Diastereoselective 6-exo radical cyclizations of oxime ethers: Total synthesis of 7-deoxypancratistatin

Article abstract of DOI:10.1021/jo9902042

The development of an approach leading to the total synthesis of 7- deoxypancratistatin is described. The key features of the approach include a 6-exo radical cyclization reaction between a benzylic radical and an O- benzyloxime ether to establish the C(4a)-C(10b) bond. The stereochemistry of this reaction was examined in both acyclic radical precursors and ones in which the aryl moiety was tethered to the C₁ oxygen substituent. It was found that the use of such a tether was essential to obtain the stereochemical result required for the synthesis. The correct absolute and relative configurations at the hydroxylated carbons C₁-C₄ were obtained using D-gulonolactone as the source of C(10b)-C(4a).

Full text of DOI:10.1021/jo9902042

J . Org. Chem. 1999, 64, 4465-4476
4465
Dia ster eoselective 6-exo Ra d ica l Cycliza tion s of Oxim e Eth er s:
Tota l Syn th esis of 7-Deoxyp a n cr a tista tin
Gary E. Keck,* Stanton F. McHardy, and J erry A. Murry
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112
Received February 2, 1999
The development of an approach leading to the total synthesis of 7-deoxypancratistatin is described.
The key features of the approach include a 6-exo radical cyclization reaction between a benzylic
radical and an O-benzyloxime ether to establish the C4a-C10b bond. The stereochemistry of this
reaction was examined in both acyclic radical precursors and ones in which the aryl moiety was
tethered to the C1 oxygen substituent. It was found that the use of such a tether was essential to
obtain the stereochemical result required for the synthesis. The correct absolute and relative
configurations at the hydroxylated carbons C1-C4 were obtained using D-gulonolactone as the source
of C10b-C4a.
In tr od u ction
opening of a vinyl aziridine with an aryl cyanocuprate
reagent and have applied their approach to the synthesis
of 2 as well. Shortly after that, we8 reported an asym-
metric synthesis of 2 utilizing a diastereoselective 6-exo
radical cycliation to an oxime ether to construct the
highly functionalized cyclohexane nucleus found in 1,9
2, and related substances. Later that year, Trost reported
the synthesis of 1 based on a palladium-catalyzed de-
symmetrization,10 and Magnus has also recently reported
a total synthesis of 1.11 Sometimes overlooked is a
synthesis of 2 by Paulsen and co-workers, who synthe-
sized 7-deoxypancratistatin en route to lycoricidine, prior
to the isolation of 2 from natural sources.12 Described
herein is an account of our studies on diastereoselective
6-exo radical cyclizations to oxime ethers,8,13 which has
led to the total synthesis of 2.
The use of Amaryllidaceous plant extracts for medici-
nal purposes dates back to at least the fourth century;1
in recent times a large number of alkaloids which possess
a wide spectrum of biological activities have been isolated
from these species. Pancratistatin (1), isolated by Pettit
and co-workers,2 displays promising antineoplastic and
antiviral activity. The 7-deoxy compound (2), isolated by
Ghosal and co-workers,3 has been shown in in vitro
antiviral assays to exhibit a better therapeutic index than
1 due to decreased toxicity.4 The biologically active
alkaloids narciclasine (3) and lycoricidine (4) are also
isolated from this plant species.5 The unique structural
characteristics and promising biological activities of this
group of alkaloids have made them attractive synthetic
targets.
(7) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J . Am. Chem. Soc. 1995,
117, 3643.
(8) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Am. Chem. Soc.
1995, 117, 7289.
(9) For previous synthetic studies on 1 and 2, see: (a) Rigby, J . H.;
Gupta, V. Synlett 1995, 547. (b) Park, T. K.; Danishefsky, S. J .
Tetrahedron Lett. 1995, 36, 195. (c) Doyle, T. J .; VanDerveer, D.;
Haseltine, J . Tetrahedron Lett. 1995, 36, 6197. (d) Doyle, T. J .; Hendrix,
M.; Haseltine, J . Tetrahedron Lett. 1994, 35, 8295. (e) Lopes, R. S. C.;
Lopes, C. C.; Heathcock, C. H. Tetrahedron Lett. 1992, 33, 6775. (f)
Angle, S. R.; Louie, M. S. Tetrahedron Lett. 1993, 34, 4751. (g)
Thompson, R. C.; Kallmerten, J . J . Org. Chem. 1990, 55, 6076.
(10) Trost, B. M.; Pulley, S. R. J . Am. Chem. Soc. 1995, 117, 10143.
(11) Magnus, P.; Sebhat, I. K. J . Am. Chem. Soc. 1998, 120, 5341.
(12) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535.
(13) For previous work on both inter- and intramolecular free radical
additions to oxime ethers, see: (a) Chiara, J . L.; Marco-Contelles, J .;
Khair, N.; Gallego, P.; Destabel, C.; Bernabe, M. J . Org. Chem. 1995,
60, 6010. (b) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron
Lett. 1995, 36, 253. (c) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya,
I.; Kiguchi, T. Tetrahedron Lett. 1994, 35, 2205. (d) Booth, S. E.;
J enkins, P. R.; Swain, C. J .; Sweeney, J . B.; J . Chem. Soc., Perkin
Trans. 1 1994, 3499. (e) Parker, K.; Fokas, D. J . Org. Chem. 1994, 59,
3927. (f) Grissom, J . W.; Klingberg, D. J . Org. Chem. 1993, 58, 6559.
(g) Pattenden, G.; Schulz, D. J . Tetrahedron Lett. 1993, 34, 6787. (h)
Hatem, J .; Henriet-Bernard, C.; Grimaldi, J .; Maurin, R. Tetrahedron
Lett. 1992, 33, 1057. (i) Marco-Contelles, J .; Pozuelo, C.; J imeno, M.
L.; Martinez, L.; Martinez-Grau, A. J . Org. Chem. 1992, 57, 2625. (j)
Marco-Contelles, J .; Ruiz, P.; Sanchez, B.; J imeno, M. L. Tetrahedron
Lett. 1992, 33, 5261. (k) Parker, K. A.; Fokas, D. J . Am. Chem. Soc.
1992, 114, 9688. (l) Marco-Contelles, J .; Martinez, L.; Martinez-Grau,
A.; Pozuelo, C.; J imeno, M. L. Tetrahedron Lett. 1991, 32, 6437. (m)
Booth, S. E.; J enkins, P. R.; Swain, C. J . J . Chem. Soc., Chem.
Commun. 1991, 1248. (n) Marco-Contelles, J .; Martinez, L.; Martinez-
Grau, A. Tetrahedron: Asymmetry 1991, 2, 961. (o) Enholm, E. J .;
Burnoff, J . A.; J aramillo, L. M. Tetrahedron Lett. 1990, 31, 3727. (p)
Parker, K. A.; Spero, D. M.; Van Epp, J . J . Org. Chem. 1988, 53, 4628.
(q) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc. 1988,
110, 1633. (r) Hart, D. J .; Seely, F. J . Am. Chem. Soc. 1988, 110, 1631.
(s) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
A considerable body of work directed toward the
synthetic reconstruction of these materials has been
reported. The first total synthesis of pancratistatin (as
the racemate) was reported by Danishefsky and Lee in
1989.6 More recently, Hudlicky and co-workers reported7
an asymmetric synthesis of 1 which relied on an SN2
(1) Hartwell, J . L. Lloydia 1967, 30, 379.
(2) (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M. J . Nat. Prod. 1984,
47, 1018. (b) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.;
Sagawa, Y. J . Chem. Soc., Chem. Commun. 1984, 1693.
(3) Ghosal, S.; Singh, S.; Kumar, Y.; Srivastava, R. S. Phytochemistry
1989, 28, 611.
(4) Gabrielsen, B.; Monath, T. P.; Huggins, J . W.; Kefauver, D. F.;
Pettit, G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J . J .; Shannon, W.
M.; Schubert, E. M.; Dare, J .; Ugarkar, B.; Ussery, M. A.; Phelan, M.
J . J . Nat. Prod. 1992, 55, 1569.
(5) For total syntheses of (and leading references to) lycoricidine,
see: (a) Hudlicky, T.; Olivo, H. F.; McKibben, B. J . Am. Chem. Soc.
1994, 116, 5108. (b) McIntosh, M. C.; Weinreb, S. M. J . Org. Chem.
1993, 58, 4823. (c) Martin, S. F.; Tso, H. Heterocycles 1993, 35, 85. (d)
Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 32, 4525.
(6) Danishefsky, S.; Lee, J . Y. J . Am. Chem. Soc. 1989, 111, 4829.
10.1021/jo9902042 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/20/1999

4466 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
of the lactol with O-benzylhydroxylamine‚HCl in the
presence of pyridine,13b which gave the desired diol 10
in 66% yield and as a 2:1 mixture of oxime isomers. (See
Experimental Section. For convenience, only one oxime
isomer will be depicted throughout.) Protection of the diol
Retr osyn th etic An a lysis
Our retrosynthetic analysis of 7-deoxypancratistatin
is outlined below. The critical aspect of interest to us was
the viability and stereochemistry of an approach which
relied upon a very late construction of the desired trans
phenanthridone ring nucleus via a 6-exo cyclization of a
radical intermediate of type 5. The radical intermediate
5 would ultimately be generated from some derivative
of the corresponding benzylic alcohol, which was envi-
sioned to arise from the coupling of an aryl bromide 6
and the oxime-aldehyde 7. A functionalized aryl bromide
such as 6 should be readily prepared from piperonal. The
oxime-aldehyde 7, which possesses the desired absolute
configurations for the oxygen substituents at C1-C4,
should be accessible from a hydroxy-aldehyde of type 8.
The structure of hydroxy-aldehyde 8, in turn, suggests
a carbohydrate approach to this subunit. We chose to
approach this material from commercially available
D-gulonolactone. Although the choices of protecting groups
for the C1 and C2 hydroxyls (pancratistatin numbering)
are in principle not critical, use of the acetonide moiety
for the C3 and C4 hydroxyls was an integral part of the
strategy, since the appendages involved in the radical
cyclization would be held cis to one another on the 1,3-
dioxolane using this approach. This would clearly be more
favorable for the cyclization process we required than if
acyclic protecting groups were employed. The two main
questions in such an approach were whether a benzylic
radical would be sufficiently reactive in such a 6-exo
radical cyclization and, if so, if such an approach could
be utilized for the synthesis of the trans phenanthridone
ring system. The construction of this subunit of the
structure is considerably more difficult than might be
apparent and has proven to be particularly problematic.14
with chloromethyl methyl ether and N,N-diisopropyl-
ethylamine afforded the corresponding bis-MOM ether.
Deprotection of the TBS group (TBAF/THF) gave the
desired alcohol 11, which was oxidized using the method
of Ley16 to afford the corresponding aldehyde. Immediate
treatment of the aldehyde so produced with the Grignard
reagent 12 (prepared from commercially available 4-bro-
mo-1,2-methylenedioxybenzene) gave the desired alcohol
13 in 82% yield. Radical precursor 14 was prepared in
60% yield (as a mixture of diastereomers which were not
separated) by treatment of alcohol 13 with 1,1′-thiocar-
bonyldiimidazole in 1,2-dichloroethane.17 With the de-
sired radical precursor in hand, studies on the radical
cyclization process were commenced.
Ra d ica l Cycliza tion Resu lts
Slow addition of a solution of Bu3SnH and AIBN in
toluene to a solution of thionocarbamate 14 at 90 °C over
12 h afforded the two cyclized products 15 and 16 in a
3:1 ratio and in 90% isolated yield.
Con str u ction of a Ra d ica l P r ecu r sor
The major isomer 15 was ultimately shown to have the
aryl group and the amine group in a cis orientation, with
the nitrogen substituent at C4a trans disposed with
respect to the adjacent oxygen at C3. Thus, in this isomer,
the stereochemistry at the nitrogen-bearing center C4a
is as required for the synthesis of 2, but the configuration
at the aryl-bearing carbon C10b is incorrect. Literature
precedent for a trans relationship between the nitrogen
and oxygen centers in such a cyclization was available
in a previous report by Marco-Contelles and co-workers.13a
Our studies on such radical cyclization to oxime ethers
began with the D-gulonolactone derivative 9.15 Treatment
of lactone 9 with DIBAL at -78 °C gave the correspond-
ing lactol. Oxime formation was carried out by treatment
(14) For a review of synthetic work in this area, see: Polt, R. In
Organic Synthesis: Theory and Application; Hudlicky, T., Ed.; J AI
Press: Greenwich, 1996; Vol. 3, p 109.
(15) Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
45, 319.

