Synthesis of isohasubanan alkaloids via enantioselective ketone allylation and discovery of an unexpected rearrangement

Article abstract of DOI:10.1021/jo802370v

A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence allowed a convergent a

Full text of DOI:10.1021/jo802370v

Synthesis of Isohasubanan Alkaloids via Enantioselective Ketone
Allylation and Discovery of an Unexpected Rearrangement
Daniel K. Nielsen, Laura L. Nielsen, Spencer B. Jones, Lawrence Toll,†
Matthew C. Asplund, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602
scastle@chem.byu.edu
ReceiVed October 23, 2008
A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was
attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-
closing metathesis sequence allowed a convergent and flexible approach. Conversion of the phenanthrenes
into the target structures was projected to involve six steps including phenolic oxidation, ketone allylation,
anionic oxy-Cope rearrangement, and acid-promoted cyclization. The final step was thwarted by a pinacol-
like rearrangement that delivered the unnatural isohasubanan alkaloid skeleton. The structures of the
products were established by exhaustive NMR experiments and confirmed by GIAO 13C NMR calculations
of runanine, isorunanine, and three other isomers. These computations revealed some inconsistencies
with the benzene solvent correction which suggest that caution should be used in employing this algorithm.
The racemic synthesis of isohasubanonine was transformed into an enantioselective synthesis by the
discovery that Nakamura’s chiral bisoxazoline-ligated allylzinc reagent mediates the enantioselective
allylation of ketone 19 in 93% ee. This method could be extended to three other structurally related
ketones (92-96% ee), and the enantioselective syntheses of two other isohasubanan alkaloids, isorunanine
and isoaknadinine, were accomplished. Racemic isohasubanonine was found to be an ineffective analgesic
agent.
Introduction
The hasubanan alkaloids are a family of over 40 natural
products sharing a common tetracyclic skeleton which have been
isolated from flowering plants of the genus Stephania.1 The
name of the family is derived from that of hasubanonine (1,
Figure 1), the first member of this compound class to be
discovered.2 The hasubanan alkaloids have been the targets of
numerous synthetic efforts that culminated in racemic products.3,4
† Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo
Park, CA 94025.
FIGURE 1. Hasubanan alkaloids (1-3) and morphine (4).
The first enantioselective total synthesis of a hasubanan alkaloid
was reported by Schultz and Wang in 1998,5 who noted the
structural resemblance between the hasubanan alkaloids and the
morphine alkaloids (see Figure 1). Although the two families
are somewhat similar in architecture, a key difference is that
the spatial relationship between the aromatic ring and the tertiary
amine is opposite in the naturally occurring enantiomers. This
(1) (a) Matsui, M. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1988; Vol. 33, pp 307-347. (b) Inubushi, Y.; Ibuka, T. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1977; Vol. 16, pp 393-
430. (c) Bentley, K. W. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1971; Vol. 13, pp 131-143.
(2) (a) Tomita, M.; Ibuka, T.; Inubushi, Y.; Watanabe, Y.; Matsui, M. Chem.
Pharm. Bull. 1965, 13, 538. (b) Tomita, M.; Ibuka, T.; Inubushi, Y.; Watanabe,
Y.; Matsui, M. Tetrahedron Lett. 1964, 2937. (c) Kondo, H.; Satomi, M.; Odera,
T. Ann. Rep. ITSUU Lab. 1951, 2, 35.
10.1021/jo802370v CCC: $40.75
Published on Web 12/12/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1187–1199 1187

Nielsen et al.
SCHEME 1. Retrosynthetic Analysis
may explain why the hasubanan alkaloids do not share the potent
analgesic activity of the morphine alkaloids.1a In addition, it
has been demonstrated that the unnatural enantiomers of
morphine alkaloids are devoid of painkilling properties.6
Recognizing the potential of the unnatural enantiomers of
hasubanan alkaloids as analgesic agents, Schultz and Wang
constructed the (+)-antipode of cepharamine.5 However, to the
best of our knowledge, no evaluation of the painkilling abilities
of this material has been disclosed. Accordingly, our interest
in determining the veracity of Schultz’s hypothesis provided
the impetus for launching a program directed at the enantiose-
lective total synthesis of hasubanan alkaloids. Herein, we
describe our efforts to construct hasubanonine (1), runanine (2),
and aknadinine (3). We developed a synthetic route which
appeared to deliver 1;7a however, attempts to prepare 2 and 3
revealed that a previously undetected rearrangement had oc-
curred in the final cyclization step.7b This process afforded an
unnatural structure that we refer to as the isohasubanan skeleton.
A significant aspect of this work was the discovery of an
enantioselective ketone allylation which proceeds in good yield
and excellent enantioselectivity (g92% ee) with several complex
ketones.
SCHEME 2. Synthesis of Iodide 8 and Boronate 14
Results
Our retrosynthetic analysis of hasubanan alkaloids 1-3 is
depicted in Scheme 1. Previously, we developed a route to the
propellane-type8 tricyclic core of the alkaloid acutumine which
entailed annulation of a pyrrolidine ring onto an aromatic
precursor. Key reactions in this sequence include a phenolic
oxidation, an anionic oxy-Cope rearrangement, and a Michael-
type cyclization.9 Due to the similarities in structure between
acutumine and the hasubanan alkaloids, we reasoned that this
process would produce 1-3 from phenolic dihydrophenan-
threnes of general structure 7 via the intermediacy of ketones 6
and homoallylic alcohols 5. In order to accomplish an enanti-
oselective synthesis of 1-3, the asymmetric allylation of 6 to
provide 5 would be required. Dihydrophenanthrenes 7 could
be prepared from the corresponding phenanthrenes, which
should be available in three simple steps from aryl iodide 8
and pinacolboronates 9 by means of Iuliano‘s method.10 An
advantage of employing this phenanthrene synthesis is that all
three targeted compounds could be constructed from 8. More-
over, additional hasubanan alkaloids and unnatural analogues
would be readily accessible by simple modifications to either
Suzuki coupling partner.
At the outset, we identified two main synthetic objectives of
this work. First, we wanted to determine if the five-step sequence
developed for synthesis of the acutumine propellane core was
directly applicable to preparation of the hasubanan skeleton or
if modifications would be required. Second, we wished to
evaluate the viability of ketones 6 as substrates for asymmetric
allylations. We approached this second goal with some trepida-
tion, as 6 differs significantly from ketones which are typically
employed in asymmetric allylation studies (vide infra). Conse-
quently, we initially focused on the first objective by embarking
on a total synthesis of (()-1.
(3) Total syntheses: (a) Ibuka, T.; Tanaka, K.; Inubushi, Y. Chem. Pharm.
Bull. 1974, 22, 907. (b) Ibuka, T.; Tanaka, K.; Inubushi, Y. Tetrahedron Lett.
1972, 1393. (c) Ibuka, T.; Tanaka, K.; Inubushi, Y. Chem. Pharm. Bull. 1974,
22, 782. (d) Ibuka, T.; Tanaka, K.; Inubushi, Y. Tetrahedron Lett. 1970, 4811.
(e) Kametani, T.; Nemoto, H.; Kobari, T.; Shishido, K.; Fukumoto, K. Chem.
Ind. (London) 1972, 538. (f) Inubushi, Y.; Kitano, M.; Ibuka, T. Chem. Pharm.
Bull. 1971, 19, 1820.
(4) Model systems, formal syntheses, and semisyntheses: (a) Nguyen, T. X.;
Kobayashi, Y. J. Org. Chem. 2008, 73, 5536. (b) Trauner, D.; Porth, S.; Opatz,
T.; Bats, J. W.; Giester, G.; Mulzer, J. Synthesis 1998, 653. (c) Schwartz, M. A.;
Wallace, R. A. Tetrahedron Lett. 1979, 3257. (d) Bruderer, H.; Knopp, D.; Daly,
J. J. HelV. Chim. Acta 1977, 60, 1935. (e) Shiotani, S.; Kometani, T. Tetrahedron
Lett. 1976, 767. (f) Monkovic´, I.; Wong, H. Can. J. Chem. 1976, 54, 883. (g)
Monkovic´, I.; Wong, H.; Belleau, B.; Pachter, I. J.; Perron, Y. G. Can. J. Chem.
1975, 53, 2515. (h) Belleau, B.; Wong, H.; Monkovic´, I.; Perron, Y. G. J. Chem.
