A second generation formal synthesis of (-)-cephalotaxine

Article abstract of DOI:10.1021/jo801540q

(Chemical Equation Presented) A second generation formal synthesis of the alkaloid (-)-cephalotaxine has been achieved using an alkylidene carbene 1,5-CH insertion reaction to establish a key quaternary stereocenter. The carbene precursor was readily derived from L-proline, and the 1,5-CH insertion reaction was performed under Ohira's conditions using lithiotrimethylsilyldiazomethane (LTDM), which gave the desired spirocyclic product in 74% yield. The hydroxymethyl group was then oxidized and then decarbonylated (93%), and this material was easily transformed into the desired Friedel-Crafts cyclization precursor. Exposure of this material to SnCl₄ then gave the desired pentacyclic product, which was identical to that previously prepared by Mori and thus represents a formal total synthesis of (-)-cephalotaxine.

Full text of DOI:10.1021/jo801540q

A Second Generation Formal Synthesis of (-)-Cephalotaxine
Abdul Hameed, Alexander J. Blake, and Christopher J. Hayes*
The School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham, NG7 2RD, U.K.
chris.hayes@nottingham.ac.uk
ReceiVed July 13, 2008
A second generation formal synthesis of the alkaloid (-)-cephalotaxine has been achieved using an alkylidene
carbene 1,5-CH insertion reaction to establish a key quaternary stereocenter. The carbene precursor was readily
derived from L-proline, and the 1,5-CH insertion reaction was performed under Ohira′s conditions using
lithiotrimethylsilyldiazomethane (LTDM), which gave the desired spirocyclic product in 74% yield. The
hydroxymethyl group was then oxidized and then decarbonylated (93%), and this material was easily
transformed into the desired Friedel-Crafts cyclization precursor. Exposure of this material to SnCl4 then
gave the desired pentacyclic product, which was identical to that previously prepared by Mori and thus represents
a formal total synthesis of (-)-cephalotaxine.
Introduction
The polycyclic alkaloid (-)-cephalotaxine1 (1) is a fascinating
target for total chemical synthesis (Figure 1) as its structure
contains a number of interesting features, including an embedded
1-azaspiro[4.4]nonane ring system.
While cephalotaxine (1) has little known biological activity,
it does represent the parent alkaloid core of a larger family of
related natural products (e.g., homoharringtonine 2) that show
clinically useful anticancer activity,2 and as a result, 1 has been
the subject of much synthetic interest.3,4 As part of our ongoing
interest in the enantioselective synthesis of 1,5a we have recently
reported an enantioselective formal total synthesis,5b and this
is summarized in Scheme 1.
FIGURE 1. Cephalotaxine (1) and homoharringtonine (2).
All of the steps up to the pentacycle 5 proceeded in acceptable
yield (60-80%), but there were some problems associated with
the conversion of 5 into “Mori’s intermediate” 8.4b Effectively,
we needed to remove the methyl group from the cyclopentene ring
5, and this was done in a six-step sequence (Scheme 1). The first
three steps (5f6) proceeded cleanly,6 but the subsequent two steps
(6f7) could only be achieved in 31% combined yield. The
problems surrounding this low yielding sequence were compounded
by the inefficient final decarbonylation reaction (7f8) which only
produced the desired compound 8 in modest yield (20-40%). As
a result of these issues, we felt it necessary to explore an alternative
synthetic approach (Scheme 2), and we now wish to report the
(1) Isolation: (a) Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem.
1963, 28, 2194. Structure elucidation: (b) Abraham, D. J.; Rosenstein, R. D.;
McGandy, E. L. Tetrahedron Lett. 1969, 4085. (c) Arora, S. K.; Bates, R. B.;
Grady, R. A.; Powell, R. G. J. Org. Chem. 1974, 39, 1269.
(2) (a) Levy, V.; Zohar, S.; Bardin, C.; Vekhoff, A.; Chaoui, D.; Rio, B.;
Legrand, O.; Sentenac, S.; Rousselot, P.; Raffoux, E.; Chast, F.; Chevret, S.;
Marie, J. P. Br. J. Cancer 2006, 95, 253. (b) Kantarjian, H. M.; Talpaz, M.;
Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92, 1591.
10.1021/jo801540q CCC: $40.75
Published on Web 09/12/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8045–8048 8045

Hameed et al.
