Toward the total synthesis of FR901483: Concise synthesis of the azatricyclic skeleton

Article abstract of DOI:10.1021/jo070732a

(Chemical Equation Presented) A concise synthesis of the azatricyclic core of FR901483 has been accomplished using a novel strategy that involves a nucleophilic addition to an N-acyl iminium ion, a ring-closing metathesis, a diastereoselective hydroborati

Full text of DOI:10.1021/jo070732a

Toward the Total Synthesis of FR901483: Concise Synthesis of the
Azatricyclic Skeleton
Suvi T. M. Simila and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin, 1 UniVersity Station A5300,
Austin, Texas 78712-0165
sfmartin@mail.utexas.edu
ReceiVed April 7, 2007
A concise synthesis of the azatricyclic core of FR901483 has been accomplished using a novel strategy
that involves a nucleophilic addition to an N-acyl iminium ion, a ring-closing metathesis, a diastereo-
selective hydroboration, and a lactone-lactam rearrangement that worked well in a preliminary model
study. Extension of this approach to the synthesis of a more highly functionalized intermediate that could
be transformed into (-)-FR901483 first required the development of a new protecting group, the
1-ethylallyloxycarbamate group, for amines that may be removed under mild conditions. However, because
the stereoselectivity in a key step in which a functionalized allyl zinc reagent was added to an intermediate
hydroxy-substituted imine was low, this route to (-)-FR901483 is no longer being pursued.
Introduction
inspiration from its putative biosynthesis and thus feature an
intramolecular aldol reaction to generate the azatricyclic core,
although other approaches involve construction of this core via
cyclizations of iminium ions.3f,4b
(-)-FR901483 (1) is a potent immunosuppressant that was
isolated in 1996 from the fermentation broth of the fungal strain
Cladobotryum sp. No. 11231 by scientists at the Fujisawa
Pharmaceutical Company in Japan.1 The structure and relative
stereochemical relationships of 1 were initially determined by
NMR spectroscopy, but the absolute configuration was eluci-
dated by Snider and Lin,2 who reported the first total synthesis
of 1. From a medicinal perspective, (-)-FR901483 is of
considerable interest because it prolongs graft survival time in
the rat skin allograft model by inhibiting purine nucleotide
synthesis, a mechanism of action that differs from that of more
commonly used immunosuppressants such as cyclosporin A and
tacrolimus (FK-506).1 Owing to its intriguing structure and its
biological activity, FR901483 has received considerable atten-
tion from members of the synthetic community, and since its
first total synthesis by Snider and Lin,2 several total syntheses
and numerous approaches to 1 have been reported.3,4 Most of
the total syntheses of FR901483 employ a strategy that drew
(3) For total syntheses of FR901483, see: (a) Scheffler, G.; Seike, H.;
Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593-4596. (b) Ousmer,
M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem.
Soc. 2001, 123, 7534-7538. (c) Ousmer, M.; Braun, N. A.; Ciufolini, M.
A. Org. Lett. 2001, 3, 765-767. (d) Maeng, J.-H.; Funk, R. L. Org. Lett.
2001, 3, 1125-1128. (e) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka,
H.; Fukuyama, T. Org. Lett. 2004, 6, 2729-2731. (f) Brummond, K. M.;
Hong, S. J. Org. Chem. 2005, 70, 907-916.
(4) For approaches to FR901438, see: (a) Quirante, J.; Escolano, C.;
Massot, M.; Bonjoch, J. Tetrahedron 1997, 53, 1391-1402. (b) Yamazaki,
N.; Suzuki, H.; Kibayashi, C. J. Org. Chem. 1997, 62, 8280-8281. (c)
Snider, B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63, 6442-
6443. (d) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667-4670. (e) Wardrop, D. J.; Zhang, W.
Org. Lett. 2001, 3, 2353-2356. (f) Brummond, K. M; Lu, J. Org. Lett.
2001, 3, 1347-1349. (g) Bonjoch, J.; Diaba, F.; Puigbo´, G.; Peidro´, E.;
Sole´, D. Tetrahedron Lett. 2003, 44, 8387-8390. (h) Panchaud, P.; Ollivier,
C.; Renaud, P.; Zigmantas, S. J. Org. Chem. 2004, 69, 2755-2759. (i)
Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb, S. M. J. Org.
Chem. 2006, 71, 2046-2055. (j) Kaden, S.; Reissig, H.-S. Org. Lett. 2006,
8, 4763-4766. (k) Gotchev, D. B.; Comins, D. L. J. Org. Chem. 2006, 71,
9393-9402. (l) Asari, A.; Angelov, P.; Auty, J. M.; Hayes, C. J. Tetrahedron
Lett. 2007, 48, 2631-2634.
(1) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44.
(2) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778-7786.
10.1021/jo070732a CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/08/2007
5342
J. Org. Chem. 2007, 72, 5342-5349

Toward the Total Synthesis of FR901483
We were attracted to the synthesis of (-)-FR901483 (1) in
the more general context of our longstanding interest in
developing novel and general approaches to alkaloid natural
products. For example, we have been interested in discovering
new reactions of iminium ions that may be implemented for
constructing heterocyclic frameworks common to different
families of alkaloids.5 In another area, we have been interested
in applications of transition-metal-catalyzed transformations
including ring-closing metathesis (RCM) and Pauson-Khand
reactions that may be used to form nitrogen heterocycles.6,7
Herein, we describe a novel approach, which differs from all
of the prior art, for the synthesis of 1, and the details of our
studies on the facile construction of the tricyclic core.8 During
the course of these studies, it was necessary to develop a new
nitrogen protecting group that may be removed under very mild
conditions.
predicted that the allylsilane 8 would add to an intermediate
imine or N-acyl iminium ion from the same face as the protected
hydroxyl group, giving the requisite stereochemistry at C(1) of
5.
Results and Discussion
Preliminary Model Studies. To establish the underlying
feasibility of our strategy to access the tricyclic skeleton of 1,
we first conducted a model study on a pyrrolidinone substrate
lacking the hydroxyl function at C(3). The Grignard reagent 7
was added to the Boc-protected lactam 9 to provide the protected
linear aminoketone 10 in 98% yield (Scheme 2).13 The Boc
SCHEME 2
The essential elements of our plan for the synthesis of
(-)-FR901483 are outlined in retrosynthetic format in Scheme
1. The endgame, which is related to that reported recently by
Weinreb,4i was envisioned to entail the stereoselective elabora-
tion of the advanced intermediate 2 via R-hydroxylation of an
amide enolate, introduction of the p-methoxybenzyl group, and
a Mitsunobu reaction involving the hydroxyl group at C(3)
(Scheme 1).9 The azatricycle 2 would be formed by the base-
SCHEME 1
protecting group was removed using trifluoroacetic acid (TFA),
and cyclization of the intermediate aminoketone formed in situ
gave the known imine 1114 in 94% yield. Although this
transformation could also be effected by using iodotrimethyl-
silane (TMSI) in a shorter reaction time (1 h) and in quantitative
yield, TFA was both more convenient and less expensive. The
imine 11 was then treated with benzyl chloroformate (CbzCl)
and the known allylsilane 815 in the presence of a stoichiometric
amount of trimethylsilyl triflate (TMSOTf) to deliver the desired
diene 12 in 42% yield. When 2,2,2-trichloroethylchloroformate
(TrocCl) was employed as the acylating reagent, 13 was isolated
in 56% yield. Silver and scandium triflates could also be used
promoted lactone-lactam rearrangement of the secondary amine
formed upon deprotection of 3, which would be produced by
lactonization of the equatorial alcohol obtained by the selective
hydroboration-oxidation of the â,γ-unsaturated ester 4.10 The
synthesis of spirocycle 4 would be achieved by the RCM of
the diene 5,11 which would be derived from the stereoselective
geminal dialkylation of the lactam carbonyl group in 6 with
the Grignard reagent 7 and the allylsilane 8. We anticipated
that the stereochemistry of this geminal alkylation would be in
accord with the findings of Woerpel et al.12 Namely, we
(6) For selected examples, see: (a) Martin, S. F.; Humphrey, J. M.; Liao,
Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K. J. Am.
