A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach

Article abstract of DOI:10.1021/jo0483567

(Chemical Equation Presented) A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented br

Full text of DOI:10.1021/jo0483567

A Formal Total Synthesis of (-)-FR901483, Using a Tandem
Cationic Aza-Cope Rearrangement/Mannich Cyclization Approach
Kay M. Brummond* and Sang-phyo Hong
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
kbrummon@pitt.edu
Received September 16, 2004
A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key
step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization
reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound.
The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely
been explored in the context of natural product syntheses. Improved stereoselectivity was observed
in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive.
A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with
L-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only
one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic
routes required late stage adjustments to at least one of these stereocenters.
Introduction
tyrosyltyrosine. An alternative strategy involves forma-
tion of the [3.3.1] bicyclic ring system 3, then ring closure
to form the pyrrole (pathway b). Our group2l and
Kibayashi’s2g have adopted the latter approach, with both
routes proceeding through a bridgehead iminium ion.
Advantages to pathway b include the ease in which the
bicyclic [3.3.1] ring systems can be formed, the confor-
mational immobility of this ring system, and finally the
potential to explore bridgehead iminium ion chemistry
in the context of natural product synthesis.3
FR901483 (1) was discovered by researchers at Fujisa-
wa Pharmaceutical Company Ltd as part of an ongoing
effort to isolate new compounds that operate as immu-
nosuppressants via a mechanism that is unique from
either cyclosporin A or FK506 (Figure 1).1 Experimental
results suggest that FR901483 is likely to operate
through an antimetabolite effect on immunocompetent
cells by interfering with the enzymes adenylosuccinate
synthetase and/or adenylosuccinase. Further information
concerning the biological activity of this compound has
not been forthcoming. However, one can speculate that
the activity may result from FR901483 serving as a
competitive inhibitor for inositol monophosphate (IMP)
or an analogue of IMP.
This compound has captured the attention of the
synthetic community due to its unprecedented bridging
tricyclic azaspirane substructure.2 Nearly all synthetic
approaches to FR901483 (1) involve initial formation of
a spirolactam 2, followed by a ring closing reaction to
form the bicyclic [3.3.1] ring system (pathway a) (Scheme
1). This strategy has been postulated to most closely
mimic the biosynthesis of the natural product from
(2) For total syntheses of (-)-FR901483, see: (a) Snider, B. B.; Lin,
H. J. Am. Chem. Soc. 1999, 121, 7778. (b) Scheffler, G.; Seike, H.;
Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (c) Ousmer,
M.; Braun, N. A.; Ciufolini, M. A. Org. Lett. 2001, 3, 765. For the total
synthesis of (()-FR901483, see: (d) Maeng, J.-H.; Funk, R. L. Org.
Lett. 2001, 3, 1125. (e) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka,
H.; Fukuyama, T. Org. Lett. 2004, 6, 2729. For approaches to FR901483
and its analogues, see: (f) Quirante, J.; Escolano, C.; Massot, M.;
Bonjoch, J. Tetrahedron 1997, 53, 1391. (g) Yamazaki, N.; Suzuki, H.;
Kibayashi, C. J. Org. Chem. 1997, 62, 8280. (h) Braun, N. A.; Ciufolini,
M. A.; Peters, K.; Peters, E.-M. Tetrahedron Lett. 1998, 39, 4667. (i)
Snider, B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63, 6442. (j)
Kropf, J. E.; Weinreb, S. M. Abstracts of Papers, 222nd National
Meeting of the American Chemical Society, Chicago, IL, August 26-
30, 2001; American Chemical Society: Washington, DC, 2001; ORGN-
373. (k) Bonjoch, J.; Diaba, F.; Puigbo, E.; Sole, D.; Segarra, V.;
Santamaria, L.; Beleta, J.; Ryder, H.; Palacios, J.-M. Biorg. Med. Chem.
1999, 7, 2891. (l) Brummond, K. M.; Lu, J. Org. Lett. 2001, 3, 1347.
(m) Bonjoch, J.; Diaba, F.; Puigbo, E.; Sole, D. Tetrahedron Lett. 2003,
44, 8387 (n) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S. J.
Org. Chem. 2004, 69, 2755.
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37.
10.1021/jo0483567 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/24/2004
J. Org. Chem. 2005, 70, 907-916
907

Brummond and Hong
of the amino aldehyde 9 and the monoketal of 1,4-
cyclohexanedione 8. Unfortunately, aldol condensations
with N-protected R-amino aldehydes are characterized
by rather low distereoselectivities.5 However, the rapid
manner in which precursor 7 can be assembled via this
aldol condensation was our incentive to investigate this
reaction. As anticipated, treatment of ketone 8 with LDA
at -78 °C, followed by addition of aminoaldehyde 9
resulted in the aldol condensation as a mixture of
products (Scheme 3). However, a major product was
obtained and readily isolated from the others via flash
chromatography. This compound was determined to
possess the stereochemistry of that needed for elaboration
of FR901483 by X-ray crystallographic analysis.6 The
stereochemistry obtained for this diastereomer is consis-
tent with a Cram chelation control model in the aldol
condensation reaction, thus, a variety of conditions were
tried in an effort to increase the selectivity. The highest
selectivity was obtained by the formation of the lithium
enolate of ketone 8 with LDA, followed by addition of 1
equiv of zinc chloride.7 Addition of aldehyde 9 to the
enolate of 8 afforded a 3.6:1 ratio of the desired isomer
to an inseparable mixture of compounds in a combined
yield of ∼72%.8
FIGURE 1.
SCHEME 1
Our approach to the core structure of FR901483 (1)
utilizes the elegant chemistry developed in the Overman
group, the tandem cationic aza-Cope rearrangement/
Mannich cyclization reaction, to afford formyl pyrroles.4
Our retrosynthetic strategy was described in an initial
communication where it was demonstrated that the
bridging tricyclic azaspirane substructure could be ob-
tained by using a tandem cationic aza-Cope rearrange-
ment/Mannich cyclization reaction on a model system
possessing only the functionality needed for the re-
arrangement.2l Based upon preliminary results from this
successful model system, we set out to prepare a fully
functionalized precursor, which upon completing the
tandem cyclization reaction, could then be converted to
FR901483. The retrosynthetic strategy is shown in
Scheme 2. First, it was envisioned that the methylamine
group of 1 could be obtained from the aldehyde of 4 via
a Curtius rearrangement. Next, the formyl pyrrolidine
of 4 should be available via a Mannich cyclization from
the intermediate iminium ion 5. The potential to control
the stereochemistry of the aldehyde during the cyclization
step seemed possible by way of the flanking axial
hydroxyl group. The iminium ion 5, in turn, is the product
of the cationic aza-Cope rearrangement of the bridgehead
iminium ion 6, which is obtained by an intramolecular
condensation reaction between the carbonyl group and
the secondary amine of compound 7. The driving force of
the aza-Cope rearrangement/Mannich cyclization should
be substantial enough to overcome the axial orientation
of both protected hydroxyl groups. Finally, compound 7
can be accessed via an aldol reaction between com-
mercially available ketone 8 and a single enantiomer of
the Boc-protected amino aldehyde 9, followed by an
amine alkylation with homoallylic halide 10 or a syn-
thetic equivalent thereof.
Next, the carbonyl of â-hydroxy ketone 11 was reduced
with NaBH4 in MeOH to afford the desired diol 14 as a
single isomer (Scheme 4).9 The excellent selectivity was
thought to be a result of the appending hydroxymethyl
and ketal groups locking the conformation of cyclo-
hexanone 11 then axial delivery of the hydride to the less
hindered face. Reaction of the MOM protected ketone 13
with NaBH4 in MeOH at -78 °C also afforded 15 as a
single isomer in a nearly quantitative yield. When the
Luche reduction protocol was used, both ketones 11 and
13 gave a 1:1 mixture of stereoisomers 14 and 15 in 96%
and 99% yield, respectively. The configuration of diol 14
was confirmed by X-ray crystallographic analysis at a
later stage in the synthesis and found to be the desired
stereochemistry.
Next, diol 14 was protected as the dibenzyl ether 16
with Ag2O and nBu4NI in benzyl bromide (neat). Typical
benzyl ether protection protocols (NaH, BnBr, Bu4NI,
DMF or NaH, neat BnBr, Bu4NI, or Ag2O, BnBr, Bu4NI,
DMF) afforded only 30-40% yield of 16.10 These latter
conditions gave significant quantities of cyclic carbamate
1711 and an unidentifiable compound. Next, the Boc
(5) For a review, see: Jurczak, J.; Golebiowski, A. Chem. Rev. 1989,
89, 149 and references therein.
(6) The X-ray crystallographic data have been included in the
Supporting Information as a CIF file and have been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition
numbers CCDC 254173 and 254174.
(7) Pridgen, L. N.; Abdel-Magid, A. F.; Lantos, I.; Shilcrat, S.;
Eggleston, D. S. J. Org. Chem. 1993, 58, 5107.
