Samarium-mediated intramolecular cross-couplings of an α,β-unsaturated N-acylpyrrole

Article abstract of DOI:10.1016/j.tetlet.2016.06.010

The first example of an α,β-unsaturated N-acylpyrrole undergoing a SmI₂-mediated cyclization is reported. In contrast to other unsaturated units, the intermediate samarium enolate readily engages in aldol-type reactions, necessitating careful control of the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2016.06.010

Tetrahedron Letters 57 (2016) 3113–3116
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Samarium-mediated intramolecular cross-couplings of an a,b-
unsaturated N-acylpyrrole
⇑
Katherine R. Law, Christopher S. P. McErlean
School of Chemistry, The University of Sydney, New South Wales 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of an
a,b-unsaturated N-acylpyrrole undergoing a SmI2-mediated cyclization is
Received 26 April 2016
Revised 19 May 2016
Accepted 1 June 2016
Available online 2 June 2016
reported. In contrast to other unsaturated units, the intermediate samarium enolate readily engages in
aldol-type reactions, necessitating careful control of the reaction conditions.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyran synthesis
Samarium
Ring-closing reaction
Pyrrole
Aldol reaction
The trans, syn, trans-fused polycyclic ether architecture of the
marine ladder toxins (Fig. 1) has stimulated a variety of strategies
for their construction.1,2 Nakata was the first to recognize the
power of the SmI2-mediated intramolecular carbonyl-ene cycliza-
tion for the reiterative synthesis of polyether units.3–7 In Nakata’s
model (Scheme 1) the coordinated samarium(II) reduced the alde-
hyde to give the ketyl radical anion 4, which subsequently under-
ing attributes, to the best of our knowledge, no studies of the com-
patibility or reactivity of ,b-unsaturated N-acylpyrrole units with
SmI2 have been reported. The outcomes of our investigation of the
SmI2-mediated intramolecular ring-closing reaction are described
in this Letter.
a
The synthesis of a suitable substrate to test the applicability of
the SmI2-mediated protocol is shown in Scheme 2. Deoxy-D-ribose
went an intramolecular radical addition onto an
a
,b-unsaturated
(6) was treated with propanedithiol and benzaldehyde dimethyl
acetal to give the dithiane 8. Conjugate addition of this compound
onto N-propiolpyrrole 9 and removal of the dithiane unit revealed
the desired aldehyde 11. We have previously demonstrated that
this molecule can undergo a completely stereoselective Stetter
reaction to generate the cyclic ketone,10 but the samarium-medi-
ated process has the potential to deliver the alcohol 12 directly,
circumventing the need for a separate reduction.
ester to form a cyclic ether 5 with the desired relative stereochem-
istry. Our continuing interest in the N-acylpyrrole8 functional
group led us to investigate whether the SmI2-mediated protocol
might be amenable to an
a,b-unsaturated N-acylpyrrole sys-
tem.9–11
While
a
,b-unsaturated esters and ketones have been employed
in SmI2-mediated cyclizations,12–14 the use of
a,b-unsaturated
amides is less well documented and to date, has been restricted
to lactams.9
N-Acylpyrroles generally have reactivity closer to a ketone than
to the corresponding amide.9 The product of hydride addition to
the N-acylpyrrole is a tetrahedral pyrrolic carbinol that is usually
stable toward isolation and purification.15,16 Treatment of the car-
binol with bases or heating, results in elimination of the pyrrole
unit and production of an aldehyde. Therefore we anticipated that
an a,b-unsaturated N-acylpyrrole could be employed as a masked
aldehyde in the SmI2-mediated cyclization. Despite these promis-
⇑
Corresponding author. Tel.: +61 2 9351 3970; fax: +61 2 9351 3329.
E-mail address: christopher.mcerlean@sydney.edu.au (C.S.P. McErlean).
Figure 1. Representative marine ladder toxins.
http://dx.doi.org/10.1016/j.tetlet.2016.06.010
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

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K. R. Law, C. S. P. McErlean / Tetrahedron Letters 57 (2016) 3113–3116
samarium enolate 13 rapidly engaged in an aldol-reaction with
another molecule of starting material 11 (Scheme 3). As both the
isolated dimeric products 14 and 15 existed as single stereoiso-
mers, we postulate that the aldol process must be under chelation
control, although we were unable to definitively assign the relative
stereochemistry at the stereocentres linking the two units.
Attempts to competitively protonate the initially generated samar-
ium enolate 13 before it could undergo aldol-coupling were unsuc-
cessful. The reaction was immune to the acidity of the alcohol
employed, with the relatively acidic trifluoroethanol and the less
acidic tert-butanol giving similar outcomes to methanol (Table 1,
entries 6 and 7). Inverting the order of addition by adding the alde-
hyde to a solution of SmI2 was the logical strategy, but the isolation
of the compound 15 was worrisome as it suggested a possible com-
peting mechanism. Two modes of SmI2-mediated ring-closure
have been documented.17 Nakata suggested aldehyde reduction
to give the ketyl radical anion 4 (Scheme 1),3,7 but the initial step
Scheme 1. Nakata’s SmI2 cyclization involving an enoate.
Under Nakata’s optimized conditions (Table 1, entry 1),3
(2.2 equiv of both SmI2 and MeOH) we did observe formation of
the desired cyclized product 12, but it was the minor product
alongside the dimeric compound 15 (Scheme 3). Surprisingly, con-
ducting the reaction at higher dilution (entries 2 and 3) or lower
temperature (entries 4 and 5) did not circumvent formation of
dimeric compounds 14 and 15. As depicted in Scheme 3, it was
apparent that aldehyde 11 underwent SmI2 induced cyclization
to give the samarium enolate 13. In contrast to results obtained
using ester or ketone substrates in SmI2-mediated processes, the
Scheme 2. Synthesis of compound 11.
Table 1
Optimization of the SmI2-mediated cyclization
Entry
Conc. (M)
Temp. (°C)
Equiv. SmI2 (equiv MeOH)
12a (%)
14a (%)
15a (%)
1
2
3
4
5
6
0.1
0
0
0
2.2 (2.2)
2.2 (2.2)
2.2 (2.2)
2.2 (2.2)
2.2 (2.2)
2.2
18
29
24
40
44
37
—
5
39
14
18
-
34
20
—
—
—
0.05
0.01
0.05
0.01
0.1
À78, 0
À78, 0
0
34
(2.2 CF3CH2OH)
2.2
7
0.1
0
25
—
34
(2.2 t-BuOH)
2.5 (10)
2.5 (10)
8
9
0.05
0.01
0
0
67
88
—
—
—
—
a
Isolated yield after chromatography.
Scheme 3. Formation of compounds 14 and 15.

