Total syntheses of hexacyclinol, 5-epi-hexacyclinol, and desoxohexacyclinol unveil an antimalarial prodrug motif

Article abstract of DOI:10.1002/anie.200504033

All sewn up: A "three-staged stitch" was used to append the A-C rings of desoxohexacyclinol (1), which was further converted into the related compounds hexacyclinol (2) and 5-epi-hexacyclinol (3). Screening of the late-staged intermediates indicated that

Full text of DOI:10.1002/anie.200504033

Angewandte
Chemie
Antimalarial Drugs
DOI: 10.1002/anie.200504033
Total Syntheses of Hexacyclinol,
5-epi-Hexacyclinol, and Desoxohexacyclinol
Unveil an Antimalarial Prodrug Motif**
James J. La Clair*
In memory of Udo Gräfe
Hexacyclinol (1) was isolated by Gräfe and co-workers from
the basidiospores collected from Panus rudis growing on dead
betula woods in Siberia.[1] In 1999, our exploration into
German fungal cultures provided a strain of P. rudis 99-329
that was not only capable of the biosynthesis of 1 but also
provided trace amounts of epi-5-hexacyclinol (2) and desoxo-
hexacyclinol (3).[2] Further study indicated that the retrocy-
cloaddition of 1 and 2 released oxygen to afford a mixture of
trienes 3 (Scheme 1). Subsequent [2+2+2] cycloaddition of 3
Scheme 2. Synthetic plan depicting the strategic intermediates A–J.
Completed bonds are shown in black, and the skeleton is depicted in
gray.
of the C17–C18 bond, and ending with installation of the C14–
C15 epoxide.
Intermediate A was developed from bis
(acetate) 4.[3]
A
Protection with TBS, deacetylation, and nosylation of the
primary alcohol afforded 5 (Scheme 3). Under these condi-
tions, nosylate 5 was obtained along with a bis(nosylate)
A
Scheme 1. Hexacyclinol interconversions: a) in vacuo, neat, 95%;
b) O2, rose bengal, MeOH, hn, 08C, 89%.
derivative (3–5% yield), which was removed after treatment
of the mixture with sodium cyanide in DMSO to convert 5
into 6. This sequence was conducted on a multigram scale to
provide 6 after a single chromatographic purification step.
The synthesis of 6 completed the installation of C7 as
indicated by the conversion of A into B (Scheme 2).
with singlet oxygen returned a mixture of 1 and 2. As this
process could be cycled, it offered a key handle in expediting
the synthesis of this family of terpenes.
The synthesis of 1 and 2 through 3 simplifies the complex-
ity of the hexacyclinol ring system by removal of the D/E rings
(Scheme 1). On the basis of this argument, a campaign to 3
was launched using the synthetic plan outlined in Scheme 2.
The plan began with an intact A ring as shown in interme-
diate A. The first stage of this project sought a rapid
appendage of C7 and C17 onto A followed by the installation
of the lower half of the B ring as given by the conversion of D
into E. From E, a series of three sequences (E!F, F !G, and
G!I, Scheme 2) were used to stitch the molecule together,
beginning with the insertion of C15–C16, followed by creation
The next stage in this synthesis involved the installation of
C17, as given by the conversion of B into C (Scheme 2). This
operation was accomplished through the conversion of 6 into
bromoacetal 7 by reaction with 1,2-dibromoethylmethyl ether
(Scheme 3).[4] Treatment of crude 7 with NaHMDS at ꢀ788C
followed by warming to room temperature resulted in 3:2
mixture of 8a/8b. Fortunately, protonation of the enolate of
8a/8b with triphenylacetic acid afforded a mixture favoring
the desired nitrile 8a by 11:1. To increase the material
throughput to 8a, the cyclization and isomerization steps were
conducted in a one-pot operation.