Total Synthesis of 7-Deoxypancratistatin
J . Org. Chem., Vol. 64, No. 12, 1999 4467
The minor isomer 16 contained the aryl and amine
groups in a trans orientation; however, the configurations
at both centers were epimeric with respect to those
needed for the synthesis of 2.
isomer (amide 20), a large coupling (J H10b-J H4a) of 11.0
Hz was observed, indicative of a trans-diaxial relation-
ship.
When amines 15 and 16 were first isolated, the 1H
NMR data did not allow for an unambiguous assignment
of stereochemistry, presumably due to distortions away
from idealized chair structures by the presence of the
fused five-membered ring. Therefore, both 15 and 16
were converted to the tetraacetate derivatives 19 and 20.
For amine 15, this sequence commenced by treatment
with benzoyl chloride/pyridine, followed by reductive
N-O bond cleavage18 using 6% Na(Hg) in EtOH, which
cleanly afforded the benzamide 17 in 84% yield. The same
sequence was performed with the minor amine isomer
16, which gave the amide 18 in 82% yield.
Encouraged by the results of the radical cyclization of
14, we next considered means by which the stereochem-
istry of the aryl group at C10b might be controlled. We
envisioned that the desired stereochemistry at C10b could
arise by conducting the key radical cyclization using a
precursor in which the aryl group was tethered to the C1
oxygen substituent as indicated generically in structure
21. The net effect of this change would be to hold the
aryl group in the desired â orientation during the radical
cyclization. Since an additional carbon, in the form of an
aryl carbonyl substituent, would eventually be required
for the synthesis of 7-deoxypancratistatin, the most
natural way to incorporate the proposed tether would be
in the form of an ester linkage as in lactone 22. Thus,
with such a lactone moiety incorporated as a means to
link the aryl unit to the hydroxyl group at C1, it can be
readily seen that the desired stereochemical outcome
translates simply into a requirement that the 6-exo
cyclization process occur so as to produce a cis ring fusion.
Said another way, this requires radical addition onto the
same face of the lactone ring that the tether terminating
in the O-benzyloxime originates from. Clearly, this would
be expected to be strongly preferred in this system.
One final stereochemical consideration is the disposi-
tion of the nitrogen substituent at C4a using this ap-
proach. It becomes clear upon inspection of molecular
models for the proposed cyclization that only two possible
dispositions of the oxime ether with respect to the
adjacent oxygen substituent allow the requisite trajectory
for radical addition in a 6-exo manner: either essentially
synperiplanar or essentially antiperiplanar. Of these, it
would reasonably be expected that the antiperiplanar
arrangement would be preferred to minimize nonbonded
interactions in the transition state. With these consid-
erations in mind, we set out to synthesize such a “cyclic”
radical precursor (23) in hopes of obtaining the correct
stereochemistry in the radical cyclization step.
Treatment of amide 17 with DOWEX-H+ resin in
MeOH cleanly removed both the acetonide and MOM
ether protecting groups to afford the corresponding
tetraol, which was then peracetylated with Ac2O/pyridine
to give the tetraacetate 19 in 76% yield. Again, the same
steps were performed on the amide 18, which gave the
tetraacetate 20 in 77% yield. These derivatives gave very
richly detailed and clean NMR spectra in which all
resonances were easily observable and assigned by de-
coupling experiments; in these materials, the expected
chair conformations were evident. In the major isomer
Con str u ction of th e Cyclic Ra d ica l P r ecu r sor
Starting from the D-gulonolactone derivative 25, DIBAL
reduction, followed by oxime formation (O-benzylhydroxyl-
amine‚HCl, pyr) gave the alcohol 26 in 89% yield (2:1
mixture of oxime isomers). Protection of 26 with MOMCl/
(amide 19), the small coupling constant (J H10b-J H4a) of
4.6 Hz was indicative of a cis relationship. In the minor
(17) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.
(18) Keck, G. E.; Fleming, S.; Nickell, D.; Weider, P. Synth.
Commun. 1979, 9, 281.
(16) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(19) Evans, D. A.; Gage, J . R.; Leighton, J . J . Am. Chem. Soc. 1992,
114, 9434.

4468 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
oxidized (TPAP, NMO) to the keto-aldehyde 32. The
keto-aldehyde 32 was not labile and was obtained in
72% overall yield from ester 31 after purification by
column chromatography.
DIEA, followed by selective deprotection19 of the primary
TBS group (HF‚Pyr) afforded the desired primary alcohol
27 in 62% yield. Oxidation (TPAP, NMO) of 27 to
aldehyde 28 was straightforward; however, additions of
various lithiated aromatic subunits to 28 proved to be
problematic. Further oxidation20 to acid 29 also occurred
readily, but attempts to add lithiated aromatic subunits
to the corresponding Weinreb amide21 again failed, yield-
ing only recovered starting material.
The keto-aldehyde 32 was converted to alcohol 33 by
a three-step sequence, which began by removal of the
TBS group using HF‚pyridine. This afforded a hydroxy-
aldehyde corresponding to 32 which existed almost
exclusively as the cyclic lactol structure. Dess-Martin
oxidation24 of this material then provided the lactone
moiety, and finally, reduction of the keto carbonyl group
using NaBH4 afforded alcohol 33. Treatment of alcohol
33 with 1,1′-TCDI as previously described afforded the
desired “cyclic” radical precursor 34.
Due to the unexpected problems encountered with
these intermolecular reactions, we next investigated the
use of an intramolecular variant of the same basic bond
construction.22 Mitsunobu esterification23 of acid 29 with
alcohol 30 cleanly afforded ester 31 in 80% yield. Treat-
ment of 31 with n-butyllithium at -98 °C, followed by
gradual warming to -78 °C, afforded the corresponding
rearranged benzylic alcohol. This alcohol unexpectedly
proved to be very unstable and thus was immediately
Radical cyclization of 34 (Bu3SnH, AIBN, toluene, 90
°C) was unexpectedly complicated by competing reduction
of the lactone moiety, and afforded amine 35 in only 25%
isolated yield. A number of conditions for this transfor-
mation were examined in an attempt to improve upon
this result, including the use of low-temperature initia-
tors,25 but in no case could we obtain more than a 30%
isolated yield of 35. Thus, the yield for the radical
cyclization process using the lactone substrate 34 was
unacceptably low. However, we were extremely gratified
to find that 35 was obtained as a single diastereomer in
which the desired relative and absolute configurations
had been established at both C10b and C4a, thus establish-
ing the viability of this aspect of the radical cyclization
approach.
(20) Kraus, G. A.; Taschner, M. J . J . Org. Chem. 1980, 45, 1175.
(21) (a) Sibi, M. P. Org. Prep. Proc. Intl. 1993, 25, 15. (b) Levin, J .
I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989. (c) Nahm,
S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (d) Aidhen, I. S.;
Ahuja, J . Tetrahedron Lett. 1992, 33, 5431. (e) Evans, D. A.; Kaldor,
S. W.; J ones, T. K.; Stout, T. J . J . Am. Chem. Soc. 1990, 112, 7001.
(22) (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15,
300. (b) Horne, S.; Rodrigo, R. J . Chem. Soc., Chem. Commun. 1992,
164. (c) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J . Am. Chem. Soc.
1994, 116, 8402. (d) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.; Smith,
S. H.; Hu, H. J . Org. Chem. 1994, 59, 5147.
(24) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(25) Nozaki, K.; Oshima, K.; Utimoto, K. J . Am. Chem. Soc. 1987,
109, 2547.
(23) Mitsunobu, O. Synthesis 1981, 1.

Total Synthesis of 7-Deoxypancratistatin
J . Org. Chem., Vol. 64, No. 12, 1999 4469
Cyclic Aceta l Rou te
Completion of the synthesis from this point required
several operations which at first glance would appear to
be largely independent of one another: (1) removal of the
MOM ether and acetonide moieties under acidic condi-
tions, (2) removal of the TFA group under basic condi-
tions, (3) rearrangement of the amino-lactone structure
to a hydroxy-amide, and (4) reductive cleavage of the
N-O bond. However, it was ultimately found experimen-
tally that a precise ordering of these steps was required.
For example, it did not prove possible to effect the lactone
to lactam rearrangement unless the acetonide was re-
moved prior to this step. It was also found that this
rearrangement could not be done using the O-benzylhy-
droxylamine; reductive cleavage of the N-O bond was
required prior to conducting this rearrangement.
Cleavage of the N-O bond in 39 was not straightfor-
ward. Treatment of 39 under hydrogenolysis26 conditions
and aluminum or sodium amalgam27 conditions was not
successful. However, reaction of 39 with SmI2/THF28
cleanly afforded amide 40. We have found this to be a
very general and useful reaction for the cleavage of N-O
bonds in O-alkylhydroxylamines and O-alkylhydroxamic
acid derivatives.29 Finally, removal of the acetonide and
MOM ether (DOWEX-H+, MeOH, 65 °C) gave the corre-
sponding triol. The triol was then treated with K2CO3 in
dry MeOH,30 which effected trifluoroacetamide removal
with concomitant lactone to lactam reorganization, pro-
ducing the natural product 7-deoxypancratistatin (2).
It did not prove practical to attempt to salvage the
lactol side products encountered in the cyclization of the
lactone substrate; thus, an alternative radical precursor
was needed in which this unexpected reduction process
was not possible. We chose to investigate the use of a
TBS silyl acetal in this context. A radical precursor very
similar to 34 was prepared which incorporated a pro-
tected lactol as a latent lactone. Keto-aldehyde 32 was
converted to the TBS-protected lactol 36 via TBS depro-
tection as described before, followed by reprotection of
the resulting lactol with TBSCl. Ketone reduction (NaBH4
MeOH) and acylation (1,1′-TCDI) as previously described
afforded radical precursor 37, which yielded 38 as a
single stereoisomer (ignoring lactol stereoisomers) upon
radical cyclization in 72% isolated yield.
Com p letion of th e Rou te to 2
Now that a satisfactory result for the critical radical
cyclization had been realized, our attention turned to
elaborating this substance to afford 2. All attempts at
deprotection of the TBS lactol and oxidation to the lactone
(in 38) in the presence of the free amine were unsuccess-
ful. Therefore, protection of the amine was required,
ideally with a group which would not require any
additional steps for its removal. This was accomplished
by acylation of 38 with TFAA to give the trifluoroaceta-
mide derivative. Removal of the TBS group (TBAF) and
oxidation (TPAP, NMO) then gave lactone 39 in 81%
overall yield.
The natural product 2 was peracetylated (Ac2O, pyri-
dine) to give the corresponding tetraacetate 41. The
tetraacetate was spectroscopically and chromatographi-
1
cally indistinguishable (Rf, H, 13C, and [R]D) from that
described by Paulsen.12
Rein vestiga tion of th e La cton e Rou te
To avoid the two extra steps nessessary for transform-
ing the TBS-lactol in 38 back to the desired lactone (i.e.,
deprotection and oxidation), a number of radical cycliza-
(26) Nikam, S. S.; Kornberg, B. E.; J ohnson, D. R.; Doherty, J . A.
Tetrahedron Lett. 1995, 36, 197.
(27) In our original study on the reductive cleavage of N-O bonds,
O-alkyl trifluorohydroxamate derivatives were not studied, see ref 18.
(28) (a) Molander, G. A. Organic Reactions; Paquette, L. A., Ed.;
J ohn Wiley and Sons: New York, 1994; Vol. 46, pp 211-367. (b)
Brandukova, N. E.; Vygodskii, Y. S.; Vinogradova, S. V. Russ. Chem.
Rev. 1994, 63, 345. (c) Molander, G. A. Chem. Rev. 1992, 92, 29. (d)
Kagan, H. B.; Namy, J . L. Tetrahedron 1986, 42, 6573.
(29) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett.
1995, 36, 7419.
(30) (a) For a closely related transformation, see ref 12. (b) For a
different outcome in a similar transformation using the same reagents,
see ref 6.

