Enantioselective total synthesis of (-)-acutumine

Article abstract of DOI:10.1021/jo902006q

(Chemical Equation Presented) An account of the total synthesis of the tetracyclic alkaloid (-)-acutumine is presented. A first-generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity in a radical cyclizat

Full text of DOI:10.1021/jo902006q

pubs.acs.org/joc
Enantioselective Total Synthesis of (-)-Acutumine
Fang Li, Samuel S. Tartakoff, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602
scastle@chem.byu.edu
Received September 16, 2009
An account of the total synthesis of the tetracyclic alkaloid (-)-acutumine is presented. A first-
generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity
in a radical cyclization. However, this work spawned a second-generation strategy in which the
spirocycle was fashioned via a radical-polar crossover reaction. This process merged an intramole-
cular radical conjugate addition with an enolate hydroxylation and created two stereocenters with
excellent diastereoselectivity. The reaction was promoted by irradiation with a sunlamp, and a ditin
reagent was required for aryl radical formation. These facts suggest that the substrate may function as a
sensitizer, thereby facilitatinghomolytic cleavageof theditinreagent. The propellane motif of thetarget
was then installed via annulation of a pyrrolidine ring onto the spirocycle. The sequence of reactions
used included a phenolic oxidation, an asymmetric ketone allylation mediated by Nakamura’s chiral
allylzinc reagent, an anionic oxy-Cope rearrangement, a one-pot ozonolysis-reductive amination, and
a Lewis acid promoted cyclization of an amine onto an R,β-unsaturated dimethyl ketal. Further studies
of the asymmetric ketone allylation demonstrated the ability of the Nakamura reagent to function well
in a mismatched situation. A TiCl4-catalyzed regioselective methyl enol etherification of a 1,3-diketone
completed the synthesis.
Introduction
and the epimeric alcohols dauricumine4 (4), dauricumidine4
(5), and dechlorodauricumine5 (6). Recently, a diethylamino
congener of 4 known as hypserpanine (7) was isolated from
Hypserpa nitida.6 Since the plants from which the acutumine
alkaloids are obtained have been used in traditional Chinese
medicine to treat fever and pain,6,7 it is not surprising that the
pure natural products possess interesting bioactivity. For
example, acutumine is endowed with both selective T-cell
cytotoxicity7 and antiamnesic properties.8
Acutumine (1, Figure 1) is a tetracyclic alkaloid that was
originally isolated by Goto and Sudzuki in 1929 from Sino-
menium acutum.1 Later, Tomita and co-workers obtained 1
from Menispermum dauricum and determined its structure via
X-ray crystallography.2 Other members of the acutumine
family include acutumidine2 (2), dechloroacutumine3 (3),
(1) Goto, K.; Sudzuki, H. Bull. Chem. Soc. Jpn. 1929, 4, 220.
(2) (a) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.;
Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Chem. Pharm. Bull. 1971, 19,
770. (b) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.;
Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 2421.
(c) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.;
Kamiya, K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 2425.
(3) Sugimoto, Y.; Inanaga, S.; Kato, M.; Shimizu, T.; Hakoshima, T.;
Isogai, A. Phytochemistry 1998, 49, 1293.
(5) Sugimoto, Y.; Matsui, M.; Takikawa, H.; Sasaki, M.; Kato, M.
Phytochemistry 2005, 66, 2627.
(6) Cheng, P.; Ma, Y.-b.; Yao, S.-y.; Zhang, Q.; Wang, E.-j.; Yan, M.-h.;
Zhang, X.-m.; Zhang, F.-x.; Chen, J.-j. Bioorg. Med. Chem. Lett. 2007, 17,
5316.
(7) Yu, B.-W.; Chen, J.-Y.; Wang, Y.-P.; Cheng, K.-F.; Li, X.-Y.; Qin,
G.-W. Phytochemistry 2002, 61, 439.
(4) Sugimoto, Y.; Babiker, H. A. A.; Saisho, T.; Furumoto, T.; Inanaga,
S.; Kato, M. J. Org. Chem. 2001, 66, 3299.
(8) Qin, G.-W.; Tang, X.-C.; Lestage, P.; Caignard, D.-H.; Renard, P.
PCT Int. Appl. WO 2004000815, 2003.
9082 J. Org. Chem. 2009, 74, 9082–9093
Published on Web 11/11/2009
DOI: 10.1021/jo902006q
r
2009 American Chemical Society

Li et al.
JOCArticle
SCHEME 1. First-Generation Retrosynthetic Analysis
FIGURE 1. Acutumine (1) and related alkaloids.
The striking molecular architecture of 1 includes a propel-
lane-type system9 and a spirocycle. The cyclopentane ring,
which is common to both of the aforementioned features,
possesses a neopentylic secondary chloride and three contig-
uous quaternary stereocenters including two all-carbon qua-
ternary centers. Shortly after the structure of acutumine was
established, Barton and co-workers postulated that it could be
derived biosynthetically from a benzylisoquinoline alkaloid
via an oxidative phenolic coupling followed by oxidation and
rearrangement steps.10 Recently, synthetic investigations by
Wipf and co-workers have suggested that modifications to the
Barton proposal may be in order.11 Sugimoto and co-workers
have determined that1 is produced in nature from two units of
tyrosine12 and that dechlorodauricumine (6) is the biosyn-
thetic precursor to 1-5.13
Despite the fact that the structure of acutumine was pub-
lished in 1967, it did not attract the attention of the synthetic
community until recently. In2005, our laboratory developed a
route to the propellane core of acutumine in which the
pyrrolidine ring was annulated onto an aromatic precursor.14
Shortly thereafter, Sorensen and Moreau disclosed a concise
sequence featuring a β-elimination-Michael additioncascade
for construction of the propellane subunit.15 Then, we fash-
ioned the spirocycle of 1 via a radical-polar crossover reac-
tion16 and subsequently elaborated this advanced inter-
mediate into the natural product.17 Herein, we provide a full
account of the development and execution of our synthetic
strategy, which culminated in the first total synthesis of
acutumine.
conversion of 8 into 1 was anticipated to be the regioselective
methyl enol etherification of a 1,3-diketone. Simplification
of 8 according to our previously developed pyrrolidine
annulation strategy14 reveals tricycle 9. Key reactions in this
section of the synthesis would include a phenolic oxidation,
an anionic oxy-Cope rearrangement, and an acid-promoted
cyclization of an amine onto an R,β-unsaturated ketal. We
hoped to fashion the spirocycle of 9 via 5-exo-trig radical
cyclization of aryl iodide 10 with trapping of the cyclic
radical intermediate by TEMPO. Cyclization substrate 10
can be dissected into two monocyclic coupling partners:
Weinreb amide 11, and enantiopure vinyl iodide 12. Amide
11 could be obtained by homologation of a benzaldehyde
derivative employed in our isohasubanan alkaloid synth-
esis.18 Vinyl iodide 12 is a single step removed from a known
alcohol19 that has been constructed by a route featuring
enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene.20
Although some precedent existed for the radical cycliza-
tion with TEMPO trapping,21 we had three major concerns
regarding this proposed transformation. First, we were un-
sure if the allylic chloride would survive the radical reaction
conditions. However, we felt that installation of the chloride
would be quite challenging after formation of the neighbor-
ing quaternary spirocyclic carbon, so we elected to introduce
this substituent at an early stage of the synthesis. Second, we
feared that the hindered nature of the trisubstituted alkene
radical acceptor in 10 might force the cyclization to proceed
via a 6-endo rather than the typically favored 5-exo pathway.
Finally, although examination of molecular models sug-
gested that TEMPO trapping of the radical intermediate
on its less-hindered face would deliver the desired adduct 9,
we were hesitant to predict the degree of stereoselectivity that
could be achieved in this reaction.
Results and Discussion
Our initial retrosynthetic analysis of acutumine is depicted
in Scheme 1. Manipulation of the oxygenated functional
groups contained in the cyclopentenone ring of 1 leads to
tetracyclic intermediate 8. The most challenging step in the
(9) For a review on the synthesis of propellane-containing natural
products, see: Pihko, A. J.; Koskinen, A. M. P. Tetrahedron 2005, 61, 8769.
(10) Barton, D. H. R.; Kirby, A. J.; Kirby, G. W. J. Chem. Soc. C 1968,
929.
(11) (a) Waller, D. L.; Stephenson, C. R. J.; Wipf, P. Org. Biomol. Chem.
2007, 5, 58. (b) Matoba, K.; Karibe, N.; Yamazaki, T. Chem. Pharm. Bull.
1984, 32, 2639.
(12) (a) Babiker, H. A. A.; Sugimoto, Y.; Saisho, T.; Inanaga, S.;
Hashimoto, M.; Isogai, A. Biosci. Biotechnol. Biochem. 1999, 63, 515.
(b) Sugimoto, Y.; Uchida, S.; Inanaga, S.; Kimura, Y.; Hashimoto, M.;
Isogai, A. Biosci. Biotechnol. Biochem. 1996, 60, 503.
(13) Sugimoto, Y.; Matsui, M.; Babiker, H. A. A. Phytochemistry 2007,
68, 493.
(18) (a) Nielsen, D. K.; Nielsen, L. L.; Jones, S. B.; Toll, L.; Asplund,
M. C.; Castle, S. L. J. Org. Chem. 2009, 74, 1187. (b) Jones, S. B.; He, L.;
Castle, S. L. Org. Lett. 2006, 8, 3757; correction: Org. Lett. 2009, 11, 785.
(19) Johnson, C. R.; Harikrishnan, L. S.; Golebiowski, A. Tetrahedron
Lett. 1994, 35, 7735.
(14) Reeder, M. D.; Srikanth, G. S. C.; Jones, S. B.; Castle, S. L. Org. Lett.
2005, 7, 1089.
(15) Moreau, R. J.; Sorensen, E. J. Tetrahedron 2007, 63, 6446.
(16) Li, F.; Castle, S. L. Org. Lett. 2007, 9, 4033.
(17) Li, F.; Tartakoff, S. S.; Castle, S. L. J. Am. Chem. Soc. 2009, 131,
6674.
(20) (a) Myers, A. G.; Hammond, M.; Wu, Y. Tetrahedron Lett. 1996, 37,
3083. (b) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth. 1995,
73, 25.
(21) Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271.
J. Org. Chem. Vol. 74, No. 23, 2009 9083

Li et al.