With intermediate C in hand, the next step required
correction of the stereochemistry at C13. As provided by 4,
this center required inversion as illustrated by the conversion
into D (Scheme 2). The process began by convertion of the
nitrile of 8a to dithiane 13 (Scheme 3). Slow addition of
DIBAL-H at ꢀ208C to 8a at ꢀ788C in toluene afforded 9 in
high yield. The resulting aldehyde 9 was subsequently
protected as dithiane 10. The acetal ring of 10 was opened
by treatment with dilute aqueous acid to provide 11, which
was in turn oxidized to the corresponding acid 12 through a
buffered Tollens oxidation followed by hydrolysis of the
incipient lactone. As noted by Smith et al.,[5] the oxidation of
[*] Dr. J. J. La Clair
Xenobe Research Institute
P.O. Box 4073, San Diego, CA 92164-4073 (USA)
Fax: (+1)858-401-3083
E-mail: i@xenobe.org
[**] A considerable portion of this work was conducted during 1999–
2002 at Bionic Bros GmbH, Germany. J.J.L.C. acknowledges the
assistance of five technicians.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 3. Access to intermediate D through the synthesis of 13.
a) TBSCl, imidazole, DMAP (cat.), CH2Cl2;b) NH , MeOH, room
3
temperature;c) NsCl, pyridine, 0 8C!RT;d) NaCN (1.5 equiv),
DMSO, 858C, 32 h, 72% from 4;e) methylvinyl ether, Br ;then add to
2
6, 2,6-lutidine (2 equiv), CH2Cl2, 08C!RT, 67%;f) NaHMDS, THF,
ꢀ788C!RT;g) NaHMDS, THF, ꢀ788C!ꢀ408C;then Ph 3CO2H,
THF, 67% from 7;h) DIBAL-H, toluene, ꢀ788C!RT;
Scheme 4. Access to intermediate E through the synthesis of 20.
a) LDA (1.1 equiv), HMPA (3 equiv), THF; ꢀ788C then nBuLi
(1.1 equiv) at ꢀ788C!ꢀ608C, 2 h;b) slow addition of 18 in THF to
14 in THF, ꢀ788C, 2 h;then ꢀ788C!RT, 62% of 19b and 15% of
19a;c) add 16 in Et2O to 15 in Et2O/pentane (8:1 v/v), ꢀ788C!08C,
i) (TMSSCH2)2CH2, ZnBr2, CH2Cl2, 59% from 8a;j) HCl in aq. THF;
k) slow addition of Ag2O in paraffin, CH2Cl2, room temperature;
l) LiOH, aq. THF;m) PPh , DIAD, CH2Cl2, room temperature, 16 h,
3
68% from 10. TBS=tert-butyldimethylsilyl, DMAP=4-dimethylamino-
pyridine, Ns=4-nitrobenzenesulfonyl, DMSO=dimethyl sulfoxide,
HMDS=hexamethyldisilazane, DIBAL-H=diisobutylaluminum
12 h, 89%;d) TPAP (cat.), NMO, CH Cl2, 92%;e) PhSH, PEt 3, DEAD,
2
CH2Cl2, 458C, 24 h, 94%. LDA=lithium diisopropylamide,
HMPA=hexamethyl
A
hydride, DIAD=diisopropyl azodicarboxylate.
TPAP=tetrapropylammonium perruthenate, NMO=N-methylmorpho-
AHCTREUNG
line-N-oxide, DEAD=diethyl azodicarboxylate.
an aldehyde in the presence of a dithiane is a nontrivial
operation. For this example, oxidation of 11 to 12 was
achieved by delivering Ag2O in wax (5% Ag2O in paraffin).[6]
Here, slow addition and transfer of Ag2O to the reaction
medium was optimal in favoring aldehyde oxidation. An
intramolecular Mitsunobu inversion of 12 to lactone 13 was
used to install the correct stereochemistry at C13.
With 13 in hand, the plan called for the simultaneous
appendage of C4–C6 and C18–C23 as indicated by the
conversion of D into E (Scheme 2). Ketone 18 provided an
ideal match for the installation of these atoms as it was rapidly
prepared from epoxide 15[7] (Scheme 4). The process was
facilitated through anchimeric-assisted addition of corre-
sponding a-lithioether 16, prepared by the methods of
Cohen and Matz,[8] to 15 to yield 17. Gram quantities of 18
were obtained after oxidation of 17 with either SO3–pyridine,
TPAP—NMO, or Dess–Martin periodinane.
