5. Other Strategies For Synthesizing γ-Hydroxy-
Unsaturated Carbonyl Compounds
Generating the Stereocenter α to a Carbonyl
Brusse Tetrahedron 2000, 56, 2491.
Zhong, Org. Lett. 2004, 6, 1637.
Krawczyk Synthesis 2008, 20, 3299.
6. Other Strategies For Synthesizing γ-Hydroxy-
Unsaturated Carbonyl Compounds
Asymmetric Functionalization of β,γ-Unsaturated Carbonyl Compounds
Tiecco, Chem. Eur. J. 2002, 8, 1118.
Bruckner, Synlett 2001, 718.
7. Other Strategies For Synthesizing γ-Hydroxy-
Unsaturated Carbonyl Compounds
Enantioselective Nucleophilic Additions to Aldehydes
Trost, Chem. Eur. J. 2012, 18, 16498.
Wang, Org. Lett. 2007, 9, 2329.
8. Advantages of phosphene γ-addition over other
strategies
• Makes use of few and easily synthesized reagents, while some other strategies make use
of numerous reagents, some of which might not be easily accessible.
• Simple one step reaction
• Can simply set up the reaction and set aside to react overnight.
• Multi step reactions require more care and attention
• Relatively mild conditions
• Reaction set up in nitrogen atmosphere, then left to react at room temperature.
• Some other strategies must be carried out in harsher conditions.
12. Synthesis
Varying the EWG of the Alkynoate
Yield:
67%
No product formation
observed for many
similar reactions
Yield:
74%
Yield:
19%
Changed synthetic route
14. Oxygen γ-Addition
Aromatic Heterocycle-Substituted Alkynoates
• Only 3-thiophen alkyne reacted well under standard reaction
conditions, other synthesized heterocycle-substituted alkynes
reacted more poorly
• The problematic alkynes were later used in slow addition reactions
over 16 hours, resulting in much better yield.
15. Oxygen γ-Addition
Indole as nucleophile
Phenyl ketone EWG
Varying nucleophile distance from aryl group
n yield ee
1 63% 96%
2 48% 97%
3 37% 97.5
%
17. Oxygen γ-Addition
n-Pentanol as nucleophile
Experiment Nucleophile
load
Additive Slow addition Concentration Yield ee
01-076-5 2 eq. None - 0.25 M 38% -
01-076-6 2 eq. 20% phenol - 0.25 M 33% -
01-086-1 4 eq. None - 0.25 M 44% -
01-084-1 2 eq. 50% pivalic acid - 0.25 M <5% -
01-084-2 2 eq. 50% 2-methoxy
phenol
- 0.25 M 34% -
01-084-3 2 eq. 50% 2-methoxy 6-
fluoro phenol
- 0.25 M 23% -
01-088-2 2 eq. None - 0.10 M 18% -
01-088-1 2 eq. None 8 h 0.10 M 26% -
01-092-2 4 eq. None - 0.25 M 42% -
01-092-1 4 eq. None 16 h 0.25 M 81% 96%
18. Summary
• 3-Thiophene was the only aromatic heterocycle substituted alkynoate with good yield
of the γ-addition product under standard reaction conditions.
• Indole-substituted alcohol as nucleophile resulted in decent yield of γ-addition product
• Varying the EWG to a phenyl ketone resulted in very low yield of γ-addition product
• Increasing the distance of the oxygen from the aryl group in nucleophile results in a
decrease in yield and increase in ee
• Ortho-methoxybenzyl substituted alkynoate reacts with slightly lower yield and ee than
observed with para-methoxybenzyl substituted alkynoate
• Phenol and pivalic acid additives did not improve the yield of γ-addition product
• Increased nucleophile loading and slow addition increase the yield of γ-addition
product
19. Later Discoveries
• Methanol as a nucleophile gave good yield and ee in slow addition reaction with both t-
Butyl and Methyl Ester Alkynoates. Transesterification to the methyl ester occurs in the
case of the t-butyl ester alkynoate.
• Many other nucleophiles which previously showed poor reactivity used in slow
addition reactions to improve their yield.
• Alkynamide alkynoates show good reactivity under standard reaction conditions.
20. Acknowledgements
• Thanks to Greg Fu, Dan Ziegler and all the other members of the Fu group for a fun
and insightful summer of work.
• Thanks to the SURF program, and all the donors who make it possible, for the
opportunity presented to me and all the other SURF students I spend the summer
with.