(8) Since the other compounds could not be separated and fully
characterized, this yield is based upon the assumption that these
products are the undesired aldol diastereomers. Indirect support for
the diastereomeric aldol adducts is the clean conversion of the mixture
compounds to pyrrole 12 upon standing neat at room temperature.
Pyrroles have been previously obtained in this manner, see: Konieczny,
M. T.; Cushman, M. Tetrahedron Lett. 1992, 33, 6939.
Results and Discussion
Construction of the rearrangement precursor 7 in-
volves an aldol condensation between a single enantiomer
(9) Thompson, S. H. J.; Mahon, M. F.; Molloy, K. C.; Hadley, M. S.;
Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1995, 379. At this point,
we could not determine the newly formed stereocenter, but it was
presumed that axial attack occurred predominantly.
(10) Kuhn, R.; Trishmann, H. Chem. Ber. 1957, 90, 203. Czernecki,
S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 17, 3535.
(11) Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahedron
Lett. 2004, 45, 905.
(3) Reviews on bridgehead imines: Warner, P. M. Chem. Rev. 1989,
89, 1067. Eguchi, S.; Okano, T.; Takeuchi, H. Heterocycles 1987, 26,
3265.
(4) For reviews, see: (a) Overman, L. E.; Ricca, D. J. Comput. Org.
Synth. 1991, 2, 1007. (b) Overman, L. E. Acc. Chem. Res. 1992, 25,
352. (c) Overman, L. E.; Kakimoto, M.-a.; Okazaki, M. E.; Meier, G. P.
J. Am. Chem. Soc. 1983, 105, 6622.
908 J. Org. Chem., Vol. 70, No. 3, 2005

A Formal Total Synthesis of (-)-FR901483
SCHEME 2
SCHEME 3
SCHEME 4
SCHEME 6
and Cs2CO3/DMF14 were tried but only starting material
was recovered. Moreover, several attempts to alkylate
amine 18 with homoallyl bromide 20, using different
SCHEME 5
n
bases (K2CO3, NaHCO3, DIPEA, BuLi, NaH or KH) in
a variety of solvents (DMF, DMSO, CH2Cl2, or THF), did
not afford the secondary amine. Addition of a catalytic
amount of nBu4NI to activate electrophile 20 was not
successful. If the reaction was done in neat bromide 20
at 80 °C, decomposition of the starting material 18 was
observed. The recalcitrant nature of this amine toward
alkylation was somewhat surprising since the model
system gave low yields of the desired alkylated product
due to over-alkylation.2l
Due to these unforeseen alkylation problems, we
turned to the acylation of amine 18 with 2-(tert-butyldi-
methylsilyloxy)but-3-enic acid 2115 using EDCI in CH2-
Cl2 that afforded the corresponding R-silyloxy amide
(Scheme 7). Removal of the silyl protecting group gave
the R-hydroxy amide 22, which was reduced with 6 equiv
of LiAlH4 in refluxing THF affording amino alcohol 23
in 60% yield. Removal of the ketal protecting group from
protecting group of 16 was selectively removed from the
amine in the presence of the ketal protecting group by
using a two-step procedure: first, treatment of protected
amine 16 with 2,6-lutidine and TBDMSOTf at 0 °C
smoothly afforded the corresponding silyl carbamate,
then exposure of the crude silyl carbamate to TBAF in
THF at 0 °C afforded amine 18 in 96% yield for two steps
Scheme 5).12
Next, alkylation of the primary amine of 18 was
investigated (Scheme 6). A number of conditions were
used in an effort to directly alkylate 18 with homoallyl
bromide 20. Initially, Jung’s protocols using CsOH/DMF13
(13) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K.-W. Org.
Lett. 1999, 1, 1893.
(14) Salvatore, R. N.; Shin, S.-I.; Flanders, V. L.; Jung, K.-W.
Tetrahedron Lett. 2001, 42, 1799.
(15) Compound 21 was prepared by treating 2-hydroxybut-3-enoic
methyl ester with TBSCl and imidazole in DMF and subsequent
hydrolysis with LiOH in THF/H2O. Stach, H.; Huggernberg, W.; Hesse,
M. Helv. Chim. Acta 1987, 70, 369.
(12) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
J. Org. Chem, Vol. 70, No. 3, 2005 909

Brummond and Hong
SCHEME 7
effecting the tandem aza-Cope/Mannich cyclization reac-
tion. To our delight, treatment of amino ketone 28 with
1.2 equiv of p-TsOH in refluxing benzene afforded alde-
hyde 25 in 3 h as indicated by two resonances at 9.81
1
and 9.82 ppm in the H NMR. Since aldehyde 25 was
unstable to column chromatography, it was directly
reduced with NaBH4 to afford the amino alcohol 29.
Extensive NMR studies of the major and minor isomer
of 29 including 1H NMR, 13C NMR, 1H-1H COSY, DEPT,
and difference nOe showed the desired tricyclic substruc-
ture was generated as a 2:1 mixture of diastereomers.
The stereochemistry of the hydroxymethyl group on the
pyrrolidine 29 was not discernible, so both isomers were
advanced through the synthetic sequence independently.
At a later stage in the synthesis, it was determined that
the desired stereoisomer 29â was the minor isomer.
Efforts were then made to obtain predominantly pyr-
rolidine 29â. For example, ketene 30 was prepared via
an oxidation of the major diastereomer of amino alcohol
29R with Jones’ reagent to afford the corresponding
amino acid (Scheme 9). The crude amino acid was
converted to acid chloride with SOCl2 and reaction of the
acid chloride with Et3N18 in THF followed by addition of
aq NaN3 at 0 °C afforded the corresponding acyl azide
31. Unfortunately, Curtius rearrangement of 31 and
reduction of the resulting methyl carbamate with LiAlH4
gave a 1:1 diastereomeric mixture of diamine 32 in 18%
yield for the 6 steps.
SCHEME 8
Next, it was thought that the stereochemistry of
aldehyde 25 could be controlled by the formation of an
enamine that would be selectively protonated from one
face then hydrolyzed to give a single stereoisomer of the
aldehyde (Scheme 10).19 Indeed, addition of L-phenyl-
alanine to aldehyde 25 resulted in a 1:2 mixture of
diastereomers favoring the desired aldehyde 25â in 71%
combined yield for two steps (entry 2, Table 1). The
addition of glycine resulted in no change in the stereo-
selectivity of 25 (entry 3). L-Proline was also tested and
gave only an inseparable mixture of products (entry 4).
Curiously, D-phenylalanine afforded a 1:1 mixture of
25R:25â in 68% yield (entry 5). Addition of L-N,N-
dimethylphenylalanine had no effect on the stereochem-
istry, suggesting that enamine formation is essential for
isomerization (entry 6). It is assumed that there is a
conformational preorganization of the enamine, imparted
by a hydrogen bond between the carboxylic acid and the
tertiary amine, that results in a selective protonation
from the R face of the enamine.
Next, aldehydes 25R and 25â were reduced with
NaBH4 in MeOH/THF to afford alcohol 29R and 29â
(Scheme 11). The major and desired diastereomer, alcohol
29â, was readily separated from the minor diastereomer
29R by column chromatography. Oxidation of alcohol 29â
with Jones’ reagent afforded the amino acid 33â in a
quantitative crude yield.
Treatment of amino acid 33â with Et3N and ethyl
chloroformate in acetone, followed by addition of aqueous
NaN3, afforded acyl azide 31â.20 The crude acyl azide was
heated at 90 °C in toluene for ∼45 min and the trans-
23 with 3 N HCl provided a compound that upon silica
1
gel chromatography gave vinyl oxazolidine 24. The H
NMR clearly showed the resonances of the vinyl protons
and 13C NMR showed the characteristic signal of the
quaternary carbon of the oxazolidine at 93.3 ppm in C6D6.
Unfortunately, all attempts to rearrange vinyl oxazoli-
dine 24 to the formyl pyrrolidine 25 by using several
different protic and Lewis acids resulted in either no
reaction or complex mixtures of unidentifiable com-
pounds.16
Thus, the hydroxyl group of 22 was reacted with Ag2O
in neat MeI to afford two diastereomers of compound 26
in 96% yield (Scheme 8).17 Attempts to convert 22 to 26
with NaH/MeI in THF or Ag2O/MeI in CH2Cl2 resulted
in isomerization of the double bond into conjugation with
the amide as indicated by the resonances at 6.41 (quartet)
and 1.91 ppm (doublet) in 1H NMR of the crude product.
The stereochemistry of a single diastereomer of 26 was
determined by X-ray crystallographic structure analysis.6
The R-methoxy amide 26 was readily reduced with
LiAlH4 in toluene to afford 27 in 97% yield. Attempted
reduction of 26 with LiAlH4 in THF resulted in a complex
mixture of compounds. The ketal group of amine 27 was
removed with 3 N HCl to afford aminoketone 28. Next,
the aminoketone 28 was subjected to the same reaction
conditions that were used on the model system2l for
(18) Baigrie, L. M.; Seiklay H. R.; Tidwell, T. T. J. Am. Chem. Soc.