SCHEME 1. Summary of the First Generation Synthesis
of 1
SCHEME 3. Preparation of Spirocycle 11
a proton until after the key CH insertion reaction. After considering
several options, we decided to prepare the ketone 17 with R2 as a
protected hydroxymethyl group via Wittig reaction of the proline-
derived aldehyde 15 and the known ylide 1610 (Scheme 3). We
felt that the TBS-protected hydroxymethyl moiety would be well
suited to the CH insertion step and that rearrangement to the
corresponding acetylene would be minimal.10 Fortunately, this
proved to be the case and the desired spirocycle 18 could be isolated
in good yield (74%) following exposure of 17 to lithio-TMS-
diazomethane.8 The hydroxymethyl group was then removed in
an efficient manner via oxidation to the aldehyde with Dess-Martin
periodinane11(85-91%) and decarbonylation with Wilkinson’s
catalyst12 (93%) to afford the desired spirocycle 11 (where R2 )
H).
SCHEME 2. Revised Retrosynthetic Analysis
Pleased by the successful formation of 11, we next turned
our attention to alkylation of the nitrogen with a suitably
functionalized electrophile. As a short diversion from our
originally planned retrosynthesis (Scheme 2), we briefly ex-
plored the possibility of accessing the aryl iodide 21, which is
(3) Racemic total syntheses: (a) Auerbach, J.; Weinreb, S. M J. Am. Chem.
Soc. 1972, 94, 7172. (b) Semmelhack, M. F.; Chong, B. P.; Jones, L. D. J. Am.
Chem. Soc. 1972, 94, 8629. (c) Semmelhack, M. F.; Chong, B. P.; Stauffer,
R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97,
2507. (d) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc. 1975, 97, 2503. (e)
Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1988, 110, 2341. (f) Kuehne,
M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta,
J. J. Org. Chem. 1988, 53, 3439. (g) Burkholder, T. P.; Fuchs, P. L. J. Am.
Chem. Soc. 1990, 112, 9601. (h) Ishibashi, H.; Okano, M.; Tamaki, H.;
Maruyama, K.; Yakura, T.; Ikeda, M. J. Chem. Soc., Chem. Commun. 1990,
1436. (i) Ikeda, M.; Okano, M.; Kosaka, K.; Kido, M.; Ishibashi, H. Chem.
Pharm. Bull. 1993, 41, 276. (j) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Am.
Chem. Soc. 1994, 116, 9791. (k) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Org.
Chem. 1996, 61, 7335. (l) Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1124. (m) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T.
Org. Lett. 2002, 4, 885. (n) Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem.
Soc. 2002, 124, 14824. (o) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931.
(p) Li, W.-D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (q) Ma, B.-C.; Wang,
Y.-Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528. (r) Li, W.-D. Z.; Wang,
X.-W. Org. Lett. 2007, 9, 1211.
(4) Enantioselective total syntheses: (a) Zhong, S.; Liu, W.; Ling, Y.; Li, R.
Zhongguo Yaowu Huaxue Zazhi 1994, 4, 84. (b) Isono, N.; Mori, M. J. Org.
Chem. 1995, 60, 115. (c) Nagasaka, T.; Sato, H.; Saeki, S.-I. Tetrahedron:
Asymmetry 1997, 8, 191. (d) Ikeda, M.; El Bialy, S. A. A.; Hirose, K.-I.; Kotake,
M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.; Gad, L. M.;
Yakura, T. Chem. Pharm. Bull. 1999, 47, 983. (e) Tietze, L. F.; Schirok, H.
J. Am. Chem. Soc. 1999, 121, 10264. (f) El Bialy, S. A. A.; Ismail, M. A.; Gad,
L. M.; Abdelal, A. M. M. Med. Chem. Res. 2002, 11, 293. (g) Planas, L.; Perard-
Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087. (h) Eckelbarger, J. D.; Wilmot,
J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370. (i) Zhao, Z.; Mariano,
P. S. Tetrahedron 2006, 62, 7266. (j) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J.
Org. Chem. 2007, 72, 7352.
results of this work which have culminated in a second generation
formal synthesis of 1.
Results and Discussion
As the alkylidene carbene 1,5-CH insertion reaction performed
well at constructing the key quaternary stereocenter (viz. 3f4),7
we wanted to retain this in our revised route and we hoped that
many of the issues surrounding the removal of the methyl group
from 5 could be avoided by changing the order of some of the
other key steps. Thus, the pentacycle 9 was disconnected via an
intramolecular Friedel-Crafts alkylation in a similar manner to
Mori4b to reveal the allylic alcohol 10, with 10 being accessed in
only a few steps from the Boc-protected spirocycle 11 (R2 ) H).