Chem. Soc. 2002, 124, 8584-8592. (b) Washburn, D. G.; Heidebrecht, R.
W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523-3525. (c) Neipp, C.; Martin,
S. F. J. Org. Chem. 2003, 68, 8867-8878. (d) Brenneman, J. B.; Machauer,
R.; Martin, S. F. Tetrahedron 2004, 60, 7301-7314. (e) Andrade, R. B.;
Martin, S. F. Org. Lett. 2005, 7, 5733-5735. (f) Deiters, A.; Pettersson,
M.; Martin, S. F. J. Org. Chem. 2006, 71, 6547-6561.
(5) For example, see: (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895-
904. See also: (b) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin,
S. F. J. Am. Chem. Soc. 2001, 123, 8003-8010. (c) Liras, S.; Lynch, C.
L.; Fryer, A. M.; Vu, B. T.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,
5918-5924. (d) Reichelt, A.; Bur, S. K.; Martin, S. F. Tetrahedron 2002,
58, 6323-6328. (e) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J. Am.
Chem. Soc. 2003, 125, 4541-4550. (f) Amorde, S. M.; Judd, A. S.; Martin,
S. F. Org. Lett. 2005, 7, 2031-2033.
(7) Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113-1116.
(8) For a preliminary account of portions of this work, see: Simila, S.
T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933-2936.
J. Org. Chem, Vol. 72, No. 14, 2007 5343

Simila and Martin
as promoters to provide 12 or 13 in similar yields, but because
TMSOTf was easier to handle than these Lewis acids, it was
employed in further experiments. It is noteworthy that nucleo-
philic addition to 11 did not proceed to any significant degree
in the absence of a Lewis acid promoter.16 We briefly explored
the possibility of converting 9 into 12 in a one-pot procedure.
However, when the lactam 9 was treated sequentially with the
Grignard reagent 7 and then the allylsilane 8 in the presence of
Lewis acids, the ketone 10 was isolated as the only product.
Under more forcing conditions, we observed protiodesilylation
of the allylsilane 8 and cleavage of the Boc group from 10 as
well as complex mixtures of compounds. Even though 13 was
obtained in higher yields than 12, we decided to use 12 in
subsequent studies because of the relative ease of removal of
the N-carbobenzyloxy group from more advanced intermediates.
Accordingly, cyclization of 12 via RCM using the Grubbs
second-generation catalyst 1417 delivered the azaspirane 15 in
95% yield.
corresponding carboxylic acid, which should have been inert,20,21
underwent reduction when BH3‚THF was employed as the
hydroborating reagent. Ultimately, we discovered that the
simultaneous hydroboration and reduction of the ester by the
reaction of 15 with BH3‚THF (3 equiv) followed by oxidation
of the alkylborane intermediate with NaBO3‚4H2O22 furnished
a diastereomeric mixture (6:1) of 16 and 17 in 99% combined
yield. Oxidation of the intermediate alkylborane using the more
conventional method of H2O2/NaOH was lower yielding (∼60
to 70%). Although the diastereomeric diols were easily separable
by column chromatography, it was not possible to unequivocally
determine the relative stereochemistry of the major diastereomer
at this stage.
The unavoidable reduction of the ester functionality upon
hydroboration of 15 was merely an inconvenience as we were
able to selectively oxidize the primary alcohol moiety of 16 to
give the γ-lactone 18 in 87% yield using PhI(OAc)2 and catalytic
TEMPO (Scheme 3).23 The Cbz group of 18 was then easily
removed by catalytic hydrogenation to provide the amine 19 in
virtually quantitative yield. The subsequent NaOMe-promoted
lactone-lactam rearrangement in MeOH using conventional
heating techniques was incomplete, even after 2 days of heating
under reflux. However, heating a solution of 19 in methanolic
NaOMe in a microwave reactor (200 W, 250 psi, 70 °C, three
45-min cycles) delivered the azatricycle 20 in 90% yield.24 The
formation of the hydroxy lactam 20 from the amino lactone 19
verified our tentative assignment of the relative stereochemistry
of the major diol diastereomer 16 in which the nitrogen atom
and the primary alcohol side chain were cis. The free hydroxyl
group at C(9) of 20 was then acetylated to provide 21, which
was amenable to full structural characterization.
At this juncture, the remaining challenge was to induce the
stereoselective hydroboration of the azaspirane 15, a reaction
for which there was little precedent in spirocyclic systems.18
However, there were several reports of hydroborations of
conformationally constrained cyclohexenes that led to equatorial
alcohols as the major products.10 It was thus our hope that a
borane reagent would react preferentially with the conformer
of 15 in which the N-carbamate moiety was in an equatorial
orientation via a transition state in which the boron atom would
be delivered preferentially from an equatorial trajectory to
establish the requisite stereochemistry at C(8) and C(9). We
also anticipated that the hydroboration of the trisubstituted olefin
would be faster than the reduction of the ester and thus
chemoselective,19 but all attempts to effect this selective
transformation using reagents including BH3‚THF, BH3‚DMS,
9-BBN, thexylborane, and dicyclohexylborane were unsuccess-
ful; concomitant reduction of the ester was invariably observed
as a side reaction. Somewhat surprisingly, the salt of the
SCHEME 3
(9) The numbering is based on the accepted numbering for
(-)-FR901483.
(10) For examples of the hydroboration-oxidation of conformationally
constrained cyclohexenes to give equatorial alcohols preferentially, see: (a)
LaLonde, R. T.; Tobias, M. A. J. Am. Chem. Soc. 1963, 85, 3771-3775.
(b) Brown, H. C.; Pfaffenberger, C. D. Tetrahedron 1975, 31, 925-928.
(c) Brown, H. C.; Liotta, R.; Brener, L. J. Am. Chem. Soc. 1977, 99, 3427-
3432.
(11) For a review, see: Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199-2238 and references therein.
