Stereoselective total synthesis of the pseudopterolide kallolide A

Article abstract of DOI:10.1021/jo980603h

A total synthesis of the pseudopterolides, kallolide A (36) and kallolide A acetate (35), has been achieved. The racemic forms were prepared from the syn adduct 20 of furan 13 and stannane 17 (BF₃·OEt₂-promoted addition) via the 15-membered propargylic allylic ether 25. [2,3]Wittig ring contraction led to the cis, anti, cis product 26. Alcohol 26 was transformed to butenolide 34 with net retention of configuration by Pd(PPh₃)₄- catalyzed carbonylation of the mesylate 27 and ensuing AgNO₃-catalyzed cyclization of the derived allenic acid 29. Solvolysis of the SEM ether (at C2) 34 in acetic acid or aqueous t-BuOH afforded racemic kallolide A acetate (35) and kallolide A (36), respectively, with inversion of stereochemistry by an S(N)1 process. Key elements of stereocontrol, including the steric outcome of the [2,3]Wittig ring contraction, the allenic ester isomerization, and the solvolysis reactions, were predicted from molecular mechanics calculations. The C8 and C2 epimers 45 and 46 of the cis, anti, cis kallolide A SEM ether precursor 34 were also prepared. The synthetic route originated from the anti adduct 19 of aldehyde 13 and the allylic chloride 16 and CuCl (cat), HSiCl₃, and i-Pr₂NEt. Adduct 19 was subjected to the same sequence as the syn counterpart 20 to produce the trans, anti, cis[2,3]Wittig ring contraction product 42. The derived alleonate 44 afforded a 1:1 mixture of butenolides 45 and 46 upon sequential treatment with TBAF and AgNO₃. Finally, the natural enantiomer (+)-36 of kallolide A was synthesized from the enantioenriched syn adduct (+)-20, prepared by addition of allylic stannane 17 to aldehyde 13 promoted by a modified chiral acyloxyborane Lewis acid.

Full text of DOI:10.1021/jo980603h

5962
J . Org. Chem. 1998, 63, 5962-5970
Ster eoselective Tota l Syn th esis of th e P seu d op ter olid e Ka llolid e A
J ames A. Marshall* and J unkai Liao
Department of Chemistry University of Virginia, Charlottesville, Virginia 22901
Received April 2, 1998
A total synthesis of the pseudopterolides, kallolide A (36) and kallolide A acetate (35), has been
achieved. The racemic forms were prepared from the syn adduct 20 of furan 13 and stannane 17
(BF3‚OEt2-promoted addition) via the 15-membered propargylic allylic ether 25. [2,3]Wittig ring
contraction led to the cis, anti, cis product 26. Alcohol 26 was transformed to butenolide 34 with
net retention of configuration by Pd(PPh3)4-catalyzed carbonylation of the mesylate 27 and ensuing
AgNO3-catalyzed cyclization of the derived allenic acid 29. Solvolysis of the SEM ether (at C2) 34
in acetic acid or aqueous t-BuOH afforded racemic kallolide A acetate (35) and kallolide A (36),
respectively, with inversion of stereochemistry by an SN1 process. Key elements of stereocontrol,
including the steric outcome of the [2,3]Wittig ring contraction, the allenic ester isomerization,
and the solvolysis reactions, were predicted from molecular mechanics calculations. The C8 and
C2 epimers 45 and 46 of the cis, anti, cis kallolide A SEM ether precursor 34 were also prepared.
The synthetic route originated from the anti adduct 19 of aldehyde 13 and the allylic chloride 16
and CuCl (cat), HSiCl3, and i-Pr2NEt. Adduct 19 was subjected to the same sequence as the syn
counterpart 20 to produce the trans, anti, cis [2,3]Wittig ring contraction product 42. The derived
allenoate 44 afforded a 1:1 mixture of butenolides 45 and 46 upon sequential treatment with TBAF
and AgNO3. Finally, the natural enantiomer (+)-36 of kallolide A was synthesized from the
enantioenriched syn adduct (+)-20, prepared by addition of allylic stannane 17 to aldehyde 13
promoted by a modified chiral acyloxyborane Lewis acid.
Sch em e 1. Syn th etic Rou te to en t-Ka llolid e Ba
Octocorals of the genus Pseudopterogorgia produce,
among other metabolites, diterpenoids of the rare pseu-
dopterane family. Several of these possess significant
biological activity. Thus pseudopterolide, the first mem-
ber of the family to be structurally elucidated, exhibits
potent cytotoxicity,1 and kallolide A, the subject of this
report, is an antiinflammatory agent with activity com-
parable to that of indomethacin.2
We recently described a synthesis of (-)-kallolide B, a
close relative of kallolide A, starting from the terpene
(-)-perillyl alcohol (Scheme 1).3,4 That synthesis featured
a remarkably diastereoselective [2,3] Wittig ring contrac-
tion (V f VI) in which the absolute stereochemistry of
the created C7/C8 stereocenters was directed by the
remote C1 isopropenyl center. Also notable was the
highly diastereoselective hydrocarbonylation (VI f VII)
and subsequent allenic ester isomerization leading to the
bridged butenolide moiety (VII f VIII) with the correct
relative configuration.
a
(a) Furan homologation; (b) side-chain extension; (c) furan
formylation-chain extension; (d) macrocyclization; (e) [2,3]Wittig
ring contraction; (f) hydrocarbonylation; (g) equilibration, then
Ag+-catalyzed allenoic acid cyclization.
(1) Bandurraga, M. M.; Fenical, W.; Donovan, S. F.; Clardy, J . J .
Am. Chem. Soc. 1982, 104, 6463.
(2) Look, S. A.; Burch, M. T.; Fenical, W.; Zhen, Q.-t.; Clardy, J . J .
Org. Chem. 1985, 50, 5741.
(3) Marshall, J . A.; Bartley, G. S.; Wallace, E. M. J . Org. Chem. 1996,
61, 5729.
(4) For a review of synthetic efforts in this area see Marshall, J . A.
Recent Res. Devel. Org. Chem. 1997, 1, 1.
The successful outcome of the foregoing total synthesis
prompted our investigation of a parallel route to kallolide
A (Scheme 2). Accordingly, construction of the macro-
cyclic ether XII, followed by [2,3]Wittig rearrangement,
would presumably lead to the trans, anti, cis carbocycle
XIII. Ensuing hydrocarbonylation and allenic ester
S0022-3263(98)00603-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

Total Synthesis of the Pseudopterolide Kallolide A
J . Org. Chem., Vol. 63, No. 17, 1998 5963
Sch em e 2. P r op osed Rou te to Ka llolid e Aa
Sch em e 3a
a
(a) Dess-Martin periodinane reagent; (b) Still-Horner-
Emmons reagent; (CF3CH2O)2POCH(Me)CO2Et, KHMDS, THF,
18-crown-6.
Horner-Emmons homologation.8 The resulting (Z)-un-
saturated ester benzoate 11 was selectively saponified
with ethanolic K2CO3. Oxidation of alcohol 12 was best
achieved with MnO2. Alternative methods (Swern,9
Dess-Martin, TPAP10) gave complex mixtures of prod-
ucts.
The next phase of our plan called for introduction of
the anti homoallylic alcohol array (IX f X) with a pro-
pargylic ether terminus appropriate for the eventual [2,3]-
Wittig ring contraction (XII f XIII). For the former
transformation we planned to employ an allylic indium
reagent generated in situ through metathesis of the
allylic stannane 17 with InBr3.11 Stannane 17 was
prepared from alcohol 15 via the transient mesylate and
Bu3SnLi (eq 1).12
a
(a) Anti-selective allylmetal addition; (b) side-chain homolo-
gation; (c) macrocyclization; (d) [2,3]Wittig ring contraction; (e)
hydrocarbonylation-equilibration; (f) Ag+-catalyzed allenoic acid
cyclization.
isomerization would produce the allenic acid XIV which
would be cyclized to the butenolide. Subsequent removal
of the alcohol protecting group would complete the syn-
thesis. These suppositions assume that the C1 isopro-
penyl grouping would maintain its dominant role in
controlling relative stereochemistry with minimal pert-
erbation by the neighboring oxygen substituent. How-
ever, the extent of that control was by no means certain.
We formulated a highly convergent construction of the
macrocyclic ether intermediate XII. Two significant
achiral fragments, aldehyde 13 and allylic stannane 17,
comprise the key elements of the synthetic approach.
Allyl and allenylmetal addition reactions were expected
to play a key role in controlling relative and ultimately
absolute stereochemistry at C1/C2 and C8. From the
precedent in Scheme 1, it could be predicted that the C7/
C8 relative stereochemistry in XIII would be influenced
by transition state considerations and by the C1 isopro-
penyl substituent.
