Formal synthesis of 6-deoxyerythronolide B

Article abstract of DOI:10.1021/ol0607241

The enantioselective synthesis of the carbon skeleton of 6-deoxyerythronolide B has been achieved in 23 linear steps from propionaldehyde. The synthesis relies on an iterative approach employing an asymmetric acyl-thiazolidinethione propionate aldol react

Full text of DOI:10.1021/ol0607241

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2191-2194
Formal Synthesis of
6-Deoxyerythronolide B
Michael T. Crimmins* and David J. Slade
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received March 24, 2006
ABSTRACT
The enantioselective synthesis of the carbon skeleton of 6-deoxyerythronolide B has been achieved in 23 linear steps from propionaldehyde.
The synthesis relies on an iterative approach employing an asymmetric acyl-thiazolidinethione propionate aldol reaction to establish eight of
nine stereogenic centers. The remaining stereogenic center at C6 was set through a Myers alkylation employing a complex alkyl iodide.
Since their discovery in the 1950s1 erythromycins have
captured the interest of biologists, synthetic chemists, and
clinicians alike. Physicians have long valued the antibacterial
properties2 of the family while the synthetic community has
been intrigued by challenges inherent in the strict polypro-
pionate backbone. Biologists, meanwhile, have focused on
the biosynthesis of the various members of the family, and
have successfully elucidated the complete biosynthetic
pathway.3 The first isolable (nonenzyme bound) intermediate
in the biosynthesis of the erythromycins is 6-deoxyerythro-
nolide B, which was first isolated in 1967 by Martin and
Rosenbrook4 from a blocked mutant of Streptomyces eryth-
reus.5 Three different multidomain enzymes, the deoxyeryth-
ronolide B synthases, have been shown to be responsible
for assembling 6 units of methylmalonyl CoA and one unit
of propionyl CoA in an iterative fashion. As the three
enzymes involved contain 31 distinct domains, nature
performs the synthesis of 6-deoxyerythronolide B in 31
sequential biosynthetic “steps”.6 6-Deoxyerythronolide B has
been the subject of substantial synthetic interest, with three
total syntheses having been previously reported.7 Masamune7c
and Evans7a each disclosed a convergent synthesis of
(1) McGuire, J. M.; Bunch, R. L.; Anderson, R. C.; Boaz, H. E.; Flynn,
E. H.; Powell, H. M.; Smith, J. W. Antibiot. Chemother. 1952, 2, 281.
(2) Nakayama, I. In Macrolide Antibiotics. Chemistry, Biology, and
Practice; Omura, S., Ed.; Academic Press: Orlando, FL, 1984; p 261.
(3) (a) Cortes, J.; Haydock, S. F.; Roberts, G. A.; Bevitt, D. J.; Leadlay,
P. F. Nature 1990, 348, 176. (b) Donadio, S.; Staver, M. J.; McAlpine, J.
B.; Swanson, S. J.; Katz, L. Science 1991, 252, 675. (c) Malpartida, F.;
Hopwood, D. A. Nature 1984, 309, 462.
Figure 1. Biosynthesis of erythromycins.
(4) Martin, J. R.; Rosenbrook, W. Biochemistry 1967, 6, 435.
(5) Staunton, J.; Wilkinson B. Chem. ReV. 1997, 97, 2611.
10.1021/ol0607241 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/15/2006

