Convergency and divergency as strategic elements in total synthesis: The total synthesis of (-)-drupacine and the formal total synthesis of (±)-cephalotaxine, (-)-cephalotaxine, and (+)-cephalotaxine

Article abstract of DOI:10.1021/jo0710883

(Chemical Equation Presented) A concise route toward the syntheses of (-)-drupacine and (+)- and (-)-cephalotaxine has been developed. The syntheses rely on Pd(II)-catalyzed aerobic oxidative heterocyclization chemistry, which was employed to rapidly cons

Full text of DOI:10.1021/jo0710883

Convergency and Divergency as Strategic Elements in Total
Synthesis: The Total Synthesis of (-)-Drupacine and the Formal
Total Synthesis of (()-Cephalotaxine, (-)-Cephalotaxine, and
(+)-Cephalotaxine
Qi Liu, Eric M. Ferreira, and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125
stoltz@caltech.edu
ReceiVed June 8, 2007
A concise route toward the syntheses of (-)-drupacine and (+)- and (-)-cephalotaxine has been developed.
The syntheses rely on Pd(II)-catalyzed aerobic oxidative heterocyclization chemistry, which was employed
to rapidly construct an important spirocyclic amine intermediate. A dynamic â-elimination/conjugate
addition process was strategically applied to complete the first asymmetric total synthesis of (-)-drupacine.
Introduction
members of this family of natural products have shown potent
antileukemic activity, especially ester derivatives at C(3) (Figure
1). For example, homoharringtonine (4) has an IC50 of 0.014
µg/mL against murine lymphoma L1210 and 0.010 µg/mL
against human epidermoid carcinoma KB cells. In addition, it
has been reported that cancer patients who had become resistant
to other forms of chemotherapy responded positively to cepha-
lotaxine esters, indicating possible multiple drug resistance
reversing activity.3 Recently, about a dozen new members of
this family have been isolated from Cephalotaxus harringtonia
var. nana., with several of them (e.g., cephalezomine A (2))
demonstrating comparable anticancer activity to homoharringto-
nine (4).4
The Cephalotaxus alkaloids are a class of complex cytotoxic
natural products first isolated from Asian plum yews Cepha-
lotaxus drupacea and Cephalotaxus fortunei.1 Their structures
were partially determined through the efforts of McKay et al.
and ultimately elucidated by X-ray diffraction analysis.2 Al-
though the core structures of these alkaloids, namely drupacine
(1) and cephalotaxine (3), are biologically inactive, several
(1) For reviews on the Cephalotaxus alkaloids, see: (a) Miah, M. A. J.;
Hudlicky, T.; Reed, J. W. Cephalotaxus alkaloids. In The Alkaloids;
Academic Press: New York, 1998; Vol. 51, pp 199-269. (b) Huang, L.;
Xue, Z. Cephalotaxus alkaloids. In The Alkaloids; Academic Press: New
York, 1984; Vol. 23, pp 157-226.
(2) (a) Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem. 1963,
28, 2194-2197. (b) Powell, R. G.; Madrigal, R. V.; Smith, C. R., Jr.;
Mikolajczak, K. L. J. Org. Chem. 1974, 39, 676-680. (c) Arora, S. K.;
Bates, R. B.; Grady, R. A.; Powell, R. G. J. Org. Chem. 1974, 39, 1269-
1271. (d) Abraham, D. J.; Rosenstein, R. D.; McGandy, E. L. Tetrahedron
Lett. 1969, 10, 4085-4086.
The significant anticancer activities and intriguing chemical
structures have made the Cephalotaxus alkaloids attractive
(3) Delfel, N. E. Phytochemistry 1980, 19, 403-408.
(4) (a) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J. Tetrahedron
2000, 56, 2929-2934. (b) Morita, H.; Yoshinaga, M.; Kobayashi, J.
Tetrahedron 2002, 58, 5489-5495.
10.1021/jo0710883 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/18/2007
7352
J. Org. Chem. 2007, 72, 7352-7358

ConVergency and DiVergency as Strategic Elements in Total Synthesis
SCHEME 1
FIGURE 1. Representative examples of Cephalotaxus alkaloids.
targets for synthetic chemists. Since the report of the first total
syntheses of (()-cephalotaxine by Weinreb5a and Semmelhack5b
in 1972, a number of elegant total syntheses of this family of
natural products have been reported in the literature.5c-q
Although the enantioselective synthesis of (-)-cephalotaxine
has been accomplished by several groups, there remains only
one total synthesis of (()-drupacine, disclosed by Fuchs in
1990.5f In this report, we present our investigations toward a
formal total synthesis of (()-cephalotaxine, a stereodivergent
formal total synthesis of (+)- and (-)-cephalotaxine, and a
stereoconvergent asymmetric synthesis of (-)-drupacine.