(12) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J.
Am. Chem. Soc. 1999, 121, 12208-12209. (b) Smith, D. M.; Tran, M. B.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149-14152. (c) Larsen,
C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am.
Chem. Soc. 2005, 127, 10879-10884.
(13) (a) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem.
1989, 54, 228-234. (b) Rudolph, A.; Machauer, R.; Martin, S. F.
Tetrahedron Lett. 2004, 45, 4895-4898.
Enantioselective Synthesis of the Tricyclic Core of
(-)-FR901483. Setting the Stage for Geminal Dialkylation
of the Imine. Having established the feasibility of accessing
the azatricyclic skeleton of FR901483 by the strategy set forth
(14) 1H NMR spectrum of 11 was consistent with the one reported in
the literature: Tehrani, K. A.; D’hooghe, M.; De Kimpe, N. Tetrahedron
2003, 59, 3099-3108.
(15) The methyl ester was prepared by methylating (K2CO3, MeI, DMF
82% yield) the corresponding acid that was prepared according to a literature
procedure: Armstrong, R. J.; Weiler, L. Can. J. Chem. 1983, 61, 2530-
2539.
(20) Brown, H. C.; Rao, S. J. Am. Chem. Soc. 1960, 82, 681-686.
(21) The reduction of carboxylic acid salts in the presence of 2 equiv of
diborane has been reported to occur rapidly. See: Yoon, N. M.; Cho, B. T.
Tetrahedron Lett. 1982, 23, 2475-2478.
(16) Yamaguchi, R.; Hatano, B.; Nakayasu, T.; Kozima, S. Tetrahedron
Lett. 1997, 38, 403-406.
(22) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930-5933.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(23) (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974-6977. (b) Hansen, T. M.; Florence, G.
J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett.
2003, 44, 57-59.
(18) Hartung, R.; Paquette, L. A. J. Org. Chem. 2005, 70, 1597-1604.
(19) Brown, H. C.; Korytnyk, W. J. Am. Chem. Soc. 1960, 82, 3866-
3869.
5344 J. Org. Chem., Vol. 72, No. 14, 2007

Toward the Total Synthesis of FR901483
in Scheme 1, we turned our attention to its application to the
enantioselective synthesis of (-)-FR901483. Toward this goal,
commercially available (R)-4-hydroxy-2-pyrrolidinone (22) was
protected as the tert-butyldiphenylsilyl (TBDPS) ether to provide
23, which was then converted into the N-Boc lactam 24 in 90%
overall yield (Scheme 4). When 24 was treated with the Grignard
reagent 7, the ketone 25 was isolated in 59% yield.
At this juncture, it was apparent that the chiral ketone 25
and the derived imine 26 were highly acid-sensitive and prone
to â-elimination. It was thus deemed essential to employ a
nitrogen protecting group that could be cleaved under very mild,
non-acidic conditions, and it occurred to us that an N-
allylcarbamate (Alloc) protecting group might be suitable. To
investigate the worthiness of this alternative, the lactam 23 was
protected as its Alloc derivative 30, which was subjected to
reaction with the Grignard reagent 7 following the procedure
previously established for preparing 25 (Scheme 5). However,
we found that extensive cleavage of the Alloc group occurred
under these conditions to give 23 as the major product. We had
previously discovered that competing nucleophilic attack by
organometallic reagents on the carbonyl group of N-carbamoyl-
2-pyrrolidinones could be minimized by either using hindered
carbamates (e.g., Boc) or conducting the reaction in the presence
of TMEDA as an additive.27 In the event, the reaction of 30
with the butenyl Grignard reagent 7 in presence of an equivalent
of TMEDA provided the ketone 31 in 15% yield. Unfortunately,
we were unable to improve the yield of this reaction by simple
operational changes, but we were able to secure sufficient
quantities of 31 to determine whether the Alloc group could
indeed be cleaved under sufficiently mild conditions to avoid
deleterious pyrrole formation. Gratifyingly, treatment of 31 with
Pd(PPh3)4 (20 mol %) in the presence of morpholine gave 26
in good yield along with N-allylmorpholine, which was insepa-
rable from 26.
SCHEME 4
SCHEME 5
Attempts to improve the yield of this reaction by longer
reaction times or use of several equivalents of the Grignard
reagent 7 were unavailing, and we discovered that 25 was prone
to â-elimination of the protected hydroxyl group to give the
conjugated ketone 29 under more forcing conditions. Owing to
the observed instability of 25, it did not elicit surprise that
removal of the N-Boc protecting group from 25 under acidic
conditions to give the chiral imine 26 proved to be troublesome.
Indeed, when 25 was treated with various Lewis and protic acids
to deprotect the nitrogen atom, the sole isolated product was
the pyrrole 27,25 resulting perhaps from â-elimination of the
protected hydroxyl group of the desired 26 and subsequent
tautomerization. A variety of hydroxyl protecting groups includ-
ing TBS, MEM, benzyl, and trityl for the lactam 24 and ketone
25 were examined as was the corresponding unprotected
hydroxy lactam, but each of the derived ketones 28 was highly
susceptible to â-elimination to provide the conjugated ketone
29 as the only isolable product. The only protected â-hydroxy-
ketone that could be isolated after the Grignard reaction was
the TBDPS ether 25, which exhibited modest stability, perhaps
because the steric bulk of the TBDPS group somehow retards
elimination.26
Development of a New N-Protecting Group. It was apparent
at this stage that a different protecting group strategy would be
necessary. The Alloc group could be removed from 31 under
sufficiently mild conditions as not to incur material loss through
â-elimination, but the yield of 31 from the addition of 7 to 30
was poor. Our previous work with lactams related to 30
suggested that increased steric bulk was needed on the N-
carbamoyl lactam moiety.27 However, there is little precedent
for substituted allyloxy carbonyl protecting groups in the
literature,28 especially those with additional branching on the
carbinol carbon atom. The isopropylallylcarbamate protecting
group has been introduced as a protecting group in peptide
synthesis, but the reported preparation of the thiopyrimidincar-
bonate reagent used to introduce this protecting group involves
four tedious synthetic steps as well as the somewhat forcing
(24) For related applications of lactone-lactam rearrangements in
alkaloid synthesis, see: Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55,
8905-8914. See also ref 5d.
(25) Patterson, J. M.; Brasch, J.; Drenchko, P. J. Org. Chem. 1962, 27,
1652-1659.
(27) (a) Rudolf, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett.
2004, 45, 4895-4898. (b) Brenneman, J. B.; Machauer, R.; Martin, S. F.
Tetrahedron 2004, 60, 7301-7314.
(26) The precise origin of the enhanced stability of 25 is unknown as
some â-hydroxy aldehydes and ketones do undergo facile â-elimination.
For example, see: Paquette, L. A.; Chang, S.-K. Org. Lett. 2005, 7, 3111-
3114.
(28) The N-cinnamylcarbamate group may be removed under the same
conditions as the Alloc group, but this protecting group lacks the requisite
steric bulk. See: Kinoshita, H.; Inomata, K.; Kameda, T.; Kotake, H. Chem.
