The tert-Butylsulfinamide lynchpin in transition-metal-mediated multiscaffold library synthesis

Article abstract of DOI:10.1021/ol100574y

Figure presented A unified synthetic approach to diverse polycyclic scaffolds has been developed using transition-metal-mediated cycloaddition and cyclization reactions of enynes and diynes. The tert-butylsulfinamide group has been identified as a particularly versatile lynchpin in these reactions, with a reactivity profile uniquely suited for efficient, stereoselective substrate synthesis and downstream transformations. This approach provides 10 distinct, functionalized scaffold classes related to common core structures in alkaloid and terpenoid natural products.

Full text of DOI:10.1021/ol100574y

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2084-2087
The tert-Butylsulfinamide Lynchpin in
Transition-Metal-Mediated Multiscaffold
Library Synthesis
Renato A. Bauer,† Christine M. DiBlasi,‡ and Derek S. Tan*,†,‡
Tri-Institutional Training Program in Chemical Biology, Molecular Pharmacology &
Chemistry Program, and Tri-Institutional Research Program, Memorial Sloan-Kettering
Cancer Center, 1275 York AVenue, Box 422, New York, New York 10065
tand@mskcc.org
Received March 9, 2010
ABSTRACT
A unified synthetic approach to diverse polycyclic scaffolds has been developed using transition-metal-mediated cycloaddition and cyclization
reactions of enynes and diynes. The tert-butylsulfinamide group has been identified as a particularly versatile lynchpin in these reactions, with
a reactivity profile uniquely suited for efficient, stereoselective substrate synthesis and downstream transformations. This approach provides
10 distinct, functionalized scaffold classes related to common core structures in alkaloid and terpenoid natural products.
Polycyclic alkaloid and terpenoid natural products exhibit a
tremendous array of chemical scaffolds and biological activi-
ties.1,2 Accordingly, these structures are attractive targets for
the synthesis of natural product-based libraries.3 Ideally, a
concise, unified synthetic route would provide an array of
distinct, polycyclic scaffolds for use in discovery screening
against a wide range of targets. The synthesis of such
multiscaffold libraries remains a major challenge in diversity-
oriented synthesis.4,5 We envisioned that the modern arsenal
of transition-metal mediated cycloaddition and cyclization
reactions6,7 would provide a powerful means to generate such
libraries from simple tethered enyne and diyne substrates.
We report herein the development of a unified synthetic
approach leading to 10 classes of polycyclic scaffolds and
the emergence of the tert-butylsulfinamide moiety8 as a
versatile lynchpin for these reactions, affording uniquely
suited reactivity and a novel motif for biological evaluation.
To identify transition-metal-mediated cycloaddition and cy-
clization reactions suitable for diversity-oriented synthesis, we
set out to evaluate candidate reactions systematically across a
panel of substrates having electronically and sterically distinct
(5) For selected key examples, see: (a) Burke, M. D.; Schreiber, S. L.
Science 2003, 302, 613–618. (b) Taylor, S. J.; Taylor, A. M.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1681–1685. (c) Oguri, H.; Schreiber,
S. L. Org. Lett. 2005, 7, 47–50. (d) Spiegel, D. A.; Schroeder, F. C.; Duvall,
J. R.; Schreiber, S. L. J. Am. Chem. Soc. 2006, 128, 14766–14767. (e) Wyatt,
E. E.; Fergus, S.; Galloway, W. R. J. D.; Bender, A.; Fox, D. J.; Plowright,
A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Chem. Commun. 2006,
3296–3298.
† Tri-Institutional Training Program in Chemical Biology.
‡ Molecular Pharmacology & Chemistry Program.
(1) See the Supporting Information for full details.
(2) (a) Messer, R.; Fuhrer, C. A.; Ha¨ner, R. Curr. Opin. Chem. Biol.
2005, 9, 259–265. (b) Koch, M. A.; Schuffenhauer, A.; Scheck, M.; Wetzel,
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(6) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127–2198.
(7) Several such reactions have been used recently in diversity-oriented
synthesis : (a) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245–
2248. (b) Zhou, Y.; Porco, J. A., Jr.; Snyder, J. K. Org. Lett. 2007, 9, 393–
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Luna, A. Chem. Soc. ReV. 2009, 38, 1162–1186. (b) Morton, D.; Stockman,
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10.1021/ol100574y  2010 American Chemical Society
Published on Web 03/31/2010

be envisioned to provide an even broader assessment of
reactivity trends in the future.
