3 Studies Towards the Total Synthesis of (–)-Lyngbyaloside B
3.4 Model System Studies
Gaunt’s copper-catalysed homoallylic carbamate alkenylation methodology tolerates the use of a variety of iodonium salts. Within the reported scope of the reaction, the generation of three carbonate examples are particularly relevant to the formation of (–)-lyngbyaloside B – allylic disubstituted carbonate 474 and allylic oxygenated compounds 475 and 476 (Table 29).158
Table 29 – Relevant substitution tolerance of the alkenyl iodonium salt 472 to Gaunt’s oxy-alkenylation158
The above examples provide evidence that the desired complex fragment coupling will be tolerated under copper-catalysed oxy-alkenylation conditions. However, no examples are shown for the transfer of iodonium salts bearing a more relevant secondary allylic ether motif. Initial efforts were therefore directed towards the investigation of a model reaction between homoallylic carbamate 317 and some more representative iodonium salt (477) (Scheme 95).
HO
317 472 (2 equiv.) 473
O O +
Scheme 95 – Model fragment coupling to give a homoallylic carbonate with a secondary allylic ether motif A three-step procedure was identified for the production of iodonium salts bearing the desired allylic substitution. The reaction sequence employs a copper-catalysed alkyne borylation,185 a boronic ester hydrolysis and a Lewis-acid promoted iodonium salt formation. Three alkenyl(aryl)iodonium salts were synthesised by this method (Table 30) in order to assess the effect of both the oxygen protecting group and the steric bulk of the iodonium salt aryl group on the outcome of the model oxy-alkenylation reaction.
Table 30 – Production of model iodonium salts 481, 482 and 483
The coupling of the new iodonium salts with model homoallylic carbamate substrate 317 was then tested (Table 31). Investigations began by employing the original coupling conditions reported by our group,158 giving moderate to good starting material conversions but little desired product formation (<8% yield in all cases, entries 1–3). Diene 484 was observed to be the major product of all the reactions (19–13%
yield), implying either the iodonium salts or the products to be unstable with respect to a deleterious elimination of the protected allylic alcohol.
TfO I Me
Me Me
317 477 (2 equiv.) 478
O O + 5.0 equiv. NaIO4 CO(CH3)2/H2O (2:1), rt, 24 h
1.2 equiv. ArI(OAc)2 1.2 equiv. BF3•OEt2
Entry Iodonium
Salt Conditions
Yield / %a
478b 484c 317
1 481 10 mol% [Cu], CH2Cl2 (0.025 M), rt, 18 h <8 19 22
2 483 10 mol% [Cu], CH2Cl2 (0.025 M), rt, 18 h <5 15 53
3 482 10 mol% [Cu], CH2Cl2 (0.025 M), rt, 18 h <7 13 13
4 481 10 mol% [Cu], CH2Cl2 (0.025 M), 0 ºC, 24 h 23 0 77
5 481 10 mol% [Cu], CH2Cl2 (0.1 M), 0 ºC, 24 h 33 0 63
6 481
10 mol% [Cu], CH2Cl2 (0.05 M), 0 ºC, 24 h 44 h
64 h
33 29 27
0 tr 8
54 44 37
7 481 10 mol% [Cu], CH2Cl2 (0.05 M), –15 ºC, 24 h 0 0 70
8 481 10 mol% [Cu], CH2Cl2 (0.05 M), 10 ºC, 24 h 20 tr 29
9 481 10 mol% [Cu], CH2Cl2 (0.05 M), 0 ºC, 24 h +10mol% [Cu], 42 h
33 29
0 tr
43 39
10 483 10 mol% [Cu], CH2Cl2 (0.05 M), 0 ºC, 24 h <5 0 66
11 482 10 mol% [Cu], CH2Cl2 (0.05 M), 0 ºC, 24 h 46 0 47
a yield determined by 1H NMR using 1,3,5-trimethoxybenzenetricarboxylate; b yield quoted as the sum of four possible diastereoisomers; c yield quoted as the sum of two possible diastereoisomers
Table 31 – Investigations into the viability of the model coupling between homoallylic carbamate 317 and iodonium salts 481, 482 and 483