Soc., Chem. Commun. 1974, 603. (i) Kametani, T.; Kobari, T.; Shishido, K.;
Fukumoto, K. Tetrahedron 1974, 30, 1059. (j) Kametani, T.; Kobari, T.;
Fukumoto, K. J. Chem. Soc., Chem. Commun. 1972, 288. (k) Evans, D. A.;
Bryan, C. A.; Sims, C. L. J. Am. Chem. Soc. 1972, 94, 2891. (l) Evans, D. A.;
Bryan, C. A.; Wahl, G. M. J. Org. Chem. 1970, 35, 4122. (m) Evans, D. A.
Tetrahedron Lett. 1969, 1573. (n) Keely, S. L., Jr.; Martinez, A. J.; Tahk, F. C.
Tetrahedron 1970, 26, 4729. (o) Tomita, M.; Kitano, M.; Ibuka, T. Tetrahedron
Lett. 1968, 3391. (p) Ibuka, T.; Kitano, M. Chem. Pharm. Bull. 1967, 15, 1944.
(q) Tomita, M.; Ibuka, T.; Kitano, M. Tetrahedron Lett. 1966, 6233.
(5) Schultz, A. G.; Wang, A. J. Am. Chem. Soc. 1998, 120, 8259.
(6) Iijima, I.; Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. J. Org.
Chem. 1978, 43, 1462.
This endeavor commenced with the preparation of aryl iodide
8 and aryl pinacolboronate 14 (Scheme 2). Nitration of
4-benzyloxy-2,3-dimethoxybenzaldehyde (10, available in two
steps from commercially available 2,3-dimethoxyphenol)11
(7) Preliminary communication: (a) Jones, S. B.; He, L.; Castle, S. L. Org.
Lett. 2006, 8, 3757. (b) Correction: Jones, S. B.; He, L.; Castle, S. L. Org. Lett.
2009, 11, 785.
(8) For a review on the synthesis of propellane-containing natural products,
see: Pihko, A. J.; Koskinen, A. M. P. Tetrahedron 2005, 61, 8769.
(9) Reeder, M. D.; Srikanth, G. S. C.; Jones, S. B.; Castle, S. L. Org. Lett.
2005, 7, 1089.
(10) Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711.
(11) Kurosawa, K.; Ollis, W. D.; Sutherland, I. O.; Gottlieb, O. R.; De
Oliveira, A. B. Phytochemistry 1978, 17, 1389.
1188 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
SCHEME 3. Coupling of 8 and 14 and Initial Attempts at Synthesizing 1
afforded 11. The unusual regioselectivity of this reaction is
precedented, as nitration of 2,3,4-trimethoxybenzaldehyde af-
fords 2,3,4-trimethoxy-6-nitrobenzaldehyde.12 The regiochem-
istry of nitro compound 11 was ultimately proven by its
successful transformation into phenanthrene 17 (see Scheme 3);
the biaryl adduct derived from the alternative nitro regioisomer
would be unable to afford a phenanthrene via ring-closing
metathesis. Then, a sequence of nitro reduction, diazotization,
and iodination delivered aryl iodide 8 in 41% yield from 11.
Attempts at direct iodination of 10 afforded the undesired
regioisomer of 8; accordingly, we adopted the multistep protocol
instead. The coupling partner of 8 was constructed in two steps
from veratraldehyde (12). Thus, regioselective iodination ac-
cording to the directed ortho metalation protocol of Comins13
produced 13, which was subjected to a Suzuki coupling with
bis(pinacolato)diboron14 to provide arylboronic ester 14.
The Suzuki coupling of 8 and 14 was performed under a slight
modification of conditions developed by Danishefsky and co-
workers for the union of aryl iodides and aryl pinacolboronates
(Scheme 3).15 The resulting biaryl dialdehyde 15 was converted
into diene 16 via Wittig olefination, and ring-closing metathesis
of 16 with the Grubbs second-generation ruthenium catalyst16
provided phenanthrene 17 in excellent yield. The three-step
synthesis of 17 from 8 and 14, which was inspired by the report
of Iuliano and co-workers,10 proceeded in 73% overall yield.
This result is noteworthy given the hindered nature of the
trisubstituted biaryl axis formed in the Suzuki coupling. Then,
cleavage of the benzyl ether and reduction of the phenanthrene
were simultaneously accomplished by high-pressure catalytic
hydrogenation, affording phenolic dihydrophenanthrene 18 in
95% yield.
At this point, we applied our previously developed sequence
for construction of the acutumine propellane core9 to the
transformation of 18 into 1. Accordingly, addition of 18 to a
solution of PhI(OAc)2 in MeOH at low temperature caused a
rapid (20 min) phenolic oxidation17 that produced masked
o-benzoquinone18 19. 1,2-Addition of allylmagnesium chloride
to 19 provided tertiary alcohol 20 in excellent yield. This alcohol
was subsequently transformed into ketone 21 via an extremely
facile anionic oxy-Cope rearrangement.19 The reaction was
complete at -10 °C within 15 min. It is likely that the presence
of additional unsaturation in conjugation with the allylic alcohol
moiety (i.e., methyl enol ether, aryl group) is responsible for
the pronounced rate acceleration relative to typical anionic oxy-
Cope rearrangements. Similar effects have been previously
noted.20 Ozonolysis of 21 was regioselective, affording the
aldehyde derived from oxidative cleavage of the terminal olefin.
However, frequent monitoring of the reaction by TLC was
necessary in order to avoid oxidation of the electron-rich but
hindered methyl enol ether. Reductive amination of the crude
aldehyde with methylamine delivered a secondary amine, which
cyclized to form hemiaminal 22. This ozonolysis–reductive
amination sequence was cleaner than our earlier work on the
acutumine core, in which competitive oxidation of the tetra-
substituted methyl enol ether by ozone forced us to halt the
reaction at ca. 50% conversion. Perhaps the less hindered nature
of the terminal olefin of 21 compared to the corresponding olefin
in the acutumine substrate9 is responsible for the improved
regioselectivity.
Surprisingly, exposure of 22 to our previously developed
conditions (TMSOTf, 4 Å MS, CH2Cl2, -10 °C) for cyclization
of an amine onto an R,ꢀ-unsaturated ketal21 did not afford 1.
Rather, an isomer of 1 was obtained, as evidenced by HRMS.
(12) (a) Lin, A. J.; Pardini, R. S.; Lillis, B. J.; Sartorelli, A. C. J. Med. Chem.
1974, 17, 668. (b) Cherkaoui, M. Z.; Scherowsky, G. New. J. Chem. 1997, 21,
1203.
(13) Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54, 3730.
(14) Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729.
(15) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(17) Yen, C.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2, 2909.
(18) For a review on the chemistry of masked o-benzoquinones, see:
Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383.
(19) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Evans, D. A.;
Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(20) Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5,
3631.
J. Org. Chem. Vol. 74, No. 3, 2009 1189

Nielsen et al.
TABLE 1. Enantioselective Allylation of 19
SCHEME 4. Conversion of 22 into 23
entry
reagenta
result
This compound was unstable to SiO2, neutral alumina, basic
alumina, and Florisil. It could be partially purified by rapid
chromatography on SiO2 that was pretreated with Et3N or
NaOH, but we were unable obtain a pure sample due to
decomposition. Our inability to purify this product precluded
us from precisely determining its structure. We tentatively
1
2
3
4
5
6
7
8
24
25
complex mixture
byproductb
racemic
no reaction
racemic
26c
27
28
29
30
31a
31b
31c
32
no reaction
racemic
1
assigned it as N,O-acetal 23 based on H NMR spectra of
25% eed
partially purified samples, but that conclusion was later shown
to be incorrect (vide infra). Formation of this undesired isomer
of 1 was quite rapid (e10 min) and could also be accomplished
by treatment of 22 with BCl3 or HCl. Unfortunately, attempts
to convert this compound into 1 were fruitless, as it decomposed
under all of the conditions examined.
9
10
11
racemic
5% eed
76% yield, 93% eed
a See Figure 2 for structures and references to reaction conditions.
b An unidentified compound was obtained, and 20 was not observed.
c Conditions: THF, -90 °C. d Determined by chiral HPLC (Chiralcel
OD-H, 99:1 hexane/i-PrOH, 1 mL/min).
After considerable experimentation, we discovered that tri-
fluoroacetic acid facilitated the transformation of 22 into a
compound whose spectral data matched reasonably well with
the available data for 1. Ultimately, we determined that this
product did not have the structure of 1. Instead, we are now
confident that N,O-acetal 23 was produced from this reaction
(Scheme 4).7b Nevertheless, this fact was initially unrecognized
due to the paucity of NMR data available for 1,22 a compound
whose structure was determined in 1964.2b Optimized conditions
for the production of 23 entailed warming a solution of 22 in
CH2Cl2 at 35 °C in the presence of 3 equiv of TFA and 10
weight equiv of 4 Å MS for 22 h (Scheme 4). Reactions
conducted at room temperature were sluggish, proceeding to
<50% completion after 24 h. To the best of our knowledge,
the skeleton represented by 23 is not produced in nature.
