Synthetic studies toward (-)-FR901483 using a conjugate allylation to install the C-1 quaternary carbon

Article abstract of DOI:10.1021/jo061677t

(Chemical Equation Presented) Two approaches to the aza-tricyclo dodecane skeleton of (-)-FR901483 are reported. Both routes utilized a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a highly diastereose

Full text of DOI:10.1021/jo061677t

Synthetic Studies Toward (-)-FR901483 Using a Conjugate
Allylation To Install the C-1 Quaternary Carbon
Dimitar B. Gotchev and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
dan_comins@ncsu.edu
ReceiVed August 11, 2006
Two approaches to the aza-tricyclo dodecane skeleton of (-)-FR901483 are reported. Both routes utilized
a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a
highly diastereoselective conjugate allylation reaction to form the quaternary center at C-1 of the natural
product in an excellent yield. Although the desired polysubstituted piperidine intermediates were prepared
regio- and stereoselectively, the construction of the C-8/C-9 bond connectivity could not be achieved.
All attempts at a pinacol cyclization or an intramolecular 6-exo-tet epoxide opening were unsuccessful
because of an unfavorable A(1,3) strain inherent in the molecule.
Introduction
as compared to cyclosporin A and FK 506; namely, (-)-
FR901483 inhibits the adenylosuccinate synthetase and/or
adenylosuccinate lyase enzymes in the purine biosynthesis.
Because of the high degree of bioactivity and the unprecedented
azatricyclic structure of (-)-FR901483, it has become a popular
target of synthetic interest.5
The immunosuppressive natural products cyclosporine A and
FK 506 are leading therapeutic agents in the organ transplant
field.1,2 The mechanism of action of both cyclosporin A and
FK 506 is the inhibition of calcineurin, a calcium-dependent
serine/threonine phosphatase. Calcineurin, in turn, leads to the
inhibition of interleukin-2 production, which is a signal molecule
that induces cytotoxic T-cells. In high doses these two com-
pounds exhibit serious side effects such as neurotoxicity and
adverse reactions in diabetic patients.3 Because of this, the search
for less toxic immunosuppressants with a different mechanism
of action has emerged. These efforts led to the isolation of (-)-
FR901483 (1) from the fermentation broth of the fungal strain
Cladobotrium species No. 11231 by the Fujisawa research
group, and it was shown to significantly prolong the graft
survival time in the rat skin allograft model.4 More importantly,
it was suggested that the mechanism of action is quite different
(5) 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 syntheses 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,; Fukujama, T.
Org. Lett. 2004, 6, 2729. (f) Brummond, K. M.; Hong, S.-P. J. Org. Chem.
2005, 70, 907. For approaches to FR901483 and its analogues, see: (g)
Quirante, J.; Escolano, C.; Massot, M.; Bonjoch, J. Tetrahedron 1997, 53,
1391. (h) Yamazaki, N.; Suzuki, H.; Kibajashi, C. J. Org. Chem. 1997, 62,
8280. (i) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667. (j) Snider, B. B.; Lin, H.; Foxman, B.
M. J. Org. Chem. 1998, 63, 6442. (k) Bonjoch, J.; Diaba, F.; Puigbo, E.;
Sole, D.; Segarra, V.; Santamaria, L.; Beleta, J.; Ryder, H.; Palacios, J.-M.
Bioorg. Med. Chem. 1999, 7, 2891. (l) Brummond, K. M.; Lu, J. Org. Lett.
2001, 3, 1347. (m) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353. (n)
Bonjoch, J.; Diaba, F.; Puigbo, E.; Sole, D. Tetrahedron Lett. 2003, 44,
8387. (o) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S. J. Org. Chem.
2004, 69, 2755. (p) Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 2046. (q) Simila, S. T. M.; Reichelt,
A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933.
(1) Cyclosporin A; Borel, J. F., Ed.; Elsevier Biochemical Press:
Amsterdam, 1982.
(2) Schreiber, S. L. Cell 1992, 70, 365.
(3) (a) Schreiber, S. L. Science 1991, 251, 283. (b) Kannedy, M. S.;
Deeg, H. J.; Storb, N.; Thomas, E. D. Transplant. Proc. 1983, 15, 471.
(4) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 46, 37.
10.1021/jo061677t CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/03/2006
J. Org. Chem. 2006, 71, 9393-9402
9393

Gotchev and Comins
SCHEME 2. Synthesis of Dihydropyridone 6a
SCHEME 1. First Generation Retrosynthetic Analysis of
(-)-FR901483
a Reaction conditions: (a) (+)-TCC chloroformate, -78 °C; then
p-OMeBnMgCl; then H3O+ (89%, dr ) 95:5); (b) NaOMe, MeOH; then
H3O+ (90%); (c) n-BuLi, THF; then PhOCOCl (98%).
aldehyde 4, which could be accessed by a conjugate addition
of an allylsilane or allyltin reagent, such as 6 to dihydropyridone
5. Vinylogous amide 5 can be accessed via a tandem conjugate
addition/oxidation in dihydropyridone 7. Finally, Grignard
addition to the chiral 1-acylpyridinium salt 8 is expected to
furnish enantiopure 7.
Results and Discussion
Our approach to the synthesis of (-)-FR901483 (1) com-
menced with Grignard addition to the chiral 1-acylpyridinium
salt prepared from 3-triisopropylsilyl-4-methoxypyridine (8) and
the chloroformate of (+)-trans-2-(R)-cumylcyclohexanol (TCC),
thus establishing the absolute stereochemistry at the C-6 position
of the resulting dihydropyridone 9 (90%, dr 95:5, Scheme 2).6,7
The resulting dihydropyridone 9 was obtained as a single
diastereomer after recrystallization from ethyl acetate/hexanes.
A one-pot reaction with sodium methoxide in methanol to
remove the chiral auxiliary, followed by protodesilylation with
10% aqueous HCl, yielded an intermediate vinylogous amide,8
which in turn was reacylated by exposure to n-BuLi and phenyl
chloroformate to give dihydropyridone 7 as a single enantiomer.
After establishing a practical route to the optically active
dihydropyridone 7, we turned our attention to the synthesis of
racemic intermediates for initial studies of the feasibility of the
proposed pinacol coupling and of reductive amination reactions
(Scheme 1). Use of the enantiopure 7 would lead to the
asymmetric synthesis of 1, since once the absolute stereochem-
istry at C-6 is established, the rest of the stereocenters will be
introduced relative to the one at C-6 in the same manner as in
the racemic route. The addition of p-methoxybenzylmagnesium
chloride to the 1-acylpyridinium salt, prepared from 4-meth-
oxypyridine (10) and phenyl chloroformate, provided dihydro-
pyridone 11 in a 77% yield (Scheme 3).6 Copper-mediated
addition of the Grignard reagent derived from 2-(2-bromoethyl)-
1,3-dioxolane to compound 11 in the presence of trimethylsi-
lylchloride (TMSCl) afforded the desired silyl enol ether 12,
which was then subjected to catalytic Pd(OAc)2 oxidative
rearrangement conditions to give vinylogous amide 13 in a 70%
yield (two steps).9 A reaction of dihydropyridone 13 with Pb-
(OAc)4 resulted in C-3 acetoxylation to give acetate 15a as the
In the previous syntheses of (-)-FR901483 (1), the pyrroli-
dine portion of the aza-tricyclo dodecane nucleus was installed
utilizing a nitrone cycloaddition/hydrogenolysis,5a an oxidative
spiroannulation,5b,c a Diels-Alder cycloaddition/aldol cyclization,5d
a Michael addition/hydrogenolysis,5e or an aza-Cope rearrange-
ment/Mannich cyclization tactic.5f Most of the approaches to
the bicyclic [3.3.1]-ring system of 1 utilized an intramolecular
aldol cyclization reaction.5a-e Alternatively, the bicyclic [3.3.1]-
ring system can be installed through an intermediate bridgehead
imminium ion, followed by an intramolecular aza-Cope
rearrangement5f or an intermolecular alkylation.5h The [3.3.1]-
nonane nucleus was also successfully introduced utilizing an
intramolecular carboradical cyclization.5g,m Our approach to the
synthesis of 1 significantly differs from the previous synthetic
endeavors in both strategy and execution. Retrosynthetically,
we envisioned that target 1 could be derived via a reductive
amination of ketone 2, followed by phosphorylation at C-9
(Scheme 1). Ketone 2, in turn, could be synthesized from diol
3 by the selective formation and reduction of a tertiary
carbocation at C-8. Unlike the other approaches to 1, we chose
to exploit a Mitsunobu-type cyclization to construct the pyrro-
lidine portion of the aza-tricyclo dodecane nucleus. This would
then be followed by an oxidative cleavage of the double bond
to give compound 2. Diol 3, in turn, could be obtained by
performing an intramolecular pinacol cyclization of keto-
(6) (a) Comins, D. L.; Zhang, Y.-M.; Joseph, S. P. Org. Lett. 1999, 1,
657. (b) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
(7) The numbering scheme adopted is based on the accepted numbering
for the natural product (-)-FR901483 ( compound 1, Scheme 1).
(8) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 4549.
(9) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D.
Tetrahedron Lett. 1995, 36, 2423.
9394 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Studies Toward (-)-FR901483
SCHEME 3. C-1 Quaternary Center Installation via
Conjugate Allylationa
SCHEME 4. Confirmation of the C-7 Stereochemistrya
a Reaction conditions: (a) Pb(OAc)4, AcOH (5 mol %), toluene, reflux,
3 days.
and H-7. In addition, JH6-H7 ) 4.9 Hz in 15b and JH6-H7 ) 2.0
Hz in 15a were observed, confirming the assignment of 15a.