4470 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
Ta ble 1. Con d ition s for th e Ra d ica l Cycliza tion of 34
dried 4 Å molecular sieves. MOMCl was freshly prepared by
a modification of the Linderman method31 and distilled prior
to use. Bu3SnH and Ph3SnH were flushed through a small
column of activated alumina prior to use. Yields were calcu-
lated for material judged homogeneous by thin-layer chroma-
tography and NMR. Thin-layer chromatography was per-
formed on Merck Kieselgel 60 F254 plates eluting with the
solvents indicated, visualized by a 254 nm UV lamp, and
stained with an ethanolic solution of 12-Molybdophosphoric
acid or p-anisaldehyde. Flash column chromatography was
performed with Davisil 62 silica gel, slurry packed with 4%
ethyl acetate/hexanes in glass columns, and flushed with
hexanes prior to use. HPLC, high-pressure liquid chromatog-
raphy, was performed with a Rainin HPXL system, utilizing
a 21.4 mm × 5 cm preparative silica gel column with UV
monitoring. Nuclear magnetic resonance spectra were acquired
at 300 MHz for 1H and 75 MHz for 13C. The abbreviations s,
d, t, q, brs, and brt stand for the resonance multiplicities
singlet, doublet, triplet, quartet, broad singlet, and broad
triplet, respectively. Analytical C and H analyses were per-
formed by Atlantic Microlab, Inc., Norcross, GA. Glassware
for all reactions was oven dried at 125 °C and cooled in a
desiccator prior to use. Liquid reagents and solvents were
introduced by oven-dried syringes through septa-sealed flasks
under a nitrogen atmosphere. In the reactions involving oxime
ethers, a ca. 2:1 mixture of oxime isomers was used. However,
for characterization purposes the major oxime isomer was
separated and fully characterized. Oxime isomers were sepa-
rated by flash chromatography, with the exception of diol 10
and alcohol 11 which were separated by preparative HPLC.
Optical rotations were measured at 23 °C unless otherwise
indicated.
P r ep a r a tion of (1S,2R)-1-{(4S,5R)-5-[(1Z)-2-Aza -2-(p h e-
n ylm et h oxy)vin yl]-2,2-d im et h yl(1,3-d ioxola n -4-yl)}-3-
(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)p r op a n e-1,2-d iol (10).
To a stirring solution of 6-O-tert-butyldimethylsilyl-2,3-O-
isopropylidene-D-gulonolactone (2.0 g, 6.0 mmol) in 40 mL of
CH2Cl2 at -78 °C was added a 1.0 M solution of DIBAL (7.2
mL, 7.2 mmol) over 1 h. After complete addition the reaction
was stirred for 45 min and then quenched with 10 mL of
MeOH. The solution was warmed to room temperature and
stirred with 100 mL of saturated Rochelle salts for 3 h. The
layers were separated, the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL), and the combined organic layers were
dried over anhydrous MgSO4. The solution was filtered and
concentrated under reduced pressure to yield a light yellow
oil.
To a stirring solution of the crude lactol prepared above in
20 mL of pyridine at room temperature was added O-benzylhy-
droxylamine‚HCl (2.9 g, 18 mmol) in one portion. After 12 h,
the reaction was diluted with 100 mL of EtOAc and washed
with 50 mL each of H2O, saturated CuSO4, H2O, and brine.
The organic layer was dried over anhydrous Na2 SO4, filtered,
and concentrated under reduced pressure. Purification was
accomplished by flash chromatography on a 4.5 × 25 cm
column, eluting with a solvent gradient of 10%, 15%, 20%, 25%,
30%, and 40% EtOAc/hexanes, collecting 20 mL fractions. The
product-containing fractions (26-50) were collected and con-
centrated to yield 1.8 g (66%) of the diol 10 as a clear colorless
oil and as a 2:1 mixture of oxime isomers (major oxime
isomer): Rf 0.49 (50% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) δ 7.54 (d, J ) 8.1 Hz, 1H), 7.23-7.33 (m, 5H), 5.05 (s,
2H), 4.71 (dd, J ) 8.1, 7.0 Hz, 1H), 4.37 (dd, J ) 7.0, 4.3 Hz,
1H), 3.55-3.68 (m, 4H), 2.87 (d, J ) 6.3 Hz, 1H), 2.72 (d, J )
4.3 Hz, 1H), 1.51 (s, 3H), 1.37 (s, 3H), 0.87 (s, 9H), 0.51 (s,
3H), 0.49 (s, 3H); 75 MHz 13C NMR (CDCl3) δ 148.4, 137.3,
128.4, 128.2, 127.9, 110.1, 79.2, 76.1, 75.0, 71.6, 69.1, 64.9, 27.2,
25.8, 25.0, 18.2, -5.5; IR (neat) 3510 cm-1; HRMS m/z (EI)
calcd C22H37NO6Si 439.2388, obsd 439.2375. Anal. Calcd for
C22H37NO6Si: C, 60.11; H, 8.48; N, 3.19. Found: C, 60.21; H,
8.37; N, 3.29.
entry
a
conditions
yield of 35, %
Bu3SnH, AIBN, 95 °C,
toluene, 12 h
25a
b
c
d
Bu3SnH, AIBN, 80 °C,
benzene, 2 h
Bu3Sn-O-SnBu3, PMHS,
p-dioxane, 95 °C
Et3B, Bu3SnH,
25a
28a
30b
0 °C to room temperature,
26 h
e
f
Ph3SnH, AIBN, 65 °C
toluene, 4.5 h
Bu3SnH, AIBN, 65 °C
toluene, 5 h
70c
28d
a
b
Remaining material was over-reduced products. No over-
reduced products observed, only remaining starting material. c No
d
over-reduced products observed. Remaining material was over-
reduced product and starting material.
tion conditions were studied in an attempt to preclude
the competing over reduction in the cyclization of 34. As
shown in Table 1, conditions employing Bu3SnH at high
temperatures (entries a, b, and c) gave the desired
product in low yield, along with considerable amounts
of the over-reduced side products. Using a low-temper-
ature radical initiation method25 (entry d), the desired
product 35 was obtained in only 30% yield; however, none
of the over-reduced products were observed, and the
remaining material was recovered 34. Attempts to im-
prove the conversion under the low-temperature Et3B/
Bu3SnH conditions were unsuccessful. Finally, it was
discovered that treatment of 34 with Ph3SnH/AIBN in
toluene at 65 °C gave a 70% yield of 35 (entry e) as a
single diastereomer; again, no over-reduced products
were observed. To confirm that this was indeed unique
to the use of Ph3SnH and not to some other, possibly
overlooked change in experimental conditions, the Bu3-
SnH reaction was repeated using the same experimental
conditions, but again gave only 28% yield (entry f). This
result provides an efficient method for the conversion of
34 to 35 without employing the previously required TBS-
lactol linkage. The cyclized product obtained in this way
was converted to intermediate 40 by acylation with
TFAA, followed by reduction with samarium iodide as
previously described.
Con clu sion s
The chemistry described herein provides an indication
of the utility of 6-exo radical cyclizations to oxime ethers
as a method for construction of the highly functionalized
trans phenanthridone ring nucleous found in various
Amaryllidacae alkaloids. The radical precursors are
easily prepared from readily available carbohydrate
derivatives. The route described herein affords 7-deoxy-
pancratistatin in 7% overall yield over 21 steps. Although
the overall synthesis is longer than we envisioned, efforts
toward shorter and more convergent approaches using
this radical cyclization strategy can now be undertaken
with confidence given the results of these studies.
Exp er im en ta l Section
Gen er a l. Solvents were purified according to the guidelines
in Purification of Common Laboratory Chemicals (Perrin,
Armarego, and Perrin, Pergamon: Oxford, 1966). Reagent
grade t-BuOH, pyridine, and 1,2-dichloroethane were pur-
chased and used without further purification. N,N-Diisopro-
pylethylamine was distilled from CaH2 and stored over oven-
(31) Linderman, R. J .; J aber, M.; Griedel, B. D. J . Org. Chem. 1994,
59, 6499.

