Highly diastereoselective synthesis of vicinal quaternary and tertiary stereocenters using the iodo-aldol cyclization

Article abstract of DOI:10.1021/ol070482k

The intramolecular iodo-aldol cyclization of α-substituted enoate aldehydes and ketones Is described. Using prochiral starting materials, the reaction produces hetero- and carbocycles containing quaternary centers adjacent to secondary or tertiary centers

Full text of DOI:10.1021/ol070482k

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1931-1934
Highly Diastereoselective Synthesis of
vicinal Quaternary and Tertiary
Stereocenters Using the Iodo-aldol
Cyclization
Frederic Douelle, Amy S. Capes, and Michael F. Greaney*
UniVersity of Edinburgh, School of Chemistry, Joseph Black Building,
King’s Buildings, West Mains Rd., Edinburgh EH9 3JJ, U.K.
michael.greaney@ed.ac.uk
Received February 25, 2007
ABSTRACT
The intramolecular iodo-aldol cyclization of
r-substituted enoate aldehydes and ketones is described. Using prochiral starting materials, the
reaction produces hetero- and carbocycles containing quaternary centers adjacent to secondary or tertiary centers. The reactions occur in
good yields and are highly selective for the trans-products, having the hydroxyl and iodomethyl groups on opposite faces of the ring system.
The iodo-aldol reaction,1,2 part of the Morita-Baylis-
Hillman (MBH) family of tandem conjugate addition/aldol
processes,3 has become an increasingly well-developed
generalized reaction is shown in Scheme 1, whereby a
Michael acceptor such as an enoate or ynoate, 1, undergoes
conjugate addition with iodide followed by intermolecular
aldol reaction with an aldehyde, 2.
strategy for C-C bond formation in recent years.4-8
A
(1) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
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(2) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27, 4767-
Scheme 1. Intermolecular Iodo-aldol Reaction
4770.
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T.; Shinokubo, H.; Oshima, K. Synlett 2002, 978-980. (e) Yagi, K.;
Turitani, T.; Shinokubo, H.; Oshima, K. Org. Lett. 2002, 4, 3111-3114.
(5) (a) Wei, H.-X.; Kim, S. H.; Caputo, T. D.; Purkiss, D. W.; Li, G.
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Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D.
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7151-7154.
When sp2 Michael acceptors are employed, the reagent
combination TiCl4/Bu4NI is particularly effective at produc-
ing the â-iodo carbonyl products, 3, rather than the eliminated
MBH products.4b As with the reductive aldol reaction, the
nucleophile is thus incorporated into the product and a chiral
center is installed adjacent to the carbonyl group. The iodo-
aldol features several strengths inherent to all MBH-type
reactions: it provides excellent atom economy and complex-
(6) Wei, H.-X.; Hu, J.; Purkiss, D. W.; Pare, P. W. Tetrahedron Lett.
2003, 44, 949-952.
(7) Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem. 2004, 45-58.
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10.1021/ol070482k CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/11/2007

ity generation, generating 1, 2, or 3 chiral centers from often
simple starting materials in a single step, it enables enolate
chemistry without the requirement of a strong base, and it
is amenable to (asymmetric) catalysis.
Scheme 3. Synthesis of Iodo-aldol Carbocyclization Substrates
14 and 16-18
A current limitation of the iodo-aldol reaction and tandem
aldol processes in general is their relative lack of application
to the construction of quaternary centers.9 Given the value
and challenge associated with quaternary center generation
in complex molecule synthesis, we were interested in
examining the scope of the iodo-aldol process for the
synthesis of hindered γ-iodoalcohols. The vast majority of
tandem aldol procedures in the literature use mono- or 1,2-
substituted Michael acceptors as substrates, whereas qua-
ternary center construction will require an R-substituted
Michael acceptor such as 4 (Scheme 2).
Scheme 2. Intramolecular Iodo-aldol Reaction for Quaternary
Center Construction
We elected to study the intramolecular iodo-aldol reaction
as our method for quaternary center generation, as this
potentially powerful variant has been the subject of only one
previous report.4e Enoate aldehydes 17 and 18 were chosen
as carbocylization substrates and synthesized as shown in
Scheme 3. Ozonolysis of cyclohexene or cycloheptene in
methanol afforded the acetal-aldehydes 9 and 10. Methyl-
enation via Bo¨hme or Eschenomser’s salt using Et3N as base
installed the enal functionality in a single step, which could
be oxidized and deprotected to give 17 and 18. It was also
of interest to prepare the enoate-ketones 14 and 16; 14 could
be accessed from cycloheptene using a similar synthetic
sequence, whereas 16 was synthesized via ozonolysis of
2-methyl cyclohexene and subsequent methylenation and
oxidation.
The iodo-aldol cyclization of enoate-aldehyde 17 was
carried out using TiCl4 (1.2 equiv) and Bu4NI (1.2 equiv) in
DCM at 0 °C, with slow addition of the substrate (Scheme
4). We were pleased to observe smooth cyclization to afford
the 1,1-disubstituted cyclopentane in 1 h. 1H NMR analysis
of the crude reaction mixture indicated an 9:1 mixture of
diastereoisomers, which could be purified by chromatography
to give the major compound in 81% isolated yield. The
stereochemistry was assigned as trans on the basis of
NOESY data showing enhancements between the C2 tertiary
proton and the iodomethyl group, indicating that the hydroxyl
and iodomethyl groups were on opposite faces of the
cyclopentane ring.
The cyclization was similarly effective for the enoate
ketone 16, forming the cyclopentane 20 as a single dia-
stereoisomer featuring Vicinal tertiary and quaternary carbon
Scheme 4. Iodo-aldol Carbocyclization
(9) Recent examples of tandem conjugate addition/aldol processes for
quaternary center construction: (a) Nishiyama, H.; Shiomi, T.; Tsuchiya,
Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972-6973. (b) Zhao, G.-
L.; Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 4527-4530. (c) Hayashi, M.;
Matsuura, Y.; Watanabe, Y. Tetrahedron Lett. 2005, 46, 5135-5138. (d)
Lee, C. A.; Floreancig, P. E. Tetrahedron Lett. 2004, 45, 7193-7196. (e)
Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811-4814.
(f) Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41, 4580-4582.
(g) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org. Lett. 2001, 3,
2181-2183. (h) Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett.
2001, 3, 1901-1903. (i) Kamimura, A.; Mitsudera, H.; Asano, S.; Kidera,
S.; Kakehi, A. J. Org. Chem. 1999, 64, 6353-6360.
1932
Org. Lett., Vol. 9, No. 10, 2007