After considerable experimentation, hydrolysis of trans-
acetate 15a was achieved by treatment with Sc(OTf)3 in a 4:1
MeOH/H2O mixture to afford the corresponding R-hydroxy
ketone (Scheme 3).12,13 Protection of the resulting secondary
alcohol as a tert-butyldimethylsilyl (TBS) ether, followed by
acetal exchange, gave dihydropyridone 16 in an 86% yield (three
steps).14 We then turned our attention to finding suitable reaction
conditions to effect the conjugate allylation of compound 16
with the known allylsilane reagent 17.15 To our disappointment,
the use of Sakurai’s conjugate allylation conditions resulted only
in the recovery of the starting materials, even at temperatures
as high as -20 °C.16
In order to enhance the reactivity of the allylation reagent in
the conjugate addition, we prepared the known allylstannane
compound 6.17 The choice of compound 6 as the nucleophilic
partner was deliberate, as allylstannane reagents of this type
are known to be more reactive than the corresponding allylsi-
lanes. This is due to the presence of a more anionic character
on the carbon atom in the C-Sn bond, which makes it a weaker
bond.18 To our delight, conjugate allylation of dihydropyridone
16 with stannane 6 gave the desired piperidone 19 as the major
product in a 65% yield (dr 5.5:1).19 The observed stereochem-
istry of the major diastereomer can be explained by stereoelec-
tronic-controlled axial approach of the nucleophile, where the
incoming allyl group adds syn to the axial substituent at C-6.20
The use of TMSOTf as the Lewis acid source in this type of
transformation proved to be extremely important, as both the
employment of BF3‚OEt2 and TiCl4 resulted in the isolation of
a Reactions conditions: (a) PhOCOCl, -78 °C; then p-MeOBnMgCl;
then H3O+ (91%); (b) CuBr‚SMe2, TMSCl, Et3N, (2-[1,3]dioxolan-2-yl-
ethyl)-magnesium bromide (used crude); (c) Pd(OAc)2 (0.1 equiv), CuCl
(1 equiv), O2, CH3CN, 65 °C (70%, two steps); (d) Pb(OAc)4, toluene,
reflux (75%, dr ) 15:1); (e) ScOTf3 (0.2 equiv), H2O:MeOH 1:4 (100%);
(f) TBSCl, imidazole (90%); (g) BF3‚OEt2, HS(CH2)3SH (95%); (h) TiCl4,
CH2Cl2; (i) TMSOTf, CH2Cl2 (65%, dr ) 5.5:1).
(12) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Tetrahedron Lett.
1999, 40, 1689.
(13) A variety of basic hydrolysis conditions (K2CO3, MeOH; KCN,
MeOH) resulted in acetate hydrolysis together with carbamate removal or
significant decomposition (DBU, MeOH; NH3, MeOH). Other acidic type
hydrolysis conditions (10% aqueous HCl, EtOH; 10% aqueous H2SO4,
EtOH; HBF4‚OEt2, MeOH) resulted in significant polymerization upon scale
up.
(14) Acetal exchange was necessary as subjection of the (1,3)-dioxolane
acetal protected version of compound 16 to the Sakurai conjugate allylation
conditions (allyl silane 17, TiCl4, CH2Cl2) resulted in the Lewis acid
coordinating to the acetal moiety leading to an attack at the side chain.
(15) (a) Trost, B. M.; Chan, D. M. T.; Nanninga, T. N. Org. Synth. 1984,
62, 58. (b) Marco´, I. E.; Plancher, J.-M. Tetrahedron Lett. 1999, 40, 5259.
(c) Dumeunier, R.; Marko´, I. E. Tetrahedron Lett. 2000, 41, 10219.
(16) Sakurai, H.; Hosomi, A.; Hayashi, J. Org. Synth. 1984, 62, 86.
(17) (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4569. (b) Kelly, D. R.; Mahdi, J. G. Tetrahedron Lett.
2002, 43, 511.
major diastereomer (75%, dr 15:1).10 The resulting trans
stereochemistry can be explained by stereoelectronic control:
in order to maintain a chairlike transition state, intramolecular
delivery of the acetate group from the enol-lead triacetate
intermediate 14 takes place from the axial direction (Scheme
3).10 The C-6 substituent is in an axial orientation due to the
A(1,3) strain, with the N-acyl group leading to the observed major
diastereomer 15a.11 The stereochemistry of the major diastere-
omer 15a was confirmed by subjecting vinylogous amide 13 to
a mixture of Pb(OAc)4 and 5% of AcOH for 3 days at reflux to
give a 4:1 mixture of C-7 acetates (Scheme 4). A large NOE
(9%) between H-6 and H-7 was observed in cis-acetate 15b.
No NOE was observed in the trans-acetate 15a between H-6
(18) Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954.
(19) The stereochemistry of the major diastereomer 19 is believed to be
as depicted on the basis of an analogy with the allylation reaction in 25,
yielding the structurally similar compound 31 with unambiguously estab-
lished stereochemical correlation of the substituents on the piperidone ring
(see Scheme 8).
(10) Comins, D. L.; Stoltze, D. A.; Thakker, P.; McArdle, C. L.
Tetrahedron Lett. 1998, 39, 5693.
(11) For reviews on A(1,3) strain, see: (a) Hoffmann, R. W. Chem. ReV.
1989, 89, 1841. (b) Johnson, F. Chem. ReV. 1968, 68, 375.
J. Org. Chem, Vol. 71, No. 25, 2006 9395

Gotchev and Comins
SCHEME 5. Epimerization of the Silyl Ether in
Dihydropyridone 19
SCHEME 6. Attempted Pinacol Coupling of Keto-Aldehyde
21a
a Reaction conditions: (a) CaCO3, MeI, H2O:CH3CN 1:9 (100%, crude);
(b) see reagents in text.
starting material 16. This, to the best of our knowledge,
represents the first example of a Lewis acid mediated conjugate
allylation performed on a substituted dihydropyridone to give
the requisite quaternary carbon R to the nitrogen atom (C-1 in
this case).21 The conjugate allylation is unplagued by 1,2-
addition and gives exclusively the 1,4-product. The reaction
proceeds with good stereocontrol, making it an attractive way
to establish quaternary centers stereoselectively in appropriately
substituted dihydropyridone systems.
Next, we turned our attention to the epimerization of the C-7
silyl ether in piperidone 19, since there is a cis stereochemical
relationship between the two substituents at C-6 and C-7 in the
natural product (Scheme 5). After considerable experimentation,22a
we obtained the desired cis-epimer 20 on treatment with DBU,
but only as a 1:1 mixture of stereoisomers at C-7. In an attempt
to increase the yield of the desired compound, piperidone 19
was subjected to more forcing epimerization conditions (DBU,
pyridine, CHCl3, 80 °C); however, a complex mixture of
products was observed, and the ratio of 20 to 19 did not improve.
Apparently, our optimal conditions led to a 1:1 thermodynamic
mixture of epimers at C-7.23 At this point we decided to
epimerize the C-7 center at a later stage in the synthesis.24
Next, hydrolysis of piperidone 19 in an aqueous iodomethane
solution gave keto-aldehyde 21 in a quantitative yield, which
was subsequently used without further purification (Scheme 6).25
We were now in a position to investigate the proposed
intramolecular pinacol coupling which would simultaneously
set the stereocenters at C-8 and C-9 of diol 3.26 Unfortunately,
after considerable effort using various conditions (VCl3/Zn;
TiCl3/Zn-Cu; SmI2), we were unable to achieve the desired
transformation. All attempts led to the recovery of the starting
materials or a complex mixture of products.
As a result of our inability to obtain the desired pinacol
cyclization product 3, we turned our attention to a second
generation retrosynthetic approach to (-)-FR901483 (1; Scheme
7). Our analysis suggested that the targeted compound 1 could
be derived via reductive amination in ketone 22, followed by
phosphorylation at C-9. The C-8/C-9 bond connectivity would,
this time, be established by taking advantage of an intramo-
lecular 6-exo-tet epoxide opening of vinyl bromide 23. This will
again be followed by a Mitsunobu-type cyclization to construct
the pyrrolidine portion of the aza-tricyclo dodecane nucleus in
ketone 22. Vinyl bromide 23 in turn would arise from R-hydroxy
ketone 24 via a stereoselective carbonyl reduction, monome-
sylation of the less hindered alcohol at C-7 and from epoxide
formation. Piperidone 24 would be accessed by the conjugate
addition of allyltin reagent 6 to dihydropyridone 25, once again
providing the C-1 quaternary center stereoselectively. Vinylo-
gous amide 25 would be synthesized from dihydropyridone 7
by our tandem conjugate addition/oxidative rearrangement
protocol, followed by a regioselective installment of the vinyl
bromide group and by introduction of the alcohol function at
C-7.
(20) (a) Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem. 1997,
62, 8182. (b) Kuethe, J. T.; Comins, D. L. Org. Lett. 1999, 1, 1031. For
discussions on stereoelectronic control in reactions of this type, see: (c)
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Perga-
mon: New York, 1983; Chapter 6. (d) Stevens, R. V. Acc. Chem. Res.
1984, 17, 289.
(21) For a few examples of conjugate allylations in dihydropyridones
unsubstituted R to the nitrogen at the vinylogous amide portion of the
molecule, see: (a) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi, C. Tetrahedron
Lett. 1996, 37, 9063. (b) Comins, D. L.; Killpack, M. O.; Despagnet, E.;
Zeller, E. Heterocycles 2002, 58, 505. (c) Kranke, B.; Hebrault, D.; Schultz-
Kukula, M.; Kunz, H. Syn. Lett. 2004, 4, 671.
Our second generation approach to the target began with
exposure of dihydropyridone 11 to copper-mediated addition
of the known Grignard reagent 2627 in the presence of TMSCl
to give silyl enol ether 27 in a quantitative yield (Scheme 8).
(22) (a) See Table 1 in Supporting Information. (b) See Table 2 in
Supporting Information.
(23) MacSpartan Pro minimization employing MMFF conformer distri-
bution of ketone 19 revealed that the compound existed in a twist-boat
conformation with no apparent thermodynamic bias for the desired
epimerization to take place.
(24) We could epimerize the C-7 acetate functionality 15a, by prolonged
exposure to acetic acid, and prepare the C-7 epimer of 16. However, all
our attempts at the conjugate allylation reaction to install the C-1 quaternary
center failed, presumably resulting from the fact that the bulky TBS ether
(which is now epimeric at C-7 in dihydropyridone 16) blocks the R face
during the addition step. Since this is the face the nucleophile has to
approach in order to maintain a low energy, chairlike transition state, an
attack does not occur.
(25) White, J. D.; Hanselmann, R.; Wardrop, D. J. J. Am. Chem. Soc.
1999, 121, 1106.