Total Synthesis of 7-Deoxypancratistatin
J . Org. Chem., Vol. 64, No. 12, 1999 4471
P r ep a r a tion of (3S,2R)-3-{(5S,4R)-5-[(1Z)-2-Aza -2-(p h e-
n ylm et h oxy)vin yl]-2,2-d im et h yl(1,3-d ioxola n -4-yl)}-2,3-
bis(m eth oxym eth oxy)p r op a n -1-ol (11). To a stirring solu-
tion of diol 10 (1.75 g, 3.99 mmol) in 40 mL of CH2Cl2 cooled
to -5 °C was added N,N-diisopropylethylamine (28.0 mL, 160
mmol), followed by chloromethyl methyl ether (9.10 mL, 120
mmol). The solution was warmed to room temperature and
stirred for 19 h and then quenched by addition of 50 mL of a
saturated NaHCO3 solution. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude oil was filtered through a silica gel plug, and the plug
was washed with 30% EtOAc/hexanes. The solvents were
removed under reduced pressure to yield a yellow oil, which
was used in the next step without further purification.
To a stirring solution of the crude bis-MOM ether (1.70 g)
prepared above in 30 mL of THF at -5 °C was added a 1.0 M
solution of tetrabutylammonium fluoride (6.30 mL, 6.30 mmol)
dropwise over 5 min. The solution was allowed to slowly warm
to room temperature, stirring for a total of 2 h, and then was
quenched with 15 mL of a saturated NH4Cl solution and
diluted with 40 mL of CH2Cl2. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure. Pu-
rification was accomplished by flash chromatography on a 2.3
× 15 cm column, eluting with a solvent gradient of 20%, 40%,
and 45% EtOAc/hexanes, collecting 15 mL fractions. The
product-containing fractions (13-28) were collected and con-
centrated to yield 1.20 g (67%) of alcohol 11 as a clear colorless
oil and as a 2:1 mixture of oxime isomers (major oxime
isomer): Rf 0.15 (35% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) δ 7.39 (d, J ) 8.4 Hz, 1H), 7.31-7.35 (m, 5H), 5.05 (s,
2H), 4.78 (d, J ) 6.9 Hz, 1H), 4.56-4.65 (m, 4H), 4.51 (t, J )
6.4 Hz, 1H), 3.63-3.74 (m, 4H), 3.38 (s, 3H), 3.37 (s, 3H), 2.98
(t, J ) 7.6 Hz, 1H), 1.46 (s, 3H), 1.35 (s, 3H); 75 MHz 13C NMR
(CDCl3) δ 147.9, 137.3, 128.4, 128.0, 109.7, 98.0, 97.3, 79.8,
77.9, 76.2, 75.5, 74.7, 62.0, 56.3, 55.9, 27.9, 25.6; IR (neat) 3500
cm-1. Anal. Calcd for C20H31NO8: C, 58.10; H, 7.56; N, 3.39.
Found: C, 57.93; H, 7.51; N, 3.42.
P r ep a r a tion of 1-(2H-Ben zo[3,4-d ]-1,3-d ioxola n -5-yl)-
(3S,2R)-3-{(5S,4R)-5-[(1Z)-2-a za -2-(p h en ylm eth oxy)vin yl]-
2,2-dim eth yl(1,3-dioxolan -4-yl)}-2,3-bis(m eth oxym eth oxy)-
p r op a n -1-ol (13). To a stirring solution of alcohol 11 (960 mg,
2.30 mmol) in 35 mL of CH2Cl2 at room temperature were
added oven-dried 4 Å molecular sieves (960 mg) and N-
methylmorpholine N-oxide (410 mg, 3.50 mmol), followed by
tetrapropylammonium perruthenate (42.0 mg, 0.120 mmol).
After 30 min, the reaction was filtered through a MgSO4/silica
gel plug with the aid of EtOAc. The resulting solution was
concentrated under reduced pressure to yield 826 mg (87%)
of the crude aldehyde, which was used in the next step without
further purification.
To a stirring solution of the Grignard reagent 12 (16.0 mL
of 0.5 M, 8.0 mmol, prepared from 4-bromo-1,2-methylene-
dioxybenzene) in 15 mL of THF at -78 °C was added the
aldehyde prepared above (826 mg, 2.01 mmol) in 8 mL of THF
dropwise. The reaction slowly warmed to -10 °C over 3.5 h
and was then quenched with 20 mL of a saturated NH4Cl
solution and warmed to room temperature. The solution was
diluted with 40 mL of Et2O, the layers were separated, and
the aqueous layer was extracted with Et2O (3 × 30 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Purification
was accomplished by flash chromatography on a 2.1 × 20 cm
column, eluting with a solvent gradient of 10%, 20%, 25%, 30%,
35%, and 40% EtOAc/hexanes, collecting 8 mL fractions. The
product-containing fractions (53-87) were collected and con-
centrated under reduced pressure to give 998 mg (82% yield)
of 13 as a light yellow oil and a mixture of diastereomers: one
diastereomer, [R]D -26.9° (c 1.8, CHCl3); Rf 0.34 (50% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3) δ 7.28-7.35 (m, 6H),
6.70-6.90 (m, 3H), 5.87 (ABq, ∆AB ) 7.3 Hz, J ) 1.5 Hz, 2H),
5.09 (s, 2H), 4.90 (t, J ) 3.6 Hz, 1H), 4.61-4.71 (m, 4H), 4.57
(d, J ) 6.9 Hz, 1H), 4.46 (d, J ) 6.9 Hz, 1H), 4.03 (d, J ) 3.0
Hz, 1H), 3.80 (t, J ) 3.7 Hz, 1H), 3.54 (dd, J ) 5.1, 3.4 Hz,
1H), 3.44 (s, 3H), 3.26 (s, 3H), 1.47 (s, 3H), 1.38 (s, 3H); 75
MHz 13C NMR (CDCl3) δ 147.8, 147.6, 146.9, 137.1, 135.1,
128.4, 128.3, 128.0, 119.9, 109.9, 108.0, 107.2, 100.9, 98.5, 98.4,
82.5, 77.2, 76.3, 76.2, 74.9, 71.6, 56.6, 56.1, 27.6, 25.5; IR (neat)
3472 cm-1; HRMS m/z (EI) calcd C27H35NO10 533.2259, obsd
533.2289.
P r ep a r a tion of [3-(2H-Ben zo[3,4-d ]1,3-d ioxola n -5-yl)-
(1S,3S,5S,2R,4R,6R)-4,5-bis(m eth oxym eth oxy)-8,8-d im e-
t h yl-7,9-d ioxa b icyclo[4.3.0]n on -2-yl](p h en ylm et h oxy)-
a m in e (15) a n d [3-(2H -Ben zo[3,4-d ]1,3-d ioxola n -5-yl)-
(1S,2S,3S,5S,4R,6R)-4,5-bis(m eth oxym eth oxy)-8,8-d im e-
t h yl-7,9-d ioxa b icyclo[4.3.0]n on -2-yl](p h en ylm et h oxy)-
a m in e (16). To a stirring solution of alcohol 13 (995 mg, 1.87
mmol) in 25 mL of 1,2-dichloroethane at room temperature
was added 4-(dimethylamino)pyridine (115 mg, 0.940 mmol),
followed by 1,1′-thiocarbonyldiimidazole (1.70 g, 9.40 mmol).
The solution was heated at reflux for 24 h and then cooled to
room temperature and poured into a separatory funnel con-
taining 50 mL of a NH4Cl solution and 50 mL of CH2Cl2. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude yellow oil was filtered through a
silica gel plug, and the plug was washed several times with
75% EtOAc/hexanes. The filtrate was concentrated under
reduced pressure to yield 724 mg of the crude thionocarbamate
14 as a light yellow foam.
The thionocarbamate (724 mg, 1.10 mmol) prepared above
was dissolved in 19 mL of toluene, and the solution was
degassed with N2 for 20 min. The solution was brought to
reflux, and a solution of tri-n-butyltin hydride (1.51 mL, 5.70
mmol) and 2,2′-azobis(2-methylpropionitrile) (56.0 mg, 0.340
mmol) in 19 mL of toluene (degassed with N2) was added over
12 h via syringe pump. After complete addition, the residual
syringe contents were added to the reaction. After 30 min, the
reaction was cooled to room temperature and concentrated
under reduced pressure. Purification was accomplished by
flash chromatography on a 2.1 × 18 cm column, eluting with
a solvent gradient of 5%, 10%, 15%, 20%, and 30% EtOAc/
hexanes, collecting 8 mL fractions. Fractions 42-53 were
collected and concentrated to yield amine 15 (371 mg, 64%
yield) as the major product. Fractions 54-61 were collected
and concentrated to yield a mixture of amines 15 and 16 (31.0
mg, 5% yield). Fractions 62-80 were collected and concen-
trated to yield amine 16 (123 mg, 21% yield). Amine 15: [R]D
+29.7° (c 3.22, CHCl3); Rf 0.52 (50% EtOAc/hexanes); 300 MHz
1H NMR (CDCl3) δ 7.22-7.35 (m, 5H), 6.87 (s, 1H), 6.71-6.79
(m, 2H), 5.92 (d, J ) 1.4 Hz, 1H), 5.91 (d, J ) 1.4 Hz, 1H),
5.80 (bs, 1H), 4.90 (d, J ) 6.4 Hz, 1H), 4.83 (d, J ) 6.9 Hz,
1H), 4.75 (d, J ) 6.4 Hz, 1H), 4.60 (ABq, ∆AB ) 15.7 Hz, J )
11.9 Hz, 2H), 4.45 (d, J ) 6.9 Hz, 1H), 4.33 (dd, J ) 5.5, 2.9
Hz, 1H), 4.10-4.18 (m, 2H), 3.83 (dd, J ) 8.1, 7.3 Hz, 1H),
3.39 (s, 3H), 3.19-3.26 (m, 2H), 2.81 (s, 3H), 1.55 (s, 3H), 1.33
(s, 3H); 75 MHz 13C NMR (CDCl3) δ 147.7, 146.4, 137.2, 131.9,
128.6, 128.4, 128.1, 127.9, 122.5, 109.8, 108.6, 108.2, 100.9,
97.3, 96.5, 81.2, 79.4, 76.5, 75.8, 61.6, 55.9, 55.5, 46.9, 27.8,
26.1; HRMS m/z (EI) calcd C27H35NO9 517.2310, obsd 517.2322.
Amine 16: [R]D +50.5° (c 1.31, CHCl3); Rf 0.44 (50% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3) δ 7.19-7.31 (m, 5H),
6.68-6.76 (m, 3H), 5.93 (s, 2H), 5.51 (bs, 1H), 4.82 (ABq, ∆AB
) 24.5, J ) 6.3 Hz, 2H), 4.58-4.70 (m, 4H), 4.20 (d, J ) 6.8
Hz, 1H), 4.16 (dd, J ) 7.2, 5.1 Hz, 1H), 3.55 (dd, J ) 10.7, 8.9
Hz, 1H), 3.40 (s, 3H), 3.33-3.39 (m, 1H), 2.90 (dd, J ) 12.0,
10.7 Hz, 1H), 2.70 (s, 3H), 1.63 (s, 3H), 1.44 (s, 3H); 75 MHz
13C NMR (CDCl3) δ 148.1, 146.9, 137.1, 132.0, 128.6, 128.4,
127.9, 122.1, 109.6, 108.5, 108.3, 101.0, 97.2, 96.5, 79.9, 79.1,
78.9, 76.8, 73.2, 60.5, 55.9, 55.4, 45.4, 27.9, 26.3.
P r ep a r a t ion of N-[3-(2H-Ben zo[3,4-d ]-1,3-d ioxolen -5-
yl)(1S,3S,5S,2R,4R,6R)-4,5-bis(m eth oxym eth oxy)-8,8-d i-
m eth yl-7,9-d ioxa bicyclo[4.3.0]n on -2-yl]ben za m id e (17).
To a stirring solution of amine 15 (51 mg, 0.10 mmol) in 2 mL
of CH2Cl2 at room temperature were added N,N-(dimethy-
lamino)pyridine (6.0 mg, 0.05 mmol) and pyridine (0.08 mL,

