Synthesis of a syn,syn,syn,syn-stereopentad precursor of the marine sponge polyketide callystatin A

Article abstract of DOI:10.1021/jo9902143

A C13-22 syn,syn,syn,syn-stereopentad precursor of the cytotoxic polyketide callystatin A has been prepared. The synthesis involved BF₃- promoted addition of the (M)-allenylstannane 28 to the α-methyl-β-OTBS aldehyde 8 to afford the syn,syn adduct homopropargylic alcohol 29. Protection as the cyclic anisylidene acetal 31 and reduction of the acetylenic triple bond with Red-Al gave the (E)-allylic alcohol 32. This was subjected to Sharpless asymmetric epoxidation and subsequent treatment with an ethylcopper reagent to yield diol 34; hydrogenolysis of the derived tosylate 37 with LiBEt₃H afforded 38. Acetal hydrogenolysis with DIBAl-H and oxidation yielded aldehyde 40 which was subjected to Horner-Emmons homologation to afford ester 41. This ester was converted to ester 44, an intermediate in the Kobayashi synthesis, with which it was found to be identical.

Full text of DOI:10.1021/jo9902143

J . Org. Chem. 1999, 64, 4477-4481
4477
Syn th esis of a syn ,syn ,syn ,syn -Ster eop en ta d P r ecu r sor of th e
Ma r in e Sp on ge P olyk etid e Ca llysta tin A
J ames A. Marshall* and Russell N. Fitzgerald
Department of Chemistry University of Virginia, Charlottesville, Virginia 22901
Received February 4, 1999
A C13-22 syn,syn,syn,syn-stereopentad precursor of the cytotoxic polyketide callystatin A has been
prepared. The synthesis involved BF3-promoted addition of the (M)-allenylstannane 28 to the
R-methyl-â-OTBS aldehyde 8 to afford the syn,syn adduct homopropargylic alcohol 29. Protection
as the cyclic anisylidene acetal 31 and reduction of the acetylenic triple bond with Red-Al gave the
(E)-allylic alcohol 32. This was subjected to Sharpless asymmetric epoxidation and subsequent
treatment with an ethylcopper reagent to yield diol 34; hydrogenolysis of the derived tosylate 37
with LiBEt3H afforded 38. Acetal hydrogenolysis with DIBAl-H and oxidation yielded aldehyde 40
which was subjected to Horner-Emmons homologation to afford ester 41. This ester was converted
to ester 44, an intermediate in the Kobayashi synthesis, with which it was found to be identical.
Sch em e 1
Recently Kobayashi and co-workers reported the isola-
tions,1 structure elucidation,1 and synthesis2 of a marine
sponge polyketide, callystatin A. Bioassay-guided puri-
fication by extraction and multiple chromatographic
separations on silica gel, then HPLC on Cosmosil 5SL,
followed by HPLC on 5C18-Ar columns afforded 1.0 mg
of pure material. This substance shows remarkably high
activity (IC50 ) 0.01 ng/mL) against KB tumor cells.
The potent cytotoxicity of callystatin A and its extreme
scarcity constitute a compelling case for total synthesis.
We were attracted by these considerations and the
presence of an all-syn-stereopentad array in a possible
synthetic precursor.2 We viewed the synthesis of this
precursor as an opportunity to expand the scope of our
synthetic approach to stereopentads by SE2′ additions of
chiral allenylmetal reagents to aldehydes.3 The all-syn
diastereomer had not previously been prepared by this
methodology.
Allenylstannane 7 of >95% ee was obtained from TBS-
protected ethyl lactate (1) by the sequence outlined in
Scheme 1.4 Addition of this stannane to aldehyde 8,5 in
the presence of BF3‚OEt2, afforded the syn,syn-adduct 9.
Partial hydrogenation over Lindlar’s catalyst6 yielded the
(Z) olefin 10. Epoxidation of olefin 10 with m-ClC6H4-
CO3H (MCPBA) afforded a single diastereomer, subse-
quently identified as epoxide 13 through independent
synthesis from the BOC derivative 11 via the iodocar-
bonate 12.7 Tirando and Prieto have shown that related
(Z)-homoallylic alcohols afford anti,syn-iodocarbonates
upon treatment with n-BuLi followed by CO2 and I2.8 The
(1) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Amok,
S. Tetrahedron Lett. 1997, 38, 2859. Murakami, N.; Wang, W.; Aoki,
M.; Tsutsui, Y.; Higuchi, K.; Aoki, S.; Kobayashi, M. Tetrahedron Lett.
1997, 38, 5533.
(2) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.;
Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349. For a second, more
recent synthesis, see: Crimmins, M. T.; King, B. W. J . Am. Chem. Soc.
1998, 120, 9084.
(3) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1998, 63, 3701.
(4) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230.
(5) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J . Org. Chem.
1987, 52, 316.
(6) Aldrich Chemical Co., Milwaukee, WI.
(7) Duan, J . J .-W.; Smith, A. B., III, J . Org. Chem. 1993, 58, 3703.
(8) Tirando, R.; Prieto, J . A. J . Org. Chem. 1993, 58, 5666.
