A pentenyl dianion-based strategy for convergent synthesis of ene-1,5-diols

Article abstract of DOI:10.1021/ja050039+

A convergent two-step process is described for the synthesis of ene-1,5-diols that provides for union of two carbonyl electrophiles via a formal pentenyl dianion equivalent. Copyright

Full text of DOI:10.1021/ja050039+

Published on Web 03/01/2005
A Pentenyl Dianion-Based Strategy for Convergent Synthesis of Ene-1,5-diols
Adilah B. Bahadoor, Alec Flyer, and Glenn C. Micalizio*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received January 4, 2005; E-mail: glenn.micalizio@yale.edu
Efforts directed at the development of efficient synthetic strate-
gies for the synthesis of polyketide-based molecular architecture
have led to the discovery and development of many stereoselective
carbon-carbon bond-forming processes.1 Advances made in itera-
tive aldol, allyl-, and allenylmetal-based methods have enabled the
syntheses of complex polyketide targets. However, whereas a
variety of linear strategies for polypropionate assembly exist,
convergent approaches lie primarily in the area of aldol methodol-
ogy. This limitation dictates the use of fragment coupling processes
that result in the formation of a central â-hydroxy ketone.2
Consequently, more flexible strategies for convergent assembly of
polypropionates are needed.3
Polypropionate architecture is a common structural motif found
in a variety of natural products that possess potent and diverse
biological activities. Importantly, members of this class often
Figure 1. Two-step sequence to access a pentenyl dianion equivalent.
contain a variety of oxidation and substitution patterns along the
polypropionate skeleton including trisubstituted olefins, 1,2-diols,
tertiary alcohols, epoxides, and deoxypropionate units. Currently,
many of these differentially functionalized polypropionate structural
motifs present a barrier that precludes targeting convergent mo-
lecular assembly at these sites.
To fill this void we sought to develop a general pentenyl dianion-
based strategy for the assembly of highly functionalized ene-1,5-
diols of general structure 1 (Figure 1). We envisioned a two-step
procedure whereby a synthetic equivalent of the pentenyl dianion
4 could serve to unite two differentially functionalized aldehydes
(2 and 3) and provide direct access to a functionalized polypro-
pionate. Importantly, the potential for subsequent stereoselective
Figure 2. Stereochemical flexibility of diastereoselective propargylation.
functionalization of the central trisubstituted olefin4,5 is expected
to greatly increase the versatility of this convergent strategy in
complex molecule synthesis and thereby complement well-
established aldol-based methods.
received relatively little attention.8 As described in Figure 2, these
reagents provide general and stereoselective access to all stereo-
isomers of the homopropargylic alcohol component 12-15 (ds >
20:1 to 5:1).9
To accomplish this goal, we set out to develop a two-step process
that would allow for: (1) DiastereoselectiVe propargylation (5 f
6), (2) carbon-carbon bond formation in the presence of a free
hydroxyl (6 f 8), (3) regioselectiVe reductiVe coupling (6 f 8),
and (4) diastereoselectiVe reductiVe coupling (6 f 8). In this
fashion, the ene-1,5-diol 8 would be available in two steps (from
aldehydes 5 and 7) whereby two carbon-carbon bonds, three new
stereogenic centers, and one stereodefined trisubstituted olefin are
establishedsall without the need for intermediate protecting-group
manipulations. This communication describes our preliminary
results aimed at realizing this convergent strategy for polypropionate
assembly.
First, to address versatility in this convergent two-step process,
we required general and selective access to all stereoisomers of
the homopropargylic alcohol component (6; Figure 1). As such,
we focused on application of chiral allenylmetal reagents in double
asymmetric6 propargylation reactions with chiral aldehydes.7 Al-
though diastereoselective propargylation reactions of chiral alde-
hydes with chiral allenylmetal reagents have been well studied, these
processes using a 2,3-pentadiene-based organometallic (16) have
After a stereochemically flexible route to the required homopro-
pargylic alcohols (12-15) was secured, attention was directed
toward defining a reductive coupling process that would enable
the general conversion 6 f 8 described in Figure 1.10 For this
purpose we selected low-valent titanium alkoxide-based methods,
as we suspected that these reagents would allow for reductive
coupling with a carbonyl electrophile in the presence of an
alkoxide.11 As described in Table 1 (entry 1), deprotonation of the
syn-anti homopropargylic alcohol 12, followed by exposure to the
combination of chlorotitanium triisopropoxide and cyclopentyl-
magnesium chloride, then addition BF3‚OEt2 and aldehyde 18,
provided the ene-1,5-diol 19 in 66% yield (ds 1.5:1) with high
regioslectivity (rs 19:1).
Next, the generality of this new highly regioselective reductive
coupling process was explored as a strategy for the synthesis of
stereochemically diverse polypropionates. As such, the four stereo-
isomeric homopropargylic alcohols 12-15 were coupled with each
enantiomer of a 2,3-anti-aldehyde (18 and ent-18). Regioselection
was high in most cases (19:1 to 7:1) and provided the ene-1,5-diol
products 19-26 as mixtures of diastereomers uniformly favoring
