Ortho-TMS benzaldehyde: An effective linchpin for type II anion relay chemistry (ARC)

Article abstract of DOI:10.1002/anie.200802301

(Chemical Equation Presented) ARC de triomphe: Ortho-TMS benzaldehyde permits efficient multicomponent union of a variety of nucleophiles and electrophiles, including the first example of a Pd-mediated ARC Type II process. A proof-of-concept synthetic sequence was designed and implemented for construction of a focused library of natural product-like compounds (see scheme). ARC: anion relay chemistry.

Full text of DOI:10.1002/anie.200802301

Communications
DOI: 10.1002/anie.200802301
Synthetic Methods
Ortho-TMS Benzaldehyde: An Effective Linchpin for Type II Anion
Relay Chemistry (ARC)**
Amos B. Smith, III,* Won-Suk Kim, and William M. Wuest
Nature, with beautiful elegance, constructs natural
products often in iterative fashion with both superb
efficiency and exquisite stereochemical control.[1] For
more than 100 years chemists have atempted to mimic
the elegance of nature with laboratory syntheses.
However, the shortcomings of many synthetic ventures
lie in the multistep sequences, often leading to mini-
mum structure augmentation, in conjunction with
isolation and purification at each stage, leading to
inefficient material advancement. Fortunately, multi-
component reactions[2] hold considerable promise of
alleviating this inefficiency by orchestrating the con-
version of simple starting materials, in a single (one-
pot) operation, to advanced intermediates of high
structural complexity without the need for multiple
isolations and purifications.[3] Towards this end, we
recently turned to the development of multicomponent
reaction sequences exploiting anion relay chemistry
(ARC).[4]
At the highest level, the ARC tactic can be divided
Scheme 1. Type I and II anion relay chemistry (ARC). ASG=anion stabilising
group.
into two processes involving anion migration, either
through bonds or though space, the latter requiring the
availability of a carrier to transport the negative charge.
A simple example of a “through-bond” anion relay is
the conjugate addition, through the p-system, with subse-
quent capture of the intermediate enolate. For “through-
space” anion relay two possibilities exist involving s-bonds
(Type I and II ARC), the difference residing in the resulting
locus of the transposed anion.
An important feature of the Type II ARC process is the
potential for iteration with a sequential series of bifunctional
linchpins, a process not dissimilar to living polymerization.[5]
In 1997, based on the early work by the groups of
Matsuda,[6] Tietze,[7] and Oshima,[8] we introduced an example
of the Type I ARC process involving mono-silyl dithianes,[9]
which, in conjunction with a solvent-controlled Brook rear-
rangement,[10] led to the development of an effective three-
component union protocol employing a wide variety of
different second electrophiles. The utility of this process was
subsequently demonstrated by completion of several natural
product total syntheses, including (+)-spongistatins 1 and 2,[11]
and more recently (À)-indolizidine 223AB and alkaloid (À)-
205B, the latter two utilizing aziridine as the second electro-
phile.[12]
Type I ARC is defined as a multicomponent coupling
(Scheme 1), wherein a linchpin nucleophile reacts with an
electrophile to generate an oxyanion that subsequently
transfers (or relays) the negative charge back to the initiating
site, followed by reaction with a suitable electrophile. The
Type II process entails reaction of a nucleophile with a
bifunctional electrophilic linchpin to generate an anionic
species that relays the negative charge to a different locus,
whence it reacts with a second electrophile.
We extended the ARC concept, in 2006, to the Type II
process, now employing bifunctional linchpins (see Figure 1
for examples, 1 and (À)-2), which, in conjunction with
[*] A. B. Smith, III, W.-S. Kim, W. M. Wuest
Department of Chemistry
Penn Center for Molecular Discovery and Monell Chemical Senses
Center
University of Pennsylvania, Philadelphia, PA 19104 (USA)
E-mail: smithab@sas.upenn.edu
[**] This work was funded by grants from the National Institutes of
Health (GM-091253 and CA-19033)and a fellowship from the
University of Pennsylvania (W.M.W.). TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802301.
Figure 1. Type II ARC bifunctional linchpins utilized in natural product
synthesis.
