Starting from ketone 3, which was in hand from the prior
studies, several approaches for C(6) nitrogen introduction
were explored. Attempts at direct nitrogen incorporation via
imine formation or reductive amination failed, as only
N-BOC-deprotected ketone 3 was returned in every case.
Eventually, resorting to a three-step sequence that featured
first BOC introduction and then ketone reduction to furnish
the sensitive alcohol 4 proved successful (Scheme 1). The
alcohol was isolated as an unbiased mixture of stereoisomers,
but Mitsunobu-type introduction5 of an azide moiety at C(6)
of this alcohol mixture delivered the desired azide as a pair
of diastereomers now favoring the R-isomer 5. In addition,
about 15% of a single diastereomer of the starting alcohol,
which was tentatively assigned the ꢀ-stereochemistry based
upon the H(6)-H(5) coupling constant (J ∼ 0 Hz), was
recovered. Speculation about the mechanism of this trans-
formation might extend to either of two extremes: (a) an
SN2 process, as per the orthodox Mitsunobu reaction, that
differentially favors reaction through the ꢀ-phosphonate
intermediate, or (b) an SN1-like reaction in which the
phosphonate ester leaving group is expelled to give an
intermediate acyl iminium ion that is quenched by azide
preferentially from the face of the cycloheptane ring opposite
of the NHBOC unit. Since C(6) is destined to become an
sp2 carbon in any event, both azide diastereomers were used
in subsequent chemistry.
describing the introduction of azide into the benzylic position
of simple aromatics under oxidative conditions6 raised the
hope that a similar process at the indolic position of 8 (a
precursor to 3, see ref 4a) would shave several steps off of
the synthesis route (Scheme 2). Scouting experiments with
the simple tryptamine derivative 6 were encouraging; the
azide function indeed could be introduced at the indolic
position in good yield under DDQ mediation. Unfortunately,
this chemistry did not translate to the dragmacidin skeleton,
as exposure of 8 to these conditions did no more than produce
the alkene-containing product 9. Apparently, an intermediate
indolic electrophile generated by DDQ-promoted oxidation
suffered proton loss in preference to bimolecular attack by
azide.
Scheme 2. Alternative C(6) Azide Introduction Attempt, Part 1
Scheme 1. Azide Introduction at C(6)
A second attempt at short-circuiting the chemistry of
Scheme 1 is detailed in Scheme 3. This approach again was
based upon direct oxidative azide introduction at the C(6)
position, but in this case the hope was that by opening the
spiroimidazolone ring more flexibility would be introduced
into the cycloheptane ring, perhaps facilitating azide addition
instead of proton elimination. To test this premise, the
cycloheptannelated indole 10, which is a precursor to 8 (see
ref 4a), was converted to the triply N-protected substrate 11.
Treatment of this species with DDQ/azide did not preform
as desired, as no azide incorporation was seen. Rather, the
now flexible methylene carbamate unit at C(5′′′) was able
to trap the nascent indolic electrophile to give the caged
Some effort was expended in examining alternative and
potentially briefer azide introduction procedures. A report
(2) (a) Whitlock, C. R.; Cava, M. P. Tetrahedron Lett. 1994, 35, 371–
374. (b) Jiang, B.; Smallheer, J. M.; Amaral-Ly, C.; Wuonola, M. A. J.
Org. Chem. 1994, 59, 6823–6827. (c) Miyake, F. Y.; Yakushijin, K.; Horne,
D. A. Org. Lett. 2000, 2, 3185–3187. (d) Kawasaki, T.; Enoki, H.;
Matsumura, K.; Ohyama, M.; Inagawa, M.; Sakamoto, M. Org. Lett. 2000,
2, 3027–3029. (e) Jiang, B.; Gu, X.-H. Heterocycles 2000, 53, 1559–1568.
(f) Kawasaki, T.; Ohno, K.; Enoki, H.; Umemoto, Y.; Sakamoto, M.
Tetrahedron Lett. 2002, 43, 4245–4248. (g) Yang, C.-G.; Wang, J.; Jiang,
B. Tetrahedron Lett. 2002, 43, 1063–1066. (h) Yang, C.-G.; Liu, G.; Jiang,
B. J. Org. Chem. 2002, 67, 9392–9396. (i) Yang, C.-G.; Wang, J.; Tang,
X.-X.; Jiang, B. Tetrahedron: Asymmetry 2002, 13, 383–394. (j) Garg, N. K.;
Stoltz, B. M. Tetrahedron Lett. 2005, 46, 2423–2426. (k) Antiss, M.; Nelson,
A. Org. Biomol. Chem. 2006, 4, 4135–4143. (l) Tonsiengsom, F.; Miyake,
F. Y.; Yakushijin, K.; Horne, D. A. Synthesis 2006, 49–54. (m) Ikoma,
M.; Oikawa, M.; Sasaki, M. Tetrahedron Lett. 2008, 49, 7197–7199.
(3) (a) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002,
124, 13179–13184. (b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am.
Chem. Soc. 2004, 126, 9552–9553. (c) Garg, N. K.; Caspi, D. D.; Stoltz,
B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. (d) Garg, N. K.; Stoltz,
B. M. J. Chem. Soc., Chem. Commun. 2006, 3769–3779. (e) Garg, N. K.;
Caspi, D. D.; Stoltz, B. M. Synlett 2006, 3081–3087.
(4) (a) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2005, 7, 5449–5452.
(b) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8, 4775–4778. (c) Huntley,
R. J. Ph.D. Thesis, Pennsylvania State University, 2008.
(5) (a) Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1396–
1398. (b) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 4596–4598.
(6) (a) Guy, A.; Lemor, A.; Doussot, J.; Lemaire, M. Synthesis 1988,
900–902. (b) Magnus, P.; Lacour, J.; Weber, W. J. Am. Chem. Soc. 1993,
115, 9347–9348.
Org. Lett., Vol. 12, No. 20, 2010
4503