Tandem semipinacol/Schmidt reaction leading to a versatile and efficient approach to azaquaternary alkaloid skeletons

Article abstract of DOI:10.1021/ol062116r

A TiCl₄-promoted tandem semipinacol/Aube's type intramolecular Schmidt reaction of α-siloxy-epoxy-azide has been designed and developed to be a general method for efficient construction of azaquaternary carbon units. As applicable examples, som

Full text of DOI:10.1021/ol062116r

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5271-5273
Tandem Semipinacol/Schmidt Reaction
Leading to a Versatile and Efficient
Approach to Azaquaternary Alkaloid
Skeletons
Peiming Gu, Yu-Ming Zhao, Yong Qiang Tu,* Yufei Ma, and Fumin Zhang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, PRC
tuyq@lzu.edu.cn
Received August 28, 2006
ABSTRACT
A TiCl4-promoted tandem semipinacol/Aube´’s type intramolecular Schmidt reaction of
r-siloxy-epoxy-azide has been designed and developed
to be a general method for efficient construction of azaquaternary carbon units. As applicable examples, some key tricyclic azaquaternary
skeletons incorporated in many important alkaloids, such as cephalotaxine, stemonamine, erythrinan, and homoerythrinan alkaloids, have
been constructed.
A number of alkaloids possessing the azaquaternary center
units are widespread in nature. In particular, those alkaloids
(e.g, serratine, stemonamine, cephalotaxine, erythrinan, and
homoerythrinan alkaloids, and so on; Figure 1) incorporating
the key intriguing tricyclic structure 4, which has a nitrogen
atom located at a highly steric tertiary carbon, exhibit
significant biological activities. For example, the esters of
cephalotaxine show important antileukemia activity and are
currently undergoing advanced clinical trials.1 Because of
their particular structures and important pharmacological
values, these alkaloids continue to attract considerable
attention from organic chemists.2-6 Although great efforts
have been made toward this subject during the past years, it
is still necessary to develop a more efficient and compact
method to construct the complex azaquaternary tricyclic
structure 4.
Following our previous studies on tandem semipinacol
rearrangement of R-hydroxy epoxide for constructing the
quaternary carbon units,7 recently we have designed and
demonstrated a novel tandem semipinacol/Aube´ type Schmidt
rearrangement of R-siloxy-epoxy-azide. This reaction could
be developed to be a general and very efficient synthetic
(2) For synthesis of cephalotaxine, see: (a) Eckelbarger, J. D.; Wilmot,
J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370-10371. (b) Tietze,
L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264-10269. (c) Li,
W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931-2934 and references
therein.
(3) Recently, we have developed an efficient strategy for erythrinan and
homoerythrinan alkaloids. See: Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua,
R.; Jiang, Y.; Zhao, Y.; Fan, X.; Zhang, S. Org. Lett. 2006, 8, 2373-2376
and other strategies cited therein.
(1) For a review, see: Kantarjian, H. M.; Talpaz, M.; Santini, V.; Murgo,
A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92, 1591-1605.
(4) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. Org. Lett. 2001, 3,
2505-2508.
10.1021/ol062116r CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/18/2006

