Hydrocarbon oxidation vs C-C bond-forming approaches for efficient syntheses of oxygenated molecules

Article abstract of DOI:10.1021/ol047800p

(Chemical Equation Presented) A hydrocarbon oxidation approach has been applied to the construction of several linear (E)-allylic alcohols that have served as intermediates in the synthesis of natural products and natural product-like molecules. In the original syntheses, these intermediates were constructed using a standard Wittig-type olefination approach. We report here that routes to these same intermediates designed around a hydrocarbon oxidation approach are more efficient both in the total number of functional group manipulations (FGMs) and overall steps, as well as in the overall yield.

Full text of DOI:10.1021/ol047800p

ORGANIC
LETTERS
2005
Vol. 7, No. 2
223-226
Hydrocarbon Oxidation vs C−C
Bond-Forming Approaches for Efficient
Syntheses of Oxygenated Molecules
Kenneth J. Fraunhoffer, Daniel A. Bachovchin, and M. Christina White*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
white@chemistry.harVard.edu
Received October 26, 2004
ABSTRACT
A hydrocarbon oxidation approach has been applied to the construction of several linear (E)-allylic alcohols that have served as intermediates
in the synthesis of natural products and natural product-like molecules. In the original syntheses, these intermediates were constructed using
a standard Wittig-type olefination approach. We report here that routes to these same intermediates designed around a hydrocarbon oxidation
approach are more efficient both in the total number of functional group manipulations (FGMs) and overall steps, as well as in the overall
yield.
A prevalent approach for introducing oxygenated functional-
ity in complex small-molecule synthesis is the joining of
preoxidized fragments via C-C bond-forming methods.
Implicit in this approach is the burden of carrying oxygenated
functionality throughout the synthesis, often necessitating the
use of functional group manipulations (FGMs) such as
alcohol protection-deprotection sequences and oxidation
state changes. An attractive, alternative approach would be
the direct oxidative functionalization of hydrocarbon units
at late stages of a synthetic sequence. In theory, routes based
on this approach would proceed with reduced FGMs,
resulting in fewer steps and increased overall yields. We
recently developed a method that allows us to test this
hypothesis. Specifically, we reported a DMSO-promoted,
Pd(OAc)2-catalyzed allylic oxidation with olefin transposition
method for the highly chemo-, regio-, and stereoselective
synthesis of linear (E)-allylic acetates from monosubstituted
olefins (Scheme 1).1,2
Scheme 1. Pd(II)/DMSO Allylic Oxidation
forming approach for their preparation involves a sequence
of Horner-Wadsworth-Emmons (HWE) or stabilized Wit-
(1) (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
Other allylic oxidation systems: Pd(II)/AcOH/BQ: (b) Hansson, S.;
Heumann, A.; Rein, T.; A° kermark, B. J. Org. Chem. 1990, 55, 975. (c)
McMurry, J. E.; Kocovsky, P. Tetrahedron Lett. 1984, 25, 4187. (d) Macsari,
I.; Szabo, K. J. Tetrahedron Lett. 1998, 39, 6345. SeO2/t-BuO2H: (e)
Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
Cu(I)/t-Butyl Perbenzoate: (f) Andrus, M. B.; Lashley, J. C. Tetrahedron
2002, 58, 845. Pd(OH)2/C/t-BuO2H: (g) Yu, J.-Q.; Corey, E. J. J. Am. Chem.
Soc. 2003, 125, 3232. Pd(II)/DMSO/O2 oxidations: (h) Grennberg, H.;
Gogoll, A.; Backvall, J.-E. J. Org. Chem. 1991, 56, 5808. (i) Larock, R.
C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584. Pd(II)/DMSO arene C-H functionalization: (j) Zhou, C.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 2302.
Linear (E)-allylic alcohols are very common intermediates
in small-molecule synthesis. The current standard C-C bond-
10.1021/ol047800p CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/30/2004