Further disconnection of 11, via the alkylidene carbene 12, revealed
the proline-derived ketone 13 to be a suitable precursor.8 It is well-
known that alkylidene carbenes such as 12 undergo rearrangement
to the corresponding acetylenes9 (e.g., 14) when R2 ) H, so we
decided to work with an R2 group that could act as surrogate for
8046 J. Org. Chem. Vol. 73, No. 20, 2008

A Second Generation Formal Synthesis of (-)-Cephalotaxine
SCHEME 4. Completion of Synthesis of Tetracycle 29
SCHEME 5. Shorter End-Game for the Formal Synthesis of
(-)-Cephalotaxine
shown in Supporting Information). Hydrolysis of the carbamate
(KOH, MeOH/H2O) then gave the amino alcohol 26 in excellent
yield. Alkylation of 26 with the known nosylate 27 produced the
desired Friedel-Crafts cyclization precursor 28, which is the
diastereoisomer of a compound previously used by Mori.4b Upon
treatment with neat polyphosphoric acid (PPA, 65 °C), 28 cyclized
to give the desired tetrahydroazepine 29, whose spectroscopic and
analytical data were identical to those previously reported by
Mori.4b
Although we were pleased to have completed a formal synthesis
of (-)-cephalotaxine (1) by accessing the known intermediate 29,
we felt that the synthesis could be improved further if we were
able to access 8 directly via Friedel-Crafts cyclization of allylic
alcohol 31 (Scheme 5). Mori prepared 8 from the dimethoxy
aromatic derivative 29 in a two-step process on the way to his
total synthesis of 1,4b so if this reaction was possible (viz. 31 f 8,
Scheme 5), then our formal synthesis would be shortened by two
steps.
The reason for not trying this transformation (31 f 8) earlier
was based on the fact that Mori reported that 32, the diastereomer
of 31, did not undergo the desired Friedel-Crafts cyclization and
instead had to resort to using the dimethoxy aromatic derivative
(i.e., the diastereoisomer of 28). We were slightly puzzled by this
observation as Kuehne3f had previously shown that Friedel-Crafts
cyclization of a very closely related amide derivative of 32 was
possible.15Furthermore, we successfully performed an electrophilic
a known precursor to 8,13 from the protected spirocycle 11
(Scheme 4). We quickly found that racemization occurs at the
quaternary stereocenter upon deprotection of 11 under a variety
of acidic conditions.14 Furthermore, only low yields of the
racemic alkylated product 21 could be obtained, and despite
much effort, we were not able to find acceptable conditions for
this transformation. We therefore returned to our original
synthetic approach to 8.
Epoxidation of 11 with DMDO gave the epoxide 22 as a single
diastereoisomer, with delivery of the oxygen occurring on the
alkene face opposite to the bulky Boc group. Purification of this
material by column chromatography (SiO2) gave the desired
epoxide 22 (48%), along with smaller amounts of two new
compounds that were not present in the crude reaction mixture.
These were later identified as the isomeric carbamates 23 (4%)
and 24 (9%), which are obviously products of acid-mediated
intramolecular epoxide opening. Rather than being problematic,
we decided to exploit this intramolecular epoxide opening by
immediately treating the DMDO epoxidation product 22 with a
Lewis acid (Ti(OiPr)4, MeCN) to provide 23 (30%) and 24 (61%)
in much improved yields. The stereochemistry of 24 was confirmed
by X-ray crystallography (see Supporting Information).
(7) For recent applications of alkylidene carbene 1,5-CH insertion reactions
in synthesis, see: (a) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2000,
41, 6859. (b) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. (c)
Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc. 2002, 124,
12416. (d) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (e) Feldman,
K. S.; Perkins, A. L.; Masters, K. M. J. Org. Chem. 2004, 69, 7928. (f) Auty,
J. M. A.; Churcher, I.; Hayes, C. J. Synlett 2004, 1443. (g) Grainger, R. S.;
Owoare, R. B. Org. Lett. 2004, 6, 2961. (h) Wardrop, D. J.; Bowen, E. G. Chem.
Commun. 2005, 5106. (i) Taber, D. F.; Liang, J.-L.; Chen, B.; Cai, L. J. Org.
Chem. 2005, 70, 8739. (j) Hayes, C. J.; Sherlock, A. E.; Selby, M. D. Org. Biol.