Scheme 1
.
Stereoselective Synthesis of Enynes and Diynes
With gram quantities of enynes 4 and diynes 5 in hand, we
evaluated their reactivities in various transition-metal-mediated
reactions. Initial experiments with Au and Ag π-acids (group
11) commonly used in such reactions13 resulted in decomposi-
tion, possibly initiated by sulfinamide cleavage. In contrast, these
substrates were compatible with various Ru, Co, Rh, and Ni
catalysts (groups 8-10), and after investigation of over 25
reactions, eight were identified as having suitable selectivity
and efficiency for use in library synthesis (Scheme 2).
Using a tert-Butylsulfinimide Tethera
The venerable Pauson-Khand reaction12b,14 was effective
for all four enynes 4a-d, providing [5,5]-bicyclic cyclo-
pentapyrrolidinone scaffolds 6a-d (Table 1). Krische’s Rh-
catalyzed reductive enyne cyclization15 provided excellent
yields of exo-pyrroline scaffolds 7a,b,d, with reagent-
controlled diastereoselectivity for the internal alkynes 4a,b,
while the TMS-alkyne 4c was unreactive under these
conditions. Evans’ Rh-catalyzed butadiene [4+2+2] cy-
cloaddition also proved useful;16 while enynes 4 underwent
AgOTf-induced sulfinamide cleavage under the reaction
conditions, consistent with our earlier findings, the reaction
proceeded effectively after oxidation to the corresponding
tert-butylsulfonamides, affording [5,8]-bicyclic cyclooctapyr-
rolidine scaffolds 8a-d in moderate yields but complete
diastereoselectivity. Enyne metathesis of 4 with Grubbs’
second-generation catalyst17 led to vinylpyrrolines 9a,b,d;
the TMS-alkyne 4c was again unreactive. Interestingly, the
diene products 9 proved recalcitrant to subsequent Diels-Alder
reactions with numerous dienophiles.18,19 However, these
reactions could be achieved after oxidation to the corre-
sponding tert-butylsulfonamides; subtle conformational ef-
fects may account for this reactivity difference. Thus,
reactions with N-phenylmaleimide provided [5,6,5]-tricyclic
benzodipyrrolidine scaffolds 10a,b,d.1 Reactions with di-
methylacetylene dicarboxylate (DMAD) afforded diastere-
omeric mixtures that converged to [5,6]-bicyclic isoindoline
dicarboxylate scaffolds 11a,b,d upon oxidation with DDQ.1
a HMPA ) hexamethylphosphoramide; LiHMDS ) lithium hexameth-
yldisilazide; TBDPS ) tert-butyldiphenylsilyl; TBS ) tert-butyldimethyl-
silyl; TMS ) trimethylsilyl.
groups at sites expected to influence reactivity. This would also
provide broad insights into the scope and efficiency of these
reactions. To assemble the requisite enyne and diyne substrates,
we initially investigated ether, carbamate (N-Boc), and sulfon-
amide (N-Ts, N-Ns) tethers. After extensive experimentation,
the tert-butylsulfinamide8 emerged as a uniquely suited lynch-
pin. This group provides asymmetric induction during substrate
assembly, can be readily deprotonated and N-alkylated, does
not exhibit rotamers on the NMR time scale, and can be
deprotected or oxidized under mild conditions. The tert-
butylsulfinamide is also a novel motif for biological evaluation,
related to sulfonamides in synthetic drugs and natural products.
Notably, although a picture of compatibility of the tert-
butylsulfinamide with metal catalysts is beginning to emerge,9
its stability and reactivity in transition-metal-mediated cycload-
ditions and cyclizations has not yet been explored in detail.