10.1021/jo9902143 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999

4478 J . Org. Chem., Vol. 64, No. 12, 1999
Marshall and Fitzgerald
Sch em e 2
iodocarbonate 21 as the sole product. Base treatment led
to the epoxide 22, also in high yield. Protection as the
MOM derivative 23 and removal of the PMB protecting
group yielded the epoxy alcohol 24. Treatment of this
intermediate with the higher order methyl cyanocuprate9
afforded the diol 25 in 61% yield (unoptimized). It
therefore seems likely that a combination of unfavorable
steric effects and the absence of a directing OH group
may be responsible for the unreactivity of epoxides 13
and 14 toward cuprate reagents. To make the comparison
more exact, we also prepared the MOM derivative of
epoxy alcohol 13 and subjected it to the higher order
methyl cyanocuprate without success. No diol product
was obtained from this reaction.
To confirm that the diol 25 was indeed the syn,syn,an-
ti,syn isomer and not the all syn adduct, we converted it
1
to the symmetric bis-TBS, MOM ether 27 (eq 1). The H
NMR spectrum and optical rotation confirmed our as-
sumption that this product was not the all-syn (meso)
compound.
desired syn,cis-epoxide could be prepared through epoxi-
dation of the (Z)-olefin 10 with J acobsen’s (S,S)-salen
epoxidation catalyst (S,S)-N,N′-bis(3,5-di-tert-butylsal-
icylidene-1,2-cyclohexanediamino)manganese(III) chlo-
ride.6 The resulting 4:1 mixture of syn,syn,syn,cis- and
syn,syn,anti,cis-epoxides 14 and 13 could be separated
by chromatography.
Attempts at SN2 displacements on epoxide 14 with
various cuprate reagents, including Me2CuCNLi2, MeCu-
CNLi, and MeMgBr‚CuI, were unsuccessful.9 Either
starting material was recovered or multiple unidentified
products were produced. The syn,syn,anti,cis-epoxide 13
was likewise unreactive.
The failure of epoxides 13 and 14 to react with methyl
cuprate reagents was surprising in view of previous
successes with epoxides of (E)-allylic alcohols.3,10 Molec-
ular mechanics calculations indicate that the ethyl sub-
stituent of these epoxides tends to orient behind the
epoxide ring, thereby blocking backside access.11 It is also
possible that the OH grouping of our previous examples
provides assistance through coordination with the at-
tacking cuprate reagent.12,13 As a point of information it
was of interest to examine the reactivity of the cis-epoxide
24 derived from the (Z)-allylic carbonate 20 (Scheme 2).
Carbonate 20 was prepared from aldehyde 8 and the
enantioenriched allenylstannane 17, as outlined in Scheme
2. Iodolactonization7 proceeded in high yield to afford
Given the apparent need for an allylic OH directing
group to facilitate epoxide opening and in view of our
previous success with epoxides of (E)-allylic alcohols, the
sequence outlined in Scheme 3 was formulated, in which
addition of an ethylcopper reagent to epoxide 33 would
produce the adduct 34 which, after protection and reduc-
tion, would be converted to the all-syn product 38. The
approach was particularly appealing since we had carried
out the synthesis of the enantiomer of epoxy alcohol 33
in connection with our recent synthesis of discoder-
molide.10
The conversion of the (M)-allenylstannane 28 to epoxy
alcohol 33 was effected as reported for the enantiomeric
series.10 Addition of EtMgBr-CuI to this epoxide afforded
diol 34 as the sole product. Selective tosylation led to the
monotosylate 35. Protection of the secondary alcohol of
35 with TBSOTf proceeded slowly and afforded the silyl
ether 36 in <50% yield. The formation of polar byprod-
ucts suggested that the sensitive PMP acetal grouping
was being cleaved by the 2,6-lutidinium triflate produced
in the silylation reaction. Silylation with Et3SiOTf pro-
ceeded more rapidly, affording the silyl ether 37 in 90%
yield.
Hydrogenolysis of the tosylate function of 37 was
effected with LiBEt3H. Selective cleavage of the anis-
ylidene acetal 38 with DIBAl-H yielded the primary
alcohol 39 which was converted to aldehyde 40 by
treatment with the Dess-Martin periodinane reagent.14
Wittig condensation of aldehyde 40 with the phosphor-
ylidene propionate reagent yielded the (E)-adduct 41, an
analogue of the TBS counterpart 44 previously reported
by Kobayashi and co-workers.2 For comparison purposes,
the silyl ether was cleaved with Bu4NF and the alcohol
42 was silylated with TBSOTf. Cleavage of the PMB
ether 43 with DDQ afforded hydroxy ester 44. Compari-
(9) Cf. Lipschutz, B. Synthetic Procedures Involving Organocopper
Reagents. In Organometallics in Synthesis; Schlosser, M., Ed.; J ohn
Wiley and Sons: Chichester, 1994; p 283.
(10) Marshall, J . A.; Lu, Z.-H.; J ohns, B. A. J . Org. Chem. 1998, 63,
817. Marshall, J . A.; J ohns, B. A. J . Org. Chem. 1998, 63, 7885.
(11) The program Macromodel V4.5 was employed for these calcula-
tions. Global minimum multiple conformer searching was achieved
with the Monte Carlo subroutine in BATCHMIN through multiple step
interations (typically 1000) until the minimum energy conformer was
found multiple times. For
a description of the program, see: (a)
Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput.
Chem. 1990, 11, 440. (b) Chang, G.; Guida, W. C.; Still, W. C. J . Am.