The synthesis of the aldehyde fragment 13, outlined
in Scheme 3, starts with the DPS ether 2 of propargyl
alcohol (1) which was subjected to our allenylstannane
homologation sequence to afford racemic 5.5 The BF3-
promoted addition of this stannane to R-(benzoyloxy)-
acetaldehyde followed by oxidation and treatment with
mild base to effect isomerization of the propargylic ketone
proceeded in high yield. The derived allenone 7 was
smoothly cyclized with catalytic AgNO3 in acetone af-
fording furan 8.6 Desilylation with TBAF and subse-
quent oxidation with the Dess-Martin periodinane re-
agent7 yielded aldehyde 10 which was subjected to Still-
Unexpectedly, addition of the allylic indium species
from stannane 17 and InBr3 afforded mainly the linear
adduct 18 in a variety of solvents and at temperatures
between 0° and -78 °C. In THF, adduct 18 was the sole
product. Reactions in other solvents (EtOAc, CH2Cl2,
Et2O) afforded linear and syn/anti mixtures of branched
adducts in modest yield (eq 2).
The branched anti adduct 19 could be synthesized by
addition of the allylic trichlorosilane, generated in situ
(8) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(9) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(10) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(5) Marshall, J . A. Chem. Rev. 1996, 96, 31.
(6) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1995, 60, 5966.
(7) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. Ireland,
R. E.; Lin, L. J . Org. Chem. 1993, 58, 2899.
(11) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1995, 60, 1920.
Marshall, J . A. Chemtracts-Org. Chem. 1997, 10, 481.
(12) Weigand, S.; Bru¨ckner, R. Synthesis 1996, 475.

5964 J . Org. Chem., Vol. 63, No. 17, 1998
Marshall and Liao
F igu r e 1. Calculated minimum energies for kallolide A and
its C2 epimer.
Sch em e 4
from allylic chloride 16.13 This addition requires nucleo-
philic assistance. With DMF as the nucleophile a 75:25
mixture of anti and syn adducts 19 and 20 was isolated
in 55% yield. 2,2′-Bipyridyl was more effective giving a
95:5 mixture of anti and syn adducts in 69% yield.14
Formation of the syn adduct 20, on the other hand, was
efficiently achieved through BF3-promoted addition of
allylic stannane 17 to aldehyde 13.
The efficiency of this latter addition reaction and the
desire to eventually prepare enantioenriched kallolide A
prompted our consideration of the syn adduct 20 as the
macrocyclic precursor. Our thinking along these lines
was influenced by the work of Abrahamson who showed
that certain furanocembranes undergo SN1 solvolysis
upon incubation (eq 3).15 This reaction has biological
preincubation in an aqueous buffer medium. The active
toxin is generated by hydrolysis of the C2 acetate. When
the incubation was performed in H218O the alcohol
product was highly 18O-enriched, suggestive of an SN1
process.
We reasoned that a similar sequence might provide a
means for epimerizing the C2 position of a kallolide A
precursor. In anticipation of such a maneuver, we per-
formed molecular mechanics calculations on kallolide A
and its C2 epimer (Figure 1).16 These calculations
indicated that the C2 epimer is substantially higher in
energy than kallolide A. Accordingly we elected to
implement this strategy.
The syn alcohol 20 was protected as the SEM ether
21 (Scheme 4). Selective deprotection of the DPS ether
gave the propargylic alcohol 22 which was converted to
chloride 23. Reduction of the ester function and treat-
ment of the derived chloro alcohol 24 with NaH and
Bu4NI in refluxing toluene (slow addition) gave the
(15) Hyde, E. G.; Thornhill, S. M.; Boyer, A. J .; Abrahamson, S. N.
J . Med. Chem. 1995, 38, 4704.
(16) The program Macromodel V5.5 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 (10 or more). 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.
implications as illustrated for bipinnatin-A (eq 3). It was
found that bipinnatin-A exhibits cytotoxicity only after
(13) Kobayashi, S.; Nishio, K. J . Org. Chem. 1994, 59, 6620.
Kobayashi, S.; Yasuda, M.; Nishio, K. Synlett 1996, 153.
(14) Angell, R. M.; Barrett, A. G. M.; Braddock, D. C.; Swallow, S.;
Vickery, B. D. Chem. Commun. 1997, 919.

Total Synthesis of the Pseudopterolide Kallolide A
J . Org. Chem., Vol. 63, No. 17, 1998 5965
Sch em e 5a
Sch em e 6
Molecular mechanics calculations provide a possible
explanation for the contrasting behavior of macrocyclic
ethers 25 and 41. Figure 2 shows the calculated global
minimum structures for 25 and 41.16 The reacting
centers in the latter structure are separated by only 3.7
Å compared to 4.4 Å in the former. In addition, the
abstracted propargylic H is more favorably oriented for
a concerted collinear removal with concomitant C-C
bond formation in 41.3,18
The mesylate derivative 43 of alcohol 42 was sub-
jected to the hydrocarbonylation-isomerization sequence
(Scheme 7). Unlike 28, allenoate 44 underwent signifi-
cant decomposition upon attempted equilibration with
Ph3P in benzene. However, ester cleavage with TBAF
and subsequent exposure of the acidic products to AgNO3
afforded a nearly 1:1 mixture of isomeric butenolides 45
and 46 in 95% yield. Evidently, isomerization of alle-
noate 44 must take place under the TBAF conditions.
Molecular mechanics calculations show an energy dif-
ference of only 0.8 kJ between allenoate 44 (R ) Me) and
its allene diastereomer.16 Thus the isolation of nearly
equal amounts of butenolides 45 and 46 suggests that
equilibration most likely occurs prior to ester cleavage.
Butenolide 46 was obtained by treatment of racemic
kallolide A with SEMCl, thereby confirming its structure,
and by inference, that of butenolide 45.
a
(a) Pd2dba3, Ph3P, CO, TMSCH2CH2OH, THF.
macrocyclic allylic propargylic ether 25 in 66% yield. This
ether underwent [2,3] Wittig ring contraction to the cis,
anti, cis product 26 in 73% yield. An unidentified
byproduct (not a stereoisomer) was formed in 10% yield.
The stereochemistry of alcohol 26 was confirmed by X-ray
structure analysis of the 2,4-dinitrobenzoate derivative.17
The conversion of alcohol 26 to butenolide 34 followed
along the lines of our kallolide B synthesis.3 Thus the
mesylate 27 afforded the allenic ester 28 with catalytic
Pd(PPh3)4 and CO in THF containing TMS ethanol. This
reaction proceeds with inversion of stereochemistry.
Treatment of ester 28 with Ph3P in benzene afforded a
95:5 mixture favoring the isomerized allenoate 31. This
outcome was predicted from molecular mechanics calcu-
lations which showed a significant energy difference (5.1
vs 13.6 kJ ) for the two isomers.16
Selective cleavage of the TMS ethyl ester was effected
with TBAF, and the derived acid 32 cyclized to butenolide
34 in the presence of catalytic AgNO3. As predicted,
solvolytic deprotection of the SEM ether 34 with HOAc
and PPTS afforded racemic kallolide A acetate 35. The
use of 3 N HCl and tert-butyl alcohol led to racemic
kallolide A (36). The H and 13C NMR spectra of both
1
compounds were identical to those of the respective
natural products. In agreement with our calculations,
kallolide A acetate contained none of the C2 epimer.
However, ca. 10% of the C2 epimer was formed in the
hydrolysis reaction of SEM ether 34.
As a matter of interest, the anti adduct 19 was likewise
subjected to the foregoing sequence. In contrast to its
cis counterpart 25, the trans macrocyclic propargylic
allylic ether 41 underwent rapid and near-quantitative
[2,3]Wittig ring contraction to the trans, anti, syn product
42 (Scheme 6).
The original structure assignment for kallolide A was
based on spectroscopic characteristics and an X-ray
crystal structure analysis of the acetate, isolated as a
minor constituent of the octocoral along with kallolide A
and B. However, the absolute configuration was not
determined. Our synthesis of (-)-kallolide B enabled
assignment of absolute configuration to that metabolite
and, since kallolide A was isolated from the same source,
it seems reasonable to assume that the two would be of
the same configuration. This assumption could be easily
tested by a minor modification of our synthetic sequence.
(17) The structure determination was performed by Dr. Michal
Sabat of this department.
(18) Wu, Y. D.; Houk, K. N.; Marshall, J . A. J . Org. Chem. 1990,
55, 1421.

5966 J . Org. Chem., Vol. 63, No. 17, 1998
Marshall and Liao
F igu r e 2. Chem 3D representations of calculated minimum energy structures for ethers 25 (R ) Me) and 41 (R ) Me) showing
interatomic distances between atoms involved in the [2,3]Wittig ring contraction.
Sch em e 7a
4 and 5, we converted alcohol (+)-20 of 90% ee to (+)-
kallolide A. The observed rotation of +133 was in ex-
cellent agreement with the reported value of +145 for
the natural product.2
These studies establish the absolute configuration of
kallolide A.21 They also reveal subtle conformational
effects engendered by the C2 oxygen substituent of cyclic
esters 25 vs 41 and allenoates 28 and 44. In addition,
they underscore the value of molecular mechanics cal-
culations as a predictive tool in these macrocyclic sys-
tems.
