Development of the [3 + 2] annulations of cyclohexenylsilanes and chlorosulfonyl isocyanate: Application to the total synthesis of (±)-peduncularine

Article abstract of DOI:10.1021/ja012152f

The synthesis of (±)-peduncularine was accomplished using the [3 + 2] annulation of an allylic silane with chlorosulfonyl isocyanate to assemble the bicyclic core of the alkaloid. The stereochemistry of the annulation product was employed to control the i

Full text of DOI:10.1021/ja012152f

Published on Web 08/28/2002
Development of the [3 + 2] Annulations of
Cyclohexenylsilanes and Chlorosulfonyl Isocyanate:
Application to the Total Synthesis of (()-Peduncularine
Claudia W. Roberson and K. A. Woerpel*
Contribution from the Department of Chemistry, UniVersity of California,
IrVine, California 92697-2025
Received September 10, 2001
Abstract: The synthesis of (()-peduncularine was accomplished using the [3 + 2] annulation of an allylic
silane with chlorosulfonyl isocyanate to assemble the bicyclic core of the alkaloid. The stereochemistry of
the annulation product was employed to control the installation of the indolylmethyl side chain at C-7 with
complete stereoselectivity.
Introduction
involving this advanced intermediate, however, does not address
a serious stereochemical problem. In the original total synthesis,
the indolylmethyl side chain was introduced without control at
the C-7 stereocenter.5
We envisioned that the azabicyclic core of peduncularine
could be assembled in a single step using a [3 + 2] annulation
reaction of a functionalized cyclohexenylsilane9 such as 4 with
chlorosulfonyl isocyanate (eq 2).8,10,11 These annulation reactions
The alkaloid peduncularine (1) was first isolated in 19711,2
from the Tasmanian shrub Aristotelia peduncularis with the
structurally related alkaloids aristoteline, aristoserratine, sorel-
line, tasmanine, and hobartine.3 Peduncularine, as well as many
other alkaloids isolated from the Aristotelia genus, is thought
to be derived biogenetically from tryptamine and a rearranged
geranyl subunit.3 These natural products have shown interesting
biological activity; in particular, peduncularine has shown
cytotoxic activity against breast cancer cell lines.3
Peduncularine represents a challenging synthetic target due
to its unusual 6-azabicyclo[3.2.1]oct-3-ene core.4 The only total
synthesis of this alkaloid, reported by Hiemstra and Speckamp
in 1989,5 proceeded via the lactam 2 (eq 1). In the past few
(including both the [3 + 2]12 and [2 + 2]13 versions) are
powerful tools for the synthesis of both carbocyclic and
(9) For examples of 3-silylcyclohexenes as nucleophiles in other reactions,
see: (a) Freppel, C.; Poirier, M.-A.; Richer, J.-C.; Maroni, Y.; Manuel, G.
Can. J. Chem. 1974, 52, 4133-4138. (b) Carter, M. J.; Fleming, I.; Percival,
A. J. Chem. Soc., Perkin Trans. 1 1981, 2415-2434. (c) Hayashi, T.;
Kabeta, K.; Yamamoto, T.; Tamao, K.; Kumada, M. Tetrahedron Lett. 1983,
24, 5661-5664. (d) Wickham, G.; Young, D.; Kitching, W. Organome-
tallics 1988, 7, 1187-1195. (e) Denmark, S. E.; Wallace, M. A.; Walker,
C. B. J. Org. Chem. 1990, 55, 5543-5545. (f) Majetich, G.; Song, J. S.;
Ringold, C.; Nemeth, G. A. Tetrahedron Lett. 1990, 31, 2239-2242. (g)
Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115,
11028-11029. (h) Clive, D. L. J.; Zhang, C. J. Org. Chem. 1995, 60, 1413-
1427. (i) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317-337. (j) Loreto, M. A.;
Tardella, P. A.; Tofani, D. Tetrahedron Lett. 1995, 36, 8295-8298.
(10) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-1435.
(11) Isaka, M.; Williard, P. G.; Nakamura, E. Bull. Chem. Soc. Jpn. 1999, 72,
2115-2116.
(12) For examples of the [3 + 2] annulation, see: (a) Whitesell, J. K.; Nabona,
K.; Deyo, D. J. Org. Chem. 1989, 54, 2258-2260. (b) Kno¨lker, H.-J.; Jones,
P. G.; Pannek, J. B. Synlett 1990, 429-430. (c) Panek, J. S.; Yang, M. J.
Am. Chem. Soc. 1991, 113, 9868-9870. (d) Kno¨lker, H.-J.; Foitzik, N.;
Goesmann, H.; Graf, R. Angew. Chem., Int. Ed. Engl. 1993, 32, 1081-
1083. (e) Danheiser, R. L.; Takahashi, T.; Berto´k, B.; Dixon, B. R.
Tetrahedron Lett. 1993, 34, 3845-3848. (f) Akiyama, T.; Yasusa, T.;
Ishikawa, K.; Ozaki, S. Tetrahedron Lett. 1994, 35, 8401-8404. (g)
Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998, 63,
5517-5522. (h) Schinzer, D.; Muller, N.; Fischer, A. K.; Priess, J. W.
Synlett 2000, 1265-1268. (i) Micalizio, G. C.; Roush, W. R. Org. Lett.
2001, 3, 1949-1952. (j) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc.
2002, 124, 3608-3613.
years, three formal syntheses of peduncularine have appeared,6,7
including our own,8 targeting the lactam 2. A formal synthesis
* Address correspondence to this author. E-mail: kwoerpel@uci.edu.
(1) Bick, I. R. C.; Bremner, J. B.; Preston, N. W.; Calder, I. C. J. Chem. Soc.,
Chem. Commun. 1971, 1155-1156.
(2) Ros, H.-P.; Kyburz, R.; Preston, N. W.; Gallagher, R. T.; Bick, I. R. C.;
Hesse, M. HelV. Chim. Acta 1979, 62, 481-487.
(3) Bick, I. R. C.; Hai, M. A. In The Alkaloids; Brossi, A., Ed.; Academic:
New York, 1985; Vol. 24, pp 113-151.
(4) For lead references on other 6-azabicyclo[3.2.1]octane systems see: (a)
Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. J. Chem. Soc.,
Chem. Commun. 1990, 1412-1414. (b) Triggle, D. J.; Kwon, Y. W.;
Abraham, P.; Pitner, J. B.; Mascarella, S. W.; Carroll, F. I. J. Med. Chem.
1991, 34, 3164-3171. (c) Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner,
K. M.; Weinreb, S. M. J. Org. Chem. 2000, 65, 6293-6306.
(5) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989,
111, 2588-2595.
(6) Rigby, J. H.; Meyer, J. H. Synlett 1999, S1, 860-862.
(7) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 2333-
2337.
(8) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-623.