Lett. 1985, 515-518.
J. Org. Chem, Vol. 72, No. 14, 2007 5345

Simila and Martin
SCHEME 6
cleavage conditions rendered this protecting group unattractive
for our needs.29 We were able to prepare 1-isopropylallylchlo-
roformate, but the yields were low and irreproducible. There
was thus an opportunity to design a new Alloc-derived protect-
ing group for primary amines.
The criteria for this new carbamate protecting group for an
amine 32 were somewhat demanding (eq 1). First, the alkyl
chloroformate 33 required for preparing the carbamate 34 in a
single operation should be accessible from commercially
available materials in a single step. Second, the alkyl group on
the carbamate had to be sufficiently bulky that the carbonyl
group would not undergo attack by strong nucleophilic bases
such as Grignard and alkyllithium reagents. Finally, it was
essential that the protecting group could be cleaved under mild
conditions, such as the palladium-catalyzed process used to
remove the Alloc group from 31. Our attention was thus focused
upon substituted Alloc groups of the general type 33. We were
initially inspired by the Boc protecting group and thus envi-
sioned that the tertiary allylic carbamate 34 (R3 ) R4 ) Me)
would satisfy our requirements. However, we quickly discovered
that 33 (R3 ) R4 ) Me), like other tertiary alkyl chloroformates,
was unstable.30,31 On the other hand, we were able to prepare a
number of branched allyl chloroformates 33 (R3 ) H; R4 )
Me, Et, Pr, and i-Bu) from the corresponding allylic alcohols
in excellent yields by reaction with triphosgene in pentane in
the presence of Na2CO3 and a catalytic amount of Et3N.32,33
Because each of these groups incorporates a stereocenter that
might complicate characterization of chiral amines, we also tried
to prepare 33 (R3 ) H; R4 ) CHdCH2) but were unsuccessful
as the product was simply too unstable.
Pr, and i-Bu) were comparable (41-48%), whereas the yields
of the corresponding ring opened products were either lower
or no better than for the preparation of 39. Inasmuch as the
allylic alcohol required to prepare 36 is less expensive than the
other commercially available alcohols, we elected to use the
ethylallyloxycarbonyl (Etalloc) protecting group in subsequent
studies.
We then screened conditions for removing the Etalloc group
from 39 to prepare the imine 11. Removal of Alloc-type
protecting groups is typically performed in the presence of a
palladium catalyst that forms a π-allyl palladium complex that
is then trapped with a suitable nucleophile, thereby releasing
the amine.34 Because we would ultimately employ this protecting
group in a situation that mandated the use of neutral or slightly
basic conditions, our initial focus was on screening secondary
amine nucleophiles, rather than the more commonly used
protocols using carboxylic acids. We thus discovered that the
reaction of 39 with pyrrolidine in CH2Cl2 in the presence of
Pd(PPh3)4 (10 mol %) led to the rapid cleavage of the Etalloc
protecting group and the formation of an inseparable mixture
(1:1) of 11 and N-(2-penten-1-yl)pyrrolidine. The cleavage
reaction was slower in the presence of morpholine and when
other solvents such as CH3CN, THF, and Et2O were used.
Having prepared the chloroformates 33 (R3 ) H; R4 ) Me,
Et, Pr, and i-Bu), we initiated a series of exploratory experiments
to examine the potential of the corresponding carbamates as
amine protecting groups. For example, we found that reaction
of 36, which was prepared in virtually quantitative yield by the
reaction of commercially available 35 with triphosgene, with
2-pyrrolidinone (37) in the presence of Et3N and DMAP gave
38 in good yield. Attempts to improve this yield under other
mild conditions were unfruitful, and the use of stronger bases
such as NaHMDS gave complex mixtures. Subsequent reaction
of 38 with 3-butenylmagnesium bromide (7) in the presence of
TMEDA gave 39 in 88% yield (Scheme 6); when the reaction
was conducted in the absence of TMEDA, the yield of 39 was
only 64%. The yields for preparing protected 2-pyrrolidinones
related to 38 using other chloroformates 33 (R3 ) H; R4 ) Me,
Although pyrrolidine proved to be an excellent nucleophile
for effecting the removal of the Etalloc group from 39, we
discovered that the alkyl pyrrolidine byproduct interfered with
the subsequent reaction of 11 with 8, giving 12 in significantly
lower yields (eq 2). In searching for an alternative nucleophile,
we discovered that the palladium-catalyzed deprotection of 39
with benzotriazole in CH2Cl2 proceeded rapidly.35 Gratifyingly,
the alkylated benzotriazole byproduct did not affect the subse-
quent reaction. Thus, when 39 was allowed to react with
benzotriazole (1.0 equiv) in the presence of Pd(PPh3)4 (10 mol
%), the deprotection step was complete within 45 min (eq 2).
Subsequent treatment of the crude mixture (ca. 1:1) of 11 and
the alkylated benzotriazole with CbzCl, allylsilane 8, and
TMSOTf provided 12 in 40% yield, a yield comparable to that
observed previously (cf. Scheme 2).
(29) Minami, I.; Yukara, M.; Tsuji, J. Tetrahedron Lett. 1987, 28, 2737-
2740.
(30) Choppin, A. R.; Rogers, J. W. J. Am. Chem. Soc. 1948, 70, 2967-
2967.
(31) Kevill, D. N.; Weitl, F. L. J. Am. Chem. Soc. 1968, 90, 6416-
6420.
(32) Deshmukh, A. R. A. S.; Gumaste, V. K. U.S. Patent US006919471B2,
2005.
(33) All allylic chloroformates were heat- and moisture-sensitive and
were used immediately after preparation.
Utilization of the Etalloc Protecting Group To Prepare
the Tricyclic Core of (-)-FR901483. The utility of any new
protecting group must be assessed on the basis of its merits for
5346 J. Org. Chem., Vol. 72, No. 14, 2007

Toward the Total Synthesis of FR901483
SCHEME 8
the preparation of a particular target. Toward this goal, the chiral
lactam 23 was treated with the chloroformate 36 in the presence
of DMAP and Et3N to give 40 in an unoptimized 36% yield
(96% based upon recovered starting material) (Scheme 7).