Exp er im en ta l Section
1-[(ter t-Bu tyld ip h en ylsilyl)oxy]-2-p r op yn e (2). To a
solution of 2.24 g (40 mmol) of propargyl alcohol and 6.8 g (100
mmol) of imidazole in 8 mL of DMF was added 13.19 g (48
mmol) of tert-butyldiphenylsilyl chloride dropwise at 0 °C. The
reaction was brought to room temperature and stirred over-
night until the starting material was totally consumed (TLC
analysis, 25% ethyl acetate in hexanes). The reaction mixture
was diluted with water and extracted with hexanes. The
combined hexane extracts were washed with water and brine
and dried over anhydrous MgSO4. The solution was concen-
trated, and the residue was directly used for next step without
further purification. A small portion was chromatographed
on silica gel (10% ether in hexanes) to give a white solid
product. 1H NMR (CDCl3): 7.74-7.70 (m, 4 H), 7.47-7.36 (m,
6 H), 4.32 (d, 2 H, J ) 2.5 Hz), 2.39 (t, 1 H, J ) 2.5 Hz), 1.07
(s, 9 H). 13C NMR (CDCl3): 135.6, 133.0, 129.8, 127.7, 73.0,
52.5, 26.7, 19.1. IR (cm -1, neat): 3316.
a
(a) Pd2dba3, Ph3P, CO, TMSCH2CH2OH, THF.
To that end, the addition of allylstannane 17 to aldehyde
13 was conducted in the presence of Keck’s Ti-BINOL
catalyst (eq 4).19 With stoichiometric amounts of the
5-[(ter t-Bu tyld ip h en ylsilyl)oxy]-3-p en tyn -2-ol (3). To
a solution of the above alkyne 2 in THF (400 mL) was added
20.8 mL of n-BuLi in hexanes (2.5 M, 52 mmol) at -78 °C.
The solution was stirred for 1 h at that temperature, and
then 8.96 mL (160 mmol) of acetaldehyde was added drop-
wise. The reaction mixture was slowly warmed to room
temperature and stirred overnight. The reaction was quenched
with saturated NH4Cl and extracted with ether. The organic
extracts were combined and washed with water and brine and
dried over MgSO4. The solution was concentrated under
reduced pressure, and the residue was used for the next step
without further purification. A small portion was chro-
matographed on silica gel (15% ethyl acetate in hexanes) to
give a clear liquid. 1H NMR (CDCl3): 7.75-7.71 (m, 4 H),
7.47-7.33 (m, 6 H), 4.44 (qt, 1 H, J q ) 6.8 Hz, J t ) 2.0 Hz),
4.37 (d, 2 H, J ) 2.0 Hz), 1.35 (d, 3 H, J ) 6.8 Hz), 1.07 (s, 9
H). 13C NMR (CDCl3): 135.7, 133.2, 129.8, 127.6, 87.1, 82.4,
58.3, 52.6, 26.7, 24.0, 19.1. IR (cm-1, neat): 3356, 1590; Anal.
Calcd for C21H26O2Si: C, 74.51; H, 7.74. Found: C, 74.43; H,
7.78.
chiral Lewis acid, adduct (+)-20 of 52% ee was obtained
in 31% yield. The Yamamoto chiral acyloxyborane
catalyst gave adduct (+)-20 of 90% ee in 24% yield.20
Again a full equivalent of the chiral Lewis acid was
required. Following the sequence outlined in Schemes
(20) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561.
Marshall, J . A.; Tang, Y. Synlett 1992, 653.
(21) The furanocembrane bipinnatin J has recently been converted
to kallolide A through photochemical ring contraction. Rodriguez, A.;
Shi, J .-G.; J . Org. Chem. 1998, 63, 420.
(19) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J . Am. Chem. Soc. 1993,
115, 8467. Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827.

Total Synthesis of the Pseudopterolide Kallolide A
J . Org. Chem., Vol. 63, No. 17, 1998 5967
1-[(ter t-Bu t yld ip h en ylsilyl)oxy]-2-(t r ib u t ylst a n n yl)-
2,3-p en ta d ien e (5). To a solution of the above alcohol 3 in
CH2Cl2 (400 mL) was added 13.95 mL (100 mmol) of Et3N,
and the mixture was cooled to -78 °C. Methanesulfonyl
chloride (3.7 mL, 48 mmol) was added dropwise by a syringe,
and the mixture was stirred for over 1 h until TLC analysis
showed no starting material. The mixture was treated with
NaHCO3, warmed to room temperature, and extracted with
ether. The extracts were combined, washed with water and
brine and dried over MgSO4. The residue was azeotropically
dried with benzene and used for the next step without further
purification.
To a solution of 11.3 mL (80 mmol) of diisopropylamine and
32 mL (80 mmol) of 2.5 M n-butyllithium in hexane in 160
mL of THF was added at 0 °C 21.5 mL (80 mmol) of tributyltin
hydride dropwise, and the mixture was stirred for 15 min at
0 °C. The solution was cooled to -78 °C, and 16.4 g (80 mmol)
of CuBr‚SMe2 was added from a powder delivery funnel. After
30 min, the above mesylate 4 in 20 mL of THF was added
dropwise. After 1 h the reaction was quenched by pouring into
saturated NH4Cl/concentrated NH4OH (9:1) (500 mL) with
stirring until the precipitate dissolved. The organic layer was
separated, and the water layer was extracted with ether. The
combined extracts were washed with water and brine and
dried over MgSO4. After removal of solvent, the residue was
chromatographed on silica gel (hexanes followed by 5% ether
in hexanes) to give 22.02 g of colorless product (90% overall
yield from propargyl alcohol). 1H NMR (CDCl3): 7.71 (d, 4 H,
J ) 6.8 Hz), 7.45-7.34 (m, 6 H), 4.68 (qt, 1 H, J q ) 7.0 Hz, J t
) 2.9 Hz), 4.35-4.22 (m, 2 H), 1.62 (d, 3 H, J ) 7.0 Hz), 1.58-
1.46 (m, 6 H), 1.37-1.24 (m, 6 H), 1.06 (s, 9 H), 0.98 (dd, 6 H,
J 1 ) 7.3 Hz, J 2 ) 9.8 Hz), 0.89 (t, 9 H, J ) 7.3 Hz). 13C NMR
(CDCl3): 202.5, 135.6, 133.9, 129.4, 127.5, 94.7, 78.0, 65.7, 29.0,
27.3, 26.8, 19.2, 14.2, 13.7, 10.4. IR (cm-1, neat): 1936, 1466.
Anal. Calcd for C33H52OSiSn: C, 64.81; H, 8.57, Found: C,
64.80; H, 8.54.
2-(Ben zoyloxy)a ceta ld eh yd e. To a solution of cis-2-
butene-1,4-diol (8.2 mL, 100 mmol) in CH2Cl2 (400 mL) was
added 40.2 mL (300 mmol) of triethylamine. The mixture was
cooled to 0 °C and 27.8 mL (240 mmol) of benzoyl chloride was
added dropwise. The reaction mixture was brought to room
temperature and stirred overnight. Water was added, and the
mixture was extracted with ether. The combined extracts were
washed with water and brine and dried over MgSO4. After
removal of solvent the residue was chromatographed on silica
gel (10% ether in hexanes) to give 26.3 g (89%) of dibenzoate.
1HNMR (CDCl3): 8.05 (d, 4 H, J ) 8.0 Hz), 7.57 (t, 2 H, J )
8.0 Hz), 7.44 (t, 4 H, J ) 8.0 Hz), 5.96 (t, 2 H, J ) 5.0 Hz),
5.02 (d, 4 H, J ) 5.0 Hz). 13C NMR (CDCl3): 166.3, 133.0,
130.0, 129.7, 128.4, 60.6.
To a solution of 23.7 g (80 mmol) of the above dibenzoate in
400 mL of wet CH2Cl2 (saturated with water before use) was
bubbled O3 at -78 °C until the solution turned blue. Excess
ozone was purged with nitrogen then 31.5 g (120 mmol) of Ph3P
was added. The solution was allowed to warm to room
temperature. After 30 min, the solvent was removed and the
residue was chromatographed on silica gel (25% EtOAc in
hexanes followed by 70% EtOAc in hexanes) to give 17.3 g
(66%) of the title compound as a colorless oil. 1H NMR
(CDCl3): 9.72 (s, 1 H), 8.12-8.08 (m, 2 H), 7.60 (m, 1 H), 7.50-
7.44 (m, 2 H), 4.89 (s, 2 H). IR (cm-1, neat): 1730, 1719.
