Studies in macrolide antibiotic synthesis: The role of tethered alkoxides in titanium alkoxide-mediated regioselective reductive coupling reactions

Article abstract of DOI:10.1021/ol0600786

A convergent route to a C1-C15 fragment precursor for erythromycin-based macrolide antibiotics is presented. These studies define a role for tethered alkoxides in the control of site-selective carbon-carbon bond formation in titanium alkoxide-mediated coupling reactions of internal alkynes and chiral aldehydes.

Full text of DOI:10.1021/ol0600786

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1181-1184
Studies in Macrolide Antibiotic
Synthesis: The Role of Tethered
Alkoxides in Titanium Alkoxide-Mediated
Regioselective Reductive Coupling
Reactions
Adilah B. Bahadoor and Glenn C. Micalizio*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
glenn.micalizio@yale.edu
Received January 11, 2006
ABSTRACT
A convergent route to a C1−C15 fragment precursor for erythromycin-based macrolide antibiotics is presented. These studies define a role
for tethered alkoxides in the control of site-selective carbon
internal alkynes and chiral aldehydes.
−carbon bond formation in titanium alkoxide-mediated coupling reactions of
Polyketides from streptomyces have played an important role
in medicine, with members of this natural product class
representing the mainstay of antibiotic therapy for the latter
half of the twentieth century.1 This medicinal value, com-
bined with their complex architectures (Figure 1), has
stimulated the development of a host of synthetic methods
and strategies designed to access their highly functionalized
skeletons.2-4 Presently, the emerging problem of antibiotic
resistance has reinvigorated the search for effective thera-
peutics. One approach to facilitate this search is to develop
powerful synthetic methods to enable facile and flexible
syntheses of complex polyketides.
In line with this goal, we initiated research aimed at
defining a general approach to macrolide antibiotics based
(1) Omura, S., Ed. Macrolide Antibiotics. Chemistry, Biology, and
Practice, 2nd ed.; Academic Press: New York, 2002.
(2) Total synthesis of erythromycin A, see: Woodward, R. B. et al. J.
Am. Chem. Soc. 1981, 103, 3215-3217. Total synthesis of erythromycin
B, see: Martin, S. F.; Hida, T.; Kym, P. R.; Loft, M.; Hodgson, A. J. Am.
Chem. Soc. 1997, 119, 3193-3194.
(3) For reviews on early synthetic work directed at macrolide antibiotic
synthesis, see: (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41,
3569-3624. (b) Mulzer, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1452-
1454.
Figure 1. Macrolide antibiotics erythromycin A and B.
10.1021/ol0600786 CCC: $33.50
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Published on Web 02/24/2006

on our recently reported convergent process for polyketide
construction.5 Herein we describe the results of our initial
investigations in this area that have established (1) a
convergent approach to a C1-C15 fragment precursor to
the erythronolides and (2) the role of tethered alkoxides in
the control of site-selective C-C bond formation in titanium
alkoxide-mediated coupling reactions of internal alkynes and
chiral aldehydes.
Scheme 2. Retrosynthetic Strategy for Macrolide Antibiotic
Aglycone Synthesis
Recently, we reported a two-step process for ene-1,5-diol
synthesis (Scheme 1a), based on the coupling of differentially
Scheme 1. Group 4 Metal Alkoxide-Mediated Coupling
Reactions for Polyketide Assembly
aldehyde 8 with 2 equiv of an R-methyl-â-silyloxy aldehyde
(10 and 11).
Our initial efforts directed at realizing such a pathway to
these targets are depicted in Scheme 3. Diastereoselective
Scheme 3. First-Generation Route to a C1-C15
Diene-Containing Fragment Precursor to the Erythronolides
functionalized carbonyl electrophiles with a formal pentenyl
dianion equivalent (6 f 1 f 4; Scheme 1b).5 Our studies
revealed that a diastereoselective pentynylation (6 f 1), in
conjunction with a group 4 metal-mediated coupling (1 f
4), provides general and flexible access to complex
polyketides.
This basic pentenyl dianion-based coupling process serves
as the foundation of our approach to the syntheses of the
macrolide antibiotic aglycones (9S)-dihydroerythronolide A
and 6-deoxyerythronolide B (Scheme 2). With the goal of
accessing both targets from a common late stage intermediate
(7),6 we targeted the C3-C4, C6-C7, C9-C10, and C12-
C13 bonds for construction with our previously described
method. Such a series of C-C bond-forming reactions would
represent a convergent route to the aglycons of this family
of macrolide antibiotics by the stepwise coupling of lact-
a Yield reported for the isolated regioisomer.
pentynylation of the TBS-protected Roche aldehyde 10,5,7
followed by protection of the resulting homopropargylic
alcohol furnished the homopropargylic ether 13. Titanium
alkoxide-mediated reductive coupling of this alkyne with
lactaldehyde 8 provided a separable 3:1 mixture of regio-
isomeric products favoring the desired allylic alcohol 14.5,8
Oxidation to the enone, followed by diastereoselective
(4) For recent studies on the syntheses of the erythronolides and
erythromycins, see: (a) Muri, D.; Lohse-Fraefel, N.; Carreira, E. M. Angew.
Chem., Int. Ed. 2005, 44, 4036-4038. (b) Peng, Z.-H.; Woerpel, K. A. J.
Am. Chem. Soc. 2003, 125, 6018-6019. (c) Hergenrother, P. J.; Hodgson,
A.; Judd, A. S.; Lee, W.-C.; Martin, S. F. Angew. Chem., Int. Ed. 2003,
42, 3278-3281. (d) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V.
J. J. Am. Chem. Soc. 1998, 120, 5921-5942.
(5) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005,
127, 3694-3695.
(6) For a review on allylic 1,3-strain as a control element for olefin
functionalization reactions, see: Hoffman, R. W. Chem. ReV. 1989, 89,
1841-1860.
(7) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812-3813.
(8) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203-
3206.
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Org. Lett., Vol. 8, No. 6, 2006