(26) (a) Dobler, M. R.; Bruce, I.; Cederbaum, F.; Cooke, N. G.; Diorazio,
L. J.; Hall, R. G.; Irving, E. Tetrahedron Lett. 2001, 42, 8281. (b) Takahara,
P. M.; Freudenberger, J. H.; Konradi, A. W.; Pedersen, S. F. Tetrahedron
Lett. 1989, 30, 7177. (c) Matsumoto, T.; Yamaguchi, H.; Tanabe, M.; Yasui,
Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8393. (d) Kawatsura, M.; Kishi,
E.; Kito, M.; Sakai, H.; Shirahama, H.; Matsuda, F. Synlett 1997, 55, 479.
(e) Molander, G. A.; Kenny, C. J. Org. Chem. 1988, 53, 2132. (f) Fleming,
M.; McMurry, J. E. Org. Synth. 1982, 60, 113. (g) McMurry, J. E. Chem.
ReV. 1989, 89, 1513. (h) Molander, G. A.; Harris, C. R. Tetrahedron 1998,
54, 3321.
9396 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Studies Toward (-)-FR901483
SCHEME 7. Second Generation Retrosynthetic Analysis
SCHEME 8. C-1 Quaternary Center Installation in
Piperidone 31a
Subjection of 27 to premixed o-iodoxybenzoic acid (IBX) and
4-methoxypyridine N-oxide (MPO) afforded the desired dihy-
dropyridone 28 in a 55% yield.28,29 The versatility of this
transformation is exemplified by the fact that the sensitive
acetylene functionality is well tolerated under the reaction
conditions.30 Removal of the terminal trimethylsilyl group in
28 yielded the corresponding acetylene, which was then
subjected to B-bromo-9-BBN to yield vinyl bromide 29 as a
single regioisomer.31 Reaction of 29 with Pb(OAc)4 resulted in
the corresponding trans-acetate.32 Sc(OTf)3-mediated hydrolysis
of the acetate group was followed by protection of the resulting
secondary alcohol as the TBS ether to yield dihydropyridone
25 (57%, three steps). Conjugate allylation with allylstannane
6 gave the desired trimethylsilyl enol ether 30 as a single
diastereomer at C-1. Interestingly, compound 30 proved to be
stable to silica gel chromatography and had to be subjected to
acidic hydrolysis to yield the desired piperidone 31 in an 85%
a Reaction conditions: (a) CuBr‚SMe2, TMSCl, Et3N, 26 (used crude);
(b) IBX (1.2 equiv), MPO‚H2O (1.2 equiv), DMSO (55%, two steps); (c)
TBAF, THF, -40 °C (93%); (d) B-9-BBN, CH2Cl2 (85%); (e) Pb(OAc)4,
toluene, reflux (69%, dr ) 15:1); (f) ScOTf3 (0.2 equiv), H2O:MeOH 1:4
(100%); (g) TBSCl, imidazole (90%); (h) TMSOTf, 6, CH2Cl2 (crude); (i)
silica gel (50 equiv), oxalic acid (0.1 equiv), MeOH:H2O 10:1 (85%, two
steps, dr > 99:1).
yield (two steps). We proceeded to establish the stereochemical
relationship between the allylic group at C-1 and the benzylic
substituent at C-6 in compound 31. Irradiation of H6 showed a
large NOE correlation to H11 (5.8%), thus confirming the
assigned stereochemistry. This result confirmed our working
model that the conjugate addition of allylstannane 6 to C-6
substituted dihydropyridones indeed operated under stereoelec-
tronic-approach control, where the incoming allylgroup adds
syn to the axial substituent at C-6 in order to maintain a chairlike
transition state.20
(27) (a) Crimmins, M. T.; Gould, L. D. J. Am. Chem. Soc. 1987, 109,
6199. (b) Rossi, R.; Carpita, A.; Ciofalo, M.; Lippolis, V. Tetrahedron 1991,
47, 8443.
Having successfully installed the C-1 quaternary center with
the desired stereochemical orientation, we then focused on the
synthesis of key epoxide intermediate 23 (Scheme 9). Depro-
tection of the TBS ether in 31 was followed by intramolecular,
stereocontrolled reduction at C-8 with tetramethylammonium
triacetoxyborohydride to give the 1,2-diol 32 as a single
stereoisomer. The selective derivatization of the C-8 position
of trans-diol 32 by reaction with benzoic anhydride yielded the
C-8 benzoate ester 33 as the major product of a 3:1 mixture of
C-8/C-7 regioisomers.33 The direction of the acylation was
(28) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996.
(29) During the course of the oxidation of 27 to 28, we observed a small
amount (15%) of the piperidone product resulting from hydrolysis of the
silyl enol ether functionality.
(30) During the course of the oxidation of 27 to 28, we were surprised
to see that exposure to our earlier catalytic oxidation conditions (Pd(OAc)2
(0.1 equiv), CuCl (1 equiv), O2, CH3CN, 65 °C) gave only the undesired
piperidone byproduct resulting from the hydrolysis of the silyl enol ether
moiety.
(31) (a) White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.;
Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop. D. L. J. Am.
Chem. Soc. 2001, 123, 8593. (b) Hara, S.; Dojo, H.; Takinami, S.; Suzuki,
A. Tetrahedron Lett. 1983, 24, 731.
1
determined by examination of the H NMR spectra of diol 32
and benzoate ester 33. The H8 hydrogen atom frequency in 33
shifted downfield as compared to the chemical shift of H7. This
(32) The product showed a small coupling constant (JH6-H7 ) 2.0 Hz)
1
in its H NMR, consistent with its trans stereochemistry.
J. Org. Chem, Vol. 71, No. 25, 2006 9397

Gotchev and Comins
SCHEME 9. Synthesis of Key Epoxide Intermediate 23a
SCHEME 10. Attempted 6-exo-tet Epoxide Opening in 23
corresponding debrominated product exclusively. A likely reason
for the cyclization failure is an inherent A(1,3) strain in the
molecule that produces a conformation unfavorable to the
desired bond formation.
Summary
Although the investigated routes to the bicyclic [3.3.1]-ring
system of (-)-FR901483 did not result in the formation of the
C-8/C-9 bond connectivity, diastereoselective methodology for
the installation of the quaternary center at C-1 utilizing a
conjugate allylation reaction was developed, and several highly
substituted piperidine derivatives were prepared regio- and
stereoselectively. Most of the stereoselective transformations
were designed based on a conformational bias caused by an
A(1,3) strain present in the molecules. Unfortunately, failure of
the attempted C-8/C-9 formation is also attributed to an allylic
strain. If an N-acyl group of a late intermediate can be
selectively removed to relieve an A(1,3) strain, ring closure may
be feasible. Further studies will be needed to determine if the
synthetic routes attempted can be modified to allow the key
bond formation.
a Reaction conditions: (a) TBAF (1.2 equiv), THF, -40 °C (crude); (b)
Me4N+BH(OEt)3, AcOH (92%, two steps); (c) (PhCO)2O (1.0 equiv), Et3N
(2.0 equiv), DMAP (cat), CH2Cl2, 0 °C (56%); (d) MsCl, Et3N (2.0 equiv),
DMAP (cat), CH2Cl2 (97%); (e) NaOH, MeOH (94%).
is to be expected as the electron withdrawing benzoate ester
group exerts a larger deshielding effect on the H8 than on the
H7, causing the observed downfield shift in its resonance. During
the course of the acylation, we also discovered that subjection
of the corresponding undesired C-7 benzoate ester to methanolic
NaOH resulted in the quantitative formation of diol 32, allowing
the C-7 isomer to be recycled. Mesylation of 33 was followed
by subjection of the benzoate ester moiety in 34 to basic
hydrolysis to give the tetrahedral intermediate 35, which, upon
collapse, yielded the desired epoxide 23 in a one-pot event.34
With epoxide 23 in hand, we turned our attention to finding
suitable conditions to afford the C-8/C-9 bond connectivity in
(-)-FR901483 by effecting an intramolecular epoxide ring
opening (Scheme 10). This type of intramolecular opening of
an epoxide with an aryllithium to form a six-membered ring
has been reported.35 Unfortunately, all of our efforts to achieve
the desired 6-exo-tet epoxide opening to afford product 36 were
unsuccessful.22b Exposure to n-butyllithium or dibutylcopper
lithium led to the recovery of the starting materials together
with products resulting from an attack at the carbamate. Similar
results were observed when tert-butyllithium was used at -78
°C. Gratifyingly, lithium-bromide exchange was achieved by
reaction with t-BuLi at -120 °C for 1 h; however, all attempts
to obtain the desired epoxide opening product 36 via formation
of a higher-order cuprate or a lower-order cuprate gave the
Experimental Section
6-(2-[1,3]Dioxolan-2-yl-ethyl)-2-(4-methoxybenzyl)-4-oxo-3,4-
dihydro-2H-pyridine-1-carboxylic Acid Phenyl Ester (13). Mag-
nesium turnings (7.57 g, 311 mmol) were mechanically activated
by stirring at rt overnight under argon, and then 50 mL of anhydrous
THF was added. A portion of 2-(2-bromoethyl)-1,3-dioxolane (9.7
mL, 83 mmol) in 50 mL of anhydrous THF was slowly added to
the mixture. Once the reaction was initiated, the mixture was cooled
to 10 °C, and the remaining bromide was continuously added over
a period of 2 h. After the addition was complete, the reaction
mixture was stirred at 10 °C for 9 h to form the corresponding
Grignard reagent. In a separate flask, a copper bromide-dimethyl
sulfide complex (22.6 g, 110 mmol) was mixed with 50 mL of
freshly distilled THF under argon and was cooled to -78 °C. A
solution of 2-(4-methoxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-
1-carboxylic acid phenyl ester (11; 7.40 g, 20.7 mmol) in THF (30
mL) was added and was followed by a premixed solution of TMSCl
(30.6 mL, 241 mmol) and Et3N (35.2 mL, 252 mmol). A solution
of the above prepared Grignard reagent in THF was then added
dropwise over a period of 1 h. Once the addition was complete,
the resulting slurry was stirred at -78 °C for 2 h and then warmed
to -45 °C. After 24 h, the reaction mixture was quenched with
100 mL of a carefully buffered solution of NH4OH and NH4Cl
(pH 8), and the phases were separated. The aqueous phase was
extracted with Et2O (3 × 150 mL), and the combined organic layers
were washed with 10% NH4OH until no further blue color was
observed in the aqueous layer. The organic layers were combined,
(33) In a previous experiment we had discovered that exposure of diol
32 to MsCl (1.0 equiv) in the presence of Et3N and DMAP resulted in the
formation of the C-8 mesylate as the major compound of a 3:1 mixture of
C-8/C-7 regioisomers. Thus, in order to obtain the desired epoxide 23 we
needed to selectively derivatize the C-8 hydroxyl first. This led to the C-8
benzoate ester formation/C-7 mesylation route.