9
11342
J. AM. CHEM. SOC. 2002, 124, 11342-11348
10.1021/ja012152f CCC: $22.00 © 2002 American Chemical Society

Total Synthesis of (±)-Peduncularine
A R T I C L E S
heterocyclic rings.14,15 The silane 4 would require a functional
group suitable for introduction of the C3-C4 double bond of
peduncularine. The silyl group at C-8 of annulation product 3
would be oxidized to a hydroxyl group, providing a handle for
installation of the exocyclic double bond of 1. The lactam
carbonyl group of 3 would serve as a precursor to an N-
acyliminium ion, which would be employed to install the side
chain at C-7. In this paper, we show that this plan culminates
in a stereoselective total synthesis of peduncularine.
A possible mechanism for the formation of vinylsilane 9 from
silyl ether 7a is shown in Scheme 1. The N-chlorosulfonyl
Scheme 1
Results and Discussion
Cyclohexenylsilanes as Nucleophiles. Initially, efforts to
prepare the functionalized bicyclic core of peduncularine focused
on the preparation of cyclohexenylsilanes bearing alkoxy groups
at C-4. This functional group pattern was chosen because
Hiemstra and Speckamp had introduced the endocyclic double
bond by elimination of acetic acid from a C-4 acetoxy
derivative.5 A stereoselective route to â-alkoxysilanes that would
be amenable to asymmetric synthesis was developed to evaluate
the viability of such a strategy. The cyclohexadiene-derived
epoxide 516,17 was treated with tert-butyldiphenylsilyllithium to
provide the SN2 product 6 in >99% isomeric purity (eq 3).18
The resulting alcohol 6 was protected as the TBDMS ether 7a
and as the benzoate 7b.
â-lactam 11 could form initially, in analogy to the reaction of
the benzoate derivative (eq 5). Ionization, likely facilitated by
chlorosulfonyl isocyanate,19 would generate â-silyl cation 12.
Silyl group migration and deprotonation would lead to N-
chlorosulfonyl lactam 13, which would form lactam 9 upon
reductive workup. The fact that this product is so prevalent
demonstrates that ionization of groups in the â-position relative
to silicon would need to be prevented.
Because solvolysis was a significant side reaction, we
evaluated the use of a cis-â-alkoxysilane as a potential solution.
cis-â-Alkoxysilanes undergo solvolysis at a much slower rate
than the analogous trans-â-alkoxysilanes,20 increasing the
possibility that the [3 + 2] annulation pathway would dominate
over elimination. To test this idea, the silanes 15a,b were
prepared as shown in eq 6. Acetylation was performed under
the Yamamoto conditions for hindered alcohols.21 Submission
of silane 15a to annulation and reduction conditions resulted in
a low yield of annulation product 16 (eq 7), although with none
of the solvolysis products. Acetate 15b provided only decom-
position products under analogous annulation conditions. At-
tempts to optimize these annulations were unsuccessful.
Submission of trans-substituted cyclohexenylsilanes 7a and
7b to annulation reaction conditions did not give acceptable
results. Reactions of the allylic silane 7a with chlorosulfonyl
isocyanate led to a low yield of the desired annulation product
8 along with significant amounts of â-lactam 9, whose structure
was suggested by 1H,1H COSY experiments (eq 4). Treatment
of the benzoate ester analogue 7b with chlorosulfonyl isocyanate
provided the [2 + 2] annulation13 product 10 in 41% yield (eq
5). Attempts to optimize the annulations by variation of solvent
and temperature were unsuccessful.
The studies with â-alkoxysilanes indicated that a different
approach would be required to install the C3-C4 double bond
of peduncularine. Besides the ionization problem encountered
with the trans-â-alkoxysilane 7a, the presence of a nearby
(16) Ramesh, K.; Wolfe, M. S.; Lee, Y.; Velde, D. V.; Borchardt, R. T. J. Org.
Chem. 1992, 57, 5861-5868.
(13) For examples of the [2 + 2] annulation, see: (a) Akiyama, T.; Kirino, M.
Chem. Lett. 1995, 723-724. (b) Uyehara, T.; Yuuki, M.; Masaki, H.;
Matsumoto, M.; Ueno, M.; Sato, T. Chem. Lett. 1995, 789-790. (c)
Akiyama, T.; Yamanaka, M. Synlett 1996, 1095-1096. (d) Kno¨lker, H.-
J.; Baum, E.; Schmitt, O. Tetrahedron Lett. 1998, 39, 7705-7708. (e)
Kno¨lker, H.-J.; Baum, G.; Schmitt, O.; Wanzl, G. Chem. Commun. 1999,
1737-1738. (f) Groaning, M. D.; Brengel, G. P.; Meyers, A. I. Tetrahedron
2001, 57, 2635-2642.
(17) Sato, T.; Gotoh, Y.; Watanabe, M.; Fujisawa, T. Chem. Lett. 1983, 1533-
1536.
(18) Clive, D. L. J.; Zhang, C.; Zhou, Y.; Tao, Y. J. Organomet. Chem. 1995,
489, C35-C37.
(19) Kim, J. D.; Han, G.; Jeong, L. S.; Park, H. J.; Zee, O. P.; Jung, Y. H.
Tetrahedron 2002, 58, 4395-4402.
(20) Lambert, J. B.; Wang, G.-T.; Finzel, R. B.; Teramura, D. H. J. Am. Chem.
Soc. 1987, 109, 7838-7845.
(14) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
(15) Kno¨lker, H.-J. J. Prakt. Chem. 1997, 339, 304-314.
(21) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996,
61, 4560-4567.
9
J. AM. CHEM. SOC. VOL. 124, NO. 38, 2002 11343

A R T I C L E S
Roberson and Woerpel
alkoxy group could inductively destabilize the carbocation
intermediate 17 required to obtain annulation products.22 Previ-
ous investigations of the [3 + 2] annulation reaction indicated
that annulation efficiency improved with â-silyl carbocation
stability.10,23-25 Our goal was to identify a structure that would
stabilize the â-silyl carbocation and provide a handle to install
a double bond. We recognized that incorporation of the double
bond at C-3 and C-4 (peduncularine numbering) into the starting
nucleophile would provide a stabilized allylic cation intermediate
(18). In addition to increasing the efficiency of the annulation,
synthesis was undertaken. As demonstrated in our formal
synthesis,8 the [3 + 2] annulation product 20b was found to be
a valuable intermediate. Our formal synthesis of the Hiemstra
and Speckamp5 intermediate 2 (eq 1) required only six steps
from commercially available materials and showcased the use
of the (Ph2CH)Me2Si group,28 which had been developed for
facile silicon-carbon oxidation.29-31 This formal synthesis,
however, did not address the lack of stereochemical control
during installation of the C-7 side chain of peduncularine (vide
supra). To solve this problem, we developed a total synthesis
that involved the carbamate 22, which was obtained by allylation
of an N-acyliminium ion derived from lactam 23 (eq 9).
this approach would produce the required C3-C4 double bond
of peduncularine directly, thereby reducing the number of steps
required to reach the target. This approach, however, would lead
to the target as a racemate because the starting cyclohexadi-
enylsilane would be achiral.
