3.4 The Total Synthesis of (–)-Dragmacidin F
3.4.3 The Scope and Mechanism of the Reductive Isomerization Reaction
Scheme 3.4.3
O TBSO
O
HO (–)-Quinic Acid (93) 95
4 steps
NSEM Li
THF, –78 °C, 30 min 1.
2. TBSCl, DMAP imidazole DMF, 50 °C
TBAF THF 23 °C, 3 min
(95% yield)
3 5
O O
TBSO O
O N
131 CDI, NaH
THF 23 °C, 20 min
(92% yield)
3 SEM 5
(82% yield, 2 steps) CO2H
HO OH
OH
HO
133
3 5
O
OTBS
N OH SEM
132
3 5
O
OTBS
N OH SEM
HO
TBSO
127 O
OTBS
N OH SEM H2 (1 atm)
10% Pd/C (2 mol %) MeOH 0 °C, 1.75 h (90% yield)
Scheme 3.4.4
O TBSO
O
HO 95
O TBSO
HO OH
134 D2 (1 atm)
10% Pd/C (2 mol %) MeOH, 0 °C
D
*
HO
O N
SEM D2 (1 atm)
10% Pd/C (2 mol %) MeOH, 0 °C
135 136
O O O
O N
SEM
D
* D-incorporation
In terms of mechanism, we considered the simple possibility that our transformation could be proceeding in a tandem fashion via hydrogenation of the olefin followed by E2 elimination (e.g., 95 → 100 → 96, Scheme 3.4.5). However, subjection of an independently prepared sample of saturated lactone 137 (1:1 dr) to the identical reaction conditions (10% Pd/C, H2, MeOH, 0 °C) led to no reaction, allowing us to dismiss its potential as a viable intermediate.60
Scheme 3.4.5
O TBSO
O
HO 100 Olefin
Reduction
E2 Elimination O
TBSO
O
HO
95 O
TBSO
HO OH
96
O TBSO
O
HO 137 (1:1 dr)
H2 (1 atm) 10% Pd/C (2 mol %)
MeOH, 0 °C No Reaction
A π-allyl mechanism could be probed by using carbonate-bearing trisubstituted olefin 135. Under π-allyl hydrogenolysis conditions, racemic 138 was obtained (Scheme 3.4.6A).41b Interestingly, analysis by chiral HPLC revealed that, under our reductive isomerization conditions at 0 °C, cyclohexene 138 was produced in 7.2% ee (Scheme 3.4.6B). In fact, by lowering the reaction temperature, up to 23.1% ee could be achieved.41b Although complete optical purity was not maintained in the product, this result suggests a reaction pathway that does not solely involve a meso-π-allylpalladium complex (e.g., 139).61
Scheme 3.4.6
Pd(II) Pd2(dba)3, P(n-Bu)3
Et3N, HCO2H
THF, 70 °C HO
O N
SEM
racemic HO
O N
SEM
H2 (1 atm) 10% Pd/C (2 mol %)
MeOH
(+)-135 138
138
O N
SEM
HO
O N
SEM 139
%ee 138 temperature
4.8 23 °C
7.2 0 °C
16.5 –25 °C → –15 °C 23.1 –78 °C → –15 °C O
O O
A B
Recently, both Sajiki and Hara have invoked a single-electron transfer (SET) mechanism for other transformations involving the use of 10% Pd/C and MeOH.62 In accordance with this hypothesis, exposing either lactone 95 or carbonate 135 to our standard conditions in the presence of tetracyanoethylene (TCNE) as a SET inhibitor completely halts all reactivity, even at 23 °C (Scheme 3.4.7).63
Scheme 3.4.7
H2 (1 atm) 10% Pd/C (2 mol %)
TCNE (50 mol %) MeOH, 23 °C O
TBSO
O HO
95
H2 (1 atm) 10% Pd/C (2 mol %)
TCNE (50 mol %) MeOH, 23 °C
135
O N
SEM
No Reaction No Reaction
CN CN NC NC
TCNE O
O O
We prepared a number of substrates to assess the generality of this reaction (Table 3.4.1).64 As a starting point, a simple variant of lactone 95 bearing an acetate on the secondary allylic alcohol was synthesized (i.e., 140). We were pleased to see that 140 could be converted to carboxylic acid 141 in good yield (entry 1). The use of allylic acetate 97 as a substrate (entry 2), on the other hand, led to an unexpected result. We anticipated that methyl ester 98 would be the observed product because acetate is a superior leaving group to silanolate (see Scheme 3.4.2, vide supra). However, the compound obtained (i.e., 129) resulted from a net loss of the OTBS group.65 Notably, none of the byproducts formed under homogeneous π-allyl protocols were observed under these heterogeneous conditions (98, 99, iv20, see Scheme 3.2.1, vide supra). In order to probe this result further, a version of 97 with exchanged protecting groups on the secondary alcohols was prepared (142, entry 3). In this case, elimination of acetate occurred.65