4472 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
1.0 mmol), followed by benzoyl chloride (0.12 mL, 1.0 mmol).
After stirring 43 h at room temperature, the reaction was
diluted with 2 mL of CH2Cl2 and quenched with 10 mL of an
aqueous NaHCO3 solution. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered through a MgSO4/silica gel plug, and concentrated
under reduced pressure. The resulting yellow oil (70 mg) was
used in the next step without further purification.
50W-8X Dowex-H+ resin (20 mg). The reaction was sealed and
heated in a 65 °C oil bath for 6.5 h and then cooled to room
temperature and filtered through a plug of Celite/silica gel
(slurry packed in MeOH), and the plug was washed thoroughly
with MeOH. The solvent was removed under reduced pressure
to yield the crude tetraol as a white solid, which was used in
the next step without further purification.
To a stirring solution of the tetraol prepared above (12 mg)
in 0.50 mL of pyridine at room temperature was added
4-(dimethylamino)pyridine (3.0 mg), followed by Ac2O (0.02
mL). After 2 h, the mixture was diluted with 2 mL of CH2Cl2
and quenched with an aqueous NaHCO3 solution. The layers
were separated, the aqueous layer was extracted with CH2Cl2
(3 × 2 mL), and the combined organic layers were dried over
anhydrous Na2SO4. The solution was filtered and then con-
centrated under reduced pressure. Purification was accom-
plished by flash chromatography on a 0.5 × 7 cm column,
eluting with a solvent gradient of 20%, 30%, and 50% EtOAc/
hexanes, collecting 0.5 mL fractions. The product-containing
fractions (21-26) were collected and concentrated under
reduced pressure to yield the tetraacetate 19 (13 mg, 76%
yield) as a colorless solid: mp 159-161 °C; [R]D +67.0° (c 1.21,
CHCl3); Rf 0.59 (75% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) δ 7.20-7.55 (m, 5H), 7.10 (d, J ) 9.1 Hz, 1H), 6.79-
6.83 (m, 3H), 6.01 (dd, J ) 12.5, 9.3 Hz, 1H), 5.89 (ABq, ∆AB
) 13.9 Hz, J ) 1.4 Hz, 2H), 5.49-5.56 (m, 2H), 5.31 (dd, J )
10.7, 2.9 Hz, 1H), 4.57-4.63 (m, 1H), 3.67 (dd, J ) 12.5, 4.6
Hz, 1H), 2.24 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H), 1.64 (s, 3H);
75 MHz 13C NMR (CDCl3) δ 170.4, 169.9, 169.1, 167.6, 158.0,
148.0, 147.1, 133.9, 131.7, 129.1, 128.4, 127.1, 121.0, 108.7,
108.5, 101.2, 71.7, 70.1, 69.8, 69.1, 52.2, 45.1, 21.0, 20.6, 20.4,
20.3; HRMS (EI) exact mass calcd. for C28H29NO11 555.1739,
found 555.1735.
To a stirring solution of the crude benzamide (70 mg) in 2
mL of EtOH at -5 oC was added Na2HPO4 (67 mg, 0.47 mmol),
followed by finely ground 6% Na(Hg) (900 mg). After 1 h, the
reaction was diluted with 2 mL of THF and filtered through a
MgSO4/Celite plug, and the plug was washed with THF. The
resulting solution was concentrated under reduced pressure
to yield an off-white solid. Purification was accomplished by
flash chromatography on a 1.3 × 10 cm column, eluting with
a solvent gradient of 20%, 30%, and 40% EtOAc/hexanes,
collecting 3 mL fractions. The product-containing fractions
(13-17) were collected and concentrated to yield amide 17 (43
mg, 84%) as a white foam: [R]D +64.6° (c 0.51, CHCl3); Rf 0.33
(50% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) δ 7.66-7.69
(m, 2H), 7.38-7.49 (m, 3H), 7.18 (d, J ) 10.5 Hz, 1H), 6.67-
6.78 (m, 3H), 5.88 (s, 2H), 4.89 (ABq, ∆AB ) 9.3 Hz, J ) 6.6
Hz, 2H), 4.71 (d, J ) 7.1 Hz, 1H), 4.52-4.61 (m, 2H), 4.40 (d,
J ) 7.1 Hz, 1H), 4.32 (dd, J ) 7.0, 3.2 Hz, 1H), 4.29 (dd, J )
3.6, 2.4 Hz, 1H), 4.21 (dd, J ) 9.8, 1.2 Hz, 1H), 3.46 (s, 3H),
3.40 (dd, J ) 9.6, 3.6 Hz, 1H), 2.96 (s, 3H), 1.63 (s, 3H), 1.37
(s, 3H); 75 MHz 13C NMR (CDCl3) δ 166.4, 147.6, 146.4, 134.5,
133.8, 131.4, 128.5, 126.7, 121.7, 109.0, 108.8, 108.1, 100.8,
96.2, 95.1, 76.6, 76.1, 75.5, 75.0, 56.2, 55.3, 51.8, 44.0, 26.6,
23.9; HRMS m/z (EI) calcd C27H33NO9 515.2154, obsd 515.2196.
P r ep a r a tion of N-[3-(2H-Ben zo[3,4-d ]-1,3-d ioxola n -5-
yl)(1S,2S,3S,5S,4R,6R)-4,5-b is(m et h oxym et h oxy)-8,8-d i-
m eth yl-7,9-d ioxa bicyclo[4.3.0]n on -2-yl]ben za m id e (18).
To a stirring solution of amine 16 (120 mg, 0.231 mmol) in 3
mL of CH2Cl2 at room temperature was added N,N-(dimeth-
ylamino)pyridine (15.0 mg, 0.120 mmol), followed by benzoyl
chloride (0.270 mL, 2.30 mmol). A condensor was attached,
and the reaction was heated at a gentle reflux for 24 h and
then cooled to room temperature and diluted with 5 mL of CH2-
Cl2 and 20 mL of an aqueous NaHCO3 solution. The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (3 × 15 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude yellow oil was used in the next step
without further purification.
To a stirring solution of the crude benzamide prepared above
in 4 mL of EtOH at -5 °C was added Na2HPO4 (133 mg, 0.940
mmol), followed by finely ground 6% Na(Hg) (1.90 g). After 1
h, the reaction was diluted with 5 mL of THF and filtered
through a MgSO4/Celite plug, and the plug was thoroughly
washed with THF. The resulting solution was concentrated
under reduced pressure to yield a light yellow solid. Purifica-
tion was accomplished by flash chromatography on a 1.5 × 13
cm column, eluting with a solvent gradient of 20%, 30%, 40%,
and 50% EtOAc/hexanes, collecting 3 mL fractions. The
product-containing fractions (16-32) were collected and con-
centrated under reduced pressure to yield amide 18 (98 mg,
82% yield) as a white foam: [R]D -15.8° (c 5.33, CHCl3); Rf
0.46 (75% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) δ 7.27-
7.46 (m, 5H), 6.67-6.81 (m, 3H), 6.07 (d, J ) 9.3 Hz, 1H), 5.83
(ABq, ∆AB ) 1.8 Hz, J ) 1.4 Hz, 2H), 4.74-4.84 (m, 3H), 4.56
(d, J ) 6.9 Hz, 1H), 4.47 (dd, J ) 5.7, 3.7 Hz, 1H), 4.29 (t, J )
5.9 Hz, 1H), 4.23 (d, J ) 6.7 Hz, 1H), 3.93 (t, J ) 6.6 Hz, 1H),
3.73 (dd, J ) 10.1, 7.0 Hz, 1H), 3.41 (s, 3H), 3.05 (dd, J )
12.4, 10.1 Hz, 1H), 2.81 (s, 3H), 1.58 (s, 3H), 1.32 (s, 3H); 75
MHz 13C NMR (CDCl3) δ 166.8, 147.7, 146.6, 134.5, 132.6,
131.3, 128.4, 126.8, 122.2, 109.5, 108.8, 108.0, 100.8, 96.7, 96.2,
79.4, 78.2, 78.0, 75.4, 55.8, 48.8, 47.7, 27.3, 25.6; HRMS m/z
(EI) calcd C27H33NO9 515.2154, obsd 515.2187.
P r ep a r a tion of 3-(2H-Ben zo[3,4-d ]-1,3-d ioxola n -5-yl)-
(1S,2S,3S,6S,4R,5R)-4,5,6-tr ia cetyloxy-2-(p h en ylca r bon -
yla m in o)cycloh exyl Aceta te (20). To a stirring solution of
amide 18 (19 mg, 0.04 mmol) in 1 mL of MeOH was added
50W-8X DOWEX-H+ resin (25 mg). The reaction was sealed,
heated in a 65 °C oil bath for 5.5 h, then cooled to room
temperature, and filtered through a plug of Celite/silica gel
(slurry packed in MeOH), and the plug was washed with
MeOH. The solvent was removed under reduced pressure to
yield the crude tetraol (13 mg) as a white solid.
To a stirring solution of the crude tetraol prepared above
in 0.5 mL of pyridine at room temperature was added 4-(di-
methylamino)pyridine (4.0 mg), followed by Ac2O (0.03 mL).
After 1.5 h, the solution was diluted with 2 mL of CH2Cl2 and
quenched with an aqueous NaHCO3 solution. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3 × 2 mL). The combined organic layers were dried with Na2-
SO4, filtered, and concentrated under reduced pressure. Pu-
rification was accomplished by flash chromatography on a 0.5
× 7 cm column, eluting with a solvent gradient of 30%, 40%,
and 50% EtOAc/hexanes, collecting 0.5 mL fractions. The
product-containing fractions (17-22) were collected and con-
centrated to yield the tetraacetate 20 (17 mg, 77% yield) as a
colorless solid: mp 173-175 °C; [R]D +21.6° (c 0.64, CHCl3);
Rf 0.55 (75% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) δ
7.28-7.45 (m, 5H), 6.69-6.74 (m, 3H), 5.89 (ABq, ∆AB ) 4.2
Hz, J ) 1.5 Hz, 2H), 5.74 (t, J ) 2.7 Hz, 1H), 5.69 (d, J ) 8.3
Hz, 1H), 5.47 (dd, J ) 10.5, 9.6 Hz, 1H), 5.20-5.27 (m, 2H),
4.73 (ddd, J ) 11.0, 8.3, 2.7 Hz, 1H), 3.19 (dd, J ) 12.5, 11.1
Hz, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.79 (s, 3H);
75 MHz 13C NMR (CDCl3) δ 170.2, 169.6, 169.5, 169.0, 166.8,
148.1, 147.4, 133.9, 131.7, 128.9, 128.6, 126.8, 122.1, 108.2,
101.2, 73.1, 71.1, 70.6, 70.0, 49.2, 47.5, 20.9, 20.6, 20.5, 20.3;
HRMS m/z (EI) calcd C28H29NO11 555.1739, obsd 555.1771.
P r ep a r a t ion of 4-[(1S)-1,2-Bis(1,1,2,2-t et r a m et h yl-1-
s i l a p r o p o x y )e t h y l ](5S ,1 R ,4 R )-7 ,7 -d i m e t h y l -3 ,6 ,8 -
tr ioxa bicyclo[3.3.0]octa n -2-on e (25). D-Gulonolactone (10.0
g, 56.2 mmol) was suspended in acetone (100 mL), and 2,2-
dimethoxypropane (50.0 mL) and p-toluenesulfonic acid (50.0
mg) were added. After stirring at room temperature for 24 h,
the reaction was neutralized with solid K2CO3, filtered, and
concentrated under reduced pressure. The resulting slurry was
P r ep a r a tion of 3-(2H-Ben zo[3,4-d ]-1,3-d ioxola n -5-yl)-
(1S,3S,6S,2R,4R,5R)-4,5,6-tr ia cetyloxy-2-(p h en ylca r bon -
yla m in o)cycloh exyl Aceta te (19). To a stirring solution of
amide 17 (16 mg, 0.03 mmol) in 1 mL of MeOH was added

Total Synthesis of 7-Deoxypancratistatin
J . Org. Chem., Vol. 64, No. 12, 1999 4473
dissolved in 100 mL of AcOH/ H2O (7:1), stirred for 12 h at
room temperature, and then concentrated and dried by
repeated concentration with toluene (3 × 100 mL). The
resulting yellow oil was dissolved in N,N-dimethylformamide
(20 mL), and imidazole (15.3 g, 225 mmol) and tert-butyldi-
methylchlorosilane (18.5 g, 123 mmol) were added. The result-
ing solution was stirred for 20 h and then poured into a
separatory funnel containing CH2Cl2 (200 mL) and H2O (200
mL). The layers were separated, and the cloudy organic layer
was washed with H2O (3 × 50 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated to yield a white
solid. Purification was accomplished by flash chromatography
on a 4.5 × 25 cm column, eluting with a solvent gradient of
5%, 8%, 12%, 15%, and 20% EtOAc/hexanes, collecting 25 mL
fractions. The product-containing fraction (22-55) were col-
lected and concentrated to yield lactone 25 (22.6 g, 90%) as a
white solid: mp 121 °C; [R]D -37.8° (c 3.63, CHCl3); Rf 0.48
dried with anhydrous MgSO4, filtered through a MgSO4/silica
gel plug, and concentrated under reduced pressure. The
resulting yellow oil was used in the next step without further
purification.
To a solution of the crude oil prepared above in 200 mL of
THF was added a pre-prepared solution consisting of HF‚
pyridine (47 g), pyridine (71 mL), and 200 mL of THF. The
solution was allowed to stand at room temperature for 3 h, at
which time it was diluted with 200 mL of EtOAc and slowly
quenched with a saturated NaHCO3 solution. The layers were
separated, and the aqueous layer was extracted with EtOAc
(3 × 50 mL). The combined organic layers were washed with
brine (150 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification was ac-
complished by flash chromatography on a 3.1 × 25 cm column,
eluting with a solvent gradient of 10%, 15%, 18%, 20%, and
25% EtOAc/hexanes, collecting 15 mL fractions. The product-
containing fractions (50-83) were collected and concentrated
to give alcohol 27 (2.43 g, 62%), as a 2:1 mixture of oxime
isomers, and as a clear colorless oil: major oxime isomer, [R]D
-40.9° (c 5.5, CHCl3); Rf 0.40 (35% EtOAc/hexanes); 300 MHz
1H NMR (CDCl3) δ 7.43 (d, J ) 8.1 Hz, 1 H), 7.32-7.36 (m, 5
H), 5.07 (s, 2H), 4.54-4.70 (m, 4 H), 3.89 (ddd, J ) 5.6, 3.4,
1.2 Hz, 1H), 3.51-3.71 (m, 3H), 3.41 (s, 3H), 2.68 (dd, J ) 7.8,
6.4 Hz, 1H), 1.50 (s, 3H), 1.37 (s, 3H), 0.88 (s, 9H), 0.057 (s,
3H), 0.034 (s, 3H); 75 MHz 13C NMR (CDCl3) δ 148.7, 137.7,
128.8, 128.6, 128.3, 110.0, 98.7, 77.7, 77.2, 76.5, 75.2, 71.8, 63.5,
56.5, 28.1, 26.2, 25.8, 18.4, -3.90, -4.50; IR (neat) 3566, 3547,
3421 cm-1. Anal. Calcd for C24H41NO7Si: C, 59.60; H, 8.54; N,
2.89. Found: C, 59.56; H, 8.56; N, 2.84.
P r ep a r a tion of (2S,3R)-3-{(4S,5R)-5-[(1Z)-2-Aza -2-(p h e-
n ylm et h oxy)vin yl]-2,2-d im et h yl(1,3-d ioxola n -4-yl)}-3-
(m eth oxym eth oxy)-2-(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)-
p r op a n oic Acid (29). To a stirring solution of alcohol 27 (2.10
g, 4.40 mmol) in 45 mL of CH2Cl2 at room temperature were
added oven-dried 4 Å molecular sieves (2.10 g), 4-methylmor-
pholine N-oxide (772 mg, 6.60 mmol), and tetrapropylammo-
nium perruthenate (75.0 mg, 0.220 mmol). After 1 h, the
solution was filtered through a plug of silica gel (slurry packed
in EtOAc) and concentrated under reduced pressure to yield
2.01 g (95% yield) of aldehyde 28 as a clear colorless oil.
The crude aldehyde was immediately dissolved in a mixture
of tert-butyl alcohol (18.0 mL) and 2-methyl-2-butene (18.0 mL)
and cooled to -5 °C. To this solution was added a 1.25 M
solution of KH2PO4 (21.1 mL, 26.4 mmol), followed by sodium
chlorite (2.00 g, 22.0 mmol). After 50 min, the reaction was
quenched with 20 mL of pH ) 4 buffer solution and diluted
with CH2Cl2 (50 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Purification
was accomplished by flash chromatography on a 2.3 × 25 cm
column, eluting with a solvent gradient of 8%, 15%, 20%, and
25% EtOAc/hexanes, collecting 8 mL fractions. The product-
containing fractions (24-70) were collected and concentrated
under reduced pressure to yield acid 29 (1.83 g, 84%), as a 2:1
mixture of oxime isomers, and as a clear colorless oil: major
oxime isomer, [R]D -14.3 (c 6.6, CHCl3); Rf 0.21 (35% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3) δ 7.45 (d, J ) 8.2 Hz,
1H), 7.23-7.32 (m, 5H), 5.05 (ABq, ∆AB ) 17.3 Hz, J ) 12.3
Hz, 2H), 4.70 (ABq, ∆AB ) 24.9 Hz, J ) 6.9 Hz, 2H), 4.60 (dd,
J ) 8.2, 6.3 Hz, 1H), 4.51 (t, J ) 6.3 Hz, 1H), 4.35 (d, J ) 3.4
Hz, 1H), 3.86 (dd, J ) 6.4, 3.4 Hz, 1H), 3.36 (s, 3H), 1.47 (s,
3H), 1.34 (s, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.01 (s, 3H); 75
MHz 13C NMR (CDCl3) δ 174.5, 147.9, 137.4, 128.4, 128.1,
127.9, 109.9, 97.5, 77.4, 76.4, 76.1, 74.5, 71.8, 56.3, 27.7, 25.8,
25.4, 18.2, -4.7, -5.3; IR (neat) 3350 1759 cm-1. Anal. Calcd
for C24H39NO8Si: C, 57.92; H, 7.90; N, 2.82. Found: C, 58.03;
H, 7.97; N, 2.81.
1
(20% EtOAc/hexanes); 300 MHz H NMR (CDCl3) δ 4.89 (m,
2H), 4.61 (dd, J ) 3.1, 8.3 Hz, 1H), 4.13 (dt, J ) 3.2, 8.3 Hz,
1H), 4.02 (dd, J ) 3.4, 11.0 Hz, 1H), 3.82 (dd, J ) 3.0, 11.0
Hz, 1H), 1.57 (s, 3H), 1.49 (s, 3H), 1.02 (s, 9H), 1.01 (s, 9H),
0.23 (s, 3H), 0.20 (s, 3H), 0.19 (s, 6H); 75 MHz 13C NMR
(CDCl3) δ 173.7, 113.7, 81.3, 76.5, 76.1, 72.1, 65.4, 26.9, 26.1,
25.9, 25.8, 18.3, 18.2, -4.6, -4.7, -5.3, -5.5; IR (CH2Cl2) 1788
cm-1. Anal. Calcd for C21H42O6Si2: C, 56.50; H, 9.42. Found:
C, 56.57; H, 9.40.
P r ep a r a tion of (1R,2R)-1-{(4S,5R)-5-[(1Z)-2-Aza -2-(p h e-
n ylm et h oxy)vin yl]-2,2-d im et h yl(1,3-d ioxola n -4-yl)}-2,3-
bis(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)p r op a n -1-ol (26). To
a stirring solution of lactone 25 (10.0 g, 22.4 mmol) in CH2Cl2
(200 mL) at -78 °C was added a 1.0 M solution of diisobut-
ylaluminum hydride (25.0 mL, 24.6 mmol) over 1 h. After
complete addition, the reaction was stirred for 0.5 h and then
quenched by slow addition of MeOH (20 mL) over 0.5 h. The
mixture was warmed to room temperature and stirred with
saturated aqueous Rochelle salts (300 mL) for 5 h. The layers
were separated, the aqueous layer was extracted with CH2Cl2
(3 × 100 mL), and the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated. The resulting
crude oil was dissolved in pyridine (80 mL), and O-benzylhy-
droxylamine‚HCl (5.40 g, 33.6 mmol) was added in one portion.
After stirring 23 h at room temperature, the reaction was
diluted with EtOAc (200 mL) and washed with 100 mL each
of H2O, a saturated CuSO4 solution, H2O, and brine. The
organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The resulting crude oil
was purified by flash chromatography on a 4.5 × 35 cm
column, eluting with a solvent gradient of 5%, 10%, 15%, 20%,
and 25% EtOAc/hexanes, collecting 20 mL fractions. The
product-containing fractions (28-75) were collected and con-
centrated to yield 26 (11.0 g, 89%) as a 2:1 mixture of oxime
isomers and as a clear colorless oil: major oxime isomer, [R]D
+ 13.4° (c 3.09, CHCl3); Rf 0.32 (20% EtOAc/hexanes); 300 MHz
1H NMR (CDCl3) δ 7.71 (d, J ) 8.4 Hz, 1H), 7.44-7.39 (m,
5H), 5.21 (s, 2H), 4.80 (dd, J ) 7.1, 8.4 Hz, 1H), 4.47 (dd, J )
7.1, 3.3 Hz, 1H), 3.82 (m, 3H), 3.63 (dd, J ) 9.5, 4.7 Hz, 1H),
2.62 (d, J ) 9.2 Hz, 1H), 1.64 (s, 3H), 1.50 (s, 3H), 1.03 (s,
9H), 1.02 (s, 9H), 0.21 (s, 3H), 0.20 (s, 3H), 0.19 (s, 6H); 75
MHz 13C NMR (CDCl3) δ 148.3, 136.9, 127.9, 127.8, 127.6,
127.3, 109.3, 76.2, 75.5, 74.9, 72.4, 68.4, 63.9, 26.9, 25.5, 24.7,
-4.6, -5.4, -5.8, -5.9; IR (neat) 3562 cm-1. Anal. Calcd for
C
28H51NO6Si2: C, 60.76; H, 9.22; N, 2.53. Found: C, 60.69; H,
9.27; N, 2.54.
P r ep a r a tion of (2R,3R)-3-{(4S,5R)-5-[(1Z)-2-Aza -2-(p h e-
n ylm et h oxy)vin yl]-2,2-d im et h yl(1,3-d ioxola n -4-yl)}-3-
(m eth oxym eth oxy)-2-(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)-
p r op a n -1-ol (27). To a stirring solution of alcohol 26 (4.5 g,
8.1 mmol) in 41 mL of CH2Cl2 were added N,N-diisopropyl-
ethylamine (10 mL, 51 mmol), LiI (5.5 g, 41 mmol), and
chloromethyl methyl ether (3.1 mL, 41 mmol), and the solution
was heated at 55-60 °C for 15 h. The resulting orange solution
was cooled to room temperature, quenched by addition of 50
mL of a saturated NaHCO3 solution, and stirred for 1 h. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
P r ep a r a tion of (6-Br om o-2H-ben zo[3,4-d ]-1,3-d ioxola n -
5-yl)m et h yl (2S,3R)-3-{(4S,5R)-5-[(1Z)-2-Aza -2-(p h en yl-
m eth oxy)vin yl]-2,2-d im eth yl(1,3-d ioxola n -4-yl)}-3-(m eth -
o x y m e t h o x y ) - 2 - ( 1 , 1 , 2 , 2 - t e t r a m e t h y l - 1 -
sila p r op oxy)p r op a n oa te (31). To a stirring solution of acid
29 (715 mg, 1.44 mmol), 4-bromo-5-hydroxymethyl-1,2-meth-

