SmI2-mediated dialdehyde cyclization cascades

Article abstract of DOI:10.1016/j.tetlet.2009.02.025

Dialdehydes undergo sequenced SmI₂-mediated cyclization cascades generating four contiguous stereocenters with high diastereocontrol.

Full text of DOI:10.1016/j.tetlet.2009.02.025

Tetrahedron Letters 50 (2009) 3224–3226
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Tetrahedron Letters
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SmI2-mediated dialdehyde cyclization cascades
*
Matthew D. Helm, David Sucunza, Madeleine Da Silva, Madeleine Helliwell, David J. Procter
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Dialdehydes undergo sequenced SmI2-mediated cyclization cascades generating four contiguous stereo-
centers with high diastereocontrol.
Received 15 January 2009
Revised 29 January 2009
Accepted 2 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Samarium
Radical
Cyclization
Cascade
Since its introduction to the synthetic community by Kagan, the
one-electron reducing agent samarium(II) iodide (SmI2) has found
widespread use in organic synthesis.1 The versatile reagent has
been used to mediate many processes ranging from functional
group interconversions to complex carbon–carbon bond-forming
sequences.1 Cyclization reactions mediated by SmI2 are valuable
tools for natural product synthesis.1f
when R = CHO
SmI2
when R = CH2I
SmI2
R
THF, HMPA
MeOH
–78 °C to 0 °C
THF, t–BuOH
0 °C to RT
H
H
HO
MeO2C
MeO2C
MeO2C
66%, >95:5 dr
82%, >95:5 dr
proposed structure
of faurinone
We have introduced several stereoselective cyclizations using
the lanthanide reagent. For example, we have developed a 4-exo-
H
O
trig cyclization of
anols2 and have exploited this reaction in the synthesis of the pest-
alotiopsin skeleton.3 We have also developed
conjugate
c,d-unsaturated aldehydes to give anti-cyclobut-
Scheme 1. SmI2-mediated cyclizations of aldehyde and halide substrates in an
approach to decorated cis-hydrindanes.
a
reduction-aldol spirocyclization sequence for the stereoselective
synthesis of oxa- and azaspirocycles4 and have used this new
transformation in an approach to stolonidiol.5 Recently, we have
reported a flexible approach to decorated cis-hydrindanes, a motif
found in many biologically active natural products, which exploits
highly diastereoselective SmI2-mediated cyclizations of aldehyde
and halide substrates.6 The approach has been applied in the syn-
thesis of the proposed structure of rac-faurinone (Scheme 1).6
In this Letter, we report our preliminary feasibility studies on
the development of dialdehyde cyclization cascades mediated by
SmI2, in which the aldehyde groups undergo stereoselective reac-
tion in a programmed sequence to give complex products.
In 2002, Takahashi and Nakata described a synthesis of mucocin
that involved the SmI2-mediated, aldehyde–alkene cyclization of
dialdehyde 1 to give 2 as the key step in their approach (Scheme
2).7
Carbonyl-alkene cyclizations using SmI2 are believed to proceed
by reduction of the aldehyde to the ketyl radical-anion followed by
addition to the alkene.1,8 The transformation of 1 to 2 is, therefore,
remarkable as only one aldehyde reacts while the other survives
the reducing conditions. While the authors did not discuss this
selectivity, they observed that the use of excess SmI2 or prolonged
reaction times led to reduction of the second aldehyde and the for-
mation of complex product mixtures. Intrigued by this result, we
speculated that a new class of sequential cyclization mediated by
SmI2 might be possible using dialdehyde substrates where each
aldehyde undergoes cyclization in a programmed sequence.
We selected dialdehyde substrates 3 for our study. We envis-
aged that aldehyde group 1 would react first through a facile 5-
exo-trig radical cyclization while aldehyde group 2 waits in line.
After radical cyclization, aldehyde group 2, in samarium enolates
4,9 would undergo aldol cyclization to form tricyclic systems 5 con-
taining a cis-hydrindane core (Scheme 3).
* Corresponding author. Fax: +44 161 275 4939.