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Table 1: Additive effects on the aryl-silyl migration.[a]
solvent-controlled Brook rearrangements, led to elaboration
of a number of advanced intermediates utilized in the
construction of a gorgonian sesquiterpene[4d] and the southern
C(1)–C(25) fragment of the marine natural product spira-
strellolide A.[4e]
The versatility of the Type II ARC tactic is, however,
limited by the number of viable, readily available bifunctional
linchpins that have been successfully implemented in the
multicomponent tactic. Convinced of the considerable syn-
thetic utility of the ARC tactic, we initiated a program to
design, synthesize, and test the viability of several new
bifunctional linchpins.[4] A central design element of any
successful bifunctional linchpin comprises the appropriate
placement of an electrophilic center relative to an anion
stabilizing group (ASG), such that intramolecular anion
transfer is both feasible and effective (Scheme 1).
Building on our earlier successful incorporation of the
dithiane,[9] nitrile,[4d] and allyl[4d] functionalities as ASGs in
bifunctional linchpins, in conjunction with the recent work of
Takeda,[13] Moser,[14] and Xian[15], we reasoned that ortho-
TMS benzaldehyde (3, TMS = trimethylsilyl) held consider-
able promise as an effective linchpin for the Type II ARC
process. Specifically, the early work of Moser and co-work-
ers[14] demonstrated that strong electron-withdrawing groups,
for example a chromium tricarbonyl moiety, are required to
facilitate the Brook rearrangement in aryl systems. The
precedent of Takeda and co-workers[13] further suggested that
additives, such as copper(I), would facilitate the silyl-transfer
process.
Entry Solvent Additive
Temperature/
Time
Yield Yield
4 [%] 5 [%]
1
2
3
4
THF
Et2O
Et2O
–
–
–
À788C/30 min
À788C/30 min
08C/30 min
87
88
88
73
0
0
0
Et2O CuI (1.2 eq)
À788C/30 min
<5
then RT/1 h
5
6
7
Et2O HMPA:THF (1:1) À788C/30 min
46
0
24
52
74
then RT/1 h
À788C/30 min
Et2O CuI (0.6 eq),
HMPA: Et2O (1:1) then RT/30 min
Et2O CuI (1.2 eq),
À788C/30 min
0
HMPA:THF (1:1) then RT/30 min
[a] TBAF=tetra-n-butylammonium fluoride, HMPA=hexamethylphos-
phoramide.
reaction proved feasible employing nBuLi, linchpin 3, and
vinyl bromide with 3 mol% [Pd(PPh3)4] to furnish 6g; the
yield was 56% (Table 2, entry 8). To our knowledge, this
result comprises the first report of a palladium-mediated
Type II ARC process. Further studies are ongoing in our
laboratory.
Accordingly, we explored a variety of reaction conditions,
discovering that low temperature and a less-polar solvent
than THF (À788C and Et2O) comprise a prerequisite for
success (Table 1). It was also evi-
To investigate further the versatility of linchpin 3, a series
of nucleophiles were employed (Table 3). Addition of the
lithium anions derived from methyl, allyl, vinyl, and phenyl
dent that when either copper
Table 2: Three-component linchpin coupling of ortho-TMS benzaldehyde with a series of electrophiles.
iodide or hexamethylphosphora-
mide (HMPA) were independently
added, only minor amounts of the
Brook-rearranged product (5)
were isolated. However, when a
1:1 mixture of HMPA and THF
containing 1.2 equivalents of CuI
was added at À788C, silyl migra-
tion was complete within 30 min
(Table 1, entry 7). Presumably,
CuI, in conjunction with HMPA,
promotes silyl transfer by stabiliz-
ing the resultant aryl carbanion.
With optimized Brook rear-
Entry
Electrophile
R
Product
Yield [%]
1
2
3
6a
6b
6c
69
55
58[a]
rangement conditions in hand, we
explored the versatility of linchpin
3 in the Type II ARC process with
a variety of electrophiles. A series
of carbon- and heteroatom-based
electrophiles proved viable, gener-
ating multicomponent products,
6a–g and 7 in modest to good
yields (Table 2). Of particular sig-
nificance, a multicomponent palla-
4
6d
64
5
6
6e
6 f
71
65
7
8
7
50[b]
56[c]
6g
[a] propargyl bromide, 12 h; [b] 2% HCl in EtOH was used to deprotect the TMS group, 1 h; [c] vinyl
bromide, 3 mol% [Pd(PPh3)4], THF.
dium-mediated
cross-coupling
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Table 3: Three-component linchpin coupling of ortho-TMS benzaldehyde
with a series of nucleophiles.