Reaction of 40 with 3-butenylmagnesium bromide (7) in the
presence of TMEDA gave the ketone 41 in 58% yield. Although
the palladium-catalyzed removal of the Etalloc group in the
presence of benzotriazole proceeded smoothly, all attempts to
isolate and purify the resultant chiral imine 26 were unsuccessful
owing to its acid sensitivity and facile transformation to the
pyrrole 27. The crude reaction mixture was therefore simply
filtered through a short pad of basic alumina, and the volume
of the collected fractions was reduced so the concentration of
26 was about 0.1 M. However, when the 26 thus obtained was
treated with CbzCl and 8 in the presence of Lewis acids such
as TMSOTf or Sc(OTf)3, none of the desired product 42 was
observed; pyrrole 27 was the major product.
with zinc in THF39,40 to form 45 (Scheme 8). The chiral imine
26, which was generated in situ by the Pd-catalyzed deprotection
of 41, was then treated with the functionalized zinc reagent 45
in the presence of TrocCl to give an inseparable mixture (45:
55) of 46 and 47 in 37% yield. When CbzCl was used as the
acylating agent, the yield was lower. The mixture of 46 and 47
thus obtained was then subjected to RCM using Grubbs second-
generation catalyst 14 to give a separable mixture of 48 and 49
in nearly quantitative yield. On the basis of NMR experiments
and especially an NOE interaction between the proton at C(3)
and a proton on C(12) of the major product, we tentatively
assigned the structure of the major diastereoisomer as being
49, which has the incorrect stereochemistry at the spirocenter.
Similarly, an NOE interaction was observed between the proton
at C(3) and one of the protons on C(11) of the minor
diastereoisomer as would be expected for 48, which has the
desired stereochemistry at the spirocenter.
SCHEME 7
The lack of diastereoselectivity in the addition reaction was
a little surprising, as we had anticipated a higher level of
stereochemical control based upon Woerpel’s studies on ste-
reoelectronic effects in nucleophilic additions to five-membered
oxocarbenium ions.12 It would thus appear that those observa-
tions may not be applicable to additions to derivatives of five-
membered imines, although further work is required before any
firm conclusions can be drawn. For example, we do not know
whether the imine or an N-acyl iminium ion is the reactive
intermediate that undergoes addition. The steric bulk associated
with the TBDPS protecting group may also be a factor. In any
case, the poor stereoselectivity in a key step of our approach to
(-)-FR901483 was clearly a major disappointment. This,
together with the recent findings of the Weinreb group, which
had encountered a number of problems with an endgame
strategy related to ours,4i persuaded us to conclude these studies
and pursue more fruitful endeavors.
Owing to the low reactivity of the allylsilane 8, it was
necessary to use a Lewis acid to promote the geminal dialkyl-
ation. It was thus apparent that such conditions were incompat-
ible with the acid-sensitive nature of 26, and we thus reasoned
that a more nucleophilic reaction partner that did not require
Lewis acid additives was needed. Inasmuch as zinc reagents
were known to add efficiently to imines,36 it occurred to us that
a functionalized allylic zinc species might be employed to solve
the problem at hand. To explore this possibility, the known allyl
chloride 4337 was first converted into the iodide 44 in 84% yield
by a Finkelstein reaction,38 and 44 was then allowed to react
Summary
(34) For a review on allylic protecting groups and their removal, see:
Guibe´, F. Tetrahedron 1998, 54, 2967-3042.
We have thus explored a novel route to the immunosuppres-
sant agent FR901483. As a prelude to working on the natural
(35) For a recent example of the use of benzotriazole as a nucleophile
in allylic allylations, see: Oliveira, R. N.; Mendonca, F. J. B., Jr.; de Melo,
S. J.; Srivastava, R. M. Synlett 2006, 18, 3049-3052.
(36) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186-195.
(37) Moreno-Dorado, F. J.; Guerra, F. M.; Manzano, F. L.; Aladro, F.
J.; Jorge, Z. D.; Massanet, G. M. Tetrahedron Lett. 2003, 44, 6691-6693.
(38) Finkelstein, H. Ber. 1910, 43, 1528-1528.
(39) Knochel, P.; Almena, J. J.; Jones, P. Tetrahedron 1998, 54, 8275-
8319 and references therein.
(40) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 18, 2701-
2719.
J. Org. Chem, Vol. 72, No. 14, 2007 5347

Simila and Martin
for 3 h, whereupon water (0.2 mL) was added with stirring. NaBO3‚
4H2O (61 mg, 0.36 mmol) and water (0.8 mL) were then added
sequentially, keeping the mixture at 0 °C. The mixture was stirred
for 3 h at 25 °C, whereupon it was poured into a separatory funnel
containing ice-cold water (5 mL). The aqueous layer was extracted
with ether (3 × 5 mL), and the combined organic layers were
washed with brine (5 mL), dried (MgSO4), and concentrated in
vacuo. The residue was purified by flash chromatography eluting
with EtOH/CH2Cl2 (3:97) to give 36 mg (86%) of 16 and 5 mg
(13%) of 17 as a clear oil (combined yield: 99%). 1H NMR
(DMSO-d6, 100 °C, major diastereomer 16) δ 7.37-7.27 (comp, 5
H), 5.08 (d, J ) 13.0 Hz, 1 H), 5.05 (d, J ) 13.0 Hz, 1 H), 3.49-
3.31 (comp, 5 H), 2.71 (dd, J ) 13.5, 6.0 Hz 1 H), 2.60-2.51 (m,
2 H), 1.97-1.83 (m, 2 H), 1.79-1.68 (comp, 3 H), 1.64-1.60
(comp, 2 H), 1.54 (p, J ) 7.0 Hz, 1 H), 1.42 (p, J ) 7.0 Hz, 1 H),
1.24-1.19 (m, 1 H), 1.16-1.08 (comp, 2 H); 13C NMR (DMSO-
d6, 100 °C, major diastereomer 16) δ 152.7, 137.1 127.7, 126.9,
126.8, 68.0, 64.7, 62.9, 59.6, 46.7, 43.2, 37.4, 36.0, 33.9, 27.4, 27.3,
21.1; IR (neat) ν 3389, 2928, 1683, 1401, 1352, 1178, 1105, 1028;
mass spectrum (CI+) m/z 334.2021 [C19H27O4N + H requires
334.2018].
product, we completed a preliminary model study featuring the
nucleophilic addition of a functionalized allylsilane to an N-acyl
iminium ion, a ring closing metathesis, a stereoselective
hydroboration, and a lactone-lactam rearrangement to elaborate
the tricyclic core of the target. Application of this chemistry
toward the enantioselective synthesis of (-)-FR901483 required
that we first develop a new amine protecting group, the Etalloc
group, which is more stable to organometallic reagents than the
Alloc group and may be easily removed under mild conditions.
Further investigations for the general utilization of this protecting
group will be reported in due course. Unfortunately, the
diastereoselectivity in a key addition of a functionalized allyl
zinc reagent to the imine 26 was low, and pleasing solutions to
this vexing problem were not apparent. This result reflects our
poor understanding of the structural factors that govern the
stereoselectivities of nucleophilic additions to five-membered
imine derivatives, whereas our ability to predict the stereo-
chemistry of such additions to six-membered imines is signifi-
cantly better.