(34) Mashimo, K.; Sato, Y. Tetrahedron 1970, 26, 803.
(35) (a) Gauthier, D. R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37,
13. (b) Hudlickly, T.; Rinner, U.; Gonzalez, D.; Akgun, H.; Schilling, S.;
Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67,
8726.
9398 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Studies Toward (-)-FR901483
dried over K2CO3, filtered through Celite, and concentrated in vacuo
to yield crude silyl enol ether 12.
as a white solid which was used directly in the next step. Mp 152-
154 °C; IR (neat) 3394, 2919, 1737, 1664, 1513, 1410, 1320, 1248,
1
1179, 1033 cm-1; H NMR (CDCl3, 300 MHz) δ 7.40 (t, J ) 5.7
To a solution of the above enol ether 12 in 100 mL of anhydrous
CH3CN under argon was added Pd(OAc)2 (15 mol %, 0.74 g, 3.3
mmol), followed by CuCl (2.95 g, 29.8 mmol). The solution was
purged with oxygen, was warmed to 60 °C under an O2 balloon
pressure atmosphere, and was stirred vigorously overnight. Upon
completion, the reaction mixture was cooled to rt and filtered
through Celite with CH2Cl2, and the solvent was removed in vacuo
to yield the crude product 13. Purification by silica gel chroma-
tography (20 to 30% EtOAc in hexanes) gave 6.75 g (70%, two
steps) of the desired product 13 as a yellow foam: IR (neat) 2922,
Hz, 1 H), 7.27 (d, J ) 3.9 Hz, 2 H), 7.10 (d, J ) 6.3 Hz, 2 H),
7.01 (d, J ) 6.0 Hz, 2 H), 6.83 (d, J ) 6.9 Hz, 2 H), 5.60 (s, 1 H),
5.09 (dt, J ) 2.1, 8.1 Hz, 1 H), 4.92 (t, J ) 7.2 Hz, 1 H), 3.96 (m,
2 H), 3.87 (m, 2 H), 3.79 (s, 3 H), 3.04 (m, 2 H), 2.81 (m, 2 H),
2.70 (d, J ) 4.2 Hz, 1 H), 1.97 (m, 2 H); 13C NMR (CDCl3, 75
MHz) δ 192.9, 158.4 (159.2 r), 152.2, 150.4, 130.6, 129.6, 128.4,
126.3, 121.5, 114.3, 110.3, 103.4, 70.7, 65.1, 65.0, 64.2, 55.4, 33.5,
32.3, 30.5. HRMS: (M + H)+ calcd for C25H27NO7 + H, 454.1866;
found, 454.1873.
1
2851, 1719, 1512, 1494, 1453, 1248, 1203, 834 cm-1; H NMR
To a solution of the above R-hydroxy ketone (550 mg, 1.22
mmol) in DMF (20 mL) at 20 °C was added imidazole (165 mg,
2.43 mmol) and tert-butyldimethylsilyl chloride (275 mg, 1.82
mmol). The resulting mixture was stirred at rt for 12 h. The reaction
mixture was quenched with saturated aqueous NaHCO3 (50 mL)
and extracted with CH2Cl2 (3 × 40 mL). The combined organic
layers were washed with brine (30 mL), dried over Na2SO4, and
filtered through Celite with CH2Cl2, and the solvent was removed
in vacuo. Purification by silica gel chromatography (30 to 40%
EtOAc in hexanes) gave 620 mg (90%) of the desired TBS-
protected alcohol as a colorless oil which was used directly in the
next step. IR (neat) 2953, 1738, 1674, 1597, 1512, 1323, 1249,
1184, 1100, 1035, 841 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.37
(dt, J ) 1.0, 7.4 Hz, 2 H), 7.23 (t, J ) 8.4 Hz, 1 H), 7.10 (d, J )
8.4 Hz, 2 H), 6.95 (d, J ) 7.7 Hz, 2 H), 6.85 (d, J ) 6.6 Hz, 2 H),
5.59 (s, 1 H), 5.09 (dt, J ) 2.0, 7.2 Hz, 1 H), 4.92 (t, J ) 4.4 Hz,
1 H), 3.95 (m, 2 H), 3.84 (m, 2 H), 3.79 (s, 3 H), 3.69 (s, 1 H),
3.11 (m, 1 H), 3.01 (m, 1 H), 2.85 (m, 2 H), 1.99 (m, 2 H), 0.83
(s, 9 H), 0.07 (s, 3 H), 0.02 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 191.9, 157.8 (158.8 r), 152.5, 150.5, 130.5, 129.7, 128.7, 126.3,
121.6, 114.3, 111.0, 103.6, 71.6, 65.7, 65.2, 65.1, 55.5, 33.2, 32.5,
30.5, 25.8, 18.2, -4.6, -5.0. HRMS: (M + H)+ calcd for C31H41-
NO7Si + H, 568.2731; found, 568.2741.
(CDCl3, 300 MHz) δ 7.38 (dt, J ) 1.2 Hz, 5.7 Hz, 2 H), 7.26 (d,
J ) 3.9 Hz, 1 H), 7.10 (d, J ) 6.0 Hz, 2 H) 7.00 (d, J ) 6.0 Hz,
2 H), 6.85 (d, J ) 6.9 Hz, 2 H), 5.63 (s, 1 H), 5.07 (q, J ) 5.1 Hz,
1 H), 4.93 (t, J ) 3.3 Hz, 1 H), 3.96 (m, 2 H), 3.86 (m, 2 H), 3.79
(s, 3 H), 3.08 (m, 2 H), 2.81 (m, 3 H), 2.43 (d, J ) 12.6 Hz, 1 H),
1.97 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 193.0, 158.5, (157.3
r), 151.5, 150.3, 130.5, 129.4, 128.8, 126.1, 121.3, 114.0, 113.2,
103.2, 64.9, 57.0, 57.2, 55.2, 39.7, 35.5, 32.3, 30.1. HRMS: (M +
H)+ calcd for C25H27NO6 + H, 438.1917; found, 438.1904.
(2S*,3S*)-3-Acetoxy-6-(2-[1,3]dioxolan-2-yl-ethyl)-2-(4-meth-
oxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic Acid
Phenyl Ester (15a). To a stirred solution of 13 (121 mg, 0.277
mmol) in 8 mL of toluene at rt was added lead(IV) acetate (160
mg, 0.36 mmol). The resulting mixture was refluxed for 3 h and
cooled to rt, and additional lead(IV) acetate (160 mg, 0.36 mmol)
was added. The mixture was refluxed for 3 h. After cooling to rt,
the solution was filtered through Celite with CH2Cl2. The solution
was washed with saturated aqueous NaHCO3 (30 mL), and the
aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phase was dried over Na2SO4, filtered through
Celite, and concentrated in vacuo to yield crude 15a. Purification
by silica gel chromatography (20 to 30% EtOAc in hexanes) gave
103 mg (75%) of 15a as a colorless oil: IR (neat) 2934, 1741,
1678, 1592, 1513, 1401, 1248, 1181, 1032, 911, 750 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.36 (t, J ) 7.4 Hz, 2 H), 7.22 (d, J ) 7.3
Hz, 1 H), 7.12 (d, J ) 8.3 Hz, 2 H), 6.86 (t, J ) 8.7 Hz, 4 H), 5.70
(s, 1 H), 5.23 (dt, J ) 1.5, 6.6 Hz,1 H), 4.93 (m, 2 H), 3.96 (m, 2
H), 3.86 (m, 2 H), 3.79 (s, 3 H), 3.13 (m, 1 H), 2.97 (m, 2 H), 2.82
(m, 1 H), 2.09 (s, 3 H), 2.01 (m, 2 H); 13C NMR (CDCl3, 75 MHz)
δ 187.6, 169.9, 159.4, (159.0 r), 151.9, 150.3, 130.6, 129.7, 127.8,
126.5, 121.3, 114.4, 112.1, 103.4, 71.4, 65.2, 65.1, 61.9, 55.4, 33.5,
32.3, 30.5, 21.0. HRMS: (M + H)+ calcd for C27H29NO8 + H,
496.1971; found, 496.1959.
To a solution of the above TBS-protected alcohol (620 mg, 1.04
mmol) in CH2Cl2 (10 mL) at 20 °C were added neat BF3‚OEt2 (60
µL, 0.44 mmol) and then 1,3-propanedithiol (170 µL, 1.64 mmol).
The resulting mixture was stirred at rt for 8 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (50 mL) and was
extracted with CH2Cl2 (3 × 40 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and filtered through
Celite with CH2Cl2, and the solvent was removed in vacuo to yield
the crude product 16. Purification by silica gel chromatography
(10 to 20% EtOAc in hexanes) gave 637 mg (95%) of 16 as a
colorless oil: IR (neat) 2929, 1738, 1673, 1597, 1249, 1182, 1096,
1
837 cm-1; H NMR (CDCl3, 300 MHz) δ 7.37 (t, J ) 7.6 Hz, 2
(2S*,3R*)-3-Acetoxy-6-(2-[1,3]dioxolan-2-yl-ethyl)-2-(4-meth-
oxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic Acid
Phenyl Ester (15b). IR (neat) 2934, 1738, 1682, 1593, 1513, 1397,
1289, 1249, 1177, 1033, 913 cm-1; 1H NMR (CDCl3, 300 MHz) δ
7.24 (m, 5 H), 6.86 (d, J ) 6.3 Hz, 2 H), 6.72 (d, J ) 6.3 Hz, 2
H), 5.83 (d, J ) 4.5 Hz, 1 H), 5.63 (s, 1 H), 5.25 (m, 1 H), 4.91
(t, J ) 3.3 Hz, 1 H), 3.96 (m, 2 H), 3.84 (m, 2 H), 3.79 (m, 3 H),
2.98 (m, 3 H), 2.81 (m, 1 H), 2.19 (s, 3 H), 2.05 (m, 1 H), 1.90 (m,
1 H); 13C NMR (CDCl3, 75 MHz) δ 189.1, 169.9, 158.7 (158.8 r),
151.3, 150.3, 130.7, 129.6, 129.1, 126.4, 121.5, 114.2, 111.6, 103.4,
73.0, 65.2, 65.1, 60.7, 55.5, 32.4, 30.7, 30.0, 20.9. HRMS: (M +
H)+ calcd for C27H29NO8 + H, 496.1971; found, 496.1961.