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SCHEME 2. Synthesis of Weinreb Amide 11 and Vinyl Iodide
12
SCHEME 3. Preparation and 6-endo Radical Cyclization of 10
was conducted under Corey’s conditions,26 affording chlori-
de 10 in 43% yield. Presumably, elimination of the chloride
to give the corresponding dienyl benzene species is at least
partially responsible for the low yield of this transformation.
Although its isolation was not pursued, the elimination
product was detected by mass spectrometry. We elected
not to optimize the chlorination, as sufficient quantities of
10 were obtained to permit examination of the radical
cyclization. When exposed to Et3B, air, and Bu3SnH27 at a
low temperature, 10 was transformed into a single tricyclic
product. Unfortunately, spectroscopic studies identified the
adduct as compound 18, product of a 6-endo radical cycliza-
tion instead of the desired 5-exo process. Apparently, steric
hindrance associated with the 5-exo pathway enabled the
typically less favored 6-endo cyclization to proceed. Since the
undesired regioisomer was formed in the cyclization, the
feasibility of trapping with TEMPO was not investigated.
Nevertheless, we were heartened by the fact that the allylic
chloride emerged unscathed from the radical cyclization.
This observation gave us confidence regarding the viability
of a radical-based approach to the acutumine spirocycle, as
long as the required 5-exo pathway could be enforced by
appropriate changes to the substrate.
We reasoned that use of an R,β-unsaturated ketone in-
stead of a simple alkene as radical acceptor would cause the
electron-rich aryl radical to cyclize onto the electron-defi-
cient β-carbon of the enone. This radical conjugate addi-
tion28 could allow us to surmount the steric obstacles
associated with the desired 5-exo cyclization. A modified
retrosynthesis of 1 based on this concept is portrayed in
Scheme 4. We did not envision our new strategy requiring
changes to the final stages of the synthesis; accordingly,
tetracycle 8 was still projected as a key precursor to 1.
However, 8 would now be derived from spirocyclic R-hydro-
xy ketone 19. Removal of the hydroxyl moiety from 19 and
disconnection of the aryl-alkyl C-C bond from the spiro-
cyclic carbon reveals enone 20, substrate for the radical
Our attempt at constructing 1 according to the plan
described above commenced with the preparation of two
coupling partners, Weinreb amide 11 and vinyl iodide 12, as
depicted in Scheme 2. We previously reported the synthesis
of pentasubstituted benzaldehyde 13 in three steps from
4-benzyloxy-2,3-dimethoxybenzaldehyde,18 itself accessible
in two steps from commercially available 2,3-dimethoxyphe-
nol.22 Wittig homologation of 13 provided aldehyde 14,
which underwent oxidation and amidation to afford 11.
Then, silylation of enantiopure alcohol 15, which was ob-
tained from a straightforward eight-step sequence beginning
with cis-3,5-diacetoxycyclopentene,19,20 afforded bis-TBS-
protected vinyl iodide 12.
Coupling of the vinyllithium reagent derived from 12 with
Weinreb amide 11 proceeded in low yield (9%). Although
not investigated in detail, it is likely that competitive deiodi-
nation of 11 was a prominent side reaction. Formation of the
corresponding vinylmagnesium reagent by treating 12 with
PhMgBr, PhCH2MgBr, or allylMgBr was a very sluggish
process. Fortunately, the protocol of Knochel and co-work-
ers, which utilizes the complex i-PrMgCl LiCl in conjunc-
3
tion with 15-crown-5,23 generated the desired Grignard
reagent from 12 in a reasonable time frame (ca. 1 h).
Addition of this species to 11 provided enone 16 in moderate
yield (Scheme 3). Then, a diastereoselective reduction of 16
was accomplished by enlisting the Corey-Bakshi-Shibata
(CBS) catalyst.24 The configuration of the newly formed
stereocenter of alcohol 17 was assigned by Mosher ester
analysis.25 The minor diastereomer was partially separable
from 17, and it could be completely removed after the
following step. Next, SN2 chlorination of the allylic alcohol
(22) Kurosawa, K.; Ollis, W. D.; Sutherland, I. O.; Gottlieb, O. R.;
De Oliveira, A. B. Phytochemistry 1978, 17, 1389.
(23) (a) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 159. (b) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun.
2005, 543. (c) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333.
(24) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(25) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(26) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,
4339.
(27) Ishibashi, H.; Inomata, M.; Ohba, M.; Ikeda, M. Tetrahedron Lett.
1999, 40, 1149.
(28) For reviews of radical conjugate additions, see: (a) Srikanth,
G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377. (b) Zhang, W. Tetra-
hedron 2001, 57, 7237.
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Li et al.
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SCHEME 4. Second-Generation Retrosynthetic Analysis
FIGURE 2. Proposed stereocontrol in enolate hydroxylation.
SCHEME 5. Synthesis of Vinyl Iodide 21
cyclization. Instead of relying on TEMPO trapping to install
the hydroxyl group, we planned to take advantage of the
R-keto radical intermediate that would form upon 5-exo-trig
cyclization of 20. These species are known to react with
reagents such as Et3B,29 Et2Zn,30 and Et3Al31 to generate
enolates, which can then participate as nucleophiles in polar
reactions. The three-step sequence of a radical process,
conversion of a radical intermediate to a polar intermediate,
and a polar process has been termed a radical-polar cross-
over reaction by Murphy.32 Thus, the transformation of 20
into 19 would constitute a radical-polar crossover reaction
that merges an intramolecular radical conjugate addition
the enolate. As a result, the hydroxyl group would likely be
delivered to the si face. Consequently, it appeared that, out of
four possibilities, the desired isomer of 19 would predomi-
nate in the planned radical-polar crossover reaction of 20.
We envisioned preparing substrate 20 via the same Wein-
reb amide-Grignard reagent coupling employed in the
previous route (Scheme 3). In fact, the identical Weinreb
amide (11) would be used in this case. However, construction
of the enone moiety required a vinyl iodide in which the two
hydroxyl groups were differentiated. Therefore, vinyl iodide
21 would be employed in place of 12.
The synthesis of 21, which largely parallels the known
route19,20 used to prepare 12, is shown in Scheme 5. Protec-
tion of enantiopure alcohol 22 (available in three steps from
cis-3,5-diacetoxycyclopentene)20 as a TES ether afforded 23,
which was subjected to pivaloate cleavage with DIBAL-H,
providing alcohol 24. Oxidation followed by iodination19
delivered R-iodo enone 26. Then, Luche reduction35 and
masking of the resulting alcohol as a TBS ether gave 21, in
which the two hydroxyl groups are differentiated.
with an enolate hydroxylation.33 A report by Kunz and Ruck
€
provided encouraging precedent, but successful reactions in
their study were limited to intermolecular conjugate addi-
tions of methyl radicals generated by homolysis of Me2AlCl
to R,β-unsaturated N-acyl oxazolidinones. Moreover, the
diastereoselectivity of the reaction was low.34 Clearly, a new
protocol would be required to enable the stereoselective
formation of 19 from 20.
In the proposed cyclization-hydroxylation of 20, two new
stereocenters would be formed. We hypothesized that the
bulky silyloxy group would direct the aryl radical to the
opposite face of the enone, thereby setting the spirocyclic
carbon in the proper configuration. Then, examination of
molecular models suggested that the aryl group would shield
the re face of the putative enolate intermediate, whereas the
neighboring chlorine atom would protrude away from the si
face (Figure 2). The pseudoequatorial orientation of the silyl
ether would minimize its impact on the steric environment of
Coupling of the Grignard reagent derived from 21 with
Weinreb amide 11 provided enone 28 (Scheme 6). As before,
Knochel’s procedure23 was essential to obtaining reproduci-
ble yields. The CBS reduction of 28 proceeded under care-
fully optimized conditions (28/CBS cat./BH3 THF =
3
1.0:0.2:1.2, -10 °C, e4 h) to give allylic alcohol 29 in 89%
yield and 9:1 dr. The configuration of the hydroxyl-bearing
carbon was determined by Mosher ester analysis and was
consistent with the CBS reduction of 16 (Scheme 3).25 The
next transformation, SN2 chlorination of 29, afforded low
and variable yields when the Corey protocol26 was em-
ployed, presumably as a result of elimination of HCl from
the product 30. Fortunately, consistent results with minimal
elimination could be achieved by enlisting MsCl and Et3N.36
(29) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403. (b) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
1041. (c) Chandrasekhar, S.; Narsihmulu, C.; Reddy, N. R.; Reddy, M. S.
Tetrahedron Lett. 2003, 44, 2583.
(30) (a) Bazin, S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. Tetrahedron
2005, 61, 4261. (b) Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.; Bertrand,
M. P. Chem. Commun. 2002, 2506. (c) Miyabe, H.; Asada, R.; Takemoto, Y.
Tetrahedron 2005, 61, 385. (d) Miyabe, H.; Asada, R.; Yoshida, K.; Takemoto,
Y. Synlett 2004, 540.
(31) Liu, J.-Y.; Jang, Y.-J.; Lin, W.-W.; Liu, J.-T.; Yao, C.-F. J. Org.
Chem. 2003, 68, 4030.
(32) (a) Murphy, J. A. In Radicals in Organic Synthesis; Renaud, P.; Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 298-315. (b) For a recent
review, see: Godineau, E.; Landais, Y. Chem.;Eur. J. 2009, 15, 3044.
(33) For a review of enolate R-hydroxylations, see: Chen, B.-C.; Zhou, P.;
Davis, F. A.; Ciganek, E. Org. React. (N.Y.) 2003, 62, 1.
(35) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(36) Artman, G. D. III; Grubbs, A. W.; Williams, R. M. J. Am. Chem.
Soc. 2007, 129, 6336.
€
(34) Ruck, K.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 694.