Chem. Soc. 1989, 111, 4379.
(12) For the use of vinyl cuprates in the opening of methyl-
substituted cis-epoxides, see: Lipshutz, B. H.; Barton, J . C. J . Org.
Chem. 1988, 53, 4495.
(13) For additional evidence on this point, see: Marshall, J . A.;
Trometer, J . D.; Cleary, D. G. Tetrahedron 1989, 45, 391.
(14) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.

Synthesis of Callystatin A
J . Org. Chem., Vol. 64, No. 12, 1999 4479
Sch em e 3
oil, bp 119-122 °C at 0.05 mmHg: 1H NMR (CDCl3, 300 MHz)
δ 4.60 (m, 1 H), 2.14-2.00 (m, 2 H), 1.60 (d, J ) 6.9 Hz, 3 H),
1.54-1.44 (m, 6 H), 1.35-1.25 (m, 6 H), 1.02 (t, J ) 7.3 Hz, 3
H), 0.94-0.86 (m, 15 H).
1
son of the H NMR spectrum of this material with that
of an authentic sample confirmed their identity.
The present findings provide a route to the all-syn-
stereopentad 39. The unreactivity of the cis-epoxides 13
and 14 toward various cuprate reagents is unexpected.
The successful opening of the cis-epoxy alcohol 24 with
cuprate reagents suggests that a neighboring hydroxyl
function may be required to activate the cuprate or the
epoxide. If so, this effect will have a bearing on future
synthetic applications of this methodology.
(4S,5R,6R)-7-(ter t-Bu tyldim eth ylsilyloxy)-4,6-dim eth yl-
5-h yd r oxy-2-h ep tyn yl P iva la te (29). To a solution of 8.0 g
(17.5 mmol) of allenylstannane 2810 and 4.60 g (22.75 mmol)
of aldehyde 85 in 50 mL of CH2Cl2 was added 5.40 mL (43.75
mmol) of BF3‚OEt2 at -78 °C. The mixture was stirred at -78
°C for 6 h, quenched with saturated NaHCO3, and stirred for
30 min. The aqueous layer was extracted with ether, and the
combined organic extracts were dried over Na2SO4. The
solution was filtered and concentrated under reduced pressure.
The residue was purified by column chromatography on silica
gel (elution with 10% EtOAc in hexanes) to give 4.58 g (71%)
of pivalate 29 as a clear oil: [R]D ) -0.3 (c 3.67, CHCl3); IR
Exp er im en ta l Section
(M)-4-(Tr ibu tylsta n n yl)-2,3-h exa d ien e (7). To a solution
of 5.18 g (52.73 mmol) of alcohol 5 in 200 mL of CH2Cl2 were
added 18.4 mL (131.8 mmol) of Et3N and 8.15 mL (105.5 mmol)
of CH3SO2Cl at -78 °C. The solution solidified after 5 min of
stirring. The solid was warmed enough to free the stir bar,
and the suspension was cooled back to -78 °C. After stirring
for 1 h, the reaction was quenched with 50 mL of saturated
NaHCO3. The layers were separated, and the aqueous layer
was extracted with ether. The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to afford crude mesylate 6 as a clear oil.
Mesylate 6 was used without further purification.
To a solution of 14.78 mL (105.5 mmol) of i-Pr2ΝΗ in 130
mL of THF was added 42.18 mL (105.46 mmol) of n-BuLi (2.5
M in hexanes) at 0 °C. The solution was stirred at 0 °C for 15
min, and 28.36 mL (105.5 mmol) of n-Bu3SnH was added
dropwise. After 30 min, the solution was cooled to -78 °C and
21.68 g (105.5 mmol) of CuBr‚SMe2 was added. The solution
was stirred for an additional 30 min followed by the addition
of 9.28 g (52.73 mmol) of mesylate 6 in 20 mL of THF. The
solution was stirred for 10 min and quenched with 1.5 L of
9:1 NH4Cl:NH4OH. The resultant mixture was stirred for 2
h, and the layers were separated. The aqueous layer was
extracted with ether, and the combined organic extracts were
washed with brine. The solution was dried over Na2SO4 and
concentrated under reduced pressure. The residue was distilled
to afford 12.5 g (65%) of allenylstannane 7 as a faint yellow
(neat) 3500, 2957, 2930, 2240, 1738 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 4.63 (d, J ) 2.1 Hz, 2 H), 3.87 (dd, J ) 9.9, 3.0
Hz, 1 H), 3.73-3.67 (m, 2 H), 3.51 (d, J ) 1.8 Hz, 1 H), 2.4 (m,
1 H), 2.1 (m, 1 H), 1.27 (d, J ) 6.9 Hz, 3 H), 1.21 (s, 9 H), 0.99
(d, J ) 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.078 (s, 6 H); 13C NMR
(CDCl3, 75 MHz) δ 177.7, 88.6, 78.3, 77.2, 76.2, 69.4, 52.6, 38.7,
36.3, 30.4, 27.0, 25.8, 18.1, 17.5, 9.4, -5.63, -5.7. Anal. Calcd
for C20H38O4Si: C, 64.82; H, 10.34. Found: C, 64.75; H, 10.39.
syn ,syn -p-An isylid en e Aceta l 30. To a solution of 3.0 g
(8.1 mmol) of pivalate 29 in 30 mL of THF was added 10.5
mL (10.5 mmol) of TBAF (1.0 M in THF) dropwise at 0 °C.