used as a starting point for a divergent approach toward the
syntheses of both (+)- and (-)-cephalotaxine and for a
convergent approach toward the synthesis of (-)-drupacine
(Scheme 1). Specifically, alkylation of amine 7a with enan-
tiopure benzylic alcohol 8 would produce diastereomers 9 and
10. First, we envisioned using the diastereomeric mixture in a
divergent fashion; upon separation of 9 and 10, each compound
could be used as a precursor toward the synthesis of each
enantiomer of cephalotaxine (i.e., 9 f (+)-3, and 10 f (-)-
3). Crucial to the success of this approach would be the
deoxygenation of the benzylic alcohol moiety at C(11), which
was initally used to define the diastereomers in the key
alkylation. Second, we hoped to apply diastereomers 9 and 10
in a convergent manner toward the enantioselective synthesis
of (-)-drupacine; each compound would undergo an identical
synthetic sequence to access the natural product. The success
of this strategy would hinge on a thermodynamic equilibration
process, redefining the configuration of the tertiary amine
stereocenter via a unique â-elimination/conjugate addition
process (vide infra).
Thus, our retrosynthetic analysis for a stereodivergent syn-
thesis of (-)-drupacine and (+)-and (-)-cephalotaxine is shown
in Scheme 2. We envisioned that (-)-drupacine could arise from
amino alcohols 15 and 16 through a sequence of oxidations and
functional group manipulations. We were intrigued by the notion
that we could take advantage of the known susceptibility of
cephalotaxine-based diketones to undergo a â-elimination/
conjugate addition process. Therefore, we hypothesized that
ketal 11 could be derived from a mixture of diastereomers 12
and 14, which would equilibrate via proposed intermediate 13.7
The R-methoxy enone moiety in diastereomer 14 is positioned
in close proximity to the benzylic alcohol at C(11), thus allowing
the formation of the bridging acetal under acidic conditions.
Retrosynthetic Analysis of (-)-Drupacine, (-)-Cephalo-
taxine, and (+)-Cephalotaxine
Arguably the most synthetically challenging structural feature
of the Cephalotaxus alkaloids is the spirocyclic amine moiety.
Recently, we have reported the use of palladium(II)-catalyzed
aerobic oxidations to access a variety of heterocyclic com-
pounds.6 We reasoned that this chemistry could be utilized to
access this challenging fragment in an efficient fashion.
Unfortunately, efforts to extend the oxidation chemistry to
enantioselective variants have met with limited success to date.
In the design of our synthetic approach, however, this drawback
was not restrictive, but empowering.
We anticipated that the generation of racemic spirocyclic
amine 7 via our palladium-catalyzed heterocyclization could be
(5) (a) Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972, 94, 7172-
7173. (b) Semmelhack, M. F.; Chong, B. P.; Jones, L. D. J. Am. Chem.
Soc. 1972, 94, 8629-8630. (c) Yasuda, S.; Yamada, T.; Hanaoka, M.
Tetrahedron Lett. 1986, 27, 2023-2026. (d) Kuehne, M. E.; Bornmann,
W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta, J. J. Org.
Chem. 1988, 53, 3439-3450. (e) Burkholder, T. P.; Fuchs, P. L. J. Am.
Chem. Soc. 1988, 110, 2341-2342. (f) Burkholder, T. P.; Fuchs, P. L. J.
Am. Chem. Soc. 1990, 112, 9601-9613. (g) Ikeda, M.; Okano, M.; Kosaka,
K.; Kido, M.; Ishibashi, H. Chem. Pharm. Bull. 1993, 41, 276-281. (h)
Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115-119. (i) Lin, X.; Kavash,
R. W.; Mariano, P. S. J. Org. Chem. 1996, 61, 7335-7347. (j) Tietze, L.
F.; Schirok, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1124-1125. (k)
Nagasaka, T.; Sato, H.; Saeki, S. I. Tetrahedron: Asymmetry 1997, 8, 191-
194. (l) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264-
10269. (m) Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem. Soc. 2002,
124, 14824-14825. (n) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T.
Org. Lett. 2002, 4, 885-888. (o) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett.
2003, 5, 2931-2934. (p) Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y. J.
Am. Chem. Soc. 2006, 128, 10370-10371. (q) Li, W.-D. Z.; Wang, X.-W.
Org. Lett. 2007, 9, 1211-1214.
(7) A similar intermediate to 13 was proposed by Mori; see ref 5h. The
dimethyl acetal derivative of 13 (i.e., i) is also a possible intermediate, as
is retro-Mannich-type intermediate ii.
(6) (a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (b) Trend, R. M.; Ramtohul,
Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778-17788.
J. Org. Chem, Vol. 72, No. 19, 2007 7353

Liu et al.