J. Org. Chem. Vol. 74, No. 23, 2009 9085

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SCHEME 6. Synthesis of Enone 20
TABLE 1. Radical-Polar Crossover Reaction of 20
entry reagent (equiv) oxidant (equiv)
solvent
THF
THF
THF
THF
19/32/33 (%)
1
2
3
4
Et3B (1)
Et3B (1)
O2
21/20/19
16/18/24
28/23/5
20/18/3
29/27/17
33/22/19
25/11/9
62/7/3
34/3/27
12/-/-
42/11/3
40/9/13
DMDO (10)
O2
DMDO (10)
Et2Zn (4)
Et2Zn (4)
Et2Zn (4)
Et3Al (1)
Et3Al (1)
Et3Al (3)
Et3Al (3)
Et3Al (3)
Et3Al (3)
Et3Al (3)
Et3Al (3)
Et3Al (1)
Et3Al (5)
5
oxaziridineb (4) THF
6
7
8
O2
THF
THF
oxaziridine (5) THF
DMDO (10)
9
t-BuOOH (5)
(Me3SiO)2
oxaziridine (5) CH2Cl2
oxaziridine (5) PhCF3
oxaziridine (5) THF/PhH 1:1 47/10/5
oxaziridine (1) THF
oxaziridine (10) THF
THF
THF
10
11
12
13
14
15
SCHEME 7. Asymmetric Nozaki-Hiyama-Kishi Coupling
9/4/-
45/6/4
aA sunlamp was used. b3-Phenyl-2-(phenylsulfonyl)-oxaziridine.
emerged as superior to O2,40 DMDO,41 t-BuOOH,42 or
(Me3SiO)2.43 After varying other parameters, we established
the optimal conditions listed in entry 8. The R-hydroxy ketone
19 was obtained in 62% yield, along with iodide 32 (7%) and
reduced compound 33 (3%). Thus, the yields of the cyclization
and hydroxylation steps were 72% and 86%, respectively.
Importantly, no diastereomers of 19, 32, or 33 were detected
in the reaction mixture, and consistent results were obtained
when the reaction was conducted on a preparative scale (59%
yield of 19 on >100 mg scale). Ketone 33 is likely produced by
reduction of the R-keto radical intermediate or protonation of
the enolate intermediate. However, the origin of iodide 32 is
less certain. It is possible that I• or I2, both of which would be
present if the aryl iodide is cleaved directly via photolysis (vide
infra), could react with the R-keto radical intermediate to
create this byproduct. Alternatively, the R-keto radical or the
enolate may react with either Bu3SnI (presumably generated by
iodine atom abstraction from 20 by Bu3Sn•) or an electrophilic
species formed upon in situ oxidation of Bu3SnI44 to form 32.
The configurations of the two stereocenters formed in the
radical-polar crossover reaction were assigned with the aid
of NOE experiments conducted on a PMB ether derivative of
19. The diagnostic correlations are illustrated in Figure 3.
These assignments were ultimately confirmed by the conver-
sion of 19 into (-)-1 and are consistent with the reaction
pathway proposed above (see Figure 2).
Then, the TES group of 30 was selectively removed with
HF pyridine, and oxidation of the resulting alcohol 31
afforded enone 20.
3
Later, we attempted to streamline the route to 20 by
examining the asymmetric Nozaki-Hiyama-Kishi cou-
pling37 of vinyl iodide 21 with aldehyde 14 (Scheme 7). Allylic
alcohol 29 could be obtained directly from this reaction.
Unfortunately, the yield and dr remained low despite at-
tempts at optimization. Since this more direct pathway was
less efficient, we continued to use the route depicted in
Scheme 6 to construct enone 20.
At this point, we commenced our investigation of the
radical-polar crossover reaction, which is summarized in
Table 1. Since tin radicals are commonly employed to
generate aryl radicals,27 we included hexabutylditin, which
functions as a source of tin radicals under nonreducing
conditions, in the reaction mixture. We found that the
desired cascade process occurred upon photolysis with a
simple sunlamp at 0 °C.38 Efforts to discover the optimal
promoter for the radical-polar crossover step revealed that
Et3Al31 was more effective than Et3B29 or Et2Zn30 (cf. entry 6
vs entries 1 and 3 or entry 7 vs entries 2 and 4). As for the
hydroxylating agent, 3-phenyl-2-(phenylsulfonyl)oxaziridine39
To improve the overall efficiency of the process, we
explored the conversion of iodide 32 into R-hydroxy ketone
19. In principle, this transformation could be accomplished
(37) (a) Wan, Z.-K.; Choi, H.-w.; Kang, F.-A.; Nakajima, K.; Demeke,
D.; Kishi, Y. Org. Lett. 2002, 4, 4431. (b) Kurosu, M.; Lin, M.-H.; Kishi, Y.
J. Am. Chem. Soc. 2004, 126, 12248.
(38) Frequent addition of ice to the cooling bath was necessary to
maintain this temperature in the presence of a sunlamp.
€
(42) Schulz, M.; Kluge, R.; Schussler, M.; Hoffmann, G. Tetrahedron
1995, 51, 3175.
(39) Davis, F. A.; Vishawakarma, L. C.; Billmers, J. G.; Finn, J. J. Org.
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M.; Prechtl, F. J. Org. Chem. 1994, 59, 2358.
(43) (a) Camici, L.; Dembech, P.; Ricci, A.; Seconi, G.; Taddei, M.
Tetrahedron 1988, 44, 4197. (b) Dahnke, K. R.; Paquette, L. A. J. Org.
Chem. 1994, 59, 885.
(44) For related observations with Bu3SnBr, see: Blaszykowski, C.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2003, 5, 1341.
9086 J. Org. Chem. Vol. 74, No. 23, 2009

Li et al.
JOCArticle
reactions run in the absence of hexabutylditin did not
proceed, and starting material was recovered. Although
further study is required to more fully elucidate the mechan-
ism of the radical-polar crossover reaction, this observation
indicates that the ditin reagent is instrumental in generating
the aryl radical intermediate from 20 and is not merely
functioning as an iodine trap. Thus, the enone moiety of 20
may be mediating homolytic cleavage of hexabutylditin by
functioning as a sensitizer, as posited above. Another possi-
bility is that coordination of the iodine atom in 20 to the ditin
reagent weakens the C-I and/or Sn-Sn bonds, thereby
facilitating the photolysis.48
FIGURE 3. Diagnostic NOE enhancements.
SCHEME 8. Conversion of Byproduct 32 into 19
Before we could fashion the propellane system of acutu-
mine, some routine functional group manipulations of spiro-
cycle 19 were necessary. Although the carbonyl carbon of
this intermediate is maintained at the same oxidation state in
1, the incompatibility of a ketone at this position with an
upcoming allylation reaction required us to perform a re-
duction-protection sequence. Accordingly, treatment of 19
with L-Selectride provided diol 34 in 9:1 dr (Scheme 9). The
cis relative stereochemistry of the diol moiety was assigned
on the basis of the coupling constant (6.6 Hz) measured for
the two R-hydroxy hydrogen atoms.49 This configuration is
consistent with attack of the bulky reducing agent on the less
hindered si face of the ketone or the face opposite the
neighboring OTBS, hydroxyl, and chloro substituents. A
stereoselective reduction of 19 was not essential, since the
alcohol would be oxidized in the final stages of the synthesis.
However, the isolation and characterization of intermediates
was simplified by working with diastereomerically pure
compounds, so the L-Selectride protocol was beneficial.
Then, the more accessible secondary alcohol of 34 was
selectively silylated. Subsequent cleavage of the benzyl ether
of 35 via hydrogenolysis afforded phenol 36.
Using a sequence of reactions devised with a model com-
pound,14 phenol 36 was transformed into amine42 as outlined
in Scheme 10. Phenolic oxidation of 36 by PhI(OAc)2 in
MeOH delivered masked o-benzoquinone 37. Masked
o-benzoquinones have great utility in organic synthesis due
to the density of functionality that is contained in a single six-
membered ring.50 We planned on utilizing each of the func-
tional groups (enone, dimethyl ketal, methyl enol ether)
created in the phenolic oxidation to complete the synthesis
of 1. Thus, this reaction was one of the cornerstones of our
strategy. Then, the neopentylic alcohol of 37 was benzylated
in preparation for the crucial asymmetric ketone allylation.
Examination of molecular models of 38 revealed that the
refaceofthe ketonewas slightly less congested than the siface.
However, the difference in steric hindrance between the two
diastereotopic faces appeared to be minor. Consequently, we
postulated that substrate-directed stereocontrol would be
minimal and that catalyst or reagent control would be
required to accomplish the allylation. During the course of
our synthesis of isohasubanan alkaloids, we discovered that
Nakamura’s chiral allylzinc reagent (S,S)-3951 was uniquely
via a radical-polar crossover reaction consisting of R-keto
radical formation, enolate generation, and hydroxylation. In
practice, the use of Et2Zn/O2 in conjunction with the oxaziri-
dine provided 19 in 62% yield (Scheme 8). This raised the
overall yield of 19 from 20 to 66%. Interestingly, the use of
Et3Al in place of Et2Zn afforded lower yields (40%).
We also examined the possibility of using SmI2/HMPA45
instead of hexabutylditin to generate the aryl radical in the
radical-polar crossover reaction. R-Hydroxy ketone 19 was
produced in low yields (ca. 15%) from these reactions, along
with 32, 33, and several other uncharacterized byproducts.
This negative outcome is likely a result of the number of
functional groups (aryl iodide, enone, allylic chloride) in 20
that are capable of reacting with SmI2.
As we pondered the role of the ditin reagent in the
radical-polar crossover reaction, we were intrigued by the
fact that the process utilized photochemical initiation. Hexa-
butylditin does not absorb light (λmax = 236 nm); accord-
ingly, photolytic reactions that employ this reagent typically
require a sensitizer.46 However, the conversion of 20 into 19
proceeds in the absence of typical sensitizing agents. Accord-
ingly, we considered two possible roles for the ditin species.
First, the enone moiety of 20 could act as a sensitizer and
mediate the homolytic cleavage of hexabutylditin into two
tributyltin radicals. Then, abstraction of the aryl iodide by
Bu3Sn• would initiate the radical-polar crossover reaction.
Alternatively, the aryl iodide might be cleaved directly by
photolysis. In this scenario, the ditin reagent would function
as an iodine trap, thereby preventing iodine radicals from
reacting with subsequent intermediates.47 If hexabutylditin
is involved in trapping iodine but not in aryl radical forma-
tion, then omitting it from the reaction mixture should
result in atom transfer cyclization47 due to the presence of
untrapped I•. In fact, the formation of R-iodo ketone 32 as a
byproduct lends some credence to the idea that the aryl
radical is formed by direct photolysis of 20. However,
(45) (a) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.; Tanaka, T. J. Org.
Chem. 2008, 73, 7145. (b) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T.
Chem. Commun. 2004, 2228.
(46) Harendza, M.; Junggebauer, J.; Lessmann, K.; Neumann, W. P.;
Tews, H. Synlett 1993, 286.
(48) We thank a reviewer for this suggestion.
(49) (a) Hartung, R. E.; Paquette, L. A. Synthesis 2005, 3209. (b) Christol,
H.; Vanel, R. Bull. Soc. Chim. Fr. 1968, 1393.