Condensation of 13 with 18 was carried out by generation
of dianion 14 by the stepwise addition of LDA and nBuLi to
13 (Scheme 4). A chromatographically separable mixture of
19a and 19b(1:4.5) was obtained after slow addition of 18 to
14 at ꢀ788C followed by gradual warming to room temper-
ature. Separation of these diastereomers was enhanced by the
selective inversion of 19b to mercaptan 20. Under these
conditions, the inversion of 19a was not observed. The fact
that 19awas returned after treatment with DEAD, PBu3, and
acetic acid suggested that the C6-carbinol was too hindered to
form the required alkoxyphosphonium intermediate. Com-
pletion of 20 involved the installation of C4–C6 and C18–C23
with the appropriate stereochemistry at C6 and provided
functional handles at C17 and C18 for fusion of the B and
C rings.
The synthesis continued by
sequence as depicted by the processing of
a
three-stage stitching
to H
E
(Scheme 2). The operation began with the installation of
C15–C16 bond as given by the conversion of E into F.
Experimentally, this was conducted by C-acylation of 20 with
pyruvonitrile (Scheme 5).[9] Oxidation of the resulting prod-
uct 21 with mCPBA followed by treatment with a catalytic
amount of CSA in methanol afforded ketosulfoxide 22.
Treatment of 22 with aqueous acid opened the MOM-
protected acetal. Analysis of the mixture by NMR spectros-
copy indicated that the resulting material existed in a complex
equilibrium that contained residues attributable to 23a and
23b.
Treatment of this mixture 23a,b with sulfene (MsCl, Et3N)
led to the formation of a single product 25 (Scheme 5),
apparently through incipient generation of mesylate 24a or
chloride 24b. The reversible nature of mesylation with sulfene
was key to this process.[10] After screening conditions, an
optimized 74–77% yield of 25 was obtained after adding an
equivalent of MsCl and triethylamine once an hour for 5 h.
Access to 25 completed the installation of the C17–C18 bond
as shown by the conversion of intermediate F into G
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Scheme 6. Synthesis of desoxohexacyclinol (3). a) KHMDS (1.1 equiv),
THF; ꢀ78 to ꢀ508C;then (BtS) , ꢀ788C; ꢀ788C!08C, 12 h;
2
b) oxone, wet 1,4-dioxane, 87% from 27;c) TBAF, wet THF, 0 8C!RT;
d) Dess–Martin periodinane, CH2Cl2, 08C!RT;e) slow addition of
DBU (1.2 equiv), DMAP (cat.), THF, ꢀ408C!RT, 10 h, 72% from 28;
f) Ph3COOH, l-(+)-diisopropyltartrate, toluene, CH2Cl2 (3:1 v/v), 92%;
g) KOTMS, THF, ꢀ108C!358C, 5 h, 69%;h) MnO 2, CH2Cl2, room
temperature;i) 34, KHMDS, ꢀ788C; ꢀ788C!ꢀ308C, 2 h;add 33 at
ꢀ788C; ꢀ788C!RT, 3 h;then room temperature, 12 h, 76% from 32;
j) cat. aq. H2SiF6, CH3CN/tBuOH (9:1 v/v), room temperature, 78%
Scheme 5. Access to intermediate G through the synthesis of 27.
a) LDA (1.1 equiv), THF; ꢀ788C!ꢀ508C;then CH 3COCN, ꢀ788C;
then ꢀ788C!08C,12 h, 92%;b) mCPBA (3.0 equiv), CH 2Cl2;c) CSA
(0.2 equiv), room temperature, wet tBuOMe, 6 h, 94% from 21;
d) TMSCl (1.2 equiv), H2O (5.0 equiv), CH2Cl2, 08C, 97%;e) add MsCl
(1 equiv) and Et3N (1 equiv) in CH2Cl2 once an hour for 5 h at ꢀ108C;
ꢀ108C!RT, 16 h, 76%;f) PhSNa (0.2 equiv), MeOH;g) TESOTf, 2,6-
lutidine, CH2Cl2, ꢀ208C!RT, 82% from 25;h) 60–70 8C, DMF, 16 h,
92%. mCPBA=meta-chloroperbenzoic acid, CSA=camphorsulfonic
acid, TMS=trimethylsilyl, Ms=methanesulfonyl, TESOTf=triethylsilyl
triflate, DMF=N,N-dimethylformamide.
