N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions

Article abstract of DOI:10.1016/j.tetlet.2015.04.006

A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a vari

Full text of DOI:10.1016/j.tetlet.2015.04.006

Accepted Manuscript
N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers
by site-, diastereo- and enantioselective vinylogous Mannich reactions
Daniel L. Silverio, Peng Fu, Emma L. Carswell, Marc L. Snapper, Amir H.
Hoveyda
PII:
S0040-4039(15)00620-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.006
TETL 46143
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
9 December 2014
30 March 2015
1 April 2015
Please cite this article as: Silverio, D.L., Fu, P., Carswell, E.L., Snapper, M.L., Hoveyda, A.H., N-Substituted tertiary
and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous
Mannich reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.006
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by
site-, diastereo- and enantioselective vinylogous Mannich reactions
Daniel L. Silverio, Peng Fu, Emma L. Carswell, Marc L. Snapper, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A readily accessible small-molecule phosphine, derived from commercially available starting
materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based
chiral complex that can be prepared and used in situ to promote a variety of enantioselective
vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners.
Transformations with unsubstituted nucleophilic components proceed efficiently and with
exceptional site- ( vs -addition), diastereo- and enantioselectivity [up to 98% yield, generally
>98:2 / and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first
examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-
methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon
stereogenic centers are presented as well. Appreciable efficiency and diastereo- and
enantioselectivity (up to >98:2 dr and >99:1 er) is accompanied by formation of -addition
products that can be oxidatively removed.
Available online
Keywords:
Amines
Catalysis
Enantioselective synthesis
Quaternary carbons
Siloxyfurans
Silver complexes
Vinylogous Mannich reactions
2009 Elsevier Ltd. All rights reserved.
Amines are present in a great number of biologically
significant molecules; reliable, efficient, diastereo- and
enantioselective methods that furnish access to such valuable
entities, particularly when promoted by easily accessible and
robust chiral catalysts, are critical to future developments in
chemistry.1 As part of a program aimed at introducing robust and
practical catalytic systems that can be used to prepare different
types of amines in high enantiomeric purity,2 we have developed
a set of amino acid based chiral phosphine compounds that are
simple to synthesize and promote enantioselective additions
efficiently. Some members of this family of chiral ligands can be
obtained by condensation of commercially available o-
diphenylphosphono benzaldehyde and various amines that are
derived from enantiomerically pure amino acids.3 A notable set
of transformations corresponds to Mannich-type additions4 that
are promoted by an in situ-generated phosphine–Ag complex5
and entail the addition of a siloxyfuran to aldimines6 or -
ketoimine esters7 (Scheme 1a); such enantioselective vinylogous
Mannich (EVM) processes8 can be used to synthesize
heterocyclic structures that contain a tertiary or a more sterically
congested quaternary N-substituted stereogenic center and
readily lend themselves to subsequent site- and/or stereoselective
modifications. From the point of view of reaction development,
the N-aryl moiety used in the above transformations offers a
critical advantage: fine tuning of the chelating ability and/or
electronic attributes of this unit can provide a significant boost to
the observed efficiency levels. Thus, the more electron donating
p-methoxyaryl group prolongs the lifetime of the more reactive
alkyl-substituted imines (vs aryl variants); together with the
stronger chelating ability of a sulfide group with a Ag metal, the
moiety proved optimal for EVM with