Hereafter, we refer to 23 and related compounds as isohasubanan
alkaloids.
Convinced that we had successfully completed the total
synthesis of racemic 1, we set out to accomplish an enantiose-
lective total synthesis. This required an enantioselective ketone
allylation (19f20, Scheme 3). Recently, numerous methods for
enantioselective ketone allylation have been reported.23,24
However, to the best of our knowledge, none of these processes
have been employed in a total synthesis; rather, the development
of this methodology has primarily been conducted with simple
acetophenone derivatives. We were anxious to determine which,
if any, of the known enantioselective ketone allylation protocols
were compatible with the sterically hindered, functional-group-
laden substrates typically encountered in a total synthesis.
The structures of the chiral allylating reagents and catalysts
which we tested are portrayed in Figure 2, and the results of
our investigation are contained in Table 1. Application of the
chromium-catalyzed procedure discovered by Sigman23b resulted
in consumption of 19, but a complex mixture was created from
which 20 could not be identified (entry 1).25 The Walsh protocol,
which employs a Ti-BINOL catalyst in conjunction with
tetraallyltin,23d gave a cleaner mixture, but the major product
was neither 20 nor the 1,4-addition product 21 (entry 2). We
attempted to modify this method by generating chiral allyltita-
nium reagent 26 via reaction of the Ti-BINOL complex with
allylmagnesium chloride. The resultant species did react with
19 to form 20; unfortunately, the allylic alcohol was produced
in racemic fashion (entry 3). The asymmetric Sakurai-Hosomi
allylation of Yamamoto23g and the copper-catalyzed enantiose-
lective allylboration of Shibasaki23k also yielded racemic
homoallylic alcohol 20 (entries 5 and 7). In our hands, the
catalysts and reagents developed by Schaus23e and Loh23j were
unreactive with 19 (entries 4 and 6). Our first promising result
came from the TADDOL-modified Grignard reagents of
(23) (a) Zhang, X.; Chen, D.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72,
5227. (b) Miller, J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752. (c)
Wooten, A. J.; Kim, J. G.; Walsh, P. J. Org. Lett. 2007, 9, 381. (d) Kim, J. G.;
Waltz, K. M.; Garcia, I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc.
2004, 126, 12580. (e) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc.
2006, 128, 12660. (f) Burns, N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.;
Leighton, J. L. Angew. Chem., Int. Ed. 2006, 45, 3811. (g) Wadamoto, M.;
Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556. (h) Canales, E.; Prasad,
K. G.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 11572. (i) Lu, J.; Hong,
M.-L.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Chem. Commun. 2005, 4217. (j) Teo,
Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743. (k) Wada, R.; Oisaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910. (l) Wu, T. R.;
Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701. (m) Cunningham, A.; Mokal-
Parekh, V.; Wilson, C.; Woodward, S. Org. Biomol. Chem. 2004, 2, 741. (n)
Cunningham, A.; Woodward, S. Synlett 2002, 43. (o) Hanawa, H.; Kii, S.;
Maruoka, K. AdV. Synth. Catal. 2001, 343, 57. (p) Casolari, S.; D’Addario, D.;
Tagliavini, E. Org. Lett. 1999, 1, 1061. (q) Yasuda, M.; Kitahara, N.; Fujibayashi,
T.; Baba, A. Chem. Lett. 1998, 743. (r) Nakamura, M.; Hirai, A.; Sogi, M.;
Nakamura, E. J. Am. Chem. Soc. 1998, 120, 5846. (s) Weber, B.; Seebach, D.
Tetrahedron 1994, 50, 6117.
(21) These conditions (reported in ref 9) are based on the work of
Matsumoto: Yasui, Y.; Koga, Y.; Suzuki, K.; Matsumoto, T. Synlett 2004, 615.
(22) We were able to locate two sets of partial low-field 1H NMR data for
1 in the literature: Singh, R. S.; Kumar, P.; Bhakuni, D. S J. Nat. Prod. 1981,
44, 664, as well as refs 2a and 2b. Both sets of data only list chemical shift
values for the aromatic hydrogens, the methoxy and N-methyl groups, and the
R-ketone hydrogens. Interestingly, the two sets of data do not agree very well
with each other; the differences in chemical shift range from 0.10 to 0.25 ppm.
We attributed these discrepancies to the existence of multiple forms of 1 (i.e.,
different salts versus the free base). Our data matched more closely to that of
Bhakuni. We also obtained COSY and HETCOR spectra which were consistent
with the connectivity of atoms shown in 1. We were unable to locate any 13C
NMR data for 1 in the literature, and a discrepancy between structure 1 and our
13C NMR data was initially overlooked due to the overlapping of two signals
(vide infra).
(24) For reviews, see: (a) Garc´ıa, C.; Mart´ın, V. S. Curr. Org. Chem. 2006,
10, 1849. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(25) This experiment was conducted by Jeremie J. Miller in the Sigman
laboratory at the University of Utah.
1190 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
FIGURE 2. Catalysts and reagents used in enantioselective ketone allylation studies.
SCHEME 5. Enantioselective Synthesis of (-)-23a
SCHEME 6. Synthesis of Boronate 34
a See Schemes 3 and 4 for conversion of 21 into 23.
MeOH),22 and -134 (c 0.82, MeOH)27 have been reported. Our
measurement ([R]25D -114 (c 0.45, MeOH)) was relatively close
to that of Kupchan and co-workers.27 Consequently, we thought
we had synthesized the natural enantiomer of hasubanonine,
and we attributed the varying optical rotation values to
concentration and solvent effects.
Seebach.23s Use of the tetraphenyl TADDOL ligand 31a
provided alcohol 20 in modest enantiomeric excess (25% ee,
entry 8). However, the reaction had to be conducted at -108
°C in order to achieve any enantioselectivity. Interestingly, the
reaction was quite rapid (ca. 30 min) at this low temperature.
Unfortunately, replacing TADDOL 31a with either tetranaphthyl
TADDOL 31b or cyclohexanone-derived TADDOL 31c led to
poorer results (entries 9 and 10).
We were anxious to determine the scope of the Nakamura
asymmetric ketone allylation and the versatility of what we
believed was a route to the hasubanan alkaloids. Accordingly,
we next embarked upon a total synthesis of (-)-runanine28 (2,
Figure 1). The structural similarities between 1 and 2 allowed
us to employ aryl iodide 8 as an intermediate in this new
endeavor. However, an arylboronic ester isomeric to 14 was
required. The preparation of this new building block was
straightforward and is detailed in Scheme 6. Veratraldehyde
(12), the precursor to 14, was the starting point for this synthesis
as well. Ag+-mediated iodination of 12 afforded known aryl
iodide 33.29 Borylation of 33 utilizing the procedure described
in Scheme 2 for iodide 13 delivered the requisite arylboronic
ester 34 in good yield. It is noteworthy that two isomeric aryl
iodides (13 and 33) can be accessed from veratraldehyde via
complementary iodination protocols.
In 1998, the Nakamura group developed a bisoxazoline-
ligated chiral allylzinc reagent (32, Figure 2) for the enantiose-
lective allylation of alkynyl ketones.23r Despite its utility for
this purpose, Nakamura’s reagent has not found wide application
in organic synthesis.26 To our delight, 32 reacted cleanly with
ketone 19, affording (-)-20 in 93% ee (entry 11). Separation
of the bisoxazoline ligand from (-)-20 was challenging but
possible, affording a 76% yield of the desired product. In
practice, we found it more convenient to perform the subsequent
anionic oxy-Cope rearrangement on crude (-)-20 and purify
the resultant ketone (-)-21 (Scheme 5). This intermediate was
then converted into (-)-isohasubanonine ((-)-23) by means of
the pathway outlined in Scheme 3 and 4. Chiral HPLC analysis
of (-)-23 indicated that no racemization occurred during the
synthesis. At the time, we still believed we had synthesized
hasubanonine instead of isohasubanonine. Accordingly, we
compared our optical rotation value to those recorded in the
literature for (-)-1. Interestingly, there is a discrepancy in the
literature regarding the magnitude of the optical rotation of
hasubanonine; values of -219 (c 0.78, EtOH),2c -214 (c 2.0,
(26) A Scifinder Scholar search failed to turn up any examples of the use of
32 other than the reactions reported in ref 23r.