Chem. 2006, 4, 193. (k) Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.;
Blake, A. J.; Selby, M. D.; Prodger, J. C. J. Org. Chem. 2008, 73, 2041.
(8) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992,
721.
Although both materials are potentially useful for the synthesis
of cephalotaxine, we decided to advance the most abundant isomer
24 through the remaining steps. Thus, 24 was converted into its
tosylate 25, and this material was then treated with DBU to induce
elimination to provide the corresponding cyclopentene 35 (structure
(9) For a comprehensive review, please see: Knorr, R. Chem. ReV. 2004,
104, 3795.
(10) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J. Org.
Chem. 2002, 67, 7613.
(11) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(5) (a) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 6011. (b) Esmieu, W. R.; Worden, S. M.; Catterick, D.; Wilson, C.; Hayes,
C. J. Org. Lett. 2008, 10, 3045.
(6) For regioselective rearrangement of epoxides to allylic alcohols, see:
Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.; Nozaki, H. J. Am. Chem.
Soc. 1974, 96, 6513.
(12) Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99.
(13) Yoshida has prepared racemic 21 (see ref 3n) and has shown that it
will undergo Heck cyclization under Tietze’s conditions (see ref 4e). Mariano
has recently reported an enantioselective synthesis of 21 (see ref 4i) but does
not report the use of this material in the Heck cyclization.
J. Org. Chem. Vol. 73, No. 20, 2008 8047

Hameed et al.
153.1 (C), 137.3 (CH), 135.1 (CH), 130.9 (CH), 129.0 (CH), 78.4
(C), 78.1 (C), 74.7 (C), 74.3 (C), 48.1 (CH2), 4.9 (CH2), 40.9 (CH2),
40.1 (CH2), 36.1 (CH2), 35.2 (CH2), 32.0 (CH2), 31.5 (CH2), 28.7
(3 × CH3), 28.6 (3 × CH3), 23.2 (CH2), 22.6 (CH2); m/z (ES+)
246.1457 (M + Na, C13H21NNaO2 requires 246.1465).
aromatic iodination on a similar methylenedioxo-substituted aro-
matic ring to afford the iodide 20,3n so, in principle, we felt that
the aromatic ring present in 31 should be nucleophilic enough to
react with the putative allylic cation electrophile that is produced
during the Friedel-Crafts reaction.
We therefore prepared 31 by alkylation of 26 with the known
nosylate 30, and we exposed this material to Kuehne’s conditions
(SnCl4, DCM/MeNO2).3f We avoided using polyphosphoric acid as
we felt that the dioxolane ring present in 31 could decompose under
these harshly acidic conditions. Pleasingly, we were able to isolate
the desired pentacycle 8 as the major new product from the reaction,
and its spectroscopic data were identical to those previously reported.4b
Since it has been shown that 8 can be converted into (-)-cephalotaxine
(1), we have successfully completed a second generation formal
synthesis of the natural product 1.
(3aS,13bS)-3,5,6,8,9,13b-Hexahydro-l1,12-dimethoxy-4H-cyclo-
penta[a]pyrrolo[2,1-b]-[3]benzazepine 29. A mixture of 28 (32 mg,
0.105 mmol) and polyphosphoric acid (0.85 g) was stirred at 65 °C
for 43 h. The reaction mixture was diluted with DCM (1.5 mL)
quenched with saturated NaHCO3 (15 mL), and the solution was made
basic (pH ) 14) by 15% NaOH (10 mL) solution. The mixture was