The critical installation of the C-7 side chain onto the bicyclic
core proceeded with high stereoselectivity (Scheme 2). Genera-
Cyclohexadienylsilanes as Nucleophiles. Cyclohexadienyl-
silanes proved to be successful partners in the annulation
reactions to construct the bicyclic core of peduncularine.26 These
substrates could be prepared easily from commercially available
materials. Treatment of 1,4-cyclohexadiene with sec-butyl-
lithium and TMEDA followed by quenching with silyl chlorides
provided, in high yield, thermally unstable cyclohexadienes
19a,b as single regioisomers (eq 8).27 The annulation reactions
Scheme 2
were performed with 19a,b under the standard conditions (CH2-
Cl2, -45 °C) followed by reduction in situ with 25% aqueous
Na2SO3 to afford the desired bicyclic lactams 20a,b as mixtures
of regioisomers. The minor regioisomers 21a,b were formed
by the reaction of the nitrogen nucleophile at the less sterically
crowded terminus of the intermediate allylic cation. The isomeric
purity could be easily improved by recrystallization.
tion of the N-acyliminium ion precursor 25 commenced with
acylation of lactam 20a (as a 96:4 mixture of regioisomers) with
the trimethylsilylethoxycarbamoyl (TEOC) group.32 The result-
ing intermediate 24 was purified by recrystallization to yield
>99% isomerically pure material. Selective reduction with i-Bu2-
AlH followed by treatment of the resultant hemiacetal with
ethanol and catalytic acid provided N,O-acetal 25 as a single
acetal epimer. Acetal 25 was then submitted to Hosomi-Sakurai
reaction conditions33,34 to yield the allylated product 26 as a
single diastereomer. The allylation proceeded with complete exo-
selectivity,35 as indicated by the absence of coupling between
Total Synthesis of Peduncularine. With the bicyclic frame-
work of peduncularine established, the completion of the
(22) For an example of the successful use of â-alkoxysilanes in [3 + 2]
annulations, see: Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461-
464.
(23) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992, 57,
6094-6097.
(28) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2000, 2, 1379-1381.
(29) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1-64.
(30) Tamao, K. In AdVances in Silicon Chemistry; JAI Press Inc.: Stamford,
CT, 1996; Vol. 3, pp 1-62.
(31) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(32) Shute, R. E.; Rich, D. H. Synthesis 1987, 346-349.
(24) Akiyama, T.; Ishikawa, K.; Ozaki, S. Chem. Lett. 1994, 627-630.
(25) Schinzer, D.; Panke, G. J. Org. Chem. 1996, 61, 4496-4497.
(26) For other work with cyclohexadienylsilanes, see: (a) Taber, D. F.; Yet,
L.; Bhamidipati, R. S. Tetrahedron Lett. 1995, 36, 351-354. (b) Fujishima,
H.; Takeshita, H.; Toyota, M.; Ihara, M. Chem. Commun. 1999, 893-894.
(c) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem. 1999,
64, 9613-9624.
(33) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295-1298.
(34) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
(35) This material gave one peak in the GC/MS, although two compounds
(presumably rotamers) were evident in the 1H NMR spectrum. To determine
whether the carbamate was two rotamers or two diastereoisomers, the
alkoxycarbonyl moiety was removed. The resulting amine was found to
be a single compound by 1H NMR spectroscopy, indicating that the
carbamate was a single diastereomer.
(27) Ihara, M.; Suzuki, S.; Tokunaga, Y.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1995, 2811-2812.
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Total Synthesis of (±)-Peduncularine
A R T I C L E S
H-7 and H-1 in 26.36 Carbamate 26 was sensitive to the Lewis
acid (BF3‚OEt2) at temperatures above -20 °C, so careful
control of the reaction temperature and optimization of the
isolation procedure were critical to the success of the reaction.
Treatment of the reaction mixture with triethylamine was
required prior to warming to room temperature to obtain a high
yield (88%) of lactam 26.
Scheme 4
Preparation of the C-7 side chain for installation of the indole
ring and construction of the tertiary amine moiety was performed
in five steps from the carbamate 26 (Scheme 3). Aldehyde 28
Scheme 3
group on silane 30 could be performed with t-BuOK in
DMSO.42 Treatment of the resultant silanol with standard Tamao
oxidation conditions (30% H2O2, KF, KHCO3) resulted in
decomposition, possibly due to N-oxide formation.43 The
oxidation conditions developed in our laboratories41 proved to
be the only method that was successful in performing a silicon-
carbon oxidation on the phenylsilane of the amine substrate.44
The total synthesis of peduncularine was completed in three
steps from acetate 31. The Fischer indole synthesis provided
alcohol 325,45 with concomitant deprotection of the C-8 alcohol
(Scheme 4). Alcohol 32 was oxidized to the ketone 33 by the
mild Parikh-Doering oxidation method.46 Methylenation of the
ketone with freshly prepared Tebbe reagent47 provided (()-
peduncularine (1) with good conversion.
was obtained by hydroboration of 26 with 9-BBN followed by
Swern oxidation. Because the carbamate group of 28 was
sensitive to acid, the aldehyde was converted to the propanediol
acetal in the presence of 2-methoxy-1,3-dioxane.37 This opera-
tion was performed both to protect the aldehyde functionality
in the following step and to improve the yield of the Fischer
indole synthesis.38 Liberation of the amino group with n-Bu4-
NF followed by reductive amination39 under neutral conditions
provided isopropylamine 30.
Oxidation of the silyl group at C-8 provided a hydroxyl group
that could be transformed to the C8-C9 alkene of peduncularine
(eq 10). Since the PhMe2Si group could not be oxidized at the
bicyclic lactam stage,40 this oxidation was performed on a
tertiary amine substrate. Using the modified oxidation conditions
Conclusion
The total synthesis of (()-peduncularine was accomplished
in 16 steps from commercially available materials. The key step
of the synthesis is the [3 + 2] annulation of an allylic silane
with chlorosulfonyl isocyanate, which provided the distinctive
bicyclic core of the natural product. This operation assembled
the bicyclic core of the alkaloid in one step, established two
stereocenters, and installed functional group handles that were
required to complete the synthesis. The stereochemistry of the
annulation product was employed to control the installation of
the indolylmethyl side chain at C-7 with complete stereoselec-
tivity. The synthesis requires a minimum number of protecting
groups that also serve dual roles as activating groups (the TEOC
and dioxane units) or functionalities that assist with isolation
(the acetate group). The successful synthesis (()-peduncularine
demonstrates the utility of annulation reactions of allylic silanes
in the synthesis of natural products.
developed in our laboratories (t-BuOOH, KH, and n-Bu4NF),41
the phenylsilane 30 was successfully converted to the alcohol
(eq 10). Because 5 equiv of n-Bu4NF was needed for the reaction
to proceed to completion, the resulting amino alcohol oxidation
product was converted to the acetate 31 to facilitate separation
from residual n-Bu4NF impurities. While exploring alternate
oxidation procedures, we found that displacement of the phenyl
Experimental Section48
3-Dimethylphenylsilyl-1,4-cyclohexadiene (19a). To a cooled (-78
°C) solution of 1,4-cyclohexadiene (10.0 mL, 109 mmol) in 110 mL
of THF were added s-BuLi (93.0 mL, 1.07 M in cyclohexane, 99 mmol)
and TMEDA (15.0 mL, 99.2 mmol). The yellow solution was warmed
to -45 °C, and after 2.5 h was treated with neat chlorodimethylphe-
(36) Krow, G. R.; Rodebaugh, R.; Hyndman, C.; Carmosin, R.; DeVicaris, G.