(27) Kupchan, S. M.; Suffness, M. I.; White, D. N. J.; McPhail, A. T.; Sim,
G. A. J. Org. Chem. 1968, 33, 4529.
(28) Zhi-Da, M.; Ge, L.; Guang-Xi, X.; Iinuma, M.; Tanaka, T.; Mizuno,
M. Phytochemistry 1985, 24, 3084 This paper contains a full set of 1H NMR
data for 2, but no 13C NMR data.
(29) (a) Ahmad-Junan, S. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans.
1 1992, 675. (b) Olivera, R.; SanMartin, R.; Dom´ınguez, E.; Solans, X.; Urtiaga,
M. K.; Arriortua, M. I. J. Org. Chem. 2000, 65, 6398.
J. Org. Chem. Vol. 74, No. 3, 2009 1191

Nielsen et al.
SCHEME 7. Synthesis of (-)-Isorunanine ((-)-43)
Arylboronic ester 34 and iodide 8 were joined in a high-
yielding Suzuki coupling, providing biaryl dialdehyde 35
(Scheme 7). We attribute the greater yield in this reaction
relative to the analogous transformation in the isohasubanonine
synthesis (99% vs 79%; see Scheme 3) to the less hindered
nature of 34 compared to 14. The subsequent Wittig reaction
and ring-closing metathesis also proceeded well, delivering
phenanthrene 37. Surprisingly, 37 was considerably more
resistant to reduction than its counterpart 17 from the isoha-
subanonine series. When 37 was exposed to the conditions used
to convert 17 into phenolic dihydrophenanthrene 18 (70 psi H2,
Pd/C, EtOAc), the major product was the corresponding
phenolic phenanthrene in which the extended aromatic system
remained intact. Increases in both pressure (up to 1200 psi) and
reaction time (up to 5 d) gave no more than minor amounts of
desired dihydrophenanthrene 38. The use of other protocols
reported to reduce phenanthrenes to dihydrophenanthrenes (Li/
NH3,30 RhCl3/70 psi H2,31 PtO2/300 psi H232) afforded complex
mixtures presumably derived from over-reduction. Our standard
hydrogenation conditions developed with phenanthrene 17
employed EtOAc as solvent due to insolubility of the starting
material in MeOH, which is often the solvent of choice for
hydrogenations. We found that the debenzylated phenanthrene
derived from 37 was soluble in MeOH; accordingly, we
attempted to hydrogenate the partially reduced compound in
this solvent. Dihydrophenanthrene 38 was produced from these
reactions; however, yields were low and variable (15-50%).
Finally, an effective solution was provided by substituting Pd
black for Pd/C. With this more active catalyst, 38 was obtained
in a single step from 37 in excellent yield (97%). It is possible
that the existence of steric strain between the C-5 methoxy group
and the C-4 hydrogen of 17, which is relieved upon reduction
of the phenanthrene, renders this substrate more reactive than
37 to hydrogenation. The latter compound does not possess a
methoxy group at C-5 and thus cannot benefit from a corre-
sponding strain release upon reduction.33
Phenolic oxidation of 38 proceeded smoothly, providing
masked o-benzoquinone 39 and setting the stage for the crucial
asymmetric allylation. We were pleased to discover that
Nakamura’s reagent 32 facilitated a clean, highly enantioselec-
tive allylation, delivering homoallylic alcohol (-)-40 in 92%
ee. As in the (-)-isohasubanonine total synthesis, this inter-
mediate was typically subjected to the anionic oxy-Cope
rearrangement in crude form. In this way, a 62% yield of ketone
(-)-41 was produced from 39. Then, ozonolysis, reductive
amination, and Michael-type cyclization afforded (-)-isoruna-
nine ((-)-43). Importantly, in the process of optimizing the
cyclization, we found that it could be conducted with fewer
equivalents of TFA than employed previously (1.5 vs 3.0).
1
Comparison of our H NMR data for (-)-43 to the data
available in the literature for (-)-228 revealed numerous
discrepancies. Moreover, our measured optical rotation for (-)-
43 ([R]25 -34 (c 0.38, CHCl3)) was significantly lower than
D
the reported value for (-)-2 ([R]25 -400 (c 0.8, CHCl3)).28
D
Thus, at this point it was clear that we had not synthesized
runanine. Furthermore, given the similarities in the 1H and 13
C
NMR spectra of 23 and 43, we began to doubt that we had
synthesized hasubanonine. Accordingly, we commenced a
thorough structural investigation of the two products. Unfortu-
nately, attempts to grow crystals suitable for X-ray diffraction
were thwarted by decomposition of the material in solution over
a period of days at room temperature. Both 23 and 43 are stable
to long-term storage at -30 °C, and they do not decompose
(30) Broering, T. J.; Morrow, G. W. Synth. Commun. 1999, 29, 1135.
(31) Amer, I.; Amer, H.; Ascher, R.; Blum, J.; Sasson, Y.; Vollhardt, K. P. C.
J. Mol. Catal. 1987, 39, 185.
(32) Bhandari, S. R.; Kapadi, A. H. Indian J. Chem., Sect. B 1985, 24B,
204.
(33) We thank the reviewers for this suggestion.
1192 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
FIGURE 3. HMBC (solid arrows) and NOE (dashed arrows) correla-
tions of 43.
noticeably during purification or overnight NMR experiments.
Nevertheless, their instability to standard crystallization condi-
tions provides indirect evidence that they are not hasubanan
alkaloids, as an X-ray structure of a hasubanan alkaloid has
been obtained previously.27
Fortunately, NOE and 2D NMR experiments were informa-
tive and allowed us to determine the structures of our products.
Isorunanine ((-)-43) was quite well-suited for NMR analysis,
as the positioning of the aryl hydrogens allowed us to observe
through-bond and through-space correlations across a large
portion of the molecule. COSY, HMQC, HMBC, and NOE
experiments were in strong agreement with the isorunanine
structure, and the diagnostic HMBC and NOE correlations are
shown in Figure 3. Particularly instructive are the H-19/C-7 and
H-21/C-7 HMBC correlations as well as the H-19/H-21 NOE
correlation, which demonstrate the presence of an N,O-acetal
moiety. Furthermore, the relative positions of C-5, C-6, and C-15
are established by the H-5/C-6 HMBC correlation combined
with NOE enhancements between H-4 and H-5, H-4 and H-15,
and H-5 and H-15. An identical set of NMR experiments
conducted on (-)-23 were also in agreement with the proposed
isohasubanan alkaloid skeleton.34
Comparison of the hasubanan and isohasubanan alkaloid
skeletons (see Figures 1 and 3) reveals a fairly simple way to
distinguish the two classes of compounds. The 13C NMR spectra
of 1 and 2 should show nine downfield signals (g90 ppm) and
twelve upfield signals (e70 ppm), whereas 10 downfield and
11 upfield signals should be observed in the corresponding
spectra of 23 and 43. Unfortunately, the signals for C-12 and
C-14 of 23 overlap precisely at 129.5 ppm. Therefore, we
initially believed there were only nine downfield signals, and
we assigned a small peak caused by an impurity at 29.9 ppm
(presumably hydrocarbon grease) as the twelfth upfield signal.
Fortunately, the C-12 and C-14 peaks in 43 are resolved (129.45
and 129.41 ppm), so proper interpretation of the 13C spectrum
of this compound was much simpler.
FIGURE 4. Difference between calculated and experimental 13C NMR
shifts for runanine (2). The average |∆δ| was 9.7 ppm, and the maximum
was 61.7 ppm.
tool in the structural assignment of organic molecules. It has
been particularly valuable in distinguishing between constitu-
tional isomers. Accordingly, we turned to these calculations as
a means of checking the validity of our proposed isorunanine
structure. Thus, the geometries of runanine (2), isorunanine (43),
and isomers 44-46 (see Figures 5–7 for structures) were
optimized at the mPW1PW91/6-31G(d,p) level, and the resultant
conformations were subjected to GIAO NMR calculations.
Isomer 45, which differs from runanine in the orientation of
the pyrrolidine ring, was included in this exercise because we
could envision a mechanism for its formation under the acidic
cyclization conditions involving the 1,2-alkyl shift of a cationic
intermediate. Although we could not formulate a reasonable
mechanistic hypothesis for the production of compounds 44 and
46, which are the carbonyl-transposed isomers of 2 and 45, we
recognized that both would possess identical spin systems to 2,
43, and 45. Since structures 44 and 46 could possibly fit our
NMR data, we included them in the computational exercise to
ensure completeness. Our results are recorded in Figures 4-8.
