Benzyl and phenylthiomethyl silanes: A new class of bifunctional linchpins for type II anion relay chemistry (ARC)

Article abstract of DOI:10.1021/ol100130x

Chemical Equation Presented A new class of bifunctional linchpins bearing electrophilic sites β or γ to a silyl group have been designed, synthesized, and demonstrated to be competent In tricomponent unions exploiting Type II Anion Relay Chemistry (ARC). High diastereoselectivities were observed when a phenyl moiety (R₂) served as an anion-stabilizing group (ASG) adjacent to a methyl susbtituent (R ₁), while diastereomeric mixtures were obtained when a phenylthiol moiety served as the ASG, irrespective of α-substitution.

Full text of DOI:10.1021/ol100130x

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1260-1263
Benzyl and Phenylthiomethyl Silanes: A
New Class of Bifunctional Linchpins for
Type II Anion Relay Chemistry (ARC)
Amos B. Smith III* and Rongbiao Tong
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received January 18, 2010
ABSTRACT
A new class of bifunctional linchpins bearing electrophilic sites ꢀ or γ to a silyl group have been designed, synthesized, and demonstrated
to be competent in tricomponent unions exploiting Type II Anion Relay Chemistry (ARC). High diastereoselectivities were observed when a
phenyl moiety (R2) served as an anion-stabilizing group (ASG) adjacent to a methyl susbtituent (R1), while diastereomeric mixtures were
obtained when a phenylthiol moiety served as the ASG, irrespective of r-substitution.
Efficient union of architecturally complex fragments con-
stitutes a critical prerequisite in natural product total syn-
theses. One such tactic, Anion Relay Chemistry (ARC), a
one-pot tricomponent union tactic, has proven highly effec-
tive in our laboratory.1 First exploited in 1997,2 two
structurally different epoxides were united in a single flask
to furnish advanced fragments for the total syntheses of (+)-
spongistatins 1 and 2.3 This tactic was subsequently em-
ployed in conjuction with a formal total synthesis of (+)-
mycoticin4 and more recently in the synthesis of the aglycon
skeleton of (+)-rimocidin.5 Now termed Type I ARC
(Scheme 1A),1 this strategy was based on the union of two
epoxides as introduced by Matsuda6a and Tietze.6b Hale and
co-workers subsequently took advantage of this protocol,
employing the Tietze homocoupling version in their formal
total synthesis of (+)-bryostatin 1.7
In 2004, we extended the Type I process to permit anion
migration along the linchpin chain to generate a new reactive
anion at a distal site (Scheme 1B).8 Termed Type II ARC,1,9
initial nucleophilic attack at the electrophilic site of the
linchpin (cf. aldehyde or epoxide) leads to an alkoxide, which
upon a silyl C(sp3)fO Brook rearrangement,8,9 triggered by
addition of a polar solvent (HMPA) or by temperature
increase, produces a new carbon anion. For silyl migration
to occur, the newly generated anionic site must possess a
viable anion stabilizing group (ASG). Capture of the derived
anion is then possible with a variety of electrophiles to
generate, in a single flask, diverse three-component adducts.
The synthetic utility of the Type II ARC protocol was
demonstrated in the construction of an advanced intermediate
(1) For reviews, see: (a) Smith, A. B., III; Adams, C. M. Acc. Chem.
Res. 2004, 37, 365. (b) Smith, A. B., III; Wuest, W. M. Chem. Commun.
2008, 5883. (c) Moser, W. H. Tetrahedron 2001, 57, 2065 Also see ref 3.
(2) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 69.
(3) (a) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar,
M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.; Sobukawa,
M. Angew. Chem., Int. Ed. 2001, 40, 191. (b) Smith, A. B., III; Lin, Q.;
Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.; Brook, C. S.;
Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40, 196. Also
see: Smith, A. B., III. et al. Tetrahedron 2009, 65, 6470; 6488.
(4) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001.
(5) Smith, A. B., III; Foley, M. A.; Dong, S.; Orbin, A. J. Org. Chem.
2009, 74, 5987.
(6) (a) Matsuda, I.; Murata, S.; Ishii, Y. J. Chem. Soc., Perkin Trans. 1
1979, 26. (b) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett
1994, 511. (c) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K.
Tetrahedron 1996, 52, 503. (d) Takaku, K.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 1998, 39, 2575.
(7) Hale, K. J.; Hummersone, M. C.; Bhatia, G. S. Org. Lett. 2000, 2,
2189.
(8) Smith, A. B., III; Duffey, M. O. Synlett 2004, 8, 1363.
(9) (a) Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem.
Soc. 2006, 128, 12368. (b) Smith, A. B., III; Xian, M. J. Am. Chem. Soc.
2006, 128, 66
.
10.1021/ol100130x  2010 American Chemical Society
Published on Web 02/24/2010