Tetrahedron Lett. 1973, 2175-2178.
(42) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.; Andersson,
P. G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487-6498.
(43) See ref 9i.
(44) Molander, G. A.; Nichols, P. J. J. Org. Chem. 1996, 61, 6040-6043.
(45) Chen, C.-Y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738-3741.
(46) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(47) Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386-2387.
(48) Additional experimental details are provided as Supporting Information.
(37) Roush, W. R.; Gillis, H. R. J. Org. Chem. 1980, 45, 4283-4287.
(38) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 609-632.
(39) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah,
R. D. J. Org. Chem. 1996, 61, 3849-3862.
(40) The bicyclic lactam was sensitive to both acid and base, so both acidic
and basic conditions that are required to oxidize the carbon-silicon bond
led to decomposition.
(41) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-6046.
9
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A R T I C L E S
Roberson and Woerpel
nylsilane (16.7 mL, 99.2 mmol). After 30 min at -45 °C, the solution
was treated with 300 mL of H2O and warmed to 23 °C. The organic
phase was diluted with 200 mL of Et2O, separated from the aqueous
phase, washed with 300 mL of brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (hexanes)
provided 19a as an oil (19.0 g, 89%): 1H NMR (400 MHz, CDCl3) δ
7.53 (m, 2H), 7.36 (m, 3H), 5.65-5.62 (m, 2H), 5.56-5.53 (m, 2H),
2.73-2.65 (m, 1H), 2.59-2.45 (m, 2H), 0.31 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 137.4, 133.9, 129.0, 127.6, 125.9, 121.9, 30.9, 26.3,
-5.4; IR (thin film) 3024, 2820, 1666, 1622 cm-1; HRMS (GC/MS,
EI) m/z calcd for C14H18Si (M)+ 214.1178, found 214.1179.
and to the solution was added camphorsulfonic acid (0.302 g, 1.30
mmol). After 16 h, the solution was treated with 400 mL of saturated
aqueous NaHCO3 and diluted with 300 mL of CH2Cl2. The organic
layer was separated from the aqueous layer and washed with 400 mL
of saturated aqueous NaHCO3. The combined aqueous layers were
extracted with 800 mL of CH2Cl2. The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash chromatography (1:1 hexanes/EtOAc to 100% EtOAc) provided
25 as an oil (10.77 g, 96%): 1H NMR (500 MHz, CDCl3) δ 7.50 (m,
2H), 7.35 (m, 3H), 6.29 (m, 0.34H), 6.12 (m, 0.66H), 5.35 (m, 1H),
4.90 (s, 0.66H), 4.74 (s, 0.34H), 4.19-4.05 (m, 3H), 3.71-3.49 (m,
2H), 2.41 (m, 1H), 2.25 (m, 1H), 2.06 (t, J ) 3.8 Hz, 0.66H), 2.01-
1.94 (m, 1.34H), 1.18 (t, J ) 7.0 Hz, 3H), 1.03-0.93 (m, 2H), 0.35 (s,
3H), 0.34 (s, 3H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.2,
155.0, 138.3, 133.6, 132.7, 132.3, 129.0, 127.7, 127.1, 126.9, 95.2,
94.7, 64.3, 64.0, 63.3, 63.2, 54.6, 54.3, 42.2, 41.7, 30.5, 29.72, 29.67,
17.9, 17.7, 15.44, 15.40, -1.6, -1.9, -2.5; IR (thin film) 3034, 2954,
1702 cm-1; HRMS (CI/ammonia) m/z calcd for C23H37NO3Si2 (M)+
431.2312, found 431.2298. Anal. Calcd for C23H37NO3Si2: C, 63.99;
H, 8.64; N, 3.24. Found: C, 63.75; H, 8.72; N, 3.28.
(1R*,5R*,8R*)-8-Dimethylphenylsilyl-6-azabicyclo[3.2.1]oct-3-en-
7-one (20a). To a cooled (-78 °C) solution of 19a (15.0 g, 70.0 mmol)
in 500 mL of CH2Cl2 was added chlorosulfonyl isocyanate (6.70 mL,
77.0 mmol). The solution was warmed to -45 °C. After 13 h at -45
°C, the solution was treated with 500 mL of 25% aqueous Na2SO3.
The biphasic mixture was warmed to 23 °C and stirred for 22 h. The
organic phase was separated from the aqueous phase, and the aqueous
phase was extracted with 400 mL of CH2Cl2. The combined organic
phases were dried over Na2SO4, filtered, and concentrated in vacuo.
Analysis of the unpurified reaction mixture by 1H NMR spectroscopy
showed a 91:9 ratio of 20a:21a. Purification by flash chromatography
(1:1 EtOAc/hexanes) provided 20a and regioisomer 21a (combined
12.27 g, 68%). Recrystallization provided a pure sample of 20a as a
white solid: mp 115-116 °C; 1H NMR (500 MHz, CDCl3) δ 7.49 (m,
2H), 7.37 (m, 3H), 6.14 (m, 1H), 5.98 (br s, 1H), 5.58 (m, 1H), 3.65
(m, 1H), 2.71 (m, 1H), 2.28 (m, 2H), 2.08 (t, J ) 3.9 Hz, 1H), 0.372
(s, 3H), 0.366 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.7, 137.5,
133.4, 131.3, 129.2, 128.7, 127.8, 51.1, 41.6, 36.1, 26.9, -2.6, -2.9;
IR (KBr) 3203, 3064, 2957, 1683, 1636 cm-1; HRMS (CI/isobutane)
m/z calcd for C15H20NOSi (M + H)+ 258.1314, found 258.1320. Anal.
Calcd for C15H19NOSi: C, 69.99; H, 7.44; N, 5.44. Found: C, 69.81;
H, 7.50; N, 5.47.
(1R*,5R*,7R*,8R*)-7-Allyl-8-dimethylphenylsilyl-6-azabicyclo-
[3.2.1]oct-3-ene-6-carboxylic Acid 2-Trimethylsilylethyl Ester (26).