Table 1. TiCl4-Promoted Tandem Reaction of
R-Siloxy-epoxy-azidea
Figure 1. Some representative natural alkaloids incorporating
azaquaternary tricyclic structures 4.
method of azaquaternary carbon units and particularly favors
the construction of azaquaternary tricyclic structure 4. Here,
we report our experimental results.
The tandem reaction we designed is outlined in Scheme
1. We envisioned that the R-siloxy-epoxy-azide substrate 1
Scheme 1. Design of a Tandem Semipinacol/Schmidt
Rearrangement
a The tandem reaction experiments were performed by using 2.2 equiv
of TiCl4 in CH2Cl2 at -78 °C for 10 min and then warmed to rt for
b additional time. c Syn/anti mixtures were used. d Isolated yield. e Mixed
isomers (1i, â/R 6:1; 2i, â/R 7:1; 1j, â/R 8:1; 2j, â/R 8:1).
could undergo a Lewis acid promoted semipinacol rear-
rangement to generate a keto-azide intermediate 3 through
a carbon-carbon 1,2-migration.7,8 Then, 3 was expected to
successively undergo a Schmidt rearrangement through a
carbon-nitrogen migration under the same conditions9-11
to give the expected ultimate product 2.
According to the above idea, initially we started our
investigation of this protocol using the simple R-siloxy-
epoxy-azide substrate12 1a (Table 1). Thus, 1a was treated
with 2.2 equiv of TiCl4 in CH2Cl2 at -78 °C for 10 min,
and then the reaction mixture was warmed to room temper-
ature and stirred for an additional 1.5 h. After quenching
with water and purification on a silica column, we obtained
the expected amide 2a in 95% yield as a white solid.
Encouraged by this result, we investigated more examples.
Thus, the analogous substrates 1b and 1c were prepared and
(8) For semipinacol rearrangement and related reaction, see: (a) Maruoka,
K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimasaki, M.; Usuchihashi,
G. J. Am. Chem. Soc. 1986, 108, 3827-3829. (b) Maruoka, K.; Ooi, T.;
Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431-6432. (c) Nagasawa,
T.; Taya, K.; Kitamura, M.; Suzuki, K. J. Am. Chem. Soc. 1996, 118, 8949-
8950. (d) Maruoka, K.; Sato, J.; Yamamoto, H. J. Am. Chem. Soc. 1991,
113, 5449-5450. (e) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993,
115, 12208-12209. (f) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc.
1995, 117, 7379-7388. (g) Jung, M. E.; D’Amico, D. C. J. Am. Chem.
Soc. 1997, 119, 12150-12158. (h) Marson, C. M.; Walker, A. J.; Pickering,
J.; Hobson, A. D.; Wrigglesworth, R.; Edge, S. J. J. Org. Chem. 1993, 58,
5944-5951.
(5) For syntheses of serratine and related alkaloids, see: Cassayre, J.;
Gagosz, F.; Zard, S. Z. Angew. Chem. 2002, 114, 1861-1863; Angew.
Chem., Int. Ed. 2002, 41, 1783-1785 and references therein.
(6) For reviews on total synthesis of the cylindricine/fasicularin/
lepadiformine family of tricyclic marine alkaloids, see: (a) Weinreb, S.
M. Acc. Chem. Res. 2003, 36, 59-65. (b) Weinreb, S. M. Chem. ReV. 2006,
106, 2531-2549.
(7) (a) Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1999, 64, 629-
633. (b) Fan, C.-A.; Wang, B.-M.; Tu, Y. Q.; Song, Z.-L. Angew. Chem.
2001, 113, 3995-3998; Angew. Chem., Int. Ed. 2001, 40, 3877-3880. (c)
Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem. 2004, 116,
1734-1737; Angew. Chem., Int. Ed. 2004, 43, 1702-1705.
(9) For studies of the intramolecular Schmidt reaction, please see: (a)
Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-8966. (b)
Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995, 117,
10449-10459.
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Org. Lett., Vol. 8, No. 23, 2006