1985, 107, 5391.
(19) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126,
450.
(16) Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.
(17) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455
910 J. Org. Chem., Vol. 70, No. 3, 2005

A Formal Total Synthesis of (-)-FR901483
SCHEME 9
SCHEME 10
Conclusions
In summary, we have demonstrated an efficient formal
total synthesis of FR901483 in 2.5% overall yield in 18
steps from commercially available ketone 8 and the Boc-
protected aminoaldehyde 9. An aldol condensation reac-
tion between the zinc enolate of ketone 8 and Boc-
protected R-amino aldehyde 9 afforded the desired amino
alcohol 11 with 3.6:1 diastereoselectivity in 56% yield.
The selectivity can be explained via a Cram chelation
model. Interestingly, there are very few reports of dias-
tereoselective aldol reactions for Boc-protected aminoal-
dehydes. Our strategy features a tandem aza-Cope/
Mannich reaction proceeding through a bridgehead
iminium ion to rapidly construct the unique tricyclic core
structure of FR901483. The tandem aza-Cope/Mannich
reaction and subsequent epimerization of the aldehyde
bearing carbon using L-phenylalanine afforded the de-
sired amino aldehyde as a major product with 2:1
selectivity. Finally, the stereochemistry of the oxygen
bearing stereocenters of FR901483 was controlled at the
outset, without need for late-stage adjustments.
TABLE 1. Isomerization of Aldehyde 25
entry
amine
ratio (25â:25â)a yield,b %
1
2
3
4
5
6
none
L-phenylalanine
glycine
L-proline
D-phenylalanine
L-N,N-dimethyl phenylalanine
2:1
1:2
2:1
63
71
72
-
68
68
c
1:1
2:1
a Isolated ratio. b Combined yield for two steps. c Complex mix-
tures.
formation of the acyl azide (1714, 2138 cm-1) to the
isocyanate (1699, 2265 cm-1) was monitored by IR. Once
the acyl azide stretch had disappeared, methanol was
added to the reaction mixture to afford methylcarbamate
34â in 78% yield for two steps. Carbamate 34â was
reacted with LiAlH4 in refluxing THF to provide diamine
32â in 82% yield. Removal of the benzyl protecting groups
of diamine 32â with Pd(OH)2/C in MeOH at 50 psi of
hydrogen pressure afforded a diol that has been prepared
previously by Ciufolini.2c Unfortunately, the solid com-
pound that we obtained from this reaction was insoluble
in CDCl3, a solvent that was used by Ciufolini to
characterize this compound.21 Therefore, the secondary
amine of 32â was protected with a Boc group then
removal of the benzyl protecting groups was accom-
plished with H2 and Pd(OH)2/C in MeOH giving diol 35â
in 78% yield. The more accessible hydroxyl group of diol
35â was selectively phosphorylated by using a two-step
procedure.22 The 1H and 13C NMR spectral data of
phosphoric ester 36â were identical with a compound
previously synthesized by Sorensen.2b Sorensen converted
36â to FR901483 using a two-step deprotection sequence
(Scheme 12).
Experimental Section
General Comments. All reactions were carried out under
nitrogen atmosphere. All commercially available compounds
were used as received, unless otherwise specified. Tetrahy-
drofuran (THF), diethyl ether (Et2O), and dichloromethane
(CH2Cl2) were purified with alumina, using a solvent purifica-
tion system. Toluene and diisopropylamine were freshly
distilled from CaH2 prior to use. Flash chromatography was
performed with silica gel (32-63 mm particle size, 60 Å pore
size). An eluting solution used for the chromatographic puri-
fication of the amines 18, 27, 29R, 29â, 32â, 34â, and 36â was
prepared by adding 480 mL of CH2Cl2, 20 mL of MeOH, and
20 mL of commercial 28-30% NH4OH into a separatory
funnel. The mixture was shaken and allowed to stand for 20
min. The aqueous phase was separated, and the organic phase
was used without further manipulations. All 1H and 13C
spectra were obtained on a 300-MHz spectrometer, and chemi-
cal shifts (δ) are reported relative to residual solvent peaks of
CHCl3 or C6H6. EI mass spectrometry was performed on a
micromass spectrometer. Melting points are uncorrected.
[2-Hydroxy-1-(4-methoxybenzyl)-2-(8-oxo-1,4-dioxa-
spiro[4.5]dec-7-yl)ethyl]carbamic Acid tert-Butyl Ester
(11). Li enolate: To a solution of diisopropylamine (1.68 mL,
12.0 mmol) in THF (100 mL) was added n-BuLi (7.50 mL of a
1.6 M solution in hexanes, 12.0 mmol) at -78 °C. This solution
was stirred for 15 min at -78 °C, then cyclohexanedione
monoketal 8 (1.25 g, 8.00 mmol) in THF (50 mL) was added
dropwise over 10 min at -78 °C. The mixture was maintained
at this temperature for 10 min, then freshly prepared amino
(20) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org.
Chem. 1978, 43, 2164.
(21) At this time the solubility differences cannot be explained.
However, large quantities of palladium catalyst were used in
the removal of the benzyl ether groups that may be a contributing
factor.
(22) Yu, L.-L.; Fraser-Reid, B. Tetrahedon Lett. 1988, 29, 979.
J. Org. Chem, Vol. 70, No. 3, 2005 911

Brummond and Hong
SCHEME 11
55.2, 51.8, 49.3, 39.1, 37.9, 35.4, 34.9, 28.4; MS (m/z) 436, 417,
399, 362, 240, 213, 197, 150, 121, 99, 86, 57; EI-HRMS calcd
for C23H33NO7 [M + H]+ (m/z) 436.2338, found 436.2335.
[2-Hydroxy-2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)-
1-(4-methoxybenzyl)ethyl]carbamic Acid tert-Butyl Es-
ter (14). NaBH4 (195 mg, 5.17 mmol) was placed in a flask,
followed by MeOH (20 mL) at -78 °C. The mixture was stirred
at that temperature for 10 min. Next, ketone 11 (1.45 g, 3.33
mmol) in THF (50 mL) was cannulated into this mixture over
15 min at -78 °C. The reaction was held at this temperature
for an additional 10 min, then warmed to room temperature.
After 20 min at room temperature, ice water was added to the
reaction and stirring was continued for an additional 30 min.
The aqueous layer was separated and extracted with Et2O (3
× 30 mL). The combined organic phases were washed with
water (2 × 10 mL) and brine (10 mL), dried with MgSO4, and
concentrated in vacuo. The crude residue was purified by flash
column chromatography over silica gel eluting with 50:50 ethyl
acetate:hexanes to give diol 14 (1.33 g, 91%) as a single
diastereomer.
SCHEME 12
Mp 160 °C; [R]25 -30.40 (c 0.015, CHCl3); IR (film) 3382
D
(br), 2963, 1683, 1513, 1247 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.16 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 5.01 (d, J
) 9.8 Hz, 1H), 4.86 (s, 1H), 3.98-3.80 (m, 5H), 3.79 (s, 3H),
3.70-3.55 (m, 1H), 3.53 (d, J ) 9.0 Hz, 1H), 2.89-2.76 (m,
3H), 1.97-1.50 (m, 7H), 1.40 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 158.4, 156.1, 131.0, 130.6, 114.2, 108.1, 79.4, 77.5,
75.9, 64.7, 64.4, 55.5, 52.9, 43.1, 38.0, 34.2, 33.5, 33.2, 28.6;
MS (m/z) 436, 377, 359, 329, 315, 275, 91; EI-HRMS calcd for
C23H35NO7 [M - H]+ (m/z) 436.2335, found 436.2329.
aldehyde 923 (2.23 g, 8.00 mmol) in THF (30 mL) was added.
The resulting solution was stirred for 20 min at -78 °C, then
saturated NH4Cl solution was added at that temperature. The
aqueous layer was separated then extracted with Et2O (3 ×
50 mL). The combined organic phases were washed with brine
(30 mL), dried with MgSO4, and concentrated in vacuo. The
crude material was purified by flash column chromatography
over silica gel eluting with 20:80 ethyl acetate:hexanes to give
hydroxyl ketone 11 (1.45 g, 42%) along with 1.21 g of an
inseparable mixture of presumed diastereomers.
[2-Benzyloxy-2-(8-benzyloxy-1,4-dioxaspiro[4.5]dec-7-
yl)-1-(4-methoxybenzyl)ethyl]carbamic Acid tert-Butyl
Ester (16). To diol 14 (468 mg, 1.07 mmol) in benzyl bromide
(6 mL) was added n-Bu4NI (39 mg, 0.11 mmol) at room
temperature. After 20 min, Ag2O (990 mg, 4.28 mmol) was
added in a single portion and the reaction was stirred for 12
h at room temperature. The mixture was filtered through
Celite and the filter cake was washed with Et2O (30 mL). The
filtrate was concentrated in vacuo and the residue was purified
by flash column chromatography over silica gel eluting with
hexanes and 20:80 ethyl acetate:hexanes to give dibenzyl ether
16 (470 mg, 71%) as a colorless oil.