To a cooled (-78 oC) solution of 25 (4.00 g, 9.27 mmol) in 165 mL of
CH2Cl2 were added sequentially allyltrimethylsilane (5.90 mL, 37.1
mmol) and BF3‚Et2O (2.28 mL, 18.5 mmol). The solution was warmed
to -45 °C. After 2 h, the reaction mixture was treated with 6.0 mL of
NEt3 and then with 100 mL of H2O. The heterogeneous solution was
allowed to warm to 23 °C. The organic layer was separated from the
aqueous layer, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (3:1 hexanes/EtOAc) provided
26 as an oil (3.48 g, 88%, >99% diastereomeric excess by GC/MS of
the unpurified reaction mixture): 1H NMR (500 MHz, CDCl3) δ 7.49
(m, 2H), 7.35 (m, 3H), 6.27 (0.4H), 6.10 (m, 0.6H), 5.77 (m, 1H),
5.47 (m, 1H), 5.01 (m, 2H), 4.18-4.07 (m, 3H), 3.55 (dd, J ) 9.9, 3.2
Hz, 0.6H), 3.46 (dd, J ) 9.8, 2.7 Hz, 0.4H), 2.64 (m, 0.6H), 2.55 (m,
0.4H), 2.34 (m, 2H), 2.07-1.96 (m, 2H), 1.70 (t, J ) 3.7 Hz, 0.6H),
1.64 (t, J ) 3.7 Hz, 0.4H), 0.98 (m, 2H), 0.34 (s, 3H), 0.33 (s, 3H),
0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.1, 155.0, 138.5, 135.9,
135.8, 133.5, 131.6, 131.1, 129.0, 128.1, 127.8, 116.74, 116.69, 66.7,
66.0, 62.9, 62.8, 54.7, 54.6, 39.5, 38.9, 38.6, 38.3, 34.20, 34.16, 31.1,
30.3, 18.0, 17.9, -1.5, -1.9, -2.5; IR (thin film) 3070, 2953, 1695,
1639 cm-1; HRMS (CI/isobutane) m/z calcd for C22H34NO2Si2 (M -
C2H3)+ 400.2128, found 400.2135. Anal. Calcd for C24H37NO2Si2: C,
67.39; H, 8.72; N, 3.27. Found: C, 67.20; H, 8.76; N, 3.28.
(1R*,5R*,8R*)-8-Dimethylphenylsilyl-7-oxo-6-azabicyclo[3.2.1]-
oct-3-ene-6-carboxylic Acid 2-Trimethylsilylethyl Ester (24). To a
cooled (-78 °C) solution of 20a (20.00 g, 96:4 ratio of 20a:21a by 1H
NMR spectroscopy, 74.59 mmol of 20a) in 600 mL of THF was added
n-BuLi (40.0 mL, 92 mmol, 2.3 M in hexanes). After 30 min at -78
°C, 2-trimethylsilylethyl chloroformate32 (155.4 mmol) was added by
cannula. Saturated aqueous ammonium chloride solution (600 mL) was
added after 45 min at -78 °C, and the reaction mixture was allowed
to warm to 23 °C. The organic layer was separated from the aqueous
layer, concentrated in vacuo, and azeotropically dried under vacuum
with 4 × 200 mL of benzene. Purification by recrystallization (hexanes/
EtOAc), followed by recrystallization of the mother liquor, provided
(1R*,5R*,7R*,8R*)-8-Dimethylphenylsilyl-7-(3-hydroxypropyl)-
6-azabicyclo[ 3.2.1]oct-3-ene-6-carboxylic Acid 2-Trimethylsilylethyl
Ester (27). To a solution of 26 (0.152 g, 0.355 mmol) in 2 mL of THF
was added solid 9-BBN dimer (0.130 g, 1.07 mmol). After 1 h at 23
°C, the reaction mixture was treated, sequentially, with 0.75 mL of
EtOH, 0.25 mL of 6 M NaOH, and 0.5 mL of 30% aqueous H2O2. The
heterogeneous solution was heated to 50 °C for 1 h. Once cooled to 23
°C, the mixture was diluted with 5 mL of Et2O and 2 mL of H2O. The
aqueous layer was saturated with K2CO3, separated from the organic
layer, and extracted with 5 mL of Et2O. The combined organic layers
were washed with 10 mL of brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (3:1
hexanes/EtOAc) provided 27 as an oil (0.126 g, 80%): 1H NMR (500
MHz, CDCl3) δ 7.50 (m, 2H), 7.37 (m, 3H), 6.27 (m, 0.2H), 6.10 (m,
0.8H), 5.46 (m, 1H), 4.16-4.05 (m, 3H), 3.67 (m, 2H), 3.56 (dd, J )
9.4, 2.9 Hz, 0.8H), 3.40 (dd, J ) 9.9, 2.6 Hz, 0.2H), 2.82 (br s, 0.8H),
2.41-2.36 (m, 1H), 2.26 (s, 0.2H), 2.21 (s, 0.8H), 2.04-1.97 (m, 1H),
1.90-1.77 (m, 2H), 1.68 (s, 0.2H), 1.66-1.33 (m, 3H), 0.98 (m, 2H),
0.35 (s, 3H), 0.34 (s, 3H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 155.3, 155.2, 138.4, 133.5, 131.7, 131.0, 129.1, 128.1, 127.8, 127.7,
66.6, 63.0, 62.6, 62.1, 54.5, 54.4, 40.5, 40.3, 34.3, 34.2, 31.4, 30.93,
30.86, 30.5, 30.3, 29.6, 17.9, 17.8, -1.5, -1.9, -2.5; IR (thin film)
1
24 in >99% isomeric purity (25.26 g, 84%): mp 113-114 °C; H
NMR (500 MHz, CDCl3) δ 7.48 (m, 2H), 7.36 (m, 3H), 6.28 (m, 1H),
5.60 (m, 1H), 4.35 (m, 1H), 4.32-4.23 (m, 2H), 2.84 (m, 1H), 2.30
(m, 2H), 1.93 (t, J ) 4.0 Hz, 1H), 1.11-1.06 (m, 2H), 0.377 (s, 3H),
0.374 (s, 3H), 0.03 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 177.1,
151.1, 136.8, 133.4, 129.8, 129.4, 128.9, 127.9, 64.9, 55.0, 43.8, 32.4,
27.1, 17.6, -1.7, -2.6, -3.0; IR (KBr) 3056, 2957, 1786, 1752, 1700
cm-1; HRMS (CI/ammonia) m/z calcd for C21H31NO3Si2 (M)+ 401.1842,
found 401.1836. Anal. Calcd for C21H31NO3Si2: C, 62.80; H, 7.78; N,
3.49. Found: C, 62.90; H, 7.78; N, 3.52.
(1R*,5R*,7R*,8R*)-8-Dimethylphenylsilyl-7-ethoxy-6-azabicyclo-
[3.2.1]oct-3-ene-6-carboxylic Acid 2-Trimethylsilylethyl Ester (25).
To a cooled (-78 °C) solution of 24 (10.40 g, 25.89 mmol) in 300 mL
of THF was added, over 20 min, a solution of i-Bu2AlH (65.0 mL, 65
mmol, 1.0 M in hexanes). After 1 h, the reaction mixture was treated
with 60 mL of saturated aqueous ammonium chloride and warmed to
23 °C. Saturated sodium potassium tartrate solution (200 mL) was added
to the solution, and the heterogeneous mixture was concentrated in
vacuo. The aqueous layer was washed with 5 × 300 mL of CH2Cl2.