The solution was warmed to room temperature and stirred for
1 h. The mixture was poured into brine, extracted with ether,
and dried over Na2SO4. After filtration and concentration
under reduced pressure, the crude diol 30 was dissolved in 50
mL of benzene and 1.90 mL (12.15 mmol) of p-anisaldehyde
dimethyl acetal was added followed by addition of a catalytic
amount of dl-camphorsulfonic acid (ca. 15 mg). The solution
was refluxed with azeotropic removal of methanol for 12 h.
The solution was cooled to rt, and 2 mL of Et3N was added
followed by removal of solvent under reduced pressure. The
residue was purified by column chromatography on silica gel
(elution with 30% EtOAc in hexanes containing 1% Et3N) to
afford 3.00 g (95%) of acetal 31 as a colorless oil: [R]D ) -2.51
(c 1.04, CHCl3); IR (neat) 2972, 2934, 2220 cm-1 1H NMR
;

4480 J . Org. Chem., Vol. 64, No. 12, 1999
Marshall and Fitzgerald
(CDCl3, 300 MHz) δ 7.40 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 8.7
Hz, 2 H), 5.43 (s, 1 H), 4.65 (d, J ) 2.1 Hz, 2 H), 4.06-4.04
(m, 2 H), 3.80 (s, 3 H), 3.67 (dd, J ) 9.9, 2.1 Hz, 1 H), 2.63 (m,
1 H), 1.96 (m, 1 H), 1.27 (d, J ) 6.6 Hz, 3 H), 1.22 (s, 9 H),
1.19 (d, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 177.7,
159.9, 131.2, 127.2, 113.6, 101.5, 86.8, 82.6, 76.37, 73.8, 55.3,
52.5, 38.7, 30.5, 28.8, 27.0, 17.5, 11.1. Anal. Calcd for
300 MHz) δ 7.8 (d, J ) 8.1 Hz, 2 H), 7.42 (d, J ) 8.7 Hz, 2 H),
7.36 (d, J ) 7.8 Hz, 2 H), 6.88 (d, J ) 8.7 Hz, 2 H), 5.47 (s, 1
H), 4.44 (dd, J ) 9.9, 3.3 Hz, 1 H), 4.13-3.98 (m, 3 H), 3.86
(dd, J ) 9.6, 2.1 Hz, 1 H), 3.79 (s, 3 H), 3.61 (m, 1 H), 2.45 (s,
3 H), 2.08 (d, J ) 6.6 Hz, 1 H), 1.86 (m, 1 H), 1.60-1.75 (m, 2
H), 1.43-1.24 (m, 2 H), 1.15 (d, J ) 6.9 Hz, 3 H), 0.95 (d, J )
6.9 Hz, 3 H), 0.83 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 75
MHz) δ 159.7, 144.9, 132.7, 131.5, 129.9, 127.8, 127.2, 113.5,
101.8, 82.1, 77.4, 77.2, 73.8, 68.8, 55.2, 43.1, 35.6, 29.6, 21.6,
19.1, 11.5, 10.9, 8.1. Anal. Calcd for C26H36O7S: C, 63.39; H,
7.37. Found: C, 63.35; H, 7.46.
syn ,syn ,syn -TES Eth er 37. To a solution of 323 mg (0.66
mmol) of tosylate 35 in 5 mL of CH2Cl2 were added 0.3 mL
(2.6 mmol) of 2,6-lutidine and 0.3 mL (1.3 mmol) of TESOTf
at 0 °C. The mixture was stirred at 0 °C for 0.5 h and quenched
with 2 mL of saturated NaHCO3. The layers were separated,
and the aqueous layer was extracted with ether. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (elution with 30%
EtOAc in hexanes containing 1% Et3N) to afford 357 mg (90%)
of TES-protected tosylate 37 as a clear oil: [R]D ) +21.56 (c
1.09, CHCl3); IR (neat) 2960, 2872, 1361 cm-1; 1H NMR (CDCl3,
300 MHz) δ 7.79 (d, J ) 8.4 Hz, 2 H), 7.41 (d, J ) 8.4 Hz, 2
H,), 7.34 (d, J ) 8.1 Hz, 2 H), 6.88 (d, J ) 9.0 Hz, 2 H), 5.41
(s, 1 H), 4.15 (dd, J ) 9.9, 3.9 Hz, 1 H), 4.05 (dd, J ) 9.6, 5.1
Hz, 1 H), 4.03 (d, J ) 1.8 Hz, 2 H), 3.79 (s, 3 H), 3.73-3.67
(m, 2 H), 2.44 (s, 3 H), 1.82 (m, 1 H), 1.73-1.65 (m, 2 H), 1.47-
1.21 (m, 2 H), 1.14 (d, J ) 3.9 Hz, 3 H), 0.93 (t, J ) 8.1 Hz, 9
H), 0.92 (d, J ) 7.8 Hz, 3 H), 0.77 (t, J ) 7.2 Hz, 3 H), 0.54 (q,
J ) 8.4 Hz, 6 H); 13C NMR (CDCl3, 75 MHz) δ 159.7, 144.7,
132.9, 131.4, 129.7, 127.9, 127.1, 133.4, 101.8, 80.9, 73.7, 70.6,
69.5, 55.2, 43.8, 37.7, 30.3, 21.5, 20.1, 11.5, 11.1, 9.1, 7.0, 6.5,
5.7, 5.5.