Table 3.4.1a
O AcO
O HO
8 4
6
81%
90%
94%
substrate yieldb
entry product time
R = Ac 1 h
4 h 20 min R = Ac HO
OR OR
OR
HO OR
OTBS
HO OTBS
OTBS OTBS
O (t-Bu)2Si O
68%
9 1 h
OMe
O O
OMe
O
NSEM O
NSEM
O N
SEM O N
SEM
OMe O OMe
O
10g 91%
HO
O O
1.3 h
NSEM N
SEM HO
OAc OAc
TBSO
HO
OTBS OTBS
AcO
HO HO
3%d 1 h
27%
1.5 h 2c
3c,e
O
OMe OMe
O
OMe O
OMe O
HO OH
O AcO
71%
15 min 1
O O O
O O O
O O O
O (t-Bu)2Si
O
O O O
10%e,f 35 min
8 min 94%
80%
15 min R = TBS
R = H 5
7
140 141
129 97
142
144 145
129 143 143
147 149 146
148
150 151
152 153
135 138
a Standard conditions: H2 (balloon, 1 atm), 10% Pd/C (2 mol % Pd), MeOH, 0 °C. b Isolated yield. c Yield based on 1H NMR integration. d 10% Pd/C (0.5 mol % Pd). e 10% Pd/C (1 mol % Pd). f Reaction performed at 23 °C. g Product formed in 7.2% ee.
Due to the success of the rigid bicyclic lactone framework in this reaction, we reasoned that the reactivity of 97 and 142 might be improved by restricting them as bicyclic carbonates (144 and 145). These carbonate-containing substrates were well tolerated and led to competent production of the corresponding methyl esters (entries 4 and 5). Additionally, carbonates with adjacent heterocyclic moieties such as pyrrole (146 and 148) and indole (150) could be converted into their reductively isomerized counterparts in excellent yields (entries 6–8 and 10). The use of an acetate protecting group on the secondary allylic alcohol (entries 1, 4, and 6), or an unprotected alcohol altogether (entry 7), did not significantly influence the overall reaction efficiency.
Interestingly, replacement of the carbonate moiety with a dioxasilyl linkage led solely to diastereoselective hydrogenation of the olefin (entry 9).66 Somewhat surprisingly, reductive isomerization using a trisubstituted olefin was also quite facile (entry 10, cf.
Scheme 3.4.6).67
A model to rationalize some of these anomalous differences in reactivity is presented in Figure 3.4.2, which is an extended version of the model conceived in our initial hypothesis (see Figure 3.4.1, vide supra). An examination of the three-dimensional structures of the starting materials in Table 3.4.1 reveals that the leaving group is positioned preferentially in an axial orientation with respect to the six-membered ring.68 Furthermore, structurally rigid bicyclic lactones and carbonates with locked axial leaving groups (e.g., 154 and 155) exhibited enhanced yields relative to their more flexible monocyclic counterparts (142 and 97). The difference in yield between substrates 142 and 97 can be attributed to leaving group ability (i.e. AcO– > Me2(t-Bu)SiO–). This leaving group effect was also observed when the carbonate functionality was replaced
with a dioxasilyl moiety (entry 9), in which case only direct olefin hydrogenation occurred.
Figure 3.4.2
OH OTBS
O AcO MeO
97 O RO
R'
155 conformationally
rigid & good leaving group
conformationally flexible & poor
leaving group RO
HO O O
154
Poor reactivity Excellent reactivity
OH OAc
O OTBS MeO
142 conformationally
flexible & good leaving group
Modest reactivity
O O
O