for 3a;81% for 36;72% for 37;84% for 38;k) O , rose bengal,
2
MeOH, hn, 08C, 82%. Bt=1-benzothiazole, TBAF=tetra-n-butyl-
A
N
The synthesis of desoxohexacyclinol (3) was accomplished
by unveiling the 7-oxabicyclo[2.2.1]heptane and thereby
(Scheme 2). The final stitch (G to H) called for the creation of
the C14–C15 bond. This process began with methanolysis of
the lactone in 25 by treatment with sodium thiophenoxide in
methanol followed by protection of the secondary alcohol to
afford 26 (Scheme 5). Thermolysis of 26 induced a regiose-
lective syn-elimination to provide 27. At this stage, the
appropriate functionality was installed to address the forma-
tion of the C14–C15 epoxide.
A Julia–Kocienski reaction was selected for this process as
the projected enone 30 was envisioned as a suitable precursor
to the C14–C15 epoxide (Scheme 6). Sulfone 28 was prepared
by a-thiolation of 27 with 2,2’-dithiobis(benzothiazole) fol-
lowed by oxidation with oxone. Selective deprotection of the
primary TBS-protected ether followed by oxidation with
Dess–Martin periodinane provided the precursor to the Julia–
Kocienski reaction 29. Slow addition of DBU with a catalytic
amount of DMAP to 29 in THF over 2 h at ꢀ408C followed
by warming to room temperature over 10 h afforded the
desired enone 30 in good yield. Epoxidation at C14–C15, as
required by H to I (Scheme 2), was effected by using the
tartrate-mediated nucleophilic epoxidation conditions devel-
oped by Porco and co-workers to yield a single epoxide 31.[11]
ACHTREUNG
completing the synthesis of the C ring (I to J, Scheme 2).
Hydrolysis of 31 with TMSOK[12] or nBu3SnOH[13] generated
the corresponding acid, which underwent subsequent b-
eliminative ring opening to provide 32 (Scheme 6). Hydrolysis
of the C14–C15 epoxide was avoided by slow addition of
TMSOK or nBu3SnOH. At this point, the final carbon atoms
C1–C3 were installed through a second Julia–Kocienski
reaction (Scheme 6). Allylic oxidation with MnO2 was
effective at converting 32 into aldehyde 33, which was in
turn filtered through dry silica gel and immediately treated
with the anion of 34 to afford 35. Remarkably, this addition
was achieved with less than 5% addition to the C14–C15
epoxide. Mild deprotection with fluorosilicic acid[14] com-
pleted the synthesis to provide 3a in an overall yield of 0.8–
1.3% from 4. Confirmation of this yield was established by
the most-recent campaign that provided 3.6 g of 3a from
1mol of 4.
Exposure of 3a to singlet oxygen[15] resulted in a
[2+2+2] cycloaddition[16] that afforded a mixture of chroma-
tographically separable 1 and 2 (8:1). Samples of synthetic
hexacyclinol (1),[17] 2,[18] and 3[19] were identical in Rf, HPLC
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Communications
concerns over the use of a dithiane. Details of this route shall be
explained in forthcoming publications.
retention, physical properties, and spectral data to authentic
samples of 1–3 isolated in our laboratories.[2] The optical
rotation of synthetic 1 ([a]D(4.0 mgmLꢀ1) = + 131.58) was
comparable to that obtained in samples of isolated 1
([a]D(4.0 mgmLꢀ1) = + 132.28) as well as that reported by
Gräfe and co-workers ([a]D(4.03 mgmLꢀ1) = + 130.58),[1]
thereby confirming the absolute stereochemistry of hexacy-
clinol (1).
[7] Epoxide 15 was prepared using a method described in: G. Anker,
J. Attaghrai, D. Picq, D. Anker, Carbohydr. Res. 1987, 159, 159.
[8] T. Cohen, J. R. Matz, J. Am. Chem. Soc. 1980, 102, 6900.
[9] G. A. Kraus, M. Shimagaki, Tetrahedron Lett. 1981, 22, 1171.
[10] The primary mesylate of 24c was the major product obtained by
treating 23a,b with MsCl in pyridine. The reversibility of
mesylation with sulfene was previously described for cyclization
procedures: P. T. Lansbury, J. J. La Clair, Tetrahedron Lett. 1993,
34, 4431.