SCHEME 2
SCHEME 3
SCHEME 4
The same acetal cannot form in diastereomer 12 because the
alcohol is anti to the enone ring, and consequently it undergoes
the â-elimination/conjugate addition process. We expected that
this dynamic isomerization equilibrium would eventually funnel
the mixture to ketal 11. Therefore, once the stereocenter at C(11)
is defined, we could access enantiomerically pure (-)-1 from
a diastereomeric mixture of 15 and 16. (+)- and (-)-cephalo-
taxine, meanwhile, could be derived from the same diastereo-
meric precursors via deoxygenation at C(11) followed by
chemistry developed by Mori. 15 and 16 could be obtained from
spirocyclic amine 7a and enantiopure alcohol 8 via a C-N bond
formation and subsequent intramolecular Heck reaction. The
key spiroamine derivative (7a) would be constructed via our
palladium(II)-catalyzed heterocyclization chemistry. Importantly,
the implementation of this strategy obviates an enantioselective
synthesis of the spiroamine functionality.
pyridine/toluene) did not proceed efficiently (i.e., <10% yield).
However, optimization of the solvent and the catalyst system
revealed that a mixture of DMF and DMSO as solvent and Pd-
(TFA)2 as catalyst are optimal conditions, affording spiroamide
20 in 88% yield.10 The resulting amide was reduced by LiAlH4
to provide desired spirocyclic pyrrolidine 7a.
As the primary amide 19 proved to be an unsuitable substrate
for our Pd(II)-catalyzed heterocyclization reaction in aprotic
solvents such as toluene, we turned our attention to sulfonamide-
based nucleophiles, which are generally more reactive substrates
in this oxidative cyclization chemistry.11 Thus, ester 18 (Scheme
4) was reduced by LiAlH4 to an alcohol, which was subse-
quently converted in two steps to sulfonamide 21, setting the
stage for the key palladium(II)-catalyzed heterocyclization
reaction. Gratifyingly, the oxidative cyclization of 21 proceeded
efficiently to provide spirocyclic tosylamide 7b. This reaction
could be easily performed on gram-scale (e.g., 1.1 g, 99% yield),
allowing access to this key intermediate in sufficient laboratory
Results and Discussion
Synthesis of Spirocyclic Amine 7a. Our synthesis of
spirocyclic amine 7a began from known allylic alcohol 17,8
which was treated with triethyl orthoacetate under Johnson
orthoester-Claisen conditions to afford ethyl ester 18 (Scheme
3). Ester 18 was smoothly transformed into primary amide 19
via saponification (LiOH/THF/H2O) followed by amide forma-
tion mediated by the Staab reagent (1,1′-carbonyldiimidazole).9
Despite extensive experimentation, the oxidative heterocycliza-
tion of 19 under our standard catalytic conditions (Pd(II)/O2/
12
quantities. Reductive cleavage of the tosyl group with LiAlH4
furnished the desired spirocyclic amine (7a).
(10) For leading references on the Pd(II)/DMSO oxidative system for
heterocyclizations, see: (a) Larock, R. C.; Hightower, T. R. J. Org. Chem.
1993, 58, 5298-5300. (b) Ro¨nn, M.; Ba¨ckvall, J.-E.; Andersson, P. G.
Tetrahedron Lett. 1995, 36, 7749-7752. (c) Larock, R. C.; Hightower, T.
R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585.
(11) For an example, see: Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew.
Chem., Int. Ed. 2002, 41, 164-166.
(8) Dreiding, A. S.; Hartman, J. A. J. Am. Chem. Soc. 1953, 75, 939-
943.
(12) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc.
1999, 121, 700-709.
(9) Staab, H. A.; Wendel, K. Org. Synth. 1968, 48, 44-46.
7354 J. Org. Chem., Vol. 72, No. 19, 2007

ConVergency and DiVergency as Strategic Elements in Total Synthesis
SCHEME 5
SCHEME 7
SCHEME 6
Synthesis of (-)-Drupacine and Formal Total Synthesis
of (-)- and (+)-Cephalotaxine
After the completion of our concise formal synthesis of (()-
cephalotaxine ((()-3), we turned our attention to our initial
synthetic routes toward (+)- and (-)-cephalotaxine and (-)-
drupacine. Enantiomerically enriched 3,4-methylenedioxyman-
delic acid14 ((R)-30, 97.5% ee) was protected as a 1,3-dioxolan-
4-one under acidic conditions in acetone (Scheme 7). Although
bromination of 31 in several common solvents (e.g., Et2O,
CHCl3, and acetic acid) was problematic, acetonitrile proved
optimal for this transformation and afforded aryl bromide 32
quantitatively. The resulting dioxolanone (32) was reduced with
DIBAL at -78 °C to give hemiacetal 33 as a 1:1 mixture of
diastereomers. The diastereomeric mixture was reacted with
spirocyclic amine 7a under reductive amination conditions to
furnish diastereomers 9 and 10 in an approximately 1:1 ratio,
which could be readily separated by silica gel column chroma-
tography.