The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was dissolved in 100 mL of EtOH,
9
11346 J. AM. CHEM. SOC. VOL. 124, NO. 38, 2002

Total Synthesis of (±)-Peduncularine
A R T I C L E S
3453, 3032, 2951, 1694 cm-1; HRMS (CI/ammonia) m/z calcd for
C24H40NO3Si2 (M + H)+ 446.2546, found 446.2548. Anal. Calcd for
C24H39NO3Si2: C, 64.67; H, 8.82; N, 3.14. Found: C, 64.45; H, 8.85;
N, 3.13.
32.9, 31.5, 25.8, -1.5, -2.1; IR (thin film) 3322, 3022, 2849, 1640
cm-1; HRMS (FAB) m/z calcd for C21H32NO2Si (M + H)+ 358.2202,
found 358.2198.
The deprotected amine (1.16 mmol) and acetone (0.426 mL, 5.80
mmol) were mixed in 12 mL of CH3CN and then treated with sodium
triacetoxyborohydride (0.369 g, 1.74 mmol). The mixture was stirred
for 14 h at 23 °C until the reactant was consumed (as determined by
GC analysis). The reaction mixture was diluted with 30 mL of CH2Cl2
and treated with 40 mL of saturated aqueous NaHCO3. The organic
layer was separated from the aqueous layer, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatography (95:
5:1 CH2Cl2/MeOH/NEt3) provided 30 as an oil (0.377 g, 81% over
two steps): 1H NMR (500 MHz, CDCl3) δ 7.50 (m, 2H), 7.30 (m,
3H), 5.82 (m, 1H), 5.57 (m, 1H), 4.46 (m, 1H), 4.07-4.03 (m, 2H),
3.72-3.66 (m, 2H), 3.47 (m, 1H), 2.68 (septet, J ) 6.2 Hz, 1H), 2.30
(m, 1H), 2.15-1.98 (m, 3H), 1.82 (m, 1H), 1.72 (t, J ) 3.7 Hz, 1H),
1.59-1.53 (m, 3H), 1.40-1.35 (m, 1H), 1.28 (m, 1H), 1.07 (d, J )
6.4 Hz, 3H), 1.05 (d, J ) 6.2 Hz, 3H), 0.33 (s, 3H), 0.31 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 139.2, 133.5, 129.6, 128.6, 128.4, 127.4,
102.1, 71.5, 66.6, 57.1, 51.0, 41.4, 35.6, 33.5, 33.2, 30.7, 25.6, 23.7,
22.6, -1.6, -2.3; IR (thin film) 3020, 2964, 1643 cm-1; HRMS (CI/
ammonia) m/z calcd for C24H38NO2Si (M + H)+ 400.2672, found
400.2674. Anal. Calcd for C24H37NO2Si: C, 72.13; H, 9.33; N, 3.50.
Found: C, 71.90; H, 9.38; N, 3.52.
(1R*,5R*,7R*,8R*)-8-Dimethylphenylsilyl-7-(3-oxopropyl)-6-
azabicyclo[3.2.1]oct-3-ene-6-carboxylic Acid 2-Trimethylsilylethyl
Ester (28). To a cooled (-78 °C) solution of DMSO (0.622 mL, 8.77
mmol) in 25 mL of CH2Cl2 was added oxalyl chloride (0.384 mL, 4.38
mmol). After 1 h, a solution of 27 (1.15 g, 2.58 mmol) in 10 mL of
CH2Cl2 was added. Triethylamine (2.70 mL, 19.4 mmol) was added to
the solution after 1 h at -78 °C. The reaction mixture was allowed to
warm to 23 °C, stirred for 1 h, and poured into 40 mL of H2O. The
organic layer was separated from the aqueous layer, dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by flash chro-
matography (3:1 hexanes/EtOAc) provided 28 as an oil (1.02 g, 89%):
1H NMR (500 MHz, CDCl3) δ 9.75 (t, J ) 1.6 Hz, 1H), 7.50 (m, 2H),
7.36 (m, 3H), 6.28 (m, 0.33H), 6.10 (m, 0.67H), 5.45 (m, 1H), 4.16-
4.05 (m, 3H), 3.52 (dd, J ) 7.8, 5.5 Hz, 0.67H), 3.40 (dd, J ) 9.0, 4.0
Hz, 0.33H), 2.52-2.36 (m, 3H), 2.19 (m, 1H), 2.02 (m, 2H), 1.75-
1.63 (m, 2H), 1.00-0.96 (m, 2H), 0.35 (s, 3H), 0.34 (s, 3H), 0.03 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 201.6, 201.2, 155.4, 155.0, 138.0,
133.2, 131.5, 131.0, 128.9, 127.6, 127.3, 66.8, 66.1, 63.1, 63.0, 54.9,
41.8, 40.9, 34.3, 34.2, 31.6, 30.8, 27.5, 18.1, -1.2, -1.6, -2.3; IR
(thin film) 3033, 2953, 2897, 2720, 1725, 1694 cm-1; HRMS
(CI/ammonia) m/z calcd for C24H38NO3Si2 (M + H)+ 444.2390, found
444.2395. Anal. Calcd for C24H37NO3Si2: C, 64.96; H, 8.40; N, 3.16.
Found: C, 64.92; H, 8.52; N, 3.16.
Acetic Acid (1R*,5R*,7R*,8R*)-7-(2-[1,3]Dioxan-2-ylethyl)-6-iso-
propyl-6-azabicyclo[3.2.1]oct-3-en-8-yl Ester (31). To a cooled (-45
°C) suspension of KH (0.113 g, 2.86 mmol) in 1 mL of DMF was
added tert-butyl hydroperoxide (0.12 mL, 0.9 mmol, 70% in H2O)
dropwise. After being warmed to 23 °C, the reaction mixture was treated
with a solution of 30 (0.052 g, 0.13 mmol) in 2 mL of DMF. After 10
min, n-Bu4NF (0.715 mL, 0.72 mmol, 1.0 M in THF) was added to
the reaction mixture. Immediately after addition was complete, the
solution foamed vigorously. The flask was fitted with a reflux
condenser, and the solution was heated to 65 °C for 4 h. Once cooled
to 23 °C, the reaction mixture was treated with 10 mL of EtOAc and
10 mL of saturated aqueous Na2S2O3. The organic layer was separated
from the aqueous layer, and the aqueous layer was washed with 2 ×
10 mL of EtOAc. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (90:10:1 CH2Cl2/MeOH/NEt3) to provide the
impure alcohol: 1H NMR (500 MHz, CDCl3) δ 5.99 (m, 1H), 5.78
(m, 1H), 4.49 (t, J ) 4.8 Hz, 1H), 4.41 (t, J ) 4.6 Hz, 1H), 4.10-4.07
(m, 2H), 3.76-3.71 (m, 2H), 3.50 (t, J ) 4.6 Hz, 1H), 2.83 (septet, J
) 6.3 Hz, 1H), 2.54 (m, 1H), 2.37 (m, 1H), 2.10-2.00 (m, 2H), 1.94
(m, 1H), 1.67-1.46 (m, 4H), 1.34-1.31 (m, 1H), 1.08 (d, J ) 6.2 Hz,
3H), 1.06 (d, J ) 6.4 Hz, 3H). A solution of the alcohol in 1 mL of
CH2Cl2 was treated with acetic anhydride (0.123 mL, 1.30 mmol),
triethylamine (0.091 mL, 0.65 mmol), and a crystal of DMAP. After
30 min at 23 °C, the reaction mixture was concentrated in vacuo.