Clearly, structures 2 and 44-46 are not good fits for the
experimentally obtained data. In particular, C-7 (N,O-acetal
carbon in 43, alkene carbon in other structures) and C-14 (alkene
carbon in 43, quaternary aliphatic carbon in other structures)
exhibited significant error (ca. 40-60 ppm difference between
calculated and observed chemical shifts). The average difference
between the computed and observed chemical shifts for
structures 2 and 44-46 ranged from 9.3 to 12.0 ppm. In contrast,
the calculated 13C NMR data for isorunanine (43) agreed much
better with our observed data. The average deviation dropped
to 3.8 ppm, and the maximum deviation was 9.8 ppm. C-4
Additional evidence in support of the isorunanine structure
was obtained from GIAO 13C NMR calculations. This technique
has been used by Bifulco,35 Rychnovsky,36 and others37 as a
(34) For details, see the Supporting Information.
(35) Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. ReV.
2007, 107, 3744.
(37) (a) Smith, S. G.; Paton, R. S.; Burton, J. W.; Goodman, J. M. J. Org.
Chem. 2008, 73, 4053. (b) Braddock, D. C.; Rzepa, H. S. J. Nat. Prod. 2008,
71, 728.
(36) Rychnovsky, S. D. Org. Lett. 2006, 8, 2895.
J. Org. Chem. Vol. 74, No. 3, 2009 1193

Nielsen et al.
FIGURE 5. Difference between calculated and experimental 13C NMR
shifts for isomer 44. The average |∆δ| was 9.3 ppm, and the maximum
was 60.1 ppm.
FIGURE 7. Difference between calculated and experimental 13C NMR
shifts for isomer 46. The average |∆δ| was 12.0 ppm, and the maximum
was 54.6 ppm.
FIGURE 6. Difference between calculated and experimental 13C NMR
shifts for isomer 45. The average |∆δ| was 10.9 ppm, and the maximum
was 61.8 ppm.
FIGURE 8. Difference between calculated and experimental 13C NMR
shifts for isorunanine (43). The average |∆δ| was 3.8 ppm, and the
maximum was 9.8 ppm.
exhibited the largest difference, with the calculated value (118.3
ppm) being significantly higher than the experimental value
(108.5 ppm, assignment verified by NOE and HMBC spectros-
copy). Perhaps the neighboring bridged ring system in 43 exerts
a shielding effect on this carbon which is not fully accounted
for by the computer algorithm. Reassuringly, the calculated
chemical shifts of C-7 and C-14 in structure 43 fit the
experimental 13C NMR data quite well, with differences of 0.1
and 5.6 ppm, respectively.
1194 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
Accordingly, aryl iodide 4739 was coupled with bis(pinacola-
to)diboron, affording arylboronic ester 48 (Scheme 8). In
contrast to previously performed couplings, the Suzuki coupling
of 48 with aryl iodide 8 was sluggish, with increased quantities
of Pd(dppf)2Cl2 required for good yields (0.25 equiv vs
0.10-0.15 equiv in earlier reactions). Presumably, the additional
steric hindrance caused by the o-MOM group retards the reaction
rate. Conversion of biaryl dialdehyde 49 into masked o-
benzoquinone 53 proceeded in analogous fashion to the isoha-
subanonine synthesis. Fortunately, the hydrogenation of 51 was
relatively facile and could be conducted with Pd/C. As with
phenanthrene 17, it is possible that strain release provides a
driving force for the reduction of 51. However, it was necessary
to prewash the EtOAc with Na2CO3 and store it over K2CO3,
as the use of untreated solvent led to concomitant cleavage of
the MOM group.
Gratifyingly, asymmetric allylation of ketone 53 with the
Nakamura reagent proceeded with 94% ee. As before, separation
of the product from the bisoxazoline ligand was accomplished
most conveniently after the anionic oxy-Cope rearrangement.
Then, ozonolyisis/reductive amination and subsequent cycliza-
tion delivered MOM-protected isoaknadinine ((-)-57). Unfor-
tunately, all attempts to cleave the phenolic MOM group were
unsuccessful. Numerous Brønsted and Lewis acids were exam-
ined, and analysis of the cleaner reactions indicated that loss of
a methyl ether was occurring in preference to MOM deprotec-
tion. This phenomenon provided yet another piece of evidence
in favor of the isohasubanan skeleton, which possesses a
relatively labile methyl enol ether. We were unable to remove
the MOM moiety from intermediates 53-56 without damaging
other acid-sensitive functional groups present in these com-
pounds. Consequently, we were forced to resort to a swap of
protecting groups.
We were reticent to introduce a group larger than the MOM
moiety into an arylboronic ester of type 48 for fear of further
impeding the Suzuki coupling. Thus, we maintained the existing
route up to phenanthrene 51 and then removed the MOM group
under standard conditions (Scheme 9). Protection of the resulting
free phenol as its triethylsilyl ether afforded 60, which was
converted into masked o-benzoquinone 62 in quantitative yield
over two steps. We were concerned that the additional steric
demand of 62 relative to the other ketones employed in the
Nakamura asymmetric allylation might be problematic. While
we did need to increase the concentration of chiral allylzinc
reagent 32 in order to obtain good yields (1.8 equiv vs 1.4 equiv
used previously), we were pleased to find that alcohol 63 was
produced in excellent ee (96%). When 63 was subjected to the
anionic oxy-Cope rearrangement, rapid TES cleavage occurred,
and the rearrangement was extremely sluggish. Therefore, the
silyl ether was removed under conventional conditions, and the
crude phenol was treated with KOt-Bu and 18-crown-6.
However, the rearrangement still did not occur. Success was
achieved by rapidly passing the crude phenol through a silica
gel column and then performing the sigmatropic rearrangement.
The presence of a free phenol in the substrate necessitated the
use of additional base (2.4 equiv) and elevated temperature (40
°C) to promote the reaction. Unfortunately, a low yield of ketone
(-)-64 was obtained (28%). We believe that the bulk of the
material was lost during the attempted purification of the
intermediate phenol, as multiple colored bands resulted from
application of the crude material to the column. Nevertheless,
FIGURE 9. Difference between calculated and experimental 13C NMR
shifts for isorunanine (43) in benzene. The average |∆δ| was 9.1 ppm,
and the maximum was 17.4 ppm.
The calculations described in Figures 4-8 were performed
with a chloroform solvent correction. Since we also acquired
the 13C NMR spectrum of isorunanine in C6D6, we performed
an identical set of calculations on all five structures with a
benzene solvent correction. Surprisingly, the calculated chemical
shifts for 43 in this case did not agree well with the experi-
mentally determined data (Figure 9). Particularly telling was
the fact that all aliphatic carbons bonded to heteroatoms
exhibited calculated chemical shifts which were significantly
lower than the observed values (-10.5 to -17.4 ppm devia-
tions). The reasons for this unusual phenomenon are unclear.
Experimentally, the differences in chemical shift between spectra
of isorunanine acquired in CDCl3 and C6D6 are slight (2.3 ppm
maximum difference; <1.0 ppm difference for most carbons).
Moreover, the differences in data calculated in both solvents
were quite minor (<1.0 ppm for the vast majority of carbons)
for structures 2 and 44-46. It is possible that the benzene
solvent correction algorithm is treating the bridged structure of
43 differently than it treats the fused propellane structures of 2
and 44-46. Whatever the reason, it appears that the benzene
solvent correction should be used cautiously when performing
GIAO 13C NMR calculations.
Prior to recognizing that our synthetic route did not provide
hasubanan alkaloids, we set our sights on constructing (-)-
aknadinine (3, Figure 1).22,27,38 We expected 3 to be more
challenging to prepare due to the presence of a free phenol on
the aromatic ring. This would require differentiation of the two
oxygen substituents on the arylboronic acid coupling partner.
(38) (a) Moza, B. K.; Bhaduri, B.; Basu, D. K. Chem. Ind. (London) 1969,
1178. (b) Moza, B. K.; Bhaduri, B.; Basu, D. K.; Kunitomo, J.; Okamoto, Y.;
Yuge, E.; Nagai, Y.; Ibuka, T. Tetrahedron 1970, 26, 427. (c) Kashiwaba, N.;
Morooka, S.; Kimura, M.; Ono, M.; Toda, J.; Suzuki, H.; Sano, T. J. Nat. Prod.
1996, 59, 476.
(39) Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255.
J. Org. Chem. Vol. 74, No. 3, 2009 1195

Nielsen et al.