in our prospective syntheses of (+)-spirastrellolides A and
phenyl or phenylthio moieties as ASGs to explore both the
viability of the Type II ARC process and the stereochemical
outcome at carbon upon Brook rearrangement and anion
capture.
B, architecturally complex sponge metabolites.10
Scheme 1. Type I and II Anion Relay Chemistry (ARC)
Early in the development of the ARC technique, the
dithiane moiety played the role of a highly effective ASG,
furnishing after Brook rearrangement, a powerful nucleophile
for reaction with a variety of electrophiles. One drawback,
however, of the dithiane moeity as an ASG is the lack of
reactivity of R-substituted linchpins such as 3 (Figure 1; R
) CH3).10b We now recognize this lack of reactivity to be
due to a preferred linchpin conformation that buries the
terminus of the electrophilic epoxide in the dithiane ring.
We therefore turned, in 2007, to possible alternative ASGs;
preliminary studies with linchpins 4 and 5, bearing cyano
or allyl groups, proved promising.11 A general search for
other viable ASGs that would extend the scope and general
utility of the ARC tactic was therefore initiated. Central to
this venture was an ASG that would prove to be competent
with R-substituted linchpins in order to access a variety of
polyketide natural products and/or natural product-like
analogues for diversity-oriented synthesis (DOS).12 In this
paper, we report on one aspect of this program, the design,
synthesis, and evaluation of a new class of bifunctional Type
II ARC linchpins that employ the phenyl or phenylthio13
group as the ASGs (Figure 1).
Unlike earlier linchpins employing a disubstituted ASG
(cf. dithiane), use of a monosubstituent ASG, such as phenyl
or phenylthio moiety, leads to introduction of an asymmetric
center at the silyl-bearing carbon. The question thus arises
as to the stereochemical outcome (i.e., retention, inversion
or racemization) resulting from capture of the Brook derived
anion. In the case of the 1,2-Brook rearrangement of R-silyl
alcohols bearing a phenyl ASG, elegant studies by Brook14b
and Mosher14c revealed that inversion occurs at carbon and
retention at silicon.14 We therefore designed a series of
enantiomerically pure linchpins (Figure 1, 6-10) possessing
Figure 1. New Bifunctional Linchpins for Type II ARC
Access to linchpins 6-10 called upon the protocol
developed by Sato and co-workers15 that entails regioselec-
tive opening of disubstituted epoxide 11.15a Reaction of 12
with 11 furnished (-)-13a and (+)-13b as a diastereomeric
mixture (ca. 1:1). Removal of the trityl group with p-TsOH
pleasingly furnished diastereomers (-)-13a and (+)-13b that
could be separated by flash chromatography. X-ray diffrac-
tion of the primary 4-bromobenzoate of diol (+)-13b,
permitted assignment of the relative and absolute configura-
tions.16 Oxidative cleavage of the diols led to aldehyde
linchpins (-)-6a and (+)-6b in excellent yields (Scheme 2).
Epoxide linchpins (-)-7a and (+)-7b were prepared from
(-)-13a and (+)-13b by monotosylation of the hydroxyl,
followed by treatment with n-BuLi. Preparation of the non-
R-substituted linchpins, (-)-8a and (+)-8b, entailed a two-
step sequence employing the readily separable chloro
alcohols (-)-15a and (+)-15b, derived from (S)-(+)-epi-
chlorohydrin. The relative and absolute configurations of (+)-
15b were established by X-ray analysis of the corresponding
3,5-dinitrobenzoate.16
Construction of the phenylthio linchpins (-)-9a, (+)-9b,
(-)-10a, and (+)-10b proceeded in similar fashion (Scheme
3). For (-)-10a and (+)-10b, a three-step sequence: (1)
acetylation, (2) mesylation, and (3) epoxide formation upon
deacetylation was employed. The relative and absolute
configurations of (-)-9a and (-)-10a were again assigned
by X-ray analysis.16
(10) (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2007, 9, 3311. (b)
Unpublished results: Atasoylu, O. University of Pennsylvania.
(11) Smith, A. B., III; Kim, D.-S.; Xian, M. Org. Lett. 2007, 9, 3307.
(12) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46.
(14) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. (b) Biernbaum,
M. S.; Mosher, H. S. J. Am. Chem. Soc. 1971, 93, 6221. (c) Brook, A. G.;
Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224. Review: Brook, A. G.
Acc. Chem. Res. 1974, 7, 77.
(13) (a) Fleming, I.; Floyd, C. O. J. Chem. Soc., Perkin Trans. 1 1981,
969. (b) Takeda, K.; Ubayama, H.; Sano, A.; Yoshi, E.; Koizumi, T.
Tetrahedron Lett. 1998, 39, 5243.
(15) (a) Kobayashi, Y.; Kitano, Y.; Sato, F. Chem. Commun. 1984, 1329.
(b) Sato, F.; Kusakabe, M.; Kobayashi, Y. Chem. Commun. 1984, 1130.
(16) See the Supporting Information for details.
Org. Lett., Vol. 12, No. 6, 2010
1261

