Total synthesis and structure confirmation of leptofuranin D

Article abstract of DOI:10.1021/jo0348930

A convergent total synthesis of leptofuranin D is described. The linear polyketide C12-C24 segment was assembled through addition of a chiral allenylzinc reagent, derived from mesylate 12, to the chiral aldehyde 11. Directed hydrostannation of the adduct 13 followed by iodinolysis and Sonogashira coupling yielded the enyne 16, which was converted to the methyl-substituted enye 20, through hydrogenolysis of the derived bromide 19. Hydrostannation of the terminal alkyne converted 21 to 22, which was then treated with iodine to afford the vinyl iodide 23. The dihydropyranone precursor 40 was prepared by addition of allenystannane 29 to aldehyde 27. Partial hydrogenation of the derived propargylic alcohol then protection as the TBS ether afforded the (Z)-olefin 34. Further homologation was effected through Witttig condensation of aldehyde 36 with the ylide derived from phosphonium bromide 37. Selective deprotection of the primary TES ether of 38, followed by conversion of alcohol 39 to iodide 40, completed the synthesis of the C1-C11 segment. Suzuki coupling of boronate 41, prepared from iodide 40, with vinyl iodide 23 led to diene 42, with the complete carbon skeleton of leptofuranin D. The synthesis was completed by oxidation of the unprotected alcohol of 42, followed by global desilylation and exposure of the resulting tetrol to MnO ₂.

Full text of DOI:10.1021/jo0348930

Tota l Syn th esis a n d Str u ctu r e Con fir m a tion of Lep tofu r a n in D
J ames A. Marshall* and Gregory M. Schaaf
Department of Chemistry, University of Virginia, P.O. Box 400319, Charlottesville, Virginia 22904
jam5x@virginia.edu
Received J une 24, 2003
A convergent total synthesis of leptofuranin D is described. The linear polyketide C12-C24 segment
was assembled through addition of a chiral allenylzinc reagent, derived from mesylate 12, to the
chiral aldehyde 11. Directed hydrostannation of the adduct 13 followed by iodinolysis and
Sonogashira coupling yielded the enyne 16, which was converted to the methyl-substituted enye
20, through hydrogenolysis of the derived bromide 19. Hydrostannation of the terminal alkyne
converted 21 to 22, which was then treated with iodine to afford the vinyl iodide 23. The
dihydropyranone precursor 40 was prepared by addition of allenystannane 29 to aldehyde 27. Partial
hydrogenation of the derived propargylic alcohol then protection as the TBS ether afforded the
(Z)-olefin 34. Further homologation was effected through Witttig condensation of aldehyde 36 with
the ylide derived from phosphonium bromide 37. Selective deprotection of the primary TES ether
of 38, followed by conversion of alcohol 39 to iodide 40, completed the synthesis of the C1-C11
segment. Suzuki coupling of boronate 41, prepared from iodide 40, with vinyl iodide 23 led to diene
42, with the complete carbon skeleton of leptofuranin D. The synthesis was completed by oxidation
of the unprotected alcohol of 42, followed by global desilylation and exposure of the resulting tetrol
to MnO2.
Leptofuranins A-D were isolated in 1996 from the
actinomycete strain Streptomyces tanashiensis (Figure
1).1 They were found to inhibit the growth of normal
human fibroblast cells while inducing apoptosis of human
cervical cancer HeLa and osteosarcoma Saos-2 cells at
nanogram per milliliter concentrations. The structures
of these four closely related compounds, exclusive of
stereochemistry, were assigned on the basis of the NMR
spectra, which were quite similar to that of leptomycin
B, an antifungal antibiotic isolated in 1983 from Strep-
tomyces sp.2 Subsequently, Kobayashi and co-workers
completed a total synthesis of leptomycin B, thereby
establishing the relative and absolute stereochemistry.3
While the stereochemistry of no leptofuranin had been
established prior to the present studies, their close
structural similarity to leptomycin B was suggestive of
close and possibly identical stereo structures, exclusive
of the C22 tetrahydrofuran stereocenter. It should be
noted that leptofuranins C and D were each isolated as
nearly 1:1 mixtures of closely related and chromato-
1
graphically inseparable stereoisomers. Their H and 13C
NMR spectra revealed the presence of two “tautomers”
in nearly equal amounts. This conclusion was verified
by HPLC analysis. Interestingly, the two HPLC peaks
coalesced at 60 °C leading to the conclusion that the two
compounds were in rapid equilibrium, suggestive of a
reversible 1,4-addition to an intermediate conjugated enal
(Figure 2).
F IGURE 1. Leptomycin B, leptofuranins A-D, and callystatin
A.
Recently, we reported a total synthesis of callystatin
A, a close relative of the leptofuranins.4 It was of interest
(1) Hayakawa, Y.; Sohda, K.-Y.; Furihata, K.; Kuzuyama, T.; Shin-
Ya, K.; Seto, H. J . Antibiot. 1996, 974.
(2) Hayakawa, Y.; Sohda, K.-Y.; Seto, H. J . Antibiot. 1996, 980.
to apply some of the methodology developed in that
(3) Kobayashi, M.; Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami,
N. Tetrahedron Lett. 1998, 39, 8291.
(4) Marshall, J . A.; Bourbeau, M. P. J . Org. Chem. 2002, 67, 2751.
10.1021/jo0348930 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/23/2003
7428
J . Org. Chem. 2003, 68, 7428-7432