2,3,3a,6,7,7a-Hexahydro-2-oxospiro[benzofuran-5(4H),2′-pyr-
rolidin]-1′-carboxylic Acid Benzyl Ester (18). Iodobenzene di-
acetate (150 mg, 0.47 mmol) and TEMPO (4 mg, 0.023 mmol)
were added to a solution of 16 (39 mg, 0.12 mmol) in CH2Cl2 (1
mL) at 25 °C, and the mixture was stirred for 20 h. CH2Cl2 (5 mL)
and aqueous 0.5 N Na2S2O3 (1 mL) were added, and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (5
× 5 mL), and the combined organic layers were washed with
NaHCO3 (5 mL) and brine (5 mL), dried (MgSO4), and concentrated
in vacuo. The residue was purified by flash chromatography eluting
with EtOAc/hexanes (1:4) to give 34 mg (87%) of 18 as a clear
Experimental Section41
2-(But-3-enyl)-2-(2-methoxycarbonylmethylallyl)-pyrrolidine-
1-carboxylic Acid Benzyl Ester (12). A mixture of CbzCl (238
µL, 1.58 mmol) and 11 (150 mg, 1.22 mmol) in CH2Cl2 (2 mL)
containing 4 Å molecular sieves was stirred at -78 °C for 10 min,
whereupon 8 (682 mg, 3.66 mmol) in CH2Cl2 (2 mL) was added
at -78 °C and stirring was continued for 1 h. TMSOTf (221 µL,
1.22 mmol) was then added, and the mixture was stirred for 16 h,
letting the mixture to warm slowly to 25 °C. The molecular sieves
were removed by filtration, and the crude reaction mixture was
concentrated in vacuo. The residue was purified by flash chroma-
tography, eluting with EtOAc/hexanes (5:95) to give 190 mg (42%)
1
oil. H NMR δ 7.36-7.27 (comp, 5 H), 5.11 (d, J ) 12.5 Hz, 1
H), 5.06 (d, J ) 12.5 Hz, 1 H), 3.91 (dt, J ) 11.0, 6.5 Hz, 1 H),
3.55-3.47 (m, 2 H), 2.77-2.72 (m, 1 H), 2.51-2.44 (m, 3 H),
2.31-2.26 (m, 1 H), 2.11-2.01 (m, 2 H), 1.92-1.87 (m, 1 H),
1.82-1.72 (comp, 3 H), 1.62-1.58 (m, 1 H), 1.39-1.33 (m, 1 H);
13C NMR δ 176.7, 154.4, 136.7, 128.5, 128.0, 127.9, 82.9, 66.6,
62.5, 47.8, 43.9, 40.1, 38.2, 36.1, 31.2, 25.4, 21.6; IR (neat) ν 2922,
1781, 1701, 1454, 1402, 1354, 1203, 1104, 1027; mass spectrum
(CI+) m/z 330.1696 [C19H23O4N + H requires 330.1705].
1
of 12 as a clear oil. H NMR (DMSO-d6, 100 °C) δ 7.37-7.27
(comp, 5 H), 5.75 (ddt, J ) 16.8, 10.4, 6.8 Hz, 1 H), 5.09 (d, J )
12.5 Hz, 1 H), 5.05 (d, J ) 12.5 Hz, 1 H), 4.99-4.88 (comp, 4 H),
3.59 (s, 3 H), 3.46-3.35 (m, 2 H), 3.00 (d, J ) 16.0 Hz, 2 H),
2.80 (d, J ) 14.0 Hz, 1 H), 2.31 (d, J ) 14.0 Hz, 1 H), 2.08-1.96
(comp, 3 H), 1.89-1.83 (comp, 2 H), 1.74-1.67 (m, 3 H); 13C
NMR (DMSO-d6, 100 °C) δ 170.1, 152.7, 138.9, 137.9, 136.7,
130.0, 127.6, 126.9, 116.9, 113.5, 65.1, 61.0, 50.5, 47.8, 42.3, 41.4,
36.8, 33.8, 27.2, 20.9; IR (neat) ν 2935, 1742, 1697, 1442, 1398,
1353, 1154; mass spectrum (CI+) m/z 372.2182 [C22H29O4N + H
requires 372.2175].
3a,6,7,7a-Tetrahydrospiro[benzofuran-5(4H),2′-pyrrolidin]-
2(3H)-one (19). A mixture of 18 (25 mg, 0.076 mmol) in MeOH
(1 mL) containing 10% Pd/C (5 mg) was stirred under a hydrogen
atmosphere (1 atm) at 25 °C for 24 h. The mixture was filtered
through a pad of Celite, and the pad was washed with MeOH (3
mL). The combined filtrate and washings were concentrated in
vacuo to give 15 mg (99%) of 19 as a clear oil. 1H NMR (Cd3Od)
δ 3.99 (dt, J ) 11.0, 4.0 Hz, 1 H), 3.41-3.36 (m, 2 H), 2.52 (dd,
J ) 16.0, 6.5 Hz, 1 H), 2.45-2.39 (m, 1 H), 2.26-2.01 (comp, 6
H), 1.95 (t, J ) 7.5 Hz, 2 H), 1.92-1.78 (comp, 4 H); 13C NMR
(Cd3Od) δ 177.9, 84.1, 68.3, 46.8, 41.9, 39.5, 37.3, 35.7, 33.7, 27.7,
23.9; IR (neat) ν 2919, 1772, 1449, 1190, 1026; mass spectrum
(CI+) m/z 196.1333 [C11H17O2N + H requires 196.1338].
7-Methoxycarbonylmethyl-1-azaspiro[4.5]dec-7-ene-1-car-
boxylic Acid Benzyl Ester (15). Grubbs second-generation catalyst
14 (19 mg, 0.02 mmol) was added to a solution of 12 (84 mg, 0.23
mmol) in CH2Cl2 (5 mL) at 25 °C, and the mixture was stirred for
20 h, whereupon the solvent was removed in vacuo. The residue
was purified by flash chromatography, eluting with EtOAc/hexanes
(2:98) to give 74 mg (95%) of 15 as a clear oil. 1H NMR (DMSO-
d6, 100 °C) δ 7.37-7.27 (comp, 5 H), 5.48 (br s, 1 H), 5.08 (d, J
) 12.5 Hz, 1 H), 5.05 (d, J ) 12.5 Hz, 1 H), 3.59 (s, 3 H), 3.57-
3.53 (m, 1 H), 3.40-3.35 (m, 1 H), 2.98-2.96 (m, 2 H), 2.92-
2.86 (m, 1 H), 2.46-2.44 (m, 1 H), 2.16-2.05 (m, 2 H), 1.83-
1.68 (comp, 5 H), 1.35 (dd, J ) 10, 4.5 Hz, 1 H); 13C NMR
(DMSO-d6, 100 °C) δ 170.6, 153.0, 136.9, 129.8, 127.7, 127.0,
126.8, 122.9, 64.9, 61.8, 50.6, 47.2, 41.6, 36.1, 35.6, 29.2, 23.3,
20.8; IR (neat) ν 2938, 1730, 1694, 1437, 1352, 1143; mass
spectrum (CI+) m/z 344.1786 [C20H25O4N + H requires 344.1784].