2
Tetrahedron
aliphatic aldimines (Scheme 1a). In a similar vein, the strongly
center (Scheme 1b). Such products have been used in the
electron withdrawing p-nitro unit proved necessary for additions
to the comparatively less reactive ketoimines (despite the
presence of an -ester moiety) to proceed efficiently (Scheme
1a). Methods to convert the N-aryl unit to the corresponding
unprotected amine have been developed as well.6,7
preparation of biologically active alkaloids.10
Initial screening studies involving aldimines derived from
benzaldehyde indicated that the optimal N-aryl unit for EVM
with Boc-protected siloxypyrrole 311 is that which was previously
utilized for reactions involving alkyl-substituted aldimines and
oxygenated heterocyclic nucleophiles (Scheme 1a). Thus, as
illustrated in Scheme 2, reaction with aldimine 2a in the presence
of isoleucine-derived phosphine ligand 1, resulted in the
formation of 4a in 96% yield, >98:2 / and diastereomeric ratio
(dr) and 97.5:2.5 enantiomeric ratio (er).12 Additions to imines
with a bromo-substituted aryl unit (cf. 4b,c), an electron
withdrawing (cf. 4d) or an electron-donating unit (cf. 4e,f)
proceeded with similar degrees of efficiency and selectivity.
With regard to the influence of the N-aryl moiety, process with
the alternative substrate derivatives was somewhat less
enantioselective. For example, the EVM involving the p-
bromophenyl o-anisidylimine (cf. 4c) gave the desired product
with complete site- and diastereoselectivity but in 88.5:11.5 er
(vs 97:3); the same process with the o-thioanisidylimine
furnished the expected diamine and in 90:10 er (>98:2 / and
dr). Heterocyclic aldimines can be used as well, as indicated by
the site-selective, diastereoselective and enantioselective
formation of furyl- and thienyl-containing products 4f,g (Scheme
2). The lower conversion in the reaction leading to 4g might be
attributed to competitive chelation of the Ag-based complex with
the S atom of the thienyl group. The stereochemical identity of
the products derived from this phase of our study was ascertained
by X-ray crystallography (cf. structure for 4c in Scheme 2).
Herein, we illustrate that the same family of amino acid based
chiral Ag complexes can be used to promote efficient and
exceptionally selective EVM8 reactions with different
siloxypyrroles serving as the nucleophilic component and which
afford two contiguous N-substituted tertiary carbon stereogenic
centers (Scheme 1b).9 These transformations deliver
enantiomerically enriched 1,2-diamine compounds that can be
functionalized in a variety of manners and cannot be accessed
readily be alternative protocols.6c In addition to the
aforementioned N-Ar group products contain an easily removable
Boc-amide (Boc = t-butoxycarbonyl). The importance of the
present type of EVM processes is underscored by a recent total
synthesis of influenza neuroaminidase inhibitor A-315675
(Scheme 1b);10 preparation of this biologically active compound
and its analogues would likely be facilitated substantially due to
the availability of the catalytic protocols that are outlined below.
We also report on the first examples of diastereo- and
enantioselective phosphine–Ag-catalyzed additions with 5-
substituted siloxyfurans, leading to the formation of O-
substituted quaternary carbon stereogenic centers that are
adjacent to a tertiary N-substituted stereogenic
The catalytic method can be extended to alkyne-substituted
aldimines (Scheme 3). Here, too, the EVM products are obtained,
under the same conditions as illustrated above, in 93–98% yield
with exceptional site- and diastereoselectivity. It is not surprising
that processes involving these less sterically demanding starting
materials proceed to higher conversion (vs those involving the
more sizeable arylimines in Scheme 2). The resident acetylene
aSee the Supporting Information for experimental and analytical details. Boc, t-
aSee the Supporting Information for experimental and analytical details.
butoxycarbonyl

