New synthetic technology for the mild and selective one-carbon homologation of hindered aldehydes in the presence of ketones

Article abstract of DOI:10.1021/ol000102u

(Formula presented) A selective, mild, and highly efficient method has been uncovered during the total synthesis of the CP molecules to accomplish the one-carbon homologation of sterically hindered aldehydes in the presence of acid- and base-labile moieties, Michael acceptors, and even other carbonyl groups such as reactive and epimerizable ketones. Mechanistic studies have revealed a neutral reagent for the rapid collapse of cyanohydrins to ketones.

Full text of DOI:10.1021/ol000102u

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1895-1898
New Synthetic Technology for the Mild
and Selective One-Carbon Homologation
of Hindered Aldehydes in the Presence
of Ketones
K. C. Nicolaou,* Georgios Vassilikogiannakis, Remo Kranich, Phil S. Baran,
Yong-Li Zhong, and Swaminathan Natarajan
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, and Department of Chemistry and Biochemistry,
UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093
kcn@scripps.edu
Received April 20, 2000
ABSTRACT
A selective, mild, and highly efficient method has been uncovered during the total synthesis of the CP molecules to accomplish the one-
carbon homologation of sterically hindered aldehydes in the presence of acid- and base-labile moieties, Michael acceptors, and even other
carbonyl groups such as reactive and epimerizable ketones. Mechanistic studies have revealed a neutral reagent for the rapid collapse of
cyanohydrins to ketones.
During the course of our recent total synthesis of the CP
molecules,1 the opportunity arose to develop a method for
the conversion of aldehyde 1 to the homologated cyanide 2
(Scheme 1). In this model study we focused our attention
on homologation at the aldehyde stage since several methods
for homologation at either the alcohol or acid stage failed
on more complex substrates. Several conventional methods
for the homologation of 1 such as the Wittig,2 Matteson,3 or
other ylide-based4 protocols led to low yields of the desired
product along with byproducts from interference of the
ketone moiety. The current strategy was based on the mild
formation of cyanohydrins in order to selectively coerce the
one-carbon elongation of hindered aldehydes such as 1 even
in the presence of exposed ketones. Treatment of 1 with Et2-
AlCN5 (5 equiv) at 0 °C for 5 min led to pure bis-
cyanohydrin 3 after workup. After dissolution in CH2Cl2 and
selective formation of the mono-thioimidazolide6 4, deoxy-
genation (nBu3SnH, AIBN, hν)7 ensued within 5 min in the
same pot as observed by TLC. To our delight, the deoxy-
genation sequence delivered not only the coveted one-carbon
elongation, but was also attended by concomitant ketone
regeneration. The sequence from 1 to 2 required only one
(1) Part 1: Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.;
Yoon, W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669.
Part 2: Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.;
Yoon, W. H.; Choi, H.-S. Angew. Chem., Int. Ed. 1999, 38, 1676. For the
asymmetric total synthesis of the CP molecules, see: Nicolaou, K. C.; Jung,
J.-Q.; Yoon, W. H.; He, Y.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 1829.
(4) Bestmann, H. J.; Zimmerman, R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; 1991; Vol. 6, pp 171-198.
(5) Nagata, W.; Yoshioka, M.; Okumura, T. Tetrahedron Lett. 1966, 847.
(6) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin. Trans. 1
1975, 1574.
(2) Nicolaou, K. C.; Ha¨rter, M. W.; Gunzner, J. L.; Nadin A. Liebigs
Ann. 1997, 1283.
(3) Matteson, D. S. Chem. ReV. 1989, 89, 1535.
(7) Critch, D.; Quintero, L. Chem. ReV. 1989, 89, 1413.
10.1021/ol000102u CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/27/2000