6-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-3-m e t h yl-1-(b e n z-
oyloxy)-4-h exyn -2-ol (6). To a mixture of 5.2 g (32 mmol)
of 2-(benzoyloxy)acetaldehyde and 9.68 g (15.8 mmol) of
allenylstannane 5 in 150 mL of CH2Cl2 was added 6.01 mL
(47.4 mmol) of BF3‚OEt2 dropwise at -78 °C. The reaction
was closely monitored by TLC. After total consumption of
allenylstannane (2 h), methanol was added followed by satu-
rated NaHCO3 to quench the reaction. The mixture was
allowed to warm to room temperature and extracted with
ether. The extracts were combined and washed with saturated
NaHCO3, water, and brine and dried over MgSO4. The solvent
was removed under vacuum, and the residue was chromato-
graphed on silica gel (20% ether in hexanes) to give 7.05 g
(92%) of a colorless oil. 1H NMR (CDCl3): 8.05 (d, 2 H, J ) 8
Hz), 7.76-7.69 (m, 4 H), 7.58 (t, 1 H, J ) 6.8 Hz), 7.49-7.35
(m, 8 H), 4.50 (dd, 1 H, J 1 ) 3.4 Hz, J 2 ) 11.7 Hz), 4.36 (d, 2
H, J ) 1.5 Hz), 4.35 (m, 1 H), 3.78 (ddd, 1 H, J 1 ) 3.4 Hz, J 2
) 3.4 Hz, J 3 ) 7.3 Hz), 2.73-2.64 (m, 1H), 2.27 (br, 1 H), 1.21
(d, 3 H, J ) 6.8 Hz), 1.05 (s, 9 H). 13C NMR (CDCl3): 135.6,
133.3, 133.1, 129.9, 129.7, 129.6, 128.4, 127.6, 85.8, 81.2, 72.9,
67.2, 52.8, 30.1, 26.7, 19.1, 16.4. IR (cm-1, neat): 3471, 2242,
1722, 1276. Anal. Calcd for C30H34O4Si: C, 74.04; H, 7.04.
Found: C, 73.92; H, 7.06.
2-(Ben zoyloxy)m eth yl-3-m eth yl-5-[[(d ip h en yl-ter t-bu -
tylsilyl)oxy]m eth yl]fu r a n (8). To a solution of 1.02 g (2.49
mmol) of Dess-Martin periodinane reagent in CH2Cl2 was
added 1.10 g (2.26 mmol) of alcohol 6. After 1 h the reaction
was quenched with a solution of 2.5 g (1.6 mmol) of Na2S2O3‚
5H2O in 10 mL of saturated NaHCO3. The resulting solution
was stirred for 10 min and extracted with ether. The extracts
were combined and washed with water and brine and dried
over MgSO4. The solvent was removed under vacuum, and
the residue was chromatographed on silica gel (20% ether in
hexanes) to give 0.99 g (90%) of a mixture of allenyl and
alkynyl ketones judging from NMR and IR. This mixture in
10 mL of CH2Cl2 and 3.45 mL (24.9 mmol) of Et3N at -78 °C
was allowed to slowly warm to room temperature with stirring
overnight. The solvent was removed under vacuum, and the
residue was passed through a pad of silica gel with 10% ether
in hexanes. After removal of solvent, the residue, allenone 7,
was used for the next step without further purification.
To the solution of the above allenone 7 in acetone was added
31 mg (0.18 mmol) of AgNO3, and the solution was heated at
reflux for 1 h. After total consumption of starting material
the mixture was passed through a pad of Celite and washed
with ether. The solvent was removed, and the residue was
chromatographed on silica gel (10% ether in hexanes) to give
furan 8, a colorless oil. 1H NMR (CDCl3): 8.12 (d, 2 H, J )
6.8 Hz), 7.79-7.74 (m, 4 H), 7.57 (tt, 1 H, J 1)1.5 Hz, J 2)7.8
Hz), 7.48-7.39 (m, 8 H), 6.07 (s, 1 H), 5.31 (s, 2 H), 4.69 (s, 2
H), 2.14 (s, 3 H), 1.13 (s, 9 H). 13C NMR (CDCl3): 166.3, 153.8,
144.4, 135.6, 133.3, 132.9, 130.1, 129.7, 129.65, 128.3, 127.6,
121.0, 110.7, 59.0, 56.9, 26.7, 19.2, 9.9. IR (neat): 1710, 1588.
Anal. Calcd. for C30H32O4Si: C, 74.35; H, 6.65. Found: C,
74.31; H, 6.65.
2-[(Ben zoyloxy)m eth yl]-3-m eth yl-5-(h yd r oxym eth yl)-
fu r a n (9). To a solution of 3.0 g (6.2 mmol) of furan 8 in 60
mL of THF was added 24.8 mL (24.8 mmol) of tetrabutyl-
amonium fluoride in THF (1.0 M) at - 78 °C. The solution
was slowly allowed to warm to room temperature with stirring
overnight. After total consumption of the starting material,
the reaction was quenched with water and extracted with
ether. The extracts were combined and washed with water
and brine and dried over MgSO4. The solvent was removed
under reduced pressure, and the residue was chromatographed
on Et3N-deactivated silica gel (25% ethyl acetate in hexanes)
to give 1.5 g (99%) of alcohol 9 as a colorless oil. 1H NMR
(CDCl3): 8.05-8.01 (m, 2 H), 7.53 (tt, 1H, J 1)1.5 Hz, J 2)7.3
Hz), 7.44-7.38 (m, 2 H), 6.14 (s, 1 H), 5.25 (s, 2 H), 4.55 (s, 2
H), 2.34 (br, 1 H), 2.09 (s, 3 H). 13C NMR (CDCl3): 166.4,
153.9, 144.9, 133.0, 129.9, 129.7, 128.3, 121.3, 111.1, 57.4, 56.8,
9.8. IR (cm-1, neat): 3397, 1722. Anal. Calcd for C14H14O4:
C, 68.28; H, 5.73. Found: C, 68.19; H, 5.76.
F u r a n Ester 11. To a solution of 3.15 g (7.68 mmol) of
Dess-Martin periodinane reagent in CH2Cl2 was added 1.40
g (5.69 mmol) of alcohol 9 at 0 °C. After total consumption of
starting material, 6.3 g (40 mmol) of Na2S2O3‚5H2O in satu-
rated NaHCO3 was added, and the solution was stirred for 10
min. The solution was extracted with ether, and the organic
extracts were combined, washed with water and brine, and
dried over MgSO4. The solvent was removed under vacuum,
and the residue, aldehyde 10, was directly used for the Still-
Horner-Emmons reaction without further purification.
To a mixture of 4.92 g (14.2 mmol) of ethyl bis(1,1,1-
trifluoroethyl) 2-phosphonopropionate and 7.52 g (28.4 mmol)
of 18-crown-6 was added 28.4 mL (14.2 mmol) of potassium
bis(trimethylsilyl)amide (0.5 M in hexane) dropwise at -78
°C. The solution was stirred for 40 min, and aldehyde 10 was
added dropwise. After 30 min, the reaction was quenched with

5968 J . Org. Chem., Vol. 63, No. 17, 1998
Marshall and Liao
saturated NH4Cl and warmed to room temperature. The
mixture was extracted with ether, and the extracts were
combined, washed with water and brine, and dried over
MgSO4. The solvent was removed under reduced pressure,
and the residue was chromatographed on Et3N-deactivated
silica gel (10% ether in hexanes) to give 1.65 g (88%) of ester
11 as a colorless oil. 1H NMR (CDCl3): 8.04 (d, 2 H, J ) 7.3
Hz), 7.54 (t, 1 H, J ) 7.3 Hz), 7.41 (t, 2 H, J ) 7.3 Hz), 6.78 (s,
1 H), 6.44 (s, 1 H), 5.25 (s, 2 H), 4.26 (q, 2 H, J ) 6.8 Hz), 2.11
(s, 3 H), 2.07 (s, 3 H), 1.29 (t, 3 H, J ) 6.8 Hz). 13C NMR
(CDCl3): 168.4, 166.2, 150.1, 145.2, 133.0, 129.9, 129.7, 128.3,
126.3, 123.3, 122.5, 115.7, 60.6, 56.7, 21.5, 14.1, 9.8. Anal.
Calcd for C19H20O5: C, 69.50; H, 6.14. Found: C, 69.62; H,
6.13.
dropwise at -78 °C. The reaction was monitored by TLC until
the starting material was consumed (normally less than 15
min). Methanol was added followed by saturated NH4Cl. The
mixture was allowed to warm to room temperature. The
organic layer was separated, and the water layer was extracted
with ether. The organic extracts were combined, washed with
saturated NH4Cl, water, and brine, dried over MgSO4, and
filtered. The solvent was removed under reduced pressure,
and the residue was chromatographed on Et3N-deactivated
silica gel (20% ether in hexanes) to yield 1.27 g (99%) of adduct
20 as a colorless liquid. 1H NMR (CDCl3): 7.76-7.71 (m, 4
H), 7.45-7.37 (m, 6 H), 6.85 (s, 1 H), 6.44 (s, 1 H), 4.75 (s, 1
H), 4.69 (s, 1 H), 4.52 (dd, 1 H, J 1 ) 6.4 Hz, J 2 ) 2.0 Hz), 4.33
(s, 2 H), 4.25 (q, 2 H, J ) 6.8 Hz), 2.67 (t, 1 H, J 1 ) 10.3 Hz,
J 2 ) 2.0 Hz), 2.29-1.95 (m, 3 H), 2.04 (s, 3 H), 1.98 (s, 3 H),
1.88 (d, 1 H, J ) 6.4 Hz), 1.66-1.56 (m, 1 H), 1.50 (s, 3 H),
1.32 (t, 3 H, J ) 6.8 Hz), 1.07 (s, 9 H). IR (cm-1, neat), 3471,
3075, 1714.