(50) For a review, see: Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem.
Rev. 2004, 104, 1383.
(47) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1989, 111,
6265.
(51) Nakamura, M.; Hirai, A.; Sogi, M.; Nakamura, E. J. Am. Chem. Soc.
1998, 120, 5846.
J. Org. Chem. Vol. 74, No. 23, 2009 9087

Li et al.
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SCHEME 9. Synthesis of Phenol 36
FIGURE 4. Proposed transition state for allylation of 38.
TABLE 2. Allylations of Ketone 38
SCHEME 10. Preparation of Amine 42
entry
reagent
yield (%)
40:400
1
2
3
(S,S)-39
allylMgBr
(R,R)-39
79
88
70
93:7
70:30
13:87
assignment based on this reasoning was eventually confirmed
by conversion of 40 into (-)-1.
To ascertain the degree of substrate-directed stereocontrol
and determine the prospects for reagent control with 39 in a
mismatched case, we performed two additional allylations of
38. These experiments are described in Table 2 along with the
allylation discussed above. The use of allylmagnesium bro-
mide in place of (S,S)-39 afforded a 70:30 mixture of 40
and its diastereomer 400 (entry 2), thereby confirming our
hypothesis regarding moderate levels of stereocontrol by the
substrate. Interestingly, allylation with (R,R)-39, the enan-
tiomeric Nakamura reagent, delivered 400 as the major
product in good yield and dr (entry 3). Thus, (R,R)-39 is
able to overcome the mismatched stereochemistry of 38,
albeit with slighty reduced yield and dr. The performance
of the Nakamura reagent in this work and in our isohasu-
banan alkaloid synthesis18a demonstrates that its scope is not
limited to the alkynyl ketones for which it was designed.51
Studies to determine the types of ketones amenable to
asymmetric allylation by 39 are in progress and will be the
subject of a future report.
Exposure of 40 to KOt-Bu and 18-crown-6 triggered an
anionic oxy-Cope rearrangement that produced ketone 41 in
excellent yield (92%, Scheme 10). Notably, this reaction was
capable of forming an extremely congested C-C bond at
0 °C. The facile nature of this process is likely a consequence
of conjugation of the trisubstituted double bond with the
methyl enol ether. Such conjugation has previously been
noted to accelerate anionic oxy-Cope rearrangements.53 The
allylation-anionic oxy-Cope sequence accomplishes a for-
mal conjugate addition of an allyl group to enone 38. The
direct 1,4-addition was not attempted due to discouraging
results with model compounds.54
effective in enantioselective allylations of achiral ketones
related to 38.18a We were pleased to discover that allylation
of 38 with (S,S)-39 proceeded in good yield (79%) and dr
(93:7) to afford homoallylic alcohol 40. Although an excess of
39 (1.6 equiv) was required to ensure a reasonable reaction
rate with the bulky ketone, the pure bisoxazoline ligand could
be reisolated from the reaction mixture.52 The configuration
of the newly formed stereocenter in alcohol 40 was tentatively
assigned by considering the six-membered cyclic transition
state for the asymmetric ketone allylation proposed by
Nakamura and co-workers51 (Figure 4). The dimethyl ketal
of 38 likely occupies an equatorial position on the ring, which
causes the sp2 alkene carbon to reside in an axial position. The
ability of the phenyl groups on the bisoxazoline ligand to
avoid steric interactions with the substrate in the orientation
shown leads to excellent facial selectivity. The stereochemical
(52) The bisoxazoline ligand is obtained as a Zn complex after chroma-
tography and can be decomplexed according to the procedure of Nakamura
and co-workers: Nakamura, M.; Arai, M.; Nakamura, E. J. Am. Chem. Soc.
1995, 117, 1179.
(53) Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003,
5, 3631.
(54) Reeder, M. D. M.S. Thesis, Brigham Young University, 2004.
9088 J. Org. Chem. Vol. 74, No. 23, 2009

Li et al.
We approached the next step, oxidative cleavage of 41
JOCArticle
TABLE 3. Development of Cyclization Conditions in Model System
followed by reductive amination of the crude aldehyde, with
some trepidation due to problems encountered in the model
studies. Specifically, ozonolysis of a compound analogous to
41 was plagued by competitive oxidation of the methyl enol
ether. Dihydroxylation was possible, but oxidative cleavage
of the resulting diol was unsuccessful.14 These challenges
persisted, as treatment of 41 with OsO4/NaIO4 returned
negligible quantities (ca. 10%) of the aldehyde. Similarly
poor results were obtained from ozonolysis reactions con-
ducted by bubbling O3 through the reaction mixture. Nu-
merous byproducts were generated, and it became apparent
that a method of controlling the stoichiometry of O3 was
required. We were intrigued by a report from Wender and
co-workers describing the use of standard solutions of O3.55
In the model system, we found EtOAc to be the most
effective solvent for the ozonolysis.14 Accordingly, we deter-
mined the concentration of a saturated solution of O3 in
EtOAc to be 0.007 M by titration with styrene.55 Addition of
1.5 equiv of O3 from this solution to a solution of 41 in
EtOAc provided ca. 30% of the aldehyde, along with 30% of
recovered 41. Greater quantities of O3 gave lower yields due
to increased byproduct formation. Fortunately, a significant
improvement was achieved by including pyridine in the
reaction mixture. This additive has been shown to modulate
the reactivity of O3.56 The best results (54% yield of amine
42, 27% recovery of 41) were obtained by adding 1.5 equiv of
O3 via standard solution to a solution of 41, pyridine, and
Et3N in EtOAc, and then conducting the reductive amina-
tion in the same pot. Amine 42 and recovered alkene 41 were
readily separable on SiO2.
The cyclization of amine 42 to give the tetracyclic frame-
work of acutumine was projected to occur via acid-promoted
ionization of the dimethyl ketal and subsequent attack of the
amine at the β-carbon of the resulting R,β-unsaturated
oxonium ion intermediate.57 In our synthesis of a model
system representing the propellane core of 1, we discovered
that TMSOTf could mediate this reaction, affording mod-
erate yields (50%) of the desired product.14 Unfortunately,
application of these conditions to the highly functionalized
substrate 42 induced decomposition, and the desired tetra-
cycle was only produced in trace amounts (<10%). Since we
possessed limited quantities of 42, we returned to the more
readily available model compound 43 in order to develop
alternative conditions for the cyclization (Table 3). In our
prior investigation, we found that enol 44, not the corres-
ponding ketone, was produced by cyclization of 43. We
believe that the combination of a stabilizing intramolecular
hydrogen bond in the enol and destabilizing steric interac-
tions in the ketone are responsible for this phenomenon.14
Our study of the cyclization of 43 is summarized in Table 3.
A brief survey of Brønsted acids (entries 1-4) showed that
reasonable yields of 44 could be obtained with TFA at 0 °C
(entry 2). Similar conditions led toan undesired rearrangement
in our attempted synthesis of hasubanan alkaloids, produc-
ing unnatural compounds that we refer to as isohasubanan
entry
conditionsa
productb
1
2
3
4
5
6
7
8
TFA (5 equiv), CH2Cl2
TFA (5 equiv), CH2Cl2, 0 °C
HCl (2 equiv), MeOH
44 (31);
44 (41);
45 (10);
44 (12);
44 (19)c
44 (27);
44 (39);
44 (38);
44 (35);
44 (39);
44 (41);
44 (37);
44 (27);
44 (31);
44 (40);
HOAc (3 equiv), MeOH
BCl3 (1 equiv), CH2Cl2
BCl3 (2 equiv), CH2Cl2
BCl3 (3 equiv), CH2Cl2
BCl3 (4 equiv), CH2Cl2
BCl3 (3 equiv), CH2Cl2, 0 °C
BCl3 (3 equiv), CH2Cl2, -15 °C
BCl3 (3 equiv), CH2Cl2, -40 °C
BCl3 (3 equiv), CH2Cl2, -78 °C
HFIP,d 0 °C
9
10
11
12
13
14
15
HFIP, -40 °C
BCl3 (3 equiv), HFIP, -40 °C
aReactions were conducted at room temperature in the presence of
4 A MS unless otherwise indicated. Percent yield is given in parentheses.
b
˚
c27% of 43 was recovered. d1,1,1,3,3,3-Hexafluoro-2-propanol.
alkaloids.18 These contrasting results reflect subtle differences
in the structures of the acutumine and hasubanan alkaloids.
Surpisingly, the use of HCl afforded low yields of hemiaminal
45 (entry 3). It is unclear why 45 was only detected under these
conditions and not in any other reactions. Switching to the
Lewis acid BCl3 yielded promising results, and detailed opti-
mization established the superiority of the conditions listed in
entry 11. Interestingly, use of the solvent hexafluoroisopropa-
nol (HFIP) without any added Lewis or Brønsted acid58
resulted in modest yields of 44 (entries 13 and 14). However,
substitution of HFIP for CH2Cl2 as solvent in the optimized
BCl3 conditions did not improve the yield further (cf. entries 11
˚
and 15). In all cases, 4 A MS were employed to suppress
cleavage of the acid-sensitive methyl enol ether of 43.
TFA and BCl3 emerged from this study as the reagents of
choice for the key cyclization reaction. Accordingly, both
were evaluated in the cyclization of amine 42. We recognized
that 42 was likely to be more acid-sensitive than the simpler
compound 43; consequently, we employed slightly milder
conditions than were optimal in the model study. When 42
was exposed to TFA at -10 °C, the desired tetracycle 46 was
1
detected by H NMR and MS. Unfortunately, it was pro-
duced in low yield (<40%) and alongside an inseparable
byproduct that was not identified. Fortunately, BCl3 (1.5
equiv) at -40 °C afforded better results, as pure 46 could be
isolated in 45% yield (Scheme 11). The modest outcome of
this cyclization is likely a consequence of the congested
nature of the C-N bond which is formed combined with
the acid sensitivity of substrate 42.
The elaboration of 46 into 1 commenced with TBAF-
mediated cleavage of the two TBS ethers. The resulting diol
was surprisingly unstable, so it was immediately converted
into the isolable 1,3-diketone 47 by treatment with TPAP and
NMO. Then, hydrogenolysis of the benzyl ether proceeded in
(55) Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am. Chem.
Soc. 2008, 130, 6658.
(56) (a) Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M. Angew. Chem.,
Int. Ed. 2008, 47, 7314. (b) Slomp, G., Jr.; Johnson, J. L. J. Am. Chem. Soc.