Upon the facile separation of diastereomers 9 and 10, we
first utilized each diastereomer in a divergent fashion toward
the formal total synthesis of (+)- and (-)-cephalotaxine. As
mentioned above, we anticipated that 9 and 10 could be
transformed into (+)- and (-)-29, respectively, which can
subsequently be transformed to (+)- and (-)-cephalotaxine via
a four-step sequence described by Mori.5h To that end, diaste-
reomer 9 was exposed to the identical Heck reaction conditions
described above to produce 15 as a single diastereomer and
enantiomer (Scheme 8). The benzylic hydroxyl group in 15 was
A Formal Total Synthesis of (()-Cephalotaxine
With a facile route to spirocyclic amine 7a in hand, we set
out to pursue a formal total synthesis of (()-cephalotaxine ((()-
3) to demonstrate the utility of this new methodology. Our
approach targeted 29 (Scheme 6), a known intermediate en route
to cephalotaxine (3) in Mori’s synthesis.5h
Our synthesis commenced with regioselective bromination
of homopiperonylic acid (22) to yield carboxylic acid 23
(Scheme 5). Amide bond formation between spirocyclic amine
7a and acid 23 afforded 24 in good yield. Reduction of amide
24 with a variety of reducing agents was complicated by the
formation of an inseparable des-bromo side product. Eventually,
alane (AlH3) was found to be capable of generating the desired
tertiary amine (25) in 70% yield without concomitant dehalo-
genation.
While we were investigating conditions for the amide
reduction, an alternative synthetic route was also pursued. To
this end, carboxylic acid 23 was converted to Weinreb amide
26, which was reduced by DIBAL to give aldehyde 27. Carbon-
nitrogen bond formation was achieved via a reductive amina-
tion13 joining the aldehyde and spirocyclic pyrrolidine fragments.
The resulting tertiary amine (25), obtained by either method
described, was subjected to the stereoselective Heck conditions
developed by Tietze5j,l to afford the target intermediate (29),
thus completing the formal total synthesis of (()-cephalotaxine
((()-3, 11 total steps to 29, 8 longest linear).
removed via an ionic deoxygenation procedure (Et3SiH, CF3-
COOH)15 to give (+)-29 ([R]D
+191° (c ) 0.15, CHCl3),
27.3
lit.5l [R]D -200° (c ) 1.0, CHCl3) for (-)-29), which completed
the formal total synthesis of (+)-cephalotaxine ((+)-3). The
other diastereomer (10) can be converted to (-)-cephalotaxine
((-)-3) using the identical synthetic route.
Having completed the stereodivergent formal synthesis of
(+)- and (-)-3, we then turned our attention to a stereocon-
(14) Neilson, D. G.; Zakir, U.; Scrimgeour, C. M. J. Chem. Soc. C 1971,
898-904.
(13) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
(15) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-
651.
J. Org. Chem, Vol. 72, No. 19, 2007 7355

Liu et al.
SCHEME 8
SCHEME 11
SCHEME 12
SCHEME 9
diastereomers (40 and 41), with the desired syn isomer (40) as
the major product (Scheme 11). This observation indicated that
an equilibrium through an open ring intermediate leads to a
diastereomeric interconversion, and syn isomer 40 is thermo-
dynamically more stable than anti isomer 41. To our delight,
when the anti R-hydroxy enone diastereomer (36) was subjected
to the same conditions for 5 h, nearly identical results were
observed.16 Therefore, we succeeded in the conversion of both
diastereomers 36 and 39 to the desired syn isomer of R-methoxy
enone (40) by employing this diastereoconvergent isomerization
process.
To complete the synthesis of (-)-drupacine (1), R-methoxy
enone 40 was reduced with NaBH4, with concomitant cleavage
of the acetate ester, to produce enantiopure 11-hydroxycepha-
lotaxine ((-)-42), another Cephalotaxus alkaloid (Scheme 12).2b
Under acidic conditions, the benzylic hydroxyl group in ((-)-
42) engaged in an acetal linkage with the enol ether, forming
(-)-drupacine (1) in 86% yield. The spectroscopic data for the
synthetic material was identical to published data for the natural
product in every respect, representing the first asymmetric total
synthesis of (-)-drupacine.
SCHEME 10
(16) When diastereomeric R-hydroxy enones 36 and 39 were indepen-
dently subjected to the dynamic isomerization conditions for prolonged
reaction times (3 days), a single major product (>60% yield) was isolated
and characterized as iii, which is optically active ([R]D25.6) -41.9 (c )
0.21, CHCl3)). When 40 was subjected to basic conditions (NaOMe/MeOH),
compound iii ([R]D27.3) -44.2 (c ) 0.22, CHCl3)) was produced as the
sole product. One possible intermediate (iv) for these transformations is
proposed.
vergent synthesis of (-)-drupacine from diastereomers 9 and
10. Therefore, the benzylic alcohol in 15 was masked as an
acetate to provide 34, which was converted to R-hydroxy enone
36 via a two-step sequence (Scheme 9). The same transforma-
tions were carried out to produce the other diastereomer (i.e.,
39) from 16 (Scheme 10).
With syn R-hydroxy enone 39 in hand, exposure to conditions
that are known to promote racemization in the cephalotaxine
series5h through a conjugate addition process, formed two
7356 J. Org. Chem., Vol. 72, No. 19, 2007

ConVergency and DiVergency as Strategic Elements in Total Synthesis
mL). The organic layers were combined, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (1:1 hexanes/EtOAc f EtOAc) to give 9 (525 mg,
45.4% yield) and 10 (538 mg, 46.5% yield) as yellow oils.