Zn enolate: To diisopropylamine (0.375 mL, 2.67 mmol) in
THF (20 mL) was added n-BuLi (1.67 mL of a 1.6 M solution
in hexanes, 2.67 mmol) at -78 °C. This solution was stirred
for 15 min at -78 °C, then cyclohexanedione monoketal 8
(0.380 g, 2.43 mmol) in THF (10 mL) was added dropwise over
10 min at -78 °C. The mixture was maintained at this
temperature for 30 min, then ZnCl2 (4.87 mL of a 0.5 M
solution in THF, 2.43 mmol) was added. The reaction was held
at -78 °C for 30 min to ensure transmetalation, then amino
aldehyde 9 (0.679 g, 2.43 mmol) in THF (30 mL) was added.
The solution was stirred for 20 min at -78 °C, then a saturated
NH4Cl solution was added at that temperature. The aqueous
layer was separated then extracted with Et2O (3 × 20 mL).
The combined organic phases were washed with brine (10 mL),
dried with MgSO4, and concentrated in vacuo. The crude
material was purified by a flash column chromatography over
silica gel eluting with 20:80 ethyl acetate:hexanes to give
ketone 11 (0.596 g, 56%) along with 0.165 g of an inseparable
mixture of presumed diastereomers (16%).
[R]25 +22.38 (c 0.048, CHCl3); IR (film) 3457, 2934, 1709,
D
1512, 1247 cm-1
;
1H NMR (300 MHz,C6D6) δ 7.20-7.00 (m,
10H), 6.85 (d, J ) 8.3 Hz, 2H), 6.55 (d, J ) 8.3 Hz, 2H), 5.18
(d, J ) 9.6 Hz, 1H), 4.43 (d, J ) 11.6 Hz, 1H), 4.35-4.25 (m,
1H), 4.15 (d, J ) 11.6 Hz, 1H), 4.14 (d, J ) 11.6 Hz, 1H), 3.98-
3.96 (m, 1H), 3.81 (d, J ) 11.6 Hz, 1H), 3.50-3.41 (m, 4H),
3.40-3.30 (m, 1H), 3.18 (s, 3H), 2.88-2.80 (m, 1H), 2.72-2.51
(m, 2H), 2.23-2.14 (m, 1H), 1.92-1.76 (m, 2H), 1.75-1.60 (m,
2H), 1.55-1.47 (m, 1H), 1.42 (s, 9H); 13C NMR (75 MHz, C6D6)
δ 158.7, 155.4, 139.9, 139.1, 131.1, 130.7, 128.6, 128.5, 127.6,
127.3, 114.2, 109.0, 78.8, 77.2, 76.3, 71.5, 70.4, 64.4, 54.7, 52.3,
41.9, 40.7, 33.6, 33.0, 28.7, 28.6; MS (m/z) 617, 544, 518, 496,
396, 334, 121, 91; EI-HRMS calcd for C37H47NO7 [M]+ (m/z)
617.3352, found 617.3332.
Mp 120 °C; [R]25 -60.41 (c 0.058, CHCl3); IR (film) 3507,
D
3382, 2974, 1704, 1513, 1246 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.11 (d, J ) 8.3 Hz, 2H), 6.77 (d, J ) 8.3 Hz, 2H), 5.12 (d, J
) 10.2 Hz, 1H), 4.03-3.72 (m, 7H), 3.72 (s, 3H), 2.80 (d, J )
7.6 Hz, 2H), 2.75-2.58 (m, 2H), 2.36-2.21 (m, 2H), 2.00-1.89
(m, 2H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 215.1, 158.1,
155.7, 130.5, 130.3, 113.9, 106.8, 79.1, 77.5, 70.6, 64.9, 64.4,
2-Benzyloxy-2-(8-benzyloxy-1,4-dioxaspiro[4.5]dec-7-
yl)-1-(4-methoxybenzyl)ethylamine (18). To dibenzyl ether
16 (900 mg, 1.46 mmol) in CH2Cl2 (50 mL) was added 2,6-
lutidine (0.51 mL, 4.4 mmol), then TBDMSOTf (0.670 mL, 2.92
mmol) at 0 °C. The reaction was allowed to warm to room
temperature and after 2 h a 0.5 N HCl solution (10 mL) was
added. The organic layer was separated and the aqueous layer
(23) Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz,
P. Tetrahedron 1998, 54, 6051. Jegham, S.; Das, B. C. Tetrahedron
Lett. 1988, 29, 4419. When the Swern oxidation was allowed to warm
to room temperature, complete racemization of the aldehyde was
observed.
912 J. Org. Chem., Vol. 70, No. 3, 2005

A Formal Total Synthesis of (-)-FR901483
was extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were washed with water (1 × 20 mL) and brine (1 ×
20 mL), dried with MgSO4, and concentrated in vacuo. The
crude residue was dissolved in THF (100 mL) and cooled to 0
°C, then TBAF (4.37 mL of a 1.0 M in THF solution, 4.37
mmol) was added. After 10 min, saturated NH4Cl was added
and the resulting solution was extracted with Et2O (3 × 30
mL). The combined organic phases were washed with brine
(20 mL), dried with MgSO4 and concentrated in vacuo. The
crude residue was purified by a flash chromatography over
silica gel eluting with 50:50 ethyl acetate:hexanes and a
solution of NH4OH/MeOH/CH2Cl2 (see general comments) to
give amine 18 (725 mg, 96%) as a colorless oil.
73.4, 71.6, 70.5, 64.6, 55.3, 51.0, 41.6, 39.6, 33.5, 32.5, 28.2;
MS (m/z) 602, 544, 480, 409, 253, 234,181, 150, 139, 121; EI-
HRMS calcd for C36H43NO7 [M + H]+ (m/z) 602.3118, found
602.3106.
7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-3-vinyl-2-oxa-5-
azatricyclo[6.3.1.01,5]dodecane (24). To LiAlH4 (97 mg, 2.6
mmol) in THF (10 mL) was cannulated amide 22 (256 mg,
0.426 mmol) in THF (10 mL) over 5 min at 0 °C. The reaction
was refluxed for 12 h, then cooled to room temperature. Next,
water (0.2 mL) was added followed by MgSO4 and the resulting
mixture was filtered through Celite. The filtrate was concen-
trated in vacuo to give amine 23 (150 mg, 60%). To amine 23
(90 mg, 0.15 mmol) in THF (5 mL) was added 3 N HCl (5 mL)
at room temperature. After the reaction was stirred for 5 h, 1
N NaOH (16 mL) was added, the organic layer was separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic phases were washed with brine (10 mL),
dried with MgSO4, and concentrated in vacuo. The crude
residue was purified by flash column chromatography over
silica gel eluting with 50:50 ethyl acetate:hexanes and ethyl
acetate to give vinyl oxazolidine 24 (66 mg, 82%) as a colorless
oil and a 1:1 mixture of diastereomers. (Data for the isomer
with a lower Rf are shown below.)
[R]25D +39.32 (c 0.053, CHCl3); IR (film) 3200 (br), 2960 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.39-7.26 (m, 10 H), 6.93 (d, J
) 8.5 Hz, 2H), 6.74 (d, J ) 8.5 Hz, 2H), 4.68 (d, J ) 11.5 Hz,
1H), 4.64 (d, J ) 11.5 Hz, 1H), 4.58 (d, J ) 11.5 Hz, 1H), 4.35
(d, J ) 11.5 Hz, 1H), 3.96 (s, 4H), 3.75 (s, 3H), 3.67-3.52 (m,
2H), 3.32-3.24 (m, 1H), 2.84 (dd, J ) 4.4, 13.3 Hz, 1H), 2.50-
2.40 (m, 2H), 2.19-2.14 (m, 1H), 2.01-1.95 (m, 1H), 1.91-
1.79 (m, 2H), 1.75-1.50 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
158.0, 139.1, 139.0, 131.6, 130.3, 128.5, 128.4, 127.8, 127.7,
127.6, 127.5, 113.9, 108.7, 82.4, 73.6, 70.5, 64.5, 64.4, 55.3, 54.5,
41.9, 41.6, 35.3, 32.4, 27.8; MS (m/z) 518, 484, 396, 290, 247,
150, 91; EI-HRMS calcd for C32H39NO5 [M]+ (m/z) 517.2828,
found 517.2877.