Scheme 1. Mild Conversion of Aldehyde 1 into Cyanide 2
without Protection of the Ketone Present in 1
Table 1. One-Carbon Homologation of Simple and Hindered
Aldehydes
purification and two reaction vessels and proceeded in an
overall yield of 83%. Herein we report the generality and
scope of this versatile and selective one-pot homologation
for hindered aldehydes in the presence and absence of
ketones as well as a proposed mechanism for the unusual
ketone regeneration observed.
We first set out to investigate the generality of this protocol
with simple aldehydes in order to optimize the overall process
(Table 1). In all cases, the reactions proceeded as efficiently
and easily as for substrate 1 with overall yields ranging from
70 to 99%.
Table 2 illustrates the versatility of this approach with a
number of complex and sterically hindered keto-aldehydes.
Overall yields are generally good to excellent for the entire
procedure (aldehyde f cyanide). The first step is extremely
mild since the presence of Michael acceptors (entries 3 and
4, Table 1; entries 1, 2, and 6,8 Table 2), base-labile (entries
1 and 2, Table 2) and even acid-sensitive (entries 3, 4, 7,
Table 1, entries 1-3, Table 2) groups did not influence (bis)-
cyanohydrin formation. Even in the case of the extremely
hindered aldehyde in entry 7 (Table 2), the reaction succeeds
furnishing 80% overall yield of the desired cyanide. Sub-
strates containing easily enolizable carbonyl groups showed
no epimerization under the reaction conditions (Table 1,
entries 3, 4, and 7; Table 2, entries 1-3, 5, and 6). This
strategy saves a number of steps since alternative routes
based on protecting group chemistry are lengthy and lower-
yielding. Intrigued by the facile and simultaneous deprotec-
tion of ketone-cyanohydrins in this neutral reaction, we set
out to determine the root of this unusual phenomenon (see
a Preparation of aldehydes in entries 1-7 will be presented in the full
account of this work. b Isolated yield over entire homologation sequence.
c Yield based on 11% recovered aldehyde.
Scheme 2). After a systematic elimination of the possible
causes for this transformation,9 we suspected that imidazole,
produced after deoxygenation,7 was responsible. Although
the deoxygenation/ketone regeneration of 4 (derived from
(12) General Experimental Procedure. All compounds reported were
fully characterized spectroscopically. To a 0.8 M solution of keto-aldehyde
(i.e., Table 2) in toluene was added 2.2 equiv of Et2AlCN (1 M solution in
toluene, Aldrich) at 0 °C. After approximately 10 min the reaction mixture
was diluted with EtOAc and Rochelle’s salt (saturated solution) was added.
After stirring for 30 min at ambient temperature, the mixture was separated
and the organic layer was washed sequentially with water and brine, dried
(MgSO4), and concentrated in vacuo to furnish the bis-cyanohydrin in 90%
purity. Only 1-2 equiv of Et2AlCN is necessary for simple aldehydes (i.e.,
Table 1). To a degassed (Ar bubbling, 10 min) solution of (bis)cyanohydrin
in CH2Cl2 (distilled from CaH2) were added 0.2 equiv of 4-DMAP and
1.1-1.2 equiv of 1,1′-thiocarbonyldiimidazole. Upon formation of the
thioimidazolide (as monitored by TLC, usually 5-30 min), nBu3SnH (5.0
equiv), and AIBN (0.2 equiv) were added, and the reaction vessel was placed
in a 20 °C water bath while exposed to light from a nearby sunlamp (simple
floodlamp) for 5-20 min (TLC monitoring). The reaction mixture was
diluted (10:1 hexanes:EtOAc) and passed through a silica plug to remove
tin impurities, and the product was eluted with hexanes:EtOAc (1:1). Flash
column chromatography was employed to obtain spectroscopically pure
material.
(8) 1 equiv of Et2AlCN was used to avoid Michael addition.
(9) Using the cyanohydrin of cyclohexanone (8), the following control
experiments were performed: (a) 8 + AIBN; (b) 8 + nBu3SnH; (c) 8 +
nBu3SnH + AIBN; (d) 8 + nBu3SnH + AIBN + hν; (e) experiment d
followed by silica gel chromatography; (f) 8 + 4-DMAP or imidazole.
Experiments a-e led to no reaction and full recovery of 8. Experiment f
led to ca. 20% conversion to cyclohexanone after 12 h.
(10) Prepared as reported in Japanese Patent application JP 79-38934
(Sumitomo Chemical Co., Ltd., Japan), see also: Chem. Abstr. 94, 139812.
(11) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem., Int. Ed. 2000, 39, 44.
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Org. Lett., Vol. 2, No. 13, 2000

Scheme 2. Mechanistic Rationale for the Concomitant
Regeneration of Ketones from Cyanohydrins during the
Deoxygenation of Thioimidazolides
Table 2. Mild and Completely Selective Homologation of
Hindered Aldehydes in the Presence of Ketones
mediate B (Scheme 2), derived from intermediate A, reacts
with 6 as depicted in Scheme 2, leading to the desired product
2. To verify the presence and participation of intermediate
B in this reaction, we synthesized it10 and probed its reactivity
with 8 as shown in Scheme 3. Thus, in the presence of B, 8
Scheme 3. Evidence for the Participation of Intermediate B in
the Regeneration of Ketones from Cyanohydrins
a Preparation of aldehydes in entries 1-3 and 5 will be presented in the
full account of this work. Aldehydes in entries 4 and 6 were commercially
available and aldehyde in entry 7 was generously supplied by J. Pfefferkorn
(this group). b Isolated yield over the entire homologation sequence.
was converted to cyclohexanone quantitatively within 5 min
1
at room temperature as observed by H and 13C NMR
spectroscopy.
1, Scheme 1) giving rise to 2 occurred in ca. 5 min, treatment
of 4 with imidazole (1 equiv) for 24 h led to a very slow
conversion (ca. 10%) to ketone 7. These results suggested
that a reactive intermediate produced during the course of
the deoxygenation reaction may be responsible for this
unique ketone regeneration. Thus, based upon the known
mechanism of this deoxygenation,6,7 we propose that inter-
In conclusion, we have developed a new and efficient
protocol for the one-carbon elongation of hindered aldehydes
even in the presence of ketones, esters, Michael acceptors,
and acid- and base-labile groupings. In the case of keto-
aldehydes, both the ketone and aldehyde are transformed to
cyanohydrins, yet the ketone grouping is regenerated auto-
matically during the reaction via a novel mechanism. Further
Org. Lett., Vol. 2, No. 13, 2000
1897

discoveries11 arising from our travels through the CP
molecule “synthetic labyrinth” will be reported in due
course.12
Glaxo, Merck, Schering Plough, Boehringer-Ingelheim, Bris-
tol-Myers Squibb, Hoffmann-LaRoche, DuPont, and Abbott
Laboratories.
Supporting Information Available: Spectral data (Rf,
IR, 1H NMR, 13C, HRMS) for compounds (Table 1, entries
2-7 and Table 2, entries 4-7). Spectral data for CP
compounds (Table 2, entries 1-3) will be reported in a full
paper. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We thank Drs. D. H. Huang and G.
Siuzdak for NMR spectroscopic and mass spectrometric
assistance, respectively. This work was financially supported
by the National Institutes of Health (USA), The Skaggs
Institute for Chemical Biology, a postdoctoral fellowship
from Bayer AG (R.K.), a doctoral fellowship from the
National Science Foundation (P.S.B.), and grants from Pfizer,
OL000102U
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Org. Lett., Vol. 2, No. 13, 2000