Purification by flash chromatography (95:5 CH2Cl2/MeOH) provided
acetate 31 as an oil (0.024 g, 57%): 1H NMR (400 MHz, CDCl3) δ
5.84 (m, 1H), 5.70 (m, 1H), 5.12 (t, J ) 4.8 Hz, 1H), 4.50 (t, J ) 4.7
Hz, 1H), 4.08 (dd, J ) 10.8, 4.9 Hz, 2H), 3.74 (td, J ) 12.1, 2.2 Hz,
2H), 3.65 (t, J ) 4.7 Hz, 1H), 2.83 (septet, J ) 6.3 Hz, 1H), 2.42 (m,
1H), 2.34 (m, 1H), 2.22 (m, 1H), 2.06 (m, 1H), 2.03 (s, 3H), 1.92-
1.87 (m, 1H), 1.68-1.44 (m, 4H), 1.32 (m, 1H), 1.05 (d, J ) 6.3 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 170.4, 129.1, 125.8, 102.0, 71.0,
68.1, 66.81, 66.78, 55.5, 50.5, 40.1, 33.2, 32.8, 32.7, 25.9, 23.1, 22.7,
(1R*,5R*,7R*,8R*)-8-Dimethylphenylsilyl-7-(2-[1,3]dioxan-2-yl-
ethyl)-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylic Acid 2-Trimethyl-
silylethyl Ester (29). A solution of aldehyde 28 (0.041 g, 0.092 mmol)
in 1 mL of THF was treated with 1,3-propanediol (0.073 mL, 1.0
mmol), 2-methoxy-1,3-dioxane37 (0.040 g, 0.33 mmol), and a crystal
of p-TsOH. After 20 min, the reaction mixture was diluted with 5 mL
of Et2O and treated with 5 mL of saturated aqueous NaHCO3. The
organic layer was separated from the aqueous layer, dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by flash chro-
matography (3:1 hexanes/EtOAc) provided 29 as an oil (0.036 g,
78%): 1H NMR (500 MHz, CDCl3) δ 7.49 (m, 2H), 7.35 (m, 3H),
6.26 (m, 0.35H), 6.07 (m, 0.65H), 5.44 (m, 1H), 4.52 (t, J ) 5.1 Hz,
0.65H), 4.49 (t, J ) 5.1 Hz, 0.35H), 4.14-4.04 (m, 5H), 3.75-3.70
(m, 2H), 3.48 (dd, J ) 9.7, 3.3 Hz, 0.65H), 3.38 (dd, J ) 9.7, 2.6 Hz,
0.35H), 2.36 (m, 1H), 2.28 (m, 1H), 2.08-1.84 (m, 3H), 1.69-1.59
(m, 3H), 1.44-1.26 (m, 2H), 1.00-0.88 (m, 2H), 0.34 (s, 3H), 0.33
(s, 3H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.3, 155.2,
138.6, 133.5, 131.8, 131.2, 129.0, 127.9, 127.8, 127.6, 102.3, 102.1,
67.52, 66.82, 66.77, 62.8, 62.7, 54.5, 40.4, 39.4, 34.2, 33.0, 32.9, 31.3,
30.4, 29.1, 28.5, 25.8, 17.9, -1.5, -1.8, -2.5; IR (thin film) 3032,
2953, 1694 cm-1; HRMS (FAB+) m/z calcd for C27H43NO4Si2 (M)+
501.2730, found 501.2725. Anal. Calcd for C27H43NO4Si2: C, 64.63;
H, 8.63; N, 2.79. Found: C, 64.78; H, 8.63; N, 2.76.
(1R*,5R*,7R*,8R*)-8-Dimethylphenylsilyl-7-(2-[1,3]dioxan-2-yl-
ethyl)-6-isopropyl-6-azabicyclo[3.2.1]oct-3-ene (30). A solution of 29
(0.581 g, 1.16 mmol) in 15 mL of CH3CN was treated with n-Bu4NF
(1.85 mL, 1.9 mmol, 1.0 M in THF) at 65 °C for 6 h. Upon being
cooled to 23 °C, the reaction mixture was concentrated in vacuo.
Purification by flash chromatography (90:10:1 CH2Cl2/MeOH/NEt3)
provided the amine as an impure residue which was used in the
subsequent step. Repurification of an aliquot provided a pure sample
of the deprotected amine as an oil: 1H NMR (500 MHz, CDCl3) δ
7.50 (m, 2H), 7.33 (m, 3H), 5.92 (m, 1H), 5.44 (m, 1H), 4.51 (t, J )
5.0 Hz, 1H), 4.07 (m, 2H), 3.73 (m, 2H), 3.50 (dd, J ) 5.8, 3.4 Hz,
1H), 2.90 (t, J ) 7.0 Hz, 1H), 2.33 (m, 1H), 2.15 (m, 1H), 2.10-2.00
(m, 2H), 1.89 (m, 1H), 1.69-1.47 (m, 3H), 1.41-1.31 (m, 3H), 0.34
(s, 3H), 0.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 139.0, 133.1,
131.8, 128.4, 127.2, 126.5, 101.8, 66.63, 66.62, 64.8, 55.2, 41.6, 35.0,
21.2; IR (thin film) 3021, 2964, 2846, 2730, 2655, 1737, 1642 cm-1
;
HRMS (CI/ammonia) m/z calcd for C18H30NO4 (M + H)+ 324.2175,
found 324.2174. Anal. Calcd for C18H29NO4: C, 66.85; H, 9.04; N,
4.33. Found: C, 66.49; H, 9.16; N, 4.34.
(1R*,5R*,7R*,8R*)-7-(1H-Indol-3-ylmethyl)-6-isopropyl-6-
azabicyclo[3.2.1]oct-3-en-8-ol (32). A solution of 1.5 mL of 4%
aqueous sulfuric acid was heated to 50 °C for 30 min. Phenylhydrazine
hydrochloride (0.025 g, 0.17 mmol) was added to the heated solution,
9
J. AM. CHEM. SOC. VOL. 124, NO. 38, 2002 11347

A R T I C L E S
Roberson and Woerpel
and the solid was allowed to dissolve over 10 min. The heated solution
was transferred to a flask containing acetal 31 (0.051 g, 0.16 mmol).