Work was directed towards disfavouring the elimination process (Table 31, entries 4–9). It was discovered that lowering the temperature of the reaction employing iodonium salt 481 to 0 ºC precluded
317 477 (2 equiv.) 478
O O + NMe2
Me
O O
O
Me
Me OP
484
O O
O
Me +
TfO I Me
Me Me
Me
OP cat. (CuOTf)2•PhH
conditions
formation of the diene and gave increased product yields (23%) despite reduced levels of starting material conversion (entry 4). Similarly, increasing the concentration of the reaction at 0 ºC (entry 5, 0.05 M) provided an improved 33% homoallylic carbonate yield, although no further increase in yield was observed at 0.1 M (entry 6). Extending the reaction time from 24 to 44 and 64 hours resulted in significant starting material decomposition and no further product formation. Finally, no improvement in carbonate yield was obtained by further varying the reaction temperature (–15 ºC for entry 7 and +10 ºC for entry 8) or by increasing the loading of the catalyst in the reaction (entry 9).
It was hoped that changing either the oxygen protecting group or the non-transferring aryl group of the iodonium salt would lead to increased oxy-alkenylation yields. As such, the conditions giving the best reactivity with benzyl-protected alkenyl(mesityl)iodonium salt 481 (0.05 M, 0 ºC, 10 mol% Cu) were applied to coupling reactions employing TIPS-protected and ortho-tolyl-bearing iodonium salts 483 and 482 (Table 31, entries 10 and 11). Although only trace product was observed with the allylic hydroxyl group being protected as a tri-iso-propylsilyl ether, the use of the less sterically-encumbered benzyl-protected iodonium salt furnished the coupled product in 46% yield. This result demonstrates that iodonium salts bearing secondary allylic ether motifs will react with homoallylic carbamates to give the corresponding carbonate in useful yields, thereby evidencing the viability of the proposed complex fragment coupling. Further, reducing the sterics of the iodonium salt appears to improve conversion.
My colleague Dean Holt extended the model coupling studies to the use of acetonide-protected iodonium salt 485, designed to bear the relative stereochemistry and oxygenation pattern of the C-5,6,7 portion of (–)-lyngbyaloside B (Scheme 96).186 Although no reaction with homoallylic carbamate 317 was detected after 24 hours at –10 ºC, carbonates 486 and 487 were obtained in 21% combined yield after a further six hours of reaction time at room-temperature and with an additional portion of catalyst.
The observed 1:1 diastereoselectivity was expected given the achiral nature of the homoallylic carbonate substrate. Despite the low yields, the production of carbonate products 486 and 487 proves that polyoxygenated and stereochemically-rich alkenyl(aryl)iodonium salts can be tolerated in our copper-catalyed oxy-alkenylation reaction. This result provides crucial evidence for the likely tolerance of our desired complex iodonium salt 471 under the same reaction manifold.
Scheme 96 – Model coupling between model substrate 317 and iodonium salt 485 – Dean Holt186
O O
NMe2
Me
317
O
Me O
OTf
I O
Me O
Me
O O
Me O
486 +
5 mol% (CuOTf)2•PhH CH2Cl2, –10 ºC, 24 h
then:
5 mol% (CuOTf)2•PhH CH2Cl2, rt, 6 h
485 (2.0 equiv.)
Me Me Me
Me Me
Me Me
21%
1:1 d.r.
O
Me O
Me
O O
Me O
487
Me Me Me
+
Efforts were next directed towards the synthesis of the key synthetic fragments. Dean Holt turned his attention towards the synthesis of homallylic carbamate 470, later investigated by Dominik Reich. The following work focuses on the synthesis of complex iodonium salt 471.