tig olefination followed by reduction.2 Herein we report that
alternative routes to the same synthetic intermediates de-
signed around a hydrocarbon oxidation approach involving
DMSO/Pd(OAc)2/BQ allylic oxidation are uniformly more
efficient on the basis of number of FGMs, overall number
of steps, and overall yield (when available).
A representative example of the general strategy used to
access functionalized linear (E)-allylic alcohols is the
reported synthesis of key (E)-allylic alcohol intermediate
(+)-4 of the miyakolide C6-C13 fragment (Scheme 2).3a The
aldol methodology (Scheme 2).3b After reductive auxiliary
cleavage and acetonide formation, the (E)-allylic alcohol unit
was deprotected to yield the targeted intermediate (+)-4. This
route required a total of 11 steps, 7 of which can be attributed
to FGMs. An alternative approach to (+)-4 was made
possible by our allylic oxidation methodology. Monooxy-
genated substrate 5 was converted into the corresponding
aldehyde and then transformed into the desired acetonide 7
using the aforementioned aldol sequence. The hydrocarbon
appendage of 7 was directly transformed into the requisite
linear (E)-allylic alcohol unit via DMSO/Pd(OAc)2/BQ allylic
oxidation (Scheme 2). Deacetylation generated (+)-4 in a
total of six steps, only two of which are FGMs, and 26%
overall yield. Notably, the acid-labile acetonide functionality
was tolerant of our mildly acidic allylic oxidation conditions.
Key to the relative brevity of our route was the ability to
use a hydrocarbon appendage, as opposed to an oxygenated
one, as a direct precursor to the target oxygenated func-
tionality.
Scheme 2. Hydrocarbon Oxidation Route vs C-C
Bond-Forming Route to (E)-Allylic Alcohol Intermediate (+)-4
of Miyakolide C6-C13 Fragment
In a similar vein, the reported synthesis of macrocycliza-
tion substrate 104 began with bis-oxygenated precursor 1,3-
propanediol 8. Multiple protective group and oxidation state
manipulations were used to enable installation of the (E)-
allylic acetate via a HWE/reduction sequence followed by
the sensitive â-sulfonyl acetate functionality via esterification.
This route proceeds in eight steps and 21% overall yield.
Four of these steps involve FGMs. By way of contrast,
starting from a monooxygenated precursor, 4-penten-1-ol 11,
we installed the â-sulfonyl acetate ester first and directly
converted the hydrocarbon appendage to the requisite (E)-
allylic acetate in three steps with no FGMs and in 57%
overall yield (Scheme 3). It is significant to note the
Scheme 3. Hydrocarbon Oxidation Route vs C-C
Bond-Forming Route to (E)-Allylic Acetate Intermediate 10 of a
Macrolide Precursor
a Conditions: Propionic acid (1R,2S)-2-[N-benzyl-N-(mesit-
ylenesulfonyl)-amino]-1-phenyl-1-propyl ester (1.2 equiv), Cy2BOTf
(2.3 equiv), NEt3 (2.8 equiv), -78 °C, 3 h; 5-hexenal, -78 °C for
b
3 h f 0 °C for 1 h, 71% (two steps). BQ ) Benzoquinone.
two ends of a symmetric, bis-oxygenated starting material,
1,4-butanediol 1, were differentially functionalized via a
series of reactions involving monoprotection, oxidation,
HWE olefination, reduction, and orthogonal protection to
generate the requisite (E)-allylic alcohol unit. The initially
protected hydroxyl was unmasked and oxidized to aldehyde
3, enabling the implementation of Masamune’s anti-selective
(2) (a) The Wittig-type reactions of aliphatic aldehydes proceed with
similar E/Z selectivities: Kelly, S. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 729.
(b) Cross-metathesis reactions of R-olefins with allylic alcohol equivalents
proceed with moderate stereoselectivities (∼4.5:1 E/Z). Chatterjee, A. K.;
Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125,
11360.
(3) (a) Yoshimitsu, T.; Song, J. J.; Wang, G.-Q.; Masamune, S. J. Org.
Chem. 1997, 62, 8978. (b) Personal communication with Professor Takehiko
Yoshimitsu.
compatibility of the sensitive â-sulfonyl acetate ester func-
tionality with our allylic oxidation methodology in contrast
(4) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4743.
Org. Lett., Vol. 7, No. 2, 2005
224