(2S*,3S*)-3-(tert-Butyldimethylsilanyloxy)-6-(2-[1,3]dithian-
2-yl-ethyl)-2-(4-methoxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-
1-carboxylic Acid Phenyl Ester (16). To a solution of 15a (23.0
mg, 0.046 mmol) in H2O:MeOH (1.0 mL, 1:4) was added ScOTf3
(20 mol %, 5.0 mg, 0.0093 mmol). The resulting mixture was stirred
at rt for 40 h. Upon completion, the reaction mixture was poured
into H2O (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined extracts were dried over Na2SO4 and filtered through
Celite with CH2Cl2, and the solvent was removed in vacuo.
Purification by silica gel chromatography (20 to 30% EtOAc in
hexanes) gave 21.0 mg (100%) of the desired R-hydroxy ketone
H), 7.22 (t, J ) 6.8 Hz, 1 H), 7.10 (d, J ) 8.4 Hz, 2 H), 6.92 (d,
J ) 6.4 Hz, 2 H), 6.84 (d, J ) 6.8 Hz, 2 H), 5.56 (s, 1 H), 4.99 (dt,
J ) 3.2, 11.2 Hz, 1 H), 4.00 (t, J ) 9.6 Hz, 1 H), 3.80 (s, 3 H),
3.71 (d, J ) 2.4 Hz, 1 H), 3.19 (m, 1 H), 2.91 (m, 1 H), 2.81 (m,
6 H), 2.05 (m, 3 H), 1.97 (m, 1 H), 0.84 (s, 9 H), 0.04 (s, 3 H),
0.00 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.8, 158.9, 157.0,
152.4, 150.6, 130.5, 129.7, 128.54, 126.3, 121.6, 114.4, 111.2, 71.7,
65.5, 55.5, 46.7, 34.1, 33.2, 33.1, 30.3, 26.0, 25.8, 18.3, -4.6, -5.0.
HRMS: (M + H)+ calcd for C32H43NO5S2Si + H, 614.2430; found,
614.2439.
(2R*,5S*,6S*)-2(2-Benzyloxymethylallyl)-5-(tert-butyldimeth-
ylsilanyloxy)-2-(2-[1,3]dithian-2-yl-ethyl)-6-(4-methoxybenzyl)-
4-oxo-piperidine-1-carboxylic Acid Phenyl Ester (19). A well-
stirred solution of dihydropyridone 16 (0.560 g, 0.912 mmol) in
20 mL of dry CH2Cl2 was cooled to -78 °C. TMSOTf (490 µL,
2.73 mmol) was added in one portion, giving rise to a deep orange
color. After 5 min, neat (2-benzyloxymethylallyl)tributylstannane
reagent 6 (1.00 g, 1.82 mmol) was added dropwise over a 10 min
period. The reaction mixture was stirred for 4 h at -78 °C, warmed
up to -45 °C, and stirred for an additional 6 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (50 mL) and
warmed to rt, during which time it became colorless. The mixture
J. Org. Chem, Vol. 71, No. 25, 2006 9399

Gotchev and Comins
was extracted with CH2Cl2 (3 × 100 mL). The organic extracts
were dried over Na2SO4 and filtered through Celite. The solvent
was removed in vacuo to yield the crude product 19. Purification
by silica chromatography (0 to 20% EtOAc in hexanes) gave 458
mg (65%) of 19 as a colorless oil: IR (neat) 2929, 2856, 1720,
activated by stirring at rt overnight under argon, and then 40 mL
of anhydrous ether was added. A portion of 4-bromo-1-trimethyl-
silyl-1-butyne (3.65 g, 178 mmol) in 20 mL of anhydrous ether
was slowly added to the mixture. Once the reaction was initiated,
the mixture was cooled to 10 °C, and the remaining bromide was
continuously added over a period of 2 h. After the addition was
complete, the reaction mixture was stirred at 10 °C for 3 h, warmed
up to rt, and stirred for an additional 4 h to form the Grignard
reagent 26. In a separate flask, a copper bromide-dimethyl sulfide
complex (6.09 g, 296 mmol) was mixed with 20 mL of freshly
distilled THF under argon and was cooled to -78 °C. To a solution
of 2-(4-methoxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxy-
lic acid phenyl ester (11; 2.00 g, 593 mmol) in THF (10 mL) was
added a premixed solution of TMSCl (8.30 mL, 652 mmol) and
Et3N (9.5 mL, 682 mmol). A solution of the above prepared
Grignard reagent 26 in Et2O (diluted with 50 mL of THF) was
added dropwise over a period of 1 h. Once the addition was
complete, the resulting slurry was stirred at -78 °C for 2 h and
was then warmed to -45 °C. After 24 h, the reaction mixture was
quenched with a carefully buffered solution (pH 8) of NH4OH and
NH4Cl (100 mL), and the phases were separated. The aqueous phase
was extracted with Et2O (3 × 50 mL), and the combined organic
layers were washed with 10% NH4OH until no further blue color
was observed in the aqueous layer. After drying over anhydrous
K2CO3 and filtering through Celite, the solvent was removed under
reduced pressure to give 3.4 g of crude 27, which was dissolved in
10 mL of anhydrous DMSO. In a separate flask, IBX (9.96 g, 356
mmol) and MPO‚H2O (4.45 g, 356 mmol) were dissolved in 20
mL of DMSO at 10 °C. The IBX/MPO mixture was stirred until
complete dissolution and was then added in one portion at 0 °C to
the crude silyl enol ether 27 solution. The mixture was stirred
vigorously at rt overnight. The reaction mixture was carefully
diluted with 5% NaHCO3 (50 mL) and was extracted with Et2O (3
× 100 mL). The combined organic phase was dried over anhydrous
MgSO4 and filtered through Celite, and the solvent was removed
in vacuo to yield the crude product 28. Purification by silica gel
chromatography (10 to 25% EtOAc in hexanes) gave 2.3 g (55%,
two steps) of 28 as a yellow foam: IR (neat) 2955, 2171, 1725,
1666, 1513, 1248, 1201, 1162, 1037, 889 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.39 (d, J ) 7.7 Hz, 2 H), 7.27 (d, J ) 7.0 Hz, 1 H),
7.15 (dd, J ) 1.8, 6.6 Hz, 2 H), 6.93 (d, J ) 7.3 Hz, 2 H), 6.82
(dd, J ) 1.8, 6.2 Hz, 2 H), 5.66 (s, 1 H), 5.10 (dq, J ) 1.5, 6.2 Hz,
1 H), 3.79 (s, 3H), 3.29 (m, 1 H), 3.10 (dd, J ) 7.3, 7.3 Hz, 1 H),
2.89 (dd, J ) 8.1, 6.2 Hz, 1 H), 2.84 (d, J ) 5.9 Hz, 1 H), 2.71 (m,
1 H), 2.55 (t, J ) 6.6 Hz, 2 H), 2.46 (d, J ) 17.2 Hz, 1 H), 0.11
(s, 9 H); 13C NMR (CDCl3, 100 MHz) δ 193.2, 158.8, 155.4, 151.8,
150.4, 130.8, 129.6, 129.2, 126.5, 121.6 (122.0 r), 114.7, 114.3,
105.0, 87.3, 58.5, 55.5, 40.3, 36.1, 35.0, 19.1, 0.2. HRMS: (M +
H)+ calcd for C27H31NO4Si + H, 462.2101; found, 462.2085.
6-(3-Bromobut-3-enyl)-2-(4-methoxybenzyl)-4-oxo-3,4-dihy-
dro-2H-pyridine-1-carboxylic Acid Phenyl Ester (29). A solution
of 28 (1.43 g, 3.10 mmol) in THF (35 mL) was cooled to -78 °C.
Tetrabutylammonium fluoride (1.0 M in THF, 3.72 mL, 3.72 mmol)
was added dropwise over a period of 10 min. After the addition
was complete, the reaction mixture was stirred at -78 °C for 30
min, warmed to rt, and stirred for an additional 1 h at rt. The reaction
mixture was poured into saturated aqueous NH4Cl (100 mL) and
was then extracted with Et2O (3 × 250 mL). The combined organic
extracts were dried over MgSO4, filtered through Celite, and
concentrated in vacuo to yield the crude acetylene product.
Purification by silica gel chromatography (10 to 25% EtOAc in
hexanes) gave 1.11 g (93%) of the desired acetylene as a colorless
oil which was used directly in the next step. IR (neat) 3286, 2932,
1738, 1665, 1598, 1512, 1402, 1333, 1301, 1247, 1162, 1040, 829,
749, 689 cm-1; 1H NMR (CDCl3, 100 MHz) δ 7.39 (t, J ) 8.0 Hz,
2 H), 7.26 (m, 1 H), 7.13 (d, J ) 8.4 Hz, 2 H), 6.94 (d, J ) 7.6
Hz, 2 H), 6.84 (d, J ) 8.4 Hz, 2 H), 5.68 (s, 1 H), 5.11 (q, J ) 7.6
Hz, 1 H), 3.79 (s, 3 H), 3.27 (m, 1 H), 3.10 (dd, J ) 7.2, 6.4 Hz,
1 H), 2.90 (dd, J ) 8.0, 5.6 Hz, 1 H), 2.87 (dd, J ) 6.0, 11.2 Hz,
1
1513, 1348, 1250, 1201, 1098, 838 cm-1; H NMR (CDCl3, 300
MHz) δ 7.39 (m, 12 H), 6.82 (d, J ) 9.2 Hz, 2 H), 5.34 (d, J )
1.2 Hz, 1 H), 5.08 (s, 1 H), 4.67 (dd, J ) 1.8, 10.8 Hz, 1 H), 4.50
(s, 2 H), 4.00 (t, J ) 6.4 Hz, 1 H), 3.96 (s, 2 H), 3.78 (s, 3 H), 3.74
(s, 1 H), 3.21 (bs, 1 H), 3.19 (d, J ) 14.0 Hz, 1 H), 2.98 (bs, 1 H),
2.80 (m, 6 H), 2.52 (bs, 1 H), 2.13 (m, 2 H), 1.90 (m, 2 H), 1.85
(m, 2 H), 0.78 (s, 9 H), -0.10 (s, 3 H), -0.24 (s, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 206.3, 158.8, 151.1, 141.8, 141.4, 138.5, 130.3,
129.7, 129.4, 128.6, 128.5, 127.6, 125.9, 122.2, 120.7, 114.4, 73.9,
72.5, 71.3, 70.6, 64.2, 55.5, 47.4, 30.8, 30.4, 30.3, 30.2, 26.1, 25.8,
25.6, 18.1, -4.9, -5.6. HRMS: (M + H)+ calcd for C43H57NO6S2-
Si + H, 776.3475; found, 776.3439.