1
IR (film) 2925, 1512, 1246, 1092 cm-1; H NMR (300 MHz,
C6D6) δ 7.43-7.10 (m, 12H), 6.86 (d, J ) 8.6 Hz, 2H), 6.11,
(ddd, J ) 17.1, 10.2, 6.9 Hz, 1H), 5.27 (d, J ) 17.0 Hz, 1H),
5.07 (d, J ) 11.6 Hz, 1H), 4.55-4.45 (m, 1H), 4.38 (d, J ) 11.6
Hz, 1H), 4.33 (d, J ) 12.1 Hz, 1H), 4.24 (d, J ) 12.1 Hz, 1H),
4.03 (d, J ) 11.6 Hz, 1H), 3.78-3.68 (m, 1H), 3.65 (t, J ) 8.5
Hz, 1H), 3.41 (s, 3H), 3.16 (dd, J ) 13.0, 9.4 Hz, 1H), 3.12-
3.04 (m, 2H), 2.97 (m, 1H), 2.88 (dd, J ) 8.8, 4.1 Hz, 1H), 2.73
(m, 1H), 2.38-2.25 (m, 2H), 2.18-2.02 (m, 2H); 13C NMR (75
MHz, C6D6) δ 158.8, 140.4, 139.6, 139.3, 131.8, 130.4, 127.5,
115.1, 114.3, 92.7, 77.9, 76.3, 74.6, 71.2, 70.5, 60.0, 54.9, 52.2,
39.4, 35.8, 30.2, 27.4, 24.9; MS (m/z) 526, 404, 376, 312, 192,
121, 91; EI-HRMS calcd for C34H39NO4 [M + H]+ (m/z)
526.2957, found 526.2934.
2-Hydroxybut-3-enoic Acid [2-Benzyloxy-2-(8-benz-
yloxy-1,4-dioxaspiro[4.5]dec-7-yl)-1-(4-methoxybenzyl)eth-
yl]amide (22). To amine 18 (580 mg, 1.12 mmol) in CH2Cl2
(50 mL) was added EDCI (1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride, 645 mg, 3.36 mmol) then acid
21 (730 mg, 3.36 mmol) at room temperature. The reaction
was stirred for 3 h at room temperature, then 0.5 N HCl was
added (20 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were washed with water (20 mL) and
brine (20 mL), dried with MgSO4, and concentrated in vacuo.
The crude residue was immediately dissolved in THF (50 mL)
and cooled to 0 °C. Next, TBAF (3.36 mL of a 1.0 M in THF
solution, 3.36 mmol) was added and the reaction was main-
tained at 0 °C. After 30 min, saturated NH4Cl was added then
the aqueous phase was separated and extracted with Et2O (3
× 30 mL). The combined organic phases were washed with
brine (20 mL), dried with MgSO4, and concentrated in vacuo.
The crude residue was purified by a flash column chromatog-
raphy over silica gel eluting with 50:50 ethyl acetate:hexanes
to give amide 22 (560 mg, 83% as a 1:1 mixture of diastereo-
mers) as a colorless oil.
2-Methoxybut-3-enoic Acid [2-Benzyloxy-2-(8-benz-
yloxy-1,4-dioxaspiro[4.5]dec-7-yl)-1-(4-methoxybenzyl)eth-
yl]amide (26). To amide 22 (713 mg, 1.19 mmol) in MeI (10
mL) was added CaSO4 (800 mg, 5.88 mmol), then Ag2O (550
mg, 2.37 mmol) in a single portion. The reaction was stirred
for 12 h at room temperature then filtered through Celite. The
filter cake was washed with Et2O (30 mL) and the filtrate was
concentrated in vacuo to give methoxy amide 26 (700 mg, 96%)
as a white solid. The white solid was purified by flash column
chromatography over silica gel eluting with 50:50 ethyl ac-
etate:hexanes.
IR (film) 3407(br), 2932, 1655, 1512, 1247 cm-1. Isomer 1:
IR (KBr) 3426, 2939, 1668, 1506, 1248 cm-1. Isomer 1: mp
1
[R]25 +18.72 (c 0.033, CHCl3); H NMR (300 MHz, CDCl3) δ
142 °C; [R]25 +32.30 (c 0.020, CHCl3); 1H NMR (300 MHz,
D
D
7.45-7.20 (m, 8H), 7.13 (m, 2H), 6.95-6.86 (m, 1H), 6.85 (d,
J ) 8.6 Hz, 2H), 6.62 (d, J ) 8.6 Hz, 2H), 5.94-5.84 (m, 1H),
5.42 (d, J ) 17.1 Hz, 1H), 5.28 (d, J ) 10.3 Hz, 1H), 4.68 (d,
J ) 11.6 Hz, 1H), 4.47-4.41 (m, 2H), 4.32 (d, J ) 11.6 Hz,
1H), 4.33-4.22 (m, 1H), 3.97-3.85 (m, 6H), 3.63 (s, 3H), 3.55-
3.30 (br s, 1H), 3.27-3.18 (m, 1H), 2.75-2.61 (m, 2H), 2.41-
2.31 (m, 1H), 2.14-2.00 (m, 1H), 1.88-1.78 (m, 1H), 1.75-
1.67 (m, 1H), 1.64-1.42 (m, 2H), 1.40-1.25 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 170.6, 158.4, 139.2, 138.6, 136.3, 130.6,
130.3, 128.8, 128.5, 128.4, 128.1, 127.5, 118.0, 114.1, 108.6,
76.8, 75.7, 73.5, 71.8, 70.5, 64.6, 55.3, 51.0, 41.7, 39.7, 33.4,
32.5, 28.2. Isomer 2: [R]25D +22.26 (c 0.027, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.45-7.20 (m, 8H), 7.13 (m, 2H), 6.90-
6.86 (m, 1H), 6.85 (d, J ) 8.5 Hz, 2H), 6.62 (d, J ) 8.5 Hz,
2H), 5.93-5.84 (m, 1H), 5.42 (d, J ) 17.1 Hz, 1H), 5.28 (d, J
) 10.2 Hz, 1H), 4.69 (d, J ) 11.6 Hz, 1H), 4.52-4.41 (m, 2H),
4.32 (d, J ) 11.6 Hz, 1H), 4.30-4.20 (m, 1H), 3.90 (s, 4H),
4.00-3.86 (m, 2H), 3.62 (s, 3H), 3.30-3.18 (m, 1H), 2.77-2.57
(m, 2H), 2.52-2.31 (m, 1H), 2.14-2.00 (m, 1H), 1.92-1.80 (m,
1H), 1.78-1.67 (m, 1H), 1.66-1.22 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 170.7, 158.4, 139.2, 138.6, 136.4, 130.6, 130.3, 128.8,
128.6, 128.4, 128.1, 127.5, 118.1, 114.1, 108.7, 77.6, 76.7, 75.4,
CDCl3) δ 7.43-7.25 (m, 7H), 7.20-7.13 (m, 3H), 6.86 (d, J )
8.5 Hz, 2H), 6.62 (d, J ) 8.5 Hz, 2H), 5.91-5.79 (ddd, J )
17.2, 10.4, 6.0 Hz, 1H), 5.47 (d, J ) 17.2 Hz, 1H), 5.35 (d, J )
10.4 Hz, 1H), 4.72 (d, J ) 11.8 Hz, 1H), 4.46 (d, J ) 11.8 Hz,
1H), 4.36-4.25 (m, 2H), 4.10 (d, J ) 6.0 Hz, 1H), 3.97 (d, J )
4.0 Hz, 1H), 3.94-3.85 (m, 6H), 3.61 (s, 3H), 3.38 (s, 3H), 3.24-
3.17 (m, 1H), 2.81-2.64 (m, 2H), 2.44-2.34 (m, 1H), 2.15-
2.03 (m, 1H), 1.91-1.83 (m, 1H), 1.75-1.65 (m, 1H), 1.65-
1.45 (m, 2H), 1.40-1.28 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
169.3, 158.4, 139.4, 138.8, 133.6, 130.7, 130.5, 128.8, 128.6,
128.4, 128.1, 127.5, 127.4, 118.7, 114.1, 108.7, 83.4, 76.8, 75.3,
71.4, 70.4, 64.6, 64.5, 57.7, 55.3, 50.4, 41.5, 39.7, 33.4, 32.7,
1
28.4. Isomer 2: [R]25 +22.58 (c 0.012, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.50-7.23 (m, 7H), 7.22-7.13 (m, 3H), 6.86
(d, J ) 8.5 Hz, 2H), 6.62 (d, J ) 8.5 Hz, 2H), 5.81-5.69 (ddd,
J ) 17.2, 10.3, 6.2 Hz, 1H), 5.40 (d, J ) 17.2 Hz, 1H), 5.30 (d,
J ) 10.3 Hz, 1H), 4.72 (d, J ) 11.8 Hz, 1H), 4.46 (d, J ) 11.8
Hz, 1H), 4.36 (d, J ) 11.6 Hz, 1H), 4.39-4.25 (m, 1H), 4.07 (d,
J ) 7.2 Hz, 1H), 4.00 (d, J ) 4.4 Hz, 1H), 3.94 (d, J ) 11.8 Hz,
1H), 3.92-3.91 (m, 4H), 3.62 (s, 3H), 3.42 (s, 3H), 3.38-3.25
(m, 1H), 2.76-2.61 (m, 2H), 2.48-2.37 (m, 1H), 2.18-2.05 (m,
1H), 1.97-1.89 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.40 (m, 4H);
J. Org. Chem, Vol. 70, No. 3, 2005 913

Brummond and Hong
13C NMR (75 MHz, CDCl3) δ 169.5, 158.1, 139.1, 138.6, 133.8,
130.5, 130.3, 128.6, 128.3, 128.2, 127.9, 127.3, 118.6, 113.8,
108.5, 83.3, 76.5, 75.3, 71.3, 70.3, 64.4, 57.8, 55.1, 50.2, 41.4,
39.5, 33.2, 32.3, 28.0; MS (m/z) 616, 544, 494, 409, 253, 181,
121, 91, 71; EI-HRMS calcd for C37H45NO7 [M + H]+ (m/z)
616.3274, found 616.3291.