1958, 80, 915.
(58) Ratnikov, M. O.; Tumanov, V. V.; Smit, W. A. Angew. Chem., Int.
Ed. 2008, 47, 9739.
(57) Yasui, Y.; Koga, Y.; Suzuki, K.; Matsumoto, T. Synlett 2004, 615.
J. Org. Chem. Vol. 74, No. 23, 2009 9089

Li et al.
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SCHEME 11. Completion of Total Synthesis of 1
sample of 1 produced by this route was identical to an
authentic natural sample of acutumine as evidenced by spec-
troscopic and chromatographic techniques.
Conclusions
We have achieved the enantioselective total synthesis of
(-)-acutumine (1). A first-generation approach to the spiro-
cyclic subunit based on a 5-exo aryl radical cyclization with
TEMPO trapping was unsuccessful, as the 6-endo pathway
prevailed. However, this result paved the way for a successful
second-generation strategy featuring a novel radical-polar
crossover reaction for construction of the spirocycle. This
cascade process comprised a 5-exo intramolecular conjugate
addition of an aryl radical onto an enone acceptor, conver-
sion of the resulting R-keto radical into an enolate, and
hydroxylation of the enolate. Both the radical cyclization
and enolate hydroxylation steps were highly stereoselective,
and a single product was generated that possessed the
requisite stereochemistry for conversion into 1. The reaction
was conducted under irradiation by a sunlamp, yet the ditin
reagent that was required for aryl radical formation does not
possess a chromophore. Thus, it is possible that the enone
moiety of the substrate may function as a sensitizing agent.
Alternatively, complexation of the aryl iodide with the ditin
reagent may facilitate photolysis.
The tetracyclic framework of the natural product was then
fashioned by annulation of a pyrrolidine ring onto the
spirocycle. The annulation sequence consisted of a phenolic
oxidation, a diastereoselective ketone allylation utilizing
Nakamura’s chiral allylzinc reagent, an anionic oxy-Cope
rearrangement, a one-pot ozonolysis-reductive amination,
and a Lewis acid promoted cyclization of an amine onto an
R,β-unsaturated dimethyl ketal. Further studies of the asym-
metric ketone allylation revealed the ability of the Nakamura
reagent to control the stereochemistry of the reaction in a
mismatched case. The successful cyclization conditions
(BCl3, CH2Cl2, -40 °C) were discovered by extensive opti-
mization of a model reaction. Finally, elaboration of the
tetracycle into 1 required four steps, including the TiCl4-
mediated regioselective methyl enol etherification of a 1,3-
diketone. We are hopeful that the methods that were devel-
oped and refined in the course of this venture will find
application in the synthesis of other complex molecules.
virtually quantitative yield without competitive reduction of
the tetrasubstituted alkene or the alkyl chloride. This facile
reaction delivered alcohol 48, the immediate precursor to
acutumine.
A multitude of protocols exist for the conversion of 1,3-
diketones into β-keto enol ethers, encompassing basic,59
Lewis acidic,60 and neutral (CH2N2)61 conditions. None-
theless, we were unsure of the prospects for a regioselective
transformation of 48 into 1. The outcomes of O-methyla-
tions of asymmetric 1,3-diketones are difficult to predict, and
equimolar mixtures of the two regioisomeric products are
often produced.61a After considering the various procedures
available, we were attracted to the method of Porta and
co-workers, which employs catalytic quantities of TiCl4 in
MeOH. This protocol was modestly selective (ca. 3:1 ratio of
products) for generation of the less hindered enol ether from
an asymmetric cyclic 1,3-diketone.60a We were also mindful
of the report by Danishefsky and co-workers of a regiose-
lective methyl enol etherification with CH2N2,61b although
the complete lack of selectivity observed by Pettus and Wang
with this reagent61a provides a sobering contrast. Unfortu-
nately, our experience resembled that of Pettus and Wang, as
exposure of 48 to CH2N2 provided 40% of 1 along with 35%
of its enol ether regioisomer 49. However, switching to
TiCl4/MeOH yielded a more favorable 3.7:1 ratio in favor
of 1. The overall yield of this reaction (66%) was lower, but
the isolated yield of 1 (52%) was greater. Accordingly, we
employed the Porta methodology in our efforts. The synthetic
Experimental Section
r-Hydroxy Ketone 19. A solution of 20 (107 mg, 0.166 mmol)
in anhydrous THF (1.5 mL) at 0 °C was treated with hexabu-
tylditin (89 μL, 102 mg, 0.168 mmol) and triethylaluminum
(1.0 M solution in THF, 490 μL, 0.49 mmol). The resultant
mixture was irradiated at 0 °C with a 660 W sunlamp for 6 h
(frequent addition of ice to the cooling bath was necessary to
maintain this temperature). Then, 3-phenyl-2-(phenylsulfonyl)-
oxaziridine39 (ca. 0.5 M solution in THF, 1.53 mL, 0.765 mmol)
was added to the mixture, and it was stirred at 0 °C (without
irradiation) for 5 h, then at rt for 2 h. The resultant mixture was
extracted with EtOAc (3 ꢀ 5 mL), dried (MgSO4), and concen-
trated in vacuo. Flash chromatography (SiO2, 1.5 ꢀ 14 cm,
10-15% EtOAc in hexanes gradient elution) afforded 19
(59) (a) Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.;
ꢀ
Blake, A. J. J. Org. Chem. 2007, 72, 4803. (b) Liang, H.; Schule, A.; Vors,
J.-P.; Ciufolini, M. A. Org. Lett. 2007, 9, 4119.
(60) (a) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
(b) Bhosale, R. S.; Bhosale, S. V.; Bhosale, S. V.; Wang, T.; Zubaidha, P. K.
Tetrahedron Lett. 2004, 45, 7187. (c) Curini, M.; Epifano, F.; Genovese, S.
Tetrahedron Lett. 2006, 47, 4697. (d) Banerjee, B.; Mandal, S. K.; Roy, S. C.
Chem. Lett. 2006, 35, 16.
(61) (a) Wang, J.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 5895.
(b) Tsukano, C.; Siegel, D. R.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2007, 46, 8840.
(52.7 mg, 0.0989 mmol, 59%) as a colorless oil: [R]25 þ26
D
(c 0.23, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.53-7.32 (m,
6H), 5.06 (s, 2H), 4.82 (t, J = 7.2 Hz, 1H), 4.45 (t, J = 6.6 Hz,
1H), 4.25 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.99 (d, J = 6.9 Hz,
9090 J. Org. Chem. Vol. 74, No. 23, 2009

Li et al.
JOCArticle
1H), 2.91 (d, J = 6.6 Hz, 1H), 2.62 (d, J = 6.9 Hz, 1H), 2.02 (d,
J = 7.2 Hz, 1H), 1.51 (br s, 1H), 0.93 (s, 9H), 0.13 (s, 3H), 0.11 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 207.5, 149.7, 149.6, 146.4,
142.5, 134.8, 127.8 (2C), 127.3, 126.4 (2C), 121.8, 103.4, 92.2,
72.1, 66.2, 64.2, 63.8, 63.1, 49.7, 42.7, 38.8, 22.2 (3C), 16.1, -4.9,
-5.0; DEPT NMR (CDCl3, 75 MHz) C 207.5, 149.7, 149.6,
146.4, 142.5, 134.8, 121.8, 64.2, 16.1; CH 127.8, 127.3, 126.4,
103.4, 92.2, 66.2, 49.7; CH2 72.1, 42.7, 38.8; CH3 63.8, 63.1, 22.2,
-4.9, -5.0; 2D 1H-1H COSY NMR (CDCl3, 500 MHz) 4.82/
reducing agent to the top (re) face of the carbonyl, which would
afford the trans isomer, is hindered by the neighboring chloride
substituent.
(þ)-(1R,2S,20S,3R,5S)-60-(Benzyloxy)-3,5-bis(tert-butyldimethyl-
silyloxy)-20-chloro-40,50-dimethoxy-20,30-dihydrospiro[cyclopentane-
1,10-inden]-2-ol (35). A solution of 34 (140 mg, 0.262 mmol) in
anhydrous CH2Cl2 (5.0 mL) under Ar was treated with Et3N
(450μL), then cooled to 0 °C. TBS-Cl (59 mg, 0.39 mmol, 1.5 equiv)
was added portionwise to the mixture, and it was stirred at 0 °C for
2 h, then at rt for 1 h. The resultant mixture was diluted with EtOAc
(5 mL), treated with satd aq NH4Cl (3 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (3 ꢀ
5 mL), dried (MgSO4), and concentrated in vacuo. Flash chroma-
tography (SiO2, 2.5 cm ꢀ 10 cm, 7.5% EtOAc-hexanes elution)
afforded 35 (148 mg, 0.228 mmol, 87%) as a light yellow oil:
1
2.62 (s), 4.82/2.11 (s), 4.45/2.99 (s), 4.45/2.91 (s); 2D H-13C
HMQC NMR (CDCl3, 500 MHz) 7.53-7.32/127.8, 7.53-7.32/
127.3, 7.53-7.32/126.4, 7.53-7.32/103.4, 5.06/72.1, 4.82/66.2,
4.45/49.7, 4.25/92.2, 3.90 and 3.84/63.8 and 63.1, 2.99/38.8,
2.91/38.8, 2.62/42.7, 2.11/42.7, 0.88/22.2, 0.13 and 0.11/-4.9
and -5.0; IR (film) νmax 3012, 2955, 2878, 2857, 1728, 1471,
1356, 1251, 1134, 1087 cm-1; HRMS (ESI) m/z 533.21177
(MHþ, C28H37O6ClSiHþ requires 533.21207).
[R]25 þ17 (c 1.2, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ
D
7.49-7.27 (m, 5H), 6.54 (s, 1H), 5.07 (s, 2H), 4.67 (dd, J = 12.6,
7.2 Hz, 1H), 4.16 (d, J = 6.9 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H),
3.71 (br s, 1H), 3.62-3.44 (m, 2H), 3.05 (t, J = 12.0 Hz, 1H), 2.70
(dd, J = 12.6, 7.5 Hz, 1H), 2.01-1.94 (m, 1H), 1.67-1.63 (m, 1H),
1.17 (s, 9H), 0.99 (s, 9H), 0.20 (s, 6H), 0.14 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 161.2, 160.4, 155.1, 151.8, 145.9, 145.6, 137.6
(2C), 136.9, 136.0 (2C), 133.7, 79.9, 79.5, 75.2, 72.6, 72.2, 70.3, 53.7,
51.8, 38.1, 34.1 (3C), 34.0 (3C), 33.2, 26.3, 17.1,-4.4 (2C), -4.5
(2C); IR (film) νmax 3577, 2897, 1610, 1442, 989 cm-1; HRMS
(ESI) m/z 649.31418 (MHþ, C34H53ClO6Si2Hþ requires
649.31420).