3
may carry an aryl (cf. 6a,b), an alkyl (cf. 6c) or a silyl
substitutent (cf. 6d). What is especially notable is that high er
values persist (93:7–97.5:2.5 er) despite the lower degree of
steric difference between the aldimine substituents (H and an
alkyne vs H and an aryl group). The alkynyl-substituted diamine
products may be converted to a variety of other useful
derivatives, including those that would be formed from EVM
with alkenylimines; this is an important point, since our attempts
to identify conditions that would afford the latter set of products
proved unsuccessful (led to complex mixtures of unidentified
side products).
since additions from this inherently less nucleophilic site are
more competitive due to lower accessibility of the  site.
Nevertheless, the yield values shown in Scheme 5 correspond to
pure -addition compounds, since entities derived from reactions
of the alternative heterocyclic site readily undergo elimination to
compounds that can be easily removed.12 This class of EVM
reactions is particularly enantioselective, regardless of the
electronic attributes of the aryl-substituted aldimine used (i.e.,
11a-e obtained in >99:1 er). The X-ray structures obtained for
11a,d serve to establish the relative and absolute stereochemical
identity of the enantiomerically enriched products.
Synthesis of an alkyl-substituted EVM product, however, can
be carried out with the same N-aryl moiety and chiral phosphine
ligand 1 without any complications. Because aliphatic aldimines
are comparatively unstable and subject to adventitious and
debilitating enamine formation, it is best that such substrates are
prepared by subjection of the aldehyde and the appropriate
aniline in the presence of a common drying agent (e.g., MgSO4,
10 min) and used in the same vessel, as illustrated in the
multicomponent process depicted in Scheme 4.6b Cyclohexyl-
substituted diamine 8 was thus obtained in 82% yield, without
the formation of any detectable amounts of -addition side
product, in >98:2 dr and 95.5:4.5 er.13
aSee the Supporting Information for experimental and analytical details.
At this point, we turned our attention to the more challenging
EVM reactions involving 5-methyl-substituted siloxyfuran 1014
that generate an O-substituted quaternary carbon stereogenic
center within the heterocyclic moiety of the product (Scheme 5).
This category of transformations has received scarce attention.
As far as we are aware, there is only one disclosure that addresses
related catalytic EVM processes with 5-methyl-substituted
siloxyfurans to access such products [chiral aminoxide ligands
and Sc(OTf)3].15 In another report it was stated that attempts to
effect the same additions with chiral Ti-diolate complexes, did
not lead to formation of any desired product.6c
aSee the Supporting Information for experimental and analytical details.
Catalytic EVM reactions performed in the presence of 5-
methyl-substituted siloxyfuran 10 can be readily extended to
alkynyl-substituted imines (Scheme 6). The same chiral ligand
employed throughout this study (phosphine 1) and the N-aryl
group utilized in the related additions to arylimines can also be
used in these instances. However, additions are more facile,
probably because of the smaller size of the alkynyl vs aryl
substituents of the electrophilic component. Similar to the
transformations presented in Scheme 5, -addition products are
detected, but the desired isomers can be isolated in high purity
(>98:2 /).
Although chiral phosphine 1 again proved to be optimal,
successful implementation of this set of transformations required
that the aldimine be rendered more electrophilic through removal
of the electron donating p-methoxy unit of the N-Ar substituent
(cf. 9a, Scheme 5); this modification likely arises from the higher
energy barrier required for the addition of the fully substituted -
carbon of the siloxyfuran 10.16 What’s more, possibly for the
same reason, higher catalyst loadings were needed to achieve
appreciable conversion values (10 vs 5.0 mol % ligand and
AgOAc). Another distinction is that in reactions with 10 larger
amounts of -addition products are observed, again probably
In brief, the studies described in this report demonstrate that
readily accessible amino acid based chiral phosphine 1 in
conjunction with commercially available AgOAc can be used to
promote a variety of EVM reactions that involve aryl-, alkyl, or