SCHEME 8. Attempted Synthesis of (-)-Isoaknadinine ((-)-58)
SCHEME 9. Synthesis of (-)-Isoaknadinine ((-)-58)
sufficient quantities of (-)-64 were acquired to enable synthesis
of isoaknadinine, so further optimization was not pursued. In
fact, the next two steps proceeded in identical fashion to our
earlier efforts, providing (-)-58. 1D and 2D NMR spectra of
(-)-58 exhibited strong similarities to spectra of (-)-23 and
(-)-43 and possessed the characteristic features of the isoha-
subanan skeleton.34
Discussion
Although these endeavors did not result in the total synthesis
of hasubanan alkaloids, there are several interesting and useful
facets of our work. Chief among them is the discovery that
Nakamura’s chiral zinc reagent 32 is extraordinarily effective
in the enantioselective allylations of ketones 19, 39, 53, and
62. Despite the fact that asymmetric ketone allylation is currently
an active area of research,23,24 we are unaware of any previous
examples of this reaction being performed on a complex ketone
in the context of a multistep synthesis. Reagent 32 was designed
specifically for use with alkynyl ketones, and it has not been
utilized in organic synthesis.26 Our finding that other, more
elaborate ketones are excellent substrates for 32 may lead to
increased usage of this reagent.
Prior to discovery of the enantioselective ketone allylation,
we accumulated sufficient quantities of racemic 23 for evaluation
of its analgesic properties. At the time, we were under the
impression that we had prepared hasubanonine. Racemic 23 did
not exhibit any affinity for the µ, κ, or δ opioid receptors. In
the mouse tail-flick assay, no painkilling activity was detected
at concentrations of 10, 30, and 56 mg/kg. Some analgesia was
observed (approximately 50% of maximum effect) at a high
concentration of 23 (100 mg/kg). Thus, it appears that (()-23
possesses weak analgesic activity that is not mediated by opioid
receptors. These results suggest that the isohasubanan alkaloids
are not useful lead structures for new painkilling agents.
We have yet to construct any natural products or known
compounds from the enantioenriched homoallylic alcohols, and
attempts to grow crystals of isohasubanan ammonium salts
possessing heavy atoms resulted in decomposition of the
samples. Thus, at this time we are limited to speculation
1196 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
data for this compound does not allow us to draw any further
conclusions regarding its structure. It is remarkable that two
different isomers of 1, but not the natural product itself, could
be produced from 22 under related conditions.
Conclusions
We designed a convergent, brief route to three hasubanan
alkaloids which entailed constructing a dihydrophenanthrene and
then annulating a pyrrolidine ring to fashion the propellane-
type ring system. Syntheses of the final cyclization precursors
were quite efficient, but the last step was thwarted in each case
by an unanticipated pinacol-like rearrangement. Structures of
the resultant isohasubanan alkaloids were established by NMR
spectroscopy and confirmed by GIAO 13C NMR calculations.
This work adds to the growing body of examples in the literature
where such calculations have proven to be a valuable aid to
structure determination.35-37 However, we also noted some
inconsistencies in calculations employing the benzene solvent
correction which suggest that caution should be used when
applying this algorithm. Initially, the pinacol-like rearrangement
went undetected because data for isohasubanonine fit well with
the reported partial NMR data for hasubanonine. We recognized
the structural discrepancies only after attempting to synthesize
hasubanan alkaloids for which more complete NMR data were
available. Thus, our experience serves as a cautionary tale
regarding the pitfalls of relying on incomplete literature data
for verification of structure.
In the course of this endeavor, we discovered that chiral
allylzinc reagent 32, which has been unused by synthetic
chemists since its discovery in 1998 by Nakamura,23r is uniquely
and remarkably effective in enantioselective allylations of
ketones 19, 39, 53, and 62. Accordingly, reagent 32 has a scope
which extends beyond its originally intended purpose of alkynyl
ketone allylations. Studies to fully define the scope and
limitations of this reagent are in progress and will be reported
in due course. We hope that our work will serve as a catalyst
for the use of 32 and other enantioselective ketone allylating
agents in the synthesis of complex molecules.
FIGURE 10. Proposed transition-state model.
SCHEME 10. Mechanistic Rationale for Isohasubanonine
Formation
concerning the absolute configurations of the allylation adducts.
Nakamura and co-workers proposed a cyclic six-membered
transition state for allylations of alkynyl ketones by 32 in which
the alkynyl and alkyl groups of the ketone occupy axial and
equatorial positions, respectively. Computational studies lent
some support to this model.23r Superimposing our substrates
onto Nakamura’s model (Figure 10) demonstrates that the bulky
dimethyl ketal can occupy the equatorial position, whereas the
axial position can be filled by the planar aryl group. The facial
selectivity of the allylation is likely dictated by the fact that the
aryl moiety of the substrate is significantly larger than the axial
vinylic hydrogen of the allyl group. Thus, the aryl group resides
in a location where it can avoid steric interactions with the
phenyl group of the bisoxazoline ligand. If this model is correct,
then alcohols 20, 40, 54, and 63 each possess the (S)-
configuration as drawn herein. It is noteworthy that ketones 53
and 62, which incorporate sterically more demanding groups
at the R2 position than do 19 and 39, undergo the allylation
with excellent enantioselectivity. This observation bodes well
for the scope of this reaction, which will be determined by
further investigations.
A postulated mechanism explaining the formation of isoha-
subanonine (23) from hemiaminal 22 is illustrated in Scheme
10. In the presence of trifluoroacetic acid, it is possible that the
dimethyl ketal moiety of 22 undergoes ionization while the
hemiaminal remains intact. The presence of an electron-deficient
oxocarbenium ion adjacent to a hemiaminal would permit a
pinacol-like rearrangement to occur, forming a ketone and
generating the bridged ring system of 23. Presumably, this
mechanism is operative in the production of each of the
isohasubanan alkaloids.
Experimental Section
5-Benzyloxy-3,4,5′,6′-tetramethoxybiphenyl-2,2′-dicarbalde-
hyde (15). A solution of aryl iodide 8 (1.18 g, 2.96 mmol),
arylboronic ester 14 (1.08 g, 3.70 mmol), K2CO3 (1.64 g, 11.8
mmol), and Pd(dppf)Cl2 ·CH2Cl2 (362 mg, 0.44 mmol) in anhydrous
DMSO (37 mL) was stirred at 80 °C under Ar for 16 h. The mixture
was diluted with brine (20 mL) and EtOAc (25 mL), the layers
were separated, and the aqueous layer was extracted with EtOAc
(3 × 25 mL). The combined organic layers were washed with brine
(2 × 20 mL), dried (Na2SO4), and concentrated in vacuo. Flash
chromatography (SiO2, 30% EtOAc in hexanes elution) afforded
1
15 (1.02 g, 2.34 mmol, 79%) as a yellow solid: H NMR (CDCl3,
500 MHz) δ 10.18 (s, 1H), 9.46 (s, 1H), 7.77 (d, J ) 8.5 Hz, 1H),
7.41-7.32 (m, 5H), 7.05 (d, J ) 9.0 Hz, 1H), 6.57 (s, 1H), 5.12
(s, 2H), 4.07 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 3.50 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 190.2, 189.3, 157.6, 157.5, 156.7, 145.9,
142.3, 138.5, 136.0, 132.0, 128.9 (2C), 128.6, 128.2, 127.6 (2C),
125.5, 123.1, 112.7, 111.7, 71.2, 62.7, 61.3, 60.7, 56.2; IR (film)
Our early attempts at converting 22 into hasubanonine utilized
Lewis acids (TMSOTf, BCl3) or strong Brønsted acids (HCl)
and afforded an unstable byproduct which we initially thought
was 23 (see Scheme 3). Identification of the product of the TFA-
mediated cyclizations as 23 forces us to revise this hypothesis.
Unfortunately, our inability to purify and store the byproduct
precluded us from characterizing it. We have identified it as an
isomer of 23 and 1 based on HRMS, but the lack of additional
ν
max 2940, 2841, 1684, 1586, 1560, 1276, 1254, 1109 cm-1; HRMS
(ESI) m/z 437.16032 (MH+, C25H24O7H requires 437.15948).
5-Benzyloxy-3,4,2′,3′-tetramethoxy-2,6′-divinylbiphenyl (16).
A suspension of methyltriphenylphosphonium bromide (purified by
flash chromatography with 5-15% MeOH in CH2Cl2 gradient
elution and then dried over P2O5 in a vacuum desiccator for 3 d,
J. Org. Chem. Vol. 74, No. 3, 2009 1197

Nielsen et al.