While the yield and complexity of this synthesis may not
be ideal for therapeutic use, the value of this synthetic route
became apparent upon screening the activity of the late-stage
intermediates. Intermediates 36–38, prepared by deprotection
of the precursors 30–32, respectively, were analyzed for their
inhibition of Plasmodium berghei.[2] Remarkably, 36, 37, and
38 displayed IC50 values of 9.3 ꢁ 2.6, 6.1 ꢁ 1.5, and 2.1 ꢁ
0.7 nm, respectively, against a chloroquine-sensitive P. ber-
ghei. In the same assay, artemisinin displayed an IC50 value of
2.5 ꢁ 0.9 nm.[2,20] Comparable activity was also obtained in in
vivo antimalarial assays, which indicated that 36, 37, and 38
displayed ED50 values of 8.9, 1.6, and 5.2 mgkgꢀ1, respectively,
against chloroquine-sensitive P. berghei. This activity was
found to be comparable to sodium artesunate, which deliv-
ered an ED50 value of 4.3 mgkgꢀ1 when examined in
parallel.[2,21] While the mode of action of these materials has
yet to be verified,[2] prior observations on 3 suggest that these
materials arise through a three-step prodrug-like motif
(Scheme 7). Efforts are now underway to determine the
[11] C. Li, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2003, 125,
5095.
[12] D. E. Pearson, C. A. Buehler, A. Calvin, Chem. Rev. 1974, 74, 45.
[13] K. C. Nicolaou, A. A. Estrada, M. Zak, S. H. Lee, B. S. Safina,
Angew. Chem. 2005, 117, 1402; Angew. Chem. Int. Ed. 2005, 44,
1378.
[14] D. R. Williams, D. C. Kammler, A. F. Donnell, W. R. F. Goun-
dry, Angew. Chem. 2005, 117, 6873; Angew. Chem. Int. Ed.
Angew. Chem. Int. Ed. Engl. 2005, 44, 6715.
[15] D. M. Nowak, P. T. Lansbury, Tetrahedron 1998, 54, 319.
[16] a) T. Tamai, K. Mizuno, I. Iiashida, Y. Otsuji, Tetrahedron Lett.
1993, 34, 2641; b) V.-H. Nguyen, H. Nishino, K. Kazu, Tetrahe-
dron Lett. 1997, 38, 1773.
[17] Physical and spectral properties of 1: Colorless solid; m.p.: 172–
1748C; Rf = 0.83 in CH3Cl/MeOH (9:1v/v); IR (film): n˜ = 3417,
3018, 2985, 2935, 1699, 1625, 1382, 1214, 1009, 1132, 996, 982,
910 cmꢀ1 1H NMR (500 MHz, CDCl3 + 1 % CDOD, J [Hz]):
;
3
d = 6.73 (dd, J = 5.3, 2.4, 1H), 5.46 (d, J = 10.1, 1H), 4.99 (br dd,
J = 5.2, 1H), 4.81 (d, J = 10.1, 1H), 3.81 (dd, J = 9.5, 1.6, 1H),
3.64 (m, 1H), 3.59 (d, J = 5.3,1H), 3.55 (m, 1H), 3.51(dd, J = 2.8,
0.5, 1H), 3.29 (d, J = 3.0, 1H), 3.24 (d, J = 3.6, 1H), 3.03 (s, 3H),
2.75 (dd, J = 5.2, 7.9, 1H), 1.77 (s, 3H), 1.73 (s, 3H), 1.27 (s, 3H),
1.15 ppm (s, 3H); HR-EIMS: calcd m/z: 416.1835; found:
416.1892. See Supporting Information for spectra.
Scheme 7. Suggested mechanism supporting the in vivo activity of 37.
a) Hydrolysis;b) decarboxylative b-elimination;c) [2 +2+2] cycloaddi-
tion with singlet oxygen.