C
22H30O5: C, 70.56; H, 8.07. Found: C, 70.6; H, 8.23.
syn ,syn -Allylic Alcoh ol 32. To a solution of 2.01 g (5.37
mmol) of propargylic pivalate 31 in 50 mL of THF was added
7.9 mL (40.3 mmol) of Red-Al (65 wt % in toluene) dropwise
at 0 °C. The mixture was stirred at 0 °C for 14 h and quenched
with 50 mL of saturated potassium sodium tartrate. After the
mixture was stirred for 1 h, the layers were separated, and
the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine and dried over Na2-
SO4. After filtration and removal of solvent under reduced
pressure, the residue was purified by column chromatography
on silica gel (elution with 30% EtOAc in hexanes containing
1% Et3N) to produce allylic alcohol 32 (1.30 g, 85%) as a white
solid: mp 77-78 °C; [R]D ) -8.8 (c 1.00, CHCl3); IR (neat)
3432, 2960, 2916, 2837 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.42 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 9.0 Hz, 2 H), 5.75 (dt, J
) 15.3, 5.4 Hz, 1 H), 5.51 (dd, J ) 15.6, 8.7 Hz, 1 H), 5.44 (s,
1 H), 4.15-4.11 (m, 2 H), 4.0 (m, 2 H), 3.80 (s, 3 H), 3.52 (dd,
J ) 10.2, 2.4 Hz, 1 H), 2.43 (m, 1 H), 1.62 (m, 1 H), 1.49 (s
broad, 1 H), 1.16 (d, J ) 6.9 Hz, 3 H), 1.11 (d, J ) 6.6 Hz, 3
H); 13C NMR (CDCl3, 75 MHz) δ 159.7, 132.7, 131.48, 130.0,
127.2, 113.5, 101.7, 83.4, 73.9, 63.4, 55.2, 38.6, 30.4, 17.4, 11.1.
Anal. Calcd for C17H24O4: C, 69.84; H, 8.27. Found: C, 69.75;
H, 8.24.
syn ,syn -Ep oxy Alcoh ol 33. To a suspension of 4 Å MS (500
mg) in 50 mL of CH2Cl2 was added 1.25 mL (5.9 mmol) of L-(+)-
diisopropyltartrate followed by addition of 1.44 mL (4.84 mmol)
of Ti(i-PrO)4 at -20 °C. The suspension was stirred at -20 °C
for 10 min, and 1.7 mL (ca. 8.42 mmol) of tert-butyl hydrop-
eroxide (TBHP) (∼5 M in decane) was added dropwise. The
mixture was stirred at -20 °C for 16 h, quenched with 2 mL
of H2O, and filtered through a short pad of Celite. The solution
was concentrated under reduced pressure and purified by
column chromatography on silica gel (elution with 50% EtOAc
in hexanes containing 1% Et3N) to afford 1.03 g (79%) of epoxy
alcohol 33 as a white solid: mp 61-63 °C; [R]D ) -9.5 (c 0.96,
CHCl3); IR (neat) 3449, 2968, 2846, 1614, 1247 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.42 (d, J ) 8.7 Hz, 2 H), 6.89 (d, J ) 9.0
Hz, 2 H), 5.48 (s, 1 H), 4.08 (dd, J ) 11.1, 2.1 Hz, 1 H), 4.01
(dd, J ) 11.1, 1.5 Hz, 1 H), 3.9 (m, 1 H), 3.80 (s, 3 H), 3.71 (dd,
J ) 9.6, 1.8 Hz, 1 H), 3.65 (m, 1 H), 3.11 (m, 1 H), 2.84 (dd, J
) 6.6, 2.4 Hz, 1 H), 1.88-1.73 (m, 3 H), 1.22 (d, J ) 8.1 Hz, 3
H), 1.07 (d, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ
159.9, 131.3, 127.2, 113.6, 102.0, 81.7, 73.7, 61.4, 57.6, 56.4,
55.3, 36.2, 30.7, 12.8, 11.8. Anal. Calcd for C17H24O5: C, 66.21;
H, 7.84. Found: C, 66.17; H, 7.78.