4
Tetrahedron
2014, 136, 3362–3365. (e) Wu, H.; Haeffner, F.; Hoveyda, A. H.
J. Am. Chem. Soc. 2014, 136, 3780–3783.
alkynyl imines. Products involving two different types of
nucleophilic entities, which can be similarly synthesized in a
straightforward manner, lead to the formation of relatively
complex products that contain vicinal C–N or vicinal C–N and
C–O bonds and are formed with high diastereo- and
enantioselectivity. In cases where the nucleophilic component
does not contain a methyl unit, exceptional  selectivity is
observed (>98:2 /), whereas in reactions with 5-methyl-
siloxyfuran, which generate an O-substituted quaternary carbon
stereogenic center, site selectivity is lower. Nonetheless, pure -
addition products can be easily obtained by simple purification
procedures in the latter cases.
3. (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem.
Soc. 2001, 123, 755–756. (b) Luchaco-Cullis, C. A.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 8192–8193. (c) Hird, A. W.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276–1279. (d)
Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 4584–4585. (e) Kacprzynski, M. A.; Kazane, S. A.;
May, T. L.; Hoveyda, A. H. Org. Lett. 2007, 9, 3187–3190. (f)
Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130,
12904–12906.
4. For enantioselective Mannich-type reactions promoted by the
present set of Ag-based chiral phosphine complexes, see: (a)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 4018–4019. (b) Josephsohn, N. S.; Snapper, M.
L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734–3735. (c)
Josephsohn, N. S.; Carswell, E. L.; Snapper, M. L.; Hoveyda, A.
H. Org. Lett. 2005, 7, 2711–2713.
5. For reviews on enantioselective reactions promoted by Ag-based
complexes, see: (a) Naodovic, M.; Yamamoto, H. Chem. Rev.
2008, 108, 3132–3148. (b) Yanagisawa, A.; Arai, T. Chem.
Commun. 2008, 1165–1172.
6. (a) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2006, 45, 7230–7233. (b) Mandai, H.; Mandai, K.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130,
17961–17969. For related studies, see: (c) Martin, S. F.; Lopez, O.
D. Tetrahedron Lett. 1999, 40, 8949–8953. (d) Akiyama, T.;
Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008, 350,
399–402. (e) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2008, 10, 2319–2322. (f) González, A. S.; Arrayás, R. G.;
Rivero, M. R.; Carretero, J. C. Org. Lett. 2008, 10, 4335–4337. (g)
Yuan, Z.-L.; Jiang, J.-J.; Shi, M. Tetrahedron 2009, 65, 6001–
6007. (h) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2009,
351, 2897–2902. (i) Hayashi, M.; Sano, M.; Funahashi, Y.;
Nakamura, S. Angew. Chem., Int. Ed. 2013, 52, 5557–5560.
7. Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2009, 131, 570–576.
8. For reviews on stereoselective vinylogous Mannich additions, see:
(a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (b)
Martin, S. F. Acct. Chem. Res. 2002, 35, 895–904. (c) Casarighi,
G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev.
2011, 111, 3076–3154.
9. For related transformations promoted by Ni-based complexes, see:
Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2010, 132, 3666–3667.
10. Barnes, D. M.; Bhagavatula, L.; DeMattei, J.; Gupta, A.; Hill, D.
R.; Manna, S.; McLaughlin, M. A.; Nichols, P.; Premchandran,
R.; Rasmussen, M. W.; Tian, Z.; Wittenberger, S. J. Tetrahedron:
Asymmetry 2003, 14, 3541–3551.
11. The siloxypyrrole can be prepared in four steps and ~50% overall
yield. See the Supporting Information for details.
aSee the Supporting Information for experimental and analytical details.
Studies aimed at the development of additional catalysts and
further methods for efficient and selective additions of different
types of nucleophilic entities to various imine substrates are in
progress and will be reported in due course.
12. See the Supporting Information for all experimental and analytic
details.
13. After completion of the present studies but prior to preparation of
this manuscript, the present catalytic system was employed by
Zanardi and co-workers to promote EVM reactions with
siloxypyrrole 3. These workers report that with alkyl-substituted
aldimines, o-thiomethyl,p-methoxyphenylimines (cf. 2a) are most
suitable, whereas, in contrast to the present studies, o-
anisidylimines are best for aryl imines. See: (a) Curti, C.;
Battistini, L.; Ranieri, B.; Pelosi, G.; Rassu, G.; Casiraghi, G.;
Zanardi, F. J. Org. Chem. 2011, 76, 2248–2252. (b) Ranieri, B.;
Curti, C.; Battistini, L.; Sartori, A.; Pinna, L.; Casiraghi, G.;
Zanardi, F. J. Org. Chem. 2011, 76, 10291–10298.
Acknowledgments
Financial support was provided by the National Institutes of
Health (GM-57212). We are grateful to Dr. Hiroki Mandai, Ms.
Kyoko Mandai and Mr. Ming-Joo Koh for helpful discussions
and assistance.
References and notes
14. 5-Methyl-siloxyfuran can be prepared in ~65% overall yield from
readily accessible starting materials. See the Supporting
Information for details.
15. Zhou, L.; Lin, L.; Ji, J.; Xie, M.; Liu, X.; Feng, X. Org. Lett. 2011,
13, 3056–3059.
16. Usually, the optimal proton source in these phosphine–Ag-
catalyzed reactions is i-PrOH (see ref 4a–b and ref 7). The reason
for use of MeOH in the transformations depicted in Schemes 2–4
is that slightly higher er values for obtained (e.g., 4a was obtained
in 88:12 and 82:18 er with MeOH and i-PrOH, respectively with
the unoptimal o-anisidylimine substrate).
1. For recent reviews on enantioselective synthesis of
enantiomerically enriched amines, see: (a) Kobayashi, S.; Mori,
Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626–2704.
(b) Chiral Amine Synthesis; Nugent, T. C., Ed.; Wiley–VCH:
Weinheim, Germany, 2010.
2. For examples involving other catalyst systems, see: (a) Vieira, E.
M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133,
3332–3335. (b) Vieira, E. M.; Haeffner, F.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2012, 51, 6618–6621. (c)
Silverio, D. L.; Torker, S.; Pilyugina, T. Vieira, E. M.; Snapper,
M. L.; Haeffner, F.; Hoveyda, A. H. Nature 2013, 494, 216–221.
(d) Mszar, N. W.; Haeffner, F.; Hoveyda, A. H. J. Am. Chem. Soc.