E-mail address: david.j.procter@manchester.ac.uk (D.J. Procter).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.025

M. D. Helm et al. / Tetrahedron Letters 50 (2009) 3224–3226
3225
O
O
O
R1
R2
6a R1 = R2 = H
OTBS
6b R1 = H, R2 = Me
6c R1 = R2 = Me
O
HO
3 eq. SmI2
EtO2C
1. R3MgBr, CuI
2. Comins' reagent
–45 °C to RT
O
O
O
O
4.4 eq. MeOH
THF, –5 °C
15 min
O
O
OBn
CO2Et
OBn
1
2
7a R1 = R2 = H, R3 = C(Me)=CH2, 81%
87%
OTf
7b R1 = H, R2 = Me, R3 = C(Me)=CH2, 78%, dr 3:1
7c R1 = R2 = H, R3 = but–3-enyl, 74%
R1
R2
OTBS
Scheme 2. Takahashi and Nakata’s SmI2-mediated cyclization en route to mucocin.
7d R1 = H, R2 = Me, R3 = but–3-enyl, 81%, dr ~3:1
7e R1 = R2 = H, R3 = Me, 73%
R3
propan–1,3–diol
7f R1 = R2 = Me, R3 = C(Me)=CH2, 64%a
While an example of a ketyl-olefin cyclization/intermolecular
aldol sequence has been reported by Enholm,10 to our knowledge,
no intramolecular variants have been reported presumably as both
aldehydes in the starting material would be expected to react with
SmI2 to give complex product mixtures. If successful, we antici-
pated that the sequential cyclizations of 3, in which four contigu-
ous stereocenters, including one quaternary stereocenter, are
generated, would occur with high diastereocontrol (vide infra).
We began by preparing a range of dialdehyde substrates 3 by
modifying our previously reported route to related substrates.6
Addition of an organocopper to cyclohexanones 6a–c gave vinyl
triflates 7a–f after trapping the intermediate enolates with Comins’
reagent.11 Organocopper addition to cyclohexenone 6b gave 7b
and 7d as a 3:1 mixture of diastereoisomers. Palladium-catalyzed
carbonylation in the presence of propan-1,3-diol gave esters 8a–f
in moderate to good yield. Deprotection and oxidation using the
Dess Martin periodinane12 gave dialdehydes 3a–f (Scheme 4).
With dialdehydes 3a–f in hand, we investigated the proposed
cyclization sequence. Pleasingly, upon treatment with SmI2, dial-
dehydes 3a–e underwent double cyclization to give tricyclic prod-
ucts 5a–e in good yield and with excellent control in the
construction of four stereocenters (Scheme 5).13 The cyclization
of 3b and 3d, 3:1 mixture of diastereoisomers, led to 5b and 5d
as similar diastereoisomeric mixtures that were readily separated
by chromatography. The structure of 5a and 5b was confirmed
by X-ray crystallography (Scheme 5).14
20–40 mol% Pd(OAc)2, CO
Ph3P, E t 3N
DMF, 40–50 °C
8a R1 = R2 = H, R3 = C(Me)=CH2, 92%
O
O
8b R1 = H, R2 = Me, R3 = C(Me)=CH2, 79%, dr 3:1
8c R1 = R2 = H, R3 = but–3-enyl, 52%
OTBS
R1
R2
OH
8d R1 = H, R2 = Me, R3 = but–3-enyl, 43%, dr ~3:1
8e R1 = R2 = H, R3 = Me, 61%
R3
8f R1 = R2 = Me, R3 = C(Me)=CH2, 83%
1. HF, py, MeCN
2. DMP, CH 2Cl2
3a R1 = R2 = H, R3 = C(Me)=CH2, 65%
3b R1 = H, R2 = Me, R3 = C(Me)=CH2, 76%, dr 3:1
3c R1 = R2 = H, R3 = but–3-enyl, 89%
O
O
R1
R2
O
O
3d R1 = H, R2 = Me, R3 = but–3-enyl, 81%, dr ~3:1
3e R1 = R2 = H, R3 = Me, 73%
R3
3f R1 = R2 = Me, R3 = C(Me)=CH2, 63%
Scheme 4. Synthesis of dialdehyde cyclization substrates 3a–f. a 7f was formed by
cuprate addition (82%), followed by triflate formation in a separate step (LDA,
Comins’ reagent, 78%).