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10.1021/ja050039+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Application to the Synthesis of Complex Polypropionates
allenylmetal reagents to formal pentenyl dianion equivalents through
a process that establishes three new stereogenic centers and one
stereodefined trisubstituted olefin. Our preliminary studies have
defined: (1) the stereochemical flexibility of propargylation (5 f
6), (2) a reductive coupling process with chiral aldehydes that is
tolerant of free hydroxylssa factor which is projected to lead to
increased efficiency in polypropionate synthesis, (3) highly regio-
selective reductive coupling reactions of internal alkynes that allow
for convergent assembly of polypropionates, and (4) defined the
levels of diastereoselection in these coupling processes based on
substrate control. Our successes in these areas have provided
impetus for future studies aimed at enhancing levels of diastereo-
selection in this highly regioselective reductive coupling process.
Finally, we have observed that the stereochemical relationship
between the aldehyde and the homopropargylic alcohol influences
levels of regioselection in these complex reductive coupling
reactions. This unusual manifestation of double asymmetric control6
is a facet of these processes that will be explored in more detail in
future studies. Overall, this formal pentenyl dianion-based strategy
is anticipated to expand flexibility in the design of convergent
approaches toward the synthesis of complex polyketide-derived
targets. Progress along these lines will be reported in due course.
Acknowledgment. We gratefully acknowledge financial support
of this work by Yale University and Eli Lilly & Co. We also thank
Novartis for a graduate fellowship to A.B.B.
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Otera, J., Ed. Modern Carbonyl Chemistry; Wiley-VCH: Weinheim, 2000.
(2) Selected examples of convergent synthesis of polypropionates: (a) Evans,
D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995,
117, 9073. (b) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 3447. (c) Bode, J. W.; Fraefel, N.; Muri, D.;
Carreira, E. M. Angew. Chem., Int. Ed. 2001, 40, 2082; for reviews see
ref 1.
(3) For a convergent approach to ene-1,5-diols centered about a disubstituted
olefin, see: Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
13644 and references therein.
(4) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(6) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int.
Ed. Engl. 1985, 24, 1.
a Yield reported for major regioisomer. b Regioselectivity determined by
1H NMR of the crude reaction mixture. c Major diastereomer is depicted.
d Addition of RCHO at -100 °C. e Deprotonation step not performed.
f Selectivity determined after isolation.
(7) (a) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem. 1986,
51, 3870. (b) Marshall, J. A.; Masxon, K. J. J. Org. Chem. 2000, 65, 630.
See also: (c) Marshall, J. A. Chem. ReV. 1996, 96, 31.
(8) Buckle, M. J. C.; Fleming, I. Tetrahedron Lett. 1993, 34, 2383.
(9) See: Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812.
(10) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203. See
also: Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047.
(11) (a) Epstein, O. L.; Kulinkovich, O. G. Tetrahedron Lett. 1998, 39, 1823.
(b) Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7329. For reviews
see. (c) Kulinkovich, O. G.; Meijere, A. Chem. ReV. 2000, 100, 2789. (d)
Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835. (e) Marek,
I., Ed. Titanium and Zirconium in Organic Synthesis; Wiley-VCH:
Weinheim, 2002.
(12) No products were observed that indicated epimerization of the aldehyde.
(13) For an interesting discussion of regioselectivity in allylic alkylation
reactions based on diastereomeric π-allyl complexes, see: Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(14) For examples of directed regioselective reductive coupling reactions with
nickel complexes, see: (a) Mahandru, G. M.; Liu, G.; Montgomery, J. J.
Am. Chem. Soc. 2004, 126, 3698. (b) Miller, K. M.; Lauanphaisarnnont,
T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130. (c)
Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342.
(15) Reductive coupling reactions of the homopropargylic alcohol 12 with
aldehydes lacking R- or â-branching were also regioselective (5:1 to 3:1).
See Supporting Information.
the Felkin products (generally g2:1).12 Interestingly, leVels of
regioselectiVity were obserVed to be a function of both the relatiVe
stereochemistry of the homopropargylic alcohol and the absolute
stereochemistry of the aldehyde.13 Whereas high regioselectivity
was observed in most cases, highest levels of regioselection for
coupling of each homopropargylic alcohol were observed in the
formation of coupled products bearing a 1,5-anti stereochemical
relationship between the allylic and homoallylic methyl substituents
(entries 1, 3, 5, and 7). Finally, to probe the significance of the
homopropropargylic alkoxide in these regioselective coupling
reactions we examined the union of the methyl ether 27 with
aldehyde 18 (entry 9). Similarly, high regioselectivity was observed
in this case, thereby indicating that the presence of a neighboring
alkoxide is not required for high levels of regioselection.14,15
Overall, we have defined a two-step procedure that enables
convergent assembly of 1,5-diols and extends the utility of
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