also successfully converted to the corresponding products
2b and 2c in 77% and 80% yields (entries 2 and 3) in the
above general procedure. Successively, the more complex
cyclic substrates 1d-h were examined also, and the corre-
sponding bicyclic lactam products 2d-h were obtained in
61-92% yields (entries 4-8). Similarly, experiments using
even more complex bicyclic substrates 1i and 1j demon-
strated the efficiency of this tandem rearrangement and gave
the synthetically valuable tricyclic lactams 2i and 2j in 78%
and 92% yields (entries 9 and 10).
Finally, it was most significant that this tandem reaction
established a new method for compact synthesis of the
azaquaternary tricyclic skeletons 4 of various alkaloids. For
example, the product 2h could be readily converted through
three steps (Scheme 3) to a 5-7-5 tricyclic system 5h, the
Scheme 3. Approach to Stemonamine/Isostemonamine and the
Cephalotaxine Alkaloid Skeleton
The main favorable characteristics of this tandem process
included the following: it was effective to a wide scope of
substrates; the quenched reaction system was clear and easy
to purify; and more importantly, the stereochemistry was well
controlled. For example, in entry 8, only one diastereoisomer
was isolated, and in entries 9 and 10, the major isomers13 2i
and 2j were also furnished. The stereochemistries of 2h and
2i were confirmed unambiguously by X-ray crystallography
analysis.
According to the above experimental results and the
literature reports,14 a possible sequential mechanism of this
tandem reaction was proposed as depicted in Scheme 2. First,
key skeleton for synthesis of stemonamine/isostemonamine
and cephalotaxine.
In addition, the example (entry 9) provided a very efficient
and short approach to the 6-5-6 tricyclic skeleton 2i of
isococculidine (Figure 1). Furthermore, another example
(entry 10) provided a direct approach to the 6-5-7 tricyclic
skeleton 2j of dihydrocomosidine (Figure 1). The stere-
ochemistries of two skeletons, 2i and 2j, were consistent with
the natural products. The possibility for absolute stereo-
chemical control of these tricyclic lactams also exists if a
certain asymmetric epoxidation procedure was applied to the
substrate preparation.15 We believe that this tandem reaction
could be applied to the total synthesis of these and more
alkaloids if proper substrates are used.
Scheme 2. Possible Reaction Mechanism
In summary, we have designed and successfully developed
a new Lewis acid promoted tandem semipinacol/Aube´ type
Schmidt reaction of R-siloxy-epoxy-azide. This tandem
process has many advantages combining both semipinacol
and Schmidt reactions. The total syntheses of stemonamine/
isostemonamine and erythrinan/homoerythrinan alkaloids are
underway in our group.
it probably proceeded through the chelate transition states 5
and 6 of titanium(IV) with two oxygens, which induced the
epoxy ring opening, and the synchronous antiperiplanar
migration of R3 led to the formation of diastereoselective
intermediate 6. Second, the sequent antiperiplanar migration
of the quaternary carbon to electron-deficient nitrogen
proceeded with retention of the configuration and provided
the final product 2.
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (No. 30271488 and 20021001) and
the Chang Jiang Scholars Program.
Supporting Information Available: General experimen-
tal procedures, characterization data for all substrates and
products, and X-ray crystallographic data for compounds 2h
and 2i which are deposited at the Cambridge Crystallographic
data center with the deposition numbers CCDC 616555 and
616556. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) For a domino reaction involving an intramolecular Schmidt reaction,
see: (a) Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41, 4316-
4318. (b) Zeng, Y.; Reddy, D. S.; Hirt, E.; Aube´, J. Org. Lett. 2004, 6,
4993-4995. (c) Zeng, Y. Y.; Aube´, J. J. Am. Chem. Soc. 2005, 127, 15712-
15713.
(11) For additional examples involving rearrangement of epoxy-azides,
see: (a) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5, 583-
585. (b) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093-3101.
(c) Lang, S.; Kennedy, A. R.; Murphy, J. A.; Payne, A. H. Org. Lett. 2003,
5, 3655-3658.
OL062116R
(12) CAUTION! Alkyl azides are potential explosion hazards in substrate
synthesis. See the Supporting Information.
(13) The mixtures of 2i and 2j were formed from the corresponding
mixed substrates 1i and 1j, respectively.
(14) For the mechanism of the intramolecular Schmidt reaction, see:
Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Reddy,
D. S.; Aube´, J. J. Am. Chem. Soc. 2003, 125, 7914-7922 and ref 9b.
(15) For tandem asymmetric allylation/diastereoselective epoxidation of
cyclic enones, see: (a) Jeon, S.-J.; Walsh, P. J. J Am. Chem. Soc. 2003,
125, 9544-9545. (b) Kim, J. G.; Waltz, K. M.; Garcia, L. F.; Kwiatkowski,
D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580-12585. (c) Jeon,
S.-J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416-16425.
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