syn ,syn ,syn -Tosyla te 35. To a suspension of 10 mg (0.03
mmol) of CuI in 5 mL of THF was added 0.4 mL (1.2 mmol) of
EtMgBr (3 M in ether) at -78 °C. After the solution was stirred
for 30 min at -78 °C, 100 mg (0.32 mmol) of epoxy alcohol 33
was added. The solution was warmed to -30 °C and stirred
for 16 h. The reaction was quenched with 9:1 NH4Cl:NH4OH
and stirred for 1.5 h. The clear layers were separated, and the
aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue, diol
34, was dissolved in 2 mL of CH2Cl2, and 0.2 mL of pyridine
was added followed by the addition of 68 mg (0.32 mmol) of
TsCl. The mixture was stirred for 18 h at room temperature
and quenched with 2 mL of saturated NaHCO3. The layers
were separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
on silica gel (elution with 40% EtOAc in hexanes containing
1% Et3N) to produce 125 mg (78%, two steps) of syn,syn,syn-
tosylate 35 as a thick amber oil: [R]D ) -3.03 (c 1.09, CHCl3);
IR (neat) 3541, 2966, 2936, 1613, 1509 cm-1; 1H NMR (CDCl3,
syn ,syn ,syn ,syn -TES Eth er 38. To a solution of 224 mg
(0.369 mmol) of tosylate 37 in 15 mL of benzene was added
1.85 mL (1.85 mmol) of LiBHEt3 (1.0 M in hexanes). The
mixture was heated to reflux and stirred for 18 h. The reaction
was quenched at 0 °C with saturated potassium sodium
tartrate and stirred for 1.5 h. The layers were separated, and
the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (elution with
20% EtOAc in hexanes containing 1% Et3N) to afford 148 mg
(92%) of TES ether 38 as a colorless oil: [R]D ) +24.07 (c 1.06,
CHCl3); IR (neat) 2958, 2873, 1613, 1517 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.45 (d, J ) 8.7 Hz, 2 H), 6.90 (d, J ) 8.7
Hz, 2 H), 5.46 (s, 1 H), 4.06 (d, J ) 1.8 Hz, 2 H), 3.8 (s, 3 H),
3.74 (dd, J ) 9.9, 2.1 Hz, 1 H), 3.51 (dd, J ) 6.6, 0.9 Hz, 1 H),
1.90 (m, 1 H), 1.75 (m, 1 H), 1.62-1.51 (m, 2 H), 1.18 (d, J )
6.9 Hz, 3 H), 1.04 (m, 1 H), 1.02 (t, J ) 7.8 Hz, 9 H), 1.0 (d, J
) 5.7 Hz, 3 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.90 (t, J ) 7.5 Hz,
3 H), 0.64 (q, J ) 8.1 Hz, 6 H); 13C NMR (CDCl3, 75 MHz) δ
159.7, 131.7, 127.2, 113.5, 101.9, 81.9, 74.9, 73.8, 55.2, 36.7,
37.2, 30.2, 25.6, 16.0, 11.9, 11.4, 9.6, 7.2, 5.8. Anal. Calcd for
C
25H44O4Si: C, 68.76; H, 10.16. Found: C, 68.93; H, 10.03.
syn ,syn ,syn ,syn -Alcoh ol 39. To a solution of 140 mg (0.320
mmol) of TES ether 38 in 6 mL of CH2Cl2 was added 3.2 mL
(3.2 mmol) of DIBAl-H (1.0 M in hexanes) at -78 °C. The
solution was warmed to -30 °C and stirred for 20 h. The
reaction was quenched with saturated potassium sodium
tartrate and stirred for 1.5 h. The layers were separated, and
the aqueous layer was extracted with ether. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (elution with
20% EtOAc in hexanes containing 1% Et3N) to produce 125
mg (89%) of alcohol 39 as a colorless oil: [R]D -0.80 (c 1.01,
CHCl3); IR (neat) 3458, 2960, 2872 cm-1; 1H NMR (CDCl3, 300
MHz) δ 7.26 (d, J ) 7.5 Hz, 2 H), 6.87 (d, J ) 9.0 Hz, 2 H),
4.49 (s, 2 H), 3.80 (s, 3 H), 3.70-3.56 (m, 2 H), 3.49-3.44 (m,
2 H), 2.02 (m, 1 H), 1.92-1.86 (m, 2 H), 1.53-1.34 (m, 2 H),
1.13 (m, 1 H), 1.02 (d, J ) 6.9 Hz, 3 H), 0.98 (t, J ) 8.1 Hz, 9
H), 0.93 (d, J ) 6.9 Hz, 3 H), 0.87 (t, J ) 7.5 Hz, 3 H), 0.84 (d,

Synthesis of Callystatin A
J . Org. Chem., Vol. 64, No. 12, 1999 4481
J ) 6.6 Hz, 3 H), 0.63 (q, J ) 8.1 Hz, 6 H); 13C NMR (CDCl3,
75 MHz) δ 159.1, 130.8, 129.2, 113.7, 81.5, 77.3, 73.8, 66.4,
51.2, 39.9, 38.7, 38.0, 26.7, 14.2, 12.2, 11.5, 11.2, 7.2, 5.6. Anal.
Calcd for C25H46O4Si: C, 68.44; H, 10.57. Found: C, 68.15; H,
10.33.
(CDCl3, 75 MHz) δ 168.1, 159.2, 144.2, 130.2, 129.4, 127.2,
113.8, 86.5, 77.9, 77.2, 74.7, 60.5, 55.2, 37.9, 37.3, 37.1, 25.9,
16.3, 14.2, 12.5, 11.2, 8.0. Anal. Calcd for C24H38O5: C, 70.90;
H, 9.42. Found: C, 70.98; H, 9.43.