Synthesis and Structure Confirmation of Leptofuranin D
SCHEME 1a
F IGURE 2. Epimerization pathway for leptofuranin C and
leptofuranin D.
a
Reagents and conditions: (a) Cy2BH then NaOH, H2O2 (95%);
(b) MeCOC(N2)PO(OMe)2, K2CO3 (75%, 2 steps); (c) Cp2ZrCl2,
AlMe3, H2O then ClCO2Me (64%).
SCHEME 2a
F IGURE 3. Principal bond-forming reactions for the synthesis
of leptomycin B and leptofuranin D.
synthesis to the leptofuranins to establish the stereo-
chemistry and eventually provide samples for evaluation
of antitumor activity. Our initial efforts were directed at
leptomycin B and leptofuranin D. We assumed that,
apart from C22, the two are stereochemically identical.
Synthetic leptofuranin D would expectedly be formed as
a nearly 1:1 mixture of stereoisomers at C22, in accord
with the natural material. The essence of our plan is
diagrammed in Figure 3. Accordingly, successive alle-
nylmetal additions to aldehyde intermediates would
provide the means for introducing most of the stereo-
centers with concomitant C-C bond formation.5 Ad-
ditional C-C bonds would be formed through Pd(0)-
catalyzed couplings and Wittig reactions. The â-methyl
acrylic acid terminus of leptomycin B lends itself to
construction by carboalumination of a terminal acetylene.
Finally, assuming a stereochemical congruence, lepto-
mycin B could be converted to leptofuranin D through
internal 1,4-addition and reduction.
a
Reagents and conditions: (a) PPTS, MeOH (91%); (b) Swern
oxidation (97%).
We also examined an alternative route to the ter-
minal acrylic acid segment on
a model substrate
through application of a Suzuki coupling (eq 1).9 For this
Our synthesis commenced with the known stereotriad
1, the product of a chiral allenyltin addition to (R)-3-
OTBS-2-methylpropanal (Scheme 1).6 Hydroboration-
oxidation of the alkyne terminus led to aldehye 2, which
was converted to alkyne 3 through treatment with the
Ohira diazo phosphonate reagent.7 Water-accelerated
carboalumination of this alkyne, under conditions devel-
oped by Wipf, followed by addition of methyl chlorofor-
mate afforded the conjugated ester 4 in 64% yield.8 In
the absence of water this reaction proceeded in less than
50% yield. As a preview of an end-game strategy we
treated 4 with TBAF whereupon the tetrahydrofuran 5
was produced as a 57:43 mixture of diastereomers.
sequence, the iodide 7 was lithiated in the presence
of B-MeO-9-BBN to form the boronate intermediate
in situ. Addition of the vinyl triflate 8 and a Pd(0) cat-
alyst afforded the coupled product 9, but in only 25%
yield.
Returning to the main sequence, the primary TBS
ether of intermediate 4 was selectively hydrolyzed through
exposure to PPTS in methanol-THF. Swern oxidation
of the derived alcohol 10 afforded aldehyde 11 in 97%
yield.10 Addition of the allenylzinc reagent, generated in
situ from the (S)-propargylic mesylate 12, gave the anti
adduct 13 as a 90:10 mixture of diastereomers in 72%
yield.6
(5) Marshall, J . A. Chem. Rev. 2000, 100, 3163.
(6) Marshall, J . A.; Schaaf, G. M. J . Org. Chem. 2001, 66, 7825.
(7) Ohira, S. Synth. Commun. 1989, 19, 561.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. Chemler, S.
R.; Travner, D.; Danishefsky, S. J . Angew Chem., Int. Ed. 2001, 40,
4545.
(8) Lim, S.; Wipf, P. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
(10) Omurka, K.; Swern, D. Tetrahedron 1978, 34, 1651.
J . Org. Chem, Vol. 68, No. 19, 2003 7429