Conclusions
In summary, we have developed a concise route toward the
syntheses of (-)-drupacine (1) and (+)- and (-)-cephalotaxine
(3). Our synthesis features a rapid and efficient construction of
the spirocyclic amine (7a) employing Pd(II)-catalyzed oxidative
heterocyclization chemistry, followed by a series of transforma-
tions that include a reductive amination and an intramolecular
Heck reaction to establish the frameworks of the target
molecules. A dynamic isomerization process was strategically
applied to funnel two diastereomers (36 and 39) into a single
enantiomer of (-)-drupacine (1) to complete the first asymmetric
total synthesis of this alkaloid. This work is highly illustrative
of the synthetic utility of the aerobic palladium(II)-catalyzed
heterocyclization chemistry we have developed thus far. It also
highlights how stereoconvergency and stereodivergency can be
employed as strategic elements that can enable the facile
synthesis of a family of naturally occurring compounds.
Investigations into an enantioselective version of the oxidative
heterocyclization and the applications of convergence and
divergence to other synthetic problems are currently underway.
9: Rf 0.25 (EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H),
6.92 (s, 1H), 5.94 (dd, J1 ) 5.4 Hz, J2 ) 1.5 Hz, 2H), 5.85 (dt, J1
) 5.7 Hz, J2 ) 2.1 Hz, 1H), 5.40 (dt, J1 ) 5.7 Hz, J2 ) 2.1 Hz,
1H), 4.90 (dd, J1 ) 10.2 Hz, J2 ) 3.0 Hz, 1H), 4.22 (br, 1H),
3.32-3.25 (m, 1H), 2.57-2.49 (m, 2H), 2.38-2.16 (m, 3H), 1.91-
1.71 (m, 5H), 1.55-1.46 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
147.9, 147.6, 135.9, 135.3, 133.6, 112.5, 112.0, 107.7, 101.9, 78.0,
69.1, 55.3, 50.4, 38.1, 32.0, 28.1, 21.6; IR (film) 3401, 2938, 1502,
1475, 1236, 1038 cm-1; HRMS-FAB (m/z) [M + H]+ calcd for
C17H20BrNO3 366.0705, found 366.0689; [R]D25.8 -17.5 (c 2.0, CH2-
Cl2).
1
10: Rf 0.20 (EtOAc); H NMR (300 MHz, CDCl3) δ 7.11 (s,
1H), 6.92 (s, 1H), 5.94 (dd, J1 ) 5.1 Hz, J2 ) 1.5 Hz, 2H), 5.76
(dt, J1 ) 5.7 Hz, J2 ) 2.1 Hz, 1H), 5.65 (dt, J1 ) 5.7 Hz, J2 ) 2.1
Hz, 1H), 4.87 (dd, J1 ) 10.2 Hz, J2 ) 3.3 Hz, 1H), 4.05 (br, 1H),
3.21-3.15 (m, 1H), 2.67-2.60 (m, 2H), 2.33-2.18 (m, 3H), 1.91-
1.81 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 147.9, 147.6, 135.5,
133.6, 132.5, 112.6, 112.0, 107.6, 101.9, 77.7, 69.3, 56.1, 51.8,
38.6, 34.0, 31.2, 22.2; IR (film) 3401, 2942, 1502, 1475, 1235,
1039 cm-1; HRMS-FAB (m/z) [M + H]+ calcd for C17H20BrNO3
Experimental Section
25.8
366.0705, found 366.0688; [R]D -36.4 (c 2.0, CH2Cl2).