to its incompatibility with the carbanion addition and
reduction steps of the HWE sequence.
Scheme 5. Hydrocarbon Oxidation Route vs C-C
Bond-Forming Route to (E)-Allylic Acetate Intermediate 20 of
(()-Isoretronecanol
Similarly, the reported synthesis of 8,9-leukotriene inter-
mediate 15 via a stabilized Wittig/reduction route began from
bis-oxygenated precursor octanedioic acid 13.5a Monoesteri-
fication followed by a two-step, selective reduction of the
other carboxylate was required to install the (E)-allylic
alcohol moiety.5b The route proceeded in five steps, three
of which were FGMs, and 28% overall yield. In contrast,
esterification of 9-decenoic acid followed by direct allylic
oxidation/deacetylation afforded (E)-allylic alcohol 15 in
three steps, with one FGM, and in 54% overall yield.
Scheme 4. Hydrocarbon Oxidation Route vs C-C
Bond-Forming Route to (E)-Allylic Acetate Intermediate 15 of
8,9-Leukotriene C3
Scheme 6. Hydrocarbon Oxidation Route vs C-C
Bond-Forming Route to (E)-Allylic Acetate Intermediate 24 of
(-)-Swainsonine
We have also observed improvements in overall yields in
cases that do not differ significantly in the number of FGMs.
Alternative routes to isoretronecanol intermediate 206 and
swainsonine intermediate 247 differ only in the sequence used
to install the (E)-allylic alcohol unit, i.e., aldehyde formation/
olefination/reduction vs allylic oxidation/deacetylation
(Schemes 5 and 6). We attribute the higher yields in the latter
to a greater compatibility of the phthalimide and primary
alkyl bromide functionalities toward the allylic oxidation
sequence than to the Wittig-type olefination sequence, which
exposes the substrate to a range of relatively harsh conditions.
These findings directly challenge the general perception that
intermolecular C-H oxidation routes would be lower yield-
ing than standard C-C bond-forming routes to oxygenated
products.
Chiral (E)-2-buten-1,4-diols, important intermediates in the
synthesis of polyhydroxylated natural products, are usually
synthesized via Wittig-type C-C bond-forming routes start-
ing with chiral R-hydroxy aldehydes. These chiral synthons
are challenging to access directly.8 For example, the reported
synthesis of key intermediate (+)-28 en route to the C17-
C26 fragment of tautomycin proceeded via a HWE/reduction
sequence from aldehyde 27 (Scheme 7).9 The latter was
prepared in multiple steps from D-valine 25 via a deamination
route9b involving numerous FGMs of the acid moiety. We
recognized that Brown’s asymmetric allylation methodol-
ogy10 followed by our allylic oxidation method should
provide a rapid route to chiral (E)-2-buten-1,4-diols.11 The
requisite homoallylic alcohol was synthesized via enantio-
selective allylboration of 2-methylpropionaldehyde. Conver-
(5) (a) Baker, S. R.; Boot, J. R.; Morgan, S. E.; Osborne, D. J.; Ross,
W. J.; Schrubsall, P. R. Tetrahedron Lett. 1983, 24, 4469. (b) Pennington,
F. C.; Celmer, W. D.; McLamore, W. M.; Bogert, V. V.; Solomons, I. A.
J. Am. Chem. Soc. 1953, 75, 109.
(6) Danishefsky, S.; McKee, R.; Singh, R. K. J. Am. Chem. Soc. 1977,
99, 4783.
(7) Swainsonine: (a) Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997,
62, 1112. Overall yield for HWE route to 5 calculated starting from
commercial 4-bromobutanol: (b) Vedejs, E.; Arnost, M. J.; Hagan, J. P. J.
Org. Chem. 1979, 44, 3230.
(8) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808.
(9) (a) Tsuboi, K.; Ichikawa, Y.; Naganawa, A.; Isobe, M.; Ubukata,
M.; Isono, K. Tetrahedron 1997, 53, 5083. (b) Ichikawa, Y.; Tsuboi, K.;
Naganawa, A.; Isobe, M. Synlett 1993, 907.
(10) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
Org. Lett., Vol. 7, No. 2, 2005
225

In summary, this study introduces a new approach for the
synthesis of linear (E)-allylic alcohol intermediates that
entails installation of oxygenated functionality late in a
synthetic sequence via direct oxidation of an inert hydro-
carbon appendage. Using this strategy, we have achieved
efficient syntheses of a variety of (E)-allylic alcohol inter-
mediates that proceed with fewer FGMs, in fewer steps, and
in higher overall yields than alternative routes involving
conventional Wittig-type C-C bond-forming sequences.
These results suggest that the development of selective C-H
oxidation reactions with general substrate profiles can
streamline synthesis.
Scheme 7. Hydrocarbon Oxidation vs C-C Bond-Forming
Route to Chiral (E)-2-Buten-1,4-diol (+)-28 Intermediate of
Tautomycin C17-C26 Fragment
Acknowledgment. This work was supported by Harvard
University, the Camille and Henry Dreyfus Foundation
(M.C.W.), an Eli Lilly Graduate Fellowship (K.J.F.), and
the Undergraduate Harvard Research Program (D.A.B.). We
are grateful to Merck for a generous gift of GC equipment
and to Dr. G. Dudek, Mr. P. Wang, and Ms. Q. Liao for
mass spectral analyses.
Supporting Information Available: Detailed experi-
mental procedures and full spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047800P
sion of the alcohol to its PMB ether 29 followed by an allylic
oxidation/deacetylation sequence afforded (+)-28 in a total
of four steps (Scheme 7). Remarkably, this allylic oxidation
proceeded in exceptionally high stereo- and regioselectivity
(no Z or branched isomers were detected by H NMR) and
with no degradation of enantiomeric purity.
(11) Chiral (E)-2-buten-1,4-diols with good to moderate enantioselec-
tivities via allylation with chiral (E)-γ-(PhMe2Si) allylboronate reagents
followed by epoxidation/Petersen elimination: (a) Roush, W. R.; Grover,
P. T. Tetrahedron Lett. 1990, 31, 7567. (b) Roush, W. R.; Pinchuk, A. N.;
Micalizio, G. C. Tetrahedron Lett. 2000, 41, 9413.
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