Marshall and Schaaf
SCHEME 3a
a
Reagents and conditions: (a) I2, CH2Cl2 (82%, 2 steps); (b) TMSCtCH, Pd(PPh3)2Cl2, CuI, Et3N (87%); (c) NaOH, MeOH-THF (90%);
(d) MsCl, Et3N, CH2Cl2; (e) LiBr, 2-butanone; (f) LiBEt3H, THF (78%, 3 steps); (g) TBSCl, Im, CH2Cl2 (82%); (h) Bu3SnH, Pd(PPh3)2Cl2,THF;
(i) I2, CH2Cl2 (82%, 2 steps).
Final construction of the C12-C24 polypropionate
array utilized a sequence that was developed both for this
segment and for a comparable segment of callystatin A.11
Accordingly, Pd(0)-catalyzed hydrostannation of the pro-
pargylic acetate 13 with Bu3SnH afforded vinylstannane
14 regioselectively in high yield (Scheme 3). The derived
vinyl iodide 15 underwent efficient Sonogashira coupling
with TMS acetylene leading to the enyne 16.12 Reduction
of the acetoxy methyl group of this intermediate was
effected in a 3-step process culminating in the hydro-
genolysis of allylic bromide 19 with LiBEt3H in 78%
overall yield.
In some preliminary model studies, we attempted to
effect the hydrogenolysis of allylic acetate 24 via π-allyl
palladium intermediates under conditions that would
preserve the terminal acrylic ester grouping, and thereby
avoid a later reoxidation to the acid moiety of leptomycin
B. However, our efforts were not rewarded. Treatment
of acetate 24 with Pd(PPh3)4 followed by triethylammo-
nium formate gave only recovered acetate.13 The use of
LiBEt3H in combination with Pd(PPh3)4 resulted in
reduction of the acetate to afford the alcohol.14 When the
allylic mesylate 25 was treated with Pd(PPh3)4 followed
by LiBEt3H, a 2:1 mixture of the (E)- and (Z)-hydro-
genolysis products was isolated (eq 2).
to protect the resulting primary allylic alcohol as the TBS
ether 21, a decision we were to later regret. Completion
of the C12-C24 segment was effected by hydrostannation
of the terminal alkyne 21 and iodinolysis of the resulting
vinylstannane 22 to afford the (E)-vinyl iodide 23 in 82%
yield (Scheme 3).
The second major segment for our proposed synthesis
of leptomycin B and leptofuranin D was the C1-C11
dihydropyrone precursor 34. Its preparation started from
the mono PMB ether 26 of ethylene glycol (Scheme 4).
Oxidation to aldehyde 27 followed by MgBr2-promoted
propargylation of aldehyde 27 with chiral (acetoxym-
ethyl)allenyl stannane 285 produced adduct 30 as a 66:
34 mixture of diastereomers. Fortunately, the related
allenyl stannane analogue 29 afforded propargyl adduct
31 as a more manageable 83:17 mixture of syn and anti
adducts in 85% yield. This mixture could be separated
by chromatography on silica gel affording the pure syn
isomer in 68% yield. The hydroxymethyl derivative of the
latter adduct was obtained through lithiation of the
terminal alkyne and addition of paraformaldehyde. The
resulting diol 32 was converted to bis-TBS ether 33,
which was cleanly reduced to (Z)-alkene 34 with H2 over
Pd on BaSO4 poisoned with quinoline.15 Cleavage of the
PMB ether with DDQ and Swern oxidation of alcohol 35
afforded aldehyde 36 in high yield. Homologation of
aldehyde 36 was effected through condensation with the
Wittig reagent 37, previously employed in our synthesis
of callystatin A, to afford diene 38.4 Selective cleavage of
the primary TES ether with methanolic PPTS and
treatment of alcohol 39 with I2, Ph3P, and imidazole
effected conversion to iodide 40.16
As the LiBEt3H hydrogenolysis of the allylic bromide
also reduced the terminal acrylic ester of 19, we elected
Coupling of the two major fragments 23 and 40 was
achieved by Suzuki methodology via boronate 41, which
(11) Marshall, J . A.; Bourbeau, M. P. Org. Lett. 2002, 4, 3931.
(12) Cf.: (a) Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 3, Chapter
2.4. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(13) Tsuji, J .; Minami, I.; Shimizu, I. Synthesis 1986, 623.
(14) Hutchins, R. O.; Learn, K. J . Org. Chem. 1982, 47, 4380.
(15) Adams, M. A.; Duggan, A. J .; Smolanoff, J .; Meinwald, J . J .
Am. Chem. Soc. 1979, 101, 5364.
(16) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1982, 681. Corey, E. J .; Pyne, S.; G. Su, W. Tetrahedron Lett. 1983,
24, 4883.
7430 J . Org. Chem., Vol. 68, No. 19, 2003