Entry
1
Nucleophile
MeLi
Product
Yield [%]
68
8a
8b
8c
8d
2
3
4
66
68
60
Scheme 2. Optimized four-component linchpin union implementing
ortho-TMS benzaldehyde.
of a diverse series of macrolides and cyclic ethers, respec-
tively. Removal of both dithiane moieties according to the
PhLi
Corey–Erickson
protocol
(NCS
and
AgNO3
in
MeCN:H2O)[20] led to diketones (À)-13a and (+)-13b in 65
and 67% yields, which in turn were subjected to acid-
mediated removal of the silyl groups[14] to provide the
epimeric “natural product-like” targets. From the perspective
of diversity-oriented synthesis, macrolactones (À)-14a and
(+)-14b were constructed employing linchpins (À)-2 and 3 in
the Type II ARC process in 13% and 12% overall yield,
respectively. Currently, we are testing this “proof of concept”
sequence by exploiting a variety of nucleophiles, electro-
philes, and acids with (À)-2 and 3 to create an array of new
“natural product-like” chemical entities (that is, those con-
taining five points of diversity) for the NIHRoadmap
Program.[21]
In summary, we have developed and implemented ortho-
TMS benzaldehyde (3) as an effective bifunctional linchpin to
expand the synthetic versatility of the Type II ARC tactic. In
addition, we uncovered a palladium-mediated cross-coupling
process applicable to the ARC tactic, the first of its kind.
Finally, the synthesis of (À)-14a and (+)-14b comprises a
“proof of concept” sequence to “natural product-like” com-
pounds.
5
8e
78[a]
[a] tBuLi, KOtBu, À788C, 30 min.
halides[16] as well as 2-methyl-1,3-dithiane[17] furnished 8a–e
with good efficiency (ca > 60%) after Brook rearrangement
and subsequent allylation. Turning next to explore the Type II
ARC process in an iterative manner, we applied the
optimized Type II conditions to a four-component union
sequence employing linchpins (À)-2 and 3 (Scheme 2).
Pleasingly, a 63% yield of the coupled product (9) was
obtained, albeit, unsurprisingly, with poor diastereoselectivity
(1.25:1) at the carbanol site. Removal of the TMS-group with
methanolic potassium carbonate[18] followed by chromato-
graphic separation of the resulting diastereomers furnished
alcohols (À)-10a and (+)-10b with an overall yield of 59%
from 2-methyl-1,3-dithiane. Single-crystal X-ray analysis
defined the relative and absolute stereochemistry of (À)-
10a, the latter by the anomalous dispersion technique. With
both diastereomers of 10 secured, we advanced each isomer
towards a “proof of concept” sequence for construction of
“natural product-like” libraries.
Experimental Section
9: KOtBu (1.0m in THF, 9.7 mL, 9.7 mmol, 1.26 equiv) and tBuLi
(1.7m in pentane, 5.7 mL, 9.7 mmol, 1.26 equiv) were added to a
precooled (À788C) solution of 2-methyl-1,3-dithiane (1.24 g,
9.2 mmol, 1.2 equiv) in THF (15 mL). The resulting solution was
stirred at À788C for 30 min, and a solution of epoxide (À)-2 (2.24 g,
7.7 mmol, 1.0 equiv) in THF (15 mL) was added. The mixture was
stirred for 20 min at À788C and then a solution of aldehyde 3 (1.64 g,
9.2 mmol, 1.2 equiv) in THF (15 mL) was added by cannula. After
stirring for 30 min at À788C, the resulting solution was transferred by
cannula to a mixture of CuI (142.6 mg, 0.75 mmol, 1.2 equiv) and
Union of both alcohols (10a,b) with 4-pentenoic acid,
followed by ring-closing metathesis (RCM), implementing
the recent conditions reported by Grubbs and co-workers,[19]
provided macrolides (À)-12a and (+)-12b in high yield
(Scheme 3). It should be noted that a wide variety of
commerically available acids or alkyl halides hold the promise
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À3.4 ppm; high resolution mass spectrum
(ES+) m/z 593.2061 [(M + Na)+; calcd for
C28H46O2S4SiNa: 593.2048]. (+)-10b:
[a]20
+ 18.6 degcm3 gÀ1 dmÀ1
D
(c 0.5 gcmÀ3 CDCl3); IR (film) n˜ = 3440
(m), 2952 (s), 2856 (s), 1468 (m), 1254 (s),
1
1092 (s), 1026 (s), 775 cmÀ1 (s); HNMR
(500 MHz, CDCl3) d = .75–7.74 (m, 1H),
7.26–7.20 (m, 2H), 7.18–7.17 (m, 1H),
6.04–5.96 (m, 1H), 5.26 (s, 1H), 5.09 (dd,
J = 10.5 and 1.5 Hz, 1H), 5.04 (dd, J = 17.0
and 1.5 Hz, 1H), 4.60–4.56 (m, 1H), 3.92
(d, J = 3.5 Hz, 1H), 3.79 (dd, J = 16.0 and
6.5 Hz, 1H), 3.58 (dd, J = 16.0 and 6.5 Hz,
1H), 3.06–3.01 (m, 1H), 2.97–2.92 (m,
1H), 2.91–2.67 (m, 7H), 2.44 (dd, J = 15.5
and 5.0 Hz, 1H), 2.32 (dd, J = 15.5 and
6.0 Hz, 1H), 1.96 (dd, J = 8.0 and 3.5 Hz,
1H), 1.94–1.80 (m, 4H), 1.72 (s, 3H), 0.91
(s, 9H), 0.22 (s, 3H), 0.20 ppm (s, 3H);
13C NMR (125 MHz, CDCl3) d = 138.6,
137.5, 137.1, 129.6, 129.3, 127.8, 125.4,
116.0, 73.0, 68.9, 58.3, 49.9, 48.0, 45.0, 37.7,
29.3, 27.6, 27.0, 26.6, 26.2, 26.1, 25.1, 24.2,
18.1, À3.4 ppm; high resolution mass
spectrum (ES+) m/z 593.2049 [(M +
Na)+;
593.2048].