(2R*,5R*,6S*)-2-(2-Benzyloxymethylallyl)-5-(tert-butyldime-
thylsilanyloxy)-2-(2-[1,3]dithian-2-yl-ethyl)-6-(4-methoxybenzyl)-
4-oxo-piperidine-1-carboxylic Acid Phenyl Ester (20). Compound
19 (120 mg, 0.155 mmol) in CH2Cl2 (5 mL) was treated with
pyridine (1 µL, 0.02 mmol) and DBU (20 µL, 0.077 mmol), and
the resulting mixture was refluxed for 60 h. The solution was cooled
to rt and quenched with 1 N aqueous HCl (1 mL). The mixture
was extracted with CH2Cl2 (3 × 15 mL), and the combined organic
extracts were dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product, a 1:1 mixture of piperidones 19 and 20, was
purified by silica gel chromatography (10 to 20% EtOAc in
hexanes) to give 60 mg (50%) of the desired product 20 as a
colorless oil: IR (neat) 2927, 2853, 1717, 1512, 1248, 1202, 1161,
1110, 838 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.32 (s, 8 H), 7.20
(d, J ) 9.2 Hz, 2 H), 6.80 (d, J ) 9.2 Hz, 2 H), 6.62 (bs, 1 H),
5.34 (d, J ) 1.6 Hz, 1 H), 5.02 (s, 1 H), 4.93 (m, 1 H), 4.62 (d, J
) 5.6 Hz, 1 H), 4.50 (s, 2 H), 3.99 (t, J ) 7.6 Hz, 1 H), 3.92 (s,
2 H), 3.74 (s, 3 H), 3.06 (bs, 1H), 3.04 (d, J ) 14.4 Hz, 1 H), 2.86
(m, 6 H), 2.67 (d, J ) 19.2 Hz, 1 H), 2.59 (dt, J ) 3.6, 12.4 Hz,
1 H), 2.48 (m, 1 H), 2.13 (m, 1 H), 1.87 (m, 5 H), 0.84 (s, 9 H),
0.08 (s, 3 H), 0.00 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 206.1,
158.4, 150.8, 142.2, 138.1, 131.2, 130.7, 129.7, 129.4, 128.6, 127.9,
125.7, 122.2, 122.0, 118.2, 114.2, 75.8, 73.5, 72.8, 62.2, 60.4, 55.6,
47.5, 47.0, 37.8, 31.2, 30.6, 26.2, 25.9, 18.6, 0.2, -4.4, -5.4.
HRMS: (M + H)+ calcd for C43H57NO6S2Si + H, 776.3475; found,
776.3439.
(2R*,5S*,6S*)-2-(2-Benzyloxymethylallyl)-5-(tert-butyldimeth-
ylsilanyloxy)-6-(4-methoxybenzyl)-4-oxo-2-(3-oxo-propyl)-pip-
eridine-1-carboxylic Acid Phenyl Ester (21). To a mixture of 19
(32 mg, 0.41 mmol) and calcium carbonate (100 mg, 0.743 mmol)
in aqueous H2O:CH3CN (2.0 mL, 1:9) was added CH3I (2.0 mL,
33 mmol). The mixture was stirred at rt overnight, diluted with
EtOAc (10 mL), and filtered through Celite. The filtrate was washed
with brine (2 × 10 mL) and was dried over Na2SO4, and the solvent
was removed in vacuo to yield 28 mg (100%) of the crude product
21 as a colorless oil. The product was used crude in the next step
without further purification: IR (neat) 2927, 2854, 1720, 1611,
1512, 1251, 1201, 1097, 841 cm-1; 1H NMR (CDCl3, 400 MHz) δ
9.74 (q, J ) 7.7 Hz, 1H), 7.32 (m, 8H), 7.12 (t, J ) 7.7 Hz, 4H),
6.84 (d, J ) 8.8 Hz, 2H), 5.36 (q, J ) 1.4 Hz, 1 H), 5.10 (s, 1H),
4.69 (dd, J ) 2.2, 9.16 Hz, 1H), 4.50 (s, 2H), 3.95 (s, 2H), 3.78 (s,
3H), 3.76 (s, 1 H), 3.23 (d, J ) 12.1 Hz, 1 H), 3.18 (d, J ) 14.0
Hz, 1 H), 2.86 (d, J ) 13.2 Hz, 2 H), 2.74 (dd, J ) 1.5, 15.8 Hz,
2H), 2.53 (m, 2H), 1.7 (bs, 1H), 1.55 (bs, 1H), 0.77 (s, 9H), -0.08
(s, 3H), -0.10 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 205.9, 159.0,
151.1, 141.3, 138.4, 130.5, 130.3, 129.8, 129.8, 128.57, 128.0,
127.9, 127.8, 126.1, 122.1, 114.6, 74.0, 72.6, 71.3, 70.6, 64.3, 55.6,
45.1, 41.2, 39.7, 29.9, 25.9, 18.1, -4.8, -5.5. HRMS: (M + H)+
calcd for C40H51NO7Si + H, 685.3435; found, 685.3411.
2-(4-Methoxybenzyl)-4-oxo-6-[4-(trimethylsilanyl)but-3-ynyl]-
3,4-dihydro-2H-pyridine-1-carboxylic Acid Phenyl Ester (28).
Magnesium turnings (2.16 g, 889 mmol) were mechanically
9400 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Studies Toward (-)-FR901483
1 H), 2.76 (m, 1 H), 2.52 (m, 2 H), 2.45 (s, 1 H), 2.07 (t, J ) 2.0
Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 193.2, 158.8, 155.3,
151.7, 150.4, 130.7, 129.7, 129.1, 128.5, 126.5, 121.5 (121.9 r),
114.3 (114.6 r), 82.4, 7.6, 58.3, 55.5, 40.2, 36.0, 34.7, 17.7.
HRMS: (M + H)+ calcd for C24H23NO4 + H, 390.1705; found,
390.1711.
5.45 (d, J ) 1.2 Hz, 1 H), 5.11 (dt, J ) 1.6, 8.0 Hz, 1 H), 3.79 (s,
4 H), 3.20 (m, 1 H), 2.97 (m, 6 H); 13C NMR (CDCl3, 100 MHz)
δ 192.3, 159.0, 157.3, 152.3, 150.5, 132.2, 130.6, 129.8, 128.2,
126.6, 121.6, 118.4, 114.4, 111.1, 70.9, 64.1, 55.5, 40.2, 34.5, 38.8.
HRMS: (M + H)+ calcd for C24H24BrNO5 + H, 486.0916; found,
486.0911.
A solution of the above acetylene (44.0 mg, 0.113 mmol) in
CH2Cl2 (1.0 mL) at 0 °C under argon was treated with 9-bromo-
9-borobicyclo[3.3.1]nonane (1.0 M in CH2Cl2, 0.17 mL, 0.17
mmol). The resulting mixture was allowed to warm to rt and stirred
for 24 h. After this time, the mixture was cooled to 0 °C, and
ethanolamine (1.1 mL) was added, followed by MeOH (2.5 mL).
The mixture was then diluted with Et2O (15 mL) and was shaken
with saturated aqueous potassium sodium tartrate (15 mL). The
aqueous phase was extracted with Et2O (2 × 15 mL), and the
combined organic extracts were dried over MgSO4, filtered through
Celite, and concentrated in vacuo to yield the crude product 29.
Purification by silica gel chromatography (10 to 15% EtOAc in
hexanes) gave 45.0 mg (85%) of 29 as a colorless oil: IR (neat)
2927, 1736, 1666, 1597, 1513, 1406, 1301, 1248, 1202, 1164, 1035,
To a solution of the above alcohol (355 mg, 0.733 mmol) in
DMF (10 mL) at 20 °C was added imidazole (100 mg, 1.47 mmol)
and tert-butyldimethylsilyl chloride (166 mg, 1.10 mmol). The
resulting mixture was stirred at rt for 24 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (50 mL) and was
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with brine (30 mL), dried over Na2SO4, and filtered
through Celite with CH2Cl2, and the solvent was removed in vacuo
to yield the crude TBS ether 25. Purification by silica gel
chromatography (30 to 40% EtOAc in hexanes) gave 397 mg (90%)
of 25 as a colorless oil: IR (neat) 2929, 2856, 1737, 1676, 1598,
1513, 1249, 1182, 841 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.38
(dt, J ) 1.6, 7.2 Hz, 2 H), 7.26 (m, 1 H), 7.10 (dd, J ) 2.0, 6.8
Hz, 2 H), 6.94 (dd, J ) 1.2, 7.5 Hz, 2 H), 6.86 (dd, J ) 2.0, 6.4
Hz, 2 H), 5.60 (m, 1 H), 5.55 (s, 1 H), 5.44 (d, J ) 1.6 Hz, 1 H),
4.98 (dt, J ) 1.6, 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.70 (d, J ) 1.2 Hz,
1 H), 3.21 (m, 1 H), 2.79 (m, 5 H), 0.84 (s, 9 H), 0.04 (s, 3 H),
0.02 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.7, 158.9, 155.9,
152.5, 150.5, 132.4, 130.5, 129.8, 128.5, 126.4, 121.5, 118.3, 114.3,
111.6, 71.5, 65.6, 55.5, 40.3, 34.3, 33.2, 25.8, 18.2, -4.6, -5.0.
HRMS: (M + H)+ calcd for C30H38BrNO5Si + H, 600.1781; found,
600.1800.