This mixture was heated at reflux for 1 h. After being cooled to 23 °C,
the reaction mixture was treated with 2 mL of saturated aqueous
NaHCO3 solution and 4 mL of EtOAc. The organic phase was separated
from the aqueous phase, and the aqueous phase was washed with 2 ×
5 mL of EtOAc. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by flash chro-
matography (90:10:0.5 CH2Cl2/MeOH/NEt3) provided 32 as a white
foam (0.035 g, 75%): 1H NMR (500 MHz, CDCl3) δ 8.01 (br s, 1H),
7.60 (d, J ) 7.9 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 1H), 7.19 (m, 1H), 7.11
(m, 1H), 6.99 (s, 1H), 5.98 (m, 1H), 5.84 (m, 1H), 4.54 (m, 1H), 3.61
(t, J ) 4.6 Hz, 1H), 2.99 (m, 2H), 2.89-2.79 (m, 2H), 2.40 (m, 1H),
2.20 (m, 1H), 1.90 (br s, 1H), 1.81-1.77 (m, 1H), 1.28 (d, J ) 6.4 Hz,
3H), 1.16 (d, J ) 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 136.2,
130.9, 127.7, 127.3, 122.0, 121.7, 119.3, 119.1, 114.9, 111.1, 69.4,
69.1, 58.7, 51.0, 41.5, 34.5, 32.1, 23.3, 22.7; IR (KBr) 3291, 3040,
2936, 1653, 1617, 1457, 1100, 739 cm-1; HRMS (CI/ammonia) m/z
calcd for C19H25N2O (M + H)+ 297.1967, found 297.1965.
(1R*,5R*,7R*)-7-(1H-Indol-3-ylmethyl)-6-isopropyl-6-azabicyclo-
[3.2.1]oct-3-en-8-one (33). To a solution of 32 (0.013 g, 0.040 mmol)
in 0.6 mL of DMSO were added sulfur trioxide-pyridine complex
(0.043 g, 0.27 mmol) and triethylamine (0.050 mL, 0.36 mmol). After
20 min at 23 °C, the reaction mixture was treated with 3 mL of saturated
aqueous NaHCO3 solution and 3 mL of EtOAc. The organic layer was
separated from the aqueous layer, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (3:1
hexanes/EtOAc to 1:3 hexanes/EtOAc) provided 33 as a foam (0.008
g, 68%): 1H NMR (500 MHz, CDCl3) δ 8.30 (br s, 1H), 7.61 (d, J )
7.9 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 1H), 7.20 (td, J ) 8.0, 1.0 Hz, 1H),
7.13 (td, J ) 7.9, 1.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1H), 5.92 (m, 1H),
5.80 (m, 1H), 3.58 (d, J ) 5.2 Hz, 1H), 3.30-3.26 (m, 2H), 3.13 (dd,
J ) 14.9, 2.6 Hz, 1H), 2.74 (ddt, J ) 18.1, 5.0, 2.5 Hz, 1H), 2.67 (dd,
J ) 14.8, 10.7 Hz, 1H), 2.43 (m, 2H), 1.39 (d, J ) 6.4 Hz, 3H), 1.19
(d, J ) 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 211.4, 136.2,
130.3, 130.0, 127.5, 122.2, 121.9, 119.3, 118.8, 113.1, 111.2, 66.6,
61.1, 50.2, 49.7, 41.5, 33.6, 22.7, 22.4; IR (thin film) 3411, 3049, 2970,
1760, 1637 cm-1; HRMS (CI/ammonia) m/z calcd for C19H23N2O (M
+ H)+ 295.1810, found 295.1807.
(()-Peduncularine (1). To a cooled (-45 °C) solution of 33 (0.025
g, 0.085 mmol) in 0.5 mL of THF was added Tebbe reagent47 (0.340
mL, 0.34 mmol, 1.0 M in toluene). The reaction mixture was maintained
at -45 °C for 30 min and then slowly warmed to 0 °C over 2.5 h. The
reaction mixture was warmed to 23 °C and stirred for 3 h. The solution
was diluted with 1 mL of THF and treated with 0.2 mL of 15% aqueous
NaOH. After being stirred for 1 h, the heterogeneous mixture was
filtered, and the precipitate was washed with 3 × 5 mL of Et2O. The
filtrates were combined and concentrated in vacuo. Purification by flash
chromatography (75:25 hexanes/EtOAc to 75:25:1 hexanes/EtOAc/
1
NEt3) provided 1 (0.014 g, 56%) as a solid:5,49 mp 145-147 °C; H
NMR (500 MHz, CDCl3) δ 7.98 (br s, 1H), 7.61 (d, J ) 7.9 Hz, 1H),
7.36 (d, J ) 8.1 Hz, 1H), 7.20 (t, J ) 7.5 Hz, 1H), 7.12 (t, J ) 7.5 Hz,
1H), 6.99 (s, 1H), 5.95 (ddt, J ) 9.3, 5.2, 2.0 Hz, 1H), 5.69 (dt, J )
9.3, 2.8 Hz, 1H), 4.95 (s, 1H), 4.82 (s, 1H), 3.84 (d, J ) 5.0 Hz, 1H),
3.00 (septet, J ) 6.2 Hz, 1H), 2.95 (d, J ) 15.4 Hz, 1H), 2.89 (d, J )
11.3 Hz, 1H), 2.71 (dd, J ) 14.7, 11.4 Hz, 1H), 2.50 (br d, J ) 4.1
Hz, 1H), 2.46 (ddt, J ) 17.6, 4.6, 2.4 Hz, 1H), 2.07 (ddt, J ) 17.6,
3.3, 1.7 Hz, 1H), 1.31 (d, J ) 6.3 Hz, 3H), 1.17 (d, J ) 6.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 150.1, 136.2, 130.6, 128.4, 127.8, 122.0,
121.3, 119.3, 119.0, 115.0, 111.0, 101.4, 69.8, 60.4, 50.9, 45.9, 40.1,
34.2, 23.6, 22.7; IR (KBr) 3416, 2969, 1684, 1626 cm-1; HRMS (CI/
ammonia) m/z calcd for C20H24N2 (M)+ 292.1939, found 292.1938.
Acknowledgment. This research was supported by a CA-
REER Award from the National Science Foundation (Grant
CHE-9701622). K.A.W. thanks AstraZeneca, the Camille and
Henry Dreyfus Foundation, Glaxo-Wellcome, Merck Research
Laboratories, Johnson & Johnson, and the Sloan Foundation
for awards to support research. C.W.R. thanks Hoffmann-La
Roche Inc. for support. We thank Dr. John Greaves and Dr.
John Mudd for mass spectrometric data.
Supporting Information Available: Additional experimental
details and selected spectra (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA012152F
(49) Dragar, C.; Bick, I. R. C. Phytochemistry 1992, 31, 3601-3603.
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11348 J. AM. CHEM. SOC. VOL. 124, NO. 38, 2002