synthesis of the natural product using a strictly linear,
iterative approach, we set out to test the applicability of
thiazolidinethione aldol reactions in the context of a synthesis
of 6-deoxyerythronolide B.
Scheme 1
The accumulated knowledge of the three previous syn-
theses7 provided a wealth of information concerning the
unique challenge of performing the macrolactonization of
the 6-deoexyerythronolide B backbone and suggested that
the Evans seco-acid 4a would be an ideal substrate to target
for a successful synthesis.7a Careful examination of seco-
acid 4a revealed that all the stereogenic centers could be
directly established through syn aldol reactions with the
possible exception of C6. Two potential approaches were
envisioned to establish the requisite stereocenter at C6: a
stereoselective hydrogenation or a Myers diastereoselective
alkylation. It was anticipated that both approaches could be
investigated through a common intermediate 11, available
from three propionate aldol iterations beginning with pro-
pionaldehyde.
The synthesis of the tetrapropionate 11 commenced with
a non-Evans syn aldol reaction between the N-propionylthi-
azolidinethione 5 and propionaldehyde. The chlorotitanium
enolate of 5 was formed by addition of 1.05 equiv of TiCl4,
followed by 1.1 equiv of i-Pr2NEt. Subsequent addition of
propionaldehyde gave alcohol 6 in 91% yield (>20:1 dr).
The reaction was readily scalable, providing reproducible
results (both yield and diastereoselectivity) on scales ranging
from 1 mmol to over 100 mmol of propionate 5. Exposure
of alcohol 6 to TIPSOTf gave the requisite silyl ether in 96%
yield. Reduction of the thioimide with i-Bu2AlH provided
aldehyde 7 in 98% yield. The second aldol iteration required
the opposite sense of asymmetric induction in the aldol
addition. Thus, aldol reaction of imide 5 with aldehyde 7
was performed by enolization with 1.0 equiv of TiCl4, 1.0
equiv of (-)-sparteine, and 1.0 equiv of NMP to provide
Evans syn aldol adduct 8 in 96% yield with excellent (>20:1
dr) diastereoselectivity. Alcohol 8 was silylated by the action
of TBSOTf in 95% yield, whereupon reduction of the imide
with i-Bu2AlH provided aldehyde 9 in 93% yield. The third
iteration of the aldol sequence was performed by buffering
the chlorotitanium enolate of thioimide 5 (2.5 equiv of i-Pr2-
NEt) during the reaction with aldehyde 9 to avoid loss or
migration of the C11 silyl ether. The non-Evans syn aldol
adduct 10 was obtained in 98% yield with excellent selectiv-
ity (>20:1 dr). Protection of alcohol 10 as its TES ether
provided the silyl ether 11 in 96% yield.
To examine the diastereoselective hydrogenation to es-
tablish the C6 stereocenter, imide 11 was converted to lactone
13. A i-Bu2AlH reduction of imide 11 provided the aldehyde
12, and a subsequent Still-Gennari11 modified Horner-
Wadsworth-Emmons reaction delivered the Z-enoate. Treat-
ment of the enoate with p-TsOH in methanol removed the
silyl ethers and effected concomitant lactonization to provide
the unsaturated lactone 13. Catalytic hydrogenation of 13
proceeded smoothly to provide the desired saturated lactone
as a single isomer 14 (structural proof provided by single-
crystal X-ray analysis). Interestingly, attempted hydrogena-
6-deoxyerythronolide B, relying on double diastereoselective
aldol reactions to assemble the polypropionate backbone. By
contrast, Danishefsky7b employed a linear approach to
6-deoxyerythronolide B based on the Lewis acid-catalyzed
diene aldehyde condensation to complete the synthesis in
44 linear steps.
Recent reports from our laboratory have described a
diastereoselective propionate aldol reaction based on the use
of thiazolidinethione chiral auxiliaries.8 The ease of removal
and facile functional group interconversion of N-acylthiazo-
lidinethiones render this aldol reaction particularly well-suited
for an iterative process for polypropionate synthesis.9 The
advantages of thiazolidinethiones in asymmetric aldol reac-
tions are (1) the use of inexpensive commercial TiCl4 as the
Lewis acid, (2) both syn aldol diastereomers of the aldol
adduct can be accessed from a single antipode of the auxiliary
simply by changing the amount and type of base used, and
(3) the thiazolidinethione can be reductively cleaved to the
aldehyde with i-Bu2AlH.7,10 Thus, the N-propionylthiazo-
lidinethione allows for a three-step iterative aldol sequence:
(1) diastereoselective aldol addition, (2) protection of the
aldol hydroxyl, and (3) reduction of the N-acylthiazolidi-
nethione to an aldehyde.
Inspired by the iterative biosynthesis of 6-deoxyerythro-
nolide B, and intrigued by the possibilty of performing a
(6) (a) Kaneda, T.; Butte, J. C.; Taubman, S. B.; Corcoran, J. W. J. Biol.
Chem. 1962, 237, 322. (b) Cane, D. E.; Hasler, H.; Liang, T. J. Am. Chem.
Soc. 1981, 103, 5960. (c) Cane, D. E.; Yang, C.-C. J. J. Am. Chem. Soc.
1987, 109, 1255. (d) Cane, D. E.; Prabhakaran, P. C.; Tan, W.; Ott, W. R.
Tetrahedron Lett. 1991, 32, 5457. (e) Yue, S.; Duncan, J. S.; Yamamoto,
Y.; Hutchinson, C. R. J. Am. Chem. Soc. 1987, 109, 1253.
(7) (a) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am.
Chem. Soc. 1998, 120, 5921. (b) Myles, D. C.; Danishefsky, S. J.; Schulte,
G. J. Org. Chem. 1990, 55, 1636. (c) Masamune, S.; Hirama, M.; Mori, S.;
Ali, S. A.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103, 1568.
(8) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
(9) (a) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J.
Am. Chem. Soc. 2005, 127, 13810. (b) Crimmins, M. T.; Caussanel, F. J.
Am. Chem. Soc. 2006, 129, 3128.
(10) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama,
S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097.
(11) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
Org. Lett., Vol. 8, No. 10, 2006
2192