4474 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
ylenedioxybenzene 30 (499 mg, 2.16 mmol), and triphenylphos-
phine (566 mg, 2.16 mmol) in 32 mL of THF at room
temperature was added diethyl azodicarboxylate (0.360 mL,
2.16 mmol) dropwise. After 42 h, the solution was concentrated
under reduced pressure to yield a yellow oil, which was
purified by flash chromatography on a 2.1 × 20 cm column,
eluting with a solvent gradient of 5%, 8%, 11%, and 15%
EtOAc/hexanes, and collecting 8 mL fractions. The product-
containing fractions (35-61) were collected and concentrated
to yield the bromo ester 31 (810 mg, 80% yield), as a 1.5:1
mixture of oxime isomers, and as a clear colorless oil: major
oxime isomer, [R]D -11.9 (c 8.30, CHCl3); Rf 0.53 (35% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3) δ 7.46 (d, J ) 8.2 Hz,
1H), 7.24-7.29 (m, 5H), 6.97 (s, 1H), 6.95 (s, 1H), 5.93 (s, 2H),
5.11 (ABq, ∆AB ) 29.2 Hz, J ) 13.0 Hz, 2H), 5.00 (ABq, ∆AB
) 16.4 Hz, J ) 12.0 Hz, 2H), 4.68 (ABq, ∆AB ) 28.5 Hz, J )
6.9 Hz, 2H), 4.60 (dd, J ) 8.2, 6.0 Hz, 1H), 4.52 (dd, J ) 6.7,
6.0 Hz, 1H), 4.33 (d, J ) 3.1 Hz, 1H), 3.88 (dd, J ) 6.7, 3.1 Hz,
1H), 3.31 (s, 3H), 1.44 (s, 3H), 1.32 (s, 3H), 0.89 (s, 9H), 0.07
(s, 3H), 0.00 (s, 3H); 75 MHz 13C NMR (CDCl3) δ 170.7, 148.2,
148.0, 147.4, 137.2, 128.3, 128.2, 128.0, 127.9, 113.9, 112.7,
110.0, 109.8, 101.8, 97.6, 77.4, 77.2, 76.1, 74.6, 72.0, 66.2, 56.2,
27.8, 25.8, 25.4, 18.3, -4.5, -5.3; IR (neat) 1761 cm-1. Anal.
Calcd for C32H44NO10SiBr: C, 54.08; H, 6.24; N, 1.97. Found:
C, 54.19; H, 6.31; N, 1.91.
P r ep a r a tion of 6-((2S,3R)-3-{(5S,4R)-5-[(1Z)-2-Aza -2-
(p h en ylm eth oxy)vin yl]-2,2-d im eth yl(1,3-d ioxola n -4-yl)}-
3-(m eth oxym eth oxy)-2-(1,1,2,2-tetr am eth yl-1-silapr opoxy)-
p r op a n oyl)-2H -b en zo[d ]-1,3-d ioxola n e-5-ca r b a ld eh yd e
(32). To a stirring solution of bromo ester 31 (478 mg, 0.670
mmol) in 17 mL of THF at -98 °C was added a 2.40 M solution
of n-BuLi (0.335 mL, 0.804 mmol) dropwise over 5 min. After
15 min, the reaction was transferred to a -78 °C bath and
was stirred for 1.5 h. The reaction was quenched at -78 °C
by addition of a saturated solution of NH4Cl (10 mL), and upon
warming to 0 °C the solution was poured into a separatory
funnel containing CH2Cl2 (30 mL) and H2O (30 mL). The layers
were separated, the aqueous layer was extracted with CH2Cl2
(3 × 30 mL), and the combined organic layers were dried over
anhydrous MgSO4. The solution was filtered, concentrated
under reduced pressure to a volume of approximately 2 mL,
and used immediately in the next reaction.
reaction was allowed to stand at room temperature for 24 h
and then diluted with 50 mL of EtOAc and slowly quenched
by addition of a saturated NaHCO3 solution. The layers were
separated, and the organic layer was washed with 50 mL of
saturated CuSO4 followed by 50 mL H2O and finally dried over
anhydrous MgSO4. The solution was filtered through a plug
of MgSO4/silica gel (slurry packed in EtOAc) and concentrated
under reduced pressure. The resulting white foam was used
in the next step without further purification.
To the crude lactol prepared above in 5 mL of N,N-
dimethylformamide was added imidazole (75.0 mg, 1.10 mmol)
followed by tert-butyldimethylchlorosilane (127 mg, 0.840
mmol). After stirring 19 h at room temperature, the solution
was diluted with CH2Cl2 (30 mL) and poured into 50 mL of
H2O. The layers were separated, and the organic layer was
washed with H2O (30 mL) and brine (30 mL). The organic layer
was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to yield the crude ketone 36 as a
yellow foam. Purification was accomplished by flash chroma-
tography on a 2.5 × 15 cm column, eluting with a solvent
gradient of 5%, 10%, 15%, and 20% EtOAc/hexanes, collecting
8 mL fractions. The product-containing fractions (22-41) were
collected and concentrated to yield 304 mg (75% yield) of
ketone 36 as a white foam and a mixture of diastereomers:
one diastereomer, [R]D + 9.1 (c 5.3, CHCl3); Rf 0.52 (35%
1
EtOAc/hexanes); 300 MHz H NMR (CDCl3) δ 7.45 (d, J ) 8.8
Hz, 1H), 7.36 (s, 1H), 7.24 (d, J ) 7.6 Hz, 2H), 7.06 (t, J ) 7.8
Hz, 2H), 6.91 (s, 1H), 6.84 (t, J ) 7.3 Hz, 1H), 6.09 (d, J ) 8.5
Hz, 2H), 5.38 (s, 1H), 5.00 (ABq, ∆AB ) 16.1 Hz, J ) 12.5 Hz,
2H), 4.87 (d, J ) 6.6 Hz, 1H), 4.56-4.62 (m, 3H), 4.38 (br m,
1H), 3.92 (d, J ) 0.7 Hz, 1H), 3.23 (s, 3H), 1.51 (s, 3H), 1.36
(s, 3H), 1.01 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H); 75 MHz 13C
NMR (CDCl3) δ 190.7, 152.5, 148.2, 147.4, 141.4, 137.8, 128.3,
128.2, 127.5, 125.3, 109.8, 105.3, 104.5, 101.9, 97.0, 93.1, 79.1,
78.8, 75.9, 74.6, 72.9, 56.2, 28.1, 25.7, 25.4, 18.1, -3.86, -5.20;
IR (CHCl3) 1695 cm-1; HRMS m/z (EI) calcd C32H43NO10Si
629.2654, obsd 629.2692.
P r ep a r a tion of [(4S,12S,12a S,11bR,3a R,4a R)-4-(Meth -
o x y m e t h o x y )-2,2-d im e t h y l-6-(1,1,2,2-t e t r a m e t h y l-1-
sila p r opoxy)(4,12,11b,12a ,3a ,4a -h exa h yd r o-9H -1,3-d ioxo-
le n o[4′′,5′′-7′,6′]isoch r om a n o[4′,3′-5,4]b e n zo[1,2-d ]1,3-
d ioxola n -12-yl)](p h en ylm eth oxy)a m in e (38). To a stirring
solution of ketone 36 (195 mg, 0.310 mmol) in 5 mL of MeOH
at room temperature was added NaBH4 (12.0 mg, 0.310 mmol)
in one portion. After 2 h, 5 mL of CH2Cl2 was added, followed
by 5 mL of a saturated NH4Cl solution. The layers were
separated, the aqueous layer was extracted with CH2Cl2 (3 ×
10 mL), and the combined organic layers were dried over
anhydrous MgSO4. The solution was filtered and concentrated
under reduced pressure to yield the crude alcohol (205 mg)
which was used in the next step without further purification.
To a stirring solution of the crude alcohol prepared above
in 6 mL of 1,2-dichloroethane were added 4-(dimethylamino)-
pyridine (20.0 mg, 0.160 mmol) and 1,1′-thiocarbonyldiimida-
zole (285 mg, 1.60 mmol) at room temperature. The reaction
was then heated at a gentle reflux for 14 h. The mixture was
cooled to room temperature, diluted with 10 mL of CH2Cl2,
and quenched with 15 mL of a saturated NH4Cl solution. The
layers were separated, and the organic layer was washed with
20 mL of H2O, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The resulting yellow oil
was dissolved in 30 mL of EtOAc, filtered through a plug of
silica gel (slurry packed in EtOAc), and concentrated under
reduced pressure to yield 177 mg (77%) of the thionocarbamate
37 as a light yellow foam.
To a stirring solution of the crude alcohol prepared above
in 20 mL of CH2Cl2 at room temperature were added oven-
dried 4 Å molecular sieves (500 mg), 4-methylmorpholine
N-oxide (118 mg, 1.01 mmol), and tetrapropylammonium
perruthenate (11.7 mg, 0.033 mmol). After 45 min, the
heterogeneous mixture was filtered through a plug of silica
gel (slurry packed in EtOAc) and concentrated under reduced
pressure. The crude oil was purified by flash chromatography
on a 2.1 × 18 cm column, eluting with a solvent gradient of
5%, 8%, 15%, and 18% EtOAc/hexanes, while collecting 8 mL
fractions. The product-containing fractions (34-50) were col-
lected and concentrated to yield 301 mg (72% yield) of keto-
aldehyde 32, as a 1.5:1 mixture of oxime isomers, and as a
clear colorless oil: major oxime isomer, [R]D -1.27° (c 4.10,
CHCl3); Rf 0.46 (35% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) δ 9.9 (s, 1H), 7.24-7.54 (m, 7H), 7.38 (d, J ) 7.1 Hz,
1H), 6.07 (s, 2H), 5.1 (s, 2H), 4.78 (d, J ) 3.2 Hz, 1H), 4.76 (d,
J ) 6.3 Hz, 1H), 4.59-4.65 (m, 2H), 4.55 (d, J ) 6.6 Hz, 1H),
3.93 (dd, J ) 7.1, 3.2 Hz, 1H), 3.10 (s, 3H), 1.41 (s, 3H), 1.34
(s, 3H), 0.867 (s, 9H), -0.009 (s, 3H), -0.203 (s, 3H); 75 MHz
13C NMR (CDCl3) δ 199.9, 190.2, 150.6, 150.2, 147.7, 137.2,
135.7, 133.2, 128.5, 128.4, 127.9, 109.9, 109.8, 107.9, 102.5,
97.2, 77.7, 77.4, 76.6, 76.3, 74.4, 56.5, 27.8, 25.8, 25.4, 18.2,
-4.2, -5.1; IR (neat) 1683 cm-1. Anal. Calcd for C32H43NO10
-
To a solution of the thionocarbamate prepared above (83.0
mg, 0.110 mmol) in 2 mL of toluene (degassed with N2 for 20
min) at reflux were added 2,2-azobis[2-methylpropionitrile]
(10.0 mg, 0.060 mmol) and tri-n-butyltin hydride (160 mg,
0.550 mmol) in 2 mL of toluene (degassed with N2 for 20 min)
over 4 h via syringe pump. After complete addition, the
residual contents of the syringe and needle were added to the
reaction. After an additional 30 min at reflux, the resulting
clear solution was cooled to room temperature and concen-
trated under reduced pressure. The crude oil was purified by
Si: C, 61.03; H, 6.88; N, 2.22. Found: C, 60.87; H, 6.94; N,
2.18.
P r ep a r a t ion of (7S)-7-((1S){(5S,4R)-5-[(1Z)-2-Aza -2-
(p h en ylm eth oxy)vin yl]-2,2-d im eth yl(1,3-d ioxola n -4-yl)}-
(m eth oxym eth oxy)m eth yl)-5-(1,1,2,2-tetr a m eth yl-1-sila -
p r op oxy)-2H -1,3-d ioxolen o[4,5-g]isoch r om a n -8-on e (36).
To a stirring solution of keto-aldehyde 32 (400 mg, 0.640
mmol) in 6 mL of THF was added a solution consisting of HF‚
pyridine (11.0 mL), pyridine (16.0 mL), and 8 mL of THF. The