Syn Alcoh ol (+)-20. A. CAB P r oced u r e. To a suspen-
sion of 84.6 mg (0.27 mmol) of mono[(2,6-dimethoxybenzoyl)-
oxy]tartaric acid in 0.15 mL of MeCN was added 0.30 mL (0.30
mmol) of BH3‚THF (1.0 M in THF) at 0 °C dropwise. Gas was
evolved, and the solid dissolved. After 1 h the solution was
cooled to -78 °C, and trifloroacetic anhydride was added
followed by furan 13 in 0.10 mL of MeCN. Allylic stannane
17 in 0.10 mL of MeCN was added by syringe pump over 3 h
at -78 °C. The reaction was kept at -78 °C for another 12 h
and quenched with MeOH followed by saturated NaHCO3. The
mixture was allowed to warm to room temperature and
extracted with ether. The extracts were combined, washed
with aqueous NaHCO3, water, and brine, dried over anhydrous
MgSO4, and filtered. The solvent was removed under reduced
pressure. The residue was chromatographed on Et3N-deacti-
vated silica gel (20% ether in hexanes) to afford 16 mg (24%)
of alcohol (+)-20 as a colorless liquid and 11 mg of recovered
aldehyde 13. Also isolated was enyne 17 (R ) H) from
protonolysis of stannane 17. The aqueous layer and washings
were combined and acidified with 4 N HCl and extracted with
ethyl acetate to recover the ligand; [R]D ) +18.7. HPLC
analysis (Chiral-OB column) of alcohol (+)-20 indicated an ee
of 90%.
B. Mod ified Keck P r oced u r e. To a solution of 57.2 mg
(0.20 mmol) of (R)-BINOL and 100 mg of flame-dried 4 Å
powered molecular sieves in 0.50 mL of CH2Cl2 was added 59
µL (0.20 mmol) of titanium tetraisopropoxide at room temper-
ature. The mixture was refluxed for 1.5 h and then cooled to
-78 °C. To this mixture were added 44.4 mg (0.20 mmol) of
aldehyde 13 and 146 mg (0.22 mmol) of stannane 17. The
mixture was brought to -20 °C and stirred for 10 h. TLC
showed only a trace of product had formed. The mixture was
brought to 0 °C for 4 h, and 1 mL of saturated NaHCO3 was
added to quench the reaction. The mixture was extracted with
ether. The combined extracts were washed with water and
brine, dried over anhydrous MgSO4, and filtered. The solvent
was removed under reduced pressure, and the residue was
chromatographed on Et3N-deactivated silica gel to give 37 mg
(31%) of product. HPLC analysis (Chiral-OB column) indi-
cated a 54:46 mixture of syn and anti adducts of 52% and
68% ee.
F u r a n Ester Ald eh yd e 13. To a solution of 2.78 g (8.47
mmol) of diester 11 in 80 mL of ethanol was added 2.80 g of
K2CO3 at room temperature. The mixture was stirred at room
temperature until all the starting material was consumed (3
h, TLC analysis), and then it was filtered through a pad of
Celite and washed with ether to remove solid K2CO3. The
solvent was removed, the residue was dissolved in 850 mL of
CH2Cl2, and 7.45 g (84.7 mmol) of MnO2 was added. After
the completion of the reaction (6 h), the mixture was filtered
through a pad of Celite and the solvent was removed. The
residue was chromatographed on Et3N-deactivated silica gel
(10% ether in hexanes) to give 1.56 g (83%) of aldehyde 13 as
a colorless solid: mp 51.5-52.5 °C. 1H NMR (CDCl3): 9.69
(s, 1 H), 6.80 (s, 1 H), 6.44 (q, 1 H, J ) 1.5 Hz), 4.29 (q, 2 H,
J ) 7.3 Hz), 2.35 (s, 3 H), 2.11 (d, 3 H, J ) 1.5 Hz), 1.32 (t, 3
H, J ) 7.3). 13C NMR (CDCl3): 168.0, 154.1, 147.6, 132.6,
121.6, 116.7, 61.2, 21.8, 14.1, 10.4. IR (cm-1, neat): 1710, 1674.
(E)-8-[(ter t-Bu tyld ip h en ylsilyl)oxy]-1-ch lor o-2-m eth yl-
2-octen -7-yn e (16). To a solution of 5.40 g (13.8 mmol) of
alcohol 15 in 20 mL of THF was added 30 mL of CCl4, 4.80
mL (27.56 mmol) of Hunig’s base, and 7.22 g (27.6 mmol) of
Ph3P. The mixture was brought to reflux for 4 h until no
starting material was detected by TLC. Most of the solvent
was removed, and the oily residue was poured into 100 mL of
hexanes. Filtration, concentration, and chromatography on
silica gel with 5% ether in hexanes provided 5.10 g (90%) of
chloride 16 as a colorless liquid. 1H NMR (CDCl3): 7.75-7.71
(m, 4 H), 7.45-7.36 (m, 6 H), 5.55 (t, 1 H, J ) 5.9 Hz), 4.32
(br, 2 H), 4.01 (s, 2 H), 2.22 (br, 4 H), 1.75 (s, 3 H), 1.07 (s, 9
H). 13C NMR (CDCl3): 135.6, 133.3, 132.9, 129.7, 128.9, 127.6,
84.8, 78.9, 52.9, 52.1, 27.2, 26.7, 19.2, 18.6, 14.3. IR (cm-1
,
neat): 2331, 1474, 1431. Anal. Calcd for C25H31ClO2Si: C,
73.05; H, 7.60. Found: C, 73.15; H, 7.69.
An ti Ad d u ct: Alcoh ol 19. To a solution of 41.0 mg (0.10
mmol) of chloride 16 in 0.20 mL of THF were added 3.0 mg
(0.03 mmol) of CuCl, 15.1 µL (0.15 mmol) of trichlorosilane,
and 26.1 µL (0.15 mmol) of Hunig’s base successively at room
temperature. After 1 h, 15.6 mg (0.1 mmol) of dipyridyl and
11.1 mg (0.05 mmol) of aldehyde 13 in 0.20 mL of CH2Cl2 was
added at -40 °C. The reaction was closely monitored by TLC,
and when the aldehyde was consumed (usually within 1 h),
the reaction was quenched with water and extracted with
ether. The combined extracts were washed with water and
brine, dried over anhydrous MgSO4, and filtered. The solvent
was removed under reduced pressure, and the residue was
chromatographed on Et3N-deactivated silica gel (20% ether in
hexanes) to give 46 mg of alcohol 19 as a colorless liquid with
a trace of the syn isomer 20 and the linear adduct 18 (19:18
) 18:1). 1H NMR (CDCl3): 7.71-7.68 (m, 4 H), 7.45-7.33 (m,
6 H), 6.92 (s, 1 H), 6.48 (s, 1 H), 5.07 (b, 1 H), 5.00 (s, 1 H),
4,49 (dd, 1 H, J 1 ) 3.4 Hz, J 2 ) 10.2 Hz), 4.27 (s, 2 H), 4.26 (q,
2 H, J ) 7.3 Hz), 2,72 (dt, 1 H, J d ) 3.4 Hz, J t ) 10.2 Hz),
2.18-1.87 (m, 2 H), 2.04 (s, 3 H), 2.03 (s, 3 H), 1.74 (s, 3 H),
1.60 (br, 1 H), 1.44-1.12 (m, 2 H), 1.32 (t, 3 H, J ) 7.3 Hz),
1.04 (s, 9 H). 13C NMR (CDCl3): 168.1, 149.33, 149.26, 143.4,
135.6, 133.3, 129.7, 127.6, 124.8, 124.7, 120.4, 116.7, 116.3,
84.9, 78.6, 66.5, 60.5, 52.9, 52.4, 27,6, 26.7, 21.5, 19.1, 17.7,
16.7, 14.2, 9.8. IR (cm-1, neat), 3493, 1710.
