Organic Letters
Letter
of hexamethylphosphoramide (HMPA) gave ketoester 7 in
65% overall yield.
With ketoester 7 in hand, we began to evaluate the proposed
oxidative cyclization of ketoester 7 for the formation of the
dimethylbicyclo[3.2.1]octane core of 8.
Initially, we Initially, we used Mn(OAc)3/Cu(OAc)2 as
oxidants9 to perform the proposed oxidative annulation of
ketoester 7, and reaction in AcOH at 70 °C for 20 h gave the
desired product 8 in 30% yield (Table 1, entry 1). The
majority of 7 decomposed under these conditions. To profile
the solvent effect on the outcome of annulation, we conducted
the annulation reaction in various solvents, i.e., MeOH, DMF,
EtOH, and DMSO. However, no significant improvement was
observed, and extensive decomposition of the starting material
was observed (Table 1, entries 2−6).
Replacement of Mn(OAc)3/CuOAc2 with Mn(acac)3/Cu-
(OAc)2 improved the yields to 50% and 60%, when the
reactions were conducted in EtOH and AcOH, respectively
(Table 1, entries 7 and 8). We speculated that high
temperatures might cause the decomposition of both the
substrate and the product. Therefore, we performed reactions
at room temperature for extended time periods, but to no avail
(Table 1, entries 9 and 10).
Figure 2. Total synthesis and model study of harziane diterpernoid.
radical cyclization6 to construct the dimethylbicyclo- [3.2.1]-
octane core of 8 from ketoester 7 (see Table 1).
Table 1. Mn/Cu-Mediated Oxidative Cyclization Reaction
With compound 8 in hand, we then turned our attention to
the preparation of enyne 9 so that its Au-catalyzed [2 + 2]
cycloaddition could be investigated (see Scheme 2). The
reagent
temperature
time
(h)
yield of 8
entry solvent
(2.1 equiv)
(°C)
(%)
1
2
3
4
5
6
HOAc
EtOH
DMF
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
70
70
70
70
70
70
20
20
20
20
20
20
30
24
25
35
<10
<10
Scheme 2. Synthesis of Enyne 9
MeOH Mn(OAc)3
DMSO Mn(OAc)3
HOAc
Mn(OAc)3·
2H2O
7
8
9
EtOH
HOAc
HOAc
HOAc
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
70
70
rt
12
12
12
24
50
60
45
56
10
rt
Therefore, a concise method for the preparation of 7 was
developed. Ketone 10 (Scheme 1) was treated with LDA at
Scheme 1. Synthesis of Ketoester 7
a
Reagents and conditions: (a) LiAlH4 (3.5 equiv), THF, 0 °C, 2 h;
(b) DMP (2.2 equiv), CH2Cl2, 0 °C, 0.5 h, 68%; (c) A (2.0 equiv),
Et2O, 0 °C, 3 h; (d) TBAF (3.0 equiv), THF, 45 °C, 6 h, 43% for two
steps; (e) B (1.3 equiv), KHMDS (1.3 equiv), 18-Crown-6 (5.0
equiv), −78 °C, 5 h, 91%; (f) LiAlH4 (3.5 equiv), THF, 0 °C, 2 h; (g)
DMP (2.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 0 °C, 0.5 h, 78% for
two steps; (h) TMSCHN2 (1.5 equiv), nBuLi (1.5 equiv), THF, −78
°C to rt, 13 h, 51%. DMP = Dess−Martin periodinane.
a
Reagents and conditions: (a) LDA (1.15 equiv), TBAI (0.5 equiv),
THF, −78 °C to −40 °C, 90%; (b) MeLi (1.2 equiv), THF, −78 °C,
1.5 h; then HCl (2 N, 2.0 equiv), −78 °C to 0 °C, 1 h, 75%; (c)
CuBr·Me2S (1.5 equiv), MeLi (3 equiv), Et2O, −78 °C to rt, 3 h; then
HMPA (4 equiv), NCCOOEt (1.2 equiv), −78 °C to rt, 12 h, 65%.
HMPA = hexamethylphosphoramide.
ketoester group in 8 was reduced with LiAlH4, and the
resultant diol was converted to ketoaldehyde 13 via DMP
oxidation. Treatment of the formed keto-aldehyde 13 with
Wittig reagent A10 and subsequent treatment with TBAF
afforded 14 in 50% yield in two steps. This low yield can be
attributed to the sterically demanding aldehyde group next to
the C6 quaternary carbon. The required (Z)-α,β-unsaturated
ester 15 was obtained in 92% yield by Still−Gennari
olefination11 of 14 via treatment with an ylide derived from
phosphate B and KHMDS. Oxidation/reduction of 15
afforded aldehyde 16. Treatment of 16 with a carbene derived
from TMSCHN2/nBuLi12 gave enyne 9 in 51% yield.
−78 °C. Alkylation between the resultant enolate and allyl
bromide gave 11 in 90% yield. By application of the protocol of
Stork and Danheiser,7 11 was converted to enone 12 in 85%
yield by treatment with MeLi, followed by reaction with HCl
(2 M) at 0 °C. Enone 12 underwent a Cu-mediated 1,4-
addition on treatment with MeLi in the presence of CuBr·
Me2S. Reaction of the resultant enolate with ethyl
cyanoformate (Mander’s reagent)8 at −78 °C in the presence
4089
Org. Lett. 2021, 23, 4088−4093