Interestingly, the sequential cyclization of 3f containing a gem-
dimethyl group gave 5f containing the opposite stereochemistry at
the quaternary stereocenter constructed during the aldol stage of
the cascade (Scheme 6). The structure of 5f was confirmed by X-
ray crystallographic analysis.14 We had previously observed a sim-
ilar switch in diastereoselectivity in the protonation of an analo-
gous Sm(III)-enolate.6 It is likely that this switch is evidence of a
different conformation for the intermediate enolate where the
most accessible face is now the top face.
The highly diastereoselective cascade reactions begin with an
anti-selective ketyl-olefin cyclization through transition structure
9 to give samarium enolates 10.8 We believe that chelation to
Sm(III) leads to selective enolate formation and subsequently to
diastereoselective aldol cyclization through six-membered transi-
tion structure 11 on the most open bottom face of enolates 10
(Scheme 7). Substrate 3f is an exception and the aldol cyclization
proceeds through attack on the top face of a Sm(III)-enolate in a
different conformation (not shown).
The origin of the selectivity for one aldehyde over the other in
our studies, and in the original reduction reported by Takahashi
and Nakata,7 remains unclear. It is thought that the reduction of
carbonyl groups with SmI2 is reversible, with the ketyl radical-an-
O
aldehyde 1
O
SmIII
O
O
O
Scheme 5. Sequential dialdehyde cyclizations mediated by SmI2.
O
O
HO
R2
R1
OH
SmIII
O
O
O
R2
R1
4
R1 R2
radical
anionic
ion being drained from the equilibrium by cyclization.15 As only
aldehyde group 1 in 3 is able to undergo facile cyclization, that
aldehyde is seen to react in the presence of the other. Alternatively,
pre-coordination of samarium to the aldehyde and ester carbonyl
aldehyde 2
R3
R3
5
3
R3
Scheme 3. Proposed sequential dialdehyde cyclizations mediated by SmI2.

3226
M. D. Helm et al. / Tetrahedron Letters 50 (2009) 3224–3226
2001, 2727; (d) Kagan, H. B. Tetrahedron 2003, 59, 10351; (e) Dahlén, A.;
Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393; (f) Edmonds, D. J.; Johnston, D.;
Procter, D. J. Chem. Rev. 2004, 104, 3371; (g) Gopalaiah, K.; Kagan, H. B. New J.
Chem. 2008, 32, 607.
2. (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett. 1999, 40, 4913;
(b) Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J. J. Chem. Soc., Perkin
Trans. 1 2000, 681.
3. (a) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org. Lett. 2001, 3,
2001; (b) Johnston, D.; Couché, E.; Edmonds, D. J.; Muir, K.; Procter, D. J. Org.
Biomol. Chem. 2003, 328; (c) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org.
Chem. 2003, 68, 3190; (d) Baker, T. M.; Edmonds, D. J.; Hamilton, D.; O’Brien, C.
J.; Procter, D. J. Angew. Chem., Int. Ed. 2008, 47, 5631.
4. (a) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345; (b) Hutton, T. K.;
Muir, K.; Procter, D. J. Org. Lett. 2003, 5, 4811; (c) Guazzelli, G.; Duffy, L. A.;
Procter, D. J. Org. Lett. 2008, 19, 4291.
Scheme 6. Sequential dialdehyde cyclization of 3f mediated by SmI2.
Sm
R3
Sm
O
O
O
R2
O
O
H
O
R2
R3
Sm
O
O
H
H
R2
R1
R1
H
5. Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett 2007, 3155.
6. Findley, T. J. K.; Sucunza, D.; Miller, L. C.; Davies, D. T.; Procter, D. J. Chem.-Eur. J.
2008, 14, 6862.
O
Sm
Sm
R1
O
11
10
9
O
O
R3
7. Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int. Ed. 2002, 41, 4751.
Sm
chelation–controlled
aldol cyclization
anti–radical cyclization
8. When the alkene is sufficiently electron deficient, as is the case with
a,b-
unsaturated esters, an alternative mechanism involving reduction of the alkene
and a subsequent radical or anionic addition to the aldehyde is also possible,
although such
a mechanism is less frequently proposed. This alternative
5a–e
3a–e
mechanism could also explain the selectivity seen in our studies and those of
Takahashi and Nakata.