SEM Eth er 21. To a solution of 1.00 g (1.67 mmol) syn-
alcohol 20 in 20 mL of CH2Cl2 was added 0.87 mL (5.0 mmol)
of Hunig’s base followed by 0.59 mL (3.3 mmol) of 2-(trimeth-
ylsilyl)ethoxymethyl chloride (SEMCl) dropwise at -78 °C. The
solution was slowly warmed to room temperature and stirred
overnight. The solvent was removed under reduced pressure,
and the residue was chromatographed on Et3N-deactivated
silica gel (10% ether in hexanes) to give 1.21 g (99%) of ether
21 as a colorless liquid. 1H NMR (CDCl3): 7.77-7.70 (m, 4
H), 7.44-7.36 (m, 6 H), 6.88 (s, 1 H), 6.47 (s, 1 H), 4.69 (s, 2
H), 4.56 (d, 1 H, J ) 6.8 Hz), 4.50 (d, 1 H, J ) 6.8 Hz), 4.49 (d,
1 H, J ) 10.2 Hz), 4.32 (s, 2 H), 4.26 (q, 2 H, J ) 7.3 Hz), 3.72
(ddd, 1 H, J 1 ) J 2 ) 8.8 Hz, J 3)1.0 Hz), 3.44 (ddd, 1 H, J 1
)
Syn Ad d u ct: Alcoh ol 20. To a solution of 0.43 g (1.9 mmol)
of aldehyde 13 and 2.55 g (3.8 mmol) of stannane 17 in
CH2Cl2 was added 0.27 mL (2.3 mmol) of BF3‚OEt2 complex
J 2 ) 8.8 Hz, J 3)1.0 Hz), 2.80 (dt, 1 H, J d ) 2.9 Hz, J t ) 10.2
Hz), 2.27-2.08 (m, 3 H), 2.04 (s, 3 H), 1.99 (s, 3 H), 1.62-1.52
(m, 1 H), 1.50 (s, 3 H), 1.32 (t, 3 H, J ) 7.3 Hz), 1.07 (s, 9 H),

Total Synthesis of the Pseudopterolide Kallolide A
J . Org. Chem., Vol. 63, No. 17, 1998 5969
0.89 (t, 2 H, J ) 8.8 Hz), 0.00 (s, 9 H). 13C NMR (CDCl3):
168.2, 149.3, 148.5, 142.8, 135.6, 133.3, 129.6, 127.6, 124.8,
124.2, 121.2, 115.9, 114.0, 92.2, 85.4, 78.4, 71.2, 65.2, 60.5, 53.0,
49.8, 29.1, 26.7, 21.5, 19.7, 19.1, 18.0, 16.8, 14.2, 9.8, -1.4.
Anal. Calcd for C43H60O6Si2: C, 70.84; H, 8.29. Found: C,
70.88; H, 8.36. IR (cm-1, neat) 3075, 1714.
Hz, J ) 13.2 Hz), 4.36 (dd, 1 H, J 1 ) 5.9 Hz, J 2 ) 13.2 Hz),
2
4.14 (br, 2 H), 3.72 (ddd, 1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz),
3.44 (ddd, 1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz), 2.82 (dt, 1 H,
J d ) 2.7 Hz, J t ) 10.3 Hz), 2.30-2.02 (m, 3 H), 1.96 (s, 3 H),
1.95 (s, 3 H), 1.61-1.53 (m, 1 H), 1.49 (s, 4 H), 0.9 (t, 2 H, J )
8.8 Hz), 0.01 (s, 9 H). 13C NMR (CDCl3):151.0, 146.8, 142.7,
136.9, 120.5, 115.7, 114.0, 111.7, 91.8, 87.3, 75.2, 70.9, 65.3,
Alcoh ol 22. To a solution of 1.60 g (2.19 mmol) of DPS
ether 21 in 25 mL of THF was added 8.8 mL (8.8 mmol) of
TBAF (1.0 M in THF) at -78 °C. After 20 min, the solution
was warmed to 0 °C. The reaction was quenched with water
after total consumption of the DPS ether (2 h). The organic
layer was separated, and the water layer was extracted with
ether. The combined extracts were washed with water and
brine, dried over anhydrous MgSO4, and filtered. The solvent
was removed under reduced pressure, and the residue was
chromatographed on Et3N-deactivated silica gel (15% ethyl
acetate in hexanes) to give 0.97 g (90%) of alcohol 22 as a
colorless liquid. 1H NMR (CDCl3): 6.60 (s, 1 H), 6.35 (br, 1
H), 4.69 (s, 2 H), 4.54 (d, 1 H, J ) 6.8 Hz), 4.49 (d, 1 H, J )
10.2 Hz), 4.48 (d, 1 H, J ) 6.8 Hz), 4.29 (q, 2 H, J ) 7.3 Hz),
4.25 (m, 2 H), 3.71 (ddd, 1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz),
3.43 (ddd, 1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz), 2.89 (dt, 1 H,
J d ) 2.9 Hz, J t ) 10.2 Hz), 2.34-2.08 (m, 4 H), 2.04 (s, 3 H),
1.97 (s, 3 H), 1.60-1.50 (m, 1 H), 1.48 (s, 3 H), 1.31 (t, 3 H, J
) 7.3 Hz), 0.9 (t, 2 H, J ) 8.8 Hz), 0.01 (s, 9 H). 13C NMR
(CDCl3): 169.3, 149.2, 148.4, 142.7, 125.2, 122.5, 121.0, 114.9,
114.2, 92.1, 85.8, 79.0, 70.8, 65.2, 60.9, 51.3, 49.3, 28.7, 21.4,
19.6, 18.1, 16.6, 14.1, 9.7, -1.4. IR (cm-1, neat), 3455 (br),
2951, 1714. Anal. Calcd for C27H42O6Si: C, 69.72; H, 8.89.
Found: C, 66.02; H, 8.69.
Ch lor id e 23. A flask charged with 0.33 g (7.8 mmol) of
LiCl was flame dried for 5 min under vacuum (1 mmHg). Then
3.0 mL of dry DMF and 0.91 mL (7.8 mmol) of 2,6-lutidine
were added, and the mixture was stirred to dissolve the LiCl.
The mixture was cooled to 0 °C, and 0.96 g (2.0 mmol) of
propargylic alcohol 22 (which was azeotropically dried with
benzene three times before use) in 3 mL of dry DMF was added
followed by 0.45 mL (5.9 mmol) of methanesulfonyl chloride.
After 12 h at 0 °C, the yellow mixture was quenched with
water and extracted with ether. The combined extracts were
washed with water and brine, dried over anhydrous MgSO4,
and filtered. The solvent was removed under reduced pres-
sure, and the residue was chromatographed on Et3N-deacti-
vated silica gel (10% ether in hexanes) to give 0.85 g (88%) of
chloride 23 as a colorless liquid and 70 mg (7%) of starting
alcohol. 1H NMR (CDCl3): 6.80 (s, 1 H), 6.45 (br, 1 H), 4.68
(s, 2 H), 4.54 (d, 1 H, J ) 6.8 Hz), 4.48 (d, 1 H, J ) 10.7 Hz),
4.47 (d, 1 H, J ) 6.8 Hz), 4.26 (q, 2 H, J ) 7.3 Hz), 4.15 (br, 2
H), 3.71 (ddd, 1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz), 3.43 (ddd,
1 H, J 1 ) 2.0 Hz, J 2 ) J 3 ) 8.8 Hz), 2.78 (dt, 1 H, J d ) 2.7 Hz,
J t ) 10.7 Hz), 2.31-2.09 (m, 4 H), 2.04 (s, 3 H), 1.97 (s, 3 H),
1.73-1.53 (m, 1 H), 1.48 (s, 3 H), 1.31 (t, 3 H, J ) 7.3 Hz),
0.90 (t, 2 H, J ) 8.8 Hz), 0.01 (s, 9 H). 13C NMR (CDCl3):
168.4, 149.3, 148,3, 142.6, 124.6, 124.2, 121.2, 115.6, 114.2,
92.1, 87.4, 75.1, 71.0, 65.3, 60.5, 49.8, 31.3, 28.9, 21.5, 19.6,
18.1, 16.8, 14.2, 9.8, -1.5. IR (cm-1, neat) 3075, 2951, 2233,
1722. Anal. Calcd for C27H41ClO5Si: C, 63.69; H, 8.12.
Found: C, 63.72; H, 8.16.
63.0, 49.8, 31.2, 28.7, 22.5, 19.3, 18.0, 16.8, 9.6, -1.5. IR (cm-1
neat): 3430, 3075, 2233.