Thus, synthesis of enynes 4 and diynes 5 began with
condensation of aldehyde 1 and (R)-tert-butylsulfinamide
(Scheme 1). The R1 side chain was designed with a TPDPS-
protected alcohol as a potential handle for later functionalization
and as a mimic of our reported TBDAS linker for future solid-
phase syntheses.10 Diastereoselective addition of terminal
alkynes afforded sulfinamides 3a-c.11 N-Alkylation with allyl
and propargyl bromide was achieved efficiently using n-BuLi/
HMPA to afford enynes 4a-c and diynes 5a-c.12 C-desily-
lation of TMS-alkynes 4c and 5c then provided terminal alkynes
4d and 5d. Additional functionalized alkenes and alkynes can
Several effective transition-metal-mediated cycloaddition
reactions were also identified for diynes 5a-d. While [2+2+2]-
cyclotrimerization with various alkynes using reported Rh(I),
Ni(0), or Ir(I) catalysts20 suffered from poor regioselectivity and
competing dimerization, treatment of 5a-d with Grubbs’ first-
generation catalyst21 and propargyl alcohol yielded [5,6]-bicyclic
isoindoline scaffolds 12a-d efficiently (Table 2). The reactions
were regioselective, except in the case of the pseudosymmetric
substrate 5d, and regioisomers were readily separated in all
cases. Diynes 5a-d also cyclotrimerized with benzyl isocyanate
(9) (a) Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077–3080. (b) Grigg, R.;
McCaffrey, S.; Sridharan, V.; Fishwick, C. W. G.; Kilner, C.; Korn, S.;
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M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304–
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(e) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127,
11269–11276. (f) Schenkel, L. B.; Ellman, J. A. J. Org. Chem. 2004, 69,
1800–1802. (g) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545–
548. (h) Souers, A. J.; Owens, T. D.; Oliver, A. G.; Hollander, F. J.; Ellman,
J. A. Inorg. Chem. 2001, 40, 5299–5301.
(13) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed.
2008, 47, 4268–4315.
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(15) Jang, H.-Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.;
Krische, M. J. J. Am. Chem. Soc. 2005, 127, 6174–6175.
(16) Robinson, J. E.; Baum, E. W.; Fazal, A. N.; Evans, P. A. J. Am.
Chem. Soc. 2002, 124, 8782–8783.
(17) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317–1382.
(18) For examples of RCM/Diels-Alder strategies, see: (a) Schurer,
S. C.; Blechert, S. Chem. Commun. 1999, 1203–1204. (b) Bentz, D.; Laschat,
S. Synthesis 2000, 1766–1773. (c) Micalizio, G. C.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2002, 41, 152–154. (d) Reference 7c. (e) Reference 5d.
(19) An exception was N-phenyltriazolinedione, which reacted with
9a,b,d at -78 °C.
(10) DiBlasi, C. M.; Macks, D. E.; Tan, D. S. Org. Lett. 2005, 7, 1777–
1780.
(11) Ding, C.-H.; Chen, D.-D.; Luo, Z.-B.; Dai, L.-X.; Hou, X.-L. Synlett
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(12) (a) Kuduk, S. D.; Marco, C. N. D.; Pitzenberger, S. M.; Tsou, N.
Tetrahedron Lett. 2006, 47, 2377–2381. (b) Hiroi, K.; Watanabe, T.
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c
-
Scheme 2.
Transition-Metal-Mediated Cycloadditions and Cyclizations of tert-Butylsulfinamide-Tethered Enynes 4a-d and Diynes 5a-da
a See Tables 1 and 2 for results. b Subsequent Diels-Alder reactions also shown (center). c BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; COD )
1,4-cyclooctadiene; Cp* ) pentamethylcyclopentadienyl; m-CPBA ) m-chloroperbenzoic acid; DDQ ) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMAD )
dimethylacetylene dicarboxylate; Grubbs I ) benzylidene-bis(tricyclohexylphosphine)dichlororuthenium; Grubbs II ) benzylidene[1,3-bis(2,4,6-trimethylphenyl)-
2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium; IMes )1,3-bis(2,4,6-trimethylphenyl)imidazoly-2-ylidene; Tf ) trifluoromethanesulfonate.
Table 1. Yields and Diastereoselectivities of Tethered
Cycloaddition and Cyclization Reactions of Enynes 4a-d
Table 2. Yields and Regioselectivities of Tethered
Cycloaddition Reactions of Diynes 5a-d
a Yield of isolated major regioisomer or of each isolated regioisomer.
a Combined yield of inseparable diastereomers. b Determined by
1H NMR. c ꢀ-Isomer obtained using (S)-BINAP; R-isomer obtained using
(R)-BINAP. d With Rh(COD)2OTf instead of Rh(COD)2BF4.
b
Determined by H NMR. c E/Z ) 74:26. d E/Z ) 68:32. e E/Z ) 87:13.
1
meric products were again readily separated. No other transition
metals were found to catalyze this reaction. Cyclotrimerizations
of 5a-d with ethyl cyanoformate proceeded effectively using
under the agency of Yamamoto’s Ru(II) catalyst22 to provide
[5,6]-bicyclic pyrrolopyridone scaffolds 13a-d, and regioiso-
(21) Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M. Chem.