centers, in a slightly attenuated 66% yield. Enoate-aldehyde
18 and ketone 14 were likewise competent substrates for
diastereoselective 6-exo iodo-aldol cyclization, forming the
neopentyl iodides 21 (73% yield) and 22 (52% yield) as
single diastereoisomers. As previously observed for the
cyclopentannulation of 16, some erosion of yield was
observed for the construction of the hindered Vicinal tertiary
and quaternary carbon centers in 22. Stereochemistry was
assigned as trans in all cases by analogy with 19, and in
light of subsequent X-ray data (vide infra).
and NTs-linked enoate hexanals 30 and 32 and the heptanals
31 and 33 in two steps. The methyl ketone 34 was prepared
in one step by reaction of ethyl bromoacrylate with acetol
(Scheme 6).
Scheme 6. Synthesis of Iodo-aldol Heterocyclization Substrates
The observed stereoselectivity can be explained using the
model shown in Scheme 5 for substrate 18, which is based
Scheme 5. Stereochemical Model for Iodo-aldol Cyclization
Iodo-cyclization was again successful, with good isolated
yields of the pyrrolidine 35, furan 36, piperidine 37, and
pyran 38 being recorded (Scheme 7). As previously, the
Scheme 7. Iodo-aldol Heterocyclization
upon the twin requirements of initial conjugate addition of
iodide giving the (Z)-enolate 23 and subsequent aldol reaction
taking place via a six-membered chelated chair transition
state that has been observed in previous iodo-aldol studies.4
Two chair-chair transition states, 24 and 25, are consistent
with a chelated (Z)-enolate, with the observed stereoselec-
tivity arising from the cis-decalin-type structure 24. Dis-
crimination between 24 and 25 is likely due to the orientation
of the bulky CH2I group, which is placed in the least hindered
equatorial position in 24, with the small H (or Me) group
occupying the axial position. The trans-decalin-type structure
25, by contrast, has the CH2I group occupying the more-
hindered axial position, accounting for the lack of cis-21
product observed in the iodo-aldol cyclization.
reaction displayed high levels of stereoselectivity for each
substrate, with H NMR showing a single diastereoisomer
1
being formed in each case. A single crystal of the 3,5-
dinitrobenzoate derivatives of the five- and six-membered
ring structures 35 and 37 could be grown, and the X-ray
data supported the trans-stereochemistry originally assigned
on the basis of NOESY data (Figure 1). The reaction could
be successfully extended to the enoate-ketone substrate 34,
but as with the analogous carbocyclization the yield of the
furan 39 was attenuated somewhat in the construction of the
extremely hindered tertiary center.
Li has recently reported the first iodo-aldol reactions that
employ catalytic amounts of Lewis acid for the inter-
molecular allenoate iodo-aldol reaction.5f We were interested
in exploring the possibility of lowering the amounts of TiCl4
employed in our own system, with a view to future
developments in asymmetric catalysis. In analogous Mu-
kaiyama aldol systems this is usually achieved through the
addition of a silylating agent that can facilitate turnover of
the Lewis acid.12 Preliminary experiments indicate that this
We next looked to extend the cyclization to heterocycle
synthesis, an area that has received little attention in previous
iodo-aldol studies.10 Using ethyl or methyl bromomethyl-
acrylate as a starting material,11 we could prepare the O-
(10) One example of a pyran-forming iodo-aldol cyclization has been
reported in ref 4e.
(11) Hediger, M. E. Bioorg. Med. Chem. 2004, 12, 4995-5010.
Org. Lett., Vol. 9, No. 10, 2007
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protocol of TiCl4 (0.2 equiv) and TMSI (2.4 equiv) in DCM
at -78 °C was catalytically fit for purpose, producing furan
39 in a slightly higher 53% yield. A similar protocol afforded
the pyran 38 in the slightly attenuated yield of 49%.
In conclusion, we have developed the intramolecular iodo-
aldol cyclization of enoate-aldehydes and ketones to afford
hetero- and carbocycles containing quaternary centers. The
reaction transforms simple, prochiral starting materials into
cyclic alcohols containing Vicinal quaternary and secondary/
tertiary stereocenters, in good yields with excellent stereo-
selectivity. In addition, the products display a collection of
orthogonal functional groups that may be further elaborated
in the synthesis of complex natural product targets, which
will be the focus of our future work in the area.
Acknowledgment. We thank the University of Edinburgh
for funding and the EPSRC mass spectrometry service at
the University of Swansea.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
including files in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 1. X-ray structure of the 3,5-dinitrobenzoate derivative of
pyrrolidine 35.
OL070482K
strategy is effective for our system: Using the O-linked
compound 34 as substrate, we were pleased to see that a
(12) Evans, D. A.; Masse, C. E.; Wu, J. Org. Lett. 2002, 4, 3375-3378.
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