1
890 cm-1; H NMR (CDCl3, 400 MHz) δ 7.38 (dt, J ) 2.0, 8.8
Hz, 2 H), 7.27 (t, J ) 1.2 Hz, 1 H), 7.08 (dd, J ) 2.8, 8.8 Hz, 2
H), 6.97 (dd, J ) 2.0, 2.8 Hz, 2 H), 6.84 (dd, J ) 2.8, 8.8 Hz, 2
H), 5.60 (dd, J ) 0.8, 1.6 Hz, 2 H), 5.44 (d, J ) 2.4 Hz, 1 H), 5.07
(dq, J ) 2.0, 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.20 (m, 1 H), 3.04 (dd,
J ) 8.8, 9.2 Hz, 1 H), 2.81 (m, 4 H), 2.45 (dt, J ) 1.6, 17.2 Hz,
2 H); 13C NMR (CDCl3, 100 MHz) δ 192.9, 158.7, 155.8, 151.6,
150.3, 132.2, 130.6, 129.7, 128.8, 126.5, 121.4, 118.3, 114.3, 114.0,
58.3, 55.6, 40.34, 40.0, 36.1, 34.4. HRMS: (M + H)+ calcd for
C24H24BrNO4 + H, 470.0967; found, 470.0959.
(2R*,5S*,6S*)-2-(2-Benzyloxymethylallyl)-2-(3-bromobut-3-
enyl)-5-(tert-butyl-dimethylsilanyloxy)-6-(4-methoxybenzyl)-4-
oxo-piperidine-1-carboxylic Acid Phenyl Ester (31). A well-
stirred solution of dihydropyridone 25 (57 mg, 0.097 mmol) in 3
mL of dry CH2Cl2 was cooled to -78 °C. TMSOTf (40 µL, 0.22
mmol) was added in one portion, giving rise to a deep orange color.
After 5 min, neat (2-benzyloxymethylallyl)tributylstannane reagent
6 (76 mg, 0.15 mmol) was added dropwise over a 10 min period.
The reaction mixture was stirred for 4 h at -78 °C, warmed to
-45 °C, and stirred for an additional 6 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (20 mL) and was
allowed to warm up to rt, during which time it became colorless.
The mixture was extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried over Na2SO4 and were filtered through
Celite. The solvent was removed in vacuo to yield 110 mg of the
crude silyl enol ether product 30, which was dissolved in wet MeOH
(5 mL). Silica gel (100 mg) was added, followed by H2O (0.5 mL)
and oxalic acid (20 mg, 0.22 mmol). The reaction mixture was
stirred at rt for 16 h. The reaction mixture was filtered and was
then extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried over Na2SO4 and filtered through Celite, and
the solvent was removed in vacuo to yield the crude piperidone
product 31. Purification by silica gel chromatography (0 to 20%
EtOAc in hexanes) gave 62 mg (85%) of 31 as a colorless oil: IR
(2S*,3S*)-6-(3-Bromobut-3-enyl)-3-(tert-butyldimethylsilany-
loxy)-2-(4-methoxybenzyl)-4-oxo-3,4-dihydro-2H-pyridine-1-car-
boxylic Acid Phenyl Ester (25). To a stirred solution of 29 (224
mg, 0.477 mmol) in 5 mL of toluene at rt was added lead(IV)
acetate (275 mg, 0.620 mmol). The resulting mixture was refluxed
for 3 h and cooled to rt, and additional lead(IV) acetate (275 mg,
0.620 mmol) was added. The mixture was refluxed for 3 h. After
cooling to rt, the solution was filtered through Celite with CH2Cl2.
The filtrate was washed with saturated aqueous NaHCO3 (40 mL),
and the aqueous phase was extracted with CH2Cl2 (3 × 40 mL).
The combined organic phase was dried over Na2SO4, filtered
through Celite, and concentrated in vacuo to yield the crude acetate.
Purification by silica gel chromatography (20 to 30% EtOAc in
hexanes) gave 173 mg (69%) of the desired product as a colorless
oil which was used directly in the next step. IR (neat) 2926, 1743,
1
1678, 1591, 1514, 1248, 1219, 1182, 1032, 839 cm-1; H NMR
(CDCl3, 400 MHz) δ 7.38 (dt, J ) 1.6, 7.2 Hz, 2 H), 7.12 (dd, J
) 2.4, 6.8 Hz, 2 H), 6.84 (m, 5 H), 5.70 (s, 1 H), 5.62 (m, 1 H),
5.47 (d, J ) 2.0 Hz, 1 H), 5.25 (dt, J ) 2.8, 7.2 Hz, 1 H), 4.94 (t,
J ) 2.0 Hz, 1 H), 3.20 (m, 1 H), 3.00 (dd, J ) 8.8, 8.8 Hz, 1 H),
2.93 (m, 4 H), 2.76 (m, 1 H), 2.65 (m, 2 H), 2.11 (s, 3 H); 13C
NMR (CDCl3, 100 MHz) δ 187.6, 169.6, 159.1, 157.6, 150.2 (152.0
r), 132.1, 130.7, 130.5, 129.9, 127.6, 126.7, 121.3, 118.4, 114.5,
112.6, 71.3, 61.9, 55.5, 40.1, 34.5, 33.5, 21.0. HRMS: (M + H)+
calcd for C26H26BrNO6 + H, 528.1022; found, 528.1022.
(neat) 2926, 2853, 1722, 1512, 1379, 1250, 1199, 1072, 844 cm-1
;
1H NMR (C6D6, 400 MHz) δ 7.20 (m, 10 H), 6.89 (t, J ) 7.6 Hz,
2H), 6.67 (d, J ) 7.6 Hz, 2H), 5.38 (s, 1H), 5.26 (m, 3H), 4.84 (m,
1H), 4.31 (s, 2H), 3.92 (s, 1H), 3.90 (s, 2H), 3.50 (d, J ) 17.2 Hz,
1H), 3.27 (s, 1H), 3.25 (s, 3H), 3.07 (dd, J ) 3.2, 13.6 Hz, 1H),
2.84 (d, J ) 17.2 Hz, 1H), 2.54 (m, 2H), 2.24 (m, 2H), 1.72 (m,
1H), 1.54 (m, 1H), 0.90 (s, 9 H), 0.00 (s, 3H), -0.20 (s, 3H); 13C
NMR (C6D6, 100 MHz) δ 205.6, 159.1, 151.7, 142.0, 138.8, 133.7,
130.5, 129.7, 129.5, 128.4, 128.2, 127.9, 127.7, 127.5, 127.1, 125.5,
122.1, 117.2, 74.1, 72.2, 70.9, 64.5, 62.5, 54.7, 45.2, 41.3, 37.5,
37.4, 25.7, 25.5, 18.2, -4.9, -5.7. HRMS: (M + H)+ calcd for
C41H52NO6BrSi + H, 761.2747; found, 761.2709.
To a solution of the above acetate (390 mg, 0.734 mmol) in
H2O:MeOH (20 mL, 1:4) was added ScOTf3 (20 mol %, 72.0 mg,
0.147 mmol). The resulting mixture was stirred at 60 °C for 24 h.
The reaction mixture was cooled to rt, poured into H2O (20 mL),
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried over Na2SO4 and filtered through Celite with
CH2Cl2, and the solvent was removed in vacuo to yield the crude
product. Purification by silica gel chromatography (20 to 30%
EtOAc in hexanes) gave 355 mg (100%) of the desired alcohol as
a white foam which was used directly in the next step. IR (neat)
(2R*,4S*,5S*,6S*)-2-(2-Benzyloxymethylallyl)-2-(3-bromobut-
3-enyl)-4,5-dihydroxy-6-(4-methoxybenzyl)piperidine-1-carbox-
ylic Acid Phenyl Ester (32). A solution of 31 (57.0 mg, 0.0758
mmol) in THF (4 mL) was cooled to -40 °C. Tetrabutylammonium
fluoride (1.0 M in THF, 91 µL, 0.091 mmol) was added dropwise
1
3376, 2919, 1738, 1666, 1589, 1513, 1248, 1179, 838 cm-1; H
NMR (CDCl3, 400 MHz) δ 7.39 (t, J ) 8.0 Hz, 2 H), 7.26 (t, J )
7.2 Hz, 1 H), 7.10 (d, J ) 8.8 Hz, 2 H), 7.00 (d, J ) 7.6 Hz, 2 H),
6.85 (d, J ) 8.4 Hz, 2 H), 5.62 (d, J ) 0.8 Hz, 1 H), 5.60 (s, 1 H),
J. Org. Chem, Vol. 71, No. 25, 2006 9401

Gotchev and Comins
over a period of 5 min. After the addition was complete, the reaction
mixture was stirred at -40 °C for 1 h, warmed to -20 °C, and
stirred for an additional 2 h. The reaction mixture was poured into
saturated aqueous NH4Cl (10 mL) and was then extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extracts were dried over
Na2SO4, filtered through Celite, and concentrated in vacuo to yield
the crude alcohol. To a solution of tetramethylammonium triac-
etoxyborohydride (80.0 mg, 0.303 mmol) in 4.0 mL of freshly
distilled acetone at rt was added acetic acid (35.0 µL, 0.607 mmol).
After stirring for 15 min, the above crude alcohol compound in
4.0 mL of freshly distilled acetone was added dropwise over a
period of 5 min. The reaction mixture was stirred at rt for 16 h.
The reaction mixture was quenched with saturated aqueous am-
monium chloride (25 mL), and one-half of the acetone was removed
in vacuo. The solution was extracted with CH2Cl2 (3 × 25 mL).