The iodide 32 (6.9 mg, 0.011 mmol, 6.4%) and reduced com-
pound 33 (3.0 mg, 0.0058 mmol, 3.5%) were also obtained. For
32: 1H NMR (CDCl3, 300 MHz) δ 7.49-7.34 (m, 6H), 5.13 (s,
2H), 4.98-4.92 (m, 1H), 4.72-4.63 (m, 1H), 4.59 (s, 1H), 3.91 (s,
3H), 3.87 (s, 3H), 3.00 (d, J = 6.6 Hz, 1H), 2.93 (d, J = 6.6 Hz,
1H), 2.65 (d, J = 6.6 Hz, 1H), 2.02 (d, J = 6.9 Hz, 1H), 0.89 (s,
9H), 0.14 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 202.1, 146.3,
146.2, 144.4, 139.1, 139.0, 120.8 (2C), 120.1 (2C), 119.5, 113.6,
91.4, 71.2, 67.1, 63.9, 63.5, 63.0, 53.2, 47.4, 41.1, 37.3, 22.0 (3C),
14.4, -4.4, -4.5; HRMS (ESI) m/z 643.11245 (MHþ, C28H36-
O5ClISiHþ requires 643.11380). For 33: 1H NMR (CDCl3,
300 MHz) δ 7.46-7.31 (m, 6H), 5.10 (s, 2H), 4.93-4.88 (m,
1H), 4.65 (t, J = 6.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.92 (d,
J = 6.6 Hz, 1H), 2.85 (d, J = 6.6 Hz, 1H), 2.65 (d, J = 6.9 Hz,
1H), 2.49 (s, 1H), 2.05 (s, 1H), 2.00 (d, J = 6.9 Hz, 1H), 0.92 (s,
9H), 0.11 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 208.2, 145.4,
144.1, 143.8, 142.6, 139.8, 120.1 (2C), 118.8, 118.3 (2C), 114.4,
96.5, 73.0, 69.6, 65.5, 63.9, 62.7, 51.2, 40.6, 40.0, 39.2, 25.8 (3C),
17.6, -4.3, -4.4; HRMS (ESI) m/z 534.23974 (M(NH4)þ,
C28H37O5ClSi(NH4)þ requires 534.24370).
(þ)-(1R,2S,20S,3R,5S)-60-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-20-chloro-40,50-dimethoxy-20,30-dihydrospiro[cyclopen-
tane-1,10-indene]-2,3-diol (34). A solution of 19 (150 mg,
0.281 mmol) in anhydrous THF (2 mL) at 0 °C under Ar
was treated with L-Selectride (1.0 M solution in THF, 280 μL,
0.28 mmol). The resultant mixture was stirred at 0 °C for 1.5 h,
then treated with satd aq NH4Cl (1 mL), and warmed to rt. The
mixture was extracted with EtOAc (3 ꢀ 3 mL), dried (MgSO4),
and concentrated in vacuo. Flash chromatography (SiO2,
2.5 cm ꢀ 11 cm, 20% EtOAc-hexanes elution) afforded 34
(132 mg, 0.247 mmol, 88%) as a pale yellow solid in 9:1 dr. A
diastereomerically pure sample could be obtained after further
purification: [R]25D þ22.7 (c 1.39, CH2Cl2); 1H NMR (CDCl3,
300 MHz) δ 7.42-7.12 (m, 5H), 6.75 (s, 1H), 5.07 (s, 2H), 4.87
(dd, J = 11.1, 5.7 Hz, 1H), 4.27 (d, J = 6.6 Hz, 1H), 4.08 (br s,
1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.64 (br s, 1H), 3.56-3.38 (m,
2H), 3.06 (t, J = 12.0 Hz, 1H), 2.89 (dd, J = 12.6, 7.2 Hz, 1H),
2.03-1.98 (m, 1H), 1.70-1.61 (m, 1H), 0.88 (s, 9H), 0.21 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 151.6, 146.4, 146.3, 144.3,
139.1, 139.0, 120.8 (2C), 120.1, 119.5 (2C), 113.6, 73.5, 71.2,
67.2, 64.0, 63.5, 63.0, 53.2, 47.4, 41.1, 37.3, 23.9, 22.0 (3C),
-4.4, -4.5; IR (film) νmax 3548, 2911, 1626, 1450, 1219, 1091,
933 cm-1; HRMS (ESI) m/z 557.20989 (MNaþ, C28H39-
ClO6SiNaþ requires 557.20966).
(þ)-(1R,2S,20S,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-20-
chloro-40,50-dimethoxy-20,30-dihydrospiro[cyclopentane-1,10-indene]-
2,60-diol (36). A solution of 35 (148 mg, 0.228 mmol) in anhydrous
MeOH (5.0 mL) was treated with 10% Pd/C (40 mg, 0.27 wt equiv).
The resultant mixture was stirred at rt under H2 (1atm) for4h, then
filtered through a plug of Celite (washed with CH2Cl2), dried
(MgSO4), and concentrated in vacuo. Flash chromatography
(SiO2, 1.5 ꢀ 8 cm, 10% EtOAc-hexanes elution) afforded 36
(123 mg, 0.220 mmol, 96%) as a pale yellow oil: [R]25D þ27 (c 1.7,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 6.82 (s, 1H), 4.43 (dd, J =
12.6, 7.2 Hz, 1H), 4.21 (d, J = 6.9 Hz, 1H), 3.91 (s, 3H), 3.88-3.84
(br s, 1H), 3.84 (s, 3H), 3.63 (br s, 1H), 3.54-3.31 (m, 2H), 2.87 (t,
J = 12.0 Hz, 1H), 2.66 (dd, J = 12.6, 7.2 Hz, 1H), 2.00-1.90 (m,
1H), 1.74-1.62 (m, 1H), 1.16 (s, 9H), 1.10 (s, 9H), 0.19 (s, 6H), 0.16
(s, 6H); 13C NMR (CDCl3, 75 MHz) δ 148.1, 142.8, 139.1, 133.2,
128.6, 128.1, 82.7, 75.8, 75.3, 69.5, 69.0, 66.5, 61.1, 40.8, 36.7, 25.8,
22.1 (6C), 13.8, -4.4 (2C), -4.5 (2C); IR (film) νmax 3212, 1258,
1122, 1077 cm-1; HRMS (ESI) m/z 559.26731 (MHþ, C27H47-
ClO6Si2Hþ requires 559.26725).
(-)-(1R,2S,20S,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-20-
chloro-2-hydroxy-40,50,50-trimethoxy-20,30-dihydrospiro[cyclopentane-
1,10-inden]-60(50H)-one (37). A solution of 36 (98.0 mg, 0.175 mmol)
in anhydrous CH3OH (3.0 mL) was added to a mixture of KHCO3
(30 mg, 0.35 mmol, 2.0 equiv), PhI(OAc)2 (62 mg, 0.19 mmol, 1.1
equiv), and anhydrous CH3OH (3.0 mL) at -10 °C under Ar. The
resulting yellow-orange mixture was stirred for 10 min, diluted with
CH2Cl2 (5 mL), and washed with brine (10 mL). The layers were
separated, and the organic layer was dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (SiO2, 2.5 cm ꢀ 10 cm, 10%
EtOAc-hexanes elution) afforded 37 (69.0 mg, 0.117 mmol,
67%) as a yellow oil: [R]25 -15 (c 1.2, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 6.25 (s, 1H), 4.55 (dd, J = 12.6, 7.5 Hz,
1H),4.13(d,J= 6.9 Hz, 1H), 3.98 (s, 3H), 3.61 (br s, 1H), 3.49-3.24
(m,2H),3.37(s,3H),3.32(s,3H),2.79(t,J= 11.8 Hz, 1H), 2.58 (dd,
J = 12.6, 7.5 Hz, 1H), 1.93-1.81 (m, 1H), 1.58-1.49 (m, 1H), 0.91
(s, 9H), 0.86 (s, 9H), 0.10 (s, 6H) 0.09 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 191.1, 142.8, 139.1, 133.2, 121.4, 117.7, 82.8, 69.9, 69.5,
69.0, 66.5, 61.1, 56.5, 56.4, 40.9, 37.7, 23.8, 22.1 (6C), 13.8, -4.4 (2C),
-4.6 (2C); IR (film) νmax 3337, 2450, 1755, 1233, 956 cm-1; HRMS
(ESI) m/z 606.30440 (M(NH4)þ, C28H49ClO7Si2(NH4)þ requires
606.30436).
The cis relative stereochemistry of 34 was assigned based on
the 6.6 Hz coupling constant of the two R-hydroxy hydrogens.
This value is similar to coupling constants reported by Hartung
and Paquette49a for related cis compounds (4.2-5.8 Hz) and
differs markedly from the value reported by Christol and
Vanel49b for a related trans compound (10 Hz). Additionally,
molecular models of 20 demonstrate that approach of the
J. Org. Chem. Vol. 74, No. 23, 2009 9091

Li et al.
JOCArticle
(-)-(1R,2S,20S,3R,5S)-2-(Benzyloxy)-3,5-bis(tert-butyldimethyl-
silyloxy)-20-chloro-40,50,50-trimethoxy-20,30-dihydrospiro[cyclo-
pentane-1,10-inden]-60(50H)-one (38). A solution of 37 (110 mg,
0.187 mmol) in anhydrous DMF (1.5 mL) at rt under Ar was
treated with NaH (60% dispersion in mineral oil, 7.6 mg,
4.6 mg NaH, 0.19 mmol), tetrabutylammonium iodide (70 mg,
0.19 mmol), and benzyl bromide (23 μL, 32.9 mg, 0.192 mmol).
The resultant brown solution was stirred at 60 °C for 5 h, cooled
to rt, diluted with CH2Cl2 (2 mL), and washed with brine (2 mL).
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (5 ꢀ 3 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Flash chromatography
(SiO2, 1.5 cm ꢀ 12 cm, 1% Et3N in 5% EtOAc-hexanes elution)
afforded38 (111mg, 0.163 mmol, 88%) as abrownoil: [R]25D -21
diluted with Et2O (2 mL). The layers were separated, and the
organic layer was dried (MgSO4) and concentrated in vacuo.