anti-Amino Alcohol 15. The amino alcohol 9 (200 mg, 0.55
mmol) was dissolved in a mixture of solvents (DMF/CH3CN/H2O
) 5 mL:5 mL:1 mL). The solution was degassed with argon for
15 min and then treated with trans-di-µ-acetatobis[2-(di-o-
tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol) and
tetra-n-butylammonium acetate (332 mg, 1.1 mmol). The resulting
solution was heated at 120 °C for 7 h. The reaction was cooled to
room temperature and filtered through a short pad of Celite. The
filtrate was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (50 mL) and extracted with saturated NaHCO3 (50 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The
organic layers were combined, dried over Na2SO4, filtered, and
concentrated to dryness. The residue was purified by flash chro-
matography (1:4 hexanes/EtOAc f EtOAc) to give alcohol 15 (107
mg, 67% yield) as a foamy solid: Rf 0.15 (EtOAc); 1H NMR (300
MHz, CDCl3) δ 7.08 (s, 1H), 6.63 (s, 1H), 5.89 (dd, J1 ) 9.0 Hz,
J2 ) 1.5 Hz, 2H), 5.81-5.79 (m, 1H), 5.52-5.50 (m, 1H), 5.20
(dd, J1 ) 9.9 Hz, J2 ) 6.9 Hz, 1H), 3.87 (t, J ) 2.4 Hz, 1H),
3.04-2.97 (m, 1H), 2.83-2.73 (m, 2H), 2.58 (t, J ) 10.8 Hz, 1H),
2.45-2.35 (m, 2H), 2.04-1.89 (m, 3H), 1.77-1.68 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 146.9, 146.2, 136.0, 132.1, 129.5, 128.8,
110.9, 104.5, 101.1, 68.3, 66.6, 62.0, 56.7, 53.4, 43.0, 34.9, 20.2;
IR (film) 3256, 2961, 1501, 1482, 1261, 1242, 1040 cm-1; HRMS-
EI (m/z) [M]+ calcd for C17H19NO3 285.1365, found 285.1370;
Spirolactam 20. DMF (20 mL) and DMSO (2 mL) were added
to a 250 mL two-necked, round-bottomed flask charged with a
magnetic stir bar. Under an atmosphere of O2, Pd(TFA)2 (333 mg,
1.0 mmol), NaOAc (1.64 g, 20 mmol), and amide 19 (1.39 g, 10.0
mmol) were added successively. The resulting mixture was heated
at 80 °C for 48 h with vigorous stirring. After the reaction mixture
was cooled to room temperature, it was passed through a short pad
of silica gel to remove insoluble solid. The filtrate was concentrated
in vacuo to give a red oil, which was purified by flash chroma-
tography (100% EtOAc) to give the spirolactam 20 (1.22 g, 87.8%
1
yield): Rf 0.30 (EtOAc); H NMR (300 MHz, CDCl3) δ 6.06 (br
s, 1H), 5.81-5.78 (m, 1H), 5.59-5.56 (m, 1H), 2.46-2.23 (m,
4H), 2.07-1.85 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7,
135.2, 133.2, 71.4, 37.9 33.9, 30.9; IR (film) 3191, 1690, 1366,
753 cm-1; HRMS-EI (m/z) [M]+ calcd for C8H11NO 137.0841,
found 137.0835.
Cyclic Sulfonamide 7b. Toluene (20 mL) was added to a 250
mL two-necked, round-bottomed flask charged with a magnetic stir
bar. Under an atmosphere of O2, 3 Å molecular sieves (1.0 g), Pd-
(TFA)2 (133 mg, 0.4 mmol), pyridine (128 mg, 131 µL, 1.6 mmol),
and sulfonamide 21 (1.12 g, 4.0 mmol) were added successively.
The resulting mixture was heated at 80 °C for 42 h with vigorous
stirring. After the reaction mixture was cooled to room temperature,
the mixture was passed through a short pad of silica gel to remove
the insoluble solid. The filtrate was concentrated in vacuo to give
a brown oil, which was purified by flash chromatography (4:1
hexanes/EtOAc) to give the cyclic sulfonamide 7b (1.10 g, 99%
yield): Rf 0.25 (4:1 hexanes/EtOAc); 1H NMR (300 MHz, CDCl3)
δ 7.64 (d, J ) 8.1 Hz, 2H), 7.19 (d, J ) 8.1 Hz, 2H), 5.76 (dt, J1
) 5.7 Hz, J2 ) 2.1 Hz, 1H), 5.33 (dt, J1 ) 5.4 Hz, J2 ) 2.1 Hz,
1H), 3.56-3.49 (m, 1H), 3.30-3.22 (m, 1H), 2.58-2.48 (m, 1H),
2.47-2.30 (m, 1H), 2.33 (s, 3H), 2.77-2.12 (m, 2H), 1.87-1.67
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 142.8, 138.7, 133.6, 132.9,
129.5, 127.5, 78.7, 49.5, 41.4, 37.3, 31.2, 23.4, 21.7; IR (film) 2927,
1598, 1494, 1446, 1335, 1153, 1092, 1060 cm-1; HRMS-EI (m/z)
[M]+ calcd for C15H19NO2S 277.1136, found 277.1149.
27.0
[R]D +57.6 (c 1.6, CHCl3).
syn-Amino Alcohol 16. The amino alcohol 10 (200 mg, 0.55
mmol) was dissolved in a mixture of solvents (DMF/CH3CN/H2O
) 5 mL:5 mL:1 mL). The solution was degassed with argon for
15 min and then treated with trans-di-µ-acetatobis[2-(di-o-
tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol) and
tetra-n-butylammonium acetate (332 mg, 1.1 mmol). The resulting
solution was heated at 120 °C for 7 h. The reaction was cooled to
room temperature and filtered through a short pad of Celite. The
filtrate was concentrated in vacuo. The residue was dissolved in
Et2O (50 mL) and extracted with saturated NaHCO3 (50 mL). The
aqueous phase was extracted with Et2O (3 × 50 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated
to dryness. The residue was purified by flash chromatography (5%
f 10% MeOH/CH2Cl2) to yield syn-amino alcohol 16 (33 mg, 21%
yield) as a clear oil. (Note: The low isolation yield of 16 is due to
its poor solubility in most organic solVents. When crude 16 was
taken to the next step, typically 60-70% yield was obtained for
two steps. Since pure 16 can be acylated in 92% yield, the yield of
Alcohols 9 and 10. To a solution of hemiacetal 33 (1.0 g, 3.17
mmol) in 1,2-dichloroethane (10 mL) was added a solution of
spiroamine 7a (410 mg, 3.33 mmol) in 1,2-dichloroethane (5 mL).