Commun. 2000, 1965–1966.
(22) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda,
S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605–613.
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Org. Lett., Vol. 12, No. 9, 2010

Scheme 3.
Pauson-Khand Reactions of anti-Enynes 17a-d1
Tanaka’s Rh(I) catalyst23 to afford [5,6]-bicyclic pyrrolopyridine
carboxylate scaffolds 14a,b,d. Notably, the reaction was regi-
oselective even for the pseudosymmetric substrate 5d, while
the TMS-alkyne 5c was unreactive. In contrast, reactions with
aryl or alkyl nitriles proceeded with low to moderate regio-
selectivity, while the use of alternative Ni(0), Co(I), or Ru(II)
catalysts24 gave no reaction or poor regioselectivity. Saito’s
Ni(0)-catalyzed [3+2+2]-cyclotrimerization25 with ethyl cy-
clopropylideneacetate provided larger [5,7]-bicyclic cyclohep-
tapyrrolidine scaffolds 15a-c as single regioisomers and
inseparable E/Z mixtures. While the E/Z ratios could not be
improved using alternative cyclopropylidenes, solvents, or
phosphine ligands, conversion to the corresponding Weinreb
amides26 16a-c allowed separation of the isomers.
To probe the potential influence of the remote sulfinamide
stereogenic center on the diastereoselectivity of the enyne
cycloaddition reactions, we also carried out Pauson-Khand
reactions with anti-enyne substrates 17a-d having the
opposite stereochemistry relative to syn-enynes 4a-d (Scheme
3).1 Increased diastereoselectivities were observed for 18a,b
versus 6a,b, suggesting a matched/mismatched scenario.12b,27
While these effects have not yet been studied in other
reactions, access to both syn- and anti-diastereomers would
provide increased stereochemical diversity in libraries.
Overall, we identified 27 reaction/substrate combinations
suitable for use in multiscaffold library synthesis (g84:16 dr
or isolable as single regioisomer), leading to a total of 32
different scaffolds related to alkaloid and terpenoid natural
products (after in silico desilylation; includes six additional
Diels-Alder products).1 To assess the structural diversity of
the multiscaffold library accessible using our synthetic strategy
and its relationship in chemical space to synthetic drugs, natural
products, and drug-like libraries, we evaluated these compounds
for 20 structural and physicochemical properties using our
reported principal component analysis. (Figure 1).1,3b,28 As
expected, our scaffolds sample a distinct region of chemical
Figure 1. Principal component analysis of 20 structural and physi-
cochemical descriptors of the 40 top-selling drugs, 60 diverse natural
products, 20 polycyclic alkaloids and terpenoids, 20 ChemBridge and
Chem Div library members, and 32 multiscaffold library members.
Average values for each parameter are indicated by group.1
space compared to drugs and drug-like libraries and overlap
with alkaloids and terpenoids. Analysis of parameter loadings
indicates that aromatic ring content and stereochemical
complexity are two major factors that distinguish natural
products and the multiscaffold library from drugs and drug-
like libraries.1
In conclusion, we have used a systematic approach to analyze
the effectiveness of transition-metal-catalyzed cycloaddition and
cyclization reactions across a range of enyne and diynes,
resulting in the identification of eight reactions suitable for use
in multiscaffold library synthesis. More broadly, our results
provide valuable insights into the effective scope of such
reactions across a panel of differentially substituted substrates
and into the reactivity of the tert-butylsulfinamide lynchpin.
Synthesis of discovery libraries using this approach is ongoing
and will set the stage for quantitative comparison of the abilities
of drug-like and natural product-like libraries to address distinct
regions of biological space through screening against a broad
range of biological targets.
Acknowledgment. We thank Dr. George Sukenick, Dr. Hui
Liu, Hui Fang, Dr. Sylvi Rusli, and Anna Dudkina for mass
spectral analyses. D.S.T. is an Alfred P. Sloan Research Fellow.
Financial support from the NIH (R21 GM104685, P41
GM076267, T32 CA062948-Gudas), NYSTAR Watson Inves-
tigator Program, Goodwin Commonweath Foundation for
Cancer Research, and MSKCC Experimental Therapeutics
Center is gratefully acknowledged.
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Supporting Information Available: Detailed experimental
procedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Cole, D. C.; Tao, Y. J. Org. Chem. 1994, 59, 1396–1406
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