Flash chromatography (SiO2, 1% Et3N in 10% EtOAc-hexanes
elution) afforded 41 (27.5 mg, 0.0381 mmol, 92%) as a colorless
1
oil: [R]25 -22 (c 1.5, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
7.52-7.34 (m, 5H), 5.88-5.76 (m, 1H), 5.27 (dd, J = 12.2, 7.0 Hz,
1H), 5.20 (s, 2H), 5.00-4.88 (m, 2H), 4.60 (d, J = 6.9 Hz, 1H),
3.91 (s, 3H), 3.58-3.42 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H), 3.10 (t,
J = 11.8 Hz, 1H), 2.98 (d, J = 14.7 Hz, 1H), 2.72 (dd, J = 12.2,
7.0 Hz, 1H), 2.56 (d, J = 15.0 Hz, 1H), 1.89-1.81 (m, 1H),
1.78-1.69 (m, 1H), 1.67-1.62 (m, 1H), 1.58-1.51 (m, 1H). 0.97
(s, 9H), 0.94 (s, 9H), 0.10 (s, 6H), 0.08 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 192.5, 147.7, 142.5, 138.8, 132.8, 124.2 (2C), 123.5,
122.9 (2C), 120.7, 104.8, 71.1, 69.6, 68.9, 68.4, 66.6, 56.6, 56.4,
52.9, 49.8, 41.2, 40.5, 37.0, 36.3, 25.3, 21.5 (3C), 21.4 (3C), 13.9
(2C), -5.0 (2C), -5.1 (2C); IR (film) νmax 3055, 2978, 2844, 1782,
1631, 1423, 1012, 941 cm-1; HRMS (ESI) m/z 721.37180 (MHþ,
C38H61ClO7Si2Hþ requires 721.37171).
1
(c 1.1, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.42-7.18 (m,
5H), 6.39 (s, 1H), 5.20 (s, 2H), 4.99 (dd, J = 12.6, 7.5 Hz, 1H),
4.76-4.72 (m, 1H), 3.92 (s, 3H), 3.63-3.46 (m, 2H), 3.56 (s, 3H),
3.51 (s, 3H), 3.14 (t, J = 11.8 Hz, 1H), 2.77 (dd, J = 12.6, 7.5 Hz,
1H), 1.83-1.71 (m, 1H), 1.49-1.38 (m, 1H), 0.98 (s, 9H), 0.97 (s,
9H); 0.089 (s, 6H), 0.086 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
192.7, 150.3, 145.1, 141.3, 135.4, 126.6 (2C), 126.0, 125.4 (2C),
123.1, 107.4, 72.1, 71.5, 71.0, 69.5, 66.0, 59.2, 59.0, 55.1, 43.4, 39.6,
27.8, 24.1 (3C), 24.0 (3C), 16.3 (2C), -4.4 (2C), -4.5 (2C); IR
(film) νmax 3284, 2566, 1727 cm-1; HRMS (ESI) m/z 679.32488
(MHþ, C35H55ClO7Si2Hþ requires 679.32476).
(-)-(1R,2S,20S,3R,5S,7a0R)-2-(Benzyloxy)-3,5-bis(tert-butyldi-
methylsilyloxy)-20-chloro-40,50,50-trimethoxy-7a0-(2-(methylamino)-
ethyl)-20,30,70,7a0-tetrahydrospiro [cyclopentane-1,10-inden]-60(50H)-
one (42). A saturated solution of O3 in EtOAc was prepared by
bubbling ozone through EtOAc at -78 °C for 10 min. The
concentration was determined to be 0.007 M as measured by
titration with styrene.55 Then, a solution of 41 (27 mg, 0.037 mmol),
pyridine (10 μL), and Et3N (16.0 μL, 11.6 mg, 0.115 mmol, 3.1
equiv) in EtOAc (0.5 mL) was cooled to -40 °C. A portion of
the previously prepared solution of O3 in EtOAc (0.007 M, 8 mL,
0.056 mmol, 1.5 equiv), which was precooled to -78 °C, was then
added to this solution. The resultant mixture was stirred at -78 °C
for 5 min, then diluted with anhydrous MeOH (1.0 mL) and treated
(-)-(1R,2S,20S,3R,5S,60S)-60-allyl-2-(benzyloxy)-3,5-bis(tert-
butyldimethylsilyloxy)-20-chloro-40,50,50-trimethoxy-20,30,50,60-tetra-
hydrospiro[cyclopentane-1,10-inden]-60-ol (40). A solution of bis((S)-
4-phenyl-4,5-dihydrooxazol-2-yl)methane62 (76 mg, 0.24 mmol)
and 2,20-dipyridyl (2 crystals) in anhydrous THF (200 μL) at
0 °C under Ar was treated dropwise with n-BuLi (1.6 M in hexanes,
250 μL, 0.40 mmol) until the mixture turned a reddish-brown color.
The solution was warmed to rt and stirred for 1 h, then treated
dropwise with allylzinc bromide (1.0 M in THF, 240 μL,
0.24 mmol), and cooled to -78 °C. A solution of ketone 38
(95 mg, 0.14 mmol) in anhydrous THF (220 μL) was added
dropwise, and the resultant mixture was stirred at -78 °C under
Ar for 1 h. The reaction was quenched by the addition of
MeOH-H2O (1:1, 1 mL), and the mixture was extracted with
Et2O (3 ꢀ 1 mL). The combined organic layers were washed with
NaOH (0.5 M, 1 mL), dried (MgSO4), and concentrated in vacuo.
Flash chromatography (SiO2, 2:23:75 Et3N-EtOAc-hexanes
˚
with powdered 4 A molecular sieves (30 mg) and CH3NH2 (2.0 M
in MeOH, 76 μL, 0.15 mmol, 4.1 equiv). This mixture was stirred at
rt under Ar for 30 min, then treated with NaBH3CN (4.8 mg, 0.076
mmol) and stirred for 16 h. It was then diluted with EtOAc (2 mL)
and washed with aq KOH (10 M, 1 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (3 ꢀ
2 mL), and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. Flash chromatography (SiO2, 1% Et3N in
15-20% EtOAc-hexanes gradient elution) afforded recovered 41
(7.3 mg, 27% recovery) and 42 (15 mg, 0.020 mmol, 54%, 74%
based on recovered 41) as a yellow oil: [R]25D -25 (c 1.4, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.52-7.32 (m, 5H), 5.05 (s, 2H),
4.83 (dd, J = 12.0, 6.9 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 4.02 (s,
3H), 3.87-3.73 (m, 2H), 3.62 (s, 3H), 3.57 (s, 3H), 3.06 (t, J =
11.8 Hz, 1H), 2.97 (s, 3H), 2.71-2.62 (m, 2H), 2.38 (dd, J = 12.2,
7.0 Hz, 1H), 2.28 (d, J = 15.0 Hz, 1H), 2.23 (br s, 1H), 2.18-2.13
(m, 1H), 2.00 (d, J = 15.0 Hz, 1H), 1.69-1.61 (m, 1H), 1.44-1.38
(m, 1H), 1.35-1.28 (m, 1H), 0.87 (s, 9H), 0.81 (s, 9H), 0.10 (s, 6H),
0.07 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 197.1, 152.4, 147.1,
137.4, 128.8 (2C), 128.1, 127.5 (2C), 109.4, 75.1, 74.1, 73.6, 73.0,
71.2, 61.2, 61.0, 54.1, 50.0, 47.0, 45.9, 45.1, 41.7, 40.9, 39.2, 29.9,
26.1(3C), 26.0(3C), 18.2(2C), -4.5 (2C), -5.0(2C);IR(film) νmax
3125, 2923, 2810, 1741, 1633, 1420, 1208, 1138, 982 cm-1; HRMS
(ESI) m/z 760.38014 (MNaþ, C38H64ClNO7Si2Naþ requires
760.38021).
elution) afforded 40 (79 mg, 0.11 mmol, 93:7 dr, 79%) as a colorless
1
oil: [R]25 -36 (c 1.2, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
7.47-7.31 (m, 5H), 6.37-6.27 (m, 1H), 6.21 (s, 1H), 5.24 (dd, J =
12.3, 7.2 Hz, 1H), 5.09 (s, 2H), 4.93-4.79 (m, 2H), 4.65 (d, J =
6.9 Hz, 1H), 3.82 (s, 3H), 3.47-3.27 (m, 3H), 3.41 (s, 3H), 3.37 (s,
3H), 3.09 (t, J = 12.0 Hz, 1H), 2.74 (dd, J = 12.3, 7.2 Hz, 1H),
1.85-1.77 (m, 1H), 1.73-1.65 (m, 1H), 1.57-1.53 (m, 1H),
1.50-1.37 (m, 1H), 0.91 (s, 9H), 0.85 (s, 9H), 0.11 (s, 6H), 0.08
(s, 6H); 13C NMR (CDCl3, 75 MHz) δ 150.3, 145.1, 141.3, 140.9,
135.4, 126.7 (2C), 126.1, 125.5 (2C), 123.3, 123.2, 107.4, 73.8, 72.1,
71.5, 71.0, 69.1, 65.4, 59.1, 59.0, 55.5, 48.0, 43.1, 39.6, 27.9, 24.1
(3C), 24.0 (3C), 16.4 (2C), -4.4 (2C), -4.5 (2C); IR (film) νmax
3087, 2991, 2836, 1629, 1467, 933 cm-1; HRMS (ESI) m/z
721.37162 (MHþ, C38H61ClO7Si2Hþ requires 721.37171).