The resulting solution was treated with NaBH(OAc)3 (1.0 g, 4.76
mmol) and stirred at room temperature for 24 h. The reaction was
poured into saturated NaHCO3 (50 mL), and the phases were
separated. The aqueous phase was extracted with Et2O (4 × 50
J. Org. Chem, Vol. 72, No. 19, 2007 7357

Liu et al.
this Heck reaction approximately 71%.) 16: Rf 0.07 (EtOAc), 0.1
(1:9 MeOH/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.87 (s, 1H),
6.72 (s, 1H), 6.00-5.97 (m, 1H), 5.94 (s, 2H), 5.90-5.88 (m, 1H),
4.75 (dd, J1 ) 8.7 Hz, J2 ) 4.8 Hz, 1H), 3.85 (m, 1H), 3.37 (dd,
J1 ) 14.1 Hz, J2 ) 8.7 Hz, 1H), 2.96-2.91 (m, 1H), 2.72-2.66
(m, 3H), 2.16 (dq, J1 ) 18.5 Hz, J2 ) 1.8 Hz, 1H), 1.98 (dt, J1 )
8.1 Hz, J2 ) 3.3 Hz, 2H), 1.89-1.71 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 147.3, 147.0, 136.1, 134.1, 132.0, 131.3, 111.4, 110.8,
101.4, 74.0, 71.0, 59.4, 55.6, 52.9, 40.0, 37.6, 20.3; IR (film): 3376,
h. The solvent was removed in vacuo. The residue was partitioned
between saturated NaCl (10 mL) and CH2Cl2 (10 mL). The aqueous
phase was extracted with CH2Cl2 (4 × 10 mL). The organic layers
were combined, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by preparative TLC (9:1 CH2Cl2/
MeOH) to yield diol 42 (5.5 mg, 90% yield) as a white powder:
1
Rf 0.15 (9:1 CH2Cl2/MeOH); H NMR (500 MHz, CDCl3) δ 6.89
(s, 1H), 6.63 (s, 1H), 5.93 (q, J ) 7.5 Hz, 2H), 4.82 (t, J ) 7.2 Hz,
1H), 4.68 (s, 1H), 4.50 (d, J ) 8.4 Hz, 1H), 3.73 (s, 3H), 3.52 (d,
J ) 8.1 Hz, 1H), 3.40-3.32 (m, 1H), 3.16-3.09 (m, 1H), 2.92-
2.87 (m, 2H), 1.98-1.86 (m, 2H), 1.77-1.68 (m, 2H) (note: 2
protons of the hydroxyl groups were not observed); 13C NMR (75
MHz, CDCl3) δ 161.6, 147.5, 147.4, 135.9, 127.0, 113.3, 113.1,
101.5, 100.2, 74.8, 74.6, 73.7, 58.2, 57.5, 51.4, 50.9, 40.0, 21.9;
IR (film): 3369, 2922, 1651, 1504, 1489, 1227 cm-1; HRMS-EI
2871, 1496, 1474, 1261, 1038 cm-1; HRMS-EI (m/z) [M]+ calcd
23.9
for C17H19NO3 285.1365; found 285.1360; [R]D
CHCl3).
-72.8 (c 0.3,
R-Methoxy Enones 40 and 41. Diketone (39 or 36) (20 mg,
0.056 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL)
and 2,2-dimethoxypropane (5 mL). The solution was treated with
p-toluenesulfonic acid monohydrate (42.6 mg, 0.224 mmol, 4.0
equiv) and heated at 90 °C for 5 or 7 h. After the reaction mixture
was cooled to room temperature, the solvent was removed in vacuo.
The residue was partitioned between saturated NaHCO3 (15 mL)
and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2-
Cl2 (4 × 20 mL). The organic layers were combined, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by preparative TLC (19:1 CH2Cl2/MeOH) to yield enone
40 (8.3 mg, 42% yield) and 41 (4.0 mg, 20% yield).
24.4
(m/z) [M]+ calcd for C18H21NO5 331.1420, found 331.1417; [R]D
-72.6 (c 0.13, CHCl3).