,
Cyclic Eth er 25. A mixture of 0.12 g (4.9 mmol) of sodium
hydride, 1.31 g (4.9 mmol) of 18-crown-6, 20 mg of tetrabu-
tylammonium iodide, and 120 mL of toluene (freshly distilled
from calcium hydride) was heated to reflux. To the mixture
was added 0.33 g (0.71 mmol) of chloro alcohol 24 in 30 mL of
toluene by syringe pump over 4 h. After the addition, the
mixture was heated for 6 h until all the chloro alcohol was
consumed. The mixture was cooled to room temperature and
filtered through a pad of silica gel. The solvent was removed,
and the residue was chromatographed on Et3N-deactivated
silica gel (10% ether in hexanes) to give 0.18 g (66%) of
macrocyclic ether 25 as a colorless liquid. 1H NMR (CDCl3):
6.08 (br, 1 H), 5.92 (s, 1 H), 4.86 (s, 1 H), 4.85 (d, 1 H, J ) 4.9
Hz), 4.78 (s, 1 H), 4.74 (d, 1 H, J ) 6.8 Hz), 4.61 (br, 2 H), 4.56
(d, 1 H, J ) 6.8 Hz), 4.15 (d, 1 H, J ) 15.1 Hz), 4.03 (d, 1 H,
J ) 15.1 Hz), 3.73 (ddd, 1 H, J 1 ) 6.8 Hz, J 2 ) J 3 )10.3 Hz),
3.45 (ddd, 1 H, J 1 ) 6.8 Hz, J 2 ) J 3 )10.3 Hz), 3.33 (ddd, 1 H,
J 1 ) J 2 ) 4.9 Hz, J 3 ) 9.8 Hz), 2.39-2.04 (m, 3 H), 2.00 (s, 3
H), 1.90 (s, 3 H), 1.78 (s, 3 H), 1.80-1.72 (m, 1 H), 0.93 (ddd,
1 H, J 1 ) 1.0 Hz, J 2 ) 3.4 Hz, J 3 ) 6.8 Hz), 0.89 (ddd, 1 H, J 1
) 1.0 Hz, J 2 ) 3.4 Hz, J 3 ) 6.8 Hz) 0.00 (s, 9 H). 13C NMR
(CDCl3): 150.5, 147.5, 144.3, 132.9, 119.1, 117.4, 113.1, 112.9,
93.0, 87.2, 77.5, 72.7, 67.5, 65.4, 56.8, 47.8, 25.6, 22.2, 21.1,
18.1, 17.2, 9.6, -1.5. IR (cm-1, neat): 3073, 2960.
Alcoh ol 26. To a solution of 100 mg (0.23 mmol) of
macrocyclic allylic propargylic ether 25 in 23 mL of THF-
pentane (1:1) was added 0.28 mL (0.69 mmol) of n-butyllithium
(2.5 M in hexanes) at -78 °C. The solution quickly turned
red. The reaction was quenched with 10 mL of saturated
ammonium chloride after 1 h and allowed to warm to room
temperature. The mixture was extracted with ether. The
combined extracts were washed with water and brine, dried
over anhydrous MgSO4, and filtered. The solvent was removed
under reduced pressure, and the residue was chromatographed
on Et3N-deactivated silica gel to give 65 mg (73%) of propar-
gylic alcohol 26 as a colorless liquid with 9 mg (10%) of an
unidentified isomer, and 11 mg (11%) of starting material.
Upon cooling, alcohol 26 solidified. 1H NMR (CDCl3): 6.04
(s, 1 H), 5.32 (s, 1 H), 5.05 (s, 1 H), 4.77 (br, 1 H), 4.75 (br, 1
H), 4.72 (s, 1 H), 4.68 (d, 1 H, J ) 6.8 Hz), 4.64 (d, 1 H, J )
6.8 Hz), 4.57 (dt, 1 H, J d ) 10.0 Hz, J t ) 2.3 Hz), 3.73 (ddd, 1
H, J 1 ) 6.8 Hz, J 2 ) J 3 ) 10.0 Hz), 3.77-3.68 (m, 1 H), 3.49
(ddd, 1 H, J 1 ) 6.8 Hz, J 2 ) J 3 ) 10.0 Hz), 2.65 (t, 1 H, J )
13.5 Hz), 2.40-2.30 (m, 1 H), 2.18 (d, 1 H, J ) 6.8 Hz), 2.01
(s, 3 H), 1.97-1.90 (m, 1 H), 1.86 (s, 3 H), 1.84 (s, 3 H), 1.72-
1.68 (m, 2 H), 0.92 (ddd, 1 H, J 1 ) 0.5 Hz, J 2 ) 1.5 Hz, J 3
)
6.8 Hz), 0.88 (ddd, 1 H, J 1) 0.5 Hz, J 2 ) 1.5 Hz, J 3)6.8 Hz),
0.00 (s, 9 H). 13C NMR (CDCl3): 150.6, 149.4, 147.8, 141.0,
118.5, 114.0, 111.4, 111.2, 92.6, 89.1, 81.3, 70.7, 65.5, 63.1, 53.3,
52.0, 26.6, 23.5, 20.6, 19.0, 18.1, 9.7, -1.5. IR (cm-1, neat):
3458, 3073, 2951. Anal. Calcd for C25H38O4Si: C, 69.72; H,
8.89. Found: C, 69.57; H, 8.90.
Alcoh ol 24. To a solution of 0.75 g (1.5 mmol) of chloride
23 in 15 mL of CH2Cl2 was added 3.68 mL (3.7 mmol) of
DIBAl-H (1.0 M in hexanes) at -78 °C. After complete
consumption of the ester, the reaction was quenched with 50
mL of saturated sodium potassium tartrate. The mixture was
allowed to warm to room temperature, another 50 mL of
saturated sodium potassium tartrate was added, and the
mixture was stirred until the solution turned clear. The
organic layer was separated, and the water layer was extracted
with ether. The combined extracts were washed with water
and brine, dried over anhydrous MgSO4, and filtered. The
solvent was removed under reduced pressure, and the residue
was chromatographed on Et3N-deactivated silica gel (25%
ethyl acetate in hexanes) to give 0.63 g (92%) of chloro alcohol
24 as a colorless liquid. 1H NMR (CDCl3): 6.02 (br, 1 H), 5.94
(s, 1 H), 4.69 (s, 2 H), 4.53 (d, 1 H, J ) 6.8 Hz), 4.48 (d, 1 H,
J ) 10.3 Hz), 4.47 (d, 1 H, J ) 6.8 Hz), 4.45 (dd, 1 H, J 1 ) 5.9
Allen ic Ester 28. To a solution of 170 mg (0.39 mmol) of
propargylic alcohol 26 in 5 mL of CH2Cl2 was added 0.32 mL
(1.80 mmol) of Hunig’s base followed by 0.10 mL (1.4 mmol)
of MsCl at -78 °C. After total consumption of the alcohol (1
h), the solution was quenched with 5 mL of saturated NH4Cl,
warmed to room temperature, and extracted with ether. The
combined extracts were washed with water and brine, dried
over anhydrous MgSO4, and filtered. The solvent was removed
under reduced pressure, and the residue was azeotropically
dried with benzene. The residue was used for next step
without further purification.
To a solution of 41 mg (0.045 mmol) of Pd2dba3 in 5 mL of
THF was added 94 mg (0.36 mmol) of Ph3P under nitrogen.
The purple solution quickly turned to yellow. After 10 min, a

5970 J . Org. Chem., Vol. 63, No. 17, 1998
Marshall and Liao
solution of the above mesylate in 1 mL of THF, 0.97 mL (6.75
mmol) of 2-(trimethylsilyl)ethanol, and 0.21 mL (1.8 mmol) of
2,6-lutidine in 3 mL of THF was added to the yellowish
solution, and the flask was rinsed with 2 mL of THF. The
solution turned green. The flask was fitted with a balloon of
carbon monoxide, and the reaction was monitored by TLC.
After total consumption of the mesylate (about 1 h), the solvent
was removed and the residue was chromatographed on Et3N-
deactivated silica gel to give 160 mg (73%) of allenic ester 28
as a colorless liquid. Extended reaction time caused isomer-
ization of this allenic ester. 1H NMR (CDCl3): 5.81 (s, 1 H),
5.66 (dd, 1 H, J 1 ) 2.4 Hz, J 2 ) 4.9 Hz), 5.07 (br, 1 H), 5.05 (s,
1 H), 4.90 (s, 1 H), 4.86-4.84 (m, 1 H), 4.84-4.82 (m, 1 H),
4.58 (d, 1 H, J ) 6.8 Hz), 4.51 (d, 1 H, J ) 6.8 Hz), 4.33 (d, 1
H, J ) 4.9 Hz), 4.22 (m, 2 H), 3.68 (ddd, 1 H, J 1 ) 6.8 Hz, J 2
butenolide 34 as a colorless solid and 2.0 mg (2%) of another
isomer (presumably the C8 epimer). 1H NMR (CDCl3): 5.87
(s, 1 H), 5.28 (s, 2 H), 5.15 (s, 1 H), 4.91 (s, 1 H), 4.76 (s, 1 H),
4.59 (s, 3 H), 3.71 (ddd, 1 H, J 1 ) 7.3 Hz, J 2 ) 9.8 Hz, J 3 ) 8.8
Hz), 3.69 (s, 1 H), 3.44 (ddd, 1 H, J 1 ) 7.3 Hz, J 2 ) 8.8 Hz, J 3
) 9.8 Hz), 2.47-2.33 (m, 3 H), 2.01-1.82 (m, 2 H), 1.97 (S, 3
H), 1.92 (S, 3 H), 1.84 (S, 3H), 0.88 (app.t. 2 H, J ) 8.8 Hz),
-0.01 (s, 9 H). 13C NMR (CDCl3): 175.1, 151.1, 149.5, 148.5,
147.6, 141.8, 135.6, 119.1, 115.6, 112.2, 111.5, 92.5, 81.8, 70.2,
65.5, 49.6, 48.9, 30.6, 23.1, 22.7, 20.5, 18.1, 9.6, - 1.5. IR
(cm-1, neat): 3075, 1755.