3.20 g, 8.96 mmol) in anhydrous THF (100 mL) was cooled to 0
°C and treated dropwise with n-BuLi (6.40 mL, 1.6 M in hexanes,
10.24 mmol). The solution was warmed to rt, stirred for 2 h, then
cooled to -78 °C and treated dropwise over 10 min with a solution
of 15 (869 mg, 1.99 mmol) in anhydrous THF (90 mL + 2 × 5
mL rinses). The resultant mixture was stirred for 10 min and then
warmed to rt and stirred for 1.5 h. The reaction was quenched by
the addition of 2 N HCl (9 mL, 18 mmol), diluted with brine (100
mL), and extracted with EtOAc (3 × 70 mL). The combined organic
layers were dried (Na2SO4), and the solvent was removed in vacuo.
Flash chromatography (SiO2, 5-15% EtOAc in hexanes gradient
elution) afforded 16 (800.8 mg, 1.85 mmol, 93%) as a colorless
1541, 1340, 1078 cm-1; HRMS (ESI) m/z 369.13084 (MNa+,
C19H22O6Na requires 369.13086).
3-Allyl-1,2,2,5,6-pentamethoxy-2,3,9,10-tetrahydrophenanthren-
3-ol (20). A solution of 19 (213 mg, 0.615 mmol) in anhydrous
Et2O (21 mL) at -78 °C under Ar was treated dropwise with
allylmagnesium chloride (2.0 M in THF, 1.69 mL, 3.38 mmol).
The resulting mixture was stirred at -78 °C for 1 h and then treated
with brine (2 mL) and allowed to warm to rt. The mixture was
diluted with additional brine (20 mL) and satd aq potassium tartrate
(5 mL) and then extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo. Flash
chromatography (SiO2, 2:10:88 Et3N/EtOAc/hexanes elution) af-
forded 20 (222 mg, 0.572 mmol, 93%) as a colorless oil: 1H NMR
(C6D6, 500 MHz) δ 7.10 (s, 1H), 6.64 (d, J ) 8.5 Hz, 1H), 6.47
(d, J ) 8.5 Hz, 1H), 6.31-6.22 (m, 1H), 5.12 (dd, J ) 17.0, 2.0
Hz, 1H), 5.02 (dd, J ) 10.5, 1.0 Hz, 1H), 3.71 (s, 3H), 3.62 (s,
3H), 3.45 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 3.05 (s, 1H), 2.91-2.85
(m, 1H), 2.79-2.74 (m, 1H), 2.54-2.45 (m, 3H), 2.43-2.37 (m,
1H); 13C NMR (C6D6, 125 MHz) δ 153.1, 149.8, 136.5, 135.9,
135.5, 132.9, 127.7, 125.7, 125.4, 123.5, 117.8, 112.5, 101.8, 80.5,
61.2, 59.9, 56.3, 51.6, 51.0, 40.0, 30.5, 24.1; IR (film) νmax 3582,
2937, 2835, 1480, 1261, 1218, 1053 cm-1; HRMS (ESI) m/z
411.17711 (MNa+, C22H28O6Na requires 411.17781).
1
oil: H NMR (CDCl3, 300 MHz) δ 7.43-7.25 (m, 6H), 6.92 (d, J
) 9.0 Hz, 1H), 6.49 (s, 1H), 6.33 (dd, J ) 11.7, 18.0 Hz, 1H),
6.21 (dd, J ) 11.1, 17.4 Hz, 1H), 5.49 (d, J ) 17.4 Hz, 1H), 5.43
(d, J ) 17.7 Hz, 1H), 5.13-5.03 (m, 3H), 4.96 (d, J ) 11.1 Hz,
1H), 3.98 (s, 3H), 3.90 (s, 6H), 3.48 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 152.7, 152.6, 151.2, 146.4, 142.4, 137.1, 135.0, 134.7,
131.6, 131.3, 130.3, 128.7 (2C), 128.1, 127.6 (2C), 124.3, 120.6,
117.7, 113.1, 112.0, 111.8, 70.8, 61.3, 60.8, 60.6, 56.0; IR (film)
νmax 2936, 2836, 1589, 1481, 1290, 1128, 912, 738 cm-1; HRMS
(ESI) m/z 433.20074 (MH+, C27H28O5H requires 433.20095).
3-Benzyloxy-1,2,5,6-tetramethoxyphenanthrene (17). A solu-
tion of 16 (367 mg, 0.849 mmol) and the Grubbs second-generation
ruthenium catalyst16 (18.2 mg, 0.021 mmol) in anhydrous CH2Cl2
(83 mL) was stirred at 40 °C under Ar for 2 h. The solvent was
removed in vacuo, and the residue was purified via flash chroma-
tography to afford 17 (340 mg, 0.841 mmol, 99%) as a white solid:
1H NMR (CDCl3, 300 MHz) δ 9.11 (s, 1H), 7.91 (d, J ) 9.3 Hz,
1H), 7.61 (d, J ) 8.7 Hz, 1H), 7.57-7.52 (m, 3H), 7.44 (t, J ) 7.8
Hz, 2H), 7.35-7.25 (m, 2H), 5.36 (s, 2H), 4.07 (s, 6H), 4.01 (s,
3H), 3.70 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 151.5, 151.2,
148.6, 146.7, 141.7, 137.4, 128.8 (2C), 128.6, 128.0, 127.3 (2C),
126.4, 125.3, 125.1, 124.3, 123.5, 118.8, 113.1, 107.0, 70.7, 61.9,
61.4, 60.1, 56.7; IR (film) νmax 2933, 2830, 1597, 1501, 1276, 1113,
742 cm-1; HRMS (ESI) m/z 427.15077 (MNa+, C25H24O5Na
requires 427.15159).
(-)-20. A solution of bis((S)-4-phenyl-4,5-dihydrooxazol-2-
yl)methane40 (13.9 mg, 0.045 mmol) and 2,2′-dipyridyl (one crystal)
in anhydrous THF (200 µL) under Ar at 0 °C was treated dropwise
with n-BuLi (1.6 M in hexanes, 0.055 mL, 0.088 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, 43.4 µL, 0.043 mmol) and cooled to -78 °C. A
solution of 19 was added dropwise (0.7 M in THF, 42 µL, 0.029
mmol), and the resultant mixture was stirred at -78 °C under
Ar for 80 min. The reaction was quenched by the addition of
MeOH–H2O (1:1, 0.5 mL), and the mixture was extracted with Et2O
(3 × 1 mL). The combined organic layers were washed with aq
NaOH (0.5 M, 0.5 mL), dried (Na2SO4), and concentrated in vacuo.
Preparative TLC (SiO2, 2:20:78 Et3N/EtOAc/hexanes elution)
afforded (-)-20 (9 mg, 0.022 mmol, 76%): [R]25 -76.1 (c 0.28,
1,2,5,6-Tetramethoxy-9,10-dihydrophenanthren-3-ol (18). A
flask containing 17 (340 mg, 0.841 mmol), 10% Pd/C (170 mg),
and EtOAc (28 mL) was placed inside a Parr apparatus, pressurized
to 70 psi with H2, and stirred for 16 h. The mixture was filtered
through a pad of Celite and concentrated in vacuo. Flash chroma-
tography (SiO2, 22% EtOAc/hexanes elution) afforded 18 (252 mg,
0.797 mmol, 95%) as a colorless oil: 1H NMR (CDCl3, 500 MHz)
δ 7.90 (s, 1H), 6.93 (d, J ) 8.0 Hz, 1H), 6.79 (d, J ) 8.0 Hz, 1H),
5.57 (s, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H),
2.76-2.71 (m, 2H), 2.68-2.64 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 152.3, 149.0, 147.4, 147.2, 139.1, 132.2, 129.0, 127.9,
124.8, 123.0, 111.3, 111.1, 61.1, 60.9, 60.4, 56.2, 29.7, 21.9; IR
(film) νmax 3421, 2937, 2834, 1568, 1096, 760 cm-1; HRMS (ESI)
m/z 317.13840 (MH+, C18H20O5H requires 317.13835).