reduction,9 protection of the C13 hydroxyl as the corre-
sponding TIPS ether, and selective deprotection of the
primary TBS ether afforded the C7-C15-containing frag-
ment 15. Oxidation to the corresponding aldehyde10 followed
by a second titanium alkoxide-mediated reductive coupling
with the homopropargylic ether 16 (derived from diastereo-
selective pentynylation of Roche aldehyde 11)12 provided
the fully functionalized C1-C15 diene 7a in 44% yield,
isolated from a 2:1 mixture of regioisomeric allylic alcohols.
Importantly, the lack of diastereoselection in this coupling
process is anticipated to be of little consequence in macrolide
antibiotic synthesis, as C7 of the natural aglycons lacks
substitution (Scheme 2).
metallacycle 19 over the bridged bicyclic isomer 20. Pro-
tonation of 19 would then afford the allylic alcohol 21 as
the predominant product.
On the basis of this speculation, we explored the effect of
tethered alkoxides on regioselection in titanium alkoxide-
mediated reductive coupling reactions of functionalized
internal alkynes and chiral aldehydes relevant for polyketide
assembly. The alkynes containing syn,syn, syn,anti, anti,anti,
and anti,syn stereochemical motifs were examined in cou-
pling reactions with the Roche aldehyde 11 to probe the
combined effect of stereochemistry and the position of a
tethered alkoxide in the control of site-selective C-C bond
formation.13
Although we were successful in realizing our goal of
assembling the C1-C15-containing diene 7a, the levels of
regioselection observed in the metal-mediated reductive
coupling reactions with homopropargylic ethers 13 and 16
were unsatisfactory (e3:1, Scheme 3). On the basis of our
previous studies of group 4 metal-mediated coupling reac-
tions of homopropargylic alcohols and chiral aldehydes,5 we
anticipated that the relative stereochemistry of the internal
alkyne component would play an important role in influenc-
ing levels of regioselection. The similar levels of regio-
selection observed in the coupling reactions of the anti,syn
and syn,syn stereoisomers of the homopropargylic ethers 13
and 16 stand in sharp contrast to this expectation. On the
basis of these observations, and related perturbations of
regioselection observed in group 4 metal-mediated coupling
reactions of homopropargylic alcohols/ethers and terminal
alkynes,11 we began investigating the role of a tethered
hydroxyl in these coupling reactions.
As depicted in Table 1, within each stereochemical series,
the substrates bearing a tris-homopropargylic alcohol (23,
Table 1. Site-Selective C-C Bond Formation Based on the
Presence and Position of a Tethered Alkoxidea
We speculated that a tethered alkoxide may influence site
selective carbon-carbon bond formation in reductive cou-
pling reactions based on the potential for interaction of the
alkoxide with the titanium center. As depicted in Scheme 4,
Scheme 4. A Potential Role of Tethered Alkoxides in
Regioselective C-C Bond Formation
a Reagents: ClTi(Oi-Pr)3, c-C5H9MgCl.
if the tethered alkoxide coordinates to the metal center to
form a bicyclic metallacyclopropene (18), and this structure
is retained in the transition state for reductive coupling, then
C-C bond formation should preferentially afford the bicyclic
a Reagents and conditions: (a) n-BuLi, PhMe, -78 °C; then ClTi(O-i-
Pr)3, C5H9MgCl, -78 to -40 °C; then BF3‚OEt2, -78 °C and aldehyde.
(b) ClTi(O-i-Pr)3, C5H9MgCl, -78 to -40 °C; then BF3‚OEt2, -78 °C and
aldehyde. (c) This experiment was performed with the enantiomeric alkyne
and aldehyde. (d) R3 ) TBDPS. (e) R3 ) TBS.
(9) Overman, L. E.; McCready, J. Tetrahedron Lett. 1982, 23, 2355-
2358.
(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(11) Shimp, H. L.; Micalizio, G. C. Org. Lett. 2005, 7, 5111-5114.
(12) See the Supporting Information for experimental details.
Org. Lett., Vol. 8, No. 6, 2006
1183