Total Synthesis of 7-Deoxypancratistatin
J . Org. Chem., Vol. 64, No. 12, 1999 4475
flash chromatography on a 1.3 × 20 cm column, eluting with
a solvent gradient of 5%, 10%, 12%, 15%, and 20% EtOAc/
hexanes, collecting 5 mL fractions. The product-containing
fractions (29-40) were collected and concentrated to yield 49.0
mg (72% yield) of 38 (3:1 mixture of lactol isomers) as a clear
colorless oil: major isomer, [R]D +29.3 (c 2.50, CHCl3); Rf 0.49
(35% EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) δ 7.26-7.39
(m, 5 H), 6.95 (s, 1 H), 6.75 (s, 1 H), 5.93 (ABq, ∆AB ) 3.4 Hz,
J ) 1.4 Hz, 2 H), 5.88 (br d, J ) 1.7 Hz, 1 H), 5.81 (s, 1 H),
4.75-4.86 (m, 4 H), 4.64 (dd, J ) 8.6, 6.4 Hz, 1 H), 4.22 (t, J
) 6.1 Hz, 1 H), 3.99-4.06 (m, 2 H), 3.39 (s, 3 H), 3.23 (ddd, J
) 11.5, 8.7, 1.5 Hz, 1 H), 2.88 (dd, J ) 11.4, 3.2 Hz, 1 H), 1.48
(s, 3 H), 1.38 (s, 3 H), 0.91 (s, 9 H), 0.17 (s, 3 H), 0.13 (s, 3 H);
75 MHz 13C NMR (CDCl3) δ 147.1, 146.9, 137.4, 131.6, 128.4,
128.3, 127.8, 126.6, 109.6, 109.5, 106.2, 100.9, 96.1, 95.1, 77.2,
76.8, 76.1, 75.5, 74.1, 62.6, 55.7, 35.9, 28.1, 25.8, 17.5, 13.6,
-3.8, -5.0; HRMS m/z (EI) calcd C32H45NO9Si 615.2861, obsd
615.2865.
The layers were separated, the aqueous was extracted with
CH2Cl2 (3 × 2 mL), and the combined organic layers were dried
over anhydrous Na2SO4 and then concentrated under reduced
pressure. Purification was accomplished by flash chromatog-
raphy on a 1.5 × 10 cm column, eluting with a solvent gradient
of 10%, 20%, 30%, 40%, and 50% EtOAc/hexanes, collecting 3
mL fractions. The product-containing fractions were collected
and concentrated to yield 25 mg (86% yield) of trifluoroaceta-
mide 40 as a colorless solid: mp 118-121 °C; [R]D +52.7° (c
0.11, CHCl3); Rf 0.22 (50% EtOAc/hexanes); 300 MHz 1H NMR
(CDCl3) δ 7.43 (s, 1H), 6.78 (d, J ) 7.8 Hz, 1H), 6.61 (s, 1H),
6.05 (s, 2H), 4.79-4.71 (m, 3H), 4.55 (dd, J ) 9.0, 5.1 Hz, 1H),
4.42-4.38 (m, 2H), 3.77 (ddd, J ) 12.2, 11.7, 8.8 Hz, 1H), 3.47
(dd, J ) 12.2, 2.7, 1H), 3.39 (s, 3H), 1.49 (s, 3H), 1.38 (s, 3H);
75 MHz 13C NMR (CDCl3) δ 163.2, 158.0, 152.5, 148.2, 135.3,
131.5, 118.3, 110.2, 109.8, 107.5, 102.3, 96.7, 77.2, 76.1, 74.4,
72.3, 56.1, 53.9, 35.9, 28.3, 25.9; 19F NMR (CDCl3) δ 116.8;
IR; HRMS m/z (EI) calcd C21H22NO9F3 489.1245, obsd 449.0929
(C3H4).
P r epar ation of N-[(12S,12aS,4R,11bR,3aR,4aR)-4-(Meth -
o x y m e t h o x y )-2,2-d im e t h y l-6-o x o (4,12,11b ,12a ,3a ,4a -
h exah ydr o-9H -1,3-dioxolen o[4′′,5′′-7′,6′]isoch r om an o[4′,3′-
5,4]b e n zo [1,2-d ]1,3-d io x o la n -12-y l)]-2,2,2-t r iflu o r o -
N-(p h en ylm eth oxy)a ceta m id e (39). To a stirring solution
of amine 38 (49 mg, 0.08 mmol) in 2 mL of CH2Cl2 at room
temperature were added 4-(dimethylamino)pyridine (5.0 mg,
0.04 mmol) and pyridine (0.01 mL, 0.16 mmol), followed by
trifluoroacetic anhydride (0.02 mL, 0.12 mmol). After stirring
for 0.5 h, the reaction was quenched with 3 mL of a saturated
NaHCO3 solution. The layers were separated, the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic layers were dried over anhydrous MgSO4. The solution
was filtered through a MgSO4/silica gel plug and concentrated
under reduced pressure to yield 51 mg of a white foam.
To a stirring solution of the crude trifluoroacetamide (51
mg, 0.07 mmol) in 2 mL of THF at -5 °C was added a 1.0 M
solution of tetrabutylammonium fluoride (0.08 mL, 0.08 mmol).
After 1 h, the reaction was quenched by the addition of a
saturated NH4Cl solution and diluted with 5 mL of CH2Cl2.
The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated under reduced pressure to yield 60 mg of the crude
lactol.
P r ep a r a tion of 7-Deoxyp a n cr a tista tin (2). To a stirring
solution of amide 40 (19 mg, 0.04 mmol) in 1 mL of MeOH
was added DOWEX-H+ (50W-X8) resin (40 mg), and the
mixture was heated at 70 °C for 5.5 h. After cooling to room
temperature, the mixture was filtered through a silica gel/
Celite pad and the pad was washed with MeOH. The solvent
was removed under reduced pressure to yield 13 mg of the
triol amide, which was used in the next reaction without
further purification.
To a stirring solution of the triol amide prepared above in
1 mL of anhydrous MeOH was added K2CO3 (70 mg, 0.51
mmol). The mixture was heated at 70 °C for 19 h and then
cooled to room temperature and filtered. The filtrate was
acidified with excess DOWEX-H+ resin (50 mg) to a pH ) 5
by litmus paper and then filtered and concentrated under
reduced pressure. The resulting white solid was purified by
flash chromatography on a 0.6 × 4 cm column, eluting with
30%, 50%, and 75% MeOH/CHCl3, collecting 0.5 mL fractions.
The product-containing fractions were collected and concen-
trated to yield 7-deoxypancratistatin (9 mg, 75% yield) as a
white film: [R]D +74.6° (c 0.85, DMF); Rf 0.44 (30% MeOH/
1
CHCl3); 300 MHz H NMR (DMSO) δ 7.31 (s, 1 H), 6.91 (s, 1
H), 6.87 (br s, 1 H), 6.07 (s, 2 H), 5.41 (d, J ) 3.9 Hz, 1 H),
5.05 (d, J ) 5.6 Hz, 2 H), 4.82 (d, J ) 7.6 Hz, 1 H), 4.32 (m, 1
H), 3.97 (m, 1 H), 3.85 (m, 1 H), 3.69 (m, 2 H), 2.98 (br d, J )
9.8 Hz, 1 H); 75 MHz 13C NMR (DMSO) δ 164.1, 150.6, 145.9,
135.4, 123.8, 106.8, 105.5, 101.6, 73.4, 70.4, 70.2, 68.7, 50.4,
40.3; HRMS m/z (EI) calcd C14H15NO7 309.0848, obsd 309.0855
P r ep a r a tion of Tetr a a ceta te 41. To a stirring solution
of 7-deoxypancratistatin (2) (9.0 mg, 0.03 mmol) in 1 mL of
CH2Cl2 at room temperature were added pyridine (0.02 mL,
0.30 mmol), 4-(dimethylamino)pyridine (1.0 mg), and acetic
anhydride (0.03 mL, 0.30 mmol). The solution was stirred for
7 h and then diluted with CH2Cl2 and quenched with a
saturated NaHCO3 solution. The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 2 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The result-
ing crude solid was purified by flash chromatography on a 0.6
× 6.5 cm column, eluting with a solvent gradient of 15%, 30%,
50%, and 70% EtOAc/hexanes, collecting 1 mL fractions. The
product-containing fractions (29-41) were collected and con-
centrated to yield 41 (9 mg, 65% yield) as a colorless solid:
mp 180-184 °C; [R]D + 68.4° (c 0.5, CHCl3); Rf 0.29 (75%
EtOAc/hexanes); 300 MHz 1H NMR (CDCl3) δ 7.55 (s, 1H), 6.54
(s, 1H), 6.24 (brs, 1H), 6.02 (ABq, ∆AB ) 3.98 Hz, J ) 1.3 Hz,
2H), 5.56 (brt, J ) 2.9 Hz, 1H), 5.44 (brt, J ) 3.0 Hz, 1H),
5.21 (t, J ) 2.9 Hz, 1H), 5.16 (dd, J ) 10.8, 3.5 Hz, 1H), 4.27
(dd, J ) 13.0, 10.8 Hz, 1H), 3.44 (dd, J ) 13.0, 2.6 Hz, 1H),
2.15 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H); 75 MHz
13C NMR (CDCl3) δ 169.9, 169.6, 169.0, 168.3, 164.9, 151.8,
147.3, 131.5, 123.2, 108.5, 103.7, 101.9, 71.7, 67.7, 66.9, 66.3,
48.2, 39.5, 20.8, 20.7, 20.6, 20.5; IR; HRMS m/z (EI) cacld
To a stirring solution of the crude lactol prepared above in
3 mL of CH2Cl2 at room temperature were added oven-dried
4 Å molecular sieves (50 mg) and N-methylmorpholine N-oxide
(13 mg, 0.11 mmol), followed by tetrapropylammonium per-
ruthenate (2.0 mg, 0.004 mmol). After 45 min, the reaction
was filtered through a plug of MgSO4/silica gel (slurry packed
in EtOAc), the plug was washed with EtOAc, and the filtrate
was concentrated under reduced pressure. Purification was
accomplished by flash chromatography on a 1.5 × 20 cm
column, eluting with a solvent gradient of 10%, 15%, 20%, and
30% EtOAc/hexanes, collecting 4 mL fractions. The product-
containing fractions (28-80) were collected and concentrated
to yield 39 mg (81% yield from 38) of the lactone 39 as a white
1
foam: Rf 0.53 (50% EtOAc/hexanes); 300 MHz H NMR data
was very complex (possibly due to the presence of the tertiary
amide); 75 MHz 13C NMR (CDCl3) δ 163.0, 158.0, 152.6, 148.3,
133.0, 129.2, 129.0, 128.7, 121.5, 118.5, 115.7 (q, J CF ) 286
Hz), 110.2, 110.0, 107.8, 102.2, 96.7, 78.0, 77.9, 77.2, 72.3, 72.1,
63.4, 56.1, 35.2, 28.3, 25.9; IR (CHCl3) 1722, 1697 cm-1; HRMS
m/z (EI) calcd C28H28NO10F3 595.1370, obsd 595.1358.
P r epar ation of N-[(12aS,4R,12R,11bR,3aR,4aR)-4-(Meth -
o x y m e t h o x y )-2,2-d im e t h y l-6-o x o (4,12,11b ,12a ,3a ,4a -
h exah ydr o-9H -1,3-dioxolen o[4′′,5′′-7′,6′]isoch r om an o[4′,3′-
5 , 4 ] b e n z o [ 1 , 2 - d ] - 1 , 3 - d i o x o l a n - 1 2 - y l ) ] - 2 , 2 , 2 -
tr iflu or oacetam ide (40). To a stirring suspension of samarium
metal (36 mg, 0.24 mmol) in 4 mL of THF was added iodine
(43 mg, 0.17 mmol) in one portion. After 1 h at gentle reflux,
the dark blue solution was cooled to -20 °C, and the lactone
39 (34 mg, 0.06 mmol) in 1.5 mL of THF was added via
cannula. The solution was allowed to slowly warm to 0 °C over
a 2.5 h period. The reaction was quenched with 2 mL of a
saturated Na2S2O3 solution and diluted with 2 mL of CH2Cl2.
C
22H23NO11 477.1270, obsd 477.1272.
P r ep a r a t ion of (7R)-7-((1R){(5S,4R)-5-[(1Z)-2-Aza -2-
(p h en ylm eth oxy)vin yl]-2,2-d im eth yl(1,3-d ioxola n -4-yl)}-