Synthesis and Structure Confirmation of Leptofuranin D
SCHEME 4a
SCHEME 5
a
Reagents and conditions: (a) BuLi, (CH2O)n, THF; (b) TBSOTf,
2,6-lut, CH2Cl2 (83%, 2 steps); (c) H2/5% Pd-BaSO4, quinoline,
toluene (90%); (d) DDQ, CH2Cl2, pH 7 (91%); (e) Swern oxidation
(98%); (f) PPTS, MeOH-THF (74%); (g) I2, PPh3, Im (94%); (h)
t-BuLi, Et2O, B-MeO-9-BBN, -78 °C.
was prepared from iodide 40 in situ with t-BuLi and
B-MeO-9-BBN.9 The most effective catalyst for the
coupling reaction was derived from Pd(dppf)Cl2 and
AsPh3, which gave rise to the fully elaborated leptofu-
ranin carbon segment 42 in 82% yield (Scheme 5).
Oxidation of the unprotected alcohol of 42 led to ketone
43 and subsequent desilylation with HF‚NEt3 produced
tetrol 44 in 74% yield. The desilylation reaction was quite
slow, requiring 6 days for completion. Attempts to
shorten the reaction time by increasing the temperature
caused decomposition of the starting material.
SCHEME 6
For the final stage of the synthesis we planned to effect
selective oxidation of the allylic alcohols with MnO2. It
was expected that such treatment would give rise to a
transient bis-enal intermediate in which the C1 aldehyde
would cyclize to the lactol 45 and be further oxidized to
the lactone.4 In fact, treatment of the tetrol with excess
MnO2 in CH2Cl2 resulted in slow conversion to multiple
intermediate products which gradually converged to a
major product. This product, a nearly 1:1 mixture of
inseparable isomers, was not the expected enal, but
rather the internal 1,4-adduct 46 of enal 45. This mixture
proved identical to leptofuranin D by comparison of the
1H NMR spectrum and optical rotation with the reported
values.2
diates and finally two inseparable products, after oxida-
tion of the lactol moiety to lactone 46. Interestingly,
Kobayashi employed an MnO2 oxidation of allylic alcohol
47 in his synthesis of leptomycin B without competing
1,4-addition of the C19 hydroxyl group to the enal product
(Scheme 6).3 That reaction was carried out in benzene
as solvent. Unfortunately, tetrol 44 was only sparingly
soluble in benzene so this option could not be explored.
While the foregoing synthesis confirms the stereochem-
istry of leptofuranin D, the route in its present form is
TLC analysis of the oxidation in progress showed the
near simultaneous formation of multiple spots. These
were slowly replaced by a single spot. Thus it appears
likely that both primary allylic alcohols are oxidized at
comparable rates and each is intercepted by proximal
hydroxyl groups leading to four diastereomeric interme-
J . Org. Chem, Vol. 68, No. 19, 2003 7431

Marshall and Schaaf
not feasible for leptomycin B. Presumably an early stage
protecting group modification for the C24 alcohol function
of the eventual oxidation substrate 44 (e.g. 43, R2 ) PMB)
would solve the problem. However, we prefer to examine
an alternative strategy that does not result in the
reduction of the terminal acrylic ester grouping of 19, or
a close relative. The results of those investigations will
be reported in due course.
Ack n ow led gm en t. Support for these studies was
provided by Grant R01 CA090383 from the U.S. Na-
tional Cancer Institute.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and selected H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0348930
7432 J . Org. Chem., Vol. 68, No. 19, 2003