26, 29, and 32, highlighted in red) provided the highest levels
of regioselection in these coupling reactions (rs g 8:1) (see
entries 1, 4, 7, and 10). Uniformly, the substrates bearing a
homopropargylic alcohol provided products with lower levels
of regioselection (rs ) 4:1 to 12:1; entries 2, 5, 8, and 11),
while the fully protected substrates were generally least
selective in coupling reactions with aldehyde 11 (entries 3,
6, 9, and 12).
Scheme 6. Second-Generation Route to a C1-C15 Diene
These data indicate that the presence of a tethered alkoxide
in the polyketide chain can have a dramatic influence on
regioselection in these titanium alkoxide-promoted coupling
reactions. To the best of our knowledge, this is the first
observation of such an alkoxide-directing effect in reductive
coupling reactions between internal alkynes and aldehydes.14
As depicted in Scheme 5, the presence of a tethered
alkoxide has the potential to modulate the structure of the
Scheme 5. Potential Variation in the Structure of the Reactive
Metallacycle Based on the Presence and Position of a Tethered
Alkoxide
primary TBS ether provided the tris-homopropargylic alcohol
32. Deprotonation, followed by titanium alkoxide-mediated
reductive coupling with the TBS-protected lactaldehyde 8
provided the allylic alcohol 39 in 75% yield with g20:1
regioselection. Oxidative formation of the PMP acetal,
followed by oxidation of the allylic alcohol, diastereoselective
reduction (ds 6:1), protection as the corresponding TIPS
ether, and reductive opening of the PMP acetal provided the
primary alcohol 15 in 66% yield. Oxidation to the corre-
sponding aldehyde, followed by a second titanium alkoxide-
mediated coupling with the alkoxide derived from 23
provided the fully functionalized C1-C15 diene 7b in 77%
yield; this coupling reaction also proceeded with g20:1
regioselection.
Overall, we have described a highly convergent route to
the synthesis of a C1-C15 functionalized diene of potential
value for macrolide antibiotic synthesis. In the course of our
studies we have defined an important role of tethered
alkoxides in the control of site-selective C-C bond formation
in titanium alkoxide-mediated reductive coupling reactions
of internal alkynes and chiral aldehydes. Future work
targeting the syntheses of macrolide antibiotics with these
highly regioselective C-C bond-forming processes will be
reported in due course.
a Not meant to exclude the possibility of higher order oligomeric
structures. bThe possibility of a dimer or higher order oligomer may
also contribute to the changes in regioselection observed, as we
realize that 37 should be destabilized by ring strain associated with
the proposed [5.1.0] unsaturated ring system.
reactive metallacycles (monocyclic, oligomeric, or bicyclic).
In the competing transition states for reductive coupling with
carbonyl electrophiles that lead to the observed regioisomeric
products, each of these metallacycles are expected to
experience unique nonbonded steric interactions as a result
of their distinct topographies.
Armed with the knowledge that a tris-homopropargylic
alkoxide, in a polyketide-derived internal alkyne (23, 26, 29,
and 32), maximizes regioselection in coupling reactions with
the Roche aldehyde 11, we re-examined our approach to the
synthesis of a C1-C15 diene precursor to the erythronolides.
As illustrated in Scheme 6, pentynylation of the TBS-
protected Roche aldehyde 10, followed by protection of the
resulting homopropargylic alcohol and deprotection of the
Acknowledgment. We gratefully acknowledge financial
support of this work by the Arnold and Mabel Beckman
Foundation, Boehringer Ingelheim, Eli Lilly & Co., and Yale
University. Additionally, we acknowledge Dr. David Spiegel
for his careful review of this manuscript.
(13) For the preparation of compounds 23-34, see the Supporting
Information.
(14) For an example of a magnesium alkoxide-directed zirconium-
catalyzed carbomagnesiation see: (a) Hoveyda, A. H.; Morken, J. P.; Houri,
A. F.; Xu, Z. J. Am. Chem. Soc. 1992, 114, 6692-6697. For olefin-directed
regioselective nickel-catalyzed reductive coupling reactions of alkynes with
aldehydes, see: (b) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem.
Soc. 2004, 126, 3698-3699. (c) Miller, K. M.; Luanphaisarnnont, T.;
Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130-4131.
(d) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342-
15343.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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