syn ,syn ,syn ,syn -TBS Eth er 43. To a solution of 51 mg
(0.125 mmol) of alcohol 42 in 3 mL of CH2Cl2 were added 0.06
mL (0.5 mmol) of 2,6-lutidine and 0.06 mL (0.25 mmol) of
TBSOTf at 0 °C. The mixture was stirred at 0 °C for 2 h and
quenched with saturated NaHCO3. The layers were separated,
and the aqueous layer was extracted with ether. The organic
extracts were washed with brine and dried over Na2SO4. The
solution was filtered, and solvent was removed under reduced
pressure. The crude material was purified by column chroma-
tography on silica gel (elution with 5% EtOAc in hexanes) to
afford 62 mg (95%) of ester 43 as a colorless oil: [R]D ) +5.16
syn ,syn ,syn ,syn -Ald eh yd e 40. To a solution of 107 mg (0.24
mmol) of alcohol 38 in 5 mL of CH2Cl2 was added 155 mg (0.37
mmol) of periodinane reagent.14 The solution was stirred for
1 h at rt and quenched by the simultaneous addition of 2 mL
of saturated NaHCO3 and 2 mL of saturated Na2S2O3. The
mixture was stirred for 40 min or until the layers were clear.
The layers were separated, and the aqueous layer was
extracted with ether. The combined organic extracts were
washed with brine and dried over Na2SO4. After filtration and
removal of solvent under reduced pressure, 107 mg (99%) of
aldehyde 40 was obtained as a clear oil. This material was
used without further purification: [R]D ) +27.16 (c 0.81,
(c 0.6, CHCl3); IR (neat) 2960, 2933, 1710 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.28 (d, J ) 10.2 Hz, 2 H), 6.89 (d, J )
9.0 Hz, 2 H), 6.63 (d, J ) 10.5 Hz, 1 H) 4.53, (d, J ) 10.5 Hz,
1 H), 4.47 (d, J ) 10.5 Hz, 1 H), 4.48-4.11 (m, 2 H), 3.81 (s,
3 H), 3.50 (dd, J ) 7.5, 2.4 Hz, 1 H), 3.26 (dd, J ) 7.5, 3.3 Hz,
1 H), 2.82 (m, 1 H), 1.86 (s, 3 H), 1.73 (m, 1 H), 1.53 (m, 1 H),
1.37-1.13 (m, 2 H), 1.29 (t, J ) 6.9 Hz, 3 H), 1.09 (d, J ) 6.9
Hz, 3 H), 0.94 (d, J ) 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.88 (t, J )
7.2 Hz, 3 H), 0.80 (d, J ) 6.9 Hz, 3 H), 0.03 (d, J ) 5.4 Hz, 6
H); 13C NMR (CDCl3, 75 MHz) δ 168.15, 159.14, 144.53, 130.83,
129.23, 126.82, 113.75, 83.77, 76.52, 74.86, 60.44, 55.23, 40.14,
39.89, 37.46, 27.39, 26.26, 18.54, 16.16, 14.24, 12.97, 12.56,
11.39, -3.38, -3.60. Anal. Calcd for C30H52O5Si: C, 69.18; H,
10.06. Found: C, 69.37; H, 10.09.
CHCl3); IR (neat) 2960, 2872, 1720, cm-1 1H NMR (CDCl3,
;