Ka llolid e A Aceta te (35). To a solution of 3.0 mg (0.007
mmol) of SEM ether 34 in 0.5 mL of acetic acid was added 1.7
mg (0.007 mmol) of PPTS at room temperature. The mixture
was stirred for 2 days until most of the starting material was
consumed. The solvent was removed, and the residue was
chromatographed on silica gel (25% ether in hexanes) to give
2.0 mg (82%) of kallolide A acetate (35). 1H NMR (CDCl3):
6.64 (br, 1 H), 5.89 (s, 1 H), 5.57 (d, 1 H, J ) 11.6 Hz), 5.40 (d,
1 H, J ) 4.9 Hz), 5.16 (br, 1 H), 5.01 (s, 1 H), 4.87 (s, 1 H),
4.77 (s, 1 H), 3.78 (d, 1 H, J ) 4.9 Hz), 3.09 (dd, 1 H, J 1 ) 7.3
Hz, J 2 ) 11.6 Hz), 2.44 (ddd, 1 H, J 1 ) 2.9 Hz, J 2 ) 13.2 Hz,
J 3 ) 13.2 Hz), 2.14 (d, 1 H, J ) 13.2 Hz), 2.05 (s, 3 H), 1.97 (s,
6 H), 1.69 (s, 3 H), 1.67 (m, 1 H), 0.44 (dt, 1 H, J ) 2.9 Hz, J
) 13.2 Hz). 13C NMR (CDCl3): 175.4, 170.5, 151.7, 147.2,
146.1, 143.8, 141.7, 137.4, 121.5, 114.9, 114.7, 112.3, 80.8, 66.6,
) 10.3 Hz, J 3 ) 13.0 Hz), 3.41 (ddd, 1 H, J 1 ) 6.8 Hz, J 2
)
10.3 Hz, J 3 ) 13.0 Hz), 2.88-2.76 (m, 1 H), 2.33 (br, 1 H),
2.13-2.02 (m, 2 H), 1.98 (s, 3 H), 1.89 (br, 6 H), 1.47 (ddd, 1
H, J 1 ) 2.4 Hz, J 2 ) 5.9 Hz, J 3 ) 13.2 Hz), 1.04-0.98 (m, 2
H), 0.92-0.85 (m, 2 H), 0.05 (s, 9 H), - 0.01 (s, 9 H). 13C NMR
(CDCl3): 212.6, 168.6, 151.9, 148.3, 147.3, 142.6, 118.1, 115.1,
111.8, 108.9, 101.3, 96.6, 92.5, 70.3, 65.4, 62.9, 50.4, 47.1, 25.9,
24.9, 21.4, 20.5, 18.1, 17.3, 9.6, -1.5, -1.6. IR (cm-1, neat):
3075, 2951, 1953, 1714. Anal. Calcd for C31H50O5Si2: C, 66.62;
H, 9.02. Found: C, 66.74; H, 9.12.
Bu t en olid e 34. To a solution of 120 mg (0.22 mmol) of
allenic ester 28 in 50 mL of benzene was added 14 mg (0.054
mmol) of Ph3P, and the mixture was refluxed over 2 days. TLC
showed little isomerization. The solution was concentrated
to 1 mL, and another 56 mg (0.22 mmol) of Ph3P was added.
The resulting mixture was refluxed for another 24 h where-
upon TLC analysis showed complete isomerization. The
solvent was removed, and the residue (allenic ester 31) was
directly used for the next step. A small portion was purified
for characterization. 1H NMR (CDCl3): 5.75 (s, 1 H), 5.60 (dd,
1 H, J 1 ) 3.9 Hz, J 2 ) 4.9 Hz), 5.13 (s, 1 H), 5.07 (s, 1 H), 4.88
(s, 1 H), 4.83 (s, 1 H), 4.64-4.62 (m, 3 H), 4.26 (d, 1 H, J ) 4.9
Hz), 4.10 (ddd, 2 H, J 1 ) 2.0 Hz, J 2 ) 7.3 Hz, J 3 ) 9.3 Hz),
3.71 (ddd, 1 H, J 1 ) 7.8 Hz, J 2 ) 9.8 Hz, J 3 ) 9.3 Hz), 3.46
(ddd, 1 H, J 1 ) 7.8 Hz, J 2 ) 9.8 Hz, J 3 ) 9.3 Hz), 2.80 (ddd, 1
H, J 1 ) 3.9 Hz, J 2 ) J 3 ) 14.2 Hz), 2.46 (ddd, 1 H, J 1 ) 2.0
Hz, J 2 ) J 3 ) 14.2 Hz), 2.42-2.32 (m, 1 H), 1.94 (s, 3 H), 1.89
(s, 3 H), 1.87 (s, 3 H), 1.74-1.64 (m, 2 H), 0.94-0.86 (m, 4 H),
0.00 (s, 18 H). 13C NMR (CDCl3): 211.8, 167.0, 147.8, 147.7,
142.3, 118.5, 113.3, 111.4. 109.3, 108.8, 103.3, 94.1, 92.7, 71.4,
65.4, 62.9, 56.4, 43.9, 33.5, 27.1, 22.5, 22.0, 18.1, 17.4, 9.8, -1.5.
Anal. Calcd for C31H50O5Si2: C, 66.62; H, 9.02. Found: C,
66.74; H, 9.12.
48.7, 46.0, 33.2, 22.0, 21.6, 20.9, 18.0, 9.5. IR (thin film, cm-1
1753, 1720.
)
Ka llolid e A (36). To a solution of 2.0 mg (0.004 mmol) of
butenolide 34 in 1 mL of tert-butyl alcohol was added 0.3 mL
of 3 M HCl. The mixture was stirred at room temperature
for 3 days. Saturated NaHCO3 was added, and the mixture
was extracted with ether. The combined ether extracts were
washed with water and brine, dried over anhydrous MgSO4,
and filtered. The solvent was removed under reduced pres-
sure, and the residue was chromatographed on silica gel (25%
ethyl acetate in hexanes) to remove a small amount of the C2
epimer (ca. 10%). Removal of solvent from the main fraction
afforded 1.1 mg (76%) of kallolide A (36) as a colorless solid.
1H NMR (CDCl3): 6.65 (br, 1 H), 5.90 (s, 1 H), 5.40 (d, 1 H, J
) 4.9 Hz), 5.29 (s, 1 H), 5.01 (dt, 1 H, J d ) 5.9 Hz, J t ) 1.5
Hz), 4.81 (s, 1 H), 4.36 (d, 1 H, J ) 11.2 Hz), 3.79 (d, 1 H, J )
4.9 Hz), 2.87 (dd, 1 H, J 1 ) 7.3 Hz, J 2 ) 11.2 Hz), 2.41 (m, 1
H), 2.11 (m, 1 H), 2.00 (s, 3 H), 1.97 (s, 3 H), 1.80 (s, 3 H), 1.63
(m, 1 H), 0.43 (m, 1 H). 13C NMR (CDCl3): 175.5, 151.2, 149.6,
146.1, 144.0, 141.7, 137.2, 119.9, 116.6, 114.9, 112.3, 80.9, 65.2,
49.8, 48.8, 33.1, 22.0, 21.6, 17.3, 9.6. IR (thin film, cm-1):
3498, 1750.
To a solution of the above allenic ester 31 in 2 mL of DMF
was added 0.43 mL (0.43 mmol) of tetrabutylammonium
fluoride (1.0 M in THF) dropwise at -78 °C, and the mixture
was brought to 0 °C after the addition. After total consump-
tion of the ester (2 h), the solution was quenched with 5 mL
of water and extracted with ether. The combined extracts were
washed with water and brine, dried over anhydrous MgSO4,
and filtered. The solvent was removed under reduced pres-
sure, and the residue was azeotropically dried with benzene.
The residue was used for next step without further purifica-
tion.
To a solution of allenic acid 32 in 5 mL of acetone was added
108 mg (0.65 mmol) of silver nitrate. The mixture was stirred
at room temperature until the acid was totally consumed
(usually more than 1 day). The mixture was filtered through
a pad of Celite, and the solvent was removed under reduced
pressure. The residue was chromatographed on silica gel (10%
ether in hexanes) to give 62 mg (60% from allenic ester 31) of
Ack n ow led gm en t. This work was supported by
Research Grant GM 29475 from the National Institutes
of Health.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
2, 3, 13, 14, 15, 18, 19, 20, 24, 25, 28, 31, 34, 35, 36, 40, 42,
44, 45, 46, eq 1. Experimental procedures and spectral data
for 14, 15, 17, 18, (+)-21, (+)-22, (+)-23, (+)-24, (+)-25, (+)-
26, 2,4-dinitrobenzoate of 26, (-)-28, (+)-34, (+)-35, (+)-36,
37, 38, 39, 40, 41, 42, 44, 45, 46 Macromodel Log Files for 25,
34/28, 41, 44/epi-44, 35, 2-epi 35, 36, 2-epi 36 (44 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O980603H