extracted with DCM (10 mL × 2), CHCl3 (10 mL), and finally with
CHCl3/IPA (2/1, 15 mL × 2), and the combined organic layers were
dried with Na2SO4, filtered, and concentrated in vacuo to give 29 as
a light yellow solid (22 mg, 73%). The crude material was judged
>90% pure by 1H and 13C NMR, and purification on neutral alumina
with eluents (EtOAc/hexane, 1:3-3:1 and 1% Et3N in EtOAc) gave
purified 29 (11 mg, 36%) for analytical purposes: [R]25 -137.4 (c
D
0.95, CHCl3), Lit. [R]21D -152.1 (c 1.03, CHCl3); νmax/cm-1 (CHCl3)
2930, 2808, 1747, 1693, 1608, 1488; δH (400 MHz, CDCl3, 298 K)
6.68 (1H, s), 6.62 (1H, s), 5.79 (1H, app dq, J ) 6, 2.2 Hz), 5.54 (1H,
app dq, J ) 6, 2.4 Hz), 3.89 (1H, m), 3.86 (3H, s), 3.84 (3H, s), 3.20
(1H, ddd, J ) 14, 12.4, 7.6 Hz), 3.08 (1H, app td, J ) 9.2, 4.8 Hz),
2.94 (1H, app td, J ) 12, 6.8 Hz), 2.76 (1H, app dq, J ) 17.6, 2.4
Hz), 2.56 (1H, dd, J ) 11.2, 7.6 Hz), 2.45-2.59 (2H, m), 2.04-1.90
(3H, m), 1.83-1.61 (2H, m); δC (100 MHz, CDCl3, 298 K) 147.7
(C), 147.2 (C), 132.6 (CH), 131.2 (C), 130.9 (C), 128.7 (CH), 144.2
(CH), 113.1 (CH), 68.2 (C), 62.4 (CH), 56.2 (CH3), 56.8 (CH3), 53.8
(CH2), 49.2 (CH2), 43.5 (CH2), 34.8 (CH2), 30.6 (CH2), 20.0 (CH2);
m/z (ES+) 286.1794 (M + H, C18H24NO2 requires 286.1802). These
data are identical to those previously reported.4b
Experimental Section
(R)-N-Boc-7-[(tert-butyldimethylsilyloxy)methyl]-1-azaspiro[4.4]
non-6-ene 18. n-Butyl lithium (11.1 mL, 2.28 M solution in hexanes,
25.4 mmol) was added dropwise to a cold (-78 °C) stirring solution
of trimethylsilyldiazomethane (14.6 mL, 2 M solution in hexanes, 29.2
mmol) in THF (39 mL), and the resulting mixture was stirred for 1 h
and 40 min at -78 °C. The ketone 17 (7.1 g, 19.1 mmol) in THF (25
mL) was added dropwise, and the resulting mixture was stirred for a
further 80 min. The reaction mixture was warmed to 0 °C and stirred
for 20 min. The reaction was quenched with NH4Cl (24 mL of a
saturated solution diluted with water (20 mL)), extracted with ether
(100 and 50 mL), dried with MgSO4, filtered, and concentrated in
vacuo to give the crude product. Purification by column chromatog-
raphy (petrol/Et2O; 10/1-5/1) afforded the product 18 (5.16 g, 74%)
as a colorless oil: [R]28D -49.56 (c 1.36, CHCl3); νmax/cm-1 (CHCl3)
2954, 2929, 2857, 1731, 1668, 1457; δH (500 MHz, C6D6, 343 K)
5.35 (1H, s); 4.12 (1H, d, J ) 13.5 Hz), 4.08 (1H, d, J ) 13.5 Hz),
3.38 (1H, br s), 3.27 (1H, app q, J ) 8 Hz), 2.52-2.30 (2H, m), 2.16
(1H, app quint, J ) 8 Hz), 1.70 (1H, m), 1.59 (2H, m,), 1.49-1.62
(2H, m), 1.41 (9H, s), 0.93 (9H, s), 0.04 (6H, s); δC (125 MHz, 298
K) (2.9:1 mixture of rotamers; signals from major rotamer marked
with *) 154.6* (C), 153.1 (C), 143.5 (C), 142.8* (C), 129.8* (CH),
129.2 (CH), 78.6* (C), 78.3 (C), 74.0* (C), 62.5 (CH2), 62.2* (CH2),
47.7 (CH2), 47.5* (CH2), 40.9* (CH2), 39.5 (CH2), 36.3* (CH2), 35.2
(CH2), 30.9* (CH2), 28.5 (3 × CH3), 28.4* (3 × CH3), 25.9 (3 ×
CH3), 22.8 (CH2), 22.5* (CH2), 18.3* (C), -5.4* (2 × CH3); m/z (ES+)
390.2430 (M + Na, C20H37NNaO3Si requires 390.2435); Anal. Calcd
for C20H37NO3: C, 65.3; H, 10.2; N, 3.8. Found: C, 64.9; H, 10.1; N,
3.9.