(-)-(1R,2S,20S,3R,5S,7a0R)-7a0-Allyl-2-(benzyloxy)-3,5-bis(tert-
butyldimethylsilyloxy)-20-chloro-40,50,50-trimethoxy-20,30,70,7a0-tetra-
hydrospiro[cyclopentane-1,10-inden]-60(50H)-one (41). A mixture of
18-crown-6 (34 mg, 0.13 mmol), KOt-Bu (14 mg, 0.13 mmol), and
anhydrous THF (700 μL) at 0 °C under Ar was stirred for 15 min,
then treated with a solution of 40 (30.0 mg, 0.0416 mmol) in
anhydrous THF (150 μL, added dropwise over 3 min). The resulting
mixture was stirred at 0 °C under Ar for 1 h. The reaction was
quenched by the addition of H2O (1 mL), and the mixture was
Tetracycle (-)-46. A mixture of 42 (15 mg, 0.020 mmol), 4 A
˚
MS (80 mg), and anhydrous CH2Cl2 (2.0 mL) was stirred at rt
under Ar for 10 min, then cooled to -40 °C. Next, BCl3 (1.0 M in
CH2Cl2, 30 μL, 0.030 mmol, 1.5 equiv) was added dropwise, and
the resultant mixture was stirred at -40 °C under Ar for 18 h, then
concentrated in vacuo. The residue was purified by flash chromato-
graphy (SiO2, 2:30:68 Et3N-EtOAc-hexanes elution), affording
46 (6.4 mg, 0.0091 mmol, 45%) as a colorless oil: [R]25D -79 (c 1.2,
CHCl3); 1H NMR (pyridine-d5, 500 MHz) δ 7.44-7.41 (m, 3H),
7.36-7.33 (m, 2H), 5.25 (dd, J = 12.2, 6.8 Hz, 1H), 5.12 (s, 2H),
4.80 (d, J = 7.0 Hz, 1H), 4.14 (s, 3H), 3.84 (s, 3H), 3.50-3.44
(m, 1H), 3.41-3.36 (m, 1H), 3.20 (t, J = 12.0 Hz, 1H), 3.11 (d,
(62) Hall, J.; Lehn, J.-M.; DeCian, A.; Fischer, J. Helv. Chim. Acta 1991,
74, 1.
9092 J. Org. Chem. Vol. 74, No. 23, 2009

Li et al.
JOCArticle
J = 15.5 Hz, 1H), 2.75-2.69 (m, 3H), 2.61 (d, J = 15.5 Hz, 1H),
2.52-2.47 (m, 1H), 2.46 (s, 3H), 1.71-1.68 (m, 1H), 1.55-1.50 (m,
1H), 1.46-1.40 (m, 1H), 0.96 (s, 9H), 0.92 (s, 9H), 0.26 (s, 3H), 0.22
(s, 3H), 0.13 (s, 6H); 13C NMR (pyridine-d5, 125 MHz) δ 192.0,
158.8, 142.3, 138.1, 129.9 (2C), 129.2, 128.4 (2C), 76.2, 75.8, 75.3,
74.2, 72.0, 67.4, 59.5, 59.2, 56.9, 52.3, 50.8, 46.3, 44.0, 40.5, 37.6,
35.4, 30.0 (3C), 29.8 (3C), 20.0 (2C), -4.1 (2C), -4.2 (2C); IR
1H),3.26(t,J=12.2Hz, 1H),3.17(d,J= 15.5 Hz, 1H), 2.82-2.74
(m, 3H), 2.65(d, J= 15.5 Hz, 1H), 2.55-2.52 (m, 1H), 2.50 (s, 3H),
1.76-1.73 (m, 1H); 13C NMR (pyridine-d5, 125 MHz) δ 203.1.
201.7, 194.1, 160.9, 140.2, 72.9, 71.7, 69.3, 60.2, 59.9, 56.8, 55.5,
53.2, 48.9, 46.1, 42.0, 38.4, 36.4; IR (film) νmax 3054, 2832, 1836,
1477, 1201, 934 cm-1; HRMS (ESI) m/z 406.10270 (MNaþ,
C18H22ClNO6Naþ requires 406.10279).
(film) νmax 3209, 2974, 2795, 1763, 1651, 1402, 1265, 912 cm-1
;
(-)-Acutumine (1). TiCl4 (0.04 M solution in CH2Cl2, 20 μL,
0.0008 mmol) was added to a solution of 48 (2.0 mg, 0.0052
mmol) in anhydrous MeOH (100 μL). The solution was stirred
at rt for 15 min, then treated with Et3N (4 μL, 2.9 mg, 0.029
mmol) and stirred at rt for 45 min. The mixture was concen-
trated in vacuo, and the residue was purified by flash chroma-
tography (SiO2, 1.5 ꢀ 6 cm, 1% Et3N in 5-15% MeOH-
CH2Cl2 gradient elution), affording 1 (1.1 mg, 0.0027 mmol,
52%) and enol ether regioisomer 49 (0.3 mg, 0.00075 mmol,
14%). For 1: white film, [R]25 -171 (c 0.81, pyridine), lit.2b
[R]25D -206 (c 0.69, pyridine); 1DH NMR (pyridine-d5, 500 MHz)
δ 8.47 (br, s, 1H), 5.61 (s, 1H), 5.20 (dd, J = 11.8, 6.8 Hz, 1H),
5.03 (s, 1H), 4.04 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H), 3.16 (t, J =
12.0 Hz, 1H), 3.07 (d, J = 15.5 Hz, 1H), 2.69-2.63 (m, 3H), 2.54
(d, J = 15.5 Hz, 1H), 2.45-2.42 (m, 1H), 2.39 (s, 3H), 1.65-1.62
(m, 1H); 13C NMR (pyridine-d5, 125 MHz) δ 201.3, 192.8, 188.9,
159.7, 138.9, 105.5, 72.9, 70.7, 68.3, 60.4, 60.1, 58.8, 57.8, 53.2,
51.6, 47.2, 41.4, 38.5, 36.3; IR (film) νmax 3410, 2899, 2817, 1655,
1641, 1364, 1205, 1079, 935 cm-1; HRMS (ESI) m/z 398.13655
HRMS (ESI) m/z 706.37199 (MHþ, C37H60ClNO6Si2Hþ requires
706.37205).
1,3-Diketone (-)-47. A solution of 46 (8.7 mg, 0.012 mmol) in
anhydrous THF (100 μL) at 0 °C under Ar was treated with
TBAF (1.0 M in THF, 27 μL, 0.027 mmol, 2.2 equiv) in one
portion. The resulting mixture was stirred at 0 °C for 20 min.
The reaction was quenched by the addition of ice water (0.5 mL),
and the mixture was extracted with cold CH2Cl2 (cooled in ice
bath, 3 ꢀ 0.5 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo in an ice bath. The unstable
crude diol was dissolved in acetone (0.5 mL) at 0 °C, and then
˚
4 A MS (50 mg), NMO (4.2 mg, 0.036 mmol), and TPAP (0.4 mg,
0.001 mmol) were added in order to the solution. The resulting
mixture was stirred at 0 °C under Ar for 30 min, then slowly
warmed to rt over 1 h and stirred at rt for 1 additional h. It was
then filtered through a plug of SiO2 (rinsed with 5 mL EtOAc),
dried (MgSO4), and concentrated in vacuo. Flash chromatogra-
phy (SiO2, 1% Et3N in 2% MeOH-CH2Cl2 elution) afforded 47
(3.3 mg, 0.0070 mmol, 57%) as a white solid: [R]25D -122 (c 0.7,
CH2Cl2); 1H NMR (pyridine-d5, 500 MHz) δ 7.46-7.42 (m, 3H),
7.39-7.37 (m, 2H), 5.20 (dd, J = 12.0, 6.5 Hz, 1H), 5.02 (s, 2H),
4.87 (s, 1H), 4.10 (s, 3H), 3.92 (d, J = 14.0 Hz, 1H), 3.80 (s, 3H),
3.74 (d, J = 14.0 Hz, 1H), 3.16 (t, J = 12.5 Hz, 1H), 3.07 (d, J =
16.0 Hz, 1H), 2.70-2.63 (m, 3H), 2.55 (d, J = 15.5 Hz, 1H),
2.45-2.41 (m, 1H), 2.40 (s, 3H), 1.65-1.62 (m, 1H); 13C NMR
(pyridine-d5, 125 MHz) δ 202.8, 201.4, 193.3, 160.2, 143.6, 139.4,
131.6 (2C), 130.9, 130.3 (2C), 73.4, 71.9, 71.2, 69.1, 60.9, 60.6,
59.3, 58.3, 52.1, 47.7, 46.9, 41.9, 39.0, 36.8; IR (film) νmax 3024,
2931, 2795, 1825, 1633, 1429, 1176, 955 cm-1; HRMS (ESI) m/z
474.16785 (MHþ, C25H28ClNO6Hþ requires 474.16779).
Alcohol (-)-48. To a solution of 47 (3.0 mg, 0.0063 mmol) in
anhydrous MeOH (1.0 mL) under Ar was added 10% Pd/C (10 mg,
3.3 wt equiv). The resulting mixture was stirred at rt under H2
(1 atm) for 2 h, then filtered through a plug of Celite (washed with
CH2Cl2), dried (MgSO4), and concentrated in vacuo. Flash chro-
matography (SiO2, 1.5 ꢀ 8 cm, 5% MeOH-CH2Cl2 elution)
afforded 48 (2.4 mg, 0.0063 mmol, 99%) as a pale yellow oil:
[R]25D -135 (c 0.6, CH2Cl2); 1H NMR (pyridine-d5, 500 MHz) δ
8.66 (br s, 1H), 5.30 (dd, J = 12.0, 6.5 Hz, 1H), 5.13 (s, 1H), 4.14 (s,
3H), 4.03 (d, J = 14.0 Hz, 1H), 3.83 (s, 3H), 3.76 (d, J = 14.0 Hz,
(MHþ, C19H24ClNO6Hþ requires 398.13649).
1
For 49: white film, [R]25 -112 (c 0.3, pyridine); H NMR
D
(pyridine-d5, 500 MHz) δ 8.40 (br, s, 1H), 5.32 (s, 1H), 5.16 (dd,
J = 12.0, 7.0 Hz, 1H), 4.94 (s, 1H), 4.07 (s, 3H), 3.74 (s, 3H), 3.57
(s, 3H), 3.13 (t, J = 12.5 Hz, 1H), 3.02 (d, J = 16.5 Hz, 1H),
2.67-2.60 (m, 3H), 2.48 (d, J = 15.5 Hz, 1H), 2.43-2.38 (m,
1H), 2.36 (s, 3H), 1.62-1.60 (m, 1H); HRMS (ESI) m/z
398.13664 (MHþ, C19H24ClNO6Hþ requires 398.13649).
Acknowledgment. We thank the National Science Foun-
dation (CHE-716991), the National Institutes of Health
(GM70483), and Brigham Young University (Graduate
Research Fellowship to F.L., Undergraduate Research
Award to S.S.T.; Mentoring Environment Grant to S.L.C.)
for financial support.
Supporting Information Available: Experimental proce-
dures and characterization data for new compounds not de-
scribed in the Experimental Section, and NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 23, 2009 9093