GSK for support of this project. We thank
Ben Whitehurst for technical assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208403.
Scheme 2. Lithiation–borylation methodology for the formation of
secondary alcohols. Cb=CON(iPr)2, sp=sparteine.
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We chose the C10 hydroxy stereogenic center as a focal
point for disconnection, to achieve high convergence in the
synthetic route. Making this disconnection gave the left-hand
fragment, carbamate 6, and right-hand fragment, boronic
ester 7 (Scheme 3). The butenolide could not be used intact as
Scheme 4. Synthesis of left-hand fragment, carbamate 6. a) i) Mg,
Et2O, ii) acrolein, 71%; b) CH3C(OEt3), EtCOOH, PhH, 84%; c) AD-
mix-b, CH3SO2NH2, tBuOH/H2O, 73%; d) LiAlH4, Et2O; e) C(CH3)2-
(OMe)2, TsOH, PhH, 75% (over 2 steps); f) PPh3, imidazole, I2;
g) PPh3, MeCN, reflux, 18 h, 84% (over 2 steps); h) NaH, CbCl, THF;
i) TCCA, TEMPO, CH2Cl2, 82% (over 2 steps); j) 9, THF, NaHMDS,
À788C, then 8, À788C to RT, 18 h, 79%. HMDS=1,1,1,3,3,3-hexame-
thyldisilazanide, TCCA=trichloroisocyanuric acid, TEMPO=2,2,6,6-tet-
ramethylpiperidine-N-oxyl, Ts=p-toluenesulfonyl.
The right hand fragment, boronic ester 7a, was synthe-
sized as outlined in Scheme 5. Reaction of but-3-enyl
magnesium bromide with (R)-epichlorohydrin, and a subse-
quent Finkelstein reaction and TBS protection led to alkene
12. Alkylation of alkene 12 with lactone 11 (synthesized by
treatment of the dianion of (phenylthio)acetic acid with (S)-
propylene oxide and then cyclization with TsOH)[21] and
Scheme 3. Retrosynthesis of (+)-giganin. TBS=tert-butyldimethylsilyl.
the stereocenter at C34 was known to be very sensitive to mild
base,[15] and so we planned to introduce it at the end by
oxidation/elimination. We also believed that the steric bulk
provided by the adjacent quaternary stereocenter in 7 might
protect the lactone from nucleophilic attack, as it has been
shown that organolithiums can be selective for addition to
hindered pinacol boronic esters over hindered tert-butyl
esters.[16] The left-hand fragment carbamate 6 could be
prepared by a Wittig olefination of aldehyde 8[17] with the
phosphonium ylide of 9, which itself could be derived from
lactone 10.[8c] Boronic ester 7 could be prepared by alkylation
of lactone 11 with iodide 12 followed by a regioselective
hydroboration of the terminal alkene.
a
subsequent regioselective hydroboration[22] with [{Ir-
Preparation of carbamate 6 began with the synthesis of
lactone 10 (Scheme 4).[8c] Reaction of tetradecyl magnesium
bromide with acrolein gave allylic alcohol 13, which was
subjected to a Johnson–Claisen rearrangement to give g,d-
unsaturated ester 14. Subsequent Sharpless dihydroxyla-
tion[18] gave the syn vicinal diol with greater than 99:1
e.r.;[19] this diol spontaneously cyclized to give lactone 10. Our
modified synthesis of lactone 10[8c] was more readily ame-
nable to scale-up. LiAlH4 reduction with subsequent acetal
formation gave acetonide 15, which was converted via the
iodide into the phosphonium salt 9.
Scheme 5. Syntheses of boronic esters 7 and lactone 11. a) i) Mg,
Et2O, ii) (R)-epichlorohydrin, CuI, 87%; b) NaI, acetone 89%; c) TBSCl,
imidazole, CH2Cl2, RT, 40 h, 94%; d) 11, LDA, 08C, 30 min, then 12,
RT, 60 h, 73%; e) R2 =pinacol: [{Ir(cod)Cl}2], dppe, (pin)BH CH2Cl2,
79%; R2 =neopentyl glycol: [{Ir(cod)Cl}2], dppb, CH2Cl2 (cat)BH;
neopentyl glycol, 59%; R2 =9-BBN: 9-BBN, THF, RT, 2 h, (after
oxidation at RT for 2 h with NaOAc/H2O2) 98%; f) i) LDA,
PhSCH2COOH, ii) TsOH, PhH, 84% (over 2 steps). 9-BBN = 9-
borabicyclo[3.3.1]nonane, cod=cycloocta-1,5-diene, dppb=1,4-bis(di-
phenylphosphanyl)butane, dppe=1,4-bis(diphenylphosphanyl)ethane,
LDA=lithium diisopropylamide, pin=pinacol.
The aldehyde coupling partner 8[17] was prepared in two
steps from 1,4-butanediol by selective monocarbamoyla-
tion[17] and subsequent mild oxidation[20] of the remaining
alcohol to the aldehyde. Treatment of phosphonium salt 9
with NaHMDS at À788C, followed by aldehyde 8 and
subsequent warming to room temperature led to carbamate
6 as a single diastereoisomer.