1,2,2,5,6-Pentamethoxy-9,10-dihydro-2H-phenanthren-3-
one (19). A mixture of KHCO3 (112.7 mg, 1.11 mmol), I,I-
diacetoxyiodobenzene (164.8 mg, 0.512 mmol), and anhydrous
CH3OH (5 mL) was cooled to -10 °C and treated dropwise over
5 min with a solution of 18 (147 mg, 0.465 mmol) in anhydrous
CH3OH (5 mL + 1 mL rinse). The resultant mixture was stirred at
-10 °C for 20 min and then diluted with brine (10 mL) and CH2Cl2
(15 mL). The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo. Flash chromatog-
raphy (SiO2, 2:8:90 Et3N/EtOAc/hexanes elution) afforded 19 (141.6
mg, 0.409 mmol, 88%) as a yellow oil that solidified upon standing:
1H NMR (C6D6, 500 MHz) δ 7.37 (s, 1H), 6.58 (d, J ) 8.0 Hz,
1H), 6.48 (d, J ) 8.0 Hz, 1H), 3.91 (s, 3H), 3.57 (s, 3H), 3.42 (s,
6H), 3.27 (s, 3H), 2.58-2.55 (m, 2H) 2.43-2.40 (m, 2H); 13C NMR
(C6D6, 125 MHz) δ 195.1, 153.6, 152.9, 150.5, 146.3, 135.9, 128
(obscured by solvent peak), 126.9, 123.4, 120.3, 115.2, 95.0, 60.4,
59.8, 56.2, 51.2 (2C), 30.3, 23.4; IR (film) νmax 2941, 2840, 1660,
D
CH2Cl2). Chiral HPLC analysis (Chiralcel OD-H, 99:1 hexane/i-
PrOH, 1 mL/min, tR ) 10.7 min, 26.1 min (major)) demonstrated
that (-)-20 was obtained in 93% ee.
(-)-4a-Allyl-1,2,2,5,6-pentamethoxy-4,4a,9,10-tetrahydro-2H-
phenanthren-3-one ((-)-21). A mixture of KO-t-Bu (70 mg, 0.62
mmol), 18-crown-6 (169 mg, 0.64 mmol), and anhydrous THF (5
mL) at -10 °C under Ar was stirred for 10 min. A solution of 20
(80 mg, 0.206 mmol) in anhydrous THF (5 mL) was added to the
mixture dropwise over 3 min, and the resultant mixture was stirred
at -10 °C for 10 min. The solution was treated with brine (10
mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. Flash
chromatography (SiO2, 2:5:93 Et3N/EtOAc/hexanes elution) af-
forded 21 (59.4 mg, 0.153 mmol, 74%) as a colorless oil: [R]25
D
-151.8 (c 0.61, CH2Cl2); 1H NMR (C6D6, 500 MHz) δ 6.81-6.76
(m, 2H), 5.61-5.50 (m, 1H), 4.96 (d, J ) 16.0 Hz, 1H), 4.90, (d,
J ) 10.0 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H), 3.59 (d,
J ) 14.0 Hz, 1H), 3.43 (s, 3H), 3.24 (s, 3H), 3.12-3.07 (m, 1H),
3.01-2.86 (m, 3H), 2.77 (td, J ) 14.0, 5.0 Hz, 1H), 2.60 (dd, J )
14.0, 8.0 Hz, 1H), 2.17 (td, J ) 14.0, 5.0 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 203.1, 151.8, 148.3, 145.7, 135.6, 135.0,
134.9, 130.0, 124.1, 118.1, 111.9, 97.9, 62.3, 60.7, 56.1, 52.7, 51.3,
49.0, 46.4, 44.8, 31.7, 23.0; IR (film) νmax 2939, 2836, 1731, 1483,
1275, 1089, 919, 808, 736 cm-1; HRMS (ESI) m/z 411.17711
(MNa+, C22H28O6Na requires 411.17781).
Hemiaminal (-)-22. A solution of 21 (30.0 mg, 0.0772 mmol)
in EtOAc (7.5 mL) at -78 °C was treated with O3 (bubbled slowly
through the mixture) until the starting material was consumed as
(40) Hall, J.; Lehn, J.-M.; DeCian, A.; Fischer, J. HelV. Chim. Acta 1991,
74, 1.
1198 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of Isohasubanan Alkaloids
indicated by TLC. The solution was then stirred for 5 min before
being treated with Et3N (33.0 µL, 0.232 mmol). The resulting
solution was stirred at rt for 16 h and then concentrated in vacuo
to afford the crude aldehyde.
EtOAc/hexanes elution) afforded 23 (5.4 mg, 0.0145 mmol, 81%)
as a light yellow oil that solidified on standing: [R]25 -114 (c
D
0.45, MeOH); 1H NMR (CDCl3, 500 MHz) δ 6.82 (d, J ) 8.5 Hz,
1H) 6.78 (d, J ) 8.5 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.72 (s,
3H), 3.51 (s, 3H), 3.42-3.34 (m, 1H), 3.22 (d, J ) 19 Hz, 1H),
3.01-2.95 (m, 1H), 2.95-2.88 (m, 1H), 2.84-2.77 (m, 2H),
2.65-2.58 (m, 1H), 2.41 (s, 3H), 2.33 (d, J ) 19 Hz, 1H),
2.20-2.12 (m, 1H), 1.49-1.44 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 205.7, 152.0, 148.4, 146.2, 135.8, 129.5 (2C), 124.0, 111.2,
92.7, 61.8, 60.8, 56.1, 51.9, 49.4, 47.7, 39.4, 34.9, 30.5, 29.5, 22.5;
The aldehyde was then dissolved in anhydrous CH3OH (1 mL)
and treated with 4 Å MS (50 mg) followed by CH3NH2 (1.7 M in
CH3OH, 181 µL, 0.308 mmol). The mixture was stirred at rt for
30 min, then treated with NaBH3CN (9.7 mg, 0.154 mmol) and
stirred for 5 h before being quenched with 0.1 N NaOH (0.5 mL),
diluted with brine (0.5 mL), and extracted with EtOAc (4 × 1.5
mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. Flash chromatography (SiO2, 2:20:78 Et3N/
EtOAc/hexanes elution) afforded 22 (19.2 mg, 0.0474 mmol, 62%)
as a colorless oil: [R]25D -190.1 (c 1.15, CH2Cl2); 1H NMR (C6D6,
500 MHz) δ 6.64 (d, J ) 8.0 Hz, 1H), 6.50 (d, J ) 8.0 Hz, 1H),
3.85 (s, 3H), 3.67 (s, 3H), 3.58 (s, 3H), 3.37 (s, 3H), 3.32 (s, 3H),
3.29-3.24 (m, 1H), 3.09 (d, J ) 12.5 Hz, 1H), 3.07-2.94 (m,
2H), 2.93 (s, 3H), 2.80-2.75 (m, 1H), 2.73-2.66 (m, 2H), 1.97
(d, J ) 11.5 Hz, 1H), 1.81 (td, J ) 13.0, 5.5 Hz, 1H), 1.40-1.24
(m, 1H), 1.18 (d, J ) 12.5 Hz, 1H); 13C NMR (C6D6, 125 MHz) δ
152.7, 150.3, 148.6, 135.8, 131.2, 131.0, 124.2, 112.2, 100.1, 86.4,
62.9, 60.8, 56.0, 52.4, 49.2, 42.6, 41.3, 37.3, 31.9, 30.6, 29.9, 22.3;
IR (film) νmax 2925, 2849, 1724, 1660, 1601, 1483, 1272 cm-1
;
HRMS(ESI)m/z374.19811(MH+,C21H27NO5Hrequires374.19620).
Acknowledgment. We thank Brigham Young University
(Undergraduate Research Awards to D.K.N., L.L.N., and S.B.J.;
Mentoring Environment Grant to S.L.C.) and the National
Science Foundation (CHE-716991) for financial support. We
also thank Jeremie J. Miller of the Sigman laboratory at the
University of Utah for conducting the experiment listed in entry
1 of Table 1 and Dr. Liwen He for his contributions to the early
stages of this work.
IR (film) νmax 3421, 2920, 2854, 1596, 1460, 1254, 1064 cm-1
;
HRMS (ESI) m/z 406.2220 (MH+, C22H31NO6H requires 406.2230).
(-)-Isohasubanonine ((-)-23). A solution of 22 (7.2 mg, 0.0178
mmol) in anhydrous CH2Cl2 (2.0 mL) was treated with 4 Å MS
(72 mg) and stirred at rt for 10 min. Trifluoroacetic acid (1.0 M in
CH2Cl2, 53 µL, 0.053 mmol) was added slowly, and the resultant
mixture was stirred at 35 °C for 22 h. The reaction was quenched
by the addition of K3PO4 (50 mg), stirred for 5 min, filtered, and
concentrated in vacuo. Flash chromatography (SiO2, 2:20:78 Et3N/
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds not
included in the Experimental Section, NMR spectra for all new
compounds, chiral HPLC traces, description of GIAO 13C NMR
calculations, and description of analgesic assays. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO802370V
J. Org. Chem. Vol. 74, No. 3, 2009 1199