Scheme 2
tion on intermediates with the hydroxyl groups protected,
times and at elevated temperatures. In an attempt to improve
the reactivity of the iodide, the C9 and C11 silyl ethers were
replaced with a sterically less demanding cyclic acetal
protecting group, and to allow intersection with Evans seco-
acid 4a, a TBS group was used to protect the C13 hydroxyl.
After substantial experimentation, it was determined that
the most effective route to the required C9-C11 cyclic acetal
was to fully deprotect iodide 17 (p-TsOH, MeOH) to obtain
the corresponding triol as a white powder (97% yield)
followed by formation of the cyclic PMP acetal as a mixture
of all four possible six-membered acetals. The desired S
for example 15 or 16 and similar variants, led to very poor
conversion, and/or poor selectivity. Due to the protecting
group difficulties inherent in the hydrogenation approach to
set the C6 stereocenter, we turned our attention to establish-
ing the C6 stereocenter via a Myers alkylation (Scheme 3).12
N-Acylthiazolidinethione 11 was reductively converted to
the primary alcohol in 94% yield. After routine conversion
to iodide 17 (85% yield), a Myers alkylation was attempted
with pseudephedrine propionate 18 (Scheme 3). Unfortu-
nately, no reaction occurred, even after extended reaction
Scheme 3
Org. Lett., Vol. 8, No. 10, 2006
2193

acetal of the C9-C11 regioisomer 19 could be easily
separated from the mixture, and after equilibration of the
undesired isomers, a 56% yield of acetal 19 was obtained
after 3 recycles.
yield. Completion of the formal synthesis of 6-deoxyeryth-
ronolide B required only protecting group manipulation and
hydrolysis of the auxiliary. Selective deprotection of the TES
ether proceeded in 99% yield by exposure of imide 25 to
HF-pyridine buffered with pyridine. The resulting C3-C5
diol was converted to the acetonide under acidic conditions
in 85% yield. Hydrolysis of the auxiliary by treatment with
LiOH provided the acid 4b in 99% yield constituting a formal
synthesis of 6-deoxyerythronolide B. Spectral data for
synthetic 4b matched the literature values in all respects.9a
Installation of the requisite TBS group proceeded in 78%
yield providing iodide 20. Myers alkylation of amide 18 with
iodide 20 proceeded in 87% yield to provide amide 21
(>98:2 dr). Removal of the chiral auxiliary in the presence
of the acetal was accomplished with lithium amido trihy-
droborate in 98% yield.12,13 Dess-Martin oxidation14 of the
resulting primary alcohol provided aldehyde 22 in 86% yield.
The stage was now set for the remaining two iterations of
the aldol reaction sequence. An Evans syn mediated protocol
employing excess enolate delivered the desired aldol adduct
23 in 84% yield (>20:1 dr). Alcohol 23 was masked as the
TES ether in 91% yield and reduction of the N-acylthiazo-
lidinethione provided aldehyde 24 in 98% yield.
In conclusion, a formal synthesis of 6-deoxyerythronolide
B has been achieved in 23 steps and 7.5% overall yield, thus
validating the utility of N-acylthiazolidinethiones in an
iterative approach to polypropionates. Aldol additions of
thiazolidinethione 5 served to establish 10 of the 11 stereo-
centers of 6-deoxyerythronolide B.
The final aldol reaction employed excess enolate under
the Evans syn protocol (1.0 equiv of TiCl4, 1.0 equiv of (-)-
sparteine, 1.0 equiv of NMP) and gave alcohol 25 in 77%
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM38904)
is acknowledged with thanks.
(12) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
L.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(13) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623.
(14) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (b) Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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