calcd
for
C28H46O2S4SiNa:
Received: May 17, 2008
Published online: July 30, 2008
Scheme 3. “Proof of concept” library of “natural product-like” compounds utilizing type II ARC.
DCC=dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine
Keywords: anion relay chemistry ·
cross-coupling · dithianes ·
molecular diversity · natural products
.
HMPA/THF (10 mL/10 mL) at 08C, then warmed to ambient
temperature and stirred for 30 min. Allyl bromide (2.0 mL,
23.1 mmol, 3.0 equiv) was next added at ambient temperature and
after 1 h, the reaction was quenched with saturated aqueous NH4Cl
solution (100 mL). The resulting mixture was then extracted with
Et2O (100 mL ” 3) and the organic layers were combined, washed
with brine (100 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Flash chromatography on silica gel (Et2O/hexane; 1/50),
provided a 1.25:1 diastereomeric mixture of 9 (3.13 g, 4.87 mmol,
63%) as pale yellow oil. Rf 0.8 (hexane/Et2O = 10/1).
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(À)-10a, (+)-10b: At ambient temperature, K2CO3 (4.17,
30.2 mmol, 10.0 equiv) was added to a methanolic (40 mL) solution
of 9 (1.94 g, 3.02 mmol, 1.0 equiv) and stirred overnight. The reaction
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2.84 mmol, 94%). Rf 0.2 (hexane/Et2O = 10/1).(À)-10a: [a]20
D
À0.90 degcm3 gÀ1 dmÀ1 (c 1.0 gcmÀ3 CDCl3); Rf 0.2 (10:1 hexane/
diethyl ether). IR (film) n˜ = 3434 (m), 2927 (s), 2855 (s), 1471 (m),
1254 (s), 1090 (s), 1028 (s), 775 cmÀ1 (s); 1HNMR (500 MHz, CDCl
)
3
d = 7.78–7.76 (m, 1H), 7.25–7.22 (m, 2H), 7.17–7.16 (m, 1H), 6.04–
5.96 (m, 1H), 5.29 (s, 1H), 5.09 (dd, J = 10.0 and 1.5 Hz, 1H), 5.03 (dd,
J = 17.0 and 2.0 Hz, 1H), 4.59–4.55 (m, 1H), 3.81 (dd, J = 16.0 and
6.5 Hz, 1H), 3.63 (br, 1H), 3.55 (dd, J = 16.0 and 6.0 Hz, 1H), 3.12–
3.06 (m, 1H), 3.03–2.94 (m, 2H), 2.85–2.62 (m, 6H), 2.44 (dd, J = 15.5
and 6.5 Hz, 1H), 2.05–1.81 (m, 6H), 1.73 (s, 3H), 0.83 (s, 9H), 0.12 (s,
3H), À0.04 ppm (s, 3H); 13C NMR (125 MHz, CDCl3) d = 138.9,
137.5, 137.0, 129.6, 129.5, 128.0, 125.6, 115.9, 73.3, 68.4, 58.3, 50.7, 48.5,
46.3, 37.9, 29.5, 27.6, 27.1, 26.7, 26.2, 26.1, 25.2, 24.0, 18.1, À3.35,
Angew. Chem. Int. Ed. 2008, 47, 7082 –7086
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