4476 J . Org. Chem., Vol. 64, No. 12, 1999
Keck et al.
(m eth oxym eth oxy)m eth yl)-8-h yd r oxy-2H -1,3-d ioxolen o-
[4,5-g]isoch r om a n -5-on e (33). To a stirring solution of keto-
aldehyde 32 (380 mg, 0.602 mmol) in 8 mL of THF was added
a solution consisting of HF‚pyridine (11.0 mL), pyridine (16.0
mL) and 8 mL of THF. The reaction was allowed to stand at
room temperature for 24 h, after which time it was diluted
with 50 mL of EtOAc and slowly quenched with saturated
NaHCO3. The layers were separated, and the organic layer
was washed with 50 mL of a saturated CuSO4 solution followed
by 50 mL of H2O and finally dried over MgSO4. The solution
was filtered through a plug of MgSO4/silica gel (slurry packed
in EtOAc) and concentrated under reduced pressure. The
resulting white foam was used in the next step without further
purification.
To a stirring solution of the crude lactol prepared above (228
mg) in 8 mL of CH2Cl2 at room temperature was added Dess-
Martin reagent (551 mg, 1.31 mmol) in one portion. After 3 h,
the reaction was dilulted with EtOAc (20 mL) and quenched
with a saturated solution (20 mL) of NaHCO3/Na2S2O3 (1:1).
The layers were separated, and the organic layer was washed
with brine (10 mL) and then dried over MgSO4 and filtered
through a silica gel pad with the aid of EtOAc. The resulting
solution was concentrated under reduced pressure to yield the
crude keto-lactone as a light yellow foam.
102.1, 98.8, 78.7, 76.3, 75.9, 75.4, 75.2, 64.4, 56.4, 27.3, 25.4;
IR (CHCl3) 3418, 1720 cm-1; HRMS m/z (EI) calcd C26H29NO10
515.1790, obsd 515.1761.
P r ep a r a tion of (12a S,4R,12R,11bR,3a R,4a R)-4-(Meth -
oxym eth oxy)-2,2-d im eth yl-12-[(p h en ylm eth oxy)a m in o]-
4,12,11b,12a,3a,4a-h exah ydr o-9H -1,3-dioxolen o[4′′,5′′-7′,6′]-
isoch r om an o[4′,3′-2,1]ben zo[4,5-d]-1,3-dioxolan -6-on e (35).
To a stirring solution of alcohol 33 (44 mg, 0.09 mmol) in 2
mL of 1,2-dichloroethane at room temperature was added 1,1′-
thiocarbonyldiimidazole (48 mg, 0.27 mmol). After 4 h, the
solution was diluted with 2 mL of CH2Cl2 and quenched with
5 mL of a saturated NH4Cl solution. The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (3 ×
4 mL). The combined organic layers were dried over anhydrous
MgSO4 and filtered through a MgSO4/silica gel plug. The
solvent was removed under reduced pressure to yield the crude
thionocarbamate 34 as a light yellow foam.
To a stirring solution of the crude thionocarbamate in 1.5
mL of toluene (degassed with N2 for 20 min) at 65 °C was
added a solution of triphenyltin hydride (0.07 mL, 0.27 mmol)
and 2,2-azobis[2-methylpropionitrile] (5.0 mg, 0.03 mmol) in
1.5 mL of toluene (degassed with N2 for 20 min) over 3.5 h.
After complete addition, the residual syringe contents were
added and the solution was stirred at 65 °C for an additional
1 h, then cooled to room temperature, and concentrated under
reduced pressure. The resulting clear colorless oil was purified
by flash chromatography on a 1.5 × 10 cm column, eluting
with a solvent gradient of 10%, 15%, 20%, 25%, and 35%
EtOAc/hexanes, collecting 4 mL fractions. The product-
containing fractions (48-65) were collected and concentrated
to yield amine 35 (30 mg, 70% yield from 33) as a clear
colorless oil: [R]D +63.1 (c 1.0, CHCl3); Rf 0.36 (50% EtOAc/
hexanes); 300 MHz 1H NMR (CDCl3) δ 7.52 (s, 1H), 7.26-7.38
(m, 5H), 6.92 (s, 1H), 6.04 (ABq, ∆AB ) 4.73 Hz, J ) 1.2 Hz,
2H), 5.75 (bs, 1H), 4.71-4.84 (m, 5H), 4.56 (dd, J ) 8.9, 4.8
Hz, 1H), 4.35-4.38 (m, 2H), 3.38 (s, 3H), 3.28 (dd, J ) 11.4,
2.9 Hz, 1H), 2.88 (dd, J ) 11.4, 8.9 Hz, 1H), 1.45 (s, 3H), 1.40
(s, 3H); 75 MHz 13C NMR (CDCl3) δ 163.5, 152.2, 147.9, 137.1,
136.3, 128.5, 128.3, 128.0, 118.5, 109.9, 109.3, 108.6, 102.0,
95.5, 78.4, 77.2, 76.7, 76.2, 72.9, 61.6, 55.9, 35.2, 28.3, 25.9;
HRMS m/z (EI) calcd C26H29NO9 499.1841, obsd 499.1889.
To a stirring solution of the keto-lactone (227 mg) prepared
above, in 7 mL of MeOH at -5 °C, was added NaBH4 (29.0
mg, 0.771 mmol) in one portion. The bath was removed, and
the reaction was slowly warmed to room temperature over 30
min, then quenched by addition of a saturated NH4Cl solution
(15 mL), and diluted with CH2Cl2 (15 mL). The layers were
separated, the aqueous layer was extracted with CH2Cl2 (3 ×
10 mL), and the combined organic layers were dried over Na2-
SO4 and concentrated under reduced pressure. The resulting
yellow oil was purified by flash chromatography on a 2.1 × 15
cm column, eluting with a solvent gradient of 10%, 15%, 20%,
25%, and 30% EtOAc/hexanes, collecting 6 mL fractions. The
product-containing fractions (36-70) were collected and con-
centrated to yield the alcohol 33 (130 mg, 42% yield from keto-
aldehyde 32) as a clear colorless oil and a mixture of diaster-
eomers: one diastereomer, [R]D -13.9° (c 2.42, CHCl3); Rf 0.22
1
(35% EtOAc/hexanes); 300 MHz H NMR (CDCl3) δ 7.48 (s, 1
H), 7.45 (d, J ) 8.1 Hz, 1 H), 7.28-7.34 (m, 5 H), 6.83 (s, 1 H),
6.05 (ABq, ∆AB ) 3.6 Hz, J ) 1.4 Hz, 2 H), 5.04 (s, 2 H), 4.74-
4.77 (m, 3 H), 4.54-4.63 (m, 3 H), 4.45 (d, J ) 3.2 Hz, 1 H),
3.93 (dd, J ) 5.0, 3.2 Hz, 1 H), 3.31 (s, 3 H), 1.53 (s, 3 H), 1.38
(s, 3 H); 75 MHz 13C NMR (CDCl3) δ 163.7, 152.4, 148.6, 148.4,
137.1, 136.9, 128.5, 128.1, 127.8, 118.4, 110.4, 109.7, 107.2,
Ack n ow led gm en t. Financial assistance provided by
the National Institutes of Health (through Grant
GM28961) and by Pfizer, Inc. is gratefully acknowledged.
J O9902042