8-Hydroxy-7-(2-hydroxyethyl)-1-azaspiro[4.5]decane-1-car-
boxylic Acid Benzyl Ester (16). A 1.0 M solution of BH3‚THF
(360 µL, 0.36 mmol) was added to a solution of 15 (43 mg, 0.12
mmol) in THF (0.5 mL) dropwise at 0 °C. The mixture was stirred
9-Hydroxy-5-azatricyclo[6.3.1.01,5]dodecan-6-one (20). A solu-
tion of NaOMe (6 mg, 0.12 mmol) and 19 (14 mg, 0.072 mmol) in
CH3OH (1 mL) was heated with stirring in a microwave reactor at
70 °C (200 W, 250 psi) for 3 × 45 min. The mixture was
concentrated in vacuo, and the residue was triturated with benzene
1
(2 × 3 mL) to give 13 mg (90%) of 20 as a clear oil. H NMR
(C6d6) δ 3.00 (dt, J ) 4.0, 8.4 Hz, 1 H), 2.74-2.65 (m, 2 H), 2.19-
2.13 (comp, 2 H), 1.69-1.52 (m, 2 H), 1.48-1.40 (comp, 3 H),
1.33-1.26 (comp, 3 H), 1.18 (t, J ) 8 Hz, 2 H), 1.05 (dt, J )
13.0, 4.5 Hz, 1 H), 0.90 (t, J ) 13.0 Hz, 1 H); 13C NMR (C6d6) δ
173.9, 74.3, 60.9, 46.3, 42.6, 39.8, 39.2, 39.1, 35.9, 32.7, 25.5; IR
(neat) ν 3239, 2923, 1663, 1410, 1303, 1168; mass spectrum (CI+)
m/z 196.1329 [C11H17O2N + H requires 196.1338].
Acetic Acid 6-Oxo-5-azatricyclo[6.3.1.01,5]dodec-9-yl Ester
(21). Acetic anhydride (12 µL, 0.128 mmol), Et3N (15 µL, 0.104
(41) All new and known compounds were judged to be >95% pure by
1H NMR spectroscopy.
5348 J. Org. Chem., Vol. 72, No. 14, 2007

Toward the Total Synthesis of FR901483
mmol), and DMAP (0.6 mg, 0.052 mmol) were added to a solution
of 20 (5 mg, 0.026 mmol) in CH2Cl2 (0.5 mL), and the mixture
was stirred at 25 °C for 6 h. CH2Cl2 (5 mL) and saturated NH4Cl
(5 mL) were added, and the organic layer was separated, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
flash chromatography eluting with MeOH/CH2Cl2 (2:98) to give
5.5 mg (90%) of 21 as a clear oil. 1H NMR δ 4.70 (dt, J ) 4.0, 8.0
Hz, 1 H), 3.48-3.44 (m, 1 H), 3.40-3.35 (m, 1 H), 3.10 (dd, J )
14.0, 6.2 Hz, 1 H), 2.77 (dt, J ) 12.8, 3.8 Hz, 1 H), 2.67 (m, 1 H),
2.07 (s, 3 H), 1.99-1.95 (m, 1 H), 1.89-1.78 (comp, 3 H), 1.75-
1.61 (comp, 4 H), 1.23-1.16 (comp, 2 H); 13C NMR δ 172.6, 170.8,
71.8, 64.1, 49.1, 39.6, 34.8, 33.8, 26.9, 25.2, 24.9, 22.7, 21.4; IR
(neat) ν 2926, 1732, 1644, 1407, 1246, 1088, 1027; mass spectrum
(CI+) m/z 238.1436 [C13H19O3N + H requires 238.1443].
was added, and the mixture was cooled to -78 °C. TrocCl (58 µL,
0.41 mmol) was added, and the mixture was stirred at -78 °C for
20 min. In another flask, 44 (202 mg, 0.62 mmol) was added
dropwise to a solution of zinc (49 mg, 0.74 mmol) in THF (0.6
mL) at room 25 °C, and the mixture was stirred for 20 min. This
solution of allyl zinc iodide was transferred via a cannula to the
above solution of the imine at -78 °C, and stirring was continued
for 18 h while allowing the cooling bath to warm to room
temperature. Saturated NH4Cl/H2O (1:1, 10 mL) was added, and
the mixture was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash
chromatography eluting with EtOAc/hexanes (1:99 to 2:98) to give
58 mg (37%) of an inseparable mixture (45:55) of 46 and 47 as a
clear oil. 1H NMR (DMSO-d6, 100 °C) δ 7.62-7.58 (comp, 4 H),
7.48-7.39 (comp, 6 H), 5.84-5.74 (m, 0.55 H), 5.71-5.62 (m,
0.45 H), 5.01-4.64 (comp, 6 H), 4.53 (p, J ) 6.8 Hz, 1 H), 3.70
(t, J ) 6.8 Hz, 1 H), 3.57-3.50 (comp, 2 H), 3.34-3.31 (m, 1 H),
2.84-2.62 (comp, 3 H), 2.25 (t, J ) 6.8 Hz, 1 H), 2.19-1.94 (comp,
6 H), 1.04 (s, 9 H), 0.87 (s, 4.05 H), 0.83 (s, 4.95 H), 0.03 (s, 2.7
H), -0.02 (s, 3.3 H); 13C NMR (DMSO-d6, 100 °C) δ 143.0, 137.8,
134.6, 132.8, 129.3, 127.2, 125.6, 117.2, 113.8, 96.0, 69.5, 61.3,
59.8, 59.4, 55.0, 41.3, 40.3, 27.4, 27.3, 26.4, 26.2, 25.2, 18.0, 17.1,
-3.8; IR (neat) ν 2930, 2858, 1721, 1403, 1105, 835, 702; mass
spectrum (CI+) m/z 752.2890 [C38H56O4NSi2Cl3 + H requires
752.2892].
1-Ethylallyl Chloroformate (36). Et3N (21 µL, 0.15 mmol) was
added to a solution of triphosgene (328 mg, 1.10 mmol) and Na2CO3
(318 mg, 3.0 mmol) in pentane (5 mL) at 0 °C, and the mixture
was stirred for 30 min. A solution of pent-1-en-3-ol (308 µL, 3.0
mmol) in pentane (5 mL) was added dropwise at 0 °C, the mixture
was allowed to warm to 25 °C, and stirring was continued for 16
h. The mixture was filtered, and the filtrate was concentrated in
1
vacuo to give 445 mg (99%) of 36 as a clear oil. H NMR (C6d6)
δ 5.31 (ddd, J ) 17.2, 10.8, 7.2 Hz, 1 H), 4.99 (dt, J ) 17.2, 1.2
Hz, 1 H), 4.86 (dt, J ) 10.8, 1.2 Hz, 1 H), 4.84-4.81 (m, 1 H),
1.37-1.18 (comp, 2 H), 0.54 (t, J ) 7.2 Hz, 3 H); 13C NMR (C6d6)
δ 149.6, 134.1, 119.2, 85.2, 26.9, 8.9; IR (neat) ν 2973, 1779, 1165,
824; mass spectrum (CI+) m/z 149.0289 [C6H9O2Cl + H requires
149.0291].