Scheme 7. Origin of diastereoselectivity in the dialdehyde cyclization sequence.
9. For a review of the chemistry of samarium enolates, see: Rudkin, I. M.; Miller, L.
C.; Procter, D. J. Organomet. Chem. 2008, 34, 19.
10. Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1994, 35, 1627.
11. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
groups may increase the reactivity of the proximal aldehyde group
1 leading to its selective reduction over the more-remote alde-
hyde.8 It is well appreciated that pre-coordination of Lewis acidic
samarium to the carbonyl and unsaturated ester components in
ketyl-olefin additions is important for promoting reaction and con-
trolling the diastereoselectivity of such additions.16
In summary, we have shown the feasibility of SmI2-mediated,
dialdehyde cyclization cascades in which one aldehyde is reduced
while the other waits in line. In the dialdehyde cyclization cascades
studied here, two rings and four contiguous stereocenters are gen-
erated with high diastereocontrol. We believe that the cascade
reaction of dialdehydes constitutes a new class of SmI2-mediated
sequence.1a
13. No minor diastereoisomers were observed in the crude 1H NMR. For spirocycle
5a: SmI2 in THF (0.1 M, 6.9 mL, 0.690 mmol) was added to degassed t-BuOH
(1.8 mL) and the resulting solution was stirred under a nitrogen atmosphere
for 20 minutes before being cooled to 0 °C (ice bath). After cooling, the
dialdehyde 3a (77 mg, 0.277 mmol) was added dropwise as a solution in THF
(2 mL), and the reaction was stirred for 30 min before excess SmI2 was
quenched by allowing air to reach the reaction. Once the solution was yellow, a
saturated aqueous solution of K/Na tartrate was added and the crude reaction
mixture was extracted with Et2O (3 Â 20 mL). The combined organic fractions
were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. The crude products were purified by chromatography
on silica gel to give spirocycle 5a (70 mg, 90%, dr >95:5) as a colorless solid. Mp
191 °C (CH2Cl2–hexane). 1H NMR (DMSO-d6, 400 MHz): d 1.04–1.18 (2H, m,
CH2), 1.28–1.4 (1H, m, CH2), 1.41–1.56 (3H, m, CH2), 1.58–1.69 (1H, m, CH2),
1.70–1.84 (2H, m, CH2), 1.76 (3H, s, CH3), 1.84–1.98 (1H, m, CH2), 2.01–2.14
(1H, m, CH2), 2.14–2.28 (1H, m, CH2), 2.42 (1H, d, J = 7.8 Hz, CHCHOH), 3.98
(1H, m, CH2CHOH), 4.23 (1H, m, 1H from CH2O), 4.33 (2H, m, CHCHOH and 1H
from CH2O), 4.57 (2H, s, @CH2), 5.56 (1H, d, J = 4.0 Hz, OH), 5.75 (1H, d,
J = 4.3 Hz, OH). 13C NMR (DMSO-d6, 100 MHz): d 18.4, 19.9, 25.5, 28.7, 29.7,
Acknowledgments
We thank the EPSRC (M.D.H. and DTA studentship to M.d.S.),
and the EC (Marie-Curie Fellowship to D.S.) for financial support.
31.4, 37.9, 49.2, 49.7, 50.0, 65.0, 71.0, 72.9, 107.2, 150.0, 173.9. mmax (thin film)
cmÀ1 3335 (br), 2924 (s), 2862 (m), 2849 (m), 1715 (s, C@O), 1632 (w), 1451
(w), 1257 (m). MS (EI+) m/z (%): 303 (100, M+Na), 281 (42, M+H). HRMS: calcd
for C16H24O4Na (M+Na): 303.1567. Found: 303.1566.
References and notes
14. The crystal structures have been deposited at the Cambridge Crystallographic
Data Center (CCDC 716348–716350).
15. Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992, 943.
16. For an illustrative example, see Ref. 3b.
1. For recent reviews on the use of samarium(II) iodide: (a) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321; (b) Kagan, H.; Namy, J. L. In
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.;
Springer: Berlin, 1999; p 155; (c) Steel, P. G. J. Chem. Soc., Perkin Trans. 1