[2-Benzyloxy-2-(8-benzyloxy-1,4-dioxaspiro[4.5]dec-7-
yl)-1-(4-methoxybenzyl)ethyl](2-methoxybut-3-enyl)-
amine (27). To amide 26 (525 mg, 0.854 mmol) in freshly
distilled toluene (20 mL) was added LiAlH4 (195 mg, 2.56
mmol) in one portion at room temperature. The suspension
was heated at 80 °C for 2 h and cooled to room temperature,
then water was added dropwise until a white solid precipi-
tated. To this mixture was added MgSO4 then it was filtered
through Celite. The filter cake was washed with Et2O (30 mL)
and the filtrate was concentrated in vacuo. The crude residue
was purified by flash column chromatography over silica gel
eluting first with 50:50 ethyl acetate:hexanes then a solution
of NH4OH/MeOH/CH2Cl2 (see general comments) to give amine
27 (497 mg, 97%) as a colorless oil.
(c 0.014, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.50-7.34 (m,
10H), 7.07 (d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 5.79-
5.67 (m, 17.5 Hz, 1H), 5.28 (d, J ) 12.0 Hz, 1H), 5.27 (d, J )
15.4 Hz, 1H), 4.66 (s, 2H), 4.63 (d, J ) 11.6 Hz, 1H), 4.46 (d,
J ) 11.6 Hz, 1H), 4.20-3.95 (m, 1H), 3.82 (s, 3H), 3.73-3.63
(m, 1H), 3.57 (t, J ) 4.6 Hz, 1H), 3.34 (s, 3H), 3.15-3.07 (m,
1H), 2.94-2.55 (m, 9H), 2.42-2.22 (m, 2H), 2.10-1.97 (m, 1H),
1.97-1.75 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 211.3, 158.1,
138.6, 137.2, 131.4, 130.2, 128.5, 128.0, 127.7, 118.0, 114.0,
82.8, 80.7, 77.0, 74.1, 73.5, 70.5, 61.2, 56.4, 55.3, 52.6, 43.4,
41.1, 37.0, 36.8, 27.7; MS (m/z) 558, 526, 436, 234, 121, 91,
71; EI-HRMS calcd for C35H43NO5 [M + H]+ (m/z) 558.3219,
found 558.3229.
[7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodec-3-yl]methanol (29). A flask equipped with
a Dean Stark apparatus was charged with ketoamine 28 (230
mg, 0.413 mmol), benzene (20 mL), then p-TsOH (94 mg, 0.50
mmol) in a single portion. The solution was slowly heated to
reflux over 30 min then maintained at that temperature for 3
h. Next, the solution was cooled to room temperature and
saturated NaHCO3 was added. The organic layer was sepa-
rated and the aqueous layer was extracted with Et2O (3 × 15
mL). The combined organic phases were washed with water
(10 mL) and brine (10 mL), dried with MgSO4, and concen-
trated in vacuo. The crude residue was dissolved in THF (20
mL) then cannulated into NaBH4 (30 mg, 0.79 mmol) in MeOH
(10 mL) at -78 °C over 10 min. The resulting solution was
allowed to warm to room temperature. At room temperature,
ice water (10 mL) was added to the reaction and the aqueous
layer was separated and extracted with Et2O (3 × 20 mL). The
combined organic phases were washed with water (10 mL) and
brine (10 mL), dried with MgSO4, and concentrated in vacuo.
The crude residue was purified by flash chromatography over
silica gel eluting with a solution of NH4OH/MeOH/CH2Cl2 (see
general comments) to give amino alcohol 29 (major 29R: 91
mg, 42%; minor 29â: 41 mg, 21%).
In situ epimerization with L-phenylalanine: A flask
equipped with a Dean Stark apparatus was charged with
ketoamine 28 (20 mg, 0.036 mmol), benzene (20 mL), then
p-TsOH (8 mg, 0.04 mmol) in a single portion. The reaction
was heated to reflux for 3 h. Upon complete consumption of
ketoamine 28 by TLC, L-phenylalanine (6 mg, 0.04 mmol) was
added and the solution was refluxed for an additional 2 h. The
reaction was cooled to room temperature and quenched with
saturated NaHCO3. The organic phase was separated and the
aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic phases were washed with water (5 mL) and
brine (5 mL), dried with MgSO4, and concentrated in vacuo.
The crude residue was dissolved in THF (5 mL) then cannu-
lated into a solution of NaBH4 (10 mg, 0.26 mmol) in MeOH
(0.2 mL) at -78 °C. The resulting solution was allowed to
warm to room temperature. At room temperature, ice water
(5 mL) was added and the aqueous layer was separated and
extracted with Et2O (3 × 10 mL). The combined organic phases
were washed with water (10 mL) and brine (10 mL), dried with
MgSO4 and concentrated in vacuo. The crude residue was
purified by flash chromatography over silica gel eluting with
a solution of NH4OH/MeOH/CH2Cl2 (see general comments)
to give amino alcohol 29 (minor 29R: 4.3 mg; major 29â: 9.0
mg).
IR (film) 3396, 2928 cm-1. Isomer 1 (29R): [R]25D +73.84 (c
0.058, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42-7.24 (m,
10H), 7.07 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 4.46
(d, J ) 11.7 Hz, 1H), 4.43 (s, 2H), 4.16 (d, J ) 11.7 Hz, 1H),
3.81 (s, 3H), 3.67 (dd, J ) 9.9, 5.2 Hz, 1H), 3.56 (dd, J ) 15.8,
5.8 Hz, 1H), 3.37-3.25 (m, 2H), 3.17 (br s, 1H), 3.08 (dd, J )
9.3, 4.0 Hz, 1H), 2.99-2.80 (m, 4H), 2.50 (s, 1H), 2.33 (br s,
1H), 2.03-1.77 (m, 5H), 1.70 (dd, J ) 12.2, 9.4 Hz, 1H), 1.60-
1.48 (m, 1H), 1.47 (dd, J ) 12.2, 6.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 158.1, 139.3, 139.2, 131.9, 130.5, 128.7, 127.8,
127.7, 114.0, 77.6, 75.7, 74.9, 71.4, 70.5, 67.8, 64.1, 60.8, 59.4,
55.5, 54.6, 51.8, 43.3, 36.7, 36.6, 36.0, 27.8, 27.5. Isomer 2
IR (film) 3345, 2960 cm-1. Isomer 1: [R]25D +57.32 (c 0.042,
CHCl3); 1H NMR (300 MHz,CDCl3) δ 7.43-7.18 (m, 10H), 6.93
(d, J ) 8.6 Hz, 2H), 6.68 (d, J ) 8.6 Hz, 2H), 5.76-5.64 (m,
1H), 5.23 (d, J ) 15.8 Hz, 1H), 5.22 (d, J ) 11.8 Hz, 1H), 4.63
(d, J ) 11.6 Hz, 1H), 4.57 (d, J ) 11.6 Hz, 1H), 4.47 (d, J )
11.4 Hz, 1H), 4.20 (d, J ) 11.4 Hz, 1H), 3.93 (s, 4H), 3.71 (s,
3H), 3.64-3.45 (m, 3H), 3.20 (s, 3H), 3.13-3.05 (m, 1H), 2.81-
2.70 (m, 3H), 2.65 (dd, J ) 12.0, 6.8 Hz, 1H), 2.47-2.35 (m,
1H), 2.18-2.07 (m, 1H), 1.95-1.91 (m, 2H), 1.83-1.75 (m, 1H),
1.69-1.50 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 157.8, 139.4,
139.1, 137.6, 132.1, 130.4, 128.4, 128.3, 127.8, 127.7, 127.5,
127.4, 117.9, 113.8, 108.9, 83.0, 80.4, 77.5, 77.0, 72.8, 70.4, 64.4,
61.4, 56.3, 55.2, 52.6, 41.5, 37.3, 35.3, 32.6, 28.0. Isomer 2:
1
[R]25 +60.70 (c 0.023, CHCl3); H NMR (300 MHz,CDCl3) δ
D
7.43-7.20 (m, 10H), 6.93 (d, J ) 8.5 Hz, 2H), 6.70 (d, J ) 8.5
Hz, 2H), 5.76-5.64 (m, 1H), 5.25 (d, J ) 15.2 Hz, 1H), 5.24 (d,
J ) 12.4 Hz, 1H), 4.67 (d, J ) 11.6 Hz, 1H), 4.59 (d, J ) 11.6
Hz, 1H), 4.49 (d, J ) 11.4 Hz, 1H), 4.18 (d, J ) 11.4 Hz, 1H),
3.94 (s, 4H), 3.72 (s, 3H), 3.72-3.61 (m, 2H), 3.54-3.46 (m,
1H), 3.29 (s, 3H), 3.13-3.05 (m, 1H), 2.90 (dd, J ) 11.8, 7.5
Hz, 1H), 2.85-2.72 (m, 2H), 2.61 (dd, J ) 11.8, 4.5 Hz, 1H),
2.53-2.43 (m, 1H), 2.20-2.11 (m, 1H), 2.00 (d, J ) 8.2 Hz,
2H), 1.87-1.78 (m, 1H), 1.73-1.53 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 158.1, 139.6, 139.4, 137.7, 132.4, 130.5, 128.6, 128.5,
128.1, 127.9, 127.7, 127.5, 118.0, 114.0, 109.1, 83.2, 80.0, 77.1,
77.0, 72.9, 70.5, 64.6, 64.5, 61.2, 56.6, 55.4, 52.8, 41.8, 37.3,
35.3, 32.7, 28.1; MS (m/z) 602, 570, 530, 480, 234, 139, 121,
91; EI-HRMS calcd for C37H47NO6 [M + H]+ (m/z) 602.3482,
found 602.3508.