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(cod)Cl}2], dppe, and pinacol borane gave the pinacol boronic
ester 7a.
owing to the unusual physical properties of the long alkyl
chain of the carbamate. Fortunately, the carbamate was
sufficiently soluble in tert-butyl methyl ether at À788C and
subsequent lithiation–borylation gave intermediate 20a in
55% yield (81% brsm[23]) and 98:2 d.r (Scheme 7).[24] By using
the diamine (À)-sparteine in place of (+)-sparteine surrogate,
intermediate 20b with the opposite configuration at the C10
carbon was obtained in 71% yield (94% brsm) and 98:2 d.r..
Alcohol 20a had the required stereochemistry for the syn-
thesis of (+)-giganin 1a. The alcohol at C10 in both
diastereomers of 20 was protected as the TBS ether and
subsequent alkylation with lactone 11 gave 22a and 22b, each
as an approximately 5:1 mixture of epimers at the C2 position
and in 66% and 68% yields respectively. Selective oxidation
of the sulfide to the sulfoxide was achieved by treatment of
22a and 22b with 1 equivalent of mCPBA, and elimination of
the sulfoxide occurred spontaneously during solvent removal
in vacuo to give the corresponding butenolides 23a and 23b,
in 89% and 85% yield, respectively. Finally, deprotection
with AcCl in MeOH led to natural (+)-giganin 1a and
(+)-C10-epi-giganin 1b in 99% and 93% yields, respectively.
The synthetic material of (+)-giganin 1a was identical to the
With all of the fragments in hand, our attention turned to
the lithiation–borylation key step, but model studies were
conducted first. Initially, boronic ester 7a was reacted with 1-
lithio-1-phenylethyldiisopropyl carbamate 16 but this only
gave 25% yield of the desired product 17 (Scheme 6).
Scheme 6. Model systems. a) 7a, b, or c, 0.5 h, À788C, warm to RT;
iii) NaOAc/H2O2; b) 19, 0.5 h, À788C, warm to RT; iii) NaOH/H2O2.
Evidently, attack of the lithiated carbamate at the lactone
carbonyl competed with reaction at the boronic ester. To try
to enhance the chemoselectivity, alternative boron derivatives
were also tested, including the less-hindered neopentyl glycol
ester 7b and the more-electrophilic 9-BBN derivative, but no
significant improvements resulted. We therefore sought to
simplify the boronic ester fragment by removing the lactone
moiety. Boronic ester 19 was prepared by an analogous
regioselective hydroboration of iodoalkene 12 with pinacol
borane. Pleasingly, this reacted cleanly with lithiated 1-
phenylethyldiisopropyl carbamate to give the desired product
18 in 73% yield. The excellent chemoselectivity for addition
of the lithiated carbamate to the boronic ester over the iodide
of 19 is also noteworthy.
1
natural product in all respects. Unsurprisingly, the H NMR
spectra of the two diastereomers were identical but differ-
ences in the 13C NMR spectra were discernible.[25]
In summary, we have completed the first synthesis of
(+)-giganin 1a in 13 steps (longest linear sequence) and 7%
overall yield by using the lithiation–borylation reaction. Not
only does the methodology lead to a convergent synthesis in
good overall yield, but it also provides complete control over
the stereochemistry at the C10 secondary alcohol, as illus-
trated by the synthesis of both (+)-giganin 1a and (+)-C10-
epi-giganin 1b with equal ease. The stitching together of large
complex fragments as part of the end game also demonstrates
the power of lithiation–borylation methodology as a practical
tool for synthesis.
Having established
a successful lithiation–borylation
reaction in our model system we moved to the real system.
However, the attempted coupling of boronic ester 19 with the
required carbamate 6, initially gave only low yields (ca. 25%)
and significant quantities of starting materials were recov-
ered. Upon close examination, it was found that the reaction
mixture had formed a gel at low temperature, presumably
Received: October 18, 2012
Published online: January 25, 2013
Keywords: borylation · carbamate · giganin · lithiation ·
.
total synthesis
Scheme 7. End game. a) i) 6, tBME, (+)-sps, sBuLi, 5 h, À788C, ii) 19, 1 h at À78 8C, iii) 18 h, 408C, iv) 2 M NaOH/H2O2 (30%) 2:1 v/v, 71%;
b) i) 6, tBME, (À)-sp, sBuLi, 5 h, À788C, ii) 19, 1 h at À788C, iii) 18 h, 408C, iv) 2 M NaOH/H2O2 (30%) 2:1 v/v, 55%; c) TBSCl, imidazole,
CH2Cl2, RT, 24 h, 20a or 20b; d) LDA, then 11, then 21a or 21b; e) mCPBA, CH2Cl2, 08C, 15 min; f) 5% AcCl in MeOH. tBME=tert-butyl methyl
ether, mCPBA=meta-chloroperoxybenzoic acid, (+)-sps=(+)-sparteine surrogate.
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