Scheme 2
.
Synthesis of Linchpins 6a, 6b, 7a, and 7b
Table 1. Anion Relay Chemistry of Linchpins 6a-8b
Scheme 3. Synthesis of Linchpins of 9a, 9b, 10a, and 10b
With linchpins 6a-10b in hand, we evaluated both their
viability as linchpins for the Type II ARC tactic and the
stereochemical outcome at carbon upon Brook rearrangement
followed by alkylation. Polar aprotic additives (cf. HMPA)
were employed to trigger the Brook rearrangement9 of the
initially generated lithium alkoxides. As illustrated in the
Tables 1 and 2, the phenyl and phenylthio moieties proved
viable as ASGs for the ARC process. Initiating nucleophiles
included n-BuLi, lithiated 2-methyl-1,3-dithiane, and lithium
di-n-butyl cuprate. Yields ranged from 50 to 81%. Of
particular note is the stereochemical outcome. Addition of
n-BuLi to linchpin (-)-6a furnished a diastereomeric mixture
(95:5) with the all-syn-product (-)-18 predominating (Table
1, entry 1). The relative stereochemistry of (-)-18 was
established by 2D NOESY analysis of the δ-lactone derived
from (-)-18 upon oxidative cleavage and lactonization.16
The stereochemical outcome at the carbinol of (-)-18 was
predicted via the Felkin-Anh model as observed by Sato
upon addition of ethyl Grignard to vinylsilyl aldehydes;15
the stereochemical outcome of alkylation after Brook rear-
rangement only had potential precedent (i.e., inversion at
carbon) based on the Brook14b and Mosher14c observations.
Interestingly, in the case of linchpin (+)-6b, addition of
n-BuLi led to the same product [(-)-18] with the same
a Isolated yields based on linchpins; diastereomer ratio was determined
by H NMR.
1
diastereoselectivity as observed with (-)-6a (entry 2). When
employing lithiated 2-methyl-1,3-dithiane as the nucleophile
both linchpins (-)-6a and (+)-6b again furnished the same
product (-)-19, with similar high selectivities (Table 1,
entries 3 and 4). Linchpins (-)-7a and (+)-7b also proved
viable substrates for the ARC process; again single products
(-)-20 or (-)-21 predominated when lithiated 2-methyl-1,3-
dithiane or lithium di-n-butyl cuprate served as nucleophiles
(entries 5-8).16 In contrast, poor diastereoselectivities were
obtained when linchpin (()-6c17 or linchpins (-)-8a and
(+)-8b, lacking the methyl subtituent were employed (Table
1262
Org. Lett., Vol. 12, No. 6, 2010