(-)-Drupacine (1). Diol 42 (2.6 mg, 7.85 µmol) was dissolved
in a mixture of THF (1.0 mL) and 1 N HCl (1.0 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 5 h and then was poured into saturated NaHCO3 (10 mL). The
mixture was extracted with CH2Cl2 (5 × 10 mL). The organic phase
was dried over Na2SO4, filtered, and concentrated to dryness. The
residue was purified by preparative TLC (9:1 CH2Cl2/MeOH) to
yield (-)-drupacine (1) (2.2 mg, 86% yield) as a white film: Rf
0.60 (9:1 CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3) δ 6.67 (s,
1H), 6.65 (s, 1H), 5.95 (q, J ) 1.5 Hz, 2H), 4.88 (d, J ) 3.9 Hz,
1H), 4.05 (d, J ) 9.9 Hz, 1H), 3.49 (d, J ) 9.3 Hz, 1H), 3.48 (s,
3H), 3.24-3.19 (m, 1H), 3.07 (m, 1H), 3.03 (d, J ) 13.2 Hz, 1H),
2.66 (d, J ) 14.4 Hz, 1H), 2.46 (q, J ) 9.0 Hz, 1H), 2.26-2.20
(m, 1H), 2.09-2.00 (m, 1H), 1.88-1.76 (m, 2H), 1.52 (d, J )
14.1 Hz, 1H) 1.36 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 148.1,
146.7, 131.2, 130.2, 112.2, 108.8, 107.9, 101.5, 78.5, 73.8, 65.5,
59.9, 56.9, 54.2, 52.4, 43.6, 35.9, 22.5; IR (film) 3369, 2929, 1503,
1488, 1372, 1060 cm-1; HRMS-EI (m/z) [M]+ calcd for C18H21-
1
40: Rf 0.45 (1:1 CH2Cl2/Et2O); H NMR (300 MHz, CDCl3) δ
6.81 (s, 1H), 6.76 (s, 1H), 6.21 (s, 1H), 5.94 (d, J ) 9.6 Hz, 2H),
5.74 (d, J ) 8.1 Hz, 1H), 3.81 (s, 3H), 3.56 (s, 1H), 3.34-3.27
(m, 1H), 3.08-3.01 (m, 1H), 2.81-2.73 (m, 2H), 2.18-2.08 (m,
1H), 2.03-1.95 (m, 1H), 1.93-1.82 (m, 2H), 1.90 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 199.3, 170.4, 159.2, 148.3, 147.2, 129.0,
127.9, 122.0, 114.5, 112.3, 101.7, 75.2, 66.3, 60.5, 57.4, 52.8, 52.4,
39.7, 20.9, 20.3; IR (film) 2961, 1726, 1629, 1506, 1489, 1371,
1231 cm-1; HRMS-FAB (m/z) [M + H]+ calcd for C20H21NO6
25.0
372.1447, found 372.1451; [R]D -63.6 (c 0.3, CH2Cl2).
1
41: Rf 0.55 (1:1 CH2Cl2/Et2O); H NMR (300 MHz, CDCl3) δ
6.94 (s, 1H), 6.71 (s, 1H), 6.38 (s, 1H), 5.95 (dd, J1 ) 3.9 Hz, J2
) 1.5 Hz, 2H), 5.55 (dd, J1 ) 9.9 Hz, J2 ) 6.9 Hz, 1H), 3.83 (s,
3H), 3.56 (s, 1H), 3.05 (m, 1H), 2.96 (dd, J1 ) 11.1 Hz, J2 ) 7.2
Hz, 1H), 2.72 (q, J ) 7.8 Hz, 1H), 2.63 (t, J ) 10.2 Hz, 1H), 2.12
(s, 3H), 2.04-1.99 (m, 2H), 1.83-1.79 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 199.9, 169.6, 159.0, 147.8, 147.0, 130.2, 126.0,
124.0, 112.9, 105.2, 101.5, 69.4, 65.5, 60.9, 57.8, 53.0, 52.7, 39.1,
21.2, 20.7; IR (film) 2931, 1724, 1624, 1504, 1485, 1370, 1233
cm-1; HRMS-FAB (m/z) [M + H - H2]+ calcd for C20H21NO6
24.7
NO5 331.1420, found 331.1433; [R]D -64.0 (c 0.1, CHCl3).
Acknowledgment. WethanktheNIH-NIGMS(R01GM65961-
01), Bristol-Myers Squibb Co. (graduate fellowship to E.M.F.),
the NSF (graduate fellowship to E.M.F.), the Dreyfus Founda-
tion, Merck Research Laboratories, Research Corporation,
Abbott Laboratories, Pfizer, Amgen, GlaxoSmithKline, Lilly,
and Johnson and Johnson for generous financial support. We
are grateful to Ernie Cruz, Sandy Ma, and John Enquist for
experimental assistance.
25.0
370.1291, found 370.1299; [R]D +13.2 (c 0.2, CHCl3).
11-Hydroxycephalotaxine (42). Enone 40 (7.0 mg, 18.8 µmol)
was dissolved in a mixture of MeOH (2.0 mL) and CH2Cl2 (0.4
mL) at 0 °C and treated with NaBH4 (18 mg, 0.47 mmol, 25 equiv).
The reaction mixture was allowed to warm to room temperature
and stirred for 1 h. The second portion of NaBH4 (18 mg, 0.47
mmol, 25 equiv) was added, and the mixture was stirred for an
additional 1 h. The third portion of NaBH4 (18 mg, 0.47 mmol, 25
equiv) was added, and the reaction was stirred for an additional 1
Supporting Information Available: Experimental details,
1
characterization data, and H and 13C NMR spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0710883
7358 J. Org. Chem., Vol. 72, No. 19, 2007