Metathesis Reactions of Acyloxysulfones for Polyene Synthesis

Reports: UNI1 49499-UNI1: Metathesis Reactions of Acyloxysulfones for Polyene Synthesis

Gregory W. O'Neil, PhD, Western Washington University

The introduction of well-defined catalysts such as 1 and 2 for olefin metathesis has had a tremendous impact on both organic and polymer synthesis (Figure 1). Despite the success of these catalysts in preparing a wide range of structurally diverse compounds, applications to polyene synthesis remain limited. This is largely the result of problems associated with chemoselectivity, that is the engagement by the metathesis catalysts of one alkene in the presence of another.

We set out to investigate the use of β-acyloxysulfones as masked alkenes, allowing for a metathesis approach to polyene subunits difficult to obtain by standard metathesis technology (Figure 2).

1,6- And 1,7-dienes, important substrates for a variety of cycloisomerization reactions, were chosen as initial targets for this reaction sequence. These compounds are particularly challenging to prepare by cross-metathesis due to a competing rapid ring-closure (Figure 3).

The requisite alkenyl-acyloxysulfones were conveniently prepared by the addition of lithiated sulfone 3 or 4 to an aldehyde followed by in situ acylation of the intermediate alkoxide, affording substrates of type 5 as approximately 1:1 mixtures of diastereomers (Scheme 1).

Grubbs' second-generation catalyst 2 proved capable of effecting the desired cross-metathesis, affording exclusively (E)-alkenyl-acyloxysulfone adducts as detectable by NMR. Reductive elimination then completed our metathesis approach to 1,6- (n = 3) and 1,7-dienes (n = 4) as summarized in Table 1.

entry	n	R¹	R²	R³	R⁴	*conditions*	yield^a	E,E:Z,E^b
1.	3	Ph	Ph	CH₂OAc	CH₂OAc	A	72%	7:1
2.	4	Ph	Ph	CH₂OAc	CH₂OAc	A	68%	9:1
3.	4	Ph	Ph	CH₂OAc	CH₂OAc	B	61%	9:1
4.	4	Ph	Ph	H	(CH₂)₅CH₃	B	80%	10:1
5.	4	Ph	Ph	H	(CH₂)₂C(O)Me	B	70%	7:1
6.	3	Ph	n-hex	CH₂OAc	CH₂OAc	C	83%	9:1
7.	3	Me	n-hex	CH₂OAc	CH₂OAc	C	85%	7:1
8.	4	Ph	Ph	CH₂OAc	CH₂OAc	C	70%	7:1
elimination conditions: (A) SmI₂ (2 eq.), HMPA (6 eq.), THF, -78 °C, 20 min. (B) SmI₂ (2 eq.), DMPU (4 eq.), THF, -78 °C, 1h. (C) Na/Hg (5%), NaH₂PO₄, MeOH/THF, rt. ^aIsolated yields for 2-steps. ^bRatios determined by ¹H NMR.

This general strategy has been extended to include the synthesis of trienyl subunits. Based on reported reactivity trends, it was anticipated that compounds of type 6 and 7 would undergo selective metathesis at the monosubstituted alkene (Scheme 2). Metathesis of both the acetyl (6a)- and benzoyloxysulfones (6b) derived from cinnamaldehyde and crotonaldehyde (7) with cis-1,4-bisacetylated butenediol (8) proceeded with high chemoselectivity. Elimination with Na/Hg or SmI₂ then completed our metathesis approach to 1,3,8-trienes.

Fully conjugated systems can also be prepared using this protocol. It was found that metathesis was best carried out prior to acylation as depicted in Scheme 3. Post-metathesis acylation/ elimination gave conjugated diene 9 and triene 10 in 55% and 58% yield respectively for the two steps. As a comparison, attempted cross-metathesis with terminal triene 11 under standard conditions gave a mixture of alkene, diene, and triene products in favor of compound 12.

The preliminary results provide proof-of-concept that a β-acyloxysulfone metathesis/elimination strategy can provide convenient access to a number of polyene systems. Efforts are ongoing to apply this reaction sequence to the preparation of increasingly complex frameworks with applications in natural product and polymer synthesis.