The combined organic extracts were washed with brine (25 mL),
dried over Na2SO4, and filtered through Celite, and the solvent was
removed in vacuo to yield the crude product. Purification by silica
gel chromatography (30 to 50% EtOAc in hexanes) gave 45 mg
(92%, over two steps) of 32 as a colorless oil: IR (neat) 3456,
2924, 1693, 1512, 1454, 1248, 1203, 1034 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.40 (t, J ) 7.6 Hz, 1H), 7.28 (m, 11H), 7.14 (dd, J
) 1.6, 7.2 Hz, 2H), 5.58 (d, J ) 1.6 Hz, 1H), 5.40 (d, J ) 2.0 Hz,
1H), 5.33 (d, J ) 1.2 Hz, 1H), 5.16 (s, 1H), 4.50 (dd, J ) 11.6, 6.0
Hz, 2H), 4.42 (bd, J ) 12.0 Hz, 1H), 4.14 (bs, 1H), 4.04 (dd, J )
12.8, 8.0 Hz, 2H), 3.79 (s, 4H), 3.12 (dd, J ) 2.8, 12.8 Hz, 1H),
3.02 (dd, J ) 14.0, 6.8 Hz, 2H), 2.83 (t, J ) 12.4 Hz, 1H), 2.73
(m, 1H), 2.48 (m, 2H), 2.14 (dd, J ) 6.0, 14.8 Hz, 1H), 1.95 (m,
2H), 1.83 (m, 1H), 1.63 (d, J ) 3.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 158.6, 154.6, 151.2, 142.4, 138.2, 133.9, 130.9, 130.2,
129.7, 128.65, 128.1, 128.0, 125.8, 122.1, 118.0, 117.2, 114.3, 74.4,
74.3, 72.4, 69.7, 64.2, 61.2, 55.5, 41.5, 40.0, 38.0, 37.4, 36.8.
HRMS: (M + H)+ calcd for C35H40BrNO6 + H, 650.2117; found,
650.2101.
catalytic amount of DMAP. The reaction mixture was stirred at 0
°C for 10 min. A freshly prepared solution of p-methanesulfonyl
chloride (0.253 M in CH2Cl2, 0.15 mL, 40 µmol) was added over
a period of 10 min. The reaction mixture was stirred at 0 °C for 2
h, warmed to 20 °C, and stirred for an additional 4 h. The reaction
mixture was quenched with saturated aqueous NaHCO3 (10 mL)
and was extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were dried over Na2SO4 and filtered through Celite, and
the solvent was removed in vacuo to yield crude 34. Purification
by silica gel chromatography (10 to 25% EtOAc in hexanes) gave
21.0 mg (97%) of 34 as a colorless oil: IR (neat) 2923, 1722, 1513,
1
1450, 1344, 1268, 1177, 1032, 949 cm-1; H NMR (CDCl3, 400
MHz) δ 8.10 (dd, J ) 0.8, 8.0 Hz, 2H), 7.66 (dt, J ) 1.2, 7.2 Hz,
1H), 7.54 (t, J ) 8.4 Hz, 2H), 7.41 (t, J ) 7.2 Hz, 2H), 7.26 (m,
9H), 6.79 (d, J ) 8.8 Hz, 2H), 5.65 (t, J ) 8.4 Hz, 1H), 5.58 (d,
J ) 1.2 Hz, 1H), 5.41 (d, J ) 2.0 Hz, 2H), 5.33 (bs, 1H), 4.91 (m,
1H), 4.88 (s, 1H), 4.52 (s, 2H), 4.14 (dd, J ) 12.8, 40.4 Hz, 2H),
3.77 (s, 3H), 3.24 (m, 2H), 2.92 (m, 3H), 2.77 (s, 3H), 2.53 (m,
3H), 2.37 (t, J ) 11.6 Hz, 1H), 1.80 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 165.5, 159.0, 151.0, 141.6, 138.3, 133.9, 133.3, 130.48,
130.0, 129.7, 129.4, 128.9, 128.6, 128.5, 128.0, 127.8, 126.0, 122.1,
118.8, 118.7, 117.4, 114.6, 78.9, 74.5, 72.41, 71.2, 61.1, 60.4, 55.4,
40.7, 38.6, 37.3, 33.2, 32.1, 29.9. HRMS: (M + H)+ calcd for
C43H46BrNO9S + H, 832.2155; found, 832.2145.
(2S*,4R*,6S*,7R*)-4-(2-Benzyloxymethylallyl)-4-(3-bromobut-
3-enyl)-2-(4-methoxybenzyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-
3-carboxylic Acid Phenyl Ester (23). A solution of 34 (14.0 mg,
16.8 µmol) in MeOH (1.0 mL) was cooled to 0 °C. Solid NaOH
(4.7 mg, 0.12 mmol) was added in one portion. The reaction mixture
was stirred at 0 °C for 30 min, warmed up to rt, and stirred for an
additional 10 min. Solid K2CO3 (100 mg) was added, followed by
CH2Cl2 (15 mL). The resulting heterogeneous mixture was filtered
through Celite, and the solvent was removed in vacuo to yield crude
23. Purification by silica gel chromatography (5 to 15% EtOAc in
hexanes) gave 10 mg (94%) of 23 as a colorless oil: IR (neat)
(2R*,4S*,5S*,6S*)-4-Benzoyloxy-2-(2-benzyloxymethylallyl)-
2-(3-bromobut-3-enyl)-5-hydroxy-6-(4-methoxybenzyl)piperidine-
1-carboxylic Acid Phenyl Ester (33). A solution of 32 (23.9 mg,
36.9 µmol) in CH2Cl2 (1.5 mL) was cooled to -20 °C. Et3N (6.0
µL, 41 µmol) was added dropwise, followed by a catalytic amount
of DMAP. The reaction mixture was stirred at -20 °C for 5 min
and was then cooled to 0 °C. A freshly prepared solution of benzoic
anhydride (0.044 M in CH2Cl2, 0.84 mL, 37 mol) was added over
a period of 10 min. The reaction mixture was stirred at 0 °C for 2
h, warmed up to rt, and stirred for an additional 2 h. The reaction
mixture was quenched with saturated aqueous NaHCO3 (10 mL)
and was extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were dried over Na2SO4 and filtered through Celite, and
the solvent was removed in vacuo to yield crude 33. Purification
by silica gel chromatography (10 to 25% EtOAc in hexanes) gave
15.5 mg (56%) of 33 as a colorless oil: IR (neat) 3434, 2910, 2848,
1
2923, 2855, 1713, 1515, 1456, 1379, 1250, 1203 cm-1; H NMR
(CDCl3, 400 MHz) δ 7.39 (t, J ) 7.6 Hz, 1H), 7.30 (m, 9H), 7.12
(d, J ) 7.2 Hz, 2H), 6.83 (d, J ) 8.8 Hz, 2H), 5.58 (s, 1H), 5.39
(d, J ) 2.0 Hz, 1H), 5.32 (d, J ) 1.2 Hz, 1H), 5.10 (s, 1H), 4.78
(m, 1H), 4.49 (dd, J ) 18.4, 5.2 Hz, 2H), 3.98 (q, J ) 12.8 Hz,
2H), 3.80 (s, 3H) 3.38 (m, 1H), 3.09 (dq, J ) 4.4, 2.8 Hz, 1H),
2.93 (d, J ) 13.6 Hz, 1H), 2.87 (dd, J ) 3.2, 12.0 Hz, 1H), 2.75
(m, 2H), 2.58 (d, J ) 13.6 Hz, 1H), 2.37 (m, 3H), 1.80 (dd, J )
4.0, 4.4 Hz, 1H), 1.60 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ
158.5, 151.1, 142.8, 138.1, 133.8, 130.7, 130.1, 129.7, 129.7, 128.7,
128.1, 128.0, 125.9, 122.1, 117.4, 117.2, 114.1, 73.6, 72.6, 59.9,
55.9, 55.4, 49.3, 48.8, 42.3, 39.0, 38.3, 37.1, 34.7 (29.9 r). HRMS:
(M + H)+ calcd for C35H38BrNO5 + H, 632.2012; found, 632.2033.
Acknowledgment. We express appreciation to the National
Institutes of Health (Grant GM 34442) for financial support of
this research. D.B.G. also thanks the Burroughs-Wellcome
Fellowship Fund for a second year graduate assistantship. The
authors thank Dr. Sabapathy Sankar for NMR interpretation.
NMR and mass spectra data were obtained at NCSU instru-
mentation laboratories, which were established by grants from
the North Carolina Biotechnology Center and the National
Science Foundation (Grant CHE-9509532 and Grant CHE-
0078253).
1719, 1510, 1451, 1272, 1243, 1200, 1104, 1066, 1024, 860 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 8.10 (d, J ) 8.4 Hz, 2H), 7.65 (t,
J ) 7.6 Hz, 1H), 7.53 (t, J ) 7.6 Hz, 2H), 7.41 (t, J ) 7.6 Hz,
2H), 7.26 (m, 9H), 6.70 (d, J ) 8.8 Hz, 2H), 5.59 (s, 1H), 5.41 (d,
J ) 1.6 Hz, 1H), 5.37 (m, 2H), 5.26 (s, 1H), 4.58 (bd, J ) 10.4
Hz, 1H), 4.51 (s, 2H), 4.08 (dq, J ) 4.4, 8.8 Hz, 2H), 3.96 (bs,
1H), 3.72 (s, 4H), 3.14 (m, 3H), 2.84 (m, 2H), 2.53 (t, J ) 8.4 Hz,
3H), 2.40 (d, J ) 7.2, 6.8 Hz, 1H), 2.36 (t, J ) 9.6 Hz, 1H), 1.80
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 158.6, 142.1, 138.3,
133.8, 133.7, 130.5, 130.4, 129.9, 129.8, 129.7, 128.8, 128.2, 128.6,
128.0, 127.8, 125.8, 122.1, 118.0, 117.3, 114.3, 75.1, 74.3, 72.4,
71.0, 62.4, 60.4, 55.4, 41.2, 39.0, 37.3, 33.0, 29.9. HRMS: (M +
H)+ calcd for C42H44BrNO7 + H, 754.2379; found, 754.2385.
(2R*,4S*,5S*,6S*)-4-Benzoyloxy-2-(2-benzyloxymethylallyl)-
2-(3-bromobut-3-enyl)-5-methanesulfonyloxy-6-(4-methoxyben-
zyl)piperidine-1-carboxylic Acid Phenyl Ester (34). A solution
of 33 (20.0 mg, 26.0 µmol) in CH2Cl2 (1.0 mL) was cooled to 0
°C. Et3N (4.0 µL, 29 µmol) was added dropwise, followed by a
Supporting Information Available: General experimental
methods, Tables 1 and 2, and 1H and 13C NMR spectra for
compounds 13, 15a,b, 16, 19-21, 23, 25, 28, 29, and 31-34. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO061677T
9402 J. Org. Chem., Vol. 71, No. 25, 2006