stereochemical outcome is not totally unexpected,20 given
that R-thio carbanions are known to be configurationally
labile,21 even at -78 °C.
Table 2. Anion Relay Chemistry of Linchpins 9a-10b
The divergence in stereochemical outcome observed with
linchpins possessing the phenyl and phenylthio ASG with
adjacent R-substituent can be understood in terms of A1,3
strain interactions available only to the linchpins possessing
the phenyl ASG (Scheme 4). A similar divergence was
observed by Beak and co-workers in their pioneering work
on directed amide alkylations.22
Scheme 4.
A1,3 Strain in Diastereoselective Alkylation
In summary, we have designed, synthesized, and evaluated
ten chiral nonracemic linchpins (6-10) for use in Anion
Relay Chemistry (ARC). Both the phenyl and phenylthio
moieties proved competent as anion stabilizing groups (ASG)
for the ARC proccess. High diastereoselectivities were
observed with linchpins possessing a methyl substituent R
to the silyl group, when a phenyl moiety serves as the ASG,
while poor diastereoselectivity is observed when a phenylthio
moiety is employed as the ASG, irrespective of the presence
of an R substituent. Studies directed toward both the design
and synthesis of related linchpins, as well as analysis of the
scope and limitations of Anion Relay Chemistry continue
in our laboratory.
a Isolated yields based on linchpins; diastereomer ratio was determined
by H NMR.
1
Acknowledgment. Financial support was provided by the
NIH through Grant No. GM-29028. We thank Drs. P. J.
Carroll and R. Kohli at the University of Pennsylvania for
assistance in obtaining X-ray diffraction and high-resolution
mass spectra, respectively.
1, entries 9-13). Although there are few reports18 on
diastereoselective alkylation of carbon anions generated via
Brook rearrangement, our results are consistent with alky-
lation of configurationally labile benzyl anions.19
The stereochemical outcome employing linchpins 9a-10b
bearing phenylthio moieties as the ASG proved different
(Table 2). Although the ARC process proceeded in good
yield (Table 2, entries 1-8), diastereomeric mixtures resulted
in all cases. That is, an R-chiral center adjacent to the reactive
anion generated via Brook rearrangement [linchpins (-)-
10a and (+)-10b] imposed little or no stereochemical bias
toward the alkylation process (Table 2, entries 5-8). This
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL100130X
(20) (a) Kuwajima et al. have also observed different diastereoselec-
tivities arising from alkyllithiums stabilized by R-phenylthio vs by R-phenyl:
see ref.19a (b) HMPA is known to be detrimental to diastereoselectivity:
see ref 21b.
(17) Calas, R.; Dounogues, J.; Bolourtchian, M. J. Organomet. Chem.
1971, 26, 195.
(21) For a review, see: (a) Basu, A.; Thayumanavan, S. Angew. Chem.,
Int. Ed. 2002, 41, 716. (b) McDougal, P. G.; Condon, B. D.; Laffosse, M. D.,
Jr.; Lauro, A. M.; VanDerveer, D. Tetrahedron Lett. 1988, 29, 2547. (c)
Hoffmann, R. W.; Dress, R. K.; Ruhland, T.; Wenzel, A. Chem. Ber. 1995,
128, 861, and references cited therein. (d) Reich, H. J.; Dykstra, R. R. J. Am.
Chem. Soc. 1993, 115, 7041, and references cited therein.
(22) Beak, P.; Hunter, J. E.; Jun, Y. M.; Wallin, A. P. J. Am. Chem.
Soc. 1987, 109, 540. Also see: Hoffmann, R. W. Chem. ReV. 1989, 89,
1841.
(18) (a) Unger, R.; Weisser, F.; Chinkov, N.; Stanger, A.; Cohen, T.;
Marek, I. Org. Lett. 2009, 11, 1853. (b) Sasaki, M.; Hashimoto, A.; Tanaka,
K.; Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803.
(19) (a) Kato, T.; Marumoto, S.; Sato, T.; Kuwajima, I. Synlett 1990,
671. (b) Marumoto, S.; Kuwajima, I. J. Am. Chem. Soc. 1993, 115, 9021.
(c) Bousbaa, J.; Ooms, F.; Krief, A. Tetrahedron Lett. 1997, 38, 7625. (d)
Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1999, 55, 2609.
Org. Lett., Vol. 12, No. 6, 2010
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