7-[2-(tert-Butyldimethylsilanyloxy)ethyl]-3-(tert-butyldiphen-
ylsilanyloxy)-1-azaspiro[4.5]dec-7-ene-1-carboxylic Acid 2,2,2-
Trichloroethyl Esters (48 and 49). A solution of 46 and 47 (36
mg, 0.048 mmol) in CH2Cl2 (0.5 mL) containing Grubbs’ catalyst
14 (8 mg, 0.005 mmol) at 25 °C was stirred for 20 h. The solvent
was removed in vacuo, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (0.5:99.5 to 2:98) to
2-Oxopyrrolidine-1-carboxylic Acid 1-Ethylallyl Ester (38).
1-Ethylallyl chloroformate 36 (175 mg, 1.18 mmol) was added to
a solution of 2-pyrrolidinone (66 mg, 0.78 mmol), Et3N (164 µL,
1.18 mmol), and DMAP (96 mg, 0.78 mmol) in CH3CN (1 mL) at
0 °C, and the mixture was stirred at 80 °C for 18 h. Saturated
NaHCO3 (5 mL) and EtOAc (5 mL) were added, the layers were
separated, and the aqueous layer was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with brine (10
mL), dried (Na2SO4), and concentrated in vacuo. The residue was
purified by flash chromatography eluting with EtOAc/hexanes (1:
5) to give 71 mg (48%) of 38 as a clear oil. 1H NMR δ 5.77 (ddd,
J ) 17.2, 10.8, 6.8 Hz, 1 H), 5.31 (dt, J ) 17.2, 1.2 Hz, 1 H),
5.20-5.17 (m, 1 H), 5.16 (dt, J ) 10.8, 1.2 Hz, 1 H), 3.76 (t, J )
7.6 Hz, 2 H), 2.48 (t, J ) 7.6 Hz, 2 H), 1.99 (p, J ) 7.6 Hz, 2 H),
1.73-1.63 (comp, 2 H), 0.89 (t, J ) 6.8 Hz, 3 H); 13C NMR δ
173.9, 151.0, 135.5, 117.5, 78.4, 46.2, 32.7, 27.0, 17.4, 9.1; IR
(neat) ν 3409, 2970, 1789, 1715, 1369, 1287; mass spectrum (CI+)
m/z 198.1134 [C10H15O3N + H requires 198.1130].
1
give 15 mg (45%) of 48 and 19 mg (54%) of 49 as clear oils. H
NMR (major diastereomer 49, major carbamate rotamer) δ 7.62-
7.59 (m, 4 H), 7.43-7.31 (comp, 6 H), 5.30-5.29 (m, 1 H), 4.86-
4.26 (m, 2 H), 4.25 (p, J ) 5.2 Hz, 1 H), 3.70-3.30 (comp, 4 H),
3.19-3.00 (m, 1 H), 2.59-2.49 (m, 2 H), 2.20-1.76 (comp, 6 H),
1.31-1.28 (m, 1 H), 1.03 (s, 9 H), 0.86 (s, 9 H), -0.01 (s, 6 H);
13C NMR (major diastereomer 49, major carbamate rotamer) δ
151.8, 135.7, 133.9, 133.4, 129.9, 127.8, 121.0, 96.1, 74.3, 70.4,
63.6, 62.2, 56.2, 44.7, 41.4, 36.8, 30.8, 29.7, 26.9, 25.9, 23.9, 19.0,
-5.2; 1H NMR (minor diastereomer 48, major carbamate rotamer)
δ 7.62-7.59 (m, 4 H), 7.43-7.31 (comp, 6 H), 5.33-5.32 (m, 1
H), 4.82-4.57 (m, 2 H), 4.27 (p, J ) 5.2 Hz, 1 H), 3.68-3.45
(comp, 4 H), 3.03-2.85 (m, 1 H), 2.59-2.49 (m, 2 H), 2.09-1.76
(comp, 6 H), 1.31-1.29 (m, 1 H), 1.03 (s, 9 H), 0.86 (s, 9 H),
-0.00 (s, 6 H); 13C NMR (minor diastereomer 48, major carbamate
rotamer) δ 151.7, 135.6, 133.6, 133.4, 129.9, 127.8, 121.4, 96.1,
74.3, 69.6, 63.2, 62.1, 56.2, 44.6, 41.1, 38.0, 31.9, 29.7, 26.8, 25.9,
24.3, 19.0, -5.2; IR (neat) ν 2926, 1719, 1400, 1104, 835, 701;
mass spectrum (CI+) m/z 724.2579 [C36H52O4NSi2Cl3 + H requires
724.2579].
tert-Butyl-(3-iodomethylbut-3-enyloxy)dimethylsilane (44). NaI
(1.28 g, 8.55 mmol) was added to a solution of tert-butyl-(3-
chloromethylbut-3-enyloxy)dimethylsilane (43)37 (400 mg, 1.71
mmol) in acetone (15 mL), and the mixture was heated under reflux
for 5 h. The solvent was removed in vacuo, Et2O (100 mL) was
added, and the resultant white solid was removed by filtration. The
filtrate was washed with water (50 mL) and brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
flash chromatography eluting with hexanes to give 480 mg (86%)
1
of 44 as a pale yellow oil. H NMR δ 5.25 (s, 1 H), 4.92 (d, J )
Acknowledgment. We thank the National Institutes of
Health (GM 25439), the Robert A. Welch Foundation, Pfizer,
Inc., and Merck Research Laboratories for their generous support
of this research. We are also grateful to Dr. Richard Pederson
(Materia, Inc.) for catalyst support and to Dr. Scott Bur and
Dr. Andreas Reichelt for helpful discussions.
1.2 Hz, 1 H), 3.95 (s, 2 H), 3.74 (t, J ) 6.8 Hz, 2 H), 2.42 (t, J )
6.8 Hz, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR δ 144.3, 115.2,
61.9, 37.2, 25.9, 18.3, 11.3, -5.3; IR (neat) ν 2954, 2857, 1471,
1388, 1256, 1098, 836; mass spectrum (CI+) m/z 327.0643 [C11H23-
OSiI + H requires 327.0641].
2-(But-3-enyl)-2-[4-(tert-butyldimethylsilanyloxy)-2-methyl-
enebutyl]-(R)-4-(tert-butyldiphenylsilanyloxy)pyrrolidine-1-car-
boxylic Acid 2,2,2-Trichloroethyl Esters (46) and (47). A solution
of benzotriazole (25 mg, 0.21 mmol), Pd(PPh3)4 (48 mg, 0.041
mmol), and 41 (106 mg, 0.21 mmol) in CH2Cl2 (1 mL) was stirred
for 1 h at 25 °C, whereupon it was quickly filtered through a short
pad of basic alumina and washed with CH2Cl2 (ca. 1 mL). After
concentration in vacuo to a volume of about 1 mL, THF (1 mL)
Supporting Information Available: Experimental procedures
and copies of 1H NMR and 13C NMR spectra for all new compounds
and a copy of 1H NMR spectrum for 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO070732A
J. Org. Chem, Vol. 72, No. 14, 2007 5349