K. R. Law, C. S. P. McErlean / Tetrahedron Letters 57 (2016) 3113–3116
3115
of the reaction may in fact be the samarium(II) reduction of the
unsaturated system to give 16 or 17 (Scheme 4),18 which could
undergo radical or anionic addition to the pendant aldehyde.
Protonation of 17 prior to ring-closure would give the samarium
enolate 18, which can undergo elimination. If this proved to be
the case, inverse addition would exacerbate the problem, and N-
acylpyrroles would not be suitable substrates for SmI2-mediated
cyclizations.
Pleasingly, the slow addition of aldehyde 11 into the SmI2 mix-
ture and competitive protonation with a tenfold excess of MeOH,
gave the desired compound 12 in excellent yields as a single
stereoisomer (Table 1, entry 8). The yield of the transformation
could be further increased at higher dilution (entry 9). NMR anal-
ysis of the isolated compound 12 demonstrated key through-space
interactions that are diagnostic of the trans, syn, trans stereochem-
ical arrangement of the newly formed tetrahydropyran (Fig. 2).
Additionally, we hypothesized that if the mechanism depicted
in Scheme 4 was operational, then the aldehyde unit of compounds
16 and 17 could be replaced with a functional group that has sim-
ilar reactivity toward nucleophiles, i.e., with an N-acylpyrrole, and
the SmI2-mediated cyclization would still operate. The redox
potentials of SmI2-additive mixtures vary from À0.89 to À1.79 V
depending on the identity of the additive.19–23 We therefore mea-
sured the reduction potentials of the N-acylpyrroles 9 and 19–22
shown in Figure 3. This confirmed that SmI2–MeOH mixtures
Scheme 4. Plausible pathways to compounds 12, 14 and 15.
would have sufficient reducing power to react with
a,b-unsatu-
rated N-acylpyrroles (9, 19–22), while saturated N-acylpyrroles
(21 and 22) would require a more powerful reductant.
As shown in Scheme 5, the product of the previous SmI2-medi-
ated ring-closure 12 underwent Michael addition onto N-propi-
olpyrrole 9 to give compound 23 in high yields. This molecule
contained both an
a,b-unsaturated N-acylpyrrole and a saturated
N-acylpyrrole. Chemoselective reduction of the unsaturated N-
acylpyrrole would produce 24, which could undergo cyclization
onto the pendant saturated N-acylpyrrole.24
Figure 2. Stereochemistry of cyclized product 12.
When compound 21 was subjected to the action of SmI2 and
MeOH, no ring-closed product was observed. Isolation of the elim-
inated product 12 confirmed that the
a,b-unsaturated N-acylpyr-
role unit was reduced under the reaction conditions, but did not
undergo intramolecular radical or anionic addition to the pendant
N-acylpyrrole. This outcome is consistent with the SmI2-mediated
carbonyl-ene cyclization onto
proceeding by initial reduction of the aldehyde unit.
In summary, we have shown that an ,b-unsaturated N-acyl-
a,b-unsaturated N-acylpyrrole 11
a
pyrrole is a suitable substrate for SmI2-mediated reductive cycliza-
tion to give a trans, syn, trans-fused tetrahydropyran. In contrast to
previously reported reductive cyclizations using unsaturated
esters and ketones, the intermediate samarium enolate 13 readily
engages in aldol-type reactions, so inverse addition is mandatory.
The application of this transformation to the construction of poly-
cyclic ethers is underway in our laboratory.
Figure 3. Reduction potentials of N-acylpyrroles 9 and 19–22.
Scheme 5. Attempted ring-closure of compound 23.

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K. R. Law, C. S. P. McErlean / Tetrahedron Letters 57 (2016) 3113–3116
7. Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999, 40, 8859–8862.
Acknowledgments
8. Although formally 1-acyl-1Hpyrroles, the term N-acylpyrrole has found
common use.
K.R.L. gratefully acknowledges receipt of an Australian
Postgraduate Award, a John A. Lamberton Research Scholarship,
and an Australian Bicentennial Scholarship Award. K.R.L. is
indebted to Prof. J.S. Clark for hosting a research stay at the
University of Glasgow.
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8236.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
010.
References and notes
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