[18] Physical and spectral properties of 2: Colorless solid; m.p.: 165–
1698C; Rf = 0.79 in CH3Cl/MeOH (9:1v/v); IR (film): n˜ = 3418,
3015, 2980, 2932, 1701, 1626, 1380, 1216, 1005, 1131, 995, 981,
validity of this mechanism as well as to identify a minimal
pharmacophore.[22]
912 cmꢀ1 1H NMR (500 MHz, CDCl3 + 1 % CDOD, J [Hz]):
;
3
d = 6.78 (dd, J = 5.4, 2.2, 1H), 5.41(d, J = 10.6, 1H), 5.01 (br dd,
J = 5.2, 1H), 4.56 (d, J = 8.2, 1H), 3.76 (dd, J = 9.5, 1.6, 1H), 3.58
(m,1H), 3.52 (m, 1H), 3.51(d, J = 5.2, 1H), 3.48 (dd, J = 2.9, 0.5,
1H), 3.32 (d, J = 2.8, 1H), 3.26 (d, J = 3.4, 1H), 3.08 (s, 3H), 2.78
(dd, J = 5.1, 7.8, 1H), 1.81 (s, 3H), 1.72 (s, 3H), 1.28 (s, 3H),
1.17 ppm (s, 3H); HR-EIMS: calcd m/z: 416.1835; found:
416.1881. See Supporting Information for spectra.
Received: November 14, 2005
Published online: February 9, 2006
Keywords: antimalarial agents · medicinal chemistry ·
.
natural products · terpenoids · total synthesis
[19] Physical and spectral properties of 3 as a 1:1 mixture of olefin
isomers: Waxy solid; Rf = 0.68 in CH3Cl/MeOH (12:1 v/v); IR
(film): n˜ = 3417, 2965, 2955, 1695, 1624, 1422, 1272, 1104, 1002,
[1] B. Schlegel, A. Hartl, H. M. Dahse, F. A. Gollmick, U. Gräfe, H.
Dorfelt, B. Kappes, J. Antibiot. 2002, 55, 814.
1
992, 972, 912 cmꢀ1; H NMR (500 MHz, CDCl3 + 1 % CDOD,
3
J [Hz]): d = 6.90 (d, J = 9.2, 1.3, 1H); 6.94 (d, J = 10.5, 0.7, 1H),
5.92 (d, J = 9.3, 1.2, 1H); 5.89 (d, J = 10.5, 0.7, 1H), 5.79 (dd, J =
5.3, 2.4, 1H), 5.56 (dd, J = 9.3, 2.4, 1H), 5.22 (dd, J = 9.3,1.8, 1H),
3.65 (dd, J = 2.1, 0.8, 1H), 3.51 (dd, J = 2.3, 1.8, 1H), 3.31 (m,
1H), 3.21 (dd, J = 8.4, 1.1, 1H), 3.16 (br d, J = 2.6, 1H), 3.16 (d,
J = 2.0, 1H), 3.06 (m, 1H) , 2.82 (s, 3H), 1.76 (s, 3H), 1.75 (s,
3H), 1.21 (s, 3H), 1.18 ppm (s, 3H); HR-EIMS: calcd m/z:
384.1937; found: 384.1911. See Supporting Information for
spectra.
[2] J. J. La Clair, unpublished results.
[3] Bis(acetate) 4 was prepared according to the procedure reported
A
in: M. Tanaka, Y. Norimine, T. Fujita, H. Suemune, K. Sakai, J.
Org. Chem. 1996, 61, 6952.
[4] G. Stork, M. Kahn, J. Am. Chem. Soc. 1985, 107, 500.
[5] A. B. Smith III, D. Lee, C. M. Adams, M. C. Kozlowski, Org.
Lett. 2002, 4, 4539.
[6] SmI2 as suggested by Smith et al.[5] also failed. An alternative
synthesis using a triethylsilylcyanohydrin was used to alleviate
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[20] W. Peters, B. L. Robinson, Ann. Trop. Med. Parasitol. 1999, 93,
325.
[21] A. M. Szpilman, E. E. Korshin, H. Rozenberg, M. D. Bachi, J.
Org. Chem. 2005, 70, 3618.
1
[22] Note added in proof: The H NMR spectra for this Communi-
cation were determined by contract services. The spectra
provided in the Supporting Information were collected by N.
Voss (Berlin, Germany). The operator added the peak for CDCl3
to the spectrum of synthetic hexacyclinol (1), however, this was
done incorrectly at d ꢂ 7.5 ppm and against the request of the
author. Additionally, one spectrum was duplicated and a copy of
the spectra for natural 5-epi-hexacyclinol was not provided.
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2773