300 MHz) δ 9.83 (d, J ) 0.9 Hz, 1 H), 7.21 (d, J ) 8.7 Hz, 2
H), 6.86 (d, J ) 8.7 Hz, 2 H), 4.43 (d, J ) 10.8 Hz, 1 H), 4.37
(d, J ) 10.8 Hz, 1 H), 3.84 (dd, J ) 6.6, 3.9 Hz, 1 H), 3.79 (s,
3 H), 3.50 (t, J ) 4.5 Hz, 1 H), 2.70 (m, 1 H), 1.86 (m, 1 H),
1.55-1.34 (m, 2 H), 1.15 (d, J ) 6.9 Hz, 3 H), 1.12 (m, 1 H),
0.99 (d, J ) 6.9 Hz, 3 H), 0.97 (t, J ) 7.8 Hz, 9 H), 0.87 (t, J
) 7.5 Hz, 3 H), 0.84 (d, J ) 6.6 Hz, 3 H), 0.62 (q, J ) 7.2 Hz,
6 H).
syn ,syn ,syn ,syn -Un sa tu r a ted Ester 41. To a solution of
184 mg (0.42) mmol of aldehyde 40 in 20 mL of CH2Cl2 was
added 380 mg (1.05 mmol) of Ph3PC(Me)CO2Et. The solution
was heated to reflux and stirred for 12 h. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography on silica gel (elution with 10%
EtOAc in hexanes) to afford 202 mg (93%) of ester 41 as a
thick oil: [R]D ) +14.3 (c 0.86, CHCl3); IR (neat) 2957, 2874,
Ester 44. To a solution of 55 mg (0.11 mmol) of ester 43 in
1 mL of CH2Cl2/H2O (18:1) were added 48 mg (0.21 mmol) of
DDQ and 17 mg (0.21 mmol) of NaHCO3 at rt. After the
solution was stirred for 2.5 h, the solvent was removed under
reduced pressure and the residue was purified by column
chromatography on silica gel (elution with 10% EtOAc in
hexanes) to afford 30 mg (71%) of ester 44 as a clear oil: [R]D
) +22.17 (c 1.15, CHCl3), lit. +20.1 (c 1.13 CHCl3);15 IR (neat)
1
1710, 1613 cm-1; H NMR (CDCl3, 300 MHz) δ 7.27 (d, J )
8.7 Hz, 2 H), 6.88 (d, J ) 8.1 Hz, 2 H), 6.60 (d, J ) 10.8 Hz, 1
H), 4.52 (d, J ) 10.5 Hz, 1 H), 4.45 (d, J ) 14.4 Hz, 1 H), 4.26-
4.12, (m, 2 H), 3.90 (s, 3 H), 3.57 (dd, J ) 8.4, 1.8 Hz, 1 H),
3.27 (dd, J ) 8.1, 2.7 Hz, 1 H), 2.82 (m, 1 H), 1.85 (s, 3 H),
1.70 (m, 1 H), 1.57 (m, 1 H), 1.36-1.13 (m, 2 H), 1.29 (t, J )
7.2 Hz, 3 H), 1.1 (d, J ) 6.6 Hz, 3 H), 0.96 (t, J ) 8.4 Hz, 3 H),
0.95 (d, J ) 7.8 Hz, 3 H), 0.90 (t, J ) 7.2 Hz, 9 H), 0.79 (d, J
) 6.6 Hz, 3 H), 0.61 (q, J ) 8.1 Hz, 6 H); 13C NMR (CDCl3, 75
MHz) δ 168.1, 159.2, 144.3, 130.8, 129.2, 127.0, 113.7, 83.6,
77.5, 77.3, 74.8, 60.4, 55.2, 40.2, 38.0, 37.7, 27.6, 16.5, 14.2,
12.5, 12.4, 11.1, 7.2, 5.6. Anal. Calcd for C30H52O5Si: C, 69.18;
H, 10.06. Found: C, 68.95; H, 10.04.
3519, 2959, 2854, 1710 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
6.50 (dd, J ) 10.5, 1.2 Hz, 1 H), 4.24-4.13 (m, 2 H), 3.66 (t, J
) 3.6 Hz, 1 H), 3.48 (d, J ) 7.2 Hz, 1 H), 2.62 (m, 1 H), 2.10
(d, J ) 4.2 Hz, 1 H), 1.86 (d, J ) 1.8 Hz, 3 H), 1.68-1.52 (m,
4 H), 1.29 (t, J ) 6.9 Hz, 3 H), 1.08 (d, J ) 6.6 Hz, 3 H), 0.91
(s, 9 H), 0.87 (t, J ) 7.2 Hz, 3 H), 0.84 (d, J ) 7.2 Hz, 3 H),
0.82 (d, J ) 6.6 Hz, 3 H), 0.08 (d, J ) 4.8 Hz, 6H); 13C NMR
(CDCl3, 75 MHz) δ 168.1, 143.7, 127.3, 79.9, 78.7, 60.5, 40.0,
38.0, 37.6, 26.1, 25.7, 18.3, 16.6, 14.7, 14.2, 12.5, 8.2, -3.4,
-4.3. Anal. Calcd for C22H44O4Si: C, 65.95; H, 11.07. Found:
C, 65.81; H, 11.04.
syn ,syn ,syn ,syn -Alcoh ol 42. To a solution of 45 mg (0.086
mmol) of TES ether 41 in 2 mL of THF was added 0.11 mL
(0.11 mmol) of TBAF (1.0 M in THF) dropwise. The solution
was stirred at rt for 1 h and quenched with saturated NH4Cl.
The layers were separated, and the aqueous layer was
extracted with ether. The combined organic layers were
washed with brine and dried over Na2SO4. After filtration and
removal of solvent under reduced pressure, the filtrate was
purified by column chromatography on silica gel (elution with
20% EtOAc in hexanes) to afford 27 mg (77%) of alcohol 42 as
a clear oil: [R]D ) +19.66 (c 0.89, CHCl3); IR (neat) 3519, 2960,
Ack n ow led gm en t. This research was supported by
Grant R01 AI31422 from the National Institutes of
Allergy and Infectious Diseases. We thank Dr. Brian
J ohns for his interest and helpful suggestions through-
out the course of these investigations.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 3-5, 9-11, and 18-27 and 1H NMR spectra for
key intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
1710 cm-1; H NMR (CDCl3, 300 MHz) δ 7.28 (d, J ) 8.4 Hz,
2 H), 6.87 (d, J ) 8.7 Hz, 2 H), 6.64 (dd, J ) 10.5, 1.5 Hz, 1
H), 4.58 (d, J ) 10.5 Hz, 1 H), 4.52 (d, J ) 10.5 Hz, 1 H), 4.25-
4.13 (m, 2 H), 3.79 (s, 3 H), 3.46-3.39 (m, 2 H), 2.88 (m, 1 H),
2.15 (d, J ) 3.6 Hz, 1 H), 1.87 (d, J ) 1.2 Hz, 3 H), 1.79 (m, 1
H), 1.55 (m, 1 H), 1.32 (m, 1 H), 1.29 (t, J ) 6.9 Hz, 3 H), 1.13
(d, J ) 6.9 Hz, 3 H), 1.11 (m, 1 H), 0.94 (d, J ) 6.9 Hz, 3 H),
0.92 (d, J ) 6.6 Hz, 3 H), 0.87 (t, J ) 7.5 Hz, 3 H); 13C NMR
J O9902143
(15) We thank Prof. Kobayashi for disclosing his rotation data for
ester 44. He informed us that the sample used for this determination
contained a small amount of a stereoisomer according to 1H NMR
analysis. By this criterion, our sample was stereochemically homoge-
neous.