(R)-N-Boc-1-azaspiro[4.4]non-6-ene 11. To a stirring solution
of 33 (260 mg, 1.03 mmol) in toluene (5.20 mL) at room
temperature was added Rh(PPh3)3Cl (953 mg, 1.03 mmol), and the
mixture was heated at reflux for 14 h. The reaction mixture was
cooled to room temperature and diluted with EtOAc (23 mL). Then,
2 N NaOH (40 mL) was added, and the layers were separated. The
aqueous layer was extracted with EtOAc (50 mL × 2). The
combined organic layers were washed with brine (50 mL), dried
with MgSO4, filtered, and concentrated in vacuo to give a brown
oil, which was purified by column chromatography (ether/pentane,
1/5-1/4) to give 11 as a yellow oil (213 mg, 93%): [R]26D -101.3
(c 0.62, C6H6); νmax/cm-1 (C6H6) 2928, 2870, 1698, 1685, 1408;
δH (270 MHz, C6D6, 343 K) 5.61 (1H, br s), 5.47 (1H, br s), 3.45
(1H, br s), 3.37-3.26 (1H, m), 2.52 (1H, m), 2.36 (1H, m), 2.15
(1H, m), 1.63 (1H, m), 1.57 (2H, m), 1.46 (9H, s), 1.43-1.35 (2H,
m); δC (125 MHz, 298 K) (1.0:0.8 mixture of rotamers) 154.2 (C),
(3aS,14bS)-3,5,6,8,9,14b-Hexahydro-4H-cyclopenta[S]-[1,3]di-
oxolo[4,5-h]pyrrolo[2,l-b]-[3]benzazepine 8. To the solution of 31 (20
mg, 0.067 mmol) in DCM/MeNO2 (1:1, 2 mL) was added SnCl4 (80 µL,
0.68 mmol) dropwise at -78 °C, and the mixture was then warmed to 50
°C and stirred at this temperature for 14 h. The reaction mixture was cooled
to room temperature and diluted with EtOAc (5 mL). Then, 1 N HCl (1
mL) was added, and the pH was adjusted to 14 by addition of 2 N NaOH.
The layers were separated, and the aqueous solution was extracted with
EtOAc (10 mL), DCM (10 mL × 2), and finally with CHCl3/MeOH (9:
1, 10 mL). The combined organic layers were dried with MgSO4 and
concentrated in vacuo to give a brown oil, which was purified by column
chromatography [1% Et3N in EtOAc/pentane (1:1)] to yield 8 (9.2 mg,
46%) as a light yellow oil: [R]24 -210.5 (c 0.25, CHCl3), Lit. [R]22
D
D
-230.8 (c 1.22, CHCl3); δH (400 MHz, CDCl3, 298 K) 6.65 (1H, s), 6.59
(1H, s), 5.89 (1H, d, J ) 1.6 Hz), 5.88 (1H, d, J ) 1.6 Hz), 5.79 (1H, app
dq, J ) 5.9, 2.4 Hz), 5.52 (1H, app dq, J ) 5.9, 2.2 Hz), 3.86 (1H, m),
3.19 (1H, ddd, J ) 13.9, 12.5, 7.4 Hz), 3.06 (1H, app td, J ) 9.0, 4.4
Hz), 2.90 (1H, app td, J ) 11.7, 6.8 Hz), 2.74 (1H, app dq, J ) 18, 2.4
Hz), 2.54 (1H, dd, J ) 11.2, 7.5 Hz), 2.40 (1H, app td, J ) 10, 6.1 Hz),
2.33 (1H, dd, J ) 14.4, 6.4 Hz), 2.02-1.90 (3H, m), 1.83-1.64 (2H, m);
δC (100 MHz, CDCl3, 298 K) 146.4 (C), 146.0 (C), 132.5 (CH), 131.9(C),
128.8 (CH), 110.9 (CH), 109.9 (CH), 100.9 (CH2), 68.1 (C), 62.5 (CH),
53.7 (CH2), 49.1 (CH2), 43.4 (CH2), 34.8 (CH2), 30.7 (CH2), 20.0 (CH2);
m/z (ES+) 270.1489 (M + H, C17H20NO2 requires 270.1498), 271 (19,
M + 2H). These data are identical to those previously reported.4b
Acknowledgment. We thank the HEC (Pakistan) for providing
a Scholarship (A.H.), and also AstraZeneca and Pfizer for providing
additional financial support of this work.
Supporting Information Available: Experimental procedure
for preparation of 17, 19, 21, 22, 24, 25, 26, 28, 31, 34, and 35,
X-ray structure of 24, and copies of the 1H and 13C NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) We have recently observed epimerization of a similar spirocycle under
acidic conditions: Asari, A.; Angelov, P.; Auty, J. M.; Hayes, C. J Tetrahedron
Lett. 2007, 48, 2631.
(15) Royer has independently confirmed the success of the Kuehne Friedel-
Crafts reaction. See ref 4g.
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