4-Benzyloxy-3-[1-benzyloxy-2-(2-methoxybut-3-enylami-
no)-3-(4-methoxyphenyl)propyl]cyclohexanone (28). To
amine 27 (497 mg, 0.827 mmol) in THF (10 mL) was added 3
N HCl (10 mL) at room temperature and the reaction was
stirred for 12 h. The resulting solution was carefully quenched
with saturated NaHCO3 solution and extracted with Et2O (3
× 30 mL). The combined organic phases were washed with
brine (20 mL), dried with MgSO4, and concentrated in vacuo.
The crude residue was purified by flash column chromatog-
raphy over silica gel eluting with 20:80 ethyl acetate:hexanes,
50:50 ethyl acetate:hexanes, and ethyl acetate to give keto-
amine 28 (414 mg, 90%) as a 1:1 mixture of diastereomers.
IR (film) 3339, 2932, 1713 cm-1. Isomer 1: 1H NMR (300
MHz, CDCl3) δ 7.40-7.25 (m, 10H), 6.98 (d, J ) 8.6 Hz, 2H),
6.77 (d, J ) 8.6 Hz, 2H), 5.68-5.57 (m, 1H), 5.22 (d, J ) 15.7
Hz, 1H), 5.20 (d, J ) 11.8 Hz, 1H), 4.55 (s, 2H), 4.53 (d, J )
11.6 Hz, 1H), 4.35 (d, J ) 11.6 Hz, 1H), 3.93-3.85 (m, 1H),
3.75 (s, 3H), 3.58-3.50 (m, 1H), 3.46 (t, J ) 4.7 Hz, 1H), 3.17
(s, 3H), 3.05-2.95 (m, 1H), 280-2.45 (m, 9H), 2.32-2.13 (m,
2H), 2.05-1.88 (m, 1H), 1.62 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 211.5, 158.1, 138.6, 138.5, 137.2, 131.4, 130.2, 128.5,
128.0, 127.7, 118.2, 114.0, 82.7, 81.2, 74.1, 73.7, 70.5, 61.4, 56.3,
55.3, 52.5, 43.3, 41.2, 37.0, 36.9, 27.7. Isomer 2: [R]25D +47.50
914 J. Org. Chem., Vol. 70, No. 3, 2005

A Formal Total Synthesis of (-)-FR901483
(29â): [R]25 +42.52 (c 0.050, CHCl3); 1H NMR (300 MHz,
yl carbamate 34â (41 mg, 0.072 mmol) in THF (10 mL) was
cannulated into LiAlH4 (16 mg, 0.43 mmol) at room temper-
ature and the reaction was refluxed for 3 h. The reaction was
cooled to room temperature, then water was added dropwise
until a white solid precipitated. To this mixture was added
MgSO4 then the solution was filtered through Celite. The filter
cake was washed with Et2O (20 mL) and the filtrate was
concentrated in vacuo. The residue was purified by flash
chromatography over silica gel eluting first with 50:50 ethyl
acetate:hexanes then a solution of NH4OH/MeOH/CH2Cl2 (see
general comments) to give amine 32â (31 mg, 82%).
D
CDCl3) δ 7.42-7.24 (m, 10H), 7.07 (d, J ) 8.6 Hz, 2H), 6.80
(d, J ) 8.6 Hz, 2H), 4.54 (d, J ) 11.6 Hz, 1H), 4.48 (d, J )
12.1 Hz, 1H), 4.42 (d, J ) 12.1 Hz, 1H), 4.16 (d, J ) 11.6 Hz,-
1H), 3.80 (s, 3H), 3.68 (dd, J ) 9.8, 4.3 Hz, 1H), 3.57-3.43 (m,
3H), 3.33 (br s, 1H), 3.07 (dd, J ) 12.9, 10.3 Hz, 1H), 2.96-
2.89 (m, 2H), 2.84 (dd, J ) 13.0, 4.8 Hz, 1H), 2.52 (s, 1H), 2.25
(m, 1H), 2.12-1.95 (m, 2H), 1.95-1.70 (m, 4H), 1.55-1.45 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 158.3, 139.3, 139.2, 131.9,
130.5, 130.4, 128.7, 128.6, 127.7, 127.5, 114.1, 76.3, 74.9, 71.4,
70.7, 68.5, 59.2, 58.9, 55.5, 52.1, 43.4, 36.9, 36.1, 36.0, 31.4,
30.0, 27.2, 23.5, 23.0; MS (m/z) 526, 436, 406, 314, 121, 91;
EI-HRMS calcd for C34H41NO4 [M - H]+ (m/z) 526.2957, found
526.2961.
[R]25D +38.40 (c 0.015, CHCl3); IR (film) 3309 (br), 2929 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 10H), 7.08 (d, J
) 8.7 Hz, 2H), 6.80 (d, J ) 8.7 Hz, 2H), 4.50 (d, J ) 11.6 Hz,
1H), 4.45 (d, J ) 12.1 Hz, 1H), 4.42 (d, J ) 12.1 Hz, 1H), 4.17
(d, J ) 11.6 Hz, 1H), 3.82 (s, 3H), 3.56 (dd, J ) 9.7, 7.6 Hz,
1H), 3.49-3.42 (m, 1H), 3.30 (m, 1H), 3.22-3.13 (m, 1H), 3.02
(dd, J ) 13.0, 10.2 Hz, 1H), 2.93-2.85 (m, 2H), 2.72 (dd, J )
9.8, 3.6 Hz, 1H), 2.48 (m, 1H), 2.36 (s, 3H), 2.20-1.92 (m, 1H),
1.97 (dd, J ) 12. 9, 8.6 Hz, 1H), 1.90-1.75 (m, 4H), 1.62 (dd,
J ) 12.8, 2.8 Hz, 1H), 1.44-1.33 (m, 1H), 1.27 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 157.9, 139.0, 138.9, 131.8, 130.2,
128.5, 127.5, 113.8, 75.9, 74.6, 71.3, 70.3, 59.5, 58.9, 56.5, 55.3,
54.6, 49.7, 47.7, 36.4, 35.7, 35.0, 30.1, 26.9, 24.5; MS (m/z) 525,
435, 405, 149, 91, 69; EI-HRMS calcd for C34H42N2O3 [M -
H]+ (m/z) 525.3117, found 525.3110.
7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodecane-3-carboxylic Acid (33â). A flask was
charged with CrO3 (48 mg, 0.48 mmol) then 1.5 M H2SO4 (0.64
mL, 0.96 mmol). To this solution was added the amino alcohol
29â in acetone (5 mL) dropwise over 5 min. The resulting
solution was stirred for 5 h at room temperature then 0.2 mL
of i-PrOH was added and the solution was stirred for an
additional 30 min. The mixture was filtered through Celite.
The filter cake was washed with CHCl3 (5 mL) and the filtrate
was concentrated in vacuo. The residue was diluted with brine
and extracted with ethyl acetate (4 × 5 mL). The combined
organic phases were washed with water (3 mL) and brine (3
mL), dried with MgSO4, and concentrated in vacuo to give
amino acid 33â (52 mg, 100%) that was used in the next step
without further purification. The 1H NMR of this material
showed a broad singlet at 12.1 ppm and the IR showed an
absorption at 2925 (OH) and 1732 cm-1 (CdO).
[7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodec-3-yl]carbamic Acid Methyl Ester (34â).
Amino acid 33â (52 mg, 0.096 mmol) was dissolved in freshly
distilled acetone (5 mL) and the solution was cooled to 0 °C.
