Scheme 2. Ynehydrazide Based Approach to Hydrazidomycin A
Analogs
Table 1. Hydrazide Ring Opening of syn-Silyl Epoxide 15
to 16
1
a
R
conditions
yield
b
c
H
NH
NH
4
Cl (2 equiv), MeOH/H
Cl (2 equiv), MeOH/H
2
O, 16 h, 65 °C
O, 16 h, 65 °C
ꢀ
c
Boc
4
2
ꢀ
b
d
H
BF
C(O) BF
BF
3
OEt
OEt
OEt
OEt
2
2
2
2
(10 mol %), THF, 16 h, rt
(10 mol %), THF, 16 h, 45 °C
(10 mol %), THF, 16 h, rt
(10 mol %), THF, 16 h, 45 °C
ꢀ
3
c,e
MeOCH
Boc
2
3
3
3
ꢀ
3
3
3
30%
75%
f
Boc
BF
a
1
.0 equiv of R NHNH
b
used. Hydrazine monohydrate used.
2
2
c
d
e
The problems encountered above prompted the investiga-
tion of alternative strategies for the stereocontrolled forma-
Near-quantitative recovery of 15. Decomposition of 15. Decomposi-
f 1
tion of hydrazide. 4.0 equiv of R NHNH used.
2
14
tion of enehydrazides. A Peterson elimination based ap-
proach was attractive due to the possibility of achieving
highly stereocontrolled formation of either Z- or E-enehy-
drazides by appropriate substrate choice or elimination
As planned, the use of Boc-carbazate in this ring-
opening reaction provides suitably differentiated hydrazine
nitrogens for subsequent site selective functionalization.
As a result, acylation of hydrazide derivative 16 provided
trisubstituted hydrazide intermediate 17 which was then
successfully converted to the natural product target 1 in
only three additional steps (Scheme 3). For convenience,
and to limit silica gel exposure of the potentially labile
Z-enehydrazide moiety, a telescoped three-step protocol
proved optimal, utilizing a KOtBu mediated Peterson
elimination followed immediately by Boc-carbamate acyl-
15,16
conditions.
The successful realization of this synthetic
plan required development of regio- and stereoselective
access to previously unknown hydrazine functionalized
vicinal silanol derivatives. In this regard, prior work on
15,16
Z-enamides
suggested that the key anti-β-silyl-β-hydra-
zidoalcohols, needed for a base mediated Peterson elimina-
tion to Z-enehydrazides, might be accessible by silyl-directed
ring opening of a cis-silyl epoxide with a hydrazine nucleo-
phile. Although sodium azide is known to regioselectively
ring-open silyl epoxides, there are very few examples of
such a reaction with other less nucleophilic heteroatom
1
7
ation and catalytic Mg(II) imide-Boc deprotection. The
total synthesis of hydrazidomycin A was thus achieved
with complete control of Z-olefin geometry, in an overall
yield of 16% over eight steps.
1
5d,e
nucleophiles
develop a new silyl epoxide hydrazine ring-opening reac-
tion using either hydrazine or MeOCH CONHNH with
and none using hydrazines. Attempts to
An attractive aspect of the Peterson based strategy to
enehydrazides is the stereospecific and stereodivergent
2
2
15a,b,16
15d,e
1
5e
either NH Cl
or BF OEt
catalysis were unsuc-
cessful (Table 1). However, the reaction of an excess of
Boc-carbazate with 15 at 45 °C under BF OEt catalysis
4
3
3
2
nature of acid or base mediated silanol elimination.
Thus, a complementary acid mediated silanol elimination
sequence of 17 conveniently furnished the corresponding
isomeric trans-hydrazidomycin A analog 18 in 50% yield
over three steps (Scheme 4). Comparison ofolefin coupling
constants for 1 (J = 9.0 Hz) with 18 (J = 14.0 Hz)
confirms the cis-stereochemical assignment for 1.
3
3
2
(
10 mol %) allowed for the regioselective and stereospecific
opening of the silyl epoxide to give 16.
(
14) For reviews on Peterson eliminations, see: (a) Ager, D. J. Org.
React. 1990, 38, 1–223. (b) Ager, D. J. Synthesis 1984, 384–398.
c) Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett
991, 764–770. (d) Kawashima, T.; Okazaki, R. Synlett 1996, 600–608.
e) van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002,
1, 195–200. (f) Ager, D. J. Sci. Synth. 2010, 47a, 85–104.
15) For examples of Peterson elimination approaches to enamides,
see: (a) Palomo, C.; Aizpurua, J. M.; Legido, M. Tetrahedron Lett. 1992,
3, 3903–3906. (b) Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org.
Adaptation of thisPetersonolefination sequence toward
the total synthesis of 2 and 3 was then undertaken using a
similar alkyne hydroalumination based route to access the
required hydrazino silanol precursors (Scheme 5). Reac-
tion of 19 and 20 with a slight excess of DIBAL-H resulted
in mixtures of the expected Z-alkenyl TBS protected
(
1
(
3
(
3
1
8
Lett. 2001, 3, 3955–3957. (c) Cuevas, J. C.; Patil, P.; Snieckus, V.
Tetrahedron Lett. 1989, 30, 5841–5844. (d) Hudrlick, P. F.; Hudrlick,
A. M.; Rona, R. J.; Misra, R. N.; Withers, G. P. J. Am. Chem. Soc. 1977,
alcohols and the corresponding O-deprotected products
9
9, 1993–1996. (e) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K.
Tetrahedron Lett. 1985, 26, 139–142.
16) For a related Peterson elimination approach to the Z-enamide
(17) Stafford, J. A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano,
N. L. Tetrahedron Lett. 1993, 34, 7873–7876.
(18) DIBAL-H is known to occasionally deprotect silyl ethers; see for
example: (a) Corey, E. J.; Jones, G. B. J. Org. Chem. 1992, 57, 1028–
1029. (b) Kuranaga, T.; Ishihara, S.; Ohtani, N.; Satake, M.; Tachibana,
K. Tetrahedron Lett. 2010, 51, 6345–6348.
(
containing crocacin natural products, see: (a) Chakraborty, T. K.;
Laxman, P. Tetrahedron Lett. 2003, 44, 4989–4992. (b) Chakraborty,
T. K.; Laxman, P. Tetrahedron Lett. 2002, 43, 2645–2648.
Org. Lett., Vol. XX, No. XX, XXXX
C