Triethylamine (0.052 mL, 0.37 mmol) and ethyl chloroformate
(0.021 mL, 0.22 mmol) were added and the reaction was stirred
for 1 h at 0 °C. Next NaN3 (0.044 mL of a 5.0 M aqueous
solution, 0.22 mmol) was added and this solution was stirred
for 1 h at 0 °C and 15 min at room temperature, then the
solution was diluted with water (3 mL) and extracted with
CHCl3 (3 × 5 mL). The combined organic phases were washed
with water (5 mL) and brine (5 mL), dried with MgSO4, and
concentrated in vacuo. The residue was azeotroped once with
benzene under reduced pressure. The IR spectra of 31â showed
acyl azide absorptions at 1714 and 2138 cm-1. The acyl azide
31â was dissolved in freshly distilled toluene (20 mL) and
heated at 90 °C for 45 min. Progress of this reaction was
followed by taking aliquots and monitoring the formation of
the isocyanate by IR (1699 and 2265 cm-1). Upon complete
disappearance of the acyl azide absorptions, MeOH (1 mL) was
added to the reaction and it was heated at 90 °C for 6 h. The
solution was cooled to room temperature and concentrated in
vacuo. The crude residue was purified by a flash chromatog-
raphy over silica gel eluting first with 50:50 ethyl acetate:
hexanes then a solution of NH4OH/MeOH/CH2Cl2 (see general
comments) to give methyl carbamate 34â (43 mg, 78%) as a
colorless oil.
[7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodec-3-yl]methylcarbamic Acid tert-Butyl
Ester. To amine 32â (13 mg, 0.027 mmol) in ethyl acetate (5
mL) was added Et3N (0.1 mL), followed by (Boc)2O (12 mg,
0.055 mmol) at room temperature. After 7 h, the solution was
concentrated in vacuo, and the residue was purified by flash
column chromatography eluting with 50:50 hexanes:ethyl
acetate to give the corresponding carbamate (15 mg, 90%).
[R]25 +19.50 (c 0.026, CHCl3); IR (film) 2928, 1687, 1247,
D
1150 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.43-7.27 (m, 10H),
7.14 (d, J ) 8.7 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 4.87 (br s,
1H), 4.58 (d, J ) 11.7 Hz, 1H), 4.51 (d, J ) 12.1 Hz, 1H), 4.46
(d, J ) 12.1 Hz, 1H), 4.21 (d, J ) 11.7 Hz, 1H), 3.80 (s, 3H),
3.70 (br s, 1H), 3.64-3.53 (m, 1H), 3.39 (br s, 1H), 3.10-2.82
(m, 4H), 2.75 (s, 3H), 2.56 (br s, 1H), 2.18-2.06 (m, 2H), 2.04-
1.82 (m, 4H), 1.80-1.65 (m, 2H), 1.58-1.45 (m, 1H), 1.45 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 158.0, 156.0, 139.1, 138.9,
131.8, 130.1, 128.5, 127.6, 127.5, 127.2, 113.8, 79.3, 74.7, 71.3,
70.4, 58.9, 58.0, 55.3, 51.1, 43.8, 36.5, 35.7, 31.6, 28.7, 26.9;
MS (m/z) 624, 569, 553, 535, 505, 449, 415, 359, 121, 91, 71;
EI-HRMS calcd for C35H41N2O5 (C39H50N2O5 - C4H9) [M]+
(m/z) 569.3015, found 569.3041.
[7,9-Dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodec-3-yl]methylcarbamic Acid tert-Butyl Es-
ter (35â). To the carbamate (13 mg, 0.029 mmol) in MeOH (5
mL) was added Pd(OH)2/C (119 mg). The vessel was flushed
with H2 and shaken for 12 h under 50 psi of H2 pressure in a
Parr hydrogenation apparatus. The resulting solution was
filtered through Celite (5 g) and the filtrate was concentrated
1
in vacuo to give diol 35â (7 mg, 78%) as colorless oil. The H
NMR spectrum shows very broad signals except for the
aromatic (doublets), methoxy (singlet), and tert-butyl (singlet)
resonances. Similar observations were seen by Snider on a
closely related substrate.2a
IR (film) 3323, 2930, 1717 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.45-7.23 (m, 10H), 7.08 (d, J ) 8.6 Hz, 2H), 6.80 (d, J )
8.6 Hz, 2H), 5.48 (br s, 1H), 4.52 (d, J ) 11.5 Hz, 1H), 4.47 (d,
J ) 12.0 Hz, 1H), 4.41 (d, J ) 12.0 Hz, 1H), 4.29 (br s, 1H),
4.18 (d, J ) 11.7 Hz, 1H), 3.82-3.75 (m, 1H), 3.80 (s, 3H),
3.64 (s, 3H), 3.62-3.51 (br s, 1H), 3.34 (br s, 1H), 3.07-2.90
(m, 4H), 2.51 (br s, 1H), 2.20 (m, 1H), 2.10-1.85 (m, 6H), 1.61
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 158.3, 156.7, 138.6, 138.3,
130.2, 128.6, 128.5, 127.7, 127.5, 127.4, 114.0, 74.6, 73.7, 71.5,
70.6, 59.2, 55.6, 55.3, 52.1, 47.2, 36.0, 34.8, 30.0, 26.4, 23.2;
MS (m/z) 569, 530, 479, 464, 449, 417, 91, 71, 57; EI-HRMS
calcd for C35H42N2O5 [M - H]+ (m/z) 569.3015, found 569.3007.
[9-(Bisbenzyloxyphosphoryloxy)-7-hydroxy-6-(4-meth-
oxybenzyl)-5-azatricyclo[6.3.1.01,5]dodec-3-yl]methylcar-
bamic Acid tert-Butyl Ester (36â). To a solution of diol 35â
(4 mg, 0.009 mmol) in dry CH2Cl2 (2 mL) was added 1H-
tetrazole (61 µL of a 3% in CH3CN solution, 0.021 mmol),
followed by addition of N,N-diisopropyl dibenzyl phosphora-
midite (6.0 µL, 0.054 mmol). The reaction was stirred at room
temperature for 2 h then cooled to 0 °C before adding t-BuOOH
(2.0 µL of 5-6 M in decane, 0.090 mmol). After 45 min, a
saturated Na2S2O3 solution was added, the organic phase was
separated, and the aqueous phase was extracted with CH2Cl2
(3 × 3 mL). The combined organic phases were washed with
[7,9-Bisbenzyloxy-6-(4-methoxybenzyl)-5-azatricyclo-
[6.3.1.01,5]dodec-3-yl]methylamine (32â). A solution of meth-
J. Org. Chem, Vol. 70, No. 3, 2005 915

Brummond and Hong
water (2 mL) and brine (2 mL), dried with MgSO4, and
concentrated in vacuo. The residue was purified by flash
chromatography eluting with a solution of NH4OH/MeOH/CH2-
Cl2 (see general comments) to give phosophate 36â (2 mg, 38%).
The 1H NMR and 13C NMR spectral data completely matched
Acknowledgment. We thank the University of
Pittsburgh and the National Institutes of Health for
supporting this research and Dr. Steven Geib, Univer-
sity of Pittsburgh, and Dr. Jeff Petersen, West Virginia
University, for X-ray crystallographic analysis. We also
thank Professor Eric Sorensen for generously providing
that reported by Sorensen.2b
1
[R]25 +7.4 (c 0.002, CHCl3); H NMR (500 MHz, CDCl3) δ
D
1
of H and 13C spectra of compound 36â. We also would
7.33-7.28 (m, 10H), 7.16 (d, J ) 8.6 Hz, 2H), 6.84 (d, J ) 8.6
Hz, 2H), 5.03-4.98 (m, 4H), 4.75 (br s, 1H), 4.33 (br s, 1H),
3.81 (s, 3H), 3.41 (m, 1H), 3.31 (m, 1H), 3.15 (br s, 1H), 2.80
(m, 2H), 2.73 (s, 3H), 2.70 (m, 1H), 2.12 (br s, 1H), 2.02 (m,
1H), 1.87 (dd, J ) 13.3, 10.4 Hz, 1H), 1.87-1.75 (m, 4H), 1.64-
like to thank Li Sha for early investigations of this
project.
1.50 (m, 2H), 1.46 (s, 9H), 1.41 (dd, J ) 13.1, 6.6 Hz, 1H); 13
C
Supporting Information Available: Spectra for all new
compounds and X-ray crystallographic data (CIF file). This
material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (75 MHz, CDCl3) δ 158.2, 156.0, 136.1, 130.9, 130.2,
128.7, 128.1, 114.0, 79.6, 75.1, 69.4, 67.0, 58.6, 58.5, 55.4, 51.5,
50.3, 43.6, 43.1, 35.9, 29.9, 28.9, 28.7; MS (m/z) 706, 675, 661,
647, 633, 619, 585, 379, 274, 207, 163, 147, 105, 91, 79; EI-
HRMS calcd for C39H52N2O8P [M + H]+ (m/z) 707.3461, found
707.3452.
JO0483567
916 J. Org. Chem., Vol. 70, No. 3, 2005